Background: Mutations in isocitrate dehydrogenase 1 (mIDH1) occur in up to 20% of intrahepatic cholangiocarcinomas (CC), leading to accumulation of 2-hydroxyglutarate (2-HG) and epigenetic dysregulation, promoting oncogenesis. Ivosidenib (IVO; AG-120), a first in-class, oral, targeted inhibitor of the mIDH1 enzyme, showed improved progression-free survival and a positive trend in overall survival versus placebo (PBO) in ClarIDHy, a global, phase 3, multicenter, double-blind study (Abou-Alfa et al. ESMO 2019 LBA10_PR; NCT02989857). Methods: Patients (pts) with unresectable or metastatic mIDH1 CC were randomized 2:1 to IVO (500 mg once daily in continuous 28-day cycles) or matched PBO, stratified by number of prior systemic therapies (1 or 2). Crossover from PBO to IVO was permitted at radiographic progressive disease. Blood samples for PK/PD analyses, a secondary endpoint, were collected predose, 0.5, 2, and 4 h postdose on day (D) 1 of cycles (C) 1–2, predose and 2 h postdose on D15 of C1–2, and predose on D1 from C3 onwards. Plasma IVO and 2-HG were measured using validated or qualified LC-MS/MS methods. Results: As of 31Jan2019, 185 pts were randomized to IVO (n = 124) or PBO (n = 61); 35 pts crossed over to IVO. PK/PD analysis was available from 156 pts receiving IVO. IVO was absorbed rapidly following single and multiple oral doses; exposure, as measured by C_max and AUC, was higher at C2D1 than after a single dose, with low accumulation. Plasma IVO reached steady state within C1 of daily dosing. In pts receiving IVO, baseline mean plasma 2-HG concentration was reduced from 1108 ng/mL to 97.7 ng/mL at C2D1, close to levels in healthy subjects (72.6±21.8 ng/mL). 2-HG inhibition was robust and persistent up to Cycle 19. An average 2-HG inhibition of 75.0% (up to 97.3%) was observed at steady-state after multiple IVO administrations. No plasma 2-HG decreases were seen with PBO. Analyses of plasma 2-HG levels and association with clinical outcomes will be presented. Conclusions: In pts with advanced mIDH1 CC, oral IVO 500 mg once-daily demonstrated good exposure, and maintained the inhibition of 2-HG to levels observed in healthy subjects, whereas 2-HG remained elevated with PBO. Clinical trial information: NCT02989857