Clinical trial of weekly intensive therapy with 5-fluorouracil on two different schedules combined with interferon alpha-2a and filgrastim in patients with advanced solid tumors: Eastern Cooperative Oncology Group Study P-Z991
Wadler, S.; Atkins, M.; Karp, D.; Neuberg, D.; Haynes, H.; Dutcher, J.P.
Cancer Journal From Scientific American 4(4): 261-268
1998
ISSN/ISBN: 1081-4442 PMID: 9689985 Document Number: 497208
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 alpha) followed by 5-fluorouracil (5-FU) could be administered in combination with 5-filgrastim support. PATIENTS AND METHODS: Patients were required to have a histologically documented solid tumor with either measurable or evaluable lesions. AU 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 mug/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 alpha, 3 MU subcutaneously, and the IFN alpha was escalated between patient cohorts to a maximum of 9 MU. Part B used the dose of IFN cc 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 alpha was 3 MU subcutaneously, and that of 5-FU, 2.6 g/m2, and the dose of IFN alpha was escalated to a maximum of 9 MU. In part D, the dose of IFN alpha 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 a, 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 alpha 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 IFNalpha and filgrastim. In parts C and D, filgrastim could be administered 6 hours after the end of the 5-FU infusion without excessive myelosuppression.