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
Abstract 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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2019-08-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-019-0679-9 |
| _version_ | 1828727401639575552 |
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| author | Kohei Shitara Taroh Satoh Satoru Iwasa Kensei Yamaguchi Kei Muro Yoshito Komatsu Tomohiro Nishina Taito Esaki Jun Hasegawa Yasuyuki Kakurai Emi Kamiyama Tomoko Nakata Kota Nakamura Hayato Sakaki Ichinosuke Hyodo |
| author_facet | Kohei Shitara Taroh Satoh Satoru Iwasa Kensei Yamaguchi Kei Muro Yoshito Komatsu Tomohiro Nishina Taito Esaki Jun Hasegawa Yasuyuki Kakurai Emi Kamiyama Tomoko Nakata Kota Nakamura Hayato Sakaki Ichinosuke Hyodo |
| author_sort | Kohei Shitara |
| collection | DOAJ |
| description | Abstract 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. Trial registration Phase 1 Study of DS-8895a in patients with advanced solid tumors (NCT02004717; 7 November 2013 to 2 February 2017); retrospectively registered on 9 December 2013. |
| first_indexed | 2024-04-12T13:57:18Z |
| format | Article |
| id | doaj.art-e6e7417efabc4c09a8c6af99cb58e3cb |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-12T13:57:18Z |
| publishDate | 2019-08-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-e6e7417efabc4c09a8c6af99cb58e3cb2022-12-22T03:30:20ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-08-017111210.1186/s40425-019-0679-9Safety, 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 tumorsKohei Shitara0Taroh Satoh1Satoru Iwasa2Kensei Yamaguchi3Kei Muro4Yoshito Komatsu5Tomohiro Nishina6Taito Esaki7Jun Hasegawa8Yasuyuki Kakurai9Emi Kamiyama10Tomoko Nakata11Kota Nakamura12Hayato Sakaki13Ichinosuke Hyodo14National Cancer Center Hospital EastOsaka University Graduate School of MedicineNational Cancer Center HospitalCancer Institute Hospital of Japan Foundation for Cancer ResearchAichi Cancer Center Hospital and Research InstituteHokkaido University HospitalNational Shikoku Cancer Center HospitalNational Hospital Organization Kyushu Cancer CenterDaiichi Sankyo Co., LtdDaiichi Sankyo Co., LtdDaiichi Sankyo Co., LtdDaiichi Sankyo Co., LtdDaiichi Sankyo Co., LtdDaiichi Sankyo Co., LtdUniversity of TsukubaAbstract 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. Trial registration Phase 1 Study of DS-8895a in patients with advanced solid tumors (NCT02004717; 7 November 2013 to 2 February 2017); retrospectively registered on 9 December 2013.http://link.springer.com/article/10.1186/s40425-019-0679-9Erythropoietin-producing hepatocellular receptor A2Gastric cancerEsophageal cancerAdvanced solid tumorsDS-8895aAntibody-dependent cellular cytotoxicity |
| spellingShingle | Kohei Shitara Taroh Satoh Satoru Iwasa Kensei Yamaguchi Kei Muro Yoshito Komatsu Tomohiro Nishina Taito Esaki Jun Hasegawa Yasuyuki Kakurai Emi Kamiyama Tomoko Nakata Kota Nakamura Hayato Sakaki Ichinosuke Hyodo 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 Journal for ImmunoTherapy of Cancer Erythropoietin-producing hepatocellular receptor A2 Gastric cancer Esophageal cancer Advanced solid tumors DS-8895a Antibody-dependent cellular cytotoxicity |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Erythropoietin-producing hepatocellular receptor A2 Gastric cancer Esophageal cancer Advanced solid tumors DS-8895a Antibody-dependent cellular cytotoxicity |
| url | http://link.springer.com/article/10.1186/s40425-019-0679-9 |
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