Phase I trial of irofulven (MGI 114) in pediatric patients with solid tumors

Purpose We performed a Phase I trial of irofulven (MGI 114) to determine the maximum tolerated dose (MTD), the dose‐limiting toxicity (DLT), and the plasma pharmacokinetics of irofulven in children ≤21 years of age with refractory/recurrent malignancies. Experimental Design Thirty‐five patients were...

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Published in:Pediatric Blood & Cancer 2006-08, Vol.47 (2), p.163-168
Main Authors: Bomgaars, Lisa R., Megason, Gail C., Pullen, Jeanette, Langevin, Anne-Marie, Dale Weitman, Steve, Hershon, Linda, Kuhn, John G., Bernstein, Mark, Blaney, Susan M.
Format: Article
Language:English
Subjects:
Adolescent
Adult
Antineoplastic Agents, Alkylating - administration & dosage
Antineoplastic Agents, Alkylating - adverse effects
Antineoplastic Agents, Alkylating - pharmacokinetics
Biological and medical sciences
Child
Child, Preschool
children
Drug Administration Schedule
Drug-Related Side Effects and Adverse Reactions
Female
General aspects
Humans
irofulven
Male
Maximum Tolerated Dose
Medical sciences
Neoplasms - drug therapy
pharmacokinetic
Sesquiterpenes - administration & dosage
Sesquiterpenes - adverse effects
Sesquiterpenes - pharmacokinetics
Tumors
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Summary:Purpose We performed a Phase I trial of irofulven (MGI 114) to determine the maximum tolerated dose (MTD), the dose‐limiting toxicity (DLT), and the plasma pharmacokinetics of irofulven in children ≤21 years of age with refractory/recurrent malignancies. Experimental Design Thirty‐five patients were entered into the study, of whom 34 were eligible. Patients received Irofulven daily × 5 days every 28 days over 10 min, following pre‐treatment with ondansetron (0.45 mg/kg) and dexamethasone (12 mg/m2). The initial dose of irofulven was 8 mg/m2 daily, with subsequent escalations to 10, 13, and 17 mg/m2. Plasma pharmacokinetic samples were obtained in a subset patients. Results Thirty‐two patients were assessable for toxicity, and 30 were assessable for response. In heavily pre‐treated patients, dose‐limiting thrombocytopenia was observed in two patients at the 8 mg/m2/day, and in one patient at the 6 mg/m2/day dose level. In less heavily pre‐treated patients, proteinuria and elevated creatinine were dose limiting in two patients at the 17 mg/m2/day dose level. At 13 mg/m2/day, constipation, hyperkalemia with elevated creatinine, and thrombocytopenia was dose limiting in three patients. There were no complete or partial responses. One patient with poorly differentiated carcinoma had stable disease and received 11 courses of therapy. Patients demonstrated a lower systemic exposure and greater clearance than adults treated at similar dose levels. Conclusion The MTD of irofulven administered daily × 5 every 28 days with concomitant ondansetron and dexamethasone is 6 mg/m2/day in heavily pre‐treated patients and 10 mg/m2/day in less heavily pre‐treated patients. © 2005 Wiley‐Liss, Inc.
ISSN:1545-5009
1545-5017
1096-911X
DOI:10.1002/pbc.20686