US 20140080760A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0080760 A1 Khong (43) Pub. Date: Mar. 20, 2014

(54) COMBINATION THERAPY FOR Publication Classi?cation TREATMENT OF (51) Int. Cl. (75) Inventor: Hung T. Khong, Mobile, AL (US) A61K 47/48 (2006.01) A61K 31/704 (2006.01) (73) Assignee: UNIVERSITY OF SOUTH A61K 31/675 (2006.01) ALABAMA, Mobile, AL (US) A61K 31/33 7 (2006.01) (52) US. Cl. (21) APP1-NO-I 14/117,832 CPC ...... A61K47/48284 (2013.01); A61K31/337 (2013.01); A61K31/704 (2013.01); A61K (22) PCT Filed: May 16, 2012 31/675 (201301)

USPC ...... 514/152 (86) PCT No.: PCT/US2012/038111 (57) ABSTRACT (§2§7(14§C]))(a1t)e’_ NOV‘ 14 2013 The present invention relates to methods and compositions ’ ' ’ for the treatment of cancer. Some embodiments include meth Related U's' Apphcatlon. . Data therapeuticods of treatin aggent cancer associated3 com risinWithgalbumin, administerin adm%nistering a chemo a (60) Provisional application No. 61/487,232, ?led on May second chemotherapeutic agent; and administering a third 17, 2011. chemotherapeutic agent. US 2014/0080760 A1 Mar. 20, 2014

COMBINATION THERAPY FOR istered on the same day and subsequently the chemotherapeu TREATMENT OF CANCER tic agent associated With or bound to albumin is administered periodically Without the second chemotherapeutic agent and RELATED APPLICATIONS the third chemotherapeutic agent. [0001] This application claims the bene?t of Us. Provi [0009] In some embodiments, on some occasions the che sional Application No. 61/487232 entitled “COMBINATION motherapeutic agent associated With or bound to albumin the THERAPY FOR TREATMENT OF CANCER” ?led May second chemotherapeutic agent and a third chemotherapeutic 17, 2011, the disclosure of Which is incorporated herein by agent are administered on the same day and on other occa reference in its entirety. sions only the chemotherapeutic agent associated With or bound to albumin is administered. FIELD OF THE INVENTION [0010] In some embodiments, the chemotherapeutic agent associated With or bound to albumin comprises an agent [0002] The present invention relates to methods and com selected from the group consisting of , , positions for the treatment of cancer. Some embodiments and rapamycin. include methods of treating cancer comprising administering [0011] In some embodiments, the chemotherapeutic agent a chemotherapeutic agent associated With or bound to albu min, administering a second chemotherapeutic agent; and associated With or bound to albumin is Abraxane. administering a third chemotherapeutic agent. [0012] In some embodiments, the second chemotherapeu tic agent comprises a . BACKGROUND OF THE INVENTION [0013] In some embodiments, the topoisomerase inhibitor is . [0003] Breast cancer is the most common cancer among [0014] In some embodiments, the third chemotherapeutic Women (excluding basal and squamous cell skin cancer) in agent comprises an alkylating agent. the Us. and is the second most common cause of cancer death among Women. In the year 2007, the estimated neW [0015] In some embodiments, the alkylating agent is cyclo cases of breast cancer among Women in the Us. is 178,480 pho sphamide. and the estimated death from breast cancer is 40,460 (1). [0016] In some embodiments, the chemotherapeutic agent [0004] Neoadjuvant for breast cancer is the associated With or bound to albumin is administered on days use of chemotherapy before de?nitive surgical therapy such 1 and 8. as lumpectomy or mastectomy. Compared With adjuvant or [0017] In some embodiments, the chemotherapeutic agent postoperative chemotherapy, neoadjuvant chemotherapy associated With or bound to albumin is administered on days alloWs higher rates of breast conservation Without compro 1, 8, 15. mising overall survival (2). In addition, neoadjuvant chemo [0018] In some embodiments, the chemotherapeutic agent therapy permits a unique opportunity to observe and evaluate associated With or bound to albumin is administered on days tumor response to treatment and therefore, serving as an in 1, 8, 15, and 22. vivo chemosensitivity assay. This may alloW the tailoring of [0019] In some embodiments, the chemotherapeutic agent treatment for individual patients based on their tumor associated With or bound to albumin is administered on days response to a particular chemotherapy regimen (3-5). This 1, 8, 15, 22, and 28. may potentially enhance response and survival and at the [0020] In some embodiments, the chemotherapeutic agent same time reduce unnecessary toxicities. associated With or bound to albumin is administered on days [0005] Not only neoadjuvant chemotherapy does result in 1, 8, and 22. similar overall survival compared With adjuvant chemo therapy, it is also associated With less adverse toxicities (6). [0021] In some embodiments, the chemotherapeutic agent Compared With adjuvant chemotherapy, neoadj uvant chemo associated With or bound to albumin is administered at an interval of at least about 5 days. therapy is associated With signi?cantly less infectious com plications and cardiotoxicity (6). In addition, there is sugges [0022] In some embodiments, the chemotherapeutic agent tive evidence that neoadj uvant chemotherapy may be superior associated With or bound to albumin is administered at an to adjuvant chemotherapy on survival outcome (7). In con interval of at least about 6 days. trast With adjuvant chemotherapy, there is currently no clear [0023] In some embodiments, the chemotherapeutic agent recommendation on neoadjuvant chemotherapy regimens. associated With or bound to albumin is administered at an There is a need for improved therapies for cancer. interval of at least about 7 days. [0024] In some embodiments, the periodic administration SUMMARY OF THE INVENTION comprises at least 2 cycles. [0006] Some embodiments of the present invention include [0025] In some embodiments, the periodic administration methods of treating a cancer in a subject in need thereof comprises at least 5 cycles. comprising administering a chemotherapeutic agent associ [0026] In some embodiments, the chemotherapeutic agent ated With or bound to albumin; administering a second che associated With or bound to albumin the second chemothera motherapeutic agent; and administering a third chemothera peutic agent and the third chemotherapeutic agent are admin peutic agent. istered on the same day and subsequently the administration [0007] In some embodiments, the chemotherapeutic agent of the chemotherapeutic agent associated With or bound to associated With or bound to albumin is administered periodi albumin is repeated for a plurality of cycles. cally. [0027] In some embodiments, the plurality of cycles for the [0008] In some embodiments, the chemotherapeutic agent subsequent administration of the chemotherapeutic agent associated With or bound to albumin the second chemothera associated With or bound to albumin comprises at least 2 peutic agent and a third chemotherapeutic agent are admin cycles. US 2014/0080760 A1 Mar. 20, 2014

