Phase I/II trial of cyclophosphamide, mitoxantrone, and escalated doses ofcarboplatin supported by peripheral-blood stem cells in women with metastatic breast cancer

Purpose: To intensify a regimen of high-dose cyclophosphamide, mitoxantrone , and carboplatin that had previously produced high complete and overall re sponse rates in metastatic breast cancer (MBC), Patients and Methods: Forty-four patients with ct median age of 43 years (r ange, 25 to 57 years) and previously untreated MBC who were responding to a nthracycline-based or single-agent taxane chemotherapy received cyclophosph amide 1.5 g/m(2)/d and mitoxantrone 16 mg/m(2)/d combined with escalating d oses of carboplatin 200 to 500 mg/m(2)/d, each given daily from days -6 to -3. Hematopoiesis was supported by mobilized peripheral-blood stem cells in fused on day 0 and by use of granulocyte-macrophage colony-stimulating fact or 300 mu g/d subcutaneously starting on day 1. Results: A total of six dose levels of carboplatin were examined. Grades 3 and 4 toxicity occurred in 10 patients and one patient, respectively, with grade 3 toxicity occurring in only five of 31 patients treated with less th an or equal to 400 mg/m(2) of carboplatin. Major dose-limiting toxicities w ere cardiac, pulmonary, and renal. Four patients developed congestive heart failure: two had persistently low ejection fraction 11 and 36 months after peripheral-blood stem-cell transplantation (PBSCT), and two recovered. Hem atologic recovery to an absolute neutrophil count of greater than 0.5 x 10( 9)/L occurred at a median of 11 days (range, 8 to 25 days) and to a platele t count of greater than 20 x 10(9)/L at a median of 10.5 days (range, 6 to 60 days). There were two toxic deaths from sepsis: one on day 27 (level 5) and one from cardiac arrest on day 42 (level 6). Conclusion: The maximum-tolerated dose of carboplatin was 400 mg/m(2)/d in combination with mitoxantrone 16 mg/m(2)/d and cyclophosphamide 1,500 mg/m( 2), all drugs given over 4 days. This regimen is being tested in a phase il l trial of high-dose chemotherapy and PBSCT versus standard treatment. J Cl in Oncol 18:2363-2368. (C) 2000 by American Society of Clinical Oncology.