Source: https://patents.google.com/patent/US9056120B2/en
Timestamp: 2018-12-19 15:50:37
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Matched Legal Cases: ['Application No. 60', 'art 1', 'art 1', 'art 1', 'art 1', 'art 1', 'art 1']

US9056120B2 - Methods of treating myelodysplastic syndromes with a combination therapy using lenalidomide and azacitidine - Google Patents
US9056120B2
US9056120B2 US13801262 US201313801262A US9056120B2 US 9056120 B2 US9056120 B2 US 9056120B2 US 13801262 US13801262 US 13801262 US 201313801262 A US201313801262 A US 201313801262A US 9056120 B2 US9056120 B2 US 9056120B2
US13801262
US20130202590A1 (en )
This application is a continuation application of U.S. patent application Ser. No. 12/777,765, filed May 11, 2010, presently pending, which is continuation-in-part of U.S. patent application Ser. No. 11/985,032, filed Nov. 12, 2007, now issued U.S. Pat. No. 7,863,297, which is continuation of U.S. patent application Ser. No. 11/654,550 filed Jan. 16, 2007, now issued U.S. Pat. No. 7,393,863, which is divisional of U.S. patent application Ser. No. 10/411,649 filed Apr. 11, 2003, now issued U.S. Pat. No. 7,189,740, which claims the benefit of U.S. Provisional Patent Application No. 60/418,468 filed on Oct. 15, 2002, the contents of each of which are incorporated by reference herein in their entireties.
The International MDS Risk Analysis (IMRA) Workshop proposed an International Prognosis Scoring System (IPSS) to decrease imprecision in predicting survival and AML risk in MDS patients. The IPSS is based on the number of cytopenias, percentage of BM blasts, and type of cytogenetic abnormalities (Table 1). Greenberg et al., Blood 1997, 89:2079-88. The latter are categorized into good (normal, −Y, del (5q), del (20q)), intermediate, and poor subgroups (complex or chromosome 7 abnormalities).
nternational Prognostic Scoring System for MDS
A group of compounds selected for their capacity to potently inhibit TNF-α production by LPS stimulated PBMC has been investigated. L. G. Corral, et al., Ann. Rheum. Dis. 58:(Suppl I) 1107-1113 (1999). These compounds, which are referred to as IMiDs™ or Immunomodulatory Drugs, show not only potent inhibition of TNF-α but also marked inhibition of LPS induced monocyte IL1β and IL12 production. LPS induced IL6 is also inhibited by IMiDs™, albeit partially. These compounds are potent stimulators of LPS induced IL10, increasing IL10 levels by 200 to 300%. Id.
5-Azacytidine (also known as azacitidine and 4-amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one; Nation Service Center designation NSC-102816; CAS Registry Number 320-67-2) has undergone NCl-sponsored trials for the treatment of MDS. See, e.g., Kornblith et al., J. Clin. Oncol. 20(10): 2441-2452 (2002); Silverman et al., J. Clin. Oncol. 20(10): 2429-2440 (2002). 5-Azacytidine may be defined as having a molecular formula of C8H12N4O5, a relative molecular weight of 244.21 and a structure of:
The additional active agent is preferably a hematopoietic growth factor, a cytokine, an anti-cancer agent, an antibiotic, an anti-fungal, an anti-inflammatory, an immunosuppressive agent such as a cyclosporin, conventional therapy for MDS, or other chemotherapeutic agent found for example in the Physician's Desk Reference. Preferred anti-cancer or cancer chemotherapeutics are apoptosis inducing agents, topoisomerase inhibitors, anti-angiogenesis compounds, microtubule stabilizing agents, alkylating agents and other known conventional cancer chemotherapy. Most preferred additional active agents are those capable of affecting or improving blood production. The active agents can be large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules). The examples of specific additional active agent include, but are not limited to, gemtuzumab ozogamicin, etanercept (Enbrel®), imatinib (Glivec®), anti-TNF-α antibodies, infliximab (Remicade®), G-CSF, GM-CSF, EPO, topotecan, irinotecan, pentoxifylline, ciprofloxacin, dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine, vinblastine, isotretinoin, and 13-cis-retinoic acid. This invention also encompasses the use of native, naturally occurring, and recombinant proteins. The invention further encompasses mutants and derivatives (e.g., modified forms) of naturally occurring proteins that exhibit, in vivo, at least some of the pharmacological activity of the proteins upon which they are based. Examples of mutants include, but are not limited to, proteins that have one or more amino acid residues that differ from the corresponding residues in the naturally occurring forms of the proteins. Also encompassed by the term “mutants” are proteins that lack carbohydrate moieties normally present in their naturally occurring forms (e.g., nonglycosylated forms). Examples of derivatives include, but are not limited to, pegylated derivatives and fusion proteins, such as proteins formed by fusing IgG1 or IgG3 to the protein or active portion of the protein of interest. See, e.g., Penichet, M. L. and Morrison, S. L., J. Immunol. Methods 248:91-101 (2001). Vaccines that cause the secretion of proteins disclosed herein as well as pharmacologically active mutants, derivatives, and fusion thereof are also encompassed by the invention.
Specific examples of immunomodulatory compounds of the invention, include, but are not limited to, cyano and carboxy derivatives of substituted styrenes such as those disclosed in U.S. Pat. No. 5,929,117; 1-oxo-2-(2,6-dioxo-3-fluoropiperidin-3-yl) isoindolines and 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidine-3-yl) isoindolines such as those described in U.S. Pat. No. 5,874,448; the tetra substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines described in U.S. Pat. No. 5,798,368; t-oxo and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl) isoindolines (e.g., 4-methyl derivatives of thalidomide and EM-12), including, but not limited to, those disclosed in U.S. Pat. No. 5,635,517; and a class of non-polypeptide cyclic amides disclosed in U.S. Pat. Nos. 5,698,579 and 5,877,200; analogs and derivatives of thalidomide, including hydrolysis products, metabolites, derivatives and precursors of thalidomide, such as those described in U.S. Pat. Nos. 5,593,990, 5,629,327, and 6,071,948 to D'Amato; aminothalidomide, as well as analogs, hydrolysis products, metabolites, derivatives and precursors of aminothalidomide, and substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles such as those described in U.S. Pat. Nos. 6,281,230 and 6,316,471; isoindole-imide compounds such as those described in U.S. patent application Ser. No. 09/972,487 filed on Oct. 5, 2001, U.S. patent application Ser. No. 10/032,286 filed on Dec. 21, 2001, and International Application No. PCT/US01/50401 (International Publication No. WO 02/059106). The entireties of each of the patents identified herein are incorporated herein by reference. Immunomodulatory compounds of the invention do not include thalidomide.
As used herein and unless otherwise indicated, the term “prodrug” means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide the compound. Examples of prodrugs include, but are not limited to, derivatives of immunomodulatory compounds of the invention that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Other examples of prodrugs include derivatives of immunomodulatory compounds of the invention that comprise —NO, —NO2, —ONO, or —ONO2 moieties. Prodrugs can typically be prepared using well known methods, such as those described in 1 Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed. 1995), and Design of Prodrugs (H. Bundgaard ed., Elselvier, N.Y. 1985).
