CLINICAL TRIAL: H-25421: ADVL0815: A PHASE I STUDY OF PAZOPANIB AS A SINGLE AGE

临床试验：H-25421：ADVL0815：单龄帕唑帕尼的 I 期研究

• 批准号: 8356731
• 负责人: PATRICK THOMPSON
• 金额: $ 0.95万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356731
• 关键词: Abdomen; Adult; Age; Biology; Blood specimen; Clinical Research; Clinical Trials; Clinical Trials Design; Common Terminology Criteria for Adverse Events; Consent; Data; Dose; Drug Formulations; Drug Kinetics; Endothelial Cells; Fibroblast Growth Factor 2; Funding; Grant; Growth; Haplotypes; Head and neck structure; Human; Image; Inhibition of Cell Proliferation; Lesion; Limb structure; Magnetic Resonance Imaging; Measurable; Measurement; Modeling; Morphologic artifacts; Motion; Mus; National Center for Research Resources; Patients; Pelvis; Phase; Phase I Clinical Trials; Phosphorylation; Placental Growth Factor; Plasma; Platelet-Derived Growth Factor Receptor; Principal Investigator; Progressive Disease; Proto-Oncogene Protein c-kit; Recurrence; Refractory; Research; Research Infrastructure; Resources; Safety; Sampling; Solid Neoplasm; Source; Suspension substance; Suspensions; Toxic effect; Tyrosine Kinase Inhibitor; United States National Institutes of Health; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Vascular Permeabilities; angiogenesis; antiangiogenesis therapy; base; cancer therapy; cohort; cost; monocyte; peripheral blood; phase 1 study; pre-clinical; receptor; research study; response; sarcoma; soft tissue; tumor; tumor xenograft

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Several recent studies have validated anti-angiogenesis by vascular endothelial growth factor (VEGF) blockade as effective cancer therapy. Pazopanib (GW786034) is a potent and selective multi-target receptor tyrosine kinase inhibitor (TKI) of VEGF receptors (VEGFR)-1, -2 and -3, c-kit and platelet derived growth factor (PDGF) receptors- and - . Preclinical experiments demonstrate that pazopanib causes significant and dose-dependent inhibitory effects on cell proliferation and inhibition of vascular endothelial growth factor (VEGF)-induced VEGFR-2 phosphorylation, growth inhibition of a variety of human tumor xenografts in mice, and inhibition of basic fibroblast growth factor- (bFGF) and VEGF induced angiogenesis in murine models. Pazopanib has been evaluated in adult subjects with solid tumors in Phase I and II studies and objective anti-tumor activity has been observed in a variety of tumor types. Pazopanib as a single agent will be administered orally on a once daily basis. Treatment cycles will be defined as 28 days in duration. Patients may receive a total of 24 cycles of therapy with pazopanib in the absence of progressive disease or unacceptable toxicity. Patients will be accrued to a dose level in cohorts of 2 to 6 using the rolling six Phase I trial design. Toxicity will be graded using CTCAE version 3.0 and response will be assessed using RECIST. Part 1 (Phase I Dose Escalation): The starting dose of pazopanib will be 275mg/m2/dose, which is approximately 60% of the adult recommended dose. Escalations in subsequent cohorts will occur in increments of approximately 30%. There will be no intrapatient dose escalation. In consenting patients, blood samples will be obtained for the pharmacokinetic analysis and correlative biology studies including VEGF haplotype, plasma levels of VEGF, placental growth factor (PlGF), soluble VEGFR1, and soluble VEGFR2 and measurement of circulating endothelial cells and peripheral blood monocytes. Changes in tumor vascular permeability in response to pazopanib will also be explored using DCE-MRI. Part 2a (Suspension Formulation Component): Once the MTD or highest dose level has been reached, the cohort will be expanded in order to obtain additional safety information and pharmacokinetic data for the suspension formulation. Pharmacokinetic studies will be required in all patients who participate in this component of the trial. Part 2b (Expanded Imaging Cohort): In addition, at the MTD or recommended Phase II dose, a cohort of up to 10 patients with recurrent/refractory soft tissue sarcoma and a measurable (at least 2 cm) lesion in the head, neck, extremity or fixed within the abdomen or pelvis such that is not sensitive to motion artifact will be accrued to further explore changes in tumor vascular permeability using dynamic contrast enhanced MRI (DCE-MRI). Imaging studies and limited pharmacokinetic sampling will be required in all patients who participate in this component of the trial.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 最近的几项研究已经验证了通过血管内皮生长因子（VEGF）阻断的抗血管生成作为有效的癌症治疗。帕唑帕尼（GW 786034）是一种有效的和选择性的多靶点受体酪氨酸激酶抑制剂（TKI）的VEGF受体（VEGFR）-1，-2和-3，c-kit和血小板衍生生长因子（PDGF）受体-和-。临床前实验表明，帕唑帕尼对细胞增殖和血管内皮生长因子（VEGF）诱导的VEGFR-2磷酸化的抑制、小鼠中多种人肿瘤异种移植物的生长抑制以及鼠模型中碱性成纤维细胞生长因子（bFGF）和VEGF诱导的血管生成的抑制具有显著的剂量依赖性抑制作用。帕唑帕尼已在I期和II期研究中在患有实体瘤的成人受试者中进行了评估，并在多种肿瘤类型中观察到了客观的抗肿瘤活性。 帕唑帕尼作为单一药剂将每日一次口服施用。治疗周期将定义为持续时间为28天。患者可在没有进行性疾病或不可接受的毒性的情况下接受总共24个周期的帕唑帕尼治疗。使用滚动6期I期试验设计，患者将在2至6个队列中累积至一个剂量水平。将使用CTCAE 3.0版对毒性进行分级，并使用RECIST评估缓解。 第1部分（I期剂量递增）：帕唑帕尼的起始剂量为275 mg/m2/剂，约为成人推荐剂量的60%。后续队列中的递增将以约30%的增量进行。将不进行患者内剂量递增。在知情同意的患者中，将获得血液样本用于药代动力学分析和相关生物学研究，包括VEGF单倍型、VEGF、胎盘生长因子（PlGF）、可溶性VEGFR 1和可溶性VEGFR 2的血浆水平以及循环内皮细胞和外周血单核细胞的测量。还将使用DCE-MRI探索肿瘤血管通透性响应于帕唑帕尼的变化。 第2a部分（混悬液制剂组分）：一旦达到MTD或最高剂量水平，将扩展队列，以获得混悬液制剂的其他安全性信息和药代动力学数据。将需要对参加本试验这一部分的所有患者进行药代动力学研究。 部分2b（扩展成像队列）：此外，在MTD或推荐的II期剂量下，最多10例复发性/难治性软组织肉瘤和可测量的（至少2 cm）头部、颈部病变，四肢或固定在腹部或骨盆内，使得对运动伪影不敏感，以使用动态对比进一步探索肿瘤血管渗透性的变化增强MRI（DCE-MRI）。需要对参加本试验这一部分的所有患者进行影像学研究和有限的药代动力学采样。