Rituximab, Acalabrutinib, and Durvalumab for Primary Central Nervous System Lymphoma: A Single-arm, Phase 1b, Multi-center Study.

Abstract

Primary central nervous system lymphoma (PCNSL) has a poor prognosis and limited treatment options. This phase 1b study evaluates the combination therapy of rituximab, acalabrutinib, and durvalumab (RAD) in relapsed/refractory PCNSL. The study was conducted with dose escalation (3+3 design) and expansion phases. Acalabrutinib (100 mg) was administered once or twice daily for dose determination; rituximab (375 mg/m²) and durvalumab (1500 mg) were treated every four weeks for up to 8 cycles. Primary endpoints assessed safety, tolerability, and the recommended phase 2 dose; secondary endpoints evaluated treatment responses and survival outcomes. Seventeen patients, including 15 with relapsed/refractory diseases, were enrolled between February 2021 and April 2024. One patient was unevaluable. No dose-limiting toxicities (DLTs) were observed in the 4-week observation period for 6 evaluable patients at dose levels 1 and 2. In the expansion cohort, 10 additional patients received dose level 2. Treatment-related adverse events (AEs) occurred in 14 patients (82%), with 59% experiencing grade 3/4 events, mainly including neutropenia, skin reactions, and transaminitis. Among 16 evaluable patients, the overall response rate was 62.5%, and complete response rate was 12.5%. All responders received dose level 2. Median overall survival (OS) and progression-free survival (PFS) were 11.9 and 4.3 months, respectively. Improved outcomes were observed for responders versus non-responders (OS, 20.6 vs. 10.2 months; PFS, 5.2 vs. 2.1 months). The RAD regimen is feasible for treating PCNSL patients and shows potential as a therapeutic option. Further large-scale trials are needed to confirm its clinical efficacy.