A phase I clinical trial of fluorouracil (5-FU) + devimistat (CPI-613) combination in previously treated patients (pts) with metastatic colorectal cancer (MCR)
Abstract
e15054 Background: MCR that failed standard lines of therapy have a poor outcome. Inhibition of glutamine metabolism potentially can synergize with chemotherapy and reverse resistance. Devimistat is a novel anti-mitochondrial agent that alters energy metabolism and redox processes, leading to apoptosis, necrosis, and autophagy. Methods: Phase Ib dose escalation (3+3 design) to determine the MTD of devimistat, when used in combination with fixed doses of bolus and infusional 5-FU, in non-resectable MCR, ECOG PS 0-3, and good organ function who have failed, or could not tolerate, prior standard therapies. A cycle was 2 weeks. Escalating doses of devimistat were given IV over 2 hrs via central line on days 1-4. On Day 2 when both devimistat and bolus 5-FU were given, devimistat was given first, followed by 5-FU bolus (400 mg/m2) followed by infusional 5-FU over 46 hrs (2,400 mg/m2) on Days 2-4. Plasma samples to measure devimistat and metabolites were collected before and after the first and last dose of devimistat on cycle 1. Results: 19 pts enrolled from 1/20/2015 to 1/16/2019. One was never treated with devimistat and was excluded from analyses. Median age was 63 (range 32-83). 10 males and 8 females. Median devimistat cycles were 4 (range 1-8). Dose levels of devimistat: 1 pt treated at 2,000 mg/m2, 1 pt treated at 2,250 mg/m2, 7 pts treated at 2,500 mg/m2, then dose was de-escalated for an additional 9 pts treated at 2,250 mg/m2. Two of 7 pts had a DLT at the devimistat…
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