G1T38 SUPERIOR DOSAGE REGIMES
A GIT38 human oral dosage regime that provides a (mean AUC(0-24),ss (h*ng/ml))/(dose (mg)) ratio of less than 5 and/or a (mean AUC(0-24),ss (h*ng/ml))/(Absolute Neutrophil Count (cells/mm3)) ratio on day 22 of dosing of not greater than 1.25.
1 . A dosing regime for treating a human with cancer, the dosing regime comprising oral administration of a solid dosage form comprising a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor compound of structure.
wherein the dosing regime provides a (mean AUC (0-24)ss (h*ng/mL))/(dose (mg)) ratio in humans of less than 5,
and wherein the solid dosage form is administered twice daily at a concentration of about 150 mg spaced about 12 hours apart.
2 . The dosing regime of claim 1 , wherein the dosing regime provides a (mean AUC (0-24)ss (h*ng/mL))/(dose (mg)) ratio in humans of less than 3.
3 . The dosing regime of claim 1 , wherein the dosing regime provides a (mean AUC (0-24)ss (h*ng/mL))/(dose (mg)) ratio in humans of less than 2.25.
4 . The dosing regime of claim 1 , wherein the dosing regime is administered for at least 24 weeks.
5 . The dosing regime of claim 1 , wherein the cancer is a CDK4/6 replication dependent cancer.
6 . The dosing regime of claim 1 , wherein the cancer is selected from the group consisting of breast cancer, non-small cell lung carcinoma, liver cancer, prostate cancer, hematological cancer, melanoma, colon cancer, pancreatic cancer, liposarcoma, and gastrointestinal stromal tumor (GIST).
7 . The dosing regime of claim 1 , wherein the cancer is selected from the group consisting of HR+/HER2− breast cancer, HR−/HER2+ breast cancer, EGFR mutant non-small cell carcinoma, KRAS mutant non-small cell lung carcinoma, hepatocellular carcinoma, uterine cancer, castrate resistant prostate cancer, mantle cell lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia, follicular lymphoma, diffuse large B-cell lymphoma, BRAF mutant melanoma, RAS mutant colorectal cancer, RAS mutant pancreatic cancer, and RAS mutant cholangiocarcinoma.
8 . The dosing regime of claim 1 , further comprising the administration of one or more additional therapeutic agents.
9 . The dosing regime of claim 8 , wherein the cancer is HR+/HER2− breast cancer and the additional therapeutic agent is an anti-estrogen compound.
10 . The dosing regime of claim 9 , wherein the anti-estrogen compound is selected from the group consisting of tamoxifen, raloxifene, fulvestrant, letrozole, anastrozole, and exemestane.
11 . The dosing regime of claim 9 , wherein Compound II and the anti-estrogen compound are administered after endocrine therapy failure.
12 . The dosing regime of claim 10 , wherein the anti-estrogen compound is fulvestrant.
13 . The dosing regime of claim 10 , wherein the anti-estrogen compound is letrozole.
14 . The dosing regime of claim 6 , wherein the cancer is liver cancer.
15 . The dosing regime of claim 7 , wherein the cancer is hepatocellular carcinoma.
16 . The dosing regime of claim 6 , wherein the cancer is a hematological cancer.
17 . The dosing regime of claim 7 , wherein the cancer is diffuse large B-cell lymphoma.
18 . The dosing regime of claim 6 , wherein the cancer is non-small cell lung carcinoma.
19 . The dosing regime of claim 1 , wherein the solid dosage form is administered twice daily at a concentration of 150 mg spaced 12 hours apart.