asta-7654 and Neoplasms

Mafosfamide is a new oxazaphosphorine that breaks down spontaneously into 4-hydroxy-cyclophosphamide. A phase I trial with cyclohexylamine and lysine salts of mafosfamide was carried out in 16 patients, using weekly IV perfusion. Dose-limiting toxicities were not hematological, but consisted in the development of severe pain along the vein during administration. A particular mucosal syndrome with sneezing and conjunctivitis was seen only after administration of the lysine salt. The dose of 700 mg/m2 per week represents the maximum tolerated dose with this weekly schedule.

Topics: Adult; Aged; Blood Cell Count; Clinical Trials as Topic; Cyclophosphamide; Drug Evaluation; Female; Humans; Infusions, Parenteral; Male; Middle Aged; Neoplasms; Pain

Mafosfamide-cyclohexylamine is a new oxazaphosphorine derivative. It was chosen for phase-I clinical testing because of an expected higher therapeutic index and lack of complete cross resistance in animal tumors compared to cyclophosphamide. The schedule consisted of a single iv dose repeated every three weeks. The compound was found to cause as it's dose limiting toxicity severe pain along the injected vein and acute irritation of mucous membranes. The maximal tolerated dose was around 1000 mg/m2 given as a slow infusion over 2-3 hours. Hematological toxicity was mild. A limited phase-I study with the lysine salt of mafosfamide showed an identical type of toxicity. Mafosfamide given iv in a high-dose intermittent schedule is of little interest for further clinical trials. It is probable, that the severe venous pain and the mucosal irritation are caused by the high local concentration of 4-hydroxy-cyclophosphamide or by a metabolite. An oxazaphosphorine derivative undergoing slower hydrolysis therefore leading to lower active drug concentrations within the injected vein may be more promising.

Topics: Adult; Aged; Antineoplastic Agents; Cyclophosphamide; Drug Evaluation; Female; Humans; Leukocyte Count; Male; Middle Aged; Neoplasms