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

描述（由申请人提供）：胸苷酸合成酶（TS）抑制剂5-氟尿嘧啶（5FU）是许多恶性肿瘤治疗的“骨干”。不幸的是，由于TS的上调，肿瘤可能对5FU产生耐药性。FAU（1-（2'-脱氧-2'-氟-2- d -阿拉伯糖脲基）尿嘧啶）是一种嘧啶核苷，可作为自杀前药，利用高TS活性作为其药物激活机制的一部分。临床前研究表明，FAU首先被人脱氧胸腺嘧啶（dThd）激酶（TK）磷酸化，然后被TS甲基化并结合到DNA中，引起细胞毒性。FAU是一种新的研究性药物，尚未在人体中进行广泛研究，也从未有过治疗目的。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）癌症治疗评估项目（CTEP）的批准，在晚期（转移性或不可切除的）实体瘤患者中开展FAU的I期临床试验，这些患者没有标准的治疗或姑息措施或不再有效。这项I期研究的主要目的是确定FAU在28天周期中1-5天输注1小时时的安全性，确定剂量限制毒性（DLT），并确定最大耐受剂量（MTD）。该I期研究的临床和药代动力学（PK）分析部分将由NCI Grant# U01-CA062487-15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，我们提交此申请以请求资助，以便对替代终点进行探索性评估，以期确定将受益于FAU的患者群体。正电子发射断层扫描（PET）产生肿瘤生理图像的能力使其在肿瘤学中的应用越来越广泛。化学治疗化合物，用正电子放射药物标记，使化学治疗药物的生物分布在体内成像，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，而未标记的治疗性FAU可以在肿瘤中测量。我们假设，表达TK和过表达TS的肿瘤将具有更高的FAU代谢/激活，导致肿瘤细胞死亡增加，并且使用示踪剂剂量的18F-FAU将预测未标记的FAU进入肿瘤和最终对治疗的反应。在本申请中，我们提出相关研究来探索这一假设，以支持I期试验。在治疗前使用18F-FAU进行相关PET成像研究，在治疗后使用未标记的FAU测量药物对肿瘤和正常组织的吸收。此外，我们将收集档案组织块或治疗前活检以进行药效学（PD）分析和治疗后活检以评估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：癌症是世界上死亡的一个主要原因，癌症患者需要更有效的治疗方案。临床试验NCI#7916旨在测试新型抗癌药物FAU在晚期实体瘤患者中的治疗效果；本申请寻求资助旨在更好地了解该药物的研究。如果成功的话，这个实验可能会为鉴别哪些病人对这种疗法或多或少会有反应指明一条道路，从而使将来的病人能够接受个体化治疗。

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.