Trial in progress: A phase 3, multi-regional, open-label, randomized study of tirabrutinib vs rituximab and temozolomide in participants with Relapsed/Refractory primary central nervous system lymphoma

Abstract Background and Significance Primary central nervous system lymphoma (PCNSL) is a rare, highly aggressive form of non-Hodgkin lymphoma localized to the brain, spinal cord, cerebrospinal fluid, and/or eyes. Although patients with PCNSL generally respond to standard high-dose methotrexate (HD-MTX) induction, 10-30% of patients have refractory disease. In a large, 1002-patient database, median progression-free survival (PFS) was 1 year, and 2-year PFS was only 36% (Houillier et al. Neurology. 2020). No approved therapies for relapsed or refractory (r/r) disease exist in the US or EU, and NCCN guideline-recommended treatment options based on small studies can be divided into high-dose chemotherapy (HDC) with or without autologous stem cell transplantation (ASCT), whole brain radiation therapy (WBRT), or treatment with better-tolerated regimens such as temozolomide (TMZ) or lenalidomide with or without rituximab (RTX), RTX, pomalidomide, ibrutinib, or pemetrexed. Although few patients with r/r PCNSL are treated with HDC-ASCT or WBRT (17% and 10%, respectively Houillier et al. Neurology. 2020), TMZ is a recommended treatment option per NCCN (with or without RTX) and EHA-ESMO guidelines. The available options are associated with substantial toxicity, limited efficacy, and short duration of response (DOR). Tirabrutinib is a highly potent, selective second-generation Bruton's tyrosine kinase inhibitor (BTKi) approved in Japan, Taiwan, and South Korea for patients with r/r PCNSL. The primary results from the Phase 2 PROSPECT study (NCT04947319) conducted in the United States reported an overall response rate (ORR) of 67% in patients with r/r PCNSL. Tirabrutinib was generally well tolerated in this population without major cardiac toxicity; the most frequent any-grade treatment-related adverse events were anemia (19%), maculopapular rash (17%), fatigue (15%), lymphocyte count decreased (15%), neutrophil count decreased (15%), pruritus (15%), and rash (15%). The aim of this Phase 3 study is to confirm the relative clinical benefits of tirabrutinib monotherapy compared with the standard treatment option with RTX-TMZ combination therapy (R-TMZ) in r/r PCNSL. Study Design and Methods This Phase 3, multi-regional, open-label, randomized study will enroll approximately 132 adult patients with r/r PCNSL. Eligibility criteria include pathologically confirmed diagnosis of r/r B-cell PCNSL with at least 1 prior HD-MTX–based therapy for PCNSL, at least 1 brain lesion with a minimum diameter ≥1 cm using gadolinium-enhanced MRI without systemic lymphoma, Eastern Cooperative Oncology Group performance status ≤2, life expectancy ≥3 months, and adequate bone marrow, renal, and hepatic function. Patients with intraocular PCNSL with no brain lesions, non–B-cell PCNSL, systemic presence of lymphoma, prior BTKi treatment, and who were refractory to TMZ with or without RTX-containing regimens in their last PCNSL treatment are ineligible. Patients will be randomized 2:1 to receive tirabrutinib 480 mg once daily in the fasted state as monotherapy or R-TMZ combination therapy; intravenous RTX (375 mg/m2) will be administered on Day (D) 1 and oral TMZ (150 mg/m2/day) will be administered in the fasted state on D1-5 from Cycle (C)1 through C6. After C1, TMZ dose can be escalated to 200 mg/m2 in the absence of grade ≥2 toxicities or reduced to 100 mg/m2 if there is toxicity, based on investigator discretion. Randomization will be stratified by age (70 vs ≥70 y) and r/r status from last therapy (relapsed vs refractory). Patients will receive study drug in 28-day cycles until they complete planned treatment (6 cycles) in the R-TMZ arm, develop progressive disease as determined by a blinded independent review committee (BIRC) assessment according to International Primary Central Nervous System Lymphoma Collaborative Group (IPCG) criteria, experience unacceptable toxicity, or withdraw consent. The primary endpoint is PFS based on BIRC assessment per IPCG criteria. Key secondary endpoints are ORR by BIRC and overall survival. Other secondary endpoints include complete response rate, best overall response, time to response, time to complete response, DOR, and disease-free survival, all by BIRC. Tumor response assessment will be performed at screening, C2D1, C3D1, then every 2 cycles through C25D1, and every 4 cycles thereafter according to IPCG criteria. ClinicalTrials.gov registration number: NCT07104032.