A First-in-Human Phase I Study of the Anticancer Stem Cell Agent Ipafricept (OMP-54F28), a Decoy Receptor for Wnt Ligands, in Patients with Advanced Solid Tumors

Abstract

Wnt signaling is implicated in tumor cell dedifferentiation 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. The 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 seven dose-escalation cohorts (0.5, 1, 2.5, 5, 10, 15, and 20 mg/kg). No further dose escalation was pursued as PK modeling indicated that the target efficacious dose was reached at 10 mg/kg, and fragility fractures occurred at 20 mg/kg. Most common related grade 1 and 2 adverse events (AEs; ≥20% 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 antidrug antibody formation (7.69%) with no impact on drug exposure. Six patients had β-C-terminal telopeptide (β-CTX) doubling from baseline, which was reversible. PD modulation of Wnt pathway genes in hair follicles occurred ≥2.5 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. .

Wnt Signaling and Drug Resistance in Cancer

“…These resistant clones may be selected by the treatment and become the dominant population of the tumor. This process has been reported in The drug combinations showed synergistic and potent tumor growth inhibition in patientderived ovarian, pancreatic, hepatocellular, breast, lung, and/or colorectal cancer xenografts (Chartier et al, 2016;Fischer et al, 2017a,b;Jimeno et al, 2017 ETC-159 in combination with one of the five PI3K/mTOR inhibitors synergistically suppressed 3D colony formation of several Wnt-addicted pancreatic and cholangiocarcinoma cell lines. ETC-159 in combination with GDC-0941 led to synergistic tumor growth inhibition in HPAF-II and AsPC-1 xenografts (Zhong et al, 2019).…”

“…In addition, neutralizing antibodies targeting Wnt receptors (Frizzleds and LRPs) and agonists (RSPOs) and soluble Fzd-based decoy receptor of Wnt ligands have been developed by different groups. Some of these have also entered clinical trials (Ettenberg et al, 2010;Gurney et al, 2012;Madan and Virshup, 2015;Chartier et al, 2016;Jimeno et al, 2017;Steinhart et al, 2017).…”

Wnt Signaling and Its Significance Within the Tumor Microenvironment: Novel Therapeutic Insights

“…Another recombinant fusion protein that blocks the Wnt signaling is OMP-54F28 (or Ipafricept). A first-in-human phase I study of this decoy receptor for Wnt ligands is presently being carried out in patients with advanced stages of solid tumors (104). It binds to the Wnt ligand through the adomain present in the extracellular part of the human Frizzled 8 receptor (fused to a human IgG1 Fc fragment).…”

Stem cells in cancer initiation and progression

“…Consistent with the critical role for Wnt pathway mutations in colon cancer initiation and progression, colon CSCs have also been shown to have high Wnt reporter activity, and exogenously activated Wnt can promote the proliferation of these cells (Vermeulen et al, 2010). In addition, Wnt signaling is critical for sustaining aggressive triple-negative breast CSCs (Jang et al, 2015), and several trials such as those with vantictumab (NCT01345201), (LGK974)189 (NCT01351103), and Ipafricept (Jimeno et al, 2017) have been initiated to target the Wnt pathway in breast cancers.…”