Improving Outcome in Patients with Advanced Intrahepatic Cholangiocarcinoma: A Randomized Phase II Study of Gemcitabine and Oxaliplatin With or Without Regional Floxuridine (FUDR)

改善晚期肝内胆管癌患者的预后：吉西他滨和奥沙利铂联合或不联合局部氟尿苷 (FUDR) 的随机 II 期研究

• 批准号: 9974070
• 负责人: Andrea Cercek
• 金额: $ 68.27万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9974070
• 关键词: Address; Adenocarcinoma; Area; Biological Markers; Biology; Biopsy; Blood; Blood flow; CDKN2A gene; Cells; Clinical; Clinical Trials; Collection; Combined Modality Therapy; Continuous Infusion; DNA analysis; DNA sequencing; Data; Diagnosis; Diagnostic radiologic examination; Disease; Disease Management; Disease Progression; Dose; Drug Screening; Enrollment; Evaluation; Evolution; Excision; FGFR2 gene; Floxuridine; Foundations; Gene Mutation; Genes; Genomics; Geography; Goals; Gold; Hepatic; Hepatic artery; Heterogeneity; Image; Incidence; Infusion procedures; Intrahepatic Cholangiocarcinoma; KRAS2 gene; Laparoscopy; Liver; Local Therapy; Malignant Neoplasms; Methods; Modality; Modeling; Molecular; Molecular Analysis; Morbidity - disease rate; Mutation; Oncology; Operative Surgical Procedures; Organoids; Outcome; Pathogenesis; Patient imaging; Patient-Focused Outcomes; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Platinum Compounds; Positive Lymph Node; Prediction of Response to Therapy; Primary Neoplasm; Progression-Free Survivals; Pump; Radiogenomics; Randomized; Regimen; Regional Chemotherapy; Reporting; Research; Research Project Grants; Resistance; Risk Factors; Risk stratification; Sampling; Site; Solid Neoplasm; Source; Specimen; Staging; Systemic Therapy; TP53 gene; Techniques; Testing; Time; Tissue Banks; Toxic effect; Treatment Failure; Treatment Protocols; Treatment outcome; Unresectable; Vascular blood supply; Work; X-Ray Computed Tomography; arm; base; biliary tract; cell free DNA; chemotherapeutic agent; chemotherapy; cohort; contrast enhanced; drug sensitivity; effective therapy; gemcitabine; genetic predictors; genetic signature; genomic data; improved; improved outcome; intrahepatic; mortality; multimodality; neoplastic cell; novel; outcome forecast; oxaliplatin; patient population; patient stratification; patient subsets; peripheral blood; phase 2 study; precision medicine; predictive marker; primary endpoint; prognostic; prospective; protein expression; quantitative imaging; radiomics; response; standard care; subclonal heterogeneity; targeted exome sequencing; targeted sequencing; targeted treatment; therapeutic target; therapy resistant; treatment response; treatment strategy; tumor; tumor DNA; tumor heterogeneity

