A Phase I Study of Pazopanib as a Single Agent for Children With Refractory Solid Tumors

Background:

• Pazopanib is a potent and selective multi-target receptor tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptors (VEGFR)-1, -2, and -3, c-kit and platelet derived growth factor (PDGF) receptors-alpha and -beta.
• Preclinical experiments demonstrate that pazopanib causes significant and dose-dependent inhibitory effects on cell proliferation and inhibition of VEGF-induced VEGFR-2 phosphorylation, growth inhibition of a variety of human tumor xenografts in mice, and inhibition of basic fibroblast growth factor-(bFGF) and VEGF-induced angiogenesis in murine models.
• Pazopanib has been evaluated in adult subjects with solid tumors in Phase I and II studies, and objective anti-tumor activity has been observed in a variety of tumor types.

Objectives:

Primary Objectives:

• To estimate maximum tolerated dose (MTD) and/or recommended Phase II dose of oral pazopanib administered on a once daily schedule to children with refractory solid tumors.
• To define the toxicities of oral pazopanib administered as either a tablet or suspension.
• To characterize the pharmacokinetics of oral pazopanib in children with refractory solid tumors.

Secondary Objectives:

• To preliminarily define the antitumor and biologic activity of oral pazopanib, and to explore the changes in tumor vascular permeability following initiation of pazopanib.
• To preliminarily assess VEGF haplotype/phenotype relationships in children with cancer.
• To explore pazopanib concentration-effect relationships with biomarkers and with clinical outcomes.

Eligibility:

• Part 1 (Phase I Dose Escalation) and 2a (Suspension Formulation Component): --Patients greater than 12 months and less than or equal to 21 years of age with measureable or evaluable relapsed or refractory solid tumors including CNS tumors with histologic verification except in patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with pineal tumors and elevation of tumor markers.
• Part 2b (Expanded Imaging Cohort): --Patients greater than 2 years and less than or equal to 25 years of age with histologically verified relapsed or refractory soft tissue sarcoma, desmoplastic small round cell tumor or extraosseus Ewing sarcoma with measurable disease (greater than or equal to 2 cm) in the head, neck, extremity or fixed within the thorax, abdomen or pelvis.
• Performance score: Karnofsky greater than or equal to 50% for patients 16 years of age; Lansky greater than or equal to 50 for patients less than or equal to 16 years of age.
• Must have fully recovered from acute toxic effects from all prior therapy which have been completed within the specified prior time frame. Have adequate organ function as determined by laboratory evaluation.

Design:

• This is a rolling six phase I trial design of pazopanib administered orally once daily continuously on a 28 day cycle.
• Therapy may continue for up to 24 cycles in the absence of progressive disease or unacceptable toxicity.
• Part 1 is the phase I dose escalation portion (Completed). Once the MTD or phase II recommended dose is defined, up to 16 additional patients will enroll in Part 2a to obtain safety and pharmacokinetic data for the suspension formulation. In addition, up to 10 patients with recurrent/refractory soft tissue sarcoma and a measurable lesion will be enrolled in Part 2b at the MTD or recommended Phase II dose to further explore changes in tumor vascular permeability using dynamic contrast enhanced MRI.
• Participation in correlative biology studies or pharmacokinetic studies will be optional in Part 1; pharmacokinetic studies will be required in Part 2a; and imaging and limited pharmacokinetic sampling will be required in Part 2b.