A phase 3 trial of acalabrutinib, obinutuzumab and venetoclax compared to obinutuzumab and venetoclax in patients with high risk chronic lymphocytic leukemia

Introduction: Fixed-duration treatment with targeted agents, particularly venetoclax and obinutuzumab (GVe), have led to significantly improved treatment outcome as compared to chemoimmunotherapy (CIT) in patients (pts) with chronic lymphocytic leukemia (CLL) and genetic risk factors, such as TP53 aberrations and complex karyotype (CKT). However, pts with high risk still progress earlier than pts with low risk CLL. Recently published results of the phase 2 CLL2-GIVe study suggest that a triple combination of monoclonal antibodies with a BTK- and BCL2-inhibitor is highly active in pts with TP53 aberrant disease. Within the phase 3 GAIA/CLL13 study recruiting only patients without TP53 aberrations, the triple combination of obinutuzumab, ibrutinib and venetoclax was superior to CIT, but not to GVe. A comparison in high risk CLL is missing yet, so further investigation in a randomized phase 3 trial is warranted. The CLL16 trial of the GCLLSG was set up to compare GVe to the triple combination of acalabrutinib, obinutuzumab and venetoclax (GAVe). Methods: The CLL16 trial is a prospective, open-label, multicenter, randomized, phase 3 trial comparing GVe to GAVe in previously untreated pts with high risk CLL exhibiting a 17p deletion, TP53 mutation or CKT. 178 pts are randomly assigned to 12 cycles of venetoclax plus 6 cycles of obinutuzumab with or without 14 cycles of acalabrutinib. In the triplet arm, pts with persisting measurable residual disease after cycle 14 will continue treatment with acalabrutinib for up to 24 cycles. Screening procedures include local immunophenotyping and testing for TP53 aberrations by FISH and sequencing, as well as central testing for CKT. The primary endpoint of the study is progression-free survival (PFS). The 3-year PFS rate for GVe is assumed with 71% and it is expected to increase with GAVe to 86%. The superiority of GAVe will be estimated based on a required hazard ratio of 0.44, with 48 events providing approximately 80% power. Secondary endpoints include event-free survival, overall survival and safety as assessed by CTCAE V5.0. Results: The study recruits in 80 study sites in Germany and Austria. 19 pts with a median age of 62 years (range 46–75) and a median CIRS score of 3 (range 1–6) have already been included, eight of the pts are female. Four serious adverse events (SAEs) have been reported so far: one infusion related reaction, one increase of liver enzymes and one ascites, all of them CTC grade 3, and furthermore one CTC grade 2 COVID infection. A Data Monitoring Committee is established for safety overview in this study, after the first meeting the study can continue as planned. Conclusions: The objective of this trial is to prove the superiority of a triple combination with GAVe over a standard treatment with GVe in pts with CLL and adverse risk factors defined as TP53 alterations and CKT. No safety concerns have been identified to date and the study continues as planned. The research was funded by: AstraZeneca Keywords: chronic lymphocytic leukemia (CLL), combination therapies, ongoing trials Conflicts of interests pertinent to the abstract. N. Kutsch Honoraria: AstraZeneca, BMS, Roche Research funding: AstraZeneca, Gilead Educational grants: AbbVie, AstraZeneca, Celgene, Gilead, Janssen A. M. Fink Honoraria: AstraZeneca Research funding: AstraZeneca, Celgene Educational grants: AbbVie S. Robrecht Honoraria: AstraZeneca E. Tausch Honoraria: AbbVie, AstraZeneca, BeiGene, Janssen, Roche Research funding: AbbVie, AstraZeneca, BeiGene, Janssen, Roche Educational grants: AbbVie, AstraZeneca, BeiGene, Janssen, Roche C. Schneider Honoraria: AbbVie, AstraZeneca C. Wendtner Honoraria: Roche, AbbVie, AstraZeneca, Janssen, Lilly, Gilead, BeiGene Research funding: Roche, AbbVie, AstraZeneca, Janssen, Lilly, Gilead, BeiGene Educational grants: Roche, AbbVie, AstraZeneca, Janssen, Lilly, Gilead, BeiGene G. Chakupurakal Honoraria: AstraZeneca, Sanofi, Novartis I. Schwaner Honoraria: AbbVie, Amgen, AstraZeneca, BeiGene, Janssen, Lilly, Roche K. Fischer Consultant or advisory role AstraZeneca Honoraria: AbbVie, Roche K. Kreuzer Honoraria: AbbVie, Roche, AstraZeneca Research funding: AbbVie, Roche, AstraZeneca Other remuneration: Speaker's Bureau: AbbVie, Roche, AstraZeneca M. Ritgen Honoraria: AstraZeneca, AbbVie, Roche, Janssen, Lilly S. Stilgenbauer Consultant or advisory role AbbVie, Acerta, Amgen, AstraZeneca, BeiGene, BMS, Gilead, Roche, Janssen, Novartis, Sunesis, Verastem Honoraria: AbbVie, Acerta, Amgen, AstraZeneca, BeiGene, BMS, Gilead, Roche, Janssen, Novartis, Sunesis, Verastem Research funding: AbbVie, Acerta, Amgen, AstraZeneca, BeiGene, BMS, Gilead, Roche, Janssen, Novartis, Sunesis, Verastem Educational grants: AbbVie, Acerta, Amgen, AstraZeneca, BeiGene, BMS, Gilead, Roche, Janssen, Novartis, Sunesis, Verastem M. Hallek Consultant or advisory role AbbVie, Roche, Janssen, AstraZeneca, Gilead, BeiGene Honoraria: AbbVie, Roche, Janssen, AstraZeneca, Gilead, BeiGene Research funding: AbbVie, Roche, Janssen, AstraZeneca, Gilead, BeiGene B. Eichhorst Honoraria: AbbVie, AstraZeneca, Janssen, Roche Research funding: AbbVie, AstraZeneca, Janssen, Roche