USOO7968569B2

(12) Unlted States Patent (10) Patent N0.: US 7,968,569 B2 Zeldis (45) Date of Patent: Jun. 28, 2011

(54) METHODS FOR TREATMENT OF MULTIPLE 2 gilllm? 6t al~ MYELOMA USING 3 _ (4 _ AMINO _ 1 _ 0X0 _ 1’3 _ 6,077,822, , A * 6/2000 Dyrsting’ ato et al...... 514/8 DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE- 6,114,355 A 90000 D>Amat0 2,6-DIONE 6,140,346 A 10/2000 Andrulis, Jr. et al. 6,228,879 B1 5/2001 Green et al. . - ' 6,235,756 B1 5/2001 D’Amato (75) Inventor Jerome B-Zeldls, Pnnceton,NJ (Us) 6,281,230 B1,, 8/2001 Muller etal, ““““““““ N 514623 (73) Ass1gnee:. Celgene Corporation, Summ1t,. NJ (US) 6,326,3886,316,471 B1 12/200111/2001 Mgnzrtzl‘aM 11 t l. 6,335,349 B1 1/2002 Muller et al. ( * ) Notice: Subject to any disclaimer, the term of this 6,380,239 B1 4/2002 Muller et al. patent is extended or adjusted under 35 6,395,754 B1 5/2002 Muller et al' U S C 154(])) b 145 da S 6,403,613 B1 6/2002 Man et a1. - ~ - Y Y - 6,420,414 B1 7/2002 D’Amato 6,458,810 B1 10/2002 Muller et al. (21) Appl. No.: 10/438,213 6,469,045 B1 10/2002 D’Amato 6,476,052 B1 11/2002 Muller et al. (22) Filed: May 15 2003 6,518,298 B2 2/2003 Green et al. ’ 6,555,554 B2 * 4/2003 Muller et al...... 514/323 _ _ _ 6,673,828 B1 1/2004 Green et al. (65) Pm" Pubhcatlon Data 7,119,106 B2* 10/2006 Muller et al. . .. 514/323 7,189,740 B2* 3/2007 Zeldis ...... 514/323 Us 2004/0029832 A1 Feb' 12’ 2004 7,393,862 B2 * 7/2008 Zeldis ...... 514/320 _ _ 7,435,745 B2 10/2008 D’Amato Related U.S. Appllcatlon Data _ (Cont1nued) (60) Provisional application No. 60/380,842, ?led on May 17, 2002, provisional application No. 60/424,600, FOREIGN PATENT DOCUMENTS ?led on Nov. 6, 2002. WO WO 92/14455 9/1992 (51) Int. Cl. (Continued) A61K 31/445 (2006.01) OTHER PUBLICATIONS (52) US. Cl...... 514/323 (58) Field of Classi?cation Search ...... 514/321, Corral et a1. Immunomodulation by thalidomide and thalidomide 5 14/323 analogues. . .Ann. Rheum. 1999; 58; 107-13.* See application ?le for complete search history. Kyle et al. (“The Application of Thalidomide in Multiple Myeloma”, Semin Oncol. Dec. 2001; 28(6):583-7).* References Cited Davies et al. (“Thalidomide and immunomodulatory derivatives aug (56) ment natural killer cell cytotoxicity in multiple myeloma”, Blood. Jul. 1, 2001;98(1):210-6).* U.S. PATENT DOCUMENTS Broder et a1. (“Dideoxycytidinez current clinical experience and 3,536,809 A 10/1970 Applezweig future prospects. A summary”, Am J Med. May 21, 3,598,123 A 8/1971 Zaffaroniet a1. 1990;88(5B):31S-33S).* 3,845,770 A 11/1974 Theeuwes et a1. Filella et al. (Cancer Detect Prey. 1996;20(1):52-6).* 3,916,899 A 11/1975 Theeuwes et a1. Raza et a1., 2001, “Thalidomide produces transfusion independence 4,008,719 A 2/1977 Theeuwes et a1. in long-standing refractory anemias of patients with myelodysplatic 4,810,643 A 3/1989 Souza 4,999,291 A 3/1991 Souza syndromes,” Blood 98(4):958-965. 5,059,595 A 10/1991 Le Grazie 5,073,543 A 12/1991 Marshall et al. (Continued) 5,120,548 A 6/1992 McClellandet al. 5,134,127 A 7/1992 Stellaet a1. Primary Examiner * Frederick Krass 5,229,496 A 7/1993 Deeley et al. Assistant Examiner * Chris E Simmons 5,354,556 A 10/1994 Sparks etal. (74) Attorney, Agent, or Firm * Jones Day 5,385,901 A 1/1995 Kaplanet al. 5,391,485 A 2/1995 Deeleyetal. 5,393,870 A 2/1995 Deeley et al. (57) ABSTRACT 5,528,823 A 6/1996 Rudy, Jr. et al. Methods of treating, preventing and/ or managing cancer as 5,580,755 A 12/1996 Souza 5,591,767 A 1/1997 Mohret a1. well as and diseases and disorders associated with, or char 5,593,990 A 1/1997 D’Amato acterized by, undesired angiogenesis are disclosed. Speci?c 5,629,327 A 5/1997 D’Amato methods encompass the administration of an immunomodu 5,635,517 A * 6/1997 Muller et al...... 514/323 latory compound alone or in combination with a second 5,639,476 A 6/1997 Oshlack et al. active ingredient. The invention further relates to methods of 5,674,533 A 10/1997 Santus etal. 5,698,579 A 12/1997 Muller reducing or avoiding adverse side effects associated with 5,712,291 A 1/1998 D’Amato chemotherapy, radiation therapy, hormonal therapy, biologi 5,731,325 A 3/1998 Andrulis, Jr. et al. cal therapy or immunotherapy which comprise the adminis 5,733,566 A 3/1998 Lewis tration of an immunomodulatory compound. Pharmaceutical 5,798,368 A 8/1998 Muller et al. 5,874,448 A 2/1999 Muller et al. compositions, single unit dosage forms, and kits suitable for 5,877,200 A 3/1999 Muller use in methods of the invention are also disclosed. 5,929,117 A 7/1999 Muller et al. 5,955,476 A 9/1999 Muller et al. 15 Claims, 1 Drawing Sheet US 7,968,569 B2 Page 2

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Vacca et al., 1999, “Bone marrow neovascularization, plasma cell Celgene Corporation, “Celgene receives fast track status from FDA angiogenic potential, and matrix metalloproteinase-2 secretion par for RevimidTM in myelodysplastic sydromes,” Press Release, Apr. allel progression of human multiple myeloma,” Blood 93(9):3064 2003. 3073. Celgene Corporation, “New RevimidTM clinical data shows potential Wohrer et al., 2004, “Effective treatment of primary plasma cell as novel approach to treating myelodysplastic syndromes (MDS),” leukemia with thalidomide and dexamethasoneia case report,” Press Release, May 2003. Hematol. J. 5(4):361-363. Celgene Corporation, “Celgene corporation reports strong operating N. Ake Jonnson, 1972, “Chemical Structure and Teratogenic Prop performance in second quarter as total sales increase 100 percent and erties,” Acta Pharm., pp. 521-542. pro?ts rise,” Press Release, Jul. 2003. 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RevimidTM in myelodysplastic sydromes at the American Society of Barlogie et al., “High-dose therapy immunomodulatory drugs in Hematology 45th annual meeting,” Press Release, Dec. 2003. multiple myeloma,” Seminars in Oncology, 2002, 29 (6):26-33. Celgene Corporation, “Celgene corporation reviews 2003 achieve Barlogie et al., “Introduction: Thalidomide and the IMiDs in multiple ments and announces 2004 ?nancial outlook,” Press Release, Jan. myeloma,” Seminars in Hematology, 2003, 40 (4): 1-2. 2004. Barlogie, “Thalidomide and CC-5013 in Multiple Myeloma: The Celgene Corporation, “RevlimidTM receives orphan drug designation University of Arkansas experience,” Seminars in Hematology, 2003, from the European commission for multiple myeloma,” Press 40 (4):33-38. Release, Feb. 2004. Bartlett et al., “The evolution of thalidomide and its IMiD derivatives Celgene Corporation, “RevlimidTM receives orphan drug designation as anticancer agents,” Nature Reviews Cancer, 2004, 4 (4): 1-9. from the European commission for myelodysplastic sydromes,” Bartlett et al., “Phase I study to determine the safety, tolerability and Press Release, Mar. 2004. immunostimulatory activity of thalidomide analogue CC-5013 in Celgene Corporation, “Celgene corporation reports record operating patients with metastatic malignant melanoma and other advanced performance in ?rst quarter with strong revenue growth and pro?ts,” Press Release, Apr. 2004. cancers,” British Journal of Cancer, 2004, 90:955-961. Celgene Corporation, “Celgene announces plans to stop phase III Battegay, “Angiogenesis: mechanistic insights, neovascular diseases, trials in melanoma due to lack of ef?cacy,” Press Release, Apr. 2004. and therapeutic prospects,” J. Mol. Med., 1995, 73:333-346. 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Prescriptions tiple myeloma ~MM),” Abstract # P222, VIIIth International up 50%. Enhanced S.T.E.P.S.