(P 415) A PHASE 1/2 TRIAL OF FOG-001, A FIRST-IN-CLASS DIRECT β-CATENIN:TCF4 INHIBITOR: SAFETY AND PRELIMINARY ANTITUMOR ACTIVITY IN PATIENTS WITH DESMOID TUMORS (DT)

Objective: Wnt pathway-activating mutations (WPAMs) are highly prevalent in DT, almost all of which harbor a WPAM in APC or CTNNB1. FOG-001 is a Helicon™ peptide that competitively inhibits the interaction between β-catenin and TCF transcription factors. Given the causal nature of WPAM mutations in desmoid tumors, targeting β-catenin offers a more direct and disease-relevant approach than γ-secretase inhibitors, which inhibit Notch signaling. We describe a first-in-human, phase 1/2, multicenter clinical trial of FOG-001 in patients (pts) with WPAM+ solid tumors, including DT. Herein we report updated data from study pts with DT.

Methods: Eligibility for DT pts: histological confirmation of DT with WPAM; ≥1 prior systemic therapy or treatment naïve but deemed appropriate for participation. The primary objective is safety/tolerability of FOG-001. Secondary objectives include preliminary anti-tumor activity and PK.

Results: As of May 11, 2025, 6 DT pts have received FOG-001 at doses ranging from 72–480 mg/m2. Median age was 34 years; 33.3% male. One pt with familial adenomatous polyposis had a DT with an APC mutation, while the remaining 5 pts had CTNNB1 mutations; 4 pts had prior treatment with nirogacestat and either progressed (n=3) or discontinued due to intolerability (n=1). FOG-001 demonstrated low PK variability and a dose-proportional increase in exposure. The most common (all-grade/grade ≥3) treatment-related adverse events were AST increase (5/1, reversable), ALT increases (4/0, reversable), alopecia (4/0; reversable), and fatigue (4/0). Median treatment duration was 28 weeks (range 2 – 81 weeks), with all pts still on study treatment at data cut-off. Three of 5 efficacy-evaluable pts, including 2 pts that had progressed on nirogacestat, achieved a partial response (PR: 60%). The remaining 2 pts had stable disease (20.4% and 15.6% tumor reduction), for a disease-control rate of 100%.

Conclusion: Preliminary data show that FOG-001 has acceptable tolerability in pts with DT. Tumor reductions were seen in all pts, including multiple PRs in pts who progressed on nirogacestat. Dose expansion in a DT-specific cohort is currently ongoing.