Use of inhibitors of Brutons tyrosine kinase (Btk)
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 for treating chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in an individual comprising:
orally administering to the individual a therapeutically effective amount of an irreversible inhibitor of Bruton's tyrosine kinase (Btk) on a continuous daily regimen until progression of the CLL or SLL or unacceptable toxicity;
wherein lymphocytosis is not considered progression of the CLL or SLL, and
wherein the irreversible inhibitor of Btk is a small organic molecule having the structure:
wherein Z′ is an optionally substituted fused heterocyclic ring system comprising from 2-4 nitrogen heteroatoms;
wherein the optionally substituted fused heterocyclic ring system consists a 5-membered ring comprising at least one nitrogen heteroatom fused to a 6-membered ring comprising at least one nitrogen heteroatom; and
wherein the irreversible inhibitor of Btk forms a covalent bond with Cys 481 of a Bruton's tyrosine kinase.
2. The method of claim 1 , wherein said administration of the therapeutically effective amount is an amount that results in >90% of the Btk active sites in the peripheral blood mononuclear cells of the individual being occupied by the irreversible inhibitor of Btk twenty-four hours following said administration.
3. The method of claim 1 , wherein the therapeutically effective amount is determined by measuring pharmacodynamic parameters of the irreversible inhibitor of Btk.
4. The method of claim 1 , wherein the therapeutically effective amount of the irreversible inhibitor of Btk is a fixed dose.
5. The method of claim 1 , wherein said administration of the therapeutically effective amount results in an AUC(0-24) of about >100 ng*h·ml.
6. The method of claim 1 , wherein the individual has CLL and the inhibitor of Btk is orally administered to the individual once daily.
7. The method of claim 1 , wherein the individual has SLL and the inhibitor of Btk is orally administered to the individual once daily.
8. A method for treating chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in an individual comprising:
orally administering to the individual a therapeutically effective amount of an irreversible inhibitor of Bruton's tyrosine kinase (Btk) on a continuous daily regimen until progression of the CLL or SLL or unacceptable toxicity;
wherein:
lymphocytosis is not considered progression of the CLL or SLL;
said administration of the therapeutically effective amount is an amount that results in >90% of the Btk active sites in the peripheral blood mononuclear cells of the individual being occupied by the irreversible inhibitor of Btk twenty-four hours following said administration; and
the irreversible inhibitor of Btk is a small organic molecule having the structure:
wherein Z′ is an optionally substituted fused heterocyclic ring system comprising from 2-4 nitrogen heteroatoms; and
wherein the optionally substituted fused heterocyclic ring system consists a 5-membered ring comprising at least one nitrogen heteroatom fused to a 6-membered ring comprising at least one nitrogen heteroatom.
9. The method of claim 1 , wherein the fused heterocyclic ring system is selected from:
10. The method of claim 1 , wherein the fused heterocyclic ring system comprises 2 nitrogen heteroatoms.
11. The method of claim 10 , wherein the fused heterocyclic ring system is selected from:
12. The method of claim 1 , wherein the fused heterocyclic ring system comprises 3 nitrogen heteroatoms.
13. The method of claim 12 , wherein the fused heterocyclic ring system is selected from:
14. The method of claim 1 , wherein the fused heterocyclic ring system comprises 4 nitrogen heteroatoms.
15. The method of claim 14 , wherein the fused heterocyclic ring system is selected from:
16. The method of claim 15 , wherein the irreversible inhibitor of Btk is
17. The method of claim 8 , wherein the fused heterocyclic ring system is selected from:
18. The method of claim 8 , wherein the fused heterocyclic ring system comprises 2 nitrogen heteroatoms.
19. The method of claim 18 , wherein the fused heterocyclic ring system is selected from:
20. The method of claim 8 , wherein the fused heterocyclic ring system comprises 3 nitrogen heteroatoms.
21. The method of claim 20 , wherein the fused heterocyclic ring system is selected from:
22. The method of claim 8 , wherein the fused heterocyclic ring system comprises 4 nitrogen heteroatoms.
23. The method of claim 22 , wherein the fused heterocyclic ring system is selected from:
24. The method of claim 23 , wherein the irreversible inhibitor of Btk is