US0091494.55B2

(12) United States Patent (10) Patent No.: US 9,149,455 B2 Desai et al. (45) Date of Patent: Oct. 6, 2015

(54) METHODS OF TREATING I6/22 (2013.01); C07K 16/2818 (2013.01); C07K 16/3053 (2013.01); A61K 2039/505 (71) Applicant: Abraxis BioScience, LLC, Los Angeles, (2013.01) CA (US) (58) Field of Classification Search CPC. A61 K31/337; A61 K9/0019; A61 K9/5169 (72) Inventors: Neil P. Desai, Los Angeles, CA (US); See application file for complete search history. Markus Renschler, San Francisco, CA (US) (56) References Cited (73) Assignee: ABRAXIS BIOSCIENCE, LLC, Los U.S. PATENT DOCUMENTS Angeles, CA (US) 5,362.478 A 11, 1994 Desai et al. (*) Notice: Subject to any disclaimer, the term of this tes A 32 CREF, al. patent is extended or adjusted under 35 5,505,932 A 4/1996 Grinstaffet al. U.S.C. 154(b) by 32 days. 5,508,021 A 4/1996 Grinstaffet al. 5,512,268 A 4/1996 Grinstaffet al. (21) Appl. No.: 13/791,841 5,560,933 A 10/1996 Soon-Shiong et al. (Continued) (22) Filed: Mar. 8, 2013 FOREIGN PATENT DOCUMENTS (65) Prior Publication Data WO WO94, 18954 A1 9, 1994 US 2014/01342.57 A1 May 15, 2014 WO WO 98,14174 A1 4f1998 Related U.S. Application Data (Continued) (60) Provisional application No. 61/724,892, filed on Nov. OTHER PUBLICATIONS 9, 2012, provisional application No. 61/763,391, filed Sietal, “Prevalence of BRAFV600E Mutation in Chinese Melanoma on Feb. 11, 2013. Patients: Large Scale Analysis of BRAF and NRAS Mutations in a 432-Case Cohort'. European Journal of Cancer 48, Jan. 2012, pp. (51) Int. Cl. 94-100, Available online: Jul 23, 2011.* A6 IK3I/337 (2006.01) Continued A6 IK38/38 (2006.01) (Continued) A6IP35/00 (2006.01) C07K 6/22 (2006.01) Primary Examiner—Rachael E. Bredefeld C07K 6/28 (2006.01) (74) Attorney, Agent, or Firm — Morrison & Foerster LLP C07K 6/30 (2006.01) A6 IK9/00 (2006.01) (57) ABSTRACT A 6LX 9/5 (2006.01) Provided herein are methods for the treatment of melanoma A61 K39/00 (2006.01) comprising administration of a composition comprising (52) U.S. Cl. nanoparticles comprising taxane and a carrier protein. CPC ...... A61 K3I/337 (2013.01); A61 K9/0019 (2013.01); A61 K9/5169 (2013.01); C07K 16 Claims, 4 Drawing Sheets

- tic Hr Events f N Events f N A Patients alo- 1821284 7s 265 Age KS5 Years usash 9 : 154 901 35 Age 265 Years -a-ol- 72; 11 86 13 Male -o- 107 1173 2: 174 Female -o- 55 91 sai 91 North America H-or- 7s 15 78f 116 Western Europe Hoa 63; 114 701 114 Australia -o-o-em-- 23.35 28f35 Metastatic stage Mia H -o- 1327 9| 21 Metastatic Stage M1 H-OH 35 | 66 42 69 Metastatic Stage Wilt Hot 114 171 125 i is co.8 XULN He-q- 80 l 138 77 39 ho.8-1. LM -Hr as 12 52 fess Ox3-2X UN H-O- 35 is1 48 iss BRAFStatus: Wildtype Ho-- 73 116 73 108 sRAFStatus: WSOE Ho-H 34f SS 47 st RAF Status: Unknow Ho-H 55: 83 56 so -a--- s S 2.0 {. Favors nob-P Fairs C US 9,149.455 B2 Page 2

(56) References Cited 2014/OO39069 A1 2/2014 Desai et al. 2014/OO39070 A1 2/2014 Desai et al. U.S. PATENT DOCUMENTS 2014.0056986 A1 2/2014 Desai et al. 2014f0072630 A1 3/2014 Tao et al. 2014f0072631 A1 3/2014 Trieu et al. 3. A 1982 Asia, a 2014f0072643 A1 3/2014 Desai et al. 5,650 156 A 7, 1997 Grinstaffet al. 2014/OO79787 A1 3, 2014 Yeo et al. 5.665.382 A 9, 1997 Grinstaffet al. 2014/OO79788 A1 3, 2014 Desai et al. 5.665,383 A 9, 1997 Grinstaffet al. 2014/OO79793 A1 3, 2014 Desai et al. 5916 596 A 6, 1999 Desai et al. 2014f0080901 A1 3, 2014 Desai et al. 5.997,904 A 12, 1999 Magdassi et al. 2014/O155344 A1 6, 2014 Desai et al. 6,096,331 A 8, 2000 Desai et al. 2014/0170228 A1 6, 2014 Desai et al. 6,506.405 B1 1/2003 Desai et al. 2014/0186447 Al 7/2014 Desai 6,528,067 B1 3/2003 Magdassi et al. 2014/O1994.03 A1 T/2014 Desai et al. 6537,579 B1 3/2003 Desai et al. 2014,0199.404 A1 T/2014 Heise 6565.842 B1 5, 2003 Desai et al. 2014/O1994.05 A1 T/2014 Pierce et al. 6.652 884 B2 11/2003 Falciani 2014/0271871 A1 9/2014 Desai et al. 6749,868 B1 6, 2004. Desai et al. 2014/0296279 A1 10, 2014 Seward et al. 6.753006 B1 6, 2004. Desai et al. 2014/0296353 A1 10, 2014 Desai et al. 775s 891 B2 7, 2010 Desai et al. 2014/0302157 A1 10, 2014 Desai et al. 777.75 B2 8, 2010 Desai et al. 2015,005035.6 A1 2, 2015 Desai et al. 7780984 B2 8, 2010 Desai et al. 2015.OO79181 A1 3/2015 Desai et al. 7,820,788 B2 10/2010 Desai et al. 7,923,536 B2 4/2011 Desai et al. FOREIGN PATENT DOCUMENTS 7,981445 B2 7, 2011 De et al. 8,034,375 B2 10/2011 Desai et al. WO WO 98,14175 A1 4f1998 8,034,765 B2 10/2011 De et al. WO WO99/OO 113 A1 1/1999 8,137,684 B2 3/2012 Desai et al. WO WO-00,64437 A1 11, 2000 8,138,229 B2 3/2012 Desai et al. WO WOOOf71079 A2 11/2000 8,257,733 B2 9, 2012 Desai et al. WO WOOOf71079 A3 11, 2000 8,268,348 B2 9, 2012 Desai et al. WO WOO1,89522 A1 11, 2001 8,314,156 B2 11/2012 Desai et al. WO WO O2/O87545 A1 11, 2002 8,735,394 B2 5, 2014 Desai et al. WO WO 03/096944 A1 11, 2003 8,846,771 B2 9, 2014 Desai et al. WO WO 2004/052401 A2 6, 2004 8,853,260 B2 10/2014 Desai et al. WO WO 2004/052401 A3 6, 2004 8,911,786 B2 12/2014 Desai et al. WO WO-2006/0892.90 A1 8/2006 8,927.019 B2 1/2015 Desai et al. WO WO 2007/027819 A2 3, 2007 8,999,396 B2 4/2015 Desai et al. WO WO 2007/027819 A3 3.2007 2003/0185894 A1 10, 2003 Zenoni et al. WO WO 2007/027941 A2 3, 2007 2003/0187062 A1 10, 2003 Zenoni et al. WO WO 2007/027941 A3 3, 2007 2003. O1994.25 A1 10, 2003. Desai et al. WO WO-2007/139930 A2 12/2007 2005, 0004.002 A1 1/2005 Desai et al. WO WO-2007/139930 A3 12/2007 2006/0263434 A1 11/2006 Desai et al. WO WO 2008/O2.7055 A1 3, 2008 2007/0082838 A1 4/2007 De et al. WO WO-2008/057562 A1 5, 2008 2007/0093547 A1 4/2007 Desai et al. WO WO 2008.076373 A1 6, 2008 2008/028.0987 A1 11/2008 Desai et al. WO WO 2008/109 163 A1 9, 2008 2009,0263483 A1 10, 2009 Desai et al. WO WO-2008,137148 A2 11/2008 20090304805 A1 12, 2009 Desai et al. WO WO-2008,137148 A3 11 2008 2010.0048499 A1 2/2010 Desai et al. WO WO 2008.150532 A1 12/2008 2010, 0166869 A1 7, 2010 Desai et al. WO WO 2009/126175 A1 10/2009 2010, 0183728 A1 7, 2010 Desai et al. WO WO 2009.126401 A1 10, 2009 2010/0215751 A1 8, 2010 Desai et al. WO WO 2009/126938 A1 10/2009 2010/0297243 A1 11/2010 Desai et al. WO WO-2010/068925 A1 6, 2010 2011/0052708 A1 3/2011 Soon-Shiong et al. WO WO 2010/105172 A1 9, 2010 2011 0118342 A1 5, 2011 De et al. WO WO 2010, 118365 A1 10/2010 2011 O151012 A1 6, 2011 Desai et al. WO WO 2010, 121000 A1 10/2010 2012,00705O2 A1 3/2012 Desai et al. WO WO-2011/025838 A1 3, 2011 2012/0076862 A1 3/2012 Desai et al. WO WO-2011 119988 A1 9, 2011 2012/O128732 A1 5, 2012 Trieu et al. WO WO-2011/123393 A1 10, 2011 2012fO1897.01 A1 7, 2012 Desai et al. WO WO-2011/123395 A1 10, 2011 2012fO23.1082 A1 9, 2012 Desai et al. WO WO-2011, 153009 A1 12/2011 2012/0283205 A1 11/2012 Desai et al. WO WO-2011, 153010 A1 12/2011 2012/0308612 A1 12/2012 De et al. WO WO-2011, 156119 A1 12/2011 2013,0045240 A1 2/2013 Tao et al. WO WO-2012/048.223 A1 4/2012 2013,007 1438 A1 3/2013 Desai et al. WO WO-2012/149451 A1 11, 2012 2013/01 15296 A1 5, 2013 Yeo et al. WO WO-2013/090634 A1 6, 2013 2013,0195922 A1 8, 2013 Desai et al. WO WO-2014, 105644 A1 T 2014 2013,0195983 A1 8, 2013 Desai et al. WO WO-2014, 110345 A1 T 2014 2013,0195984 A1 8, 2013 Desai et al. WO WO-2014/110408 A1 T 2014 2013/0202709 A1 8, 2013 Desai et al. WO WO-2014f1 10443 A1 T 2014 2013/0209518 A1 8, 2013 Desai et al. WO WO-2014, 123612 A1 8, 2014 2013,0244952 A1 9, 2013 Desai et al. WO WO-2014, 143613 A1 9, 2014 2013/0266659 A1 10, 2013 Desai et al. WO WO-2014, 151853 A1 9, 2014 2013/0280336 A1 10, 2013 Desai et al. WO WO-2014/159171 A1 10, 2014 2013/0280337 A1 10, 2013 Desai et al. 2014/0017315 A1 1/2014 Desai et al. OTHER PUBLICATIONS 2014, OO1731.6 A1 1/2014 Desai et al. Miele et al.'Albumin-Bound Formulation of Paclitaxel (Abraxane 2014, OO17323 A1 1/2014 Desai et al. ABI-007) in the Treatment of Breast Cancer'. International Journal 2014/OO23717 A1 1/2014 Desai et al. of , 2009: 4, pp. 99-105.* US 9,149.455 B2 Page 3

(56) References Cited Nishimura, H. et al. (Jan. 12, 2001). “Autoimmune Dilated Cardiomyopathy in PD-1 Receptor-Deficient Mice.” Science OTHER PUBLICATIONS 291:319-322. Ott, P. A. et al. (2012, e-pub. Oct. 12, 2012). "Oblimersen in Com Altmayer, P. et al. (Oct. 1995). "Propofol Binding to Human Blood bination With Temozolomide and Albumin-Bound Paclitaxel in Patients.” Arzneim.-Forsch/Drug Res.45:1053-1056. Atkins, Metal. (Jul. 1999). "High-Dose Recombinant Interleukin 2 Patients With Advanced Melanoma: A Phase I Trial. Cancer for Patients With Metastatic Melanoma: Analysis of 270 Chemother: Pharmacol. 71:183-191. Patients Treated Between 1985 and 1993.” Journal of Clinical Oncol Paál. K. et al. (2001). “High Affinity Binding of Paclitaxel to Human ogy 17(7):2105-2116. Serum Albumin.” Eur: J. Biochem. 268(7):2187-2191 Balch, C.M. et al. (Dec. 20, 2009). “Final Version of 2009 AJCC Phan, G. et al. (Aug. 1, 2001). “Factors Associated with Responses to Melanoma Staging and Classification.” Journal of Clinical High-Dose interleukin-2 in Patients With Metastatic Melanoma.” 27(36):6199-6206. Journal of Clinical Oncology 19(15): 3477-3482. Butte, M.J. etal. (Jul. 2007). “PD-L1 Interacts Specifically with B7-1 Purcell, M. et al. (2000). “Interaction of Taxol With Human Serum to Inhibit T Cell Proliferation.” Immunity 27(1): 111-122, 22 pages. Albumin.” Biochim. Biophy's. Acta 1478:61-68. Carter, D.C. et al. (1994). "Structure of Serum Albumin.” Adv. Pro SEER Cancer Statistics Review. (2012). Surveillance Epidemiology tein. Chem. 45:153-203. and End Results Cancer Statistics Review 2005-2009, last visited on Chemnitz, J.M. et al. (2004). “SHP-1 and SHP-2 Associate With Oct. 6, 2012, located at . 1 page. Death 1 Upon Primary Human T Cell Stimulation, but Only Receptor Spagnolo, F. etal. (2012). "Upcoming Strategies for the Treatment of Ligation Prevents T Cell Activation.” J. Immunol. 173:945-954. Metastatic Melanoma.” Archives of Research 304:177 Curry, S. et al. (Sep. 1998). "Crystal Structure of Human Serum 184. Albumin Complexed With Fatty Acid Reveals an Asymmetric Dis Subudhi, S.K. et al. (Mar. 2004). “Local Expression of B7-H1 Pro tribution of Binding Sites.” Nat. Struct. Biol. 5(9):827-835. motes Organ-Specific Autoimmunity and Transplant Rejection.” J. Davies, H. etal. (Jun. 2002). "Mutations of the BRAF Gene in Human Clin. Invest. 113(5):694-700. Cancer.' Nature 417:949-954. Sugio, S. et al. (1999). "Crystal Structure of Human Serum Albumin Eisenhauer, E.A. etal. (2009). "New Response Evaluation Criteria in at 2.5 A Resolution.” Protein. Eng. 12(6):439-446. Solid Tumours: Revised RECIST Guideline (version 1.1).” Eur: J Tamura, H. et al. (Mar. 2001). "B7-H1 Costimulation Preferentially Cancer 45(2):228-247. Enhances CD28-Independent T-Helper Cell Function.” Blood Fehske, K.J. et al. (1981). "The Location of Drug Binding Sites in 97(6): 1809-1816. Human Serum Albumin.” Biochem. Pharmcol. 30(7):687-692. Tullis, J.L. (Jan. 24, 1977). "Albumin 1. Background and Use.” JAMA Finlayson, J.S. (1980). "Albumin Products.” Seminars in Thrombosis 237(4):355-360. and Hemostasis 6(2):85-120. Tullis, J.L. (Jan. 31, 1977). "Albumin 2. Guidelines for Clinical Use.” Finn, L. et al. (2012). "Therapy for Metastatic Melanoma: The Past, JAMA 237(5):460-463. Present, and Future.” BMC 10(23): 1-10. Urien, S. et al. (May 1996). “Docetaxel Serum Protein Binding With Garrido, M.J. et al. (1994). “Binding Characteristics of Propofol to High Affinity to Alpha-Acid Glycoprotein.” Invest. New Drugs Plasma Proteins and Possible Interactions.” Rev. Esp. Anestestiol. 14:147-151. Reanin. 41:308-312. Villanueva, J. et al. (Dec. 14, 2010). “Acquired Resistance to BRAF Hauser, C.J. et al. (Jun. 1980). "Oxygen Transport Responses to Inhibitors Medicated by a RAF Kinase Switch in Melanoma Can be Colloids and Crystalloids in Critically Ill Surgical Patients.” ; Overcome by Co-Targeting MEK and IGF-1R/PI3K.” Cell 18(6): Gynecology and 150(6):811-816. 683-695, 1-25 pages. He, A.M. et al. (Jul. 16, 1992). "Atomic Structure and Chemistry of Vorum, H. (Nov. 1999). “Reversible Ligand Binding to Human Human Serum Albumin.” Nature 358:209-215. Serum Albumin.” Dan. Med. Bull. 5(46):379-399. Hersh, E.M. et al. (Jan. 1, 2010). “A Phase 2 Clinical Trial of nab Yamazaki, T. et al. (2002). “Expression of Programmed Death 1 Paclitaxel in Previously Treated and Chemotherapy-Naive Patients Ligands by Murine T Cells and APC,” J. Immunol. 169:5538-5545. With Metastatic Melanoma,” Cancer 116:155-163. Non-Final Office Action mailed on Feb. 13, 2014, for U.S. Appl. No. Hill. G. et al. (Mar. 15, 1984). "Dimethyl Triazeno imidazole 13/781,479, filed Feb. 28, 2013, 39 Pages. Carboxamide and Combination Therapy for Melanoma.” Cancer International Search Report mailed on Feb. 27, 2014, for PCT Patent 53(6): 1299-1305. Application No. PCT/US2013/072877, filed on Dec. 3, 2013, ten Hurst, E.A. etal. (Aug. 2003). "Ocular Melanoma. A Review and the pages. Relationship to Cutaneous Melanoma.” Archives of Dermatology US 8,968,752, 3/2015. Desai et al. (withdrawn). Research 139: 1067-1073. U.S. Appl. No. 14/273,319, filed May 8, 2014, for Desai et al. Kottschade, L.A. et al. (Apr. 15, 2011, e-pub. Nov. 8, 2010). “A Phase U.S. Appl. No. 14/362,382, filed Jun. 2, 2014, for Foss et al. II Trial of Nab-Paclitaxel (ABI-007) and Carboplatin in Patients With U.S. Appl. No. 14/468,127, filed Aug. 25, 2014, for Desai et al. 2. Unresectable Stage IV Melanoma,”, Cancer 117: 1704-1710. U.S. Appl. No. 14/505.452, filed Oct. 2, 2014, for Desai et al. Kottschade, L.A. et al. (Feb. 1, 2013, e-pub. Aug. 22, 2012). “A U.S. Appl. No. 14/626,678, filed Feb. 19, 2015, by Desai et al. Randomized Phase 2 Study of Temozolomide and Bevacizumab or U.S. Appl. No. 14?631,671, filed Feb. 25, 2015, by Desai et al. nab-Paclitaxel, Carboplatin, and Bevacizumab in Patients With U.S. Appl. No. 14/660,872, filed Mar. 17, 2015, by Desai et al. Unresectable Stage IV Melanoma, Cancer 119(3):586-592. Non-Final Office Action mailed on Feb. 11, 2015, for U.S. Appl. No. Kragh-Hansen, U. (Feb. 1990). "Structure and Ligand Binding Prop 13/701,001, Internationally filed on May 20, 2011, 15 pages. erties of Human Serum Albumin.” Dan. Med. Bull, 37(1):57-84. Non-Final Office Action mailed on Feb. 12, 2015, for U.S. Appl. No. Nishimura, H. etal. (1996). “Developmentally Regulated Expression 13/782,992, filed Mar. 1, 2013, 15 pages. of the PD-1 Protein on the Surface of Double-Negative (CD4-CD8) Final Office Action mailed on Jul. 10, 2015, for U.S. Appl. No. Thymocytes.” Int. Immunol. 8(5):773-780. 13/263,723, filed May 4, 2012, 42 pages. Nishimura, H. et al. (Aug. 1999). “Development of Lupus-Like U.S. Appl. No. 14/714, 131, filed May 15, 2015, by Seward et al. Autoimmune Diseases by Disruption of the PD-I Gene Encoding an ITIM Motif-Carrying Immunoreceptor.” Immunity 11:141. * cited by examiner U.S. Patent Oct. 6, 2015 Sheet 1 of 4 US 9,149,455 B2

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US 9,149,455 B2 1. 2 METHODS OF TREATING MELANOMA al., BMC Medicine, 2012, 10:23. Additionally, most patients who initially respond to treatment with BRAF inhibitors RELATED APPLICATIONS relapse, indicating the development of drug resistance and demonstrating the limitations of targeting only one pathway This application claims priority from U.S. Provisional 5 to eradicate melanoma. Villanueva Jet al., Cancer Cell, 2010, Patent Application No. 61/724,892, filed Nov. 9, 2012, and 18(6): 683-695; Spagnolo F et al., Archives of Dermatology U.S. Provisional Patent Application No. 61/763,391, filed Research, 2012, 304: 177-184. Ipilimumab can induce long Feb. 11, 2013, the contents of which are incorporated herein term responses in a Subset of patients, but its utility is limited by reference in its entirety. by its low response rate of 10% to 15% and by the fact that it 10 improves median survival time by only two months. Finn Let TECHNICAL FIELD al., BMC Medicine, 2012, 10:23. Thus, there remains a seri ous need for additional for treatment of melanoma. The present invention relates to methods, compositions, All references cited herein, including patent applications and kits for the treatment of melanoma by administering and publications, are incorporated by reference in their compositions comprising nanoparticles comprising taxane 15 entirety. and a carrier protein. SUMMARY OF THE INVENTION BACKGROUND Provided herein are methods of treating melanoma in an Melanoma is a cancer characterized by the uncontrolled individual (e.g., human) comprising administering to the growth of pigment-producing cells (melanocytes). Malignant individual an effective amount of a composition comprising melanoma develops from a neoplastic transformation of mel nanoparticles comprising a taxane (e.g., paclitaxel) and a anocytes, which are predominantly found in the basal layer of carrier protein (e.g., albumin). In some embodiments, the the epidermis and the eye. Spagnolo F et al., Archives of melanoma is cutaneous melanoma. In some embodiments, Dermatology Research, 2012, 304: 177-184: Hurst EA et al., 25 the melanoma is metastatic melanoma. In some embodi Archives of Dermatology Research, 2003, 139: 1067-1073. ments, the melanoma is metastatic malignant melanoma. In Malignant melanoma is the most aggressive form of skin Some embodiments, the melanoma is stage IV melanoma. In cancer. It is estimated that 76,250 persons would be diag Some embodiments, the individual has distant metastases. In nosed with melanoma in 2012 and 9,180 persons would die Some embodiments, the metastatic melanoma is at Stage Mla. from it. Spagnolo Fetal. Archives of Dermatology Research, 30 In some embodiments, the metastatic melanoma is at stage 2012, 304: 177-184: Surveillance Epidemiology and End M1b. In some embodiments, the metastatic melanoma is at Results Cancer Statistics Review 2005-2009 (accessed on stage M1c. In some embodiments, the individual has measur Oct. 6, 2012 at http://seer.cancer.gov/csr/1975 able disease. In some embodiments, the individual has brain 2009 pops09/results single/sect 01 table.01.pdf). metastases. In some embodiments, the individual does not Although Surgical removal of early melanoma lesions 35 have brain metastases. In some embodiments, the taxane is leads to a cure rate of 90%, advanced melanoma resists che paclitaxel. In some embodiments, the carrier protein is albu motherapy and tends to quickly metastasize (Spagnolo F et min Such as human serum albumin or human albumin. al., Archives of Dermatology Research, 2012,304: 177-184); In some embodiments of any of the methods described for these reasons, prognosis for advanced melanoma is poor, herein, the individual has not been previously treated for with 5-year survival rates of 78% for patients with stage IIIA, 40 melanoma. In some embodiments, the individual has not 59% for patients with stage IIIB, and 40% for patients with received prior cytotoxic chemotherapy for the metastatic stage IIIC, respectively. Balch C Met al., Journal of Clinical malignant melanoma. In some embodiments, the individual Oncology, 2009,27(36): 6199-6206. For patients with distant has not received prior adjuvant cytotoxic chemotherapy. In metastases, the prognosis significantly worsens, with 1 year Some embodiments, the individual is a human. In some survival rates of 62% for stage M1a, 53% for stage M1b and 45 embodiments, the individual is a male. In some embodiments, only 33% for stage M1c. Balch C Met al., Journal of Clinical the individual is a female. In some embodiments, the indi Oncology, 2009, 27(36): 6199-6206. vidual is under about 65 years old. In some embodiments, the The treatment options for metastatic melanoma are lim individual is at least about 65 years old (for example at least ited. Prior to 2011, only two therapies for metastatic mela about any of 70, 75, or 80 years old). In some embodiments, noma had been approved by the FDA: dacarbazine and high 50 the individual has elevated serum lactate dehydrogenase dose interleukin 2 (“HD IL-2), neither of which increased (“LDH) level. In some embodiments, the individual has median overall survival. Hill Get al., Cancer, 1984, 53:1299 normal LDH level. In some embodiments, the individual has 1305; Atkins Met al., Journal of Clinical Oncology, 1999, serum LDH of less than about 0.8.x upper limit of normal 17(7): 2105-2116; Phan Get al., Journal of Clinical Oncol (“ULN'). In some embodiments, the individual has serum ogy, 2001, 19(15): 3477-3482. Moreover, dacarbazine is lim 55 LDH at about 0.8.x to about 1.1 xULN. In some embodiments, ited by a low response rate of 10% to 15%, while HDIL-2 has the individual has serum LDH of between greater than about an even lower response rate of 6% to 10%. Finn Let al., BMC 1.1.x to about 2.0xULN. In some embodiments, the mela Medicine, 2012, 10:23. During 2011, the FDA approved two noma comprises wild-type BRAF. In some embodiments, the more therapies for advanced melanoma, Vemurafenib (Zelbo melanoma comprises a mutation in BRAF. In some embodi rafTM) and ipilimumab. Finn Let al., BMC Medicine, 2012, 60 ments, the melanoma comprises a V600E mutation in BRAF. 10:23. While vemurafenib has demonstrated good clinical In some embodiments of any of the methods described activity with a high response rate and low toxicity, its appli herein, the composition comprising nanoparticles comprising cability is limited to the 40%-60% of melanoma patients who taxane (e.g., paclitaxel) and a carrier protein (e.g., an albu harbor an activating mutation in the BRAF gene that leads to min) is used as a monotherapy for treating the melanoma. In constitutive activation of the mitogen-activated protein 65 some embodiments of any of the methods described herein, kinase pathway (“MAPK), which causes increased cellular the method further comprises a second therapy. In some proliferation as well as increased oncogenic activity. Finn Let embodiments, the second therapy is selected from the group US 9,149,455 B2 3 4 consisting of chemotherapy, immunotherapy, Surgery, radia In some embodiments, the method is used as a first line tion therapy, targeted therapy, or a combination thereof. In therapy. In some embodiments, the method is used as a sec Some embodiments, the method comprises administration of ond line therapy. at least one other therapeutic agent. In some embodiments, In some embodiments, the composition comprising nano the one other therapeutic agent is a BRAF inhibitor. In some particles comprising paclitaxel and an albumin is adminis embodiments, the one other therapeutic agent is ipilimumab. tered intravenously. In some embodiment, the dose of pacli In some embodiments, the method is used as a first line taxel in the nanoparticle composition is about 80 mg/m to therapy. In some embodiments, the method is used as a sec about 200 mg/m (for example about 150 mg/m). In some ond line therapy. embodiments, the composition comprising nanoparticles In some embodiments of any of the methods described 10 comprising paclitaxel and an albuminis administered weekly, herein, the composition comprising nanoparticles comprising for example administered on days 1, 8, and 15 of the 28-day taxane (e.g., paclitaxel) and a carrier protein (e.g., albumin) is treatment cycle. administered intravenously. In some embodiments, the dose In some embodiments the albumin is human serum albu of taxane (e.g., paclitaxel) in the nanoparticle composition is min. In some embodiments, the nanoparticles in the compo 15 sition have an average diameter of no greater than about 200 about 50 mg/m to about 400 mg/m. In some embodiments, nm. In some embodiments, the weight ratio of albumin and the dose of taxane (e.g., paclitaxel) in the nanoparticle com paclitaxel in the nanoparticle composition is about 9:1 or less. position is about 100 mg/m to about 200 mg/m. In some In some embodiments, the paclitaxel in the nanoparticles are embodiments, the dose of taxane (e.g., paclitaxel) in the nano coated with the albumin. particle composition is about 150 mg/m. In some embodi In some embodiments, there is provided a kit comprising ments, the composition comprising nanoparticles comprising (i) a composition comprising nanoparticles comprising pacli taxane (e.g., paclitaxel) and a carrier protein (e.g., albumin) is taxel and an albumin, and (ii) an instruction for administering administered weekly. In some embodiments, the method the nanoparticle composition for treating melanoma. comprises at least one 28-day treatment cycle. In some It is to be understood that one, some, or all of the properties embodiments, the composition comprising nanoparticles 25 of the various embodiments described herein may be com comprising taxane (e.g., paclitaxel) and a carrier protein (e.g., bined to form other embodiments of the present invention. albumin) is administered on days 1, 8, and 15 of the 28-day These and other aspects of the invention will become appar treatment cycle. In some embodiments, the carrier protein is ent to one of skill in the art. albumin. In some embodiments, the albumin is human serum albumin. In some embodiments, the albumin is human albu 30 BRIEF DESCRIPTION OF THE FIGURES min. In some embodiments, the albumin is recombinant albu min. In some embodiments, the nanoparticles in the compo FIG. 1 shows the study design for the phase III study of Nab-paclitaxel (or Abraxane(R) versus dacarbazine in chemo sition have an average diameter of no greater than about 200 therapy-naive patients with metastatic malignant melanoma. nm. In some embodiments, the weight ratio of albumin and 35 DCR, disease control rate; ECOG, Eastern Cooperative taxane (e.g., paclitaxel) in the nanoparticle composition is Oncology Group; LDH, lactate dehydrogenase; ORR, objec about 9:1 or less. In some embodiments, the weight ratio of tive response rate; OS, overall survival; PFS, progression-free albuminand taxane (e.g., paclitaxel) in the nanoparticle com survival; RECIST, Response Evaluation Criteria In Solid position is about 9:1. In some embodiments, the taxane (e.g., Tumors; ULN, upper limit of normal. paclitaxel) in the nanoparticles are coated with the albumin. 40 FIG. 2 shows progression free survival by independent In some embodiments, the taxane is paclitaxel. In some review. PFS for Nab-paclitaxel (or Abraxane(R) embodiments, there is provided a method of treating mela arm: 4.8 months; PFS for dacarbazine arm: 2.5 months noma in an individual (e.g., human) comprising administer (P=0.044). CI, confidence interval; HR, hazard ratio. ing to the individual an effective amount of a composition FIG. 3 shows overall survival planned interim analysis comprising nanoparticles comprising paclitaxel and albumin 45 from the study. Median OS for Nab-paclitaxel (or Abrax (e.g., human albumin or human serum albumin). ane(R) arm: 12.8 months; median OS for dacarbazine arm: In some embodiments, there is provided a method of treat 10.7 months. * indicates that at the time of PFS analysis, 64% ing melanoma in a human individual comprising administer of patients had an event. ing to the individual an effective amount of a composition FIG. 4 shows overall survival interim analysis for specific comprising nanoparticles comprising paclitaxel and an albu 50 Subgroups. min. In some embodiments, the individual is selected for treatment based on the individual having metastatic mela DETAILED DESCRIPTION noma at stage M1c. In some embodiments, the individual is selected for treatment based on the individual having a serum Provided herein are methods for treatment of melanoma LDH level of between greater than about 1.1.x to about 2.0x 55 (e.g., stage IV or metastatic cutaneous melanoma) in an indi ULN. In some embodiments, the individual is selected for vidual using a composition comprising nanoparticles com treatment based on the individual having a melanoma com prising a taxane and a carrier protein. prising wild-type BRAF. In some embodiments, the indi A phase III study using an albumin stabilized nanoparticle vidual is selected for treatment based on the individual having formulation of paclitaxel (Nab-paclitaxel, or Abraxane.R.) a melanoma comprising a mutation in BRAF (Such as a 60 Versus dacarbazine was conducted in chemotherapy-naive V600E mutation in BRAF). patients with metastatic malignant melanoma. Dacarbazine is In some embodiments, the method further comprises a the only FDA-approved chemotherapy since 1975 for meta second therapy, for example a second therapy comprising static melanoma. The study showed that Abraxane(R) almost administration of at least one other therapeutic agent. In some doubled the progression-free survival (“PFS) compared to embodiments, the other therapeutic agent is a BRAF inhibi 65 dacarbazine (PFS: 4.8 months for Abraxane(R) versus 2.5 tor. In some embodiments, the other therapeutic agent is months for dacarbazine, P=0.044). Abraxane(R) is the first Ipilimumab. single-agent chemotherapy to demonstrate a statistically sig US 9,149,455 B2 5 6 nificant improvement over dacarbazine in 37 years. The tion of the disease state, and remission (whether partial or present invention thus provides methods, compositions, and total). Also encompassed by “treatment' is a reduction of kits for treatment of melanoma in an individual by adminis pathological consequence of a proliferative disease Such as tration of a composition comprising nanoparticles compris cancer (e.g., melanoma). The methods provided herein con ing a taxane and a carrier protein. template any one or more of these aspects of treatment. In some embodiments, there is provided a method of treat The term “effective amount’ used herein refers to an ing melanoma in an individual comprising administering to amount of a compound or composition, when used alone or in the individual a composition comprising nanoparticles com combination with a second therapy, is sufficient to treat a prising a taxane and a carrier protein. In some embodiments, specified disorder, condition or disease such as ameliorate, the individual has stage IV or metastatic melanoma (e.g., 10 palliate, lessen, and/or delay one or more of its symptoms. In stage IV or metastatic cutaneous melanoma). In some reference to cancers or other unwanted cell proliferation, an embodiments, the melanoma is metastatic malignant mela effective amount comprises an amount Sufficient to cause a noma. In some embodiments, the metastatic melanoma is at tumor to shrink and/or to decrease the growth rate of the stage M1a, stage M1b, or stage M1c. In some embodiments, tumor (Such as to suppress tumor growth) or to prevent or the metastatic melanoma is at stage M1 c. In some embodi 15 delay other unwanted cell proliferation. An effective amount ments, the melanoma comprises a mutation in BRAF. In some can be administered in one or more administrations. In the embodiments, the melanoma does not comprise a mutation in case of melanoma, the effective amount of the drug or com BRAF. In some embodiments, the melanoma does not com position may: (i) reduce the number of melanoma cells; (ii) prise BRAF mutant such as a BRAF mutant with increased reduce melanoma tumor size; (iii) inhibit, retard, slow to activity (for example, increased kinase activity, and/or Some extent and for example stop melanoma cell infiltration increased activity as compared to wild-type BRAF) or a into peripheral organs; (iv) inhibit (i.e., slow to some extent BRAF gain-of-function mutant. In some embodiments, the and for example stop) melanoma tumor metastasis; (V) inhibit melanoma does not comprise BRAF V600E mutation (e.g., melanoma tumor growth; (vi) prevent or delay occurrence the melanoma comprises wild-type BRAF). In some embodi and/or recurrence of melanoma tumor, and/or (vii) relieve to ments, the melanoma comprises a BRAF mutant such as a 25 Some extent one or more of the symptoms associated with the BRAF mutant with increased activity (for example, increased melanoma. kinase activity, and/or increased activity as compared to wild As used herein, by “combination therapy” is meant that a type BRAF) or a BRAF gain-of-function mutant. In some first agent be administered in conjunction with another agent. embodiments, the melanoma comprises BRAF V600E muta “In conjunction with refers to administration of one treat tion. In some embodiments, the individual has elevated serum 30 ment modality in addition to another treatment modality, Such lactate dehydrogenase (“LDH) level (for example, elevated as administration of a nanoparticle composition described LDH levelas compared to a normal level such as normal LDH herein in addition to administration of the other agent to the level known in the art or normal LDH level in an individual same individual. As such, “in conjunction with refers to without melanoma or cancer). In some embodiments, the administration of one treatment modality before, during, or individual has normal serum LDH level. In some embodi 35 after delivery of the other treatment modality to the indi ments, the individual has serum LDH of less than about 0.8x vidual. upper limit of normal (“ULN'). In some embodiments, the As used herein, by “pharmaceutically acceptable' or individual has serum LDH at about 0.8.x to about 1.1 xULN. “pharmacologically compatible' is meant a material that is In some embodiments, the individual has serum LDH of not biologically or otherwise undesirable, e.g., the material between greater than about 1.1.x to about 2.0xULN. In some 40 may be incorporated into a pharmaceutical composition embodiments, the individual has serum LDH of between administered to an individual or patient without causing any about 1.1.x to about 2.0xULN. In some embodiments, the significant undesirable biological effects or interacting in a individual is a human (e.g., male or female). In some embodi deleterious manner with any of the other components of the ments, the taxane is paclitaxel. In some embodiments, the composition in which it is contained. Pharmaceutically carrier protein is albumin. 45 acceptable carriers or excipients have for example met the Also provided herein are compositions (such as pharma required Standards of toxicological and manufacturing testing ceutical compositions), articles of manufacture, , and/or are included on the Inactive Ingredient Guide prepared kits, and unit dosages useful for the methods described by the U.S. Food and Drug administration. herein. Also provided herein are certain combination thera As used herein and in the appended claims, the singular pies methods, kits, and compositions for the treatment of 50 forms “a,” “an and “the include plural reference unless the melanoma. context clearly indicates otherwise. Reference to “about a value or parameter herein includes DEFINITIONS (and describes) embodiments that are directed to that value or parameter perse. For example, description referring to “about The term “individual' refers to a mammal, including 55 X” includes description of “X” humans. An individual includes, but is not limited to, human, It is understood that aspect and variations of the invention bovine, horse, feline, canine, rodent, or primate. In some described herein include “consisting and/or “consisting embodiments, the individual is human. The term “individual' essentially of aspects and variations. also includes human patients described in the Examples. Methods of Treating Melanoma As used herein, “treatment' is an approach for obtaining 60 The present invention provides methods for treatment of beneficial or desired clinical results. Beneficial or desired melanoma in an individual (e.g., human) using a composition clinical results may include, but are not limited to, any one or comprising nanoparticles comprising a taxane and a carrier more of alleviation of one or more symptoms, diminishment protein. of extent of disease, stabilized (i.e., not worsening) state of In some embodiments, the melanoma is cutaneous mela disease, preventing or delaying spread (e.g., metastasis) of 65 noma. In some embodiments, the melanoma is metastatic disease, preventing or delaying occurrence or recurrence of melanoma. In some embodiments, the melanoma is meta disease, delay or slowing of disease progression, ameliora static malignant melanoma. In some embodiments, the mela US 9,149,455 B2 7 8 noma is stage IV melanoma (e.g., stage IV cutaneous mela the melanoma is (e.g., mucosal mela noma). In some embodiments, the metastatic melanoma is at noma in nose, mouth, throat, or genital area). In some stage Mla. In some embodiments, the metastatic melanoma embodiments, the melanoma is ocular melanoma. In some is at stage M1b. In some embodiments, the metastatic mela embodiments, the melanoma is uveal melanoma. In some noma is at stage M1c. In some embodiments, the individual embodiments, the melanoma is choroidal melanoma. For has not received prior therapy (e.g., prior cytotoxic chemo example, in some embodiments, there is provided a method of therapy) for the melanoma (e.g., metastatic melanoma). In treating cutaneous melanoma (e.g., metastatic or stage IV Some embodiments, the melanoma comprises a mutation in cutaneous melanoma) in an individual (e.g., human) compris BRAF. In some embodiments, the melanoma comprises a ing administering to the individual a composition comprising BRAF V600E mutation. In some embodiments, the mela 10 nanoparticles comprising a taxane (e.g., paclitaxel) and a noma does not comprise a mutation in BRAF (e.g., the mela carrier protein (e.g., albumin). In some embodiments, the noma comprises wild-type BRAF). In some embodiments, individual has stage IV or metastatic melanoma. In some the melanoma does not comprise BRAF mutant such as a embodiments, the melanoma is metastatic malignant mela BRAF mutant with increased activity (for example, increased noma. In some embodiments, the metastatic melanoma is at kinase activity, and/or increased activity as compared to wild 15 stage M1a, stage M1b, or stage M1c. In some embodiments, type BRAF) or a BRAF gain-of-function mutant. In some the metastatic melanoma is at stage M1 c. In some embodi embodiments, the melanoma does not comprise a constitutive ments, the melanoma comprises a mutation in BRAF. In some active BRAF mutant. In some embodiments, the melanoma embodiments, the melanoma does not comprise a mutation in does not comprise BRAF V600E mutation (e.g., the mela BRAF. In some embodiments, the melanoma does not com noma comprises wild-type BRAF). In some embodiments, prise BRAF mutant such as a BRAF mutant with increased the melanoma comprises wild-type BRAF (e.g., the mela activity (for example, increased kinase activity, and/or noma cells have wild-type BRAF). In some embodiments, the increased activity as compared to wild-type BRAF) or a melanoma comprises a BRAF mutant such as a BRAF mutant BRAF gain-of-function mutant. In some embodiments, the with increased activity (for example, increased kinase activ melanoma does not comprise a constitutive active BRAF ity, and/or increased activity as compared to wild-type 25 mutant. In some embodiments, the melanoma does not com BRAF) or a BRAF gain-of-function mutant. In some embodi prise BRAF V600E mutation (e.g., the melanoma comprises ments, the melanoma comprises a constitutive active BRAF wild-type BRAF). In some embodiments, the melanoma mutant. In some embodiments, the melanoma comprises comprises wild-type BRAF (e.g., the melanoma cells have BRAF V600E mutation. In some embodiments, the indi wild-type BRAF). In some embodiments, the melanoma vidual has elevated serum lactate dehydrogenase (“LDH') 30 comprises a BRAF mutant such as a BRAF mutant with level. In some embodiments, the individual has serum LDH of increased activity (for example, increased kinase activity, less than about 0.8.x upper limit of normal (“ULN'). In some and/or increased activity as compared to wild-type BRAF) or embodiments, the individual has serum LDH at about 0.8.x to a BRAF gain-of-function mutant. In some embodiments, the about 1.1 xULN. In some embodiments, the individual has melanoma comprises BRAF V 600E mutation. In some serum LDH of between greater than about 1.1.x to about 35 embodiments, the melanoma comprises a constitutively 2.0xULN. In some embodiments, the individual has serum active BRAF mutant. In some embodiments, the melanoma LDH of between about 1.1.x to about 2.0xULN. In some does not comprise a constitutively active BRAF mutant. In embodiments, the individual is under about 65 years old. In Some embodiments, the methodofusing taxane nanoparticles some embodiments, the individual is at least about 65 years for treating melanoma is used as a monotherapy. In some old (for example at least about any of 70, 75, or 80 years old). 40 embodiments, the method of treating melanomausing taxane In some embodiments, the individual is a male. In some nanoparticles does not further comprise one other therapeutic embodiments, the individual is a female. In some embodi agent (Such as one other chemotherapeutic agent or immuno ments, the individual has one or more of the characteristics of therapeutic agent). In some embodiments, the method does the patients described in Examples 1 and 2 of the present not further comprise a cytotoxic chemotherapeutic agent. disclosure. For example, the individual may have at least one 45 Melanoma described herein may be any of the following: (e.g., at least any of 2, 3, 4, 5, 6, or 7) of the following cutaneous melanoma, extracutaneous melanoma, Superficial characteristics: (1) Histologically or cytologically confirmed spreading melanoma, malignant melanoma, nodular malig cutaneous malignant melanoma with evidence of metastasis nant melanoma, nodular melanoma, polypoid melanoma, (Stage IV); (2) No prior cytotoxic chemotherapy for meta acral lentiginous melanoma, lentiginous malignant mela static malignant melanoma; (3) No prior adjuvant cytotoxic 50 noma, , lentigo maligna melanoma, chemotherapy; (4) Male or non-pregnant and non-lactating mucosal lentignous melanoma, mucosal melanoma, Soft-tis female - 18 years of age; (5) No other current active malig Sue melanoma, ocular melanoma, desmoplastic melanoma, nancy within the past 3 years; (6) Radiographically-docu or metastatic malignant melanoma. mented measurable disease (for example, the presence of at In some embodiments, the melanoma to be treated is stage least 1 radiographically documented measurable lesion); and 55 0, stage I, stage II, stage III, or stage IV. In some embodi (7) ECOG performance status 0-1. In some embodiments, the ments, the melanoma to be treated is stage 0, stage IA, stage individual does not have history or current evidence of brain IB, stage IIA, stage IIB, stage IIC, stage IIIA, stage IIIB, stage metastases, including leptomeningeal involvement. In some IIIC, or stage IV. In some embodiments, the melanoma is embodiments, the individual does not have pre-existing metastatic melanoma. In some embodiments, the metastatic peripheral neuropathy of NCICTCAE Scale of Grade 2. 60 melanoma is at Stage Mla. In some embodiments, the meta In some embodiments, the melanoma is cutaneous mela static melanoma is at stage M1b. In some embodiments, the noma. In some embodiments, the melanoma is melanoma of metastatic melanoma is at stage M1c. Staging of melanoma the skin. In some embodiments, the melanoma is Superficial may be based on a method known to one skilled in the art. spreading melanoma. In some embodiments, the melanoma is Staging of melanoma may be according to the criteria nodular melanoma. In some embodiments, the melanoma is 65 included in 2009 AJCC Melanoma Staging and Classifica acral lentiginous melanoma. In some embodiments, the mela tion. See Balch C Met al., J. Clin Oncol. 2009, 27(36):6199 noma is lentigo maligna melanoma. In some embodiments, 206 (the contents disclosed therein are incorporated by refer US 9,149,455 B2 9 10 ence in their entirety). For example, the staging of melanoma TABLE 2-continued may be according to the criteria set forth in Tables 1 and 2. Anatomic Stage Groupings for Cutaneous Melanoma TABLE 1. Clinical Staging Pathologic Stagingi

TNM Staging Categories for Cutaneous Melanoma T N M T N M Classification IIIC T1-4b N1b MO

T Thickness (mm) Ulceration Status. Mitoses 10 Any T N3 MO Tis NA NA IV Any T Any N M1 IV Any T Any N M1 T1 s1.00 a: Without ulceration Clinical staging includes microstaging of the primary melanoma and clinical radiologic and mitosis <1/mm. evaluation for metastases. By convention, it should be used after complete excision of the b: With ulceration or primary melanoma with clinical assessment for regional and distant metastases, Pathologic staging includes microstaging of the primary melanoma and pathologic infor mitoses e1/mm mation about the regional lymph nodes after partial (i.e., sentinel node biopsy) or complete T2 1.01-2.OO a: Without ulceration 15 lymphadenectomy, Pathologic stage 0 or stage LA patients are the exception; they do not b: With ulceration require pathologic evaluation of their lymph nodes, T3 2.01-4.OO a: Without ulceration b: With ulceration In some embodiments, the melanoma is early stage mela T4 >4.OO a: Without ulceration noma (e.g., early stage cutaneous melanoma). In some b: With ulceration embodiments, the melanoma is late stage melanoma (e.g., late stage cutaneous melanoma). In some embodiments, the N No. of Metastatic Nodes Nodal Metastatic Burden melanoma is advanced melanoma. In some embodiments, the NO O NA individual has measurable disease. In some embodiments, the N1 1 a: Micrometastasis melanoma is metastatic melanoma (e.g., metastatic cutane b: Macrometastasis 25 ous melanoma). In some embodiments, the melanoma is N2 2-3 a: Micrometastasis metastatic malignant melanoma (e.g., metastatic malignant b: Macrometastasis cutaneous melanoma). In some embodiments, the melanoma c: In transit metastases satellites without is stage IV melanoma (e.g., stage IV cutaneous melanoma). metastatic nodes In some embodiments, the individual has measurable disease. N3 4+ metastatic nodes, or 30 A measurable disease may be determined using methods matted nodes, or in transit known to one skilled in the art. In some embodiments, a metastases satellites with measurable disease refers to the presence of at least 1 radio metastatic nodes graphically documented measurable lesion. In some embodi ments, the melanoma is a melanoma with one or more meta M Site Serum LDH 35 static sites in the brain. MO No distant metastases NA In some embodiments, the melanoma is non-metastatic M1a Distant skin, Subcutaneous, or Normal melanoma. In some embodiments, the melanoma is meta nodal metastases static melanoma. In some embodiments, the melanoma is a M1b Lung metastases Normal primary melanoma tumor. In some embodiments, the primary M1c All other visceral metastases Normal 40 melanoma tumor has metastasized. In some embodiments, Any distant metastasis Elevated the melanoma is locally advanced melanoma. In some embodiments, the melanoma is recurrent melanoma. In some Abbreviations: NA, not applicable; LDH, lactate dehydrogenase. embodiments, the melanoma has reoccurred after remission. Micrometastases are diagnosed after sentinel lymph node biopsy, Macrometastases are defined as clinically detectable nodal metastases confirmed patho In some embodiments, the melanoma is progressive mela logically, 45 noma. In some embodiments, the melanoma is melanoma in remission. In some embodiments, the individual has distant metastases. Distant metastases may be based on methods TABLE 2 known in the art, and may refer to distant skin, Subcutaneous, Anatomic Stage Groupings for Cutaneous Melanoma or nodal metastases or metastases in distant organ Such as 50 lung metastases. In some embodiments, the individual does Clinical Staging Pathologic Staging not have distant metastases. In some embodiments, the indi vidual has locoregional cutaneous metastases. In some T N M N M embodiments, the individual has distant skin, Subcutaneous, 0 Tis NO MO O Tis NO MO or nodal metastases. In some embodiments, the individual has IA T1a NO MO IA T1a. NO MO 55 IB T1b NO MO IB T1b NO MO visceral metastases. In some embodiments, the individual T2a NO MO T2a NO MO does not have visceral metastases. In some embodiments, the IIA T2b NO MO IIA T2b NO MO individual has metastases of melanoma in lung, liver, bone or T3a NO MO T3a NO MO brain. In some embodiments, the individual does not have IIB T3b NO MO IIB T3b NO MO metastases of melanoma in brain. In some embodiments, the T4a NO MO T4a NO MO IIC T4b NO MO IIC T4b NO MO 60 melanoma is localized resectable, localized unresectable, or III Any T N > NO MO IIIA T1-4a N1a MO unresectable. In some embodiments, the individual has pre T1-4a N2a MO viously been treated with a BRAF inhibitor such as, for IIIB T1-4b N1a MO T1-4b N2a MO example, Vemurafenib (Zelboraf) or Sorafenib (Nexavar). T1-4a N1b MO For example, there is provided a method of treating stage T1-4a N2b MO 65 IV melanoma (e.g., stage IV cutaneous melanoma) in an T1-4a N2c MO individual (e.g., human) comprising administering to the individual a composition comprising nanoparticles compris US 9,149,455 B2 11 12 ing a taxane (e.g., paclitaxel) and a carrier protein (e.g., albu been previously treated with a cytokine. In some embodi min). In some embodiments, there is provided a method of ments, the individual has been previously treated with an treating metastatic melanoma (e.g., metastatic cutaneous adjuvant therapy (e.g., interferon, GM-CSF, or vaccine). For melanoma) (Such as melanoma at metastatic stage Mla, M1b. example, there is provided a method of treating melanoma or M1c) in an individual (e.g., human) comprising adminis (e.g., metastatic cutaneous melanoma) in an individual (e.g., tering to the individual a composition comprising nanopar human) comprising administering to the individual a compo ticles comprising a taxane (e.g., paclitaxel) and a carrier pro sition comprising nanoparticles comprising a taxane (e.g., tein (e.g., albumin). In some embodiments, the metastatic paclitaxel) and a carrier protein (e.g., albumin), wherein the melanoma is at any of stage M1a, stage M1b, or stage M1c. In individual has not received prior therapy or prior chemo Some embodiments, there is provided a method of treating 10 therapy (Such as prior cytotoxic chemotherapy) for the mela metastatic cutaneous melanoma with metastatic stage M1c in noma. In some embodiments, the melanoma comprises a an individual (e.g., human) comprising administering to the mutation in BRAF. In some embodiments, the melanoma individual a composition comprising nanoparticles compris does not comprise a mutation in BRAF. In some embodi ing a taxane (e.g., paclitaxel) and a carrier protein (e.g., albu ments, the melanoma does not comprise BRAF mutant Such min). In some embodiments, the melanoma comprises a 15 as a BRAF mutant with increased activity (for example, mutation in BRAF. In some embodiments, the melanoma increased kinase activity, and/or increased activity as com does not comprise a mutation in BRAF. In some embodi pared to wild-type BRAF) or a BRAF gain-of-function ments, the melanoma does not comprise BRAF mutant Such mutant. In some embodiments, the melanoma does not com as a BRAF mutant with increased activity (for example, prise BRAF V600E mutation (e.g., the melanoma comprises increased kinase activity, and/or increased activity as com wild-type BRAF). In some embodiments, the melanoma pared to wild-type BRAF) or a BRAF gain-of-function comprises wild-type BRAF. In some embodiments, the mela mutant. In some embodiments, the melanoma does not com noma comprises a BRAF mutant such as a BRAF mutant with prise BRAF V600E mutation (e.g., the melanoma comprises increased activity (for example, increased kinase activity, wild-type BRAF). In some embodiments, the melanoma and/or increased activity as compared to wild-type BRAF) or comprises wild-type BRAF. In some embodiments, the mela 25 a BRAF gain-of-function mutant. In some embodiments, the noma comprises a BRAF mutant such as a BRAF mutant with melanoma comprises BRAF V 600E mutation. In some increased activity (for example, increased kinase activity, embodiments, the method of using taxane nanoparticles for and/or increased activity as compared to wild-type BRAF) or treating melanoma is used as a monotherapy. In some a BRAF gain-of-function mutant. In some embodiments, the embodiments, the method of treating melanomausing taxane melanoma comprises BRAF V600E mutation. In some 30 nanoparticles does not further comprise one other therapeutic embodiments, the method of using taxane nanoparticles for agent (Such as one other chemotherapeutic agent or immuno treating melanoma is used as a monotherapy. In some therapeutic agent). In some embodiments, the method does embodiments, the method of treating melanoma using taxane not further comprise a cytotoxic chemotherapeutic agent. nanoparticles does not further comprise one other therapeutic Any individual having normal or elevated lactate dehydro agent (Such as one other chemotherapeutic agent or immuno 35 genase (“LDH) level (such as normal or elevated serum therapeutic agent). In some embodiments, the method does LDH level) may be treated with a method described herein. In not further comprise a cytotoxic chemotherapeutic agent. some embodiments, the individual has normal LDH level In Some embodiments, the individual has melanoma tumor Such as normal serum LDH level (e.g., a normal serum LDH with thickness of less than about any of 0.5 millimeter baseline level or normal serum LDH at the time of diagnosis (“mm), 1 mm, 1.5 mm, 2 mm, 2.5 mm, 3 mm, 3.5 mm, 4 mm, 40 of melanoma). In some embodiments, the individual has 4.5 mm, 5 mm, 5.5 mm, 6 mm, 6.5 mm, 7 mm, 7.5 mm, or 8 