UCSF

Abstract Mutations in isocitrate dehydrogenase (mIDH) are common in lower-grade glioma (LGG; mIDH1, 80%; mIDH2, 4%) and lead to epigenetic and genetic changes that promote oncogenesis via production of the oncometabolite 2-hydroxyglutarate (2-HG). AG-120 (ivosidenib) is a first-in-class oral mIDH1 inhibitor associated with a favorable safety profile in an ongoing phase 1 study in 66 glioma patients. AG-881 is a brain-penetrant oral mIDH1/2 inhibitor with an acceptable safety profile at dose levels <100 mg in an ongoing phase 1 study in 52 glioma patients. In an orthotopic mIDH1-R132H glioma model, ivosidenib and AG-881 suppressed 2-HG by 85% and 98%, respectively. This multicenter, open-label, phase 1 study is designed to measure brain tumor 2-HG concentration and drug exposure at two dose levels each of ivosidenib or AG-881 in patients with mIDH1 LGG undergoing craniotomy (NCT03343197). The study will enroll ~45 adults with recurrent WHO 2016-classified Grade 2 or 3 mIDH1 oligodendroglioma/astrocytoma eligible for resection. Key eligibility criteria include: nonenhancing disease by T2 FLAIR MRI, mIDH1-R132H, and Karnofsky Performance Score 60. Cohort 1 patients will be randomized 2:2:1 to 500 mg QD ivosidenib (n=10), 50 mg QD AG-881 (n=10), or no treatment (n=5). Based on the safety, 2-HG, and pharmacokinetic data from cohort 1, cohort 2 may enroll an additional 20 patients randomized 1:1 to 250 mg BID ivosidenib or 10 mg QD AG-881. Patients randomized to either drug will receive treatment for 4 weeks preoperatively and may continue treatment after surgery. Untreated patients can opt to be randomized to either drug postoperatively. The primary endpoint is 2-HG concentration in surgically resected tumors. Secondary endpoints include safety, tumor and plasma pharmacokinetics, and RANO LGG response. Exploratory endpoints include 2-HG and pharmacokinetics in cerebrospinal fluid, and 2-HG magnetic resonance spectroscopy. This study is currently enrolling in the USA.