Randomised Phase II study of acalabrutinib in combination with R-CHOP treatment for diffuse large B-cell lymphoma confirms safety and unimpaired treatment delivery

Abstract Introduction The phase Ib/II ACCEPT study (NCT03571308) assessed acalabrutinib (A), a second generation Bruton's tyrosine kinase inhibitor with enhanced kinase selectivity, in combination with R-CHOP in a single arm study for patients (pts) with de novo DLBCL. The maximum tolerated dose was not reached. At the recommended phase II dose of A 100mg bd, R-CHOP+A resulted in in a 95% 24-month progression-free survival (PFS). Efficacy was seen across all cell-of-origin phenotypes (COO). In older pts there was no difference in safety and no compromise of R-CHOP, in contrast to the PHOENIX trial of ibrutinib with R-CHOP. Methods REMoDL-A is a stratified open-label UK multicentre randomised phase II study. Eligible pts had newly diagnosed DLBCL requiring full course R-CHOP. Initially, all pts received 1 cycle of R-CHOP chemotherapy prior to 2:1 randomisation between R-CHOP+A or R-CHOP for a further 5 cycles. The randomisation was stratified by molecular subtyping by gene expression profiling (GEP), International Prognostic Index (IPI) and age. In March 2023, Pola-R-CHP was commissioned in the UK for pts with DLBCL and an IPI score of 2-5. REMoDL-A was therefore amended such that pts with IPI 0-1 continued to be randomised but those with IPI 2-5 were, all assigned to R-CHOP+A. Bayesian dynamic borrowing of historical information via a Meta-Analytic Prior (MAP) approach will be used to incorporate R-CHOP treated patients' data from the REMoDL-B trial (ISRCTN51837425) into the efficacy analysis. The primary endpoint is progression free survival (PFS). Secondary endpoints include PFS by COO and genomic subtypes, duration of response, overall survival, event free survival, toxicity and quality of life. The trial was powered to detect a hazard ratio of 0.67 with 90% power with a maximum 1-sided significance level of 20% and required ~375 patients. REMoDL-A is a UK Blood Cancer Research Network multicentre trial coordinated by Southampton Clinical Trials Unit and endorsed by CRUK (C30423/A29680). Trial registration: NCT04546620. Results From Nov 2021 to May 2025, 261 eligible pts from 46 sites were enrolled into REMoDL-A. 54 pts were randomised to R-CHOP and 119 to R-CHOP+A. A further, 82 pts with IPI score 2-5 were directly allocated to R-CHOP+A following the amendment (6 pts GEP failed and were allocated to R-CHOP). Median age was 64 years (range 17-83); 76% stage III/IV; 63% elevated LDH; 30% B symptoms; 44% bulk; 20% high IPI; 55% high-intermediate IPI. By GEP, 30% had Activated B-cell molecular profile, 45% Germinal Centre B-cell, 6% Molecular High Grade, 16% unclassified and 3% GEP fail. At the data cutoff on 19May2025 221/261 pts had finished treatment. 93% (54/58) of pts on R-CHOP and 93% (152/163) on R-CHOP+A had completed all 6 cycles of R-CHOP treatment. 85% of pts. allocated to R-CHOP+A received all 5 cycles of A. 18% of pts had a dose reduction in A. Relative dose intensity (RDI) of all R-CHOP components were similar by arm and age with similar RDI values observed to those in REMoDL-B. Median RDI was ≥ 97% for all R-CHOP components for pts aged≥ 65 years on RCHOP+A and was not significantly different by arm (p-values>0.05). A similar proportion of pts experienced an adverse event (AE) of any grade; R-CHOP 95% vs. 96% on R-CHOP+A (grade≥3 48% vs 52%). The same % of pts experienced at least one serious AE (SAE) on R-CHOP vs R-CHOP+A; 41%. The most common AEs of any grade were fatigue (51%) constipation (45%) and nausea (39%), both similar by arm. There was slightly more neutropenia in pts treated with R-CHOP+A than R-CHOP (all grade 16% vs 12%: Grade≥3 10% vs 7%), but less febrile neutropenia (4% vs 7%) and all cause infection was similar (14% vs 15%). The same pattern was observed by age and grade≥3 (differences not significantly different). There was more grade≥3 gastrointestinal toxicity observed in pts aged≥65 treated with R-CHOP+A than R-CHOP (13% vs 0%, p-value 0.07) but no difference in younger pts (7%). There were 5 fatal AEs across all arms, only 1 was considered possibly related to R-CHOP+A (bronchial pneumonia). Conclusions The addition of A to R-CHOP does not impact upon dose delivery of R-CHOP across all age groups. Some additional GI toxicity was observed in older pts but overall, the AE profile was similar by arm and age. The final PFS trial results will be available in 2027. R-CHOP+A is also being assessed in the randomised ESCALADE (NCT04529772) trial for younger patients with non-GC DLBCL.

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