A phase I clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies.

We report the results of a multi-center Phase I dose escalation study of the selective BTK inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. There were 9 dose escalation cohorts ranging from 20mg once daily (OD) to 600mg OD with twice daily (BID) regimens of 240mg and 300mg BID also investigated. 24/25 (96%) evaluable chronic lymphocytic leukemia (CLL) patients responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis in most patients. 11/12 (92%) evaluable patients with Mantle Cell Lymphoma (MCL) responded and 8 remain on study (median treatment duration, 40 weeks). 11/31 (35%) non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL) patients responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events being CTC-AE V4.0 Grade 1 or Grade 2. Grade 3/4 adverse events were mainly hematological and recovered spontaneously during ongoing therapy. One CLL patient experienced a Grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the NHL cohort, 4 patients developed a DLT at higher doses, yielding an MTD of 480mg OD. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This clinical trial is registered to www.clinicaltrials.gov as NCT01659255.