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

BMC Cancer. 2021 Nov 24;21(1):1269. doi: 10.1186/s12885-021-08973-4.

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.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Acetylation
  • Aged
  • Androstadienes / adverse effects
  • Androstadienes / pharmacokinetics
  • Androstadienes / therapeutic use*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Aromatase Inhibitors / therapeutic use
  • Benzamides / adverse effects
  • Benzamides / pharmacokinetics
  • Benzamides / therapeutic use*
  • Breast Neoplasms / blood
  • Breast Neoplasms / chemistry
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Female
  • Histone Deacetylase Inhibitors / therapeutic use
  • Humans
  • Hypophosphatemia / chemically induced
  • Japan
  • Lymphocyte Activation
  • Middle Aged
  • Nausea / chemically induced
  • Platelet Count
  • Progression-Free Survival
  • Pyridines / adverse effects
  • Pyridines / pharmacokinetics
  • Pyridines / therapeutic use*

Substances

  • Androstadienes
  • Antineoplastic Agents
  • Aromatase Inhibitors
  • Benzamides
  • Histone Deacetylase Inhibitors
  • Pyridines
  • entinostat
  • exemestane

Associated data

  • ClinicalTrials.gov/NCT02623751