G1T38 superior dosage regimes

1. A dosing regime for treating a human with cancer, the dosing regime comprising oral administration of a solid dosage form comprising crystalline Form B of the structure

wherein Form B is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three 2θ values selected from 6.5±0.2, 9.5±0.2, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.7±0.2°, and 22.4±0.2°, wherein the dosing regime provides a (mean AUC (0-24)ss (h*ng/mL))/(dose (mg)) ratio in humans of less than 5.

2. The dosing regime of claim 1 , wherein Form B is characterized by an XRPD pattern comprising at least the 2θ value of 9.5±0.2°.

3. The dosing regime of claim 1 , wherein Form B is characterized by an XRPD pattern with an absence of a 2θ value of 5.0±0.2°.

4. The dosing regime of claim 1 , wherein Form B is characterized by differential scanning calorimetry (DSC) onset endotherms of about 105±20° C., about 220±20° C., and about 350±20° C.

5. The dosing regime of claim 1 , wherein the (mean AUC (0-24)ss (h*ng/mL))/(dose (mg)) ratio is less than 3.

6. The dosing regime of claim 2 , wherein the (mean AUC (0-24)ss (h*ng/mL))/(dose (mg)) ratio is less than 2.25.

7. The dosing regime of claim 1 , wherein the solid dosage form is administered at least once a day.

8. The dosing regime of claim 1 , wherein the solid dosage form is administered at least twice a day.

9. The dosing regime of claim 1 , wherein the dosing regime is administered for at least 24 weeks.

10. The dosing regime of claim 1 , wherein the cancer is a cyclin dependent kinase (CDK)-4/6 replication dependent cancer.

11. The dosing regime of claim 1 , wherein the cancer is selected from the group consisting of breast cancer, non-small cell carcinoma, liver cancer, prostate cancer, hematological cancer, melanoma, colon cancer, pancreatic cancer, endometrial cancer, and gastrointestinal stromal tumor (GIST).

12. 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, 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.

13. The dosing regime of claim 1 , further comprising the administration of one or more additional therapeutic agents.

14. A dosing regime for treating a human with cancer, the dosing regime comprising oral administration of a solid dosage form comprising crystalline Form B of the structure

wherein Form B is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three 2θ values selected from 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.7±0.2°, and 22.4±0.2°, wherein the dosing regime provides a (mean AUC (0-24)ss (h*ng/mL))/(Absolute Neutrophil Count (cells/mm 3 )) ratio in humans of less than 1.25 on day 22 of dosing.

15. The dosing regime of claim 14 , wherein Form B is characterized by an XRPD pattern comprising at least the 2θ value of 9.5±0.2°.

16. The dosing regime of claim 14 , wherein Form B is characterized by an XRPD pattern with an absence of a 2θ value of 5.0±0.2°.

17. The dosing regime of claim 14 , wherein Form B is characterized by differential scanning calorimetry (DSC) onset endotherms of about 105±20° C., about 220±20° C., and about 350±20° C.

18. The dosing regime of claim 14 , wherein the mean AUC (0-24)ss (h*ng/mL))/(Absolute Neutrophil Count (cells/mm 3 )) ratio is less than 1.0.

19. The dosing regime of claim 14 , wherein the solid dosage form is administered at least once a day.

20. The dosing regime of claim 14 , wherein the solid dosage form is administered at least twice a day.

21. The dosing regime of claim 14 , wherein the dosing regime provides a V d /F of greater than about 10,000 L.

22. The dosing regime of claim 14 , wherein the dosing regime is administered for at least 24 weeks.

23. The dosing regime of claim 14 , wherein the cancer is a cyclin dependent kinase (CDK)-4/6 replication dependent cancer.

24. The dosing regime of claim 14 , wherein the cancer is selected from the group consisting of breast cancer, non-small cell carcinoma, liver cancer, prostate cancer, hematological cancer, melanoma, colon cancer, pancreatic cancer, endometrial cancer, and gastrointestinal stromal tumor (GIST).

25. The dosing regime of claim 14 , 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, 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.