[0028] In some embodiments, the plurality of cycles for the [0048] In some embodiments, the third chemotherapeutic subsequent administration of the chemotherapeutic agent agent comprises an alkylating agent. associated With or bound to albumin comprises at least 5 [0049] In some embodiments, the alkylating agent is cyclo cycles. pho sphamide. [0029] In some embodiments, each cycle for the subse [0050] In some embodiments, the chemotherapeutic agent quent administration of the chemotherapeutic agent associ associated With or bound to albumin is administered on days ated With orbound to albumin comprises at least about 5 days. 1 and 8. [0030] In some embodiments, each cycle for the subse [0051] In some embodiments, the chemotherapeutic agent quent administration of the chemotherapeutic agent associ associated With or bound to albumin is administered on days ated With orbound to albumin comprises at least about 6 days. 1, 8, 15. [0031] In some embodiments, each cycle for the subse [0052] In some embodiments, the chemotherapeutic agent quent administration of the chemotherapeutic agent associ associated With or bound to albumin is administered on days ated With orbound to albumin comprises at least about 7 days. 1, 8, l5, and 22. [0032] In some embodiments, each cycle for the subse [0053] In some embodiments, the chemotherapeutic agent quent administration of the chemotherapeutic agent associ associated With or bound to albumin is administered on days ated With or bound to albumin comprises at least about 1 1, 8, 15, 22, and 28. Week. [0054] In some embodiments, the chemotherapeutic agent [0033] In some embodiments, at least about 100 mg/m2 associated With or bound to albumin is administered on days Abraxane is administered on day l and 8, at least about 50 1, 8, and 22. mg/m2 doxorubicin is administered on day l, and at least [0055] In some embodiments, the chemotherapeutic agent about 500 mg/m2 is administered on day associated With or bound to albumin is administered at an l. interval of at least about 5 days. [0034] Some embodiments also include administering Peg [0056] In some embodiments, the chemotherapeutic agent ?lgrastim on day 9. associated With or bound to albumin is administered at an [0035] In some embodiments, the cancer is breast cancer. interval of at least about 6 days. [0036] In some embodiments, the cancer is HER2 negative [0057] In some embodiments, the chemotherapeutic agent breast cancer. associated With or bound to albumin is administered at an [0037] In some embodiments, the cancer is triple negative interval of at least about 7 days. breast cancer. [0058] In some embodiments, the periodic administration [0038] In some embodiments, the dose of Abraxane is comprises at least 2 cycles. betWeen about 50 mg/m2 and about 200 mg/m2. [0059] In some embodiments, the periodic administration [0039] In some embodiments, the dose of Abraxane is comprises at least 5 cycles. selected from the group consisting of 100 mg/m2 and 150 [0060] In some embodiments, the chemotherapeutic agent mg/m2. associated With or bound to albumin the second chemothera [0040] Some embodiments include use of a combination peutic agent and the third chemotherapeutic agent are admin comprising a chemotherapeutic agent associated With or istered on the same day and subsequently the administration bound to albumin, a second chemotherapeutic agent, and a of the chemotherapeutic agent associated With or bound to third chemotherapeutic agent for the treatment of cancer. albumin is repeated for a plurality of cycles. [0041] In some embodiments, the the chemotherapeutic [0061] In some embodiments, the plurality of cycles for the agent associated With or bound to albumin is administered subsequent administration of the chemotherapeutic agent periodically. associated With or bound to albumin comprises at least 2 [0042] In some embodiments, the chemotherapeutic agent cycles. associated With or bound to albumin the second chemothera [0062] In some embodiments, the plurality of cycles for the peutic agent and a third chemotherapeutic agent are admin subsequent administration of the chemotherapeutic agent istered on the same day and subsequently the chemotherapeu associated With or bound to albumin comprises at least 5 tic agent associated With or bound to albumin is administered cycles. periodically Without the second chemotherapeutic agent and [0063] In some embodiments, each cycle for the subse the third chemotherapeutic agent. quent administration of the chemotherapeutic agent associ [0043] In some embodiments, on some occasions the che ated With orbound to albumin comprises at least about 5 days. motherapeutic agent associated With or bound to albumin the [0064] In some embodiments, each cycle for the subse second chemotherapeutic agent and a third chemotherapeutic quent administration of the chemotherapeutic agent associ agent are administered on the same day and on other occa ated With orbound to albumin comprises at least about 6 days. sions only the chemotherapeutic agent associated With or [0065] In some embodiments, each cycle for the subse bound to albumin is administered. quent administration of the chemotherapeutic agent associ [0044] In some embodiments, the chemotherapeutic agent ated With orbound to albumin comprises at least about 7 days. associated With or bound to albumin comprises an agent [0066] In some embodiments, each cycle for the subse selected from the group consisting of paclitaxel, docetaxel, quent administration of the chemotherapeutic agent associ and rapamycin. ated With or bound to albumin comprises at least about 1 [0045] In some embodiments, the chemotherapeutic agent Week. associated With or bound to albumin is Abraxane. [0067] In some embodiments, at least about 100 mg/m2 [0046] In some embodiments, the second chemotherapeu Abraxane is administered on day l and 8, at least about 50 tic agent comprises a topoisomerase inhibitor. mg/m2 doxorubicin is administered on day l, and at least [0047] In some embodiments, the topoisomerase inhibitor about 500 mg/m2 cyclophosphamide is administered on day is doxorubicin. l. US 2014/0080760 A1 Mar. 20, 2014

[0068] Some embodiments also include administering Peg tions in the adjuvant and neoadjuvant settings. A Weekly ?lgrastim on day 9. nab-paclitaxel is superior to every-three Week docetaxel in [0069] In some embodiments, the cancer is breast cancer. both e?icacy and toxicity in patients With metastatic breast [0070] In some embodiments, the cancer is HER2 negative cancer. Provided herein are results of a single center phase I breast cancer. study in Which nab-paclitaxel replaces docetaxel in the con [0071] In some embodiments, the cancer is triple negative ventional TAC regimen. breast cancer. [0072] In some embodiments, the dose of Abraxane is Albumin-Associated or Albumin-Bound Chemotherapeutic betWeen about 50 mg/m2 and about 200 mg/m2. Agents [0073] In some embodiments, the dose of Abraxane is selected from the group consisting of 100 mg/m2 and 150 [0080] Some embodiments of the methods and composi mg/m2. tions described herein include chemotherapeutic agents asso ciated With or bound to albumin. Examples of chemothera DETAILED DESCRIPTION peutic agents Which may be associated With or bound to [0074] The present invention relates to methods and com albumin include Vmca alkaloids (e.g., , Vincris positions for the treatment of cancer. Some embodiments tine, Vin?unine, , ) (e.g., Caba include methods of treating cancer comprising administering Zitaxel, Docetaxel, , , Paclitaxel, a chemotherapeutic agent associated With or bound to albu ) and (e.g., ), dihydrofolate min, administering a second chemotherapeutic agent; and reductase inhibitors (e.g., , , Pem administering a third chemotherapeutic agent. etrexed, ), thymidylate synthase inhibitors (e. g., [0075] Currently, there is no cure for patients With meta , ), inhibitors static breast cancer. Therefore, treating patients With early (e.g., ), ribonucleotide reductase inhibitors (e.g., stage breast cancer, either before surgery (neoadjuvant) or , , ), (e.g., after surgery (adjuvant) is an important strategy to reduce the Thioguanine, ), thymidylate synthase inhibi chance of cancer recurrence locally or distally, thereby reduc tors (e.g., , , , , ing morbidity and mortality. ), DNA polymerase inhibitors (e.g., ), [0076] Triple-negative breast cancer includes breast can ribonucleotide reductase inhibitors (e.g., ), cers that do not express the genes for estrogen receptor (ER), hypomethylating agents (e.g., , ), ribo progesterone receptor (PR) or HerZ/neu. This subtype of nucleotide reductase inhibitors (e.g., ), breast cancer is clinically characteriZed as more aggressive Topoisomerase inhibitors (e.g., , , and less responsive to standard treatment and associated , , , , , poorer overall patient prognosis. Basal-like or triple negative such as , , Doxoru breast cancer cells express high levels of Secreted protein, bicin, , , , , Valru acidic, cysteine-rich (SPARC) protein, also knoWn as bicin, , and Anthracenediones such as Mitox osteonectin, Which binds and entraps albumin. Overexpres antrone, ), Alkylating agents (e.g., sion of SPARC protein has also been reported in many human Mechlorethamine, Cyclophosphamide such as such as, prostate and colon cancers. and , such as , Predni [0077] Expression of SPARC protein by cancer cells can be mustine, as Well as , , useful to target chemotherapeutic agents to a tumor. In an such as , , , . example pathWay, activation of a speci?c receptor (gp60) on . StreptoZocin, Alkyl sulfonates such as Busul the endothelial cell Wall in turn activates the protein, caveolin fan, , and , and such as l . Caveolin-l can initiate the formation of caveolae Which can , , , and Triethylen transport materials, such as chemotherapeutic agents associ emelamine), Platinums (e.g., , , Nedapl ated With albumin to the tumor interstitium (l7). SPARC atin, , Triplatin tetranitrate, and ), protein expressed by the tumor may bind and entrap the (e.g., ), (e.g., Dacarba chemotherapeutic agents associated With orbound to albumin Zine, ), , and , Inter (18). Abraxane is an example of a chemotherapeutic agent calation agents (e.g., Actinomycin, , Mitomycin, associated With albumin. ). More examples of chemotherapeutic agents [0078] There is currently no clear recommendation on neo include , , Porphyrin deriva adjuvant chemotherapy regimens. Doxorubicin (Adriamy tives (e.g., Por?mer sodium, Talapor?n, Temopor?n, Verte cin) and taxanes are active drugs against breast cancer. A por?n), Enzyme inhibitors (e.g., , , regimen of Taxotere, Adriamycin, and Cyclophosphamide , , , TiaZofurine, Masopro (TAC) administered every three Weeks for 6 cycles, is among col, , , ), , Bexaro the most active regimens in the adjuvant and neoadjuvant tene, , , , , Tre settings (3, l3, 14). However, the pathologic complete tinoin, , , , response rate, Which is a surrogate for long term survival, is , , , , Lucan quite loW for this regimen. A regimen of Abraxane adminis thone, , , , Omacetaxine tered Weekly can provide an increased positive response in mepesuccinate, Everolimus, and Temsirolimus. patients With loWer side effects, compared to a regimen of [0081] In some embodiments, the chemotherapeutic agent administering Taxotere every 3 Weeks. Some methods and albumin comprise a nanoparticle. Examples nanoparticle described herein include regimens including administration include Nab -paclitaxel (Abraxane®). Abraxane is a novel of Nab-paclitaxel, Adriamycin, and Cytoxan (NAC). biologically interactive albumin-bound paclitaxel combining [0079] The TAC regimen (docetaxel, doxorubicin, and a protein With a chemotherapeutic agent in the particle form. cyclophosphamide) is among the most active drug combina Abraxane is an example of an interactive nanoparticle lever US 2014/0080760 A1 Mar. 20, 2014

aging this gp-60/caveolin-1/caveolae/ SPARC pathway to [0087] Median time to tumor progression (TTP) Was sig increase intra-tumoral concentration of the drug and reducing ni?cantly longer With Abraxane than With Taxol for all toxic drug in normal tissue. patients (23.0v16.9 Weeks, respectively; haZard ratio [HR] [0082] In some embodiments of the methods and uses pro :0.75; P:0.006). There Was a trend for greater median sur vided herein, tWo or more of the chemotherapeutic agents vival for all patients treated With Abraxane than With Taxol described herein can be administered to a subject in need (65.0 v 55.7 Weeks, respectively; P:0.374). Although no dif thereof. In some embodiments, three or more of the chemo ference in survival Was observed in ?rst-line patients, the therapeutic agents described herein can be administered to a difference Was statistically signi?cant in patients Who subject in need thereof. In some such embodiments, at least received Abraxane, compared With Taxol, as second-line or one of the chemotherapeutic agents administered to the sub greater therapy (56.4 v 46.7 Weeks, respectively; HR:0.73; ject comprises a chemotherapeutic agent associated With or P:0.024) (23). bound to albumin. [0088] The incidence of hypersensitivity reactions (any Preclinical and Clinical Studies With Abraxane grade) Was loW for both arms (1% for Abraxane and 2% for [0083] Preclinical studies comparing Abraxane to Taxol Taxol). No severe (grade 3 or 4) treatment-related hypersen demonstrated loWer toxicities, With a maximum tolerated sitivity reactions occurred in any of the patients in the Abrax dose (MTD) approximately 50% higher for Abraxane com ane group despite the absence of premedication. In contrast, pared to Taxol. At equal doses there Was less myelosuppres grade 3 hypersensitivity reactions occurred in the Taxol group sion and improved ef?cacy in a xenograft tumor model of despite standard premedication (chest pain, tWo patients; human mammary adenocarcinoma. At equitoxic doses of allergic reaction, three patients). Per protocol, corticosteroids paclitaxel, Abraxane Was found to be markedly more ef?ca and antihistamines Were not administered routinely to cious than Taxol (19). patients in the Abraxane group; hoWever, premedication Was administered for emesis, myalgia/arthralgia, or anorexia in 18 Every 3 Weeks Schedule patients (8%) in the Abraxane group in 2% of the treatment [0084] In a phase I study, the MTD of Abraxane Was deter cycles, Whereas 224 patients (>99%) in the Taxol group mined to be 300 mg/m2 by 30 minute infusion every 3 Weeks, received premedication in 95% of the cycles. Without