A Phase 3 Trial Comparing the Efficacy and Safety of Acalabrutinib in Combination with Venetoclax with or without Obinutuzumab, Compared with Investigator's Choice of Chemoimmunotherapy in Patients with Previously Untreated Chronic Lymphocytic Leukemia (CLL) without Del(17p) or TP53 Mutation

Background: Chronic lymphocytic leukemia (CLL) is the most prevalent type of adult leukemia. In many countries, chemoimmunotherapy (CIT) remains the standard of care for frontline treatment of patients without high-risk cytogenetics. Although in most patients the disease responds initially, CIT can be associated with early and late toxicity and limited progression-free survival (PFS), requiring subsequent treatment. Novel chemotherapy-free targeted agents are highly effective but need to be taken continuously, which is associated with development of resistance clones and considerable medical and financial toxicities. Therefore, there is a need to evaluate potentially less toxic frontline chemotherapy-free regimens that could improve outcomes with a fixed duration of treatment. Acalabrutinib is a highly selective, potent, covalent Bruton tyrosine kinase inhibitor (BTKi), which has shown promising efficacy and safety in CLL. In a phase 1/2 trial of 99 patients with untreated CLL, the overall response rate (ORR) was 99% after a median time on study of 33 (1-39) months (Byrd et al.Blood 2018;132:692). Recently completed phase 3 trials showed acalabrutinib ± obinutuzumab (obi) improved PFS vs chemotherapy in untreated patients (ELEVATE TN: AstraZeneca Press release 06/06/2019), and acalabrutinib improved PFS vs idelalisib or bendamustine + rituximab in relapsed/refractory patients (ASCEND: Ghia et al. EHA 2019;273259:LB2606). Combining a BTKi with an anti-CD20 antibody (obi) and a BCL-2 inhibitor (venetoclax [ven]) has the potential to achieve deeper responses and enhance rates of undetectable minimal residual disease (uMRD). In the phase 3 CLL-14 trial in untreated patients with CLL, fixed duration treatment with obi (6 months) + ven (12 months) was more efficacious than obi (6 months) + chlorambucil (12 months), achieving a longer PFS and higher rate of uMRD (Fischer et al. NEJM 2019;380:2225-36).

Study design and methods: ACE-CL-311 (NCT03836261) is a 3-arm phase 3, randomized (1:1:1), global, multicenter, open-label trial evaluating the efficacy and safety of acalabrutinib + ven (Arm A) vs acalabrutinib + ven + obi (Arm B) vs CIT (Arm C: fludarabine/cyclophosphamide/rituximab [FCR; only for patients ≤ 65 years of age] or bendamustine/rituximab [BR]).

The trial opened in February 2019 and is recruiting adult patients with untreated CLL without del(17p) or TP53 mutation. The enrollment target is 780 patients across about 250 sites. Patients must have an Eastern Cooperative Oncology Group performance status of ≤2 and fulfill iwCLL 2018 criteria for CLL diagnosis and treatment (Hallek et al. Blood 2018;131:2745-60). Adequate organ function requirements include serum aspartate aminotransferase and alanine aminotransferase ≤2.5× upper limit of normal (ULN); total bilirubin ≤2× ULN; and estimated creatinine clearance of ≥50 mL/min (≥70 mL/min for FCR). Key exclusion criteria include stroke or intracranial hemorrhage, significant cardiovascular disease (asymptomatic or controlled atrial fibrillation allowed), bleeding disorders, or a requirement for treatment with warfarin or equivalent vitamin K antagonists or a strong cytochrome P450 inhibitor.

Patients will be randomized to receive oral acalabrutinib 100 mg twice daily in 28-day cycles for up to 14 cycles + once-daily oral ven (cycles 3-14; ramp-up followed by 400 mg/day) ± infusions of obi (cycles 2-7), or up to 6 cycles of FCR or BR. Patients will be evaluated for efficacy per iwCLL 2018 guidelines and observed until progressive disease, with survival followed post-progression. The primary efficacy endpoint is independent review committee (IRC)-assessed PFS in Arm A vs Arm C. Secondary efficacy endpoints include IRC- and investigator-assessed PFS, uMRD rates, ORR, event-free survival, duration of response, time-to-next therapy, and overall survival. Safety objectives include incidence and severity of adverse events. Exploratory efficacy endpoints include patient-reported outcomes. The study is powered to achieve ~90% power to detect a hazard ratio of 0.65 in PFS comparing Arm A to Arm C, assuming median PFS of 44.7 months in FCR/BR at the 2-sided significance level of 0.05. Patients will be stratified based on age (>65 vs ≤65 years), IGHV mutational status (mutated vs unmutated), Rai stage risk (high [≥3] vs non-high [<3]), and geographic location (North America vs Europe vs Other).