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A Phase I Study of Continuous Infusion Doxorubicin and Paclitaxel Chemotherapy with Granulocyte Colony-Stimulating Factor for Relapsed Epithelial Ovarian Cancer¹

Vincent Gynecology, Division of Gynecologic Oncology [L. R. D., A. G., A. F. F., N. N.], Division of Hematology and Oncology [R. P., J. G. S., T. M., M. V. S.], and Division of Biostatistics [D. M. F.], Massachusetts General Hospital [J. G., K. B.], Boston, Massachusetts 02114

A Phase I study of paclitaxel and doxorubicin administered as concurrent 96-h continuous i.v. infusion was performed to determine the maximum tolerated dose (MTD), principal toxicities, and pharmacokinetics of this combination in women with relapsed epithelial ovarian cancer. The paclitaxel dose was fixed at 100 mg/m² (25 mg/m²/day for 4 days). The dose of doxorubicin was escalated from 30 mg/m² (7.5 mg/m²/day for 4 days) in increments of 10 mg/m² until dose-limiting toxicity was observed. All patients received granulocyte colony-stimulating factor 5 µg/kg/day prophylactically. Apparent steady-state plasma levels of both drugs were determined in the final cohort of patients treated at the MTD. A total of 17 patients received 52 cycles of therapy. The median age was 58 years, and all patients had previously received one to five different regimens (median, 2) of chemotherapy, including both platinum and paclitaxel. The treatment was tolerated well, with grade 1–2 nausea being the most frequent side effect (73% of cycles). Anemia, neutropenia, thrombocytopenia, and mucositis became dose limiting at the fourth dose level, defining the MTD of doxorubicin in this regimen as 50 mg/m². There were four partial responses and one complete response in 15 evaluable patients. Apparent steady-state plasma concentrations (mean ± SD) of paclitaxel and doxorubicin in the three patients treated at the MTD were 33.9 ± 12.5 nM and 15.7 ± 1.3 nM, respectively. Paclitaxel and doxorubicin by continuous infusion is a well-tolerated and active chemotherapy regimen for recurrent ovarian cancer.