Combination therapy for treating cancer
The present invention relates to compositions comprising inhibitors of human histone methyltransferase DOT1L and one or more therapeutic agents, particularly anticancer agents, and methods of combination therapy for administering to subjects in need thereof for the treatment of cancer.
1. A combination comprising Compound A2:
or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from ara-C, daunorubicin, decitabine, azacitidine, mitoxantrone, JQ1, IBET151, panobinostat, vorinostat, quizartinib, midostaurin, tranylcypromine, LSD1 inhibitor II, and navitoclax.
2. The combination of claim 1 , wherein the one or more therapeutic agents are selected from ara-C, daunorubicin, and azacitidine.
3. A pharmaceutical composition comprising the combination of claim 1 .
4. A method of treating a cancer or a precancerous condition comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 3 .
5. A method of treating or alleviating a symptom of cancer comprising administering to a subject in need thereof a therapeutically effective dose of Compound A2:
or a pharmaceutically acceptable salt thereof, prior to administering a therapeutically effective dose of the combination of claim 1 .
6. The combination of claim 1 , wherein the one or more therapeutic agents is a hypomethylating agent.
7. The combination of claim 1 , wherein the one or more therapeutic agents is azacitidine.
8. A method of treating or alleviating a symptom of cancer comprising administering to a subject in need thereof a therapeutically effective dose of Compound A2:
or a pharmaceutically acceptable salt thereof and one or more therapeutic agents selected from ara-C, daunorubicin, decitabine, azacitidine, mitoxantrone, JQ1, IBET151, panobinostat, vorinostat, quizartinib, midostaurin, tranylcypromine, LSD1 inhibitor II, and navitoclax; wherein Compound A2 or the pharmaceutically acceptable salt thereof and the one or more therapeutic agents are administered simultaneously, sequentially, or in alternation.
9. The method of claim 8 , wherein Compound A2 or the pharmaceutically acceptable salt thereof is administered prior to administration of the one or more therapeutic agents.
10. The method of claim 8 , wherein Compound A2 or the pharmaceutically acceptable salt thereof is administered at a dosage of 0.01 mg/kg per day to about 1000 mg/kg per day.
11. The method of claim 8 , wherein the one or more therapeutic agents are selected from ara-C, daunorubicin, and azacitidine.
12. The method of claim 8 , wherein the subject has leukemia.
13. The method of claim 12 , wherein the leukemia is characterized by a chromosomal rearrangement.
14. The method of claim 13 , wherein the chromosomal rearrangement is chimeric fusion of mixed lineage leukemia gene (MLL) or partial tandem duplication of MLL (MLL-PTD).
15. The method of claim 8 , wherein the subject has an increased level of HOXA9, Fms-like tyrosine kinase 3 (FLT3), MEIS1, and/or DOT1L.
16. The method of claim 8 , wherein the one or more therapeutic agents is azacitidine.
17. The method of claim 8 , wherein the symptom of cancer is influenced by modulating the methylation status of histones or other proteins.
18. The method of claim 17 , wherein the methylation status is mediated at least in part by the activity of DOT1L.
19. The method of claim 8 , wherein Compound A2 or the pharmaceutically acceptable salt thereof and the one or more therapeutic agents are administered simultaneously.
20. The method of claim 8 , wherein Compound A2 or the pharmaceutically acceptable salt thereof and the one or more therapeutic agents are administered sequentially.
21. The method of claim 8 , wherein Compound A2 or the pharmaceutically acceptable salt thereof and the one or more therapeutic agents are administered in alternation.
22. The method of claim 8 , wherein Compound A2 or the pharmaceutically acceptable salt thereof and the one or more therapeutic agents are administered as a co-formulation.
23. The method of claim 8 , wherein Compound A2 or the pharmaceutically acceptable salt thereof and the one or more therapeutic agents are administered as separate formulations.