Data from Devimistat in combination with gemcitabine and cisplatin in biliary tract cancer: Pre-clinical evaluation and phase 1b multicenter clinical trial (BilT-04)

AbstractPurpose: Devimistat (CPI-613®) is a novel inhibitor of tumoral mitochondrial metabolism. We investigated effect of devimistat in vitro and in a phase 1b clinical trial in patients with advanced biliary tract cancer (BTC). Patients and Methods: Cell viability assays of devimistat +/- GC were performed and effect of devimistat on mitochondrial respiration via oxygen consumption rate (OCR) was evaluated. A phase 1b/2 trial was initiated in patients with untreated advanced BTC. In phase 1b, devimistat was infused over 2 hours in combination with GC on days 1 and 8 every 21 days with a primary objective to determine recommended phase 2 dose (RP2D). Secondary objectives included safety, overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: In vitro, devimistat with GC had synergistic effect on two cell lines. Devimistat significantly decreased OCR at higher doses and in arms with divided dosing. In the phase 1b trial, 20 patients received a median of 9 cycles (range 3-19). One DLT was observed and the RP2D of devimistat was determined to be 2000 mg/m2 in combination with GC. Most common grade 3 toxicities included neutropenia (n=11, 55%), anemia (n=4, 20%), and infection (n=3, 15%); with no grade 4 toxicities. After a median follow-up of 15.6 months, ORR is 45% and median PFS is 10 months (95% CI, 7.1 – 14.9). Median OS is not yet estimable. Conclusion: Devimistat in combination with GC is well tolerated and has an acceptable safety profile in patients with untreated advanced BTC.