elevated LDH level such as elevated serum LDH level (e.g., mm. In some embodiments, the individual has melanoma an elevated serum LDH baseline level or elevated serum LDH tumor with thickness of at least about any of 0.5 mm, 1 mm, at the time of diagnosis of melanoma). In some embodiments, 1.5 mm, 2 mm, 2.5 mm, 3 mm, 3.5 mm, 4 mm, 4.5 mm, 5mm, the individual has substantially elevated serum LDH level. In 5.5 mm, 6 mm, 6.5 mm, 7 mm, 7.5 mm, or 8 mm. In some 45 some embodiments, the individual has serum LDH level embodiments, the individual has melanoma tumor with thick increased by at least about any of 10%, 20%, 30%, 40%, 50%, ness of about any of 0.5 mm, 1 mm, 1.5 mm, 2 mm, 2.5 mm, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 175%, or 3 mm, 3.5 mm, 4 mm, 4.5 mm, 5mm, 5.5 mm, 6mm, 6.5 mm, 200% compared to the normal serum LDH value or serum 7 mm, 7.5 mm, or 8 mm. In some embodiments, the individual LDH value for an individual without melanoma. The serum has melanoma tumor with thickness of about any of 0-1 mm, 50 LDH level may be determined by a person skilled in the art 1-2 mm, 2-3 mm, 3-4 mm, 4-5 mm, 5-6 mm, 1-4 mm, 1-6 mm, using methods known in the art. In some embodiments, the 2-4 mm, 2-6 mm, or 4-6 mm. serum LDH level can be determined via immunoassay, e.g., Any individual having melanoma (e.g., metastatic mela ELISA or sandwich ELISA. In some embodiments, the serum noma Such as metastatic cutaneous melanoma) may be LDH level can be determined by a colorimetric assay in treated using a method described herein. In some embodi 55 which either the reduction of NAD+ (oxidation of lactate to ments, the individual is chemotherapy-naive or has not been pyruvate) or the oxidation of NADH (reduction of pyruvate to treated with chemotherapy. In some embodiments, the indi lactate) is monitored by the change in absorbance at 340 nm. vidual has not been previously treated for the melanoma. In In some embodiments, LDH level can be determined via Some embodiments, the individual has not been previously electrophoresis using a chromogenic LDH activity stain. In treated for the metastatic melanoma. In some embodiments, 60 some embodiments, the LDH level described herein refers to the individual has not received prior therapy or prior chemo baseline LDH level. In some embodiments, the LDH level therapy (Such as prior cytotoxic chemotherapy) for the mela described herein refers to the LDH level at the time of diag noma (e.g., the metastatic malignant melanoma). In some nosis of melanoma. In some embodiments, the LDH level embodiments, the individual has not received prior adjuvant described herein refers to the LDH level at the time of diag therapy (e.g., adjuvant cytotoxic chemotherapy). In some 65 nosis of stage IV or metastatic melanoma. In some embodi embodiments, the individual has been previously treated with ments, the LDH level described herein is compared to an a kinase inhibitor. In some embodiments, the individual has individual without melanoma. In some embodiments, the US 9,149,455 B2 13 14 LDH level is elevated compared to a normal LDH level Some embodiments, the carrier protein is albumin. In some known in the art or a LDH level in an individual without embodiments, the method of using taxane nanoparticles for melanoma or cancer. In some embodiments, the LDH level is treating melanoma is used as a monotherapy. In some elevated compared to a normal LDH level range known in the embodiments, the method of treating melanomausing taxane art or a LDH level in a healthy individual. In some embodi nanoparticles does not further comprise one other therapeutic ments, the LDH level refers to the total LDH level (LDH agent (Such as one other chemotherapeutic agent or immuno isoenzymes combined together). therapeutic agent). In some embodiments, the method does In some embodiments, the individual has serum LDH level not further comprise a cytotoxic chemotherapeutic agent. of at least about any of 0.6x upper limit of normal (“ULN'), For another example, there is provided a method of treating 0.7xULN, 0.8xULN, 0.9XULN, 1.0xULN, 1.1XULN, 1.2x 10 melanoma (e.g., metastatic cutaneous melanoma) in an indi ULN, 1.3XULN, 1.4xULN, 1.5xULN, 1.6xULN, 1.7xULN, vidual (e.g., human) comprising administering to the indi 1.8xULN, 1.9xULN, 2.0xULN, 2.1XULN, or 2.2xULN. In vidual a composition comprising nanoparticles comprising a some embodiments, the individual has serum LDH level of taxane (e.g., paclitaxel) and a carrier protein (e.g., albumin), lower than about any of 0.6xULN, 0.7xULN, 0.8xULN, 0.9x wherein the individual has elevated serum LDH level. In ULN, 1.0xULN, 1.1XULN, 1.2xULN, 1.3XULN, 1.4xULN, 15 some embodiments, the individual has serum LDH of one of 1.5xULN, 1.6XULN, 1.7xULN, 1.8xULN, 1.9XULN, 2.0x the following: serum LDH level of less than about 0.8xULN, ULN, 2.1XULN, 2.2xULN, 2.3XULN, 2.4xULN, 2.5xULN, serum LDH level of about 0.8.x to about 1.1 xULN, or serum 2.6xULN, 2.7xULN, 2.8xULN, or 3.0xULN. In some LDH of between greater than about 1.1.x to about 2.0xULN. embodiments, the individual has serum LDH level of about In some embodiments, the individual has stage IV or meta any of 0.6xULN, 0.7xULN, 0.8xULN, 0.9xULN, 1.0xULN, static melanoma (e.g., stage IV or metastatic cutaneous mela 1.1XULN, 1.2xULN, 1.3XULN, 1.4xULN, 1.5xULN, 1.6x noma). In some embodiments, the melanoma is metastatic ULN, 1.7xULN, 1.8xULN, 1.9XULN, 2.0xULN, 2.1XULN, malignant melanoma. In some embodiments, the metastatic O r2.2xULN. In some embodiments, the individual has serum melanoma is at stage M1a, stage M1b, or stage M1c. In some DH level of about any of 0.4xULN-0.8xULN, 0.6xULN embodiments, the metastatic melanoma is at stage M1c. In 5XULN, 0.8xULN-2.0xULN, 0.8xULN-1.5xULN, 0.8x 25 Some embodiments, the melanoma comprises a mutation in L 1.2xULN, 0.8xULN-1.1XULN, 0.9xULN-1.1XULN, BRAF. In some embodiments, the melanoma comprises a 8 U LN-1.2xULN, 1.0xULN-2.2xULN, 1.1XULN-2.0x constitutively active BRAF mutant. In some embodiments, L >1.1XULN-2.0xULN, >1.2xULN-2.0xULN, 1.2x the melanoma comprises a BRAF mutant such as a BRAF L 2.2xULN, 1.2xULN-2.0xULN, 1.5xULN-2.0XULN, mutant with increased activity (for example, increased kinase 2 LN-5.0xULN, 1.2xULN-4.0xULN,O 2.0xULN-4.0x 30 activity, and/or increased activity as compared to wild-type LN, 1.2xULN-3.5xULN, 1.2xULN-3.0xULN, 1.2xULN BRAF) or a BRAF gain-of-function mutant. In some embodi 5 xULN, 1.1XULN-1.8xULN, 1.1XULN-1.5xULN, 1.2x ments, the melanoma comprises BRAF V600E mutation. In L N-1.5xULN, 1.2xULN-1.8xULN, or 1.3XULN-1.8x Some embodiments, the individual is a human (e.g., male or LN. In some embodiments, the individual has serum LDH female). In some embodiments, the taxane is paclitaxel. In of less than about 0.8.x upper limit of normal (“ULN'). In 35 Some embodiments, the carrier protein is albumin. In some some embodiments, the individual has serum LDH at about embodiments, the method of using taxane nanoparticles for 0.8x to about 1.1 xULN. In some embodiments, the individual treating melanoma is used as a monotherapy. In some has serum LDH of between greater than about 1.1.x to about embodiments, the method of treating melanomausing taxane 2.0xULN. In some embodiments, the individual has serum nanoparticles does not further comprise one other therapeutic LDH of between about 1.1x to about 2.0xULN. For example, 40 agent (Such as one other chemotherapeutic agent or immuno there is provided a method of treating melanoma (e.g., meta therapeutic agent). In some embodiments, the method does static cutaneous melanoma) in an individual (e.g., human) not further comprise a cytotoxic chemotherapeutic agent. comprising administering to the individual a composition BRAF is a protein encoded by BRAF gene. The gene may comprising nanoparticles comprising a taxane (e.g., pacli also be referred to as proto-oncogene B-Rafand v-Rafimurine taxel) and a carrier protein (e.g., albumin), wherein the indi 45 sarcoma viral oncogene homolog B1. Mutations in BRAF vidual has normal serum LDH level. In some embodiments, have been identified in , including a mutation at the melanoma is metastatic malignant melanoma. In some codon 600 (e.g., valine to glutamate mutation at codon 600). embodiments, the metastatic melanoma is at Stage M1a, stage The V600E mutation was previously known as V599E muta M1b, or stage M1c. In some embodiments, the metastatic tion and was renamed based on additional sequence data. See melanoma is at Stage M1c. In some embodiments, the mela 50 Davies H et al., Nature 2002, 417:949-54. In some embodi noma comprises a mutation in BRAF. In some embodiments, ments of the methods described herein, the melanoma com the melanoma does not comprise a mutation in BRAF. In prises wild-type BRAF (e.g., the melanoma cells have wild some embodiments, the melanoma does not comprise BRAF type BRAF). In some embodiments, the melanoma comprises mutant such as a BRAF mutant with increased activity (for a mutation in BRAF. In some embodiments, the melanoma example, increased kinase activity, and/or increased activity 55 does not comprise a mutation in BRAF. In some embodi as compared to wild-type BRAF) or a BRAF gain-of-function ments, the melanoma comprises a mutation at codon 600 in mutant. In some embodiments, the melanoma does not com BRAF (such as Val mutated to Glu, Asp, Lys, or Arg). In some prise BRAF V600E mutation (e.g., the melanoma comprises embodiments, the melanoma does not comprise a mutation wild-type BRAF). In some embodiments, the melanoma V600E in BRAF (e.g., the melanoma cells are negative for comprises wild-type BRAF. In some embodiments, the mela 60 BRAF V600E mutation). In some embodiments, the mela noma comprises a BRAF mutant such as a BRAF mutant with noma comprises BRAF V600E mutation. In some embodi increased activity (for example, increased kinase activity, ments, the melanoma cells are characterized by homozygous and/or increased activity as compared to wild-type BRAF) or V600E BRAF genotype. In some embodiments, the mela a BRAF gain-of-function mutant. In some embodiments, the noma cells are characterized by heterozygous V 600E BRAF melanoma comprises BRAF V600E mutation. In some 65 genotype. In some embodiments a mutation in BRAF can be embodiments, the individual is a human (e.g., male or determined via allele-specific real-time PCR. In some female). In some embodiments, the taxane is paclitaxel. In embodiments, a mutation in BRAF can be determined via US 9,149,455 B2 15 16 shifted termination assay (STA). In some embodiments, a sition comprising nanoparticles comprising a taxane (e.g., mutation in BRAF can be determined via nucleic acid paclitaxel) and a carrier protein (e.g., albumin), wherein the sequencing. In some embodiments, a mutation in BRAF can melanoma comprises BRAF V 600E mutation. In some be determined using a commercially available kit, such as is embodiments, the individual has stage IV or metastatic mela available from, e.g., Roche, Neogenomics, Lab 2, or other noma (e.g., stage IV or metastatic cutaneous melanoma). In companies. Some embodiments, the melanoma is metastatic malignant In some embodiments, the melanoma does not comprise melanoma. In some embodiments, the metastatic melanoma BRAF mutant such as a BRAF mutant with increased or is at stage M1a, stage M1b, or stage M1c. In some embodi elevated activity (for example, increased kinase activity, and/ ments, the metastatic melanoma is at stage M1c. In some or increased activity as compared to wild-type BRAF) or a 10 embodiments, the individual has elevated serum LDH level. BRAF gain-of-function mutant. In some embodiments, the In some embodiments, the individual has serum LDH of melanoma does not comprise a constitutive active BRAF about any of the following: <0.8xULN, 0.4–0.8xULN, 0.8- mutant. In some embodiments, the melanoma does not com 1.1XULN, 0.9-1.1XULN, 0.8-1.2xULN, 1.1-1.5xULN, 1.2- prise BRAF V600E mutation (e.g., the melanoma comprises 1.5xULN, 1.1-2xULN, or 1.5-2xULN. In some embodi wild-type BRAF). In some embodiments, the melanoma 15 ments, the individual has serum LDH of less than about comprises wild-type BRAF. In some embodiments, the mela 0.8xULN. In some embodiments, the individual has serum noma comprises a BRAF mutant such as a BRAF mutant with LDH at about 0.8.x to about 1.1 xULN. In some embodiments, increased activity (for example, increased kinase activity, the individual has serum LDH of between greater than about and/or increased activity as compared to wild-type BRAF) or 1.1.x to about 2.0xULN. In some embodiments, the individual a BRAF gain-of-function mutant. In some embodiments, the has serum LDH of between about 1.1.x to about 2.0xULN. In melanoma comprises a BRAF constitutive active mutant. In Some embodiments, the individual is a human (e.g., male or some embodiments, the mutant BRAF has elevated activity female). In some embodiments, the taxane is paclitaxel. In Such as elevated kinase activity. In some embodiments, the Some embodiments, the carrier protein is albumin. In some mutant BRAF is again-of-function mutant. In some embodi embodiments, the method of using taxane nanoparticles for ments, the mutation in BRAF is in the kinase domain. In some 25 treating melanoma is used as a monotherapy. In some embodiments, the melanoma comprise one or more of the embodiments, the method of treating melanomausing taxane following BRAF mutations: R461 I, I462S, G463E, G463V. nanoparticles does not further comprise one other therapeutic G465A, G465E, G465V, G468A, G468E, N580S, E585K, agent (Such as one other chemotherapeutic agent or immuno D593V, F594L G595R, L596V, T598I, V599D, V599E, therapeutic agent). In some embodiments, the method does V599K, V599R, K600E, or A727V. In some embodiments, 30 not further comprise a cytotoxic chemotherapeutic agent. the melanoma comprises BRAF V600E mutation. In some embodiments of any of the methods described Mutation(s) in BRAF may be identified using methods herein, the melanoma comprises a mutation in BRAF. In known in the art. some embodiments, the melanoma comprises a V600E For example, there is provided a method of treating mela BRAF mutation. In some embodiments, the melanoma does noma (e.g., metastatic cutaneous melanoma) in an individual 35 not comprise a mutation in BRAF or is negative for BRAF (e.g., human) comprising administering to the individual a mutation. In some embodiments, the melanoma comprises composition comprising nanoparticles comprising a taxane wild-type BRAF. In some embodiments of any of the methods (e.g., paclitaxel) and a carrier protein (e.g., albumin), wherein described herein, the melanoma comprises a mutation in neu the melanoma does not comprise BRAF mutant such as a roblastoma RAS viral (v-ras) oncogene homolog (“NRAS). BRAF mutant with increased activity (for example, increased 40 In some embodiments, the melanoma does not comprise a kinase activity, and/or increased activity as compared to wild mutation in NRAS or is negative for NRAS mutation. In some type BRAF) or a BRAF gain-of-function mutant. In some embodiments, the melanoma comprises wild-type NRAS. In embodiments, there is provided a method of treating mela some embodiments of any of the methods described herein, noma (e.g., metastatic cutaneous melanoma) in an individual the melanoma comprises a mutation in phosphatase and (e.g., human) comprising administering to the individual a 45 tensin homolog (“PTEN”). In some embodiments, the mela composition comprising nanoparticles comprising a taxane noma does not comprise a mutation in PTEN or is negative for (e.g., paclitaxel) and a carrier protein (e.g., albumin), wherein PTEN mutation. In some embodiments, the melanoma com the melanoma does not comprise BRAF V600E mutation prises wild-type PTEN. In some embodiments, the melanoma (e.g., the melanoma comprises wild-type BRAF). In some comprises (i) wild-type BRAF or a mutation in BRAF; (ii) embodiments, there is provided a method of treating mela 50 wild-type NRAS or a mutation in NRAS; and/or (iii) wild noma (e.g., metastatic cutaneous melanoma) in an individual type PTEN or a mutation in PTEN. In some embodiments, the (e.g., human) comprising administering to the individual a melanoma is triple negative melanoma or comprises wild composition comprising nanoparticles comprising a taxane type BRAF, wild-type NRAS, and wild-type PTEN. Methods (e.g., paclitaxel) and a carrier protein (e.g., albumin), wherein known in the art may be used to determine whether the mela the melanoma comprises wild-type BRAF. In some embodi 55 noma or an individual having the melanoma comprises wild ments, there is provided a method of treating melanoma (e.g., type for a gene or protein or mutation(s) in a gene or protein metastatic cutaneous melanoma) in an individual (e.g., described herein. human) comprising administering to the individual a compo An individual described herein in some embodiments is a sition comprising nanoparticles comprising a taxane (e.g., human. In some embodiments, the individual is a male. In paclitaxel) and a carrier protein (e.g., albumin), wherein the 60 Some embodiments, the individual is a female. In some melanoma comprises a BRAF mutant such as a BRAF mutant embodiments, the individual is at least about any of 25, 30, 35, with increased activity (for example, increased kinase activ 40, 45, 50, 55, 60, 65,70, 75,80, 85, or 90 years old. In some ity, and/or increased activity as compared to wild-type embodiments, the individual is under about any of 25, 30, 35, BRAF) or a BRAF gain-of-function mutant. In some embodi 40, 45, 50, 55, 60, 65,70, 75,80, 85, or 90 years old. In some ments, there is provided a method of treating melanoma (e.g., 65 embodiments, the individual is about any of 25, 30.35, 40, 45, metastatic cutaneous melanoma) in an individual (e.g., 50, 55, 60, 65, 70, 75, 80, 85, or 90 years old. In some human) comprising administering to the individual a compo embodiments, the individual is under about 65 years old. In US 9,149,455 B2 17 18 some embodiments, the individual is at least about 65 years prior treatment but has progressed on the prior treatment. In old (for example at least about any of 70, 75, or 80 years old). Some embodiments, the individual is not responsive to the In some embodiments, the individual has a single lesion at prior treatment. presentation. In some embodiments, the individual has mul Methods described herein may be used as a first line tiple lesions at presentation. An individual that may be treated therapy. Methods described herein may also be used as a with a method described herein may be any one of the fol second line or third line therapy after the prior treatment for lowing: Caucasian ethnicity or race, Asian ethnicity or race, melanoma has failed or has substantially failed, or the mela African or African American ethnicity or race. Hispanic eth noma is substantially refractory to the first line therapy. In nicity or race, Latino ethnicity or race, or Hawaiian or Pacific Some embodiments, the melanoma is substantially refractory Islander ethnicity or race. 10 to first line therapy with a BRAF inhibitor. In some embodi In some embodiments, the individual is a human who ments, the individual has received at least one line of therapy exhibits one or more symptoms associated with having mela (e.g., chemotherapy or immunotherapy) for treating mela noma (e.g., stage IV or metastatic melanoma). In some noma (e.g., stage IV or metastatic melanoma) prior to receiv embodiments, the individual is genetically or otherwise pre ing the treatment described herein. In some embodiments, the disposed (e.g., having a risk factor) to developing melanoma. 15 patient has received 1 line of therapy or 2 lines of therapy These risk factors include, but are not limited to, age, sex, (e.g., 1 line of chemotherapy or immunotherapy or 2 lines of race, diet, history of previous disease, life style or habit, chemotherapy or immunotherapy). Thus, the treatment genetic (e.g., hereditary) considerations, and environmental described herein may be used as a second line therapy or a exposure (such as exposure to Sunlight). In some embodi third line therapy. The prior line of therapy described herein ments, the individual is positive for SPARC expression (for may be prior line of chemotherapy or immunotherapy. The example based on IHC standard). In some embodiments, the first line of therapy may comprise any of the following: dac individual is negative for SPARC expression. arbazine or DTIC (also known as DIC, DTIC-Dome, or Imi The methods provided herein may be practiced in an adju dazole Carboxamide), Oblimersen (or Genasense), an immu vant setting. Adjuvant setting may refer to a clinical setting in notherapy (such as interleukin-2 (IL-2) or interferon (IFN), a which an individual has had a history of a cancer described 25 BRAF inhibitor (such as Vemurafenib (or Zelboraf), GDC herein, and generally (but not necessarily) been responsive to 0879, PLX-4720, (available from Symansis), Dabrafenib (or therapy, which includes, but is not limited to, Surgery (e.g., GSK21 18436), LGX 818, CEP-32496, UI-152, RAF 265, Surgery resection), radiotherapy, and chemotherapy; how Regorafenib (BAY 73-4506), CCT239065, or Sorafenib (or ever, because of their history of cancer, these individuals are Sorafenib Tosylate, or Nexavar R)), or Ipilimumab (or MDX considered at risk of development of the disease. Treatment or 30 010, MDX-101, or Yervoy). administration in the adjuvant setting refers to a Subsequent In some embodiments, there is provided a method of treat mode of treatment. The degree of risk (e.g., when an indi ing melanoma (e.g., metastatic cutaneous melanoma) in an vidual in the adjuvant setting is considered as "high risk” or individual comprising administering to the individual an “low risk”) depends upon several factors, most usually the effective amount of a composition comprising nanoparticles extent of disease when first treated. 35 comprising a taxane (e.g., paclitaxel) and a carrier protein In some embodiments, the method is practiced in a neoad (e.g., albumin), wherein the method is used as a second line or juvant setting, i.e., the method may be carried out before the third line therapy. In some embodiments, there is provided a primary/definitive therapy. In some embodiments, the method of treating melanoma in an individual comprising method is used to treat an individual who has previously been administering to the individual an effective amount of a com treated. Any of the methods of treatment provided herein may 40 position comprising nanoparticles comprising a taxane (e.g., be used to treat an individual who has not previously been paclitaxel) and a carrier protein (e.g., albumin), wherein the treated. method is used in an adjuvant setting. In some embodiments, Methods described herein may be used to treat an indi there is provided a method of treating melanoma in an indi vidual having melanoma who has previously been treated for vidual comprising administering to the individual an effective the melanoma. The prior treatment may include a chemo 45 amount of a composition comprising nanoparticles compris therapy agent such as dacarbazine or DTIC (also known as ing a taxane (e.g., paclitaxel) and a carrier protein (e.g., albu DIC, DTIC-Dome, or Imidazole Carboxamide). In some min), wherein the method is used in a neoadjuvant setting. In embodiments, the prior treatment comprises Oblimersen (or Some embodiments, the individual has stage IV or metastatic Genasense, available from Genta Inc.). In some embodi melanoma (e.g., stage IV or metastatic cutaneous melanoma). ments, the prior treatment comprises an immunotherapy 50 In some embodiments, the melanoma is metastatic malignant (such as interleukin-2 (IL-2) or interferon (IFN)). In some melanoma. In some embodiments, the metastatic melanoma embodiments, the prior treatment comprises a BRAF inhibi is at stage M1a, stage M1b, or stage M1c. In some embodi tor, such as Vemurafenib (or Zelboraf, available from Genen ments, the metastatic melanoma is at stage M1c. In some tech USA, Inc.), GDC-0879 (available from Tocris Bio embodiments, the melanoma comprises a mutation in BRAF. science), PLX-4720 (available from Symansis), Dabrafenib 55 In some embodiments, the melanoma does not comprise a (or GSK21 18436), LGX818, CEP-32496, UI-152, RAF 265, mutation in BRAF. In some embodiments, the melanoma Regorafenib (BAY 73-4506), CCT239065, or Sorafenib (or does not comprise BRAF mutant such as a BRAF mutant with Sorafenib Tosylate or Nexavar R, available from Bayer Phar increased activity (for example, increased kinase activity, maceuticals Corp.). In some embodiments, the prior treat and/or increased activity as compared to wild-type BRAF) or ment comprises Ipilimumab (or MDX-010, MDX-101, or 60 a BRAF gain-of-function mutant. In some embodiments, the Yervoy, available from Bristol-Myers Squibb). In some melanoma does not comprise BRAF V600E mutation (e.g., embodiments, the individual has been previously treated for the melanoma comprises wild-type BRAF). In some embodi the melanoma and the individual is substantially refractory to ments, the melanoma comprises wild-type BRAF. In some the prior treatment. In some embodiments, the individual has embodiments, the melanoma comprises a BRAF mutant Such been previously treated for the melanoma and is no longer or 65 as a BRAF mutant with increased activity (for example, only partially responsive to the prior treatment. In some increased kinase activity, and/or increased activity as com embodiments, the individual is initially responsive to the pared to wild-type BRAF) or a BRAF gain-of-function US 9,149,455 B2 19 20 mutant. In some embodiments, the melanoma comprises wherein the melanoma comprises wild-type BRAF. In some BRAF V600E mutation. In some embodiments, the indi embodiments, there is provided a method of treating stage IV vidual has elevated serum LDH level. In some embodiments, or metastatic melanoma (e.g., stage IV or metastatic cutane the individual has serum LDH of about any of the following: ous melanoma) in an individual (e.g., human) comprising <0.8xULN, 0.4–0.8xULN, 0.8-1.1XULN, 0.9-1.1XULN, 0.8- administering to the individual a composition comprising 1.2xl JLN, 1.1-1.5xULN, 1.2-1.5xULN, 1.1-2xULN, or 1.5- nanoparticles comprising paclitaxel and albumin, wherein the 2xULN. In some embodiments, the individual has serum melanoma comprises wild-type BRAF, wherein the pacli LDH of less than about 0.8xULN. In some embodiments, the taxel in the nanoparticles is coated with the albumin. In some individual has serum LDH at about 0.8.x to about 1.1 xULN. embodiments, there is provided a method of treating stage IV In some embodiments, the individual has serum LDH of 10 or metastatic melanoma (e.g., stage IV or metastatic cutane between greater than about 1.1.x to about 2.0xULN. In some ous melanoma) in an individual (e.g., human) comprising embodiments, the individual has serum LDH of between administering to the individual a composition comprising about 1.1.x to about 2.0xULN. In some embodiments, the nanoparticles comprising paclitaxel and albumin, wherein the individual is a human (e.g., male or female). In some embodi melanoma comprises wild-type BRAF, wherein the pacli ments, the taxane is paclitaxel. In some embodiments, the 15 taxel in the nanoparticles is coated with the albumin, wherein carrier protein is albumin. In some embodiments, the method the average or mean particle size of the nanoparticles in the of using taxane nanoparticles for treating melanoma is used composition is no greater thanabout 200 nm (such as less than as a monotherapy. In some embodiments, the method of treat about 200 nm). In some embodiments, the albumin is human ing melanoma using taxane nanoparticles does not further albumin. In some embodiments, the albumin is human serum comprise one other therapeutic agent (Such as one other che albumin. In some embodiments, the albumin is recombinant motherapeutic agent or immunotherapeutic agent). In some albumin. In some embodiments, the method of using taxane embodiments, the method does not further comprise a cyto nanoparticles for treating melanoma is used as a mono toxic chemotherapeutic agent. therapy. In some embodiments, the method of treating mela In some embodiments, there is provided a method of treat noma using taxane nanoparticles does not further comprise ing stage IV or metastatic melanoma (e.g., stage IV or meta 25 one other therapeutic agent (Such as one other chemothera static cutaneous melanoma) in an individual (e.g., human) peutic agent or immunotherapeutic agent). In some embodi comprising administering to the individual a composition ments, the method does not further comprise a cytotoxic comprising nanoparticles comprising a taxane (e.g., pacli chemotherapeutic agent. taxel) and a carrier protein (e.g., albumin), wherein the mela In some embodiments, there is provided a method of treat noma does not comprise BRAF mutant such as a BRAF 30 ing stage IV or metastatic melanoma (e.g., stage IV or meta mutant with increased activity (for example, increased kinase static cutaneous melanoma) in an individual (e.g., human) activity, and/or increased activity as compared to wild-type comprising administering to the individual a composition BRAF) or a BRAF gain-of-function mutant. In some embodi comprising nanoparticles comprising paclitaxel and albumin, ments, there is provided a method of treating stage IV or wherein the melanoma comprises a BRAF mutation Such as metastatic melanoma (e.g., stage IV or metastatic cutaneous 35 BRAF V600E mutation. In some embodiments, there is pro melanoma) in an individual (e.g., human) comprising admin vided a method of treating stage IV or metastatic melanoma istering to the individual a composition comprising nanopar (e.g., stage IV or metastatic cutaneous melanoma) in an indi ticles comprising a taxane (e.g., paclitaxel) and a carrier pro vidual (e.g., human) comprising administering to the indi tein (e.g., albumin), wherein the melanoma comprises wild vidual a composition comprising nanoparticles comprising type BRAF. In some embodiments, there is provided a 40 paclitaxel and albumin, wherein the melanoma comprises a method of treating stage IV or metastatic melanoma (e.g., BRAF mutation such as BRAFV600E mutation, wherein the stage IV or metastatic cutaneous melanoma) in an individual paclitaxel in the nanoparticles is coated with the albumin. In (e.g., human) comprising administering to the individual a Some embodiments, there is provided a method of treating composition comprising nanoparticles comprising a taxane stage IV or metastatic melanoma (e.g., stage IV or metastatic (e.g., paclitaxel) and a carrier protein (e.g., albumin), wherein 45 cutaneous melanoma) in an individual (e.g., human) compris the melanoma comprises a BRAF mutant such as a BRAF ing administering to the individual a composition comprising mutant with increased activity (for example, increased kinase nanoparticles comprising paclitaxel and albumin, wherein the activity, and/or increased activity as compared to wild-type melanoma comprises a BRAF mutation such as BRAF BRAF) or a BRAF gain-of-function mutant. In some embodi V600E mutation, wherein the paclitaxel in the nanoparticles ments, there is provided a method of treating stage IV or 50 is coated with the albumin, wherein the average or mean metastatic melanoma (e.g., stage IV or metastatic cutaneous particle size of the nanoparticles in the composition is no melanoma) in an individual (e.g., human) comprising admin greater than about 200 nm (such as less than about 200 nm). istering to the individual a composition comprising nanopar In some embodiments, the albumin is human albumin. In ticles comprising a taxane (e.g., paclitaxel) and a carrier pro Some embodiments, the albumin is human serum albumin. In tein (e.g., albumin), wherein the melanoma comprises BRAF 55 Some embodiments, the albumin is recombinant albumin. In V600E mutation. In some embodiments, the taxane in the Some embodiments, the methodofusing taxane nanoparticles nanoparticles is coated with the carrier protein. In some for treating melanoma is used as a monotherapy. In some embodiments, the average or mean particle size of the nano embodiments, the method of treating melanomausing taxane particles in the composition is no greater than about 200 nm nanoparticles does not further comprise one other therapeutic (such as less than about 200 nm). In some embodiments, the 60 agent (Such as one other chemotherapeutic agent or immuno taxane is paclitaxel. In some embodiments, the carrier protein therapeutic agent). In some embodiments, the method does is albumin Such as human serum albuminor human albumin. not further comprise a cytotoxic chemotherapeutic agent. In some embodiments, there is provided a method of treat In some embodiments, there is provided a method of treat ing stage IV or metastatic melanoma (e.g., stage IV or meta ing stage IV or metastatic melanoma (e.g., stage IV or meta static cutaneous melanoma) in an individual (e.g., human) 65 static cutaneous melanoma) with metastatic stage M1c in an comprising administering to the individual a composition individual (e.g., human) comprising administering to the comprising nanoparticles comprising paclitaxel and albumin, individual a composition comprising nanoparticles compris US 9,149,455 B2 21 22 ing a taxane (e.g., paclitaxel) and a carrier protein (e.g., albu vided a method of treating stage IV or metastatic melanoma min), wherein the melanoma does not comprise BRAF (e.g., stage IV or metastatic cutaneous melanoma) with meta mutant such as a BRAF mutant with increased activity (for static stage M1c in an individual (e.g., human) comprising example, increased kinase activity, and/or increased activity administering to the individual a composition comprising as compared to wild-type BRAF) or a BRAF gain-of-function nanoparticles comprising paclitaxel and albumin, wherein the mutant. In some embodiments, there is provided a method of melanoma comprises a BRAF mutation such as BRAF treating stage IV or metastatic melanoma (e.g., stage IV or V600E mutation, wherein the paclitaxel in the nanoparticles metastatic cutaneous melanoma) with metastatic stage Mlic is coated with the albumin. In some embodiments, there is in an individual (e.g., human) comprising administering to provided a method of treating stage IV or metastatic mela the individual a composition comprising nanoparticles com 10 noma (e.g., stage IV or metastatic cutaneous melanoma) with prising a taxane (e.g., paclitaxel) and a carrier protein (e.g., metastatic stage M1c in an individual (e.g., human) compris albumin), wherein the melanoma comprises wild-type ing administering to the individual a composition comprising BRAF. In some embodiments, there is provided a method of nanoparticles comprising paclitaxel and albumin, wherein the treating stage IV or metastatic melanoma (e.g., stage IV or melanoma comprises a BRAF mutation such as BRAF metastatic cutaneous melanoma) with metastatic stage Mlic 15 V600E mutation, wherein the paclitaxel in the nanoparticles in an individual (e.g., human) comprising administering to is coated with the albumin, wherein the average or mean the individual a composition comprising nanoparticles com particle size of the nanoparticles in the composition is no prising a taxane (e.g., paclitaxel) and a carrier protein (e.g., greater than about 200 nm (such as less than about 200 nm). albumin), wherein the melanoma comprises a BRAF mutant In some embodiments, the albumin is human albumin. In such as a BRAF mutant with increased activity (for example, Some embodiments, the albumin is human serum albumin. In increased kinase activity, and/or increased activity as com Some embodiments, the albumin is recombinant albumin. In pared to wild-type BRAF) or a BRAF gain-of-function Some embodiments, the methodofusing taxane nanoparticles mutant. In some embodiments, there is provided a method of for treating melanoma is used as a monotherapy. In some treating stage IV or metastatic melanoma (e.g., stage IV or embodiments, the method of treating melanomausing taxane metastatic cutaneous melanoma) with metastatic stage Mlic 25 nanoparticles does not further comprise one other therapeutic in an individual (e.g., human) comprising administering to agent (Such as one other chemotherapeutic agent or immuno the individual a composition comprising nanoparticles com therapeutic agent). In some embodiments, the method does prising a taxane (e.g., paclitaxel) and a carrier protein (e.g., not further comprise a cytotoxic chemotherapeutic agent. albumin), wherein the melanoma comprises BRAF V600E In some embodiments, there is provided a method of treat mutation. In some embodiments, the taxane in the nanopar 30 ing melanoma (Such as metastatic melanoma) in a human ticles is coated with the carrier protein. In some embodi individual, comprising administering to the individual a) an ments, the average or mean particle size of the nanoparticles effective amount of a composition comprising nanoparticles in the composition is no greater than about 200 nm (such as comprising paclitaxel and an albumin, wherein the individual less than about 200 nm). In some embodiments, the taxane is has been previously treated for the melanoma with at least one paclitaxel. In some embodiments, the carrier protein is albu 35 BRAF inhibitor (such as, for example, Vemurafenib (Zelbo min Such as human serum albumin or human albumin. In raf) or Sorafenib). In some embodiments, there is provided a Some embodiments, there is provided a method of treating method of treating melanoma (such as metastatic melanoma) stage IV or metastatic melanoma (e.g., stage IV or metastatic in a human individual, comprising administering to the indi cutaneous melanoma) with metastatic stage M1c in an indi vidual a) an effective amount of a composition comprising vidual (e.g., human) comprising administering to the indi 40 nanoparticles comprising paclitaxel and an albumin, wherein vidual a composition comprising nanoparticles comprising the dose of the nanoparticle composition is between about 50 paclitaxel and albumin, wherein the melanoma comprises mg/m to about 200 mg/m (such as, for example, about 100 wild-type BRAF. In some embodiments, there is provided a mg/m to about 150 mg/m, for example about 100 mg/m), method of treating stage IV or metastatic melanoma (e.g., wherein the individual has been previously treated for the stage IV or metastatic cutaneous melanoma) with metastatic 45 melanoma with at least one BRAF inhibitor (such as, for stage M1c in an individual (e.g., human) comprising admin example, Vemurafenib (Zelboraf) or Sorafenib), and wherein istering to the individual a composition comprising nanopar the individual is substantially refractory to prior treatment ticles comprising paclitaxel and albumin, wherein the mela with a BRAF inhibitor. In some embodiments, there is pro noma comprises wild-type BRAF, wherein the paclitaxel in vided a method of treating melanoma (such as metastatic the nanoparticles is coated with the albumin. In some embodi 50 melanoma) in a human individual, comprising administering ments, there is provided a method of treating stage IV or to the individual a) an effective amount of a composition metastatic melanoma (e.g., stage IV or metastatic cutaneous comprising nanoparticles comprising paclitaxel and an albu melanoma) with metastatic stage M1c in an individual (e.g., min, wherein the dose of the nanoparticle composition is human) comprising administering to the individual a compo about 100 mg/m, wherein the individual has been previously sition comprising nanoparticles comprising paclitaxel and 55 treated for the melanoma with at least one BRAF inhibitor albumin, wherein the melanoma comprises wild-type BRAF, (such as, for example, Vemurafenib (Zelboraf) or Sorafenib), wherein the paclitaxel in the nanoparticles is coated with the and wherein the individual is substantially refractory to prior albumin, wherein the average or mean particle size of the treatment with a BRAF inhibitor. nanoparticles in the composition is no greater than about 200 In some embodiments, there is provided a method of treat nm (such as less than about 200 nm). In some embodiments, 60 ing stage IV or metastatic melanoma (e.g., stage IV or meta there is provided a method of treating stage IV or metastatic static cutaneous melanoma) in an individual (e.g., human) melanoma (e.g., stage IV or metastatic cutaneous melanoma) comprising administering to the individual a composition with metastatic stage M1c in an individual (e.g., human) comprising nanoparticles comprising a taxane (e.g., pacli comprising administering to the individual a composition taxel) and a carrier protein (e.g., albumin), wherein the mela comprising nanoparticles comprising paclitaxel and albumin, 65 noma does not comprise BRAF mutant such as a BRAF wherein the melanoma comprises a BRAF mutation Such as mutant with increased activity (for example, increased kinase BRAF V600E mutation. In some embodiments, there is pro activity, and/or increased activity as compared to wild-type US 9,149,455 B2 23 24 BRAF) or a BRAF gain-of-function mutant, wherein the indi taxel. In some embodiments, the carrier protein is albumin vidual has serum LDH of any one of: less than about 0.8x Such as human serum albumin or human albumin. In some ULN, about 0.8.x to about 1.1 xULN, between greater than embodiments, there is provided a method of treating stage IV about 1.1.x to about 2.0xULN, or between about 1.1.x to about or metastatic melanoma (e.g., stage IV or metastatic cutane 2.0xULN. In some embodiments, there is provided a method ous melanoma) in an individual (e.g., human) comprising of treating stage IV or metastatic melanoma (e.g., stage IV or administering to the individual a composition comprising metastatic cutaneous melanoma) in an individual (e.g., nanoparticles comprising paclitaxel and albumin, wherein the human) comprising administering to the individual a compo melanoma comprises wild-type BRAF, wherein the indi sition comprising nanoparticles comprising a taxane (e.g., vidual has serum LDH of any one of: less than about 0.8x paclitaxel) and a carrier protein (e.g., albumin), wherein the 10 ULN, about 0.8.x to about 1.1 xULN, between greater than melanoma comprises wild-type BRAF, wherein the indi about 1.1.x to about 2.0xULN, or between about 1.1.x to about vidual has serum LDH of any one of the following: less than 2.OXULN. about 0.8xULN, about 0.8.x to about 1.1 xULN, between In some embodiments, there is provided a method of treat greater than about 1.1.x to about 2.0xULN, or between about ing stage IV or metastatic melanoma (e.g., stage IV or meta 1.1.x to about 2.0xULN. In some embodiments, there is pro 15 static cutaneous melanoma) in an individual (e.g., human) vided a method of treating stage IV or metastatic melanoma comprising administering to the individual a composition (e.g., stage IV or metastatic cutaneous melanoma) in an indi comprising nanoparticles comprising paclitaxel and albumin, vidual (e.g., human) comprising administering to the indi wherein the melanoma comprises wild-type BRAF, wherein vidual a composition comprising nanoparticles comprising a the paclitaxel in the nanoparticles is coated with the albumin, taxane (e.g., paclitaxel) and a carrier protein (e.g., albumin), wherein the individual has serum LDH of any one of: less than wherein the melanoma comprises a BRAF mutant such as a about 0.8xULN, about 0.8.x to about 1.1XULN, between BRAF mutant with increased activity (for example, increased greater than about 1.1.x to about 2.0xULN, or between about kinase activity, and/or increased activity as compared to wild 1.1.x to about 2.0xULN. In some embodiments, there is pro type BRAF) or a BRAF gain-of-function mutant, wherein the vided a method of treating stage IV or metastatic melanoma individual has serum LDH of any one of the following: less 25 (e.g., stage IV or metastatic cutaneous melanoma) in an indi than about 0.8xULN, about 0.8.x to about 1.1 xULN, between vidual (e.g., human) comprising administering to the indi greater than about 1.1.x to about 2.0xULN, or between about vidual a composition comprising nanoparticles comprising 1.1.x to about 2.0xULN. In some embodiments, there is pro paclitaxel and albumin, wherein the melanoma comprises vided a method of treating stage IV or metastatic melanoma wild-type BRAF, wherein the paclitaxel in the nanoparticles (e.g., stage IV or metastatic cutaneous melanoma) in an indi 30 is coated with the albumin, wherein the average or mean vidual (e.g., human) comprising administering to the indi particle size of the nanoparticles in the composition is no vidual a composition comprising nanoparticles comprising a greater than about 200 nm (such as less than about 200 nm), taxane (e.g., paclitaxel) and a carrier protein (e.g., albumin), wherein the individual has serum LDH of any one of: less than wherein the melanoma comprises BRAF V600E mutation, about 0.8xULN, about 0.8.x to about 1.1XULN, between wherein the individual has serum LDH of any one of the 35 greater than about 1.1.x to about 2.0xULN, or between about following: less than about 0.8xULN, about 0.8.x to about 1.1.x to about 2.0xULN. In some embodiments, there is pro 1.1 xULN, between greater than about 1.1.x to about 2.0x vided a method of treating stage IV or metastatic melanoma ULN, or between about 1.1.x to about 2.0xULN. (e.g., stage IV or metastatic cutaneous melanoma) in an indi In some embodiments, there is provided a method of treat vidual (e.g., human) comprising administering to the indi ing stage IV or metastatic melanoma (e.g., stage IV or meta 40 vidual a composition comprising nanoparticles comprising static cutaneous melanoma) in an individual (e.g., human) paclitaxel and albumin, wherein the melanoma comprises a comprising administering to the individual a composition BRAF mutation such as BRAFV600E mutation, wherein the comprising nanoparticles comprising a taxane (e.g., pacli individual has serum LDH of any one of less than about taxel) and a carrier protein (e.g., albumin), wherein the mela 0.8xULN, about 0.8.x to about 1.1xULN, between greater noma comprises wild-type BRAF, wherein the individual has 45 than about 1.1.x to about 2.0xULN, or between about 1.1.x to serum LDH of less than about 0.8xULN. In some embodi about 2.0xULN. In some embodiments, there is provided a ments, there is provided a method of treating stage IV or method of treating stage IV or metastatic melanoma (e.g., metastatic melanoma (e.g., stage IV or metastatic cutaneous stage IV or metastatic cutaneous melanoma) in an individual melanoma) in an individual (e.g., human) comprising admin (e.g., human) comprising administering to the individual a istering to the individual a composition comprising nanopar 50 composition comprising nanoparticles comprising paclitaxel ticles comprising a taxane (e.g., paclitaxel) and a carrier pro and albumin, wherein the melanoma comprises a BRAF tein (e.g., albumin), wherein the melanoma comprises wild mutation such as BRAF V600E mutation, wherein the pacli type BRAF, wherein the individual has serum LDH of about taxel in the nanoparticles is coated with the albumin, wherein 0.8.x to about 1.1 xULN. In some embodiments, there is pro the individual has serum LDH of any one of: less than about vided a method of treating stage IV or metastatic melanoma 55 0.8xULN, about 0.8.x to about 1.1xULN, between greater (e.g., stage IV or metastatic cutaneous melanoma) in an indi than about 1.1.x to about 2.0xULN, or between about 1.1.x to vidual (e.g., human) comprising administering to the indi about 2.0xULN. vidual a composition comprising nanoparticles comprising a In some embodiments, there is provided a method of treat taxane (e.g., paclitaxel) and a carrier protein (e.g., albumin), ing stage IV or metastatic melanoma (e.g., stage IV or meta wherein the melanoma comprises wild-type BRAF, wherein 60 static cutaneous melanoma) in an individual (e.g., human) the individual has serum LDH of between greater than about comprising administering to the individual a composition 1.1.x to about 2.0xULN or between about 1.1.x to about 2.0x comprising nanoparticles comprising paclitaxel and albumin, ULN. In some embodiments, the taxane in the nanoparticles wherein the melanoma comprises a BRAF mutation Such as is coated with the carrier protein. In some embodiments, the BRAF V600E mutation, wherein the paclitaxel in the nano average or mean particle size of the nanoparticles in the 65 particles is coated with the albumin, wherein the average or composition is no greater thanabout 200 nm (such as less than mean particle size of the nanoparticles in the composition is about 200 nm). In some embodiments, the taxane is pacli no greater than about 200 nm (such as less than about 200 US 9,149,455 B2 25 26 nm), wherein the individual has serum LDH of any one of: method of treating stage IV or metastatic melanoma (e.g., less than about 0.8xULN, about 0.8.x to about 1.1 xULN, stage IV or metastatic cutaneous melanoma) in an individual between greater than about 1.1.x to about 2.0xULN, or (e.g., human) comprising administering to the individual a between about 1.1.x to about 2.0xULN. In some embodi composition comprising nanoparticles comprising paclitaxel ments, the individual has serum LDH of less than about and an albumin, wherein the individual has serum LDH of any 0.8xULN. In some embodiments, the individual has serum one of the following: less than about 0.8xULN, about 0.8.x to LDH of less than about 0.8xULN about 0.8.x to about 1.1 x about 1.1 xULN, between greater than about 1.1.x to about ULN. In some embodiments, the individual has serum LDH 2.0xULN, or between about 1.1.x to about 2.0xULN, wherein of between greater than about 1.1.x to about 2.0xULN, or the paclitaxel in the nanoparticles is coated with the albumin. between about 1.1.x to about 2.0xULN. In some embodi 10 In some embodiments, there is provided a method of treating ments, the albuminis human albumin. In some embodiments, stage IV or metastatic melanoma (e.g., stage IV or metastatic the albumin is human serum albumin. In some embodiments, cutaneous melanoma) in an individual (e.g., human) compris the albumin is recombinant albumin. In some embodiments, ing administering to the individual a composition comprising the method of using taxane nanoparticles for treating mela nanoparticles comprising paclitaxel and an albumin, wherein noma is used as a monotherapy. In some embodiments, the 15 the individual has serum LDH of any one of the following: method of treating melanoma using taxane nanoparticles less than about 0.8xULN, about 0.8.x to about 1.1 xULN, does not further comprise one other therapeutic agent (Such as between greater than about 1.1.x to about 2.0xULN, or one other chemotherapeutic agent or immunotherapeutic between about 1.1.x to about 2.0xULN, wherein the paclitaxel agent). In some embodiments, the method does not further in the nanoparticles is coated with the albumin, wherein the comprise a cytotoxic chemotherapeutic agent. average or mean particle size of the nanoparticles in the In some embodiments, there is provided a method of treat composition is no greater thanabout 200 nm (such as less than ing stage IV or metastatic melanoma (e.g., stage IV or meta about 200 nm). In some embodiments, the individual has static cutaneous melanoma) in an individual (e.g., human) serum LDH of less than about 0.8xULN. In some embodi comprising administering to the individual a composition ments, the individual has serum LDH of less than about comprising nanoparticles comprising a taxane (e.g., pacli 25 0.8xULN about 0.8.x to about 1.1XULN. In Some embodi taxel) and a carrier protein (e.g., albumin), wherein the indi ments, the individual has serum LDH of between greater than vidual has serum LDH of any one of the following: less than about 1.1.x to about 2.0xULN, or between about 1.1.x to about about 0.8xULN, about 0.8.x to about 1.1 xULN, between 2.0xULN. In some embodiments, the albuminis human albu greater than about 1.1.x to about 2.0xULN, or between about min. In some embodiments, the albumin is human serum 1.1.x to about 2.0xULN. In some embodiments, there is pro 30 albumin. In some embodiments, the albumin is recombinant vided a method of treating stage IV or metastatic melanoma albumin. In some embodiments, the method of using taxane (e.g., stage IV or metastatic cutaneous melanoma) in an indi nanoparticles for treating melanoma is used as a mono vidual (e.g., human) comprising administering to the indi therapy. In some embodiments, the method of treating mela vidual a composition comprising nanoparticles comprising a noma using taxane nanoparticles does not further comprise taxane (e.g., paclitaxel) and a carrier protein (e.g., albumin), 35 one other therapeutic agent (Such as one other chemothera wherein the individual has serum LDH of less than about peutic agent or immunotherapeutic agent). In some embodi 0.8xULN. In some embodiments, there is provided a method ments, the method does not further comprise a cytotoxic of treating stage IV or metastatic melanoma (e.g., stage IV or chemotherapeutic agent. metastatic cutaneous melanoma) in an individual (e.g., In some embodiments, there is provided a method of treat human) comprising administering to the individual a compo 40 ing stage IV or metastatic melanoma (e.g., stage IV or meta sition comprising nanoparticles comprising