® launched. Pilot d-MPH data pre Myeloma Workshop, May 4-8, 2001. sented,” Press Release, Oct. 2001. Dibbs et al., “Thalidomide and thalidomide analogs suppress TNFOL Celgene Corporation, “Celgene expands clinical development pro secretion by myocytes,” Abstract # 1284, Circulation, 1998. gram for RevimidTM iFive additional trials of Revimid initiated in Dimopoulos et al., “Results of thalidomide and IMIDs in multiple hematological and solid tumor cancers,” Press Release, Jun. 2002. myeloma,”, Abstract # P12.1.4, International Multiple Myeloma Celgene Corporation, “Celgene Corporation announces third quarter Workshop, May 23-27, 2003. results. THALOMID® (thalidomide) revenue increases 41% to Dimopoulos et al., “Treatment of plasma cell dyscrasias with $30.5 million. Pivotal programs for THALOMID and REVIMIDTM thalidomide and its derivatives,” Journal of Clinical Oncology, Dec. ?nalized. Peer-reviewed publications of THALOMID and 1, 2003, 21 (23)4444-4454. REVIMID data. First JNK inhibitor advanced to Phase I clinical Dimopoulos et al., “Study of lenalidomide plus dexamethasone ver trial,” Press Release, Oct. 2002. sus dexamethasone alone in relapsed or refractory multiple myeloma Celgene Corporation, “Blood reports RevimidTM has anti-tumor (MM): Results ofa phase 3 Study (MM-010),”, Abstract # 6, Ameri activity in patients with relapsed and refractory multiple myeloma,” can Society ofHematology, Dec. 10-13, 2005. Press Release, Nov. 1, 2002. Dredge et al., A costimulatory thalidomide analog enhances the par Celgene Corporation, “Celgene provides update on clinical pipeline. tial anti-tumor immunity of an autologous vaccination in a model of Celgene Announces ?rst target indication for ACTIMIDTM, colorectal cancer, Abstract # 491, American Association for Cancer CC-8490. SeICIDTM program to advance based on results from Phase Research, Apr. 6-10, 2002. 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Okamoto, T., Kotsuzuiikeisei Shoukougun to Men-eki Ijo, Bessatsu Inhibits Angiogenesis and Growth in Drug Resistant Multiple Nihon Rinsho. Syndrome Series for each area, No. 22, Blood Syn Myeloma (MM) in vivo. Abstract # 1976. American Society of dromes III, Nihon Rlnshou, 213-216 (in Japanese), (Oct. 1998). Hematology, Dec. 7-11, 2001. Merck Manual, 17’h ed. Japanese version, 1999, 951-952. Park, Y., Kim. S.A., Kim, C.J., Chung, J.H., Mechanism ofthe Effect Notice ofAllowance from US. Appl. No. 11/096,155 dated Jan. 12, of Thalidomide on Human Multiple Myeloma Cells. Abstract #2685. 2010. American Society of Clinical Oncology, May 12-17, 2001. 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P.G., Schlossman, R.L., Extracts from drug databases: retrieved from http://www.nextbio. Adams, J ., Anderson, K.C., NF-KB as a Therapeutic Target in Mul com/b/search/ov/IMiD3%20cpd on Nov. 26, 2010 and http:// tiple Myeloma (MM). Abstract # 1581. American Society of Hema pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid:216326 on tology. Dec. 7-11, 2001. Nov. 26, 2010. Lentsch, S.. Rogers, M., LeBlanc, R., Birsner, A., Shah, J ., Anderson K., D’Amato R., 3-Amino-Phthalimido-Glutarimidde (S-3APG) * cited by examiner US. Patent Jun. 28,2011 US 7,968,569 B2

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Legend: Q Thalidomide I IMiDl A Revimilim . IMSDZ US 7,968,569 B2 1 2 METHODS FOR TREATMENT OF MULTIPLE example, enhanced or unregulated angiogenesis has been MYELOMA USING 3-(4-AMINO-1-OXO-1,3 implicated in a number of diseases and medical conditions DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE including, but not limited to, ocular neovascular diseases, 2,6-DIONE choroidal neovascular diseases, retina neovascular diseases, rubeosis (neovascularization of the angle), viral diseases, This application claims the bene?t of US. provisional genetic diseases, in?ammatory diseases, allergic diseases, application No. 60/380,842, ?led May 17, 2002, and No. and autoimmune diseases. Examples of such diseases and 60/424,600, ?led Nov. 6, 2002, the entireties of which are conditions include, but are not limited to: diabetic retinopa incorporated herein by reference. thy; retinopathy of prematurity; corneal graft rejection; neovascular glaucoma; retrolental ?broplasia; and prolifera 1. FIELD OF THE INVENTION tive vitreoretinopathy. Accordingly, compounds that can control angiogenesis or This invention relates to methods of treating, preventing inhibit the production of certain cytokines, including TNF-(x, and/ or managing speci?c cancers, and other diseases includ may be useful in the treatment and prevention of various ing, but not limited to, those associated with, or characterized diseases and conditions. by, undesired angiogenesis, by the administration of one or 2.2 Methods of Treating Cancer more immunomodulatory compounds alone or in combina Current cancer therapy may involve surgery, chemo tion with other therapeutics. In particular, the invention therapy, hormonal therapy and/or radiation treatment to encompasses the use of speci?c combinations, or “cocktails,” eradicate neoplastic cells in a patient (see, for example, of drugs and other therapy, e.g., radiation to treat these spe 20 Stockdale, 1998, Medicine, vol. 3, Rubenstein and Federman, ci?c cancers, including those refractory to conventional eds., Chapter 12, Section IV). Recently, cancer therapy could therapy. The invention also relates to pharmaceutical compo also involve biological therapy or immunotherapy. All of sitions and dosing regimens. these approaches pose signi?cant drawbacks for the patient. Surgery, for example, may be contraindicated due to the 2. BACKGROUND OF THE INVENTION 25 health of a patient or may be unacceptable to the patient. Additionally, surgery may not completely remove neoplastic 2.1 Pathobiology of Cancer and Other Diseases tissue. Radiation therapy is only effective when the neoplastic Cancer is characterized primarily by an increase in the tissue exhibits a higher sensitivity to radiation than normal number of abnormal cells derived from a given normal tissue, tissue. Radiation therapy can also often elicit serious side invasion of adjacent tissues by these abnormal cells, or lym 30 effects. Hormonal therapy is rarely given as a single agent. phatic or blood-borne spread of malignant cells to regional Although hormonal therapy can be effective, it is often used lymph nodes and to distant sites (metastasis). Clinical data to prevent or delay recurrence of cancer after other treatments and molecular biologic studies indicate that cancer is a mul have removed the majority of cancer cells. Biological thera tistep process that begins with minor preneoplastic changes, pies and immunotherapies are limited in number and may which may under certain conditions progress to neoplasia. 35 produce side effects such as rashes or swellings, ?u-like The neoplastic lesion may evolve clonally and develop an symptoms, including fever, chills and fatigue, digestive tract increasing capacity for invasion, growth, metastasis, and het problems or allergic reactions. erogeneity, especially under conditions in which the neoplas With respect to chemotherapy, there are a variety of che tic cells escape the host’s immune surveillance. Roitt, I., motherapeutic agents available for treatment of cancer. A Brostoff, J and Kale, D., Immunology, 17.1-17.12 (3rd ed., 40 majority of cancer chemotherapeutics act by inhibiting DNA Mosby, St. Louis, Mo., 1993). synthesis, either directly, or indirectly by inhibiting the bio There is an enormous variety of cancers which are synthesis of deoxyribonucleotide triphosphate precursors, to described in detail in the medical literature. Examples prevent DNA replication and concomitant cell division. Gil includes cancer of the lung, colon, rectum, prostate, breast, man et al., Goodman and Gilman’s: The Pharmacological brain, and intestine. The incidence of cancer continues to 45 Basis of Therapeutics, Tenth Ed. (McGraw Hill, New York). climb as the general population ages, as new cancers develop, Despite availability of a variety of chemotherapeutic and as susceptible populations (e.g., people infected with agents, chemotherapy has many drawbacks. Stockdale, Medi AIDS or excessively exposed to sunlight) grow. A tremen cine, vol. 3, Rubenstein and Federman, eds., ch. 12, sect. 10, dous demand therefore exists for new methods and composi 1998. Almost all chemotherapeutic agents are toxic, and che tions that can be used to treat patients with cancer. 