Preservation of immune response during chemotherapy regimens

• US 11,529,352 B2
• Filed: 06/05/2019
• Issued: 12/20/2022
• Est. Priority Date: 12/05/2016
• Status: Active Grant

• Current Assignee: G1 Therapeutics, Inc
• Original Assignee: G1 Therapeutics, Inc
• Inventors: Sorrentino, Jessica A., Lai, Anne Y., Strum, Jay C., Roberts, Patrick Joseph
• Primary Examiner(s): Puttlitz, Karl J
• Application Number:
  US16/432,244
• Publication Number:
  US 20190321370A1
• Time in Patent Office: 1,294 Days
• Field of Search: None
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/555 containing heavy metals, e.g. hemin, hematin, melarsoprol
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61K 38/1774 Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The addition of a selective, fast-acting, short half-life CDK 4/6 inhibitor in a very specific dosage regimen to the combination of chemotherapy with a checkpoint inhibitor provides superior results in the treatment of a tumor or cancer. The unexpected discovery is that the short pulsatile specifically-timed administration of a selective, fast-acting, short half-life CDK 4/6 inhibitor during administration of the chemotherapy portion of the triple combination therapy has a profound effect on the immune cells in the cancer microenvironment.

Claims

1. A method of treating a human having cancer comprising administering to the human a therapeutic regimen comprising a) an induction phase and b) a maintenance phase,

a) the induction phase comprising:

i) administering to the human an effective amount of a selective Cyclin Dependent Kinase 4/6 (CDK4/6) inhibitor of structure;

2. The method of claim 1 wherein the immune checkpoint inhibitor is selected from the group consisting of a Programmed Cell Death-1 (PD-1) inhibitor, a Programmed Cell Death-Ligand 1 (PD-L1) inhibitor, and a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor.

3. The method of claim 2, wherein the immune checkpoint inhibitor is a PD-L1 inhibitor.

4. The method of claim 3, wherein the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, and durvalumab.

5. The method of claim 2, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.

6. The method of claim 5, wherein the PD-1 inhibitor is selected from the group consisting of nivolumab, pidilizumab, and pembrolizumab.

7. The method of claim 2, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.

8. The method of claim 7, wherein the CTLA-4 inhibitor is selected from the group consisting of ipilimumab and tremelimumab.

9. The method of claim 1, wherein the chemotherapeutic agent is selected from the group consisting of a protein synthesis inhibitor, a DNA-damaging chemotherapeutic, an akylating agent, a topoisomerase inhibitor, an RNA synthesis inhibitor, a DNA complex binder, a thiolate alkylating agent, a guanine alkylating agent, a tubulin binder, a DNA polymerase inhibitor, an anticancer enzyme, a RAC1 inhibitor, a thymidylate synthase inhibitor, an oxazophosphorine compound, an integrin inhibitor, an antifolate, a folate antimetabolite, and a combination thereof.

10. The method of claim 1, wherein the chemotherapeutic agent is selected from the group consisting of carboplatin, cisplatin, oxaliplatin, 5-fluorouracil, floxuridine, capecitabine, gemcitabine, mytomycin, cyclophosphamide, decarbazine, abraxane, ifosfamide, topotecan, irinotecan, docetaxel, temozolomide, paclitaxel, etoposide, pemetrexed, and a combination thereof.

11. The method of claim 1, wherein, during the induction phase, the CDK4/6 inhibitor is only administered about 30 minutes or less prior to the administration of the chemotherapeutic agent.

12. The method of claim 1, wherein the immune checkpoint inhibitor is administered to the subject every three weeks during the induction phase and maintenance phase.

13. The method of claim 1, wherein the cancer is selected from the group consisting of small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, bladder cancer, gastroesophageal cancer, cholangiocarcinoma, cervical cancer, and soft tissue sarcoma.

28. The method of claim 1, wherein the maintenance phase further comprises administering to the subject an effective amount of the CDK 4/6 inhibitor.

29. The method of claim 13, wherein the cancer is bladder cancer.

30. The method of claim 29, wherein the immune checkpoint inhibitor is a PD-L1 inhibitor.

31. The method of claim 30, wherein the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, and durvalumab.

32. The method of claim 31, wherein the PD-L1 inhibitor is avelumab.

33. The method of claim 29, wherein the chemotherapeutic agent is selected from the group consisting of gemcitabine, carboplatin, cisplatin, and a combination thereof.

