Alliance A041702: A Randomized Phase III Study of Ibrutinib Plus Obinutuzumab Versus Ibrutinib Plus Venetoclax and Obinutuzumab in Untreated Older Patients (≥ 70 Years of Age) with Chronic Lymphocytic Leukemia (CLL)
Authors: Woyach Jennifer , Ruppert Amy S. , Perez Gabriela , Booth Allison M , Feldman Diane , Dib Elie G , Jatoi Aminah , Le-Rademacher Jennifer , Heerema Nyla A. , Lozanski Gerard , Little Richard , Ding Wei , Hill Brian T. , Stone Richard M. , Mandrekar Sumithra J , Byrd John C. 
Published: November 2019

Background
The phase 3 trial A041202 solidified the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib as a standard of care for older patients with previously untreated CLL by showing superior progression-free survival (PFS) as compared with bendamustine plus rituximab. While ibrutinib is highly effective in previously untreated CLL, there do remain disadvantages to this therapy, specifically the low rate of complete response (CR) and therefore the need for continuous administration, which increases cost and toxicity. In older patients especially, toxicities with ibrutinib are common; 17% of patients had atrial fibrillation and 29% had grade 3 or higher hypertension on the A041202 study. Thus, strategies to decrease the exposure time to ibrutinib are of interest. Venetoclax is an inhibitor of BCL2 that has shown efficacy as a single agent and in combination with monoclonal antibodies, specifically the anti-CD20 monoclonal antibody obinutuzumab for patients with previously untreated CLL. One significant advantage to venetoclax is the ability to produce CRs and minimal residual disease negative (MRD-) responses. In this study, we compare ibrutinib plus obinutuzumab (IO) to ibrutinib plus venetoclax plus obinutuzumab (IVO) with a response-dependent discontinuation. While other studies have been designed with the goal of discontinuation of ibrutinib through combinations with venetoclax, no other study has been presented using a response-dependent discontinuation strategy.
Study Design and Methods
A041702 is a randomized phase 3 study led by the Alliance for Clinical Trials in Oncology that is currently enrolling through the NCI National Clinical Trials Network (NCTN).
CLL patients age 70 years or older who are previously untreated and in need of therapy are eligible. Previous treatment of autoimmune complications with steroids or rituximab is allowed. Patients must have intermediate- or high-risk Rai stage, ECOG performance status 0-2, ANC ≥ 1000/mm3 unless due to marrow involvement, and platelets ≥ 30,000/mm3. CrCl must be ≥ 40 mL/min and AST/ALT ≤ 2.5x upper limit of normal. Patients with hepatitis B must have undetectable viral load, and patients must not have an intercurrent illness that is expected to limit survival to < 5 years. Warfarin and strong inhibitors or inducers of CYP3A4/5 are not permitted.
Patients are initially preregistered to the study and submit a peripheral blood sample for central FISH analysis of del(17p). Patients who are registered are randomized 1:1 to Arm 1 (IO) or Arm 2 (IVO), and are stratified by Rai stage and presence of del(17p). IO consists of I daily starting cycle 1 day 1, and O dosed as standard starting cycle 1 day 1 and continuing to cycle 6 day 1. IVO consists of IO as in Arm 1, with V starting cycle 3 day 1 with standard 5-week ramp-up and continuing until cycle 14 day 28. At the end of 14 cycles, patients in both arms undergo response evaluation with central peripheral blood and bone marrow MRD testing. Patients on IO then continue I indefinitely. Patients on IVO who are in a bone marrow MRD- CR discontinue all therapy, and those who are not continue I indefinitely.
The primary objective of the study is to compare PFS between IO and IVO using the strategy of response-dependent discontinuation. There is 90% power to detect a hazard ratio for PFS of 0.55 (corresponding to 5-year PFS rates of 70% and 82.187% for IO and IVO, respectively), at a one-sided significance level of 0.025 by a log-rank test. This design requires 128 events and 431 total evaluable patients assuming uniform accrual over the course of 3 years and minimum follow-up of 5 years. The study includes two interim analyses for superiority when 50% and 75% of the expected number of events have been observed and three interim analyses for futility when 25%, 50%, and 75% of the expected number of events have been observed.
Conclusions
A041702 is an ongoing phase 3 clinical trial using a novel response-dependent discontinuation method. Results of this study have the potential to change the standard of care for older patients with previously untreated CLL. The study is expected to accrue for 3 years beginning January 2019, and we welcome participation from sites throughout the NCTN.
Support: U10CA180821, U10CA180882, UG1CA189823, U24CA196171; U10CA180820 (ECOG-ACRIN); https://acknowledgments.alliancefound.org; ClinicalTrials.gov Identifier: NCT03737981

Disclosures
Woyach: Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Lozanski:Beckman Coulter: Research Funding; Boehringer Ingelheim: Research Funding; Stemline Therapeutics Inc.: Research Funding; Genentec: Research Funding. Ding:Merck: Research Funding; DTRM Biopharma: Research Funding. Hill:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding; TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Stone:Argenx, Celgene, Takeda Oncology: Other: Data and Safety Monitoring Board/Committee: ; Novartis, Agios, Arog: Research Funding; AbbVie, Actinium, Agios, Argenx, Arog, Astellas, AstraZeneca, Biolinerx, Celgene, Cornerstone Biopharma, Fujifilm, Jazz Pharmaceuticals, Amgen, Ono, Orsenix, Otsuka, Merck, Novartis, Pfizer, Sumitomo, Trovagene: Consultancy. Byrd:Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Acerta: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; BeiGene: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Genentech: Research Funding; BeiGene: Research Funding; Genentech: Research Funding; Acerta: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau.