Background: Low-grade gliomas (LGGs; WHO grade II) are incurable and ultimately progress to high-grade gliomas. The current treatment options consist of surgery followed by observation (“watch and wait”) for pts with lower risk for disease progression or post-operative chemo-radiotherapy (high-risk population). There are no approved targeted therapies. IDH1 and IDH2 mutations (mIDH1/2) occur in approximately 70% and 4% of LGGs, respectively, and promote tumorigenesis via neomorphic production of D-2-hydroxyglutarate (2-HG). VOR, an oral, potent, reversible, brain-penetrant inhibitor of mIDH1/2, was evaluated in 76 pts with glioma in two phase 1 studies (dose escalation and perioperative) and was associated with a favorable safety profile at doses of < 100 mg daily. Preliminary clinical activity was observed in non-enhancing glioma pts in both studies, most recently with an objective response rate (ORR) of 30.8% at 50 mg QD in the perioperative study and > 90% 2-HG suppression at this dose level relative to untreated control samples (Mellinghoff et al., J Clin Oncol 2019). Methods: Approximately 366 pts will be randomized 1:1 to VOR (50 mg QD) or matched placebo and stratified by 1p19q status (intact vs co-deleted). Key eligibility criteria include: age ≥12 years; grade 2 oligodendroglioma or astrocytoma (per WHO 2016 criteria) not in need of immediate treatment and without high-risk features; centrally confirmed mIDH1/2 status; ≥1 prior surgery for glioma within the previous 5 years but no other anticancer therapy; Karnofsky performance status ≥80%; and centrally confirmed measurable, non-enhancing disease evaluable by magnetic resonance imaging. Crossover from placebo to the VOR arm is permitted upon centrally confirmed radiographic progression per RANO-LGG criteria. Primary endpoint is progression-free survival assessed by independent review. Secondary endpoints include safety and tolerability, tumor growth rate assessed by volume, time to next intervention, ORR, overall survival, quality of life assessed by the Functional Assessment of Cancer Therapy–Brain questionnaire, and plasma pharmacokinetics. Exploratory endpoints include seizure activity and neuro-cognitive function. Clinical data will be reviewed regularly throughout the study by an independent data monitoring committee. The study is currently enrolling pts in the US, with additional countries planned (NCT04164901). Clinical trial information: NCT04164901.