50 motherapy causes signi?cant, and often dangerous side Many types of cancers are associated with new blood ves effects including severe nausea, bone marrow depression, and sel formation, a process known as angiogenesis. Several of immunosuppression. Additionally, even with administration the mechanisms involved in tumor-induced angiogenesis of combinations of chemotherapeutic agents, many tumor have been elucidated. The most direct of these mechanisms is cells are resistant or develop resistance to the chemothera the secretion by the tumor cells of cytokines with angiogenic 55 peutic agents. In fact, those cells resistant to the particular properties. Examples of these cytokines include acidic and chemotherapeutic agents used in the treatment protocol often basic ?broblastic growth factor (a,b-FGF), angiogenin, vas prove to be resistant to other drugs, even if those agents act by cular endothelial growth factor (VEGF), and TNF-(x. Alter different mechanism from those of the drugs used in the natively, tumor cells can release angiogenic peptides through speci?c treatment. This phenomenon is referred to as pleio the production of proteases and the subsequent breakdown of 60 tropic drug or multidrug resistance. Because of the drug resis the extracellular matrix where some cytokines are stored tance, many cancers prove refractory to standard chemothera (e.g., b-FGF). Angiogenesis can also be induced indirectly peutic treatment protocols. through the recruitment of in?ammatory cells (particularly Other diseases or conditions associated with, or character macrophages) and their subsequent release of angiogenic ized by, undesired angiogenesis are also dif?cult to treat. cytokines (e.g., TNF-(x, bFGF). 65 However, some compounds such as protamine, hepain and A variety of other diseases and disorders are also associ steroids have been proposed to be useful in the treatment of ated with, or characterized by, undesired angiogenesis. For certain speci?c diseases. Taylor et al., Nature 297:307 (1982); US 7,968,569 B2 3 4 Folkman et al., Science 221:719 (1983); and US. Pat. Nos. tory compound, or a pharmaceutically acceptable salt, sol 5,001,116 and 4,994,443. Thalidomide and certain deriva vate, hydrate, stereoisomer, clathrate, or prodrug thereof. tives of it have also been proposed for the treatment of such In other methods of the invention, an immunomodulatory diseases and conditions. US. Pat. Nos. 5,593,990, 5,629,327, compound is administered in combination With a therapy 5,712,291, 6,071,948 and 6,114,355 to D’Amato. conventionally used to treat, prevent or manage diseases or Still, there is a signi?cant need for safe and effective meth disorders associated With, or characterized by, undesired ods of treating, preventing and managing cancer and other angiogenesis. Examples of such conventional therapies diseases and conditions, particularly for diseases that are include, but are not limited to, surgery, chemotherapy, radia refractory to standard treatments, such as surgery, radiation tion therapy, hormonal therapy, biological therapy and immu therapy, chemotherapy and hormonal therapy, While reducing notherapy. or avoiding the toxicities and/ or side effects associated With This invention encompasses pharmaceutical composi the conventional therapies. tions, single unit dosage forms, dosing regimens and kits 2.3 IMIDSTM Which comprise an immunomodulatory compound, or a phar A number of studies have been conducted With the aim of maceutically acceptable salt, solvate, hydrate, stereoisomer, providing compounds that can safely and effectively be used clathrate, or prodrug thereof, and a second, or additional, active agent. Second active agents include speci?c combina to treat diseases associated With abnormal production of tions, or “cocktails,” of drugs. TNF-(x See, e.g., Marriott, J. B., et al., Expert Opin. Biol. The}: 1(4): 1-8 (2001); G. W. Muller, et al., Journal ofMedici 4. BRIEF DESCRIPTION OF FIGURE nal Chemistry 39(17): 3238-3240 (1996); and G. W. Muller, 20 et al, Bioorganic & Medicinal Chemistry Letters 8: 2669 FIG. 1 shows a comparison of the effects of 3-(4-amino-1 - 2674 (1998). Some studies have focused on a group of com oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (Re pounds selected for their capacity to potently inhibit TNF-(x vimidTM) and thalidomide in inhibiting the proliferation of production by LPS stimulated PBMC. L. G. Corral, et al., multiple myeloma (MM) cell lines in an in vitro study. The Ann. Rheum. Dis. 58:(Suppl I) 1107-1113 (1999). These 25 uptake of [3H]-thymidine by different MM cell lines (MM. compounds, Which are referred to as IMiDSTM (Celgene Cor 1S, Hs Sultan, U266 and RPMI-8226) was measured as an poration) or Immunomodulatory Drugs, shoW not only potent indicator of the cell proliferation. inhibition of TNF-(x but also marked inhibition of LPS induced monocyte IL1[3 and IL12 production. LPS induced 5. DETAILED DESCRIPTION OF THE IL6 is also inhibited by immunomodulatory compounds, 30 INVENTION albeit partially. These compounds are potent stimulators of LPS induced IL10. Id. Particular examples of IMiDTMs A ?rst embodiment of the invention encompasses methods include, but are not limited to, the substituted 2-(2,6-dioxopi of treating, managing, or preventing cancer Which comprises peridin-3-yl) phthalimides and substituted 2-(2,6-dioxopip administering to a patient in need of such treatment or pre eridin-3-yl)-1-oxoisoindoles described in US. Pat. Nos. 35 vention a therapeutically or prophylactically effective 6,281,230 and 6,316,471, both to G. W. Muller, et al. amount of an immunomodulatory compound of the inven tion, or a pharmaceutically acceptable salt, solvate, hydrate, 3. SUMMARY OF THE INVENTION stereoisomer, clathrate, or prodrug thereof. In particular methods encompassed by this embodiment, This invention encompasses methods of treating and pre 40 the immunomodulatory compound is administered in combi venting certain types of cancer, including primary and meta nation With another drug (“second active agent”) or method of static cancer, as well as cancers that are refractory or resistant treating, managing, or preventing cancer. Second active to conventional chemotherapy. The methods comprise agents include small molecules and large molecules (e.g., administering to a patient in need of such treatment or pre proteins and antibodies), examples of Which are provided vention a therapeutically or prophylactically effective 45 herein, as well as stem cells. Methods, or therapies, that can amount of an immunomodulatory compound, or a pharma be used in combination With the administration of the immu ceutically acceptable salt, solvate, hydrate, stereoisomer, nomodulatory compound include, but are not limited to, sur clathrate, or prodrug thereof. The invention also encompasses gery, blood transfusions, immunotherapy, biological therapy, methods of managing certain cancers (e. g., preventing or radiation therapy, and other non-drug based therapies pres prolonging their recurrence, or lengthening the time of remis 50 ently used to treat, prevent or manage cancer. sion) Which comprise administering to a patient in need of Another embodiment of the invention encompasses meth such management a prophylactically effective amount of an ods of treating, managing or preventing diseases and disor immunomodulatory compound of the invention, or a pharma ders other than cancer that are characterized by undesired ceutically acceptable salt, solvate, hydrate, stereoisomer, angiogenesis. These methods comprise the administration of clathrate, or prodrug thereof. 