CLINICAL TRIAL: A PHASE I STUDY OF SUNITINIB (SU11248), AN ORAL MULTI-TARGETED T

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Sunitinib is an oral receptor tyrosine kinase inhibitor with specific activity against VEGFR, PDGFR, c- KIT, and flt-3. The drug has recently been approved for use in adults with refractory GIST or metastatic renal cell carcinoma. A number of receptors inhibited by sunitinib have been implicated in several pediatric solid tumors. Aside from limited compassionate use in patients with refractory GIST between 12 and 17 years of age, sunitinib has not yet been formally tested in children. This study will be a phase I dose escalation trial of oral sunitinib in children with refractory solid tumors. We aim to determine the maximum tolerated dose of sunitinib when given on the recommended adult schedule of once daily for 28 days followed by 14 days of rest. The starting dose of sunitinib will be 20 mg/m2/day given orally once daily. The maximum tolerated dose will be determined based on toxicities reported during the first 42- day cycle of treatment. We will also report the toxicity of sunitinib in patients who receive more than one cycle of therapy. Pharmacokinetic studies will be performed during cycle 1 with the aim of reporting standard pharmacokinetic parameters. Pharmacodynamic studies will also be performed, including measurements of circulating endothelial cells, peripheral blood monocytes, and plasma levels of VEGF, placental growth factor, soluble VEGFR1, and soluble VEGFR2. We will also explore changes in tumor vascular permeability in response to sunitinib using DCE-MRI during cycle 1 of treatment. Finally, within the confines of a phase I study, we plan to report the activity profile of sunitinib in pediatric solid tumors. This trial is a phase I dose escalation study of sunitinib in children with refractory solid tumors. We intend to initiate treatment at 70% of the adult MTD with inter-patient dose escalation to a maximum of 140% of the adult MTD. Given the risk of tumor associated bleeding, patients with primary CNS tumors or known CNS metastases will be excluded. We will evaluate DCE-MRI, circulating endothelial cells, and plasma angiogenic factors as surrogate markers of antiangiogenic effect. We will also explore changes in tumor vascular permeability in response to sunitinib using DCE-MRI during cycle 1 of treatment. Finally, within the confines of a phase I study, we plan to report the activity profile of sunitinib in pediatric solid tumors. SPECIFIC AIMS:Primary 1. To determine the maximum tolerated dose (MTD) and recommend a Phase 2 dose of sunitinib administered orally once daily for 28 days followed by 14 days of rest in children with refractory solid tumors. 2. To define and describe the toxicities of sunitinib administered on this schedule. 3. To characterize the pharmacokinetics of oral sunitinib in children with refractory solid tumors. Secondary Aims: 1. To determine, in a preliminary manner, the antitumor effects of oral sunitinib in children with refractory solid tumors. 2. To describe changes in peripheral blood monocyte counts, circulating endothelial cells, and plasma angiogenic factors during treatment with sunitinib. 3. To explore changes in tumor vascular permeability using dynamic contrastenhanced MRI (DCE-MRI) in patients receiving sunitinib.