Phase II pharmacodynamic trial of dose-intensive, weekly parenteral hydroxyurea and fluorouracil administered with interferon alfa-2a in patients with refractory malignancies of the gastrointestinal tract

Purpose: Combined depletion of pyrimidine and purine DNA precursors has res ulted in therapeutic synergism in vitro. The aims of the current study were to test this strategy in patients with refractory tumors and to assess ifs effects on selected nucleotide pools. Patients and Methods: A single-institution phase II trial was initiated in patients with advanced carcinomas of the stomach and pancreas. Patients had measurable disease and had no prior chemotherapy except adjuvant fluoroura cil (5FU) or gemcitabine. 5FU was administered by CADD + pump at 2.6 g/m(2) intravenously by 24-hour infusion on days 1, 8, 15, 22, 29, and 36. parent eral hydroxyurea (HU) was administered at 4.3 g/m(2) as a 24-hour infusion concurrently with 5FU, Interferon alfa aa (IFN-alpha 2a) wets administered at 9 million units subcutaneously on days 1, 3, and 5 each week, No drug wa s administered in weeks 7 and 8, Pharmacodynamic studies were performed to assess drug effects on levels of deoxyuridine triphosphate (dUTP) and thymi dine triphosphate (TTP) pools in peripheral-blood mononuclear cells (PBMCs) before and 6 hours after-treatment using a highly sensitive DNA polymerase assay. Results: There were 53 patients enrolled onto the study (gastric carcinoma, 31; pancreatic carcinoma, 22). The median age was 61 years, with 22% of pa tients greater than or equal to 70 years old. The predominant grade 3 to 4 toxicities were leukopenia (49%), granulocytopenia (55%), and thrombocytope nia (22%), Severe diarrhea occurred in 12%, mucositis in 0%, and vomiting i n 10% of patients. Patients greater than or equal to 70 years had no greate r incidence of toxicities, Among the 30 assessable patients with gastric ca rcinoma, there were two (7%) complete responders and 11 (37%) partial respo nders (median duration, 7 months). Among the 21 assessable patients with pa ncreatic carcinoma, there was one responder. Median survival among all pati ents with gastric carcinoma was 10 months and 13 months far patients with p ancreatic carcinoma. Twenty-three patients herd samples studied for levels of dUTP and TTP. There was no change in the levels of TTP before and after treatment, Furthermore, dUTP was detected in only five of 28 samples after treatment with no increase in the dUTP/TTP ratio. Conclusion: Combination therapy with high-dose, weekly infusional HU and 5F U with IFM-alpha 2a modulation wets well-tolerated with activity in gastric cancer, patients greater than or equal to 70 years tolerated therapy as we ll as younger patients. This was the first study to correlate levels of TTP and dUTP after treatment with clinical outcome. In PBMCs used as a surroga te tissue, HU abrogated the 5FU-induced increase in dUTP levels without rev ersing the overall efficacy of the regimen. (C) 1999 by American Society of Clinical Oncology.