Phase I study of the botanical formulation PHY906 with capecitabine in advanced pancreatic and other gastrointestinal malignancies

Purpose: The botanical formulation, PHY906, has been used widely in Eastern countries to treat gastrointestinal symptoms including diarrhea, nausea and vomiting. PHY906 may also have anti-tumor properties and may potentiate the action of several chemotherapeutic agents based on pre-clinical studies. We conducted a Phase I study using PHY906 in combination with capecitabine in patients with advanced pancreatic and gastrointestinal malignancies to determine the maximum tolerated dose (MTD) of capecitabine in combination with PHY906. Patients and Methods: This study was a single institution, open-label, Phase I study of PHY906 800 mg BID on days 1-4 in combination with escalating doses of capecitabine (1000, 1250, 1500, and 1750 mg/m(2)) orally twice daily on days 1-7 of a 14-day cycle (7/7 schedule). Capecitabine was increased until the appearance of dose limiting toxicities (DLTs). Measurements of efficacy included tumor response by Response Evaluation Criteria in Solid Tumors (RECIST). Results: Twenty-four patients with a median age of 67 years (range 40-84) with pancreatic cancer (15), colon cancer (6), cholangiocarcinoma (1), esophageal cancer (1) and unknown primary (1) received a total of 116 cycles (median 5 cycles; range 1-17 cycles) over 4 dose levels of capecitabine. One DLT (Grade 4 AST/ALT, Grade 3 hyponatremia) was observed in the 1000 mg/m2 cohort of patients. No further DLT was observed in the subsequent cohorts and doses of capecitabine were escalated to 1750 mg/m2 BID. There were no DLTs at the maximum dose level of 1750 mg/m2, however, the delivered dose-intensity of capecitabine was similar at the 1750 mg/m2 dose level as the 1500 mg/m2 dose level. Therefore, the MTD was defined at 1500 mg/m(2) of capecitabine in this dosing schedule with PHY906. One patient achieved a partial response, and 13 patients had stable disease that lasted more than six weeks. Conclusion: The MTD of capecitabine was determined to be 1500 mg/m2 BID administered in a 7/7 schedule, in combination with PHY906 800 mg BID on days 1-4. This combination was well tolerated and warrants further study. (C) 2010 Published by Elsevier GmbH.