Majic: A Phase 3 Prospective, Multicenter, Randomized, Open-Label Trial of Acalabrutinib Plus Venetoclax Versus Venetoclax Plus Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Abstract Background: Novel targeted agents, namely Bruton tyrosine kinase inhibitors (BTKis), B-cell leukemia/lymphoma-2 inhibitors (BCL-2is), and anti-CD20 monoclonal antibodies, have advanced chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) treatment beyond traditional chemoimmunotherapy. While 1-year fixed-duration venetoclax-obinutuzumab (VO) is effective, about 25% of patients do not achieve peripheral blood (PB) undetectable minimal residual disease (uMRD). This regimen contains intravenous therapy with obinutuzumab, which presents potential additional toxicities such as infusion reactions and tumor lysis syndrome as well as the potential inconvenience of an intravenous drug. Moreover, patients with higher-risk genomic features such as TP53-aberrant disease or unmutated IGHV have shorter progression-free survival (PFS) than lower-risk cohorts. Whether extending the course of venetoclax beyond 1 year in patients with detectable MRD improves PFS remains unknown. Preclinical data support combining BTKi and BCL-2i, and recent studies with the first-generation BTKi ibrutinib plus venetoclax (IV) have demonstrated deep/durable responses with uMRD rates similar to VO in previously untreated patients with CLL; however, toxicities of this regimen (e.g., cardiac events, neutropenia, etc.) may be challenging, particularly in older patients and those with comorbidities. Acalabrutinib, a highly selective next-generation BTKi, showed an improved safety profile versus ibrutinib in a phase 3 head-to-head trial in relapsed/refractory CLL, and was very effective and well tolerated in a phase 2 study combined with VO. We hypothesize that time-limited doublet therapy with acalabrutinib plus venetoclax (AV) would induce PFS and levels of uMRD similar to those of VO in treatment-naïve (TN) CLL/SLL irrespective of genomic risk features and offer the convenience and favorable tolerability of an all-oral regimen. Moreover, we hypothesize that MRD-guided therapy duration approach will help to define the optimal duration of therapy for both VO and AV. Methods: MAJIC is a phase 3, open-label, randomized, multicenter, global study evaluating AV vs VO in patients aged ≥18 years with TN CLL/SLL. The primary objective of the MAJIC trial is to evaluate investigator-assessed PFS of MRD-guided AV vs MRD-guided VO in a noninferiority design. Key secondary endpoints include uMRD rates at sequential time points, complete and overall response rate, event-free survival, overall survival, quality of life/patient-reported outcomes, and safety. After the screening period, approximately 600 patients will be randomized (1:1, with stratification by age, TP53, and IGHV status) to receive either AV: acalabrutinib (100 mg twice daily with 2 lead-in cycles) then combined with venetoclax introduced at cycle 3 (including dose ramp-up) for 12 cycles, or VO: intravenous obinutuzumab at standard dosing with venetoclax initiated per standard dosing at day 22 cycle 1 (including dose ramp-up) for 6 cycles, followed by 6 cycles of venetoclax monotherapy, for a total of 12 cycles of venetoclax therapy in both arms. Patients with detectable MRD (10 -5 sensitivity by clonoSEQ ® next-generation sequencing) at that time will continue therapy for an additional 12 cycles with either AV (acalabrutinib-containing cohort) or venetoclax monotherapy (for the VO cohort) for a total of 24 months of therapy in both arms, unless they experience progressive disease or unacceptable toxicity. All patients will discontinue study therapy after 24 months, regardless of MRD status at that time point. Response assessments including MRD will occur at the end of 12 months of venetoclax (and 24 months if receiving a second year of therapy) in both arms, and patients with PB uMRD by clonoSEQ at 10 -5 sensitivity at that time point will discontinue therapy. Further correlative studies such as association of baseline genetic markers with clinical outcomes and MRD kinetics will be conducted. Key exclusion criteria are clinically significant cardiovascular disease, history of bleeding diathesis, and history of significant cerebrovascular disease/event. Patient enrollment is to begin at the end of 2021. Summary: This trial in progress is to inform the choice of which of these doublet therapy approaches might be most appropriate for patients with previously untreated CLL/SLL without restriction by genetic background or age. Disclosures Davids: Eli Lilly and Company: Consultancy; BMS: Consultancy, Research Funding; Merck: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy; AbbVie: Consultancy; Surface Oncology: Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Research to Practice: Consultancy; Adaptive Biotechnologies: Consultancy; Takeda: Consultancy; BeiGene: Consultancy; Astra-Zeneca: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Mato: DTRM BioPharma: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Genmab: Research Funding; Nurix: Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; MSKCC: Current Employment; LOXO: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding. Hum: AstraZeneca: Current Employment. Wargo: AstraZeneca: Current Employment. Emeribe: AstraZeneca: Current Employment, Current holder of stock options in a privately-held company. Shahkarami: Astrazeneca: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Sokolowski: AbbVie: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Biondo: Roche: Current holder of individual stocks in a privately-held company; Genentech, Inc.: Current Employment. Abhyankar: Genentech, Inc: Current Employment; Roche: Current equity holder in publicly-traded company. Hermann: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Sharman: AbbVie: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; BMS: Consultancy; Lilly: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Consultancy; TG Therapeutics: Consultancy. OffLabel Disclosure: Investigational study

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