Phase I / II trial of human recombinant granulocyte-colony-stimulating factor (filgrastim) and escalating doses of cyclophosphamide, mitoxantrone, and 5-FU in the treatment of advanced breast cancer

Abstract

Purpose: We performed a phase I/II dose-escalation trial of cyclophosphamide, mitoxantrone, and 5-fluorouracil (CNF) in combination with human recombinant granulocyte-colony-stimulating factor (G-CSF, filgrastim) in patients with advanced breast cancer. The objectives of this trial were (1) to gain experience with filgrastim given to patients with advanced breast cancer and receiving standard-dose CNF, and (2) to determine the maximum tolerated dose of CNF that could be given with filgrastim support by incremental dose escalation of two components of the CNF regimen, cyclophosphamide and mitoxantrone. Methods: Four patients who had received prior therapy for advanced disease received standard-dose CNF with filgrastim support. Sequentially enrolled patients who had received no prior chemotherapy for advanced disease were treated with standard-dose CNF without filgrastim (5 patients), standard-dose CNF with filgrastim (15 patients), or were entered into sequential cohorts of 3–6 patients to be treated with increasing doses of CNF with filgrastim support (29 patients). Results: The maximum tolerated doses that could be given with filgrastim support were 1500 mg/m² cyclophosphamide, 20 mg/m² mitoxantrone, and 500 mg/m² 5-FU. Overall, 7 complete (14%) and 13 partial responses (26%) were observed. Despite the use of filgrastim, repeated cycles of CNF at doses of 2000 mg/m² cyclophosphamide, 25 mg/m² mitoxantrone, and 500 mg/m² 5-FU could not be given because of neutropenia and thrombopenia. Among 18 patients with bidimensionally measurable disease there were 3 complete (17%) and 5 partial (28%) responses. The median progression-free survival of all patients was 236 days (34 weeks). Conclusion: The use of filgrastim allows CNF to be given at approximately twice the dose intensity of “standard”-dose CNF. Because non-hematopoietic toxicity was not dose-limiting, further dose escalation of this regimen might be possible with more effective hematopoietic support. The response rate and survival of patients treated in this study were within the range expected with standard-dose chemotherapy.