34. The method of claim 13, wherein the cancer is triple negative breast cancer.

35. The method of claim 34, wherein the immune checkpoint inhibitor is a PD-1 inhibitor selected from the group consisting of nivolumab, pembrolizumab, and pidilizumab.

36. The method of claim 35, wherein the PD-1 inhibitor is pembrolizumab.

37. The method of claim 34, wherein the chemotherapeutic agent is selected from the group consisting of cyclophosphamide, doxorubicin, paclitaxel, carboplatin, and a combination thereof.

44. The method of claim 13, wherein the cancer is non-small cell lung cancer.

45. The method of claim 44, wherein the immune checkpoint inhibitor is a PD-1 inhibitor selected from the group consisting of nivolumab, pembrolizumab, and pidilizumab.

46. The method of claim 45, wherein the PD-1 inhibitor is pembrolizumab.

48. The method of claim 1, wherein, during the induction phase, the CDK4/6 inhibitor is only adminsitered about 4 hours or less prior to the administration of the chemotherapeutic agent.

14. A method of treating a human having small cell lung cancer comprising administering to the human a therapeutic regimen comprising a) an induction phase comprising a 21-day cycle and b) a maintenance phase comprising a 21-day cycle,

a) the induction phase comprising:

i) administering to the human an effective amount of a selective CDK4/6 inhibitor of structure;

15. The method of claim 14, wherein, during the induction phase, the CDK4/6 inhibitor is only administered about 4 hours or less prior to administration of the carboplatin and/or etoposide.

16. The method of claim 14, wherein, during the induction phase, the CDK4/6 inhibitor is only administered about 30 minutes or less prior to the administration of the carboplatin and/or etoposide.

17. The method of claim 14, wherein the CDK4/6 inhibitor is administered intravenously at a dose of between about 220 and 260 mg/m².

18. The method of claim 17, wherein the CDK4/6 inhibitor is administered intravenously at a dose of about 240 mg/m².

19. The method of claim 14, wherein the carboplatin is administered intravenously at a dose that provides an AUC of about 5.

20. The method of claim 14, wherein the etoposide is administered intravenously at a dose of about 100 mg/m².

21. The method of claim 14, wherein the atezolizumab is administered in a dose of about 1200 mg.

22. The method of claim 14, wherein the induction phase is repeated at least 2 times.

23. The method of claim 14, wherein the induction phase is repeated at least 3 times.

24. The method of claim 14, wherein the induction phase is repeated at least 4 times.

25. The method of claim 14, wherein the maintenance phase is repeated at least 2 times.

26. The method of claim 14, wherein the maintenance phase is repeated at least 3 times.

27. The method of claim 14, wherein the maintenance phase is repeated at least 4 times.

38. A method of treating a human having urothelial carcinoma comprising administering to the human a therapeutic regimen comprising a) an induction phase and b) a maintenance phase,

(a) the induction phase comprising:

i) administering to the human an effective amount of a selective CDK4/6 inhibitor of structure;

39. The method of claim 38, wherein the CDK4/6 inhibitor and chemotherapeutic agent are administered in a 21-day cycle.

40. The method of claim 39, wherein the 21-day cycle is repeated four or more times.

41. The method of claim 38, wherein the PD-L1 inhibitor is selected from the group consisting of atezolizumab, durvalumab, and avelumab.

42. The method of claim 41, wherein the PD-L1 inhibitor is avelumab.

49. The method of claim 38, wherien, during the induction phase, the CDK4/6 inhibitor is only administered about 4 hours or less prior to the administration of the chemotherapeutic agent.

43. A method of treating a human having triple negative breast cancer comprising administering to the human a therapeutic regimen comprising:

i) administering to the human an effective amount of a selective CDK4/6 inhibitor of structure;

50. The method of claim 43, wherein, during the induction phase, the CDK4/6 inhibitor is administered about 4 or less prior to the administration of the chemotherapeutic agent.

47. A method of treating a human having metastatic non-squamous non-small cell lung cancer comprising administering to the human a therapeutic regimen comprising a) an induction phase comprising a 21-day cycle and b) a maintenance phase comprising a 21-day cycle,

a) the induction phase comprising:

i) administering to the human an effective amount of a selective CDK4/6 inhibitor of structure;

51. The method of claim 47, wherein, during the induction phase, the CDK4/6 inhibitor is only administered about 4 hours or less prior to the administration of carboplatin and/or pemetrexed.