TY - JOUR
T1 - Anti-PD-1 monoclonal antibody MEDI0680 in a phase i study of patients with advanced solid malignancies
AU - Naing, Aung
AU - Infante, Jeffrey
AU - Goel, Sanjay
AU - Burris, Howard
AU - Black, Chelsea
AU - Marshall, Shannon
AU - Achour, Ikbel
AU - Barbee, Susannah
AU - May, Rena
AU - Morehouse, Chris
AU - Pollizzi, Kristen
AU - Song, Xuyang
AU - Steele, Keith
AU - Elgeioushi, Nairouz
AU - Walcott, Farzana
AU - Karakunnel, Joyson
AU - Lorusso, Patricia
AU - Weise, Amy
AU - Eder, Joseph
AU - Curti, Brendan
AU - Oberst, Michael
N1 - Publisher Copyright:
© 2019 The Author(s).
PY - 2019/8/22
Y1 - 2019/8/22
N2 - 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 IFNγand 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.
AB - 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 IFNγand 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.
KW - Immunotherapy
KW - Kidney cancer
KW - MEDI0680
KW - Melanoma
KW - PD-1
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UR - http://www.scopus.com/inward/citedby.url?scp=85071271469&partnerID=8YFLogxK
U2 - 10.1186/s40425-019-0665-2
DO - 10.1186/s40425-019-0665-2
M3 - Article
C2 - 31439037
AN - SCOPUS:85071271469
SN - 2051-1426
VL - 7
JO - Journal for immunotherapy of cancer
JF - Journal for immunotherapy of cancer
IS - 1
M1 - 225
ER -