INCLUSION CRITERIA:
1. Age: Patients must be greater than or equal to 2 years of age and less than or equal to 21 years of age at the time of study entry.
2. Diagnosis: Patients must have had histologic verification of solid malignancy at original diagnosis. Patients with recurrent or refractory solid tumors are eligible, including primary CNS tumors or patients with known CNS metastases.
3. Disease Status: Patients must have either measurable or evaluable disease.
4. Therapeutic Options: Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life.
5. Performance Level: Karnofsky greater than or equal to 50 for patients greater than 10 years of age and Lansky greater than or equal to 50 for patients less than or equal to 10 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
6. Prior Therapy: Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
a. Myelosuppressive chemotherapy: Must not have received within 3 weeks of entry onto this study (6 weeks if prior nitrosourea).
b. Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor.
c. Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.
d. XRT: Greater than or equal to 2 wks for local palliative XRT (small port); greater than or equal to 6 months must have elapsed if greater than or equal to 50% radiation of pelvis; greater than or equal to 6 wks must have elapsed if other substantial BM radiation.
e. Stem Cell Transplant or Rescue without TBI: No evidence of active graft vs. host disease and greater than or equal to 3 months must have elapsed.
7. Organ Function Requirements:
-1. Adequate Bone Marrow Function Defined As:
a. Patients must have:
-Peripheral absolute neutrophil count (ANC) greater than or equal to 1000/microL.
-Platelet count greater than or equal to 100,000/microL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment.)
-Hemoglobin greater than or equal to 8.0 gm/dL (may receive RBC transfusions).
b. Patients with known bone marrow metastatic disease will be not be eligible.
-2. Adequate Renal Function Defined As:
- Creatinine clearance or radioisotope GFR greater than or equal to 70ml/min/1.73 m(2) or
-A serum creatinine based on age/gender as follows:
Age 2 to less than 6 years Maximum SerumCreatinine (mg/dL) Male 0.8 and Females 0.8
Age 6 to less than 10 years Maximum SerumCreatinine (mg/dL) Male 1 and Females 1
Age 10 to less than 13 years Maximum SerumCreatinine (mg/dL) Male 1.2 and Females 1.2
Age 13 to less than 16 years Maximum SerumCreatinine (mg/dL) Male 1.5 and Females 1.4
Age greater than or equal to 16 years Maximum SerumCreatinine (mg/dL) Male 1.7 and Females 1.4
The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC.
-3. Adequate Liver Function Defined As:
-Total bilirubin (sum of conjugated plus unconjugated) less than or equal to 1.5 times upper limit of normal (ULN) for age, and
-SGPT (ALT) less than or equal to 110 U/L (approx. 2.5 times ULN). For the purpose of this study, the ULN for SGPT is 45 U/L.
- Serum albumin greater than or equal to 2 g/dL.
-4. Adequate Cardiac Function Defined As:
-Shortening fraction or ejection fraction greater than the LLN (institutional norm), and
- Corrected QT interval less than or equal to 450 msec.
-5. Normal Pancreatic Function Defined As:
- Serum amylase less than 1.5 times ULN and
- Serum lipase less than or equal to 1.5 times ULN.
-6. Blood Pressure Within The Upper Limit Of Normal Defined as:
- A blood pressure (BP) less than or equal to the 95th percentile for age, height, and gender (Appendix IX) measured as described in Section 8.1, and not receiving medication for treatment of hypertension.
8. Informed Consent: All patients and/or their parents or legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
EXCLUSION CRITERIA:
1. Prior Anthracycline Treatment: Patients previously treated with anthracyclines (any dose) are not eligible.
2. Prior Cardiac Radiation: Patients previously treated with a radiation field that included the heart (including total body or craniospinal irradiation) are not eligible.
3. Pregnancy or Breast-Feeding: Animal studies indicate an increased risk of death of pregnant female rats and rabbits exposed to sunitinib. Cleft lip and palate were observed in some fetuses exposed in utero to sunitinib. There is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.
4. Concomitant Medications
-Growth factor(s): Growth factors that support platelet or white cell number or function must not have been administered within the past 7 days.
- Investigational Drugs: Patients who are currently receiving another investigational drug.
-Anti-cancer Agents: Patients who are currently receiving other anticancer agents.
-The following CYP3A4 inducers are prohibited 12 days before the start of sunitinib and during the study with sunitinib: rifampin, rifabutin, carbamazepine, phenobarbital, phenytoin, St. John's wort, efavirenz, and tipranavir.
-Anti-thrombotic and anti-platelet agents: warfarin (coumadin [Registered], heparin, low molecular weight heparin, aspirin, and/or ibuprofen, or other NSAIDs.
-The following CYP3A4 inhibitors are prohibited 7 days before the start of sunitinib and during the study with sunitinib: azole antifungals (itraconazole, ketoconazole); clarithromycin, erythromycin, diltiazem, verapamil, HIV protease inhibitors (indinavir, saquinavir, ritonavir, atazanavir, nelfinavir); delavirdine.
5. Infection: Patients who have an uncontrolled infection.
6. Pleural-based tumors: Pediatric patients treated on a phase II trial with imatinib had a higher than expected rate of hemorrhagic pleural effusions. Sunitinib inhibits two of the same receptor tyrosine kinases as imatinib, PDGFR and c-KIT. Patients with tumors involving or abutting the pleural surface will be excluded from study. Patients with pulmonary metastatic lesions, should be monitored closely for the development of hemorrhagic pleural effusions.
7. Patient size: Due to dosing limitations, patients with body surface area less than 0.5 m(2) will be excluded from study.
8. Patients who cannot swallow sunitinib capsules will be excluded from study.
9. Patients with a pre-existing thyroid abnormality (hyper- or hypothyroidism) with unstable thyroid function will be excluded from study. For the purposes of this study, unstable thyroid function will be defined as thyroid function abnormalities requiring more than one change in thyroid medication in the 6 months prior to study entry.
10. Patients with history of allergic reaction attributed to sunitinib or component of sunitinib capsules.
11. Prior use of sunitinib: Patients who have previously received sunitinib are not eligible for study.
12. Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.
13. Patients with known bone marrow metastases.
National Institutes of Health Clinical Center
Bethesda, Maryland 20892. Last update: 01/13/2009