CN117797149A - 西达本胺联合r-chop的应用及联合药物 - Google Patents
西达本胺联合r-chop的应用及联合药物 Download PDFInfo
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- CN117797149A CN117797149A CN202311474046.2A CN202311474046A CN117797149A CN 117797149 A CN117797149 A CN 117797149A CN 202311474046 A CN202311474046 A CN 202311474046A CN 117797149 A CN117797149 A CN 117797149A
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Abstract
本发明涉及药物技术领域，公开了西达本胺联合R‑CHOP的应用及联合药物。本发明提出了对B细胞淋巴瘤具备协同治疗作用的西达本胺联合R‑CHOP的治疗方案应用，并通过临床试验验证了西达本胺联合R‑CHOP方案治疗弥漫大B细胞淋巴瘤相比于R‑CHOP方案效果更优，所述应用能够更高效的治疗B细胞淋巴瘤患者。
Description
本申请是申请日为2019年3月25日，申请号为CN201910228406.8，发明名称为“西达本胺联合R-CHOP的应用及联合药物”的中国发明专利申请的分案申请。
技术领域
本发明涉及药物技术领域，具体涉及西达本胺联合R-CHOP的应用及联合药物。
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。弥漫性大B细胞淋巴瘤(DLBCL)是非霍奇金淋巴瘤(NHL)中最常见的类型，在欧美地区占成人NHL的31～34％，在亚洲国家一般＞40％。DLBCL临床病程呈侵袭性，约50％的患者初诊时为III-IV期。国内外临床诊疗指南和共识均推荐利妥昔单抗、环磷酰胺、阿霉素、长春新碱和强的松(R-CHOP)方案作为标准一线治疗方案。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。
MYC/BCL2双表达(DEL)弥漫大B细胞淋巴瘤，其特征为MYC/BCL2同时过表达且不伴有MYC/BCL2/BCL6基因中任两个的重排。DEL临床检出率达32～36％。因DEL具有独特的临床特征，所以在2016年WHO淋巴瘤分类中被作为新的预后因素单独列出。患者往往具备一些预后差的临床病理特征，包括年龄大、高的肿瘤分期、多个部位受累、高国际预后指数(IPI)、高增殖指数等。常规治疗方案对DEL的治疗效果差。研究显示，经过R-CHOP方案治疗后，DEL患者的完全缓解率(CR)率明显低于非DEL患者(66％vs.84％，p<0.001)，并且DEL患者总生存期(OS)和无进展生存期(PFS)均较非DEL患者显著缩短(5年OS率：36％vs.71％,p<0.05；5年PFS率：32％vs.65％,p<0.05)，因此，在R-CHOP标准一线方案的基础上，探索DLBCL中DEL患者人群有效且相对安全的新型药物组合，是临床上一个尚未满足的需求。
发明内容
有鉴于此，本发明的目的在于提供西达本胺联合R-CHOP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。其中，R-CHOP指本领域中R-CHOP联合用药方案，即利妥昔单抗(R)联合环磷酰胺(CTX)、阿霉素或表阿霉素(ADR/EPI)、长春新碱(VCR)、强的松(Pred)的联合药物方案；在本发明具体实施方式中，以弥漫大B细胞淋巴瘤为具体治疗疾病进行临床试验，同时针对具体亚型MYC/BCL2双表达(DEL)弥漫大B细胞淋巴瘤进行临床试验。
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联合R-CHOP在治疗弥漫大B细胞淋巴瘤中具有协同作用，特别是对初治、高危、老年DLBCL患者有较佳的效果；采用本发明联合用药策略后中期评估，共31例可评估患者，CR率90.3％，PR率为6.5％。末期评估，共23例可评估患者，CR率87％，ORR为100％。本临床试验结果显示R-CHOP联合西达本胺治疗初治、老年、高危弥漫大B细胞淋巴瘤相比于R-CHOP方案具有显著的疗效提高。
同时，本发明也发现西达本胺联合R-CHOP在治疗MYC/BCL2双表达弥漫大B细胞淋巴瘤中具有协同作用，有较佳的效果；采用本发明联合用药策略后，在可评估的MYC/BCL2双表达弥漫大B细胞淋巴瘤患者中，CR率为100％，1年PFS82.8％，1年OS100％；同时，在R-CHOP联合西达本胺治疗初治、MYC/BCL2双表达弥漫大B细胞淋巴瘤的临床观察中，在可评估的MYC/BCL2双表达弥漫大B细胞淋巴瘤患者中，CR率为86％。本临床试验结果显示R-CHOP联合西达本胺治疗MYC/BCL2双表达弥漫大B细胞淋巴瘤相比于R-CHOP方案具有显著的疗效提高。
基于此技术效果，本发明根据所提出的应用，具体提供了一种联合药物，其包含用于同时、分别或依次给药的具有有效剂量的西达本胺、利妥昔单抗、环磷酰胺、阿霉素或表阿霉素、长春新碱和强的松。