premedication or G-CSF support (20). No severe [0089] Although the patients in the Abraxane group hypersensitivity reactions occurred With Abraxane despite received an average paclitaxel dose-intensity 49% greater the absence of premedication. Dose-limiting toxicities than that received by patients in the Taxol group, the inci included sensory neuropathy, stomatitis, and super?cial dence of treatment-related grade 4 neutropenia Was signi? keratopathy, Which occurred at a dose of 375 mg/m2. cantly loWer in the Abraxane group than in the Taxol group [0085] TWo multicenter phase II studies have evaluated 2 (9% v 22%, respectively; P<0.001), With a higher mean neu dose levels of Abraxane (300 mg/m2, n:63, and 175 mg/m2, trophil nadir (1 .67 v 1 .31><109/L, respectively; P:0.046), sug n:43) in patients With metastatic breast cancer (21, 22). The gesting that polyethylated castor oil may have contributed to overall response rates in these 2 phase II trials Were 40% (95% this toxicity in patients Who received standard paclitaxel. CI 25-54%) for the 175 mg/m2 dose, and 48% (95% CI [0090] As expected With a higher dose of paclitaxel, treat 35-60%) for the 300 mg/m2 dose. Of 39 patients receiving ment-related grade 3 sensory neuropathy occurred more fre 300 mg/m2 as ?rst-line therapy for metastatic breast cancer, quently in the Abraxane arm than in the Taxol arm (10% v 2%, 64% (95% CI 49-79%) responded. This Was contrasted With respectively; P<0.001); hoWever, these episodes improved a 45% response rate in similar patients at the loWer dose level. With interruption of treatment to grade 2 or 1 in a median 22 Grade 4 neutropenia Was noted in 24% of patients at the days and Were easily managed With treatment interruption higher dose level, occurred primarily during the ?rst cycle and dose reduction. By day 28 after its ?rst occurrence, the and resolved rapidly. number of patients With persistent grade 3 sensory neuropa [0086] A Phase III trial in patients With metastatic breast thy Was the same (n:4) in both study arms. No episodes of cancer compared Abraxane 260 mg/m2 to Taxol 175 mg/m2 motor neuropathy or grade 4 sensory neuropathy Were given every 3 Weeks (23). Ef?cacy analyses Were based on the reported in either group. intent-to-treat (ITT) population. The overall response rate [0091] The only clinical chemistry value that Was notably (ORR) Was signi?cantly greater for Abraxane than for Taxol different betWeen the tWo treatment arms Was higher serum for all patients (33% v 19%, respectively; P:0.001), patients glucose levels in the Taxol-treated patients, Who also had a Who received ?rst-line therapy (42% v 27%, respectively; higher incidence of hyperglycemia reported as an adverse P:0.029), patients Who received second-line or greater effect (AE) compared With Abraxane-treated patients (7% v therapy (27% v 13%, respectively; P:0.006), and patients 1% respectively; P:0.003). Who had received prior therapy in either the [0092] Subgroup analyses revealed that the safety pro?les adjuvant/metastatic setting (34% v 18%, respectively; P:0. of Abraxane and Taxol in patients Who received the drugs as 002) or the metastatic setting only (27% v 14%, respectively; ?rst-line therapy Were similar to those in the overall study P:0.010). Tumor response rate Was also signi?cantly higher population. In subgroup analyses by age, the reported AEs for Abraxane than for Taxol in patients With visceral domi Were similar in patients less than 65 years old and patients >65 nant lesions (34% v 19%, respectively; P:0.002) and in years old in both groups. Of the patients >65 years old, the patients aged younger than 65 years (34% v 19%, respec incidences of the folloWing AEs Were notably loWer in the tively; P<0.001). ORR also Was greater for Abraxane com Abraxane group than in the Taxol group: neutropenia (23% v pared With standard paclitaxel in patients With nonvisceral 59%, respectively), leukopenia (10% v 31%, respectively), dominant lesions (34% v 19%, respectively) and in patients nausea (20% v 38%, respectively), hyperglycemia (0% v 265 years old (27% v 19%, respectively), but the results did 19%, respectively), and ?ushing (0% v 16%, respectively). not reach statistical signi?cance because of the small number These data indicate no additional safety concerns for Abrax of patients in these subsets. ane in patients >65 years old compared With youngerpatients. US 2014/0080760 A1 Mar. 20, 2014

[0093] Six patients (3%) in the Abraxane group and eight employed upfront in the TAC regimen (Taxotere, Adriamy patients (4%) in the standard paclitaxel group died during the cin, Cyclophosphamide) may be omitted or reduced When study, all as a result of disease progression. No treatment Taxotere is replaced by Abraxane. This may also help reduce related deaths occurred in the Abraxane group; one patient the toxicity and overall cost of treatments (Neulasta is an (<1%) in the Taxol group died of multiorgan failure, Which expensive drug and adds considerably to the cost of treat Was considered by the investigator to be possibly related to ments). treatment but may also have been a result of sepsis and/or progressive disease. Commercial Chemotherapy

Weekly for 3 Weeks, Every 4 Weeks Schedule [0098] Doxorubicin and cyclophosphamide are commer cially available drugs that are commonly used in the treatment [0094] Thirty-nine patients Were enrolled into A Phase I of breast cancer. See e.g., the Physicians’ Desk Reference, study of Abraxane administered Weekly for 3 Weeks folloWed incorporated herein by reference in its entirety. by a 1 Week rest in patients With advanced solid tumors (24). The MTDs for heavily and lightly pre-treated patients Were Method for Treating Cancer 100 and 150 mg/m2 respectively. Dose limiting toxicities included grade 4 neutropenia and grade 3 sensory neuropathy. [0099] Some embodiments include methods of treating a Premedication Was not required, and unexpected, non- cancer in a subject in need thereof. In some embodiments, the associated toxicities Were not observed. cancer is breast cancer. In some embodiments, the cancer is HER2 negative breast cancer. In some embodiments, the can [0095] In a Phase II trial in heavily pretreated patients With cer is triple negative breast cancer. Some such methods taxane-refractory metastatic breast cancer, objective antitu include administering a chemotherapeutic agent associated mor responses occurred in 15% of Women treated WithAbrax With or bound to albumin, administering a second chemo ane 100 mg/m2 on this schedule (25). Abraxane Weekly regi therapeutic agent; and administering a third chemotherapeu men Was Well tolerated. 