This study is being carried out to assess the best dose of a new drug, called tefinostat, in treating liver cancer.
Tefinostat is a new drug that blocks enzymes called histone deacetylases (pronounced dee-as-et-isle-azes). Cells need these enzymes to grow and divide. Blocking them may stop cancer growing. Drugs that block these enzymes are called histone deacetylase inhibitors or 'HDAC inhibitors'.
Tefinostat has never been given to patients with liver cancer before so it isn't known which dose is best at treating liver cancer. To find this out the study will be testing one dose and if that is safe, then test a higher dose and so on.
The aim of this study is to find the best dose of tefinostat without causing side effects. The study will be looking closely at any side effects patients might experience from this treatment.

开始日期2013-01-01

申办/合作机构

Queen Mary University of London

[+1]

NCT00820508 / Completed临床1期

A Phase I Study to Evaluate the Safety and Tolerability of the Histone Deacetylase Inhibitor, CHR-2845, in Patients With Advanced or Treatment Refractory Haematological Diseases or Lymphoid Malignancies

The purpose of this study is to determine whether the histone deacetylase inhibitor CHR-2845 is tolerated in patients with haematological diseases and lymphoid malignancies.

开始日期2008-12-01

申办/合作机构

Chroma Therapeutics Ltd.

100 项与 Tefinostat 相关的临床结果

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100 项与 Tefinostat 相关的转化医学

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100 项与 Tefinostat 相关的专利（医药）

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项与 Tefinostat 相关的文献（医药）

2016-03-29·Oncotarget

The targeted histone deacetylase inhibitor tefinostat (CHR-2845) shows selective in vitro efficacy in monocytoid-lineage leukaemias

Article

作者: Knapper, Steven ; Davidson, Alan ; Hills, Robert ; Zabkiewicz, Joanna ; Gilmour, Marie ; Vyas, Pares ; Burnett, Alan ; Bone, Elizabeth

Tefinostat (CHR-2845) is a novel monocyte/macrophage-targeted histone deacetylase (HDAC) inhibitor which is cleaved into its active acid by the intracellular esterase human carboxylesterase-1 (hCE-1). The in vitro efficacy of tefinostat was characterised in cell lines and in a cohort of 73 primary AML and CMML samples. Dose-dependent induction of apoptosis and significant growth inhibitory effects were seen in myelomonocytic (M4), monocytic/monoblastic (M5) and CMML samples in comparison to non-monocytoid AML sub-types (p = 0.007). Importantly, no growth inhibitory effects were seen in normal bone marrow CD34+ cells exposed to AML-toxic doses of tefinostat in clonogenic assays. Expression of hCE-1 was measured by intracellular flow cytometry and immunoblotting across the cohort, with highest levels seen in M5 AML patients. hCE-1 levels correlated with significantly increased tefinostat sensitivity (low EC50) as measured by growth inhibition assays (p = 0.001) and concomitant elevation of the mature monocytoid marker CD14+. Strong induction of intracellular histone protein acetylation was observed in tefinostat-responsive samples, as were high levels of the DNA damage sensor γ-H2A.X, highlighting potential biomarkers of patient responsiveness. Synergistic interaction between tefinostat and the current standard treatment cytarabine was demonstrated in dose response and clonogenic assays using simultaneous drug addition in primary samples (median Combination Index value = 0.51). These data provide a strong rationale for the further clinical evaluation of tefinostat in monocytoid-lineage haematological neoplasms including CMML and monocyte-lineage AMLs.

