WO2020103778A1 - 西达本胺的应用 - Google Patents

西达本胺的应用

Info

Publication number
WO2020103778A1
WO2020103778A1 PCT/CN2019/119094 CN2019119094W WO2020103778A1 WO 2020103778 A1 WO2020103778 A1 WO 2020103778A1 CN 2019119094 W CN2019119094 W CN 2019119094W WO 2020103778 A1 WO2020103778 A1 WO 2020103778A1
Authority
WO
WIPO (PCT)
Prior art keywords
cell lymphoma
treatment
lymphoma
cidabenamide
application
Prior art date
Application number
PCT/CN2019/119094
Other languages
English (en)
French (fr)
Inventor
鲁先平
黄慧强
李文瑜
付鑫
Original Assignee
深圳微芯生物科技股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 深圳微芯生物科技股份有限公司 filed Critical 深圳微芯生物科技股份有限公司
Priority to KR1020217018969A priority Critical patent/KR20210133207A/ko
Priority to EP19887759.9A priority patent/EP3884944A4/en
Priority to US17/295,490 priority patent/US20220000848A1/en
Priority to JP2021527821A priority patent/JP7489384B2/ja
Priority to AU2019385370A priority patent/AU2019385370A1/en
Priority to CA3120206A priority patent/CA3120206A1/en
Priority to BR112021009608-6A priority patent/BR112021009608A2/pt
Priority to SG11202105136WA priority patent/SG11202105136WA/en
Publication of WO2020103778A1 publication Critical patent/WO2020103778A1/zh
Priority to PH12021551137A priority patent/PH12021551137A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to the field of pharmaceutical technology, and specifically to the application of cidabenamine.
  • B-cell lymphoma mainly includes diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), marginal zone B-cell lymphoma (MZL), mantle cell lymphoma (MCL), etc.
  • the object of the present invention is to provide the use of cidabenamide in the preparation of a medicament for the treatment of B-cell lymphoma and / or the treatment of B-cell lymphoma.
  • FL follicular lymphoma
  • MALT marginal zone B-cell lymphoma
  • LPL lymphoplasmacytic lymphoma
  • SLL small lymphocyte B-cell lymphoma
  • DLBCL diffuse large B-cell lymphoma
  • other relapsed or refractory B-cell lymphomas are undergoing clinical trials for specific treatment of diseases.
  • Chidamide (Chidamide) is a subtype selective histone deacetylase (HDAC) inhibitor independently researched and developed in China, which is a new class 1.1 drug.
  • HDAC histone deacetylase
  • Cidabenamide mainly targets subtypes 1, 2, and 3 of type I HDAC and subtype 10 of type IIb, and has a regulatory effect on abnormal epigenetic function of tumors.
  • chromatin remodeling by inhibiting related HDAC subtypes to increase the acetylation level of chromatin histones, and thus produces changes in gene expression (ie epigenetic changes) against multiple signaling pathways, thereby inhibiting tumor cells Cycle, induce tumor cell apoptosis, and have overall regulatory activity on the body's cellular immunity, and induce and enhance natural killer cells (NK) and antigen-specific cytotoxic T cells (CTL) mediated tumor killing.
  • NK natural killer cells
  • CTL antigen-specific cytotoxic T cells
  • Cidabenamide also has the functions of inducing the differentiation of tumor stem cells and reversing the epithelial mesenchymal phenotype transformation (EMT) of tumor cells through epigenetic regulation mechanism, thereby restoring the sensitivity of drug-resistant tumor cells to drugs and inhibiting tumors Play a potential role in metastasis and relapse.
  • EMT epithelial mesenchymal phenotype transformation
  • the present invention unexpectedly finds that cidabenamide monotherapy is effective in the treatment of B-cell lymphomas, especially relapsed or refractory lymphomas, especially diffuse large B-cell lymphomas and mutations with specific epigenetic regulatory genes Of relapsed or refractory follicular lymphoma; therefore, preferably, the B-cell lymphoma is relapsed or refractory follicular lymphoma and / or diffuse large B with specific epigenetic regulatory gene mutations Cell lymphoma.
  • the present invention also provides a preparation for preparing B-cell lymphoma, which uses cidabenamine as the main active drug, and adds other active ingredients and / or pharmaceutical excipients that do not affect each other.
  • the other active ingredients that do not affect each other may be active ingredients for treating B-cell lymphoma, active ingredients for treating other diseases, or a combination of both.
  • the present invention also provides a method for treating B-cell lymphoma by administering an effective dose of cidabenamide.