55 a therapeutically or prophylactically effective amount of an In particular methods of the invention, an immunomodu immunomodulatory compound, or a pharmaceutically latory compound is administered in combination With a acceptable salt, solvate, hydrate, stereoisomer, clathrate, or therapy conventionally used to treat, prevent or manage can prodrug thereof. cer. Examples of such conventional therapies include, but are Examples of diseases and disorders associated With, or not limited to, surgery, chemotherapy, radiation therapy, hor 60 characterized by, undesired angiogenesis include, but are not monal therapy, biological therapy and immunotherapy. limited to, in?ammatory diseases, autoimmune diseases, This invention also encompasses methods of treating, man viral diseases, genetic diseases, allergic diseases, bacterial aging or preventing diseases and disorders other than cancer diseases, ocular neovascular diseases, choroidal neovascular that are associated With, or characterized by, undesired angio diseases, retina neovascular diseases, and rubeosis (neovas genesis, Which comprise administering to a patient in need of 65 cularization of the angle). such treatment, management or prevention a therapeutically In particular methods encompassed by this embodiment, or prophylactically effective amount of an immunomodula the immunomodulatory compound is administer in combina US 7,968,569 B2 5 6 tion with a second active agent or method of treating, man Pat. Nos. 5,593,990, 5,629,327, and 6,071,948 to D’Amato; aging, or preventing the disease or condition. Second active aminothalidomide, as well as analogs, hydrolysis products, agents include small molecules and large molecules (e.g., metabolites, derivatives and precursors of aminothalidomide, proteins and antibodies), examples of which are provided and substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and herein, as well as stem cells. Methods, or therapies, that can substituted 2-(2,6-dioxopiperidin-3 -yl)-1-oxoisoindoles be used in combination with the administration of the immu such as those described in US. Pat. Nos. 6,281,230 and nomodulatory compound include, but are not limited to, sur 6,316,471; isoindole-imide compounds such as those gery, blood transfusions, immunotherapy, biological therapy, described in US. patent application Ser. No. 09/972,487 ?led radiation therapy, and other non-drug based therapies pres on Oct. 5, 2001, US. patent application Ser. No. 10/032,286 ently used to treat, prevent or manage disease and conditions ?led on Dec. 21, 2001, and lntemational Application No. associated with, or characterized by, undesired angiogenesis. The invention also encompasses pharmaceutical composi PCT/U S01/ 50401 (lntemational Publication No. WO tions (e.g., single unit dosage forms) that can be used in 02/059106). The entireties of each of the patents and patent methods disclosed herein. Particular pharmaceutical compo applications identi?ed herein are incorporated herein by ref sitions comprise an immunomodulatory compound of the erence. lmmunomodulatory compounds of the invention do invention, or a pharmaceutically acceptable salt, solvate, not include thalidomide. hydrate, stereoisomer, clathrate, or prodrug thereof, and a Other speci?c immunomodulatory compounds of the second active agent. invention include, but are not limited to, 1-oxo- and 1,3 5.1 lmmunomodulatory Compounds dioxo-2-(2,6-dioxopiperidin-3-yl) isoindolines substituted Compounds used in the invention include immunomodu 20 with amino in the benzo ring as described in US. Pat. No. latory compounds that are racemic, stereomerically enriched 5,635,517 which is incorporated herein by reference. These or stereomerically pure, and pharmaceutically acceptable compounds have the structure I: salts, solvates, hydrates, stereoisomers, clathrates, and pro drugs thereof. Preferred compounds used in the invention are small organic molecules having a molecular weight less than 25 about 1,000 g/mol, and are not proteins, peptides, oligonucle o otides, oligosaccharides or other macromolecules. x R2 As used herein and unless otherwise indicated, the terms \ H “immunomodulatory compounds” and “lMiDsTM” (Celgene / Corporation) encompasses small organic molecules that 30 Y markedly inhibit TNF-(x, LPS induced monocyte IL1[3 and HZN@[ Niiill O IL12, and partially inhibit 1L6 production. Speci?c immuno modulatory compounds are discussed below. TNF-(x is an in?ammatory cytokine produced by macroph in which one of X andY is C:O, the other of X andY is C:O ages and monocytes during acute in?ammation. TNF-(x is 35 or CH2, and R2 is hydrogen or lower alkyl, in particular responsible for a diverse range of signaling events within methyl. Speci?c immunomodulatory compounds include, but cells. TNF-(x may play a pathological role in cancer. Without are not limited to: being limited by theory, one of the biological effects exerted 1-oxo-2-(2,6-dioxopiperidin-3 -yl)-4-aminoisoindoline; by the immunomodulatory compounds of the invention is the reduction of synthesis of TNF-(x. lmmunomodulatory com 40 1-oxo-2-(2,6-dioxopiperidin-3 -yl)-5-aminoisoindoline; pounds of the invention enhance the degradation of TNF 1-oxo-2-(2,6-dioxopiperidin-3 -yl)-6-aminoisoindoline; (meNA. 1-oxo-2-(2,6-dioxopiperidin-3 -yl)-7-aminoisoindoline; Further, without being limited by theory, immunomodula tory compounds used in the invention may also be potent 1,3 -dioxo-2-(2, 6-dioxopiperidin-3-yl)-4-aminoisoindoline; co-stimulators of T cells and increase cell proliferation dra 45 and matically in a dose dependent manner. lmmunomodulatory 1,3 -dioxo-2-(2, 6-dioxopiperidin-3-yl)-5-aminoisoindoline. compounds of the invention may also have a greater co Other speci?c immunomodulatory compounds of the stimulatory effect on the CD8+ T cell subset than on the CD4+ T cell subset. In addition, the compounds preferably invention belong to a class of substituted 2-(2,6-dioxopiperi din-3 -yl) phthalimides and substituted 2-(2,6-dioxopiperi have anti-in?ammatory properties, and ef?ciently co-stimu 50 late T cells. din-3-yl)-1-oxoisoindoles, such as those described in US. Speci?c examples of immunomodulatory compounds of Pat. Nos. 6,281,230; 6,316,471; 6,335,349; and 6,476,052, the invention, include, but are not limited to, cyano and car and lntemational Patent Application No. PCT/U S97/ 13375 boxy derivatives of substituted styrenes such as those dis (lntemational Publication No. WO 98/ 03502), each of which closed in US. Pat. No. 5,929,117; 1-oxo-2-(2,6-dioxo-3 55 is incorporated herein by reference. Compounds representa ?uoropiperidin-3-yl) isoindolines and 1,3-dioxo-2-(2,6 tive of this class are of the formulas: dioxo-3-?uoropiperidine-3-yl) isoindolines such as those described in US. Pat. No. 5,874,448; the tetra substituted 2-(2,6-dioxopiperdin-3-yl)-1-oxoisoindolines described in US. Pat. No. 5,798,368; 1-oxo and 1,3-dioxo-2-(2,6-diox 60 opiperidin-3-yl) isoindolines (e.g., 4-methyl derivatives of thalidomide and EM-12), including, but not limited to, those disclosed in US. Pat. No. 5,635,517; and a class of non polypeptide cyclic amides disclosed in US. Pat. Nos. 5,698, 579 and 5,877,200; analogs and derivatives of thalidomide, 65 including hydrolysis products, metabolites, derivatives and precursors of thalidomide, such as those described in US. US 7,968,569 B2 7 8 -continued R5 is (Cl-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, ben 0 zyl, aryl, or (C2-C5)heteroaryl; H o each occurrence of R6 is independently H, (C1-C8)alkyl, I \N N/ H (C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl, (C2-C5)het / eroaryl, or (CO-C8)all

40

\nmCHZ—UO , mCHZ—US or R7 R7

45

and pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates, and mix tures of stereoisomers thereof, Wherein: 50 Wherein Q is O or S, and each occurrence of R7 is indepen one of X andY is C:O and the other is CH2 or C:O; dently H, (C1-C8)alkyl, benzyl, CHZOCH3, or CH2CHZOCH3. In other speci?c compounds of formula II, R1 is C(O)R3. In other speci?c compounds of formula II, R3 is (CO-C4) 55 alkyl-(CZ-C5)heteroaryl, (C1-C5)alkyl, aryl, or (CO-C4)alkyl 0R5. In other speci?c compounds of formula II, heteroaryl is R2 is H, F, benzyl, (Cl-C8)alkyl, (C2-C8)alkenyl, or (C2 pyridyl, furyl, or thienyl. C8)a1kyny1; In other speci?c compounds of formula II, R1 is C(O)OR4. R3 and R3’ are independently (Cl-C8)alkyl, (C3-C7)cy 60 In other speci?c compounds of formula II, the H of C(O) cloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl, (CO NHC(O) can be replaced With (C 1-C4)alkyl, aryl, or benzyl. C4)alkyl(Cl-C6)heterocycloalkyl, (CO-C4)alkyl-(C2-C5)het Still other speci?c immunomodulatory compounds of the eroaryl, (CO-C8)alkyl-N(R6)2, (C1-C8)allprodrugs include, but are not limited to, derivatives of immu invention are 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindo nomodulatory compounds of the invention that comprise bio line-1,3-dione and 3 -(4-amino-1-oxo-1,3 -dihydro -isoindol hydrolyzable moieties such as biohydrolyzable amides, bio 2-yl)-piperidine-2,6-dione. The compounds can be obtained hydrolyzable esters, biohydrolyzable carbamates, via