Subtype-selective Histone Deacetylase Inhibitor Research Articles

Sintilimab (anti-PD-1 antibody) plus chidamide (histone deacetylase inhibitor) in relapsed or refractory extranodal natural killer T-cell lymphoma (SCENT): a phase Ib/II study.

Anti-PD-1 antibodies are a favorable treatment for relapsed or refractory extranodal natural killer T cell lymphoma (RR-ENKTL), however, the complete response (CR) rate and the duration of response (DOR) need to be improved. This phase 1b/2 study investigated the safety and efficacy of sintilimab, a fully human anti-PD-1 antibody, plus chidamide, an oral subtype-selective histone deacetylase inhibitor in 38 patients with RR-ENKTL. Expected objective response rate (ORR) of combination treatment was 80%. Patients received escalating doses of chidamide, administered concomitantly with fixed-dose sintilimab in 21-days cycles up to 12 months. No dose-limiting events were observed, RP2D of chidamide was 30 mg twice a week. Twenty-nine patients were enrolled in phase 2. In the intention-to-treat population (n = 37), overall response rate was 59.5% with a complete remission rate of 48.6%. The median DOR, progression-free survival (PFS), and overall survival (OS) were 25.3, 23.2, and 32.9 months, respectively. The most common grade 3 or higher treatment-emergent adverse events (AEs) were neutropenia (28.9%) and thrombocytopenia (10.5%), immune-related AEs were reported in 18 (47.3%) patients. Exploratory biomarker assessment suggested that a combination of dynamic plasma ctDNA and EBV-DNA played a vital prognostic role. STAT3 mutation shows an unfavorable prognosis. Although outcome of anticipate ORR was not achieved, sintilimab plus chidamide was shown to have a manageable safety profile and yielded encouraging CR rate and DOR in RR-ENKTL for the first time. It is a promising therapeutic option for this population.

Efficacy and safety of tucidinostat in patients with advanced hormone receptor-positive human epidermal growth factor receptor 2-negative breast cancer: real-world insights.

Tucidinostat, which is a subtype-selective histone deacetylase inhibitor, has been approved in China for the treatment of hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). However, existing evidence mainly stemmed from randomized controlled trials, and might have limitations in representing the complexities of clinical practice and diverse patient populations. Therefore, there is a need to explore the efficacy and optimal therapeutic modality for tucidinostat in real-world clinical settings. The objective of this real-world study was to analyze the clinical data of 47 patients with HR+/HER2- ABC who received tucidinostat treatment at West China Hospital, Sichuan University, between August 2020 and May 2023. The primary outcomes were progression-free survival (PFS) and clinical benefit rate [CBR; defined as partial response (PR) and stable disease (SD) for ≥6 months on clinical evaluation]. A total of 47 patients were included, and the median follow-up time was 18.20 months. The median line of tucidinostat therapy was 3 (range, 1-9). In all, 52.17% patients were treated with tucidinostat plus fulvestrant, while 38.30% were treated with tucidinostat plus aromatase inhibitors. Notably, 10.64% of the patients with rapidly progressing visceral metastases received tucidinostat plus endocrine therapy as maintenance treatment after achieving disease control with chemotherapy. The median PFS was 4.43 months [95% confidence interval (CI), 2.77-10.53], and the median overall survival was 19.57 months (95% CI, 12.83-not reached). The 6-month CBR for the overall population was 41.86%. Patients undergoing maintenance therapy demonstrated a significantly longer PFS than did those who did not receive it as maintenance therapy (14.13 vs. 3.93 months; P=0.01). Univariate Cox regression analysis showed that use of tucidinostat in lines 1-2, use of tucidinostat plus fulvestrant, presence of one metastatic site, and lack of brain metastasis were favorable factors for PFS. Thrombocytopenia was the most frequently reported adverse event, with an incidence rate of 31.91% at all grades and 14.89% at grade ≥3. Four (8.51%) patients discontinued the treatment. For patients with HR+/HER2- ABC, tucidinostat combination therapy offers certain survival benefits with controllable safety. Furthermore, compared with non-maintenance therapy, maintenance therapy after chemotherapy may have promising efficacy.

PD-1 Antibody (Sintilimab) Plus Histone Deacetylase Inhibitor (Chidamide) for the Treatment of Refractory or Relapsed Extranodal Natural Killer/T Cell Lymphoma, Nasal Type (r/r ENKTL): Updates of the Phase Ib/II Scent Study

