Abstract
13008 Background. Ifosfamide (IFM) is a bi-functional alkylator with wide spectrum of activity in solid tumors and has an auto-inductive liver metabolism through P450 cytochromes. Auto-induction might permit a better therapeutic index for combination therapy. Methods. A phase I trial with interpatient dose escalation of a single dose of IFM given every 2 wks in advanced solid tumor pts. IFM, its dechloroethylated and active 4-hydroxy metabolites, were measured at cycle 1 & 2 at the end of infusion, 2 and 5h later, using gas chromatography. IFM elimination was considered as following a monocompartimental model kinetics. Results From January 2004 to June 2006; 20 pts of PS<2 were included :10 F, 10 M, median age 61 years (39–78), median previous chemotherapies: 2 (0–5). Primary tumor was most often ovarian (5), peritoneal (3), sarcoma (2), melanoma (2), or miscellaneous (8). 10 pts received 2.5g/m2 and other 10 pts received 3g/m2. A total of 79 cycles were evaluable for toxicity. median number of cycles: 4 (1–8). No Grade (Gr) 3–4 hematologic toxicity, no alopecia. Gr2 nausea and fatigue were the most common toxicities at 3g/m2. No toxicity-related fatal event was noted. One objective response was noted in pancreatic cancer pt and one sustained CA125 decline in a heavily pretreated ovarian cancer pt. A slight (7–10%) but reproducible decrease of AUC was detectable at cycle 2, at both dose levels, related to auto-inductive metabolism (see table below). The other PK results are available and will be presented (Table). Intra individual variations (large SD) were noticed for each pharmacokinetic (PK) parameter. Conclusions: A slight non dose- dependent but rather patient-dependent auto-induction of IFM metabolism was detected. The toxicity profile allows the development of every 2 wks IFM-based combination therapies. [Table: see text] No significant financial relationships to disclose.
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