91% of patients Were treated at the tic agent. In some embodiments, the chemotherapeutic agent full dose of 100 mg/m2 of Abraxane Without dose reductions. associated With or bound to albumin is administered periodi Based on the activity and loW toxicity documented With the cally. In some embodiments, the chemotherapeutic agent Abraxane 100 mg/m2 Weekly regimen, this study Was associated With or bound to albumin comprises an agent expanded to evaluate the e?icacy and safety/tolerability of a selected from the group consisting of paclitaxel, docetaxel, higher dose of Abraxane 125 mg/m2 Weekly regimen in 75 and rapamycin. In particular embodiments, the chemothera additional patients. Results of this dose-?nding study con?rm peutic agent associated With orbound to albumin isAbraxane. the dose of Abraxane 100 mg/m2 as the appropriate dose for further study in this patient population (26). [0100] In some embodiments, the second chemotherapeu tic agent comprises a topoisomerase inhibitor. Examples of Weekly Schedule topoisomerase inhibitors are described herein and can include doxorubicin. In some embodiments, the third chemothera [0096] The NSABP studied the administration of Abraxane peutic agent comprises an alkylating agent. Examples of in a neoadjuvant setting to patients With locally advanced alkylating agents are described herein and can include cyclo breast cancer at a dose of 100 mg/m2 Weekly for 12 Weeks, phosphamide. With no break (27). Four cycles of FEC Were administered [0101] In some embodiments, the chemotherapeutic agent sequentially based on patients’ HER2 status: HER2 negative associated With or bound to albumin is administered on days patients received EEC-100 (F: 500 mg/m2, E: 100 mg/m2, C: 1 and 8, or on days 1, 8, 15, or on days 1, 8, 15, and 22, or on 500 mg/m2 Q3 Weeks) and HER2 positive patients received days 1, 8, 15, 22, and 28, or on days 1, 8, and 22. In some Weekly trastuZumab in addition to EEC-75 (F: 500 mg/m2, E: embodiments, the chemotherapeutic agent associated With or 75 mg/m2, C: 500 mg/m2 Q3 Weeks). Weekly trastuZumab bound to albumin is administered at an interval of at least Was permitted during Abraxane and EEC-75 treatment at the about 2 days, at least about 3 days, at least about 4 days, at discretion of the investigator. The primary objective of the least about 5 days, at least about 6 days, at least about 7 days, trial Was to determine the pathologic complete response rate at least about 8 days, at least about 9 days, and at least about (pCR) in the breast. At the time of initial report at SABCS 10 days. In some embodiments, the administration of the 2006, 65 patients had been entered on study and Were evalu chemotherapeutic agent associated With orbound to albumin; able for cCR and safety. Following 12 Weeks of Abraxane, a the administration of the second chemotherapeutic agent; clinical complete response rate (cCR) of 32% Was noted. The and/ or the administration of the third chemotherapeutic agent therapy Was Well tolerated, With 48/65 patients receiving 12 are repeated for a plurality of cycles. In some embodiments, doses in 12 Weeks and 13/65 receiving 12 doses in 13-14 the plurality of cycles is at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 Weeks. The incidence of peripheral (sensory) neuropathy Was cycles. loW (11% grade 2 and 5% grade 3) as Was neutropenia (3% [0102] In some embodiments, the dose of a chemothera grade 3 and no grade 4). The authors concluded that the peutic agent associated With or bound to albumin, such as administration of Abraxane 100 mg/m2 Weekly><12 Was both Abraxane, is betWeen about 50 mg/m2 and about 200 mg/m2. effective and tolerable. In some embodiments, the dose of a chemotherapeutic agent [0097] A recent phase II study has also demonstrated that associated With or bound to albumin, such as Abraxane, is Weekly Abraxane is superior to every-three Week Taxotere in selected from the group consisting of about 100 mg/m2 and both e?icacy and toxicity pro?le, in the treatment of patients about 150 mg/m2. With advanced or metastatic breast cancer (28). The rate of [0103] In some embodiments, at least about 100 mg/m2 grade 4 neutropenia Was 75% in the Taxotere group, com Abraxane is administered on day 1 and 8, at least about 50 pared to only 5% of the Weekly Abraxane groups. Therefore, mg/m2 doxorubicin is administered on day 1, and at least the use of groWth factor support such as Neulasta that is often about 500 mg/m2 cyclophosphamide is administered on day US 2014/0080760 A1 Mar. 20, 2014

1. Some such embodiments also include, administering Peg Example 2 ?lgrastim. In some embodiments, Peg?lgrastim is adminis tered on day 9. Determination of Dosage Regimens [0109] Other dosage regimens for chemotherapy With a EXAMPLES combination of tWo or more of the chemotherapeutic agents described herein, such as nanoparticle albumin bound pacli Example 1 taxel, doxorubicin, and/ or cyclophosphamide (NAC), can be tested in patients, such as patients With stages II-III HER-2 Phase I Study of Neoadjuvant Chemotherapy With negative breast cancer. A series of studies are carried out With Nanoparticle Albumin Bound Paclitaxel, a combination of different chemotherapeutic agents. In each Doxorubicin, and Cyclophosphamide study, the period of providing a particular chemotherapeutic [0104] A Phase I study of neoadjuvant chemotherapy With agent is different, for example, the particular chemotherapeu nanoparticle albumin bound paclitaxel, doxorubicin, and tic agent is periodically administered to a patient at an interval cyclophosphamide (NAC) in patients With stages II-III ofl day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, HER-2 negative breast cancer Was carried out. 9 days, or 10 days, or 1 Week, 2 Weeks, 3 Weeks, or 4 Weeks. [0105] Background: The TAC regimen (docetaxel, doxoru The pCR for each study group is determined. bicin, and cyclophosphamide) is among the most active drug [0110] Likewise, the period of providing the second and/or combinations in the adjuvant and neoadjuvant settings. A third chemotherapeutic agent may be varied and the second Weekly nab-paclitaxel is superior to every-three Week doc and/or third chemotherapeutic agents may be administered etaxel in both e?icacy and toxicity in patients With metastatic simultaneously With, on the same day as, or on a different day as the ?rst or second chemotherapeutic agent in order to breast cancer. Provided herein are results of a single center phase I study in Which nab-paclitaxel replaces docetaxel in identify a treatment regimen that provides desirable results. the conventional TAC regimen. In addition, regimens in Which one or more of the chemo [0106] Methods: Women With HER-2 negative stages II-III therapeutic agents are administered one or more times and the sub sequent administrations of tho se chemotherapeutic agents breast cancer Were enrolled. Eligible patients received 6 cycles of the NAC regimen: nab-paclitaxel (100-150 mg/m2, discontinued While administration of the remaining one or days 1 and 8), doxorubicin (50 mg/m2, day 1), and cyclophos more chemotherapeutic agents is continued may be evaluated phamide (500 mg/m2, day 1). Peg-?lgrastim Was given on day to identify regimens that provide desirable results. 