Phase I study of pegylated liposomal doxorubicin in combination with ifosfamide in pretreated ovarian cancer patients

Objectives: 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 (1170) to patients with recurrent, advanced ovarian cancer (AOC). Methods: Patients with progressing platinum-sensitive or resistant disease were included in 5 dose levels consisting of PLD (25 mg/m(2) to 45 mg/m(2), day 1) combined with a fixed IFO dose administered as a continuous infusion (1700 mg/m(2)/d, day I 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). Results: Forty-eight patients were treated. The MTD was determined in the first 29 patients to be dose level V (45 mg/m(2)), with 2 cases of febrile neutropenia. The recommended dose (level IV) combines 40 mg/m(2) PLD on day I and 1700 mg/m(2)/d IFO day I 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%). Northernatological toxicity essentially consisted of grade 3/4 nausea and vomiting (14%). Nineteen additional patients were included in levels III (I I 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. Conclusion: This study regimen presents an acceptable tolerance. The preliminary assessment of efficacy merits confirmation in a phase 11 study.