a taxane (e.g., static cutaneous melanoma) in an individual (e.g., human) paclitaxel) and a carrier protein (e.g., albumin), wherein the comprising administering to the individual a composition individual has serum LDH of about 0.8.x to about 1.1 xULN. comprising nanoparticles comprising a taxane (e.g., pacli In some embodiments, there is provided a method of treating taxel) and a carrier protein (e.g., albumin), wherein the mela stage IV or metastatic melanoma (e.g., stage IV or metastatic 45 noma does not comprise BRAF mutant such as a BRAF cutaneous melanoma) in an individual (e.g., human) compris mutant with increased activity (for example, increased kinase ing administering to the individual a composition comprising activity, and/or increased activity as compared to wild-type nanoparticles comprising a taxane (e.g., paclitaxel) and a BRAF) or a BRAF gain-of-function mutant, wherein the indi carrier protein (e.g., albumin), wherein the individual has vidual is a human (female or male). In some embodiments, serum LDH of between greater than about 1.1.x to about 50 there is provided a method of treating stage IV or metastatic 2.0xULN or between about 1.1.x to about 2.0xULN. In some melanoma (e.g., stage IV or metastatic cutaneous melanoma) embodiments, the taxane in the nanoparticles is coated with in an individual (e.g., human) comprising administering to the carrier protein. In some embodiments, the average or the individual a composition comprising nanoparticles com mean particle size of the nanoparticles in the composition is prising a taxane (e.g., paclitaxel) and a carrier protein (e.g., no greater than about 200 nm (such as less than about 200 55 albumin), wherein the melanoma comprises a BRAF V600E nm). In some embodiments, the taxane is paclitaxel. In some mutation, wherein the individual is a human (female or male). embodiments, the carrier protein is albumin Such as human In some embodiments, there is provided a method of treat serum albumin or human albumin. In some embodiments, ing stage IV or metastatic melanoma (e.g., stage IV or meta there is provided a method of treating stage IV or metastatic static cutaneous melanoma) in an individual (e.g., human) melanoma (e.g., stage IV or metastatic cutaneous melanoma) 60 comprising administering to the individual a composition in an individual (e.g., human) comprising administering to comprising nanoparticles comprising a taxane (e.g., pacli the individual a composition comprising nanoparticles com taxel) and a carrier protein (e.g., albumin), wherein the mela prising paclitaxel and an albumin, wherein the individual has noma comprises wild-type BRAF, wherein the individual is a serum LDH of any one of the following: less than about human (female or male). In some embodiments, there is pro 0.8xULN, about 0.8.x to about 1.1xULN, between greater 65 vided a method of treating stage IV or metastatic melanoma than about 1.1.x to about 2.0xULN, or between about 1.1.x to (e.g., stage IV or metastatic cutaneous melanoma) in an indi about 2.0xULN. In some embodiments, there is provided a vidual (e.g., human) comprising administering to the indi US 9,149,455 B2 27 28 vidual a composition comprising nanoparticles comprising a embodiments, there is provided a method of treating stage IV taxane (e.g., paclitaxel) and a carrier protein (e.g., albumin), or metastatic melanoma (e.g., stage IV or metastatic cutane wherein the melanoma comprises a BRAF mutant such as a ous melanoma) in an individual comprising administering to BRAF mutant with increased activity (for example, increased the individual a composition comprising nanoparticles com kinase activity, and/or increased activity as compared to wild prising paclitaxel and albumin, wherein the melanoma com type BRAF) or a BRAF gain-of-function mutant, wherein the prises a BRAF mutation such as BRAF V600E mutation, individual is a human (female or male). In some embodi wherein the paclitaxel in the nanoparticles is coated with the ments, there is provided a method of treating stage IV or albumin, wherein the individual is a human (female or male). metastatic melanoma (e.g., stage IV or metastatic cutaneous In some embodiments, there is provided a method of treating melanoma) in an individual (e.g., human) comprising admin 10 stage IV or metastatic melanoma (e.g., stage IV or metastatic istering to the individual a composition comprising nanopar cutaneous melanoma) in an individual comprising adminis ticles comprising a taxane (e.g., paclitaxel) and a carrier pro tering to the individual a composition comprising nanopar tein (e.g., albumin), wherein the melanoma comprises BRAF ticles comprising paclitaxel and albumin, wherein the mela V600E mutation, wherein the individual is a human (female noma comprises a BRAF mutation such as BRAF V600E or male). In some embodiments, there is provided a method of 15 mutation, wherein the paclitaxel in the nanoparticles is coated treating stage IV or metastatic melanoma (e.g., stage IV or with the albumin, wherein the average or mean particle size of metastatic cutaneous melanoma) in an individual (e.g., the nanoparticles in the composition is no greater than about human) comprising administering to the individual a compo 200 nm (such as less than about 200 nm), wherein the indi sition comprising nanoparticles comprising a taxane (e.g., vidual is a human (female or male). In some embodiments, paclitaxel) and a carrier protein (e.g., albumin), wherein the the albumin is human albumin. In some embodiments, the melanoma comprises wild-type BRAF, wherein the indi albumin is human serum albumin. In some embodiments, the vidual is a human female. In some embodiments, there is albumin is recombinant albumin. In some embodiments, the provided a method of treating stage IV or metastatic mela individual is a human male. In some embodiments, the indi noma (e.g., stage IV or metastatic cutaneous melanoma) in an vidual is a human female. In some embodiments, the method individual (e.g., human) comprising administering to the 25 of using taxane nanoparticles for treating melanoma is used individual a composition comprising nanoparticles compris as a monotherapy. In some embodiments, the method of treat ing a taxane (e.g., paclitaxel) and a carrier protein (e.g., albu ing melanoma using taxane nanoparticles does not further min), wherein the melanoma comprises wild-type BRAF, comprise one other therapeutic agent (Such as one other che wherein the individual is a human male. In some embodi motherapeutic agent or immunotherapeutic agent). In some ments, the taxane in the nanoparticles is coated with the 30 embodiments, the method does not further comprise a cyto carrier protein. In some embodiments, the average or mean toxic chemotherapeutic agent. particle size of the nanoparticles in the composition is no In some embodiments, there is provided a method of treat greater than about 200 nm (such as less than about 200 nm). ing stage IV or metastatic melanoma (e.g., stage IV or meta In some embodiments, the taxane is paclitaxel. In some static cutaneous melanoma) in an individual (e.g., human) embodiments, the carrier protein is albumin Such as human 35 comprising administering to the individual a composition serum albumin or human albumin. In some embodiments, comprising nanoparticles comprising a taxane (e.g., pacli there is provided a method of treating stage IV or metastatic taxel) and a carrier protein (e.g., albumin), wherein the mela melanoma (e.g., stage IV or metastatic cutaneous melanoma) noma does not comprise BRAF mutant such as a BRAF in an individual comprising administering to the individual a mutant with increased activity (for example, increased kinase composition comprising nanoparticles comprising paclitaxel 40 activity, and/or increased activity as compared to wild-type and albumin, wherein the melanoma comprises wild-type BRAF) or a BRAF gain-of-function mutant, wherein the indi BRAF, wherein the individual is a human (female or male). In vidual is a human (female or male), wherein the individual is Some embodiments, there is provided a method of treating under about 65 years old or at least about 65 years old (for stage IV or metastatic melanoma (e.g., stage IV or metastatic example at least about any of 70, 75, or 80 years old). In some cutaneous melanoma) in an individual comprising adminis 45 embodiments, there is provided a method of treating stage IV tering to the individual a composition comprising nanopar or metastatic melanoma (e.g., stage IV or metastatic cutane ticles comprising paclitaxel and albumin, wherein the mela ous melanoma) in an individual (e.g., human) comprising noma comprises wild-type BRAF, wherein the paclitaxel in administering to the individual a composition comprising the nanoparticles is coated with the albumin, wherein the nanoparticles comprising a taxane (e.g., paclitaxel) and a individual is a human (female or male). In some embodi 50 carrier protein (e.g., albumin), wherein the melanoma com ments, there is provided a method of treating stage IV or prises wild-type BRAF, wherein the individual is a human metastatic melanoma (e.g., stage IV or metastatic cutaneous (female or male), wherein the individual is under about 65 melanoma) in an individual comprising administering to the years old or at least about 65 years old (for example at least individual a composition comprising nanoparticles compris about any of 70, 75, or 80 years old). In some embodiments, ing paclitaxel and albumin, wherein the melanoma comprises 55 there is provided a method of treating stage IV or metastatic wild-type BRAF, wherein the paclitaxel in the nanoparticles melanoma (e.g., stage IV or metastatic cutaneous melanoma) is coated with the albumin, wherein the average or mean in an individual (e.g., human) comprising administering to particle size of the nanoparticles in the composition is no the individual a composition comprising nanoparticles com greater than about 200 nm (such as less than about 200 nm), prising a taxane (e.g., paclitaxel) and a carrier protein (e.g., wherein the individual is a human (female or male). In some 60 albumin), wherein the melanoma comprises a BRAF mutant embodiments, there is provided a method of treating stage IV such as a BRAF mutant with increased activity (for example, or metastatic melanoma (e.g., stage IV or metastatic cutane increased kinase activity, and/or increased activity as com ous melanoma) in an individual comprising administering to pared to wild-type BRAF) or a BRAF gain-of-function the individual a composition comprising nanoparticles com mutant, wherein the individual is a human (female or male), prising paclitaxel and albumin, wherein the melanoma com 65 wherein the individual is under about 65 years old or at least prises a BRAF mutation such as BRAF V600E mutation, about 65 years old (for example at least about any of 70, 75, wherein the individual is a human (female or male). In some or 80 years old). In some embodiments, there is provided a US 9,149,455 B2 29 30 method of treating stage IV or metastatic melanoma (e.g., years old or at least about 65 years old). In some embodi stage IV or metastatic cutaneous melanoma) in an individual ments, there is provided a method of treating stage IV or (e.g., human) comprising administering to the individual a metastatic melanoma (e.g., stage IV or metastatic cutaneous composition comprising nanoparticles comprising a taxane melanoma) in an individual (e.g., human) comprising admin (e.g., paclitaxel) and a carrier protein (e.g., albumin), wherein istering to the individual a composition comprising nanopar the melanoma comprises BRAF V600E mutation, wherein ticles comprising a taxane (e.g., paclitaxel) and a carrier pro the individual is a human (female or male), wherein the indi tein (e.g., albumin), wherein the individual has serum LDH of vidual is under about 65 years old or at least about 65 years old between greater than about 1.1.x to about 2.0xULN or (for example at least about any of 70, 75, or 80 years old). In between about 1.1.x to about 2.0xULN, wherein the indi Some embodiments, there is provided a method of treating 10 vidual is a human (female or male) (e.g., under about 65 years stage IV or metastatic melanoma (e.g., stage IV or metastatic old or at least about 65 years old). In some embodiments, the cutaneous melanoma) in an individual (e.g., human) compris taxane in the nanoparticles is coated with the carrier protein. ing administering to the individual a composition comprising In some embodiments, the average or mean particle size of the nanoparticles comprising a taxane (e.g., paclitaxel) and a nanoparticles in the composition is no greater than about 200 carrier protein (e.g., albumin), wherein the melanoma com 15 nm (such as less than about 200 nm). In some embodiments, prises wild-type BRAF, wherein the individual is a human the taxane is paclitaxel. In some embodiments, the carrier (female or male), wherein the individual is under about 65 protein is albumin Such as human serum albumin or human years old. In some embodiments, there is provided a method albumin. In some embodiments, the method of using taxane of treating stage IV or metastatic melanoma (e.g., stage IV or nanoparticles for treating melanoma is used as a mono metastatic cutaneous melanoma) in an individual (e.g., therapy. In some embodiments, the method of treating mela human) comprising administering to the individual a compo noma using taxane nanoparticles does not further comprise sition comprising nanoparticles comprising a taxane (e.g., one other therapeutic agent (Such as one other chemothera paclitaxel) and a carrier protein (e.g., albumin), wherein the peutic agent or immunotherapeutic agent). In some embodi melanoma comprises wild-type BRAF, wherein the indi ments, the method does not further comprise a cytotoxic vidual is a human (female or male), wherein the individual is 25 chemotherapeutic agent. at least about 65 years old (for example at least about any of The methods described herein are useful for various 70, 75, or 80 years old). In some embodiments, the average or aspects of melanoma treatment. In some embodiments, there mean particle size of the nanoparticles in the composition is is provided a method for treatment of melanoma in an indi no greater than about 200 nm (such as less than about 200 vidual (e.g., human) using an effective amount of a compo nm). In some embodiments, the taxane is paclitaxel. In some 30 sition comprising nanoparticles comprising a taxane and a embodiments, the carrier protein is albumin Such as human carrier protein. In some embodiments, an effective amount is serum albuminor human albumin. In some embodiments, the an amount sufficient to delay development of melanoma. In method of using taxane nanoparticles for treating melanoma Some embodiments, an effective amount is an amount Suffi is used as a monotherapy. In some embodiments, the method cient to prevent or delay occurrence and/or recurrence of of treating melanoma using taxane nanoparticles does not 35 melanoma. In some embodiments, an effective amount com further comprise one other therapeutic agent (Such as one prises an amount Sufficient to produce a complete response other chemotherapeutic agent or immunotherapeutic agent). when an individual is treated with any of the methods In some embodiments, the method does not further comprise described herein for melanoma. In some embodiments, an a cytotoxic chemotherapeutic agent. effective amount comprises an amount Sufficient to produce a In some embodiments, there is provided a method of treat 40 partial response when an individual is treated with any of the ing stage IV or metastatic melanoma (e.g., stage IV or meta methods described herein for melanoma. static cutaneous melanoma) in an individual (e.g., human) In some embodiments, the effective amount of a composi comprising administering to the individual a composition tion comprising nanoparticles comprising taxane (e.g., pacli comprising nanoparticles comprising a taxane (e.g., pacli taxel) and a carrier protein (e.g., albumin) produces a com taxel) and a carrier protein (e.g., albumin), wherein the indi 45 plete response, a partial response, reduction in size of a vidual has serum LDH of any one of the following: less than melanoma tumor, reduction in metastasis, stable disease, and/ about 0.8xULN, about 0.8.x to about 1.1 xULN, between oran increase in overall response rate. In some embodiments, greater than about 1.1.x to about 2.0xULN, or between about the taxane is paclitaxel. In some embodiments, the carrier 1.1.x to about 2.0xULN, wherein the individual is a human protein is albumin. The efficacy parameters (such as complete (female or male) (e.g., under about 65 years old or at least 50 response or partial response) described herein may be deter about 65 years old). In some embodiments, there is provided mined by any of the methods known to one skilled in the art. a method of treating stage IV or metastatic melanoma (e.g., For example, the efficacy parameters may be determined stage IV or metastatic cutaneous melanoma) in an individual according to RECIST such as RECIST version 1.0 or 1.1 (e.g., human) comprising administering to the individual a criteria. RECIST version 1.1 criteria are described in Eisen composition comprising nanoparticles comprising a taxane 55 hauer EA et al. 2009, Eur J. Cancer, 45(2):228-47, the dis (e.g., paclitaxel) and a carrier protein (e.g., albumin), wherein closure of which is incorporated herein by reference in its the individual has serum LDH of less than about 0.8xULN, entirety. wherein the individual is a human (female or male) (e.g., In some embodiments, there is provided a method of inhib under about 65 years old or at least about 65 years old). In iting melanoma cell proliferation in an individual, comprising Some embodiments, there is provided a method of treating 60 administering to the individual an effective amount of a com stage IV or metastatic melanoma (e.g., stage IV or metastatic position comprising nanoparticles comprising a taxane (e.g., cutaneous melanoma) in an individual (e.g., human) compris paclitaxel) and a carrier protein (e.g., albumin). In some ing administering to the individual a composition comprising embodiments, the taxane is paclitaxel. In some embodiments, nanoparticles comprising a taxane (e.g., paclitaxel) and a the carrier protein is albumin. In some embodiments, there is carrier protein (e.g., albumin), wherein the individual has 65 provided a method of inhibiting melanoma cell proliferation serum LDH of between 0.8.x to about 1.1 xULN, wherein the in an individual, comprising administering to the individual individual is a human (female or male) (e.g., under about 65 an effective amount of a composition comprising nanopar US 9,149,455 B2 31 32 ticles comprising paclitaxel and albumin. In some embodi ments, the melanoma comprises a mutation in BRAF. In some ments, at least about 10% (including for example at least embodiments, the melanoma comprises a BRAF V600E about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, 91%, mutation. In some embodiments, the melanoma does not 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) cell comprise a mutation in BRAF. In some embodiments, the proliferation is inhibited. In some embodiments, the indi melanoma does not comprise BRAF mutant such as a BRAF vidual has stage IV or metastatic melanoma (e.g., stage IV or mutant with increased activity (for example, increased kinase metastatic cutaneous melanoma). In some embodiments, the activity, and/or increased activity as compared to wild-type melanoma is metastatic malignant melanoma. In some BRAF) or a BRAF gain-of-function mutant. In some embodi embodiments, the metastatic melanoma is at Stage M1a, stage ments, the melanoma does not comprise BRAFV600E muta M1b, or stage M1c. In some embodiments, the metastatic 10 tion (e.g., the melanoma comprises wild-type BRAF). In melanoma is at Stage M1c. In some embodiments, the mela Some embodiments, the melanoma comprises wild-type noma comprises a mutation in BRAF. In some embodiments BRAF. In some embodiments, the melanoma comprises a the melanoma comprises a BRAF V600E mutation. In some BRAF mutant such as a BRAF mutant with increased activity embodiments, the melanoma does not comprise a mutation in (for example, increased kinase activity, and/or increased BRAF. In some embodiments, the melanoma does not com 15 activity as compared to wild-type BRAF) or a BRAF gain prise BRAF mutant such as a BRAF mutant with increased of-function mutant. In some embodiments, the melanoma activity (for example, increased kinase activity, and/or comprises BRAF V600E mutation. In some embodiments, increased activity as compared to wild-type BRAF) or a the individual has elevated serum LDH level. In some BRAF gain-of-function mutant. In some embodiments, the embodiments, the individual has normal serum LDH level. In melanoma does not comprise a BRAF V600E mutation (e.g., some embodiments, the individual has serum LDH of about the melanoma comprises wild-type BRAF). In some embodi any of the following: <0.8xULN, 0.4–0.8xULN, 0.8-1.1x ments, the melanoma comprises wild-type BRAF. In some ULN, 0.9-1.1XULN, 0.8-1.2xULN, 1.1-1.5XULN, 1.2-1.5.x embodiments, the melanoma comprises a BRAF mutant Such ULN, 1.1-2xULN, or 1.5-2xULN. In some embodiments, the as a BRAF mutant with increased activity (for example, individual has serum LDH of less than about 0.8xULN. In increased kinase activity, and/or increased activity as com 25 some embodiments, the individual has serum LDH at about pared to wild-type BRAF) or a BRAF gain-of-function 0.8x to about 1.1 xULN. In some embodiments, the individual mutant. In some embodiments, the melanoma comprises has serum LDH of between greater than about 1.1.x to about BRAF V600E mutation. In some embodiments, the indi 2.0xULN. In some embodiments, the individual has serum vidual has elevated serum LDH level. In some embodiments, LDH of between about 1.1.x to about 2.0xULN. In some the individual has normal serum LDH level. In some embodi 30 embodiments, the individual is a human (e.g., male or ments, the individual has serum LDH of about any of the female). following: <0.8xULN, 0.4–0.8xULN, 0.8-1.1xULN, 0.9- In some embodiments, there is provided a method of reduc 1.1 xULN, 0.8-1.2xULN, 1.1-1.5xULN, 1.2-1.5xULN, 1.1- ing size of a melanoma tumor or reducing melanoma tumor 2xULN, or 1.5-2xULN. In some embodiments, the indi Volume in an individual, comprising administering to the vidual has serum LDH of less than about 0.8xULN. In some 35 individual an effective amount of a composition comprising embodiments, the individual has serum LDH at about 0.8.x to nanoparticles comprising a taxane (e.g., paclitaxel) and a about 1.1 xULN. In some embodiments, the individual has carrier protein (e.g., albumin). In some embodiments, the serum LDH of between greater than about 1.1.x to about taxane is paclitaxel. In some embodiments, the carrier protein 2.0xULN. In some embodiments, the individual has serum is albumin. In some embodiments, there is provided a method LDH of between about 1.1.x to about 2.0xULN. In some 40 of reducing size of a melanoma tumor or reducing melanoma embodiments, the individual is a human (e.g., male or tumor Volume in an individual, comprising administering to female). the individual an effective amount of a composition compris In some embodiments, there is provided a method of pre ing nanoparticles comprising paclitaxel and albumin. In some venting or inhibiting metastasis of melanoma in an indi embodiments, the tumor size or tumor Volume is reduced at vidual, comprising administering to the individual an effec 45 least about 10% (including for example at least about any of tive amount of a composition comprising nanoparticles 20%, 30%, 40%, 60%, 70%, 80%, 90%, 95%, or 100%). In comprising a taxane (e.g., paclitaxel) and a carrier protein Some embodiments, the individual has stage IV or metastatic (e.g., albumin). In some embodiments, the taxane is pacli melanoma (e.g., stage IV or metastatic cutaneous melanoma). taxel. In some embodiments, the carrier protein is albumin. In In some embodiments, the melanoma is metastatic malignant Some embodiments, there is provided a method of preventing 50 melanoma. In some embodiments, the metastatic melanoma or inhibiting metastasis of melanoma in an individual, com is at stage M1a, stage M1b, or stage M1c. In some embodi prising administering to the individual an effective amount of ments, the metastatic melanoma is at stage M1c. In some a composition comprising nanoparticles comprising pacli embodiments, the melanoma comprises a mutation in BRAF. taxel and albumin. In some embodiments, at least about 10% In some embodiments, the melanoma comprises a BRAF (including for example at least about any of 20%, 30%, 40%, 55 V600E mutation. In some embodiments, the melanoma does 60%, 70%, 80%, 90%. 95%, or 100%) metastasis is inhibited. not comprise a mutation in BRAF. In some embodiments, the In some embodiments, there is provided a method of delaying melanoma does not comprise BRAF mutant such as a BRAF or slowing metastasis of melanoma in an individual, compris mutant with increased activity (for example, increased kinase ing administering to the individual an effective amount of a activity, and/or increased activity as compared to wild-type composition comprising nanoparticles comprising a taxane 60 BRAF) or a BRAF gain-of-function mutant. In some embodi and a carrier protein (e.g., albumin). In some embodiments, ments, the melanoma does not comprise BRAFV600E muta the individual has stage IV or metastatic melanoma (e.g., tion (e.g., the melanoma comprises wild-type BRAF). In stage IV or metastatic cutaneous melanoma). In some Some embodiments, the melanoma comprises wild-type embodiments, the melanoma is metastatic malignant mela BRAF. In some embodiments, the melanoma comprises a noma. In some embodiments, the metastatic melanoma is at 65 BRAF mutant such as a BRAF mutant with increased activity stage M1a, stage M1b, or stage M1c. In some embodiments, (for example, increased kinase activity, and/or increased the metastatic melanoma is at stage M1 c. In some embodi activity as compared to wild-type BRAF) or a BRAF gain US 9,149,455 B2 33 34 of-function mutant. In some embodiments, the melanoma LDH of between about 1.1.x to about 2.0xULN. In some comprises BRAF V600E mutation. In some embodiments, embodiments, the individual is a human (e.g., male or the individual has elevated serum LDH level. In some female). embodiments, the individual has normal serum LDH level. In In some embodiments, there is provided a method of pro some embodiments, the individual has serum LDH of about 5 longing Survival of an individual having melanoma, compris any of the following: <0.8xULN, 0.4–0.8xULN, 0.8-1.1x ing administering to the individual an effective amount of a ULN, 0.9-1.1XULN, 0.8-1.2xULN, 1.1-1.5XULN, 1.2-1.5.x composition comprising nanoparticles comprising a taxane ULN, 1.1-2xULN, or 1.5-2xULN. In some embodiments, the (e.g., paclitaxel) and a carrier protein (e.g., albumin). In some individual has serum LDH of less than about 0.8xULN. In embodiments, the taxane is paclitaxel. In some embodiments, some embodiments, the individual has serum LDH at about 10 the carrier protein is albumin. In some embodiments, there is 0.8x to about 1.1 xULN. In some embodiments, the individual provided a method of prolonging Survival of an individual has serum LDH of between greater than about 1.1.x to about having melanoma, comprising administering to the indi 2.0xULN. In some embodiments, the individual has serum vidual an effective amount of a composition comprising LDH of between about 1.1.x to about 2.0xULN. In some 15 nanoparticles comprising a paclitaxel and albumin. In some embodiments, the individual is a human (e.g., male or embodiments, the method prolongs the survival of the indi female). vidual by at least about any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, In some embodiments, there is provided a method of pro 12, 18, or 24 months. In some embodiments, the individual longing time to disease progression of melanoma in an indi has stage IV or metastatic melanoma (e.g., stage IV or meta vidual, comprising administering to the individual an effec static cutaneous melanoma). In some embodiments, the mela tive amount of a composition comprising nanoparticles noma is metastatic malignant melanoma. In some embodi comprising a taxane (e.g., paclitaxel) and a carrier protein ments, the metastatic melanoma is at stage M1a, stage M1b. (e.g., albumin). In some embodiments, the taxane is pacli or stage M1c. In some embodiments, the metastatic mela taxel. In some embodiments, the carrier protein is albumin. In noma is at stage M1c. In some embodiments, the melanoma Some embodiments, there is provided a method of prolonging 25 comprises a mutation in BRAF. In some embodiments, the time to disease progression of melanoma in an individual, melanoma comprises a BRAF V600E mutation. In some comprising administering to the individual an effective embodiments, the melanoma does not comprise a mutation in amount of a composition comprising nanoparticles compris BRAF. In some embodiments, the melanoma does not com ing paclitaxel and albumin. In some embodiments, the prise BRAF mutant such as a BRAF mutant with increased method prolongs the time to disease progression by at least 30 activity (for example, increased kinase activity, and/or about any of 1,2,3,4,5,6,7,8,9, 10, 11, 12, 13, 14, 15, 16, increased activity as compared to wild-type BRAF) or a 17, 18, 19, 20, 2, 24, 26, 28, 30, 35, 40, 45, or 50 weeks. In BRAF gain-of-function mutant. In some embodiments, the Some embodiments, the individual has stage IV or metastatic melanoma does not comprise BRAF V600E mutation (e.g., melanoma (e.g., stage IV or metastatic cutaneous melanoma). 35 the melanoma comprises wild-type BRAF). In some embodi In some embodiments, the melanoma is metastatic malignant ments, the melanoma comprises wild-type BRAF. In some melanoma. In some embodiments, the metastatic melanoma embodiments, the melanoma comprises a BRAF mutant Such is at stage M1a, stage M1b, or stage M1c. In some embodi as a BRAF mutant with increased activity (for example, ments, the metastatic melanoma is at stage M1c. In some increased kinase activity, and/or increased activity as com embodiments, the melanoma comprises a mutation in BRAF. 40 pared to wild-type BRAF) or a BRAF gain-of-function In some embodiments, the melanoma comprises a V600E mutant. In some embodiments, the melanoma comprises BRAF mutation. In some embodiments, the melanoma does BRAF V600E mutation. In some embodiments, the indi not comprise a mutation in BRAF. In some embodiments, the vidual has elevated serum LDH level. In some embodiments, melanoma does not comprise BRAF mutant such as a BRAF the individual has normal serum LDH level. In some embodi mutant with increased activity (for example, increased kinase 45 ments, the individual has serum LDH of about any of the activity, and/or increased activity as compared to wild-type following: <0.8xULN, 0.4–0.8xULN, 0.8-1.1xULN, 0.9- BRAF) or a BRAF gain-of-function mutant. In some embodi 1.1 xULN, 0.8-1.2xULN, 1.1-1.5xULN, 1.2-1.5xULN, 1.1- ments, the melanoma does not comprise a BRAF V600E 2xULN, or 1.5-2xULN. In some embodiments, the indi mutation (e.g., the melanoma comprises wild-type BRAF). In vidual has serum LDH of less than about 0.8xULN. In some Some embodiments, the melanoma comprises wild-type 50 embodiments, the individual has serum LDH at about 0.8x to BRAF. In some embodiments, the melanoma comprises a about 1.1 xULN. In some embodiments, the individual has BRAF mutant such as a BRAF mutant with increased activity serum LDH of between greater than about 1.1.x to about (for example, increased kinase activity, and/or increased 2.0xULN. In some embodiments, the individual has serum activity as compared to wild-type BRAF) or a BRAF gain LDH of between about 1.1.x to about 2.0xULN. In some of-function mutant. In some embodiments, the melanoma 55 embodiments, the individual is a human (e.g., male or comprises BRAF V600E mutation. In some embodiments, female). In some embodiments, the taxane is paclitaxel. In the individual has elevated serum LDH level. In some Some embodiments, the carrier protein is albumin. embodiments, the individual has normal serum LDH level. In The method of using taxane nanoparticles for treating some embodiments, the individual has serum LDH of about melanoma may be used as a monotherapy. In some embodi any of the following: <0.8xULN, 0.4–0.8xULN, 0.8-1.1x 60 ments, there is provide a method of treating melanoma in an ULN, 0.9-1.1XULN, 0.8-1.2xULN, 1.1-1.5XULN, 1.2-1.5.x individual (e.g., human) comprising administering to the ULN, 1.1-2xULN, or 1.5-2xULN. In some embodiments, the individual an effective amount of a composition comprising individual has serum LDH of less than about 0.8xULN. In nanoparticles comprising a taxane (e.g., paclitaxel) and a some embodiments, the individual has serum LDH at about carrier protein (e.g., albumin), wherein the method is used as 0.8x to about 1.1 xULN. In some embodiments, the individual 65 a monotherapy. In some embodiments, a method described has serum LDH of between greater than about 1.1.x to about herein does not further comprise one other therapeutic agent 2.0xULN. In some embodiments, the individual has serum (such as one other chemotherapeutic agent or immunothera US 9,149,455 B2 35 36 peutic agent). In some embodiments, a method described paclitaxel), wherein the dose of paclitaxel in the nanoparticle herein does not further comprise a cytotoxic chemotherapeu composition is between about 80 mg/m to about 175 mg/m tic agent. (such as between about 90 mg/m to about 150 mg/m). In In some embodiments, there is provided a method of treat Some embodiments, there is provided a method of treating ing melanoma in an individual (e.g., human) comprising 5 metastatic melanoma (Such as stage IV melanoma or M1c administering (such as intravenously administering) to the melanoma) in an individual (e.g., human) comprising admin individual an effective amount of a composition comprising istering (such as intravenously administering) to the indi nanoparticles comprising paclitaxel and albumin (such as vidual an effective amount of a composition comprising Nab-paclitaxel, for example about 5 mg/ml Nab-paclitaxel), nanoparticles comprising paclitaxel and albumin (such as wherein the dose of paclitaxel in the nanoparticle composi- 10 Nab-paclitaxel, for example about 5 mg/ml Nab-paclitaxel), tion is between about 80 mg/m to about 175 mg/m (such as wherein the dose of paclitaxel in the nanoparticle composi between about 90 mg/m to about 150 mg/m). In some tion is between about 90 mg/m to about 150 mg/m (for embodiments, there is provided a method of treating mela example about 90 mg/m, about 120 mg/m, or about 150 noma in an individual (e.g., human) comprising administer mg/m), wherein the nanoparticle composition is adminis ing (such as intravenously administering) to the individual an 15 tered weekly. In some embodiments, there is provided a effective amount of a composition comprising nanoparticles method of treating metastatic melanoma (Such as stage IV comprising paclitaxel and albumin (such as Nab-paclitaxel, metastatic melanoma or M1c melanoma) in an individual for example about 5 mg/ml Nab-paclitaxel), wherein the dose (e.g., human) comprising administering (such as intrave of paclitaxel in the nanoparticle composition is between nously administering) to the individual an effective amount of about 90 mg/m to about 150 mg/m (for example about 90 20 a composition comprising nanoparticles comprising pacli mg/m, about 120 mg/m, or about 150 mg/m), wherein the taxel and albumin (such as Nab-paclitaxel, for example about nanoparticle composition is administered weekly. In some 5 mg/ml Nab-paclitaxel), wherein the dose of paclitaxel in the embodiments, there is provided a method of treating mela nanoparticle composition is between about 90 mg/m to about noma in an individual (e.g., human) comprising administer 150 mg/m (for example about 90 mg/m, about 120 mg/m. ing (such as intravenously administering) to the individual an 25 or about 150 mg/m), wherein the nanoparticle composition effective amount of a composition comprising nanoparticles is administered weekly, three out of four weeks. In some comprising paclitaxel and albumin (such as Nab-paclitaxel, embodiments, there is provided a method of treating meta for example about 5 mg/ml Nab-paclitaxel), wherein the dose static melanoma (such as stage IV metastatic melanoma or of paclitaxel in the nanoparticle composition is between M1c melanoma) in human individual who has previously about 90 mg/m to about 150 mg/m (for example about 90 30 been treated for melanoma, comprising administering (Such mg/m, about 120 mg/m, or about 150 mg/m), wherein the as intravenously administering) to the individual an effective nanoparticle composition is administered weekly, three out of amount of a composition comprising nanoparticles compris four weeks. In some embodiments, there is provided a method ing paclitaxel and albumin (Such as Nab-paclitaxel, for of treating melanoma in human individual who has previ example about 5 mg/ml Nab-paclitaxel), wherein the dose of ously been treated for melanoma, comprising administering 35 paclitaxel in the nanoparticle composition is between about (such as intravenously administering) to the individual an 90 mg/m to about 150 mg/m (for example about 90 mg/m, effective amount of a composition comprising nanoparticles about 120 mg/m, or about 150 mg/m), wherein the nano comprising paclitaxel and albumin (such as Nab-paclitaxel, particle composition is administered weekly, three out of four for example about 5 mg/ml Nab-paclitaxel), wherein the dose weeks. In some embodiments, there is provided a method of of paclitaxel in the nanoparticle composition is between 40 treating metastatic melanoma (such as stage IV metastatic about 90 mg/m to about 150 mg/m (for example about 90 melanoma or M1c melanoma) in human individual who is mg/m, about 120 mg/m, or about 150 mg/m), wherein the chemotherapy naive, comprising administering (such as nanoparticle composition is administered weekly, three out of intravenously administering) to the individual an effective four weeks. In some embodiments, there is provided a method amount of a composition comprising nanoparticles compris of treating melanoma in human individual who is chemo- 45 ing paclitaxel and albumin (Such as Nab-paclitaxel, for therapy naive, comprising administering (Such as intrave example about 5 mg/ml Nab-paclitaxel), wherein the dose of nously administering) to the individual an effective amount of paclitaxel in the nanoparticle composition is between about a composition comprising nanoparticles comprising pacli 90 mg/m to about 150 mg/m (for example about 90 mg/m, taxel and albumin (such as Nab-paclitaxel, for example about about 120 mg/m, or about 150 mg/m), wherein the nano 5 mg/ml Nab-paclitaxel), wherein the dose of paclitaxel in the 50 particle composition is administered weekly, three out of four nanoparticle compositionis between about 90 mg/m to about weeks. In some embodiments, the individual is a male. In 150 mg/m (for example about 90 mg/m, about 120 mg/m. Some embodiments, the individual is a female. In some or about 150 mg/m), wherein the nanoparticle composition embodiment, the individual is a human who is at least 65 is administered weekly, three out of four weeks. In some years old (including for example at least 70, 75, or 80 years embodiments, the individual is a male. In some embodiments, 55 old). In some embodiments, the individual is a human who is the individual is a female. In some embodiment, the indi less than 65 years old (including for example less than 60, 50. vidual is a human who is at least 65 years old (including for or 40 years old). example at least 70, 75, or 80 years old). In some embodi In some embodiments, there is provided a method of treat ments, the individual is a human who is less than 65 years old ing melanoma in an individual (e.g., human) who comprises (including for example less than 60, 50, or 40 years old). 60 wild-type BRAF, comprising administering (Such as intrave In some embodiments, there is provided a method of treat nously administering) to the individual an effective amount of ing metastatic melanoma (such as stage IV metastatic mela a composition comprising nanoparticles comprising pacli noma or M1c melanoma) in an individual (e.g., human) com taxel and albumin (such as Nab-paclitaxel, for example about prising administering (Such as intravenously administering) 5 mg/ml Nab-paclitaxel), wherein the dose of paclitaxel in the to the individual an effective amount of a composition com- 65 nanoparticle compositionis between about 80 mg/m to about prising nanoparticles comprising paclitaxel and albumin 175 mg/m (such as between about 90 mg/m to about 150 (such as Nab-paclitaxel, for example about 5 mg/ml Nab mg/m). In some embodiments, there is provided a method of US 9,149,455 B2 37 38 treating melanoma in an individual (e.g., human) who com paclitaxel), wherein the dose of paclitaxel in the nanoparticle prises wild-type BRAF, comprising administering (Such as composition is between about 90 mg/m to about 150 mg/m intravenously administering) to the individual an effective (for example about 90 mg/m, about 120 mg/m, or about 150 amount of a composition comprising nanoparticles compris mg/m), wherein the nanoparticle composition is adminis ing paclitaxel and albumin (Such as Nab-paclitaxel, for 5 tered weekly. In some embodiments, there is provided a example about 5 mg/ml Nab-paclitaxel), wherein the dose of method of treating melanoma in an individual (e.g., human) paclitaxel in the nanoparticle composition is between about who comprises a BRAFV600E mutation, comprising admin 90 mg/m to about 150 mg/m (for example about 90 mg/m, istering (such as intravenously administering) to the indi about 120 mg/m, or about 150 mg/m), wherein the nano vidual an effective amount of a composition comprising particle composition is administered weekly. In some 10 nanoparticles comprising paclitaxel and albumin (such as embodiments, there is provided a method of treating mela Nab-paclitaxel, for example about 5 mg/ml Nab-paclitaxel), nomain an individual (e.g., human) who comprises wild-type wherein the dose of paclitaxel in the nanoparticle composi BRAF, comprising administering (such as intravenously tion is between about 90 mg/m to about 150 mg/m (for administering) to the individual an effective amount of a example about 90 mg/m, about 120 mg/m, or about 150 composition comprising nanoparticles comprising paclitaxel 15 mg/m), wherein the nanoparticle composition is adminis and albumin (such as Nab-paclitaxel, for example about 5 tered weekly, three out of four weeks. In some embodiments, mg/ml Nab-paclitaxel), wherein the dose of paclitaxel in the there is provided a method of treating melanoma in an indi nanoparticle compositionis between about 90 mg/m to about vidual (e.g., human) who comprises a BRAFV600E mutation 150 mg/m (for example about 90 mg/m, about 120 mg/m. and has previously been treated for melanoma, comprising or about 150 mg/m), wherein the nanoparticle composition administering (such as intravenously administering) to the is administered weekly, three out of four weeks. In some individual an effective amount of a composition comprising embodiments, there is provided a method of treating mela nanoparticles comprising paclitaxel and albumin (such as nomain an individual (e.g., human) who comprises wild-type Nab-paclitaxel, for example about 5 mg/ml Nab-paclitaxel), BRAF and has previously been treated for melanoma, com wherein the dose of paclitaxel in the nanoparticle composi prising administering (Such as intravenously administering) 25 tion is between about 90 mg/m to about 150 mg/m (for to the individual an effective amount of a composition com example about 90 mg/m, about 120 mg/m, or about 150 prising nanoparticles comprising paclitaxel and albumin mg/m), wherein the nanoparticle composition is adminis (such as Nab-paclitaxel, for example about 5 mg/ml Nab tered weekly, three out of four weeks. In some embodiments, paclitaxel), wherein the dose of paclitaxel in the nanoparticle there is provided a method of treating melanoma in an indi composition is between about 90 mg/m to about 150 mg/m 30 vidual (e.g., human) who comprises a BRAFV600E mutation (for example about 90 mg/m, about 120 mg/m, or about 150 and is chemotherapy naive, comprising administering (Such mg/m), wherein the nanoparticle composition is adminis as intravenously administering) to the individual an effective tered weekly, three out of four weeks. In some embodiments, amount of a composition comprising nanoparticles compris there is provided a method of treating melanoma in an indi ing paclitaxel and albumin (Such as Nab-paclitaxel, for vidual (e.g., human) who comprises wild-type BRAF and is 35 example about 5 mg/ml Nab-paclitaxel), wherein the dose of chemotherapy naive, comprising administering (such as paclitaxel in the nanoparticle composition is between about intravenously administering) to the individual an effective 90 mg/m to about 150 mg/m (for example about 90 mg/m, amount of a composition comprising nanoparticles compris about 120 mg/m, or about 150 mg/m), wherein the nano ing paclitaxel and albumin (Such as Nab-paclitaxel, for particle composition is administered weekly, three out of four example about 5 mg/ml Nab-paclitaxel), wherein the dose of 40 weeks. In some embodiments, the individual is a male. In paclitaxel in the nanoparticle composition is between about Some embodiments, the individual is a female. In some 90 mg/m to about 150 mg/m (for example about 90 mg/m. embodiment, the individual is a human who is at least 65 about 120 mg/m, or about 150 mg/m), wherein the nano years old (including for example at least 70, 75, or 80 years particle composition is administered weekly, three out of four old). In some embodiments, the individual is a human who is weeks. In some embodiments, the individual is a male. In 45 less than 65 years old (including for example less than 60, 50. Some embodiments, the individual is a female. In some or 40 years old). embodiment, the individual is a human who is at least 65 In some embodiments, there is provided a method of treat years old (including for example at least 70, 75, or 80 years ing metastatic melanoma (Such as stage IV metastatic mela old). In some embodiments, the individual is a human who is noma or M1c melanoma) in an individual (e.g., human) who less than 65 years old (including for example less than 60, 50. 50 comprises wild-type BRAF, comprising administering (Such or 40 years old). as intravenously administering) to the individual an effective In some embodiments, there is provided a method of treat amount of a composition comprising nanoparticles compris ing melanoma in an individual (e.g., human) who comprises ing paclitaxel and albumin (Such as Nab-paclitaxel, for a BRAF V600E mutation, comprising administering (such as example about 5 mg/ml Nab-paclitaxel), wherein the dose of intravenously administering) to the individual an effective 55 paclitaxel in the nanoparticle composition is between about amount of a composition comprising nanoparticles compris 80 mg/m to about 175 mg/m (such as between about 90 ing paclitaxel and albumin (Such as Nab-paclitaxel, for mg/m to about 150 mg/m). In some embodiments, there is example about 5 mg/ml Nab-paclitaxel), wherein the dose of provided a method of treating metastatic melanoma (such as paclitaxel in the nanoparticle composition is between about stage IV metastatic melanoma or M1c melanoma) in an indi 80 mg/m to about 175 mg/m (such as between about 90 60 vidual (e.g., human) who comprises wild-type BRAF, com mg/m to about 150 mg/m). In some embodiments, there is prising administering (such as intravenously administering) provided a method of treating melanoma in an individual to the individual an effective amount of a composition com (e.g., human) who comprises a BRAFV600E mutation, com prising nanoparticles comprising paclitaxel and albumin prising administering (Such as intravenously administering) (such as Nab-paclitaxel, for example about 5 mg/ml Nab to the individual an effective amount of a composition com 65 paclitaxel), wherein the dose of paclitaxel in the nanoparticle prising nanoparticles comprising paclitaxel and albumin composition is between about 90 mg/m to about 150 mg/m (such as Nab-paclitaxel, for example about 5 mg/ml Nab (for example about 90 mg/m, about 120 mg/m, or about 150 US 9,149,455 B2 39 40 mg/m), wherein the nanoparticle composition is adminis or about 150 mg/m), wherein the nanoparticle composition tered weekly. In some embodiments, there is provided a is administered weekly. In some embodiments, there is pro method of treating metastatic melanoma (such as stage IV vided a method of treating metastatic melanoma (such as metastatic melanoma or M1c melanoma) in an individual stage IV metastatic melanoma or M1c melanoma) in an indi (e.g., human) who comprises wild-type BRAF, comprising vidual (e.g., human) who comprises a BRAF V600E muta administering (such as intravenously administering) to the tion, comprising administering (such as intravenously admin individual an effective amount of a composition comprising istering) to the individual an effective amount of a nanoparticles comprising paclitaxel and albumin (such as composition comprising nanoparticles comprising paclitaxel Nab-paclitaxel, for example about 5 mg/ml Nab-paclitaxel), and albumin (such as Nab-paclitaxel, for example about 5 wherein the dose of paclitaxel in the nanoparticle composi 10 mg/ml Nab-paclitaxel), wherein the dose of paclitaxel in the tion is between about 90 mg/m to about 150 mg/m (for nanoparticle compositionis between about 90 mg/m to about example about 90 mg/m, about 120 mg/m, or about 150 150 mg/m (for example about 90 mg/m, about 120 mg/m. mg/m), wherein the nanoparticle composition is adminis or about 150 mg/m), wherein the nanoparticle composition tered weekly, three out of four weeks. In some embodiments, is administered weekly, three out of four weeks. In some there is provided a method of treating metastatic melanoma 15 embodiments, there is provided a method of treating meta (such as stage IV metastatic melanoma or M1c melanoma) in static melanoma (such as stage IV metastatic melanoma or an individual (e.g., human) who comprises wild-type BRAF M1c melanoma) in an individual (e.g., human) who com and has previously been treated for melanoma, comprising prises a BRAF V600E mutation and has previously been administering (such as intravenously administering) to the treated for melanoma, comprising administering (such as individual an effective amount of a composition comprising intravenously administering) to the individual an effective nanoparticles comprising paclitaxel and albumin (such as amount of a composition comprising nanoparticles compris Nab-paclitaxel, for example about 5 mg/ml Nab-paclitaxel), ing paclitaxel and albumin (Such as Nab-paclitaxel, for wherein the dose of paclitaxel in the nanoparticle composi example about 5 mg/ml Nab-paclitaxel), wherein the dose of tion is between about 90 mg/m to about 150 mg/m (for paclitaxel in the nanoparticle composition is between about example about 90 mg/m, about 120 mg/m, or about 150 25 90 mg/m to about 150 mg/m (for example about 90 mg/m, mg/m), wherein the nanoparticle composition is adminis about 120 mg/m, or about 150 mg/m), wherein the nano tered weekly, three out of four weeks. In some embodiments, particle composition is administered weekly, three out of four there is provided a method of treating metastatic melanoma weeks. In some embodiments, there is provided a method of (such as stage IV metastatic melanoma or M1c melanoma) in treating metastatic melanoma (such as stage IV metastatic an individual (e.g., human) who comprises wild-type BRAF 30 melanoma or M1c melanoma) in an individual (e.g., human) and is chemotherapy naive, comprising administering (Such who comprises a BRAF V600E mutation and is chemo as intravenously administering) to the individual an effective therapy naive, comprising administering (such as intrave amount of a composition comprising nanoparticles compris nously administering) to the individual an effective amount of ing paclitaxel and albumin (Such as Nab-paclitaxel, for a composition comprising nanoparticles comprising pacli example about 5 mg/ml Nab-paclitaxel), wherein the dose of 35 taxel and albumin (such as Nab-paclitaxel, for example about paclitaxel in the nanoparticle composition is between about 5 mg/ml Nab-paclitaxel), wherein the dose of paclitaxel in the 90 mg/m to about 150 mg/m (for example about 90 mg/m, nanoparticle compositionis between about 90 mg/m to about about 120 mg/m, or about 150 mg/m), wherein the nano 150 mg/m (for example about 90 mg/m, about 120 mg/m. particle composition is administered weekly, three out of four or about 150 mg/m), wherein the nanoparticle composition weeks. In some embodiments, the individual is a male. In 40 is administered weekly, three out of four weeks. In some Some embodiments, the individual is a female. In some embodiments, the individual is a male. In some embodiments, embodiment, the individual is a human who is at least 65 the individual is a female. In some embodiment, the indi years old (including for example at least 70, 75, or 80 years vidual is a human who is at least 65 years old (including for old). In some embodiments, the individual is a human who is example at least 70, 75, or 80 years old). In some embodi less than 65 years old (including for example less than 60, 50. 