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: 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
• 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

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）仍然是肿瘤学中的一个具有挑战性的问题。GEC仍然是世界上第四大最常见恶性肿瘤和第二大最常见死亡原因。胃食管交界处（GEJ）腺癌在美国的发病率在过去的二三十年中估计增加了350%，原因尚不清楚。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）。患者内部异质性通过空间（原发肿瘤到转移性淋巴结到远端转移，甚至跨越不同的转移）和时间（赋予生长/转移优势的基因组畸变的自然选择，以及随着时间的推移耐药克隆的进化）表现出来。在最近的一些临床试验中，使用“一刀切”的方法测试新型分子靶向治疗方法，患者之间和患者内部的肿瘤异质性可能导致了负面结果。肿瘤异质性是实现个性化治疗的重大障碍，特别是在使用标准/可接受的临床试验设计时。该提案旨在通过基于预定义的预测性分子“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。这些是在GEC细胞系和肿瘤组织中最常观察到的分子类别。在入组时，将对原发肿瘤和转移性疾病部位（肝、肺或腹膜）进行诊断时的肿瘤综合分子谱分析，所有患者将根据其转移性肿瘤分子谱通过一种新的治疗分配算法进行评估，被分配到五种特定治疗中的一种。[这种治疗算法是在大量潜在治疗组与进行这样的试验和获得许多必要的研究药物的可行性之间的妥协。转移性疾病将被统一用于描述肿瘤，以便通过空间来解决患者内部肿瘤的异质性，这可能占大约10-15%的不一致率，导致亚群错误分类。此外，患者将计划在每个进展点进行系列活组织检查，以确定分子随时间和治疗的演变。纳入本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部异质性的理解，也将有助于阐明如何最好地解决这些障碍，以便真正使用针对特定分子靶点的分子疗法进行治疗，尽管每种分子类别发生的频率相对较低。与最近在这些GEC患者中观察到的大约12个月的历史对照相比，这项新[试点试验]的可行性和安全性终点伴随着初步的总生存期疗效终点[对于HER2+和MET+亚组（N=68）]。[次要终点将包括所有五个亚组的总生存期和其他临床终点分析，预计约104例患者]。该临床试验设计在生物统计学方法上具有创新性，并试图提高我们对疾病分子生物学的理解，解决疾病中患者间和患者内部的组织异质性，并实现我们的分子个性化癌症治疗的最终目标，以显着改善临床结果。