Correlative Studies for NCI Study#7916: Phase I Clinical Trial of Intravenous FAU

NCI研究的相关研究

• 批准号: 7761433
• 负责人: PATRICIA M. LORUSSO
• 金额: $ 33.44万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7761433
• 关键词: 2' -Deoxythymidine; Aftercare; Antineoplastic Agents; Biodistribution; Biological Assay; Biopsy; Cancer Patient; Cancer Therapy Evaluation Program; Cause of Death; Cell Death; Clinical; Clinical Trials; Correlative Study; DNA; Diagnostic; Dose; Dose-Limiting; Drug Kinetics; Fluorouracil; Funding; Future; Hour; Human; Image; Infusion procedures; Institutes; Intravenous; Investigation; Kinetics; Label; Lead; Malignant Neoplasms; Maximum Tolerated Dose; Measurement; Measures; Messenger RNA; Metabolic Pathway; Metabolism; National Cancer Institute; Normal tissue morphology; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Phosphotransferases; Physiology; Pilot Projects; Positron; Positron-Emission Tomography; Prodrugs; Proteins; Pyrimidine Nucleosides; Radiolabeled; Radiopharmaceuticals; Research Design; Resistance; Safety; Services; Solid Neoplasm; Staging; Suicide; Surrogate Endpoint; Testing; Therapeutic; Therapeutic Agents; Thymidylate Synthase; Thymidylate Synthase Inhibitor; Time; Tissues; Toxic effect; Tracer; Translational Research; Tumor Tissue; Unresectable; Up-Regulation; Uracil; Vertebral column; base; cancer therapy; cytotoxicity; design; drug mechanism; effective therapy; in vivo; neoplastic cell; novel; oncology; overexpression; palliative; patient population; preclinical study; public health relevance; radiotracer; research study; response; tool; tumor; tumor progression; uptake

DESCRIPTION (provided by applicant): The thymidylate synthase (TS) inhibitor 5-fluorouracil (5FU) is the "backbone" of cancer treatment in many malignancies. Unfortunately, tumors can be resistant to 5FU due to upregulation of TS. FAU (1-(2'-deoxy-2'- fluoro-2-D-arabinofuranosyl) uracil) is a pyrimidine nucleoside which acts as a suicide prodrug, taking advantage of high TS activity as part of its mechanism of drug activation. Preclinical studies have shown that FAU is first phosphorylated by human deoxythymidine (dThd) kinase (TK), then methylated by TS and incorporated into DNA, inducing cytotoxicity. FAU is a novel investigational agent that has not been extensively studied in humans and never with therapeutic intent. The Karmanos Cancer Institute (KCI) Phase I service has recently received approval from the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) to conduct a Phase I clinical trial of FAU in patients with advanced stage (metastatic or unresectable) solid tumors for which standard curative or palliative measures do not exist or are no longer effective. The primary aims of this Phase I study are to determine the safety profile of FAU when administered as a 1-hour infusion on days 1-5 of a 28-day cycle, to determine the dose limiting toxicities (DLT), and to establish the maximum tolerated dose (MTD). The clinical and pharmacokinetic (PK) analysis portions for this Phase I study will be funded by NCI Grant# U01-CA062487-15. However, because Translational Research Initiative (TRI) funding is no longer provided by the NCI to support critical correlative investigations, we are submitting this application to request funding that will enable the exploratory assessment of surrogate endpoints in hopes of defining a patient population that will benefit from FAU. The ability of positron emission tomography (PET) to produce images of tumor physiology has led to its increasing application in oncology. Chemotherapeutic compounds, labeled with positron emitting radiopharmaceuticals, allow biodistribution of the chemotherapeutic to be imaged in vivo, as well as determination of its uptake and retention in tumors. Our pilot studies demonstrate that 18F-radiolabeled FAU can be imaged and unlabeled therapeutic FAU can be measured in tumors. We hypothesize that tumors expressing TK and over expressing TS will have higher metabolism/activation of FAU, leading to increased tumor cell death, and that the use of tracer doses of 18F-FAU will be predictive of the uptake of unlabeled FAU into tumors and ultimate response to treatment. In this application, we propose correlative studies to explore this hypothesis in support of the Phase I trial. Correlative PET imaging studies using 18F-FAU will be conducted prior to therapy and following treatment with unlabeled FAU to measure uptake of drug into tumor and normal tissues. In addition, we will collect archival tissue blocks or pre-treatment biopsies to perform pharmacodynamic (PD) analyses and post- treatment biopsies to assess FAU metabolism. Both TS and TK will be measured in tumor tissue and compared to imaging and therapeutic results. PUBLIC HEALTH RELEVANCE: Cancer is a major cause of death in the world and cancer patients are in need of more effective treatment options. The clinical trial NCI#7916 is designed to test treatment of the novel cancer drug FAU in patients with advanced solid tumors; this application seeks funding for studies designed to obtain a better understanding of this drug. If successful, the proposed experiments may point the way to assays that identify patients who are more or less likely to respond to this therapy, thereby permitting individualized therapy of patients in the future.

