A first-in-human Phase 1 study of the anti-cancer stem cell agent ipafricept (OMP-54F28), a decoy receptor for Wnt ligands, in patients with advanced solid tumors

Summary

Wnt signaling is implicated in tumor cell de-differentiation and cancer stem cell function. Ipafricept (OMP-54F28) is a first-in-class recombinant fusion protein with the extracellular part of human Frizzled 8 receptor fused to a human IgG1 Fc fragment that binds Wnt ligands. This trial evaluated ipafricept in patients with solid tumors. A 3+3 design was used; ipafricept was given intravenously every 3 weeks. Objectives were determination of dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and preliminary efficacy. 26 patients were treated in 7 dose-escalation cohorts (0.5, 1, 2.5, 5, 10, 15 and 20 mg/kg). Most common related Grade 1 and 2 adverse events (AEs; ³20% of patients) were dysgeusia, decreased appetite, fatigue, and muscle spasms. Ipafricept-related Grade 3 TEAEs included hypophosphatemia and weight decrease (1 subject each, 3.8%). Ipafricept half-life was ~4 days, and had low incidence of anti-drug antibody formation (7.69%) with no impact on drug exposure. Six patients had _-C-terminal telopeptide (_-CTX) doubling from baseline, which was reversible. PD modulation of Wnt pathway genes in hair follicles occurred ³2.5 mg/kg. Two desmoid tumor and a germ cell cancer patient experienced stable disease for >6 months. Ipafricept was well tolerated, with RP2D of 15 mg/kg Q3W. Prolonged SD was noted in desmoid tumor and germ cell cancer patients.