OBJECTIVES/GOALS: Selinexor is a novel XPO1 inhibitor that blocks nuclear export, thus impairing DNA repair and causing apoptosis. Our goal was to conduct preclinical and clinical studies to test our hypothesis that selinexor’s efficacy is boosted by priming with temozolomide and is associated with a tissue biomarker. METHODS/STUDY POPULATION: We leveraged a team science approach through the NCI Cancer Therapy Evaluation Program (CTEP) to design preclinical experiments, develop a novel RNAseq analysis pipeline, and use pre-existing clinical experience to open an early phase clinical trial for recurrent glioblastoma. Team members included a CTEP medical officer, cancer biologist, pharmacist, industry scientist, translational scientist, and early career clinician scientist mentored by an expert clinician scientist. Based on preclinical results, participants in the clinical trial experimental arm will receive sequential temozolomide 150mg/m2 on days 1-5 and a starting dose of selinexor 60mg on days 8 and 15 of a 28-day cycle. Participants in the control arm will receive monotherapy temozolomide. RESULTS/ANTICIPATED RESULTS: Sequential treatment of U87 cells and intracranial xenografts had superior DNA damage (É£H2A.X, cleaved PARP) and overall survival compared to combination or single-agent (HR 0.25 [95% CI, 0.07-0.84]; p=0.01, log-rank). We used the top-scoring gene pair method to identify an RNAseq signature associated with response to selinexor. We then designed a trial for first recurrent MGMT methylated glioblastoma. Primary objectives are safety and preliminary efficacy. Secondary objectives are overall response rate, efficacy, and validation of a molecular signature. Phase 1 dose finding (n=12) will be followed by a randomized phase 2 (n=72); using proportional hazards regression, RHR 0.5 with p DISCUSSION/SIGNIFICANCE: The NCI CTEP Project Team employs team science as a framework to successfully develop multidisciplinary collaborations, build investigator trial experience, and lead the way to future research opportunities. Our trial addresses a significant unmet need to offer novel therapies and molecular biomarkers in glioblastoma.