HIGH-DOSE PACLITAXEL, CYCLOPHOSPHAMIDE, AND CISPLATIN WITH AUTOLOGOUSHEMATOPOIETIC PROGENITOR-CELL SUPPORT - A PHASE-I TRIAL

Purpose: To determine the maximal-tolerated dose (MTD) of paclitaxel i n combination with high-dose cyclophosphamide (CPA) and cisplatin (cDD P) followed by autologous hematopoietic progenitor-cell support (AHPCS ). Patients and Methods: Forty-nine patients with poor-prognosis breas t cancer, non-Hodgkin's lymphoma (NHL), or ovarian cancer were treated with escalating doses of paclitaxel infused over 24 hours, followed b y CPA (5,625 mg/m(2) intravenously over 1 hour in three divided doses) and cDDP (165 mg/m(2) intravenously as a continuous infusion over 72 hours) and AHPCS. Pharmacokinetic measurements for each drug were perf ormed. Results: Dose-limiting toxicities were encountered in two patie nts at 825 mg/m(2) of paclitaxel; one patient died of multiorgan failu re that involved the lungs, CNS, and kidneys, and the other developed grade 3 respiratory, CNS, and renal toxicity, which resolved. The MTD of this combination was determined to be paclitaxel 775 mg/m(2), CPA 5 ,625 mg/m(2), and cDDP 165 mg/m(2) followed by AHPCS. Sensory polyneur opathy and mucositis were prominent toxicities, but both were reversib le and tolerable. The pharmacokinetics of paclitaxel correlated signif icantly with the severity of mucositis (P < .001) and peripheral neuro pathy (P < .00004). Eighteen of 33 patients (54%) with measurable, hea vily pretreated metastatic breast cancer achieved a partial response ( PR). Responses were also observed in patients with NHL (four of five p atients) and ovarian cancer (two of two). Conclusion: It is possible t o escalate the dose of paclitaxel to 775 mg/m(2) in combination with 5 ,625 mg/m(2) of CPA, 165 mg/m(2) of cDDP, and AHPCS. An encouraging re sponse rate in poor-prognosis patients with breast cancer, NHL, and ov arian cancer warrants further study. (C) 1996 by American Society of C linical Oncology.