45 ments, the individual is a human who is less than 65 years old or 40 years old). (including for example less than 60, 50, or 40 years old). In some embodiments, there is provided a method of treat In some embodiments, there is provided a method of treat ing metastatic melanoma (such as stage IV metastatic mela ing metastatic melanoma (Such as stage IV metastatic mela noma or M1c melanoma) in an individual (e.g., human) who noma or M1c melanoma) in the liver in an individual (e.g., comprises a BRAF V600E mutation, comprising administer 50 human) comprising administering (such as administering by ing (such as intravenously administering) to the individual an hepatic arterial infusion) to the individual an effective amount effective amount of a composition comprising nanoparticles of a composition comprising nanoparticles comprising pacli comprising paclitaxel and albumin (such as Nab-paclitaxel, taxel and albumin (such as Nab-paclitaxel, for example about for example about 5 mg/ml Nab-paclitaxel), wherein the dose 5 mg/ml Nab-paclitaxel), wherein the dose of paclitaxel in the of paclitaxel in the nanoparticle composition is between 55 nanoparticle compositionis between about 80 mg/m to about about 80 mg/m to about 175 mg/m (such as between about 175 mg/m (such as between about 90 mg/m to about 150 90 mg/m to about 150 mg/m). In some embodiments, there mg/m). In some embodiments, there is provided a method of is provided a method of treating metastatic melanoma (Such treating metastatic melanoma (such as stage IV metastatic as stage IV metastatic melanoma or M1c melanoma) in an melanoma or M1c melanoma) in the liver in an individual individual (e.g., human) who comprises a BRAF V600E 60 (e.g., human) who comprises wild-type BRAF, comprising mutation, comprising administering (such as intravenously administering (such as administering by hepatic arterial infu administering) to the individual an effective amount of a sion) to the individual an effective amount of a composition composition comprising nanoparticles comprising paclitaxel comprising nanoparticles comprising paclitaxel and albumin and albumin (such as Nab-paclitaxel, for example about 5 (such as Nab-paclitaxel, for example about 5 mg/ml Nab mg/ml Nab-paclitaxel), wherein the dose of paclitaxel in the 65 paclitaxel), wherein the dose of paclitaxel in the nanoparticle nanoparticle composition is between about 90 mg/m to about composition is between about 80 mg/m to about 175 mg/m 150 mg/m (for example about 90 mg/m, about 120 mg/m. (such as between about 90 mg/m to about 150 mg/m). In US 9,149,455 B2 41 42 Some embodiments, the nanoparticle composition is admin years old (including for example at least 70, 75, or 80 years istered weekly. In some embodiments, the nanoparticle com old). In some embodiments, the individual is a human who is position is administered weekly, three out of four weeks. In less than 65 years old (including for example less than 60, 50. Some embodiments, the individual is a male. In some embodi or 40 years old). ments, the individual is a female. In some embodiment, the In some embodiments, there is provided a method of treat individual is a human who is at least 65 years old (including ing uveal melanoma (such as unresectable uveal melanoma or for example at least 70, 75, or 80 years old). In some embodi metastatic uveal melanoma) in an individual (e.g., human) ments, the individual is a human who is less than 65 years old comprising administering (such as intravenous administra (including for example less than 60, 50, or 40 years old). tion) to the individual an effective amount of a composition In some embodiments, there is provided a method of treat 10 comprising nanoparticles comprising paclitaxel and albumin ing metastatic melanoma (such as stage IV metastatic mela (such as Nab-paclitaxel, for example about 5 mg/ml Nab noma or M1c melanoma) in the liver in an individual (e.g., paclitaxel). In some embodiments, the uveal melanoma is any human) who comprises wild-type BRAF, comprising admin of Choroidal melanoma, ciliary body melanoma, or iris mela istering (such as administering by hepatic arterial infusion) to noma. In some embodiments, the uveal melanoma is Poste the individual an effective amount of a composition compris 15 rior uveal melanoma. ing nanoparticles comprising paclitaxel and albumin (such as In some embodiments, there is provided a method of treat Nab-paclitaxel, for example about 5 mg/ml Nab-paclitaxel), ing uveal melanoma in an individual (e.g., human) compris wherein the Nab-paclitaxel dose is between about 130 mg/m ing administering (such as intravenous administration) to the to about 285 mg/m (such as, for example, about 130 mg/m. individual an effective amount of a composition comprising about 170 mg/m, about 220 mg/m, or about 285 mg/m). In nanoparticles comprising paclitaxel and albumin (such as Some embodiments, there is provided a method of treating Nab-paclitaxel, for example about 5 mg/ml Nab-paclitaxel), metastatic melanoma (Such as stage IV metastatic melanoma wherein the dose of paclitaxel in the nanoparticle composi or M1c melanoma) in the liver in an individual (e.g., human) tion is between about 80 mg/m to about 175 mg/m (such as who comprises a BRAFV600E mutation, comprising admin between about 100 mg/m to about 150 mg/m). In some istering (such as administering by hepatic arterial infusion) to 25 embodiments, there is provided a method of treating meta the individual an effective amount of a composition compris static uveal melanoma in an individual (e.g., human) com ing nanoparticles comprising paclitaxel and albumin (such as prising administering (such as intravenous administration) to Nab-paclitaxel, for example about 5 mg/ml Nab-paclitaxel), the individual an effective amount of a composition compris wherein the Nab-paclitaxel dose is between about 130 mg/m ing nanoparticles comprising paclitaxel and albumin (such as to about 285 mg/m (such as, for example, about 130 mg/m. 30 Nab-paclitaxel, for example about 5 mg/ml Nab-paclitaxel), about 170 mg/m, about 220 mg/m, or about 285 mg/m). In wherein the dose of paclitaxel in the nanoparticle composi some embodiments, the nanoparticle composition is admin tion is between about 80 mg/m to about 175 mg/m (such as istered via hepatic artery one day every three weeks. In some between about 100 mg/m to about 150 mg/m). In some embodiments, the nanoparticle composition is administered embodiments, there is provided a method of treating unresec via hepatic arterial infusion over 30 minutes every three 35 table uveal melanoma in an individual (e.g., human) compris weeks. In some embodiments, the individual is a human who ing administering (such as intravenous administration) to the is at least 65 years old (including for example at least 70, 75 individual an effective amount of a composition comprising or 80 years old). In some embodiments, the individual is a nanoparticles comprising paclitaxel and albumin (such as human who is less than 65 years old (including, for example, Nab-paclitaxel, for example about 5 mg/ml Nab-paclitaxel), less than 60, 50, or 40 years old). 40 wherein the dose of paclitaxel in the nanoparticle composi In some embodiments, there is provided a method of treat tion is between about 80 mg/m to about 175 mg/m (such as ing metastatic melanoma (such as stage IV metastatic mela between about 100 mg/m to about 150 mg/m). In some noma or M1c melanoma) in the liver in an individual (e.g., embodiments, the nanoparticle composition is administered human) comprising administering (such as administering by weekly. In some embodiments, the nanoparticle composition hepatic arterial infusion) to the individual an effective amount 45 is administered weekly, three out of four weeks. In some of a composition comprising nanoparticles comprising pacli embodiments, the nanoparticle composition is administered taxel and albumin (such as Nab-paclitaxel, for example about intravenously. In some embodiments, the nanoparticle com 5 mg/ml Nab-paclitaxel), wherein the dose of paclitaxel in the position is administered intravenously over 30 minutes at a nanoparticle composition is between about 80 mg/m to about dose of 150 mg/m weekly. In some embodiments, the nano 175 mg/m (such as between about 100 mg/m to about 150 50 particle composition is administered intravenously over 30 mg/m). In some embodiments, there is provided a method of minutes at a dose of 150 mg/m weekly for three out of four treating metastatic melanoma (Such as stage IV metastatic weeks. In some embodiments, the individual comprises wild melanoma or M1c melanoma) in the liver in an individual type BRAF. In some embodiments, the individual comprises (e.g., human) who comprises a BRAFV600E mutation, com a BRAF mutation. In some embodiments, the individual com prising administering (such as administering by hepatic arte 55 prises a BRAF V600E mutation. In some embodiments, the rial infusion) to the individual an effective amount of a com individual is a male. In some embodiments, the individual is position comprising nanoparticles comprising paclitaxel and a female. In some embodiment, the individual is a human who albumin (such as Nab-paclitaxel, for example about 5 mg/ml is at least 65 years old (including for example at least 70, 75, Nab-paclitaxel), wherein the dose of paclitaxel in the nano or 80 years old). In some embodiments, the individual is a particle composition is between about 80 mg/m to about 175 60 human who is less than 65 years old (including for example mg/m (such as between about 100 mg/m to about 150 less than 60, 50, or 40 years old). mg/m). In some embodiments, the nanoparticle composition In some embodiments, there is provided a method of treat is administered weekly. In some embodiments, the nanopar ing uveal melanoma in an individual (e.g., human) compris ticle composition is administered weekly, three out of four ing administering (such as intravenous administration) to the weeks. In some embodiments, the individual is a male. In 65 individual an effective amount of a composition comprising Some embodiments, the individual is a female. In some nanoparticles comprising paclitaxel and albumin (such as embodiment, the individual is a human who is at least 65 Nab-paclitaxel, for example about 5 mg/ml Nab-paclitaxel), US 9,149,455 B2 43 44 wherein the dose of paclitaxel in the nanoparticle composi by the presence of at least one radiographically documented tion is between about 80 mg/m to about 175 mg/m (such as measurable lesion), comprising administering (such as intra between about 100 mg/m to about 150 mg/m). In some venously administering) to the individual an effective amount embodiments, there is provided a method of treating meta of a composition comprising nanoparticles comprising pacli static uveal melanoma in an individual (e.g., human) com taxel and albumin (such as Nab-paclitaxel, for example about prising administering (such as intravenous administration) to 5 mg/ml Nab-paclitaxel), wherein the dose of paclitaxel in the the individual an effective amount of a composition compris nanoparticle composition is between about 100 mg/m to ing nanoparticles comprising paclitaxel and albumin (such as about 150 mg/m (for example 150 mg/m), wherein the Nab-paclitaxel, for example about 5 mg/ml Nab-paclitaxel), nanoparticle composition is administered weekly, three out of wherein the dose of paclitaxel in the nanoparticle composi 10 four weeks. In some embodiments, the individual has meta tion is between about 80 mg/m to about 175 mg/m (such as static melanoma of stage M1c. In some embodiments, the between about 100 mg/m to about 150 mg/m). In some individual has metastatic melanoma of stage M1c or M1b. In embodiments, there is provided a method of treating unresec Some embodiments, the individual has metastatic melanoma table uveal melanoma in an individual (e.g., human) compris at stage M1a, M1b, or M1c. In some embodiments, the indi ing administering (such as intravenous administration) to the 15 vidual has LDH level of no greater than about 2.0xULN (such individual an effective amount of a composition comprising as LDH of about 1.1-2xULN). In some embodiments, the individual Nab-paclitaxel, for example about 5 mg/ml Nab-paclitaxel), comprises wild-type BRAF. In some embodiments, the indi wherein the dose of paclitaxel in the nanoparticle composi vidual has a BRAF mutation. In some embodiments, the tion is between about 80 mg/m to about 175 mg/m (such as individual has a BRAF V600E mutation. In some embodi between about 100 mg/m to about 150 mg/m). In some ments, the individual is a male. In some embodiments, the embodiments, the nanoparticle composition is administered individual is a female. In some embodiment, the individual is weekly. In some embodiments, the nanoparticle composition a human who is at least 65 years old (including for example at is administered weekly, three out of four weeks. In some least 70, 75, or 80 years old). In some embodiments, the embodiments, the individual comprises a BRAF V600E 25 individual is a human who is less than 65 years old (including mutation. In some embodiments, the individual is a male. In for example less than 60, 50, or 40 years old). Some embodiments, the individual is a female. In some In some embodiments, there is provided a method of treat embodiment, the individual is a human who is at least 65 ing melanoma in a human individual, comprising administer years old (including for example at least 70, 75, or 80 years ing (such as intravenously administering) to the individual an old). In some embodiments, the individual is a human who is 30 effective amount of a composition comprising nanoparticles less than 65 years old (including for example less than 60, 50. comprising paclitaxel and albumin (Such as Nab-paclitaxel, or 40 years old). for example about 5 mg/ml Nab-paclitaxel), wherein the dose In some embodiments, there is provided a method of treat of paclitaxel in the nanoparticle composition is between ing melanoma in a human individual, comprising administer about 80 mg/m to about 175 mg/m (such as between about ing (such as intravenously administering) to the individual an 35 100 mg/m to about 150 mg/m, for example 150 mg/m), effective amount of a composition comprising nanoparticles wherein the nanoparticle composition is administered comprising paclitaxel and albumin (such as Nab-paclitaxel, weekly, three out of four weeks, and wherein the individual is for example about 5 mg/ml Nab-paclitaxel), wherein the dose substantially refractory to prior treatment with a BRAF of paclitaxel in the nanoparticle composition is between inhibitor. In some embodiments, there is provided a method about 80 mg/m to about 175 mg/m (such as between about 40 of treating stage IV cutaneous melanoma in a human indi 100 mg/m to about 150 mg/m, for example 150 mg/m), vidual, comprising administering (such as intravenously wherein the nanoparticle composition is administered administering) to the individual an effective amount of a weekly, three out of four weeks. In some embodiments, there composition comprising nanoparticles comprising paclitaxel is provided a method of treating stage IV cutaneous mela and albumin (such as Nab-paclitaxel, for example about 5 noma in a human individual, comprising administering (Such 45 mg/ml Nab-paclitaxel), wherein the dose of paclitaxel in the as intravenously administering) to the individual an effective nanoparticle composition is between about 100 mg/m to amount of a composition comprising nanoparticles compris about 150 mg/m (for example 150 mg/m), wherein the ing paclitaxel and albumin (Such as Nab-paclitaxel, for nanoparticle composition is administered weekly, three out of example about 5 mg/ml Nab-paclitaxel), wherein the dose of four weeks, and wherein the individual is substantially refrac paclitaxel in the nanoparticle composition is between about 50 tory to prior treatment with a BRAF inhibitor. 100 mg/m to about 150 mg/m (for example 150 mg/m), In some embodiments, there is provided a method of treat wherein the nanoparticle composition is administered ing metastatic melanoma in a human individual who com weekly, three out of four weeks. In some embodiments, there prises wild-type BRAF, comprising administering (Such as is provided a method of treating stage IV cutaneous mela intravenously administering) to the individual an effective noma in a human individual who is chemotherapy naive, 55 amount of a composition comprising nanoparticles compris comprising administering (Such as intravenously administer ing paclitaxel and albumin (Such as Nab-paclitaxel, for ing) to the individual an effective amount of a composition example about 5 mg/ml Nab-paclitaxel), wherein the dose of comprising nanoparticles comprising paclitaxel and albumin paclitaxel in the nanoparticle composition is between about (such as Nab-paclitaxel, for example about 5 mg/ml Nab 80 mg/m to about 175 mg/m (such as between about 100 paclitaxel), wherein the dose of paclitaxel in the nanoparticle 60 mg/m to about 150 mg/m, for example 150 mg/m), composition is between about 100 mg/m to about 150 mg/m wherein the nanoparticle composition is administered (for example 150 mg/m), wherein the nanoparticle compo weekly, three out of four weeks. In some embodiments, there sition is administered weekly, three out of four weeks. In is provided a method of treating unresectable stage IIIc or Some embodiments, there is provided a method of treating stage IV metastatic melanoma in a human individual having stage IV cutaneous melanoma in a human individual who is 65 a wild-type BRAF, comprising administering (such as intra chemotherapy naive, wherein the individual has radiographi venously administering) to the individual an effective amount cally-documented measurable disease (for example defined of a composition comprising nanoparticles comprising pacli US 9,149,455 B2 45 46 taxel and albumin (such as Nab-paclitaxel, for example about Some embodiments, the individual has metastatic melanoma 5 mg/ml Nab-paclitaxel), wherein the dose of paclitaxel in the of stage M1c. In some embodiments, the individual has meta nanoparticle composition is between about 100 mg/m to static melanoma of stage M1c or M1b. In some embodiments, about 150 mg/m (for example 150 mg/m), wherein the the individual has metastatic melanoma at stage Mla, M1b, or nanoparticle composition is administered weekly, three out of 5 M1c. In some embodiments, the individual has LDH level of four weeks. In some embodiments, there is provided a method no greater than about 2.0xULN (such as LDH of about 1.1-2x noma in a human individual having a wild-type BRAF, ULN). In some embodiments, the individual is a male. In wherein the individual has failed treatment with ipilimumab, Some embodiments, the individual is a female. In some comprising administering (Such as intravenously administer 10 embodiment, the individual is a human who is at least 65 ing) to the individual an effective amount of a composition years old (including for example at least 70, 75, or 80 years comprising nanoparticles comprising paclitaxel and albumin old). In some embodiments, the individual is a human who is (such as Nab-paclitaxel, for example about 5 mg/ml Nab less than 65 years old (including for example less than 60, 50. paclitaxel), wherein the dose of paclitaxel in the nanoparticle or 40 years old). composition is between about 100 mg/m to about 150 mg/m 15 In some embodiments, there is provided a method of treat (for example 150 mg/m), wherein the nanoparticle compo ing melanoma by following any one of the dosing regimens sition is administered weekly, three out of four weeks. In provided in Table 3. TABLE 3 Clinical Studies with Nab-paclitaxel Monotherapy

Melanoma Patient Line of Setting Treatment Clinical Trial Title Study Design

Metastatic First line Phase III Study of Hepatic Abraxane (R Dose Escalation: Arterial Infusion of Nab 100 mg/m, 135 mg/m, 170 mg/m. paclitaxel (or Abraxane (R) 260 mg/m - Cycle q21 days. in Patients with Metastatic Treatment duration: to progression Melanoma in the Liver or unacceptable toxicity. Metastatic Chemo-naive, A Phase 2 Clinical Trial of Nab-paclitaxel Dose: previously Nab-paclitaxel (or Weekly for 3 of 4 weeks at 100 treated Abraxane (R)) in Previously mg/m (in previously treated Treated and Chemotherapy patients) or 150 mg/m (in Naive Patients With chemotherapy- naive patients). Metastatic Melanoma Metastatic First line An open-label, multicenter, Dosing Regimen: phase III trial of Nab Nab-paclitaxel at 150 mg/m’ paclitaxel (or Abraxane (R) weekly X3/4 weeks or (NP) versus dacarbazine Dacarbazine 1000 mg/m Q3 W. (DTIC) in previously Dosage reductions of Nab untreated patients (PTs) paclitaxel to 120 and 90 mg/m and with metastatic malignant of Dacarbazine to 800 and 600 melanoma (MMM) mg/m and the use offilgrastim for neutropenic fever allowed. Unresectable, Chemo-naive, A Phase 2 Study Of Weekly Nab-paclitaxel Dose: Metastatic previously Infusion Nab-paclitaxel 150 mg/m weekly for 3 of 4 weeks treated (Paclitaxel Protein-bound every 28 days. Particles for Injectable Suspension) (or Abraxane (R)) In Patients With Unresectable And Metastatic Uveal Melanoma Unresectable Chemo-naive, An Open-Label, NAB-PACLITAXELDose: Stage III, previously Multicenter, Phase II Trial Cohort I (previously treated) Unresectable treated of NAB-PACLITAXEL (or received NAB-PACLITAXEL on Stage IV Nab-paclitaxel or days 1, 8, and 15. Cohort II Abraxane (R)) (A (chemotherapy-naive) received Cremophor (R-Free, Protein NAB-PACLITAXEL at a higher Stabilized, Nanoparticle dose than Cohort I. Paclitaxel) in Previously Treatment Duration: every 4 weeks Treated Patients With in the absence of disease Metastatic Melanoma progression or unacceptable toxicity. Metastatic Chemotherapy Phase III study of Nab Arm I: Nab-paclitaxel at 150 malignant naive paclitaxel v. dacarbazine in mg/m on days 1, 8, and 15, 28 day melanoma; chemotherapy-naive cycle stage IV patients with metastatic Arm II: Dacarbazine at 1000 malignant melanoma mg/m, day 1, 21 day cycle US 9,149,455 B2 47 48 TABLE 3-continued Clinical Studies with Nab-paclitaxel Monotherapy Melanoma Patient Line of Setting Treatment Clinical Trial Title Study Design Second line Wildtype Abraxane (R) v. DTIC in Arm 1: Nab-paclitaxel at 150 metastatic BRAF wild-type BRAF metastatic mg/m·days 1, 8, 15 melanoma metastatic melanoma patients who Arm 2: DTIC 1000 mg/m every 3 unresectable melanoma failed treatment with weeks stage IIIc & patients who ipilimumab IV failed treatment with ipilimumab

15 The methods described herein may further comprise In some embodiments, there is provided a method of treating selecting patients for treatment (e.g., identifying an indi- melanoma (for example metastatic melanoma) in an indi vidual who is suitable for treatment for melanoma). Thus, for vidual comprising: a) determining the melanoma Subtype or example, in some embodiments, a method described herein 2O staging characteristics (such as stages M1a, M1b. Mlc) of the further comprises identifying the individual having one of the individual; b) selecting the individual for treatment based on characteristics described herein, such as melanoma Subtype the melanoma Subtype or staging characteristics (such as or staging characteristics, LDH level, or BRAF status stages M1a, M1b, M1c) of the individual; and c) administer described herein. In some embodiments, there is provided a ing to the individual an effective amount of a composition method of treating melanoma in an individual (e.g., human) as comprising nanoparticles comprising paclitaxel and albumin comprising the steps of (a) determining whether the indi (such as Nab-paclitaxel, for example about 5 mg/ml Nab vidual has melanoma Such as a melanoma described herein, paclitaxel). In some embodiments, an individual who has and (b) administering to the individual an effective amount of stage M1a melanoma is treated. In some embodiments, an a composition comprising nanoparticles comprising a taxane individual who has stage M1b melanoma is treated. In some (e.g., paclitaxel) and a carrier protein (e.g., albumin). In some 30 embodiments, an individual who has stage M1c melanoma is embodiments, there is provided a method of treating mela treated. In some embodiments, an individual who has cuta noma in an individual (e.g., human) comprising the steps of neous metastatic melanoma is treated. Treatment decision (a) determining whether the individual has a BRAF status can also be based on the Subtype of the melanoma, such as any described herein, and (b) administering to the individual an subtype of the melanoma described herein. In some embodi effective amount of a composition comprising nanoparticles 35 ments, the method comprises intravenously administering comprising a taxane (e.g., paclitaxel) and a carrier protein (for example over a period of about 30 to about 40 minutes) to (e.g., albumin). In some embodiments, there is provided a the individual an effective amount of Nab-paclitaxel (such as method of treating melanoma in an individual (e.g., human) about 5 mg/ml Nab-paclitaxel), wherein the dose of paclitaxel comprising the steps of (a) determining whether the indi in the nanoparticle composition is about 80 to about 200 vidual has a LDH level described herein, and (b) administer- 40 mg/m (including for example about 90 mg/m, about 120 ing to the individual an effective amount of a composition mg/m, or about 150 mg/m) on days 1, 8, 15 of every 28 day comprising nanoparticles comprising a taxane (e.g., pacli cycle. In some embodiments, the individual is treated for at taxel) and a carrier protein (e.g., albumin). least about 2 months, including for example at least about any In some embodiments, there is provided a method of treat of 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. ing melanoma (for example metastatic melanoma) in an indi- 45 In some embodiments, there is provided a method of treat vidual comprising administering to the individual an effective ing melanoma (for example metastatic melanoma) in an indi amount of a composition comprising nanoparticles compris vidual comprising administering to the individual an effective ing paclitaxel and albumin (Such as Nab-paclitaxel, for amount of a composition comprising nanoparticles compris example about 5 mg/ml Nab-paclitaxel), wherein the indi ing paclitaxel and albumin (Such as Nab-paclitaxel, for vidual is selected for treatment based on melanoma subtype 50 example about 5 mg/ml Nab-paclitaxel), wherein the indi or staging characteristics (such as stages Mla, M1b, M1c). In vidual is selected for treatment based on melanoma Subtype Some embodiments, there is provided a method of treating or staging characteristics being stage M1c. In some embodi melanoma (for example metastatic melanoma) in an indi ments, there is provided a method of treating melanoma (for vidual comprising: a) determining the melanoma Subtype or example metastatic melanoma) in an individual comprising: staging characteristics (such as stages Mla, M1b. Mlc) of the 55 a) determining the melanoma Subtype or staging characteris individual; and b) administering to the individual an effective tics (such as stages M1a, M1b, M1c) of the individual; and b) amount of a composition comprising nanoparticles compris administering to the individual an effective amount of a com ing paclitaxel and albumin (Such as Nab-paclitaxel, for position comprising nanoparticles comprising paclitaxel and example about 5 mg/ml Nab-paclitaxel). In some embodi albumin (such as Nab-paclitaxel, for example about 5 mg/ml ments, there is provided a method of treating melanoma (for 60 Nab-paclitaxel), wherein the individual is selected for treat example metastatic melanoma) in an individual comprising: ment if the individual has a melanoma at stage M1c. In some a) selecting the individual for treatment based on the mela embodiments, there is provided a method of treating mela noma Subtype or staging characteristics (such as stages M1a, noma (for example metastatic melanoma) in an individual M1b, M1c) of the individual; and b) administering to the comprising: a) selecting the individual for treatment based on individual an effective amount of a composition comprising 65 the melanoma Subtype being at stage M1c, and b) adminis nanoparticles comprising paclitaxel and albumin (such as tering to the individual an effective amount of a composition Nab-paclitaxel, for example about 5 mg/ml Nab-paclitaxel). comprising nanoparticles comprising paclitaxel and albumin US 9,149,455 B2 49 50 (such as Nab-paclitaxel, for example about 5 mg/ml Nab In some embodiments, there is provided a method of treat paclitaxel). In some embodiments, there is provided a method ing melanoma (for example metastatic melanoma) in an indi of treating melanoma (for example metastatic melanoma) in vidual comprising administering to the individual an effective an individual comprising: a) determining the melanoma Sub amount of a composition comprising nanoparticles compris type or staging characteristics (Such as stages Mla, M1b. ing paclitaxel and albumin (Such as Nab-paclitaxel, for M1c) of the individual; b) selecting the individual for treat example about 5 mg/ml Nab-paclitaxel), wherein the indi ment based on the melanoma Subtype being at stage M1 c, and vidual is selected for treatment if the individual comprises a c) administering to the individual an effective amount of a wild-type BRAF. In some embodiments, there is provided a composition comprising nanoparticles comprising paclitaxel method of treating melanoma (for example metastatic mela 10 noma) in an individual comprising: a) determining the BRAF and albumin (such as Nab-paclitaxel, for example about 5 status of the individual; and b) administering to the individual mg/ml Nab-paclitaxel). In some embodiments, an individual an effective amount of a composition comprising nanopar who has cutaneous metastatic melanoma is treated. In some ticles comprising paclitaxel and albumin (Such as Nab-pacli embodiments, the method comprises intravenously adminis taxel, for example about 5 mg/ml Nab-paclitaxel), wherein tering (for example over a period of about 30 to about 40 15 the individual is selected for treatment if the individual com minutes) to the individual an effective amount of Nab-pacli prises a wild-type BRAF. In some embodiments, there is taxel (such as about 5 mg/ml Nab-paclitaxel), wherein the provided a method of treating melanoma (for example meta dose of paclitaxel in the nanoparticle composition is about 80 static melanoma) in an individual comprising: a) selecting the to about 200 mg/m (including for example about 90 mg/m. individual for treatment based on the individual comprising a about 120 mg/m, or about 150 mg/m) on days 1, 8, 15 of wild-type BRAF; and b) administering to the individual an every 28 day cycle. In some embodiments, the individual is effective amount of a composition comprising nanoparticles treated for at least about 2 months, including for example at comprising paclitaxel and albumin (Such as Nab-paclitaxel, least about any of 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. for example about 5 mg/ml Nab-paclitaxel). In some embodi In some embodiments, there is provided a method of treat ments, there is provided a method of treating melanoma (for ing melanoma (for example metastatic melanoma) in an indi 25 example metastatic melanoma) in an individual comprising: vidual comprising administering to the individual an effective a) determining the BRAF status of the individual; b) selecting amount of a composition comprising nanoparticles compris the individual for treatment based on the individual compris ing paclitaxel and albumin (Such as Nab-paclitaxel, for ing a wild-type BRAF; and c) administering to the individual example about 5 mg/ml Nab-paclitaxel), wherein the indi an effective amount of a composition comprising nanopar vidual is selected for treatment based on BRAF status of the 30 ticles comprising paclitaxel and albumin (Such as Nab-pacli individual. In some embodiments, there is provided a method taxel, for example about 5 mg/ml Nab-paclitaxel). In some of treating melanoma (for example metastatic melanoma) in embodiments, the method comprises intravenously adminis an individual comprising: a) determining the BRAF status of tering (for example over a period of about 30 to about 40 the individual; and b) administering to the individual an effec minutes) to the individual an effective amount of Nab-pacli tive amount of a composition comprising nanoparticles com 35 taxel (such as about 5 mg/ml Nab-paclitaxel), wherein the prising paclitaxel and albumin (such as Nab-paclitaxel, for dose of paclitaxel in the nanoparticle composition is about 80 example about 5 mg/ml Nab-paclitaxel). In some embodi to about 200 mg/m (including for example about 90 mg/m. ments, there is provided a method of treating melanoma (for about 120 mg/m, or about 150 mg/m) on days 1, 8, 15 of example metastatic melanoma) in an individual comprising: every 28 day cycle. In some embodiments, the individual is a) determining the BRAF status of the individual; b) selecting 40 treated for at least about 2 months, including for example at the individual for treatment based on the BRAF status of the least about any of 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. individual; and c) administering to the individual an effective In some embodiments, there is provided a method of treat amount of a composition comprising nanoparticles compris ing melanoma (for example metastatic melanoma) in an indi ing paclitaxel and albumin (Such as Nab-paclitaxel, for vidual comprising administering to the individual an effective example about 5 mg/ml Nab-paclitaxel). In some embodi 45 amount of a composition comprising nanoparticles compris ments, there is provided a method of treating melanoma (for ing paclitaxel and albumin (Such as Nab-paclitaxel, for example metastatic melanoma) in an individual comprising: example about 5 mg/ml Nab-paclitaxel), wherein the indi a) selecting the individual for treatment based on the BRAF vidual is selected for treatment if the individual comprises a status of the individual; and b) administering to the individual BRAF mutation (such as a BRAF V600E mutation). In some an effective amount of a composition comprising nanopar 50 embodiments, there is provided a method of treating mela ticles comprising paclitaxel and albumin (such as Nab-pacli noma (for example metastatic melanoma) in an individual taxel, for example about 5 mg/ml Nab-paclitaxel). In some comprising: a) determining the BRAF status of the indi embodiments, an individual who comprises wild-type BRAF vidual; and b) administering to the individual an effective is treated. In some embodiments, an individual who com amount of a composition comprising nanoparticles compris prises a BRAF mutation (such as a BRAFV600E mutation) is 55 ing paclitaxel and albumin (Such as Nab-paclitaxel, for treated. Treatments based on any other BRAF status example about 5 mg/ml Nab-paclitaxel), wherein the indi described herein are also contemplated. In some embodi vidual is selected for treatment if the individual comprises a ments, the method comprises intravenously administering BRAF mutation (such as a BRAF V600E mutation). In some (for example over a period of about 30 to about 40 minutes) to embodiments, there is provided a method of treating mela the individual an effective amount of Nab-paclitaxel (such as 60 noma (for example metastatic melanoma) in an individual about 5 mg/ml Nab-paclitaxel), wherein the dose of paclitaxel comprising: a) selecting the individual for treatment based on in the nanoparticle composition is about 80 to about 200 the individual comprising a BRAF mutation (such as a BRAF mg/m (including for example about 90 mg/m, about 120 V600E mutation); and b) administering to the individual an mg/m, or about 150 mg/m) on days 1, 8, 15 of every 28 day effective amount of a composition comprising nanoparticles cycle. In some embodiments, the individual is treated for at 65 comprising paclitaxel and albumin (Such as Nab-paclitaxel, least about 2 months, including for example at least about any for example about 5 mg/ml Nab-paclitaxel). In some embodi of 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. ments, there is provided a method of treating melanoma (for US 9,149,455 B2 51 52 example metastatic melanoma) in an individual comprising: amount of a composition comprising nanoparticles compris a) determining the BRAF status of the individual; b) selecting ing paclitaxel and albumin (Such as Nab-paclitaxel, for the individual for treatment based on the individual compris example about 5 mg/ml Nab-paclitaxel), wherein the indi ing a BRAF mutation (such as a BRAFV600E mutation); and vidual is selected for treatment based on the individual having c) administering to the individual an effective amount of a an elevated LDH level. In some embodiments, there is pro composition comprising nanoparticles comprising paclitaxel vided a method of treating melanoma (for example metastatic and albumin (such as Nab-paclitaxel, for example about 5 melanoma) in an individual comprising: a) determining the mg/ml Nab-paclitaxel). In some embodiments, the method LDH level of the individual; and b) administering to the comprises intravenously administering (for example over a individual an effective amount of a composition comprising period of about 30 to about 40 minutes) to the individual an 10 nanoparticles comprising paclitaxel and albumin (such as effective amount of Nab-paclitaxel (such as about 5 mg/ml Nab-paclitaxel, for example about 5 mg/ml Nab-paclitaxel), Nab-paclitaxel), wherein the dose of paclitaxel in the nano wherein the individual is selected for treatment based on particle composition is about 80 to about 200 mg/m (includ having an elevated LDH level. In some embodiments, there is ing for example about 90 mg/m, about 120 mg/m, or about provided a method of treating melanoma (for example meta 150 mg/m) on days 1, 8, 15 of every 28 day cycle. In some 15 static melanoma) in an individual comprising: a) selecting the embodiments, the individual is treated for at least about 2 individual for treatment based on the individual having an months, including for example at least about any of 3, 4, 5, 6, elevated LDH level; and b) administering to the individual an 7, 8, 9, 10, 11, or 12 months. effective amount of a composition comprising nanoparticles In some embodiments, there is provided a method of treat comprising paclitaxel and albumin (Such as Nab-paclitaxel, ing melanoma (for example metastatic melanoma) in an indi for example about 5 mg/ml Nab-paclitaxel). In some embodi vidual comprising administering to the individual an effective ments, there is provided a method of treating melanoma (for amount of a composition comprising nanoparticles compris example metastatic melanoma) in an individual comprising: ing paclitaxel and albumin (Such as Nab-paclitaxel, for a) determining the LDH level of the individual; b) selecting example about 5 mg/ml Nab-paclitaxel), wherein the indi the individual for treatment based on the individual having an vidual is selected for treatment based on LDH level of the 25 elevated LDH level; and c) administering to the individual an individual. In some embodiments, there is provided a method effective amount of a composition comprising nanoparticles of treating melanoma (for example metastatic melanoma) in comprising paclitaxel and albumin (Such as Nab-paclitaxel, an individual comprising: a) determining the LDH level of the for example about 5 mg/ml Nab-paclitaxel). In some embodi individual; and b) administering to the individual an effective ments, an individual whose LDH level is greater than about amount of a composition comprising nanoparticles compris 30 1.1 to about 2.0xULN is treated. In some embodiments, the ing paclitaxel and albumin (Such as Nab-paclitaxel, for method comprises intravenously administering (for example example about 5 mg/ml Nab-paclitaxel). In some embodi over a period of about 30 to about 40 minutes) to the indi ments, there is provided a method of treating melanoma (for vidual an effective amount of Nab-paclitaxel (such as about 5 example metastatic melanoma) in an individual comprising: mg/ml Nab-paclitaxel), wherein the dose of paclitaxel in the a) selecting the individual for treatment based on the LDH 35 nanoparticle composition is about 80 to about 200 mg/m level of the individual; and b) administering to the individual (including for example about 90 mg/m, about 120 mg/m, or an effective amount of a composition comprising nanopar about 150 mg/m) on days 1, 8, 15 of every 28 day cycle. In ticles comprising paclitaxel and albumin (such as Nab-pacli some embodiments, the individual is treated for at least about taxel, for example about 5 mg/ml Nab-paclitaxel). In some 2 months, including for example at least about any of 3, 4, 5, embodiments, there is provided a method of treating mela 40 6, 7, 8, 9, 10, 11, or 12 months. noma (for example metastatic melanoma) in an individual In some embodiments, an individual is identified for treat comprising: a) determining the LDH level of the individual; ment based on two or more of the following characteristics: b) selecting the individual for treatment based on the LDH melanoma Subtype or staging characteristics, BRAF Status, level of the individual; and c) administering to the individual and LDH level. For example, in some embodiments, there is an effective amount of a composition comprising nanopar 45 provided a method of treating melanoma (for example meta ticles comprising paclitaxel and albumin (such as Nab-pacli static melanoma) in an individual comprising administering taxel, for example about 5 mg/ml Nab-paclitaxel). In some to the individual an effective amount of a composition com embodiments, an individual whose LDH level is greater than prising nanoparticles comprising paclitaxel and albumin about 1.1 to about 2.0xULN is treated. In some embodiments, (such as Nab-paclitaxel, for example about 5 mg/ml Nab an individual whose LDH level is between about 0.8.x to 50 paclitaxel), wherein the individual is selected for treatment about 1.1 xULN is treated. In some embodiments, an indi based on melanoma Subtype or staging characteristics (such vidual whose LDH level is less than about 0.8xULN is as stages M1a, M1b, M1c) and BRAF status. In some treated. Treatments of individuals having any other LDH embodiments, there is provided a method of treating mela levels described herein are also contemplated. In some noma (for example metastatic melanoma) in an individual embodiments, the method comprises intravenously adminis 55 comprising: a) determining the melanoma Subtype or staging tering (for example over a period of about 30 to about 40 characteristics (such as stages M1a, M1b, M1c) and BRAF minutes) to the individual an effective amount of Nab-pacli status of the individual; and b) administering to the individual taxel (such as about 5 mg/ml Nab-paclitaxel), wherein the an effective amount of a composition comprising nanopar dose of paclitaxel in the nanoparticle composition is about 80 ticles comprising paclitaxel and albumin (Such as Nab-pacli to about 200 mg/m (including for example about 90 mg/m. 60 taxel, for example about 5 mg/ml Nab-paclitaxel). In some about 120 mg/m, or about 150 mg/m) on days 1, 8, 15 of embodiments, there is provided a method of treating mela every 28 day cycle. In some embodiments, the individual is noma (for example metastatic melanoma) and BRAF Status in treated for at least about 2 months, including for example at an individual comprising: a) selecting the individual for treat least about any of 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. ment based on the melanoma Subtype or staging characteris In some embodiments, there is provided a method of treat 65 tics (such as stages M1a, M1b, M1c) of the individual; and b) ing melanoma (for example metastatic melanoma) in an indi administering to the individual an effective amount of a com vidual comprising administering to the individual an effective position comprising nanoparticles comprising paclitaxel and US 9,149,455 B2 53 54 albumin (such as Nab-paclitaxel, for example about 5 mg/ml chemotherapeutic agent or immunotherapeutic agent). In Nab-paclitaxel). In some embodiments, there is provided a Some embodiments, the individual has stage IV or metastatic method of treating melanoma (for example metastatic mela melanoma (e.g., stage IV or metastatic cutaneous melanoma). noma) and BRAF status in an individual comprising: a) deter In some embodiments, the melanoma is metastatic malignant mining the melanoma Subtype or staging characteristics (such melanoma. In some embodiments, the metastatic melanoma as stages M1a, M1b, M1c) and BRAF status of the individual; is at stage M1a, stage M1b, or stage M1c. In some embodi b) selecting the individual for treatment based on the mela ments, the metastatic melanoma is at stage M1c. In some noma Subtype or staging characteristics (such as stages M1a, embodiments, the melanoma comprises a mutation in BRAF. M1b, M1c) of the individual; and c) administering to the In some embodiments, the melanoma does not comprise a individual an effective amount of a composition comprising 10 mutation in BRAF. In some embodiments, the melanoma nanoparticles comprising paclitaxel and albumin (such as does not comprise BRAF mutant such as a BRAF mutant with Nab-paclitaxel, for example about 5 mg/ml Nab-paclitaxel). increased activity (for example, increased kinase activity, In some embodiments, an individual who has stage Mla and/or increased activity as compared to wild-type BRAF) or melanoma and comprises wild-type BRAF is treated. In some a BRAF gain-of-function mutant. In some embodiments, the embodiments, an individual who has stage M1b melanoma 15 melanoma does not comprise BRAF V600E mutation (e.g., and comprises wild-type BRAF is treated. In some embodi the melanoma comprises wild-type BRAF). In some embodi ments, an individual who has stage M1c melanoma and com ments, the melanoma comprises wild-type BRAF. In some prises wild-type BRAF is treated. In some embodiments, an embodiments, the melanoma comprises a BRAF mutant Such individual who has cutaneous metastatic melanoma and wild as a BRAF mutant with increased activity (for example, type BRAF is treated. Treatment decision can also be based increased kinase activity, and/or increased activity as com on the Subtype of the melanoma, Such as any Subtype of the pared to wild-type BRAF) or a BRAF gain-of-function melanoma described herein, and other BRAF status, such as mutant. In some embodiments, the melanoma comprises any of the BRAF status described herein, are also contem BRAF V600E mutation. In some embodiments, the indi plated. In some embodiments, the method comprises intrave vidual has elevated serum LDH level. In some embodiments, nously administering (for example over a period of about 30 25 the individual has serum LDH of about any of the following: to about 40 minutes) to the individual an effective amount of <0.8xULN, 0.4–0.8xULN, 0.8-1.1XULN, 0.9-1.1XULN, 0.8- Nab-paclitaxel (such as about 5 mg/ml Nab-paclitaxel), 1.2xl JLN, 1.1-1.5xULN, 1.2-1.5xULN, 1.1-2xULN, or 1.5- wherein the dose of paclitaxel in the nanoparticle composi 2xULN. In some embodiments, the individual has serum tion is about 80 to about 200 mg/m (including for example LDH of less than about 0.8xULN. In some embodiments, the about 90 mg/m, about 120 mg/m, or about 150 mg/m) on 30 individual has serum LDH at about 0.8.x to about 1.1 xULN. days 1, 8, 15 of every 28 day cycle. In some embodiments, the In some embodiments, the individual has serum LDH of individual is treated for at least about 2 months, including for between greater than about 1.1.x to about 2.0xULN. In some example at least about any of 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 embodiments, the individual has serum LDH of between months. about 1.1.x to about 2.0xULN. In some embodiments, the In some embodiments, the method of using taxane nano 35 individual is a human (e.g., male or female). In some embodi particles for treating melanoma described herein is used as a ments, the taxane is paclitaxel. In some embodiments, the monotherapy. In some embodiments, the method of treating carrier protein is albumin. In some embodiments, the one melanoma using taxane nanoparticles does not further com other agent is a chemotherapeutic agent or immunotherapeu prise one other therapeutic agent (Such as one other chemo tic agent. In some embodiments, the one other agent is a therapeutic agent or immunotherapeutic agent). In some 40 platinum-based agent such as carboplatin. embodiments, the method does not further comprise a cyto An exemplary and non-limiting list of chemotherapeutic toxic chemotherapeutic agent. agents contemplated is provided herein. Suitable chemo It is understood that reference to and description of meth therapeutic agents include, for example, platinum-based ods of treating melanoma as described herein is exemplary agents (such as carboplatin), Vinca alkaloids, agents that dis and that this description applies equally to and includes meth 45 rupt microtubule formation, anti-angiogenic agents, thera ods of treating melanoma using combination therapy. peutic antibodies, EGFR targeting agents, tyrosine kinase Methods of Combination Therapies targeting agent (such as tyrosine kinase inhibitors), transi The present invention further provides combination tional metal complexes, proteasome inhibitors, antimetabo therapy for treating melanoma. Provided herein are methods lites (such as nucleoside analogs), alkylating agents, anthra of treating melanoma comprising administering to an indi 50 cycline antibiotics, topoisomerase inhibitors, macrollides, vidual an effective amount of a composition comprising therapeutic antibodies, retinoids; geldanamycin or a deriva nanoparticles comprising a taxane (e.g., paclitaxel) and a tive thereof, and other standard chemotherapeutic agents well carrier protein (e.g., albumin) and a second therapy. The recognized in the art. second therapy may be surgery, radiation, gene therapy, In some embodiments, the other agent is one of the follow immunotherapy, bone marrow transplantation, stem cell 55 ing: a platinum-based agent (e.g., carboplatin or cisplatin), an transplantation, hormone therapy, targeted therapy, cryo anti-VEGF antibody (e.g., bevacizumab), dacarbazine or therapy, ultrasound therapy, photodynamic therapy, and/or DTIC (also known as DIC, DTIC-Dome, or Imidazole Car chemotherapy (e.g., one or more compounds or pharmaceu boxamide), Oblimersen (or Genasense), interleukin-2 (IL-2), tically acceptable salts thereofuseful for treating melanoma). interferon (IFN), Interferon C-2b, a BRAF inhibitor (such as The nanoparticle composition is administered either prior to 60 Vemurafenib (or Zelboraf), GDC-0879 (available from Tocris or after the administration of the second therapy. Bioscience), PLX-4720 (available from Symansis), or Sor In some embodiments, there is provided a method of treat afenib (or Sorafenib Tosylate or Nexavar (available from ing melanoma in an individual (e.g., human) comprising Bayer Pharmaceuticals Corp.)), Dabrafenib (GSK21 18436), administering to the individual a) an effective amount of a LGX-818, CEP-32496, UI-152, RAF 265, Regorafenib composition comprising nanoparticles comprising a taxane 65 (BAY 73-4506), or CCT239065), an antibody against the (e.g., paclitaxel) and a carrier protein (e.g., albumin), and b) Programmed Death 1 (PD-1) receptor (such as BMS-936558, an effective amount of at least one other agent (Such as a available from Bristol Myers Squibb), an antibody against the US 9,149,455 B2 55 56 PD-1 Ligand (anti-PD-L1 antibody), or anti-CTLA-4 anti tive amount of a platinum-based agent (Such as carboplatin or body such as Ipilimumab (or MDX-010, MDX-101, or Yer cisplatin). In some embodiments, there is provided a method Voy), or a DNA alkylating agent Such as Temozolomide. of treating unresectable stage IV melanoma in a human indi Programmed Death Receptor 1 (PD-I) is a member of the vidual (including a chemotherapy naive individual and an CD28/CTLA4 family that is expressed on activated, but not 5 individual who has previously been treated for melanoma), resting T cells (Nishimura et al. (1996) Int. Immunol. 8:773). comprising administering (such as intravenously administer Ligation of PD-I by its ligands mediates an inhibitory signal ing) to the individuala) an effective amount of a composition that results in reduced cytokine production, and reduced T comprising nanoparticles comprising paclitaxel and albumin cell survival (Nishimura et al. (1999) Immunity 11:141; Nish (such as Nab-paclitaxel, for example about 5 mg/ml Nab imura et al. (2001) Science 291:319; Chemnitz et al. (2004).J. 10 paclitaxel), and b) an effective amount of carboplatin. In some Immunol. 