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DS-8895a is a humanized anti-EPHA2 IgG1 monoclonal antibody afucosylated to enhance antibody-dependent cellular cytotoxicity activity. We conducted a two-step, phase I, multicenter, open-label study to determine the safety, tolerability, and pharmacokinetics of DS-8895a in patients with advanced solid tumors.\n\nMETHODS:\nStep 1 was a dose escalation cohort in advanced solid tumor patients (six dose levels, 0.1-20 mg/kg) to determine Step 2 dosing. Step 2 was a dose expansion cohort in EPHA2-positive esophageal and gastric cancer patients. DS-8895a was intravenously administered every 2 weeks for the duration of the study, with a 28-day period to assess dose-limiting toxicity (DLT). Safety, pharmacokinetics, tumor response, and potential biomarkers were evaluated.\n\nRESULTS:\nThirty-seven patients (Step 1: 22, Step 2: 15 [9: gastric cancer, 6: esophageal cancer]) were enrolled. Although one DLT (Grade 4 platelet count decreased) was observed in Step 1 (dose level 6, 20 mg/kg), the maximum tolerated dose was not reached; the highest dose (20 mg/kg) was used in Step 2. Of the 37 patients, 24 (64.9%) experienced drug-related adverse events (AEs) including three (8.1%) with Grade ≥ 3 AEs. Infusion-related reactions occurred in 19 patients (51.4%) but were manageable. All patients discontinued the study (evident disease progression, 33; AEs, 4). Maximum and trough serum DS-8895a concentrations increased dose-dependently. One gastric cancer patient achieved partial response and 13 patients achieved stable disease. Serum inflammatory cytokines transiently increased at completion of and 4 h after the start of DS-8895a administration. The proportion of CD16-positive natural killer (NK) cells (CD3-CD56+CD16+) decreased 4 h after the start of DS-8895a administration, and the ratio of CD3-CD56+CD137+ to CD3-CD56+CD16+ cells increased on day 3.\n\nCONCLUSIONS:\nTwenty mg/kg DS-8895a infused intravenously every 2 weeks was generally safe and well tolerated in patients (n = 21) with advanced solid tumors. 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Safety, tolerability, pharmacokinetics, and pharmacodynamics of the afucosylated, humanized anti-EPHA2 antibody DS-8895a: a first-in-human phase I dose escalation and dose expansion study in patients with advanced solid tumors
http://hdl.handle.net/2241/00159740
http://hdl.handle.net/2241/00159740b561b546-7eac-4646-8408-51f208bd2d40
名前 / ファイル | ライセンス | アクション |
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JITC_7-219 (1.1 MB)
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Item type | Journal Article(1) | |||||||||||
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公開日 | 2020-03-17 | |||||||||||
タイトル | ||||||||||||
言語 | en | |||||||||||
タイトル | Safety, tolerability, pharmacokinetics, and pharmacodynamics of the afucosylated, humanized anti-EPHA2 antibody DS-8895a: a first-in-human phase I dose escalation and dose expansion study in patients with advanced solid tumors | |||||||||||
言語 | ||||||||||||
言語 | eng | |||||||||||
資源タイプ | ||||||||||||
資源 | http://purl.org/coar/resource_type/c_6501 | |||||||||||
タイプ | journal article | |||||||||||
著者 |
兵頭, 一之介
× 兵頭, 一之介
WEKO
713
× Shitara, Kohei× Satoh, Taroh× Iwasa, Satoru× Yamaguchi, Kensei× Muro, Kei× Komatsu, Yoshito× Nishina, Tomohiro× Esaki, Taito× Hasegawa, Jun× Kakurai, Yasuyuki× Kamiyama, Emi× Nakata, Tomoko× Nakamura, Kota× Sakaki, Hayato |
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抄録 | ||||||||||||
内容記述タイプ | Abstract | |||||||||||
内容記述 | BACKGROUND: Erythropoietin-producing hepatocellular receptor A2 (EPHA2) is overexpressed on the cell surface in many cancers and predicts poor prognosis. DS-8895a is a humanized anti-EPHA2 IgG1 monoclonal antibody afucosylated to enhance antibody-dependent cellular cytotoxicity activity. We conducted a two-step, phase I, multicenter, open-label study to determine the safety, tolerability, and pharmacokinetics of DS-8895a in patients with advanced solid tumors. METHODS: Step 1 was a dose escalation cohort in advanced solid tumor patients (six dose levels, 0.1-20 mg/kg) to determine Step 2 dosing. Step 2 was a dose expansion cohort in EPHA2-positive esophageal and gastric cancer patients. DS-8895a was intravenously administered every 2 weeks for the duration of the study, with a 28-day period to assess dose-limiting toxicity (DLT). Safety, pharmacokinetics, tumor response, and potential biomarkers were evaluated. RESULTS: Thirty-seven patients (Step 1: 22, Step 2: 15 [9: gastric cancer, 6: esophageal cancer]) were enrolled. Although one DLT (Grade 4 platelet count decreased) was observed in Step 1 (dose level 6, 20 mg/kg), the maximum tolerated dose was not reached; the highest dose (20 mg/kg) was used in Step 2. Of the 37 patients, 24 (64.9%) experienced drug-related adverse events (AEs) including three (8.1%) with Grade ≥ 3 AEs. Infusion-related reactions occurred in 19 patients (51.4%) but were manageable. All patients discontinued the study (evident disease progression, 33; AEs, 4). Maximum and trough serum DS-8895a concentrations increased dose-dependently. One gastric cancer patient achieved partial response and 13 patients achieved stable disease. Serum inflammatory cytokines transiently increased at completion of and 4 h after the start of DS-8895a administration. The proportion of CD16-positive natural killer (NK) cells (CD3-CD56+CD16+) decreased 4 h after the start of DS-8895a administration, and the ratio of CD3-CD56+CD137+ to CD3-CD56+CD16+ cells increased on day 3. CONCLUSIONS: Twenty mg/kg DS-8895a infused intravenously every 2 weeks was generally safe and well tolerated in patients (n = 21) with advanced solid tumors. The exposure of DS-8895a seemed to increase dose-dependently and induce activated NK cells. |
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書誌情報 |
en : Journal for ImmunoTherapy of Cancer 巻 7, p. 219, 発行日 2019-08 |
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ISSN | ||||||||||||
収録物識別子タイプ | ISSN | |||||||||||
収録物識別子 | 2051-1426 | |||||||||||
PubMed番号 | ||||||||||||
識別子タイプ | PMID | |||||||||||
関連識別子 | 31412935 | |||||||||||
DOI | ||||||||||||
識別子タイプ | DOI | |||||||||||
関連識別子 | 10.1186/s40425-019-0679-9 | |||||||||||
権利 | ||||||||||||
権利情報 | © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. | |||||||||||
著者版フラグ | ||||||||||||
値 | publisher | |||||||||||
出版者 | ||||||||||||
出版者 | BMC |