2013-07-01·British journal of haematology2区 · 医学

A phase I first‐in‐human study with tefinostat – a monocyte/macrophage targeted histone deacetylase inhibitor – in patients with advanced haematological malignancies

2区 · 医学

Article

作者: Hooftman, Leon ; Debnam, Phillip M. ; Ossenkoppele, Gert J. ; Lowenberg, Bob ; Van de Loosdrecht, Arjan A. ; Wells, Graham ; Vey, Norbert ; Toal, Martin ; Breems, Dimitri ; Needham, Lindsey ; Davidson, Alan H. ; Bawden, Lindsay ; Zachee, Pierre

Summary:

Tefinostat (CHR‐2845) is a monocyte/macrophage targeted histone deacetylase inhibitor (HDACi). This first‐in‐human, standard 3 + 3 dose escalating trial of oral, once daily tefinostat was conducted to determine the safety, tolerability, pharmacokinetic and pharmacodynamic profile of tefinostat in relapsed/refractory haematological diseases. Eighteen patients were enrolled at doses of 20–640 mg. Plasma concentrations of tefinostat exceeded those demonstrated to give in vitro anti‐proliferative activity. Flow cytometric pharmacodynamic assays demonstrated monocyte‐targeted increases in protein acetylation, without corresponding changes in lymphocytes. Dose‐limiting toxicities (DLTs) were not observed and dose escalation was halted at 640 mg without identification of the maximum tolerated dose. Drug‐related toxicities were largely Common Toxicity Criteria for Adverse Events grade 1/2 and included nausea, anorexia, fatigue, constipation, rash and increased blood creatinine. A patient with chronic monomyelocytic leukaemia achieved a bone marrow response, with no change in peripheral monocytes. An acute myeloid leukaemia type M2 patient showed a >50% decrease in bone marrow blasts and clearance of peripheral blasts. In conclusion, tefinostat produces monocyte‐targeted HDACi activity and is well tolerated, without the DLTs, e.g. fatigue, diarrhoea, thrombocytopenia, commonly seen with non‐targeted HDACi. The early signs of efficacy and absence of significant toxicity warrant further evaluation of tefinostat in larger studies. (clinicaltrials.gov identifier: NCT00820508).

Biomolecules

Efficacy of HDAC Inhibitors in Driving Peroxisomal β-Oxidation and Immune Responses in Human Macrophages: Implications for Neuroinflammatory Disorders

Article

作者: Berger, Johannes ; Weinhofer, Isabelle ; Rommer, Paulus ; Ponleitner, Markus ; Waidhofer-Söllner, Petra ; Heuböck, Elisabeth ; Parzer, Patricia ; Villoria-González, Andrea ; Göpfert, Jens ; Forss-Petter, Sonja ; Zierfuss, Bettina ; Zujovic, Violetta

Elevated levels of saturated very long-chain fatty acids (VLCFAs) in cell membranes and secreted lipoparticles have been associated with neurotoxicity and, therefore, require tight regulation. Excessive VLCFAs are imported into peroxisomes for degradation by β-oxidation. Impaired VLCFA catabolism due to primary or secondary peroxisomal alterations is featured in neurodegenerative and neuroinflammatory disorders such as X-linked adrenoleukodystrophy and multiple sclerosis (MS). Here, we identified that healthy human macrophages upregulate the peroxisomal genes involved in β-oxidation during myelin phagocytosis and pro-inflammatory activation, and that this response is impaired in peripheral macrophages and phagocytes in brain white matter lesions in MS patients. The pharmacological targeting of VLCFA metabolism and peroxisomes in innate immune cells could be favorable in the context of neuroinflammation and neurodegeneration. We previously identified the epigenetic histone deacetylase (HDAC) inhibitors entinostat and vorinostat to enhance VLCFA degradation and pro-regenerative macrophage polarization. However, adverse side effects currently limit their use in chronic neuroinflammation. Here, we focused on tefinostat, a monocyte/macrophage-selective HDAC inhibitor that has shown reduced toxicity in clinical trials. By using a gene expression analysis, peroxisomal β-oxidation assay, and live imaging of primary human macrophages, we assessed the efficacy of tefinostat in modulating VLCFA metabolism, phagocytosis, chemotaxis, and immune function. Our results revealed the significant stimulation of VLCFA degradation with the upregulation of genes involved in peroxisomal β-oxidation and interference with immune cell recruitment; however, tefinostat was less potent than the class I HDAC-selective inhibitor entinostat in promoting a regenerative macrophage phenotype. Further research is needed to fully explore the potential of class I HDAC inhibition and downstream targets in the context of neuroinflammation.

