Phase I Study of Single-Agent Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Patients with Advanced Cancer CLINICAL CANCER RESEARCH Segal, N. H., He, A. R., Doi, T., Levy, R., Bhatia, S., Pishvaian, M. J., Cesari, R., Chen, Y., Davis, C. B., Huang, B., Thall, A. D., Gopal, A. K. 2018; 24 (8): 1816–23


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.

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