LAUSR

This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (1L) chronic lymphocytic leukemia. Venetoclax dose initially was escalated (100-400 mg) in a 3+3 design to define the MTD combined with standard-dose obinutuzumab. Patients received venetoclax (Schedule A) or obinutuzumab (Schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by venetoclax monotherapy until disease progression (R/R) or fixed-duration 1 year of treatment (1L). 50 R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLS per schedule). Schedule B and 400 mg dose of venetoclax was chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%). Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% (CR/CRi, 37%) in R/R and 100% (CR/CRi, 78%) in 1L patients. Rate of undetectable (<10-4) minimal residual disease (MRD) in peripheral blood for R/R and 1L patients respectively was 64% and 91% ≥3 months after last obinutuzumab dose. Therapy with venetoclax and obinutuzumab had an acceptable safety profile and elicited durable responses and high rates of undetectable MRD. The study is registered to https://clinicaltrials.gov as NCT01685892.