Goal 1: Reduce mortality of patients with advanced hepatocellular carcinoma (HCC) by testing a novel strategy of increasing cancer immunogenicity to enhance the activity of immune checkpoint inhibitors. Objective 1: Assess the response rate (primary endpoint) of combining two clinical drugs with known safety profiles including a splicing modulator, E7820, and a checkpoint inhibitor, pembrolizumab, in a phase II trial in patients with advanced HCC. Objective 2: Assess the overall survival, progression free survival, duration of response, and safety (secondary endpoints) of combination immunotherapy. Goal 2: Develop pharmacodynamic markers and elucidate mechanisms of resistance to E7820 and...

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Goal 1: Reduce mortality of patients with advanced hepatocellular carcinoma (HCC) by testing a novel strategy of increasing cancer immunogenicity to enhance the activity of immune checkpoint inhibitors. Objective 1: Assess the response rate (primary endpoint) of combining two clinical drugs with known safety profiles including a splicing modulator, E7820, and a checkpoint inhibitor, pembrolizumab, in a phase II trial in patients with advanced HCC. Objective 2: Assess the overall survival, progression free survival, duration of response, and safety (secondary endpoints) of combination immunotherapy. Goal 2: Develop pharmacodynamic markers and elucidate mechanisms of resistance to E7820 and pembrolizumab therapy. Objective 1: Confirm on-target engagement of E7820 in tumor specimens by assessing for RBM39 levels and splicing changes using immunohistochemistry and massive parallel RNA sequencing. Objective 2: Develop blood based pharmacodynamic markers based on T-cell phenotypes (detected by mass cytometry) and T-cell repertoire (detected by T-cell receptor sequencing) using in vivo HCC models and patient specimens. Objective 3: Evaluate RBM39 levels, splicing changes, and immune responses in patient specimens collected at the time of progression. Goal 3: Develop an expertise in clinical trial investigations and transition towards an independent clinical investigator role. Objective 1: Enhance my knowledge in trial implementation, biomarker development, biostatistics, grant writing, and clinical pharmacology through didactic courses and conducting a phase II trial. Objective 2: Understand regulatory requirements and medical product development through didactic courses on drug development, and Food and Drug Administration workshops for clinical investigators. Objective 3: Develop leadership and management skills necessary for independent investigation through the tutelage of my mentors and participation in leadership training.

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