A Phase I, Open-Label, Dose-Escalation Study of the OX40 Agonist Ivuxolimab in Patients with Locally Advanced or Metastatic Cancers

  • Clin Cancer Res. 2022 Jan 1;28(1):71-83. doi: 10.1158/1078-0432.CCR-21-0845.
Adi Diab  1 ,  Omid Hamid  2 ,  John A Thompson  3 ,  Willeke Ros  4 ,  Ferry A L M Eskens  5 ,  Toshihiko Doi  6 ,  Siwen Hu-Lieskovan  7 ,  Samuel J Klempner  8 ,  Bishu Ganguly  9 ,  Catherine Fleener  9 ,  Xiao Wang  9 ,  Tenshang Joh  9 ,  Ken Liao  9 ,  Shahram Salek-Ardakani  9 ,  Carrie Turich Taylor  9 ,  Jeffrey Chou  9 ,  Anthony B El-Khoueiry  10
Affiliations
  • 1. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. [email protected].
  • 2. Immuno-Oncology and Cutaneous Malignancies, The Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles, California.
  • 3. Division of Medical Oncology, University of Washington School of Medicine/Seattle Cancer Care Alliance, Seattle, Washington.
  • 4. Department of Pharmacology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • 5. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
  • 6. Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
  • 7. Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California.
  • 8. Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
  • 9. Pfizer, New York, New York.
  • 10. Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
PMID: 34615725 DOI: 10.1158/1078-0432.CCR-21-0845
Abstract

Purpose: Stimulation of effector T cells is an appealing immunotherapeutic approach in oncology. OX40 (CD134) is a costimulatory receptor expressed on activated CD4+ and CD8+ T cells. Induction of OX40 following antigen recognition results in enhanced T-cell activation, proliferation, and survival, and OX40 targeting shows therapeutic efficacy in preclinical studies. We report the monotherapy dose-escalation portion of a multicenter, phase I trial (NCT02315066) of ivuxolimab (PF-04518600), a fully human immunoglobulin G2 agonistic monoclonal antibody specific for human OX40.

Patients and methods: Adult patients (N = 52) with selected locally advanced or metastatic cancers received ivuxolimab 0.01 to 10 mg/kg. Primary endpoints were safety and tolerability. Secondary/exploratory endpoints included preliminary assessment of antitumor activity and biomarker analyses.

Results: The most common all-causality adverse events were fatigue (46.2%), nausea (28.8%), and decreased appetite (25.0%). Of 31 treatment-related adverse events, 30 (96.8%) were grade ≤2. No dose-limiting toxicities occurred. Ivuxolimab exposure increased in a dose-proportionate manner from 0.3 to 10 mg/kg. Full peripheral blood target engagement occurred at ≥0.3 mg/kg. Three (5.8%) patients achieved a partial response, and disease control was achieved in 56% of patients. Increased CD4+ central memory T-cell proliferation and activation, and clonal expansion of CD4+ and CD8+ T cells in peripheral blood were observed at 0.1 to 3.0 mg/kg. Increased immune cell infiltrate and OX40 expression were evident in on-treatment tumor biopsies.

Conclusions: Ivuxolimab was generally well tolerated with on-target immune activation at clinically relevant doses, showed preliminary antitumor activity, and may serve as a partner for combination studies.

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