Phase I clinical trial of topotecan and pegylated liposomal doxorubicin.

Background: The objective of this study was to determine the feasibility and maximum tolerated dose (MTD) of combination topotecan and pegylated liposomal doxorubicin (PLD) administered in 4- or 3-week cycles in patients with advanced or refractory solid tumors.
Patients and Methods: Patients were treated with intravenous topotecan (0.75-1.25 mg/m2) for 3 days followed by PLD (25-40 mg/m2) on Day 4. The following dose combinations (topotecan/PLD, mg/m2) were explored: 0.75/40, 1.0/40, and 1.25/40 every 28 days; and 1.0/25 and 1.0/30 every 21 days.
Results: Thirty-two patients were enrolled, and all had received prior chemotherapy. Most (84 percent) patients had ovarian cancer. A total of 157 cycles (median, 4 cycles; range, 1-19 cycles) of chemotherapy were administered. Dose-limiting toxicities were Grade 4 neutropenia and death at dose level 3 (1.25/40 mg/m2 every 28 days), and neutropenic fever, Grade 3 stomatitis, and Grade 3 peripheral neuropathy (all in one patient) at dose level 5 (1/30 mg/m2 every 21 days). Myelosuppression was the most common serious toxicity. Twenty-six patients were evaluable for response and 7 (27 percent) had partial responses. All responses were seen in patients with ovarian cancer.
Conclusions: This combination is feasible and well tolerated; encouraging activity was observed in heavily pretreated patients with ovarian cancer. The recommended regimens for a Phase II study are topotecan 1.0 mg/m2 on Days 1-3 followed by PLD 40 mg/m2 on Day 4 of a 28-day cycle, and topotecan 1.0 mg/m2 on Days 1-3 and PLD 30 mg/m2 on Day 4 of a 21-day cycle.