A phase I study of imexon inj plus gemcitabine as first-line therapy for advanced pancreatic cancer with preclinical mechanistic study of dose limiting toxicity

4619 Background: Imexon, inj. (Amplimexon, AMP) is a novel cyanoaziridine (MW: 111) which depletes thiols inducing oxidative stress and apoptosis. Like gemcitabine (Gem), AMP inhibits ribonucleotide reductase and has synergistic cytotoxicity with Gem. This phase I combination study assessed the maximum tolerated dose (MTD) and dose limiting toxicity (DLT). Methods: 96 chemotherapy naive, advanced pancreatic cancer patients received Gem on days 1, 8, 15 of a 28 day cycle and AMP on days 1–5/15–19 (n=19) or days 1,8, 15 (n=77). Doses of AMP ranged from 200–1,300 mg/m2 with Gem 800 or 1,000 mg/m2. With abdominal cramping as the primary DLT, tissue distribution was tested with 14C AMP in the rat. AMP was evaluated on the isolated guinea pig ileum. Results: Patient characteristics: median age 63 years (range 39–86), ECOG PS 0/1 (%): 38/ 62, metastatic/locally advanced (%): 93/ 7. The MTD was 1,000 mg/m2 of Gem with 875 mg/m2 of AMP days 1, 8, 15 Q 28 days. DLT was grade 3 cramping, abdominal pain and explosive...