Clinical trial of weekly intensive therapy with 5-fluorouracil on two different schedules combined with interferon α-2a and filgrastim in patients with advanced solid tumors: Eastern cooperative oncology group study P-Z991

PURPOSE: The hematopoietic growth factor filgrastim has been shown to reduce both chemotherapy-induced myelosuppression and mucosal toxicities. The aim of this study was to conduct four separate pilot trials to determine the maximum-tolerated doses at which interferon alpha (IFN α) followed by 5- fluorouracil (5-FU) could be administered in combination with filgrastim support. PATIENTS AND METHODS: Patients were required to have a histologically document, ed solid tumor with either measurable or evaluable lesions. All patients were fully ambulatory; had adequate bone marrow, renal, and hepatic function; had recovered from surgery; and gave informed consent. Trials were conducted sequentially. In parts A and B, patients received 5-FU as a continuous intravenous infusion daily for 5 days, followed by weekly bolus therapy at the same dose. In parts C and D, patients received 5-FU as a weekly high-dose, 24-hour infusion. Interferon was administered immediately before the 5-FU three times a week Filgrastim was administered at 5 μg/kg subcutaneously either four (parts A, B) or five (parts C, D) times a week. In part A, the starting doses were as follows: 5-FU, 750 mg/m², and IFN α, 3 MU subcutaneously, and the IFN α was escalated between patient cohorts to a maximum of 9 MU. Part B used the dose of IFN α established from part A, and the 5-FU was escalated to the maximum-tolerated dose between patient cohorts. In part C, the starting dose of IFN α was 3 MU subcutaneously, and that of 5-FU, 2.6 g/m², and the dose of IFN α was escalated to a maximum of 9 MU. In part D, the dose of IFN α was determined from part C, and the dose of 5- FU was escalated. The maximum tolerated dose was the highest dose at which three of three or five of six patients were able to tolerate therapy. RESULTS: There were 71 patients entered into the four parts of this trial. In part A (12 patients), the dose of IFN α, was escalated to 9 MU subcutaneously three times a week with only one patient experiencing dose- limiting toxicity. In part B (13 patients), the dose of 5-FU could not be escalated beyond 750 mg/m² because of sepsis (one patient) and gastrointestinal hemorrhage (one patient). The predominant toxicities were diarrhea (46%), vomiting (23%), and mucositis (31%). In part C (24 patients), two patients experienced dose-limiting toxicities (staphylococcal sepsis [one patient] and neuropsychiatric [one patient]). The dose of IFN α was escalated to 9 MU. In part D (21 patients), the dose of 5-FU was escalated to 3.4 g/m² administered weekly. No patients at this dose level experienced serious toxicities. At the next highest dose level, 3.6 g/m², one patient each experienced gastrointestinal hemorrhage and diarrhea. There were no additive constitutional symptoms resulting from the combination of IFN α and filgrastim. In parts C and D, filgrastim could be administered 6 hours after the end of the 5-FU infusion without excessive myelosuppression. CONCLUSIONS: The addition of filgrastim allowed escalation of the dose of 5-FU on the weekly, high-dose schedule, but not on the weekly bolus schedule. IFN α and filgrastim can be administered without additive toxicities. Filgrastim can be safely administered < 24 hours after completion of the weekly, high dose 5- FU infusion.