Azacitidine in combination with venetoclax, gilteritinib, midostaurin or other compounds for treating leukemia or myelodysplastic syndrome

Patent metadata

Field	Value
Publication number	US-12447171-B2
Application number	US-202017620545-A
Country	US
Kind code	B2
Filing date	Jun 19, 2020
Priority date	Jun 20, 2019
Publication date	Oct 21, 2025
Grant date	Oct 21, 2025

Abstract

Provided herein are methods for using 5-azacytidine in combination with additional agents to treat diseases and disorders including AML.

First claim

What is claimed is:

1. A method of treating a human subject having acute myeloid leukemia (AML), wherein the method comprises administering to the subject a combination of (i) a pharmaceutical composition comprising 5-azacytidine, (ii) at least one additional therapeutic agent, and (iii) a lysine specific demethylase-1 (LSD-1) inhibitor or a pharmaceutically acceptable salt thereof,
wherein the LSD-1 inhibitor is a compound having the structure:

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the subject is not eligible for intensive induction chemotherapy.

3. The method of claim 1 , wherein:
(a) the 5-azacytidine and the at least one additional therapeutic agent are administered concomitantly; or
(b) the 5-azacytidine and the at least one additional therapeutic agent are administered sequentially wherein the 5-azacytidine is administered first.

4. The method of claim 1 , wherein:
(a) the 5-azacytidine and the at least one additional therapeutic agent are co-formulated as a single unit dosage form; or
(b) the 5-azacytidine and the at least one additional therapeutic agent are formulated as separate dosage forms.

5. The method of claim 1 , wherein:
(a) the 5-azacytidine and the LSD-1 inhibitor, or a pharmaceutically acceptable salt thereof, are administered concomitantly; or
(b) the 5-azacytidine and the LSD-1 inhibitor, or a pharmaceutically acceptable salt thereof, are administered sequentially.

6. The method of claim 1 , wherein:
(a) the 5-azacytidine, the at least one additional therapeutic agent, and the LSD-1 inhibitor, or a pharmaceutically acceptable salt thereof, are administered concomitantly; or
(b) the 5-azacytidine, the at least one additional therapeutic agent, and the LSD-1 inhibitor, or a pharmaceutically acceptable salt thereof, are administered sequentially.

7. The method of claim 1 , wherein the 5-azacytidine is administered:
(a) subcutaneously or intravenously; and/or
(b) at a dose of about 75 mg/m 2 to about 100 mg/m 2 subcutaneously or intravenously; and/or
(c) at a dose of about 75 mg/m 2 subcutaneously or intravenously; and/or
(d) subcutaneously or intravenously daily for the first seven days of a 28-day cycle.

8. The method of claim 1 , wherein the 5-azacytidine is administered:
(a) at a dose of about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or 600 mg orally; and/or
(b) at a dose of about 200 mg; and/or
(c) at a dose of about 300 mg; and/or
(d) for the first seven, fourteen, or twenty-one days of a 28 day cycle; and/or
(e) to the human subject one or two times per day; and/or;
(f) in the form of a capsule or a tablet.

9. The method of claim 8 , wherein the 5-azacytidine is administered in the form of a non-enteric-coated tablet.

10. The method of claim 1 , wherein the 5-azacytidine is administered orally:
(a) at a dose of about 200 mg per day for 14 days in a 28-day cycle;
(b) at a dose of about 300 mg per day for 14 days in a 28-day cycle;
(c) at a dose of about 200 mg per day for 21 days in a 28-day cycle; or
(d) at a dose of about 300 mg per day for 21 days in a 28-day cycle.

11. The method of claim 1 , wherein the 5-azacytidine is administered orally:
(a) daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or greater than 14 days, optionally followed by a treatment dosing holiday of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or greater than 14 days;
(b) daily for 14 or more days, optionally followed by a treatment dosing holiday of 7 or more days;
(c) for 21 or more days, optionally followed by a treatment dosing holiday of 7 or more days;
(d) for 14 days, optionally followed by a treatment dosing holiday of 14 days;
(e) for 21 or more days, followed by a treatment dosing holiday of 7 or more days; or
(f) for 14 days, followed by a treatment dosing holiday of 14 days.

12. The method of claim 1 , wherein the 5-azacytidine is administered orally:
(a) at a dose of about 300 mg daily for 14 days, followed by a treatment dosing holiday of 14 days;
(b) at a dose of about 200 mg daily for 14 days, followed by a treatment dosing holiday of 14 days;
(c) at a dose of about 300 mg daily for 21 days, followed by a treatment dosing holiday of 7 days; or
(d) at a dose of about 200 mg daily, followed by a treatment dosing holiday of 7 days.

13. The method of claim 1 , wherein the 5-azacytidine is administered orally:
(a) using a treatment cycle comprising administration of 5-azacytidine per day for 7 days in a 28-day cycle;
(b) using a treatment cycle comprising administration of 5-azacytidine per day for 14 days in a 28-day cycle; or
(c) using a treatment cycle comprising administration of 5-azacytidine per day for 21 days in a 28-day cycle.

14. The method of claim 1 , wherein the at least one additional therapeutic agent comprises gilteritinib, midostaurin, quizartinib, enasidenib, ivosidenib, and/or venetoclax.

15. The method of claim 14 , wherein the at least one additional therapeutic agent is venetoclax.

16. The method of claim 15 , wherein the venetoclax is administered:
(a) orally; and/or
(b) in a form of a tablet; and/or
(c) daily; and/or
(d) at a dose of about 400 mg.

17. The method of claim 1 , wherein the LSD-1 inhibitor, or a pharmaceutically acceptable salt thereof, is administered:
(a) orally; and/or
(b) in a form of a tablet or capsule; and/or
(c) once a week; and/or
(d) at a dose of about 20 mg, about 40 mg, or about 60 mg.

18. The method of claim 1 , wherein:
(a) the AML is resistant to treatment with the 5-azacytidine alone; and/or
(b) the AML is resistant to treatment with the at least one additional therapeutic agent alone; and/or
(c) the AML is resistant to treatment with the LSD-1 inhibitor, or a pharmaceutically acceptable salt thereof alone; and/or
(d) the combination of the 5-azacytidine, the at least one additional therapeutic agent, LSD-1 inhibitor, and a pharmaceutically acceptable salt thereof, increases AML cell death as compared to the 5-azacytidine alone; and/or
(e) the combination of the 5-azacytidine, the at least one additional therapeutic agent, LSD-1 inhibitor, and a pharmaceutically acceptable salt thereof, increases AML cell death as compared to the 5-azacytidine alone by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%; and/or
(f) the combination of the 5-azacytidine, the at least one additional therapeutic agent, LSD-1 inhibitor, and a pharmaceutically acceptable salt thereof, increases AML cell death as compared to at least one additional therapeutic agent alone; and/or
(g) the combination of the 5-azacytidine, the at least one additional therapeutic agent, LSD-1 inhibitor, and a pharmaceutically acceptable salt thereof, increases AML cell death as compared to the at least one additional therapeutic agent alone by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%; and/or
(h) the combination of 5-azacytidine, the at least one additional therapeutic agent, LSD-1 inhibitor, and a pha

Assignees

• Celgene Quanticel Res Inc

Inventors

• Beach C L
• Rose Shelonitda
• Dunshee Diana R
• Menezes Daniel E Lopes De
• Macbeth Kyle
• Dai Yumin
• Jang Jessica
• Frattini Mark

Classifications

• A61L2103/05

  Living organisms or biological materials · CPC title

• A61L2/16

  using chemical substances · CPC title

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/407

  condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine · CPC title