Use of inhibitors of bruton's tyrosine kinase (Btk)
Inventors
Honigberg, Lee • Loury, David J.
Assignees
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Publication Number
US-10478439-B2
Publication Date
2019-11-19
Expiration Date
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.
Core Innovation
The invention relates to methods of inhibiting proliferation and survival of activated B-cells in a human subject suffering from a B-cell proliferative disorder by orally administering 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). The administration is carried out on a continuous once-daily regimen until progression of the disorder or unacceptable toxicity, and the disclosed target pharmacokinetic and pharmacodynamic performance links oral exposure to BTK active-site occupancy in peripheral blood mononuclear cells.
A key aspect is that the therapeutically effective amount results in AUC(0-24) of >about 100 ng*h/ml and in >90% of the Btk active sites in the peripheral blood mononuclear cells being occupied twenty-four hours following administration. The performance requirement defines a dosing and response relationship for the desired biological effect and is used to inhibit proliferation and survival of activated B-cells.
The background and clinical-context description further indicate that inhibition of BTK activity is evaluated in relation to mobilizing malignant cells from hematological malignancies and to B-cell lymphoproliferative disorder biomarkers. The partial content states that examples and pooled clinical trial descriptions across CLL/SLL and other B-cell lymphomas include efficacy, safety, PK/PD assessment, Btk occupancy using a fluorescent probe, and biomarker measurements such as CD69.
Claims Coverage
The provided content identifies two independent claims. Across them, the inventive features focus on oral administration of Compound 13 and BTK active-site occupancy in peripheral blood mononuclear cells as a defining pharmacokinetic/pharmacodynamic target, coupled to inhibition of activated B-cell proliferation and survival. One independent claim further requires AUC(0-24) of >about 100 ng*h/ml and a continuous once-daily regimen until progression or unacceptable toxicity.
Oral administration of compound 13 with continuous once-daily regimen
Orally administering 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) to a human subject suffering from a B-cell proliferative disorder on a continuous once-daily regimen until progression of the disorder or unacceptable toxicity.
AUC(0-24) and BTK active-site occupancy pharmacokinetic/pharmacodynamic thresholds
Providing a therapeutically effective amount of Compound 13 such that administration results in AUC(0-24) of >about 100 ng*h/ml and results in >90% of the Btk active sites in peripheral blood mononuclear cells being occupied twenty-four hours following said administration.
BTK active-site occupancy-defined oral inhibition of activated B-cell proliferation and survival
Orally administering Compound 13 to inhibit proliferation and survival of activated B-cells in a human subject suffering from a B-cell proliferative disorder, where the therapeutically effective amount results in >90% of the Btk active sites in peripheral blood mononuclear cells being occupied twenty-four hours following said administration.
Across the independent claims, the core claim coverage is a method using oral administration of Compound 13 to a human subject with a B-cell proliferative disorder, defined by a pharmacokinetic/pharmacodynamic target of >90% BTK active-site occupancy in peripheral blood mononuclear cells 24 hours post-dose, with one independent claim further requiring AUC(0-24) of >about 100 ng*h/ml and a continuous once-daily regimen until progression or unacceptable toxicity.
Stated Advantages
Inhibiting proliferation and survival of activated B-cells in a human subject suffering from a B-cell proliferative disorder.
Improved exposure to additional therapies.
Increased availability of lymphoid cells for biomarker screening.
Documented Applications
Treating multiple B-cell malignancies including MALT lymphoma, nodal and splenic marginal zone B-cell lymphoma, Burkitt lymphoma, Waldenström macroglobulinemia, multiple myeloma, and leukemia by mobilizing cells from the malignancy and analyzing mobilized cells using peripheral blood concentration and/or peripheral blood cell counting and duration of mobilization.
Guiding selection or administration of a second cancer treatment regimen using biomarker expression and biomarker mutation profiles obtained from mobilized lymphoid-cell subpopulations analyzed in peripheral blood.
Treatment contexts explicitly mentioned include CLL/SLL, high-risk CLL/SLL, non-Hodgkin lymphoma subtypes including DLBCL, ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, and marginal zone lymphomas, Waldenström macroglobulinemia, and leukemias/myeloid malignancies.
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