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

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.

• Authors: Antonio Jimeno, Michael Gordon, Rashmi Chugh, Wells Messersmith, David Mendelson, Jakob Dupont, Robert Stagg, Ann M Kapoun, Lu Xu, Shailaja Uttamsingh, Rainer K Brachmann, David C Smith
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 24 Pg. 7490-7497 (Dec 15 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 28954784 (Publication Type: Clinical Trial, Phase I, Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Immunoconjugates
• Immunoglobulin Fc Fragments
• Ligands
• Receptors, G-Protein-Coupled
• Recombinant Fusion Proteins
• OMP-54F28

Topics

• Adult
• Aged
• Dose-Response Relationship, Drug
• Drug-Related Side Effects and Adverse Reactions (classification, pathology)
• Female
• Humans
• Immunoconjugates (administration & dosage, adverse effects)
• Immunoglobulin Fc Fragments (administration & dosage, adverse effects)
• Ligands
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy, genetics, pathology)
• Neoplastic Stem Cells (drug effects, pathology)
• Receptors, G-Protein-Coupled (administration & dosage)
• Recombinant Fusion Proteins (administration & dosage, adverse effects, pharmacokinetics)
• Wnt Signaling Pathway (drug effects)