Combination therapy for treating cancer
View Patent ↗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 composition comprising Compound A2:
or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from MAP/MEK inhibitors, ara-C, daunorubicin, decitabine, azacitidine, mitoxantrone, IBET151, quizartinib, midostaurin, tranylcypromine, navitoclax, and a combination thereof.
2. The composition of claim 1 , wherein the one or more therapeutic agents are MAP/MEK inhibitors.
3. The composition of claim 1 , wherein the one or more therapeutic agents are selected from ara-C, daunorubicin, decitabine, azacitidine, mitoxantrone, IBET151, quizartinib, midostaurin, tranylcypromine, navitoclax, and combinations thereof.
4. The composition of claim 1 , wherein the one or more therapeutic agents are ara-C, daunorubicin, or selumetinib (AZD-6244).
5. A pharmaceutical composition comprising a therapeutically effective amount of composition of claim 1 and a pharmaceutically acceptable carrier.
6. A method of treating cancer or a precancerous condition comprising administering to a subject in need thereof a therapeutically effective amount of a composition of claim 1 .
7. The method of claim 6 , wherein the cancer or the precancerous condition can be influenced by modulating the methylation status of histones or other proteins.
8. The method of claim 7 , wherein the methylation status is mediated at least in part by the activity of DOT1L.
9. 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 MAP/MEK inhibitors, ara-C, daunorubicin, decitabine, azacitidine, mitoxantrone, IBET151, quizartinib, midostaurin, tranylcypromine, navitoclax, and a combination thereof, wherein Compound A2 or a pharmaceutically acceptable salt thereof and the one or more therapeutic agents are administered simultaneously or sequentially.
10. The method of claim 9 , wherein Compound A2 or a pharmaceutically acceptable salt thereof is administered prior to administration of the one or more therapeutic agents.
11. 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 a composition of claim 1 .
12. The method of claim 6 , wherein the composition of claim 1 is administered to the subject in need thereof at a dosage of 0.01 mg/kg per day to about 1000 mg/kg per day.
13. The method of claim 9 , wherein Compound A2 or a pharmaceutically acceptable salt thereof is administered at a dosage of 0.01 mg/kg per day to about 1000 mg/kg per day.
14. The method of claim 9 , wherein each of the one or more therapeutic agents is administered at a dosage of 0.01 mg/kg per day to about 1000 mg/kg per day.
15. The method of claim 6 , wherein the subject has demonstrated resistance to any one of the components of the composition of claim 1 when administered as a single agent.
16. The method of claim 6 , wherein the one or more therapeutic agents are ara-C, daunorubicin, or selumetinib (AZD-6244).
17. The method of claim 6 , wherein the subject has leukemia.
18. The method of claim 17 , wherein the leukemia is characterized by a chromosomal rearrangement.
19. The method of claim 18 , wherein the chromosomal rearrangement is chimeric fusion of mixed lineage leukemia gene (MLL) or partial tandem duplication of MLL (MLL-PTD).
20. The method of claim 6 , wherein the subject has an increased level of HOXA9, Fms-like tyrosine kinase 3 (FLT3), MEIS1, and/or DOT1L.
21. The method of claim 11 , wherein the composition of claim 1 is administered to the subject in need thereof at a dosage of 0.01 mg/kg per day to about 1000 mg/kg per day.
22. The method of claim 11 , wherein Compound A2 or a pharmaceutically acceptable salt thereof is administered at a dosage of 0.01 mg/kg per day to about 1000 mg/kg per day.
23. The method of claim 11 , wherein each of the one or more therapeutic agents is administered at a dosage of 0.01 mg/kg per day to about 1000 mg/kg per day.