173:945). embodiments, there is provided a method of treating unresec Programmed Death Receptor Ligand 1 (PD-L1) is a B7 table stage IV melanoma in a human individual (including a family member that is expressed on many cell types, includ chemotherapy naive individual and an individual who has ing APCs and activated T cells (Yamazaki et al. (2002) J. previously been treated for melanoma), comprising adminis Immunol. 169:5538). PD-L1 binds to both PD-I and B7-1. 15 tering (such as intravenously administering) to the individual Both binding of T-cell-expressed B7-1 by PD-L1 and binding a) an effective amount of a composition comprising nanopar of T-cell-expressed PD-L1 by B7-1 result in T cell inhibition ticles comprising paclitaxel and albumin (Such as Nab-pacli (Butte et al. (2007) Immunity 27:111). There is also evidence taxel, for example about 5 mg/ml Nab-paclitaxel), wherein that, like other B7 family members, PD-L1 can also provide the dose of paclitaxel in the nanoparticle composition is costimulatory signals to T cells (Subudhi et al. (2004).J. Clin. 20 between about 80 mg/m to about 175 mg/m (such as Invest. 113:694; Tamura et al. (2001) Blood 97:1809). between about 100 mg/m to about 150 mg/m); and b) an Trametinib (GSK1 120212) is an orally bioavailable inhibi effective amount of carboplatin. In some embodiments, there tor of mitogen-activated protein kinase kinase (MEKMAPK/ is provided a method of treating unresectable stage IV mela ERK kinase). National Cancer Institute, Drug Dictionary noma in a human individual (including a chemotherapy naive (World Wide Web at cancer.gov/drugdictionary- 25 individual and an individual who has previously been treated ?cdrid=599034, accessed on Feb. 11, 2013). Trametinib spe for melanoma), comprising administering (such as intrave cifically binds to and inhibits MEK1 and 2, resulting in an nously administering) to the individuala) an effective amount inhibition of growth factor-mediated cell signaling and cel of a composition comprising nanoparticles comprising pacli lular proliferation in various cancers. Id. MEK1 and 2 are taxel and albumin (such as Nab-paclitaxel, for example about dual specificity threonine/tyrosine kinases which are often 30 5 mg/ml Nab-paclitaxel), wherein the dose of paclitaxel in the upregulated in various cancer cell types and play a key role in nanoparticle compositionis between about 80 mg/m to about the activation of the RAS/RAF/MEK/ERK signaling path 175 mg/m (such as between about 100 mg/m to about 150 way that regulates cell growth. Id. mg/m); and b) an effective amount of carboplatin (for TH-302 is a hypoxia-activated prodrug consisting of a example carboplatin at the dose of AUC2, AUC3, AUC4. 2-nitroimidazole phosphoramidate conjugate with potential 35 AUC5, or AUC6). In some embodiments, the nanoparticle antineoplastic activity. National Cancer Institute, Drug Dic composition and the carboplatin are administered on days 1, tionary (World Wide Web at cancer.gov/drugdictionary 8, 15 of a 28 day cycle. In some embodiments, the nanopar 2CdrID=560194 accessed on Feb. 11, 2013). The 2-nitroimi ticle composition is administered on days 1, 8, 15 of a 28 day dazole moiety of hypoxia-activated prodrug TH-302 acts as a cycle, and the carboplatin is administered on day 1. In some hypoxic trigger, releasing the DNA-alkylating dibromo iso- 40 embodiments, the method further comprises administering to phosphoramide mustard moiety within hypoxic regions of the individual an effective amount of Sorafenib (for example tumors. Id. The hypoxia-specific activity of this agent reduces Sorafenib at the daily dose of about 400 mg). In some embodi systemic toxicity. Id. ments, the method further comprises administering to the The present application thus in Some embodiments pro individual an effective amount of bevacizumab (for example vides methods of combination therapy. In some embodi- 45 between about 5 mg/kg to about 15 mg/kg, Such as about 10 ments, there is provided a method of treating melanoma (Such mg/kg bevacizumab). In some embodiments, the method fur as metastatic melanoma, stage III melanoma, or stage IV ther comprises administering to the individual one or more of melanoma) in an individual (Such as a human individual), the following: temozolomide, interleukin-2, interferon (such comprising administering to the individual a) an effective as interferon C-2b), and oblimersen. In some embodiments, amount of a composition comprising nanoparticles compris- 50 the individual is chemotherapy naive. In some embodiments, ing a taxane (e.g., paclitaxel) and a carrier protein (e.g., albu the individual has previously been treated for melanoma. In min), and b) an effective amount of a chemotherapeutic agent. Some embodiments, the individual is at stage IV melanoma. In some embodiments, there is provided a method of treating In some embodiments, the individual is at stage M1c mela melanoma (Such as metastatic melanoma, stage III mela noma. In some embodiments, the individual comprises wild noma, or stage IV melanoma) in a human individual, com- 55 type BRAF. In some embodiments, the individual comprises prising administering to the individuala) an effective amount a BRAF mutation (such as a BRAF V600E mutation). In of a composition comprising nanoparticles comprising pacli Some embodiments, the individual is a male. In some embodi taxel and albumin (such as Nab-paclitaxel, for example about ments, the individual is a female. In some embodiments, the 5 mg/ml Nab-paclitaxel), and b) an effective amount of a individual is a human who is at least 65 years old (including chemotherapeutic agent. 60 for example at least 70, 75, or 80 years old). In some embodi Thus, for example, in some embodiments, there is provided ments, the individual is a human who is less than 65 years old a method of treating melanoma (such as metastatic mela (including for example less than 60, 50, or 40 years old). In noma, stage III melanoma, or stage IV melanoma) in a human some embodiments, the individual has a normal LDH level. In individual, comprising administering to the individual a) an some embodiments, the individual has an elevated LDH level. effective amount of a composition comprising nanoparticles 65 In some embodiments, there is provided a method of treat comprising paclitaxel and albumin (such as Nab-paclitaxel, ing melanoma (Such as metastatic melanoma, stage III mela for example about 5 mg/ml Nab-paclitaxel), and b) an effec noma, or stage IV melanoma) in a human individual, com US 9,149,455 B2 57 58 prising administering to the individuala) an effective amount 150 mg/m (such as 150 mg/m), wherein the nanoparticle of a composition comprising nanoparticles comprising pacli composition is administered on days 1, 8, 15 of a 28 day cycle, taxel and albumin (such as Nab-paclitaxel, for example about and b) an effective amount of bevacizumab, wherein the dose 5 mg/ml Nab-paclitaxel), and b) an effective amount of a of bevacizumab is between about 5 mg/kg to about 15 mg/kg therapeutic antibody (such as an anti-VEGF antibody, for (such as about 10 mg/kg), wherein the bevacizumab is admin example bevacizumab). In some embodiments, there is pro istered on days 1 and 15 of a 28 day cycle. In some embodi vided a method of treating stage III or stage IV melanoma in ments, there is provided a method of treating unresectable a human individual (including a chemotherapy naive indi stage IIIc or stage IV metastatic melanoma in a human indi vidual and an individual who has previously been treated for vidual having wild-type BRAF, comprising intravenously melanoma), comprising administering (such as intravenously 10 administering to the individual a) an effective amount of a administering) to the individual a) an effective amount of a composition comprising nanoparticles comprising paclitaxel composition comprising nanoparticles comprising paclitaxel albumin (such as Nab-paclitaxel, for example about 5 mg/ml and albumin (such as Nab-paclitaxel, for example about 5 Nab-paclitaxel), wherein the dose of paclitaxel in the nano mg/ml Nab-paclitaxel), and b) an effective amount of beva particle composition is between about 100 mg/m to about cizumab. In some embodiments, there is provided a method 15 150 mg/m (such as 150 mg/m), wherein the nanoparticle of treating stage III or stage IV melanoma in a human indi composition is administered on days 1, 8, 15 of a 28 day cycle, vidual (including a chemotherapy naive individual and an and b) an effective amount of bevacizumab, wherein the dose individual who has previously been treated for melanoma), of bevacizumab is between about 5 mg/kg to about 15 mg/kg comprising administering (Such as intravenously administer (such as about 10 mg/kg), wherein the bevacizumab is admin ing) to the individuala) an effective amount of a composition istered on days 1 and 15 of a 28 day cycle. In some embodi comprising nanoparticles comprising paclitaxel and albumin ments, the individual is chemotherapy naive. In some (such as Nab-paclitaxel, for example about 5 mg/ml Nab embodiments, the individual has previously been treated for paclitaxel), wherein the dose of paclitaxel in the nanoparticle melanoma. In some embodiments, the individual is at stage composition is between about 80 mg/m to about 175 mg/m IV melanoma. In some embodiments, the individual is at (such as between about 100 mg/m to about 150 mg/m); and 25 stage M1c melanoma. In some embodiments, the individual b) an effective amount of bevacizumab (for example about 5 comprises wild-type BRAF. In some embodiments, the indi mg/kg to about 15 mg/kg, such as about 10 mg/kg bevaci vidual comprises a BRAF mutation (such as a BRAF V600E Zumab). In some embodiments, the method further comprises mutation). In some embodiments, the individual is a male. In administering to the individual an effective amount of carbo Some embodiments, the individual is a female. In some platin. In some embodiments, the individual is chemotherapy 30 embodiments, the individual is a human who is at least 65 naive. In some embodiments, the individual has previously years old (including for example at least 70, 75, or 80 years been treated for melanoma. In some embodiments, the indi old). In some embodiments, the individual is a human who is vidual is at stage IV melanoma. In some embodiments, the less than 65 years old (including for example less than 60, 50. individual is at stage M1c melanoma. In some embodiments, or 40 years old). In some embodiments, the individual has a the individual comprises wild-type BRAF. In some embodi 35 normal LDH level. In some embodiments, the individual has ments, the individual comprises a BRAF mutation (such as a an elevated LDH level. BRAF V600E mutation). In some embodiments, the indi In some embodiments, there is provided a method of treat vidual is a male. In some embodiments, the individual is a ing melanoma (Such as metastatic melanoma, stage III mela female. In some embodiments, the individual is a human who noma, or stage IV melanoma) in a human individual, com is at least 65 years old (including for example at least 70, 75, 40 prising administering to the individuala) an effective amount or 80 years old). In some embodiments, the individual is a of a composition comprising nanoparticles comprising pacli human who is less than 65 years old (including for example taxel and albumin (such as Nab-paclitaxel, for example about less than 60, 50, or 40 years old). In some embodiments, the 5 mg/ml Nab-paclitaxel), and b) an effective amount of a individual has a normal LDH level. In some embodiments, the temozolomide. In some embodiments, there is provided a individual has an elevated LDH level. 45 method of treating metastatic melanoma in a human indi In some embodiments, there is provided a method of treat vidual (including a chemotherapy naive individual and an ing melanoma (Such as metastatic melanoma, stage III mela individual who has previously been treated for melanoma), noma, or stage IV melanoma) in a human individual (such as comprising administering (such as intravenously administer an individual having wild-type BRAF), comprising adminis ing) to the individuala) an effective amount of a composition tering (such as intravenously administering) to the individual 50 comprising nanoparticles comprising paclitaxel and albumin a) an effective amount of a composition comprising nanopar (such as Nab-paclitaxel, for example about 5 mg/ml Nab ticles comprising paclitaxel albumin (such as Nab-paclitaxel, paclitaxel), and b) an effective amount oftemozolomide. In for example about 5 mg/ml Nab-paclitaxel), wherein the dose Some embodiments, there is provided a method of treating of paclitaxel in the nanoparticle composition is between metastatic melanoma in a human individual (including a che about 100 mg/m to about 150 mg/m (such as 150 mg/m), 55 motherapy naive individual and an individual who has previ and b) an effective amount of bevacizumab, wherein the dose ously been treated for melanoma), comprising administering of bevacizumab is between about 5 mg/kg to about 15 mg/kg (such as intravenously administering) to the individuala) an (such as about 10 mg/kg). In some embodiments, there is effective amount of a composition comprising nanoparticles provided a method of treating melanoma (such as metastatic comprising paclitaxel and albumin (Such as Nab-paclitaxel, melanoma, stage III melanoma, or stage IV melanoma) in a 60 for example about 5 mg/ml Nab-paclitaxel), wherein the dose human individual (such as an individual having wild-type of paclitaxel in the nanoparticle composition is between BRAF), comprising administering (such as intravenously about 80 mg/m to about 175 mg/m (such as between about administering) to the individual a) an effective amount of a 100 mg/m to about 150 mg/m); and b) an effective amount composition comprising nanoparticles comprising paclitaxel of tomozolomide. In some embodiments, the method further albumin (such as Nab-paclitaxel, for example about 5 mg/ml 65 comprises administering to the individual an effective Nab-paclitaxel), wherein the dose of paclitaxel in the nano amount of oblimersen. In some embodiments, the individual particle composition is between about 100 mg/m to about is chemotherapy naive. In some embodiments, the individual US 9,149,455 B2 59 60 has previously been treated for melanoma. In some embodi (including a chemotherapy naive individual and an individual ments, the individual is at stage M1c melanoma. In some who has previously been treated for melanoma), comprising embodiments, the individual comprises wild-type BRAF. In administering (such as intravenously administering) to the some embodiments, the individual comprises a BRAF muta individuala) an effective amount of a composition compris tion (such as a BRAF V600E mutation). In some embodi 5 ing nanoparticles comprising paclitaxel and albumin (such as ments, the individual is a male. In some embodiments, the Nab-paclitaxel, for example about 5 mg/ml Nab-paclitaxel), individual is a female. In some embodiments, the individual is and b) an effective amount of TH-302. In some embodiments, a human who is at least 65 years old (including for example at there is provided a method of treating stage III or stage IV least 70, 75, or 80 years old). In some embodiments, the melanoma in a human individual (including a chemotherapy individual is a human who is less than 65 years old (including 10 naive individual and an individual who has previously been for example less than 60, 50, or 40 years old). In some treated for melanoma), comprising administering (Such as embodiments, the individual has a normal LDH level. In some intravenously administering) to the individuala) an effective embodiments, the individual has an elevated LDH level. amount of a composition comprising nanoparticles compris In some embodiments, there is provided a method of treat ing paclitaxel and albumin (Such as Nab-paclitaxel, for ing melanoma (Such as metastatic melanoma, stage III mela 15 example about 5 mg/ml Nab-paclitaxel), wherein the dose of noma, or stage IV melanoma) in a human individual, com paclitaxel in the nanoparticle composition is between about prising administering to the individuala) an effective amount 80 mg/m to about 175 mg/m (such as between about 100 of a composition comprising nanoparticles comprising pacli mg/m to about 150 mg/m); and b) an effective amount of taxel and albumin (such as Nab-paclitaxel, for example about TH-302. In some embodiments, the individual is chemo 5 mg/ml Nab-paclitaxel), and b) an effective amount of a therapy naive. In some embodiments, the individual has pre MEK inhibitor (such as Trametinib (GSK1 120212)). In some viously been treated for melanoma. In some embodiments, embodiments, there is provided a method of treating stage III the individual is at stage IV melanoma. In some embodi or stage IV melanoma in a human individual (including a ments, the individual is at stage M1c melanoma. In some chemotherapy naive individual and an individual who has embodiments, the individual comprises wild-type BRAF. In previously been treated for melanoma), comprising adminis 25 some embodiments, the individual comprises a BRAF muta tering (such as intravenously administering) to the individual tion (such as a BRAF V600E mutation). In some embodi a) an effective amount of a composition comprising nanopar ments, the individual is a male. In some embodiments, the ticles comprising paclitaxel and albumin (such as Nab-pacli individual is a female. In some embodiments, the individual is taxel, for example about 5 mg/ml Nab-paclitaxel), and b) an a human who is at least 65 years old (including for example at effective amount of a MEK inhibitor (such as Trametinib 30 least 70, 75, or 80 years old). In some embodiments, the (GSK1 120212)). In some embodiments, there is provided a individual is a human who is less than 65 years old (including method of treating stage III or stage IV melanoma in a human for example less than 60, 50, or 40 years old). In some individual (including a chemotherapy naive individual and an embodiments, the individual has a normal LDH level. In some individual who has previously been treated for melanoma), embodiments, the individual has an elevated LDH level. comprising administering (Such as intravenously administer 35 In some embodiments, there is provided a method of treat ing) to the individuala) an effective amount of a composition ing melanoma (Such as metastatic melanoma, stage III mela comprising nanoparticles comprising paclitaxel and albumin noma, or stage IV melanoma) in a human individual, com (such as Nab-paclitaxel, for example about 5 mg/ml Nab prising administering to the individuala) an effective amount paclitaxel), wherein the dose of paclitaxel in the nanoparticle of a composition comprising nanoparticles comprising pacli composition is between about 80 mg/m to about 175 mg/m 40 taxel and albumin (such as Nab-paclitaxel, for example about (such as between about 100 mg/m to about 150 mg/m); and 5 mg/ml Nab-paclitaxel), and b) an effective amount of b) an effective amount of a MEK inhibitor (such as Trame oblimersen. In some embodiments, there is provided a tinib (GSK1 120212)). In some embodiments, the individual method of treating metastatic melanoma in a human indi is chemotherapy naive. In some embodiments, the individual vidual (including a chemotherapy naive individual and an has previously been treated for melanoma. In some embodi 45 individual who has previously been treated for melanoma), ments, the individual is at stage IV melanoma. In some comprising administering (such as intravenously administer embodiments, the individual is at Stage M1c melanoma. In ing) to the individuala) an effective amount of a composition Some embodiments, the individual comprises wild-type comprising nanoparticles comprising paclitaxel and albumin BRAF. In some embodiments, the individual comprises a (such as Nab-paclitaxel, for example about 5 mg/ml Nab BRAF mutation (such as a BRAF V600E mutation). In some 50 paclitaxel), and b) an effective amount of oblimersen. In some embodiments, the individual is a male. In some embodiments, embodiments, there is provided a method of treating meta the individual is a female. In some embodiments, the indi static melanoma in a human individual (including a chemo vidual is a human who is at least 65 years old (including for therapy naive individual and an individual who has previ example at least 70, 75, or 80 years old). In some embodi ously been treated for melanoma), comprising administering ments, the individual is a human who is less than 65 years old 55 (such as intravenously administering) to the individuala) an (including for example less than 60, 50, or 40 years old). In effective amount of a composition comprising nanoparticles some embodiments, the individual has a normal LDH level. In comprising paclitaxel and albumin (Such as Nab-paclitaxel, some embodiments, the individual has an elevated LDH level. for example about 5 mg/ml Nab-paclitaxel), wherein the dose In some embodiments, there is provided a method of treat of paclitaxel in the nanoparticle composition is between ing melanoma (Such as metastatic melanoma, stage III mela 60 about 80 mg/m to about 175 mg/m (such as between about noma, or stage IV melanoma) in a human individual, com 100 mg/m to about 150 mg/m); and b) an effective amount prising administering to the individuala) an effective amount of oblimersen. In some embodiments, the method further of a composition comprising nanoparticles comprising pacli comprises administering to the individual an effective taxel and albumin (such as Nab-paclitaxel, for example about amount of temozolomide. In some embodiments, the indi 5 mg/ml Nab-paclitaxel), and b) an effective amount of 65 vidual is chemotherapy naive. In some embodiments, the TH-302. In some embodiments, there is provided a method of individual has previously been treated for melanoma. In some treating stage III or stage IV melanoma in a human individual embodiments, the individual is at stage IV melanoma. In US 9,149,455 B2 61 62 Some embodiments, the individual is at Stage M1c melanoma. ments, the individual is a human who is less than 65 years old In some embodiments, the individual comprises wild-type (including for example less than 60, 50, or 40 years old). In BRAF. In some embodiments, the individual comprises a BRAF mutation (such as a BRAF V600E mutation). In some some embodiments, the individual has a normal LDH level. In embodiments, the individual is a male. In some embodiments, some embodiments, the individual has an elevated LDH level. the individual is a female. In some embodiments, the indi In some embodiments, the method of treating melanoma vidual is a human who is at least 65 years old (including for comprises any one of the dosing regimens provided in Table example at least 70, 75, or 80 years old). In some embodi 4. TABLE 4 Clinical studies with Nab-paclitaxel (or Abraxane & Melanoma Patient Line of Combination Setting Treatment Clinical Trial Title Study Design Treatment Unresectable, Chemo A Phase II Trial of Dosing Regimen: Carboplatin Stage IV naive, Carboplatin and 28 day cycle: Abraxane (R) Previously Abraxane (R) in Patients at 100 mg/m in treated with Unresectable Stage combination with IV Melanoma (NCCTG Carboplatin area under the Study NO57E) curve (AUC2) on days 1, 8, and 15. Stage III, First line Phase II trial of Nab Dosing Regimen: Bevacizumab Stage IV paclitaxel and 28 day cycle: Nab bevacizumab as first line paclitaxel at 150 mg/mon therapy in patients with ays 1, 8, 15 in unresectable melanoma combination with Bevacizumab at 10 mg/kg on days 1, 15. Treatment Duration: treated to progression or ose limiting toxicity. If he subject had a CR, osed with 2 more cycles; if the subject had a PR or SD for 4 months, dosed with 4 more cycles then iscontinue treatment with Nab-paclitaxel and continue bevacizumab. If he subject had disease progression after iscontinuing Nab paclitaxel because of clinical benefit, restart Nab-paclitaxel and continue combination therapy. Metastatic, Chemo Phase II Study of ABX, Dosing Regimen: Carboplatin Stage IV. naive, Carboplatin, and 28 day cycle: Nab Sorafenib Unresectable previously Sorafenib in Metastatic paclitaxel at 100 mg/m on Stage III treated Melanoma days 1, 8, and 15 in combination with Carboplatin AUC = 6 on day 1, and Sorafenib at 400 mg bid po daily from day 2 to day 27. Treatment Duration: continued until progression or unacceptable toxicity. Stage IV. Chemo A randomized phase II Dosing Regimen: Carboplatin Unresectable naive study oftemozolomide 28 day cycle: (Arm A) Bevacizumab and bevacizumab or Nab Temozolomide at 200 paclitaxel, carboplatin, mg/m on days 1 to 5 and and bevacizumab in Bevacizumab at 10 mg/kg patients with unresectable on days 1 to 15 vs. (Arm stage IV melanoma: A B) Nab-paclitaxel at North Central Cancer 100 mg/m (80 mg/m post Treatment Group Study, addendum 5 on days 1, 8, NO775 Nab-paclitaxel, and 15 in combination carboplatin, and with Carboplatin at AUC bevacizumab in NO77 6 on day 1 AUC 5 post addendum 5, and Bevacizumab at 10 mg/kg on days land 15.

US 9,149,455 B2 65 TABLE 4-continued Clinical studies with Nab-paclitaxel (or Abraxane & Melanoma Patient Line of Combination Setting Treatment Clinical Trial Title Study Design Treatment Unresectable First line Abraxane (R) in Arm I: Nab-paclitaxel at Bevacizumab stage IIIc & therapy combination with 150 mg/m·days 1, 8, 15 IV metastatic bevacizumab vs. of a 28 day cycle, melanoma ipilimumab in patients treatment until PD or with unresectable wild- unacceptable toxicity type BRAF metastatic Arm II: ipilimumab on melanoma day 1 every three weeks, 21-day cycle, 4 doses Metastatic, Chemo- Safety, efficacy, and Dosage Regimen: Ipilimumab Stage III, naive immunological effect of 28 day cycle: Abraxane (R) Stage IV Abraxane (R) plus at 150 mg/m on days 1, Ipilimumab in patients 8, and 15 in combination with metastatic with Ipilimumab at melanoma 3 mg/kg every 21 days for a total of four doses. Treatment Duration: Until disease progression. Metastatic Previously Phase II trial of Dosage Regimen: treated Abraxane (R) plus Avastin (Arm 1) Abraxane (R) at in 1 line BRAF wild 150 mg/mon days 1, 8, type patient with and 15 in combination metastatic melanoma with Bevacizumab at 10 mg/kg on days 1 and 8 for every 28 day cycle vs. (Arm 2) Ipilimumab at 3 mg/kg on day 1 every 3 weeks for a total of four doses. Treatment Duration: Abraxane (R) and Bevacizumab treatment until disease progression. Metastatic NA A pilot study of the Dosage Regimen: Temozolomide combination of Nab- 28 day cycle: Abraxane (R) Bevacizumab paclitaxel, on days 1, 8, and 15 in Temozolomide and combination with Bevacizumab in patients Temozolomide on days 1 with metastatic o 5, and Bevacizumab at melanoma with brain O mg/kg every 2 weeks. metastases Treatment Duration: Until disease progression or intolerance. NA A phase II randomized, Dosage Regimen: Ipilimumab open-label, trial of (Cohort 1) Abraxane (R) at Ipilimumab and Nab- 50 mg/m on days 1 and paclitaxel in treatment of 8 every three weeks for a naive patients with otal of two cycles unresectable or ollowed by Ipilimumab metastatic melanoma at 10 mg/kg every three weeks for a total of four cycles; (Cohort 2) pilimumab at 10 mg/kg every three weeks for a otal of two cycles ollowed by Abraxane (R) at 150 mg/m’on days 1 and 8 for a total of two cycles followed by pilimumab at 10 mg/kg every three weeks for a otal of two cycles. Stage IV NA Dosage Regimen: Vemurafenib 28 day cycle: Abraxane (R) at 100 mg/m on days 1, 8, and 15 in combination with Vemurafenib at 960 mg twice a day. Treatment Duration: Until disease progression. US 9,149,455 B2 67 68 TABLE 4-continued Clinical studies with Nab-paclitaxel (or Abraxane & Melanoma Patient Line of Combination Setting Treatment Clinical Trial Title Study Design Treatment Stage IV NA Phase III trial of Dosage Regimen: Trametinib GSK1120212 and Nab- Abraxane (R) in paclitaxel in metastatic combination with melanoma Trametinib. Stage IV NA A Phase III trial of Dosage Regimen: TH-302 Abraxane (R) in Abraxane (R) in combination with TH- combination with TH-302 302 in patients with advanced melanoma Stage IV Previously Targeted nanoparticle Dosage Regimen: Bevacizumab Treated therapy for advanced 28 day cycle (+/-3 days): melanoma: Nab-paclitaxel Abraxane (R) at 125 mg/m2 (Abraxane (R/Bevacizumab in combination with complex (nano AB)) bevacizumab 50 mg/m2 on days 1, 8, and 15. Treatment Duration: Until disease progression, patient refusal, or unacceptable toxicity. Dosage Escalation Regimen: 28 day cycle (+/-days): Abraxane (R) at 75, 100, 25, 150, or 175 mg/m2 in combination with Bevacizumab 30, 40, 50, 60, or 70 mg/m2 on days , 8, and 15, respectively. Treatment Duration: Until isease progression, patient refusal, or unacceptable toxicity.

35 In some embodiments, there is provided a method of treat 1.5xULN, 1.1-2xULN, or 1.5-2xULN. In some embodi ing melanoma in an individual (e.g., human) comprising ments, the individual has serum LDH of less than about administering to the individual a) an effective amount of a 0.8xULN. In some embodiments, the individual has serum composition comprising nanoparticles comprising a taxane LDH at about 0.8.x to about 1.1 xULN. In some embodiments, (e.g., paclitaxel) and a carrier protein (e.g., albumin), and b) 40 the individual has serum LDH of between greater than about Surgery, , or a combination of Surgery and 1.1.x to about 2.0xULN. In some embodiments, the individual radiation therapy. In some embodiments, the individual has has serum LDH of between about 1.1.x to about 2.0xULN. In stage IV or metastatic melanoma (e.g., stage IV or metastatic Some embodiments, the individual is a human (e.g., male or cutaneous melanoma). In some embodiments, the melanoma female). In some embodiments, the taxane is paclitaxel. In is metastatic malignant melanoma. In some embodiments, the 45 Some embodiments, the carrier protein is albumin. metastatic melanoma is at stage M1a, stage M1b, or stage In some embodiments, there is a method of treating mela M1 c. In some embodiments, the metastatic melanoma is at noma (Such as metastatic melanoma) in a human individual, stage M1c. In some embodiments, the melanoma comprises a comprising administering to the individual a) an effective mutation in BRAF. In some embodiments, the melanoma amount of a composition comprising nanoparticles compris does not comprise a mutation in BRAF. In some embodi- 50 ing paclitaxel and an albumin, and b) an effective amount of ments, the melanoma does not comprise BRAF mutant Such bevacizumab. In some embodiments, there is a method of as a BRAF mutant with increased activity (for example, treating melanoma (Such as metastatic melanoma) in a human increased kinase activity, and/or increased activity as com individual, comprising administering to the individual a) an pared to wild-type BRAF) or a BRAF gain-of-function effective amount of a composition comprising nanoparticles mutant. In some embodiments, the melanoma does not com- 55 comprising paclitaxel and an albumin, and b) an effective prise BRAF V600E mutation (e.g., the melanoma comprises amount of bevacizumab, wherein the dose of the nanoparticle wild-type BRAF). In some embodiments, the melanoma composition is between about 50 mg/m to about 200 mg/m comprises wild-type BRAF. In some embodiments, the mela (such as, for example, between about 100 mg/m to about 150 noma comprises a BRAF mutant such as a BRAF mutant with mg/m, and for example about 100 mg/m), and wherein the increased activity (for example, increased kinase activity, 60 dose of bevacizumab is between about 5 mg/kg to about 15 and/or increased activity as compared to wild-type BRAF) or mg/kg (Such as, for example, between about 8 mg/kg to about a BRAF gain-of-function mutant. In some embodiments, the 12 mg/kg, and for example about 10 mg/kg). In some embodi melanoma comprises BRAF V600E mutation. In some ments, there is a method of treating melanoma (Such as meta embodiments, the individual has elevated serum LDH level. static melanoma) in a human individual, comprising admin In some embodiments, the individual has serum LDH of 65 istering to the individual a) an effective amount of a about any of the following: <0.8xULN, 0.4–0.8xULN, 0.8- composition comprising nanoparticles comprising paclitaxel 1.1XULN, 0.9-1.1XULN, 0.8-1.2xULN, 1.1-1.5xULN, 1.2- and an albumin, and b) an effective amount of bevacizumab, US 9,149,455 B2 69 70 wherein the dose of the nanoparticle composition is between comprising nanoparticles comprising paclitaxel and an albu about 50 mg/m to about 200 mg/m (such as, for example, min, wherein the dose of the nanoparticle composition is between about 100 mg/m to about 150 mg/m, and for between about 100 mg/m to about 150 mg/m, and b) an example about 100 mg/m), wherein the dose of the nanopar effective amount of a BRAF inhibitor (such as, for example, ticle composition is administered on days 1, 8, and 15 of a 28 5 Vemurafenib (Zelboraf)). In some embodiments, there is pro day cycle, wherein the dose of bevacizumab is between about vided a method of treating melanoma (such as metastatic 5 mg/kg to about 15 mg/kg (such as, for example, between melanoma) in a human individual, comprising administering about 8 mg/kg to about 12 mg/kg, and for example about 10 to the individual a) an effective amount of a composition mg/kg), and wherein the dose of bevacizumab is administered comprising nanoparticles comprising paclitaxel and an albu on days 1 and 15 of a 28 day cycle. In some embodiments, 10 min, wherein the dose of the nanoparticle composition is there is a method of treating melanoma (Such as metastatic about 100 mg/m, and b) an effective amount of a BRAF melanoma) in a human individual, comprising administering inhibitor (such as, for example, Vemurafenib). In some to the individual a) an effective amount of a composition embodiments, there is provided a method of treating mela comprising nanoparticles comprising paclitaxel and an albu noma (Such as metastatic melanoma) in a human individual, min, and b) an effective amount of bevacizumab, wherein the 15 comprising administering to the individual a) an effective dose of the nanoparticle composition is about 100 mg/m and amount of a composition comprising nanoparticles compris is administered intravenously on days 1, 8, and 15 of a 28 day ing paclitaxel and an albumin, wherein the dose of the nano cycle, and wherein the dose of bevacizumab is about 10 particle composition is about 100 mg/m, wherein the nano mg/kg and is administered intravenously on days 1 and 15 of particle composition is administered on days 1, 8, and 15 of a a 28 day cycle. In some embodiments, there is a method of 28 day cycle, and b) an effective amount of a BRAF inhibitor treating melanoma (Such as metastatic melanoma) in a human (such as, for example, Vemurafenib). In some embodiments, individual, comprising administering to the individual a) an there is provided a method of treating melanoma (Such as effective amount of a composition comprising nanoparticles metastatic melanoma) in a human individual, comprising comprising paclitaxel and an albumin, and b) an effective administering to the individual a) an effective amount of a amount of bevacizumab, wherein the dose of the nanoparticle 25 composition comprising nanoparticles comprising paclitaxel composition is about 100 mg/m and is administered intrave and an albumin, wherein the dose of the nanoparticle compo nously over 30 minutes on days 1, 8, and 15 of a 28 day cycle, sition is about 100 mg/m, wherein the nanoparticle compo wherein the dose of bevacizumab is about 10 mg/kg and is sition is administered intravenously over 30 minutes on days administered intravenously over 90 minutes on days 1 and 15 1, 8, and 15 of a 28 day cycle, and b) an effective amount of a of a 28 day cycle. In some embodiments, the individual is 30 BRAF inhibitor (such as, for example, Vemurafenib). In some chemotherapy naive. In some embodiments, the individual embodiments, the individual is chemotherapy naive. In some has previously been treated for melanoma. In some embodi embodiments, the individual has previously been treated for ments, the individual is at stage IV melanoma. In some melanoma. In some embodiments, the individual is at stage embodiments, the individual is at Stage M1c melanoma. In IV melanoma. In some embodiments, the individual is at Some embodiments, the individual comprises wild-type 35 stage M1c melanoma. In some embodiments, the individual BRAF. In some embodiments, the individual comprises a comprises wild-type BRAF. In some embodiments, the indi BRAF mutation (such as a BRAF V600E mutation). In some vidual comprises a BRAF mutation (such as a BRAF V600E embodiments, the individual is a male. In some embodiments, mutation). In some embodiments, the individual is a male. In the individual is a female. In some embodiments, the indi Some embodiments, the individual is a female. In some vidual is a human who is at least 65 years old (including for 40 embodiments, the individual is a human who is at least 65 example at least 70, 75, or 80 years old). In some embodi years old (including for example at least 70, 75, or 80 years ments, the individual is a human who is less than 65 years old old). In some embodiments, the individual is a human who is (including for example less than 60, 50, or 40 years old). In less than 65 years old (including for example less than 60, 50. some embodiments, the individual has a normal LDH level. In or 40 years old). In some embodiments, the individual has a some embodiments, the individual has an elevated LDH level. 45 normal LDH level. In some embodiments, the individual has In some embodiments, there is provided a method of treat an elevated LDH level. ing melanoma (Such as metastatic melanoma) in a human In some embodiments, there is provided a method of treat individual, comprising administering to the individual a) an ing melanoma (Such as metastatic melanoma) in a human effective amount of a composition comprising nanoparticles individual, comprising administering to the individual a) an comprising paclitaxel and an albumin, and b) an effective 50 effective amount of a composition comprising nanoparticles amount of a BRAF inhibitor. Suitable BRAF inhibitors comprising paclitaxel and an albumin, and b) an effective include, for example, Vemurafenib (Zelboraf), GDC-0879, amount of another chemotherapeutic agent, wherein the indi PLX-4720, Dabrafenib (or GSK21 18436), LGX 818, CEP vidual has been previously treated for the melanoma with at 32496, UI-152, RAF 265, Regorafenib (BAY 73-4506), least one BRAF inhibitor (such as, for example, Vemurafenib CCT239065, or Sorafenib (or Sorafenib Tosylate, or Nexa 55 (Zelboraf) or Sorafenib), and wherein the individual is sub var(R). In some embodiments, there is provided a method of stantially refractory to prior treatment with a BRAF inhibitor. treating melanoma (Such as metastatic melanoma) in a human In some embodiments, there is provided a method of treating individual, comprising administering to the individual a) an melanoma (Such as metastatic melanoma) in a human indi effective amount of a composition comprising nanoparticles vidual, comprising administering to the individuala) an effec comprising paclitaxel and an albumin, wherein the dose of the 60 tive amount of a composition comprising nanoparticles com nanoparticle composition is between about 50 mg/m to about prising paclitaxel and an albumin, wherein the dose of the 200 mg/m, and b) an effective amount of a BRAF inhibitor nanoparticle compositionis between about 50 mg/m to about (such as, for example, Vemurafenib (Zelboraf), Dabrafenib, 200 mg/m, and b) an effective amount of another chemo Regorafenib, or Sorafenib). In some embodiments, there is therapeutic agent, wherein the individual has been previously provided a method of treating melanoma (such as metastatic 65 treated for the melanoma with at least one BRAF inhibitor melanoma) in a human individual, comprising administering (such as, for example, Vemurafenib (Zelboraf) or Sorafenib), to the individual a) an effective amount of a composition and wherein the individual is substantially refractory to prior US 9,149,455 B2 71 72 treatment with a BRAF inhibitor. In some embodiments, example, Vemurafenib (Zelboraf) or Sorafenib), and wherein there is provided a method of treating melanoma (Such as the individual is substantially refractory to prior treatment metastatic melanoma) in a human individual, comprising with a BRAF inhibitor. In some embodiments, there is pro administering to the individual a) an effective amount of a vided a method of treating melanoma (such as metastatic composition comprising nanoparticles comprising paclitaxel melanoma) in a human individual, comprising administering and an albumin, wherein the dose of the nanoparticle compo to the individual an effective amount of a composition com sition is between about 100 mg/m to about 150 mg/m, and prising nanoparticles comprising paclitaxel and an albumin, b) an effective amount of another chemotherapeutic agent, wherein the dose of the nanoparticle composition is between wherein the individual has been previously treated for the about 100 mg/m to about 150 mg/m, wherein the individual melanoma with at least one BRAF inhibitor (such as, for 10 has been previously treated for the melanoma with at least one example, Vemurafenib (Zelboraf) or Sorafenib), and wherein BRAF inhibitor (such as, for example, Vemurafenib (Zelbo the individual is substantially refractory to prior treatment raf) or Sorafenib), and wherein the individual is substantially with a BRAF inhibitor. In some embodiments, there is pro refractory to prior treatment with a BRAF inhibitor. In some vided a method of treating melanoma (Such as metastatic embodiments, there is provided a method of treating mela melanoma) in a human individual, comprising administering 15 noma (Such as metastatic melanoma) in a human individual, to the individual a) an effective amount of a composition comprising administering to the individual an effective comprising nanoparticles comprising paclitaxel and an albu amount of a composition comprising nanoparticles compris min, wherein the dose of the nanoparticle composition is ing paclitaxel and an albumin, wherein the dose of the nano about 100 mg/m, and b) an effective amount another chemo particle composition is about 100 mg/m, wherein the indi therapeutic agent, wherein the individual has been previously vidual has been previously treated for the melanoma with at treated for the melanoma with at least one BRAF inhibitor least one BRAF inhibitor (such as, for example, Vemurafenib (such as, for example, Vemurafenib (Zelboraf) or Sorafenib), (Zelboraf) or Sorafenib), and wherein the individual is sub and wherein the individual is substantially refractory to prior stantially refractory to prior treatment with a BRAF inhibitor. treatment with a BRAF inhibitor. In some embodiments, In some embodiments, there is provided a method of treating there is provided a method of treating melanoma (Such as 25 melanoma (Such as metastatic melanoma) in a human indi metastatic melanoma) in a human individual, comprising vidual, comprising administering to the individual an effec administering to the individual a) an effective amount of a tive amount of a composition comprising nanoparticles com composition comprising nanoparticles comprising paclitaxel prising paclitaxel and an albumin, wherein the dose of the and an albumin, wherein the dose of the nanoparticle compo nanoparticle composition is about 100 mg/m, wherein the sition is about 100 mg/m, wherein the nanoparticle compo 30 nanoparticle composition is administered on days 1, 8, and 15 sition is administered on days 1, 8, and 15 of a 28 day cycle, of a 28 day cycle, wherein the individual has been previously and b) an effective amount of another chemotherapeutic treated for the melanoma with at least one BRAF inhibitor agent, wherein the individual has been previously treated for (such as, for example, Vemurafenib (Zelboraf) or Sorafenib), the melanoma with at least one BRAF inhibitor (such as, for and wherein the individual is substantially refractory to prior example, Vemurafenib (Zelboraf) or Sorafenib), and wherein 35 treatment with a BRAF inhibitor. In some embodiments, the the individual is substantially refractory to prior treatment individual is at Stage IV melanoma. In some embodiments, with a BRAF inhibitor. In some embodiments, the individual the individual is at stage M1c melanoma. In some embodi is at stage IV melanoma. In some embodiments, the indi ments, the individual comprises wild-type BRAF. In some vidual is at stage M1c melanoma. In some embodiments, the embodiments, the individual comprises a BRAF mutation individual comprises wild-type BRAF. In some embodi 40 (such as a BRAF V600E mutation). In some embodiments, ments, the individual comprises a BRAF mutation (such as a the individual is a male. In some embodiments, the individual BRAF V600E mutation). In some embodiments, the indi is a female. In some embodiments, the individual is a human vidual is a male. In some embodiments, the individual is a who is at least 65 years old (including for example at least 70, female. In some embodiments, the individual is a human who 75, or 80 years old). In some embodiments, the individual is is at least 65 years old (including for example at least 70, 75, 45 a human who is less than 65 years old (including for example or 80 years old). In some embodiments, the individual is a less than 60, 50, or 40 years old). In some embodiments, the human who is less than 65 years old (including for example individual has a normal LDH level. In some embodiments, the less than 60, 50, or 40 years old). In some embodiments, the individual has an elevated LDH level. individual has a normal LDH level. In some embodiments, the In some embodiments, there is provided a method of treat individual has an elevated LDH level. 50 ing melanoma (Such as metastatic melanoma) in a human In some embodiments, there is provided a method of treat individual, comprising administering to the individual a) an ing melanoma (Such as metastatic melanoma) in a human effective amount of a composition comprising nanoparticles individual, comprising administering to the individual an comprising paclitaxel and an albumin, and b) an effective effective amount of a composition comprising nanoparticles amount of Ipilimumab. In some embodiments, there is pro comprising paclitaxel and an albumin, wherein the individual 55 vided a method of treating melanoma (such as metastatic has been previously treated for the melanoma with at least one melanoma) in a human individual, comprising administering BRAF inhibitor (such as, for example, Vemurafenib (Zelbo to the individual a) an effective amount of a composition raf) or Sorafenib), and wherein the individual is substantially comprising nanoparticles comprising paclitaxel and an albu refractory to prior treatment with a BRAF inhibitor. In some min, wherein the dose of the nanoparticle composition is embodiments, there is provided a method of treating mela 60 between about 50 mg/m to about 200 mg/m, and b) an noma (such as metastatic melanoma) in a human individual, effective amount of Ipilimumab, wherein the dose of Ipili comprising administering to the individual an effective mumab is between about 1 mg/kg to about 5 mg/kg. In some amount of a composition comprising nanoparticles compris embodiments, there is provided a method of treating mela ing paclitaxel and an albumin, wherein the dose of the nano noma (Such as metastatic melanoma) in a human individual, particle composition is between about 50 mg/m to about 200 65 comprising administering to the individual a) an effective mg/m, wherein the individual has been previously treated for amount of a composition comprising nanoparticles compris the melanoma with at least one BRAF inhibitor (such as, for ing paclitaxel and an albumin, wherein the dose of the nano

