Data from Devimistat in Combination with Gemcitabine and Cisplatin in Biliary Tract Cancer: Preclinical Evaluation and Phase Ib Multicenter Clinical Trial (BilT-04)

Abstract

<div>AbstractPurpose:<p>Devimistat (CPI-613) is a novel inhibitor of tumoral mitochondrial metabolism. We investigated the effect of devimistat <i>in vitro</i> and in a phase Ib clinical trial in patients with advanced biliary tract cancer (BTC).</p>Patients and Methods:<p>Cell viability assays of devimistat ± gemcitabine and cisplatin (GC) were performed and the effect of devimistat on mitochondrial respiration via oxygen consumption rate (OCR) was evaluated. A phase Ib/II trial was initiated in patients with untreated advanced BTC. In phase Ib, devimistat was infused over 2 hours in combination with GC on days 1 and 8 every 21 days with a primary objective to determine the recommended phase II dose (RP2D). Secondary objectives included safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).</p>Results:<p><i>In vitro</i>, devimistat with GC had a synergistic effect on two cell lines. Devimistat significantly decreased OCR at higher doses and in arms with divided dosing. In the phase Ib trial, 20 patients received a median of nine cycles (range, 3–19). One DLT was observed, and the RP2D of devimistat was determined to be 2,000 mg/m<sup>2</sup> in combination with GC. Most common grade 3 toxicities included neutropenia (<i>n</i> = 11, 55%), anemia (<i>n</i> = 4, 20%), and infection (<i>n</i> = 3, 15%). There were no grade 4 toxicities. After a median follow-up of 15.6 months, ORR was 45% and median PFS was 10 months (95% confidence interval, 7.1–14.9). Median OS is not yet estimable.</p>Conclusions:<p>Devimistat in combination with GC is well tolerated and has an acceptable safety profile in patients with untreated advanced BTC.</p></div>