Additional active agents can be large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules). The additional active agents include but are not limited to hematopoietic growth factors, cytokines, anti-cancer agents, antibiotics, proteasome inhibitors, immunosuppressive agents and other therapeutics discussed herein. Particular agents include, but are not limited to, G-CSF, GM-CSF, EPO, dexamethasone, topotecan, pentoxifylline, irinotecan, ciprofloxacin, vinorelbine, IL2, IL8, IL18, Ara-C, isotretinoin, 13-cis-retinoic acid, 12-O-tetradecanoylphorbol-13-acetate (TPA), 5-AZA2′-deoyxcytidine, 9-nitrocamp-tothecin, transretinoic acid, amifostine, amphotericin B and liposomal amphotericin B, anti-CD-20 monoclonal antibody, anti-thymocyle globulin (ATG), arsenic trioxide, azacytidine, bevacizumab, bismuth monoclonal antibody, bryostatin, busulfan, caspofungin acetate, celocoxib, cladribine, cyclophosphamide, cyclosporine, cytarabine, cytosine, daunorubicin, depsipeptide, etoposide, farresy transferase inhibitor, flavopiridol, Flt3 ligand, fludarabine, gentuzumab ozogomicin (mylotarg), etanercept (Enbrel®), imatinib (Glivec®), anti-TNF-α antibodies, infliximab (Remicade®), humanized monoclonal anti-VEGF antibody, idarubicine, leucovorin, melphalan, mitoxantrone, monoclonal antibody ABX-CBL, monoclonal antibody CD52, mycophenolate mofetil, oblimersen, omega-3 fatty acids, pentostatin, phenylbutyrate, PR1 leukemia peptide vaccine, montanide, proteasome inhibitor, sodium phenylbutyrate, sodium salicylate, temozolomide, thymoglobulin, troxatyl, tumor necrosis factor receptor IgG chimera, Yttrium Y 90 humanized monoclonal antibody M195. In a specific embodiment of the invention, an immunomodulatory compound of the invention is used in combination with pentoxifylline, ciprofloxacin, and/or dexamethasone.
1. A method of treating myelodysplastic syndrome, which comprises administering to a patient in need thereof about 1 mg to about 25 mg per day of a compound having the formula:
2. The method of claim 1, wherein the myelodysplastic syndrome is refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or chronic myelomonocytic leukemia.
and is not a pharmaceutically acceptable salt, solvate or stereoisomer.
7. The method of claim 1, wherein the patient is not previously treated for a myelodysplastic syndrome.
8. The method of claim 1, wherein the patient has been previously treated for a myelodysplastic syndrome.
10. The method of claim 9, wherein the second active agent is dexamethasone.
11. The method of claim 9, wherein the second active agent is azacitidine.
12. The method of claim 1, wherein the compound is administered before, during or after transplanting umbilical cord blood, placental blood, peripheral blood stem cell, hematopoietic stem cell preparation or bone marrow in the patient.
13. The method of claim 1, wherein the compound is administered cyclically.
14. The method of claim 1, wherein compound is administered for 21 consecutive days followed by seven consecutive days of rest in a 28 day cycle.
15. The method of claim 1, which comprises cyclically administering the compound until disease progression or unacceptable toxicity.
16. The method of claim 1, wherein the compound is administered in an amount of about 2.5 mg per day.
17. The method of claim 1, wherein the compound is administered in an amount of about 5 mg per day.
18. The method of claim 1, wherein the compound is administered in an amount of about 10 mg per day.
19. The method of claim 1, wherein the compound is administered in an amount of about 15 mg per day.
20. The method of claim 1, wherein the compound is administered in an amount of about 20 mg per day.
21. The method of claim 1, wherein the compound is administered in an amount of about 25 mg per day.
22. The method of claim 1, wherein the compound is administered in an amount from about 5 mg per day to about 25 mg per day for 21 consecutive days followed by seven consecutive days of rest in a 28 day cycle.
23. The method of claim 1, wherein the compound is administered in an amount of about 10 mg per day or about 15 mg per day for 21 consecutive days followed by seven consecutive days of rest in a 28 day cycle.
24. The method of claim 1, wherein the compound is administered orally.
25. The method of claim 24, wherein the compound is administered in the form of a capsule or tablet.
26. The method of claim 25, wherein the compound is administered in a capsule in an amount from about 1 mg to about 25 mg.
27. The method of claim 25, wherein the compound is administered in a capsule in an amount of about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg or about 25 mg.
