Phase I Study of Pegylated Liposomal Doxorubicin in Combination With Ifosfamide in Pretreated Ovarian Cancer Patients

Abstract

To determine the dose limiting toxicity, the maximum tolerated dose and the recommended dose of pegylated liposomal doxorubicin (PLD) in association with a fixed dose of ifosfamide (IFO) to patients with recurrent, advanced ovarian cancer (AOC). Patients with progressing platinum-sensitive or resistant disease were included in 5 dose levels consisting of PLD (25 mg/m2 to 45 mg/m2, day 1) combined with a fixed IFO dose administered as a continuous infusion (1700 mg/m2/d, day 1 to 3) to define the MTD on the basis of acute toxicity during the first 2 cycles, then confirm the MTD, by the evaluation of delayed toxicity (hand-foot syndrome). Forty-eight patients were treated. The MTD was determined in the first 29 patients to be dose level V (45 mg/m2), with 2 cases of febrile neutropenia. The recommended dose (level IV) combines 40 mg/m2 PLD on day 1 and 1700 mg/m2/d IFO day 1 to day 3. The principal toxicity was hematotoxicity (grade 3-4 neutropenia 61.8% of patients, grade 3/4 thrombcytopenia 7.2%, and grade 3/4 anemia 21.8%). Nonhematological toxicity essentially consisted of grade 3/4 nausea and vomiting (14%). Nineteen additional patients were included in levels III (11 patients) and IV (8 patients), to evaluate late-onset toxicity. No hand-foot syndrome was observed in the 48 treated patients, confirming the identification of dose level IV as recommended dose. This study regimen presents an acceptable tolerance. The preliminary assessment of efficacy merits confirmation in a phase II study.