  • the present invention proposes the application of cidabenamide with a therapeutic effect on B-cell lymphoma, and has verified through clinical trials that cidabenamide monotherapy for diffuse large B-cell lymphoma and concomitant Recurring or refractory follicular lymphoma with specific epigenetic regulatory gene mutations has a more prominent effect, and the application can more effectively treat patients with B-cell lymphoma.
  • the present invention discloses the application of cidabenamine, and those skilled in the art can refer to the content of this article and appropriately improve the process parameters to achieve.
  • all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.
  • the application of the present invention has been described through preferred embodiments, and it is obvious that relevant persons can modify or appropriately modify and combine the applications described herein without departing from the content, spirit, and scope of the present invention to implement and apply the technology of the present invention. .
  • Example 1 Phase II clinical study of cidabenamide monotherapy for relapsed or refractory B-cell lymphoma
  • Cidabenamide tablets off-white tablets, 5mg / tablet. Produced by Shenzhen Weixin Biotechnology Co., Ltd.
  • Dosing regimen 30 mg twice a week, and the interval between two doses should not be less than 3 days (such as Monday and Thursday, Tuesday and Friday, Wednesday and Saturday, etc.). Take medicine 30 minutes after breakfast, every 3 weeks for a treatment cycle. Throughout the study period, all subjects continued to receive study treatment until any of the following conditions occurred: disease progression, intolerable adverse reactions, death, withdrawal from treatment, withdrawal of informed consent, or loss of follow-up.
  • Pathological subtypes include: follicular lymphoma (FL) grade 1-3, marginal zone B-cell lymphoma (MALT), lymphoplasmacytic lymphoma Tumor (LPL), small lymphocyte B-cell lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL).
  • FL follicular lymphoma
  • MALT marginal zone B-cell lymphoma
  • LPL lymphoplasmacytic lymphoma Tumor
  • SLL small lymphocyte B-cell lymphoma
  • DLBCL diffuse large B-cell lymphoma
  • B-cell lymphoma including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) grade I-III, marginal zone B-cell lymphoma (MALT) , Lymphoid plasma cell lymphoma (LPL), small lymphocyte B-cell lymphoma (SLL), mantle cell lymphoma (MCL), transformed lymphoma (TL);
  • DLBCL diffuse large B-cell lymphoma
  • FL follicular lymphoma
  • MALT marginal zone B-cell lymphoma
  • LPL Lymphoid plasma cell lymphoma
  • SLL small lymphocyte B-cell lymphoma
  • MCL mantle cell lymphoma
  • TL transformed lymphoma
  • Sensitive definition disease remission, efficacy evaluation is PR or CR (confirmed or unconfirmed); disease relapses after 6 months of remission);
  • the first-line treatment plan needs to include anthracycline combination chemotherapy, such as CHOP; high-dose chemotherapy supported by autologous stem cell transplantation is regarded as a treatment plan; the treatment is defined as a new treatment combination or drug, and the change from CVP to CHOP is Therapy, when using the same therapy or medication again is not a new therapy;
  • anthracycline combination chemotherapy such as CHOP
  • high-dose chemotherapy supported by autologous stem cell transplantation is regarded as a treatment plan
  • the treatment is defined as a new treatment combination or drug
  • the change from CVP to CHOP is Therapy, when using the same therapy or medication again is not a new therapy
  • At least one measurable lesion the longest diameter is greater than 1.5cm, or the shortest diameter is greater than 1.0cm;
  • the ECOG score is 0-2;
  • PKT Platelet
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase AST ⁇ 2.5 ⁇ ULN, if accompanied by liver metastasis, ALT and AST ⁇ 5 ⁇ ULN
  • LVEF left ventricular ejection fraction
  • the patient took cidabenamide orally according to the aforementioned dosing regimen, and evaluated the safety and efficacy according to the prescribed time.
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • TBIL total bilirubin
  • DBIL direct bilirubin
  • GTT glutamyl transpeptidase
  • ALB albumin
  • Renal function urea nitrogen (BUN), creatinine (Cr)
  • Electrolytes potassium, sodium, chlorine, calcium, magnesium
  • LDH Lactate dehydrogenase
  • Curative effect evaluation time The curative effect evaluation is conducted every 6 weeks.
