Remodl‐a: a randomised phase ii evaluation of molecular guided therapy for diffuse large b‐cell lymphoma (dlbcl) with acalabrutinib — ongoing trial

Introduction: R-CHOP remains the standard of care in DLBCL yet for up to 40% of patients (pts.) it fails either through refractory lymphoma or relapse after achieving an initial remission. In the phase Ib/II ACCEPT study (NCT03571308), acalabrutinib (A), a second generation Bruton Tyrosine Kinase inhibitor with enhanced kinase selectivity and a potential for better tolerability, was assessed in combination with R-CHOP in patients with de novo DLBCL. There were no dose-limiting toxicities and the maximum tolerated dose was not reached, At the recommended phase II dose of A 100 mg bd, R-CHOP+A demonstrated a 95% 24 month progression-free survival (PFS). In older patients there was no difference in safety and no compromise of delivery of full course R-CHOP. Efficacy was preserved across cell-of-origin and genomic sub-groups. The REMoDL-A study now builds upon these findings to examine efficacy of R-CHOP+A against R-CHOP. Methods: REMoDL-A is a stratified open-label, multicentre, randomised phase II study. Eligible patients have untreated histologically confirmed DLBCL requiring full course R-CHOP. All patients receive 1 cycle of R-CHOP chemotherapy. FFPE diagnostic pathology blocks have molecular profiling and are assigned subtype Germinal Centre B-cell, Activated B-Cell, Molecular High Grade, Unclassifiable, or failed RNA extraction (GEP Fail). Patients whose biopsies are successfully sub-typed are randomised 2:1 between R-CHOP+A (Arm B) or R-CHOP for a further 5 cycles (Arm A). The randomisation is stratified by molecular subtype, International Prognostic index and age. The primary endpoint for the study is progression free survival (PFS) in the modified intention to treat (ITT) population (non-Fail ITT population). Secondary endpoints include PFS related to the cell of origin and genomic subtypes, duration of response, overall survival, event free survival, toxicity and quality of life. Exploratory analyses will investigate how dynamic molecular (including CTDNA) and PET based biomarkers predict risk and can be incorporated into a dynamic risk prediction model. An early interim analysis is planned to explore safety in the ≥65 years population. The trial is powered to detect a hazard ratio of 0.668 with 90% power with 1-sided significance level of 20%. The number of patients to be randomised is 453 (302:151 per arm). To date 155 patients have been recruited. Of the FFPE diagnostic pathology blocks that have undergone molecular profiling, failed RNA extraction (GEP fail) has occurred in only 4 patients. This is a UK National Cancer Research Institute multicentre trial coordinated by Southampton Clinical Trials Unit. Molecular profiling is performed in HMDS, Leeds. Trial registration: ISRCTN14251143/ NCT04546620 The trial has been supported by an investigator initiated grant and drug access from AstraZeneca (ESR-19-20180) and has endorsement from Cancer Research UK (CRUKE/19/017). Keywords: aggressive B-cell non-Hodgkin lymphoma, combination therapies, ongoing trials Conflicts of interests pertinent to the abstract G. P. Collins Honoraria: Roche, AstraZeneca C. Fox Consultant or advisory role Abbvie, AstraZeneca, Atarabio, BMS, GenMab, Gilead/Kite, Incyte, Lilly, Morphosys, Ono, Roche, Takeda Research funding: Beigene Educational grants: Roche, BMS G. Griffiths Honoraria: AstraZeneca P. Johnson Honoraria: Takeda, InCyte, Genmab, Epizyme A. J. Davies Consultant or advisory role Celgene, Roche, Kite, Takeda, Incyte Honoraria: Celgene, Roche, Kite, Takeda Research funding: Celgene, Roche, Kite, Takeda, Janssen, GSK Educational grants: Celgene, Roche