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Relation between Irofulven (MGI-114) Systemic Exposure and Tumor Response in Human Solid Tumor Xenografts¹

Departments of Pharmaceutical Sciences [M. L., C. F. S.], Molecular Pharmacology [M. H. W., P. J. C., J. K. P., P. J. H.], Biostatistics [C. B.], and Hematology-Oncology [M. F.], St. Jude Children’s Research Hospital, Memphis, Tennessee 38105; The Center for Pediatric Pharmacokinetics and Therapeutics [C. F. S., P. J. H.], University of Tennessee, Memphis, Tennessee 38163; and Department of Pediatrics, Duke University Medical School, Durham, North Carolina 27710 [M. F., H. S. F.]

Irofulven is a novel, small molecular weight semisynthetic compound, derived from a family of mushroom toxins known as illudins. This DNA alkylating agent has a chemical structure unlike any other chemotherapeutic agent in clinical use. The molecule is currently being studied in several Phase I, II, and III trials. The objectives of this study were to evaluate the antitumor activity of Irofulven in a panel of 20 pediatric solid tumor xenografts and to relate the Irofulven systemic exposure, defined as area under the concentration time curve, to the antitumor dose associated with tumor regression in the tumor models. Irofulven was administered i.v. daily for 5 days with courses repeated every 21 days for a total of three cycles. The minimum effective dose of Irofulven causing objective regression (50% volume regression) of advanced tumors was determined for each of 19 of 20 independently derived tumor models (12 brain tumors, 4 neuroblastomas, and 4 rhabdomyosarcomas). At the maximum tolerated dose for three cycles of treatment (4.6 mg/kg/day) objective regressions were determined in 14 of 18 tumor lines (78%). However, the dose-response relationship was acute. At 2 mg/kg only 3 of 15 tumors tested demonstrated objective regressions, and in 3 additional tumors volume regressions were not achieved at a higher dose level (3 mg/kg), hence were not additionally tested. After administering the maximum tolerated dose (tolerated for one or two cycles of treatment) of Irofulven, 7 mg/kg, to mice bearing sensitive and resistant human tumors plasma concentration-time profiles were determined. Tumors were highly sensitive to Irofulven, but the systemic exposure required for a significant rate of objective response in this panel of tumors is in excess of that achievable in patients at tolerable doses, using this schedule of drug administration.

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