Acalabrutinib and Venetoclax (AV) Combination for 2 Years for Patients with Previously Treated CLL/SLL - the Avenue-2 Trial

Background:

Acalabrutinib (A), a second generation BTKi, is approved for treatment of CLL as monotherapy until progression or intolerance. Venetoclax (V), a BCL2 inhibitor, in combination with anti-CD20 antibodies is approved for fixed-duration and as monotherapy until progression or intolerance. Combination of BTK and BCL2 inhibitors for treatment of CLL provides an option of time-limited and all oral regimen. Clinical trials that studied the combination of the first generation BTKi ibrutinib and V have shown the feasibility and efficacy of the regimen. Given the favorable safety profile and sustained efficacy of acalabrutinib, combination regimens with venetoclax without (AV) or with obinutuzumab [O] (AVO) have been studied in the first line setting, and favorable efficacy and safety have been reported. The AMPLIFY (chemoimmunotherapy vs. AV vs. AVO) and MAJIC (AV vs. VO) are 2 randomized trials for previously untreated pts, and the former may result in an approval AV or AVO combination in the first line setting. Here, we are studying the safety and efficacy of AV regimen for 2-years in patients with previously treated CLL/SLL.

Study Design and Methods:

AVENUE-2 is a single-institution, investigator-initiated trial (NCT04941716) conducted at Fred Hutchinson Cancer Center/University of Washington in Seattle, WA.

Major eligibility criteria:

Patients (≥ age 18) with CLL/SLL who meet the treatment indication per iwCLL 2018 criteria and have measurable disease are eligible if they had at least one prior line of therapy. Adequate marrow and organ function are required. Prior treatment with a BTKi or venetoclax is allowed unless patients had progressive disease while on a BTKi or venetoclax or if they were intolerant to acalabrutinib or venetoclax. Prior malignancy (or any other malignancy requiring active treatment), except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, low-grade prostate carcinoma (Gleason grade ≤ 6) or other cancer from which the subject has been disease free for ≥ 2 years or which will not limit survival to < 3 years. Patients with significant cardiovascular disease, absorption issues, active bleeding or history of bleeding diathesis or required/currently receiving anticoagulation with warfarin or equivalent vitamin K antagonists were excluded.

Objectives:

Primary Objective: To determine the rate of undetectable measurable residual disease (uMRD4 by flow cytometry) in peripheral blood after 26 cycles of treatment with AV.

Secondary objectives: To determine the clinical efficacy (ORR, CR, PR, PFS and OS) per iwCLL 2018 criteria and to assess the toxicity of the combination.

Tertiary Objective(s): To determine the rate of uMRD4 in the bone marrow at the end of treatment (26 cycles). Rate of uMRD6 (using clonoSEQ with sensitivity of 1:10^-6) in peripheral blood at the end of treatment (26 cycles) in patients with negative uMRD4. To evaluate the occurrence of tumor lysis syndrome (TLS) and the rate of downgrading the TLS risk category after the lead-in phase (3 months treatment with acalabrutinib).

Exploratory Objective(s): To monitor the emergence of BTKi and venetoclax resistance mutations before, during, and at the end of treatment.

Treatment schedule: The duration of treatment on the study is 26 cycles (28-day cycles). Acalabrutinib will start on cycle 1 and continue for a total of 26 cycles (cycle 1-26). Venetoclax will start on cycle 4 (dose ramp-up) and continue for a total of 23 cycles (cycle 4-26). Treatment will stop after cycle 26 irrespective of the MRD status.

Statistical considerations: The plan is to enroll 20 patients. Analysis of primary, secondary, and exploratory endpoints will be descriptive.

Summary:

The AVENUE-2 trial studies the 2-year fixed-duration treatment with acalabrutinib and venetoclax (AV) in previously treated CLL/SLL patients. Clinical responses including uMRD4 at the end of treatment and the safety profile will be assessed. The trial is actively enrolling at Fred Hutchinson Cancer Center/University of Washington.