Muhit Özcan, MD, on CLL/SLL: Report on a Still-Recruiting International Study of Nemtabrutinib, Venetoclax, and Rituximab

[Inaudible 00:00:08] is a standard of care option for patients with CLL, SLL, who have relapsed after at least one line of prior therapy. However, there is an unmet need for more effective treatments. Bruton tyrosine kinase, BTK, plays an important role in the pathogenesis of CLL. Nemtabrutinib is a BTK inhibitor that targets both wild-type and C-481 mutant forms of BTK, in the ongoing BELLWAVE-001 study, nemtabrutinib demonstrates manageable safety and durable anti-tumor activity in patients with refractory relapse, CLL, SLL, with and without C-481 mutations. The randomized open-label phase III BELLWAVE zero-tense study is designed to evaluate the efficacy and safety of nemtabrutinib plus venetoclax versus VR as a second line or later treatment for patients with RR CLL, SLL. Eligible patients are aged more than 18 years with active refractory relapse CLL, SLL after at least one line on prior therapy per IW-CLL 2018 criteria, and equal performance status of zero to two approximately 720 patients will be enrolled in two parts. Part one is an open-label, non-randomized dose escalation and confirmation phase to evaluate safety, and determine the optimal dose of nemtabrutinib plus venetoclax. Part one will enroll 30 patients to establish the dose of nemtabrutinib, using a modified toxicity probability interval design. Patients will receive nemtabrutinib at two dose levels. 45 milligram per day parallel Q-day, starting dose. Escalating to six five milligram parallel Q-day for 28 days, followed by nemtabrutinib plus venetoclax ramp up over four weeks. Part two is an open-label parallel group randomized phase comparing the efficacy and safety of nemtabrutinib plus venetoclax with VR. In part two, approximately 690 patients will be randomly assigned one-to-one to receive either nemtabrutinib at recommended dose for 28 days, followed by the nemtabrutinib plus venetoclax, or venetoclax plus rituximab. Study treatment will continue for approximately two years, or until an acceptable toxicity, disease progression, or other discontinuation criteria are met. Randomization will be certified by BTKC-481 mutation status, geographic region, and risk group. The primary endpoint for part two is progression free survival by Blinded Independent Central Review, BICR, per IWCLL 2018 criteria. Secondary endpoints for part two are: Undetectable, minimal residual disease in bone marrow at month 14 by central laboratory assessment, objective response rate and duration of response by BICR per IWCLL 2018 criteria, Overall survival and safety. Exploratory endpoints are overall response rate, including partial response with lymphocytosis, pharmacokinetics, and heart-related quality of life. Recruitment is ongoing.