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A phase Ib study of utomilumab (PF-05082566) in combination with mogamulizumab in patients with advanced solid tumors

Authors
  • Cohen, Ezra E. W.1
  • Pishvaian, Michael J.2
  • Shepard, Dale R.3
  • Wang, Ding4
  • Weiss, Jared5
  • Johnson, Melissa L.6
  • Chung, Christine H.7
  • Chen, Ying8
  • Huang, Bo9
  • Davis, Craig B.8
  • Toffalorio, Francesca10
  • Thall, Aron8
  • Powell, Steven F.11
  • 1 University of California San Diego, 3855 Health Sciences Drive, La Jolla, CA, 92093, USA , La Jolla (United States)
  • 2 Georgetown University Medical Center, Washington, DC, USA , Washington (United States)
  • 3 Cleveland Clinic, Cleveland, OH, USA , Cleveland (United States)
  • 4 Henry Ford Hospital, Detroit, MI, USA , Detroit (United States)
  • 5 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA , Chapel Hill (United States)
  • 6 Sarah Cannon Research Institute, Nashville, TN, USA , Nashville (United States)
  • 7 Moffit Cancer Center, Tampa, FL, USA , Tampa (United States)
  • 8 Pfizer Inc, La Jolla, CA, USA , La Jolla (United States)
  • 9 Pfizer Inc, New York, NY, USA , New York (United States)
  • 10 Pfizer Inc, Milan, Italy , Milan (Italy)
  • 11 Sanford Research, Sioux Falls, SD, USA , Sioux Falls (United States)
Type
Published Article
Journal
Journal for ImmunoTherapy of Cancer
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Dec 04, 2019
Volume
7
Issue
1
Identifiers
DOI: 10.1186/s40425-019-0815-6
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundExpressed on activated T and natural killer cells, 4-1BB/CD137 is a costimulatory receptor that signals a series of events resulting in cytokine secretion and enhanced effector function. Targeting 4-1BB/CD137 with agonist antibodies has been associated with tumor reduction and antitumor immunity. C-C chemokine receptor 4 (CCR4) is highly expressed in various solid tumor indications and associated with poor prognosis. This phase Ib, open-label study in patients with advanced solid tumors assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of utomilumab (PF-05082566), a human monoclonal antibody (mAb) agonist of the T-cell costimulatory receptor 4-1BB/CD137, in combination with mogamulizumab, a humanized mAb targeting CCR4 reported to deplete subsets of regulatory T cells (Tregs).MethodsUtomilumab 1.2–5 mg/kg or 100 mg flat dose every 4 weeks plus mogamulizumab 1 mg/kg (weekly in Cycle 1 followed by biweekly in Cycles ≥2) was administered intravenously to 24 adults with solid tumors. Blood was collected pre- and post-dose for assessment of drug pharmacokinetics, immunogenicity, and pharmacodynamic markers. Baseline tumor biopsies from a subset of patients were also analyzed for the presence of programmed cell death-ligand 1 (PD-L1), CD8, FoxP3, and 4-1BB/CD137. Radiologic tumor assessments were conducted at baseline and on treatment every 8 weeks.ResultsNo dose-limiting toxicities occurred and the maximum tolerated dose was determined to be at least 2.4 mg/kg per the time-to-event continual reassessment method. No serious adverse events related to either treatment were observed; anemia was the only grade 3 non-serious adverse event related to both treatments. Utomilumab systemic exposure appeared to increase with dose. One patient with PD-L1–refractory squamous lung cancer achieved a best overall response of partial response and 9 patients had a best overall response of stable disease. No patients achieved complete response. Objective response rate was 4.2% (95% confidence interval: 0.1–21.1%) per RECIST 1.1. Depletion of Tregs in peripheral blood was accompanied by evidence of T-cell expansion as assessed by T-cell receptor sequence analysis.ConclusionsThe combination of utomilumab/mogamulizumab was safe and tolerable, and may be suitable for evaluation in settings where CCR4-expressing Tregs are suppressing anticancer immunity.Trial registrationClinicalTrials.gov identifier: NCT02444793.

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