项与 Tefinostat 相关的新闻（医药）

2022-09-18

·生物制药小编

抑制TAMs促肿瘤活性

一、靶向髓系细胞检查点和调节分子髓单核细胞的功能受到许多直接抑制或转移其效应功能的负调控因子的严格控制。信号调节蛋白α (SIRPα)、唾液酸结合免疫球蛋白样凝集素(SIGLEC)和白细胞免疫球蛋白样受体B (LILRB)家族是较为常见的几类髓系细胞检查点。其他相关分子包括清道夫受体(scavenger receptors)。此类受体能够介导巨噬细胞清除碎片和死亡细胞，这一功能对缓解炎症(在消退阶段)和防止组织损伤至关重要。巨噬细胞表达的髓系检查点和其他抑制受体。Nat Rev Drug Discov (2022).（1）SIRPα-CD47轴阻断剂靶向CD47-SIRPα轴可能同时使巨噬细胞更具吞噬能力并增加其抗原负载，从而增强抗原向T细胞的提呈。因此，靶向CD47的疗法可能与T细胞检查点抑制剂联合用药或结合开发，首先改善吞噬和抗原递呈，其次释放活化的T细胞的反应。SIRPα-CD47轴靶向方法包括抗CD47抗体(如Hu5F9-G4 (NCT02216409)、SRF231 (NCT035123)、IBI188 (NCT03763149)和抗SIRPα (BI-765063 (NCT03990233))两种不同的作用设计。临床前模型显示，抗CD47的治疗联合对那些已经有针对肿瘤抗原的靶向治疗的肿瘤特别有效，如表达CD20的淋巴瘤，表达HER2的乳腺癌和表达EGFR的CRC等。目前已有的研究以血液瘤为主。西妥昔单抗与抗CD47抗体的联合显著增加了巨噬细胞抗体依赖的吞噬作用，目前正在CRC的临床试验中进行测试(NCT02953782)；一项Ib期研究中，CD47阻断剂联合利妥昔单抗在淋巴瘤患者中显示活性；对肺癌、乳腺癌和其他类型癌症细胞系的临床前研究结果表明，巨噬细胞介导的吞噬作用可以极大地促进抗体的治疗功能并触发适应性免疫反应CD47靶向疗法具有潜在的红细胞毒性。目前的处理方法为：阻断SIRPα；使用具有弱杀伤特性的CD47抗体。如具有IgG4尾巴的抗体，从而减少NK细胞参与；增加肿瘤靶点的特异性。如使用识别CD47和肿瘤相关抗原的双特异性试剂，也可以降低肿瘤外效应。（2）SIGLEC抑制剂SIGLEC1又称CD169，由部分巨噬细胞表达，并在肿瘤中高表达，其表达与更糟糕的预后相关。相关研究和靶点开发进展包括：乳腺癌小鼠模型中，去除CD169+ TAMs可以有效地减少肿瘤负担和转移；SIGLEC7和SIGLEC9在人源化小鼠模型中被靶向，显著减少了肿瘤负担；唾液糖蛋白信号换能器CD24已被评估为一种抗吞噬分子，由多种癌细胞表达，有望作为一种具有治疗潜力的额外检查点；卵巢癌临床前模型中，CD24与SIGLEC10结合后，SIGLEC10被TAMs过度表达，抑制肿瘤细胞的吞噬作用，并用抗SIGLEC10的单抗干扰该轴，可拯救巨噬细胞的能力，限制肿瘤生长。（3）LILRB阻断剂肿瘤细胞可以利用MHC I类作为一种逃避吞噬作用的机制，通过与LILRB家族成员相互作用。LILRB家族中常见且相似的两个成员为LILRB1和LILRB2。肿瘤细胞中MHC I类的表达与CD47抗体的耐药程度相关，CD47抗体诱导的吞噬作用可被LILRB1阻断抗体恢复；巨噬细胞也表达LILRB2，阻断其表达可增强其促炎激活和吞噬活性。不过目前LILRB2的检查点活性是阻断吞噬作用还是调节巨噬细胞活化仍有待阐明。