  • Efficacy evaluation methods The same imaging methods as the baseline (neck chest / abdominal pelvic enhanced CT, PET / CT, MRI, X-rays, abdominal ultrasound, etc.) and physical examination methods were used to evaluate lymph node and organ lesions.
  • Efficacy evaluation criteria Refer to the International Working Group ’s non-Hodgkin lymphoma efficacy evaluation criteria (IWC) for evaluation.
  • IWC non-Hodgkin lymphoma efficacy evaluation criteria
  • Clinical trial results 10 patients have been enrolled, 8 patients have been evaluated, ORR is 37.5%, benefit rate is 62.5%.
  • Example 2 Multi-center, single-arm, open clinical trial of cidabenamide tablets for the treatment of relapsed or refractory follicular lymphoma (FL) with specific epigenetic regulatory gene mutations
  • Cidabenamide tablets off-white tablets, 5mg / tablet. Produced by Shenzhen Weixin Biotechnology Co., Ltd.
  • Dosing regimen 30 mg twice a week, and the interval between two doses should not be less than 3 days (such as Monday and Thursday, Tuesday and Friday, Wednesday and Saturday, etc.). Take medicine 30 minutes after breakfast, every 3 weeks for a treatment cycle. Throughout the study period, all subjects continued to receive study treatment until any of the following conditions occurred: disease progression, intolerable adverse reactions, death, withdrawal from treatment, withdrawal of informed consent, or loss of follow-up.
  • Number of cases A total of 33 patients are planned to be included in this clinical trial, including 10 patients in the first phase.
  • At least one of the following conditions ⁇ 3 affected lymph node areas, each ⁇ 3cm in diameter; any lymph node or extranodal tumor ⁇ 7cm; presence of B symptoms; splenomegaly; pleural effusion or ascites; blood cell reduction (leukocytes ⁇ 1.0 ⁇ 10 9 / L, platelets ⁇ 100 ⁇ 10 9 / L); leukemia;
  • the second-generation sequencing test confirmed CREBBP and / or EP300 specific gene mutations
  • the age is between 18-75 years old, male or female;
  • This trial includes the screening period, treatment period and follow-up period.
  • patient screening is conducted through medical history collection, physical examination, laboratory examination, and tumor evaluation.
  • the first genetic test sample and test are collected during the screening period;
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • TBIL total bilirubin
  • DBIL direct bilirubin
  • GTT glutamyl transpeptidase
  • ALB albumin
  • Renal function urea nitrogen (BUN), creatinine (CR)
  • Electrolytes potassium, sodium, chlorine, calcium, magnesium
  • LDH Lactate dehydrogenase
  • Efficacy evaluation methods through imaging (CT or PET / CT), clinical physical examination, bone marrow aspiration and biopsy, etc., lymph node and organ lesions, skin lesions and other assessments. Patients must use the same imaging methods at all follow-up points.
  • Efficacy evaluation criteria CT scanners are evaluated according to the 1999 International Working Group ’s Non-Hodgkin Lymphoma Efficacy Evaluation Criteria (IWG); PET / CT scanners are evaluated according to the revised guidelines of the 2007 International Coordination Plan ( Appendix 1).
  • Sample collection for genetic testing If the efficacy evaluation during treatment is disease progression (PD), a second sample collection and testing for genetic testing (PD sample) will be performed. Collect biopsy specimens from patients with residual enlarged lesions or FDG uptake of high metabolic sites collected during PD.
  • PD sample tissue biopsy specimens from patients with residual enlarged lesions or FDG uptake of high metabolic sites collected during PD.
  • the follow-up time started after the end of treatment and lasted for 2 years, until the subject's tumor progressed or died. It can be a telephone follow-up.
  • ORR Objective response rate
  • CR complete response
  • CRu unconfirmed complete response
  • PR partial response
  • DCR Disease control rate
  • CR complete remission
  • CRu unconfirmed complete remission
  • PR partial remission
  • SD stable
  • PFS Progression-free survival
  • Clinical experiment results A total of 11 patients with B-NHL with apparent mutation were observed in the preliminary test.
  • the ORR was 72.7% and the CR rate was 36.3%.
  • cidabenamide is more effective in treating relapsed or refractory follicular lymphoma (FL) with specific epigenetic regulatory gene mutations.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

