Randomized, Phase III Study of Early Intervention with Venetoclax and Obinutuzumab Versus Delayed Therapy with Venetoclax and Obinutuzumab in Newly Diagnosed Asymptomatic High-Risk Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Evolve CLL/SLL Study (SWOG S1925;NCT#04269902)

ABSTRACT

Background: Currently, asymptomatic patients with CLL/SLL are observed without treatment until development of symptoms or cytopenias. Historically, early intervention studies in patients with CLL/SLL with non-specific chemoimmunotherapy agents have not resulted in an overall survival (OS) benefit and have resulted in toxicity. The introduction of targeted therapies, such as venetoclax (an oral BCL2 inhibitor;V) and obinutuzumab (an intravenous anti-CD20 monoclonal antibody;O), have provided tolerable/efficacious options for patients with CLL. In the CLL14 study, symptomatic patients with CLL receiving frontline therapy with VO had longer progression-free survival (PFS) and deeper remissions [more undetectable minimal residual disease (uMRD)] compared with those receiving chlorambucil and O (Fischer 2019). The CLL-International Prognostic Index (CLL-IPI;Table 1) is a validated prognostic model to predict which patients are at highest risk of a shorter time to first therapy and shorter OS. A score of ≥4 is considered high-risk on this scale. We aim to use VO as early intervention in asymptomatic, high-risk CLL patients, assessed by CLL-IPI, to potentially improve OS and thus alter the natural history of the disease. Methods: On 12/14/20, we activated the S1925 study (NCT#04269902 ) for adult patients with CLL or SLL, who were diagnosed within 12 months of enrollment. Eligible patients have a CLL-IPI score ≥4 (Table 1) or complex cytogenetics (≥3 cytogenetic abnormalities) and do not meet any criteria for initiation of treatment by the International Working Group for CLL (IWCLL;Hallek 2018) guidelines. Enrolled patients are randomized in a 21 manner to early versus delayed (at the time IWCLL indication for treatment is met) therapy with VO (Figure 1). VO is administered as previously described (Fischer 2019). The primary endpoint is OS. We hypothesize that early intervention with VO will improve the rate of 6-year OS from 60% to 80%. This design requires 222 eligible patients for 88% power (2-sided a=0.05) for the primary comparison. To allow for 10% ineligibility, we will enroll 247 patients. Estimated accrual time is 4 years. Secondary endpoints include rates of response, PFS, and relapse-free survival;safety;time to second CLL-directed therapy;and quality of life (assessed by FACT-Leukemia). As COVID19 is an infection with particularly high morbidity and mortality in patients with CLL, incidence of this infection and complications including death will be recorded and compared between patients followed on the early versus delayed intervention arms. The primary translational objective is to evaluate the prognostic association between OS and peripheral blood MRD status at 15 months after treatment initiation by flow cytometry. Secondary translational objectives include describing the association of other clinical outcomes, baseline prognostic factors, and IWCLL-defined response with MRD status at multiple timepoints. Current Status At the time of submission, 7 patients have been registered and randomized per protocol. Accrual is ongoing. [Formula presented] Disclosures Stephens Adaptive Membership on an entity's Board of Directors or advisory committees;TG Therapeutics Membership on an entity's Board of Directors or advisory committees;Epizyme Membership on an entity's Board of Directors or advisory committees;Beigene Membership on an entity's Board of Directors or advisory committees;Innate Pharma Membership on an entity's Board of Directors or advisory committees;AstraZeneca Consultancy;CSL Behring Consultancy;Celgene Consultancy;Novartis Research Funding;Abbvie Consultancy;JUNO Research Funding;Arqule Research Funding;Mingsight Research Funding;Karyopharm Membership on an entity's Board of Directors or advisory committees, Research Funding. Moseley BioSight Ltd Consultancy. Hill AbbVie Consultancy, Honoraria, Research Funding;Gentenech Consultancy, Honoraria, Research Funding;Beigene Consultancy, Honoraria, Research Funding;Pfizer Consultancy, Honoraria;Kite, Gilead Company Consultancy, Honoraria, Other Travel