Preservation of immune response during chemotherapy regimens
AssigneeG1 Therapeutics, Inc.
InventorsJessica A. Sorrentino, Anne Y. Lai, Jay C. Strum, Patrick Joseph Roberts
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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.
Claims51
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:
- or a pharmaceutically acceptable salt thereof,
- ii) administering to the human an effective amount of a chemotherapeutic agent, and
- iii) administering to the human an effective amount of an immune checkpoint inhibitor,
- wherein, during the induction phase, the CDK4/6 inhibitor is only administered 24 hours or less prior to the administration of the chemotherapeutic agent, and
- wherein the chemotherapeutic agent is cytotoxic to immune effector cells;
- b) the maintenance phase comprising:
- i) administering to the human 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.
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:
- or a pharmaceutically acceptable salt thereof, on day 1, day 2, and day 3 of the 21-day cycle,
- ii) administering to the human an effective amount of carboplatin on day 1 of the 21-day cycle,
- iii) administering to the human an effective amount of etoposide on day 1, day 2, and day 3 of the 21-day cycle, and
- iv) administering to the human an effective amount of atezolizumab on day 1 of the 21-day cycle;
- wherein, during the induction phase, the CDK4/6 inhibitor is only administered 24 hours or less prior to the administration of carboplatin and/or etoposide;
- b) the maintenance phase comprising:
- i) administering to the human an effective amount of atezolizumab on day 1 of the 21-day cycle,
- wherein the maintenance phase is administered following the cessation of the induction phase.
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:
- or a pharmaceutically acceptable salt thereof,
- ii) administering to the human an effective amount of a chemotherapeutic agent selected from the group consisting of cisplatin, carboplatin gemcitabine, and a combination thereof,
- wherein, during the induction phase, the CDK4/6 inhibitor is only administered 24 hours or less prior to the administration of the chemotherapeutic agent;
- b) the maintenance phase comprising:
- i) administering to the human an effective amount of a programmed death ligand 1 (PD-L1) inhibitor, and,
- ii) administering to the human an effective amount of the CDK4/6 inhibitor,
- wherein the maintenance phase is administered following cessation of the induction phase.
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:
- or a pharmaceutically acceptable salt thereof,
- ii) administering to the human an effective amount of a chemotherapeutic agent selected from the group consisting of doxorubicin, cyclophosphamide, paclitaxel, carboplatin, and a combination thereof,
- iii) administering to the human an effective amount of pembrolizumab, wherein the CDK4/6 inhibitor is administered 24 hours or less prior to the administration of the chemotherapeutic agent.
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:
- or a pharmaceutically acceptable salt thereof, on day 1 of the 21-day cycle,
- ii) administering to the human an effective amount of carboplatin on day 1 of the 21-day cycle,
- iii) administering to the human an effective amount of pemetrexed on day 1 of the 21-day cycle, and
- iv) administering to the human an effective amount of pembrolizumab on day 1 of the 21-day cycle;
- wherein, during the induction phase, the CDK4/6 inhibitor is only administered 24 hours or less prior to the administration of carboplatin and/or pemetrexed;
- b) the maintenance phase comprising:
- i) administering to the human an effective amount of pembrolizumab on day 1 of the 21-day cycle,
- wherein the maintenance phase is administered following the cessation of the induction phase.
Dependencies are inferred from the claim text.