同时，本发明也提供了一种制备B细胞淋巴瘤的制剂，其以上述联合药物作为主要活性药物，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，同时、分别或依次给予具有有效剂量的西达本胺、利妥昔单抗、环磷酰胺、阿霉素或表阿霉素、长春新碱和强的松。
由以上技术方案可知，本发明提出了对B细胞淋巴瘤具备协同治疗作用的西达本胺联合R-CHOP的治疗方案应用，并通过临床试验验证了西达本胺联合R-CHOP方案治疗弥漫大B细胞淋巴瘤相比于R-CHOP方案效果更优，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联合R-CHOP的应用及联合药物，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联合R-CHOP的应用及联合药物做进一步说明。
实施例1：西达本胺联合R-CHOP方案治疗治疗初治、老年、高危弥漫大B细胞淋巴瘤的前瞻性、单臂、开放II期研究
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。R-CHOP联合化疗药物：利妥昔单抗(R)联合环磷酰胺(CTX)、阿霉素或表阿霉素(ADR/EPI)、长春新碱(VCR)、强的松(Pred)。
病例数：本临床试验共计划入组49例患者。
入选标准：患者须满足下列全部标准才能入组。
1、组织学病理学确诊为弥漫大B细胞淋巴瘤，且CD20阳性；
2、年龄≧61岁，≦75岁；
3、ECOG体力状态评分为0、1或2分；
4、既往无恶性肿瘤病史；无同时发生其他肿瘤；
5、研究者判断预期寿命至少有6个月的患者；
6、患者或其法定代理人必须在进行任何研究特殊检查或程序前提供书面知情同意。
7、国际预后指数(IPI)>1分。
治疗方案：
1、研究药物名称和剂量，患者采用以下表格中的给药方式：
表1
受试者先后接受6个疗程R-CHOP方案联合西达本胺治疗，每21天一次。受试者将在治疗完成后继续接受评估(患者将进入时间和事件表中描述的随访期)，直至规定的随访期结束(总研究持续时间为3年)或直至患者符合退出标准。
继续治疗的必要条件，如果符合以下情况，下一个疗程将按计划进行：
(1)经历骨髓相抑制后，中性粒和血小板计数处于上升阶段；
(2)下一疗程的第1天血中性粒≧1.0×109/L,WBC≧3.0×109/L；
(3)下一疗程的第1天血小板计数≧75×109/L；
如果未达到，下一疗程应延迟3-4天，同时重复血细胞检查。如果仍未达到上述指标，治疗将再延迟3-4天，直至达到上述可化疗标准。如果延迟治疗超过14天仍不达到标准，患者将退出治疗并记录为不良事件。根据方案要求将继续随访该患者。
细胞毒性药物的减量标准：
出现2级以上神经毒性，VCR减为1mg，
(2)在中性粒或血小板计数不足时，考虑化疗药物的减量。可以参照以下标准执行：
①下一疗程延迟时间在0-7天内：维持原有剂量
②下一疗程延迟时间在8-14天内或上一疗程出现4级骨髓抑制，剂量调整为：
CTX 75％
EPI 75％
VCR 100％
Pred 100％
西达本胺 100％
西达本胺：若病情未进展或未出现不能耐受的不良反应，建议持续服药。整个治疗过程中，若出现3-4级骨髓抑制，暂停用药，待中性粒细胞绝对值恢复至≥1.5×109/L，血小板恢复至≥75.0×109/L可继续本品治疗。
3、合并用药及治疗：
首程化疗肿瘤负荷较大(巨大肿块或乳酸脱氢酶大于等于500u/L)或PS等于2或胃肠道NHL(预防胃肠道穿孔)的患者，给予别嘌呤醇、小苏打，先口服强的松，必要时化疗分2天执行，以预防肿瘤溶解综合征。
粒细胞击落刺激因子(G-CSF)：治疗医师根据临床提示判断认为有必要，才能使用。G-CSF的应用要记录在CRF表中。
由于不良事件而给予的伴随性治疗，如果符合报告标准，也需要予以报告，该内容应填写在CRF表的不良事件页。必要时可给予患者足够的支持性治疗，包括输注全血和血制品，抗生素治疗，止吐治疗等治疗的原因，剂量和治疗的日期也应该记录在CRF表中。
对于大包块的患者，由研究者决定是否需要放疗。
临床试验结果：该研究共纳入49例弥漫大B细胞淋巴瘤患者，中期评估，共31例可评估患者，CR率90.3％，PR率为6.5％。末期评估，共23例可评估患者，CR率87％，ORR为100％。
本临床试验结果显示R-CHOP联合西达本胺治疗初治、老年、高危弥漫大B细胞淋巴瘤相比于R-CHOP方案具有显著的疗效提高。
此外，49例弥漫大B细胞淋巴瘤患者中10例为MYC/BCL2双表达弥漫大B细胞淋巴瘤患者。这10例MYC/BCL2双表达弥漫大B细胞淋巴瘤患者的疗效为CR率为100％，1年PFS82.8％，1年OS100％。
本临床试验结果显示R-CHOP联合西达本胺治疗初治、老年、MYC/BCL2双表达弥漫大B细胞淋巴瘤相比于R-CHOP方案具有显著的疗效提高。
实施例2：R-CHOP联合西达本胺治疗初治、MYC/BCL2双表达弥漫大B细胞淋巴瘤的临床观察
试验药物：西达本胺片：类白色片，5mg/片。由深圳微芯生物科技股份有限公司生产。R-CHOP联合化疗药物：利妥昔单抗(R)联合环磷酰胺(CTX)、阿霉素(ADM)、长春新碱(VCR)、强的松(Pred)。
治疗方案：
研究药物名称和剂量，本研究为单组试验，患者采用表2给药方式：
表2
| 药品名称 | 剂量 | 给药方法 | 用药时间 |
| R | 375mg/m2 | 静脉推注 | 第0天 |
