Phase 1b vorasidenib (dual mutant IDH1/IDH2 inhibitor) plus lomustine alkylator in recurrent IDH-mutant glioma

This Phase 1b, open-label, dose-escalation study (VALIENT) is designed to test whether vorasidenib—a brain-penetrant small-molecule mutant IDH1/IDH2 inhibitor marketed as Voranigo by Servier—can be combined safely with lomustine (CCNU), an oral DNA-alkylating nitrosourea from longstanding generic manufacturers, in recurrent/progressive IDH1- and/or IDH2-mutant glioma. The main goal is to define an “optimal” vorasidenib dose for a future Phase 2 efficacy study while lomustine is kept at 110 mg/m² every 42 days, with planned vorasidenib dose levels of 40 mg, 20 mg, and 10 mg. Eligible patients include progressive, recurrent grade 2–4 astrocytoma or oligodendroglioma in the 2nd line or later setting, where IDH mutations are common (particularly in lower-grade diffuse gliomas). The key scientific/commercial angle is extending an IDH-targeted therapy with proven disease-control in earlier-grade 2 disease into a salvage combination intended to deepen or prolong benefit beyond chemotherapy alone. In this population, today’s care after recurrence often includes re-resection when feasible, radiation if not previously given, and systemic therapy such as temozolomide or lomustine (sometimes with bevacizumab for symptom control), with no uniformly effective targeted option for later-line disease.