All plasma samples were stored at ?10 C to ?30 C until analysis

All plasma samples were stored at ?10 C to ?30 C until analysis. A validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was used to determine the plasma concentrations of chidamide (18,19) by Covance Analytical Laboratory (Shanghai, China). 3 in more than 2 patients were neutropenia (35%), thrombocytopenia (30%), and leucopenia (20%). The plasma exposure of exemestane was consistent in the presence or absence of chidamide. A slight increase in chidamide exposure was noted in the presence of exemestane, probably due to the inter- and intra-patient variations. The best response in 16 evaluable patients was assessed by Response Evaluation Criteria in Solid Tumors (RECIST), including 4 patients with partial response, 10 patients with stable disease. The median progression-free survival (PFS) was 7.6 months. Conclusions The combination of chidamide with exemestane was generally well tolerated with promising preliminary efficacy in HR+ ABC patients. The overall results from this study encourage further pivotal trial in this patient population. and preclinical studies (7-9). Furthermore, in a randomized phase II trial the addition of entinostat to exemestane showed a potential prolonged progression-free survival (PFS) and overall survival (OS) in patients with previously treated hormone-sensitive metastatic breast cancer (10). Chidamide (CS055/Tucidinostat/Epidaza?) is an oral benzamide class of HDAC inhibitor with broad antitumor activities by selectively inhibiting HDAC1, 2, 3 and 10 (11), and has been approved by the China Food and Drug Administration (CFDA) as a treatment for relapsed or refractory peripheral T cell lymphoma (PTCL) (12). Previous studies have shown that benzamide class of HDAC subtype-selective inhibitors, including chidamide and entinostat, enhance tumor Artn immune surveillance via activation of natural killer (NK) cell and antigen-specific cytotoxic T lymphocyte (CTL)-mediated cellular anti-tumor 1,2,3,4,5,6-Hexabromocyclohexane immunity, which differentiates them from other non-selective HDAC inhibitors (13-16). Chidamide has also been demonstrated to down-regulate estrogen-independent growth factor signaling pathways and restore the sensitivity to anti-estrogen brokers in preclinical investigations (17). Exemestane is usually a steroidal aromatase inhibitor (AI) with well-established efficacy in HR+, human epidermal growth factor receptor 2 (HER2)-unfavorable advanced breast cancer (ABC) patients progressed on previous endocrine 1,2,3,4,5,6-Hexabromocyclohexane therapy, including tamoxifen and/or nonsteroidal AIs (i.e., letrozole or anastrozole). This exploratory clinical study was thus performed to evaluate the safety, pharmacokinetics (PK), and preliminary efficacy of chidamide in combination with exemestane in postmenopausal women with HR+ and HER2-unfavorable ABC that 1,2,3,4,5,6-Hexabromocyclohexane recurrent or progressed to at least one endocrine therapy. Materials and methods Study design The study design was a single-arm, open-label, exploratory trial of chidamide in combination with exemestane in HR+ ABC patients. The Institutional Review Board at each participating center approved the study, which was conducted by the principles of Good Clinical Practice, the provisions of the Declaration of Helsinki, and other applicable local regulations. The study was registered on ClinicalTrials.gov (No. “type”:”clinical-trial”,”attrs”:”text”:”NCT02482753″,”term_id”:”NCT02482753″NCT02482753). The primary objective was to determine the safety and PK profiles of chidamide with exemestane in ABC patients. The secondary goal was to evaluate the preliminary efficacy, including objective response rate (ORR) and PFS. In the 4-day-run-in period, patients received single-agent exemestane 25 mg (provided by Pfizer Inc.) on d 1 and chidamide 30 mg (supplied by Shenzhen Chipscreen Biosciences, Ltd.) on d 2. From d 5, patients started combination treatment with exemestane 25 mg daily and chidamide 30 mg twice a week (BIW). A treatment cycle was defined as 28 d. Before study entry, patients underwent a complete history and physical examination, and all prior anticancer treatments and their residual side effects were recorded, if any. Baseline imaging evaluations were obtained to define the extent of disease. Baseline laboratory tests included a complete blood cell, platelet counts and blood chemistry. Physical examination, laboratory assessments and radiological evaluations were repeated every 8 weeks. Toxicities were graded using the National Cancer Institute Common Toxicity Criteria (NCICTC), version 4.0. Patients continued on treatment until they had disease progression, or were unable to tolerate with therapy, or withdrew consent. Patients and eligibility criteria Written informed consent was.