Phase 3 Randomized Study of Tirabrutinib Versus Rituximab-Temozolomide in Relapsed/Refractory Primary Central Nervous System Lymphoma

The primary objective is to compare the efficacy of tirabrutinib monotherapy with rituximab-temozolomide in relapsed/refractory primary central nervous system lymphoma, measured by progression-free survival according to blinded Independent Review Committee assessment using International Primary Central Nervous System Lymphoma Collaborative Group criteria. This endpoint is clinically relevant because it assesses disease control over time. Secondary objectives are to compare overall response rate, overall survival, and detailed clinical efficacy outcomes, including complete response rate, best overall response, time to response, time to complete response, duration of response, and disease-free survival. Additional objectives include evaluation of corticosteroid requirements and safety profile between treatment arms.

The trial population consisted of 58 participants with relapsed/refractory primary central nervous system lymphoma. Both female and male participants were included, and the age range was broad, covering pediatric and adult patients. The population was selected based on written informed consent, a pathology-confirmed diagnosis of B-cell PCNSL, relapsed or refractory disease after at least one prior high-dose methotrexate-based therapy, measurable brain lesions on gadolinium-enhanced MRI, an Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate bone marrow, renal, and hepatic function. Participants were also required to comply with contraceptive requirements. No additional information was provided regarding general health status beyond these eligibility requirements, and no lifestyle details such as diet, physical activity, or habits were reported.

This Phase 3, multi-regional, open-label, randomized, controlled study evaluates tirabrutinib monotherapy versus rituximab-temozolomide combination therapy in participants with relapsed or refractory primary central nervous system lymphoma. The primary objective is to assess efficacy by progression-free survival using blinded Independent Review Committee assessment according to International Primary Central Nervous System Lymphoma Collaborative Group criteria. After written informed consent, the screening visit confirms eligibility, including pathology-confirmed B-cell disease, prior high-dose methotrexate-based therapy, measurable brain lesions on gadolinium-enhanced MRI, ECOG performance status of 0 to 2, adequate organ function, and agreement to contraceptive requirements. Eligible participants are randomized to one of the study treatments and followed through scheduled study visits for efficacy and safety assessments, including disease evaluation and corticosteroid dose review. The end-of-study visit is performed at completion of participation or after early discontinuation. The overall trial is planned from 2026-05-30 to 2029-10-15, and expected participant involvement is up to the duration of individual study follow-up within this period. Early termination may occur for progressive disease, death, initiation of subsequent anticancer therapy, withdrawal of consent, or other protocol-defined reasons.

Tirabrutinib was administered as an oral tablet at a dose of 480 mg. The treatment was given by oral use as monotherapy. The study compared this experimental regimen with a rituximab-temozolomide combination regimen.

Rituximab was administered as a solution for infusion by intravenous infusion at a dose of 375 mg/m2. The comparator arm included Truxima 500 mg concentrate for solution for infusion and Truxima 100 mg concentrate for solution for infusion. Temozolomide was administered as hard capsules by oral route at a dose of 200 mg/m2. The comparator arm included Temomedac 20 mg hard capsules, Temomedac 5 mg hard capsules, and Temomedac 100 mg hard capsules. The rituximab-temozolomide regimen was used as the non-experimental treatment in the study.

Efficacy will be assessed by progression-free survival based on blinded Independent Review Committee assessment according to International Primary Central Nervous System Lymphoma Collaborative Group criteria, defined as the time from randomization to progressive disease or death due to any cause, whichever occurs first. Secondary efficacy assessments will include overall response rate, overall survival, complete response rate, best overall response, time to response, time to complete response, duration of response, disease-free survival, and change from baseline in corticosteroid dose, all evaluated by blinded Independent Review Committee assessment according to International Primary Central Nervous System Lymphoma Collaborative Group criteria where specified.