.

Pharmaceutical Business Intelligence

  • Anticipate P&T budget requirements
  • Evaluate market entry opportunities
  • Find generic sources and suppliers
  • Predict branded drug patent expiration

► Plans and Pricing

Upgrade to enjoy subscriber-only features like email alerts and data export. See the Plans and Pricing

DrugPatentWatch Database Preview

Claims for Patent: 8,680,124

« Back to Dashboard

Claims for Patent: 8,680,124

Title:Treatment of cancers with acquired resistance to kit inhibitors
Abstract: The present invention provides compositions and uses thereof for treating cancers which have acquired resistance to a KIT inhibitor by administering effective amounts of DAST (4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyrid- ine-2-carboxylic acid methylamide).
Inventor(s): Wilhelm; Scott (Morristown, NJ), Gedrich; Richard W. (Louisville, CO)
Assignee: Bayer Healthcare LLC (Whippany, NJ)
Application Number:12/523,652
Patent Claims: 1. A method of treating a cancer in a subject in need thereof, wherein said cancer was initially sensitive to KIT tyrosine kinase inhibitor and acquired resistance to said KIT tyrosine kinase inhibitor, said method comprising: administering to said subject, an effective amount of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridi- ne-2-carboxylic acid methylamide of the formula I below including all polymorphs, hydrates, pharmaceutically acceptable salts, metabolites, prodrugs, solvates or combinations thereof. ##STR00006##

2. A method as in claim 1 wherein the cancer has acquired resistance to one of the following KIT inhibitors: imatinib mesylate, salts of imatinib mesylate; PP1(4-Amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimi- dine); MLN518 (CT53518); PD180970; SU112481 SU5416; SU5414; SU6597; SU6663 or SU6561.

3. A method as in claim 1 wherein said cancer is one or more of a malignant gastrointestinal stromal tumor (GIST), a benign gastrointestinal stromal tumor (GIST), a mesenchymal tumor of the intestinal tract, chronic myelogenous leukemia (CML), a mast cell tumor, SCLC, a germ cell tumors, breast cancer, and/or neuroblastoma.

4. A method as in claim 1 wherein the cancer has acquired resistance to imatinib mesylate.

5. A method of claim 1, wherein said acquired resistance of said cancer is associated with a secondary mutation in a KIT gene mutated in the primary tumor.

6. A method of claim 5, wherein said secondary mutation is in the kinase catalytic domain.

7. A method as in aspect claim 5 wherein the mutation is in Exons 13, 14, and or 17.

8. A method as in claim 5 wherein the mutation is at residues 654, 670, 716.816, 820, 822, and 823.

9. A method as in claim 5 wherein the mutation is at residues 650-654.

10. A method as in claim 5 wherein the mutation is at residues 670-674.

11. A method as in claim 5 wherein the mutation is at residues 816-824.

12. A method as in claim 5 wherein the secondary mutation is one or more of V654A (Exon 13), T670I (Exon 14), T670E, D716N, S709F (Exon 14), D816G, D816E (Exon 17), D820E, D820Y, D820G N822K, Y823D (Exon 17), or deletions and other amino acid substitutions at such positions or adjacent positions.

13. A method as in claim 5 wherein the secondary mutation is one or more of i) deletion of amino acid residues 557-558; ii) deletion of amino acid residues 551-555; iii) deletion of amino acid residues 550-558; iv) deletion of amino acid residues 559-560; v) deletion of amino acid residues 557-561; vi) deletion of amino acid residues 554-558; vii) deletion of amino acid residues 552-557; viii) mutations at residue 559, including V559D, V559A, or V559G; ix) mutations at residue 560, including V560D, V560E, or V560G; x) W557S, alone, or in combination with a deletion of amino acids 552-556; xi) mutations at amino acid residue 557, including W557R; and xii) mutations at amino acid residue 576, including L576P.

14. A method as in claim 5 wherein the secondary mutation is deletion of residues 557-558 and at least one of the following mutations: V654A, T670I, D820Y, N822K, or Y823D.

15. A method of treating a cancer in a subject in need thereof said cancer having a primary and/or secondary KIT gene mutation in the primary tumor, said method comprising: administering to said subject, an effective amount of the compound 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridi- ne-2-carboxylic acid methylamide of the formula I below including all polymorphs, hydrates, pharmaceutically acceptable salts, metabolites, ester prodrugs, solvates or combinations thereof. ##STR00007##

16. A method of claim 15, wherein said primary and/or secondary KIT gene mutation in the primary tumor is associated with acquired resistance of said cancer to KIT tyrosine kinase inhibitors.