本发明涉及药物技术领域，公开了西达本胺的应用。本发明提出了对B细胞淋巴瘤具备治疗作用的给予西达本胺的治疗方案应用，并通过临床试验验证了西达本胺单药治疗弥漫大B细胞淋巴瘤和伴有特定表观遗传调控基因突变的复发或难治性滤泡性淋巴瘤具备更加突出的效果，所述应用能够更高效的治疗B细胞淋巴瘤患者。

Description

西达本胺的应用
本申请要求于2018年11月20日提交中国专利局、申请号为201811385440.8、发明名称为“西达本胺的应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及药物技术领域，具体涉及西达本胺的应用。
背景技术
B细胞淋巴瘤主要包括弥漫大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、边缘带B细胞淋巴瘤(MZL)、套细胞淋巴瘤(MCL)等。现有利妥昔单抗(R)联合环磷酰胺(CTX)、阿霉素(ADR)、长春新碱(VCR)、强的松(Pred)的R-CHOP方案作为目前弥漫大B细胞淋巴瘤(DLBCL)的标准一线治疗方案，其并取得良好的远期生存。在现有常规免疫化疗下，仍有1/3的患者治疗无效或复发，疗效仍有提高的空间，例如改变常规化疗的组合或增加靶向药物等。高危老年DLBCL患者对于R-CHOP疗效差，CR率仅70％左右，长期生存差，疗效亟待提高。
同时，对于复发及难治患者，化疗仍是挽救治疗的主要手段。二线治疗常用的方案包括与一线方案无交叉耐药，同时对造血影响较小，不影响后续干细胞采集的方案例如DICE，ICE及GemOx方案等进行挽救治疗，但仍有相当部分患者无法得到疾病改善。文献报道，复发或难治性的B细胞淋巴瘤患者接受DICE方案再诱导的整体总有效率约为50-60％，有相当部分患者无法得到疾病改善，因此在目前复发或难治性的B细胞淋巴瘤患者，需要探寻更高疗效的解救方案。
发明内容
有鉴于此，本发明的目的在于提供西达本胺在制备用于治疗B细胞淋巴瘤的药物和/或治疗B细胞淋巴瘤中的应用。在本发明具体实施方式中，以滤泡性淋巴瘤(FL)、边缘带B细胞淋巴瘤(MALT)、淋巴浆细胞淋 巴瘤(LPL)、小淋巴细胞B细胞淋巴瘤(SLL)，弥漫大B细胞淋巴瘤(DLBCL)等多种复发或难治性B细胞淋巴瘤为具体治疗疾病进行临床试验。
西达本胺(Chidamide，爱谱沙)是我国自主研发的亚型选择性组蛋白去乙酰化酶(HDAC)抑制剂，为1.1类新药。西达本胺的首个适应症——单药治疗复发或难治性外周T细胞淋巴瘤(PTCL)，于2014年12月23日获国家食品药品监督管理总局(CFDA)上市批准，是全球首个该适应症获批上市的口服亚型选择性HDAC抑制剂。西达本胺主要针对第I类HDAC中的1、2、3亚型和第IIb类的10亚型，具有对肿瘤异常表观遗传功能的调控作用。其通过抑制相关HDAC亚型以增加染色质组蛋白的乙酰化水平来引发染色质重塑，并由此产生针对多条信号传递通路基因表达的改变(即表观遗传改变)，进而抑制肿瘤细胞周期、诱导肿瘤细胞凋亡，同时对机体细胞免疫具有整体调节活性，诱导和增强自然杀伤细胞(NK)和抗原特异性细胞毒T细胞(CTL)介导的肿瘤杀伤作用。西达本胺还通过表观遗传调控机制，具有诱导肿瘤干细胞分化、逆转肿瘤细胞的上皮间充质表型转化(EMT)等功能，进而在恢复耐药肿瘤细胞对药物的敏感性和抑制肿瘤转移、复发等方面发挥潜在作用。
西达本胺I期临床试验结果显示，西达本胺单药治疗T细胞型非霍奇金恶性淋巴瘤的有效缓解率达80％，但是入组的3例B细胞型非霍奇金淋巴瘤病人，其中1例经西达本胺治疗后疾病进展，另外2例疾病稳定但都未显示出疗效，上述结果说明西达本胺单药并不具备对于B细胞淋巴瘤的治疗有效性。
然而，本发明出乎意料地发现西达本胺单药治疗B细胞淋巴瘤有效，尤其是复发或难治性淋巴瘤，尤其是弥漫大B细胞淋巴瘤和伴有特定表观遗传调控基因突变的复发或难治性滤泡性淋巴瘤；因此，作为优选，所述B细胞淋巴瘤为伴有特定表观遗传调控基因突变的复发或难治性滤泡性淋巴瘤和/或弥漫大B细胞淋巴瘤。
同时，本发明也提供了一种制备B细胞淋巴瘤的制剂，其以西达本胺作为主要活性药物，添加其他互不影响的活性成分和/或药用辅料。所述 其他互不影响的活性成分可以是治疗B细胞淋巴瘤的活性成分，也可以是治疗其他疾病的活性成分或两者的组合。
此外，本发明还提供一种治疗B细胞淋巴瘤的方法，给予具有有效剂量的西达本胺。
