PANGEA: Personalized Antibodies for GastroEsophageal Adenocarcinoma Pilot Trial

PANGEA：用于胃食管腺癌试点试验的个性化抗体

基本信息

批准号：
8767709
负责人：
Daniel Catenacci
金额：
$ 16.91万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-11 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8767709
关键词：
Accounting Address Adenocarcinoma Adenocarcinoma Cell Aftercare Algorithms Antibodies Biopsy Cancer Patient Categories Cause of Death Cell Line Clinical Clinical Trials Clinical Trials Design Diagnosis Disease Disorder by Site Distant Metastasis ERBB2 gene ERBB3 gene Enrollment Epidermal Growth Factor Receptor Ethnic Origin Event Evolution Experimental Models FGFR2 gene Fluorescent in Situ Hybridization Future Gene Mutation Genomics Goals Growth Heterogeneity Histology Immunohistochemistry In Vitro Incidence Individual KRAS2 gene Light Liver Location Lung Malignant Neoplasms Mass Spectrum Analysis Mediator of activation protein Metastatic Lesion Metastatic to Molecular Molecular Biology Molecular Evolution Molecular Profiling Molecular Target Monitor Mutation Natural Selections Neoplasm Metastasis Oncogene Proteins Oncogenic Outcome PIK3CG gene Patients Pattern Peritoneum Pharmacologic Substance Primary Neoplasm Progression-Free Survivals Proteomics Reaction Research Design Resistance Safety Science Second Primary Neoplasms Staging Subgroup Testing Therapeutic Uses Time Tissues Tumor Suppressor Proteins Tumor Tissue United States Vertebral column arm base cancer care chemotherapy gastroesophageal junction adenocarcinoma improved innovation lymph nodes meetings next generation sequencing novel oncology patient population pilot trial public health relevance randomized placebo controlled trial standard care therapy resistant tumor

项目摘要

DESCRIPTION (provided by applicant): Gastroesophageal adenocarcinoma (GEC) remains a challenging problem in oncology. GEC remains the fourth most common malignancy and the second most common cause of death worldwide. Gastroesophageal junction (GEJ) adenocarcinomas have an estimated 350% increase in incidence in the US in the last two to three decades for unclear reasons. GEC is a molecularly heterogeneous disease both between patients (inter-patient) and within an individual patient (intra-patient). Intra-patient heterogenety manifests through space (primary tumor to metastatic lymph nodes to distant metastases, and even across different metastases) and time (natural selection of genomic aberrations conferring growth/metastatic advantage, as well as evolution of treatment resistant clones over time). Inter- and intra-patient tumor heterogeneity has likely contributed to negative results in a number of recent clinical trials testing novel molecularly targeted therapeutics using a 'one-size-fits-all' approach. Tumor heterogeneity poses a significant hurdle to achieving personalized treatment, particularly when using standard/accepted clinical trial designs. This proposal seeks to address inter-patient tumor heterogeneity by assigning treatment based on predefined predictive molecular 'oncogenic driver' categories, namely, HER2, MET, FGFR2, EGFR/HER3, and KRAS/PI3K-like. These are the most frequently observed molecular categories within GEC cell lines and tumor tissues. A comprehensive molecular profiling of the tumor at diagnosis will be done on the primary tumor and a metastatic disease site (liver, lung, or peritoneum) at enrollment, and all patients will be assigned to one of five specific treatments based on their metastatic tumor molecular profile as assessed via a novel treatment assignment algorithm. [This treatment algorithm is a compromise between the vast number of potential treatment groups and the feasibility of conducting such a trial and acquiring the many investigational agents necessary.] Metastatic disease will be uniformly used to profile the tumor in order to address intra-patient tumor heterogeneity through space, which can account for an approximate 10-15% discordant rate, resulting in subset misclassification. Additionally, patients will have planned serial biopsies at each progression point to determine molecular evolution over time and treatment. The correlative science incorporated into this study design will greatly improve our understanding of the disease with respect to inter-patient and intra-patient heterogeneity, and also will help to shed light on how to best address these hurdles in order to truly treat with molecular therapies for specific molecular targets, despite each molecular category occurring relatively infrequently. The feasibility and safety endpoints of this novel [pilot trial] are accompanied by a preliminary efficacy endpoint of overall survival [for the HER2+ and MET+ subgroups (N=68)], as compared to recent historical controls of approximately 12 months as seen in these GEC patients. [Secondary endpoints will include analysis of overall survival and other clinical endpoints amongst all five subgroups, anticipated to be approximately 104 patients]. This clinical trial design is innovative with its biostastistical approach and in its atempt to improve our understanding of the molecular biology of the disease, address inter- and intra-patient tissue heterogeneity within the disease, and to achieve our ultimate goal of molecularly personalized cancer care in order to significantly improve clinical outcomes.

描述（由申请人提供）：胃食管腺癌（GEC）仍然是肿瘤学中的一个具有挑战性的问题。 GEC 仍然是全球第四大常见恶性肿瘤和第二大常见死亡原因。过去 2 至 30 年间，美国胃食管连接部 (GEJ) 腺癌的发病率估计增加了 350%，原因尚不清楚。 GEC 是一种分子异质性疾病，无论是在患者之间（患者间）还是在个体患者内部（患者内）。患者内部的异质性通过空间（原发肿瘤到转移淋巴结到远处转移，甚至跨不同的转移）和时间（基因组畸变的自然选择赋予生长/转移优势，以及随着时间的推移治疗抗性克隆的进化）表现出来。最近许多使用“一刀切”方法测试新型分子靶向疗法的临床试验中，患者间和患者内的肿瘤异质性可能导致了阴性结果。肿瘤异质性对实现个性化治疗构成了重大障碍，特别是在使用标准/公认的临床试验设计时。该提案旨在通过根据预定义的预测分子“致癌驱动因素”类别（即 HER2、MET、FGFR2、EGFR/HER3 和 KRAS/PI3K 样）分配治疗来解决患者间肿瘤异质性。这些是 GEC 细胞系和肿瘤组织中最常见的分子类别。诊断时将对原发性肿瘤和入组时的转移性疾病部位（肝、肺或腹膜）进行全面的肿瘤分子分析，所有患者将根据其转移性肿瘤分子被分配到五种特定治疗中的一种通过新颖的治疗分配算法评估概况。 [这种治疗算法是大量潜在治疗组与进行此类试验和获取许多必要的研究药物的可行性之间的折衷。]转移性疾病将统一用于对肿瘤进行分析，以解决患者体内的肿瘤问题空间上的异质性，可导致大约 10-15% 的不一致率，从而导致子集错误分类。此外，患者将计划在每个进展点进行连续活检，以确定分子随时间和治疗的演变。本研究设计中纳入的相关科学将极大地提高我们对该疾病在患者间和患者内异质性方面的理解，也将有助于阐明如何最好地解决这些障碍，以便真正用分子疗法进行治疗尽管每种分子类别出现的频率相对较低，但针对特定的分子靶标。这项新颖的[试点试验]的可行性和安全性终点伴随着总生存期的初步疗效终点[对于 HER2+ 和 MET+ 亚组 (N=68)]，与这些研究中看到的最近约 12 个月的历史对照相比。 GEC 患者。 [次要终点将包括对所有五个亚组（预计大约有 104 名患者）的总体生存率和其他临床终点的分析]。该临床试验设计具有创新性，采用生物统计方法，试图提高我们对疾病分子生物学的理解，解决疾病内患者间和患者内的组织异质性，并实现分子个性化癌症护理的最终目标以显着改善临床结果。