17. A method of claim 15, wherein said secondary mutation is in the kinase catalytic domain.

18. A method as in claim 15 wherein the mutation is in Exons 13, 14, and or 17.

19. A method as in claim 15 wherein the mutation is at residues 654, 670, 716, 816, 820, 822, and 823.

20. A method as in claim 15 wherein the mutation is at residues 650-654.

21. A method as in claim 15 wherein the mutation is at residues 670-674.

22. A method as in claim 15 wherein the mutation is at residues 816-824.

23. A method as in claim 15 wherein the secondary mutation is one or more of V654A (Exon 13), T670I (Exon 14), T670E, D716N, S709F (Exon 14), D816G, D816E (Exon 17), D820E, D820Y, D820G N822K, Y823D (Exon 17), or deletions and other amino acid substitutions at such positions or adjacent positions.

24. A method as in claim 15 wherein the secondary mutation is one or more of i) deletion of amino acid residues 557-558; ii) deletion of amino acid residues 551-555; iii) deletion of amino acid residues 550-558; iv) deletion of amino acid residues 559-560; v) deletion of amino acid residues 557-561; vi) deletion of amino acid residues 554-558; vii) deletion of amino acid residues 552-557; viii) mutations at residue 559, including V559D, V559A, or V559G; ix) mutations at residue 560, including V560D, V560E, or V560G; x) W557S, alone, or in combination with a deletion of amino acids 552-556; xi) mutations at amino acid residue 557, including W557R; and xii) mutations at amino acid residue 576, including L576P.

25. A method as in claim 15 wherein the secondary mutation is deletion of residues 557-558 and at least one of the following mutations: V654A, T670I, D820Y, N822K, or Y823D.

26. A method of treating a cancer in a subject in need thereof said cancer having a primary and/or secondary KIT gene mutation associated with resistance or acquired resistance to imatinib mesylate or salts of imatinib mesylate, said method comprising: administering to said subject, an effective amount of the compound 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridi- ne-2-carboxylic acid methylamide of the formula I below including all polymorphs, hydrates, pharmaceutically acceptable salts, metabolites, ester prodrugs, solvates or combinations thereof. ##STR00008##

27. A method for treating cancer in a human subject with imatinib mesylate or salts of imatinib mesylate, which additionally comprises: administering to said human subject, an effective amount of the compound 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridi- ne-2-carboxylic acid methylamide of the formula I below including all polymorphs, hydrates, pharmaceutically acceptable salts, metabolites, ester prodrugs, solvates or combinations thereof. ##STR00009##

