PHASE-II TRIAL OF PALA AND 6-METHYLMERCAPTOPURINE RIBOSIDE (MMPR) IN COMBINATION WITH 5-FLUOROURACIL IN ADVANCED PANCREATIC-CANCER

The biochemical modulators PALA, an inhibitor of aspartate transcarbamylase which depletes uridine nucleotide pools, and 6-methylmercaptopurine riboside (MMPR) which inhibits purine metabolism, selectively potentiate the antitumor activity of 5-fluorouracil (5-FU) in preclinical models. Based on a phase I trial of this combination, we performed a phase II trial in patients with advanced pancreatic cancer. PALA 250 mg/m(2) was administered i.v. on day 1, followed 24h later by MMPR 150 mg/m(2) as a bolus i.v. injection, and 5-FU 2300 mg/m(2) by 24h infusion. Treatments were repeated weekly. Seventeen patients, all previously untreated with chemotherapy, were entered, of whom 14 are evaluable for response. Toxicity greater than or equal to grade 2 included nausea (6/17), vomiting (4/17), diarrhea (3/17), stomatitis (5/17), and neurotoxicity (2/17). Among 14 evaluable patients there were no partial responses, and two patients with stable disease. Pretreatment with PALA and MMPR is insufficient to enhance the activity of 5-FU in pancreatic cancer.