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: 10478946
• 负责人: Andrea Cercek
• 金额: $ 64.94万
• 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/10478946
• 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; 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; Prognosis; Progression-Free Survivals; Pump; Radiogenomics; Randomized; Regimen; Regional Chemotherapy; Reporting; Research; Research Project Grants; Resistance; Risk Factors; 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 computed tomography; drug sensitivity; effective therapy; gemcitabine; genetic predictors; genetic signature; genomic data; improved; improved outcome; intrahepatic; mortality; multimodality; neoplastic cell; novel; oxaliplatin; patient population; patient stratification; patient subsets; peripheral blood; phase 2 study; precision medicine; predictive marker; primary endpoint; prognostic; prospective; protein expression; quantitative imaging; radiological imaging; radiomics; response; risk stratification; 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）是胆道腺癌的一种亚型，预后较差， 发病率上升。 SEER 数据最近记录了过去十年平均增长 4.4%。同样，一个 跨越 18 年的分析表明，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 患者的糟糕生存率，后者报告的中位数约为 6 几个月。大多数 IHC 患者在诊断时都患有无法切除的疾病，即使是少数足够幸运的患者 进行切除术通常会复发。对于这些患者来说，治疗选择有限，需要全身治疗 化疗代表标准，并且在大多数情况下是唯一的方法。联合治疗 吉西他滨 (GEM) 和铂剂是当前的黄金标准，但其益处有限，提供中位数 总生存期约为12个月。近期，我们课题组完成了II期单臂研究 持续输注肝动脉（HAI）氟尿苷（FUDR）联合GEM的区域化疗 和奥沙利铂（OX）。中位总生存期为 25 个月，其中 4 名患者对治疗反应充分 进行切除术。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 添加到最活跃的全身治疗方案 (GEM/OX) 中，用于治疗不可切除的 IHC 多中心随机 II 期研究，主要终点为无进展生存期。 IHC 管理的进一步改进在很大程度上受到了对以下方面了解不足的阻碍： 该疾病的生物学。 IHC 是基因组异质性最强的实体瘤之一，由 广泛的危险因素和多种潜在的起源细胞。不仅表现出显着的异质性 从一个病人到另一个病人，甚至在同一个肿瘤内。此功能妨碍了精确表征 分子发病机制，使得很难确定有效的靶向治疗，并导致不准确的结果 基于单次活检的突变情况评估。拟议的临床试验提供了 弥补这些差距的绝佳机会。我们将使用靶向外显子组评估瘤内异质性 (ITH) 对大量患者的多个肿瘤活检和游离 DNA (cfDNA) 进行测序，并使用这些 研究结果对患者的反应和生存进行分层。对于在治疗过程中出现进展的患者子集 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 通过肿瘤 DNA 和 cfDNA 测序来评估治疗耐药性。使用这些相同的样本，我们将建立 源自患者的类器官模型，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入性分层并量化异质性程度。使用 这些研究采用综合分析方法，将为 IHC 的多模式风险分层奠定基础。