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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 舒尼替尼是一种口服受体酪氨酸激酶抑制剂，对VEGFR、PDGFR、c-KIT和flt-3具有特异性活性。该药物最近已被批准用于患有难治性GIST或转移性肾细胞癌的成人。舒尼替尼抑制的许多受体与几种儿科实体瘤有关。除了在12至17岁的难治性GIST患者中有限的同情使用外，舒尼替尼尚未在儿童中进行正式测试。本研究将是口服舒尼替尼治疗难治性实体瘤儿童的I期剂量递增试验。我们的目的是确定舒尼替尼的最大耐受剂量时，推荐的成人时间表，每天一次，28天，然后休息14天。舒尼替尼的起始剂量为20 mg/m2/天，每日一次口服给药。最大耐受剂量将根据前42天治疗周期内报告的毒性确定。我们还将报告舒尼替尼在接受超过一个周期治疗的患者中的毒性。将在第1周期进行药代动力学研究，目的是报告标准药代动力学参数。还将进行药效学研究，包括测量循环内皮细胞、外周血单核细胞和VEGF、胎盘生长因子、可溶性VEGFR 1和可溶性VEGFR 2的血浆水平。我们还将在第1个治疗周期中使用DCE-MRI探索肿瘤血管通透性对舒尼替尼的反应变化。最后，在I期研究的范围内，我们计划报告舒尼替尼在儿科实体瘤中的活性特征。 本试验是舒尼替尼治疗儿童难治性实体瘤的I期剂量递增研究。我们打算以成人MTD的70%开始治疗，患者间剂量递增至成人MTD的最大140%。考虑到肿瘤相关出血的风险，将排除患有原发性CNS肿瘤或已知CNS转移的患者。 我们将评价DCE-MRI、循环内皮细胞和血浆血管生成因子作为抗血管生成效应的替代标志物。我们还将在第1个治疗周期中使用DCE-MRI探索肿瘤血管通透性对舒尼替尼的反应变化。最后，在I期研究的范围内，我们计划报告舒尼替尼在儿科实体瘤中的活性特征。 具体目标：初级1。确定难治性实体瘤儿童的最大耐受剂量（MTD），并推荐舒尼替尼的II期剂量，每日一次口服给药，持续28天，随后停药14天。 2.定义并描述按此方案给药的舒尼替尼的毒性。 3.描述口服舒尼替尼在儿童难治性实体瘤中的药代动力学特征。 次要目标：1。初步确定口服舒尼替尼对儿童难治性实体瘤的抗肿瘤作用。 2.描述舒尼替尼治疗期间外周血单核细胞计数、循环内皮细胞和血浆血管生成因子的变化。 3.采用动态增强MRI（DCE-MRI）研究舒尼替尼治疗患者肿瘤血管通透性的变化。

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.