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Phase I Clinical Trial of Oxaliplatin in Children and Adolescents With Refractory Solid Tumors

Sheri L. Spunt, Burgess B. Freeman, III, Catherine A. Billups, Valerie McPherson, Raja B. Khan, Charles B. Pratt, Clinton F. Stewart

From the Departments of Oncology, Pharmaceutical Sciences, Biostatistics, and Radiological Sciences, St Jude Children's Research Hospital; and the Department of Pediatrics and the Center for Pediatric Pharmacokinetics and Therapeutics, The University of Tennessee College of Medicine, Memphis, TN

Address reprint requests to Sheri L. Spunt, MD, Department of Oncology, St Jude Children's Research Hospital, 332 N Lauderdale St, Memphis, TN 38105-2794; e-mail: sheri.spunt{at}stjude.org

Purpose: To evaluate the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), and adverse effect profile of oxaliplatin in pediatric patients with refractory solid tumors and to determine whether carbamazepine reduces oxaliplatin-induced neurotoxicity.

Patients and Methods: Three regimens of oxaliplatin (given intravenously over 2 hours) were tested: regimen A (100 mg/m², 130 mg/m², or 160 mg/m² every 3 weeks to determine the MTD of oxaliplatin); regimen B (to determine whether carbamazepine starting 24 hours before and ending 48 hours after oxaliplatin reduced the dose-limiting neurotoxicity and increased the MTD of regimen A); and regimen C (to evaluate the safety of a fixed dose two-thirds the MTD of regimen A given every 2 weeks [more frequent administration but comparable dose intensity]).

Results: Twenty-six patients were enrolled on regimens A (n = 11), B (n = 6), and C (n = 9). The DLT was grade 3 pharyngolaryngeal dysesthesia, sensory neuropathy, and ataxia at 160 mg/m². The MTD was 130 mg/m² every 3 weeks. At the MTD, the median clearance rate of ultrafiltrable platinum was 9.7 L/h/m² (range, 6.5 to 15.5 L/h/m²). Addition of carbamazepine permitted dose escalation to 160 mg/m² without DLT. DLT was not observed with a fixed dose of 85 mg/m² given every 2 weeks. On all regimens, hematologic toxicity was mild. No significant nephrotoxicity, ototoxicity, or cumulative neurologic toxicity was observed.

Conclusion: The DLT, MTD, PK, and adverse effect profile of oxaliplatin in pediatric patients with refractory solid tumors are similar to those observed in adults. Carbamazepine may reduce the dose-limiting neurotoxicity of oxaliplatin.

Deceased.

Supported by Cancer Center Grant No. CA 23099 and Cancer Center Support Grant No. P30 CA 21765 from the National Cancer Institute, and by the American Lebanese Syrian Associated Charities.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.