Background: Gastric cancer remains a significant health problem in the US and globally with more than 951,600 annual cases worldwide. Moreover, the incidence of GEJ-centered adenocarcinoma is increasing dramatically in Western countries. First line chemotherapy has a < 12month median survival. In 2nd line, ramucirumab, a monoclonal antibody against VEGFR2 is approved as single agent or with paclitaxel. Hypoxia mimetic agents such as ramucirumab down-regulate homologous recombination and sensitize tumors to Poly ADP ribose polymerase inhibition (PARPi). Gastric cancer is also known to have a homologous recombination deficiency (HRD) subtype. We therefore proposed combining the PARPi olaparib with ramucirumab in metastatic gastric and GEJ adenocarcinoma. Methods: The study is sponsored by the Clinical Therapy Evaluation Program and is active throughout the Extended Therapeutics Clinical Trials Network. A phase 1 3+3 dose escalation is followed by an open-label single arm phase 2. The primary objective of phase 1 is to establish the safe dose of olaparib with ramucirumab. The phase 2 primary objective is to measure efficacy by the objective response rate (ORR). Eligible patient received ≥ 1 line of prior chemotherapy, no prior angiogenesis inhibitors or PARPi, have measurable disease, usual laboratory parameters, and ECOG PS 0-1. Phase 1 will enroll 9-18 patients depending on DLT. In phase 2, the BROCA-HR gene panel is an integrated biomarker. This panel includes 87 DNA repair genes, 17 of which would be expected to confer HRD when mutated. In gastric cancer these HRD genes are mutated in up to 35% of tumors reported in COSMIC and TCGA. However, given the uncertainty of the biomarker distribution in our study, 40 patients will be enrolled in phase 2 and the ORR will be stratified by biomarker distribution. The H₀ is ORR of < 5% based on the historical control for ramucirumab. The H₁ is 25% ORR for the BROCA-HR positive cohort and 20% for the negative cohort. A pre-treatment biopsy for BROCA-HR testing is required. Other studies include detecting mutational signatures, PAR substrate analysis, and PDX generation. Phase 1 is currently enrolling. Clinical trial information: NCT03008278