Use of inhibitors of Bruton's tyrosine kinase (Btk)
Inventors
Buggy, Joseph J. • Fyfe, Gwen • Honigberg, Lee • Loury, David J.
Assignees
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Publication Number
US-10751342-B2
Publication Date
2020-08-25
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 treating chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in an individual using an irreversible inhibitor of Bruton's tyrosine kinase (Btk) with a specific chemical structure. The method comprises orally administering a dose of 420 mg of the Btk inhibitor on a continuous once-daily regimen until progression of the CLL or SLL or unacceptable toxicity, and lymphocytosis is not considered progression of the CLL or SLL.
The invention further requires that the individual achieves a complete response. Dependent claim refinements emphasize measurable exposure and target engagement, including pharmacokinetic exposure expressed as AUC (0-24) and pharmacodynamic target engagement expressed as Btk active-site occupancy in peripheral blood mononuclear cells, with additional constraints on regimen duration.
The disclosed partial content also defines generic chemical structures for compounds of Formula (F), including substituted fused biaryl moieties and detailed substituent variables, and mentions additional embodiment coverage by listing compound structures selected from Formula (A), Formula (B), Formula (C), and Formula (D). These structures are associated with the Btk inhibitor used in the treatment methods.
Claims Coverage
The independent claims cover related treatment methods for CLL or SLL using orally administered Btk inhibitors with a specified structure, dose, and continuous once-daily regimen, while excluding lymphocytosis from being treated as progression and requiring achievement of a complete response. Across the claim sets, the inventive features also include pharmacokinetic and pharmacodynamic thresholds and minimum regimen duration.
Continuous once-daily oral 420 mg Btk inhibition for CLL or SLL until progression or unacceptable toxicity with lymphocytosis excluded
Orally administering to the individual a dose of 420 mg of an inhibitor of Bruton's tyrosine kinase (Btk) on a continuous once-daily regimen until progression of the CLL or SLL or unacceptable toxicity, wherein lymphocytosis is not considered progression of the CLL or SLL.
Complete response requirement for CLL or SLL treatment using the structured Btk inhibitor
The method wherein the inhibitor of Btk has the structure as defined in the claim and wherein the individual achieves a complete response.
Pharmacokinetic and target-occupancy constraints tied to continuous dosing
Administering such that the individual achieves AUC (0-24) greater than about 100 ng*h/ml and more than 90% of the Btk active sites in peripheral blood mononuclear cells being occupied 24 hours after administration.
Minimum continuous once-daily regimen duration
Continuing the once-daily regimen for at least 6 months.
Across the independent claims, the core coverage centers on oral administration of a 420 mg Btk inhibitor with the specified structural definition, delivered on a continuous once-daily regimen with progression or unacceptable-toxicity stopping criteria. The claims exclude lymphocytosis from being treated as progression and require complete response, while dependent claims further specify exposure and Btk active-site occupancy thresholds and minimum regimen duration.
Stated Advantages
Lymphocytosis is not considered progression of the CLL or SLL.
The method aims for a complete response.
The G group can be varied to tailor Michael acceptor reactivity and physicochemical properties, including solubility, lipophilicity, PK, metabolism, and off-target/toxicity.
Allows treatment until progression of the CLL or SLL or unacceptable toxicity while excluding lymphocytosis from being considered progression.
Requires achievement of a complete response.
Documented Applications
Treating relapsed or refractory CLL or SLL in an individual by orally administering a Btk inhibitor.
Treating CLL or SLL in an individual by orally administering a Btk inhibitor.
Using immunophenotyping/FACS on peripheral blood post-Btk-dose to build biomarker profiles for prognosis and therapy decisions.
Administering a second cancer treatment regimen after peripheral blood mobilization metrics change.
Treating relapsed or refractory CLL or SLL in an individual using oral administration of an inhibitor of Bruton's tyrosine kinase (Btk) on a continuous once-daily regimen.
Treating CLL or SLL in an individual using oral administration of an inhibitor of Bruton's tyrosine kinase (Btk) on a continuous once-daily regimen.
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