In a new study, David Lavie, MD, of the Hadassah Medical Center, and colleagues will investigate the efficacy and safety of nemtabrutinib + venetoclax versus venetoclax + rituximab (VR) as a second-line or later treatment for patients with relapsed or refractory chronic lymphocytic leukemia (R/R CLL). The BELLWAVE-010 study is a phase 3, randomized, open-label, active-controlled trial.

The study design and methods involve two parts. The first part is an open-label, nonrandomized dose escalation and confirmation phase, where the objective is to evaluate safety and determine the optimal dose of nemtabrutinib in combination with venetoclax. This part of the study will enroll about 30 patients who will take nemtabrutinib at two dose levels for 28 days, followed by the combination of nemtabrutinib and venetoclax for an additional period. The dosing levels will be 45 mg PO QD starting dose, escalating to 65 mg PO QD.

In the second part of the study, approximately 690 patients will be randomly assigned to receive either nemtabrutinib at the recommended dose followed by the combination of the same with venetoclax, or venetoclax in combination with rituximab. This part of the study will follow an open-label, parallel-group, randomized phase. Here, the venetoclax dose will go up from 20 to 400 mg PO QD over 4 weeks, and rituximab would be given at 375 mg/m2 at week 6 followed by 500 mg/m2 Q4W at week 10 until week 26. Patients will receive treatment for approximately 2 years or until any unacceptable toxicity, disease progression, or other discontinuation criteria are met.

Dr Lavie and his team will assess the treatment responses every 12 weeks up to week 97 and every 24 weeks thereafter, or more as clinically indicated, through the use of imaging, physical examination, consideration of constitutional symptoms, hematological evaluations, and bone marrow biopsy. Additionally, adverse events will be monitored for up to 30 days after treatment cessation, or 90 days for serious adverse events. Collectively, this data will contribute toward the primary endpoint for the first part of this study, which is safety and tolerability. The second part has the primary endpoint as progression-free survival, assessed per the iwCLL 2018 criteria by a blinded independent central review. Secondary endpoints include undetectable minimal residual disease, overall response rate (ORR), duration of response, overall survival, and safety. Further exploratory endpoints include ORR that includes partial response with lymphocytosis, pharmacokinetics, and health-related quality of life.

The first part of the study is set to evaluate the safety and optimal dose of nemtabrutinib in combination with venetoclax. The second part will compare the outcomes of patients receiving a combination of nemtabrutinib and venetoclax versus those who receive venetoclax in combination with rituximab. To measure treatment responses, assessments will be made at regular intervals up to nearly two years, with primary and secondary endpoints defined to evaluate the progression of disease, patient safety, and overall response rate. This study aims to contribute valuable insights into the effectiveness of the therapeutic approach in patients with CLL.

Lavie D, Ozcan M, Chaudhry A, Zhou X et al. Bellwave-010: Phase 3, Open-Label, Randomized Study of Nemtabrutinib Plus Venetoclax Versus Venetoclax Plus Rituximab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Following at Least One Prior Therapy. Presented at: the 2023 ASH Annual Meeting & Exposition; December 9-12, 2023; San Diego, CA, and virtual; Abstract 3287