Phase I study of paclitaxel, carboplatin, and increasing days of prolongedoral etoposide in ovarian, peritoneal, and tubal carcinoma: A Gynecologic Oncology Group study

Purpose: Given the activity of prolonged oral etoposide in platinum and pac litaxel-resistant ovarian carcinoma, a phase 1 trial was conducted that com bined increasing days of oral etoposide therapy with paclitaxel and carbopl atin in chemotherapy-naive patients with ovarian peritoneal and tubal carci noma to establish a maximum-tolerated dose (MTD) of this combination. Patients and Methods: Paclitaxel at 175 mg/m(2) given over 3 hours and carb oplatin at an area under the curve of 5 were administered on day 1 followed by oral etoposide 50 mg/m(2)/d beginning on day 2. The number of days of e toposide therapy wets escalated on the basis of toxicity. Toxicity end poin ts included neutropenic sepsis, grade 4 thrombocytopenia, or grade 3 neutro penia or thrombocytopenia during etoposide administration. Cycles were repe ated every 21 days for a maximum of six courses. Due to hematologic toxicit y, the duration of the paclitaxel infusion was decreased to 1 hour for a se cond stage of accrual. Results: Of 52 patients studied, 29 were in the first stage of accrual. Dos e-limiting toxicity occurred with 8 days of oral etoposide, making the MTD six days of therapy. Twenty-three patients were entered into the second sta ge of accrual. Dose-limiting toxicity occurred at 12 days of oral etoposide , making the MTD 10 days of therapy. Three patients developed acute myeloid leukemia 16, 27, and 35 months after receiving a cumulative dose of 200 mg /m(2), 1,200 mg/m(2), and 2,400 mg/m(2), respectively. Conclusion: One-hour paclitaxel, carboplatin, and oral etoposide at 50 mg/m (2)/d for 10 days is tolerable without supportive therapy. The leukemogenic potential is cause for concern and precludes its use in chemotherapy-naive ovarian carcinoma. (C) 2000 by American Society of Clinical Oncology.