CTNI-34. PHASE 1B SAFETY RESULTS OF VORASIDENIB IN COMBINATION WITH TEMOZOLOMIDE IN PATIENTS WITH MUTANT IDH1 OR IDH2 GLIOMA

Abstract Vorasidenib is an oral, brain-penetrant, dual inhibitor of mutant isocitrate dehydrogenase 1/2 (mIDH1/2) approved as monotherapy for grade 2 mIDH1/2 gliomas following surgery. Combining vorasidenib with temozolomide (TMZ) may exploit the molecular vulnerabilities of higher grade mIDH1/2 gliomas while controlling more rapidly proliferative tumor cells. No clinical study has yet reported the safety or efficacy of an IDH inhibitor in combination with standard-of-care (SOC) chemotherapy. Phase 1b of this study (NCT06478212) was designed to evaluate the safety and tolerability of vorasidenib + TMZ and establish the recommended combination dose (RCD) for Phase 2. Phase 1b recruited participants with grade 2, 3 or 4 mIDH1/2 gliomas who were eligible for TMZ as post-radiotherapy adjuvant therapy or as treatment for first recurrence after prior radiotherapy and/or chemotherapy. Participants received 40 mg vorasidenib QD + SOC TMZ in 28-day cycles. RCD was determined using a Bayesian optimal interval design. As of May 6, 2025, seven participants were dosed (median age: 36 years [range 29–67]; female n=4; astrocytoma n=5, oligodendroglioma n=2; grade 3 n=5, grade 4 n=2; frontline setting n=5, recurrent setting n=2; previous TMZ exposure n=3). All participants reported a treatment-emergent adverse event (AE); 2 participants experienced grade ≥3 AEs, and 3 required dose reduction (vorasidenib n=1, due to grade 2 alanine transaminase elevation [AE of special interest]; TMZ n=2, due to myelosuppression). No dose-limiting toxicities were reported. All participants remain on vorasidenib + TMZ as of May 6, 2025. Based on safety review committee evaluation, vorasidenib 40 mg QD + SOC TMZ was confirmed as RCD. In Phase 2, approximately 35 participants with newly diagnosed grade 4 mIDH1/2 astrocytoma who have completed radiotherapy + concurrent TMZ will be enrolled and receive vorasidenib + TMZ as post-radiotherapy adjuvant therapy. Phase 2 will evaluate the safety and preliminary efficacy of the combination therapy.