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.

Unconventional protein post-translational modifications: the helmsmen in breast cancer

“…For example, in ER positive subtype; the combination of pan-HDAC inhibitor vorinostat (400 mg/day) and tamoxifen reverse hormone resistance in patients with ER-positive metastatic breast cancer [ 237 ]. Moreover, the combination therapy with entinostat plus exemestane showed safety and encouraging efficacy in ER positive advanced breast cancer patients [ 234 , 235 , 238 ]. In HER2 positive subtype; pan-sirtuin inhibitor, sirtinol, increases the sensitivity of lapatinib in anti-HER2 targeted treatment in breast cancer [ 70 ].…”

“…For example, a phase I study analyzed the safety, maximum tolerated dose, pharmacokinetics, and bioavailability of oral panobinostat (20 mg, three times weekly) and confirmed that panobinostat can be safely administrated for antitumor activity [ 233 ]. Several clinical trials demonstrated the combination therapy with entinostat plus exemestane showed safety and encouraging efficacy in ER positive advanced breast cancer patients [ 234 , 235 , 238 ]. A phase II clinical trial reported that the combination of vorinostat (400 mg/day) and tamoxifen reverse hormone resistance in patients with ER-positive metastatic breast cancer [ 237 ].…”

Personalized tumor combination therapy optimization using the single-cell transcriptome

“…After obtaining the various drug responses of the trajectories, a bipartite graph model was built and solved. For patient su008, entinostat, a benzamide histone deacetylase inhibitor targeting HDAC1 and HDAC3 treated as monotherapy [79] or combinatorial drug together with immunotherapy to various cancers [80,81], was ranked 4th in comboSC prediction results as a drug that can be paired with immunotherapy. Also, a recent study reported the role of entinostat in inducing changes in multiple myeloid cell types, reducing immunosuppression, increasing antitumor immune responses, and improving sensitivity to immunotherapy for HER2 + breast cancer [82], which indicated the combinatorial effects of entinostat with immunotherapy for middle immune score samples.…”

Epithelial Mesenchymal Transition: The Ultimate Driver of Cancer on Difficult Paths

“…Phytochemicals inhibit or modulate various cell signaling pathways involved in EMT, repress EMT-TFs, restore E-cadherin, and downregulate mesenchymal characteristics (Vimentin, Fibronectin, and MMPs) [176][177][178][179][180][181]. Natural phytochemicals have specific action and selective killing against cancer cells and have shown no harmful effects on non-malignant cells [182]. Despite the great potential of phytochemicals, one of the key apprehensions to using phytochemicals as anticancer agents is the poor solubility, limited bioavailability, and rapid metabolism in the human body.…”