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Published on: July 5, 2019
A First-in-Human Phase I Study of the Anticancer Stem Cell Agent Ipafricept (OMP-54F28), a Decoy Receptor for Wnt
Antonio Jimeno1, Michael Gordon2, Rashmi Chugh3
1University of Colorado School of Medicine, Aurora, Colorado. antonio.jimeno@ucdenver.edu.
Abstract:
Purpose: 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.Experimental design: 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.Results: 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.Conclusions: Ipafricept was well tolerated, with RP2D of 15 mg/kg Q3W. Prolonged SD was noted in desmoid tumor and germ cell cancer patients. Clin Cancer Res; 23(24); 7490-7. ©2017 AACR.
Insights
Ipafricept, a Wnt signaling inhibitor, showed good tolerability in solid tumor patients. The recommended dose was 15 mg/kg every 3 weeks, with some patients achieving prolonged stable disease.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Wnt signaling plays a crucial role in tumor cell dedifferentiation and cancer stem cell biology.
- Ipafricept (OMP-54F28) is a novel recombinant fusion protein designed to inhibit Wnt ligands.
Purpose of the Study:
- To evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of ipafricept in patients with solid tumors.
- To determine the dose-limiting toxicities (DLTs) and establish the recommended phase 2 dose (RP2D) for ipafricept.
Main Methods:
- A Phase 1 dose-escalation study using a 3+3 design.
- Ipafricept administered intravenously every 3 weeks across seven dose cohorts (0.5 to 20 mg/kg).
- Assessment of safety, PK, immunogenicity, PD markers (Wnt pathway gene modulation), and clinical activity.
Main Results:
- Ipafricept was generally well-tolerated up to 15 mg/kg; fragility fractures occurred at 20 mg/kg.
- Common adverse events included dysgeusia, decreased appetite, fatigue, and muscle spasms; Grade 3 events were infrequent (hypophosphatemia, weight decrease).
- Pharmacokinetic modeling suggested target dose at 10 mg/kg; PD modulation of Wnt pathway genes observed at ≥2.5 mg/kg. Prolonged stable disease (>6 months) in two desmoid tumor and one germ cell cancer patient.
Conclusions:
- Ipafricept demonstrated an acceptable safety profile with a recommended phase 2 dose (RP2D) of 15 mg/kg Q3W.
- The drug showed potential for prolonged stable disease in specific tumor types, warranting further investigation.
