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Cancer Therapy: Clinical

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

Antonio Jimeno, Michael Gordon, Rashmi Chugh, Wells Messersmith, David Mendelson, Jakob Dupont, Robert Stagg, Ann M. Kapoun, Lu Xu, Shailaja Uttamsingh, Rainer K. Brachmann and David C. Smith
Antonio Jimeno
University of Colorado School of Medicine, Aurora, Colorado.
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  • For correspondence: antonio.jimeno@ucdenver.edu
Michael Gordon
Pinnacle Oncology Hematology, Scottsdale, Arizona.
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Rashmi Chugh
University of Michigan, Ann Arbor, Michigan.
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Wells Messersmith
University of Colorado School of Medicine, Aurora, Colorado.
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David Mendelson
Pinnacle Oncology Hematology, Scottsdale, Arizona.
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Jakob Dupont
OncoMed Pharmaceuticals, Redwood City, California.
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Robert Stagg
OncoMed Pharmaceuticals, Redwood City, California.
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Ann M. Kapoun
OncoMed Pharmaceuticals, Redwood City, California.
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Lu Xu
OncoMed Pharmaceuticals, Redwood City, California.
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Shailaja Uttamsingh
OncoMed Pharmaceuticals, Redwood City, California.
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Rainer K. Brachmann
OncoMed Pharmaceuticals, Redwood City, California.
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David C. Smith
University of Michigan, Ann Arbor, Michigan.
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DOI: 10.1158/1078-0432.CCR-17-2157 Published December 2017
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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.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Prior Presentations: Presented at the 2013 AACR-NCI-EORTC, Boston, MA; and 2014 American Society of Clinical Oncology Annual Meeting, Chicago, IL.

  • NCT: 01608867

  • Received July 25, 2017.
  • Revision received August 30, 2017.
  • Accepted September 20, 2017.
  • ©2017 American Association for Cancer Research.
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Clinical Cancer Research: 23 (24)
December 2017
Volume 23, Issue 24
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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
Antonio Jimeno, Michael Gordon, Rashmi Chugh, Wells Messersmith, David Mendelson, Jakob Dupont, Robert Stagg, Ann M. Kapoun, Lu Xu, Shailaja Uttamsingh, Rainer K. Brachmann and David C. Smith
Clin Cancer Res December 15 2017 (23) (24) 7490-7497; DOI: 10.1158/1078-0432.CCR-17-2157

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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
Antonio Jimeno, Michael Gordon, Rashmi Chugh, Wells Messersmith, David Mendelson, Jakob Dupont, Robert Stagg, Ann M. Kapoun, Lu Xu, Shailaja Uttamsingh, Rainer K. Brachmann and David C. Smith
Clin Cancer Res December 15 2017 (23) (24) 7490-7497; DOI: 10.1158/1078-0432.CCR-17-2157
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Clinical Cancer Research
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