Anti-PD-1 monoclonal antibody MEDI0680 in a phase I study of patients with advanced solid malignancies
| Autor: | Michael Oberst, Howard A. Burris, Chris Morehouse, Sanjay Goel, Chelsea Black, Joyson Karakunnel, Susannah Barbee, Kristen Pollizzi, Ikbel Achour, Xuyang Song, Nairouz Elgeioushi, Rena May, Farzana Walcott, Joseph Paul Eder, Brendan D. Curti, Patricia LoRusso, Amy Weise, Jeffrey R. Infante, Keith E Steele, Shannon Marshall, Aung Naing |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Cancer Research medicine.medical_specialty medicine.medical_treatment Immunology lcsh:RC254-282 Gastroenterology 03 medical and health sciences 0302 clinical medicine Antineoplastic Agents Immunological Pharmacokinetics Internal medicine PD-1 Clinical endpoint Immunology and Allergy Medicine Humans Adverse effect Melanoma Pharmacology business.industry Antibodies Monoclonal Kidney cancer Immunotherapy Middle Aged lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease 030104 developmental biology Treatment Outcome Oncology 030220 oncology & carcinogenesis Pharmacodynamics Disease Progression Molecular Medicine Granzyme K Female MEDI0680 business Research Article |
| Zdroj: | Journal for ImmunoTherapy of Cancer, Vol 7, Iss 1, Pp 1-15 (2019) Journal for Immunotherapy of Cancer |
| ISSN: | 2051-1426 |
| Popis: | 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 IFNγ 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. Electronic supplementary material The online version of this article (10.1186/s40425-019-0665-2) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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