目前已有处于1期临床阶段的候选产品（如MK-4830，NCT03564691）；LILRB4存在于多种肿瘤的免疫细胞上，在TAMs上最为显著，可强烈抑制肿瘤免疫。LILRB4阻断剂可重塑肿瘤浸润T细胞，并可调整TAM向非抑制性表型分化。（4）清道夫受体多种清除受体在TAM中大量表达。CD163：CD163+的巨噬细胞与胰腺癌、黑色素瘤等几种肿瘤的进展存在显著关联；CD163通过与血管内溶血形成的结合珠蛋白-血红蛋白复合物结合，使巨噬细胞能够清除受损的红细胞，其表达通常与M2样巨噬细胞相关；CD163+巨噬细胞的减少可导致对抗PD1治疗耐药的黑素瘤小鼠模型的肿瘤消退。其治疗后表现为TME再教育，特征为细胞毒性T细胞和炎症单核细胞浸润。CD206(又称MRC1)：CD206除了结合病原体片段(如黏蛋白)外，还可结合多种内源性配体。巨噬细胞上的甘露糖受体(MR)通过粘蛋白或激动剂抗MR单抗，诱导免疫抑制表型，增加IL-10的产生。RP-182肽可与MRC1结合并诱导构象改变。小鼠模型中：合成肽RP-182部分耗尽CD206+巨噬细胞，并将剩余的TAMs重新编程为抗肿瘤M1样效应物，增加炎症细胞因子的产生和吞噬癌细胞的能力，从而达到抑制肿瘤生长，延长生存期的结果。可与联合免疫疗法协同。MARCO具有胶原结构的巨噬细胞受体(MARCO)在TAMs上高表达。分化表达MARCO的巨噬细胞表现为免疫抑制表型。临床前模型中显示其机制为：并未减少TAMs的数量，而是通过将TAMs重编程为促炎效应物诱导抗肿瘤免疫反应；MARCO相关的免疫抑制表型可通过沉默IL-37或阻断其受体，经IL-1R8信号来挽救；通过TRAIL途径激活NK细胞杀伤最近被认为是抗MARCO单抗的作用机制之一。小鼠黑色素瘤模型显示：MARCO单抗在体内作用时不涉及CD8+ T细胞，而仅由NK细胞介导。Clever1(又称Stabilin1)表达于循环单核细胞、淋巴和窦状内皮细胞，以及M2样巨噬细胞等多种细胞。在稳态条件下可导致巨噬细胞抑制和Th1淋巴细胞激活受损。临床前模型：Clever1阻断抗体导致TAMs从免疫抑制表型转换到促炎症、激活T细胞反应和延迟肿瘤生长的表型。（5）PD-1表达的PD-1的TAMs可抑制吞噬和肿瘤免疫，扭转了PD-1/PD-L1轴作为特定T细胞检查点的传统观点。因此，肿瘤细胞上PD-L1的表达可能同时导致逃避T细胞的细胞毒性和巨噬细胞介导的吞噬作用，提示阻断该轴可能通过适应性和先天机制释放抗肿瘤免疫。不过PD-1参与巨噬细胞的吞噬抑制机制尚不明确，也没有诱导PD-1上调的信号。（6）TREM2髓系细胞上表达的触发受体2 (TREM2)由多种组织的巨噬细胞表达，并在人和小鼠肿瘤中的TAMs上上调。小鼠模型中显示TREM2+巨噬细胞为靶点可限制肿瘤生长，并使抗PD1治疗反应敏化。（7）PSGL1PSGL1在造血来源细胞中广泛表达，在巨噬细胞中M2极化信号强烈上调，在TAMs中高水平表达。临床前实验中显示一款抗PSGL1抗体相较PD-1单抗，可致炎症微环境更为增强，包括M2:M1巨噬细胞比例降低、抗原呈递增加、促炎介质以及效应 T 细胞浸润和活化。（8）IL-1IL-1能够推动紧急造血和MDSCs的生成和招募，以及促进TAM的免疫抑制和肿瘤促进功能。例如：肾细胞癌模型中，联合抗IL-1β和抗PD1或多靶点酪氨酸激酶抑制剂cabozantinib治疗可产生协同抗肿瘤作用，MDSCs明显减少，TAMs极化；IL-1还可以直接作为靶点或者通过抑制炎症小体来上调。