PF515 A PHASE I STUDY OF THE BTK INHIBITOR ABIVERTINIB (AC0010) IN PATIENTS WITH RELAPSED OR REFRACTORY B‐CELL LYMPHOMA
Authors: M. Yang, J. Qian, J. Huang, Y. Jiao, W. Tang, X. Xu, W. Xu, F.R. Luo, J. Jin
Journal: HemaSphere (2019)

Background: Bruton's tyrosine kinase (BTK) is a clinically validated target for the treatment of B‐cell malignancies, including relapsed/refractory (R/R) mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), and Waldenström's macroglobulinemia (WM). Abivertinib is a highly selective, irreversible, potent inhibitor of BTK activity, which is being investigated in an open‐label phase I study with dose escalation (part 1) and dose expansion (part 2) (NCT03060850). Aims: This ongoing study is designed to determine the recommended Phase 2 dose (RP2D) of abivertinib in patients with pre‐treated R/R B‐cell lymphoma (part 1) and to evaluate the safety and preliminary efficacy in patients with selected disease (part 2). Methods: In part 1, eligible patients aged 18–75 y, with Eastern Cooperative Oncology Group performance status of 0 or 1, and diagnosed with R/R B‐cell lymphoma were enrolled. Patients received abivertinib until progressive disease or unacceptable toxicity. The primary endpoint of part 1 is to determine RP2D based on dose limited toxicity (DLT), adverse event (AE), tolerability, BTK receptor occupancy, pharmacokinetics and preliminary efficacy. Abivertinib was given twice a day (BID) or once a day in 28‐day treatment cycles in ascending/descending dose cohorts, the starting dose was 200 mg BID. Here, we report the preliminary safety and efficacy outcomes in part 1, and part 2 will be initiated upon determinate of RP2D. Results: As of November 15, 2018, 21 patients with R/R B‐cell malignancy were enrolled for treatment in part 1, including CLL (n = 9), SLL (n = 1), MZL (n = 1), MCL (n = 5), follicular lymphoma (n = 1), lymphoplasmacytic lymphoma (n = 3), mucosa‐associated lymphoid tissue (n = 1). Patients received treatment with abivertinib in 3 dose cohorts (300 mg BID, n = 3; 200 mg BID, n = 14; 150 mg BID, n = 4). The median treatment duration was 27 (range 1–85) weeks; 66.9% (14/21) of patients are still on treatment. Three (14.3%) DLT events of platelet count decrease were reported, 1 at 300 mg BID and 2 at 200 mg BID. Overall, treatment emergent AE occurred in 85.7% (18/21) of patients, with 47.6% (10/21) of grade 3/4 AE. The most common grade 3/4 AE regardless of causality (≥10%) was thrombocytopenia (4/21, 19.0%), followed by neutropenia (3/21, 14.3%). Treatment emergent serious adverse event (SAE) occurred in 23.8% (5/21) of patients, only 1 case (4.8%) of drug‐related SAE abdominal infection was reported. No death occurred during the treatment period. The efficacy was analyzed in the 13 response evaluable patients, 61.5% (8/13) of patients achieved partial response (PR) across 3 dose cohorts and 87.5% (7/8) of patients achieved PR at 200 mg BID. Furthermore, &gt;90% BTK occupancy in peripheral blood was achieved at all 3 dose levels. Summary/Conclusion: Abivertinib was safe and tolerable with encouraging clinical efficacy in patients with R/R B‐cell malignancies, which warrants further evaluation in part 2 of the study.