CTIM-19. 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 GLIOMA: TRIAL IN PROGRESS

Abstract BACKGROUND Vorasidenib (VOR) is an oral, brain-penetrant dual inhibitor of isocitrate dehydrogenase 1/2 mutant (mIDH1/2) enzymes. VOR is being investigated in a phase 3 study in residual or recurrent grade 2 non-enhancing gliomas, in which interim analysis showed VOR significantly improved progression-free survival and delayed time to next intervention. A prior neoadjuvant perioperative study in recurrent, non-enhancing grade 2/3 gliomas showed that VOR treatment was associated with interferon signal activation and increased T-cell infiltration, suggesting 2-hydroxyglutarate suppression may prime the tumor immune microenvironment for immune checkpoint blockade. This study (NCT05484622) evaluates the safety and tolerability of VOR+pembrolizumab to determine the recommended combination dose (RCD) of VOR (safety lead-in phase) and evaluates CD3+ T-cell infiltration in tumors following a 28-day preoperative period. METHODS Enrollment: US patients with recurrent or progressive grade 2/3 mIDH1 R132H glioma. Key eligibility: measurable enhancing disease, Karnofsky Performance Status ≥70, resectable (perioperative phase only). Following a March 2024 protocol amendment, inclusion criteria were expanded to include patients with oligodendroglioma in addition to patients with astrocytoma. Safety lead-in dosing: Cohort 1, VOR 40mg QD+pembrolizumab 200mg Q3W in 21-day cycles. The perioperative phase is randomized 1:1:1 to preoperative combination, VOR 40mg QD, or untreated for 28 (+7) days; all patients could opt to receive the VOR RCD in combination with pembrolizumab 200mg Q3W postoperatively. Primary objectives: safety and tolerability of VOR RCD administered with pembrolizumab; CD3+ T-cell infiltration in resected tumors following presurgical treatment with combination compared to untreated tumors. RESULTS Seven patients with recurrent or progressive enhancing grade 2/3 astrocytoma with an mIDH1 R132H were dosed in the safety lead-in phase. No dose-limiting toxicities were detected during this phase. CONCLUSION VOR 40mg QD+pembrolizumab 200mg Q3W was confirmed as the RCD for the perioperative phase. This phase was opened to enrollment in May 2023, and recruitment is ongoing.