RTID-02. A PHASE 1, SAFETY LEAD-IN AND RANDOMIZED, OPEN-LABEL, PERIOPERATIVE STUDY OF VORASIDENIB COMBINED WITH PEMBROLIZUMAB IN RECURRENT OR PROGRESSIVE ENHANCING IDH-1 MUTANT ASTROCYTOMAS: TRIAL IN PROGRESS

Abstract

Abstract BACKGROUND Astrocytomas are a subset of diffuse gliomas defined by intact 1p and 19q arms. Isocitrate dehydrogenase 1 mutations (mIDH-1) occur in ~70% of grade 2/3 gliomas, leading to accumulation of 2-hydroxyglutarate (2-HG). Vorasidenib (VOR) is an oral, brain-penetrant dual inhibitor of mIDH1/2 enzymes being investigated in a phase 3 study in non-enhancing gliomas. In an ongoing perioperative study in grade 2/3 gliomas, treatment with VOR was associated with interferon (IFN) signaling activation and increased T-cell infiltration, suggesting adequate 2-HG suppression renders the tumor immune microenvironment for immune checkpoint blockade, and supporting investigation of VOR in combination with an anti-programmed cell death (PD-1) antibody such as pembrolizumab in recurrent IDH-mutant gliomas treatment. This study will evaluate the safety and tolerability of VOR plus pembrolizumab to determine the recommended combination dose (RCD) of VOR, and evaluate CD3+ T-cell infiltration in tumors following preoperative treatment with the combination or VOR. METHODS This study will enroll ~70 patients with recurrent or progressive Grade 2/3 mIDH-1 astrocytoma. Key eligibility: enhancing disease, mIDH1-R132H, Karnofsky Performance Status ≥70, eligible for resection (perioperative phase only). Safety lead-in: Cohort 1 (Nf~6): VOR 40 mg QD plus pembrolizumab 200 mg Q3W in 21-day cycles. Based on DLT evaluation, cohort 2 may enroll an additional ~6 patients at VOR 20 mg QD plus pembrolizumab 200 mg Q3W. Randomized, perioperative phase (Nf~60): randomized 1:1:1 to the combination, VOR 40 mg QD, or untreated for 4 weeks preoperatively; all patients can opt to receive the combination postoperatively. Primary objectives: safety and tolerability, and VOR RCD with pembrolizumab; CD3+ T-cell infiltration in resected tumors following presurgical treatment with the combination compared to untreated tumors. Secondary objectives include clinical activity, VOR PK in tumor and blood, 2-HG concentration in tumors, and overall survival. This study will be active in the United States.