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: 9120837
• 负责人: Daniel Catenacci
• 金额: $ 16.85万
• 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/9120837
• 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; KRAS2 gene; Light; Liver; Location; Lung; Malignant Neoplasms; Mass Spectrum Analysis; Mediator of activation protein; Metastatic to; Molecular; Molecular Biology; Molecular Evolution; Molecular Profiling; Molecular Target; Monitor; Mutation; Natural Selections; Neoplasm Metastasis; Oncogenes; Oncogenic; Outcome; PIK3CG gene; Patients; Pattern; Peritoneum; Pharmacologic Substance; Primary Neoplasm; Progression-Free Survivals; Proteomics; Reaction; Research Design; Resistance; Safety; Science; Second Primary Neoplasms; Site; Staging; Subgroup; Testing; Therapeutic Uses; Time; Tissues; Tumor Suppressor Proteins; Tumor Tissue; United States; Vertebral column; arm; base; chemotherapy; gastroesophageal junction adenocarcinoma; genomic aberrations; improved; individual patient; innovation; lymph nodes; meetings; molecular subtypes; next generation sequencing; novel; oncology; patient population; personalized cancer care; personalized medicine; pilot trial; profiles in patients; randomized placebo controlled trial; standard care; targeted treatment; therapy resistant; treatment group; tumor; tumor heterogeneity

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（由申请方提供）：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。在过去的二三十年里，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是患者之间（患者间）和个体患者内（患者内）的分子异质性疾病。患者内的异质性通过空间（原发性肿瘤到转移性淋巴结到远处转移，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，以及耐药克隆随时间的演变）表现出来。患者间和患者内的肿瘤异质性可能导致了最近一些使用“一刀切”方法测试新型分子靶向治疗剂的临床试验中的阴性结果。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。 该提案旨在通过基于预定义的预测性分子“致癌驱动”类别（即HER 2、MET、FGFR 2、EGFR/HER 3和KRAS/PI 3 K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。将在入组时对原发性肿瘤和转移性疾病部位（肝、肺或腹膜）进行诊断时肿瘤的全面分子特征分析，并根据通过新型治疗分配算法评估的转移性肿瘤分子特征，将所有患者分配至5种特定治疗之一。[This治疗算法是大量潜在治疗组与进行此类试验和获得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描述肿瘤，以解决患者内肿瘤空间异质性，这可能导致约10-15%的不一致率，导致亚组错误分类。此外，患者将在每个进展点进行计划的连续活检，以确定随时间和治疗的分子演变。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异质性疾病的理解，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，尽管每个分子类别发生相对较少。 这项新的[初步试验]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HER 2+和MET+亚组（N=68）]，与这些GEC患者中观察到的约12个月的近期历史对照相比。[次要终点将包括所有5个亚组的总生存期和其他临床终点分析，预计约104例患者]。该临床试验设计具有创新性，其生物统计学方法旨在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组织异质性，并实现我们的最终目标分子个性化癌症护理，以显着改善临床结局。

项目成果

Mass-spectrometry-based quantitation of Her2 in gastroesophageal tumor tissue: comparison to IHC and FISH.

• DOI: 10.1007/s10120-015-0566-0
• 发表时间: 2016-10
• 期刊: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association
• 作者: Catenacci DVT;Liao WL;Zhao L;Whitcomb E;Henderson L;O'Day E;Xu P;Thyparambil S;Krizman D;Bengali K;Uzzell J;Darfler M;Cecchi F;Blackler A;Bang YJ;Hart J;Xiao SY;Lee SM;Burrows J;Hembrough T
• 通讯作者: Hembrough T

Perioperative therapy for locally advanced gastroesophageal cancer: current controversies and consensus of care.

• DOI: 10.1186/1756-8722-6-66
• 发表时间: 2013-09-05
• 期刊: Journal of hematology & oncology
• 影响因子: 28.5
• 作者: Sehdev A;Catenacci DV
• 通讯作者: Catenacci DV

Update on Gastroesophageal Adenocarcinoma Targeted Therapies.

• DOI: 10.1016/j.hoc.2017.01.009
• 发表时间: 2017-06
• 期刊: Hematology/oncology clinics of North America
• 作者: Maron SB;Catenacci DVT
• 通讯作者: Catenacci DVT

Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial.

• DOI: 10.1016/s1470-2045(17)30566-1
• 发表时间: 2017-11
• 期刊: The Lancet. Oncology
• 作者: Catenacci DVT;Tebbutt NC;Davidenko I;Murad AM;Al-Batran SE;Ilson DH;Tjulandin S;Gotovkin E;Karaszewska B;Bondarenko I;Tejani MA;Udrea AA;Tehfe M;De Vita F;Turkington C;Tang R;Ang A;Zhang Y;Hoang T;Sidhu R;Cunningham D
• 通讯作者: Cunningham D

Novel Targeted Therapies for Esophagogastric Cancer.

• DOI: 10.1016/j.soc.2016.10.002
• 发表时间: 2017-04
• 期刊: Surgical oncology clinics of North America
• 影响因子: 1.9
• 作者: Maron SB;Catenacci DV
• 通讯作者: Catenacci DV