Use of inhibitors of bruton's tyrosine kinase (Btk)
View Patent ↗Disclosed herein are methods for treating a cancer comprising: a. administering a Btk inhibitor to a subject sufficient to result in an increase or appearance in the blood of a subpopulation of lymphocytes defined by immunophenotyping; b. determining the expression profile of one or more biomarkers from one or more subpopulation of lymphocytes; and c. administering a second agent based on the determined expression profile.
1. A method of inhibiting proliferation and survival of activated B-cells in a human subject suffering from a B-cell proliferative disorder, comprising: orally administering to the human subject suffering from a B-cell proliferative disorder a therapeutically effective amount of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 13), on a continuous once-daily regimen until progression of the disorder or unacceptable toxicity,
wherein said administration of the therapeutically effective amount results in an AUC (0-24) of >about 100 ng*h/ml; and
wherein said administration of the therapeutically effective amount results in >90% of the Btk active sites in the peripheral blood mononuclear cells of the human subject being occupied by Compound 13 twenty-four hours following said administration.
2. The method of claim 1 , wherein the once daily regimen is continued for at least 6 months.
3. The method of claim 1 , wherein the B-cell proliferative disorder is a hematological malignancy.
4. The method of claim 3 , wherein the hematological malignancy is a non-Hodgkin lymphoma.
5. The method of claim 3 , wherein the hematological malignancy is selected from the group consisting of chronic lymphocytic leukemia, small lymphocytic lymphoma, and Waldenstrom's macroglobulinemia.
6. The method of claim 3 , wherein the hematological malignancy is selected from the group consisting of mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, and ABC-diffuse large B-cell lymphoma.
7. The method of claim 1 , wherein the human subject has previously undergone a bone marrow transplant.
8. The method of claim 7 , wherein the human subject has previously undergone an autologous bone marrow transplant.
9. The method of claim 3 , wherein the hematological malignancy is relapsed or refractory.
10. A method of inhibiting proliferation and survival of activated B-cells in a human subject suffering from a B-cell proliferative disorder, comprising:
orally administering to the human subject suffering from a B-cell proliferative disorder a therapeutically effective amount of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 13),
wherein the therapeutically effective amount of Compound 13 is an amount that results in >90% of the Btk active sites in the peripheral blood mononuclear cells of the human subject being occupied by Compound 13 twenty-four hours following said administration, and
wherein proliferation and survival of the activated B-cells in the human are inhibited.
11. The method of claim 10 , wherein the B-cell proliferative disorder is a hematological malignancy.
12. The method of claim 11 , wherein the hematological malignancy is a non-Hodgkin lymphoma.
13. The method of claim 11 , wherein the hematological malignancy is selected from the group consisting of chronic lymphocytic leukemia, small lymphocytic lymphoma, and Waldenstrom's macroglobulinemia.
14. The method of claim 11 , wherein the hematological malignancy is selected from the group consisting of mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, and ABC-diffuse large B-cell lymphoma.
15. The method of claim 10 , wherein the human subject has previously undergone a bone marrow transplant.
16. The method of claim 15 , wherein the human subject has previously undergone an autologous bone marrow transplant.
17. The method of claim 11 , wherein the hematological malignancy is relapsed or refractory.