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

• 批准号: 8926365
• 负责人: Daniel Catenacci
• 金额: $ 16.89万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 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/8926365
• 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; 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; Health; 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; chemotherapy; gastroesophageal junction adenocarcinoma; improved; innovation; lymph nodes; meetings; next generation sequencing; novel; oncology; patient population; personalized cancer care; personalized medicine; pilot trial; randomized placebo controlled trial; standard care; targeted treatment; therapy resistant; tumor

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(申请人提供)：胃食管腺癌(GEC)在肿瘤学中仍然是一个具有挑战性的问题。GEC仍然是全球第四种最常见的恶性肿瘤和第二种最常见的死亡原因。在过去的二三十年里，由于不明原因，胃食道交界处(GEJ)腺癌在美国的发病率估计增加了350%。GEC是一种分子异质性疾病，既存在于患者之间(患者间)，也存在于单个患者内部(患者内部)。患者内部的异质性通过空间(原发肿瘤到转移淋巴结再到远处转移，甚至跨越不同转移)和时间(赋予生长/转移优势的基因组异常的自然选择，以及随着时间的推移耐药克隆的进化)来表现。患者之间和患者内部的肿瘤异质性可能是最近一些临床试验的负面结果的原因之一，这些临床试验使用的是“一刀切”的方法来测试新的分子靶向疗法。肿瘤的异质性是实现个体化治疗的重要障碍，特别是在使用标准/公认的临床试验设计时。这项建议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-like来分配治疗，从而解决患者之间的肿瘤异质性。这些是在GEC细胞系和肿瘤组织中最常见的分子类别。在登记时，将对原发肿瘤和转移性疾病部位(肝、肺或腹膜)进行全面的肿瘤分子图谱分析，所有患者将根据其转移性肿瘤分子图谱通过新的治疗分配算法被分配到五种特定治疗方案中的一种。[这种治疗算法是在大量潜在的治疗小组和进行这样的试验并获得必要的许多研究试剂的可行性之间的妥协。]转移性疾病将统一用于描述肿瘤，以解决患者内部肿瘤在空间上的异质性，这可能占到大约10%-15%的不符合率，导致子集错误分类。此外，患者将在每个进展点进行计划的系列活组织检查，以确定随着时间和治疗的分子进化。纳入这项研究设计的相关科学将极大地提高我们对患者间和患者内异质性的理解，也将有助于阐明如何最好地解决这些障碍，以便真正针对特定分子靶点进行分子治疗，尽管每个分子类别相对较少出现。这项新的[试点试验]的可行性和安全性终点伴随着一个初步的疗效终点：总体存活率[HER2+和MET+亚组(N=68)]，与这些GEC患者最近约12个月的历史对照相比。[次级终点将包括对所有五个亚组的总存活率和其他临床终点的分析，预计约为104名患者]。这项临床试验设计以其生物统计方法和锐利的态度创新，以提高我们对疾病分子生物学的理解，解决患者之间和患者内部组织的异质性，并实现我们的最终目标，即分子个性化癌症治疗，以显著改善临床结果。