Bruton's tyrosine kinase (Btk) plays a key role in the signaling pathway from the B cell receptor (BCR) that contributes to the proliferation and survival of malignancies of B cell origin. AVL-292 is an orally available and highly selective covalent inhibitor of Btk that is currently undergoing Phase 1b clinical development for CLL and B-NHL. Using a novel covalent probe that enables precise and quantitative assessment of Btk molecular target engagement by AVL-292, we have pursued an innovative early clinical development approach in healthy adult volunteers based on this translational capability. 5 cohorts of up to 8 subjects (6 active, 2 placebo) were enrolled in a single ascending dose, placebo controlled clinical study. The objectives of this study were to determine safety, pharmacokinetics, and to determine the minimum dose and plasma concentration of AVL-292 required to achieve complete Btk engagement. Single oral doses of 0.5-7.0 mg/kg were administered to up to 6 subjects per cohort. Samples for AVL-292 PK and Btk occupancy in peripheral blood mononuclear cells enriched for B cells were collected immediately prior to dosing and at several time points after dosing to determine the PK-PD relationship. AVL-292 was found to be safe and well tolerated following oral administration at all dose levels. All subjects that received an oral dose of 1.0 mg/kg of AVL-292 achieved >80% Btk occupancy. 5 of the 6 subjects administered AVL-292 at 2.0 mg/kg achieved complete Btk occupancy that was sustained through 24 hours even after plasma levels of AVL-292 had declined. This prolonged duration of activity demonstrates that covalent inhibition of Btk with AVL-292 enables continued activity without requiring persistence of circulating drug. The minimum dose that achieved complete target occupancy in this study (125 mg) was carried forward as the starting dose in a Phase 1b study of hematological malignancies of B cell origin. Subjects diagnosed with B cell malignancies received single daily oral doses of AVL-292 in continuous 28 day cycles. Total Btk content was determined in peripheral blood mononuclear cells at pre-dose, and Btk occupancy was determined 4 and 24 hours post dose on Day 1 and Day 28. Btk occupancy in this Phase 1b clinical study confirmed observations in healthy volunteer subjects. The relationship between inhibition of Btk activity and clinical response will be determined in the current and future clinical studies. Performing dose escalation in healthy volunteers enables rapid determination of an active dose level for Btk occupancy and inhibition by AVL-292. This innovative clinical trial design precludes the administration of sub-therapeutic dose levels to patients with high medical need and rapidly identified the therapeutic dose range and schedule for AVL-292 for use in treatment of patients with B cell malignancies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1745. doi:1538-7445.AM2012-1745