描述（由申请人提供）：胸苷酸合成酶（TS）抑制剂5-氟尿嘧啶（5 FU）是许多恶性肿瘤癌症治疗的“支柱”。不幸的是，由于TS的上调，肿瘤可能对5 FU具有抗性。FAU（1-（2 '-脱氧-2'-氟-2-D-阿拉伯呋喃糖基）尿嘧啶）是一种嘧啶核苷，作为自杀前药，利用高TS活性作为其药物活化机制的一部分。临床前研究表明，FAU首先被人脱氧胸苷（dThd）激酶（TK）磷酸化，然后被TS甲基化并掺入DNA，诱导细胞毒性。FAU是一种新的研究药物，尚未在人体中进行广泛研究，也从未有过治疗意图。Karmanos癌症研究所（KCI）I期服务最近获得了美国国家癌症研究所（NCI）癌症治疗评估计划（CTEP）的批准，可以在标准治疗或姑息措施不存在或不再有效的晚期（转移性或不可切除）实体瘤患者中进行FAU的I期临床试验。这项I期研究的主要目的是确定FAU在28天周期的第1-5天以1小时输注给药时的安全性特征，以确定剂量限制性毒性（DLT），并确定最大耐受剂量（MTD）。这项I期研究的临床和药代动力学（PK）分析部分将由NCI资助#U 01-CA 062487 -15资助。然而，由于NCI不再提供转化研究计划（TRI）资金来支持关键的相关研究，因此我们提交了此申请，以申请资金，从而能够对替代终点进行探索性评估，以期确定将从FAU中受益的患者人群。正电子发射断层扫描（PET）产生肿瘤生理学图像的能力导致其在肿瘤学中的应用越来越多。用发射正电子的放射性药物标记的化学治疗化合物允许在体内成像化学治疗剂的生物分布，以及确定其在肿瘤中的摄取和保留。我们的初步研究表明，18F-放射性标记的FAU可以成像和未标记的治疗FAU可以在肿瘤中测量。我们假设，表达TK和过表达TS的肿瘤将具有较高的FAU代谢/活化，导致肿瘤细胞死亡增加，并且使用示踪剂剂量的18F-FAU将预测未标记FAU进入肿瘤的摄取和对治疗的最终反应。在本申请中，我们提出了相关的研究来探索这一假设，以支持I期试验。将在治疗前和用未标记的FAU治疗后进行使用18F-FAU的相关PET成像研究，以测量肿瘤和正常组织的药物摄取。此外，我们将收集存档组织块或治疗前活检以进行药效学（PD）分析，并收集治疗后活检以评估FAU代谢。将在肿瘤组织中测量TS和TK，并与成像和治疗结果进行比较。公共卫生相关性：癌症是世界上主要的死亡原因，癌症患者需要更有效的治疗选择。临床试验NCI#7916旨在测试新型癌症药物FAU在晚期实体瘤患者中的治疗;该申请旨在为旨在更好地了解该药物的研究寻求资金。如果成功的话，拟议的实验可能会指明一条道路，以确定患者谁是或多或少可能对这种疗法作出反应的测定，从而允许在未来的患者个性化治疗。