Background Extranodal natural killer/T-cell lymphoma (ENKTL) is a highly aggressive of non-Hodgkin's lymphoma (NHL) closely related to Epstein-Barr virus (EBV), with a higher incidence in Asia than in Europe and North America. Patients with r/r ENKTL have a poor prognosis after failing asparaginase based regimen, and there is lack of effective treatment. Anti-programmed death 1 (anti-PD-1) antibody monotherapy represented a favorable treatment for the patients with rr-ENKTL. ORIENT-4 trial demonstrated sintilimab(anti-PD-1antibody ) was effective and well tolerated in r/r ENKTL. The efficacy of chidamide monotherapy, an oral subtype-selective histone deacetylase inhibitor (HDACi) was reported on the patients with rr-ENKTL . Moreover, accumulating evidences have shown the synergism between epigenetic modulator and PD-1 antibody. In 2020 ASH meeting, we reported the preliminary results of sintilimab plus chidamide (SC) for treatment of r/r ENKTL orally. This report is an update of this trial with cumulative data of approximately 40 months. Methods This multicenter, single-arm, phase Ib/II clinical trial enrolled eligible patients with histologically confirmed r/r-ENKTL failing from asparaginase-based regimen. This study consisted of a Phase Ib (dose escalation) portion followed by a Phase II expansion portion. In the Phase Ib escalation portion, a standard “3+3” design was utilized to identify the maximum tolerated dose (MTD), dose limited toxicity (DLT) and recommended Phase II dosage (RP2D) of chidamide. Patients received oral escalating doses of chidamide (20, 25, 30 mg) twice a week and 200 mg of sintilimab intravenously every 3 weeks. In the phase II expansion portion, patients received six cycles of SC every 3 weeks. Patients with complete response (CR) or partial response (PR) received SC every 3 weeks for up to 1 year, until disease progression, intolerable toxicity. The primary endpoint was objective response rate (ORR) assessed by investigators per RECIL 2017criteria. Key secondary endpoints included time to response (TTR), duration of response (DOR) and progression-free survival (PFS), overall survival (OS) and safety. Adverse events (AEs) were defined according to National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). This trial was registered at ClinicalTrials.gov (NCT 03820596). Results From March 2019 to May 2020, 41 patients were screened, and 37 eligible patients were enrolled. Overall, median age 48 years (range, 20-72), 26 (70.3%) patients with Stage IV, 20 (54.1%) patients with PINK-E score ≥ 3 points, 16 (43.2%) patients received ≥ 2 lines of prior systemic therapy. RP2D of chidamide was 30 mg twice a week. Of 36 response evaluable patients, 21 patients (58.3%) achieved an objective response including 16 (44.4%) patients with CR. The median time to initial response was 6.0 weeks (range, 5.0 to12.4). Cut-off data was July 28, 2023. The median cycles of SC were 6 (range, 2 to 44). Median follow-up time of whole cohort was 38.3 (range, 0.9 to 51.5; Interquartile range [IQR] range 8.5 to 46.3) months, 3-year OS rate was 56% (95% CI: 0.44-0.75, Figure 1 A), median PFS was 23.4 months (Figure 1 B). Twenty-one patients still alive, median follow-up time for this group was 44.9 (IQR 43.2 to 49.3) months. Estimated 4-year PFS rate was 76% (95% CI: 0.51-0.89, Figure 1 C). Median follow-up time of 21 responded(CR+PR) patients was 43.4 (IQR 34.3 to 47.6) months, estimated 4-year DOR was 68% (95% CI: 0.45-0.83, Figure 1 D). Twenty-six (26, 70.3%) patients reported treatment-related AEs (TRAEs). There were no new safety signals were identified after August 2020. The most frequently observed (≥10%) TRAEs were neutropenia (21,56.8%), thrombocytopenia (17, 45.9%), transaminase increased (11, 29.7%), nausea (9, 24.3%). The most frequent Grade (G) ≥3 TRAEs were neutropenia (6, 16.2%) and thrombocytopenia (4, 10.8%). Immune-related AEs were reported in 16 (43.2%) patients including a G4 exfoliative dermatitis, and the most common irAEs were G1 hypothyroidism and rash. TEAEs that led to permanent treatment discontinuation occurred in only one (2.7%) patient. No death was related to the study drug. Conclusion Sintilimab combined with Chidamide showed long-lasting therapeutic effects with manageable toxicity in patients with r/r-ENKTL. Epigenetic modulator can synergize with anti-PD-1 antibody to enhance antitumor activity to r/r-ENKTL.

Chidamide Combined with a Modified Bu-Cy Conditioning Regimen Improves Survival in Patients with T-Cell Acute Lymphoblastic Leukemia/Lymphoma Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Backgrounds: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL). Relapse post-HSCT remains the major cause of mortality, highlighting the urgent need for more effective conditioning regimens in reducing relapse rates and improving outcomes for T-cell malignancy. Chidamide, as the first oral subtype-selective histone deacetylase inhibitor (HDACi) approved in China, can lead to a more relaxed chromatin structure through chromatin remodeling, particularly hyperacetylation of lysine residues in the histone tails, which facilitates the expression of tumor suppressor genes as well as the action of alkylating agents busulfan. To date, the role of chidamide in T-ALL/LBL conditioning regimens in allo-HSCT has not been explored. Methods: We retrospectively compared the clinical efficacy and safety between chidamide combined with a modified Busulfan-Cyclophosphamide (mBuCy) and mBuCy conditioning regimen for T-ALL/LBL patients undergoing allo-HSCT. The chidamide combined with mBuCy regimen was presented in Figure1. Results: Twenty-two patients received chidamide combined with mBuCy conditioning regimen (Chi group). A matched-pair control (CON) group of 44 patients (matched 1:2) received mBuCy only. The median follow-up time was 683 (range 296-1168) days. Patients in the Chi group showed better 2-year overall survival (OS) and leukemia-free survival (LFS) (85.4 vs. 52.9%, respectively, P = 0.021; 69.1 vs. 42.9%, respectively, P = 0.031). Multivariate analysis showed that chidamide combined with mBuCy was a major positive risk factor for OS (HR 0.18, 95%CI, 0.05-0.63; P = 0.007) and LFS (HR 0.32; 95%CI, 0.13-0.80; P = 0.015). The cumulative incidence rates of grade II-IV and grade III-IV aGVHD were similar (36.4 vs. 38.6%, respectively, P = 0.858; 13.6 vs. 20.5%, respectively, P = 0.735). Patients in the Chi group showed higher incidence of elevated γ-glutamyltransferase and hemorrhagic cystitis than that in the mBuCy group (90.9 vs. 65.9%, respectively, P = 0.029; 36.4 vs. 13.6%, respectively, P = 0.007). No transplantation-related mortality was documented within the first 100 days after transplantation. Conclusions: Our data demonstrate that the conditioning regimen containing chidamide improves the survival of T-ALL/LBL patients without increasing the incidence of transplant-related mortality. A prospective clinical trial is expected to confirm these findings.

A phase II clinical trial of chidamide in combination with toripalimab in patients with advanced soft tissue sarcoma.

11566 Background: Chidamide is an oral subtype-selective histone deacetylase inhibitor which is effective on the patients with hematological tumors and reported to enhance the efficacy of checkpoint blockade therapies and regulate the host immune response. Here, we report preliminary results of Chidamide in combination with Toripalimab in soft tissue sarcoma (STS) patients. Methods: An open, single arm, phase II study of Chidamide with Toripalimab in patients with advanced soft tissue sarcoma after failure of standard treatment was conducted. Eligible patients could have any number of prior therapies, excluding HDAC inhibitors and immune checkpoint inhibitors treatment. All patients received Chidamide orally at 30mg twice weekly in combination with intravenous Toripalimab 240mg every 21 days until progression or unaccepted toxicity. The primary endpoint was RECIST1.1 objective response rate (ORR). The secondary endpoint included progression free survival (PFS), overall survival (OS), disease control rate(DCR) and safety. Results: Forty-six patients with advanced soft tissue sarcoma were enrolled. The median age of the patients was 47 years and the median prior lines of therapy were 3. The main subtypes included leiomyosarcoma (30.4%), well/dedifferentiated liposarcoma (30%), myxoid/round cell liposarcoma (7%), undifferentiated sarcoma(9%), and osteosarcoma (7%). Treatment was well tolerated with the most common adverse events mainly in grade Ⅰ and grade Ⅱ, including thrombocytopenia (43.5%), nausea(28.3%), neutropenia(23.9%), fatigue (17.4%) and hypothyroidism(15.2%). Among 46 efficacy-evaluable patients, the overall response rate and disease control rate were 23.9% and 80.4%, respectively. The median time to an initial response was 3 months (range, 2 to 14), and the 3-mon and 6-mon progression-free survival rate were 92.7% and 58.9%, respectively. Conclusions: Chidamide with Toripalimab every 21 days was well tolerated and showed promising efficacy in patients with advanced STS. Clinical trial information: NCT04025931 .

Neoadjuvant tucidinostat combined with chemotherapy for hormone receptor-positive, HER2-negative breast cancer.

e12617 Background: Both neoadjuvant chemotherapy and endocrine therapy only result in trivial pathological complete response rates and moderate objective response rate (ORR) in hormone receptor (HR)-positive, HER2-negative breast cancer, more promising alternatives are urgently needed. Tucidinostat is an oral subtype-selective histone deacetylase inhibitor that has shown efficacy and safety when used in combination with exemestane in patients with advanced HR+ breast cancer. This MUKDEN 05 study aimed to assess the efficacy and toxicity of the combination of tucidinostat and EC-T as a neoadjuvant strategy in patients with HR+/HER2-, stage II-III breast cancer. Methods: This study is a multicenter, single-arm, phase II study. Eligible patients received 20 mg tucidinostat orally twice a week (on days 1, 4, 8, and 11), 2 weeks on, 1 week off. The dose and administration schedule of EC-T were as follows: 4 cycles of epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks, followed by 4 cycles of docetaxel 100 mg/m2 every 3 weeks. The primary endpoint was the proportion of residual cancer burden (RCB) 0-I. Key secondary endpoints included pathological complete response (pCR), objective response rate (ORR), and safety. Results: Between May 2022 and August 2022, a total of 35 patients were enrolled. 27 patients were pathologically evaluable. The remaining 8 patients have completed neoadjuvant treatment and wait for operation. The ratio of RCB 0-I was 37% (95% CI, 23.2-53.7%). ORR was 86% (95% CI, 70.6-93.7%). Four (15%; 95% CI, 5.91-32.5%) patients achieved bpCR, and one (4%; 95% CI, 0.67-18.3%) patients achieved tpCR. Most adverse events (AEs) were grade 1 or 2. Grade 3/4 AEs included neutropenia (21.1%), and thrombocytopenia (15.8%). Conclusions: The combination of Tucidinostat and EC-T had an acceptable safety profile and encouraging clinical responses, offering a neoadjuvant treatment option for patients with early HR+/HER2- breast cancer. Further research is required to validate these findings. Clinical trial information: NCT05400993 .

Synthesis and Crystal Structure Analysis of Histone Deacetylase Inhibitor Chidamide

Chidamide is the first oral subtype-selective histone deacetylase inhibitor approved in China for the treatment of relapsed and refractory peripheral T cell lymphoma. Due to the existence of isomers, many articles or patents have mistaken its structure. Herein we explored the synthesis of the key intermediate (E)-4-((3-(pyridin-3-yl)acrylamido)methyl)benzoic acid (A-3) and chidamide, using the condensing agent HBTU, instead of the unstable N,N'-carbonyldiimidazole. The single crystal of chidamide was determined by X-ray diffraction study. The optimized preparation process was easy to operate, and the purity of the final product can be up to 99.76%. Moreover, the structure of chidamide was established to be (E)-N-(2-amino-4-fluorophenyl)-4-((3-(pyridin-3-yl)acrylamido)methyl)benzamide.

Abstract P3-01-12: Chidamide combined with fulvestrant in the treatment of HR-positive and HER2-negative advanced breast cancer after failure of previous endocrine therapy:A single-arm, single-center, phase 2 study

Abstract Background: Chidamide is an oral subtype-selective histone deacetylase inhibitor. The ACE study demonstrated that chidamide plus exemestane improved progression-free survival compared with placebo plus exemestane in patients (pts) with advanced, HR-positive, HER2-negative breast cancer that progressed after previous endocrine therapy. This phase 2 study aims to evaluate the efficacy and safety of chidamide plus fulvestrant in the treatment of HR-positive and HER2-negative advanced breast cancer that had progressed after previous endocrine therapy. Methods: Eligible pts were women aged 18-75 years with histologically confirmed HR-positive, HER2-negative, advanced invasive breast cancer, whose disease relapsed or progressed after at least one endocrine therapy with or without a CDK4/6i (either in the advanced or metastatic or adjuvant setting). Eligible pts were treated with oral chidamide (30mg twice a week for 4 consecutive weeks in a 4-week cycle) plus intramuscular fulvestrant (500 mg intramuscular injection; on days 0, 14, 28, then every 28 days thereafter) till disease progression or intolerant toxicity. Premenopausal women received a concomitant GnRH analogue. The primary endpoint is progression-free survival (PFS) and the secondary endpoints include overall response rate (ORR), duration of response (DoR), disease control rate (DCR), overall survival (OS), and safety. Results: Between Mar 8, 2021 and May 20, 2022, a total of 18 pts were enrolled. Median age was 53.5 years (range 45-67), 18 (100%) pts had ECOG PS 1, 16 (89%) had visceral disease, 14 (78%) pts had prior treatments with the median lines of 2, including 12 (86%) received endocrine treatment, and 11 (79%) received chemotherapy in the metastatic setting. At data cutoff (Jul 3, 2022), 8 (44.4%) pts were still receiving the drug regimen. The median PFS was 7.2 (95% CI, 5.83-8.49) months. In the 17 efficacy evaluable pts, the ORR was 17.6% (95% CI, 3.8%-43.4%), DCR was 88.2% (95% CI, 63.6%-98.5%). Treatment related adverse events (TRAEs) of any grade occurred in 18 (100%) pts, in which 4 (22.2%) were ≥ grade 3. The most common grade 3 or 4 TRAEs (incidence ≥10%) were leucopenia (22.2%), and neutropenia (22.2%). No treatment-related deaths occurred. The trial is ongoing. Conclusions: Chidamide combined with fulvestrant showed encouraging antitumor activity and tolerable toxicity in pts with HR-positive and HER2-negative advanced breast cancer that had progressed after previous endocrine therapy. Clinical trial information: ChiCTR2100044282. Research Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd and Shenzhen Chipscreen Biosciences Co., Ltd. Baseline characteristics Citation Format: Wei Li, La Zou, Xiaohua Zeng. Chidamide combined with fulvestrant in the treatment of HR-positive and HER2-negative advanced breast cancer after failure of previous endocrine therapy:A single-arm, single-center, phase 2 study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-01-12.

Therapeutic potential of tucidinostat, a subtype-selective HDAC inhibitor, in cancer treatment.

Histone deacetylase (HDAC) is one of the most characterized epigenetic modifiers, modulating chromatin structure and gene expression, which plays an important role in cell cycle, differentiation and apoptosis. Dysregulation of HDAC promotes cancer progression, thus inhibitors targeting HDACs have evidently shown therapeutic efficacy in multiple cancers. Tucidinostat (formerly known as chidamide), a novel subtype-selective HDAC inhibitor, inhibits Class I HDAC1, HDAC2, HDAC3, as well as Class IIb HDAC10. Tucidinostat is approved in relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL), advanced breast cancer and R/R adult T-cell leukemia-lymphoma (ATLL). Compared with other HDAC inhibitors, tucidinostat shows notable antitumor activity, remarkable synergistic effect with immunotherapy, and manageable toxicity. Here, we comprehensively summarize recent advances in tucidinostat as both monotherapy and a regimen of combination therapy in both hematological and solid malignancies in clinic. Further studies will endeavor to identify more combination strategies with tucidinostat and to identify specific clinical biomarkers to predict the therapeutic effect.

The Therapeutic Response of Chidamide Was Associated with Elevated H3 Acetylation Level in Patients with Refractory/Relapsed Non-Hodgkin Lymphoma (R/R-NHL)

INTRODUCTIONChidamide as the first oral subtypeselective histone deacetylase inhibitor (HDACI) has been approved for treatment of refractory/relapsed peripheral T-cell lymphoma (R/R PTCL) by the China Food and Drug Administration (CFDA).(Lu X, Intractable Rare Dis Res. 2016) A multicenter phase II study showed that the overall response rate (ORR) was 28 % and complete response (CR/CRu) ratewas14 %.(Shi Y, Ann Oncol. 2015) However, the association between therapeutic efficacy and H3 acetylation level change inprevious HDACI clinical studies is not well defined. The objectives of the current study were to evaluate the clinical response and toxicity of R/R-NHLpatients treated with chidamide, and try to investigatethe association between objective response and H3 acetylation level. (NCT 02878278) METHODSPatients with R/R-NHL were enrolled in this Phase II, open-label study. Two-dosing schedule of chidamidemonotherapy was administrated (10mg QD and 30 mg BIW). Blood samples were collected predose and up to 4, 8, 16, 20, 24h after each chidamide dose on day 1 and day 22. Response, safety profile and H3 acetylation level were assessed. Total histones were isolated and purified from WBC samples collected at referred time points. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) 18.0 software. RESULTSTwenty-five R/R-NHL patients who had failed to standard therapy were enrolled, and allpatients already have been treated ≧ 2 lines of chemotherapy (median 4, and range, 2-8) Dosing schedule of chidamide included 10mg QD group, n = 16 ,and 30 mg BIW group, n = 9, respectively. Final response was evaluable in 23 (92.0 %) patients(figure 1), while2 patients withdrew from study due to progressive disease (PD) two weeks after chidamide administration. Serum samples detection showed, thatH3 acetylation level increase was consistent and slightly escalation during dosing on 10mg QD, while fluctuating change during dosing on 30mg BIW. The H3 acetylation level increased by 2.06 folds from the first dose at day 1, and was maintained at a high levelat day 22 in 10 mg QD group. In the 30 mg BIW group, the H3 acetylation level was also increased by 1.53 folds from the first dose at day 1, and slightly accumulated at a high level subsequent administration, although there was a period of low acetylation in the middle of the two administrations. Patients with increased H3 acetylation level would likely to getobjective responses tochidamide treatment compared to progressed patients without increased H3 acetylation. (14: 9 patients at day 1, and 14:7 patients at day 22, respectively.) A significant positive association between therapeutic response of chidamide and elevated H3 acetylation level in plasma was found in our cohort (P = 0.017, day 1, and P = 0.034, day 22, figure 2 ). Subgroup analysis showed that CR/PR/SD patients (n = 8)had statistical increased H3 acetylation levels compared to PD patients (n = 7) in 10 mg QD group. (median fold : 3.80 vs 1.43, day 1, p = 0.028 ,and 5.54 vs 1.12, day 22, p = 0.042 ) The similar results was found in 30 mg BIW group, however, not reach statistically significant (median fold : 1.72 vs 1.28, day 1, p = 0.183 and 1.80 vs 1.18, day 22, p = 0.233 ). The main adverse events (AEs) were hematologic toxicity and mild gastrointestinal toxicity. There were no statistical difference of the H3 acetylation level in CR/PR/SD patients between 10mg QD and 30 mg BIW group (p = 0.315), and there were no significant association between the H3 acetylation level and toxicity of chidamide.(table 1) ConclusionsPreliminary results of the present study suggestedthatchidamide monotherapy yielded promising efficacy with mild toxicity for patients with R/R-NHL. Our findings suggested that elevated H3 acetylation level might be a response biomarkerfor chidamide. Further investigation is urgently needed. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Chidamide, a subtype-selective histone deacetylase inhibitor, enhances Bortezomib effects in multiple myeloma therapy.

Drug resistance is the major cause for disease relapse and patient death in multiple myeloma (MM). It is an urgent need to develop new therapies to overcome drug resistance in MM. Chidamide (CHI), a novel oral HDAC inhibitor targeting HDAC1, 2, 3 and 10, has shown potential therapeutic effect in MM. In this study, we determined that CHI exhibited significant anti-tumor effect on MM cells both in vitro and in vivo, which was positively correlated with the expression of HDAC1. Meanwhile, CHI enhanced Bortezomib (BTZ) effects synergistically in MM cells and a combination of CHI with BTZ induced myeloma cell apoptosis and G0/G1 arrest in vitro and in vivo. Mechanistically, the synergistic anti-tumor effect of CHI and BTZ was related with the increased production of reactive oxygen species (ROS) dependent DNA damage and the changes of cell apoptosis and cycle pathways. Our data indicate that CHI may be a suitable drug to sensitize BTZ in MM cells, which provides novel insight into the therapy for MM patients.

Why ACE—overview of the development of the subtype-selective histone deacetylase inhibitor chidamide in hormone receptor positive advanced breast cancer

Why ACE—overview of the development of the subtype-selective histone deacetylase inhibitor chidamide in hormone receptor positive advanced breast cancer

Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial

Tucidinostat (formerly known as chidamide) is an oral subtype-selective histone deacetylase inhibitor. In an exploratory study, the combination of tucidinostat with exemestane showed preliminary signs of encouraging anti-tumour activity in patients with advanced hormone receptor-positive breast cancer. To build on these findings, we aimed to assess the efficacy and safety of this combination in a randomised trial in a larger population of postmenopausal patients with advanced, hormone receptor-positive breast cancer. We did the randomised, double-blind, placebo-controlled, phase 3 ACE trial at 22 specialist cancer centres in China. Eligible patients were postmenopausal women (aged ≥60 years or aged <60 years if their serum follicle-stimulating hormone and oestradiol concentrations were within postmenopausal ranges) with hormone receptor-positive, HER2-negative breast cancer, whose disease had relapsed or progressed after at least one endocrine therapy (either in advanced or metastatic or adjuvant setting), and who had at least one measurable lesion, adequate organ function, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate haematological and biochemical parameters. Endocrine therapy did not have to be the most recent therapy before randomisation, but recurrence or progression after the most recent therapy was a prerequisite. Patients were randomly assigned (2:1) by a dynamic randomisation scheme via an interactive web-response system to receive 30 mg oral tucidinostat or placebo twice weekly. All patients in both groups also received 25 mg oral exemestane daily. Randomisation was stratified according to the presence of visceral metastases (yes vs no). Patients, investigators, study site staff, and the sponsor were masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival. Efficacy analyses were done in the full analysis set population, comprising all patients who received at least one dose of any study treatment, and safety analyses were done in all patients who received at least one dose of any study treatment and for whom at least one safety case report form was available. This study is registered with ClinicalTrials.gov, number NCT02482753. The study has reached the required number of events for final analysis of the primary endpoint. The trial is no longer enrolling patients, but follow-up for investigation of overall survival is ongoing. Between July 20, 2015, and June 26, 2017, 365 patients were enrolled and randomly assigned, 244 to the tucidinostat group and 121 to the placebo group. The median duration of follow-up was 13·9 months (IQR 9·8-17·5). Investigator-assessed median progression-free survival was 7·4 months (95% CI 5·5-9·2) in the tucidinostat group and 3·8 months (3·7-5·5) in the placebo group (HR 0·75 [95% CI 0·58-0·98]; p=0·033). The most common grade 3 or 4 adverse events in either group were neutropenia (124 [51%] of 244 patients in the tucidinostat group vs three [2%] of 121 patients in the placebo group), thrombocytopenia (67 [27%] vs three [2%]), and leucopenia (46 [19%] vs three [2%]). Serious adverse events of any cause occurred in 51 (21%) of 244 patients in the tucidinostat group and seven (6%) of 121 patients in the placebo group. No treatment-related deaths were reported. Tucidinostat plus exemestane improved progression-free survival compared with placebo plus exemestane in patients with advanced, hormone receptor-positive, HER2-negative breast cancer that progressed after previous endocrine therapy. Grade 3-4 haematological adverse events were more common in the tucidinostat plus exemestane group than in the placebo plus exemestane group. Tucidinostat plus exemestane could represent a new treatment option for these patients. Chipscreen Biosciences.

Determination of chidamide in rat plasma and cerebrospinal fluid

Chidamide is a new subtype-selective histone deacetylase inhibitor (HDACi), which has been approved for the treatment of recurrent or refractory peripheral T-cell lymphoma (PTCL) in China. However, there are few studies about the application of chidamide in PTCL with central nervous system (CNS) involvement. It is essential to investigate the penetration of chidamide in the blood brain barrier (BBB). LC-MS methods were established firstly to determine the concentration of chidamide in rat plasma and CSF. Then five rats were anaesthetized and the plasma and CSF samples were collected at the time of 5, 15, 30, 60, 120, 180, 240, 360 and 480 min after being administered 1 mg/kg chidamide by intravenous injection, respectively. All samples were analyzed with the established LC-MS method by using the precursor/product transitions (m/z) of 391.1/265.1 for chidamide and 441.1/138.2 for internal standard (IS). The PK parameters were calculated after both of the concentrations of chidamide in plasma and CSF were determined. The penetration ratio of chidamide in BBB ranged from 0.19% to 0.67%. Result indicated chidamide could pass through the BBB, enter into the CNS and have the potential to be utilized in PTCL with CNS involvement.

