Pazopanib led to disease control in 20% of children with refractory solid tumors.

  • Major finding: Pazopanib led to disease control in 20% of children with refractory solid tumors.

  • Mechanism: Pazopanib reduced plasma-soluble VEGFR2 and endoglin levels and tumor blood volume and permeability.

  • Impact: Pazopanib may have an antiangiogenic effect and clinical benefit in the pediatric setting.

Pazopanib is a multitargeted inhibitor of VEGF receptors as well as several other receptor tyrosine kinases involved in angiogenesis that has been approved by the FDA for treatment of adults with renal cell carcinoma or refractory advanced soft-tissue sarcomas. Glade Bender and colleagues conducted a phase I dose-escalation study to evaluate the toxicities, pharmacokinetics, and pharmacodynamics of two different formulations of pazopanib (tablet and suspension) in 51 children with soft-tissue sarcomas or other refractory solid tumors. Dose-limiting toxicities included elevation of lipase, amylase, or alanine transaminase; proteinuria; and hypertension; other hematologic and nonhematologic toxicities were generally mild. Although there were no significant differences in the pharmacokinetic characteristics of the tablet and suspension formulations, there was a high degree of intrapatient variability and a lack of a dose-dependent increase in steady-state plasma concentration, which could be attributable to the large age range of the patients enrolled in the trial (3.8 to 23.9 years). Two (4%) patients, one with desmoplastic small round cell tumor and one with hepatoblastoma, had partial responses, and eight (16%) patients, seven of whom had soft-tissue sarcomas, had stable disease for 6 months or longer. Overall, pazopanib treatment significantly reduced levels of plasma-soluble VEGFR2 and the vascular endothelium component endoglin, and increased levels of placenta growth factor 1, which antagonizes VEGF-induced angiogenesis. Tumor blood volume and vascular permeability also were significantly decreased in patients evaluable by dynamic contrast-enhanced MRI, further indicating that pazopanib has on-target antiangiogenic activity in pediatric patients with refractory solid tumors. These results support further development of pazopanib in this population.

Glade Bender JL, Lee A, Reid JM, Baruchel S, Roberts T, Voss SD, et al. Phase I pharmacokinetic and pharmacodynamic study of pazopanib in children with soft tissue sarcoma and other refractory solid tumors: a Children's Oncology Group phase I consortium report. J Clin Oncol 2013 Jul 15 [Epub ahead of print].