Background: Patients (pts) with advanced biliary tract cancers (BTC) have a poor prognosis despite systemic chemotherapy. Gemcitabine (G) and cisplatin (C) is a standard first-line systemic therapy with a reported overall response rate (ORR) of 26% and median overall survival (OS) of 11.7 months (mo). CPI-613/Devimistat (D) is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and a-ketoglutarate dehydrogenase enzymes of the tricarboxylic (TCA) cycle, preferentially within the mitochondria of cancer cells augmenting chemotherapeutic cytotoxicity. Methods: An investigator-initiated, multi-institutional phase 1b/2 trial is underway across 10 sites in the US investigating the combination of G 1000 mg/m², C 25 mg/m² and D (dose levels: (-1) 500, (1) 1000, (2) 1500 and (3) 2000 mg/m²) (GCD) on days 1 and 8 every 21 days in pts with previously untreated advanced BTC. The primary objective of the phase 1b portion (n = 20 pts; TiTE-CRM methodology) was to determine the recommended phase 2 dose (RP2D). The primary objective of the ongoing phase 2 portion (n = 48-58 pts; 2:1 randomization with Bayesian control arm) is to determine the best ORR with an alternative hypothesis of 43% (null of 25%); with 80% power and one-sided alpha of 0.05. Secondary objectives include evaluation of progression-free survival (PFS), OS, and safety. Exploratory objectives include targeted exome/ transcriptomic analysis using tissue, and metabolomic analysis using plasma (pre-, on- and post-treatment). Results: 20 pts were enrolled on phase 1b; median age 65 years (range 43-75), ECOG PS 0/1 (9/11), male/female (11/9), Caucasian (85%), intrahepatic/hilar/distal cholangiocarcinoma and gallbladder (9/5/3/3), and metastatic/locally advanced stage (15/5). CPI-613 dose level assignments were 1 pt each for (-1) and (1), 2 pts on (2), and 16 pts on (3). Median follow-up was 9.4 mos and median number of cycles was 9. Only 1 pt had dose-limiting toxicity (grade 2 creatinine elevation). RP2D for CPI-613 was 2000 mg/m². In phase 1b, ORR was 40% (7 PR, 1 CR). Median PFS not estimable (NE) but probability of PFS at 9 months was 68.1% [95% CI, 38.1%-85.8%]. Median OS is 16.3 months [95% CI, 9.1-NE]. One locally advanced pt was resected with pathologic CR. Conclusions: The combination of GCD was well tolerated and demonstrates encouraging efficacy with ORR, PFS and OS in phase 1b. The randomized phase 2 portion of the trial is open and accruing patients. Clinical trial information: NCT04203160.