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-2023158009-A1
Application number	US-202318101499-A
Country	US
Kind code	A1
Filing date	Jan 25, 2023
Priority date	Jun 6, 2016
Publication date	May 25, 2023
Grant date	—

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, preventing, 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.

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, and/or vitamin D supplementation.

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

17 . The method of claim 15 , wherein the subject is administered calcium, calcitriol, and vitamin D supplementation at least 3 days prior to administration of Compound 1 on day 1 of the cycle.

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

19 . 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).

20 . 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).

21 . 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.

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

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

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

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

26 . The method of claim 24 , wherein Compound 1 is administered on days 1 to 5 of a 28 day treatment cycle.

27 . The method of claim 24 , wherein Compound 1 is administered on days 1 to 5 of a 42 day treatment cycle.

28 . The method of claim 24 , wherein Compound 1 is administered on days 1 to 3 of a 28 day treatment cycle.

29 . The method of claim 24 , wherein Compound 1 is administered on days 1 to 5 and days 15 to 19 of a 28 day treatment cycle.

30 . The method of claim 26 , wherein the treatment cycle is repeated at least once.

31 . The method of claim 26 , wherein the treatment cycle is repeated 2 to 4 times.

32 . The method of claim 24 , wherein Compound 1 is administered in a dose of about 0.1 mg to about 10 mg.

33 . The method of claim 24 , wherein Compound 1 is administered in a dose from about 0.3 mg to about 8.1 mg.

34 . The method of claim 24 , 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.

35 . The method of claim 24 , 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.

36 . The method of claim 24 , wherein the subject is administered one or more of calcium, calcitriol, and/or vitamin D supplementation.

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

38 . The method of claim 36 , wherein the subject is administered one or more of calcium, calcitriol, and vitamin D supplementation at least 3 days prior to administration of Compound 1 on day 1 of the cycle.

39 . The method of claim 24 , wherein the subject does not have a disorder disrupting normal calcium homeostasis or preventing calcium supplementation.

40 . The method of claim 24 comprising administering a polymorph of (2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide).

41 . The method of claim 24 comprising administering an amorphous form of (2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide).

42 . The method of claim 24 comprising administering a lyophilized formulation of Compound 1, wherein the lyophilized formulation comprises Compound 1, a buffer and a bulking agent.

43 . The method of claim 24 , further comprising administering a therapeutically effective amount of a second active agent or a supportive care therapy.

44 . The method of claim 24 , 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

• 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

• A61K31/454 Primary

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

• A61P35/02

  specific for leukemia · CPC title