US 9,149,455 B2 75 76 comprising paclitaxel and an albumin, b) an effective amount ments, the individual is a human who is less than 65 years old of Ipilimumab, and c) an effective amount of bevacizumab. In (including for example less than 60, 50, or 40 years old). In Some embodiments, there is provided a method of treating some embodiments, the individual has a normal LDH level. In melanoma (Such as metastatic melanoma) in a human indi some embodiments, the individual has an elevated LDH level. vidual, comprising administering to the individuala) an effec 5 In some embodiments, there is provided a method of treat tive amount of a composition comprising nanoparticles com ing melanoma (Such as metastatic melanoma) in a human prising paclitaxel and an albumin, b) an effective amount of individual, comprising administering to the individual a) an Ipilimumab, and c) an effective amount of bevacizumab, effective amount of a composition comprising nanoparticles wherein the dose of the nanoparticle composition is between comprising paclitaxel and an albumin, b) an effective amount about 50 mg/m to about 200 mg/m, wherein the dose of 10 of Ipilimumab, c) an effective amount of bevacizumab, and d) Ipilimumab is between about 1 mg/kg to about 5 mg/kg, and an effective amount oftemozolomide. In some embodiments, wherein the dose of bevacizumab is between about 5 mg/kg to there is provided a method of treating melanoma (Such as 15 mg/kg. In some embodiments, there is provided a method metastatic melanoma) in a human individual, comprising of treating melanoma (such as metastatic melanoma) in a administering to the individual a) an effective amount of a human individual, comprising administering to the individual 15 composition comprising nanoparticles comprising paclitaxel a) an effective amount of a composition comprising nanopar and an albumin, b) an effective amount of Ipilimumab, c) an ticles comprising paclitaxel and an albumin, b) an effective effective amount of bevacizumab, and d) an effective amount amount of Ipilimumab, and c) an effective amount of bevaci oftemozolomide, wherein the dose of the nanoparticle com Zumab, wherein the dose of the nanoparticle composition is position is between about 50 mg/m to about 200 mg/m. between about 100 mg/m to about 150 mg/m, wherein the (such as, for example, between about 100 mg/m to about 150 dose of Ipilimumab is between about 2 mg/kg to about 4 mg/m, and for example about 100 mg/m), wherein the dose mg/kg, and wherein the dose of bevacizumab is between of Ipilimumab is between about 1 mg/kg to about 5 mg/kg, about 8 mg/kg to 12 mg/kg. In some embodiments, there is (such as, for example, between about 2 mg/kg to about 4 provided a method of treating melanoma (such as metastatic mg/kg, and for example about 3 mg/kg), wherein the dose of melanoma) in a human individual, comprising administering 25 bevacizumab is between about 5 mg/kg to 15 mg/kg, (Such as, to the individual a) an effective amount of a composition for example, between about 7 mg/kg and 12 mg/kg, and for comprising nanoparticles comprising paclitaxel and an albu example about 10 mg/kg), and wherein the dose oftemoZo min, b) an effective amount of Ipilimumab, and c) an effective lomide is between about 25 mg/m and 125 mg/m. (such as, amount of bevacizumab, wherein the dose of the nanoparticle for example, between about 50 mg/m to about 100 mg/m. composition is about 100 mg/m, wherein the dose of Ipili 30 and for example about 75 mg/m). In some embodiments, mumab is about 3 mg/kg, and wherein the dose of the beva there is provided a method of treating melanoma (Such as cizumab is about 10 mg/kg. In some embodiments, there is metastatic melanoma) in a human individual, comprising provided a method of treating melanoma (such as metastatic administering to the individual a) an effective amount of a melanoma) in a human individual, comprising administering composition comprising nanoparticles comprising paclitaxel to the individual a) an effective amount of a composition 35 and an albumin, b) an effective amount of Ipilimumab, c) an comprising nanoparticles comprising paclitaxel and an albu effective amount of bevacizumab, and d) an effective amount min, b) an effective amount of Ipilimumab, and c) an effective oftemozolomide, wherein the dose of the nanoparticle com amount of bevacizumab, wherein the dose of the nanoparticle position is about 100 mg/m, wherein the dose of Ipilimumab composition is about 100 mg/m and is administered on days is about 3 mg/kg, wherein the dose of the bevacizumab is 1, 8, and 15 of a 28 day cycle, wherein the dose of Ipilimumab 40 about 10 mg/kg, and wherein the dose of temozolomide is is about 3 mg/kg and is administered on day 1 of a 21 day about 75 mg/m. In some embodiments, there is provided a cycle, and wherein the dose of bevacizumab is about 10 method of treating melanoma (such as metastatic melanoma) mg/kg and is administered on days 1 and 15 of a 28 day cycle. in a human individual, comprising administering to the indi In some embodiments, there is provided a method of treating vidual a) an effective amount of a composition comprising melanoma (Such as metastatic melanoma) in a human indi 45 nanoparticles comprising paclitaxel and an albumin, b) an vidual, comprising administering to the individuala) an effec effective amount of Ipilimumab, c) an effective amount of tive amount of a composition comprising nanoparticles com bevacizumab, and d) an effective amount of temozolomide, prising paclitaxel and an albumin, b) an effective amount of wherein the dose of the nanoparticle composition is about 100 Ipilimumab, and c) an effective amount of bevacizumab, mg/m and is administered on days 1, 8, and 15 of a 28 day wherein the dose of the nanoparticle composition is about 100 50 cycle, wherein the dose of Ipilimumab is about 3 mg/kg and mg/m and is administered intravenously on days 1,8, and 15 is administered on day 1 of a 21 day cycle, wherein the dose of a 28 day cycle, wherein the dose of Ipilimumab is about 3 of bevacizumab is about 10 mg/kg and is administered on mg/kg and is administered intravenously on day 1 of a 21 day days 1 and 15 of a 28 day cycle, and wherein the dose of cycle, and wherein the dose of bevacizumab is about 10 temozolomide is about 75 mg/m and is administered on days mg/kg and is administered intravenously on days 1 and 15 of 55 1 to 42. In some embodiments, there is provided a method of a 28 day cycle. In some embodiments, the individual is che treating melanoma (Such as metastatic melanoma) in a human motherapy naive. In some embodiments, the individual has individual, comprising administering to the individual a) an previously been treated for melanoma. In some embodi effective amount of a composition comprising nanoparticles ments, the individual is at stage IV melanoma. In some comprising paclitaxel and an albumin, b) an effective amount embodiments, the individual is at Stage M1c melanoma. In 60 of Ipilimumab, c) an effective amount of bevacizumab, and d) Some embodiments, the individual comprises wild-type an effective amount oftemozolomide, wherein the dose of the BRAF. In some embodiments, the individual comprises a nanoparticle composition is about 100 mg/m and is admin BRAF mutation (such as a BRAF V600E mutation). In some istered intravenously on days 1, 8, and 15 of a 28 day cycle, embodiments, the individual is a male. In some embodiments, wherein the dose of Ipilimumab is about 3 mg/kg and is the individual is a female. In some embodiments, the indi 65 administered intravenously on day 1 of a 21 day cycle, vidual is a human who is at least 65 years old (including for wherein the dose of bevacizumab is about 10 mg/kg and is example at least 70, 75, or 80 years old). In some embodi administered intravenously on days 1 and 15 of a 28 day US 9,149,455 B2 77 78 cycle, and wherein the dose of temozolomide is about 75 response rate of more than about any of 20%, 25%, 30%, mg/m and is administered on days 1 to 42. In some embodi 35%, 40%, 45%, 50%, 55%, 60%, 64%, 65%, 70%, 75%, ments, the individual is chemotherapy naive. In some 80%, 85%, or 90% among a population of individuals treated embodiments, the individual has previously been treated for with the taxane nanoparticle composition. Responses of an melanoma. In some embodiments, the individual is at stage 5 individual to the treatment of the methods described herein IV melanoma. In some embodiments, the individual is at can be determined using methods known in the field. stage M1c melanoma. In some embodiments, the individual In some embodiments, the amount of the composition is comprises wild-type BRAF. In some embodiments, the indi Sufficient to prolong progression-free Survival of the indi vidual comprises a BRAF mutation (such as a BRAF V600E vidual. In some embodiments, the amount of the composition mutation). In some embodiments, the individual is a male. In 10 is sufficient to prolong survival of the individual. In some Some embodiments, the individual is a female. In some embodiments, the amount of the composition is Sufficient to embodiments, the individual is a human who is at least 65 improve quality of life of the individual. In some embodi years old (including for example at least 70, 75, or 80 years ments, the amount of the composition (for example when old). In some embodiments, the individual is a human who is administered alone) is sufficient to produce clinical benefit of less than 65 years old (including for example less than 60, 50. 15 more than about any of 50%, 60%, 70%, or 77% among a or 40 years old). In some embodiments, the individual has a population of individuals treated with the taxane nanoparticle normal LDH level. In some embodiments, the individual has composition. an elevated LDH level. In some embodiments, the amount of the composition, first In some embodiments, the individual has stage IV or meta therapy, second therapy, or combination therapy is an amount static melanoma (e.g., stage IV or metastatic cutaneous mela Sufficient to decrease the size of a melanoma tumor, decrease noma). In some embodiments, the melanoma is metastatic the number of melanoma tumor cells, or decrease the growth malignant melanoma. In some embodiments, the metastatic rate of a melanoma tumor by at least about any of 10%, 20%, melanoma is at stage M1a, stage M1b, or stage M1c. In some 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% com embodiments, the metastatic melanoma is at stage M1c. In pared to the corresponding tumor size, number of melanoma Some embodiments, the melanoma comprises a mutation in 25 tumor cells, or tumor growth rate in the same individual prior BRAF. In some embodiments, the melanoma comprises one to treatment or compared to the corresponding activity in or more of the following BRAF mutations: R461 I, I462S, other individuals not receiving the treatment. Methods that G463E, G463V, G465A, G465E, G465V, G468A, G468E, can be used to measure the magnitude of this effectare known N580S, E585K, D593V, F594L G595R, L596V, T598I, in the field. V599D, V599E, V599K, V599R, K600E, or A727V. In some 30 In some embodiments, the amount of the taxane (e.g., embodiments, the melanoma does not comprise a mutation in paclitaxel) in the composition is below the level that induces BRAF. In some embodiments, the melanoma comprises a a toxicological effect (i.e., an effect above a clinically accept BRAF mutant such as a BRAF mutant with increased activity able level of toxicity) or is at a level where a potential side (for example, increased kinase activity, and/or increased effect can be controlled or tolerated when the composition is activity as compared to wild-type BRAF) or a BRAF gain 35 administered to the individual. of-function mutant. In some embodiments, the melanoma In some embodiments, the amount of the composition is does not comprise BRAF mutant such as a BRAF mutant with close to a maximum tolerated dose (MTD) of the composition increased activity (for example, increased kinase activity, following the same dosing regimen. In some embodiments, and/or increased activity as compared to wild-type BRAF) or the amount of the composition is more than about any of 80%, a BRAF gain-of-function mutant. In some embodiments, the 40 90%. 95%, or 98% of the MTD. melanoma comprises a BRAF mutant such as a BRAF mutant In some embodiments, the amount of a taxane (e.g., pacli with decreased activity (for example, decreased kinase activ taxel) in the composition is included in any of the following ity, and/or decreased activity as compared to wild-type ranges: about 0.1 mg to about 500 mg, about 0.1 mg to about BRAF) or a BRAF loss-of-function mutant. In some embodi 2.5 mg, about 0.5 to about 5 mg, about 5 to about 10 mg, about ments, the melanoma comprises a constitutively active 45 10 to about 15 mg, about 15 to about 20 mg, about 20 to about BRAF. In some embodiments, the melanoma does not com 25 mg, about 20 to about 50 mg, about 25 to about 50 mg. prise a constitutively active BRAF. In some embodiments, the about 50 to about 75 mg, about 50 to about 100 mg, about 75 melanoma comprises a BRAF V600E mutation. In some to about 100 mg, about 100 to about 125 mg, about 125 to embodiments, the melanoma does not comprise a BRAF about 150 mg, about 150 to about 175 mg, about 175 to about V600E mutation (e.g., the melanoma comprises wild-type 50 200 mg, about 200 to about 225 mg, about 225 to about 250 BRAF). In some embodiments, the melanoma comprises mg, about 250 to about 300 mg, about 300 to about 350 mg. wild-type BRAF. about 350 to about 400 mg, about 400 to about 450 mg. or Modes of Administration about 450 to about 500 mg. In some embodiments, the The dose of the taxane nanoparticle compositions admin amount of a taxane (e.g., paclitaxel) in the effective amount of istered to an individual (such as a human) may vary with the 55 the composition (e.g., a unit dosage form) is in the range of particular composition, the mode of administration, and the about 5 mg to about 500 mg, such as about 30 mg to about 300 type of melanoma described herein being treated. The dose of mg or about 50 mg to about 200 mg. In some embodiments, the taxane nanoparticle compositions administered to an indi the concentration of the taxane (e.g., paclitaxel) in the com vidual (Such as a human) may also be adjusted (such as position is dilute (about 0.1 mg/ml) or concentrated (about reduced) based on an individual’s symptoms (such as adverse 60 100 mg/ml), including for example any of about 0.1 to about reactions). In some embodiments, the amount of the compo 50 mg/ml, about 0.1 to about 20 mg/ml, about 1 to about 10 sition is effective to result in a response. In some embodi mg/ml, about 2 mg/ml to about 8 mg/ml, about 4 to about 6 ments, the amount of the composition is effective to result in mg/ml, or about 5 mg/ml. In some embodiments, the concen an objective response (such as a partial response or a com tration of the taxane (e.g., paclitaxel) is at least about any of plete response). In some embodiments, the amount of the 65 0.5 mg/ml, 1.3 mg/ml, 1.5 mg/ml, 2 mg/ml, 3 mg/ml. 4 taxane nanoparticle composition administered (for example mg/ml, 5 mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml, 10 when administered alone) is sufficient to produce an overall mg/ml, 15 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml. 40 mg/ml. US 9,149,455 B2 79 80 or 50 mg/ml. In some embodiments, the concentration of the daily, every two days, every three days, every four days, every taxane (e.g., paclitaxel) is no more than about any of 100 five days, every six days, weekly withoutbreak, weekly for mg/ml, 90 mg/ml, 80 mg/ml, 70 mg/ml, 60 mg/ml, 50 mg/ml, three out of four weeks, once every three weeks, once every 40 mg/ml, 30 mg/ml, 20 mg/ml, 10 mg/ml, or 5 mg/ml. two weeks, or two out of three weeks. In some embodiments, Exemplary effective amounts of a taxane (e.g., paclitaxel) 5 the composition is administered about once every 2 weeks, in the nanoparticle composition include, but are not limited once every 3 weeks, once every 4 weeks, once every 6 weeks, to, at least about any of 25 mg/m, 30 mg/m, 50 mg/m, 60 or once every 8 weeks. In some embodiments, the composi mg/m, 75 mg/m, 80 mg/m, 90 mg/m, 100 mg/m, 120 tion is administered at least about any of 1x, 2x, 3x, 4x, 5x, mg/m, 125 mg/m, 150 mg/m, 160 mg/m, 175 mg/m, 180 6x, or 7x (i.e., daily) a week. In some embodiments, the mg/m,200 mg/m, 210 mg/m, 220 mg/m,250 mg/m,260 10 intervals between each administration are less than about any mg/m,300 mg/m,350 mg/m, 400 mg/m, 500 mg/m, 540 of 6 months, 3 months, 1 month, 20 days, 15, days, 14 days, mg/m, 750 mg/m, 1000 mg/m, or 1080 mg/m of a taxane 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 (e.g., paclitaxel). In various embodiments, the composition days, 5 days, 4 days, 3 days, 2 days, or 1 day. In some includes less than about any of 350 mg/m, 300 mg/m, 250 embodiments, the intervals between each administration are mg/m, 200 mg/m, 150 mg/m, 120 mg/m, 100 mg/m, 90 15 more than about any of 1 month, 2 months, 3 months, 4 mg/m, 50 mg/m, or 30 mg/m of a taxane (e.g., paclitaxel). months, 5 months, 6 months, 8 months, or 12 months. In some In some embodiments, the amount of the taxane (e.g., pacli embodiments, there is no break in the dosing schedule. In taxel) per administration is less than about any of 25 mg/m. Some embodiments, the interval between each administration 22 mg/m. 20 mg/m, 18 mg/m, 15 mg/m, 14 mg/m, 13 is no more than about a week. mg/m, 12 mg/m, 11 mg/m, 10 mg/m.9 mg/m, 8 mg/m. In some embodiments, the dosing frequency is once every 7 mg/m, 6 mg/m, 5 mg/m, 4 mg/m, 3 mg/m, 2 mg/m, or two days for one time, two times, three times, four times, five 1 mg/m. In some embodiments, the effective amount of a times, six times, seven times, eight times, nine times, ten taxane (e.g., paclitaxel) in the composition is included in any times, and eleven times. In some embodiments, the dosing of the following ranges: about 1 to about 5 mg/m, about 5 to frequency is once every two days for five times. In some about 10 mg/m, about 10 to about 25 mg/m, about 25 to 25 embodiments, the taxane (e.g., paclitaxel) is administered about 50 mg/m, about 50 to about 75 mg/m, about 75 to overa period of at least ten days, wherein the interval between about 100 mg/m, about 100 to about 125 mg/m, about 100 each administration is no more than about two days, and to about 200 mg/m, about 125 to about 150 mg/m, about wherein the dose of the taxane (e.g., paclitaxel) at each 125 to about 175 mg/m, about 150 to about 175 mg/m, administration is about 0.25 mg/m to about 250 mg/m. about 175 to about 200 mg/m, about 200 to about 225 30 about 0.25 mg/m to about 150 mg/m, about 0.25 mg/m to mg/m, about 225 to about 250 mg/m, about 250 to about about 75 mg/m, such as about 0.25 mg/m to about 25 300 mg/m, about 300 to about 350 mg/m, or about 350 to mg/m, about 25 mg/m to about 50 mg/m, or about 50 about 400 mg/m. In some embodiments, the effective mg/m to about 100 mg/m. amount of a taxane (e.g., paclitaxel) in the composition is The administration of the composition can be extended included in any of the following ranges: about 10 mg/m to 35 over an extended period of time, such as from about a month about 400 mg/m, about 25 mg/m to about 400 mg/m, about up to about seven years. In some embodiments, the compo 50 mg/m to about 400 mg/m, about 75 mg/m to about 350 sition is administered over a period of at least about any of 2. mg/m, about 75 mg/m to about 300 mg/m, about 75 mg/m 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 36, 48, 60, 72, or 84 to about 250 mg/m, about 75 mg/m to about 200 mg/m. months. about 75 mg/m to about 150 mg/m, about 75 mg/m to about 40 In some embodiments, the dosage of a taxane (e.g., pacli 125 mg/m, about 100 mg/m to about 260 mg/m, about 100 taxel) in a nanoparticle composition can be in the range of mg/m to about 250 mg/m, about 100 mg/m to about 200 5-400 mg/m when given on a 3 week schedule, or 5-250 mg/m, or about 125 mg/m to about 175 mg/m. In some mg/m (such as 75-200 mg/m, 100-200 mg/m, for example embodiments, the effective amount of a taxane (e.g., pacli 125-175 mg/m) when given on a weekly schedule. For taxel) in the composition is about 5 to about 300 mg/m, about 45 example, the amount of a taxane (e.g., paclitaxel) is about 60 100 to about 200 mg/m, about 100 to about 150 mg/m, to about 300 mg/m (e.g., about 100 mg/m, 125 mg/m, 150 about 50 to about 150 mg/m, about 75 to about 150 mg/m. mg/m, 175 mg/m, 200 mg/m, 225 mg/m, 250 mg/m, or about 75 to about 125 mg/m, or about 70 mg/m, about 80 260 mg/m) on a three week schedule. In some embodiments, mg/m, about 90 mg/m, about 100 mg/m, about 110 mg/m. the amount of a taxane (e.g., paclitaxel) is about 60 to about about 120 mg/m, about 130 mg/m, about 140 mg/m, about 50 300 mg/m (e.g., about 100 mg/m, 125 mg/m, 150 mg/m. 150 mg/m, about 160 mg/m, about 170 mg/m, about 180 175 mg/m, 200 mg/m, 225 mg/m, 250 mg/m, or 260 mg/m, about 190 mg/m, about 200 mg/m, about 250 mg/m) administered weekly. In some embodiments, the mg/m, about 260 mg/m, or about 300 mg/m. amount of a taxane (e.g., paclitaxel) is about 60 to about 300 In some embodiments of any of the above aspects, the mg/m (e.g., about 100 mg/m, 125 mg/m, 150 mg/m, 175 effective amount of a taxane (e.g., paclitaxel) in the compo 55 mg/m, 200 mg/m, 225 mg/m, 250 mg/m, or 260 mg/m) sition includes at least about any of 1 mg/kg, 2.5 mg/kg, 3.5 administered weekly for three out of a four week schedule. mg/kg, 5 mg/kg, 6.5 mg/kg, 7.5 mg/kg, 10 mg/kg, 15 mg/kg, Other exemplary dosing schedules for the administration 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 of the nanoparticle composition (e.g., paclitaxel/albumin mg/kg, 50 mg/kg, 55 mg/kg, or 60 mg/kg. In various embodi nanoparticle composition) include, but are not limited to, 100 ments, the effective amount of a taxane (e.g., paclitaxel) in the 60 mg/m, weekly, without break; 75 mg/m weekly, 3 out of composition includes less than about any of 350 mg/kg, 300 four weeks; 100 mg/m, weekly, 3 out of 4 weeks; 125 mg/m. mg/kg, 250 mg/kg, 200 mg/kg, 150 mg/kg, 100 mg/kg, 50 weekly, 3 out of 4 weeks; 150 mg/m, weekly, 3 out of 4 mg/kg, 25 mg/kg, 20 mg/kg, 10 mg/kg, 7.5 mg/kg, 6.5 mg/kg, weeks; 175 mg/m, weekly, 3 out of 4 weeks; 125 mg/m. 5 mg/kg, 3.5 mg/kg, 2.5 mg/kg, or 1 mg/kg of a taxane (e.g., weekly, 2 out of 3 weeks; 130 mg/m, weekly, withoutbreak; paclitaxel). 65 175 mg/m, once every 2 weeks; 260 mg/m, once every 2 Exemplary dosing frequencies for the administration of the weeks; 260 mg/m, once every 3 weeks; 180-300 mg/m. nanoparticle compositions include, but are not limited to, every three weeks; 60-175 mg/m, weekly, without break; US 9,149,455 B2 81 82 20-150 mg/m twice a week; and 150-250 mg/m twice a Some embodiments, the melanoma is metastatic malignant week. The dosing frequency of the composition may be melanoma. In some embodiments, the metastatic melanoma adjusted over the course of the treatment based on the judg is at stage M1a, stage M1b, or stage M1c. In some embodi ment of the administering . ments, the metastatic melanoma is at stage M1c. In some In some embodiments, the individual is treated for at least embodiments, the melanoma comprises a mutation in BRAF. about any of one, two, three, four, five, six, seven, eight, nine, In some embodiments, the melanoma does not comprise a or ten treatment cycles. mutation in BRAF. In some embodiments, the melanoma The compositions described herein allow infusion of the does not comprise BRAF mutant such as a BRAF mutant with composition to an individual over an infusion time that is increased activity (for example, increased kinase activity, shorter than about 24 hours. For example, in some embodi 10 and/or increased activity as compared to wild-type BRAF) or ments, the composition is administered over an infusion a BRAF gain-of-function mutant. In some embodiments, the period of less than about any of 24 hours, 12 hours, 8 hours, melanoma does not comprise BRAF V600E mutation (e.g., 5 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, or the melanoma comprises wild-type BRAF). In some embodi 10 minutes. In some embodiments, the composition is admin ments, the melanoma comprises wild-type BRAF. In some istered over an infusion period of about 30 minutes. 15 embodiments, the melanoma comprises a BRAF mutant Such Other exemplary doses of the taxane (in some embodi as a BRAF mutant with increased activity (for example, ments paclitaxel) in the nanoparticle composition include, but increased kinase activity, and/or increased activity as com is not limited to, about any of 50 mg/m, 60 mg/m, 75 pared to wild-type BRAF) or a BRAF gain-of-function mg/m, 80 mg/m, 90 mg/m, 100 mg/m, 120 mg/m, 140 mutant. In some embodiments, the melanoma comprises mg/m, 150 mg/m, 160 mg/m, 175 mg/m,200 mg/m,210 BRAF V600E mutation. In some embodiments, the indi mg/m, 220 mg/m, 260 mg/m, and 300 mg/m. For vidual has elevated serum LDH level. In some embodiments, example, the dosage of paclitaxel in a nanoparticle composi the individual has serum LDH of about any of the following: tion can be in the range of about 100-400 mg/m when given <0.8xULN, 0.4–0.8xULN, 0.8-1.1XULN, 0.9-1.1XULN, 0.8- on a 3 week schedule, or about 50-250 mg/m when given on 1.2xl JLN, 1.1-1.5xULN, 1.2-1.5xULN, 1.1-2xULN, or 1.5- a weekly schedule. 25 2xULN. In some embodiments, the individual has serum In some embodiments, there is provided a method of treat LDH of less than about 0.8xULN. In some embodiments, the ing melanoma in an individual (e.g., human) comprising individual has serum LDH at about 0.8.x to about 1.1 xULN. administering to the individual an effective amount of a com In some embodiments, the individual has serum LDH of position comprising nanoparticles comprising a taxane (e.g., between greater than about 1.1.x to about 2.0xULN. In some paclitaxel) and a carrier protein (e.g., albumin Such as human 30 embodiments, the individual has serum LDH of between serum albumin or human albumin), wherein the dose of tax about 1.1.x to about 2.0xULN. In some embodiments, the ane in the nanoparticle composition is between about 50 m individual is a human (e.g., male or female). In some embodi g/m to about 400 mg/m (including for example about 100 ments, the taxane is paclitaxel. In some embodiments, the mg/m to about 300 mg/m, about 100 mg/m to about 200 carrier protein is albumin. mg/m, or about 125 mg/m to about 175 mg/m). In some 35 The nanoparticle compositions can be administered to an embodiments, the effective amount of taxane in the nanopar individual (such as human) via various routes, including, for ticle composition is between about 100 mg/m to about 300 example, parenteral, intravenous, intraventricular, intra-arte mg/m (e.g., about 100 mg/m to about 200 mg/m). In some rial, intraperitoneal, intrapulmonary, oral, inhalation, intrave embodiments, the effective amount of taxane in the nanopar Sicular, intramuscular, intra-tracheal. Subcutaneous, ticle composition is between about 125 mg/m to about 175 40 intraocular, intrathecal, transmucosal, and transdermal. In mg/m (e.g., about 100 mg/m or about 150 mg/m). In some Some embodiments, Sustained continuous release formula embodiments, the nanoparticle composition is administered tion of the composition may be used. In some embodiments, weekly for three weeks of four weeks or weekly. In some the composition is administered intravenously. In some embodiments, the carrier protein is albumin Such as human embodiments, the composition is administered intraportally. serum albuminor human albumin. In some embodiments, the 45 In some embodiments, the composition is administered taxane is paclitaxel. intraarterially. In some embodiments, the composition is In some embodiments, there is provided a method of treat administered intraperitoneally. In some embodiments, the ing melanoma in an individual (e.g., human) comprising composition is administered intrathecally. In some embodi administering to the individual an effective amount of a com ments, the composition is administered through a ported cath position comprising nanoparticles comprising a taxane (e.g., 50 eter to spinal fluid. In some embodiments, the composition is paclitaxel) and a carrier protein (e.g., albumin Such as human administered intraventricularly. In some embodiments, the serum albumin or human albumin), wherein the dose of tax composition is administered systemically. In some embodi ane in the nanoparticle composition is between about 50 m ments, the composition is administered by infusion. In some g/m to about 400 mg/m (including for example about 100 embodiments, the composition is administered by infusion mg/m to about 300 mg/m, about 100 mg/m to about 200 55 through implanted pump. In some embodiments, the compo mg/m, or about 125 mg/m to about 175 mg/m). In some sition is administered by a Ventricular catheter. In some embodiments, the effective amount of taxane in the nanopar embodiments, the composition is administered through a port ticle composition is between about 100 mg/m to about 300 or portacath. In some embodiments, the port or portacath is mg/m (e.g., about 100 mg/m to about 200 mg/m such as inserted into a vein (Such as jugular vein, Subclavian vein, or about 100 mg/m or about 150 mg/m). In some embodi 60 Superior Vena cava). ments, the effective amount of taxane in the nanoparticle The dosing regimens described herein apply to both mono composition is between about 100 mg/m to about 200 mg/m therapy and combination therapy settings. The modes of (e.g., about 100 mg/m or about 150 mg/m). In some administration for combination therapy methods are further embodiments, the nanoparticle composition is administered described below. weekly for three weeks of four weeks or weekly. In some 65 Modes of Administration for Combination Therapy embodiments, the individual has stage IV or metastatic mela Provided herein are modes and administrations for treat noma (e.g., stage IV or metastatic cutaneous melanoma). In ment melanomausing combination therapy. In some embodi US 9,149,455 B2 83 84 ments, there is provided a method of treating melanoma in an example for about any one of 1,2,3,4,5,6,7,8,9, 10, 11, or individual (e.g., human) comprising administering to the 12 months) after the termination of the administration of the individuala) an effective amount of a composition compris nanoparticle composition. In some embodiments, the admin ing nanoparticles comprising a taxane (e.g., paclitaxel) and a istration of the nanoparticle composition and the other agent carrier protein (e.g., albumin), and b) an effective amount of 5 stop at about the same time and the administration of the other at least one other agent (Such as a chemotherapeutic agent or agent is initiated after (for example after about any one of 1. immunotherapeutic agent). The modes and administrations 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or we months) the initiation of the for using a composition comprising nanoparticles comprising administration of the nanoparticle composition. a taxane (e.g., paclitaxel) and a carrier protein (e.g., albumin) In some embodiments, the administration of the nanopar and the other agent are described herein. 10 ticle composition and the other agent (e.g., carboplatin) are The composition comprising nanoparticles comprising concurrent, i.e., the administration period of the nanoparticle taxane (also referred to as "nanoparticle composition') and composition and that of the other agent overlap with each the other agent can be administered simultaneously (i.e., other. In some embodiments, the administrations of the nano simultaneous administration) and/or sequentially (i.e., particle composition and the other agent are initiated at about sequential administration). 15 the same time (for example, within any one of 1, 2, 3, 4, 5, 6, In some embodiments, the nanoparticle composition and or 7 days). In some embodiments, the administration of the the other agent (including the specific agents described nanoparticle composition and the other agent are terminated herein) are administered simultaneously. The term “simulta at about the same time (for example, within any one of 1,2,3, neous administration, as used herein, means that the nano 4, 5, 6, or 7 days). In some embodiments, the administration particle composition and the other agent are administered of the other agent continues (for example for about any one of with a time separation of no more than about 15 minute(s), 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) after the such as no more than about any of 10, 5, or 1 minutes. When termination of the administration of the nanoparticle compo the drugs are administered simultaneously, the drug in the sition. In some embodiments, the administration of the other nanoparticles and the other agent may be contained in the agent is initiated after (for example after about any one of 1. same composition (e.g., a composition comprising both the 25 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) the initiation of the nanoparticles and the other agent) or in separate compositions administration of the nanoparticle composition. In some (e.g., the nanoparticles are contained in one composition and embodiments, the administrations of the nanoparticle com the other agent is contained in another composition). position and the other agent are initiated and terminated at In some embodiments, the nanoparticle composition and about the same time. In some embodiments, the administra the other agent are administered sequentially. The term 30 tions of the nanoparticle composition and the other agent are "sequential administration' as used herein means that the initiated at about the same time and the administration of the drug in the nanoparticle composition and the other agent are other agent continues (for example for about any one of 1, 2, administered with a time separation of more than about 15 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) after the termination minutes, such as more than about any of 20, 30, 40, 50, 60 or of the administration of the nanoparticle composition. In more minutes. Either the nanoparticle composition or the 35 Some embodiments, the administration of the nanoparticle other agent may be administered first. The nanoparticle com composition and the other agent stop at about the same time position and the other agent are contained in separate com and the administration of the other agent is initiated after (for positions, which may be contained in the same or different example after about any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, packages. or 12 months) the initiation of the administration of the nano In some embodiments, the administration of the nanopar 40 particle composition. In some embodiments, the method ticle composition and the other agent are concurrent, i.e., the comprises more than one treatment cycles, wherein at least administration period of the nanoparticle composition and one of the treatment cycles comprise the administration of (a) that of the other agent overlap with each other. In some an effective amount of a composition comprising nanopar embodiments, the nanoparticle composition is administered ticles comprising a taxane (such as paclitaxel) and a carrier for at least one cycle (for example, at least any of 2, 3, or 4 45 protein (e.g., albumin); and (b) an effective amount of at least cycles) prior to the administration of the other agent. In some one other agent. In some embodiments, the treatment cycle embodiments, the other agent is administered for at least any comprises no less than about (such as about) 21 days (e.g., 4 of one, two, three, or four weeks. In some embodiments, the weeks). In some embodiments, the treatment cycle comprises administrations of the nanoparticle composition and the other less than about 21 days (for example weekly or daily). In agent are initiated at about the same time (for example, within 50 Some embodiments, the treatment cycle comprises about 28 any one of 1, 2, 3, 4, 5, 6, or 7 days). In some embodiments, days. the administrations of the nanoparticle composition and the In some embodiments, the administration of the nanopar other agent are terminated at about the same time (for ticle composition and the other agent are non-concurrent. For example, within any one of 1, 2, 3, 4, 5, 6, or 7 days). In some example, in Some embodiments, the administration of the embodiments, the administration of the other agent continues 55 nanoparticle composition is terminated before the other agent (for example for about any one of 1,2,3,4,5,6,7,8,9, 10, 11, is administered. In some embodiments, the administration of or 12 months) after the termination of the administration of the other agent is terminated before the nanoparticle compo the nanoparticle composition. In some embodiments, the sition is administered. The time period between these two administration of the other agent is initiated after (for non-concurrent administrations can range from about two to example after about any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 60 eight weeks, such as about four weeks. or we months) the initiation of the administration of the The dosing frequency of the drug-containing nanoparticle nanoparticle composition. In some embodiments, the admin composition and the other agent may be adjusted over the istrations of the nanoparticle composition and the other agent course of the treatment, based on the judgment of the admin are initiated and terminated at about the same time. In some istering physician. When administered separately, the drug embodiments, the administrations of the nanoparticle com 65 containing nanoparticle composition and the other agent can position and the other agent are initiated at about the same be administered at different dosing frequency or intervals. For time and the administration of the other agent continues (for example, the drug-containing nanoparticle composition can US 9,149,455 B2 85 86 be administered weekly, while another agent can be admin nanoparticle composition and/or the other agent is more than istered more or less frequently. In some embodiments, Sus about 50%, 40%, 30%, 20%, or 10% of the MTD of the agent tained continuous release formulation of the drug-containing when administered alone. nanoparticle and/or other agent may be used. Various formu In some embodiments, the amount of a taxane (e.g., pacli lations and devices for achieving Sustained release are known taxel) in the composition is included in any of the following in the art. Exemplary dosing frequencies are further provided ranges: about 0.5 to about 5 mg, about 5 to about 10 mg, about herein. 10 to about 15 mg, about 15 to about 20 mg, about 20 to about The nanoparticle composition and the other agent can be 25 mg, about 20 to about 50 mg, about 25 to about 50 mg. administered using the same route of administration or dif about 50 to about 75 mg, about 50 to about 100 mg, about 75 10 to about 100 mg, about 100 to about 125 mg, about 125 to ferent routes of administration. Exemplary administration about 150 mg, about 150 to about 175 mg, about 175 to about routes are further provided herein. In some embodiments (for 200 mg, about 200 to about 225 mg, about 225 to about 250 both simultaneous and sequential administrations), the tax mg, about 250 to about 300 mg, about 300 to about 350 mg. ane in the nanoparticle composition and the other agent are about 350 to about 400 mg, about 400 to about 450 mg. or administered at a predetermined ratio. For example, in some 15 about 450 to about 500 mg. In some embodiments, the embodiments, the ratio by weight of the taxane in the nano amount of a taxane (e.g., paclitaxel) or derivative thereof in particle composition and the other agent is about 1 to 1. In the effective amount of the composition (e.g., a unit dosage some embodiments, the weight ratio may be between about form) is in the range of about 5 mg to about 500 mg. Such as 0.001 to about 1 and about 1000 to about 1, or between about about 30 mg to about 300 mg or about 50 mg to about 200 mg. 0.01 to about 1 and 100 to about 1. In some embodiments, the In some embodiments, the concentration of the taxane (e.g., ratio by weight of the taxane in the nanoparticle composition paclitaxel) in the composition is dilute (about 0.1 mg/ml) or and the other agent is less than about any of 100:1, 50:1, 30:1. concentrated (about 100 mg/ml), including for example any 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, and 1:1 In some of about 0.1 to about 50 mg/ml, about 0.1 to about 20 mg/ml, embodiments, the ratio by weight of the taxane in the nano about 1 to about 10 mg/ml, about 2 mg/ml to about 8 mg/ml. particle composition and the other agent is more than about 25 about 4 to about 6 mg/ml, about 5 mg/ml. In some embodi any of 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 30:1, 50:1, ments, the concentration of the taxane (e.g., paclitaxel) is at 100:1. Other ratios are contemplated. least about any of 0.5 mg/ml, 1.3 mg/ml, 1.5 mg/ml, 2 mg/ml. The doses required for the taxane and/or the other agent 3 mg/ml. 4 mg/ml, 5 mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 may (but not necessarily) be lower than what is normally mg/ml, 10 mg/ml, 15 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml. required when each agent is administered alone. Thus, in 30 40 mg/ml, or 50 mg/ml. Some embodiments, a subtherapeutic amount of the drug in Exemplary effective amounts of a taxane (e.g., paclitaxel) the nanoparticle composition and/or the other agent are in the nanoparticle composition include, but are not limited administered. “Subtherapeutic amount’ or “subtherapeutic to, at least about any of 25 mg/m, 30 mg/m, 50 mg/m, 60 level” refer to an amount that is less than therapeutic amount, mg/m, 75 mg/m, 80 mg/m, 90 mg/m, 100 mg/m, 120 that is, less than the amount normally used when the drug in 35 mg/m, 125 mg/m, 150 mg/m, 160 mg/m, 175 mg/m, 180 the nanoparticle composition and/or the other agent are mg/m,200 mg/m, 210 mg/m, 220 mg/m,250 mg/m,260 administered alone. The reduction may be reflected in terms mg/m,300 mg/m,350 mg/m, 400 mg/m, 500 mg/m, 540 of the amount administered at a given administration and/or mg/m, 750 mg/m, 1000 mg/m, or 1080 mg/m of a taxane the amount administered over a given period of time (reduced (e.g., paclitaxel). In various embodiments, the composition frequency). 40 includes less than about any of 350 mg/m, 300 mg/m, 250 In some embodiments, enough other agent is administered mg/m, 200 mg/m, 150 mg/m, 120 mg/m, 100 mg/m, 90 so as to allow reduction of the normal dose of the drug in the mg/m, 50 mg/m, or 30 mg/m of a taxane (e.g., paclitaxel). nanoparticle composition required to effect the same degree In some embodiments, the amount of the taxane (e.g., pacli of treatment by at least about any of 5%, 10%, 20%, 30%, taxel) per administration is less than about any of 25 mg/m. 50%, 60%, 70%, 80%, 90%, or more. In some embodiments, 45 22 mg/m, 20 mg/m, 18 mg/m, 15 mg/m, 14 mg/m, 13 enough drug in the nanoparticle composition is administered mg/m, 12 mg/m, 11 mg/m, 10 mg/m.9 mg/m, 8 mg/m. So as to allow reduction of the normal dose of the other agent 7 mg/m, 6 mg/m, 5 mg/m, 4 mg/m, 3 mg/m, 2 mg/m, or required to effect the same degree of treatment by at least 1 mg/m. In some embodiments, the effective amount of a about any of 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, taxane (e.g., paclitaxel) in the composition is included in any 90%, or more. 50 of the following ranges: about 1 to about 5 mg/m, about 5 to In some embodiments, the dose of both the taxane in the about 10 mg/m, about 10 to about 25 mg/m, about 25 to nanoparticle composition and the other agent are reduced as about 50 mg/m, about 50 to about 75 mg/m, about 75 to compared to the corresponding normal dose of each when about 100 mg/m, about 100 to about 125 mg/m, about 125 administered alone. In some embodiments, both the taxane in to about 150 mg/m, about 150 to about 175 mg/m, about the nanoparticle composition and the other agent are admin 55 175 to about 200 mg/m, about 200 to about 225 mg/m. istered at a subtherapeutic, i.e., reduced, level. In some about 225 to about 250 mg/m, about 250 to about 300 embodiments, the dose of the nanoparticle composition and/ mg/m, about 300 to about 350 mg/m, or about 350 to about or the other agent is substantially less than the established 400 mg/m. In some embodiments, the effective amount of a maximum toxic dose (MTD). For example, the dose of the taxane (e.g., paclitaxel) in the composition is about 5 to about nanoparticle composition and/or the other agent is less than 60 300 mg/m, such as about 20 to about 300 mg/m, about 50 to about 50%, 40%, 30%, 20%, or 10% of the MTD. about 250 mg/m, about 100 to about 150 mg/m, about 120 In some embodiments, the dose of taxane and/or the dose mg/m, about 130 mg/m, or about 140 mg/m, or about 260 of the other agent is higher than what is normally required mg/m. when each agent is administered alone. For example, in some In some embodiments of any of the above aspects, the embodiments, the dose of the nanoparticle composition and/ 65 effective amount of a taxane (e.g., paclitaxel) in the compo or the other agent is substantially higher than the established sition includes at least about any of 1 mg/kg, 2.5 mg/kg, 3.5 maximum toxic dose (MTD). For example, the dose of the mg/kg, 5 mg/kg. 6.5 mg/kg, 7.5 mg/kg, 10 mg/kg, 15 mg/kg, US 9,149,455 B2 87 88 or 20 mg/kg. In various embodiments, the effective amount of amount of a taxane (e.g., paclitaxel) can be about 60 to about a taxane (e.g., paclitaxel) in the composition includes less 300 mg/m (e.g., about 260 mg/m) when given on a three than about any of 350 mg/kg, 300 mg/kg, 250 mg/kg, 200 week schedule. mg/kg, 150 mg/kg, 100 mg/kg, 50 mg/kg, 25 mg/kg, 20 Other exemplary dosing schedules for the administration mg/kg, 10 mg/kg, 7.5 mg/kg, 6.5 mg/kg, 5 mg/kg, 3.5 mg/kg, 5 of the nanoparticle composition (e.g., paclitaxel/albumin 2.5 mg/kg, or 1 mg/kg of a taxane (e.g., paclitaxel). nanoparticle composition) include, but are not limited to, 100 Exemplary dosing frequencies for the nanoparticle com mg/m, weekly, without break; 75 mg/m weekly, 3 out of position (and as indicated below for the other agent) include, four weeks; 100 mg/m, weekly, 3 out of4 weeks; 125 mg/m. but are not limited to, weekly withoutbreak; weekly, three out weekly, 3 out of 4 weeks; 125 mg/m, weekly, 2 out of 3 10 weeks; 130 mg/m, weekly, withoutbreak; 175 mg/m, once of four weeks; once every three weeks; once every two weeks: every 2 weeks; 260 mg/m, once every 2 weeks; 260 mg/m. weekly, two out of three weeks. In some embodiments, the once every 3 weeks; 180-300 mg/m, every three weeks; composition is administered about once every 2 weeks, once 60-175 mg/m, weekly, withoutbreak; 20-150 mg/m, twice every 3 weeks, once every 4 weeks, once every 6 weeks, or a week; and 150-250 mg/m twice a week. The dosing fre once every 8 weeks. In some embodiments, the composition 15 quency of the composition may be adjusted over the course of is administered at least about any of 1x, 2x, 3x, 4x, 5.x, 6.x, or the treatment based on the judgment of the administering 7x (i.e., daily) a week, or three times daily, two times daily. In physician. Some embodiments, the intervals between each administra In some embodiments, the individual is treated for at least tion are less than about any of 6 months, 3 months, 1 month, about any of one, two, three, four, five, six, seven, eight, nine, 20 days, 15 days, 12 days, 10 days, 9 days, 8 days, 7 days, 6 or ten treatment cycles. The compositions described herein days, 5 days, 4 days, 3 days, 2 days, or 1 day. In some allow infusion of the composition to an individual over an embodiments, the intervals between each administration are infusion time that is shorter than about 24 hours. For example, more than about any of 1 month, 2 months, 3 months, 4 in some embodiments, the composition is administered over months, 5 months, 6 months, 8 months, or 12 months. In some an infusion period of less than about any of 24 hours, 12 embodiments, there is no break in the dosing schedule. In 25 hours, 8 hours, 5 hours, 3 hours, 2 hours, 1 hour, 30 minutes, Some embodiments, the interval between each administration 20 minutes, or 10 minutes. In some embodiments, the com is no more than about a week. position is administered over an infusion period of about 30 In some embodiments, the taxane in the nanoparticle com minutes. position is administered weekly. In some embodiments, the Other exemplary dose of the taxane (in some embodiments taxane in a nanoparticle composition is administered every 30 paclitaxel) in the nanoparticle composition include, but is not two weeks. In some embodiments, the taxane in the nanopar limited to, about any of 50 mg/m, 60 mg/m, 75 mg/m, 80 ticle composition is administered every three weeks. In some mg/m, 90 mg/m, 100 mg/m, 120 mg/m, 160 mg/m, 175 embodiments, the other agent is administered 1x, 2x, 3x, 4x. mg/m,200 mg/m, 210 mg/m, 220 mg/m, 260 mg/m, and 5.x, 6x, or 7 times a week. In some embodiments, the other 300 mg/m. For example, the dosage of paclitaxel in a nano agent is administered every two weeks or two out of three 35 particle composition can be in the range of about 100-400 weeks. In some embodiments, the taxane is paclitaxel. In mg/m when given on a 3 week schedule, or about 50-250 Some embodiment, the other agent is a platinum-based agent mg/m when given on a weekly schedule. (such as carboplatin). In some embodiments of the above The dosage of the other agent (e.g., a platinum-based agent dosages and/or administrations, the taxane is paclitaxel and Such as carboplatin) may be determined using methods the other agent is carboplatin. 40 known in the field. For example, the dosage of the other agent The administration of the nanoparticle composition (and may be determined by calculating the area under the blood for the other agent) can be extended over an extended period plasma concentration curve (AUC) by methods known in the of time, such as from about a month up to about seven years. field, taking into account the individual’s creatinine clearance In some embodiments, the composition is administered over rate. The dosage of the other agent may be adjusted (e.g., a period of at least about any of 2,3,4,5,6,7,8,9, 10, 11, 12, 45 reduced) based on the individual’s symptoms (such as 18, 24, 30, 36, 48, 60, 72, or 84 months. In some embodi adverse reactions). In some embodiments, the dosage of the ments, the taxane (e.g., paclitaxel) is administered over a other agent for combination treatment along with the taxane period of at least one month, wherein the interval between nanoparticles is calculated to provide an AUC of about 0.1-10 each administration is no more than about a week, and mg/ml min, about 1-8 mg/ml min, about 1.5 to about 7.5 wherein the dose of the taxane (e.g., paclitaxel) at each 50 mg/ml min, about 2 to about 6 mg/ml minor about any of 1. administration is about 0.25 mg/m to about 75 mg/m, such 2, 3, 4, 5, 6, or 7 mg/ml min. The other agent Such as carbo as about 0.25 mg/m to about 25 mg/m or about 25 mg/m to platin may be administered systematically. The other agent about 50 mg/m. may be administered intravenously. The other agent may be The dosing frequency of the other agent (e.g., a platinum administered over a period of about 10 to about 300 minutes, based agent Such as carboplatin) can be the same or different 55 about 30 to about 180 minutes, about 45 to about 120 minutes from that of the nanoparticle composition. Exemplary fre or about 60 minutes. quencies are provided above. As further example, the other Other exemplary amounts of the other agent (e.g., a plati agent can be administered three times a day, two times a day, num-based agent such as carboplatin) include, but are not daily, 6 times a week, 5 times a week, 4 times a week, 3 times limited to, any of the following ranges: about 0.5 to about 5 a week, two times a week, weekly, weekly for two weeks of 60 mg, about 5 to about 10 mg, about 10 to about 15 mg, about 15 three weeks, or weekly for three weeks of four weeks. In some to about 20 mg, about 20 to about 25 mg, about 20 to about 50 embodiments, the other agent is administered twice daily or mg, about 25 to about 50 mg, about 50 to about 75 mg, about three times daily. 50 to about 100 mg, about 75 to about 100 mg, about 100 to In some embodiments, the dosage of a taxane (e.g., pacli about 125 mg, about 125 to about 150 mg, about 150 to about taxel) in a nanoparticle composition can be in the range of 65 175 mg, about 175 to about 200 mg, about 200 to about 225 5-400 mg/m when given on a 3 week schedule, or 5-250 mg, about 225 to about 250 mg, about 250 to about 300 mg. mg/m when given on a weekly schedule. For example, the about 300 to about 350 mg, about 350 to about 400 mg, about US 9,149,455 B2 89 90 400 to about 450 mg, or about 450 to about 500 mg. For about 40 mg/kg to about 60 mg/kg, about 60 mg/kg to about example, the other agent can be administered at a dose of 80 mg/kg, about 80 mg/kg to about 100 mg/kg, about 100 about 1 mg/kg to about 200 mg/kg (including for example mg/kg to about 120 mg/kg, about 120 mg/kg to about 140 about 1 mg/kg to about 20 mg/kg, about 20 mg/kg to about 40 mg/kg, about 140 mg/kg to about 200 mg/kg). In some mg/kg, about 40 mg/kg to about 60 mg/kg, about 60 mg/kg to embodiments, the effective amount of taxane in the nanopar about 80 mg/kg, about 80 mg/kg to about 100 mg/kg, about ticle composition is between about 80 mg/m to about 150 100 mg/kg to about 120 mg/kg, about 120 mg/kg to about 140 mg/m and the effective amount of the other agent is about 1 mg/kg, about 140 mg/kg to about 200 mg/kg). mg/kg to about 200 mg/kg (including for example about 1 The dosage of the other agent (e.g., carboplatin) may be mg/kg to about 20 mg/kg, about 20 mg/kg to about 40 mg/kg, determined by calculating the area under the blood plasma 10 about 40 mg/kg to about 60 mg/kg, about 60 mg/kg to about concentration curve (AUC) by methods known in the field, 80 mg/kg, about 80 mg/kg to about 100 mg/kg, about 100 taking into account the individual’s creatinine clearance rate. mg/kg to about 120 mg/kg, about 120 mg/kg to about 140 The dosage of the other agent may be adjusted (e.g., reduced) mg/kg, about 140 mg/kg to about 200 mg/kg). In some based on the individual’s symptoms (such as adverse reac embodiments, the effective amount of taxane (e.g., pacli tions). In some embodiments, the dosage of the other agent 15 taxel) in the nanoparticle composition is about 100 mg/m. In Such as carboplatin for combination treatment along with the some embodiments, the effective amount of taxane in the taxane nanoparticles is calculated to provide an AUC of about nanoparticle composition is between about 170 mg/m to 0.1-10 mg/ml min, about 1-8 mg/ml min, about 1.5 to about about 200 mg/m and the effective amount of the other agent 7.5 mg/ml min, about 2 to about 6 mg/ml minor about any of is about 1 mg/kg to about 200 mg/kg (including for example 1, 2, 3, 4, 5, 6, or 7 mg/ml min. The other agent such as about 1 mg/kg to about 20 mg/kg, about 20 mg/kg to about 40 carboplatin may be administered systematically. The other mg/kg, about 40 mg/kg to about 60 mg/kg, about 60 mg/kg to agent Such as carboplatin may be administered intravenously. about 80 mg/kg, about 80 mg/kg to about 100 mg/kg, about The other agent such as carboplatin may be administered via 100 mg/kg to about 120 mg/kg, about 120 mg/kg to about 140 portacath. The other agent such as carboplatin may be admin mg/kg, about 140 mg/kg to about 200 mg/kg). In some istered over a period of about 10 to about 300 minutes, about 25 embodiments, the effective amount of taxane in the nanopar 30 to about 180 minutes, about 45 to about 120 minutes or ticle composition is between about 200 mg/m to about 350 about 60 minutes. mg/m and the effective amount of the other agent is about 1 The dosing frequency of the other agent can be the same or mg/kg to about 200 mg/kg (including for example about 1 different from that of the nanoparticle composition. Exem mg/kg to about 20 mg/kg, about 20 mg/kg to about 40 mg/kg, plary frequencies are provided above. As further example, the 30 about 40 mg/kg to about 60 mg/kg, about 60 mg/kg to about other agent can be administered three times a day, two times 80 mg/kg, about 80 mg/kg to about 100 mg/kg, about 100 a day, daily, 6 times a week, 5 times a week, 4 times a week, mg/kg to about 120 mg/kg, about 120 mg/kg to about 140 3 times a week, two times a week, weekly. In some embodi mg/kg, about 140 mg/kg to about 200 mg/kg). In some ments, the other agent is administered twice daily or three embodiments, the effective amount of taxane (e.g., pacli times daily. 