Zanubrutinib monotherapy and combination therapy for relapsed and refractory primary CNS lymphoma (PRiZM+): study protocol for a multi-centre, open-label, Bayesian phase II platform trial

Primary central nervous system lymphoma is a high-grade malignancy of the brain or spinal cord. Relapsed or refractory disease (rrPCNSL) is common and confers a poor prognosis. Effective new therapies are urgently needed to improve survival, whilst minimising toxicities in this vulnerable patient group. Bruton tyrosine kinase inhibition is active against rrPCNSL. The combination of CD19-targeting with tafasitamab and immunomodulation with lenalidomide is effective in systemic large B-cell lymphoma. PRiZM + is a platform trial designed to identify novel therapies with sufficient activity against rrPCNSL that warrant further investigation in randomised controlled trials. PRiZM + is an open-label, phase II platform trial. Cohorts of 20 patients will be recruited to sequential treatment arms. Key eligibility criteria include CD20-positive large B-cell lymphoma confined to the CNS, relapsed or refractory disease following at least one cycle of high-dose methotrexate, disease measurable by MRI, and no previous exposure to the experimental drug classes. Patients with impaired functional status or cognitive dysfunction due to PCNSL are eligible. The primary outcome is overall response rate (ORR) according to local MRI assessment after two cycles of treatment. Secondary outcomes include quality of response including central review, survival, and safety. Exploratory outcomes investigate pharmacokinetics, genomic and transcriptomic profiling, and molecular and imaging correlates of response. Patients recruited to cohort 1 receive zanubrutinib monotherapy, 160 mg twice daily, in continuous 28-day cycles. Cohort 2 investigates the addition of 12 cycles of tafasitamab (weekly, then fortnightly doses of 12 mg/kg) and lenalidomide (25 mg daily, days 1 to 21) to continuous zanubrutinib. Treatment continues until disease progression, unacceptable side effects, or patient choice. Bayesian statistics will be used to determine the probability that the true ORR to each experimental regimen is sufficiently high to warrant further investigation. PRiZM+ accelerates the development of novel therapies for rrPCNSL, an area of high unmet need. The platform design maximises efficiency, as different regimens are sequentially tested using a master protocol and a network of expert sites. The eligibility criteria and schedule of assessments promote participation and validity. Translational sub-studies will bring further insights into PCNSL biology, including informing future therapeutic approaches. ISRCTN90634455.