Phase 1/1b multicenter trial of TPST-1120, a peroxisome proliferator-activated receptor alpha (PPARα) antagonist as a single agent (SA) or in combination in patients with advanced solid tumors.

Abstract

TPS2665 Background: Tumor cells initially favor glucose metabolism via aerobic glycolysis. As tumors rapidly proliferate and metastasize, glucose stores are depleted and facilitated by a hypoxic tumor microenvironment (TME) and metabolic reprogramming shifts intracellular metabolism(IcM) towards fatty acid oxidation (FAO). Fatty acids support metabolism of suppressive immune cells in the TME in addition to tumor growth. PPARα is a ligand-activated nuclear transcription factor which regulates lipid metabolism and FAO. TPST-1120 is a first in class, oral selective PPARα antagonist that blocks transcription of PPARα target genes leading to an intracellular metabolism shift from FAO to glycolysis. Reduction of fatty acids in the TME leads to direct killing of tumor cells dependent on FAO, skews macrophages from immune suppressive M2 phenotype to an effector M1 phenotype and facilitates the cytotoxicity of immune effector cells. TPST-1120 also restores thrombospondin-1, a known natural inhibitor of angiogenesis, to homeostatic levels within the TME. TPST-1120 has an IC50 of 0.04 nM with > 35 fold selectivity over other PPAR isoforms. Preclinical studies in multiple tumor models show efficacy of TPST-1120 as a SA and in combination(combo) with an anti-PD1 monoclonal antibody (mAb) and chemotherapy. Methods: We have initiated a phase 1/1b multicenter, open label Dose Escalation (DEs) and Dose Expansion (DEx) trial to evaluate TPST-1120 as a SA and in combo with nivolumab, an anti-PD1 mAb; docetaxel, a chemotherapeutic agent and cetuximab, an anti-EGFR mAb. Objectives: 1) evaluate safety and tolerability of continuous dosing of TPST-1120 2) identify a recommended phase 2 dose (RP2D) and 3) evaluate efficacy. Eligibility: 1) patients with select advanced solid tumors who have failed 1 and up to 5 prior therapies. This phase 1/1b adaptive design has 4 DEs arms, 1 SA arm and 3 combination arms in which TPST-1120 is combined with nivolumab, docetaxel or cetuximab. The RP2D of TPST-1120 to proceed to DEx will be determined by safety and biomarkers during DEs. The DEx arms have 8 histology-specific cohorts, 4 SA arms and 4 combo arms and will follow a 2-stage expansion design. Biomarker analyses include gene expression profiling of PPARα-associated genes, tumor markers of immune modulation and serum lipid profiling. The total sample size is up to 338 pts. This trial is accruing at U.S sites. Clinical trial information: NCT03829436.