Phase I trial and pharmacokinetic study of bevacizumab in pediatric patients with refractory solid tumors: a Children's Oncology Group Study.
OBJECTIVE
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.


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.


CONCLUSIONS
BV is well tolerated in children. Phase II pediatric studies of BV in combination with chemotherapy in dosing schedules similar to adults are planned.
Glade Bender
Julia L
JL
College of Physicians and Surgeons of Columbia University, New York, NY, USA. jg589@columbia.edu
Adamson
Peter C
PC
Reid
Joel M
JM
Xu
Lu
L
Baruchel
Sylvain
S
Shaked
Yuval
Y
Kerbel
Robert S
RS
Cooney-Qualter
Erin M
EM
Stempak
Diana
D
Chen
Helen X
HX
Nelson
Marvin D
MD
Krailo
Mark D
MD
Ingle
Ashish M
AM
Blaney
Susan M
SM
Kandel
Jessica J
JJ
Yamashiro
Darrell J
DJ
D000293:Adolescent; D000328:Adult; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D019540:Area Under Curve; D000068258:Bevacizumab; D002648:Child; D002675:Child, Preschool; D005260:Female; D006207:Half-Life; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D009367:Neoplasm Staging; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D012307:Risk Factors; D015996:Survival Rate; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab