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|Ref Type||Journal Article|
|Authors||Segal NH, He AR, Doi T, Levy R, Bhatia S, Pishvaian MJ, Cesari R, Chen Y, Davis CB, Huang B, Thall AD, Gopal AK|
|Title||Phase I Study of Single-Agent Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Patients with Advanced Cancer.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2018 Apr 15|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||Merkel cell carcinoma||not applicable||Utomilumab||Phase I||Actionable||In a Phase I trial, Utomilumab (PF-05082566) treatment resulted in an overall objective response rate of 13.3% (2/15, 1 complete response, 1 partial response) in patients with Merkel cell carcinoma (PMID: 29549159; NCT01307267).||29549159|
|Unknown unknown||Advanced Solid Tumor||not applicable||Utomilumab||Phase I||Actionable||In a Phase I trial, Utomilumab (PF-05082566) treatment resulted in an overall objective response rate of 3.8% (2/53), a median progression-free survival of 1.7 months, and a median overall survival of 11.2 months in patients with advanced solid tumors (PMID: 29549159; NCT01307267).||29549159|
|Unknown unknown||colorectal cancer||no benefit||Utomilumab||Phase I||Actionable||In a Phase I trial, Utomilumab (PF-05082566) treatment resulted in no overall objective response (0/12) in patients with colorectal cancer (PMID: 29549159; NCT01307267).||29549159|