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 12 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.