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Cancer Therapy: Clinical

Phase I Study of Single-Agent Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Patients with Advanced Cancer

Neil H. Segal, Aiwu R. He, Toshihiko Doi, Ronald Levy, Shailender Bhatia, Michael J. Pishvaian, Rossano Cesari, Ying Chen, Craig B. Davis, Bo Huang, Aron D. Thall and Ajay K. Gopal
Neil H. Segal
Memorial Sloan Kettering Cancer Center, New York, New York.
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  • For correspondence: segaln@mskcc.org
Aiwu R. He
Georgetown University, Lombardi Comprehensive Cancer Center, Washington, D.C.
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Toshihiko Doi
National Cancer Center Hospital East, Chiba, Japan.
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Ronald Levy
Stanford University Cancer Center, Stanford, California.
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Shailender Bhatia
University of Washington/Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, Seattle, Washington.
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Michael J. Pishvaian
Georgetown University, Lombardi Comprehensive Cancer Center, Washington, D.C.
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Rossano Cesari
Pfizer Oncology, Milan, Italy.
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Ying Chen
Pfizer Oncology, San Diego, California.
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Craig B. Davis
Pfizer Oncology, San Diego, California.
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Bo Huang
Pfizer Oncology, Groton, Connecticut.
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Aron D. Thall
Pfizer Oncology, San Diego, California.
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Ajay K. Gopal
University of Washington/Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, Seattle, Washington.
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DOI: 10.1158/1078-0432.CCR-17-1922
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Abstract

Purpose: Utomilumab (PF-05082566) is an agonistic mAb that engages the immune costimulatory molecule 4-1BB/CD137. In this first-in-human, phase I, open-label, multicenter, multiple-dose study (NCT01307267) we evaluated safety, tolerability, pharmacokinetics, preliminary clinical activity, and pharmacodynamics of single-agent utomilumab in patients with advanced malignancies.

Experimental Design: Dose escalation was based on a standard 3+3 design for doses of utomilumab from 0.006 to 0.3 mg/kg every 4 weeks and a time-to-event continual reassessment method for utomilumab 0.6 to 10 mg/kg every 4 weeks. The primary study endpoint was dose-limiting toxicity (DLT) in the first two cycles.

Results: Utomilumab demonstrated a well-tolerated safety profile (N = 55). None of the patients experienced a DLT at the dose levels evaluated. The most common treatment-related adverse events were fatigue, pyrexia, decreased appetite, dizziness, and rash (<10% of patients). Only one (1.8%) patient experienced a grade 3–4 treatment-related adverse event (fatigue), and no clinically relevant elevations in transaminases were noted. Utomilumab demonstrated linear pharmacokinetics at doses ranging from 0.006 to 10 mg/kg, with similar safety and pharmacokinetics in anti-drug antibody (ADA)-negative and ADA-positive patients. The overall objective response rate was 3.8% (95% CI, 0.5%–13.0%) in patients with solid tumors and 13.3% in patients with Merkel cell carcinoma, including a complete response and a partial response. Circulating biomarkers support 4-1BB/CD137 engagement by utomilumab and suggest that circulating lymphocyte levels may influence probability of clinical benefit.

Conclusions: The favorable safety profile and preliminary antitumor activity demonstrated by utomilumab warrant further evaluation in patients with advanced malignancies. Clin Cancer Res; 1–8. ©2018 AACR.

Footnotes

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

  • Clinical Trial registration ID: NCT01307267

  • Received August 8, 2017.
  • Revision received November 28, 2017.
  • Accepted January 24, 2018.
  • Published first April 6, 2018.
  • ©2018 American Association for Cancer Research.
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Published OnlineFirst March 16, 2018
doi: 10.1158/1078-0432.CCR-17-1922

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Phase I Study of Single-Agent Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Patients with Advanced Cancer
Neil H. Segal, Aiwu R. He, Toshihiko Doi, Ronald Levy, Shailender Bhatia, Michael J. Pishvaian, Rossano Cesari, Ying Chen, Craig B. Davis, Bo Huang, Aron D. Thall and Ajay K. Gopal
Clin Cancer Res March 16 2018 DOI: 10.1158/1078-0432.CCR-17-1922

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Phase I Study of Single-Agent Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Patients with Advanced Cancer
Neil H. Segal, Aiwu R. He, Toshihiko Doi, Ronald Levy, Shailender Bhatia, Michael J. Pishvaian, Rossano Cesari, Ying Chen, Craig B. Davis, Bo Huang, Aron D. Thall and Ajay K. Gopal
Clin Cancer Res March 16 2018 DOI: 10.1158/1078-0432.CCR-17-1922
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Clinical Cancer Research
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