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

• Published in: Clinical cancer research Vol. 23; no. 24; pp. 7490 - 7497
• Main Authors: Jimeno, Antonio, Gordon, Michael, Chugh, Rashmi, Messersmith, Wells, Mendelson, David, Dupont, Jakob, Stagg, Robert, Kapoun, Ann M., Xu, Lu, Uttamsingh, Shailaja, Brachmann, Rainer K., Smith, David C.
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 15.12.2017
• Subjects: Adult; Aged; Anticancer properties; Appetite loss; Cancer; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions - classification; Drug-Related Side Effects and Adverse Reactions - pathology; Experimental design; Fatigue; Female; Follicles; Fractures; Fragility; Frizzled protein; Fusion protein; Humans; Hypophosphatemia; Immunoconjugates - administration & dosage; Immunoconjugates - adverse effects; Immunogenicity; Immunoglobulin Fc Fragments - administration & dosage; Immunoglobulin Fc Fragments - adverse effects; Immunoglobulin G; Ligands; Male; Maximum Tolerated Dose; Middle Aged; Muscles; Muscular fatigue; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - pathology; Outer membrane proteins; Patients; Pharmacodynamics; Pharmacokinetics; Pharmacology; Quality; Receptors, G-Protein-Coupled - administration & dosage; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - adverse effects; Recombinant Fusion Proteins - pharmacokinetics; Signaling; Solid tumors; Spasms; Stem cells; Toxicity; Tumors; Wnt protein; Wnt Signaling Pathway - drug effects
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-17-2157

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.