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（由申请人提供）：胃食管腺癌（GEC）仍然是肿瘤学的挑战性问题。 GEC仍然是全球第四大最常见的恶性肿瘤和第二大死亡原因。由于不明确的原因，在过去的两到三十年中，胃癌（GEJ）腺癌估计在美国发病率增加了350％。 GEC是患者（患者间）和个体患者（患者内）之间的一种分子异质性疾病。病因的异质体通过空间（原发性肿瘤转移到转移性转移酶，甚至在不同的转移酶中）和时间（自然选择基因组畸变，赋予生长/转移性优势的自然选择，以及随着时间的推移抗药性克隆的演变）。在许多最近的临床试验中，使用“单一尺寸拟合所有”方法测试新的分子靶向治疗方法，病倒肿瘤的异质性可能导致负面结果。肿瘤异质性在实现个性化治疗方面构成了重大障碍，尤其是在使用标准/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分子“致癌驱动器”类别来解决患者间的肿瘤异质性，即HER2，MET，FGFR2，EGFR/HER3和KRAS/PI3K样。这些是GEC细胞系和肿瘤组织中最常观察到的分子类别。诊断时肿瘤的全面分子分析将在入学时在原发性肿瘤和转移性疾病部位（肝脏，肺或腹膜）进行，所有患者将根据通过新型治疗治疗分配算法评估，根据其转移性肿瘤分子谱分配给五种特定疗法之一。 [该治疗算法是大量潜在治疗组与进行此类试验并获取必要的许多研究剂的可行性之间的妥协。此外，患者将计划在每个进展点进行连续活检，以确定随时间和治疗的分子进化。本研究设计中纳入的相关科学将大大提高我们对患者间和患者内异质性的理解，并且还将有助于阐明如何最好地解决这些障碍，以便通过每种分子类别都相对无频率地处理特定的分子靶标的分子疗法来真正治疗特定的分子靶标。 与最近大约12个月的历史对照相比，这些小说[试验试验]的可行性和安全终点伴随着总生存期的初步疗效（对于HER2+和MET+亚组（n = 68）]。 [次要终点将包括对所有五个亚组之间的总生存期和其他临床终点的分析，预计约为104名患者]。该临床试验设计具有创新性，其生物统计方法是为了提高我们对疾病分子生物学的理解，解决该疾病内的患者间和内部组织异质性，并实现分子个性化的癌症护理的最终目标，以显着改善分子个性化的癌症护理。