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
Year: 2025
Type: conference-abstract
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.
Source: Blood
Authors: Hyungwoo Cho, Jaewon Hyung, Dong Won Baek, Ho Sup Lee, Hye Jin Kang, Gyeong-Won Lee, Jeong-Ok Lee, Myung-Won Lee, Sung-Nam Lim, Sung Yong Oh, Ho-Jin Shin, Kwai Han Yoo, Young Rok Do, Jae-Yong Kwak, Yong-pyo Lee, Deok-Hwan Yang, Dok Hyun Yoon
Institutions: Asan Medical Center, University of Ulsan, Kyungpook National University Hospital, Kyungpook National University, Kyungpook National University Medical Center, Kosin University, Korea Institute of Radiological and Medical Sciences, Gyeongsang National University, Gyeongsang National University Hospital, Seoul National University, Seoul National University Bundang Hospital, Chungnam National University, Chungnam National University Hospital, Inje University Haeundae Paik Hospital, Dong-A University Hospital, Pusan National University Hospital, Gachon University Gil Medical Center, Gachon University Medical Center, Keimyung University Dongsan Medical Center, Keimyung University Dongsan Hospital, Keimyung University, Jeonbuk National University Hospital, Jeonbuk National University, Chungbuk National University, Chungbuk National University Hospital, Chonnam National University, Chonnam National University Hwasun Hospital
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W7108739199
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