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Phase I Trial and Pharmacokinetic Study of Bevacizumab in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Study

Julia L. Glade Bender, Peter C. Adamson, Joel M. Reid, Lu Xu, Sylvain Baruchel, Yuval Shaked, Robert S. Kerbel, Erin M. Cooney-Qualter, Diana Stempak, Helen X. Chen, Marvin D. Nelson, Mark D. Krailo, Ashish M. Ingle, Susan M. Blaney, Jessica J. Kandel, Darrell J. Yamashiro

From the College of Physicians and Surgeons of Columbia University, New York, NY; Children's Hospital of Philadelphia, Philadelphia, PA; Mayo Clinic and Foundation, Rochester, MN; Genentech Inc, South San Francisco; Children's Hospital, Los Angeles; Children's Oncology Group, Arcadia, CA; Hospital for Sick Children; Sunnybrook and Women's College Health Sciences Centre, Toronto, Canada; National Cancer Institute, Bethesda, MD; and the Texas Children's Cancer Center, Houston, TX

Corresponding author: Julia Glade Bender, MD, Pediatric Oncology, Irving Pavilion 7, 169 Ft. Washington Ave, New York, NY 10032; e-mail: jg589{at}columbia.edu.

Purpose We conducted a pediatric phase I trial of the vascular endothelial growth factor (VEGF)–neutralizing antibody bevacizumab (BV). Primary aims included estimating the maximum-tolerated dose (MTD) and determining the dose-limiting toxicities (DLTs), pharmacokinetics, and biologic effects of BV in children with cancer.

Patients and Methods BV (5, 10, 15 mg/kg) was administered intravenously every 2 weeks in 28-day courses to children with refractory solid tumors.

Results Twenty-one patients enrolled, 20 (median age, 13 years) were eligible, and 18 completed one course and were fully assessable for toxicity. A total of 67 courses were administered (median, three courses per patient; range, one to 16 courses). Treatment was well tolerated with no DLTs observed. Non-DLTs included infusional reaction, rash, mucositis, proteinuria, and lymphopenia. Increases in systolic and diastolic blood pressure not meeting Common Terminology Criteria for Adverse Events (CTCAEv3) pediatric-specific criteria for hypertension were observed. There was no hemorrhage or thrombosis. Growth perturbation was not detected in a limited sample over the first course. The serum exposure to BV as measured by area under the concentration-time curve (AUC) seemed to increase in proportion to dose. The median clearance of BV was 4.1 mL/d/kg (range, 3.1 to 15.5 mL/d/kg), and the median half-life was 11.8 days (range, 4.4 to 14.6 days). No objective responses were observed. Exploratory analyses on circulating endothelial mobilization and viability are consistent with the available adult data.

Conclusion BV is well tolerated in children. Phase II pediatric studies of BV in combination with chemotherapy in dosing schedules similar to adults are planned.

Supported by Grant No. CA97452 from the National Cancer Institute, Bethesda, MD; the Pediatric Cancer Foundation, Scarsdale, NY; Genentech Inc, South San Francisco, CA; and COG Grant No. CA 98543. A complete listing of grant support for research conducted by CCG and POG before initiation of the COG grant in 2003 is available online at http://www.childrensoncologygroup.org/admin/grantinfo.htm.

Sponsored by the National Cancer Institute (NCI) Cancer Therapy Evaluation Program, under the Clinical Research and Development Agreement (CRADA) between NCI and Genentech Inc.

Presented in part at the 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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