standard, synthetic methods (see e. g., U.S. Pat. No. 5,635, biohydrolyzable carbonates, biohydrolyzable ureides, and 517, incorporated herein by reference). The compounds are 40 biohydrolyzable phosphate analogues. Other examples of available from Celgene Corporation, Warren, N.J. prodrugs include derivatives of immunomodulatory com 4-(Amino)-2-(2,6-dioxo(3 -piperidyl))-isoindoline-1,3-dione pounds of the invention that comprise iNO, iNO2, (ACTIMIDTM) has the following chemical structure: 4ONO, or 4ONO2 moieties. Prodrugs can typically be pre pared using well-known methods, such as those described in 45 1 Burger’s Medicinal Chemistry and Drug Discovery, 172 0 178, 949-982 (Manfred E. Wolff ed., 5th ed. 1995), and Design ofProdrugs (H. Bundgaard ed., Elselvier, NY. 1985). As used herein and unless otherwise indicated, the terms N o “biohydrolyzable amide,” “biohydrolyzable ester,” “biohy N drolyzable carbamate,” “biohydrolyzable carbonate,” “bio O \ hydrolyzable ureide,” “biohydrolyzable phosphate” mean an NH2 0 H amide, ester, carbamate, carbonate, ureide, or phosphate, respectively, of a compound that either: 1) does not interfere The compound 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2 with the biological activity of the compound but can confer yl)-piperidine-2,6-dione (REVIMIDTM) has the following upon that compound advantageous properties in vivo, such as chemical structure: uptake, duration of action, or onset of action; or 2) is biologi cally inactive but is converted in vivo to the biologically active compound. Examples of biohydrolyzable esters 0 include, but are not limited to, lower alkyl esters, lower acy loxyalkyl esters (such as acetoxylmethyl, acetoxyethyl, ami nocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxy N o ethyl esters), lactonyl esters (such as phthalidyl and N thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such \ as methoxycarbonyl-oxymethyl, ethoxycarbonyloxyethyl NH2 0 H 65 and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters, and acylamino alkyl esters (such as acetami domethyl esters). Examples of biohydrolyzable amides US 7,968,569 B2 11 12 include, but are not limited to, lower alkyl amides, (x-amino believed that certain combinations work synergistically in the acid amides, alkoxyacyl amides, and alkylaminoalkylcarbo treatment of particular types of cancer and certain diseases nyl amides. Examples of biohydrolyzable carbamates and conditions associated with, or characterized by, undes include, but are not limited to, lower alkylamines, substituted ired angiogenesis. lmmunomodulatory compounds can also ethylenediamines, amino acids, hydroxyalkylamines, hetero work to alleviate adverse effects associated with certain sec cyclic and heteroaromatic amines, and polyether amines. ond active agents, and some second active agents can be used Various immunomodulatory compounds of the invention to alleviate adverse effects associated with immunomodula contain one or more chiral centers, and can exist as racemic tory compounds. mixtures of enantiomers or mixtures of diastereomers. This One or more second active ingredients or agents can be invention encompasses the use of stereomerically pure forms used in the methods and compositions of the invention of such compounds, as well as the use of mixtures of those together with an immunomodulatory compound. Second forms. For example, mixtures comprising equal or unequal active agents can be large molecules (e. g., proteins) or small amounts of the enantiomers of a particular immunomodula molecules (e.g., synthetic inorganic, organometallic, or tory compounds of the invention may be used in methods and organic molecules). compositions of the invention. These isomers may be asym Examples of large molecule active agents include, but are metrically synthesized or resolved using standard techniques not limited to, hematopoietic growth factors, cytokines, and such as chiral columns or chiral resolving agents. See, e.g., monoclonal and polyclonal antibodies. Typical large mol Jacques, 1., et al., Enantiomers, Racemates and Resolutions ecule active agents are biological molecules, such as naturally (Wiley-lnterscience, New York, 1981); Wilen, S. H., et al., occurring or arti?cially made proteins. Proteins that are par Tetrahedron 3312725 (1977); Eliel, E. L., Stereochemistry of 20 ticularly useful in this invention include proteins that stimu Carbon Compounds (McGraw-Hill, N.Y., 1962); and Wilen, late the survival and/ or proliferation of hematopoietic precur S. H., Tables ofResolvingAgents and Optical Resolutions p. sor cells and immunologically active poietic cells in vitro or 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, in vivo. Others stimulate the division and differentiation of 1nd., 1972). committed erythroid progenitors in cells in vitro or in vivo. As used herein and unless otherwise indicated, the term 25 Particular proteins include, but are not limited to: interleu “stereomerically pure” means a composition that comprises kins, such as lL-2 (including recombinant lL-ll (“rlL2”) and one stereoisomer of a compound and is substantially free of canarypox lL-2), lL-10, lL-12, and lL-18; interferons, such other stereoisomers of that compound. For example, a stereo as interferon alfa-2a, interferon alfa-2b, interferon alfa-n1, merically pure composition of a compound having one chiral interferon alfa-n3, interferon beta-l a, and interferon center will be substantially free of the opposite enantiomer of 30 gamma-l b; GM-CF and GM-CSF; and EPO. the compound. A stereomerically pure composition of a com Particular proteins that can be used in the methods and pound having two chiral centers will be substantially free of compositions of the invention include, but are not limited to: other diastereomers of the compound. A typical stereomeri ?lgrastim, which is sold in the United States under the trade cally pure compound comprises greater than about 80% by name Neupogen® (Amgen, Thousand Oaks, Calif.); sargra weight of one stereoisomer of the compound and less than 35 mostim, which is sold in the United States under the trade about 20% by weight of other stereoisomers of the com name Leukine® (lmmunex, Seattle, Wash.); and recombinant pound, more preferably greater than about 90% by weight of EPO, which is sold in the United States under the trade name one stereoisomer of the compound and less than about 10% Epogen® (Amgen, Thousand Oaks, Calif.). by weight of the other stereoisomers of the compound, even Recombinant and mutated forms of GM-CSF can be pre more preferably greater than about 95% by weight of one 40 pared as described in US. Pat. Nos. 5,391,485; 5,393,870; stereoisomer of the compound and less than about 5% by and 5,229,496; all of which are incorporated herein by refer weight of the other stereoisomers of the compound, and most ence. Recombinant and mutated forms of G-CSF can be preferably greater than about 97% by weight of one stereoi prepared as described in US. Pat. Nos. 4,810,643; 4,999,291; somer of the compound and less than about 3% by weight of 5,528,823; and 5,580,755; all of which are incorporated the other stereoisomers of the compound. As used herein and 45 herein by reference. unless otherwise indicated, the term “stereomerically This invention encompasses the use of native, naturally enriched” means a composition that comprises greater than occurring, and recombinant proteins. The invention further about 60% by weight of one stereoisomer of a compound, encompasses mutants and derivatives (e.g., modi?ed forms) preferably greater than about 70% by weight, more preferably of naturally occurring proteins that exhibit, in vivo, at least greater than about 80% by weight of one stereoisomer of a 50 some of the pharmacological activity of the proteins upon compound. As used herein and unless otherwise indicated, which they are based. Examples of mutants include, but are the term “enantiomerically pure” means a stereomerically not limited to, proteins that have one or more amino acid pure composition of a compound having one chiral center. residues that differ from the corresponding residues in the Similarly, the term “stereomerically enriched” means