35 taxel) in the nanoparticle composition is about 260 mg/m. In In some embodiments, the effective amount of taxane in some embodiments of any of the above methods, the effective the nanoparticle composition is between about 45 mg/m to amount of the other agent is about 20-30 mg/kg, about 30-40 about 350 mg/m and the effective amount of the other agent mg/kg, about 40-50 mg/kg, about 50-60 mg/kg, about 60-70 is about 1 mg/kg to about 200 mg/kg (including for example mg/kg, about 70-80 mg/kg, about 80-100 mg/kg, or about about 1 mg/kg to about 20 mg/kg, about 20 mg/kg to about 40 40 100-120 mg/kg. mg/kg, about 40 mg/kg to about 60 mg/kg, about 60 mg/kg to In some embodiments, the effective amount of taxane in about 80 mg/kg, about 80 mg/kg to about 100 mg/kg, about the nanoparticle composition is between about 45 mg/m to 100 mg/kg to about 120 mg/kg, about 120 mg/kg to about 140 about 350 mg/m and the effective amount of the other agent mg/kg, about 140 mg/kg to about 200 mg/kg). In some is about 80 mg to about 1000 mg (including for example about embodiments, the effective amount of taxane in the nanopar 45 80 to about 100 mg, about 100 to about 200 mg, about 200 to ticle composition is between about 80 mg/m to about 350 about 300 mg, about 300 to about 400 mg, about 400 to about mg/m and the effective amount of the other agent is about 1 500 mg, about 500 to about 600 mg, about 600 to about 700 mg/kg to about 200 mg/kg (including for example about 1 mg, about 700 to about 800 mg, about 800 to about 900 mg. mg/kg to about 20 mg/kg, about 20 mg/kg to about 40 mg/kg, about 900 mg to about 1000 mg). In some embodiments, the about 40 mg/kg to about 60 mg/kg, about 60 mg/kg to about 50 effective amount of taxane in the nanoparticle composition is 80 mg/kg, about 80 mg/kg to about 100 mg/kg, about 100 between about 80 mg/m to about 350 mg/m and the effec mg/kg to about 120 mg/kg, about 120 mg/kg to about 140 tive amount of the other agent is about 80 mg to about 1000 mg/kg, about 140 mg/kg to about 200 mg/kg). In some mg (including for example about 80 to about 100 mg, about embodiments, the effective amount of taxane in the nanopar 100 to about 200 mg, about 200 to about 300 mg, about 300 to ticle composition is between about 80 mg/m to about 300 55 about 400 mg, about 400 to about 500 mg, about 500 to about mg/m and the effective amount of the other agent is about 1 600 mg, about 600 to about 700 mg, about 700 to about 800 mg/kg to about 200 mg/kg (including for example about 1 mg, about 800 to about 900 mg, about 900 mg to about 1000 mg/kg to about 20 mg/kg, about 20 mg/kg to about 40 mg/kg, mg). In some embodiments, the effective amount of taxane in about 40 mg/kg to about 60 mg/kg, about 60 mg/kg to about the nanoparticle composition is between about 80 mg/m to 80 mg/kg, about 80 mg/kg to about 100 mg/kg, about 100 60 about 300 mg/m and the effective amount of the other agent mg/kg to about 120 mg/kg, about 120 mg/kg to about 140 is about 80 mg to about 1000 mg (including for example about mg/kg, about 140 mg/kg to about 200 mg/kg). In some 80 to about 100 mg, about 100 to about 200 mg, about 200 to embodiments, the effective amount of taxane in the nanopar about 300 mg, about 300 to about 400 mg, about 400 to about ticle composition is between about 150 mg/m to about 350 500 mg, about 500 to about 600 mg, about 600 to about 700 mg/m and the effective amount of the other agent is about 1 65 mg, about 700 to about 800 mg, about 800 to about 900 mg. mg/kg to about 200 mg/kg (including for example about 1 about 900 mg to about 1000 mg). In some embodiments, the mg/kg to about 20 mg/kg, about 20 mg/kg to about 40 mg/kg, effective amount of taxane in the nanoparticle composition is US 9,149,455 B2 91 92 between about 150 mg/m to about 350 mg/m and the effec about 100 mg/m, or about 150 mg/m) and the effective tive amount of the other agent is about 80 mg to about 1000 amount of the other agent (e.g., carboplatin) is about AUC1 to mg (including for example about 80 to about 100 mg, about about AUC7 (including for example about AUC2 to about 100 to about 200 mg, about 200 to about 300 mg, about 300 to AUC6, or about any of AUC1, AUC2, AUC3, AUC4, AUC5, about 400 mg, about 400 to about 500 mg, about 500 to about or AUC6). In some embodiments, the nanoparticle composi 600 mg, about 600 to about 700 mg, about 700 to about 800 tion is administered weekly for three weeks of four weeks or mg, about 800 to about 900 mg, about 900 mg to about 1000 weekly. In some embodiments, the other agent is adminis mg). In some embodiments, the effective amount of taxane in tered weekly for three weeks of four weeks or weekly. In the nanoparticle composition is between about 80 mg/m to Some embodiments, the carrier protein is albumin Such as about 150 mg/m and the effective amount of the other agent 10 human serum albumin or human albumin. In some embodi is about 80 mg to about 1000 mg (including for example about ments, the taxane is paclitaxel. In some embodiments, the one 80 to about 100 mg, about 100 to about 200 mg, about 200 to other agent is a platinum-based agent. In some embodiments, about 300 mg, about 300 to about 400 mg, about 400 to about the one other agent is carboplatin. 500 mg, about 500 to about 600 mg, about 600 to about 700 The nanoparticle composition (and the other agent) mg, about 700 to about 800 mg, about 800 to about 900 mg. 15 described herein can be administered to an individual (such as about 900 mg to about 1000 mg). In some embodiments, the human) via various routes, including, for example, intrave effective amount of taxane in the nanoparticle composition is nous, intra-arterial, intraperitoneal, intrapulmonary, oral, between about 170 mg/m to about 200 mg/m and the effec inhalation, intravesicular, intramuscular, intra-tracheal, Sub tive amount of the other agent is about 80 mg to about 1000 cutaneous, intraocular, intrathecal, transmucosal, and trans mg (including for example about 80 to about 100 mg, about dermal. In some embodiments, Sustained continuous release 100 to about 200 mg, about 200 to about 300 mg, about 300 to formulation of the composition may be used. In one variation about 400 mg, about 400 to about 500 mg, about 500 to about of the invention, nanoparticles (such as albumin nanopar 600 mg, about 600 to about 700 mg, about 700 to about 800 ticles) can be administered by any acceptable route including, mg, about 800 to about 900 mg, about 900 mg to about 1000 but not limited to, orally, intramuscularly, transdermally, mg). In some embodiments, the effective amount of taxane in 25 intravenously, through an inhaler or other air borne delivery the nanoparticle composition is between about 200 mg/m to systems and the like. Any of the routes that may be used to about 350 mg/m and the effective amount of the other agent administer a nanoparticle composition described herein may is about 80 mg to about 1000 mg (including for example about be used to administer the other agent. The other agent 80 to about 100 mg, about 100 to about 200 mg, about 200 to described herein can be administered to an individual (such as about 300 mg, about 300 to about 400 mg, about 400 to about 30 human) via various routes, such as parenterally, including 500 mg, about 500 to about 600 mg, about 600 to about 700 intravenous, intraventricular, intra-arterial, intraperitoneal, mg, about 700 to about 800 mg, about 800 to about 900 mg, intrapulmonary, oral, inhalation, intravesicular, intramuscu about 900 mg to about 1000 mg). In some embodiments, the lar, intra-tracheal. Subcutaneous, intraocular, intrathecal, or effective amount of taxane (e.g., paclitaxel) in the nanopar transdermal. In some embodiments, the other agent is admin ticle composition is about 100 mg/m. In some embodiments 35 istrated systemically. In some embodiments, the other agent of any of the above methods, the effective amount of the other is administrated intravenously. In some embodiments, the agent is about 100-200 mg, about 200-300 mg, about 300-400 other agent is administrated by infusion. In some embodi mg, about 400-500 mg. ments, the other agent is administrated by a port or portacath. In some embodiments, the effective amount of taxane in In some embodiments, the nanoparticle composition is the nanoparticle composition is between about 50 mg/m to 40 administered orally. about 400 mg/m (including for example about 100 mg/m to As will be understood by those of ordinary skill in the art, about 300 mg/m, about 75 mg/m to about 150 mg/m, or the appropriate doses of other agents will be approximately about 100 mg/m to about 150 mg/m) and the effective those already employed in clinical therapies wherein the amount of the other agent (e.g., carboplatin) is about AUC1 to other agent are administered alone or in combination with about AUC7 (including for example about AUC2 to about 45 other agents. Variation in dosage will likely occur depending AUC6, or about any of AUC1, AUC2, AUC3, AUC4, AUC5, on the condition being treated. As described above, in some or AUC6). In some embodiments, the effective amount of embodiments, the other agents may be administered at a taxane in the nanoparticle composition is between about 100 reduced level. mg/m to about 300 mg/m (e.g., about 100 mg/m to about A combination of the administration configurations 150 mg/m) and the effective amount of the other agent is 50 described herein can be used. The combination therapy meth about AUC2 to about AUC6 (e.g., about any of AUC2, AUC3, ods described herein may be performed alone or in conjunc AUC4, AUC5, or AUC6). In some embodiments, the effective tion with an additional therapy, Such as chemotherapy, radia amount of taxane in the nanoparticle composition is between tion therapy (e.g., whole brain radiation therapy), Surgery, about 100 mg/m to about 150 mg/m and the effective hormone therapy, gene therapy, immunotherapy, chemoim amount of the other agent is about AUC4 to about AUC6 (e.g., 55 munotherapy, cryotherapy, ultrasound therapy, liver trans about any of AUC4, AUC5, or AUC6). plantation, local ablative therapy, radiofrequency ablation In some embodiments, there is provided a method of treat therapy, photodynamic therapy, and the like. Additionally, a ing melanoma in an individual (e.g., human) comprising person having a greater risk of developing the proliferative administering to the individual (a) an effective amount of a disease may receive treatments to inhibit and/or delay the composition comprising nanoparticles comprising a taxane 60 development of the disease. (e.g., paclitaxel) and a carrier protein (e.g., albumin Such as Nanoparticle Compositions human serum albuminor human albumin) and (b) an effective The nanoparticle compositions described herein comprise amount of at least one other agent (e.g., carboplatin), wherein nanoparticles comprising (in various embodiments consist the dose of taxane in the nanoparticle composition is between ing essentially of) a taxane (such as paclitaxel) and a carrier about 50 mg/m to about 400 mg/m (including for example 65 protein (e.g., an albumin Such as human serum albumin or about 100 mg/m to about 300 mg/m, about 100 mg/m to human albumin) Nanoparticles of poorly water soluble drugs about 200 mg/m, or about 100 mg/m to about 150 mg/m, or (such as taxane) have been disclosed in, for example, U.S. US 9,149,455 B2 93 94 Pat. Nos. 5,916,596: 6,506,405; 6,749,868, 6,537,579, 7,820, In some embodiments, the weight ratio of albumin (such as 788, and also in U.S. Pat. Pub. Nos. 2006/0263434, and human albuminor human serum albumin) and a taxane in the 2007/0082838; PCT Patent Application WO08/137148, each nanoparticle composition is about 18:1 or less, such as about of which is incorporated by reference in their entirety. 15:1 or less, for example about 10:1 or less. In some embodi In some embodiments, the composition comprises nano ments, the weight ratio of albumin (such as human albuminor particles with an average or mean diameter of no greater than human serum albumin) and taxane in the composition falls about 1000 nanometers (nm). Such as no greater than about within the range of any one of about 1:1 to about 18:1, about (or less than about) any of 900, 800, 700, 600, 500, 400, 300, 2:1 to about 15:1, about 3:1 to about 13:1, about 4:1 to about 200, and 100 nm. In some embodiments, the average or mean 12:1, about 5:1 to about 10:1. In some embodiments, the 10 weight ratio of albuminand taxane in the nanoparticle portion diameters of the nanoparticles is no greater than about 200 nm of the composition is about any one of 1:2, 1:3, 1:4, 1:5, 1:9. (such as less than about 200 nm). In some embodiments, the 1:10, 1:15, or less. In some embodiments, the weight ratio of average or mean diameters of the nanoparticles is no greater the albumin (such as human albumin or human serum albu than about 150 nm. In some embodiments, the average or min) and the taxane in the composition is any one of the mean diameters of the nanoparticles is no greater than about 15 following: about 1:1 to about 18:1, about 1:1 to about 15:1, 100 nm. In some embodiments, the average or mean diameter about 1:1 to about 12:1, about 1:1 to about 10:1, about 1:1 to of the nanoparticles is about 20 to about 400 nm. In some about 9:1, about 1:1 to about 8:1, about 1:1 to about 7:1, about embodiments, the average or mean diameter of the nanopar 1:1 to about 6:1, about 1:1 to about 5:1, about 1:1 to about 4:1, ticles is about 40 to about 200 nm. In some embodiments, the about 1:1 to about 3:1, about 1:1 to about 2:1, about 1:1 to nanoparticles are sterile-filterable. about 1:1. In some embodiments, the nanoparticles in the composi In some embodiments, the nanoparticle composition com tion described herein have an average diameter of no greater prises one or more of the above characteristics. than about 200 nm, including for example no greater than The nanoparticles described herein may be present in a dry about any one of 190, 180, 170, 160, 150, 140, 130, 120, 110, formulation (such as lyophilized composition) or Suspended 100, 90, 80, 70, or 60 nm. In some embodiments, at least 25 in a biocompatible medium. Suitable biocompatible media about 50% (for example at least about any one of 60%, 70%, include, but are not limited to, water, buffered aqueous media, 80%, 90%, 95%, or 99%) of the nanoparticles in the compo saline, buffered saline, optionally buffered solutions of amino sition have a diameter of no greater than about 200 nm, acids, optionally buffered solutions of proteins, optionally including for example no greater than about any one of 190, buffered solutions of sugars, optionally buffered solutions of 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, or 60 30 vitamins, optionally buffered solutions of synthetic poly nm. In some embodiments, at least about 50% (for example at mers, lipid-containing emulsions, and the like. least any one of 60%, 70%, 80%, 90%. 95%, or 99%) of the In some embodiments, the pharmaceutically acceptable nanoparticles in the composition fall within the range of about carrier comprises a carrier protein (e.g., albumin Such as 20 to about 400 nm, including for example about 20 to about human albuminor human serum albumin) Examples of Suit 200 nm, about 40 to about 200 nm, about 30 to about 180 nm, 35 able carrier proteins include proteins normally found in blood and any one of about 40 to about 150, about 50 to about 120, or plasma, which include, but are not limited to, albumin, and about 60 to about 100 nm. immunoglobulin including IgA, lipoproteins, apolipoprotein In some embodiments, the carrier protein (e.g., albumin) B, C-acid glycoprotein, B-2-macroglobulin, thyroglobulin, has sulfhydral groups that can form disulfide bonds. In some transferrin, fibronectin, factor VII, factor VIII, factor IX, fac embodiments, at least about 5% (including for example at 40 tor X, and the like. In some embodiments, the carrier protein least about any one of 10%, 15%, 20%, 25%, 30%, 40%, 50%, is non-blood protein, Such as casein, C.-lactalbumin, B-lacto 60%, 70%, 80%, or 90%) of carrier protein (e.g., albumin) in globulin. The proteins may either be natural in origin or the nanoparticle portion of the composition are crosslinked synthetically prepared. In some embodiments, the protein is (for example crosslinked through one or more disulfide albumin, such as human albuminor human serum albumin. In bonds). 45 Some embodiments, the albumin is a recombinant albumin. In some embodiments, the nanoparticles comprise the tax Human serum albumin (HSA) is a highly soluble globular ane (Such as paclitaxel) coated with a carrier protein (e.g., an protein of Mr 65K and consists of 585 amino acids. HSA is albumin Such as human albuminor human serum albumin). In the most abundant protein in the plasma and accounts for Some embodiments, the composition comprises a taxane in 70-80% of the colloid osmotic pressure of human plasma. both nanoparticle and non-nanoparticle forms (e.g., in the 50 The amino acid sequence of HSA contains a total of 17 form of paclitaxel solutions or in the form of soluble carrier disulphide bridges, one free thiol (CyS 34), and a single tryp protein/nanoparticle complexes), wherein at least about any tophan (Trp 214). Intravenous use of HSA solution has been one of 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the taxane indicated for the prevention and treatment of hypovolumic in the composition are in nanoparticle form. In some embodi shock (see, e.g., Tullis, JAMA, 237, 355-360, 460-463, ments, the taxane in the nanoparticles constitutes more than 55 (1977)) and Houser et al., Surgery, Gynecology and Obstet about any one of 50%, 60%, 70%, 80%, 90%. 95%, or 99% of rics, 150, 811-816 (1980)) and in conjunction with exchange the nanoparticles by weight. In some embodiments, the nano transfusion in the treatment of neonatal hyperbilirubinemia particles have a non-polymeric matrix. In some embodi (see, e.g., Finlayson, Seminars in Thrombosis and Hemosta ments, the nanoparticles comprise a core of a taxane that is sis, 6, 85-120. (1980)). Other albumins are contemplated, Substantially free of polymeric materials (such as polymeric 60 Such as bovine serum albumin Use of such non-human albu matrix). mins could be appropriate, for example, in the context of use In some embodiments, the composition comprises a carrier of these compositions in non-human mammals, such as the protein (e.g., albumin) in both nanoparticle and non-nanopar Veterinary (including domestic pets and agricultural context). ticle portions of the composition, wherein at least about any Human serum albumin (HSA) has multiple hydrophobic one of 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the carrier 65 binding sites (a total of eight for fatty acids, an endogenous protein (e.g., albumin) in the composition are in non-nano ligand of HSA) and binds a diverse set of taxanes, especially particle portion of the composition. neutral and negatively charged hydrophobic compounds US 9,149,455 B2 95 96 (Goodman et al., The Pharmacological Basis of Therapeutics, 20-25° C.) or refrigerated conditions (such as 4°C.)). For 9th ed, McGraw-Hill New York (1996)). Two high affinity example, a suspension is stable at a storage temperature if it binding sites have been proposed in subdomains IIA and IIIA exhibits no flocculation or particle agglomeration visible to of HSA, which are highly elongated hydrophobic pockets the naked eye or when viewed under the optical microscope at with charged lysine and arginine residues near the Surface 1000 times, at about fifteen minutes after preparation of the which function as attachment points for polar ligand features Suspension. Stability can also be evaluated under accelerated (see, e.g., Fehske et al., Biochem. Pharmcol., 30, 687-92 testing conditions, such as at a temperature that is higher than (198a), Vorum, Dan. Med. Bull., 46, 379-99 (1999), Kragh about 40° C. Hansen, Dan. Med. Bull., 1441, 131-40 (1990), Curry et al., In some embodiments, the carrier protein (e.g., albumin) is Nat. Struct. Biol. 5, 827-35 (1998), Sugio et al., Protein. 10 present in an amount that is sufficient to stabilize the taxane in Eng., 12, 439-46 (1999). He et al., Nature, 358, 209-15 an aqueous Suspension at a certain concentration. For (199b), and Carter et al., Adv. Protein. Chem., 45, 153-203 example, the concentration of the taxane in the composition is (1994)). Paclitaxel and propofol have been shown to bind about 0.1 to about 100 mg/ml, including for example any of HSA (see, e.g., Paal et al., Eur. J. Biochem., 268(7), 2187-91 about 0.1 to about 50 mg/ml, about 0.1 to about 20 mg/ml, (200a), Purcell et al., Biochim Biophys. Acta, 1478(a), 61-8 15 about 1 to about 10 mg/ml, about 2 mg/ml to about 8 mg/ml. (2000). Altmayer et al., Arzneimittelforschung, 45, 1053-6 about 4 to about 6 mg/ml, or about 5 mg/ml. In some embodi (1995), and Garrido et al., Rev. Esp. Anestestiol. Reanim., 41, ments, the concentration of the taxane is at least about any of 308-12 (1994)). In addition, docetaxel has been shown to bind 1.3 mg/ml, 1.5 mg/ml, 2 mg/ml, 3 mg/ml. 4 mg/ml, 5 mg/ml. to human plasma proteins (see, e.g., Urien et al., Invest. New 6 mg/ml, 7 mg/ml, 8 mg/ml.9 mg/ml, 10 mg/ml, 15 mg/ml, 20 Drugs, 14(b), 147-51 (1996)). mg/ml, 25 mg/ml, 30 mg/ml. 40 mg/ml, and 50 mg/ml. In The carrier protein (e.g., albumin Such as human albumin Some embodiments, the carrier protein (e.g., albumin) is or human serum albumin) in the composition generally serves present in an amount that avoids use of Surfactants (such as as a carrier for the taxane, i.e., the albumin in the composition Cremophor), so that the composition is free or Substantially makes the taxane more readily Suspendable in an aqueous free of surfactant (such as Cremophor). medium or helps maintain the Suspension as compared to 25 In some embodiments, the composition, in liquid form, compositions not comprising a carrier protein. This can avoid comprises from about 0.1% to about 50% (w/v) (e.g. about the use of toxic solvents (or surfactants) for solubilizing the 0.5% (w/v), about 5% (w/v), about 10% (w/v), about 15% taxane, and thereby can reduce one or more side effects of (w/v), about 20% (w/v), about 30% (w/v), about 40% (w/v), administration of the taxane into an individual (such as a or about 50% (w/v)) of carrier protein (e.g., albumin). In some human). Thus, in some embodiments, the composition 30 embodiments, the composition, in liquid form, comprises described herein is substantially free (such as free) of surfac about 0.5% to about 5% (w/v) of carrier protein (e.g., albu tants, such as Cremophor (or polyoxyethylated castor oil) min). (including Cremophor ELR) (BASF)). In some embodiments, In some embodiments, the weight ratio of a carrier protein the nanoparticle composition is Substantially free (Such as (e.g., albumin) to the taxane in the nanoparticle composition free) of surfactants. A composition is “substantially free of 35 is such that a Sufficient amount of taxane binds to, or is Cremophor” or “substantially free of surfactant' if the transported by, the cell. While the weight ratio of a carrier amount of Cremophor or Surfactant in the composition is not protein (e.g., albumin) to taxane will have to be optimized for sufficient to cause one or more side effect(s) in an individual different carrier protein (e.g., albumin) and taxane combina when the nanoparticle composition is administered to the tions, generally the weight ratio of carrier protein (e.g., albu individual. In some embodiments, the nanoparticle composi 40 min), to taxane (w/w) is about 0.01:1 to about 100:1, about tion contains less than about any one of 20%, 15%, 10%, 0.02:1 to about 50:1, about 0.05:1 to about 20:1, about 0.1:1 7.5%. 5%, 2.5%, or 1% organic solvent or surfactant. In some to about 20:1, about 1:1 to about 18:1, about 2:1 to about 15:1, embodiments, the carrier protein is an albumin. In some about 3:1 to about 12:1, about 4:1 to about 10:1, about 5:1 to embodiments, the albuminis human albuminor human serum about 9:1, or about 9:1. In some embodiments, the carrier albumin. In some embodiments, the albumin is recombinant 45 protein (e.g., albumin) to taxane weight ratio is about any of albumin. 18:1 or less, 15:1 or less, 14:1 or less, 13:1 or less, 12:1 or less, The amount of a carrier protein Such as albumin in the 11:1 or less, 10:1 or less, 9:1 or less, 8:1 or less, 7:1 or less, 6:1 composition described herein will vary depending on other or less, 5:1 or less, 4:1 or less, and 3:1 or less. In some components in the composition. In some embodiments, the embodiments, the carrier protein is albumin. In some embodi composition comprises a carrier protein Such as an albumin in 50 ments, the weight ratio of the albumin (such as human albu an amount that is sufficient to stabilize the taxane in an aque minor human serum albumin) to the taxane in the composi ous Suspension, for example, in the form of a stable colloidal tion is any one of the following: about 1:1 to about 18:1, about Suspension (such as a stable Suspension of nanoparticles). In 1:1 to about 15:1, about 1:1 to about 12:1, about 1:1 to about Some embodiments, the carrier protein Such as albumin is in 10:1, about 1:1 to about 9:1, about 1:1 to about 8:1, about 1:1 an amount that reduces the sedimentation rate of the taxane in 55 to about 7:1, about 1:1 to about 6:1, about 1:1 to about 5:1, an aqueous medium. For particle-containing compositions, about 1:1 to about 4:1, about 1:1 to about 3:1, about 1:1 to the amount of the carrier protein such as albumin also about 2:1, about 1:1 to about 1:1. depends on the size and density of nanoparticles of the taxane. In some embodiments, the carrier protein (e.g., albumin) A taxane is 'stabilized in an aqueous Suspension if it allows the composition to be administered to an individual remains Suspended in an aqueous medium (such as without 60 (such as human) without significant side effects. In some visible precipitation or sedimentation) for an extended period embodiments, the carrier protein (e.g., albumin Such as of time, such as for at least about any of 0.1, 0.2,0.25, 0.5, 1. human serum albuminor human albumin) is in an amount that 2,3,4,5,6,7,8,9, 10, 11, 12, 24, 36, 48, 60, or 72 hours. The is effective to reduce one or more side effects of administra Suspension is generally, but not necessarily, Suitable for tion of the taxane to a human. The term “reducing one or more administration to an individual (such as human). Stability of 65 side effects of administration of the taxane' refers to reduc the Suspension is generally (but not necessarily) evaluated at tion, alleviation, elimination, or avoidance of one or more a storage temperature (such as room temperature (such as undesirable effects caused by the taxane, as well as side US 9,149,455 B2 97 98 effects caused by delivery vehicles (such as solvents that coated with an albumin (Such as human albumin or human render the taxanes suitable for injection) used to deliver the serum albumin), wherein the nanoparticles have an average taxane. Such side effects include, for example, myeloSup diameter of no greater than about 150 nm. In some embodi pression, neurotoxicity, hypersensitivity, inflammation, ments, the nanoparticle compositions described herein com venous irritation, phlebitis, pain, skin irritation, peripheral prises nanoparticles comprising a taxane (such as paclitaxel) neuropathy, neutropenic fever, anaphylactic reaction, Venous coated with an albumin (Such as human albumin or human thrombosis, extravasation, and combinations thereof. These serum albumin), wherein the nanoparticles have an average side effects, however, are merely exemplary and other side diameter of about 130 nm. In some embodiments, the nano effects, or combination of side effects, associated with tax particle compositions described herein comprises nanopar anes can be reduced. 10 In some embodiments, the nanoparticle compositions ticles comprising paclitaxel coated with human albumin described herein comprises nanoparticles comprising a tax (such as human serum albumin), wherein the nanoparticles ane (such as paclitaxel) and an albumin (such as human have an average diameter of about 130 nm. albuminor human serum albumin), wherein the nanoparticles In some embodiments, the nanoparticle compositions have an average diameter of no greater than about 200 nm. In 15 described herein comprises nanoparticles comprising a tax Some embodiments, the nanoparticle compositions described ane (such as paclitaxel) coated with an albumin (such as herein comprises nanoparticles comprising a taxane (such as human albumin or human serum albumin), wherein the paclitaxel) and an albumin (such as human albuminor human weight ratio of the albumin and the taxane in the composition serum albumin), wherein the nanoparticles have an average is no greater than about 9:1 (such as about 9:1). In some diameter of no greater than about 150 nm. In some embodi embodiments, the nanoparticle compositions described ments, the nanoparticle compositions described herein com herein comprises nanoparticles comprising a taxane (such as prises nanoparticles comprising a taxane (such as paclitaxel) paclitaxel) coated with an albumin (such as human albuminor and an albumin (such as human albumin or human serum human serum albumin), wherein the nanoparticles have an albumin), wherein the nanoparticles have an average diam average diameter of no greater than about 200 nm, wherein eter of about 130 nm. In some embodiments, the nanoparticle 25 the weight ratio of the albumin and the taxane in the compo compositions described herein comprises nanoparticles com sition is no greater than about 9:1 (such as about 9:1). In some prising paclitaxel and human albumin (such as human serum embodiments, the nanoparticle compositions described albumin), wherein the nanoparticles have an average diam herein comprises nanoparticles comprising a taxane (such as eter of about 130 nm. paclitaxel) coated with an albumin (such as human albuminor In some embodiments, the nanoparticle compositions 30 human serum albumin), wherein the nanoparticles have an described herein comprises nanoparticles comprising a tax average diameter of no greater than about 150 nm, wherein ane (such as paclitaxel) and an albumin (such as human the weight ratio of the albumin and the taxane in the compo albuminor human serum albumin), wherein the nanoparticles sition is no greater than about 9:1 (such as about 9:1). In some have an average diameter of no greater than about 200 nm, embodiments, the nanoparticle compositions described wherein the weight ratio of the albumin and the taxane in the 35 herein comprises nanoparticles comprising a taxane (such as composition is no greater than about 9:1 (Such as about 9:1). paclitaxel) coated with an albumin (such as human albuminor In some embodiments, the nanoparticle compositions human serum albumin), wherein the nanoparticles have an described herein comprises nanoparticles comprising a tax average diameter of about 150 nm, wherein the weight ratio of ane (such as paclitaxel) and an albumin (such as human the albumin and the taxane in the composition is no greater albuminor human serum albumin), wherein the nanoparticles 40 than about 9:1 (such as about 9:1). In some embodiments, the have an average diameter of no greater than about 150 nm, nanoparticle compositions described herein comprises nano wherein the weight ratio of the albumin and the taxane in the particles comprising paclitaxel coated with human albumin composition is no greater than about 9:1 (Such as about 9:1). (such as human serum albumin), wherein the nanoparticles In some embodiments, the nanoparticle compositions have an average diameter of about 130 nm, wherein the described herein comprises nanoparticles comprising a tax 45 weight ratio of albumin and the taxane in the composition is ane (such as paclitaxel) and an albumin (such as human about 9:1. albuminor human serum albumin), wherein the nanoparticles In some embodiments, the nanoparticle compositions have an average diameter of about 150 nm, wherein the described herein comprises nanoparticles comprising a tax weight ratio of the albumin and the taxane in the composition ane (such as paclitaxel) stabilized by an albumin (such as is no greater than about 9:1 (such as about 9:1). In some 50 human albumin or human serum albumin). In some embodi embodiments, the nanoparticle compositions described ments, the nanoparticle compositions described herein com herein comprises nanoparticles comprising paclitaxel and prises nanoparticles comprising a taxane (such as paclitaxel) human albumin (such as human serum albumin), wherein the stabilized by an albumin (such as human albumin or human nanoparticles have an average diameter of about 130 nm, serum albumin), wherein the nanoparticles have an average wherein the weight ratio of albumin and the taxane in the 55 diameter of no greater than about 200 nm. In some embodi composition is about 9:1. ments, the nanoparticle compositions described herein com In some embodiments, the nanoparticle compositions prises nanoparticles comprising a taxane (such as paclitaxel) described herein comprises nanoparticles comprising a tax stabilized by an albumin (such as human albumin or human ane (such as paclitaxel) coated with an albumin (such as serum albumin), wherein the nanoparticles have an average human albumin or human serum albumin). In some embodi 60 diameter of no greater than about 150 nm. In some embodi ments, the nanoparticle compositions described herein com ments, the nanoparticle compositions described herein com prises nanoparticles comprising a taxane (such as paclitaxel) prises nanoparticles comprising a taxane (such as paclitaxel) coated with an albumin (Such as human albumin or human stabilized by an albumin (such as human albumin or human serum albumin), wherein the nanoparticles have an average serum albumin), wherein the nanoparticles have an average diameter of no greater than about 200 nm. In some embodi 65 diameter of about 130 nm. In some embodiments, the nano ments, the nanoparticle compositions described herein com particle compositions described herein comprises nanopar prises nanoparticles comprising a taxane (such as paclitaxel) ticles comprising paclitaxel stabilized by human albumin US 9,149,455 B2 99 100 (such as human serum albumin), wherein the nanoparticles obtained can be further lyophilized. Suitable organic solvent have an average diameter of about 130 nm. include, for example, ketones, esters, ethers, chlorinated Sol In some embodiments, the nanoparticle compositions vents, and other solvents known in the art. For example, the described herein comprises nanoparticles comprising a tax organic solvent can be methylene chloride or chloroform/ ane (such as paclitaxel) stabilized by an albumin (Such as ethanol (for example with a ratio of 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, human albumin or human serum albumin), wherein the 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, or 9:1). weight ratio of the albumin and the taxane in the composition Other Components in the Nanoparticle Compositions is no greater than about 9:1 (such as about 9:1). In some The nanoparticles described herein can be present in a embodiments, the nanoparticle compositions described composition that includes other agents, excipients, or stabi herein comprises nanoparticles comprising a taxane (such as 10 lizers. For example, to increase stability by increasing the paclitaxel) stabilized by an albumin (Such as human albumin negative Zeta potential of nanoparticles, one or more of nega or human serum albumin), wherein the nanoparticles have an tively charged components may be added. Such negatively average diameter of no greater than about 200 nm, wherein charged components include, but are not limited to bile salts the weight ratio of the albumin and the taxane in the compo of bile acids consisting of glycocholic acid, cholic acid, sition is no greater than about 9:1 (such as about 9:1). In some 15 chenodeoxycholic acid, taurocholic acid, glycochenodeoxy embodiments, the nanoparticle compositions described cholic acid, taurochenodeoxycholic acid, litocholic acid, herein comprises nanoparticles comprising a taxane (such as urSodeoxycholic acid, dehydrocholic acid and others; phos paclitaxel) stabilized by an albumin (Such as human albumin pholipids including lecithin (egg yolk) based phospholipids or human serum albumin), wherein the nanoparticles have an which include the following phosphatidylcholines: palmitoy average diameter of no greater than about 150 nm, wherein loleoylphosphatidylcholine, palmitoyllinoleoylphosphati the weight ratio of the albumin and the taxane in the compo dylcholine, stearoyllinoleoylphosphatidylcholine stearoylo sition is no greater than about 9:1 (such as about 9:1). In some leoylphosphatidylcholine, embodiments, the nanoparticle compositions described Stearoylarachidoylphosphatidylcholine, and dipalmi herein comprises nanoparticles comprising a taxane (such as toylphosphatidylcholine. Other phospholipids including paclitaxel) stabilized by an albumin (Such as human albumin 25 L-O-dimyristoylphosphatidylcholine (DMPC), dio or human serum albumin), wherein the nanoparticles have an leoylphosphatidylcholine (DOPC), distearyolphosphatidyl average diameter of about 150 nm, wherein the weight ratio of choline (DSPC), hydrogenated soy phosphatidylcholine the albumin and the taxane in the composition is no greater (HSPC), and other related compounds. Negatively charged than about 9:1 (such as about 9:1). In some embodiments, the Surfactants or emulsifiers are also suitable as additives, e.g., nanoparticle compositions described herein comprises nano 30 sodium cholesteryl sulfate and the like. particles comprising paclitaxel Stabilized by human albumin In some embodiments, the composition is suitable for (such as human serum albumin), wherein the nanoparticles administration to a human. In some embodiments, the com have an average diameter of about 130 nm, wherein the position is Suitable for administration to a mammal Such as, in weight ratio of albumin and the taxane in the composition is the Veterinary context, domestic pets and agricultural ani about 9:1. 35 mals. There are a wide variety of suitable formulations of the In some embodiments, the nanoparticle composition com nanoparticle composition (see, e.g., U.S. Pat. Nos. 5,916,596, prises Nab-paclitaxel (or Abraxane(R). In some embodi 6,096,331, and 7.820,788). The following formulations and ments, the nanoparticle composition is Nab-paclitaxel (or methods are merely exemplary and are in no way limiting. Abraxane(R). Abraxane(R) is a formulation of paclitaxel stabi Formulations suitable for oral administration can consist of lized by human albumin USP, which can be dispersed in 40 (a) liquid Solutions, such as an effective amount of the com directly injectable physiological solution. The weight ratio of pound dissolved in diluents, such as water, saline, or orange human albuminand paclitaxel is about 9:1. When dispersed in juice, (b) capsules, Sachets or tablets, each containing a pre a suitable aqueous medium such as 0.9% sodium chloride determined amount of the active ingredient, as Solids or gran injection or 5% dextrose injection, Nab-paclitaxel (or Abrax ules, (c) Suspensions in an appropriate liquid, and (d) Suitable ane(R) forms a stable colloidal suspension of paclitaxel. The 45 emulsions. Tablet forms can include one or more of lactose, mean particle size of the nanoparticles in the colloidal Sus mannitol, corn starch, potato starch, microcrystalline cellu pension is about 130 nanometers. Since HSA is freely soluble lose, acacia, gelatin, colloidal silicon dioxide, croScarmellose in water, Nab-paclitaxel (or Abraxane(R) can be reconstituted Sodium, talc, magnesium Stearate, Stearic acid, and other in a wide range of concentrations ranging from dilute (0.1 excipients, colorants, diluents, buffering agents, moistening mg/ml paclitaxel) to concentrated (20 mg/ml paclitaxel), 50 agents, preservatives, flavoring agents, and pharmacologi including for example about 2 mg/ml to about 8 mg/ml, or cally compatible excipients. Lozenge forms can comprise the about 5 mg/ml. active ingredient in a flavor, usually Sucrose and acacia or Methods of making nanoparticle compositions are known tragacanth, as well as pastilles comprising the active ingredi in the art. For example, nanoparticles containing taxanes ent in an inert base. Such as gelatin and glycerin, or Sucrose (such as paclitaxel) and carrier protein (e.g., albumin Such as 55 and acacia, emulsions, gels, and the like containing, in addi human serum albumin or human albumin) can be prepared tion to the active ingredient, such excipients as are known in under conditions of high shear forces (e.g., Sonication, high the art. pressure homogenization, or the like). These methods are Examples of Suitable carriers, excipients, and diluents disclosed in, for example, U.S. Pat. Nos. 5,916,596: 6,506, include, but are not limited to, lactose, dextrose, Sucrose, 405; 6,749,868, 6,537,579 and 7,820,788 and also in U.S. Pat. 60 Sorbitol, mannitol, starches, gum acacia, calcium phosphate, Pub. Nos. 2007/0082838, 2006/0263434 and PCT Applica alginates, tragacanth, gelatin, calcium silicate, microcrystal tion WOO871371.48. line cellulose, polyvinylpyrrolidone, cellulose, water, Saline Briefly, the taxane (Such as paclitaxel) is dissolved in an Solution, syrup, methylcellulose, methyl and propylhydroxy organic solvent, and the Solution can be added to a carrier benzoates, talc, magnesium Stearate, and mineral oil. The protein Solution Such as an albumin Solution. The mixture is 65 formulations can additionally include lubricating agents, Subjected to high pressure homogenization. The organic Sol wetting agents, emulsifying and Suspending agents, preserv vent can then be removed by evaporation. The dispersion ing agents, Sweetening agents or flavoring agents. US 9,149,455 B2 101 102 Formulations suitable for parenteral administration as buffers and interpretative information. The present appli include aqueous and non-aqueous, isotonic sterile injection cation thus also provides articles of manufacture, which Solutions, which can contain anti-oxidants, buffers, bacteri include vials (such as sealed vials), unit dosages or unit dos ostats, and Solutes that render the formulation compatible age forms, bottles, jars, flexible packaging, and the like. with the blood of the intended recipient, and aqueous and The instructions relating to the use of the nanoparticle non-aqueous sterile Suspensions that can include Suspending compositions generally include information as to dosage, agents, solubilizers, thickening agents, stabilizers, and pre dosing schedule, and route of administration for the intended servatives. The formulations can be presented in unit-dose or treatment. The containers may be unit doses, bulk packages multi-dose sealed containers, such as ampules and vials, and (e.g., multi-dose packages) or Sub-unit doses. For example, can be stored in a freeze-dried (lyophilized) condition requir 10 kits may be provided that contain Sufficient dosages of the ing only the addition of the sterile liquid excipient, for taxane (such as taxane) as disclosed herein to provide effec example, water, for injections, immediately prior to use. tive treatment of an individual for an extended period, Such as Extemporaneous injection Solutions and Suspensions can be any of a week, 8 days, 9 days, 10 days, 11 days, 12 days, 13 prepared from sterile powders, granules, and tablets of the days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, kind previously described. Injectable formulations are pre 15 4 months, 5 months, 7 months, 8 months, 9 months, or more. ferred. Kits may also include multiple unit doses of the taxane and In some embodiments, the composition is formulated to pharmaceutical compositions and instructions for use and have a pH range of about 4.5 to about 9.0, including for packaged in quantities sufficient for storage and use in phar example pH ranges of any of about 5.0 to about 8.0, about 6.5 macies, for example, hospital and compounding to about 7.5, and about 6.5 to about 7.0. In some embodi pharmacies. ments, the pH of the composition is formulated to no less than Also provided are medicines, compositions, and unit dos about 6, including for example no less than about any of 6.5, age forms useful for the methods described herein. In some 7, or 8 (such as about 8). The composition can also be made to embodiments, there is provided a medicine (or composition be isotonic with blood by the addition of a suitable tonicity or the unit dosage form) for use in treating melanoma in an modifier, such as glycerol. 25 individual, comprising effective amount of nanoparticles Articles of Manufacture, Kits, Compositions, and Medicines comprising a taxane (e.g., paclitaxel) and a carrier protein The invention also provides kits, medicines, compositions, (e.g., an albumin Such as human serum albumin or human unit dosage forms, and articles of manufacture for use in any albumin). In some embodiments, there is provided a medicine of the methods described herein. (or composition or a unit dosage form) for use in treating Kits of the invention include one or more containers com 30 melanoma in an individual in conjunction with another agent, prising taxane-containing nanoparticle compositions (or unit comprising nanoparticles comprising a taxane and a carrier dosage forms and/or articles of manufacture) and/or another protein (e.g., an albumin such as human serum albumin). agent (such as at least one other agent described herein), and in some embodiments, further comprise instructions for use Additional Exemplary Embodiments in accordance with any of the methods described herein. The 35 kit may further comprise a description of selection of indi In some embodiments, there is a method of treating mela vidual suitable for treatment. Instructions supplied in the kits noma (Such as metastatic melanoma or metastatic malignant of the invention are typically written instructions on a label or melanoma) in a human individual comprising administering package insert (e.g., a paper sheet included in the kit), but to the individual an effective amount of a composition com machine-readable instructions (e.g., instructions carried on a 40 prising nanoparticles comprising paclitaxel and albumin magnetic or optical storage disk) are also acceptable. (such as nanoparticles having average particle size of no For example, in Some embodiments, the kit comprises a greater than about 200 nm). In some embodiments, there is a composition comprising nanoparticles comprising a taxane method of treating cutaneous melanoma (such as metastatic and a carrier protein (e.g., albumin Such as human serum cutaneous melanoma Such as metastatic malignant cutaneous albumin or human albumin). In some embodiments, the kit 45 melanoma) in a human individual comprising administering further comprises instructions for administering the nanopar to the individual an effective amount of a composition com ticle composition for treatment of melanoma in an individual. prising nanoparticles comprising paclitaxel and albumin For another example, in some embodiments, the kit com (such as nanoparticles having average particle size of no prises a) a composition comprising nanoparticles comprising greater than about 200 nm). In some embodiments, there is a a taxane (e.g., paclitaxel) and a carrier protein (e.g., albumin 50 method of treating melanoma (Such as metastatic melanoma Such as human serum albumin or human albumin), b) an or metastatic malignant melanoma) in a human individual effective amount of at least one other agent described herein. comprising administering to the individual an effective In some embodiments, the kit further comprises instructions amount of a composition comprising nanoparticles compris for administering the nanoparticle composition and at least ing paclitaxel coated with albumin (such as nanoparticles one other agent for treatment of melanoma in an individual. 55 having average particle size of no greater than about 200 nm, The nanoparticles and the other agents can be present in for example Nab-paclitaxel). In some embodiments, there is a separate containers or in a single container. For example, the method of treating cutaneous melanoma (such as metastatic kit may comprise one distinct composition or two or more cutaneous melanoma Such as metastatic malignant cutaneous compositions wherein one composition comprises nanopar melanoma) in a human individual comprising administering ticles and one composition comprises another agent. The 60 to the individual an effective amount of a composition com instructions may be on a package insert or a package label. prising nanoparticles comprising paclitaxel coated with albu The treatment may be according to any one of the methods min (such as nanoparticles having average particle size of no described herein. greater than about 200 nm, for example Nab-paclitaxel). In The kits of the invention are in Suitable packaging. Suitable Some embodiments, there is a method of treating cutaneous packaging include, but is not limited to, vials, bottles, jars, 65 melanoma (Such as metastatic cutaneous melanoma Such as flexible packaging (e.g., sealed Mylar or plastic bags), and the metastatic malignant cutaneous melanoma) in a human indi like. Kits may optionally provide additional components such vidual comprising intravenously administering (for example US 9,149,455 B2 103 104 infusing over about 30-40 minutes) to the individual an effec nanoparticles comprising paclitaxel coated with albumin tive amount of Nab-paclitaxel (for example about 5 mg/ml (such as nanoparticles having average particle size of no Nab-paclitaxel), wherein the dose of paclitaxel in the nano greater than about 200 nm, for example Nab-paclitaxel). In particle composition is about 80 to about 200 mg/m (includ Some embodiments, there is a method of treating melanoma ing for example about 90 mg/m, about 120 mg/m, or about 5 (such as metastatic melanoma or metastatic malignant mela 150 mg/m). In some embodiments, there is a method of noma) in a human individual, wherein said individual has not treating cutaneous melanoma (Such as metastatic cutaneous previously been treated for melanoma or has not received melanoma Such as metastatic malignant cutaneous mela prior cytotoxic chemotherapy Such as prior adjuvant cyto noma) in a human individual comprising intravenously toxic therapy, comprising intravenously administering (for administering by infusing over about 30-40 minutes to the 10 example infusing over about 30-40 minutes) to the individual individual an effective amount of Nab-paclitaxel (for an effective amount of Nab-paclitaxel (for example about 5 example about 5 mg/ml Nab-paclitaxel), wherein the dose of mg/ml Nab-paclitaxel), wherein the dose of paclitaxel in the paclitaxel in the nanoparticle composition is about 150 nanoparticle composition is about 80 to about 200 mg/m mg/m on days 1, 8, 15 of every 28 day cycle. In some (including for example about 90 mg/m, about 120 mg/m, or embodiments, there is a method of treating cutaneous mela 15 about 150 mg/m). In some embodiments, there is a method noma (such as metastatic cutaneous melanoma Such as meta of treating melanoma (Such as metastatic melanoma or meta static malignant cutaneous melanoma) in a human individual static malignant melanoma) in a human individual, wherein comprising intravenously administering by infusing over said individual has not previously been treated for melanoma about 30-40 minutes to the individual an effective amount of or has not received prior cytotoxic chemotherapy such as Nab-paclitaxel (for example about 5 mg/ml Nab-paclitaxel), prior adjuvant cytotoxic therapy, comprising intravenously wherein the dose of paclitaxel in the nanoparticle composi administering by intravenously administering (such as infu tion is about 120 mg/mon days 1,8, 15 of every 28 day cycle. sion over about 30-40 minutes) to the individual an effective In some embodiments, there is a method of treating cutaneous amount of Nab-paclitaxel (for example about 5 mg/ml Nab melanoma (Such as metastatic cutaneous melanoma Such as paclitaxel), wherein the dose of paclitaxel in the nanoparticle metastatic malignant cutaneous melanoma) in a human indi 25 composition is about 80 to about 200 mg/m (including for vidual comprising intravenously administering by infusing example about 90 mg/m, about 120 mg/m, or about 150 over about 30-40 minutes to the individual an effective mg/m) on days 1, 8, 15 of every 28 day cycle. In some amount of Nab-paclitaxel (for example about 5 mg/ml Nab embodiments, there is a method of treating melanoma (Such paclitaxel), wherein the dose of paclitaxel in the nanoparticle as metastatic melanoma or metastatic malignant melanoma) composition is about 90 mg/m on days 1, 8, 15 of every 28 30 in a human individual, wherein said individual has not previ day cycle. In some embodiments, the individual is treated for ously been treated for melanoma or has not received prior at least about 2 months, including for example at least about cytotoxic chemotherapy such as prior adjuvant cytotoxic any of 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In some therapy, comprising intravenously administering by infusing embodiments, the individual is chemotherapy naive. In some over about 30-40 minutes to the individual an effective embodiments, the melanoma is stage IV melanoma. In some 35 amount of Nab-paclitaxel (for example about 5 mg/ml Nab embodiments, the individual has distant metastases. In some paclitaxel), wherein the dose of paclitaxel in the nanoparticle embodiments, the metastatic melanoma is at stage Mla. In composition is about 150 mg/m on days 1, 8, 15 of every 28 Some embodiments, the metastatic melanoma is at Stage M1b. day cycle. In some embodiments, there is a method of treating In some embodiments, the metastatic melanoma is at stage melanoma (such as metastatic melanoma or metastatic malig M1c. In some embodiments, the individual has measurable 40 nant melanoma) in a human individual, wherein said indi disease. In some embodiments, the individual has melanoma vidual has not previously been treated for melanoma or has with brain metastases. In some embodiments, the individual not received prior cytotoxic chemotherapy such as prior adju does not have brain metastases. In some embodiments, the vant cytotoxic therapy, comprising intravenously administer individual comprises a wild-type BRAF. In some embodi ing by infusing over about 30-40 minutes to the individual an ments, the individual comprises a mutant BRAF (such as 45 effective amount of Nab-paclitaxel (for example about 5 BRAF with a V600E mutation). In some embodiments, the mg/ml Nab-paclitaxel), wherein the dose of paclitaxel in the individual has elevated LDH level. In some embodiments, the nanoparticle composition is about 120 mg/m on days 1, 8, 15 individual is a female. In some embodiments, the individual is of every 28 day cycle. In some embodiments, there is a under about 65 years old. In some embodiments, the indi method of treating melanoma (Such as metastatic melanoma vidual is at least about 65 years old (for example at least about 50 or metastatic malignant melanoma) in a human individual, any of 70, 75, or 80 years old). wherein said individual has not previously been treated for In some embodiments, there is a method of treating mela melanoma or has not received prior cytotoxic chemotherapy noma (Such as metastatic melanoma or metastatic malignant Such as prior adjuvant cytotoxic therapy, comprising intrave melanoma) in a human individual, wherein said individual nously administering by infusing over about 30-40 minutes to has not previously been treated for melanoma or has not 55 the individual an effective amount of Nab-paclitaxel (for received prior cytotoxic chemotherapy Such as prior adjuvant example about 5 mg/ml Nab-paclitaxel), wherein the dose of cytotoxic therapy, comprising administering to the individual paclitaxel in the nanoparticle composition is about 90 mg/m an effective amount of a composition comprising nanopar on days 1, 8, 15 of every 28 day cycle. In some embodiments, ticles comprising paclitaxel and albumin (such as nanopar the individual is treated for at least about 2 months, including ticles having average particle size of no greater thanabout 200 60 for example at least about any of 3, 4, 5, 6, 7, 8, 9, 10, 11, or nm). In some embodiments, there is a method of treating 12 months. In some embodiments, the melanoma is stage IV melanoma (such as metastatic melanoma or metastatic malig melanoma. In some embodiments, the individual has distant nant melanoma) in a human individual, wherein said indi metastases. In some embodiments, the metastatic melanoma vidual has not previously been treated for melanoma or has is at stage Mla. In some embodiments, the metastatic mela not received prior cytotoxic chemotherapy such as prior adju 65 noma is at stage M1b. In some embodiments, the metastatic vant cytotoxic therapy, comprising administering to the indi melanoma is at stage M1c. In some embodiments, the indi vidual an effective amount of a composition comprising vidual has measurable disease. In some embodiments, the US 9,149,455 B2 105 106 individual has melanoma with brain metastases. In some wherein said individual has previously been treated for mela embodiments, the individual does not have brain metastases. noma or has received prior cytotoxic chemotherapy Such as In some embodiments, the individual comprises a wild-type prior adjuvant cytotoxic therapy, comprising infusing over BRAF. In some embodiments, the individual comprises a about 30-40 minutes to the individual an effective amount of mutant BRAF (such as BRAF with a V600E mutation). In Nab-paclitaxel (for example about 5 mg/ml Nab-paclitaxel), some embodiments, the individual has elevated LDH level. In wherein the dose of paclitaxel in the nanoparticle composi Some embodiments, the individual is a female. In some tion is about 120 mg/m on days 1, 8, 15 of every 28 day cycle. embodiments, the individual is under about 65 years old. In In some embodiments, there is a method of treating mela some embodiments, the individual is at least about 65 years noma (Such as metastatic melanoma or metastatic malignant old (for example at least about any of 70, 75, or 80 years old). 