The Lynx Group

Phase 3 Trial Compares Acalabrutinib plus Venetoclax with or without Obinutuzumab versus Chemoimmunotherapy as First-Line Therapy in Patients with Chronic Lymphocytic Leukemia and No del(17p) or TP53 Mutations

Conference Correspondent

Although most patients with chronic lymphocytic leukemia (CLL) respond to initial treatment with chemoimmunotherapy, these combination regimens can be associated with early and late toxicity, and limited progression-free survival (PFS). Novel targeted agents, such as Bruton tyrosine kinase inhibitors, are highly effective but need to be administered continuously. These treatments have been associated with development of resistance clones, long-term toxicities, and patient financial burden over time. Therefore, there is a need to evaluate novel first-line chemotherapy-free regimens that can be given for a fixed duration of time with fewer toxicities.

One novel approach is being studied in a phase 3 clinical trial called ACE-CL-311 (NCT03836261). This 3-arm, randomized, global, open-label trial is comparing the efficacy and safety of acalabrutinib (Calquence) plus venetoclax (Venclexta; Arm A) versus acalabrutinib plus venetoclax plus obinutuzumab (Gazyva; Arm B) versus chemoimmunotherapy (Arm C; fludarabine [Fludara] plus cyclophosphamide plus rituximab [Rituxan; FCR] for patients aged ≤65 years or bendamustine [Bendeka] plus rituximab [BR]) as first-line therapy.

As of February 2019, ACE-CL-311 is recruiting adult patients with untreated CLL who do not have a del(17p) or TP53 mutation. The enrollment target is 780 patients in approximately 250 clinical trial sites. Patients must have an Eastern Cooperative Oncology Group performance status of ≤2 and fulfill International Workshop on CLL (iwCLL) 2018 criteria for CLL diagnosis and treatment. They also must have adequate organ function. Key exclusion criteria include stroke or intracranial hemorrhage, significant cardiovascular disease, bleeding disorders, or a requirement for treatment with warfarin or equivalent vitamin K antagonists or a strong cytochrome P450 inhibitor. Patients with asymptomatic or controlled atrial fibrillation are allowed in the trial.

Patients enrolled in ACE-CL-311 will be randomized to receive oral acalabrutinib 100 mg twice daily in 28-day cycles for up to 14 cycles plus once-daily oral venetoclax (cycles 3-14; ramp-up followed by 400 mg per day) with or without infusions of obinutuzumab (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 end point of ACE-CL-311 is Independent Review Committee (IRC)-assessed PFS in Arm A versus Arm C. Secondary efficacy end points include IRC- and investigator-assessed PFS, rates of undetectable minimal residual disease, overall response rate, event-free survival, duration of response, time to next therapy, and overall survival. Exploratory efficacy end points include patient-reported outcomes. Safety objectives in ACE-CL-311 include rate and severity of adverse events. Patients will be stratified based on age (>65 vs ≤65 years), IGHV mutational status (mutated vs unmutated), Rai stage risk (high risk [stages III or IV] vs nonhigh risk [stages 0, I, or II]), and geographic location (North America vs Europe vs other).

This important phase 3 study is expected to provide valuable new information about the potential of chemotherapy-free fixed duration treatment in CLL and MCL.

Source: Brown JR, et al. ASH Abstract 4318.

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