A Phase I Trial of Prolonged Oral Etoposide and Liposomal Doxorubicin in Ovarian, Peritoneal, and Tubal Carcinoma: A Gynecologic Oncology Group Study

Abstract

Objectives. In an effort to explore second-line therapy in ovarian, peritoneal, and tubal carcinoma, a phase I trial combining prolonged oral etoposide and liposomal doxorubicin was conducted by the Gynecologic Oncology Group.Methods. Liposomal doxorubicin (20 mg/m2) was administered intravenously over 1 h followed by oral etoposide at 50 mg/m2/day beginning on day 2. In the first phase of accrual, the number of days of oral etoposide was increased until its maximum tolerated dose (MTD) was determined based on hematologic toxicity. In the second phase, etoposide was given at the MTD while the dose of liposomal doxorubicin was escalated until its maximum tolerated dose was reached based on hematologic or nonhematologic toxicity. Cycles were repeated every 28 days for a maximum of 12 courses. Dose-limiting toxicity was defined as neutropenic sepsis, grade 4 thrombocytopenia, absolute neutrophil count <1000/μl or platelets <50,000 during treatment with etoposide, or ≥grade 3 mucositis/stomatitis, palmar–plantar erythrodyesthesia, or rash.Results. Fifteen patients were accrued to the study's first phase, and 3 were accrued to the second phase. Dose-limiting hematologic toxicity occurred with 14 days of oral etoposide in combination with liposomal doxorubicin at 20 mg/m2. Efforts to escalate the dose of liposomal doxorubicin to 30 mg/m2 in combination with 12 days of oral etoposide at 50 mg/m2 resulted in dose-limiting hematologic toxicity. Five of 17 (29%; 95% CI: 13–53%) evaluable patients experienced a response.Conclusion. The regimen of oral etoposide at 50 mg/m2/day for 12 days in combination with liposomal doxorubicin at a dose of 20 mg/m2 is tolerable without supportive therapy. While this dose of oral etoposide has demonstrated activity as a single agent in ovarian cancer, liposomal doxorubicin has only been effective in ovarian cancer at higher doses. There are no immediate plans to study this combination further.