28. A method as in claim 1 wherein the cancer which is treated is: Accelerated Phase Chronic Myelogenous Leukemia; Acute Erythroid Leukemia; Acute Lymphoblastic Leukemia; Acute Lymphoblastic Leukemia in Remission; Acute Lymphocytic Leukemia; Acute Monoblastic and Acute; Monocytic Leukemia; Acute Myelogenous Leukemia; Acute Myeloid Leukemia; Adenocarcinoma of the Prostate; Adenoid Cystic Carcinoma of the Head and Neck; Advanced Gastrointestinal Stromal Tumor; Agnogenic Myeloid; Metaplasia; Anaplastic Oligodendroglioma; Astrocytoma; B-Cell Adult Acute Lymphoblastic Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Bone Metastases; Brain Tumor; Breast Cancer; Cancer; Central Nervous System Cancer; Childhood Acute Lymphoblastic Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Central Nervous System Germ Cell Tumor; Childhood Chronic Myelogenous Leukemia; Childhood Soft Tissue Sarcoma; Chordoma; Chronic Eosinophilic Leukemia (CEL); Chronic Idiopathic Myelofibrosis; Chronic Myelogenous Leukemia; Chronic Myeloid Leukemia; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Colon Cancer; Colorectal Cancer; Dermatofibrosarcoma; Dermatofibrosarcoma Protuberans (DFSP); Desmoid Tumor; Eosinophilia; Epidemic Kaposi's Sarcoma; Essential Thrombocythemia; Ewing's Family of Tumors; Extensive Stage Small Cell Lung Cancer; Fallopian Tube Cancer; Familiar Hypereosinophilia; Fibrosarcoma; Gastric Adenocarcinoma; Gastrointestinal Neoplasm; Gastrointestinal Stromal Tumor; Glioblastoma; Glioma; Gliosarcoma; Grade I Meningioma; Grade II Meningioma; Grade BI Meningioma; Hematopoietic and Lymphoid Cancer; High-Grade Childhood Cerebral Astrocytoma; Hypereosinophilic Syndrome; Idiopathic Pulmonary Fibrosis; L1 Adult Acute Lymphoblastic Leukemia; L2 Adult Acute Lymphoblastic Leukemia; Leukemia, Lymphocytic, Acute L2; Leukemia, Myeloid, Chronic; Leukemia, Myeloid, Chronic Phase; Liver Dysfunction and Neoplasm; Lung Disease; Lymphoid Blastic Phase of Chronic Myeloid Leukemia; Male Breast Cancer; Malignant Fibrous Histiocytoma; Mastocytosis; Meningeal Hemangiopericytoma; Meningioma; Meningioma; Meningioma; Metastatic Cancer; Metastatic Solid Tumors; Myelofibrosis; Myeloid Leukemia, Chronic; Myeloid Leukemia, Chronic Accelerated-Phase; Myeloid Leukemia, Chronic, Chronic-Phase; Myeloid Metaplasia; Myeloproliferative Disorder (MPD) with Eosinophilia; Neuroblastoma; Non-T, Non-B Childhood Acute Lymphoblastic Leukemia; Oligodendroglioma; Osteosarcoma; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Ovarian Neoplasms; Pancreatic Cancer; Pelvic Neoplasms; Peritoneal Cavity Cancer; Peritoneal Neoplasms; Philadelphia Chromosome Positive Chronic Myelogenous Leukemia; Philadelphia Positive Acute Lymphoblastic Leukemia; Philadelphia Positive Chronic Myeloid Leukemia in Myeloid Blast Crisis; Polycythemia Vera; Pulmonary Fibrosis; Recurrent Adult Brain Tumor; Recurrent Adult Soft Tissue Sarcoma; Recurrent Breast Cancer; Recurrent Colon Cancer; Recurrent Esophageal Cancer; Recurrent Gastric Cancer; Recurrent Glioblastoma Multiforme (GBM); Recurrent Kaposi's Sarcoma; Recurrent Melanoma; Recurrent Merkel Cell Carcinoma; Recurrent Ovarian Epithelial Cancer; Recurrent Pancreatic Cancer; Recurrent Prostate Cancer; Recurrent Rectal Cancer; Recurrent Salivary Gland Cancer; Recurrent Small Cell Lung Cancer; Recurrent Tumors of the Ewing's Family; Recurrent Uterine Sarcoma; Relapsing Chronic Myelogenous Leukemia; Rheumatoid Arthritis; Salivary Gland Adenoid Cystic Carcinoma; Sarcoma; Small Cell Lung Cancer; Stage II Melanoma; Stage II Merkel Cell Carcinoma; Stage III Adult Soft Tissue Sarcoma; Stage III Esophageal Cancer; Stage III Merkel Cell Carcinoma; Stage III Ovarian Epithelial Cancer; Stage III Pancreatic Cancer; Stage III Salivary Gland Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Adult Soft Tissue Sarcoma; Stage W Breast Cancer; Stage IV Colon Cancer; Stage IV Esophageal Cancer; Stage IV Gastric Cancer; Stage IV Melanoma; Stage IV Ovarian Epithelial Cancer; Stage IV Prostate Cancer; Stage IV Rectal Cancer; Stage IV Salivary Gland Cancer; Stage IVA Pancreatic Cancer; Stage IVB Pancreatic Cancer; Systemic Mastocytosis; T-Cell Childhood Acute Lymphoblastic Leukemia; Testicular Cancer; Thyroid Cancer; Unresectable or Metastatic Malignant Gastrointestinal Stromal Tumor (GIST); Unspecified Adult Solid Tumor; Untreated Childhood Brain Stem Glioma; Uterine Carcinosarcoma, and Uterine Sarcoma.

29. A method of treating a cancer in a subject who has acquired resistance to imatinib, comprising: administering an effective amount of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridi- ne-2-carboxylic acid methylamide of the formula I below including all polymorphs, hydrates, pharmaceutically acceptable salts, metabolites, prodrugs, solvates or combinations thereof, to said subject. ##STR00010##

30. A method of treating a malignant gastrointestinal stromal tumor (GIST) or a benign gastrointestinal stromal tumor (GIST), in a subject who has been treated with imatinib, salts of imatinib mesylate, PP1(4-Amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine); MLN518 (CT53518); PD180970; SU112481; SU5416; SU5414; SU6597; SU6663 or SU6561, said method comprising administering an effective amount of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridi- ne-2-carboxylic acid methylamide of the formula I to said subject ##STR00011##

31. A method of treating a malignant gastrointestinal stromal tumor (GIST) or a benign gastrointestinal stromal tumor (GIST), in a subject who has been treated with imatinib, said method comprising administering an effective amount of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridi- ne-2-carboxylic acid methylamide of the formula I to said subject ##STR00012##

32. A method of treating a malignant gastrointestinal stromal tumor (GIST) or a benign gastrointestinal stromal tumor (GIST), said method comprising administering an effective amount of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridi- ne-2-carboxylic acid methylamide of the formula I to said subject ##STR00013##

33. A method of claim 32 wherein said subject has not been treated with imatinib.

34. A method of claim 32 wherein said subject has not acquired resistance to cKit inhibitor.
« Back to Dashboard

For more information try a trial or see the database preview and plans and pricing

How are People Using DrugPatentWatch?

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verifification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.

`abc