Abstract
4560 Background: Oxaliplatin (OX), gemcitabine (GEM) and capecitabine (CAP) are all active agents against various gastrointestinal and other malignancies and have different mechanisms of action and toxicity profiles. This Phase I study aims to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) associated with this triplet regimen. Methods: The modified Fibonacchi 3/cohort dose escalation schema was used to determine the MTD and DLT of OX, GEM and CAP. Oxalipaltin [85–100 mg/m2] IV over 2 hours and gemcitabine [800–1,000 mg/m2] were given at a constant rate infusion of 10 mg/m2/min on days 1 & 15, while CAP [600–800 mg/m2] was given PO BID on days 1–7 and 15–21. 1 cycle = 28 days. Pharmacogenomic correlates including ERCC2, GSTP1, TYMS, TS del and TSER G>C were also obtained. A structured neurological toxicity assessment and questionnaire was also performed. Once MTD was established, additional patients were treated at the MTD and pharmacokinetic studies were performed on these additional patients. Results: 30 patients (M:F 2:1; 23% non-caucasian) with median age of 62 (range: 38–78) and PS of 0–1 were enrolled from 3/05 to 8/06. All patients had advanced GI malignancies (19 pancreatic, 6 biliary, 2 duodenal, 1 gastric, 1 esophageal, 1 GI unknown primary). Dose levels, # patients, DLT and best responses are tabulated below. Conclusions: The MTD of this triplet regimen is OX at 100 mg/m2, GEM at 800 mg/m2 days 1 & 15 with CAP at 800 mg/m2 PO BID days 1–7, 15–21. DLTs for this regimen include grade 3 fatigue and dyspnea as well as Grade 4 thrombocytopenia. CR is achieved in 2 patients (cholangiocarcinoma and pancreatic), while a patient with a GI unknown primary achieved PR. Several patients with pancreatic cancer achieved prolonged SD. An exploration of any association of toxicities and response with pharmacogenomic correlates is ongoing. A Phase II study in patients with pancreaticobiliary cancers is planned. This study is supported by Sanofi-Aventis Pharmaceuticals. [Table: see text] [Table: see text]
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