a ste naturally occurring forms of the proteins. Also encompassed reomerically enriched composition of a compound having 55 by the term “mutants” are proteins that lack carbohydrate one chiral center. moieties normally present in their naturally occurring forms It should be noted that if there is a discrepancy between a (e.g., nonglycosylated forms). Examples of derivatives depicted structure and a name given that structure, the include, but are not limited to, pegylated derivatives and depicted structure is to be accorded more weight. In addition, fusion proteins, such as proteins formed by fusing lgGl or if the stereochemistry of a structure or a portion of a structure 60 lgG3 to the protein or active portion of the protein of interest. is not indicated with, for example, bold or dashed lines, the See, e.g., Penichet, M. L. and Morrison, S. L., J. Immunol. structure or portion of the structure is to be interpreted as Methods 248191-101 (2001). encompassing all stereoisomers of it. Antibodies that can be used in combination with com 5.2 Second Active Agents pounds of the invention include monoclonal and polyclonal lmmunomodulatory compounds can be combined with 65 antibodies. Examples of antibodies include, but are not lim other pharmacologically active compounds (“second active ited to, trastuzumab (Herceptin®), rituximab (Rituxan®), agents”) in methods and compositions of the invention. It is bevacizumab (AvastinTM), pertuzumab (OmnitargTM), tositu US 7,968,569 B2 13 14 momab (Bexxar®), edrecolomab (Panorex®), and G250. broman; piposulfan; piroxantrone hydrochloride; Compounds of the invention can also be combined With, or plicamycin; plomestane; por?mer sodium; por?romycin; used in combination With, anti-TNF-(x antibodies. prednimustine; procarbaZine hydrochloride; puromycin; Large molecule active agents may be administered in the puromycin hydrochloride; pyrazofurin; riboprine; sa?ngol; form of anti-cancer vaccines. For example, vaccines that sa?ngol hydrochloride; semustine; simtrazene; sparfosate secrete, or cause the secretion of, cytokines such as lL-2, sodium; sparsomycin; spirogermanium hydrochloride; spiro G-CSF, and GM-CSF can be used in the methods, pharma mustine; spiroplatin; streptonigrin; streptozocin; sulofenur; ceutical compositions, and kits of the invention. See, e.g., talisomycin; tecogalan sodium; taxotere; tegafur; telox Emens, L. A., et al., Curr. Opinion Mol. The}: 3(1):77-84 antrone hydrochloride; temopor?n; teniposide; teroxirone; (2001). testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; In one embodiment of the invention, the large molecule tirapazamine; toremifene citrate; trestolone acetate; tricirib active agent reduces, eliminates, or prevents an adverse effect ine phosphate; trimetrexate; trimetrexate glucuronate; trip associated With the administration of an immunomodulatory torelin; tubulozole hydrochloride; uracil mustard; uredepa; compound. Depending on the particular immunomodulatory vapreotide; vertepor?n; vinblastine sulfate; vincristine sul compound and the disease or disorder begin treated, adverse fate; vindesine; vindesine sulfate; vinepidine sulfate; vingly effects can include, but are not limited to, drowsiness and cinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vin somnolence, diZZiness and orthostatic hypotension, neutro rosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; penia, infections that result from neutropenia, increased HIV Zinostatin; and zorubicin hydrochloride. viral load, bradycardia, Stevens -Johnson Syndrome and toxic Other anti-cancer drugs include, but are not limited to: epidermal necrolysis, and seizures (e.g., grand mal convul 20 20-epi-l,25 dihydroxyvitamin D3; 5-ethynyluracil; abirater sions). A speci?c adverse effect is neutropenia. one; aclarubicin; acylfulvene; adecypenol; adozelesin; Second active agents that are small molecules can also be aldesleukin; ALL-TK antagonists; altretamine; ambamus used to alleviate adverse effects associated With the adminis tine; amidox; amifostine; aminolevulinic acid; amrubicin; tration of an immunomodulatory compound. However, like amsacrine; anagrelide; anastrozole; andrographolide; angio some large molecules, many are believed to be capable of 25 genesis inhibitors; antagonist D; antagonist G; antarelix; anti providing a synergistic effect When administered With (e.g., dorsaliZing morphogenetic protein-1 ; antiandrogen, prostatic before, after or simultaneously) an immunomodulatory com carcinoma; antiestrogen; antineoplaston; antisense oligo pound. Examples of small molecule second active agents nucleotides; aphidicolin glycinate; apoptosis gene modula include, but are not limited to, anti-cancer agents, antibiotics, tors; apoptosis regulators; apurinic acid; ara-CDP-DL immunosuppressive agents, and steroids. 30 PTBA; arginine deaminase; asulacrine; atamestane; Examples of anti-cancer agents include, but are not limited atrimustine; axinastatin l; axinastatin 2; axinastatin 3; aza to: acivicin; aclarubicin; acodazole hydrochloride; acronine; setron; azatoxin; azatyrosine; baccatin Ill derivatives; bal adozelesin; aldesleukin; altretamine; ambomycin; amet anol; batimastat; BCR/ABL antagonists; benzochlorins; ben antrone acetate; amsacrine; anastrozole; anthramycin; zoylstaurosporine; beta lactam derivatives; beta-alethine; asparaginase; asperlin; azacitidine; azetepa; azotomycin; 35 betaclamycin B; betulinic acid; bFGF inhibitor; bicaluta batimastat; benzodepa; bicalutamide; bisantrene hydrochlo mide; bisantrene; bisaZiridinylspermine; bisna?de; bistratene ride; bisna?de dimesylate; bizelesin; bleomycin sulfate; bre A; bizelesin; bre?ate; bropirimine; budotitane; buthionine quinar sodium; bropirimine; busulfan; cactinomycin; calus sulfoximine; calcipotriol; calphostin C; camptothecin deriva terone; caracemide; carbetimer; carboplatin; carmustine; tives; capecitabine; carboxamide-amino-triazole; carboxya carubicin hydrochloride; carzelesin; cede?ngol; celecoxib 40 midotriazole; CaRest M3; CARN 700; cartilage derived (COX-2 inhibitor); chlorambucil; cirolemycin; cisplatin; inhibitor; carzelesin; casein kinase inhibitors (ICOS); cladribine; crisnatol mesylate; cyclophosphamide; cytara castanospermine; cecropin B; cetrorelix; chlorlns; chloroqui bine; dacarbaZine; dactinomycin; daunorubicin hydrochlo noxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; ride; decitabine; dexormaplatin; dezaguanine; dezaguanine clomifene analogues; clotrimazole; collismycin A; collismy mesylate; diaZiquone; docetaxel; doxorubicin; doxorubicin 45 cin B; combretastatin A4; combretastatin analogue; conage hydrochloride; droloxifene; droloxifene citrate; dromo nin; crambescidin 816; crisnatol; cryptophycin 8; cryptophy stanolone propionate; duazomycin; edatrexate; e?omithine cin A derivatives; curacin A; cyclopentanthraquinones; hydrochloride; elsamitrucin; enloplatin; enpromate; epipro cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic fac pidine; epirubicin hydrochloride; erbulozole; esorubicin tor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; hydrochloride; estramustine; estramustine phosphate 50 deslorelin; dexamethasone; dexifosfamide; dexrazoxane; sodium; etanidazole; etoposide; etoposide phosphate; eto dexverapamil; diaZiquone; didemnin B; didox; diethylnor prine; fadrozole hydrochloride; fazarabine; fenretinide; spermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamy ?oxuridine; ?udarabine phosphate; ?uorouracil; ?urocitab cin; diphenyl spiromustine; docetaxel; docosanol; dolas ine; fosquidone; fostriecin sodium; gemcitabine; gemcitab etron; doxi?uridine; doxorubicin; droloxifene; dronabinol; ine hydrochloride; hydroxyurea; idarubicin hydrochloride; 55 duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolo ifosfamide; ilmofosine; iproplatin; irinotecan; irinotecan mab; e?omithine; elemene; emitefur; epirubicin; epristeride; hydrochloride; lanreotide acetate; letrozole; leuprolide estramustine analogue; estrogen agonists; estrogen antago acetate; liarozole hydrochloride; lometrexol sodium; lomus nists; etanidazole; etoposide phosphate; exemestane; fadro tine; losoxantrone hydrochloride; masoprocol; maytansine; Zole; fazarabine; fenretinide; ?lgrastim; ?nasteride; ?a