PMID- 34819039 OWN - NLM STAT- MEDLINE DCOM- 20220221 LR - 20220221 IS - 1471-2407 (Electronic) IS - 1471-2407 (Linking) VI - 21 IP - 1 DP - 2021 Nov 24 TI - Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer. PG - 1269 LID - 10.1186/s12885-021-08973-4 [doi] LID - 1269 AB - 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. CI - (c) 2021. The Author(s). FAU - Masuda, Norikazu AU - Masuda N AUID- ORCID: 0000-0002-7302-0278 AD - Department of Surgery, Breast Oncology, National Hospital Organization Osaka National Hospital, Osaka, Japan. nmasuda@alpha.ocn.ne.jp. AD - Present address: Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. nmasuda@alpha.ocn.ne.jp. FAU - Tamura, Kenji AU - Tamura K AD - Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan. AD - Present address: Department of Medical Oncology, Shimane University Hospital, Izumo, Shimane, Japan. FAU - Yasojima, Hiroyuki AU - Yasojima H AD - Department of Surgery, Breast Oncology, National Hospital Organization Osaka National Hospital, Osaka, Japan. FAU - Shimomura, Akihiko AU - Shimomura A AD - Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan. AD - Present address: Department of Breast and Medical Oncology, National Center for Global Health and Medicine, Tokyo, Japan. FAU - Sawaki, Masataka AU - Sawaki M AD - Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan. FAU - Lee, Min-Jung AU - Lee MJ AD - Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. FAU - Yuno, Akira AU - Yuno A AD - Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. AD - Present address: Department of Oral and Maxillofacial Surgery, Kumamoto University Hospital, Kumamoto, Japan. FAU - Trepel, Jane AU - Trepel J AD - Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. FAU - Kimura, Ryoko AU - Kimura R AD - R&D Division, Kyowa Kirin Co., Ltd., Tokyo, Japan. FAU - Nishimura, Yozo AU - Nishimura Y AD - R&D Division, Kyowa Kirin Co., Ltd., Tokyo, Japan. FAU - Saji, Shigehira AU - Saji S AD - Department of Medical Oncology, Fukushima Medical University, Fukushima, Japan. FAU - Iwata, Hiroji AU - Iwata H AD - Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan. LA - eng SI - ClinicalTrials.gov/NCT02623751 PT - Clinical Trial, Phase I PT - Journal Article DEP - 20211124 PL - England TA - BMC Cancer JT - BMC cancer JID - 100967800 RN - 0 (Androstadienes) RN - 0 (Antineoplastic Agents) RN - 0 (Aromatase Inhibitors) RN - 0 (Benzamides) RN - 0 (Histone Deacetylase Inhibitors) RN - 0 (Pyridines) RN - 1ZNY4FKK9H (entinostat) RN - NY22HMQ4BX (exemestane) SB - IM MH - Acetylation MH - Aged MH - Androstadienes/adverse effects/pharmacokinetics/*therapeutic use MH - Antineoplastic Agents/adverse effects/pharmacokinetics/*therapeutic use MH - Antineoplastic Combined Chemotherapy Protocols/adverse effects/pharmacokinetics/*therapeutic use MH - Aromatase Inhibitors/therapeutic use MH - Benzamides/adverse effects/pharmacokinetics/*therapeutic use MH - Breast Neoplasms/blood/chemistry/*drug therapy/pathology MH - Female MH - Histone Deacetylase Inhibitors/therapeutic use MH - Humans MH - Hypophosphatemia/chemically induced MH - Japan MH - Lymphocyte Activation MH - Middle Aged MH - Nausea/chemically induced MH - Platelet Count MH - Progression-Free Survival MH - Pyridines/adverse effects/pharmacokinetics/*therapeutic use PMC - PMC8611843 OTO - NOTNLM OT - Acetylation OT - Aromatase inhibitors OT - Drug resistance OT - Epigenomics OT - Histone deacetylases COIS- This study was supported by Kyowa Kirin Co., Ltd., who was involved in the study design, data collection, data analysis, and preparation of the manuscript. NM reports grants from Kyowa Kirin, during the conduct of the study; grants and/or personal fees from Chugai, AstraZeneca, Kyowa Kirin, MSD, Novartis, Pfizer, Eli Lilly, Eisai, Nihon Kayaku, and Daiichi Sankyo, outside the submitted work; and board membership of the Japanese Breast Cancer Society and the Japan Breast Cancer Research Group Association. KT reports grants and non-financial support from Kyowa Kirin, during the conduct of the study; grants, personal fees, and/or non-financial support from Pfizer, Daiichi Sankyo, Chugai, Eli Lilly, AstraZeneca, and MSD, outside the submitted work. AS reports grants and/or personal fees from Chugai, AstraZeneca, Pfizer, Eli Lilly, Eisai, Daiichi Sankyo, Novartis, Mochida, Kyowa Kirin, Taiho, and MSD, outside the submitted work. RK is an employee of Kyowa Kirin. YN is an employee of Kyowa Kirin. SS reports personal fees from Kyowa Kirin, during the conduct of the study; and grants and/or personal fees from Chugai, Kyowa Kirin, Eli Lilly, AstraZeneca, Pfizer, MSD, Novartis, Eisai, Takeda, and Taiho, outside the submitted work. HI reports grants, personal fees, and non-financial support from Kyowa Kirin, during the conduct of the study; and grants and/or personal fees from Chugai, Pfizer, Eli Lilly, AstraZeneca, Taiho, Novartis, Daiichi Sankyo, MSD, Eisai, Bayer, and GSK, outside the submitted work. The other authors declare that they have no competing interests. EDAT- 2021/11/26 06:00 MHDA- 2022/02/22 06:00 PMCR- 2021/11/24 CRDT- 2021/11/25 05:35 PHST- 2021/03/15 00:00 [received] PHST- 2021/11/05 00:00 [accepted] PHST- 2021/11/25 05:35 [entrez] PHST- 2021/11/26 06:00 [pubmed] PHST- 2022/02/22 06:00 [medline] PHST- 2021/11/24 00:00 [pmc-release] AID - 10.1186/s12885-021-08973-4 [pii] AID - 8973 [pii] AID - 10.1186/s12885-021-08973-4 [doi] PST - epublish SO - BMC Cancer. 2021 Nov 24;21(1):1269. doi: 10.1186/s12885-021-08973-4.