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.

摘要 肝内胆管细胞癌(IHC)是胆道腺癌的一种亚型，预后较差。 发病率不断上升。SEER最近的数据显示，过去十年的平均涨幅为4.4%。类似地，一个 跨越18年的分析报告，发病率每年增加7%，是所有胆道亚型中最高的。 这两项研究都强调了IHC患者极差的存活率，后者报告的中位数约为6 月份。大多数IHC患者在确诊时都有无法切除的疾病，即使是那些足够幸运的人也是如此。 切除是常见的复发。对于这些患者，治疗选择有限，全身 化疗是标准的，而且在大多数情况下，是唯一的方法。联合治疗与 吉西他滨(GEM)和铂类药物是目前的黄金标准，但其益处有限，提供的中位数 总体生存时间约为12个月。最近，我们小组完成了一项第二阶段的单臂研究 肝动脉持续灌注氟尿嘧啶核苷联合吉西他滨区域化疗 奥沙利铂(OX)。中位总生存期为25个月，其中4名患者对 接受切除手术。基于这些有希望的结果，这项提议的主要目标是建立疗效 在最有效的系统方案(GEM/OX)中加入HAI-FUDR治疗不能切除的肝细胞癌 以无进展生存为主要终点的多中心随机II期研究。 IHC管理的进一步改进在很大程度上是因为对 这种疾病的生物学特征。IHC是基因组最具异质性的实体瘤之一，其原因是 广泛的风险因素和多个潜在的起源细胞。显著的异质性不仅表现在 从一个病人到另一个病人，但即使在同一个肿瘤内也是如此。这一特征排除了对 分子发病机制，使有效的靶向治疗难以确定，并导致不准确 基于一次活检对突变情况的评估。拟议的临床试验提供了一个 解决这些差距的理想机会。我们将使用靶向外显子组来评估肿瘤内异质性(ITH) 对大量患者的多次肿瘤活检和无细胞DNA(CfDNA)进行测序，并使用这些 根据患者的反应和生存情况对患者进行分层。对于进展缓慢的患者子集 进入试验后，我们将获得肿瘤活检组织和进展时的血液以阐明其发病机制(S) 通过肿瘤DNA和cfDNA测序分析耐药情况。使用这些相同的样本，我们将确定 患者衍生的器官模型用于治疗反应的遗传预测因子的功能评估。最后， 我们将使用放射基因组学，或定量成像与分子分析的结合，来探索非 根据突变模式对患者进行侵袭性分层，并量化其异质性程度。vbl.使用 作为一种综合分析方法，这些研究将为国际HC的多式联运风险分层提供基础。