PRESERVATION OF IMMUNE RESPONSE DURING CHEMOTHERAPY REGIMENS

• US 20190321370A1
• Filed: 06/05/2019
• Published: 10/24/2019
• Est. Priority Date: 12/05/2016
• Status: Active Grant

• Current Assignee: G1 Therapeutics, Inc
• Original Assignee: G1 Therapeutics, Inc
• Inventors: Sorrentino, Jessica A., Lai, Ann Y., Strum, Jay C., Roberts, Patrick Joseph
• Granted Patent: US 11,529,352 B2
• Time in Patent Office: Days
• 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 subject having cancer comprising administering to the subject a therapeutic regimen comprising an a) induction phase and b) a maintenance phase,

the induction phase comprising:

i) administering an effective amount of a selective Cyclin Dependent Kinase 4/6 (CDK4/6) inhibitor,

ii) administering an effective amount of a chemotherapeutic agent, and

iii) administering an effective amount of an immune checkpoint inhibitor,

wherein the CDK4/6 inhibitor is only administered prior to or concomitantly with the administration of the chemotherapeutic agent, and

wherein the chemotherapeutic agent is cytotoxic to immune effector cells;

the maintenance phase comprising;

i) administering at least one dose of an effective amount of the immune checkpoint inhibitor, and

wherein the maintenance phase is administered following the cessation of the induction phase.

2. The method of claim 1, wherein the selective, fast-acting, short half-life CDK4/6 inhibitor is selected from the group consisting of:

3. 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.

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

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

6. The method of claim 3, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.

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

8. The method of claim 3, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.

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

10. 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, DNA polymerase inhibitor, an anticancer enzyme, RAC1 inhibitor, thymidylate synthase inhibitor, oxazophosphorine compound, integrin inhibitor such as cilengitide, camptothecin or homocamptothecin, antifolate and folate antimetabolite.

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

12. The method of claim 1, wherein the CDK4/6 inhibitor is a compound of formula:

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

14. 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.

15. The method of claim 1, wherein the immune checkpoint inhibitor is administered to the subject only once during both the induction phase and maintenance phase.

16. 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.

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

the induction phase comprising:

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

18. The method of claim 17, wherein the CDK4/6 inhibitor is administered about 4 hours or less prior to administration of the carboplatin and/or etoposide.

19. The method of claim 17, wherein the CDK4/6 inhibitor is administered about 30 minutes prior to administration of the carboplatin and/or etoposide.

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

21. The method of claim 20, wherein the CDK4/6 inhibitor is administered intravenously at a dose of about 240 mg/m².

22. The method of claim 17, wherein the carboplatin is administered intravenously at a dose that provides an AUC of about 5.

23. The method of claim 17, wherein the etoposide is administered intravenously at a dose of about 100 mg/m².

24. The method of claim 17, wherein the atezolizumab is administered in a dose of about 1200 mg.

25. The method of claim 17, wherein the induction phase is repeated at least 2 times.

26. The method of claim 17, wherein the induction phase is repeated at least 3 times.

27. The method of claim 17, wherein the induction phase is repeated at least 4 times.

28. The method of claim 17, wherein the maintenance phase is repeated at least 2 times.

29. The method of claim 17, wherein the maintenance phase is repeated at least 3 times.

30. The method of claim 17, wherein the maintenance phase is repeated at least 4 times.