Support, Research Funding;Karyopharm Consultancy, Honoraria, Research Funding;AstraZenica Consultancy, Honoraria;Celgene (BMS) Consultancy, Honoraria, Research Funding;Novartis Consultancy, Honoraria, Research Funding;Epizyme Consultancy, Honoraria;Incyte/Morphysis Consultancy, Honoraria, Research Funding. Pagel Pharmacyclics/AbbVie Consultancy;Actinium Pharmaceuticals Consultancy;Incyte/MorphoSys Consultancy;BeiGene Consultancy;Epizyme Consultancy;Kite, a Gilead Company Consultancy;AstraZeneca Consultancy;Gilead Consultancy;MEI Pharma Consultancy. Shadman Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab Research Funding;Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune, Mustang Bio and Atara Biotherapeutics Consultancy. Danilov Genentech Consultancy, Honoraria, Research Funding;Takeda Oncology Research Funding;TG Therapeutics Consultancy, Research Funding;Abbvie Consultancy, Honoraria;Beigene Consultancy, Honoraria;Pharmacyclics Consultancy, Honoraria;Gilead Sciences Research Funding;Bristol-Meyers-Squibb Honoraria, Research Funding;Rigel Pharm Honoraria;Bayer Oncology Consultancy, Honoraria, Research Funding;SecuraBio Research Funding;Astra Zeneca Consultancy, Honoraria, Research Funding. Mato Pharmacyclics LLC, an AbbVie Company Consultancy, Research Funding;DTRM BioPharma Consultancy, Research Funding;Acerta/AstraZeneca Consultancy, Research Funding;Sunesis Consultancy, Research Funding;BeiGene Consultancy, Research Funding;Johnson and Johnson Consultancy, Research Funding;Genentech Consultancy, Research Funding;AbbVie Consultancy, Research Funding;Nurix Research Funding;Genmab Research Funding;LOXO Consultancy, Research Funding;Janssen Consultancy, Research Funding;AstraZeneca Consultancy;Adaptive Biotechnologies Consultancy, Research Funding;MSKCC Current Employment;TG Therapeutics Consultancy, Other DSMB, Research Funding. Brander Juno Therapeutics/Celgene/Bristol Myers Squibb Research Funding;Pfizer Consultancy, Other Biosimilars outcomes research panel;TG Therapeutics Consultancy, Research Funding;Novartis Research Funding;ArQule/Merck Consultancy;Verastem Consultancy;BeiGene Research Funding;ArQule Research Funding;NCCN Other panel member;AstraZeneca Research Funding;Pharmacyclics LLC, an AbbVie Company Consultancy, Research Funding;LOXO Research Funding;Ascentage Research Funding;Genentech Consultancy, Research Funding;DTRM Research Funding;MEI Pharma Research Funding;AbbVie Consultancy, Other informCLL registry steering committee, Research Funding. Coutre Janssen Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Pharmacyclics Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;AbbVie Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;AstraZeneca Consultancy, Membership on an entity's Board of Directors or advisory committees;Beigene Consultancy, Membership on an entity's Board of Directors or advisory committees, Other Data Safety Monitoring Committee, Research Funding;Genentech Consultancy, Membership on an entity's Board of Directors or advisory committees;Acerta Other Data Safety Monitoring Committee, Research Funding. O'Brien Kite, Regeneron, Acerta, Caribou, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis Research Funding;Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc., Vaniam Group LLC, AbbVie, Alexion, Verastem, Juno Therapeutics, Vida Ventures, Autolus, Johnson and Johnson, Merck, Bristol Myers Squibb, NOVA Research Company, El Lill Consultancy. Erba AbbVie Inc;Agios Pharmaceuticals Inc;Bristol Myers Squibb;Celgene, a Bristol Myers Squibb company;Incyte Corporation;Jazz Pharmaceuticals Inc;Novartis Speakers Bureau;AbbVie Inc Other Independent review committee;AbbVie Inc;Agios Pharmaceuticals Inc;ALX Oncology;Amgen Inc;Daiichi Sankyo Inc;FORMA Therapeutics;Forty Seven Inc;Gilead Sciences Inc;GlycoMimetics Inc;ImmunoGen Inc;Jazz Pharmaceuticals Inc;MacroGenics Inc;Novartis;PTC Therapeutics Research Funding;AbbVie Inc;Agios Pharmaceuticals Inc;Astellas;Bristol Myers Squibb;Celgene, a Bristol Myers Squibb company;Daiichi Sankyo Inc;Genentech, a member of the Roche Group;GlycoMimetics Inc;Incyte Corporation;Jazz Pharmaceuticals Inc;Kura Oncology;Nov Other Advisory Committee. OffLabel Disclosure The trial studies early intervention with venetoclax and obinutuzumab in patients with CLL/SLL who are asymptomatic and observation would be standardly recommended.