USE OF INHIBITORS OF BRUTON'S 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 a hematological malignancy in an individual in need thereof, comprising:
administering to the individual an amount of a Btk inhibitor sufficient to mobilize a plurality of cells from the malignancy; and
analyzing the mobilized plurality of cells.
2 . The method of claim 1 , wherein the amount of the Btk inhibitor is sufficient to induce lymphocytosis of a plurality of cells from the malignancy.
3 .- 4 . (canceled)
5 . The method of claim 1 , wherein the hematological malignancy is a B-cell malignancy.
6 . The method of claim 1 , wherein the hematological malignancy is a leukemia, lymphoproliferative disorder, or myeloid.
7 . The method of claim 1 , wherein the mobilized cells are myeloid cells or lymphoid cells.
8 .- 12 . (canceled)
13 . The method of claim 1 , wherein analyzing the mobilized plurality of cells comprises counting the number of mobilized plurality of cells in the peripheral blood.
14 . The method of claim 13 , further comprising administering a second cancer treatment regimen after the number of mobilized plurality of cells in the peripheral blood increases as compared to the number before administration of the Btk inhibitor.
15 . The method of claim 14 , wherein administering the second cancer treatment regimen occurs after a subsequent decrease in the number of mobilized plurality of cells in the peripheral blood.
16 .- 23 . (canceled)
24 . The method of claim 1 , wherein the hematological malignancy is a chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma.
25 . The method of claim 1 , wherein the hematological malignancy is follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, marginal zone lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, extranodal marginal zone B cell lymphoma, acute or chronic myelogenous (or myeloid) leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia., relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma, relapsed or refractory follicular lymphoma, relapsed or refractory CLL, relapsed or refractory SLL, or relapsed or refractory multiple myeloma.
26 .- 28 . (canceled)
29 . The method of claim 1 , wherein the Btk inhibitor is (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one.
30 . The method of claim 1 , wherein the amount of the irreversible Btk inhibitor is from 300 mg/day up to, and including, 1000 mg/day.
31 .- 32 . (canceled)
33 . The method of claim 1 , wherein the amount of the Btk inhibitor is about 420 mg/day.
34 . The method of claim 1 , wherein the AUC 0-24 of the Btk inhibitor is between about 150 and about 3500 ng*h/mL.
35 . (canceled)
36 . The method of claim 1 , wherein the Btk inhibitor is administered orally.
37 . The method of claim 1 , wherein the Btk inhibitor is administered once per day, twice per day, or three times per day.
38 .- 47 . (canceled)
48 . The method of claim 14 , wherein the second cancer treatment regimen comprises chlorambucil, ifosphamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof.
49 . The method of claim 14 , wherein the second cancer treatment regimen comprises cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone.
50 . The method of claim 14 , wherein the second cancer treatment regimen comprises bendamustine, and rituximab.
51 . The method of claim 14 , wherein the second cancer treatment regimen comprises fludarabine, cyclophosphamide, and rituximab.
52 . The method of claim 14 , wherein the second cancer treatment regimen comprises cyclophosphamide, vincristine, and prednisone, and optionally, rituximab.
53 . The method of claim 14 , wherein the second cancer treatment regimen comprises etoposide, doxorubicin, vinristine, cyclophosphamide, prednisolone, and optionally, rituximab.
54 . The method of claim 14 , wherein the second cancer treatment regimen comprises dexamethasone and lenalidomide.
55 . The method of claim 1 , wherein the Btk inhibitor has the following structure:
wherein:
L a is CH 2 , O, NH or S;
Ar is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;
Y is an optionally substituted group selected from among alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
Z is C(═O), OC(═O), NHC(═O), C(═S), S(═O) x , OS(═O) x , NHS(═O) x , where x is 1 or 2;
R 6 , R 7 , and R 8 are each independently selected from among H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 3 alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 4 alkyl(aryl), substituted or unsubstituted C 1 -C 4 alkyl(heteroaryl), substituted or unsubstituted C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), or substituted or unsubstituted C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); or
R 7 and R 8 taken together form a bond; and pharmaceutically active metabolites, or pharmaceutically acceptable solvates, pharmaceutically acceptable salts, or pharmaceutically acceptable prodrugs thereof.
56 . The method of claim 55 , wherein La is O.
57 . The method of claim 55 , wherein Ar is phenyl.
58 . The method of claim 55 , wherein: Z is C(═O), NHC(═O), or S(═O) 2 .
59 . The method of claim 55 , wherein:
each of R 7 and R 8 is H.
60 . The method of claim 55 , wherein:
Y is a 4-, 5-, 6-, or 7-membered cycloalkyl ring; or
Y is a 4-, 5-, 6-, or 7-membered heterocycloalkyl ring.
61 .- 129 . (canceled)
130 . The method of claim 1 , wherein the Btk inhibitor is administered daily or every other day.
131 . The method of claim 49 , herein the second cancer treatment regimen further comprises rituximab.
132 . The method of claim 1 , wherein the Btk inhibitor is an irreversible Btk inhibitor.
133 . A method for treating a hematological malignancy in an individual in need thereof, comprising: administering to the individual an amount of a Btk inhibitor sufficient to fully occupy the active site of Btk.
134 . The method of claim 133 , wherein >95% of the Btk is occupied by the Btk inhibitor at 4 hours post dose.
135 . The method of claim 133 , wherein the hematological malignancy is follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, marginal zone lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, extranodal marginal zone B cell lymphoma, acute or chronic myelogenous (or myeloid) leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma, relapsed or refractory follicular lymphoma, relapsed or refractory CLL, relapsed or refractory SLL, or relapsed or refractory multiple myeloma.
136 . The method of claim 133 , wherein the amount of the Btk inhibitor is between 1.25-17.5 mg/kg/day.
137 . The method of claim 133 , wherein the amount of the Btk inhibitor is 1.25 mg/kg.
138 . The method of claim 133 , wherein the Btk inhibitor is administered orally.