Development of a Novel Resolvin-Based Therapy for Treatment of Pancreatic Cancer

ABSTRACT Pancreatic cancer (PC) is a highly lethal disease with a 5-year survival rate between 5% and 10%. PC incidence and mortality are projected to more than double over the next ten years. However, existing systemic chemotherapies have limited efficacy along with significant side effects and safety issues, and targeted and immunotherapies have not been effective. Emerging data demonstrates that cellular debris in the tumor microenvironment and protumor inflammation are major causes of PC progression, metastasis and resistance. To address this opportunity, Thetis is developing TP-317, a Resolvin E1 (RvE1) therapy for PC. RvE1 is an autacoid discovered by Professor Charles Serhan (Harvard) that stimulates the clearance of cell debris, resolves inflammation and promotes anti-tumor immunity. Preliminary research conducted in collaboration with Dr. Dipak Panigrahy’s Lab (Harvard Medical School) has shown that TP-317 can suppress tumor growth in multiple animal models as a single agent and has an additive effect with chemotherapy. Additionally, based on its non- immunosuppressive mechanism of action as an endogenous lipid and extensive nonclinical and clinical toxicology data, TP-317 is anticipated to have a favorable safety profile. Thus, TP-317 is well positioned to improve patient survival and transform the standard of care for PC. The overall goal of this Fast Track grant is to complete key preclinical studies to support an investigational new drug (IND) application and advance TP-317 into clinical trials for the treatment of PC. This goal will be met through the following aims: Phase I, Specific Aim 1: To investigate TP-317 in Murine Pancreatic Cancer Models. The efficacy of TP- 317 will be assessed in two established mouse models of PC, the KPC model and a patient derived xenograft model. In addition, we will evaluate the effect of TP-317 on multiple biomarkers (e.g., inflammatory cytokines, immune cell phenotyping via flow cytometry, and RNA sequencing). Phase I Milestones: Improvement in survival and tumor volume greater than 25% with TP-317 monotherapy or combination arm compared to placebo or active comparator and identification of biomarkers that correlate with response/non-response preclinically, are clinically significant in PC and are easily assayed in clinical trials. Phase II, Specific Aim 2. Evaluate Subcutaneous TP-317 Safety and Tolerability in Rat and Dog. The toxicity and toxicokinetic profile of TP-317 will be assessed under GLP conditions in rats and dogs for 28 days. Phase II, Specific Aim 3. Manufacture and Stability Testing of GMP Drug Product. Clinical trial material (CTM) will be produced under good manufacturing practice (GMP) conditions for the Phase 1 clinical trial. Phase II Milestones: Aim 2 − Demonstration of an acceptable toxicity profile in both species, in which all adverse findings are clinically reversible, not clinically severe, irrelevant to humans, or relevant but monitorable in the clinic. Aim 3 − Manufacture of CTM meeting release specifications and ICH Guidelines for Phase 1 studies.