Trial in progress: Treatment of CNS lymphoma with zanubrutinib and tislelizumab: A phase ib/II investigator-initiated study

Abstract Background: Outcomes of patients with relapsed / refractory (r/r) central nervous system (CNS) lymphoma are extremely poor, especially in patients who progress during or soon after completing induction chemotherapy. Novel strategies which are effective and tolerable in a heavily pre-treated population are needed. The vast majority of primary CNS lymphomas (PCNSL) are diffuse large B-cell lymphoma with most being non-germinal centre (non-GCB) subtype.[1] In non-GCB DLBCL, mutations in the B-cell receptor pathway are frequently found especially in CD79B and MYD88.[2] Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib, have shown significant response rates in PCNSL of 55-60% but progression free survival is often short (median ~2 months).[3] Furthermore, copy number gains at the programmed death (PD) ligand 1 / programmed death ligand 2 locus, namely chromosome 9p24.1, have been described suggesting that immune evasion may play a role in primary CNS lymphoma.[4] Pre-clinical mouse models of lymphoma have shown synergy between BTK inhibitors and checkpoint inhibitors suggesting this may be an effective combination therapy in CNS lymphoma.[5,6] This study ('BICICL’; ACTRN12622000547741) combines zanubrutinib, BTK inhibitor, with tislelizumab, a monoclonal antibody against PD-1, in patients with CNS lymphoma. Study design and methods: This is an open label multicentre phase Ib/II trial. The trial is currently recruiting and 15 out of 30 patients with CNS lymphoma have been recruited from 3 Australian sites. Eligibility includes patients aged >18 years with r/r high-grade B-cell CNS lymphoma with performance status of 0-2. A subset of patients with secondary CNS lymphoma with isolated CNS relapse and treatment-naïve patients unsuitable for chemotherapy are included. Patients with low-grade CNS lymphoma, T-cell lymphoma or double or triple hit DLBCL are excluded. Treatment consists of 1 cycle (28 days) of zanubrutinib monotherapy (320mg daily) and then, from cycle 2, combination therapy with tislelizumab (200mg IV 3-weekly) and zanubrutinib ongoing (every 21 days) for up to 2 years. The primary endpoint is ORR at 8 weeks from commencement of combination therapy. Secondary endpoints include: ORR and CR rate after 4 weeks of zanubrutinib monotherapy, safety of combination therapy, time to treatment failure, progression free survival and overall survival, and patient-reported outcomes as measured by EORTC QLQ-C30 and EORTC QLQ-BN20. Exploratory endpoints include: CSF pharmacokinetics of zanubrutinib, blood, CSF and tissue biomarkers including molecular profiling, circulating tumour cell-free DNA and mutation testing. Study assessments include: MRI brain, biomarker blood and CSF collection and patient reported outcome measures at baseline and then every 4 cycles. Response assessment according to the immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria. Safety assessments before each cycle until 30 days after administration of the final dose of study drug according to CTCAEv5.0. Futility analysis occurs after 12 patients have been recruited with assessment of the primary endpoint with futility reached if the ORR is <50%. Kaplan-Meier analysis is used for survival probabilities.