10 melanoma) in a human individual, wherein said individual In some embodiments, there is a method of treating mela has previously been treated for melanoma or has received noma (Such as metastatic melanoma or metastatic malignant prior cytotoxic chemotherapy Such as prior adjuvant cyto melanoma) in a human individual, wherein said individual toxic therapy, comprising infusing over about 30-40 minutes has previously been treated for melanoma or has received to the individual an effective amount of Nab-paclitaxel (for prior cytotoxic chemotherapy Such as prior adjuvant cyto 15 example about 5 mg/ml Nab-paclitaxel), wherein the dose of toxic therapy, comprising administering to the individual an paclitaxel in the nanoparticle composition is about 90 mg/m effective amount of a composition comprising nanoparticles on days 1, 8, 15 of every 28 day cycle. In some embodiments, comprising paclitaxel and albumin (such as nanoparticles the individual is treated for at least about 2 months, including having average particle size of no greater than about 200 nm). for example at least about any of 3, 4, 5, 6, 7, 8, 9, 10, 11, or In some embodiments, there is a method of treating mela 12 months. In some embodiments, the melanoma is stage IV noma (Such as metastatic melanoma or metastatic malignant melanoma. In some embodiments, the individual has distant melanoma) in a human individual, wherein said individual metastases. In some embodiments, the metastatic melanoma has previously been treated for melanoma or has received is at stage Mla. In some embodiments, the metastatic mela prior cytotoxic chemotherapy Such as prior adjuvant cyto noma is at stage M1b. In some embodiments, the metastatic toxic therapy, comprising administering to the individual an 25 melanoma is at stage M1c. In some embodiments, the indi effective amount of a composition comprising nanoparticles vidual has measurable disease. In some embodiments, the comprising paclitaxel coated with albumin (Such as nanopar individual has melanoma with brain metastases. In some ticles having average particle size of no greater thanabout 200 embodiments, the individual does not have brain metastases. nm, for example Nab-paclitaxel). In some embodiments, In some embodiments, the individual comprises a wild-type there is a method of treating melanoma (Such as metastatic 30 BRAF. In some embodiments, the individual comprises a melanoma or metastatic malignant melanoma) in a human mutant BRAF (such as BRAF with a V600E mutation). In individual, wherein said individual has previously been some embodiments, the individual has elevated LDH level. In treated for melanoma or has received prior cytotoxic chemo Some embodiments, the individual is a female. In some therapy Such as prior adjuvant cytotoxic therapy, comprising embodiments, the individual is under about 65 years old. In intravenously administering (for example infusing over about 35 some embodiments, the individual is at least about 65 years 30-40 minutes) to the individual an effective amount of Nab old (for example at least about any of 70, 75, or 80 years old). paclitaxel (for example about 5 mg/ml Nab-paclitaxel), In some embodiments, there is a method of treating mela wherein the dose of paclitaxel in the nanoparticle composi noma (Such as metastatic melanoma or metastatic malignant tion is about 80 to about 200 mg/m (including for example melanoma) in a human individual, wherein said individual about 90 mg/m, about 120 mg/m, or about 150 mg/m). In 40 has an elevated LDH level, comprising administering to the Some embodiments, there is a method of treating melanoma individual an effective amount of a composition comprising (such as metastatic melanoma or metastatic malignant mela nanoparticles comprising paclitaxel and albumin (such as noma) in a human individual, wherein said individual has nanoparticles having average particle size of no greater than previously been treated for melanoma or has received prior about 200 nm). In some embodiments, there is a method of cytotoxic chemotherapy Such as prior adjuvant cytotoxic 45 treating melanoma (Such as metastatic melanoma or meta therapy, comprising intravenously administering (for static malignant melanoma) in a human individual, wherein example infusing over about 30-40 minutes) to the individual said individual has an elevated LDH level, comprising admin an effective amount of Nab-paclitaxel (for example about 5 istering to the individual an effective amount of a composition mg/ml Nab-paclitaxel), wherein the dose of paclitaxel in the comprising nanoparticles comprising paclitaxel coated with nanoparticle composition is about 80 to about 200 mg/m 50 albumin (such as nanoparticles having average particle size of (including for example about 90 mg/m, about 120 mg/m, or no greater than about 200 nm, for exampleNab-paclitaxel). In about 150 mg/m) on days 1, 8, 15 of every 28 day cycle. In Some embodiments, there is a method of treating melanoma Some embodiments, there is a method of treating melanoma (such as metastatic melanoma or metastatic malignant mela (such as metastatic melanoma or metastatic malignant mela noma) in a human individual, wherein said individual has an noma) in a human individual, wherein said individual has 55 elevated LDH level, comprising intravenously administering previously been treated for melanoma or has received prior (for example infusing over about 30-40 minutes) to the indi cytotoxic chemotherapy Such as prior adjuvant cytotoxic vidual an effective amount of Nab-paclitaxel (for example therapy, comprising infusing over about 30-40 minutes to the about 5 mg/ml Nab-paclitaxel), wherein the dose of paclitaxel individual an effective amount of Nab-paclitaxel (for in the nanoparticle composition is about 80 to about 200 example about 5 mg/ml Nab-paclitaxel), wherein the dose of 60 mg/m (including for example about 90 mg/m, about 120 m paclitaxel in the nanoparticle composition is about 150 g/m, or about 150 mg/m). In some embodiments, there is a mg/m on days 1, 8, 15 of every 28 day cycle. In some method of treating melanoma (Such as metastatic melanoma embodiments, the individual is treated for at least about 2 or metastatic malignant melanoma) in a human individual, months, including for example at least about any of 3, 4, 5, 6, wherein said individual has an elevated LDH level, compris 7, 8, 9, 10, 11, or 12 months. In some embodiments, there is 65 ing intravenously administering (for example infusing over a method of treating melanoma (Such as metastatic melanoma about 30-40 minutes) to the individual an effective amount of or metastatic malignant melanoma) in a human individual, Nab-paclitaxel (for example about 5 mg/ml Nab-paclitaxel), US 9,149,455 B2 107 108 wherein the dose of paclitaxel in the nanoparticle composi Some embodiments, there is a method of treating melanoma tion is about 80 to about 200 mg/m (including for example (such as metastatic melanoma or metastatic malignant mela about 90 mg/m, about 120 mg/m, or about 150 mg/m) on noma) in a human individual, wherein said individual com days 1, 8, 15 of every 28 day cycle. In some embodiments, prises wild-type BRAF, comprising intravenously adminis there is a method of treating melanoma (Such as metastatic tering (for example infusing over about 30-40 minutes) to the melanoma or metastatic malignant melanoma) in a human individual an effective amount of Nab-paclitaxel (for individual, wherein said individual has an elevated LDH example about 5 mg/ml Nab-paclitaxel), wherein the dose of level, comprising infusing over about 30-40 minutes to the paclitaxel in the nanoparticle composition is about 80 to about individual an effective amount of Nab-paclitaxel (for 200 mg/m (including for example about 90 mg/m, about example about 5 mg/ml Nab-paclitaxel), wherein the dose of 10 120 mg/m, or about 150 mg/m) on days 1, 8, 15 of every 28 paclitaxel in the nanoparticle composition is about 150 day cycle. In some embodiments, there is a method of treating mg/m on days 1, 8, 15 of every 28 day cycle. In some melanoma (such as metastatic melanoma or metastatic malig embodiments, there is a method of treating melanoma (Such nant melanoma) in a human individual, wherein said indi as metastatic melanoma or metastatic malignant melanoma) vidual comprises wild-type BRAF, comprising infusing over in a human individual, wherein said individual has an elevated 15 about 30-40 minutes to the individual an effective amount of LDH level, comprising infusing over about 30-40 minutes to Nab-paclitaxel (for example about 5 mg/ml Nab-paclitaxel), the individual an effective amount of Nab-paclitaxel (for wherein the dose of paclitaxel in the nanoparticle composi example about 5 mg/ml Nab-paclitaxel), wherein the dose of tion is about 150 mg/mon days 1,8, 15 of every 28 day cycle. paclitaxel in the nanoparticle composition is about 120 In some embodiments, there is a method of treating mela mg/m on days 1, 8, 15 of every 28 day cycle. In some noma (Such as metastatic melanoma or metastatic malignant embodiments, there is a method of treating melanoma (Such melanoma) in a human individual, wherein said individual as metastatic melanoma or metastatic malignant melanoma) comprises wild-type BRAF, comprising infusing over about in a human individual, wherein said individual has an elevated 30-40 minutes to the individual an effective amount of Nab LDH level, comprising infusing over about 30-40 minutes to paclitaxel (for example about 5 mg/ml Nab-paclitaxel), the individual an effective amount of Nab-paclitaxel (for 25 wherein the dose of paclitaxel in the nanoparticle composi example about 5 mg/ml Nab-paclitaxel), wherein the dose of tion is about 120 mg/m on days 1, 8, 15 of every 28 day cycle. paclitaxel in the nanoparticle composition is about 90 mg/m In some embodiments, there is a method of treating mela on days 1, 8, 15 of every 28 day cycle. In some embodiments, noma (Such as metastatic melanoma or metastatic malignant the individual is treated for at least about 2 months, including melanoma) in a human individual, wherein said individual for example at least about any of 3, 4, 5, 6, 7, 8, 9, 10, 11, or 30 comprises wild-type BRAF, comprising infusing over about 12 months. In some embodiments, the individual has serum 30-40 minutes to the individual an effective amount of Nab LDH at about 0.8.x to about 1.1 xULN. In some embodiments, paclitaxel (for example about 5 mg/ml Nab-paclitaxel), the individual has serum LDH of between greater than about wherein the dose of paclitaxel in the nanoparticle composi 1.1.x to about 2.0xULN. In some embodiments, the individual tion is about 90 mg/m on days 1, 8, 15 of every 28 day cycle. comprises a wild-type BRAF. In some embodiments, the 35 In some embodiments, the individual is treated for at least individual comprises a mutant BRAF (such as BRAF with a about 2 months, including for example at least about any of 3. V600E mutation). In some embodiments, the individual has 4,5,6,7,8,9, 10, 11, or 12 months. In some embodiments, the stage M1c metastatic melanoma. In some embodiments, the individual has stage M1c melanoma. In some embodiments, individual is a female. In some embodiments, the individual is the individual has elevated LDH level. In some embodiments, under about 65 years old. In some embodiments, the indi 40 the individual is a female. In some embodiments, the indi vidual is at least about 65 years old (for example at least about vidual is under about 65 years old. In some embodiments, the any of 70, 75, or 80 years old). individual is at least about 65 years old (for example at least In some embodiments, there is a method of treating mela about any of 70, 75, or 80 years old). noma (Such as metastatic melanoma or metastatic malignant In some embodiments, there is a method of treating mela melanoma) in a human individual, wherein said individual 45 noma (Such as metastatic melanoma or metastatic malignant comprises wild-type BRAF, comprising administering to the melanoma) in a human individual, wherein said individual individual an effective amount of a composition comprising comprises a mutation in BRAF (such as a V600E mutation), nanoparticles comprising paclitaxel and albumin (such as comprising administering to the individual an effective nanoparticles having average particle size of no greater than amount of a composition comprising nanoparticles compris about 200 nm). In some embodiments, there is a method of 50 ing paclitaxel and albumin (Such as nanoparticles having treating melanoma (such as metastatic melanoma or meta average particle size of no greater than about 200 nm). In static malignant melanoma) in a human individual, wherein Some embodiments, there is a method of treating melanoma said individual comprises wild-type BRAF, comprising (such as metastatic melanoma or metastatic malignant mela administering to the individual an effective amount of a com noma) in a human individual, wherein said individual com position comprising nanoparticles comprising paclitaxel 55 prises a mutation in BRAF (such as a V600E mutation), coated with albumin (Such as nanoparticles having average comprising administering to the individual an effective particle size of no greater than about 200 nm, for example amount of a composition comprising nanoparticles compris Nab-paclitaxel). In some embodiments, there is a method of ing paclitaxel coated with albumin (such as nanoparticles treating melanoma (such as metastatic melanoma or meta having average particle size of no greater than about 200 nm, static malignant melanoma) in a human individual, wherein 60 for example Nab-paclitaxel). In some embodiments, there is a said individual comprises wild-type BRAF, comprising intra method of treating melanoma (Such as metastatic melanoma venously administering (for example infusing over about or metastatic malignant melanoma) in a human individual, 30-40 minutes) to the individual an effective amount of Nab wherein said individual comprises a mutation in BRAF (such paclitaxel (for example about 5 mg/ml Nab-paclitaxel), as a V600E mutation), comprising intravenously administer wherein the dose of paclitaxel in the nanoparticle composi 65 ing (for example infusing over about 30-40 minutes) to the tion is about 80 to about 200 mg/m (including for example individual an effective amount of Nab-paclitaxel (for about 90 mg/m, about 120 mg/m, or about 150 mg/m). In example about 5 mg/ml Nab-paclitaxel), wherein the dose of US 9,149,455 B2 109 110 paclitaxel in the nanoparticle composition is about 80 to about albumin) is administered intravenously. In some embodi 200 mg/m (including for example about 90 mg/m, about ments, the effective amount of taxane (e.g., paclitaxel) in the 120 mg/m, or about 150 mg/m). In some embodiments, nanoparticle composition is about 50 mg/m to about 400 there is a method of treating melanoma (Such as metastatic mg/m. In some embodiments, the effective amount of taxane melanoma or metastatic malignant melanoma) in a human (e.g., paclitaxel) in the nanoparticle composition is about 100 individual, wherein said individual comprises a mutation in mg/m to about 200 mg/m. In some embodiments, the effec BRAF (such as a V600E mutation), comprising intravenously tive amount of taxane (e.g., paclitaxel) in the nanoparticle administering (for example infusing over about 30-40 min composition is about 150 mg/m. In some embodiments, the utes) to the individual an effective amount of Nab-paclitaxel composition comprising nanoparticles comprising taxane (for example about 5 mg/ml Nab-paclitaxel), wherein the 10 (e.g., paclitaxel) and a carrier protein (e.g., albumin) is dose of paclitaxel in the nanoparticle composition is about 80 administered weekly. In some embodiments, the method to about 200 mg/m (including for example about 90 mg/m. comprises at least one 28-day treatment cycle. In some about 120 mg/m, or about 150 mg/m) on days 1, 8, 15 of embodiments, the composition comprising nanoparticles every 28 day cycle. In some embodiments, there is a method comprising taxane (e.g., paclitaxel) and a carrier protein (e.g., of treating melanoma (Such as metastatic melanoma or meta 15 albumin) is administered on days 1, 8, and 15 of the 28-day static malignant melanoma) in a human individual, wherein treatment cycle. said individual comprises a mutation in BRAF (such as a In some embodiments, the albumin is human serum albu V600E mutation), comprising infusing over about 30-40 min min. In some embodiments, the albuminis human albumin. In utes to the individual an effective amount of Nab-paclitaxel Some embodiments, the albumin is recombinant albumin. In (for example about 5 mg/ml Nab-paclitaxel), wherein the Some embodiments, the nanoparticles in the composition dose of paclitaxel in the nanoparticle composition is about have an average diameter of no greater than about 200 nm. In 150 mg/m on days 1, 8, 15 of every 28 day cycle. In some Some embodiments, the weight ratio of albumin and taxane embodiments, there is a method of treating melanoma (Such (e.g., paclitaxel) in the nanoparticle composition is about 9:1 as metastatic melanoma or metastatic malignant melanoma) or less. In some embodiments, the weight ratio of albuminand in a human individual, wherein said individual comprises a 25 taxane (e.g., paclitaxel) in the nanoparticle composition is mutation in BRAF (such as a V600E mutation), comprising about 9:1. In some embodiments, the taxane (e.g., paclitaxel) infusing over about 30-40 minutes to the individual an effec in the nanoparticles are coated with the albumin. In some tive amount of Nab-paclitaxel (for example about 5 mg/ml embodiments, the taxane is paclitaxel. In some embodiments, Nab-paclitaxel), wherein the dose of paclitaxel in the nano there is provided a method of treating melanoma in an indi particle composition is about 120 mg/m on days 1, 8, 15 of 30 vidual (e.g., human) comprising administering to the indi every 28 day cycle. In some embodiments, there is a method vidual an effective amount of a composition comprising of treating melanoma (such as metastatic melanoma or meta nanoparticles comprising paclitaxel and albumin (e.g., static malignant melanoma) in a human individual, wherein human albumin or human serum albumin). said individual comprises a mutation in BRAF (such as a The present application in some embodiments provides a V600E mutation), comprising infusing over about 30-40 min 35 method of treating melanoma in a human individual compris utes to the individual an effective amount of Nab-paclitaxel ing administering to the individual an effective amount of a (for example about 5 mg/ml Nab-paclitaxel), wherein the composition comprising nanoparticles comprising paclitaxel dose of paclitaxel in the nanoparticle composition is about 90 and an albumin. mg/m on days 1, 8, 15 of every 28 day cycle. In some In Some embodiments according to (or as applied to) any of embodiments, the individual is treated for at least about 2 40 the embodiments above, the melanoma is cutaneous mela months, including for example at least about any of 3, 4, 5, 6, Oa. 7, 8, 9, 10, 11, or 12 months. In some embodiments, the In Some embodiments according to (or as applied to) any of individual has stage M1c melanoma. In some embodiments, the embodiments above, the melanoma is metastatic mela the individual has elevated LDH level. In some embodiments, Oa. the individual is a female. In some embodiments, the indi 45 In Some embodiments according to (or as applied to) any of vidual is under about 65 years old. In some embodiments, the the embodiments above, the melanoma is metastatic malig individual is at least about 65 years old (for example at least nant melanoma. about any of 70, 75, or 80 years old). In Some embodiments according to (or as applied to) any of In some embodiments of any of the methods described the embodiments above, the melanoma is stage IV melanoma. herein, the composition comprising nanoparticles comprising 50 In Some embodiments according to (or as applied to) any of paclitaxel and an albumin is used as a monotherapy for treat the embodiments above, the individual has distant ing the melanoma. metaStaSeS. Also provided herein are methods of combination therapy In Some embodiments according to (or as applied to) any of comprising a therapy comprising administration of the nano the embodiments above, the metastatic melanoma is at stage particle compositions described herein and a second therapy. 55 M1a. In some embodiments, the second therapy is selected from the In Some embodiments according to (or as applied to) any of group consisting of chemotherapy, immunotherapy, Surgery, the embodiments above, the metastatic melanoma is at stage radiation therapy, targeted therapy, or a combination thereof. M1b. In some embodiments, the method comprises administration In Some embodiments according to (or as applied to) any of of at least one other therapeutic agent. In some embodiments, 60 the embodiments above, the metastatic melanoma is at stage the one other therapeutic agent is a BRAF inhibitor. In some M1 c. embodiments, the one other therapeutic agent is Ipilimumab. In Some embodiments according to (or as applied to) any of In some embodiments, the method is used as a first line the embodiments above, the individual has measurable dis therapy. In some embodiments, the method is used as a sec CaSC. ond line therapy. In some embodiments of any of the methods 65 In Some embodiments according to (or as applied to) any of described herein, the composition comprising nanoparticles the embodiments above, the individual does not have brain comprising taxane (e.g., paclitaxel) and a carrier protein (e.g., metaStaSeS. US 9,149,455 B2 111 112 In some embodiments according to (or as applied to) any of In Some embodiments according to (or as applied to) any of the embodiments above, the individual has not been previ the embodiments above, the method is used as a second line ously treated for melanoma. therapy. In some embodiments according to (or as applied to) any of In Some embodiments according to (or as applied to) any of the embodiments above, the composition comprising nano the embodiments above, the individual has not received prior particles comprising paclitaxel and an albumin is adminis cytotoxic chemotherapy for the metastatic malignant mela tered intravenously. Oa. In Some embodiments according to (or as applied to) any of In some embodiments according to (or as applied to) any of the embodiments above, the dose of paclitaxel in the nano the embodiments above, the individual has not received prior particle composition is about 50 mg/m to about 400 mg/m. adjuvant cytotoxic chemotherapy. 10 In Some embodiments according to (or as applied to) any of In some embodiments according to (or as applied to) any of the embodiments above, the dose of paclitaxel in the nano the embodiments above, the individual is a male. particle composition is about 100 mg/m to about 200 mg/m. In some embodiments according to (or as applied to) any of In Some embodiments according to (or as applied to) any of the embodiments above, the dose of paclitaxel in the nano the embodiments above, the individual is a female. 15 particle composition is about 150 mg/m. In some embodiments according to (or as applied to) any of In Some embodiments according to (or as applied to) any of the embodiments above, the individual is under about 65 the embodiments above, the composition comprising nano years old. particles comprising paclitaxel and an albumin is adminis In some embodiments according to (or as applied to) any of tered weekly. the embodiments above, the individual is at least about 65 In Some embodiments according to (or as applied to) any of years old (for example at least about any of 70, 75, or 80 years the embodiments above, the method comprises at least one old). 28-day treatment cycle. In some embodiments according to (or as applied to) any of In Some embodiments according to (or as applied to) any of the embodiments above, the individual has elevated serum the embodiments above, the composition comprising nano lactate dehydrogenase (“LDH) level. 25 particles comprising paclitaxel and an albumin is adminis In some embodiments according to (or as applied to) any of tered on days 1, 8, and 15 of the 28-day treatment cycle. the embodiments above, the individual has serum LDHofless In Some embodiments according to (or as applied to) any of the embodiments above, the albumin is human serum albu than about 0.8.x upper limit of normal (“ULN'). min. In some embodiments according to (or as applied to) any of In Some embodiments according to (or as applied to) any of the embodiments above, the individual has serum LDH at 30 the embodiments above, the albumin is human albumin. about 0.8.x to about 1.1XULN. In Some embodiments according to (or as applied to) any of In some embodiments according to (or as applied to) any of the embodiments above, the albuminis recombinant albumin. the embodiments above, the individual has serum LDH of In Some embodiments according to (or as applied to) any of between greater than about 1.1.x to about 2.0xULN. the embodiments above, the nanoparticles in the composition In some embodiments according to (or as applied to) any of 35 have an average diameter of no greater than about 200 nm. the embodiments above, the melanoma comprises wild-type In Some embodiments according to (or as applied to) any of BRAF. the embodiments above, the weight ratio of albumin and In some embodiments according to (or as applied to) any of paclitaxel in the nanoparticle composition is about 9:1 or less. the embodiments above, the melanoma comprises a mutation In Some embodiments according to (or as applied to) any of in BRAF. 40 the embodiments above, the weight ratio of albumin and In some embodiments according to (or as applied to) any of paclitaxel in the nanoparticle composition is about 9:1. the embodiments above, the melanoma comprises a V600E In Some embodiments according to (or as applied to) any of mutation in BRAF. the embodiments above, the paclitaxel in the nanoparticles In some embodiments according to (or as applied to) any of are coated with the albumin. Those skilled in the art will recognize that several embodi the embodiments above, the composition comprising nano 45 ments are possible within the scope and spirit of this inven particles comprising paclitaxel and an albumin is used as a tion. The invention will now be described in greater detail by monotherapy for treating the melanoma. reference to the following nonlimiting examples. The follow In some embodiments according to (or as applied to) any of ing examples further illustrate the invention but, of course, the embodiments above, the method further comprises a sec should not be construed as in any way limiting its scope. ond therapy. 50 In some embodiments according to (or as applied to) any of EXAMPLES the embodiments above, the second therapy is selected from Example 1 the group consisting of chemotherapy, immunotherapy, Sur gery, radiation therapy, targeted therapy, or a combination A Phase 3 Study of Nab-Paclitaxel Versus thereof. 55 Dacarbazine in Chemotherapy-Naive Patients with In some embodiments according to (or as applied to) any of Metastatic Malignant Melanoma the embodiments above, the method further comprises administration of at least one other therapeutic agent. Chemotherapy-naive patients with stage IV cutaneous In some embodiments according to (or as applied to) any of metastatic malignant melanoma were enrolled. The patients the embodiments above, the one other therapeutic agent is a 60 had Eastern Cooperative Oncology Group (ECOG) PS 0-1, BRAF inhibitor. measurable disease, and lactate dehydrogenase (LDH) levels s2.0x Upper Limit of Normal (ULN), and had no current In some embodiments according to (or as applied to) any of brain metastases. The patient baseline characteristics are the embodiments above, the one other therapeutic agent is shown in Table 5. The patients were divided into two arms: (1) Ipilimumab. Nab-paclitaxel (“Nab-P” AbraxaneR) 150 mg/m, intrave In some embodiments according to (or as applied to) any of 65 nous, no premedication, on days 1, 8, and 15 of 28-day cycle; the embodiments above, the method is used as a first line (2) dacarbazine (DTIC) 1000 mg/m, intravenous, on day 1 of therapy. 21-day cycle. FIG. 1 shows the phase 3 study design. US 9,149,455 B2 113 114 TABLE 5 The PFS and interim OS analysis of the study by BRAF status is shown in Table 7. Baseline Characteristics TABLE 7 Nab- All paclitaxel Dacarbazine Patients PFS and Interim OS by BRAF Status Variable (n = 264) (n = 265) (N = 529) Nab- HR Age Median years 62 (21,85) 64 (28,87) 63 (21,87) paclitaxel Dacarbazine (Nab- P (min, max) BRAF Status (n = 264) (n = 265) P/DTIC) value Sex Male, 9% 66 66 66 10 Region North America, 44 44 44 Wild Type N 116 108 % Median PFS, 5.4 2.5 0.715 O.088 Western Europe, 43 43 43 months % Median OS, 12.7 11.1 O.845 O.330 Australia, 96 13 13 13 15 months ECOG 0,96 74 68 71 V6OOE N 65 67 PS 1,9% 26 31 28 Mutation Median PFS, 5.3 3.5 O.883 O.656 Metastatic M1a, 96 10 8 9 months Stage M1b, 9% 25 26 26 Median OS, 16.9 11.2 O688 O.132 M1c, 9% 65 66 65 months LDH <0.8 x ULN,9% 52 52 52 Unknown N 83 90 category 0.8-1.1 x ULN, 27 26 27 Median PFS, 3.7 2.2 O.684 0.066 % months >1.1-2 x ULN, 19 21 2O Median OS, 11.1 9.9 O.837 O.381 % months BRAF Known, % 69 66 67 25 Status V60OE,% 36 38 37 Wild Type 64 62 63 FIG. 4 shows the OS interim analysis of the subgroups Prior Metastatic 7 9 8 based on various patient characteristics. FIG. 4 shows Therapy whether a certain subgroup favors the treatment of Nab-pa 30 clitaxel versus the DTIC treatment and the extent thereof. The primary efficacy endpoint was progression-free Sur The adverse events from the study are shown in Table 8. vival (“PFS) based on a blinded radiology assessment (ac cording to Response Evaluation Criteria in Solid Tumors TABLE 8 (“RECIST) v1.0). The secondary efficacy endpoint was 35 Grade e3 Treatment-related Adverse overall survival (“OS). Other endpoints included objective Events (TRAES) in 5% Patients response rate (“ORR), disease control rate (“DCR), and safety/tolerability. Nab-paclitaxel Dacarbazine Preferred Term (n = 257) (n = 258) FIG. 2 shows the PFS results of the study (PFS was con 40 Patients with at least 1 TRAE,% 50 28 ducted by independent radiology review). FIG. 3 shows the Patients with at least 1 serious TRAE,% 9 7 OS results of the planned interim analysis of the study. Other Nonhematologic Adverse Events, %* efficacy endpoints from the study are shown in Table 6. Peripheral Neuropathy'* 25 O Fatigue 8 2 TABLE 6 Alopecia 5 O 45 Hematologic Adverse events, %* Other Efficacy Endpoints Neutropenia 2O 10 Blinded Response Rate Leukopenia 12 7 Radiology Nab-paclitaxel Dacarbazine Ratio (PP Lymphocytopenia 8 11 Assesment (n = 264) (n = 265) PDTIc) P-value Thrombocytopenia O 6 50 Anemia 2 5 ORR, 9% 15 11 1.30S O.239 Neuropathy, median days (95% CI) (10.5, 19.1) (7.5, 15.1) (0.837, 2.035) DCR, 9% 39 27 1.442 O.004 Time to Onset 101 (95% CI) (32.8, 44.5) (21.5, 32.1) (1.123, 1.852) Time to Improvement by 1 grade 28 PR, 9% 15 11 Time to Improvement to grades 1 67 SD 16 24 15 55 weeks, 96 *Except for lymphocytopenia, all events P × 0.05 Best 0.00173 ** All but 2 neuropathy cases were grade 3 Response PR, 9% 15 11 SD, 9% 25 16 The results showed that this study met its primary endpoint PD, 9% 35 48 60 of PFS: 4.8 vs 2.5 months (P=0.044, Nab-paclitaxel vs dac Not 25 25 arbazine). The interim OS analysis showed a trend in favor of Evaluable, 96 the Nab-paclitaxel arm. Other endpoints (ORR, DCR) and *Include confirmed PR+ SD+PD subgroups showed consistent benefit in favor of the Nab P: proportion of improved patients; PD; progressive; paclitaxel arm. Most notable AE was grade 23 neuropathy in PR: partial response; 65 the Nab-paclitaxel arm, which improved within a month. This SD: stable disease study demonstrated that Nab-paclitaxel was Superior to stan dard dacarbazine chemotherapy. US 9,149,455 B2 115 116 Example 2 the study, and signs the Informed Consent form prior to participation in any study-related activities. A Phase 3 Study of Nab Paclitaxel Versus Exclusion criteria include: (1) History or current evidence Dacarbazine in Previously Untreated Patients with of brain metastases, including leptomeningeal involvement; Metastatic Malignant Melanoma (2) Patient has pre-existing peripheral neuropathy of NCI CTCAE Scale of Grade 22; (3) Prior radiation to a target The main purpose of this study is to compare the safety, lesion is permitted only if there has been clear progression of tolerability, and anti-tumor activity of an investigational drug, the lesion since radiation was completed; (4) Clinically sig Nab-paclitaxel (Abraxane(R) versus dacarbazine in patients nificant concurrent illness; (4) Unlikely to be able to complete with metastatic melanoma who have not previously received 10 the study through the End of Study (EOS) visit; (5) Current chemotherapy. enrollment in a different clinical study in which investiga Treatment arm A: Patients who receive Nab-paclitaxel tional therapeutic procedures are performed or investiga would be dosed intravenously over approximately 30 minutes tional therapies are administered while participating in this without steroid pre-medication and without G-CSF prophy study; (6) Serious medical factor involving any of the major laxis (unless modified as described below); 150 mg/m, on 15 organ systems such that the investigator considers it unsafe days 1, 8, and 15 every 4 weeks. Treatment arm B: Patients for the patient to receive an experimental research drug. who receive dacarbazine would be dosed intravenously at 1000 mg/m on Day 1 with steroid and antiemetic pre-medi Example 3 cation; treatment repeated every 21 days. The primary efficacy endpoint is progression-free Survival Phase I Study of Hepatic Arterial Infusion of (PFS) based on a blinded radiology assessment of response Nab-Paclitaxel (Abraxane(R) in Patients with using RECIST response guidelines. The secondary outcome Metastatic Melanoma in the Liver measures include the following: (1) patient Survival as sec ondary efficacy endpoint; (2) progression-free Survival based This is an open-label, Phase I dose-escalation study to on investigator assessment; (3) number (%) of patients who 25 determine the response rate of metastatic melanoma to the achieve an objective confirmed complete or partial response; liver when treated with Abraxane(R) administered via hepatic (4) number (%) of patients with stable disease for-16 weeks, artery one day every three weeks. Secondary objectives are to or confirmed complete or partial response (i.e., total determine the duration of response in the liver, survival (over response); (5) duration of response in responding patients; (6) all Survival or progression-free Survival), and safety. correlation of SPARC and other molecular biomarkers with 30 Patients meeting all inclusion/exclusion criteria are efficacy outcomes; (7) incidence of treatment-emergent and enrolled in groups of 3 to 6 to receive AbraxaneR infusion treatment related adverse events (AEs) and serious adverse once every 21 days. The maximum tolerable dose is deter events (SAEs); (8) laboratory abnormalities; (9) nadir of mined after two cycles of study treatment. Dose limiting myelosuppression during study drug dosing: (10) incidence toxicity is defined as: agrade 3 non-hematologic toxicity (or of patients experiencing dose modifications, dose interrup 35 the receipt of optimal symptomatic treatment for agrade 3 tions, and/or premature discontinuation of study drug; (11) nausea, vomiting, or diarrhea), any grade 4 transaminitis, the pharmacokinetic parameters being the maximum plasma grade 3 neutropenia with fever requiring hospitalization for drug concentration (Cmax), the area under the plasma con parenteral antibiotics, grade 4 neutropenia lasting a 7 days or centration versus time curve (AUC and AUCinf), the half-life complicated by infection, or a platelet count of <25,000/mm. of the apparent terminal portion of the concentration versus 40 Toxicity of treatment is graded using the NCI Common Tox time curve (T1/2), total body clearance (CL), and the volume icity Criteria (CTC), Version 3.0. Response to therapy is of distribution (VZ). measured using RECIST. Four dose levels are examined: 130 The patients enrolled in the study must be 18 years or older. mg/m, 170 mg/m, 220 mg/m and 285 mg/m; these are Both males and females are eligible for the study. infused via hepatic artery over 30 minutes every three weeks. Inclusion criteria include: (1) Histologically or cytologi 45 cally confirmed cutaneous malignant melanoma with evi Example 4 dence of metastasis (Stage IV); (2) No prior cytotoxic che motherapy for metastatic malignant melanoma (prior A Phase II Study of Weekly Infusion Nab-Paclitaxel treatment with kinase inhibitors or cytokines is permitted): (Abraxane(R) in Patients with Unresectable and (3) No prior adjuvant cytotoxic chemotherapy (prior adjuvant 50 Metastatic Uveal Melanoma therapy with interferon, GM-CSF and/or vaccines is permit ted); (4) Male or non-pregnant and non-lactating females 18 This is a Phase II study to determine the overall response years of age; (5) No other current active malignancy within rate to single agent Nab-paclitaxel (Abraxane.R.) in the treat the past 3 years; (6) Radiographically-documented measur ment of metastatic uveal melanoma. Secondary objectives are able disease (for example, measurable disease may refer to 55 to determine median progression free Survival and overall the presence of at least 1 radiographically documented mea Survival. Inclusion criteria are: (1) histologically or cytologi Surable lesion.); (7) The patient has the following blood cally confirmed evidence of metastatic/unresectable uveal counts at Baseline: (a) ANC >1.5x10 cells/L.; (b) platelets melanoma; (2) measurable disease, defined as at least one >100x10 cells/L. (c) Hgb >9 g/dL; (8) The patient has the lesion that can be accurately measured in at least one dimen following blood chemistry levels at Baseline: (a) AST 60 sion and is a 10 mm by spiral CT scan; (3) age 218 years or (SGOT), ALT (SGPT) s2.5.x upper limit of normal range older; (4) ECOG performance status of 0 or 1; (5) no known (ULN) (s.5.0xULN if hepatic metastases present); (b) total HIV or Hepatitis B or C; (6) normal organ/marrow function as bilirubins ULN; (c) creatinine s 1.5 mg/dL; (d) LDH s2.0 defined by: (a) absolute neutrophil count 1.5x10/L; (b) ULNa; (9) Patient has expected survival of >12 weeks; (10) platelets-100,000x10/L; (c) hemoglobind9.0gm/100 mL.; Patient has ECOG performance status 0-1; (11) Patient or 65 (d) total bilirubin s1.5; (e) AST and ALT s2.5xULN; (f) his/her legally authorized representative or guardian is creatinine s1.8 mg/mL, (g) calcium s 12 mg/dL when cor informed about the nature of the study, agrees to participate in rected for levels of serum albumin; (h) up to one prior sys US 9,149,455 B2 117 118 temic therapy. Exclusion criteria are: (1) chemotherapy or registration; (3) use of any anti-cancer therapy s4 weeks prior radiotherapy within 4 weeks prior to study entry; (2) simul to registration; (4) prior treatment with Ipilimumab, or tax taneous receipt of other study agents; (3) prior malignancy ane-based chemotherapy regimens, or agents disrupting (except for adequately treated basal cell cancer or other can VEGF activity or targeting VEGFR; (5) major surgical pro cer for which patient has been disease-free for two years); (4) cedure, open biopsy, or significant traumatic injury s4 weeks serious infections or other uncontrolled medical illnesses; (5) prior to registration; (6) other medical conditions; (7) exist significant psychiatric illness; (5) pregnancy; (6) peripheral ence of peripheral sensory neuropathy a2 (from any cause); neuropathy of >grade 2. Abraxane R is administered via intra (8) palliative radiation therapy s2 weeks prior to randomiza venous bolus over 30 minutes at a dose of 150 mg/m weekly tion; (9) active or recent history of hemoptysis s30 days prior for 3 of 4 weeks every 28 days. 10 to registration; (10) known hypersensitivity to any of the Example 5 components of Ipilimumab, bevacizumab, or Abraxane R; (11) history of inflammatory bowel disease (e.g., Crohn's A Randomized Phase II Study of AB (Abraxane(R) ulcerative colitis); (12) patients with diagnosis of autoim Plus Bevacizumab) Versus Ipilimumab for First Line 15 mune disease, regardless of whether or not they are currently Therapy of Unresectable Stage IV Metastatic receiving treatment at the time of registration; (13); systemic Malignant Melanoma (BRAF V600E Negative) use of corticosteroids s2 weeks prior to registration, regard less of indication. This is a randomized, two-arm Phase II study of the effi Tables 5 and 6 describe the two arms for this study. cacy of the Abraxane(R) plus bevacizumab (AB) combination regimen in patients undergoing first line therapy for meta TABLE 5 static melanoma (BRAF V600E negative) as it compares to the current standard of care, Ipilimumab. The primary goal of ArmA: Abraxane (R), Bevacizumab this study is to assess whether the combination of Abraxane(R) Agent Dose Schedule Route Retreatment plus bevacizumab prolongs progression-free status relative to 25 Bevacizumab 10 mg/kg Days 1 IV over 90 Every 28 days Ipilimumab as a first line treatment in patients with unresec and 15 minutes'* (+2 days) until table stage IV melanoma. The primary endpoint is progres progression sion-free survival defined as time from randomization to the Abraxane (R) 150 mg/m. Days 1, IV over 30 earliest documentation of progression as defined by the 8, 15 minutes 30 RECIST criteria (version 1.1) or death from any cause with *Drugs are administered in the order listed above. Bevacizumab is always infused first, out the documentation of progression. The secondary end **Subsequent infusions of bevacizumab are administered over 60 or over 30 minutes, if points include overall survival (time from randomization to tolerated. death due to any cause) as well as tumor response (using One treatment cycle = 28 days + 2 days. RECIST criteria, v. 1.1). Correlative goals are to examine the changes in: biomark 35 TABLE 6 ers of angiogenesis (Arm A) and biomarkers of immunity (Arm A and Arm B), as well as to examine the pharmacoki Arm B. pilimumab netics of paclitaxel when combined with bevacizumab therapy. Plasma levels of the following angiogenesis media Drug Dose Schedule Route Retreatment tors are determined: angiopoietin-2, BMP-9, EGF, endoglin, 40 Ipilimumab 3 mg/kg Day 1 IV over 90 Every 21 days endothelin-1, FGF-1, FGF-2, follistatin, G-CSF, HB-EGF, minutes for a maximum HGF, IL-8, leptin, PLGF, VEGF-A, VEGF-C, and VEGF-D. of 4 cycles Samples of peripheral blood (pre-treatment for all cycles) are One treatment cycle = 21 days+ 2 days, analyzed for numbers and activation status of T cells, B cells, NK cells, and dendritic cells, and peripheral blood samples 45 are also analyzed for CD3, CD4, CD8, CD20, CD69, CD4/ Example 6 25, CD8/25, CD16/56, CD80, CD86, and HLA-DR. Inclusion criteria are: (1) histologic proof of Surgically A Phase II Study of Abraxane(R) Plus Ipilimumab in unresectable stage IV malignant melanoma; (2) no prior sys Patients with Metastatic Melanoma temic therapy for metastatic melanoma; (3) BRAF V600E 50 wild type mutation not detected in metastatic tumor speci This is an open-label, single-arm Phase II study to deter men; (4) measurable disease defined as at least one lesion mine the efficacy and safety of Abraxane(R-Ipilimumab com whose longest diameter can be accurately measured as 22.0 bination administered intravenously to patients with chemo cm with chest X-ray, or as a 1.0 cm with CT scan, MRI scan, therapy naive metastatic malignant melanoma. The primary or CT component of a PET/CT scan; (5) life expectancy of 4 55 objectives are to determine if the combination of Abraxane(R) months; (6) age 18 years; (7) ECOG performance score of 0 and Ipilimumab can delay disease progression in patients or 1; (8) the following laboratory values obtained s14 days with metastatic melanoma, and to determine the rate of pro prior to registration or randomization: (a) ANC >1500 mL.; gression-free survival at 6 months of the Abraxane(R) plus (b) platelet count 100,000x10/L; (c) hemoglobin 9 g/dL: Ipilimumab combination. The secondary objectives are: (1) (d) creatinines 1.5xULN; (e) total bilirubins 1.5 mg/dL (f) 60 to determine the efficacy of the Abraxane(R) plus Ipilimumab SGOT (AST)s2.5xULN; (g) absence of proteinuria at combination as measured by complete and partial response screening: (h) negative serum pregnancy test for women of rate, response duration, and overall Survival in patients with childbearing potential: (i) adequate use of contraception metastatic unresectable stage III/IV melanoma; (2) to deter throughout the trial and for 12 weeks after the last dose of mine the safety of the combination of Abraxane(R) plus Ipili study drug; and () signed informed consent. 65 mumab when given intravenously for the treatment of Exclusion criteria are: (1) brain metastases per MRI or CT: patients with metastatic melanoma; and (3) to study the (2) use of other investigational agents s4 weeks prior to immunologic changes in patients who receive this therapy. US 9,149,455 B2 119 120 The starting dose of Abraxane R for this trial is 150 mg/m of clarity of understanding, the descriptions and examples to be administered on days 1, 8, and 15 every 28 days. Abrax should not be construed as limiting the scope of the invention. aneR is dosed intravenously over approximately 30 minutes without steroid premedication and without G-CSF prophy What is claimed is: laxis. The dose of Ipilimumab for this trial is 3 mg/kg intra 1. A method of treating melanoma in a human individual venously every 3 weeks for 4 doses only; this dose of Ipili comprising administering to the individual an effective mumab will not be increased. amount of a composition comprising nanoparticles compris Inclusion criteria are: (1) histologically documented diag ing paclitaxel and an albumin, wherein the individual is nosis of advanced stage IV or unresectable stage III mucosal Selected for treatment based on the individual having a mela or cutaneous melanoma; (2) recurrent melanoma with mea 10 noma comprising a V600E mutation in BRAF and wherein Surable or evaluable sites of disease, 1.0 cm or larger, in order the composition is administered intravenously and the dose of to assess the response to treatment by the immune-related paclitaxel in the composition is about 80 mg/m to about 200 response criteria (irRC); (3) no previous treatment with cyto mg/m. toxic drugs and immunotherapeutic agents for unresectable 2. The method of claim 1, wherein the individual is selected Stage III or Stage IV disease; (4) patient is between 12 and 70 15 for treatment based on the individual having metastatic mela years of age with an ECOG performance status of 0 or 1; (5) noma at stage M1c. normal blood counts with a white blood cell count of more 3. The method of claim 1, wherein the individual is selected than or equal to 3000/mm, an absolute neutrophil count of for treatment based on the individual having a serum LDH more than or equal to 1500 mm and a platelet count of more level of between about 1.1.x to about 2.0xULN. than 100,000/mm, hemoglobin >9.0 g/dL, no impairment of 4. The method of claim 1, wherein the method further renal function (serum creatinine less than 1.1 mg/dL for comprises a second therapy. females and less than 1.4 mg/dL for males), no impairment of 5. The method of claim 4, wherein the method comprises hepatic function (serumbilirubin levelofless than 1.5 mg/dL, administration of at least one other therapeutic agent. AST and ALTs2.5xULN unless there is hepatic metastasis in 6. The method of claim 5, wherein the other therapeutic which case AST and ALT s5 ULN are acceptable), and no 25 agent is a BRAF inhibitor. evidence of significant cardiac or pulmonary dysfunction; (6) 7. The method of claim 5, wherein the other therapeutic no significant concurrent illness such as an active infection agent is Ipilimumab. associated with fever lasting more than 24 hours requiring 8. The method of claim 1, wherein the method is used as a antibiotics, uncontrolled psychiatric illness, hypercalcemia first line therapy. (calcium greater than 11 mg), or active gastrointestinal bleed 30 9. The method of claim 1, wherein the method is used as a ing; (7) females of child-bearing potential must use accept second line therapy. 10. The method of claim 1, wherein the dose of paclitaxel able contraception and have a negative serum or urine preg in the nanoparticle composition is about 150 mg/m. nancy test within 72 hours prior to beginning treatment on this 11. The method of claim 1, wherein the composition com trial, and sexually active men must also use contraceptive prising nanoparticles comprising paclitaxel and an albuminis methods for the duration of the study; (8) signed informed 35 administered weekly. COnSent. 12. The method of claim 11, wherein the composition Exclusion criteria are: (1) metastatic uveal melanoma; (2) comprising nanoparticles comprising paclitaxel and an albu bone metastases only; (3) symptomatic brain or spinal cord minis administered on days 1, 8, and 15 of a 28-day treatment metastases, steroid therapy or leptomeningeal disease; (4) cycle. significant cardiac illness; (5) significant impairment of pull 40 13. The method of claim 1, wherein the albumin is human monary function on account of chronic bronchitis, emphy serum albumin. Sema or chronic obstructive pulmonary disease which results 14. The method of claim 1, wherein the nanoparticles in the in impairment of vital capacity of FEV1 to less than 75% of composition have an average diameter of no greater than predicted normal values; (6) symptomatic effusions on about 200 nm. account of pleural, pericardial or peritoneal metastases of 45 melanoma; (7) history of second malignant tumor, other than 15. The method of claim 1, wherein the weight ratio of the common skin cancers—basal and squamous carcino albumin and paclitaxel in the nanoparticle composition is mas—within the past 3 years; (8) >grade 2 sensory neuropa about 9:1 or less. thy at baseline. 16. The method of claim 1, wherein the paclitaxel in the Although the foregoing invention has been described in 50 nanoparticles are coated with the albumin. 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