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

Inclusion Criteria:

- Diagnosis of 1 of the following:

NOTE: Histologic confirmation not required for intrinsic brain stem cell tumor, optic
pathway gliomas, pineal tumors and elevations of cerebrospinal fluid, and serum tumor
markers including alpha-fetoprotein or beta-human chorionic gonadotropin.

- Histologically confirmed relapsed or refractory solid tumors at original diagnosis
including CNS tumors* (Part 1 and Part 2a)

- Neurologic deficits in patients with CNS tumors must have been relatively stable
for ≥ 1 week

- Histologically confirmed soft tissue sarcoma, desmoplastic small round cell tumor, or
extraosseus Ewing sarcoma at original diagnosis including the following (Part 2b):

- Tumor in the head, neck, or extremity or fixed within the abdomen or pelvis that
it is not sensitive to motion artifact

- No isolated pulmonary metastases

- Disease with no known curative therapy or no therapy proven to prolong
survival with acceptable quality of life

- Measurable or evaluable disease (Part 1 and Part 2a)

- Measurable tumor that is ≥ 2 cm in its longest diameter (Part 2b)

- Patients must be:

- > 2 years of age and ≤ 21 years of age (Part 1 and Part 2a)

- > 2 years of age and ≤ 25 years of age (Part 2b)

- Body surface area ≥ 0.48 m^2 (Part 1 and Part 2b)

- For patients with CNS tumors or CNS metastasis, there must be no evidence of new
CNS hemorrhage of more than punctate size and/or > 3 foci of punctate hemorrhage
on baseline MRI for primary CNS tumors ≥ 14 days prior to study entry

- Karnofsky performance status (PS) 50-100% (> 16 years of age)

- Lansky PS 50-100% (≤ 16 years of age)

- Platelet count ≥ 100,000/mm^3 (transfusion independent)

- ANC ≥ 1,000/mm^3

- Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions)

- Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR serum creatinine based
on age/gender as follows:

- 0.6 mg/dL (1 to < 2 years of age)

- 0.8 mg/dL (2 to < 6 years of age)

- 1 mg/dL (6 to < 10 years of age)

- 1.2 mg/dL (10 to < 13 years of age)

- 1.5 mg/dL (male ) or 1.4 mg/dL (female) (13 to < 16 years of age)

- 1.7 mg/dL (male) or 1.4 mg/dL (female) ( ≥ 16 years of age)

- Urine protein:creatinine ratio < 1 OR urinalysis negative for protein OR 24-hour
urine protein level < 1 g

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- ALT ≤ 110 U/L

- PT and PTT ≤ 1.2 times ULN

- INR ≤ 1.2

- Serum albumin ≥ 2 g/dL

- No grade > 1 abnormalities of potassium, calcium, magnesium, or phosphorous

- Supplementation allowed

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Oral contraceptives are not considered effective

- Adequate cardiac function defined as any of the following:

- Shortening fraction of ≥ 27% by echocardiogram

- Ejection fraction of ≥ 50% by gated radionuclide study

- QTc < 450 msec

- No history of myocardial infarction, severe or unstable angina, or peripheral
vascular disease or familial QTc prolongation

- Adequate blood pressure defined as ≤ 95th percentile for age, height, and gender

- Known history of well-controlled seizures allowed

- Able to swallow whole tablets (Part 1 and Part 2b)

- No uncontrolled infection

- No evidence of active bleeding, intratumoral hemorrhage, or bleeding diathesis

- None of the following conditions within the past 6 months:

- Arterial thromboembolic events, including transient ischemic attack or
cerebrovascular accident

- Pulmonary embolism

- Deep vein thrombosis

- Other venous thromboembolic event

- No hemoptysis within the past 6 weeks

- No serious or non-healing wound, ulcer, or bone fracture

- No significant traumatic injury within the past 28 days

- No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
within the past 28 days

- No patients who, in the opinion of the investigator, may not be able to comply
with the safety monitoring requirements of the study

- No fine-needle aspiration within 48 hours before day 1 of therapy

- Fully recovered from all prior therapy (e.g., chemotherapy, immunotherapy, or
radiotherapy)

- At least 3 weeks since prior myelosuppressive chemotherapy (6 weeks for prior
nitrosourea)

- At least 7 days since prior hematopoietic growth factor

- At least 21 days since prior VEGF-Trap

- No prior pazopanib hydrochloride

- At least 7 days since prior VEGF-blocking tyrosine kinase inhibitor or other
biological agents

- At least 3 half-lives since prior monoclonal antibody, including bevacizumab

- At least 21 days since any other prior anticancer antibody therapy

- At least 2 weeks since prior local palliative radiotherapy (small port)

- At least 3 months since prior total-body irradiation, craniospinal radiotherapy,
or ≥ 50% radiotherapy to the pelvis

- At least 6 weeks since prior other substantial bone marrow radiotherapy

- At least 2 months since stem cell transplantation and no evidence of
graft-vs-host disease

- Thyroid replacement therapy allowed provided a stable dose has been received for
≥ 4 weeks

- No concurrent medication for cardiac function or hypertension

- Concurrent corticosteroids allowed provided dose is stable or decreasing for > 7
days (for patients enrolled in Part 1 and Part 2a of study)

- No concurrent corticosteroids for patients enrolled in Part 2b of the study

- No other concurrent anticancer agents or radiotherapy

- No other concurrent investigational drugs

- No concurrent enzyme-inducing anticonvulsants

- No concurrent anticoagulation therapy with coumadin and/or low molecular weight
heparin

- Prophylactic anticoagulation therapy (i.e., intraluminal heparin) of venous or
arterial access devices allowed

- No concurrent aspirin, ibuprofen, or other NSAIDs

- No concurrent drugs metabolized through several of the specific P450 cytochrome
isoform including inducers or inhibitors of CYP3A4

- No concurrent drugs with a known risk of torsades de pointes

- At least 28 days since prior major surgical procedure, laparoscopic procedure,
or open biopsy

- Port placement or central line placement 48 hours before day 1 of therapy allowed

- No core biopsy within the past 7 days