例如：小鼠黑色素瘤模型中，对肿瘤来源的NLRP3(炎症小体的传感器成分)的药理抑制，限制了MDSC介导的T细胞抑制和肿瘤生长。（9）补体3-甲基胆蒽诱导的肉瘤形成的小鼠肿瘤模型和两个移植的肉瘤模型：凝集素途径依赖的C3a-C3aR轴在TAM募集和功能倾斜中发挥主导作用，驱动免疫抑制和肿瘤促进；鳞癌模型：尿激酶(uPA)+巨噬细胞在癌前进展过程中调节C3-独立的C5a释放，这反过来促进了C5aR1+肥大细胞和巨噬细胞的致瘤特性，包括抑制T细胞的细胞毒性；可溶性模式识别分子戊曲辛3 (PTX3)可以作为一种外源性肿瘤抑制基因，通过调节补体依赖和巨噬细胞持续的肿瘤促进实体瘤中的炎症；临床中：补体分子，特别是C4d、C5a和C5aR1已在不同类型的癌症中作为诊断和/或预后的标志物；透明细胞RCC模型：产生C1q的TAMs浸润与免疫抑制的TME相关，其特征是免疫检查点分子(PD1, LAG3, PDL1和PDL2)的高表达，表明补体激活和T细胞衰竭之间存在相关性；补体和PD-1药物联用：肺癌模型：C5a和PD-1阻断剂的联合使用显著降低了肿瘤的生长和转移，延长了生存期。这种效应与肿瘤中CD8+ T细胞频率的增加和MDSCs频率的降低有关；与单独抗PD1或C3aR治疗相比，C3aR拮抗剂与抗PD-1治疗联合使用可显著降低原发性肿瘤的生长和发病率，提示补体抑制可增加ICB的临床疗效。补体系统由三种不同途径激活的级联顺序蛋白水解反应，下一步的补体策略开发可能着重于评估不同肿瘤或肿瘤亚群中不同补体通路的实际参与情况。二、靶向TAM代谢途径（1）通过抑制IIa类组蛋白去乙酰化酶(HDACs)进行表观遗传调控是利用巨噬细胞抗肿瘤潜能的一种有前景的方法。TMP195，是一种选择性的IIa类HDAC抑制剂，能够改变巨噬细胞的转录谱。临床前乳腺癌模型：TMP195导致巨噬细胞介导的肿瘤生长减少。Tefinostat (CHR-2845)，是一种HDAC抑制剂，通过非特异性酯酶肝羧酸酯酶1 (CES1)与活性酸结合，其表达仅限于单核细胞系细胞和一些肝细胞，使活性药物在单核细胞内选择性积累。相关产品已用于晚期血液系统恶性肿瘤1期临床阶段。(NCT00820508)（2）阻断糖酵解的策略可能对TAMs有积极的重编程作用。TME中，缺氧和营养剥夺的极端代谢条件与巨噬细胞招募后功能受损的情况有因果关系。肿瘤细胞产生的乳酸是糖酵解的副产物，可使巨噬细胞向M2样表型分化，以高表达精氨酸酶为特征。然而，同样的糖酵解途径是巨噬细胞对抗肿瘤细胞活性的基础，而ROS的产生和吞噬需要葡萄糖供应。也因此，大多数旨在糖酵解逆转巨噬细胞极化的研究都依赖于糖酵解抑制剂，如2-脱氧- d-葡萄糖(2- DG)等高度缺乏异质性的靶点。目前该方向的药物开发包括二甲双胍。临床前模型中，二甲双胍能够调节TME，降低TAMs的密度并增加其吞噬功能。（3）通过小分子阻断谷氨酰胺代谢或抑制其合成酶可通过调节抑制性髓系细胞来降低肿瘤生长。（4）TAMs增加吲哚胺2,3-双加氧酶1 (IDO1)的表达导致色氨酸的消耗。色氨酸是一种对T细胞功能激活至关重要的氨基酸。因此，TAMs消耗色氨酸会严重影响T细胞的功能状态，有利于产生具有免疫抑制活性的调节性T细胞。IDO抑制剂目前最快已有进入3期临床的产品。但其联合派姆单抗治疗转移性黑色素瘤的结果呈阴性。类似的酶如色氨酸2,3-双加氧酶(TDO)和IDO2的代偿表达可能是一种可能的机制。（5）通过羟甾醇受体LXR转录因子激活免疫抑制通路。在TAMs中常见的代谢紊乱中，以脂类紊乱最为突出。