9. Table 1 shoWs Abraxane dose schedules. [0111] Using particular regimens, the pCR is at least 30%, 40, 50%, 60%, 70%, 80%, 90% or 95%. The optimum period for providing the particular chemotherapeutic agent in com TABLE 1 bination With at least one other chemotherapeutic agent is Dose level Abraxane dose (mgm2) Dose schedule (days) determined. [0112] The above description discloses several composi —1 100 1, 8, rest tions and methods of the present invention. This invention is 0 100 1,8, 15, 22, 29, rest 1 150 1, 8, rest, 22, 29, rest susceptible to modi?cations in the methods and materials, as 2 150 1, 8, 15, 22, 29, rest Well as alterations in the fabrication methods and equipment. Such modi?cations Will become apparent to those skilled in the art from a consideration of this disclosure or practice of [0107] Results: Sixteen patients enrolled in the study, one the invention disclosed herein. Consequently, it is not of Which Was a screen failure. Median tumor siZe Was 6 cm. intended that this invention be limited to the speci?c embodi Median age Was 54 years (40-69). ER+ tumors accounted for ments disclosed herein, but that it cover all modi?cations and 53%, and 47% Were triple negative. There Were tWo in?am alternatives coming Within the true scope and spirit of the matory breast cancers. After the ?rst three patients on dose invention. level 0 (nab-paclitaxel of 100 mg/m2, Weekly 5 on 1 off, Q 6 [0113] All references cited herein including, but not limited Weeks) experienced several dose delays because of grades 3 to, published and unpublished applications, patents, and lit and 4 neutropenia, the protocol Was amended such that dose erature references, are incorporated herein by reference in level —1 (nab-paclitaxel of 100 mg/m2, Weekly 2 on 1 off, Q 3 their entirety and are hereby made a part of this speci?cation. Weeks) Would be the neW starting point and there Would be no To the extent publications and patents or patent applications further dose escalation. There Was no dose limiting toxicity incorporated by reference contradict the disclosure contained (DLT). To date, a total of 57 cycles of dose level —1 Were in the speci?cation, the speci?cation is intended to supersede given. 43.8% required dose delay. There Were tWo episodes of and/ or take precedence over any such contradictory material. febrile neutropenia. The pathologic complete response (pCR) [0114] The term “comprising” as used herein is synony by physical examination Was 93.3%. One patient had a mini mous With “including,” “containing,” or “characterized by,” mal response. The median number of cycles required before a and is inclusive or open-ended and does not exclude addi pCR Was 2. Even thoughpCR Was not a primary endpoint, We tional, unrecited elements or method steps. observed a very favorable pCR rate. Eight patients already [0115] The folloWing references are incorporated herein by underWent surgery. The pCR rate for this group Was 50%. reference in their entireties. Another patient had a near pCR, With microscopic residual disease. The pCR for the 4 triple negative patients Was 100%. REFERENCES [0108] Conclusions: This single center phase I study dem onstrated safety and dramatic activity for the neoadjuvant 1 . American Cancer Society: Cancer Facts and Figures 2007. NAC regimen in patients With stages II-III HER-2 negative Atlanta: American Cancer Society; 2007. breast cancer. This regimen Was highly effective With impres [0116] 2. Fisher B, BroWn A, Mamounas E, Wieand S, sive clinical and pathologic complete responses. Robidoux A, Margolese R G. Effect of preoperative chemo US 2014/0080760 A1 Mar. 20, 2014

therapy on local-regional disease in Women With operable 14. G. Von MinckWitZ, J. Blohmer, P. Vogel, C. Hanusch, H. breast cancer: ?ndings from National Surgical Adjuvant Eidtmann, J. Hilfrich, B. Gerber, J. Huober, S. Costa and M. Breast and Bowel Project B-18. J Clin Oncol. 1997 Jul.;15 Kaufmann. Comparison of neoadjuvant 6 vs 8 cycles of doc (7):2483-93. etaxel/doxorubicin/cyclophosphamide (TAC) in patients 3. von MinckWitZ G, Blohmer J U, Raab G, LohrA, Gerber B. early responding to TACx2-the GEPARTRIO Study. Journal In vivo chemo sensitivity-adapted preoperative chemotherapy of Clinical Oncology, 2006 ASCO Annual Meeting Proceed in patients With early-stage breast cancer: the GEPARTRIO ings (Post-Meeting Edition). No 18S (June 20 Supplement), pilot study. Ann Oncol. 2005 Jan;16(1):56-63. 2006: 576 4. Bear H D, Anderson S, Smith R E, Geyer C E Jr, Mamounas 15. Sledge GW, Neuberg D, Bernardo P, Ingle J N, Martino S, E P, Fisher B, BroWn A M, Robidoux A, Margolese R, Kahl RoWinsky E K, Wood W C. Phase III trial of doxorubicin, enberg M S, Paik S, Soran A, Wickerham D L, Wolmark N. paclitaxel, and the combination of doxorubicin and paclitaxel Sequential preoperative or postoperative docetaxel added to as front-line chemotherapy for metastatic breast cancer: an preoperative doxorubicin plus cyclophosphamide for oper intergroup trial (E1193). J Clin Oncol. 2003 Feb 15;21(4): able breast cancer: National Surgical Adjuvant Breast and 588-92. BoWel Project Protocol B-27. J Clin Oncol. 2006 May 1:24 16. MaZouni C, Kau S W, Frye D, Andre F, Kuerer H M, (13):2019-27. BuchholZ TA, Symmans W F, Anderson K, Hess K R, GonZa 5. Smith I C, Heys S D, HutcheonA W, MillerI D, Payne S, leZ-Angulo A M, Hortobagyi G N, BuZdar A U, PusZtai L. Gilbert F J, Ah-See A K, Eremin 0, Walker L G, Sarkar T K, Inclusion of taxanes, particularly Weekly paclitaxel, in pre Eggleton S P, Ogston K N. Neoadjuvant chemotherapy in operative chemotherapy improves pathologic complete breast cancer: signi?cantly enhanced response With doc response rate in estrogen receptor-positive breast cancers. etaxel. J Clin Oncol. 2002 Mar 15;20(6):1456-66. Ann Oncol. 2007 May;18(5): 874-80. 6. Mieog J S, van der Hage J A, van de Velde C J. Neoadjuvant 17. Desai N, Trieu V, Yao R, Labao E, Soon-Shiong P: chemotherapy for operable breast cancer. Br J Surg. 2007 Increased endothelial transcytosis of nanoparticle albumin Oct;94(10):1189-200. bound paclitaxel (ABI-007) by gp60-receptors: a pathWay inhibited by taxol. 2004 SABCS. Abstract No. 1071. 7. Norman Wolmark, M. D., “Preoperative Therapy in 18. Desai N, Trieu V, Yao R, Frankel T, Soon-Shiong P: Invasive Breast Cancer: RevieWing the State of the Science SPARC expression in breast tumors may correlate to and Exploring NeW Research Directions,” National Cancer increased tumor distribution of nanoparticle albumin-bound Institute, Natcher Conference Center, Bethesda, Md., Mar. paclitaxel (ABI-007) vs taxol. 2004 SABCS. Abstract No. 26-27, 2007. 206. [0117] 8. van der Hage J A, van de Velde C J, Julien J P, 19. Desai N, Trieu V, Yao Z, et al: IncreasedAntitumorActiv Tubiana-Hulin M, Vandervelden C, Duchateau L. Preopera ity, Intratumor Paclitaxel Concentrations and Endothelial tive chemotherapy in primary operable breast cancer: results Cell Transport of Cremophor-Free, Albumin-Bound Pacli from the European Organization for Research and Treatment taxel, ABI-007, Compared With Cremophor-Based Pacli of Cancer trial 10902. J Clin Oncol. 2001 Nov 15;19(22): taxel. Clin Cancer Res. 2006; 12(4). 1317-1324. 4224-37. 20. Ibrahim N K, Desai N, Legha S, et al: Phase I and Phar 9. Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B. macokinetic Study of ABI-007, a Cremophor-free, Protein Preoperative chemotherapy in patients With operable breast stabiliZed, Nanoparticle Formulation of Paclitaxel. Clin Can cancer: nine-year results from National Surgical Adjuvant cer Research. 