Combination

• US 20170100449A1
• Filed: 12/20/2016
• Published: 04/13/2017
• Est. Priority Date: 01/11/2011
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Kumar, Rakesh
• Granted Patent: US 10,449,226 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4155 non condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 38/005 Enzyme inhibitors protease inhibitors A61K38/55
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention relates to a method of treating cancer in a human and to pharmaceutical combinations useful in such treatment. In particular, the method relates to a cancer treatment method that includes administering a proteasome inhibiting compound, and N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, and optional additional antineoplastic agents, to a human in need thereof.

Claims

1. A combination comprising:

(i) a compound of Structure (I);

2. A combination kit comprising a combination according to claim 1 together with a pharmaceutically acceptable carrier or carriers.

3. A combination according to claim 1 where the amount of the compound of Structure (I) is 1.5 mg/m², and that amount is administered intravenously or subcutaneously once per week.

4. A method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of claim 1, to such human,

wherein the amount of bortezomib is selected from 1.35 to 2.0 mg/m² and that amount is administered intravenously or subcutaneously once per week,

wherein the combination is administered within a specified period, and

wherein the combination is administered for a duration of time.

5. A method according to claim 4 wherein the amount of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, is selected from about 50 mg to about 300 mg, and that amount is administered once per day, and the amount of bortezomib is selected from 1.35 to 2.0 mg/m², and that amount is administered intravenously or subcutaneously once per week.

6. A method according to claim 5 wherein the amount of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, is selected from about 60 mg to about 300 mg, and that amount is administered once per day, and bortezomib is administered intravenously or subcutaneously once a week in an amount of 1.5 mg/m².

7. A method according to claim 6 wherein bortezomib and N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride are administered within 12 hours of each other for 1 day during a seven day period and N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride is administered alone for the remaining days of the 7 day period, optionally followed by one or more cycles of repeat dosing.

8. A method according to claim 7 wherein the cancer is selected from:

brain (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm'"'"'s tumor, Ewing'"'"'s sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid,

Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia,

malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt'"'"'s lymphoma, follicular lymphoma,

neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.

9. A method according to claim 4 wherein the cancer is multiple myeloma.

10. A method according to claim 5 wherein the cancer is multiple myeloma.

11. A method treating a cancer selected from:

brain (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm'"'"'s tumor, Ewing'"'"'s sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid,

Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia,

malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt'"'"'s lymphoma, follicular lymphoma,

neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer;

in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of bortezomib, and N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, to such human,

wherein the compounds of the combination are administered sequentially, and

wherein the amount of bortezomib is selected from 1.35 to 2.0 mg/m² and that amount is administered intravenously or subcutaneously once or twice per week.

12. A method according to claim 11 wherein the amount of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, is selected from about 50 mg to about 300 mg, and that amount is administered once per day, and the amount of bortezomib is selected from 1.35 to 2.0 mg/m², and that amount is administered intravenously or subcutaneously once per week.

13. A method according to claim 12 wherein the amount of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, is selected from about 60 mg to about 300 mg, and that amount is administered once per day, and bortezomib is administered intravenously or subcutaneously once a week in an amount of 1.5 mg/m².

14. A method according to claim 13 wherein bortezomib is administered, followed by an optional drug holiday of from 1 to 14 days, followed by administration of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride for from 1 to 30 days.

15. A method according to claim 14 wherein the cancer is multiple myeloma.

16. A method according to claim 15 wherein the cancer is multiple myeloma.

17. A combination comprising:

(i) a compound of Structure (I);

18. A combination kit comprising a combination according to claim 17 together with a pharmaceutically acceptable carrier or carriers.

19. A combination according to claim 17 where the amount of the compound of Structure (I) is 1.3 mg/m², and that amount is administered subcutaneously once or twice per week.

20. A method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of claim 17, to such human,

wherein the amount of bortezomib is selected from 0.5 to 1.3 mg/m² and that amount is administered subcutaneously once or twice per week,

wherein the combination is administered within a specified period, and

wherein the combination is administered for a duration of time.