CLL-092: Phase 3 Trial of Acalabrutinib in Combination with Venetoclax, With and Without Obinutuzumab Versus Chemoimmunotherapy for Previously Untreated Chronic Lymphocytic Leukemia (CLL)

Context Acalabrutinib is a next-generation Bruton tyrosine kinase inhibitor (BTKi) approved in patients with relapsed/refractory or treatment-naive (TN) CLL/small lymphocytic lymphoma based on two phase 3 trials (ASCEND and ELEVATE-TN). Combining a BTKi with an anti-CD20 antibody (obinutuzumab [obi]) and a BCL-2 inhibitor (venetoclax [ven]) has the potential to achieve deeper responses and prolong progression-free survival (PFS). Objective To evaluate the efficacy and safety of acalabrutinib in combination with ven ± obi vs chemoimmunotherapy (CIT) in TN CLL. Design Phase 3, randomized (1:1:1), open-label trial (ACE-CL-311; NCT03836261). Setting Global, multicenter study. Patients Adult patients with untreated CLL without del(17p) or TP53 mutation. Interventions Patients are randomized to receive oral acalabrutinib 100 mg BID (28-day cycles, up to 14 cycles) + oral ven QD (cycles 3–4; ramp-up followed by 400 mg/day) (Arm A), acalabrutinib + ven + infusion of obi (cycles 2–7) (Arm B), or CIT (Arm C: up to 6 cycles of fludarabine/cyclophosphamide/rituximab [only in patients aged ≤65 years] or bendamustine/rituximab [BR]). Main outcome measures ACE-CL-311 began in February 2019 and is currently recruiting (target enrollment: 780 patients, >200 sites). Patients must have an Eastern Cooperative Oncology Group performance status ≤2, fulfill International Workshop on Chronic Lymphocytic Leukemia 2018 criteria for CLL diagnosis and treatment, and adequate organ function. Key exclusion criteria include stroke or intracranial hemorrhage, significant cardiovascular disease, bleeding disorders, or required treatment with warfarin or equivalent vitamin K antagonists or a strong cytochrome P450 inhibitor. Patients will be evaluated for efficacy and observed until progressive disease. Primary efficacy endpoint is independent review committee (IRC)-assessed PFS (Arm A vs C). Secondary efficacy endpoints include IRC- and investigator-assessed PFS, undetectable minimal residual disease rates, objective response rate, event-free survival, duration of response, time to next therapy, and overall survival. Safety objectives include incidence and severity of adverse events. Patients will be stratified based on age (>65 vs ≤65 years), immunoglobulin heavy chain variable region mutational status, Rai stage risk (≥3 vs Results Trial in progress. Conclusion Study is currently recruiting.