2002 May; 8: 1038-1044 Breast and BoWel Project B-18. J Natl Cancer Inst Monogr. 21. Ibrahim N K, Samuels B, Page R, et al: Multicenter Phase 2001;(30):96-102. II Trial of ABI-007, anAlbumin-Bound Paclitaxel, in Women 10. Cleator S J, MakrisA, Ashley S E, Lal R, PoWles T J. Good With Metastatic Breast Cancer. J Clin Oncol 23:6019-6026, clinical response of breast cancers to neoadjuvant chemoen 2005. docrine therapy is associated With improved overall survival. 22. Investigator’s Brochure. Abraxane® (Paclitaxel Albumin Ann Oncol. 2005 Feb;16(2):267-72. Nanoparticle for Injectable Suspension) (ABI-007). Ameri 11. SemiglaZov V F, TopuZov E E, Bavli J L, Moiseyenko V can BioScience, Inc. M, Ivanova O A, SeleZnev I K, Orlov A A, Barash N Y, Golubeva O M, Chepic O F. Primary (neoadjuvant) chemo 23. Gradishar W J, Tjulandin S, Davidson N, ShaW H, Desai therapy and radiotherapy compared With primary radio N, Bhar P, HaWkins M, O’Shaughnessy J. Phase III trial of therapy alone in stage IIb-IIIa breast cancer. Ann Oncol. 1994 nanoparticle albumin-bound paclitaxel compared With poly Sep;5(7):591-5. ethylated castor oil-based paclitaxel in Women With breast cancer. J Clin Oncol. 2005 23(31):7794-803 12. Kaufmann M, Hortobagyi G N, Goldhirsch A, Scholl S, Makris A, Valagussa P, Blohmer J U, Eiermann W, J ackesZ R, 24. Nyman D W, Campbell K J, Hersh, E, et al: Phase I and J onat W, Lebeau A, Loibl S, Miller W, Seeber S, SemiglaZov Pharmacokinetics Trial of ABI-007, a Novel Nanoparticle V, Smith R, Souchon R, Stearns V, Untch M, von MinckWitZ Formulation of Paclitaxel in Patients With Advanced Nonhe G. Recommendations from an international expert panel on matologic Malignancies. J Clin Oncol 23:7785-7793, 2005 the use of neoadjuvant (primary) systemic treatment of oper 25. Blum J L, et al: Long-term Disease Control in Taxane able breast cancer: an update. J Clin Oncol. 2006 Apr 20;24 Refractory Metastatic Breast Cancer Treated With nab pacli (12):1940-9. Erratum in: J Clin Oncol. 2006 Jul 1;24(19): taxel. 2004 ASCO Annual Meeting Proceedings (Post-Meet 3221. ing Edition). Vol 22, No 14S (July 15 Supplement), 2004: 13. Martin M, PienkoWski T, Mackey J, PaWlicki M, Abstract No. 543. Guastalla J P, Weaver C, Adjuvant docetaxel for node-positive 26. OShaughnessy J A, Blum J L, Sandbach J F, et al: Weekly breast cancer. N Engl J Med. 2005 Jun 2;352(22):2302-13. Nanoparticle Albumin Paclitaxel (Abraxane) Results in US 2014/0080760 A1 Mar. 20, 2014

Long-Term Disease Control in Patients With TaXane-Refrac 13. The method of any one of claims 1-10, Wherein the tory Metastatic Breast Cancer. 2004 SABCS. Abstract No. chemotherapeutic agent associated With or bound to albumin 1070 is administered on days 1, 8, 15, and 22. 27. Robidoux A, Buyse M, BuZdar A, et al. Neoadjuvant 14. The method of any one of claims 1-10, Wherein the chemotherapy With sequential Weekly nanoparticle albumin chemotherapeutic agent associated With or bound to albumin bound paclitaxel (ABl-007, Abraxane®) followed by 5-?uo is administered on days 1, 8, 15, 22, and 28. rouracil, epirubicin and cyclophosphamide (FEC) in locally 15. The method of any one of claims 1-10, Wherein the advanced breast cancer (LABC): a phase II trial of the chemotherapeutic agent associated With or bound to albumin NSABP Foundation research programs (FRP) [poster]. Pre is administered on days 1, 8, and 22. sented at: SanAntonio Breast Cancer Symposium; December 16. The method of any one of claims 1-10, Wherein the 14-17, 2006; San Antonio, Tex. Abs 3068. chemotherapeutic agent associated With or bound to albumin 28. Gradishar W, Krasnojon D, Cheporov S, et al. Random is administered at an interval of at least about 5 days. iZed comparison of Weekly or every-3-Week (q3W) nab-pa 17. The method of any one of claims 1-10, Wherein the clitaxel compared to q3W docetaxel as ?rst-line therapy in chemotherapeutic agent associated With or bound to albumin patients (pts) With metastatic breast cancer (MBC). J Clin is administered at an interval of at least about 6 days. Oncol, 2007 ASCO Annual Meeting Proceedings. 25 (18S) 18. The method of any one of claims 1-10, Wherein the (June 20 Supplement), 2007: 1032 chemotherapeutic agent associated With or bound to albumin What is claimed is: is administered at an interval of at least about 7 days. 1. A method of treating a cancer in a subject in need thereof 19. The method of any one of claim 2-10, Wherein the comprising: periodic administration comprises at least 2 cycles. administering a chemotherapeutic agent associated With or 20. The method of any one of claim 2-10, Wherein the bound to albumin; periodic administration comprises at least 5 cycles. administering a second chemotherapeutic agent; and 21. The method of claim 3, Wherein the chemotherapeutic administering a third chemotherapeutic agent. agent associated With or bound to albumin the second che motherapeutic agent and the third chemotherapeutic agent are 2. The method of claim 1, Wherein the chemotherapeutic administered on the same day and subsequently the adminis agent associated With or bound to albumin is administered tration of the chemotherapeutic agent associated With or periodically. bound to albumin is repeated for a plurality of cycles. 3. The method of any one of claim 1 or 2, Wherein the 22. The method of claim 21, Wherein the plurality of cycles chemotherapeutic agent associated With or bound to albumin for the subsequent administration of the chemotherapeutic the second chemotherapeutic agent and a third chemothera agent associated With or bound to albumin comprises at least peutic agent are administered on the same day and subse 2 cycles. quently the chemotherapeutic agent associated With or bound to albumin is administered periodically Without the second 23. The method of claim 21, Wherein the plurality of cycles chemotherapeutic agent and the third chemotherapeutic for the subsequent administration of the chemotherapeutic agent. agent associated With or bound to albumin comprises at least 5 cycles. 4. The method of any one of claim 1 or 2, Wherein on some 24. The method of claim 21, Wherein each cycle for the occasions the chemotherapeutic agent associated With or subsequent administration of the chemotherapeutic agent bound to albumin the second chemotherapeutic agent and a associated With or bound to albumin comprises at least about third chemotherapeutic agent are administered on the same 5 days. day and on other occasions only the chemotherapeutic agent associated With or bound to albumin is administered. 25. The method of claim 21, Wherein each cycle for the subsequent administration of the chemotherapeutic agent 5. The method of any one of claims 1-4, Wherein the che associated With or bound to albumin comprises at least about motherapeutic agent associated With or bound to albumin 6 days. comprises an agent selected from the group consisting of 26. The method of claim 21, Wherein each cycle for the paclitaxel, docetaxel, and rapamycin. subsequent administration of the chemotherapeutic agent 6. The method of any one of claims 1-4, Wherein the che associated With or bound to albumin comprises at least about motherapeutic agent associated With or bound to albumin is 7 days. Abraxane. 