TAMs在脂质处理方面的缺陷与通过羟甾醇受体LXR转录因子激活的免疫抑制通路直接相关。目前已有合成的LXR激动剂，但尚未在肿瘤中应用。巨噬细胞系列文章巨噬细胞分类及标志物肿瘤相关巨噬细胞的两种来源及异质性炎症的基础：巨噬细胞和TAM分子增强TAMs抗肿瘤活性参考资料：Mantovani, A., Allavena, P., Marchesi, F. et al. Macrophages as tools and targets in cancer therapy. Nat Rev Drug Discov (2022). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41573-022-00520-5Xiang X, Wang J, Lu D, Xu X. Targeting tumor-associated macrophages to synergize tumor immunotherapy. Signal Transduct Target Ther. 2021 Feb 23;6(1):75. doi: 10.1038/s41392-021-00484-9. PMID: 33619259; PMCID: PMC7900181.Nguyen, P . et al. 862 T argeting PSGL-1, a novel macrophage checkpoint, repolarizes suppressive macrophages, induces an inflammatory tumor microenvironment, and suppresses tumor growth. J. Immunother. Cancer 8, https://doi-org.libproxy1.nus.edu.sg/10.1 136/ jitc-2020-SITC2020.0862 (2020).

免疫疗法抗体

100 项与 Tefinostat 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15321

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
肝细胞癌	临床2期	英国	Chroma Therapeutics Ltd.	2013-01-01
炎症	临床2期	英国	Chroma Therapeutics Ltd.	2012-07-29
慢性粒单核细胞白血病	临床2期	英国	University of Cardiff	-
费城染色体阳性慢性粒细胞白血病	临床2期	-	Chroma Therapeutics Ltd.	-
淋巴瘤	临床1期	比利时	Chroma Therapeutics Ltd.	2008-12-01
淋巴瘤	临床1期	法国	Chroma Therapeutics Ltd.	2008-12-01
淋巴瘤	临床1期	荷兰	Chroma Therapeutics Ltd.	2008-12-01

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT00820508 (Pubmed \| Br J Haematol)	临床1期	血液肿瘤	18	Tefinostat	廠築遞積淵顧範艱範夢(積夢淵淵淵觸範淵繭壓) = 網簾積齋艱顧憲製糧衊繭衊襯醖壓憲淵顧築廠 (顧顧築網齋齋淵築壓憲 )	积极	2013-07-01