26. The dosing regime of claim 14 , further comprising the administration of one or more additional therapeutic agents.

27. A dosing regime for treating a human with cancer, the dosing regime comprising oral administration of a solid dosage form comprising the structure

or a pharmaceutically acceptable salt thereof, wherein the dosing regime provides a (mean AUC (0-24)ss (h*ng/mL))/(dose (mg)) ratio in humans of less than 5.

28. The dosing regime of claim 27 , wherein the (mean AUC (0-24)ss (h*ng/mL))/(dose (mg)) ratio is less than 3.

29. The dosing regime of claim 27 , wherein the (mean AUC (0-24)ss (h*ng/mL))/(dose (mg)) ratio is less than 2.25.

30. The dosing regime of claim 27 , wherein the solid dosage form is administered at least once a day.

31. The dosing regime of claim 27 , wherein the solid dosage form is administered at least twice a day.

32. The dosing regime of claim 27 , wherein the dosing regime is administered for at least 24 weeks.

33. The dosing regime of claim 27 , wherein the cancer is a cyclin dependent kinase (CDK)-4/6 replication dependent cancer.

34. The dosing regime of claim 27 , wherein the cancer is selected from breast cancer, non-small cell carcinoma, liver cancer, prostate cancer, hematological cancer, melanoma, colon cancer, pancreatic cancer, endometrial cancer, and gastrointestinal stromal tumor (GIST).

35. The dosing regime of claim 27 , 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, 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.

36. The dosing regime of claim 27 , further comprising the administration of one or more additional therapeutic agents.

37. A dosing regime for treating a human with cancer, the dosing regime comprising oral administration of a solid dosage form comprising the structure

or a pharmaceutically acceptable salt thereof, wherein the dosing regime provides a (mean AUC (0-24)ss (h*ng/mL))/(Absolute Neutrophil Count (cells/mm 3 )) ratio in humans of less than 1.25 on day 22 of dosing.

38. The dosing regime of claim 37 , wherein the mean AUC (0-24)ss (h*ng/mL))/(Absolute Neutrophil Count (cells/mm 3 )) ratio is less than 1.0.

39. The dosing regime of claim 37 , wherein the solid dosage form is administered at least once a day.

40. The dosing regime of claim 37 , wherein the solid dosage form is administered at least twice a day.

41. The dosing regime of claim 37 , wherein the dosing regime provides a V d /F of greater than about 10,000 L.

42. The dosing regime of claim 37 , wherein the dosing regime is administered for at least 24 weeks.

43. The dosing regime of claim 37 , wherein the cancer is a cyclin dependent kinase (CDK)-4/6 replication dependent cancer.

44. The dosing regime of claim 37 , wherein the cancer is selected from the group consisting of breast cancer, non-small cell carcinoma, liver cancer, prostate cancer, hematological cancer, melanoma, colon cancer, pancreatic cancer, gastrointestinal stromal tumor (GIST).

45. The dosing regime of claim 37 , 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, 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.

46. The dosing regime of claim 37 , further comprising the administration of one or more additional therapeutic agents.

47. The dosing regime of claim 13 , wherein the cancer is HR+/HER2- breast cancer and the additional therapeutic agent is an anti-estrogen compound.

48. The dosing regime of claim 47 , wherein the anti-estrogen compound is selected from the group consisting of tamoxifen, raloxifene, fulvestrant, letrozole, anastrozole, and exemestane.

49. The dosing regime of claim 26 , wherein the cancer is HR+/HER2- breast cancer and the additional therapeutic agent is an anti-estrogen compound.

50. The dosing regime of claim 49 , wherein the anti-estrogen compound is selected from the group consisting of tamoxifen, raloxifene, fulvestrant, letrozole, anastrozole, and exemestane.

51. The dosing regime of claim 46 , wherein the cancer is HR+/HER2- breast cancer and the additional therapeutic agent is an anti-estrogen compound.

52. The dosing regime of claim 51 , wherein the anti-estrogen compound is selected from the group consisting of tamoxifen, raloxifene, fulvestrant, letrozole, anastrozole, and exemestane.