Background: Prostaglandin E2 (PGE2) is a bioactive lipid that promotes cancer through diverse mechanisms including stimulating tumor proliferation, enhancing angiogenesis and suppressing immune function in the tumor microenvironment. PGE2 produced by tumor cells through upregulation of cyclooxygenase-2 (COX-2) is also a key mediator of adaptive resistance to immune checkpoint inhibitor therapy. While PGE2 signaling is important in cancer, how best to inhibit PGE2 for cancer treatment is under investigation. Inhibition of COX enzymes (e.g., with NSAIDS) has shown promise in large observational studies, but inconsistent results in prospective studies. Importantly, COX inhibition alters multiple prostanoids beyond PGE2, resulting in toxicity that limits therapeutic dosing for cancer. PGE2 signals through four receptors, EP1-4, that are variably expressed and have distinct activities. The tumor promoting and immunosuppressive activities of PGE2 predominantly arise from signaling through the EP2 and EP4 receptors, while signaling through the EP1 and EP3 receptors generally is pro-inflammatory. TPST-1495 is designed to be an oral, highly specific, antagonist of the EP2 and EP4 receptors, sparing the EP1 and EP3 receptors and the COX enzymes. Preclinical studies suggest that blocking EP2 and EP4 with TPST-1495 inhibits tumor proliferation and stimulates anti-cancer immunity better than inhibiting all 4 receptors together, the EP2 or EP4 receptors singly, or the upstream COX-2 enzyme. Methods: TPST-1495-001 is a first-in-human Phase 1 study (NCT04344795). In the Dose and Schedule Optimization Stage, the primary objectives are to characterize the safety and tolerability (including dose limiting toxicities) and determine the recommended phase 2 dose (RP2D) of TPST-1495 as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors. Additional objectives include characterization of PK, PD, and evaluation of potential biomarkers, including through paired (pre- and on-treatment) tumor biopsies. Monotherapy dose-finding employs a modified 3+3 design evaluating BID and QD TPST-1495 schedules along with continuous or intermittent (Days 1-5 every 7 days) dosing. For the pembrolizumab combination, the starting dose and schedule of TPST-1495 are determined by safety, PK and PD of monotherapy. Indication-specific Expansion Stage cohorts will evaluate TPST-1495 at the selected RP2D and schedule for both monotherapy and combination in endometrial cancer, squamous cell carcinoma of the head and neck, and microsatellite stable colorectal cancer (combination only), as well as in a biomarker-specific cohort enrolling patients with pathogenic tumor PIK3CA gene mutation. Dose and Schedule Optimization enrollment (monotherapy and combination) is ongoing at abstract submission while Expansion Stages are planned after identification of the RP2Ds. Clinical trial information: NCT04344795.