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- W2588264520 abstract "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 naïve, 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 diarrhea, seen in 3/5 patients at 1,300 mg/m2 AMP. At 1,150, 1,000, and 875 mg/m2 AMP, these toxicities were grade 1–2 in 6/9, 7/13, and 5/19 patients, respectively, and ameliorated with atropine. Fatigue (66%), anemia (62%), nausea (55%), vomiting (45%), leukopenia (44%) were other treatment related toxicities (any grade). Of 62 evaluable patients for response, 11 (18%) had partial responses and 31 (50%) stable disease. The median number of cycles was 3 (range 0 -25). In the rat, 14C localized in the pancreas, bowel, and kidneys and excretion was 85% urinary and 15% fecal. AMP at a concentration of 100–1,000 ug/ml contracted the isolated guinea pig ileum similar to acetylcholine and was reversible with atropine. Conclusions: The AMP + gemcitabine combination was well tolerated at full doses of each agent and encouraging antitumor activity was seen. The DLT of the combination is explained by gastrointestinal localization and an atropine reversible cholinergic effect. Phase II studies are planned. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amplimed Amplimed Amplimed" @default.
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- W2588264520 date "2008-05-20" @default.
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- W2588264520 title "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" @default.
- W2588264520 doi "https://doi.org/10.1200/jco.2008.26.15_suppl.4619" @default.
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