Therapeutic effects of the novel subtype-selective histone deacetylase inhibitor chidamide on myeloma-associated bone disease.

Histone deacetylases are promising therapeutic targets in hematological malignancies. In the work herein, we investigated the effect of chidamide, a new subtype-selective histone deacetylase inhibitor that was independently produced in China, on multiple myeloma and its associated bone diseases using different models. The cytotoxicity of chidamide toward myeloma is due to its induction of cell apoptosis and cell cycle arrest by increasing the levels of caspase family proteins p21 and p27, among others. Furthermore, chidamide exhibited significant cytotoxicity against myeloma cells co-cultured with bone mesenchymal stromal cells and chidamide-pretreated osteoclasts. Importantly, chidamide suppressed osteoclast differentiation and resorption in vitro by dephosphorylating p-ERK, p-p38, p-AKT and p-JNK and inhibiting the expression of Cathepsin K, NFATc1 and c-fos. Finally, chidamide not only prevented tumor-associated bone loss in a disseminated murine model by partially decreasing the tumor burden but also prevented rapid receptor activator of nuclear factor κ-β ligand (RANKL)-induced bone loss in a non-tumor-bearing mouse model. Based on our results, chidamide exerted dual anti-myeloma and bone-protective effects in vitro and in vivo. These findings strongly support the potential clinical use of this drug as a treatment for multiple myeloma in the near future.

Exploratory clinical study of chidamide, an oral subtype-selective histone deacetylase inhibitor, in combination with exemestane in hormone receptor-positive advanced breast cancer.

ObjectiveThe recurrence or progression under endocrine therapy in hormone receptor-positive (HR+) advanced breast cancer (ABC) remained a critical clinical challenge. Chidamide is an oral subtype-selective histone deacetylase (HDAC) inhibitor with multiple functions in tumor growth inhibition and microenvironment modulation via epigenetic reprogramming. The purpose of this study was to evaluate the safety, pharmacokinetics (PK), and preliminary efficacy of chidamide in combination with exemestane in HR+ ABC patients.MethodsEligible patients were postmenopausal women with HR+ ABC recurrent or progressed to at least one endocrine therapy. Blood samples were obtained in the run-in period and the first day of combination treatment for PK analysis. In combination treatment, patients were given exemestane 25 mg daily and chidamide 30 mg twice a week (BIW) until progression of disease or intolerable toxicities. A treatment cycle was defined as 4 weeks. Safety, PK parameters, and preliminary efficacy were evaluated.ResultsA total of 20 patients were enrolled between July and December, 2015. The median number of treatments cycle was 5.2 (20.8 weeks) with 2 patients still on treatment at the data cut-off date of October, 2017. The treatment-related adverse events (AE) ≥ grade 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.ConclusionsThe 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.

Pilot trial of chidamide, an oral histone deacetylase (HDAC) inhibitor, in combination with exemestane in hormone receptor-positive advanced breast cancer.

e12543 Background: Chidamide (CHI) is a novel benzamide type of subtype-selective histone deacetylase inhibitor approved in China for refractory and relapsed peripheral T-cell lymphoma with a dosage of 30 mg PO twice a week. A randomized, double blind and placebo-controlled phase 3 clinical trial of CHI plus exemestane (EXE) is currently ongoing in patients (pts) with hormone receptor-positive (HR+) advanced breast cancer (ABC). This abstract reports the results from the pilot study preceded the phase 3 trial. Methods: Eligible pts were postmenopausal women recurrent or progressed to at least one endocrine therapy. In the run-in period for pharmacokinetic (PK) analysis, pts received EXE 25 mg on day (D) 1 and CHI 30 mg on D 2. From D 5 pts started combination treatment having EXE 25 mg daily and CHI 30 mg twice a week until progression of disease (PD) or intolerable toxicities. A treatment cycle was defined as 28 days. Safety, PK parameters and preliminary efficacy were assessed. Results: 20 pts with HR+ and HER-2 negative were enrolled between Jul and Dec, 2015. Median duration of treatment was 5 cycles (range 0-16), with 4 pts still on treatment. 3 pts discontinued due to adverse events (AE). Drug-related AEs ≥ grade 3 in 2 or more pts were neutropenia (35%), thrombocytopenia (30%), and leucopenia (20%). Similar plasma exposure of EXE was observed in the absence and presence of CHI ( 73 ± 27 vs. 80 ± 29 ng·hr/mL). A potential increased plasma exposure of CHI was noted in the presence of EXE compared with CHI alone ( 2232 ± 973 vs 1787 ± 946 ng·hr/mL), apparently related to the inter-patient variations in CHI plasma concentrations. Best response in 18 pts was assessed by RECIST, including 3 pts with partial response, 12 pts with stable disease and 3 pts with PD. Median progression free survival was 7.6 months. Conclusions: The combination of CHI and EXE was generally well tolerated. Most AEs were related to the CHI single-agent treatment that are generally manageable. Encouraging antitumor activity was observed. The overall results from this pilot trial enabled the next-stage clinical development of this combination regimen in HR+ ABC pts. Clinical trial information: NCT02482753.

