A Phase I Study of Sunitinib (SU11248), an Oral Multi-Targeted Tyrosine Kinase Inhibitor, in Children With Refractory Solid Tumors

Inclusion Criteria:

- Histologically confirmed solid tumor (not required for patients with intrinsic brain
stem tumors or optic pathway gliomas)

- Recurrent or refractory disease

- Measurable or evaluable disease

- No known curative therapy or therapy proven to prolong survival with an acceptable
quality of life exists

- Patients with metastatic bone marrow disease are eligible but are not evaluable for
hematologic toxicity

- Must not be refractory to red blood cell or platelet transfusions

- Primary CNS tumors or known CNS metastases allowed

- Neurological deficits must have been relatively stable for ≥ 1 week before study
enrollment

- No imaging evidence of prior intracranial hemorrhage

- No evidence of new CNS hemorrhage on baseline MRI obtained within 14 days before
study enrollment (ECHO gradient MRI sequences per institutional guidelines
required for evaluation of CNS hemorrhage)

- The presence of small punctuate CNS hemorrhage on these scans will exclude
a patient from participation

- No known bone marrow metastatic disease

- No tumors involving the pleural surface

- Karnofsky performance status (PS) 50-100% (> 10 years of age) OR Lansky PS 50-100% (≤
10 years of age)

- Absolute neutrophil count ≥ 1,000/mm³*

- Platelet count ≥ 100,000/mm³ (transfusion independent)*

- Hemoglobin ≥ 8.0 g/dL (transfusions allowed)*

- Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR
creatinine based on age/gender as follows:

- No greater than 0.8 mg/dL (2 to 5 years of age)

- No greater than 1 mg/dL (6 to 9 years of age)

- No greater than 1.2 mg/dL (10 to 12 years of age)

- No greater than 1.5 mg/dL (male) OR 1.4 mg/dL (female) (13 to 15 years of age)

- No greater than 1.7 mg/dL (male) OR 1.4 mg/dL (female) (≥ 16 years of age)

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

- ALT and AST ≤ 2.5 times ULN (≤ 5 times ULN for liver metastases)

- Albumin ≥ 2 g/dL

- LVEF or shortening fraction normal

- Corrected QT interval ≤ 450 msec

- Amylase ≤ 1.5 times ULN

- Lipase ≤ 1.5 times ULN

- Body surface area ≥ 0.5 m² (≥ 0.4 m² for part B)

- Blood pressure within ULN

- Not pregnant or nursing

- Fertile patients must use effective contraception

- No uncontrolled infection

- Able to swallow sunitinib malate capsules (part A only)

- No pre-existing thyroid abnormality (hyper- or hypothyroidism) with unstable thyroid
function

- No prior CNS hemorrhage

- No history of allergic reaction attributed to sunitinib malate or component of
sunitinib malate capsules

- No allergy to both applesauce and yogurt (part B only)

- Recovered from prior therapy

- No prior sunitinib malate

- No prior anthracycline (any dose)

- No prior radiotherapy to a radiation field that included the heart(including total
body or craniospinal irradiation)

- At least 3 months since prior stem cell transplantation or rescue (without total-body
irradiation) and no evidence of graft-vs-host disease

- At least 2 weeks since prior local, palliative, small-port radiotherapy (at least 6
months for radiation to ≥ 50% of pelvis)

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

- At least 3 weeks since prior myelosuppressive therapy (6 weeks for nitrosoureas)

- At least 1 week since prior antineoplastic biologic agents

- At least 1 week since prior and no concurrent hematopoietic growth factors

- At least 12 days since prior and no concurrent CYP3A4 inducers, including any of the
following:

- Rifampin

- Rifabutin

- Carbamazepine

- Phenobarbital

- Phenytoin

- Hypericum perforatum (St. John's wort)

- Efavirenz

- Tipranavir

- At least 7 days since prior and no concurrent CYP3A4 inhibitors, including any of the
following:

- Azole antifungals (e.g., itraconazole or ketoconazole)

- Clarithromycin

- Erythromycin

- Diltiazem

- Verapamil

- HIV protease inhibitors (e.g., indinavir, saquinavir, ritonavir, atazanavir, or
nelfinavir)

- Delavirdine

- No more than 1 concurrent antihypertensive agent

- No concurrent major surgery

- No concurrent antithrombotic or antiplatelet agents, including any of the following:

- Warfarin

- Heparin

- Low molecular weight heparin

- Acetylsalicylic acid (aspirin)

- Ibuprofen

- Other nonsteroidal anti-inflammatory drugs

- No concurrent medication for the treatment of hypertension

- No other concurrent investigational drugs

- No other concurrent anticancer agents, including chemotherapy, radiotherapy,
immunotherapy, or biologic therapy