由以上技术方案可知，本发明提出了对B细胞淋巴瘤具备治疗作用的给予西达本胺的治疗方案应用，并通过临床试验验证了西达本胺单药治疗弥漫大B细胞淋巴瘤和伴有特定表观遗传调控基因突变的复发或难治性滤泡性淋巴瘤具备更加突出的效果，所述应用能够更高效的治疗B细胞淋巴瘤患者。
具体实施方式
本发明公开了西达本胺的应用，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明所述应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述应用进行改动或适当变更与组合，来实现和应用本发明技术。
以下就本发明所提供的西达本胺的应用做进一步说明。
实施例1：西达本胺单药治疗复发或难治性B细胞淋巴瘤的II期临床研究
试验药物：西达本胺片：类白色片，5mg/片。由深圳微芯生物科技有限责任公司生产。
给药方案：每周给药2次，每次30mg，两次给药间隔不应少于3天(如周一和周四、周二和周五、周三和周六等)。早餐30分钟后服药，每3周为一个治疗周期。整个研究期间，所有受试者均持续接受研究治疗至出现以下任一情况：疾病进展、出现不可耐受的不良反应、死亡、退出治疗、撤回知情同意或失访。
病例数：采用Simon最佳两阶段设计，共入组72例患者，病理亚型包括：滤泡性淋巴瘤(FL)1-3级、边缘带B细胞淋巴瘤(MALT)、淋巴浆 细胞淋巴瘤(LPL)、小淋巴细胞B细胞淋巴瘤(SLL)，弥漫大B细胞淋巴瘤(DLBCL)。
入选标准：
1、根据WHO 2008诊断标准，组织病理确诊为B细胞淋巴瘤，包括弥漫大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)I-III级、边缘带B细胞淋巴瘤(MALT)、淋巴浆细胞淋巴瘤(LPL)、小淋巴细胞B细胞淋巴瘤(SLL)、套细胞淋巴瘤(MCL)、转化型淋巴瘤(TL)；
2、患者既往对含细胞毒性药物方案敏感
(注：敏感定义：疾病缓解，疗效评价为PR或CR(确认或未确认)；缓解6个月后疾病复发)；
3、DLBCL、FL3级、MALT、LPL、SLL亚型患者既往接受过至少2种化疗方案；
FL1-2级患者既往接受过至少3种化疗方案；
注：一线治疗方案需包含蒽环类的联合化疗，如CHOP；自体干细胞移植支持下大剂量化疗算为一种治疗方案；疗法定义为新的治疗组合或药物，从CVP到CHOP的变化属于新疗法，再次使用同样疗法或药物治疗时不属于新疗法；
4、至少有一处可测量病灶，最长径大于1.5cm，或短径大于1.0cm；
5、年龄18-75岁；
6、ECOG评分为0-2；
7、预计生存期≥3个月；
8、主要器官功能在治疗前7天内，符合下列标准：
(1)血常规检查标准(14天内未输血状态下)：
血红蛋白(HB)≥80g/L；
中性粒细胞绝对值(ANC)≥1.5×109/L；
血小板(PLT)≥60×109/L；
(2)生化检查需符合以下标准：
总胆红素(TBIL)≤1.5倍正常值上限(ULN)；
丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶AST≤2.5×ULN，如伴肝转移，则ALT和AST≤5×ULN
血清肌酐(Cr)≤1.5×ULN或肌酐清除率(CCr)≥60ml/min；
9、心脏多普勒超声评估：左室射血分数(LVEF)≥正常值低限(50％)；
10、育龄期男性和女性在整个研究期间及研究治疗结束后4周内同意采取可靠的避孕手段；
11、患者自愿参加本次研究，签署知情同意书。
治疗方案：
患者按照前述给药方案口服西达本胺，并按规定时间进行安全性与疗效评价。
1、安全性评价
(1)每周进行一次血常规检查
(2)每3周进行一次体格检查，记录生命体征及ECOG评分
(3)每3周进行一次血生化检查，包括：
肝功能：谷丙转氨酶(ALT)、谷草转氨酶(AST)、总胆红素(TBIL)、直接胆红素(DBIL)、谷氨酰转肽酶(GGT)、白蛋白(ALB)
肾功能：尿素氮(BUN)、肌酐(Cr)
空腹血糖
电解质：钾、钠、氯、钙、镁
乳酸脱氢酶(LDH)
每6周进行一次其它安全性检查，包括：
尿常规
12导联心电图(同时计算QTc)
2、疗效评价
疗效评价时间：每6周进行一次疗效评价。
疗效评价手段：采用与基线相同的影像学手段(颈胸/腹盆部增强CT、PET/CT，核磁共振、X胸片、腹部超声波检查等)和体检方法，进行淋巴结及器官病灶的评估。
疗效评价标准：参照国际工作组的非霍奇金淋巴瘤疗效评价标准(IWC)分别进行评定。
治疗结束后随访期
对全部受试者进行治疗结束后随访，随访时间自治疗结束后开始，持续至最后一例受试者完成研究治疗后2年。