| CTX | 750mg/m2 | 静脉推注 | 第1天 |
| ADM | 50mg/m2 | 静脉推注 | 第1天 |
| VCR | 1.4mg/m2 | 静脉推注 | 第1天 |
| Pred | 60mg/m2 | 口服 | 第1－5天 |
| 西达本胺 | 20mg/d | 口服 | 第1、4、8、11天 |
| 重复时间 | 第21天 |
受试者先后接受6个疗程R-CHOP方案联合西达本胺治疗，每21天一次。
临床观察结果：共观察29例可评估的MYC/BCL2双表达弥漫大B细胞淋巴瘤患者，CR率为86％。
本临床试验结果显示R-CHOP联合西达本胺治疗初治、MYC/BCL2双表达弥漫大B细胞淋巴瘤相比于R-CHOP方案具有显著的疗效提高。
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.西达本胺联合R-CHOP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细胞淋巴瘤为弥漫大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，所述弥漫大B细胞淋巴瘤为MYC/BCL2双表达弥漫大B细胞淋巴瘤。
4.一种联合药物，其特征在于，包含用于同时、分别或依次给药的具有有效剂量的西达本胺、利妥昔单抗、环磷酰胺、阿霉素或表阿霉素、长春新碱和强的松。
5.一种治疗B细胞淋巴瘤的制剂，其特征在于，以权利要求4所述联合药物为主要活性成分，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，同时、分别或依次给予具有有效剂量的西达本胺、利妥昔单抗、环磷酰胺、阿霉素或表阿霉素、长春新碱和强的松。
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- 2019-03-25 CN CN202311474046.2A patent/CN117797149A/zh active Pending
- 2019-11-18 KR KR1020217018968A patent/KR20210104059A/ko active Search and Examination
- 2019-11-18 CA CA3120207A patent/CA3120207A1/en active Pending
- 2019-11-18 JP JP2021551329A patent/JP7489397B2/ja active Active
- 2019-11-18 EP EP19887480.2A patent/EP3884943A4/en active Pending
- 2019-11-18 BR BR112021009627-2A patent/BR112021009627A2/pt unknown
- 2019-11-18 TW TW108141826A patent/TWI768263B/zh active
- 2019-11-18 WO PCT/CN2019/119170 patent/WO2020103788A1/zh active Application Filing
- 2019-11-18 AU AU2019385373A patent/AU2019385373A1/en active Pending
- 2019-11-18 US US17/295,494 patent/US20220016147A1/en active Pending
- 2019-11-18 SG SG11202105137RA patent/SG11202105137RA/en unknown
-
2021
- 2021-05-19 PH PH12021551138A patent/PH12021551138A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP3884943A4 (en) | 2022-07-06 |
| SG11202105137RA (en) | 2021-06-29 |
| AU2019385373A1 (en) | 2021-06-24 |
| TWI768263B (zh) | 2022-06-21 |
| PH12021551138A1 (en) | 2022-02-21 |
| US20220016147A1 (en) | 2022-01-20 |
| CN111195249A (zh) | 2020-05-26 |
| JP7489397B2 (ja) | 2024-05-23 |
| JP2022511126A (ja) | 2022-01-28 |
| CA3120207A1 (en) | 2020-05-28 |
| WO2020103788A1 (zh) | 2020-05-28 |
| KR20210104059A (ko) | 2021-08-24 |
| EP3884943A1 (en) | 2021-09-29 |
| BR112021009627A2 (pt) | 2021-08-10 |
| TW202033194A (zh) | 2020-09-16 |
| CN111195249B (zh) | 2023-11-28 |
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