A phase 3, randomized, open-label, multicenter study of sonrotoclax (BGB-11417) plus anti-CD20 antibody therapies vs venetoclax plus rituximab in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL-RR1/CELESTIAL-RRCLL)

Abstract

Abstract Introduction: Treatment options for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) remain limited. While several fixed-duration combination therapies have been introduced in the frontline setting as alternatives to continuous treatment, approved fixed-duration options in the R/R setting are currently limited to the BCL2 inhibitor venetoclax combined with the anti-CD20 antibody rituximab (VR). Although VR has demonstrated efficacy in R/R CLL, many patients do not experience deep remissions with undetectable minimal residual disease (uMRD), and most patients eventually relapse. Obinutuzumab, a type II anti-CD20 antibody, has shown greater efficacy than rituximab as first-line CLL treatment, but randomized data are currently lacking for R/R CLL. Sonrotoclax (BGB-11417), a next-generation BCL2 inhibitor, is a more selective and more pharmacologically potent inhibitor of BCL2 than venetoclax, with a shorter half-life and no drug accumulation. In an ongoing phase 1/1b study (NCT04277637; BGB-11417-101), sonrotoclax monotherapy has demonstrated preliminary antitumor activity in patients with R/R CLL, and sonrotoclax combination treatments are currently being evaluated in separate study cohorts. The CLL-RR1/CELESTIAL-RRCLL study is designed to evaluate whether sonrotoclax in combination with anti-CD20 antibodies can provide superior clinical outcomes compared with the current venetoclax-based standard treatment in patients with R/R CLL or SLL. An exploratory analysis will evaluate the efficacy of MRD-guided vs. fixed-duration therapy in this population. Methods: CLL-RR1/CELESTIAL-RRCLL (NCT06943872) is an ongoing phase 3, randomized, open-label, multicenter study conducted in collaboration between BeOne Medicines Ltd and the German CLL Study Group. Approximately 630 adults with active R/R CLL or SLL who have received ≥1 prior treatment will be randomized 2:2:1:2 to sonrotoclax plus obinutuzumab (SO), sonrotoclax plus rituximab (SR), SO with MRD-guided therapy (SO-MRD), or venetoclax plus rituximab (VR). Randomization will be stratified by del(17p)/TP53 mutation status, prior BCL2 inhibitor treatment, and refractoriness to prior BTK inhibitor treatment (ie, prior progression on BTK inhibitor therapy). Patients must meet iwCLL 2018 treatment criteria and have received ≥1 prior therapy for CLL/SLL; those with prior BCL2 inhibitor treatment are eligible if they achieved a remission lasting ≥3 years and have been off treatment for ≥2 years, consistent with ESMO CLL treatment recommendations. A minimum of 80% of the study population must have received prior therapy with a targeted agent. Patients with Richter transformation are excluded from the study. SO, SR, or VR will be administered for 25 cycles, each cycle lasting 28 days. Patients in the SO-MRD arm will receive 14 cycles of treatment and will either stop treatment if MRD is confirmed to be undetectable (<10−4) in peripheral blood or will complete a total of 25 cycles if MRD ≥10−4. On day 1 of cycle 1, oral sonrotoclax (SO, SR, SO-MRD arms) will be initiated using a ramp-up to the target dose (320 mg) or oral venetoclax (VR arm) will be initiated with a ramp-up to the target dose (400 mg). Rituximab (SR, VR arms) will be administered intravenously at 375 mg/m2 on day 1 of cycle 2 and at 500 mg/m2 on day 1 of cycles 3 to 7. Obinutuzumab (SO, SO-MRD arms) will be administered intravenously at 1,000 mg on days 1/2, 8, and 15 of cycle 2 and on day 1 of cycles 3 to 7. The primary endpoint of the trial is progression-free survival (PFS) of SO vs VR, determined by a blinded independent review committee. The key secondary (powered) endpoint is the PFS of SR vs VR; additional secondary endpoints include uMRD rates at cycle 14, complete response rates, overall survival, and safety/tolerability. The SO-MRD arm is considered exploratory and is designed to evaluate the efficacy and feasibility of shortening MRD-guided treatment in the context of achieving deeper remissions with SO. Further exploratory analyses will evaluate baseline molecular and cytogenetic features, MRD dynamics, and potential predictors of response or resistance. The study is enrolling at approximately 150 sites across North America, Europe, Asia-Pacific, including Australia/New Zealand and China/Korea, and Latin America. Recruitment began in June 2025 and is currently ongoing.