ABSTRACT
Ifosfamide (IFOS) is a bifunctional alkylator with a wide spectrum of activity in solid tumors and has an autoinductive liver metabolism through P450 cytochromes. Autoinduction might permit a better therapeutic index for combination therapy. A phase I trial was investigated with interpatient dose escalation of a single dose of IFOS given every 2 weeks in advanced solid tumor patients. IFOS, its dechloroethylated and active 4-hydroxy metabolites, were measured at cycles 1 and 2 at the end of infusion, 2 and 5 h later, using gas chromatography. IFOS elimination was considered as following monocompartimental model kinetics. The results of 20 patients from January 2004 to June 2006 were included. The median of previous chemotherapies was 2 (0-5). The primary tumor was most often ovarian (5), peritoneal (3), sarcoma (2), melanoma (2) or miscellaneous (8). Ten patients received 2.5 g/m2 and the other 10 patients received 3 g/m2. A total of 79 cycles were evaluable for toxicity. The median number of cycles was 4 (1-8). No grade 3-4 toxicity, no alopecia at first dose level and no toxicity-related fatal events were noted. One objective response was noted in a pancreatic cancer patient and one sustained CA125 decline in a heavily pretreated ovarian cancer patient. A slight (7-10%) but reproducible decrease of areas under the curve was detectable at cycle 2, at both dose levels, related to autoinductive metabolism. Intraindividual variations (large SD) were noticed for each pharmacokinetic parameter. A patient-dependent autoinduction of IFOS metabolism was detected rather than a slight nondose-dependent autoinduction. The toxicity profile allows the development of bi-weekly IFOS-based combination therapies.