治疗结束后第1年，每3个月进行一次随访。治疗结束后第2年， 每6个月进行一次随访。
临床试验结果：已入组10例，已评价患者8例，ORR为37.5％，获益率62.5％。
结果显示西达本胺单药治疗B细胞淋巴瘤有效。
实施例2：西达本胺片治疗伴有特定表观遗传调控基因突变的复发或难治性滤泡性淋巴瘤(FL)的多中心、单臂、开放临床试验
试验药物：西达本胺片：类白色片，5mg/片。由深圳微芯生物科技有限责任公司生产。
给药方案：每周给药2次，每次30mg，两次给药间隔不应少于3天(如周一和周四、周二和周五、周三和周六等)。早餐30分钟后服药，每3周为一个治疗周期。整个研究期间，所有受试者均持续接受研究治疗至出现以下任一情况：疾病进展、出现不可耐受的不良反应、死亡、退出治疗、撤回知情同意或失访。
病例数：本临床试验共计划入组33例患者，其中第一阶段入组10例。
入选标准：
1、根据WHO 2008诊断标准，组织病理确诊为滤泡性淋巴瘤(FL)1级，2级和3a级；
2、既往至少接受过一次系统性治疗(包括含利妥昔单抗方案、造血干细胞移植等)无缓解或缓解后复发的患者；
3、至少具有下列条件之一：受累淋巴结区≥3个，每个直径≥3cm；任何淋巴结或结外肿瘤≥7cm；存在B症状；脾大；胸腔积液或腹水；血细胞减少(白细胞<1.0×10 9/L，血小板<100×10 9/L)；白血病；
4、经二代测序检测证实具有CREBBP和/或EP300特定基因突变；
5、具有至少一处可评估病灶；
6、年龄为18-75岁之间，男、女不限；
7、ECOG体力评分0-1分；
8、中性粒细胞绝对值≥1.5×10 9/L，血小板≥80×10 9/L，血红蛋白≥90g/L；
9、预期生存时间≥3个月；
10、入组前4周内未接受过放疗、化疗、靶向治疗或造血干细胞移植等治疗；
11、自愿签署书面知情同意书。
研究步骤：
本试验包括筛选期、治疗期和随访期。
1、筛选期
在获得知情同意后，通过病史采集、体检、实验室检查、肿瘤评估进行患者筛选，筛选期采集第一次基因检测样本及检测(基线样本)；
伴有CREBBP和/或EP300突变的患者经过筛选合格后进入试验。
2、治疗期
患者按照方案口服西达本胺，并按规定时间进行下列安全性、疗效随访：
(1)安全性随访
①每周进行一次血常规检查；
②每6周进行一次体格检查，记录生命体征及ECOG评分；
③每6周进行一次血生化检查，包括：
肝功能：谷丙转氨酶(ALT)、谷草转氨酶(AST)、总胆红素(TBIL)、直接胆红素(DBIL)、谷氨酰转肽酶(GGT)、白蛋白(ALB)
肾功能：尿素氮(BUN)、肌酐(CR)
空腹血糖；
电解质：钾、钠、氯、钙、镁
乳酸脱氢酶(LDH)
④每6周进行一次其它安全性检查，包括：
尿常规
12导联心电图(同时计算QTc)
(2)疗效随访
随访间隔：每6周进行一次疗效评估；治疗结束时进行一次疗效随访。
疗效评价手段：通过影像学(CT或PET/CT)、临床体检、骨髓穿刺和活检等方式，进行淋巴结及器官病灶、皮肤病灶等评估。患者在所有随访点采用的影像学手段必须相同。
疗效评价标准：进行CT扫描者，按照1999年国际工作组的非霍奇金淋巴瘤疗效评价标准(IWG)进行评定；进行PET/CT扫描者，按照2007年国际协调计划修正后的指南标准(附录1)。
基因检测样本采集：如治疗期间疗效评价为疾病进展(PD)，则进行第二次基因检测样本采集及检测(PD样本)。收集患者PD时采集的残留肿大病灶或FDG摄取高代谢部位重复活检标本。
2、随访期
对全部受试者进行治疗结束后随访，随访时间自治疗结束后开始，共持续2年，至受试者肿瘤进展或死亡。可以是电话随访。
治疗结束后第1年，每3个月进行一次随访。治疗结束后第2年，每6个月进行一次随访。
疗效指标：
(1)主要疗效指标
客观缓解率(ORR)，包括完全缓解(CR)、未确认的完全缓解(CRu)以及部分缓解(PR)例数及比例
(2)次要疗效指标
疾病控制率(DCR)，包括完全缓解(CR)、未确认的完全缓解(CRu)、部分缓解(PR)以及稳定(SD)例数及比例；
无进展生存期(PFS)；
总生存期(OS)；
疗效与特定突变的相关性分析；
临床实验结果：预试验观察伴表观突变B-NHL患者共11例，ORR为72.7％，CR率36.3％。
结果显示西达本胺治疗伴有特定表观遗传调控基因突变的复发或难治性滤泡性淋巴瘤(FL)的效果更好。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (6)

