High-dose ifosfamide with mesna uroprotection: a phase I study.

Area of Science:

• Oncology
• Clinical Pharmacology

Background:

• Standard ifosfamide doses in Phase II trials range from 5 to 8 g/m2 per course.
• Continuous infusion schedules are being explored to optimize ifosfamide delivery and toxicity profiles.

Purpose of the Study:

• To determine the maximum-tolerated dose (MTD) of ifosfamide administered via 4-day continuous infusion.
• To identify the nonhematologic dose-limiting toxicities (DLTs) associated with escalating ifosfamide doses.
• To evaluate the efficacy and toxicity of high-dose ifosfamide in heavily pretreated patients with advanced solid tumors.

Main Methods:

• A Phase I dose-escalation study involving 29 patients treated with ifosfamide (8-18 g/m2) over 4 days.
• Mesna was co-administered at an equivalent dose via continuous infusion for 5 days for uroprotection.
• Dose escalation was planned with autologous bone marrow support if specific granulocyte recovery criteria were not met.

Main Results:

• The MTD was not reached within the planned escalation; however, dose-limiting renal insufficiency and prolonged granulocytopenia (median 11 days) were observed at 18 g/m2.
• Myelosuppression, mucositis, and renal tubular acidosis demonstrated a dose-dependent relationship.
• Nine responses (two complete) were observed in 27 assessable patients, including seven responses in 20 patients with advanced refractory sarcoma.

Conclusions:

• Ifosfamide can be escalated significantly beyond standard doses with mesna uroprotection before encountering nonhematologic DLTs.
• Ifosfamide exhibits broad cytotoxicity against solid tumors, suggesting its utility in high-dose combination chemotherapy regimens.
• Further investigation into high-dose ifosfamide regimens is warranted for advanced and refractory malignancies.