Synergistic activity of PHY906 with capecitabine in pancreatic carcinoma.

2007 ASCO Annual Meeting

Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 15116

M. W. Saif, S. Liu, A. Elfiky, Z. Jiang, Y. Cheng

Background: Preclinical data indicates that PHY906, a traditional Chinese botanical formulation, can reduce chemo-induced gastrointestinal toxicity while simultaneously enhancing therapeutic efficacy of a broad-spectrum of common anticancer agents.

Methods: Male NCR athymic nude mice were transplanted with human PANC-1 cells. To determine the best dose of combinational regimen, two dose ranges of capecitabine, 60 and 180 mg/kg bid for 14 consecutive days with two dose ranges of PHY906, 300 and 900 mg/kg bid on days 1-4 and days 8-11 were administered by gavage in the first experiment. In the second experiment, PHY906 was fixed at 500 mg/kg bid at days 1-4 and 8-11 while dose of capecitabine was increased to 360 mg/kg bid for 14 consecutive days. A dose of 180 mg/kg of capecitabine was also included for comparison with previous experiments. In the third experiment, capecitabine at 360 mg/kg was selected to evaluate effect of different doses of PHY906 ranging from 100 mg/kg to 500 mg/kg on enhancement of antitumor activity of capecitabine. PHY906 was always administered 30 minutes prior to capecitabine. Tumor size, body weight and mortality were monitored daily and mice were sacrificed when tumor size reached 10% of body weight or on Day 21.

Results: PHY906 showed enhancement of antitumor activity of capecitabine when both doses of PHY906 were co-administered with both doses of capecitabine in first experiment. In second experiment, increase of capecitabine dose from 180 mg/kg to 360 mg/kg significantly increased disparity of tumor growth rates between capecitabine alone and concomitant use of both PHY906 and capecitabine. Similar results were obtained in third experiment using a dose of 360 mg/kg of capecitabine and 500 mg/kg of PHY906 (p= 0.0018) as compared with control, capecitabine or PHY906 alone. Similar observation was found in mice bearing PAN-2 murine pancreatic cancer.

Conclusions: The studies demonstrate that PHY906 potentiates antitumor activity of capecitabine in human pancreatic carcinoma xenograft mouse model in all capecitabine and PHY906 dosing regimens examined. Observed effect appeared to be dependant on dosage of capecitabine. Therefore, we are employing a dose intense weekly schedule for capecitabine with PHY906 in a phase I/II study in patients with advanced pancreatic cancer.