TPS3169 Background: Constitutive activation of the Wnt/β-catenin pathway drives malignancy in a wide range of cancers, where β-catenin has been notoriously difficult to drug due to its disordered nature, lack of defined drug-binding pockets, and associated toxicities. Biomolecular condensates are membraneless organelles that orchestrate cellular processes, biological pathways, and protein activity by compartmentalizing biomolecules. DPTX-3186 is a small molecule condensate modulator (c-mod) that acts via a novel mechanism of action, sequestering β-catenin into inactive condensate depots. This sequestration selectively inhibits β-catenin-driven transcription and induces robust cancer cell death. DPTX3186 is an orally bioavailable small molecule c-mod that demonstrates strong anti-tumor activity across multiple tumor types driven by various defects along the Wnt/β-catenin pathway. Studies in xenographs show that DPTX-3186 modulates Wnt pathway activity as evidenced by formation of inactive β-catenin condensates and modulation of β-catenin-driven gene transcription. Profound pharmacological efficacy, including regressions and complete responses, has been observed in murine models of gastric cancer as monotherapy. The molecule has been granted Fast Track and Orphan Drug Designations by the FDA. Methods: This first-in-human, phase 1/2, multicenter, open-label, dose-escalation (phase 1) and dose-expansion (phase 2) study evaluates the safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor effects of DPTX3186 monotherapy in patients with known Wnt pathway activated solid tumors. Eligible patients must have no other approved treatment options available. In Phase 1, DPTX3186 is administered orally in a 4 days on / three days off schedule, at escalating dose levels, evaluated sequentially in a BOIN design. Phase 2 dose expansion will utilize a TOP-BOIN design and will evaluate DPTX3186 monotherapy in patients with histologically or cytologically confirmed non-resectable gastric adenocarcinoma who are refractory to prior treatment. Primary endpoints are safety and tolerability of DPTX-3186, including dose-limiting toxicities (DLT) and the determination of the MTD and recommended dose for expansion. Secondary endpoints are PK, PD, and preliminary anti-tumor activity (e.g. overall response rate, duration of response, progression-free survival, disease control rate, and overall survival). 40 patients are planned to be enrolled in Part 1, which is currently enrolling in the USA. Clinical trial information: NCT07312903 .
Spira et al. (Thu,) studied this question.