SUMMARY Intrahepatic cholangiocarcinoma (IHC) is a subtype of biliary tract adenocarcinoma with a poor prognosis and rising incidence. SEER data recently documented an average 4.4% rise over the past decade. Similarly, an analysis spanning 18 years reported a 7% annual increase in incidence, the highest of any biliary tract subtype. Both studies highlight the abysmal survival of patients with IHC, the latter reporting a median of approximately 6 months. Most patients with IHC have unresectable disease at diagnosis, and even those few fortunate enough to undergo resection recur commonly. For these patients, treatment options are limited, with systemic chemotherapy representing the standard, and in most cases, the only approach. Combination therapy with gemcitabine (GEM) and a platinum agent is the current gold standard, but its benefit is limited, offering a median overall survival of approximately 12 months. Recently, our group completed a phase II single-arm study of regional chemotherapy using continuous infusion hepatic arterial (HAI) floxuridine (FUDR) combined with GEM and oxaliplatin (OX). The median overall survival was 25 months, with four patients responding sufficiently to undergo resection. Based on these promising results, the primary goal of this proposal is to establish the efficacy of HAI FUDR added to the most active systemic regimen (GEM/OX) for the treatment of unresectable IHC in a multi-center randomized phase II study, with the primary endpoint of progression-free survival. Further improvements in the management of IHC have been hindered in large part by a poor understanding of the biology of the disease. IHC is among the most genomically heterogeneous solid tumor, resulting from the wide array of risk factors and multiple potential cells of origin. Significant heterogeneity has been shown not only from patient to patient, but even within the same tumor. This feature has precluded precise characterization of molecular pathogenesis, made it difficult to identify effective targeted therapies, and results in inaccurate assessment of the mutational landscape when based on a single biopsy. The proposed clinical trial provides an ideal opportunity to address these gaps. We will evaluate intratumoral heterogeneity (ITH) using targeted exome sequencing of multiple tumor biopsies and cell-free DNA (cfDNA) from a large cohort of patients and use these findings to stratify patients with respect to response and survival. For the subset of patients that progress while enrolled in the trial, we will obtain tumor biopsies and blood at the time of progression to elucidate mechanism(s) of treatment resistance by tumor DNA and cfDNA sequencing. Using these same samples, we will establish patient-derived organoid models for functional evaluation of genetic predictors of treatment response. Finally, we will use radiogenomics, or the merger of quantitative imaging with molecular analyses, to explore non- invasive stratification of patients based on mutational patterns and to quantify the degree of heterogeneity. Using an integrated analysis approach, these studies will provide a foundation for multimodal risk stratification for IHC.

概括 肝内胆管癌（IHC）是胆道腺癌的亚型，预后不良和 发病率上升。 SEER数据最近记录了过去十年中平均增长4.4％。同样，一个 跨越18年的分析报告说，每年发病率增加了7％，这是任何胆道亚型中最高的。 两项研究都强调了IHC患者的糟糕生存率，后者报告中位数约为6 月份。大多数IHC患者在诊断时患有无法切除的疾病，甚至少数很幸运 通常会复发切除。对于这些患者，治疗选择有限，全身性 化学疗法代表标准，在大多数情况下，唯一的方法。结合疗法与 吉西他滨（宝石）和铂剂是当前的金标准，但其好处有限，提供中位数 总生存率约为12个月。最近，我们的小组完成了一项II期单臂研究 使用连续输注肝动脉（HAI）氟吡啶（FUDR）与GEM结合的区域化疗 和奥沙利铂（OX）。中位总生存期为25个月，四名患者对 进行切除。基于这些有希望的结果，该提案的主要目标是确定功效 HAI FUDR的添加到最活跃的系统性方案（GEM/OX）中，用于治疗A 多中心随机II期研究，具有无进展生存的主要终点。 对IHC管理的进一步改善，很大程度上是由于对 疾病的生物学。 IHC是基因组最异构的实体瘤之一，由 广泛的危险因素和多个潜在的原始细胞。显着的异质性不仅显示 从患者到患者，甚至在同一肿瘤内。此功能排除了精确表征 分子发病机理，难以识别有效的靶向疗法，并导致不准确 基于单个活检时，评估突变景观。拟议的临床试验提供了 解决这些差距的理想机会。我们将使用靶向外观评估肿瘤内异质性（ITH） 来自大量患者的多个肿瘤活检和无细胞DNA（CFDNA）的测序 针对反应和存活的患者分层的发现。对于进展的患者子集 参加试验后，我们将在进展时获得肿瘤活检和血液，以阐明机制 肿瘤DNA和CFDNA测序的治疗耐药性。使用这些相同的样本，我们将建立 患者衍生的类器官模型，用于评估治疗反应的遗传预测因子。最后， 我们将使用放射基因组学或定量成像与分子分析的合并来探索非 - 根据突变模式对患者进行侵入性分层，并量化异质性程度。使用 这些研究将是一种综合分析方法，为IHC的多模式风险分层提供了基础。