Phase I/II study of zanubrutinib in combination with rituximab, ifosfamide, carboplatin, and etoposide (ZR-ICE) in Relapsed/Refractory diffuse large B-cell lymphoma: Results of the Phase I portion

Abstract Background The prognosis of relapsed or refractory systemic diffuse large B-cell lymphoma (R/R DLBCL) is poor. Furthermore, the outcomes are particularly dismal for R/R central nervous system (CNS) lymphomas (primary CNS lymphoma [PCNSL] or secondary CNS lymphoma [SCNSL]). R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) chemotherapy has shown efficacy in these patients but the durability of response is limited. Recently, BTK inhibitors have demonstrated encouraging efficacy outcomes in systemic R/R non-GCB DLBCL and R/R CNS lymphomas. This single-arm, open-label, phase I/II study aims to evaluate the efficacy, safety and feasibility of combining zanubrutinib, a second-generation BTK inhibitor, with R-ICE (ZR-ICE) in two cohorts: cohort A, R/R systemic non-GCB DLBCL; and cohort B, R/R CNS lymphomas (PCNSL or SCNSL). Here, we report the safety and efficacy results from the phase I portion of the study. Methods Patients with R/R systemic non-GCB DLBCL or R/R CNS lymphomas were treated with zanubrutinib at 2 dose levels (160 mg [dose level 1] or 320 mg daily [dose level 2]) in combination with R-ICE. The R-ICE regimen consisted of rituximab 375 mg/m² IV (D1), ifosfamide 1670 mg/m² IV (D1-3), etoposide 100 mg/m²/day IV (D1-3), and carboplatin AUC 5 IV (D2). Patients who were candidates for upfront autologous stem cell transplantation (ASCT) and achieved a complete response (CR) or partial response (PR) after the third cycle of ZR-ICE proceeded to upfront ASCT. For patients who are not considered as candidate for upfront ASCT, 6 cycles of ZR-ICE were administered. For cohort B patients who achieved CR or PR after 6 cycles of ZR-ICE or 3 cycles of ZR-ICE followed by ASCT, zanubrutinib 320 mg daily was administered as maintenance treatment for 24 months or until disease progression, unacceptable toxicity, or patient refusal. The standard 3+3 dose escalation design was used to determine the recommended phase 2 dose (RP2D) of ZR-ICE. The primary endpoint of the phase I portion was determining the maximum tolerated dose and RP2D of ZR-ICE. Results A total of 12 patients enrolled in the phase I portion of this study; 7 patients with R/R systemic non-GCB DLBCL, and 5 patients with R/R CNS lymphoma (3 PCNSL and 2 SCNSL). The median age was 66 years (range, 51–72), and 6 patients were male (50.0%). Most of the patients had non-GCB subtype (n = 11, 91.7%), the median number of prior lines of therapy was 1 (range, 1–3), and 5 patients (41.7%) had refractory disease to the last line of therapy. No dose-limiting toxicity (DLT) was observed at dose level 1 (n = 6). At dose level 2, 2 DLTs occurred among 6 enrolled patients (grade 4 neutropenia lasting more than 7 days; grade 3 tumor hemorrhage that did not resolve within 21 days). One patient withdrew consent before completing the DLT evaluation period due to grade 3 skin rash. Thus, dose level 1 was determined as the recommended phase 2 dose (RP2D). The most frequent grade 3 or 4 adverse events were neutropenia (58.3%), thrombocytopenia (50.0%), and anemia (25.0%). Febrile neutropenia was observed in one patient (8.0%). Treatment response was evaluable in 9 patients, and the best overall response rate and the complete response rate were 100.0% and 77.8%, respectively. With a median follow-up duration of 11.9 months (95% CI, 7.6–NA), 1-year progression-free survival rate was 60.6% (95% CI, 36.8–99.8) and 1-year overall survival rate was 60.6% (95% CI, 36.8–99.8), respectively. Four patients proceeded to upfront ASCT after 3 cycles of ZR-ICE, and 3 of these patients (75%) remained in remission as of data cut-off (May 30, 2025). Conclusion ZR-ICE demonstrated a favorable safety profile with manageable toxicities in patients with R/R systemic non-GCB DLBCL and R/R CNS lymphomas, and dose level 1 (zanubrutinib 160 mg daily) was established as the RP2D. The combination showed highly promising efficacy with overall response rate of 100.0% and 77.8% complete response rate. These results support the ongoing phase II portion of this study.