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 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.

Keywords: Acetylation; Aromatase inhibitors; Drug resistance; Epigenomics; Histone deacetylases.

Conflict of interest statement

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.

© 2021. The Author(s).

Figures

Fig. 1

Objective response and PFS. The censored patient did not receive ENT 3 times during Cycle 2 (after the end of the DLT observation period), thereby meeting one of the criteria for discontinuation, namely that patients who did not take ENT three times within one cycle, or who did not take ENT three times in a row regardless of cycle, should be discontinued. The patient then started post-discontinuation treatment before diagnostic imaging was performed to assess possible progression. Therefore, we censored the patient at the time of the previous imaging at study entry. BOR best overall response, DLT dose-limiting toxicity, ENT entinostat, NE not evaluable, PD progressive disease, PFS progression-free survival, SD stable disease

Fig. 2

Plasma ENT concentration-time profiles and PK parameters of ENT. a Plasma ENT concentration-time profiles in each cohort. Each point represents the mean + S.D. ENT was administered at points of reverse triangle in combination with EXE 25 mg once daily during the shaded time period. b Dose proportionality of PK parameters of ENT. Each point represents individual subject value after the first administration of ENT. Linear regression lines are superimposed with fixing (broken line) and without fixing (solid line) the y-intercept to origin. AUC0–168 area under the plasma concentration-time curve from time 0–168 h, Cmax maximum plasma concentration, ENT entinostat, EXE exemestane, PK pharmacokinetic, S.D. standard deviation

Fig. 3

Dose proportionality of Ac-K parameters of ENT and the relationship between PK and Ac-K. Profiles of Ac-K levels in CD19+ B cells and plasma ENT concentration. a Dose proportionality of Ac-K levels in CD19+ B cells. Each open circle represents the Ac-K level (change from baseline) in each patient. b Relationship between PK and Ac-K levels in CD19+ B cells. Each open circle, filled circle, and filled square represents each Ac-K level (change from baseline) in Cohort 1, Cohort 2, and Cohort 3, respectively. c Time course of Ac-K levels and plasma ENT concentration in each cohort. Each filled circle represents Ac-K level (median fluorescence intensity) and each open circle represents plasma ENT concentration (ng/mL). In Cohort 3, ENT was not administered at a dosing point marked with an asterisk (*). Each peripheral blood mononuclear cell sample was collected before ENT/EXE administration. Ac-K lysine acetylation, ENT entinostat, EXE exemestane, PK pharmacokinetics