  1. 西达本胺在制备用于治疗B细胞淋巴瘤的药物和/或治疗B细胞淋巴瘤中的应用。
  2. 根据权利要求1所述应用，其特征在于，所述B细胞淋巴瘤为复发或难治性B细胞淋巴瘤。
  3. 根据权利要求1或2所述应用，其特征在于，所述B细胞淋巴瘤为弥漫大B细胞淋巴瘤。
  4. 根据权利要求1或2所述应用，其特征在于，所述B细胞淋巴瘤为伴有特定表观遗传调控基因突变的复发或难治性滤泡性淋巴瘤。
  5. 一种治疗B细胞淋巴瘤的制剂，其特征在于，以西达本胺为主要活性成分，添加其他互不影响的活性成分和/或制剂辅料。
  6. 一种治疗B细胞淋巴瘤的方法，其特征在于，给予具有有效剂量的西达本胺。
PCT/CN2019/119094 2018-11-20 2019-11-18 西达本胺的应用 WO2020103778A1 (zh)

Priority Applications (9)

Application Number Priority Date Filing Date Title
KR1020217018969A KR20210133207A (ko) 2018-11-20 2019-11-18 치다마이드의 응용
EP19887759.9A EP3884944A4 (en) 2018-11-20 2019-11-18 USE OF CHIDAMID
US17/295,490 US20220000848A1 (en) 2018-11-20 2019-11-18 Application of chidamide
JP2021527821A JP7489384B2 (ja) 2018-11-20 2019-11-18 シダミドの適用
AU2019385370A AU2019385370A1 (en) 2018-11-20 2019-11-18 Application of chidamide
CA3120206A CA3120206A1 (en) 2018-11-20 2019-11-18 Application of chidamide
BR112021009608-6A BR112021009608A2 (pt) 2018-11-20 2019-11-18 aplicação de chidamida
SG11202105136WA SG11202105136WA (en) 2018-11-20 2019-11-18 Application of chidamide
PH12021551137A PH12021551137A1 (en) 2018-11-20 2021-05-19 Application of chidamide

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811385440.8 2018-11-20
CN201811385440 2018-11-20

Publications (1)

Publication Number Publication Date
WO2020103778A1 true WO2020103778A1 (zh) 2020-05-28

Family

ID=70741812

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/119094 WO2020103778A1 (zh) 2018-11-20 2019-11-18 西达本胺的应用

Country Status (12)

Country Link
US (1) US20220000848A1 (zh)
EP (1) EP3884944A4 (zh)
JP (1) JP7489384B2 (zh)
KR (1) KR20210133207A (zh)
CN (1) CN111195251A (zh)
AU (1) AU2019385370A1 (zh)
BR (1) BR112021009608A2 (zh)
CA (1) CA3120206A1 (zh)
PH (1) PH12021551137A1 (zh)
SG (1) SG11202105136WA (zh)
TW (1) TWI781356B (zh)
WO (1) WO2020103778A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4201426A1 (en) * 2021-12-23 2023-06-28 Fundació Institut de Recerca Contra la Leucèmia Josep Carreras Pharmaceutical compositions for inducing hdac7 expression

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018017858A1 (en) * 2016-07-20 2018-01-25 The Trustees Of Columbia University In The City Of New York Histone acetyltransferase activators and compositions and uses thereof
CN109371128A (zh) * 2018-10-22 2019-02-22 广东省人民医院(广东省医学科学院) 一种用于检测crebbp基因突变位点的引物及试剂盒和应用

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103833626B (zh) * 2012-11-27 2015-11-25 深圳微芯生物科技有限责任公司 西达本胺的晶型及其制备方法与应用
CN104771363A (zh) * 2014-01-14 2015-07-15 深圳微芯生物科技有限责任公司 一种西达本胺固体分散体及其制备方法与应用
CN104083763A (zh) * 2014-07-16 2014-10-08 中国人民解放军军事医学科学院野战输血研究所 组蛋白去乙酰化酶抑制剂在制备潜伏病毒激活剂中的应用
TWI794171B (zh) * 2016-05-11 2023-03-01 美商滬亞生物國際有限公司 Ｈｄａｃ抑制劑與ｐｄ-ｌ１抑制劑之組合治療

