Treatment of a hematologic malignancy with 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

Patent metadata

Field	Value
Publication number	US-10245258-B2
Application number	US-201715614434-A
Country	US
Kind code	B2
Filing date	Jun 5, 2017
Priority date	Jun 6, 2016
Publication date	Apr 2, 2019
Grant date	Apr 2, 2019

Abstract

Provided herein are methods of treating, preventing, managing, and/or ameliorating leukemia or myelodysplastic syndrome comprising administering 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide or a stereoisomer or mixture of stereoisomers, an isotopologue, pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate, or polymorph thereof to a patient.

First claim

What is claimed:

1. A method for treating, managing, or ameliorating a hematological cancer comprising administering to a subject in need thereof 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide, which has the following structure:

or a stereoisomer or mixture of stereoisomers, isotopologue, pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate, or polymorph thereof (Compound 1), wherein Compound 1 is administered to the subject in a dose of about 0.1 mg to about 20 mg, and the subject is further administered one or more of calcium, calcitriol, or vitamin D supplementation.

2. The method of claim 1 , wherein the hematological cancer is acute myeloid leukemia.

3. The method of claim 2 , wherein the acute myeloid leukemia is refractory or relapsed acute myeloid leukemia.

4. The method of claim 1 , wherein Compound 1 is administered on days 1 to 5 of a 28 day treatment cycle.

5. The method of claim 4 , wherein the treatment cycle comprises a rest period of 23 days.

6. The method of claim 1 , wherein Compound 1 is administered on days 1 to 5 of a 42 day treatment cycle.

7. The method of claim 1 , wherein Compound 1 is administered on days 1 to 3 of a 28 day treatment cycle.

8. The method of claim 1 , wherein Compound 1 is administered on days 1 to 5 and days 15 to 19 of a 28 day treatment cycle.

9. The method of claim 4 , wherein the treatment cycle is repeated at least once.

10. The method of claim 4 , wherein the treatment cycle is repeated 2 to 4 times.

11. The method of claim 1 , wherein Compound 1 is administered in a dose of about 0.1 mg to about 10 mg.

12. The method of claim 1 , wherein Compound 1 is administered in a dose from about 0.3 mg to about 8.1 mg.

13. The method of claim 1 , wherein Compound 1 is administered in a dose of about 0.3 mg, 0.6 mg, 1.2 mg, 2.4 mg, 3.6 mg, 5.4 mg or 8.1 mg.

14. The method of claim 1 , wherein Compound 1 is administered in a dose of about 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg, or 3.6 mg.

15. The method of claim 1 , wherein the subject is administered one or more of calcium, calcitriol, or vitamin D supplementation prior to administration of Compound 1.

16. The method of claim 1 , wherein the subject is administered one or more of calcium, calcitriol, or vitamin D supplementation at least 3 days prior to administration of Compound 1 on day 1 of the cycle.

17. The method of claim 1 , wherein the subject does not have a disorder disrupting normal calcium homeostasis or preventing calcium supplementation.

18. The method of claim 1 comprising administering a polymorph of (2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide).

19. The method of claim 1 comprising administering an amorphous form of (2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide).

20. The method of claim 1 comprising administering a lyophilized formulation of Compound 1, wherein the lyophilized formulation comprises Compound 1, a buffer and a bulking agent.

21. The method of claim 1 , further comprising administering a therapeutically effective amount of a second active agent or a supportive care therapy.

22. The method of claim 1 , wherein the subject is a patient 18 years or older.

23. The method of claim 1 , wherein the hematological cancer is myelodysplastic syndrome.

24. The method of claim 23 , wherein the myelodysplastic syndrome is refractory or relapsed myelodysplastic syndrome.

25. The method of claim 23 , wherein Compound 1 is administered on days 1 to 5 of a 28 day treatment cycle.

26. The method of claim 23 , wherein Compound 1 is administered on days 1 to 5 of a 42 day treatment cycle.

27. The method of claim 23 , wherein Compound 1 is administered on days 1 to 3 of a 28 day treatment cycle.

28. The method of claim 23 , wherein Compound 1 is administered on days 1 to 5 and days 15 to 19 of a 28 day treatment cycle.

29. The method of claim 25 , wherein the treatment cycle is repeated at least once.

30. The method of claim 25 , wherein the treatment cycle is repeated 2 to 4 times.

31. The method of claim 23 , wherein Compound 1 is administered in a dose of about 0.1 mg to about 10 mg.

32. The method of claim 23 , wherein Compound 1 is administered in a dose from about 0.3 mg to about 8.1 mg.

33. The method of claim 23 , wherein Compound 1 is administered in a dose of about 0.3 mg, 0.6 mg, 1.2 mg, 2.4 mg, 3.6 mg, 5.4 mg or 8.1 mg.

34. The method of claim 23 , wherein Compound 1 is administered in a dose of about 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg, or 3.6 mg.

35. The method of claim 23 , wherein the subject is administered one or more of calcium, calcitriol, or vitamin D supplementation.

36. The method of claim 35 , wherein the subject is administered one or more of calcium, calcitriol, or vitamin D supplementation prior to administration of Compound 1.

37. The method of claim 35 , wherein the subject is administered one or more of calcium, calcitriol, or vitamin D supplementation at least 3 days prior to administration of Compound 1 on day 1 of the cycle.

38. The method of claim 23 , wherein the subject does not have a disorder disrupting normal calcium homeostasis or preventing calcium supplementation.

39. The method of claim 23 comprising administering a polymorph of (2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide).

40. The method of claim 23 comprising administering an amorphous form of (2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide).

41. The method of claim 23 comprising administering a lyophilized formulation of Compound 1, wherein the lyophilized formulation comprises Compound 1, a buffer and a bulking agent.

42. The method of claim 23 , further comprising administering a therapeutically effective amount of a second active agent or a supportive care therapy.

43. The method of claim 23 , wherein the subject is a patient 18 years or older.

Assignees

• Celgene Corp

Inventors

• Carrancio Soraya
• Hollenbach Paul
• Lopez-Girona Antonia
• Macbeth Kyle
• Pourdehnad Michael
• Rappley Irit
• Lu Gang

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61K9/0019

  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 title

• A61K31/454 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61K9/19

  lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} · CPC title