ABCL-607 Trial in Progress: Phase 1 Study With Dose Expansion of Acalabrutinib and Durvalumab (MEDI 4736) in Primary Central Nervous System Lymphoma

Primary central nervous system lymphoma (PCNSL) is difficult to treat due to limited therapies that cross the blood−brain barrier. Bruton's tyrosine kinase (BTK) inhibition and checkpoint inhibition have both shown promise in treatment as PCNSL often is of non-germinal center phenotype and has aberrancies in the PD-1/PD-L1 pathway. Single-agent BTK inhibitors as well as immune checkpoint inhibitors have shown activity in PCNSL. There is also evidence in preclinical models and clinical studies in other B-cell lymphomas of synergy between BTK and checkpoint inhibition. We seek to evaluate the combination of durvalumab, an anti−PD-L1 monoclonal antibody, and acalabrutinib, a second-generation BTK inhibitor, in patients with relapsed/refractory PCNSL. This is a multicenter, phase 1, investigator-initiated trial with dose expansion enrolling at Washington University in St. Louis and The Ohio State University. The primary objective is to determine safety and tolerability of the combination of durvalumab with acalabrutinib in patients with PCNSL. The primary endpoints are safety based on frequency of toxicities and tolerability as defined by tolerable dose (defined as dose with <2 DLTs); secondary endpoints include overall response rate, time to response, duration of response, progression-free survival, and overall survival. Key eligibility criteria are: (1) biopsy-proven PCNSL relapsed/refractory to 1 prior line of therapy or ineligible for high-dose methotrexate; and (2) ECOG PS 0-2 with adequate hematologic and organ function. Patients with secondary CNS lymphoma or primary vitreoretinal lymphoma will be excluded. The phase 1 portion will have a 3+3 design studying the combination of acalabrutinib and durvalumab. All patients will receive durvalumab at 1500 mg IV Q4W, and acalabrutinib will be evaluated at 2 doses (DL1: 100 mg BID, DL2: 200 mg BID). There will be an expansion cohort of 12 patients at the optimal dose determined by the phase 1 portion. Treatment with the combination will continue until disease progression or intolerable toxicity. Correlative studies include assessment of response via PET/MRI imaging and evaluation of pharmacokinetics of acalabrutinib via blood and cerebrospinal fluid levels. The study was activated on September 15, 2022, and the dose-expansion portion is currently enrolling. Supported by AstraZeneca. NCT04462328.