Chidamide tablets: HDAC inhibition to treat lymphoma.

Chidamide is the first oral subtype-selective histone deacetylase inhibitor (HDACI) approved in China as well as the first HDACI of the benzamide class approved for the treatment of relapsed and refractory peripheral T-cell lymphoma (PTCL). This review addresses detailed information regarding chidamide, including the mechanism of action, preclinical pharmacology, pharmacokinetics and metabolism, clinical studies and application, safety, drug interactions and ongoing clinical trials. Although twice-weekly chidamide monotherapy has been recommended based on the evidence from preclinical and clinical studies with tolerable toxicities, its clinical efficacy could be further increased by combination with multidrug chemotherapy or chemo-free regimens. Further investigations into the mechanism of chidamide will facilitate the identification of optimal combined therapy approaches and suitable treatment populations. This review will contribute to a comprehensive understanding and better use of chidamide in clinical practice.

A phase I trial of an oral subtype-selective histone deacetylase inhibitor, chidamide, in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer.

Objective This phase I study was to evaluate safety, maximum tolerated dose, pharmacokinetics and preliminary antitumor activity of chidamide, a novel subtype-selective histone deacetylase (HDAC) inhibitor, in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer (NSCLC). Methods Ten patients received oral chidamide 20, 25, or 30 mg twice per week continuously with paclitaxel (175 mg/m2) and carboplatin [area under the curve (AUC) 5 mg/mL/min] administered in a 3-week cycle. Patients with response and stable disease after four cycles maintained chidamide monotherapy until disease progression or unacceptable toxicity. Blood samples were collected for pharmacokinetic analysis after the first single oral of chidamide and first combination treatment in cycle 1 from all patients. Results Two dose-limiting toxicities were recorded in the 30 mg cohort, including thrombocytopenia and prolonged neutropenia in the first cycle. Grade 3/4 neutropenia in any cycle was observed in all patients, but was not associated with significant complications. Other grade 3/4 hematologic toxicities included thrombocytopenia and leucopenia. No significant changes were observed in pharmacokinetic parameters for both chidamide and paclitaxel. One patient in the 20 mg cohort had confirmed partial response (PR). Two out of 5 patients with brain metastases had intracranial complete remission after 4-cycle treatment. Conclusions Chidamide combined with paclitaxel and carboplatin was generally tolerated without unanticipated toxicities or clinically relevant pharmacokinetic interactions. The recommended dose for chidamide in this combination was established at 20 mg, and a phase II trial is ongoing with this regimen in patients with advanced NSCLC.

Increased PRAME-Specific CTL Killing of Acute Myeloid Leukemia Cells by Either a Novel Histone Deacetylase Inhibitor Chidamide Alone or Combined Treatment with Decitabine

As one of the best known cancer testis antigens, PRAME is overexpressed exclusively in germ line tissues such as the testis as well as in a variety of solid and hematological malignant cells including acute myeloid leukemia. Therefore, PRAME has been recognized as a promising target for both active and adoptive anti-leukemia immunotherapy. However, in most patients with PRAME-expressing acute myeloid leukemia, PRAME antigen-specific CD8+ CTL response are either undetectable or too weak to exert immune surveillance presumably due to the inadequate PRAME antigen expression and PRAME-specific antigen presentation by leukemia cells. In this study, we observed remarkably increased PRAME mRNA expression in human acute myeloid leukemia cell lines and primary acute myeloid leukemia cells after treatment with a novel subtype-selective histone deacetylase inhibitor chidamide in vitro. PRAME expression was further enhanced in acute myeloid leukemia cell lines after combined treatment with chidamide and DNA demethylating agent decitabine. Pre-treatment of an HLA-A0201+ acute myeloid leukemia cell line THP-1 with chidamide and/or decitabine increased sensitivity to purified CTLs that recognize PRAME100–108 or PRAME300–309 peptide presented by HLA-A0201. Chidamide-induced epigenetic upregulation of CD86 also contributed to increased cytotoxicity of PRAME antigen-specific CTLs. Our data thus provide a new line of evidence that epigenetic upregulation of cancer testis antigens by a subtype-selective HDAC inhibitor or in combination with hypomethylating agent increases CTL cytotoxicity and may represent a new opportunity in future design of treatment strategy targeting specifically PRAME-expressing acute myeloid leukemia.