Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer

Abstract Background Entinostat is an oral inhibitor of class I histone deacetylases intended for endocrine therapy-resistant patients with hormone receptor-positive (HR+) advanced or metastatic breast cancer (BC). We examined the safety, efficacy, and pharmacokinetics of entinostat monotherapy and c...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Norikazu Masuda, Kenji Tamura, Hiroyuki Yasojima, Akihiko Shimomura, Masataka Sawaki, Min-Jung Lee, Akira Yuno, Jane Trepel, Ryoko Kimura, Yozo Nishimura, Shigehira Saji, Hiroji Iwata
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Acetylation Aromatase inhibitors Drug resistance Epigenomics Histone deacetylases Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/9dfbd51172f74073a43eee623bd9f903
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:9dfbd51172f74073a43eee623bd9f903
record_format	dspace
spelling	oai:doaj.org-article:9dfbd51172f74073a43eee623bd9f9032021-11-28T12:27:48ZPhase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer10.1186/s12885-021-08973-41471-2407https://doaj.org/article/9dfbd51172f74073a43eee623bd9f9032021-11-01T00:00:00Zhttps://doi.org/10.1186/s12885-021-08973-4https://doaj.org/toc/1471-2407Abstract Background Entinostat is an oral inhibitor of class I histone deacetylases intended for endocrine therapy-resistant patients with hormone receptor-positive (HR+) advanced or metastatic breast cancer (BC). We examined the safety, efficacy, and pharmacokinetics of entinostat monotherapy and combined entinostat/exemestane in Japanese patients. Methods This phase 1 study (3 + 3 dose-escalation design) enrolled postmenopausal women with advanced/metastatic HR+ BC previously treated with nonsteroidal aromatase inhibitors. Dose-limiting toxicities (DLTs) of entinostat monotherapy (3 mg/qw, 5 mg/qw, or 10 mg/q2w) and entinostat+exemestane (5 mg/qw + 25 mg/qd) were assessed. Pharmacokinetics, lysine acetylation (Ac-K), and T-cell activation markers were measured at multiple time points. Results Twelve patients were enrolled. No DLTs or grade 3–5 adverse events (AEs) occurred. Drug-related AEs (≥ 2 patients) during DLT observation were hypophosphatemia, nausea, and platelet count decreased. Six patients (50%) achieved stable disease (SD) for ≥ 6 months, including one treated for > 19 months. Median progression-free survival was 13.9 months (95% CI 1.9–not calculable); median overall survival was not reached. Area under the plasma concentration-time curve and Ac-K in peripheral blood CD19+ B cells increased dose-proportionally. The changing patterns of entinostat concentrations and Ac-K levels were well correlated. T-cell activation markers increased over time; CD69 increased more in patients with SD ≥ 6 months vs. SD < 6 months. Conclusions Entinostat monotherapy and combined entinostat/exemestane were well tolerated in Japanese patients, with no additional safety concerns compared with previous reports. The correlation between pharmacokinetics and Ac-K in peripheral blood CD19+ B cells, and also T-cell activation markers, merits further investigation. Trial registration JAPIC Clinical Trial Information, JapicCTI-153066 . Registered 12 November 2015. ClinicalTrials.gov, NCT02623751 . Registered 8 December 2015.Norikazu MasudaKenji TamuraHiroyuki YasojimaAkihiko ShimomuraMasataka SawakiMin-Jung LeeAkira YunoJane TrepelRyoko KimuraYozo NishimuraShigehira SajiHiroji IwataBMCarticleAcetylationAromatase inhibitorsDrug resistanceEpigenomicsHistone deacetylasesNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENBMC Cancer, Vol 21, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Acetylation Aromatase inhibitors Drug resistance Epigenomics Histone deacetylases Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Acetylation Aromatase inhibitors Drug resistance Epigenomics Histone deacetylases Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Norikazu Masuda Kenji Tamura Hiroyuki Yasojima Akihiko Shimomura Masataka Sawaki Min-Jung Lee Akira Yuno Jane Trepel Ryoko Kimura Yozo Nishimura Shigehira Saji Hiroji Iwata Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer
description	Abstract Background Entinostat is an oral inhibitor of class I histone deacetylases intended for endocrine therapy-resistant patients with hormone receptor-positive (HR+) advanced or metastatic breast cancer (BC). We examined the safety, efficacy, and pharmacokinetics of entinostat monotherapy and combined entinostat/exemestane in Japanese patients. Methods This phase 1 study (3 + 3 dose-escalation design) enrolled postmenopausal women with advanced/metastatic HR+ BC previously treated with nonsteroidal aromatase inhibitors. Dose-limiting toxicities (DLTs) of entinostat monotherapy (3 mg/qw, 5 mg/qw, or 10 mg/q2w) and entinostat+exemestane (5 mg/qw + 25 mg/qd) were assessed. Pharmacokinetics, lysine acetylation (Ac-K), and T-cell activation markers were measured at multiple time points. Results Twelve patients were enrolled. No DLTs or grade 3–5 adverse events (AEs) occurred. Drug-related AEs (≥ 2 patients) during DLT observation were hypophosphatemia, nausea, and platelet count decreased. Six patients (50%) achieved stable disease (SD) for ≥ 6 months, including one treated for > 19 months. Median progression-free survival was 13.9 months (95% CI 1.9–not calculable); median overall survival was not reached. Area under the plasma concentration-time curve and Ac-K in peripheral blood CD19+ B cells increased dose-proportionally. The changing patterns of entinostat concentrations and Ac-K levels were well correlated. T-cell activation markers increased over time; CD69 increased more in patients with SD ≥ 6 months vs. SD < 6 months. Conclusions Entinostat monotherapy and combined entinostat/exemestane were well tolerated in Japanese patients, with no additional safety concerns compared with previous reports. The correlation between pharmacokinetics and Ac-K in peripheral blood CD19+ B cells, and also T-cell activation markers, merits further investigation. Trial registration JAPIC Clinical Trial Information, JapicCTI-153066 . Registered 12 November 2015. ClinicalTrials.gov, NCT02623751 . Registered 8 December 2015.
format	article
author	Norikazu Masuda Kenji Tamura Hiroyuki Yasojima Akihiko Shimomura Masataka Sawaki Min-Jung Lee Akira Yuno Jane Trepel Ryoko Kimura Yozo Nishimura Shigehira Saji Hiroji Iwata
author_facet	Norikazu Masuda Kenji Tamura Hiroyuki Yasojima Akihiko Shimomura Masataka Sawaki Min-Jung Lee Akira Yuno Jane Trepel Ryoko Kimura Yozo Nishimura Shigehira Saji Hiroji Iwata
author_sort	Norikazu Masuda
title	Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer
title_short	Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer
title_full	Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer
title_fullStr	Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer
title_full_unstemmed	Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer
title_sort	phase 1 trial of entinostat as monotherapy and combined with exemestane in japanese patients with hormone receptor-positive advanced breast cancer
publisher	BMC
publishDate	2021
url	https://doaj.org/article/9dfbd51172f74073a43eee623bd9f903
work_keys_str_mv	AT norikazumasuda phase1trialofentinostatasmonotherapyandcombinedwithexemestaneinjapanesepatientswithhormonereceptorpositiveadvancedbreastcancer AT kenjitamura phase1trialofentinostatasmonotherapyandcombinedwithexemestaneinjapanesepatientswithhormonereceptorpositiveadvancedbreastcancer AT hiroyukiyasojima phase1trialofentinostatasmonotherapyandcombinedwithexemestaneinjapanesepatientswithhormonereceptorpositiveadvancedbreastcancer AT akihikoshimomura phase1trialofentinostatasmonotherapyandcombinedwithexemestaneinjapanesepatientswithhormonereceptorpositiveadvancedbreastcancer AT masatakasawaki phase1trialofentinostatasmonotherapyandcombinedwithexemestaneinjapanesepatientswithhormonereceptorpositiveadvancedbreastcancer AT minjunglee phase1trialofentinostatasmonotherapyandcombinedwithexemestaneinjapanesepatientswithhormonereceptorpositiveadvancedbreastcancer AT akirayuno phase1trialofentinostatasmonotherapyandcombinedwithexemestaneinjapanesepatientswithhormonereceptorpositiveadvancedbreastcancer AT janetrepel phase1trialofentinostatasmonotherapyandcombinedwithexemestaneinjapanesepatientswithhormonereceptorpositiveadvancedbreastcancer AT ryokokimura phase1trialofentinostatasmonotherapyandcombinedwithexemestaneinjapanesepatientswithhormonereceptorpositiveadvancedbreastcancer AT yozonishimura phase1trialofentinostatasmonotherapyandcombinedwithexemestaneinjapanesepatientswithhormonereceptorpositiveadvancedbreastcancer AT shigehirasaji phase1trialofentinostatasmonotherapyandcombinedwithexemestaneinjapanesepatientswithhormonereceptorpositiveadvancedbreastcancer AT hirojiiwata phase1trialofentinostatasmonotherapyandcombinedwithexemestaneinjapanesepatientswithhormonereceptorpositiveadvancedbreastcancer
_version_	1718407973032689664

Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer

Ejemplares similares