27. The method of claim 21, Wherein each cycle for the 7. The method of any one of claims 1-4, Wherein the second subsequent administration of the chemotherapeutic agent chemotherapeutic agent comprises a topoisomerase inhibitor. associated With or bound to albumin comprises at least about 8. The method of claim 7, Wherein the topoisomerase 1 Week. inhibitor is doxorubicin. 28. The method of claim 1, Wherein at least about 100 9. The method of any one of claims 1-8, Wherein the third mg/m2 Abraxane is administered on day 1 and 8, at least about chemotherapeutic agent comprises an alkylating agent. 50 mg/m2 doxorubicin is administered on day 1, and at least 10. The method of claim 9, Wherein the alkylating agent is about 500 mg/m2 cyclophosphamide is administered on day cyclophosphamide. 1. 11. The method of any one of claims 1-10, Wherein the 29. The method of claim 28, further comprising adminis chemotherapeutic agent associated With or bound to albumin tering Peg?lgrastim on day 9. is administered on days 1 and 8. 30. The method of any one of claims 1-29, Wherein said 12. The method of any one of claims 1-10, Wherein the cancer is breast cancer. chemotherapeutic agent associated With or bound to albumin 31. The method of any one of claims 1-29, Wherein the is administered on days 1, 8, 15. cancer is HER2 negative breast cancer. US 2014/0080760 A1 Mar. 20, 2014

32. The method of any one of claims 1-29, wherein the 50. The use of any one of claims 35-44, Wherein the che cancer is triple negative breast cancer. motherapeutic agent associated With or bound to albumin is 33. The method of claim 6, Wherein the dose of Abraxane administered at an interval of at least about 5 days. is betWeen about 50 mg/m2 and about 200 mg/m2. 51. The use of any one of claims 35-44, Wherein the che 34. The method of claim 6, Wherein the dose of Abraxane motherapeutic agent associated With or bound to albumin is is selected from the group consisting of 100 mg/m2 and 150 administered at an interval of at least about 6 days. mg/m2. 52. The use of any one of claims 35-44, Wherein the che 35. Use of a combination comprising a chemotherapeutic motherapeutic agent associated With or bound to albumin is agent associated With or bound to albumin, a second chemo administered at an interval of at least about 7 days. therapeutic agent, and a third chemotherapeutic agent for the 53. The use of any one of claim 36-44, Wherein the periodic treatment of cancer. administration comprises at least 2 cycles. 36. The use of claim 35, Wherein the chemotherapeutic 54. The use of any one of claim 36-44, Wherein the periodic agent associated With or bound to albumin is administered administration comprises at least 5 cycles. periodically. 55. The use of claim 37, Wherein the chemotherapeutic 37. The use of any one of claim 35 or 36, Wherein the agent associated With or bound to albumin the second che chemotherapeutic agent associated With or bound to albumin motherapeutic agent and the third chemotherapeutic agent are the second chemotherapeutic agent and a third chemothera administered on the same day and subsequently the adminis peutic agent are administered on the same day and subse tration of the chemotherapeutic agent associated With or quently the chemotherapeutic agent associated With or bound bound to albumin is repeated for a plurality of cycles. to albumin is administered periodically Without the second 56. The use of claim 55, Wherein the plurality of cycles for chemotherapeutic agent and the third chemotherapeutic the subsequent administration of the chemotherapeutic agent agent. associated With or bound to albumin comprises at least 2 38. The use ofany one ofclaim 35 or 36, Wherein on some cycles. occasions the chemotherapeutic agent associated With or 57. The use of claim 55, Wherein the plurality of cycles for bound to albumin the second chemotherapeutic agent and a the subsequent administration of the chemotherapeutic agent third chemotherapeutic agent are administered on the same associated With or bound to albumin comprises at least 5 day and on other occasions only the chemotherapeutic agent cycles. associated With or bound to albumin is administered. 58. The use of claim 55, Wherein each cycle for the subse 39. The use of any one of claims 35-38, Wherein the che quent administration of the chemotherapeutic agent associ motherapeutic agent associated With or bound to albumin ated With orbound to albumin comprises at least about 5 days. comprises an agent selected from the group consisting of 59. The use of claim 55, Wherein each cycle for the subse paclitaxel, docetaxel, and rapamycin. quent administration of the chemotherapeutic agent associ 40. The use of any one of claims 35-38, Wherein the che ated With orbound to albumin comprises at least about 6 days. motherapeutic agent associated With or bound to albumin is 60. The use of claim 55, Wherein each cycle for the subse Abraxane. quent administration of the chemotherapeutic agent associ 41. The use of any one of claims 35-38, Wherein the second ated With orbound to albumin comprises at least about 7 days. chemotherapeutic agent comprises a topoisomerase inhibitor. 61. The use of claim 55, Wherein each cycle for the subse 42. The use of claim 41, Wherein the topoisomerase inhibi quent administration of the chemotherapeutic agent associ tor is doxorubicin. ated With or bound to albumin comprises at least about 1 43. The use of any one of claims 35-42, Wherein the third Week. chemotherapeutic agent comprises an alkylating agent. 62. The use of claim 35, Wherein at least about 100 mg/m2 44. The use of claim 43, Wherein the alkylating agent is Abraxane is administered on day l and 8, at least about 50 cyclophosphamide. mg/m2 doxorubicin is administered on day l, and at least 45. The use of any one of claims 35-44, Wherein the che about 500 mg/m2 cyclophosphamide is administered on day motherapeutic agent associated With or bound to albumin is l. administered on days 1 and 8. 63. The use of claim 62, further comprising administering 46. The use of any one of claims 35-44, Wherein the che Peg?lgrastim on day 9. motherapeutic agent associated With or bound to albumin is 64. The use of any one of claims 35-63, Wherein said cancer administered on days 1, 8, 15. is breast cancer. 47. The use of any one of claims 35-44, Wherein the che 65. The use of any one of claims 35-63, Wherein the cancer motherapeutic agent associated With or bound to albumin is is HER2 negative breast cancer. administered on days 1, 8, l5, and 22. 66. The use of any one of claims 35-63, Wherein the cancer 48. The use of any one of claims 35-44, Wherein the che is triple negative breast cancer. motherapeutic agent associated With or bound to albumin is 67. The use of claim 40, Wherein the dose of Abraxane is administered on days 1, 8, 15, 22, and 28. betWeen about 50 mg/m2 and about 200 mg/m2. 49. The use of any one of claims 35-44, Wherein the che 68. The use of claim 40, Wherein the dose of Abraxane is motherapeutic agent associated With or bound to albumin is selected from the group administered on days 1, 8, and 22. * * * * *