ADVL0612: A Phase I Study of Sunitinib (SU11248), an Oral Multi-Targeted Tyrosine Kinase Inhibitor, in Children with Refractory Solid Tumors
Date Last Modified:
Date First Published: 1/29/2006
| Type | Status | Age Range (yrs.) | Sponsor | Protocol ID |
|---|
| Treatment | Active | 2 - 21 | COG | ADVL0612 |
Outline
This is a multicenter, dose-escalation study of sunitinib malate.
Patients receive oral sunitinib malate once daily on days 1-28. Treatment repeats every 42 days for up to 9 courses in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of sunitinib malate until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
Blood is collected on days 1, 7, 14, 21, and 28 of course 1 for pharmacokinetic studies using liquid chromatography/mass spectrometry.
After completion of study treatment, patients are followed for 30 days.
Objectives
Primary
- Determine the maximum tolerated dose and recommended phase II dose of sunitinib malate in pediatric patients with refractory solid tumors.
- Determine the toxicity of this regimen in these patients.
- Characterize the pharmacokinetics of this regimen in these patients.
Secondary
- Determine, preliminarily, the antitumor effects of this regimen in these patients.
Projected Accrual
A total of 42 patients will be accrued for this study.
Mechanism of Action for Sunitinib malate
Sunitinib malate is a receptor tyrosine kinase inhibitor involved in tumor proliferation and angiogenesis, specifically inhibiting platelet derived growth factor receptor, vascular endothelial growth factor receptor, stem cell factor receptor, Fms-like tyrosine kinase-3 receptor, and ret proto-oncogene.
Sunitinib malate is metabolized primarily by liver enzymes, particularly CYP3A4. Dose reduction with the CYP3A4 inhibitors is recommended, based on clinical symptoms. Concomitatnt treatment with dysrhythmic drugs, i.e.
terfenadine, quinidine, procainamide, sotalol, probucol, bepridil, haloperidol, risperidone, and indapamide, is not recommended.
Sunitinib metabolism depends on cytochrome P450 3A4. Significant changes in plasma sunitinib levels have been documented with inhibitors and inducers of cytochrome P450 3A4. These drugs should be avoided on study.
Entry Criteria
Disease Characteristics:
- Histologically confirmed solid tumor:
- Recurrent or progressive 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
- No primary CNS tumors or known CNS metastases
- No tumors involving the pleural surface
Patient Characteristics:
Age
Performance status
- Karnofsky 50-100% (for patients > 10 years of age)
- Lansky 50-100% (for patients ≤ 10 years of age)
Life expectancy
Hematopoietic
- Absolute neutrophil count ≥ 1,000/mm3*
- Platelet count ≥ 100,000/mm3 (transfusion independent)*
- Hemoglobin ≥ 8.0g/dL (transfusions allowed)*
NOTE: *For patients without bone marrow involvement
Hepatic
- Bilirubin ≤ 1.5 times upper limit of normal (ULN)
- ALT ≤ 2.5 times ULN
- Albumin ≥ 2.0 g/dL
Pancreatic
- Amylase ≤ 1.5 times ULN
- Lipase ≤ 1.5 times ULN
Renal
- Creatinine clearance or radioisotope glomerular filtration rate ≥ 70mL/min/1.73m² or
- Creatinine based on age as follows:
- No greater than 0.8 mg/dL (for patients age 2 to 5)
- No greater than 1.0 mg/dL (for patients age 6 to 9)
- No greater than 1.2 mg/dL (for patients age 10 to 12)
- No greater than 1.5 mg/dL (male) or 1.4 mg/dL (female) (for patients age 13 to 15)
- No greater than 1.7 mg/dL (male) or 1.4 mg/dL (female) (for patients age 16 and over)
Cardiovascular
- LVEF or shortening fraction normal
- Corrected QT interval ≤ 450 msec
Pulmonary
Other
- Body surface area ≥ 0.5 m²
- Not pregnant or nursing
- Fertile patients must use effective contraception
- Able to swallow sunitinib malate capsules
- No uncontrolled infection
- No history of allergic reaction attributed to sunitinib malate or component of sunitinib malate capsules
- No pre-existing thyroid abnormality (hyper- or hypothyroidism) with unstable thyroid function
Prior/Concurrent Therapy:
Biologic therapy
- Recovered from all prior therapy
- At least 1 week prior and no concurrent hematopoietic growth factors
- At least 1 week since prior antineoplastic biologic agents
- At least 3 months since prior stem cell transplantation or rescue (without total-body irradiation) and no evidence of graft-vs-host disease
- No other concurrent biologic therapy
- No prior sunitinib malate
Chemotherapy
- Recovered from all prior therapy
- At least 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas)
- No other concurrent chemotherapy
Endocrine therapy
- No other concurrent immunotherapy
Radiotherapy
- Recovered from all prior therapy
- At least 2 weeks since prior local palliative small port radiotherapy
- At least 6 months since prior total-body irradiation, craniospinal radiotherapy, or radiation to > 50% of pelvis
- At least 6 weeks since other prior substantial bone marrow radiotherapy
- No concurrent radiotherapy
Surgery
- No concurrent major surgery
Other
- 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 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 other concurrent investigational drugs Who should I contact for more information?
Rebecca Turner, MS, CCRP
Cincinnati Children's Hospital Medical Center
Division of Hematology / Oncology
3333 Burnet Ave., Cincinnati, OH 45229-3039
Phone: 513-636-2279
cancer@cchmc.org
