JAK PI3K/mTOR COMBINATION THERAPY

• US 20130040973A1
• Filed: 08/10/2012
• Published: 02/14/2013
• Est. Priority Date: 08/10/2011
• Status: Active Grant

• Current Assignee: Incyte Corporation, Novartis Pharma AG (Novartis Ag)
• Original Assignee: Incyte Corporation, Novartis Pharma AG (Novartis Ag)
• Inventors: Vannucchi, Alessandro M., Bogani, Costanza, Bartalucci, Niccolo
• Granted Patent: US 9,358,229 B2
• Time in Patent Office: Days
• US Class Current: 514/265.1
• 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 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• 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
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid

Abstract

Provided herein is a combination therapy comprising a JAK kinase inhibitor and a dual PI3K/mTOR inhibitor, as well as methods of treating various cancers through the use of such a combination therapy.

Claims

1. A method of treating cancer in a subject in need thereof comprising administering to the subject an effective amount of a combination therapy comprising a compound of formula I:

2. The method of claim 1, wherein the cancer is a myeloproliferative neoplasm.

3. The method of claim 2, wherein the myeloproliferative neoplasm is selected from the group consisting of chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary or idiopathic myelofibrosis (PMF), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, hypereosinophilic syndrome, systemic mastocytosis, and atypical chronic myelogenous leukemia.

4. The method of claim 2, wherein the myeloproliferative neoplasm is selected from the group consisting of polycythemia vera (PV), essential thrombocythemia (ET), or primary myelofibrosis (PMF).

5. The method of claim 1, wherein the cancer is a solid tumor.

6. The method of claim 5, wherein the solid tumor is a tumor of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric area, ovaries, colon, rectum, prostate, pancreas, lung, vagina, thyroid, neck or head.

7. The method of claim 1, wherein the cancer is Waldenströ

m'"'"'s macroglobulinemia.

8. The method of claim 1, wherein the subject is human.

9. The method of claim 1, wherein the compound of formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.

10. The method of claim 1, wherein the compound of formula II is 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile, or a pharmaceutically acceptable salt thereof.

11. The method of claim 1, wherein the compound of formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile phosphoric acid salt.

12. The method of claim 1, wherein the compound of formula I and the compound of formula II are in a single formulation or unit dosage form.

13. The method of claim 1, wherein the compound of formula I and the compound of formula II are in separate formulations or unit dosage forms.

14. The method of claim 1, wherein the treatment comprises administering the compound of formula I and the compound of formula II at substantially the same time.

15. The method of claim 1, wherein the treatment comprises administering compound of formula I and the compound of formula II at different times.

16. The method of claim 1, wherein the compound of formula I is administered to the subject, followed by administration of the compound of formula II.

17. The method of claim 1, wherein the compound of formula II is administered to the subject, followed by administration of the compound of formula I.

18. The method of claim 1, wherein the compound of formula I and/or compound of formula II is administered at dosages that would not be effective when one or both of the compound of formula I and compound of formula II is administered alone, but which amounts are effective in combination.

19. A combination therapy for the treatment of a myeloproliferative neoplasm comprising (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, and 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile, or a pharmaceutically acceptable salt thereof.

20. A combination therapy for the treatment of a solid tumor comprising (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, and 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile, or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising a compound of formula I:

22. The composition of claim 21, wherein the compound of formula II is 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile, or a pharmaceutically acceptable salt thereof.

23. The composition of claim 21, wherein the compound of formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.

24. The composition of claim 21, wherein the compound of formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile phosphoric acid salt.

25. The composition of claim 21, further comprising a pharmaceutically acceptable carrier.