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

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; 24(8); 1816-23. ©2018 AACR.

• Authors: 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, Ajay K Gopal
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 24 Issue 8 Pg. 1816-1823 (04 15 2018) ISSN: 1557-3265 [Electronic] United States
• PMID: 29549159 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents, Immunological
• Biomarkers, Tumor
• Immunoglobulin G
• TNFRSF9 protein, human
• Tumor Necrosis Factor Receptor Superfamily, Member 9
• utomilumab

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Antineoplastic Agents, Immunological (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Biomarkers, Tumor
• Combined Modality Therapy
• Humans
• Immunoglobulin G (administration & dosage, adverse effects, therapeutic use)
• Middle Aged
• Molecular Targeted Therapy
• Neoplasm Metastasis
• Neoplasm Staging
• Neoplasms (diagnosis, drug therapy, metabolism, mortality)
• Treatment Outcome
• Tumor Necrosis Factor Receptor Superfamily, Member 9 (agonists, blood)