Phase I clinical trial of isophosphamide (NSC-109724).

An initial clinical phase I trial of isophosphamide has been carried out at dose levels of 200-10,000 mg/m2 of body surface area using a single-dose, every-3-week schedule. Significant toxicity was not seen at isophosphamide dose levels less than 2900 mg/m2. At higher doses, nausea and vomiting was nearly universal. Hematologic toxicity manifested by leukopenia occurred in 12 of 20 patients treated with doses of 3800-7000 mg/m2. Thrombocytopenia to 100,000 platelets/mm3 was not seen in any patient. Urinary bladder toxicity manifested by hemorrhagic cystitis was seen in 15 of 23 patients treated with doses of 3800-10,000 mg/m2. Hemorrhagic cystitis could be completely prevented by bladder irrigation with N-acetyl-L-cysteine (1% solution, 2000 ml/day). With careful attention to hydration, renal toxicity was largely prevented with blood urea nitrogen elevations to 30 mg/dl in only two of 14 patients receiving isophosphamide doses of 5000-7000 mg/m2. Another side effect was central nervous system toxicity in seven of 17 patients at doses of 5000-10,000 mg/m2. For phase II trials a dose of 5000 mg/m2 is recommended, with careful attention to the state of hydration in the patient and with the knowledge that bladder irrigation may be necessary for the prevention and/or amelioration of bladder toxicity.