mechlorethamine hydrochloride; megestrol acetate; 60 vopiridol; ?ezelastine; ?uasterone; ?udarabine; melengestrol acetate; melphalan; menogaril; mercaptopu ?uorodaunorunicin hydrochloride; forfenimex; formestane; rine; methotrexate; methotrexate sodium; metoprine; meture fostriecin; fotemustine; gadolinium texaphyrin; gallium depa; mitindomide; mitocarcin; mitocromin; mitogillin; nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcit mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone abine; glutathione inhibitors; hepsulfam; heregulin; hexam hydrochloride; mycophenolic acid; nocodazole; nogalamy 65 ethylene bisacetamide; hypericin; ibandronic acid; idarubi cin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomy cin; idoxifene; idramantone; ilmofosine; ilomastat; imatinib cin; pentamustine; peplomycin sulfate; perfosfamide; pipo (e.g., Gleevec®), imiquimod; immunostimulant peptides; US 7,968,569 B2 15 16 insulin-like growth factor-1 receptor inhibitor; interferon trimetrexate; triptorelin; tropisetron; turosteride; tyrosine agonists; interferons; interleukins; iobenguane; iododoxoru kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; bicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; iso urogenital sinus-derived growth inhibitory factor; urokinase homohalicondrin B; itasetron; jasplakinolide; kahalalide F; receptor antagonists; vapreotide; variolin B; velaresol; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; veramine; verdins; vertepor?n; vinorelbine; vinxaltine; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and factor; leukocyte alpha interferon; leuprolide+estrogen+ zinostatin stimalamer. progesterone; leuprorelin; levamisole; liarozole; linear Speci?c second active agents include, but are not limited polyamine analogue; lipophilic disaccharide peptide; lipo to, oblimersen (Genasense®), remicade, docetaxel, cele philic platinum compounds; lissoclinamide 7; lobaplatin; coxib, melphalan, dexamethasone (Decadron®), steroids, lombricine; lometrexol; lonidamine; losoxantrone; loxorib gemcitabine, cisplatinum, temozolomide, etoposide, cyclo ine; lurtotecan; lutetium texaphyrin; lysofylline; lytic pep phosphamide, temodar, carboplatin, procarbazine, gliadel, tides; maitansine; mannostatin A; marimastat; masoprocol; tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere, maspin; matrilysin inhibitors; matrix metalloproteinase ?uorouracil, leucovorin, irinotecan, xeloda, CPT-ll, inter inhibitors; menogaril; merbarone; meterelin; methioninase; feron alpha, pegylated interferon alpha (e. g., PEG INTRON metoclopramide; MIF inhibitor; mifepristone; miltefosine; A), capecitabine, cisplatin, thiotepa, ?udarabine, carboplatin, mirimostim; mitoguazone; mitolactol; mitomycin analogues; liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, mitona?de; mitotoxin ?broblast growth factor-saporin; vinblastine, lL-2, GM-CSF, dacarbazine, vinorelbine, mitoxantrone; mofarotene; molgramostim; Erbitux, human zoledronic acid, palmitronate, biaxin, busulphan, prednisone, chorionic gonadotrophin; monophosphoryl lipidA+myobac 20 bisphosphonate, arsenic trioxide, vincristine, doxorubicin terium cell wall sk; mopidamol; mustard anticancer agent; (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustine mycaperoxide B; mycobacterial cell wall extract; myriapor sodium phosphate (Emcyt®), sulindac, and etoposide. one; N-acetyldinaline; N-substituted benzamides; nafarelin; 5.3 Methods of Treatments and Prevention nagrestip; naloxone+pentazocine; napavin; naphterpin; nar Methods of this invention encompass methods of treating, tograstim; nedaplatin; nemorubicin; neridronic acid; niluta 25 preventing and/ or managing various types of cancer and dis mide; nisamycin; nitric oxide modulators; nitroxide antioxi eases and disorders associated with, or characterized by, dant; nitrullyn; oblimersen (Genasense®); undesired angiogenesis. As used herein, unless otherwise O6-benzylguanine; octreotide; okicenone; oligonucleotides; speci?ed, the term “treating” refers to the administration of a onapristone; ondansetron; ondansetron; oracin; oral cytokine compound of the invention or other additional active agent inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; 30 after the onset of symptoms of the particular disease or dis paclitaxel; paclitaxel analogues; paclitaxel derivatives; order. As used herein, unless otherwise speci?ed, the term palauamine; palmitoylrhizoxin; pamidronic acid; panax “preventing” refers to the administration prior to the onset of ytriol; panomifene; parabactin; pazelliptine; pegaspargase; symptoms, particularly to patients at risk of cancer, and other peldesine; pentosan polysulfate sodium; pentostatin; pentro diseases and disorders associated with, or characterized by, zole; per?ubron; perfosfamide; perillyl alcohol; phenazino 35 undesired angiogenesis. The term “prevention” includes the mycin; phenylacetate; phosphatase inhibitors; picibanil; pilo inhibition of a symptom of the particular disease or disorder. carpine hydrochloride; pirarubicin; piritrexim; placetin A; Patients with familial history of cancer and diseases and placetin B; plasminogen activator inhibitor; platinum com disorders associated with, or characterized by, undesired plex; platinum compounds; platinum-triamine complex; por angiogenesis are preferred candidates for preventive regi ?mer sodium; por?romycin; prednisone; propyl bis-acri 40 mens . As used herein and unless otherwise indicated, the term done; prostaglandin J2; proteasome inhibitors; protein “managing” encompasses preventing the recurrence of the A-based immune modulator; protein kinase C inhibitor; pro particular disease or disorder in a patient who had suffered tein kinase C inhibitors, microalgal; protein tyrosine phos from it, and/or lengthening the time a patient who had suf phatase inhibitors; purine nucleoside phosphorylase inhibi fered from the disease or disorder remains in remission. tors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin As used herein, the term “cancer” includes, but is not polyoxyethylene conjugate; raf antagonists; raltitrexed; limited to, solid tumors and blood born tumors. The term ramosetron; ras famesyl protein transferase inhibitors; ras “cancer” refers to disease of skin tissues, organs, blood, and inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhe vessels, including, but not limited to, cancers of the bladder, nium Re 186 etidronate; rhizoxin; ribozymes; RH retinamide; bone or blood, brain, breast, cervix, chest, colon, rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; 50 endrometrium, esophagus, eye, head, kidney, liver, lymph sa?ngol; saintopin; SarCNU; sarcophytol A; sargramostim; nodes, lung, mouth, neck, ovaries, pancreas, prostate, rectum, Sdi l mimetics; semustine; senescence derived inhibitor 1; stomach, testis, throat, and uterus. Speci?c cancers include, sense oligonucleotides; signal transduction inhibitors; sizo? but are not limited to, advanced malignancy, amyloidosis, ran; sobuzoxane; sodium borocaptate; sodium phenylacetate; neuroblastoma, meningioma, hemangiopericytoma, multiple solverol; somatomedin binding protein; sonermin; sparfosic 55 brain metastase, glioblastoma multiforms, glioblastoma, acid; spicamycin D; spiromustine; splenopentin; spongistatin brain stem glioma, poor prognosis malignant brain tumor, l; squalamine; stipiamide; stromelysin inhibitors; sul? malignant glioma, recurrent malignant giolma, anaplastic nosine; superactive vasoactive intestinal peptide antagonist; astrocytoma, anaplastic oligodendroglioma, neuroendocrine suradista; suramin; swainsonine; tallimustine; tamoxifen tumor, rectal adenocarcinoma, Dukes C & D colorectal can methiodide; tauromustine; tazarotene; tecogalan sodium; 60 cer, unresectable colorectal carcinoma, metastatic hepatocel tegafur; tellurapyrylium; telomerase inhibitors; temopor?n; lular carcinoma, Kaposi’s sarcoma, karotype acute myelo teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; blastic leukemia, Hodgkin’s lymphoma, non-Hodgkin’s thiocoraline; thrombopoietin; thrombopoietin mimetic; thy lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell malfasin; thymopoietin receptor agonist; thymotrinan; thy lymphoma, diffuse large B-Cell lymphoma, low grade folli roid stimulating hormone; tin ethyl etiopurpurin; tira 65 cular lymphoma, malignant melanoma, malignant mesothe pazamine; titanocene bichloride; topsentin; toremifene; lioma, malignant pleural effusion mesothelioma syndrome, translation inhibitors; tretinoin; triacetyluridine; triciribine; peritoneal carcinoma, papillary serous carcinoma, gyneco US 7,968,569 B2 17 18 logic sarcoma, soft tissue sarcoma, scelroderma, cutaneous This invention encompasses methods of treating patients vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, who have been previously treated for cancer or diseases or ?brodysplasia ossi?cans progressive, hormone refractory disorders associated with, or characterized by, undesired prostate cancer, resected high-risk soft tissue sarcoma, angio genesis, but are non-responsive to standard therapies, as unrescectable hepatocellular carcinoma, Waldenstrom’s well as those who have not previously been treated. The macroglobulinemia, smoldering myeloma, indolent invention also encompasses methods of treating patients myeloma, fallopian tube cancer, androgen independent pros regardless of patient’s age, although some diseases or disor tate cancer, androgen dependent stage IV non-metastatic ders are more common in certain age groups. The invention pro state cancer, hormone-insensitive prostate cancer, chemo further encompasses methods of treating patients who have therapy-insensitive prostate cancer, papillary thyroid carci undergone surgery in an attempt to treat the disease or con dition at issue, as well as those who have not. Because patients noma, follicular thyroid carcinoma, medullary thyroid carci with cancer and diseases and disorders characterized by noma, and leiomyoma. In a speci?c embodiment, the cancer undesired angiogenesis have heterogenous clinical manifes is metastatic. In another embodiment, the cancer is refractory tations and varying clinical outcomes, the treatment given to or resistance to chemotherapy or radiation; in particular, a patient may vary, depending on his/her prognosis. The refractory to thalidomide. skilled clinician will be able to readily determine without As used herein to refer to diseases and conditions other undue experimentation speci?c secondary agents, types of than cancer, the terms “diseases or disorders associated with, surgery, and types of non-drug based standard therapy that or characterized by, undesired angiogenesis,” “diseases or can be effectively used to treat an individual patient with disorders associated with undesired angiogenesis,” and “dis 20 cancer and other diseases or disorders. eases or disorders characterized by undesired angiogenesis” Methods encompassed by this invention comprise admin refer to diseases, disorders and conditions that are caused, istering one or more immunomodulatory compound of the mediated or attended by undesired, unwanted or uncontrolled invention, or a pharrnaceutically acceptable salt, solvate, angiogenesis, including, but not limited to, in?ammatory dis hydrate, stereoisomer, clathrate, or prodrug thereof, to a eases, autoimmune diseases, genetic diseases, allergic dis 25 patient (e.g., a human) suffering, or likely to suffer, from eases, bacterial diseases, ocular neovascular diseases, chor cancer or a disease or disorder mediated by undesired angio oidal neovascular diseases, and retina neovascular diseases. genesis. Examples of such diseases or disorders associated with In one embodiment of the invention, an immunomodula undesired angiogenesis include, but are not limited to, dia tory compound of the invention can be administered orally betic retinopathy, retinopathy of prematurity, corneal graft 30 and in single or divided daily doses in an amount of from rejection, neovascular glaucoma, retrolental ?broplasia, pro about 0.10 to about 150 mg/ day. In a particular embodiment, liferative vitreoretinopathy, trachoma, myopia, optic pits, 4-(amino)-2-(2, 6-dioxo (3-piperidyl))-isoindoline-l ,3 -dione epidemnic keratoconjunctivitis, atopic keratitis, superior lim (ActimidTM) may be administered in an amount of from about bic keratitis, pterygium keratitis sicca, sj ogrens, acne rosacea, 0.1 to about 1 mg per day, or alternatively from about 0.1 to phylectenulosis, syphilis, lipid degeneration, bacterial ulcer, 35 about 5 mg every other day. In a preferred embodiment, fungal ulcer, Herpes simplex infection, Herpes zoster infec 3-(4-amino- l -oxo-l ,3-dihydro-isoindol-2-yl-piperidine-2,6 tion, protozoan infection, Kaposi sarcoma, Mooren ulcer, dione (RevimidTM) may be administered in an amount of from Terrien’s marginal degeneration, mariginal keratolysis, rheu about 5 to 25 mg per day, or alternatively from about 10 to matoid arthritis, systemic lupus, polyarteritis, trauma, Wege about 50 mg every other day. ners sarcoidosis, Scleritis, Steven’s Johnson disease, periph 40 In a speci?c embodiment, 4-(amino)-2-(2,6-dioxo(3-pip igoid radial keratotomy, sickle cell anemia, sarcoid, eridyl))-isoindoline-l,3-dione (ActimidTM) may be adminis pseudoxanthoma elasticum, Pagets disease, vein occlusion, tered in an amount of about 1, 2, or 5 mg per day to patients artery occlusion, carotid obstructive disease, chronic uveitis, with relapsed multiple myeloma. In a particular embodiment, chronic vitritis, Lyme’s disease, Eales disease, Bechets dis 3 -(4-amino- l -oxo-l ,3-dihydro -isoindol-2 -yl)-piperidine-2, ease, retinitis, choroiditis, presumed ocular histoplasmosis, 45 6-dione (RevimidTM) may be administered initially in an Bests disease, Stargarts disease, pars planitis, chronic retinal amount of 5 mg/ day and the dose can be escalated every week detachment, hyperviscosity syndromes, toxoplasmosis, to 10, 20, 25, 30 and 50 mg/day. In a speci?c embodiment, rubeosis, sarcodisis, sclerosis, soriatis, psoriasis, primary RevimidTM can be administered in an amount of up to about sclerosing cholangitis, proctitis, primary biliary srosis, idio 30 mg/day to patients with solid tumor. In a particular pathic pulmonary ?brosis, and alcoholic hepatitis. 50 embodiment, RevimidTM can be administered in an amount of In speci?c embodiments of the invention, diseases or dis up to about 40 mg/day to patients with glioma. orders associated with undesired angiogenesis do not include 5.3.1 Combination Therapy with a Second Active Agent congestive heart failure, cardiomyopathy, pulmonary edema, Speci?c methods of the invention comprise administering endotoxin-mediated septic shock, acute viral myocarditis, an immunomodulatory compound of the invention, or a phar cardiac allograft rejection, myocardial infarction, HIV, hepa 55 maceutically acceptable salt, solvate, hydrate, stereoisomer, titis, adult respiratory distress syndrome, bone-resorption clathrate, or prodrug thereof, in combination with one or disease, chronic obstructive pulmonary diseases, chronic pul more second active agents, and/ or in combination with radia monary in?ammatory disease, dermatitis, cystic ?brosis, sep tion therapy, blood transfusions, or surgery. Examples of tic shock, sepsis, endotoxic shock, hemodynamic shock, sep immunomodulatory compounds of the invention are dis sis syndrome, post ischemic reperfusion injury, meningitis, 60 closed herein (see, e.g., section 5.1). Examples of second psoriasis, ?brotic disease, cachexia, graft rejection, rheuma active agents are also disclosed herein (see, e.g., section 5.2). toid spondylitis, osteoporosis, Crohn’s disease, ulcerative Administration of the immunomodulatory compounds and colitis, in?ammatory-bowel disease, multiple sclerosis, sys the second active agents to a patient can occur simultaneously temic lupus erythremato sus, erythema nodo sum leprosum in or sequentially by the same or different routes of administra leprosy, radiation damage, asthma, hyperoxic alveolar injury, 65 tion. The suitability of a particular route of administration malaria, mycobacterial infection, and opportunistic infec employed for a particular active agent will depend on the tions resulting from HIV. active agent itself (e.g., whether it can be administered orally