Background: GEC is the second highest cause of cancer mortality worldwide. The promise of ‘personalized’ cancer care with therapies toward specific molecular aberrations has potential to improve outcomes. However, there is recognized molecular heterogeneity within GEC (inter-patient heterogeneity), and within an individual (intra-patient heterogeneity) through space (primary tumor to metastatsis) and time (resistance to treatment) - a hurdle to advancing GEC treatment. Current trial design paradigms are challenged by heterogeneity, as they are unable to test targeted therapeutics against low frequency genomic aberrations with adequate power. Accrual difficulties to GEC trials are exacerbated by low frequencies of molecular ‘oncogenic drivers.’ Oncogenic drivers of GEC including MET and others have even less frequent genomic activation than HER2. To address this challenge, there is need for novel clinical trial designs/strategies implementing novel technologies to account for inter-patient molecular diversity and scarce tissue for analysis. Importantly, there is also need for predefined treatment priority algorithms given multiple aberrations observed within any one individual. Finally, access to multiple therapeutic agents are required to be available for treatment. Intra-patient heterogeneity may be addressed by post-treatment biopsy. Methods: We present a novel trial design 'Personalized Anti-Neoplastics for Gastro-Esophageal Adenocarcinoma' for metastatic GEC, integrating medium throughput proteomic/genomic assays with a practical biomarker assessment/treatment algorithm. Analysis of 50 GEC patients was performed to determine feasibility/timing of testing and treatment assignment into 5 major molecular categories. Results: 50 GEC tumors had biomarker assessment and mock treatment assignment within 60 days, revealing HER2 (26%), MET (30%), FGFR2 (8%), EGFR (20%), KRAS/PI3K (26%). Conclusions: Comprehensive molecular profiling of FFPE tissue was feasible and timely. Tumors were classified into major molecular subgoups. PANGEA is a compromise between the number of potential treatment categories and feasibility of conducting such a trial.