Originally published as JCO Early Release 10.1200/JCO.2007.15.2306 on September 15 2008

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Pediatric Phase I and Pharmacokinetic Study of Erlotinib Followed by the Combination of Erlotinib and Temozolomide: A Children's Oncology Group Phase I Consortium Study

Regina I. Jakacki, Marta Hamilton, Richard J. Gilbertson, Susan M. Blaney, Jean Tersak, Mark D. Krailo, Ashish M. Ingle, Stephan D. Voss, Janet E. Dancey, Peter C. Adamson

From the Children's Hospital of Pittsburgh, Pittsburgh; Children's Hospital of Philadelphia, Philadelphia, PA; OSI Pharmaceuticals, Boulder, CO; St Jude Children's Research Hospital, Memphis, TN; Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX; Children's Hospital Boston, Boston, MA; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD; Children's Oncology Group, Arcadia, CA

Corresponding author: Regina I. Jakacki, MD, Children's Hospital of Pittsburgh, 3705 Fifth Ave, Pittsburgh, PA 15213; e-mail: regina.jakacki{at}chp.edu

Purpose We conducted a phase I and pharmacokinetic study of the epidermal growth factor receptor (EGFR) inhibitor erlotinib as a single agent and in combination with temozolomide in children with refractory solid tumors.

Patients and Methods Erlotinib was administered orally once daily to cohorts of three to six children for a single 28-day course. Patients then received the combination of daily erlotinib and temozolomide daily for 5 days for all subsequent 28-day courses. An oral erlotinib solution was administered during the dose-finding phase and a tablet formulation was subsequently studied at the maximum-tolerated dose (MTD). Pharmacokinetic studies and ERBB-receptor expression and signaling studies were performed.

Results Forty-six patients, median age 11.5 years, received erlotinib at doses of 35, 50, 65, 85, or 110 mg/m²/d. At 110 mg/m²/d, two of four patients had dose-limiting toxicity (DLT) consisting of rash and hyperbilirubinemia, whereas one of six patients developed dose-limiting rash at 85 mg/m²/d. The most frequent non-DLTs included diarrhea, rash, and hyperbilirubinemia. The combination of erlotinib and temozolomide was well tolerated. The median apparent erlotinib clearance was 3.1 L/h/m² and the median terminal half-life was 8.7 hours. One patient with a neurocytoma had stable disease for 19 months, two patients with neuroblastoma remained on study for 23 and 24 months, and one patient with myoepithelioma had a mixed response.

Conclusion The recommended phase II dose of erlotinib in recurrent pediatric solid tumors is 85 mg/m²/d, either alone or in combination with temozolomide.

published online ahead of print at www.jco.org on September 15, 2008.

Supported in part by Grant No. CA97452 from the National Cancer Institute, Bethesda, MD; the Molecular Clinical Trials Core at St Jude's is supported by the St Jude Cancer Center Core Grant No. (P30CA021765) and the American Lebanese and Syrian Associated Charities.

Presented at 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

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

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