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

Aung Naing, Jeffrey Infante, Sanjay Goel, Howard Burris, Chelsea Black, Shannon Marshall, Ikbel Achour, Susannah Barbee, Rena May, Chris Morehouse, Kristen Pollizzi, Xuyang Song, Keith Steele, Nairouz Elgeioushi, Farzana Walcott, Joyson Karakunnel, Patricia Lorusso, Amy Weise, Joseph Eder, Brendan CurtiMichael Oberst

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Article number225
JournalJournal for ImmunoTherapy of Cancer
Volume7
Issue number1
DOIs
StatePublished - Aug 22 2019

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Kidney Neoplasms
Melanoma
Pharmacokinetics
Monoclonal Antibodies
T-Lymphocytes
Safety
Granzymes
Chemokines
Neoplasms
Cell Death
Cell Proliferation
Gene Expression
Antibodies
Serum
Therapeutics

Keywords

  • Immunotherapy
  • Kidney cancer
  • MEDI0680
  • Melanoma
  • PD-1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Anti-PD-1 monoclonal antibody MEDI0680 in a phase i study of patients with advanced solid malignancies. / Naing, Aung; Infante, Jeffrey; Goel, Sanjay; Burris, Howard; Black, Chelsea; Marshall, Shannon; Achour, Ikbel; Barbee, Susannah; May, Rena; Morehouse, Chris; Pollizzi, Kristen; Song, Xuyang; Steele, Keith; Elgeioushi, Nairouz; Walcott, Farzana; Karakunnel, Joyson; Lorusso, Patricia; Weise, Amy; Eder, Joseph; Curti, Brendan; Oberst, Michael.

In: Journal for ImmunoTherapy of Cancer, Vol. 7, No. 1, 225, 22.08.2019.

Research output: Contribution to journalArticle

Naing, A, Infante, J, Goel, S, Burris, H, Black, C, Marshall, S, Achour, I, Barbee, S, May, R, Morehouse, C, Pollizzi, K, Song, X, Steele, K, Elgeioushi, N, Walcott, F, Karakunnel, J, Lorusso, P, Weise, A, Eder, J, Curti, B & Oberst, M 2019, 'Anti-PD-1 monoclonal antibody MEDI0680 in a phase i study of patients with advanced solid malignancies', Journal for ImmunoTherapy of Cancer, vol. 7, no. 1, 225. https://doi.org/10.1186/s40425-019-0665-2
Naing, Aung ; Infante, Jeffrey ; Goel, Sanjay ; Burris, Howard ; Black, Chelsea ; Marshall, Shannon ; Achour, Ikbel ; Barbee, Susannah ; May, Rena ; Morehouse, Chris ; Pollizzi, Kristen ; Song, Xuyang ; Steele, Keith ; Elgeioushi, Nairouz ; Walcott, Farzana ; Karakunnel, Joyson ; Lorusso, Patricia ; Weise, Amy ; Eder, Joseph ; Curti, Brendan ; Oberst, Michael. / Anti-PD-1 monoclonal antibody MEDI0680 in a phase i study of patients with advanced solid malignancies. In: Journal for ImmunoTherapy of Cancer. 2019 ; Vol. 7, No. 1.
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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 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.",
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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

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.

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KW - Melanoma

KW - PD-1

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