This Phase 3 study is designed to compare the investigational fixed-duration combination of sonrotoclax plus zanubrutinib with acalabrutinib plus venetoclax in adults with previously untreated chronic lymphocytic leukemia requiring therapy. The objective is to evaluate whether these regimens differ with respect to progression‑free survival (PFS) and depth of minimal residual disease following completion of fixed‑duration treatment.
This is a global, open‑label, randomized study. Approximately 500 patients are planned for enrollment and randomized 1:1 to one of two fixed‑duration treatment arms following BTK inhibitor lead‑in periods. Randomization is stratified by age, immunoglobulin heavy chain variable region mutation status, and the presence of del(17p) and/or TP53 mutations.
Key inclusion criteria include a confirmed diagnosis of previously untreated chronic lymphocytic leukemia requiring treatment per iwCLL 2018 criteria, measurable disease confirmed by CT/MRI, ECOG performance status of 0–2, and adequate hematologic and organ function.
Key exclusion criteria include prior systemic therapy for chronic lymphocytic leukemia, a diagnosis of prolymphocytic leukemia or Richter transformation, known central nervous system involvement, a history of confirmed progressive multifocal leukoencephalopathy, uncontrolled hypertension, or clinically significant cardiovascular disease.
The primary endpoint is PFS, assessed by an independent review committee (PFS-IRC).
The intermediate endpoint is the rate of undetectable minimal residual disease at 10⁻⁴ sensitivity (uMRD4) in blood and bone marrow, assessed using next‑generation sequencing (clonoSEQ) at the first post‑treatment follow‑up visit.
Key secondary endpoints include overall survival and PFS-IRC in high‑risk subgroups. Other secondary endpoints include overall response rate and complete response assessed by IRC and investigator (INV), uMRD5, PFS-INV, duration of response by IRC and INV, time to next treatment, patient‑reported outcomes, and safety and tolerability.