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018017858A1 (en) * 2016-07-20 2018-01-25 The Trustees Of Columbia University In The City Of New York Histone acetyltransferase activators and compositions and uses thereof
CN109371128A (zh) * 2018-10-22 2019-02-22 广东省人民医院(广东省医学科学院) 一种用于检测crebbp基因突变位点的引物及试剂盒和应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEN, JUAN ET AL.: "Research Progress of Chidamide in Treatment of Tumor Diseases", INTERNATIONAL JOURNAL OF BLOOD TRANSFUSION AND HEMATOLOGY, vol. 41, no. 1, 24 May 2018 (2018-05-24), pages 60 - 64, XP009529331, ISSN: 1673-419X, DOI: 10.3760/cma.j.issn.1673-419X.2018.01.011 *
See also references of EP3884944A4
ZHANG, PEIPEI: "Mechanisms of Chidamide in Diffuse Large B-Cell Lymphoma Cell Lines with Distinctive Proliferative Characteristics", CHINA MASTER’S THESES FULL-TEXT DATABASE, no. 2, 15 February 2017 (2017-02-15), pages 1 - 66, XP055817958 *

Also Published As

Publication number Publication date
JP2022509100A (ja) 2022-01-20
SG11202105136WA (en) 2021-06-29
TWI781356B (zh) 2022-10-21
KR20210133207A (ko) 2021-11-05
US20220000848A1 (en) 2022-01-06
TW202031258A (zh) 2020-09-01
AU2019385370A1 (en) 2021-06-24
EP3884944A4 (en) 2022-08-31
CA3120206A1 (en) 2020-05-28
CN111195251A (zh) 2020-05-26
JP7489384B2 (ja) 2024-05-23
PH12021551137A1 (en) 2022-02-21
BR112021009608A2 (pt) 2021-08-10
EP3884944A1 (en) 2021-09-29

Similar Documents

Publication Publication Date Title
Maiti et al. Venetoclax and BCR-ABL tyrosine kinase inhibitor combinations: outcome in patients with philadelphia chromosome-positive advanced myeloid leukemias
Cohen et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis
Arico Langerhans cell histiocytosis in adults: more questions than answers?
JP2020152734A (ja) ヒトにおける固形腫瘍の処置のためのＣ．ｎｏｖｙｉ
JP2016516080A (ja) 骨髄性白血病の処置方法
DeAngelo et al. Safety and efficacy of oral panobinostat plus chemotherapy in patients aged 65 years or younger with high-risk acute myeloid leukemia
Eyre et al. Idelalisib-Rituximab induces clinical remissions in patients with TP53 disrupted B cell prolymphocytic leukaemia.
Chai et al. First-line chemoradiation with or without chidamide (tucidinostat) in patients with intermediate-and high-risk early-stage extranodal nasal-type natural killer/T-cell lymphoma: A randomized phase 2 study in China
TWI781356B (zh) 西達本胺的應用
Yen et al. Uterine sarcoma part III—Targeted therapy: The Taiwan Association of Gynecology (TAG) systematic review
TW202034955A (zh) 使用免疫調節治療癌症之新穎方法
CN117797149A (zh) 西达本胺联合r-chop的应用及联合药物
CN111195250A (zh) 西达本胺联合dice的应用及联合药物
Kontrimiene et al. Cutaneous Rosai-Dorfman disease: a case report of disease limited only to skin
TWI702949B (zh) 用於治療白血病的聯合用藥物及其在製備用於治療急性髓性白血病的藥物中的用途
Molin et al. Arsenic trioxide affects the trace element balance in tissues in infected and healthy mice differently
Ung et al. AML-080 Superior Anti-Leukemic Effects of Combined Acid Ceramidase and Bcl-2 Inhibition in Acute Myeloid Leukemia
JP7174370B2 (ja) 予後改善剤
Roberts et al. Five years follow-up of patients with non-melanoma skin cancer treated with HeberFERON
Basu et al. Filarial huge splenomegaly dramatically regressed by anti-filarial medication: A rare clinical scenario
Ryu Tiger et al. Phase II study of the novel antifolate agent pralatrexate in combination with the histone deacetylase inhibitor romidepsin for the treatment of patients with mature T-cell lymphoma
Kuznar Universal CAR T-Cells a Promising Off-the-Shelf Therapy for T-Cell ALL.
FILIZ et al. Metastatic uveal melanoma complete response with nivolumab: A case report
Parovichnikova et al. Development of program therapy for patients with acute myeloid leukemia under the age of 60 years, based on the principles of differentiated effects
Sheldon Arsenic: It’s Not Just for Rats. The Benefits of Arsenic Trioxide for the Treatment of Acute Promyelocytic Leukemia

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19887759

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3120206

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2021527821

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112021009608

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 2019385370

Country of ref document: AU

Date of ref document: 20191118

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2019887759

Country of ref document: EP

Effective date: 20210621

ENP Entry into the national phase

Ref document number: 112021009608

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20210518