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Entinostat: a promising treatment option for patients with advanced breast cancer.

ABSTRACT: Entinostat is a synthetic benzamide derivative histone deacetylase (HDAC) inhibitor, which potently and selectively inhibits class I and IV HDAC enzymes. This action promotes histone hyperacetylation and transcriptional activation of specific genes, with subsequent inhibition of cell proliferation, terminal differentiation and apoptosis. This oral HDAC inhibitor has been evaluated in Phase I and II trials in patients with advanced malignancies, and is in general well tolerated. Entinostat does not currently have regulatory approval for clinical use; however promising preclinical and clinical data exist in hormone-resistant breast cancer. An ECOG-ACRIN Phase III registration study is ongoing in advanced breast cancer (E2112, NCT02115282) and aims to confirm the overall survival advantage observed with the combination of exemestane and entinostat/placebo in the Phase II setting (ENCORE301 trial). This article provides an overview of the chemistry, pharmacokinetics/pharmacodynamics and available clinical data for entinostat with a focus on advanced breast cancer.

SUBMITTER: Connolly RM

PROVIDER: S-EPMC5618943 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Entinostat: a promising treatment option for patients with advanced breast cancer.

Connolly Roisin M RM Rudek Michelle A MA Piekarz Richard R

Future oncology (London, England) 20170309 13

Entinostat is a synthetic benzamide derivative histone deacetylase (HDAC) inhibitor, which potently and selectively inhibits class I and IV HDAC enzymes. This action promotes histone hyperacetylation and transcriptional activation of specific genes, with subsequent inhibition of cell proliferation, terminal differentiation and apoptosis. This oral HDAC inhibitor has been evaluated in Phase I and II trials in patients with advanced malignancies, and is in general well tolerated. Entinostat does n ...[more]

PMID: 28326839

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Project description:ObjectiveTo summarize the function and efficacy of immunotherapy as an adjunctive therapy in the treatment of advanced chordoma.MethodsLiterature search was conducted by two reviewers independently. Case reports, case series and clinical trials of immunotherapy for chordoma were retrieved systematically from Pubmed, Web of Science, Scoupus and Cochrane Library. Clinical outcome data extracted from the literature included median progression-free survival (PFS), median overall survival (OS), clinical responses and adverse events (AEs).ResultsAll studies were published between 2015 and 2022. Twenty-two eligible studies were selected for systemic review. PD-1/PD-L1 immune checkpoint inhibitors (ICIs) were the most common used immunotherapy agents in chordoma, among which Pembrolizumab was the most frequently prescribed. CTLA-4 antibody was only used as combination therapy in chordoma. Dose Limiting Toxicity (DLT) was not observed in any vaccine targeting brachyury, and injection site response was the most frequent AV. The response evaluation criteria in solid tumors (RECIST) were the most generally used evaluation standard in chordoma immunotherapy, and none of the included studies employed the Choi criteria.ConclusionsNo clinical data have demonstrated that CTLA-4 ICIs combined with PD-1/PD-L1 ICIs is more effective than ICIs monotherapy in treating chordoma, and ICIs in combination with other therapies exhibit more toxicity than monotherapy. PD-1/PD-L1 ICIs monotherapy is recommended as an immunotherapy in patients with advanced chordoma, which may even benefit PD-L1-negative patients. The brachyury vaccine has shown good safety in chordoma patients, and future clinical trials should focus on how to improve its therapeutic efficacy. The use of immunomodulatory agents is a promising therapeutic option, though additional clinical trials are required to evaluate their safety and effectiveness. RECIST does not seem to be an appropriate standard for assessing medications of intratumoral immunotherapy.

Project description:BackgroundBreast cancer has an unacceptably high recurrence rate when any residual disease is found following neoadjuvant treatment of high-risk disease. Based on clinical data suggesting an adjuvant role for epigenetic modifying agents in breast cancer and preclinical data suggesting synergistic activity of entinostat combined with capecitabine, we conducted a phase I, open-label study of these agents in metastatic breast cancer (MBC). Both agents have published doses for use in combination therapy, but the agents had not previously been combined with each other in a human trial.MethodsA multisite phase I dose escalation study was performed at two academic centers. Patients with pretreated, HER2-negative MBC, and measurable disease were enrolled. Dual dose escalation was performed via a Bayesian partial order continual assessment method. Dose levels ranged from entinostat 3 mg to 5 mg and capecitabine 800 mg/m2 to 1000 mg/m2.ResultsThirteen patients with MBC and a median of 4 lines of prior therapy were enrolled across four dose level combinations. The most common toxicities were neutropenia, thrombocytopenia, and palmar-plantar dysesthesia, which were expected toxicities. No new safety signals were observed. One dose-limiting toxicity was observed, which did not exceed a prespecified toxicity rate of 25%. The median treatment duration was 2.37 months. No partial nor complete responses were observed. The study was halted early prior to entering an expansion phase, due to drug supply limitations.ConclusionThe tested dosing combinations of entinostat and capecitabine are likely safe in heavily pretreated metastatic breast cancer. This study's clinical investigation of entinostat in breast cancer was halted, but drug development of this agent continues outside the US. There remains a need for postoperative adjuvant drug therapy for the subpopulation of breast cancer patients with high-risk residual cancer after curative therapy. This trial is registered with NCT03473639.

Project description: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.

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Entinostat: a promising treatment option for patients with advanced breast cancer.

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Entinostat: a promising treatment option for patients with advanced breast cancer.

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