A Phase I Study Of The Oral Btk Inhibitor ONO-4059 In Patients With Relapsed/Refractory B-Cell Lymphoma

Abstract

Bruton's tyrosine kinase (Btk) is a critical kinase in B-cell receptor (BCR) signal transduction and recent studies support that targeting Btk is effective in the treatment of B-cell malignancies. ONO-4059 is a selective, highly potent oral Btk inhibitor that has demonstrated anti-tumour activity in pre-clinical models. This Phase I study was initiated to determine the safety, tolerability, dose-limiting toxicity (DLT), pharmacokinetics and pharmacodynamics of ONO-4059 given as monotherapy (QD) to patients with relapsed/refractory NHL. We present the safety and efficacy data on 14 evaluable patients (mantle cell lymphoma n = 7, follicular lymphoma n = 3, plasmablastic-DLBCL n = 1, ABC-DLBCL n = 1, small lymphocytic lymphoma n = 1 and Waldenstrom's macroglobulinaemia n = 1), with a median age 64 years (range 48-88). Patients received a median of 3 prior therapies (range 2-8) and 93% (13/14) having prior exposure to a rituximab- containing regimen. Patients received ONO-4059 at doses ranging from 20-160 mg (cohorts 1-4). ONO-4059 was well tolerated, with no DLTs. A total of 18 ONO-4059-related adverse events were reported in 6 out of 14 patients; 15 adverse events were CTCAE-V4.0 G1 (n = 10) and G2 (n = 5). Three G3 haematological toxicities were reported in 2 patients; thrombocytopenia(x2) and anemia. No ONO-4059-related G4 events, or SAEs or infections were reported. Responses have occurred at doses of 40, 80 and 160 mg, with a best overall response rate of 42%; with 5 PR, 4 SD, 2 PD (both MCL). Three MCL patients have achieved PR resulting in a best ORR of 50%. Almost all patients experienced clinically meaningful rapid reductions in lymphadenopathy observed within the first cycle. 10/14 patients are still on study with a median progression-free survival of 93.5 days [Range 8-268]. In conclusion, ONO-4059 is a selective, highly potent oral Btk inhibitor showing a favourable safety profile with promising efficacy in this difficult-to-treat patient population. The study is currently ongoing with additional dose escalation cohorts.