Use of inhibitors of bruton's tyrosine kinase (btk)

Abstract

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 - 129 . (canceled) 
     
     
         130 . A solid pharmaceutical formulation of a Btk inhibitor, comprising
 a. 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), and   b. at least one pharmaceutically acceptable excipient,   wherein once-daily oral administration to an adult human of said solid pharmaceutical formulation sufficient to deliver a dose of about 420 mg of Compound 13 results in an AUC (0-24)  of >100 ng*hr/ml.   
     
     
         131 . The solid pharmaceutical formulation of  claim 130 , wherein >90% of the Btk active sites in the peripheral blood mononuclear cells of the adult human is occupied by Compound 13 twenty-four hours following said administration. 
     
     
         132 . The solid pharmaceutical formulation of  claim 130 , wherein the adult human has an activated B-cell proliferative disorder and further wherein when said administration carried out on a continuous once-daily regimen delays progression of the activated B-cell proliferative disorder. 
     
     
         133 . The solid pharmaceutical formulation of  claim 130 , wherein the pharmaceutical formulation is administered to the adult human once-daily in three capsules, each of the capsules comprising about 140 mg of Compound 13. 
     
     
         134 . The solid pharmaceutical formulation of  claim 130 , wherein the Compound 13 is in particulate form. 
     
     
         135 . The solid pharmaceutical formulation of  claim 130 , wherein the Compound 13 is in milled form. 
     
     
         136 . The solid pharmaceutical formulation of  claim 133 , wherein the Compound 13 is in particulate form. 
     
     
         137 . The solid pharmaceutical formulation of  claim 133 , wherein the Compound 13 is in milled form. 
     
     
         138 . The solid pharmaceutical formulation of  claim 130 , further comprising about 20-70% binder 
     
     
         139 . The solid pharmaceutical formulation of  claim 134 , further comprising about 20-70% binder. 
     
     
         140 . The solid pharmaceutical formulation of  claim 135 , further comprising about 20-70% binder. 
     
     
         141 . The solid pharmaceutical formulation of  claim 136 , further comprising about 20-70% binder. 
     
     
         142 . The solid pharmaceutical formulation of  claim 137 , further comprising about 20-70% binder. 
     
     
         143 . The solid pharmaceutical formulation of  claim 138 , further comprising about 20-70% binder. 
     
     
         144 . A solid pharmaceutical formulation of a Btk inhibitor, comprising
 a. 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) in particulate form, and   b. about 20-70% binder,   wherein once-daily oral administration to an adult human of said solid pharmaceutical formulation sufficient to deliver a dose of about 420 mg of Compound 13 results in an AUC (0-24)  of >100 ng*hr/ml.   
     
     
         145 . A solid dosage capsule formulation, comprising
 (a) about 140 mg 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), and   (b) at least one pharmaceutically acceptable excipient,   wherein once-daily oral administration to an adult human of three capsules comprising the formulation results in an AUC (0-24)  of >100 ng*hr/ml.   
     
     
         146 . The solid dosage capsule formulation of  claim 145 , wherein >90% of the Btk active sites in the peripheral blood mononuclear cells of the adult human is occupied by Compound 13 twenty-four hours after the once-daily oral administration. 
     
     
         147 . The solid dosage capsule formulation of  claim 145 , wherein the adult human has an activated B-cell proliferative disorder and continuous once-daily administration to the adult human of the three capsules comprising the formulation delays progression of the activated B-cell proliferative disorder. 
     
     
         148 . The solid dosage capsule formulation of  claim 145 , wherein the Compound 13 is in particulate form. 
     
     
         149 . The solid dosage capsule formulation of  claim 145 , wherein the Compound 13 is in milled form. 
     
     
         150 . The solid dosage capsule formulation of  claim 145 , further comprising a surfactant. 
     
     
         151 . The solid dosage capsule formulation of  claim 145 , further comprising about 20-70% binder. 
     
     
         152 . The solid dosage capsule formulation of  claim 148 , further comprising about 20-70% binder. 
     
     
         153 . The solid dosage capsule formulation of  claim 149 , further comprising about 20-70% binder. 
     
     
         154 . The solid dosage capsule formulation of  claim 150 , further comprising about 20-70% binder. 
     
     
         155 . The solid dosage capsule formulation of  claim 151 , further comprising a surfactant. 
     
     
         156 . The solid dosage capsule formulation of  claim 152 , further comprising a surfactant. 
     
     
         157 . The solid dosage capsule formulation of  claim 153 , further comprising a surfactant. 
     
     
         158 . A solid dosage capsule formulation of a Btk inhibitor, comprising
 a. about 140 mg 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) in particulate form, and   b. about 20-70% binder,   wherein once-daily oral administration to an adult human of three capsules comprising the formulation results in an AUC (0-24)  of >100 ng*hr.   
     
     
         159 . The solid dosage capsule formulation of  claim 158 , further comprising a surfactant.