Anti-PD-1 monoclonal antibody MEDI0680 in a phase I study of patients with advanced solid malignancies.

ABSTRACT: BACKGROUND:The safety, efficacy, pharmacokinetics, and pharmacodynamics of the anti-programmed cell death-1 antibody MEDI0680 were evaluated in a phase I, multicenter, dose-escalation study in advanced solid malignancies. METHODS:MEDI0680 was administered intravenously once every 2 weeks (Q2W) or once every 3 weeks at 0.1, 0.5, 2.5, 10 or 20?mg/kg. Two cohorts received 20?mg/kg once a week for 2 or 4?weeks, then 20?mg/kg Q2W. All were treated for 12?months or until progression. The primary endpoint was safety. Secondary endpoints were efficacy and pharmacokinetics. Exploratory endpoints included pharmacodynamics. RESULTS:Fifty-eight patients were treated. Median age was 62.5?years and 81% were male. Most had kidney cancer (n?=?36) or melanoma (n?=?9). There were no dose-limiting toxicities. Treatment-related adverse events occurred in 83% and were grade???3 in 21%. Objective clinical responses occurred in 8/58 patients (14%): 5 with kidney cancer, including 1 with a complete response, and 3 with melanoma. The relationship between dose and serum levels was predictable and linear, with apparent receptor saturation at 10?mg/kg Q2W and all 20?mg/kg cohorts. CONCLUSIONS:MEDI0680 induced peripheral T-cell proliferation and increased plasma IFN? and associated chemokines regardless of clinical response. CD8+ T-cell tumor infiltration and tumoral gene expression of IFNG, CD8A, CXCL9, and granzyme K (GZMK) were also increased following MEDI0680 administration. TRIAL REGISTRATION:NCT02013804 ; date of registration December 12, 2013.

SUBMITTER: Naing A 

PROVIDER: S-EPMC6704567 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature