Abstract
BackgroundEntinostat 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.MethodsThis 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.ResultsTwelve 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.ConclusionsEntinostat 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 registrationJAPIC Clinical Trial Information, JapicCTI-153066. Registered 12 November 2015. ClinicalTrials.gov, NCT02623751. Registered 8 December 2015.
Highlights
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)
Protein lysine acetylation (Ac-K) Ac-K levels in CD19+ cells were increased in an ENT dose-dependent manner by about 1.5-fold in Cohort 1, 1.9-fold in Cohort 2, and 2.7-fold in Cohort 3 at 24 h after first administration of study drug compared with the levels prior to administration (Fig. 3a)
Ac-K levels in Peripheral blood mononuclear cell (PBMC) measured 24 h after first administration of ENT were increased in a plasma ENT concentration-dependent manner (Fig. 3b)
Summary
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). The goal of treatment for patients with advanced or metastatic breast cancer (BC) is to control the disease, prolong survival, and improve quality of life. Each combination therapy has demonstrated a significant prolongation of progression-free survival (PFS) compared with hormonal monotherapy [1, 5,6,7]. CDK4/6 inhibitors showed a statistically significant prolongation of overall survival (OS) as a secondary endpoint when used in combination with fulvestrant [8,9,10,11]. There is a need for new agents that can be combined with endocrine therapy
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