A phase I/II study of GSK3145095 alone and in combination with anticancer agents including pembrolizumab in adults with selected solid tumors.

Abstract

TPS4165 Background: The immunosuppressive myeloid infiltrate characteristic of the tumor microenvironment in pancreatic cancer represents a major therapeutic barrier in this disease. Modulation of this infiltrate may increase sensitivity to immune checkpoint blockade in this and other tumors with a similar phenotype. The receptor interacting protein 1 (RIP1) is a serine/threonine kinase that becomes active upon homeostatic disruptions. Bound to RIP3 and mixed lineage kinase domain-like protein (MLKL), RIP1 kinase activity drives necroptosis. However, RIP1 also signals in response to inflammatory stimuli independently of its association with RIP3. A correlation between increased RIP1 protein expression and a worse prognosis has been reported in a variety of solid tumors. Furthermore, in an unbiased screen RIP1 was identified as a top gene contributing to resistance to immunotherapy (Manguso 2017). In murine models, RIP1 kinase activity has been reported to drive pancreatic oncogenesis. Inhibition of RIP1 in the pancreatic TME leads to the replacement of tumor-permissive myeloid infiltrates with innate cells promoting an anti-tumor response by the adaptive immune system (Seifert 2016; Wang 2018) and synergized with anti-PD-1 treatment. These data suggest that the small molecule RIP1 inhibitor GSK3145095 may have therapeutic potential in multiple tumor types. Methods: This is a four-part phase 1/2 study designed to evaluate the safety, PK, PD, and preliminary activity of GSK3145095 given orally to participants with selected advanced or recurrent solid tumors. Part 1 will be conducted in approximately 30 adults with pancreatic cancer with escalating doses of GSK3145095. Part 2 will combine escalating doses of GSK3145095 with 200 mg pembrolizumab and may be conducted in a broader population of selected solid tumors. Part 3 represents a cohort expansion of Part 2. Part 4 may investigate the combination of additional anticancer agent(s) with one or more doses of GSK3145095 identified as safe in Part 1.