28. A method of treating transfusion dependent anemia due to low to intermediate-1-risk myelodysplastic syndrome, which comprises administering to a patient in need thereof about 1 mg to about 25 mg per day of a compound having the formula:
30. The method of claim 28, wherein the compound is a pharmaceutically acceptable salt.
31. The method of claim 28, wherein the compound is a pharmaceutically acceptable solvate.
32. The method of claim 28, wherein the compound is a pharmaceutically acceptable stereoisomer.
33. The method of claim 28, wherein the patient is not previously treated for a myelodysplastic syndrome.
34. The method of claim 28, wherein the patient has been previously treated for a myelodysplastic syndrome.
35. The method of claim 28, which further comprises administering a therapeutically effective amount of a second active agent.
36. The method of claim 35, wherein the second active agent is dexamethasone.
37. The method of claim 35, wherein the second active agent is azacitidine.
38. The method of claim 28, wherein the compound is administered before, during or after transplanting umbilical cord blood, placental blood, peripheral blood stem cell, hematopoietic stem cell preparation or bone marrow in the patient.
39. The method of claim 28, wherein the compound is administered cyclically.
40. The method of claim 28, wherein compound is administered for 21 consecutive days followed by seven consecutive days of rest in a 28 day cycle.
41. The method of claim 28, which comprises cyclically administering the compound until disease progression or unacceptable toxicity.
42. The method of claim 28, wherein the compound is administered in an amount of about 2.5 mg per day.
43. The method of claim 28, wherein the compound is administered in an amount of about 5 mg per day.
44. The method of claim 28, wherein the compound is administered in an amount of about 10 mg per day.
45. The method of claim 28, wherein the compound is administered in an amount of about 15 mg per day.
46. The method of claim 28, wherein the compound is administered in an amount of about 20 mg per day.
47. The method of claim 28, wherein the compound is administered in an amount of about 25 mg per day.
48. The method of claim 28, wherein the compound is administered in an amount from about 5 mg per day to about 25 mg per day for 21 consecutive days followed by seven consecutive days of rest in a 28 day cycle.
49. The method of claim 28, wherein the compound is administered in an amount of about 10 mg per day or about 15 mg per day for 21 consecutive days followed by seven consecutive days of rest in a 28 day cycle.
50. The method of claim 28, wherein the compound is administered orally.
51. The method of claim 50, wherein the compound is administered in the form of a capsule or tablet.
52. The method of claim 51, wherein the compound is administered in a capsule in an amount from about 1 mg to about 25 mg.
53. The method of claim 51, wherein the compound is administered in a capsule in an amount of about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg or about 25 mg.
US13801262 2002-10-15 2013-03-13 Methods of treating myelodysplastic syndromes with a combination therapy using lenalidomide and azacitidine Active US9056120B2 (en)
US14517280 Continuation US9925207B2 (en) 2002-10-15 2014-10-17 Methods of treating myelodysplastic syndromes using lenalidomide
US20130202590A1 true US20130202590A1 (en) 2013-08-08
US9056120B2 true US9056120B2 (en) 2015-06-16
US12777765 Active 2023-10-28 US8404716B2 (en) 2002-10-15 2010-05-11 Methods of treating myelodysplastic syndromes with a combination therapy using lenalidomide and azacitidine
US13801262 Active US9056120B2 (en) 2002-10-15 2013-03-13 Methods of treating myelodysplastic syndromes with a combination therapy using lenalidomide and azacitidine
US14517280 Active 2023-05-14 US9925207B2 (en) 2002-10-15 2014-10-17 Methods of treating myelodysplastic syndromes using lenalidomide
US15926740 Pending US20180207185A1 (en) 2002-10-15 2018-03-20 Methods of treating myelodysplastic syndromes with a combination therapy using lenalidomide and azacitidine
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2018-09-11 IPR Aia trial proceeding filed before the patent and appeal board: inter partes review
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