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抗肿瘤药联合用药的早期临床方案设计思路及主要问题｜2019DDI

2019-10-30 MedSci MedSci原创

抗肿瘤药联合疗法早期临床方案设计思路
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2019年第五届药物研发创新大会于2019年10月23-25日在上海顺利召开。

2019年第五届药物研发创新大会于2019年10月23-25日在上海顺利召开。本次会议汇聚诸多药物研发科学家、法规事务人员、临床研发人员和投资者，共商解决临床问题的药物研发模式，聚焦真正有影响力的新药。


会议期间，天士力控股集团有限公司副总裁，上海交通大学医学院教授，原美国FDA专家主审官孙鹤博士以抗肿瘤药联合用药的早期临床方案设计思路及主要问题为题发表精彩讲话。

抗肿瘤药创新是研究热门领域，为了追求更大的临床获益，联合疗法逐渐成为研究热门方向。

为什么要做联合药物？

靶点不同，毒副作用会减小
协同、累积作用，因此剂量更小
可能可以保护正常细胞，同时对癌细胞产生细胞毒性作用。
......

联合用药有何研究思路？

孙博士举了个例子，caspase抑制剂如Z-DEVD-fmk与诱导凋亡剂的联合疗法。具体来说，表达p-糖蛋白的Z-DEVD-FMK耐药癌细胞将泵出Z-DEVD-FMK，大多数正常细胞不表达p-糖蛋白，因此它们会直接受到Z-DEVD-FMK的影响。该方法可显著提高肿瘤治疗指数，产生更强的细胞毒性作用。

此外，持续单药治疗会诱导癌细胞产生耐药，比如，在阿奇霉素治疗下，腺癌细胞会上调一种ATP依赖泵来消除药物，导致耐药。而联合用药能在更短的周期产生更有效的治疗作用，所以减少了耐药的发生率，这也是一种联合思路。

第三个思路，由于非选择性治疗途径，化疗本质上不会消除肿瘤干细胞CSCs。然而包含了靶向CSCs药物的联合疗法能减少药物耐药和复发概率。

在中国，可以研究中药联合抗癌药能增加疗效，比如五味子能够提高抗癌药药物活性甚至逆转耐药性，因为五味子能延长药物的半衰期。如果中药能够在某个剂量的联合下，使药物半衰期变长，抗癌药在血液中维持高于癌细胞抑制浓度的时间就能延长。这也是很有价值的研究思路。
孙博士强调，抗癌联合治疗有各种各样的类型，从各种角度可能都能做到联合。

临床上还有何挑战？

孙博士表示，主要的临床挑战在于做临床联合用药研究时，如何做临床中期分析和疗效评估。比如能不能做中期试验分析，观察点能不能提高，能不能改变，是否可以用Bio-marker或治疗指标来替代生存率。这些都会带来新的挑战，也会带来新的机会。

更好的动物模型和验证临床前试验
更好的剂量和治疗来避免毒性同时保证疗效
更好的基准、终点和临床试验设计
考虑研究哪种联合疗法
选择最可能对联合疗法有反应的病人
更多关于癌症分子机制与相互影响作用的基础研究
优化试验联合疗法的临床前研究
基于基础知识
改善联合疗法的临床试验

Prioritizing Combinations

使用更严格的临床前基准疗效，如肿瘤缩小，并在多个动物模型中显示一致的效果
显示足够的药物动力学和临床相关剂量的靶活性证据
进行高通量的药物联合体外筛选，以检测协同作用
对每个级别的最佳药物进行优先排序
使用遗传分析和生物标志物
研究联合用药，优化已批准药物的效益

改善联合疗法的方法

另外孙博士还提到了设计上的一些问题。比如怎么选择病人、适应性试验设计、重复的肿瘤活检、确定适当的剂量、适当的终点等。

通过化验分析选择更好的反应患者
在试验过程中使用适应性实验设计来确定最佳的联合剂量以及患者选择的生物标志物
使用适合的终点并为疗效设置更高的标准
多中心研究设立单一机构审查委员会
对患者的肿瘤进行重复活检以评估疗效
在有限数量的患者中进行联合用药测试

在联合疗法的试验设计上，孙博士提到了四种不同设计，包括篮式试验、伞式试验、普通对照试验和适应性试验，其各有优缺点。

篮式试验有助于将罕见基因突变的患者于靶向基因疗法相匹配，它能同时比较几种药物的疗效。但是试验会随着臂的增加而变得复杂，并且不同肿瘤类型的突变影响可以忽略不计。

伞式试验研究单一癌症类型的多药研究，并根据特定的分子畸变对患者进行最适合的治疗。与篮式实验相同，基因型状态的测试不能解释肿瘤随时间的变化，且随着臂的增加，试验复杂性增加。

对照试验通过将多个臂与单一对照组进行比较来减少复杂性。优点是速度快，但是难以确定合适的对照组。

适应性试验通过在试验开始前批准修改协议来加速进程，而实时分析提供了适应试验和对意外事件作出相应的灵活性。但是，试验早期不确定数据可能导致错误结论，频繁的中期分析也会影响试验完整性。

孙鹤博士以其丰富的经验和知识为参会人员讲解了抗肿瘤药联合用药的早期临床方案设计的不同思路以及研究过程中的一些主要问题，可以说给相关行业人员带来了新的启发和灵感。

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    2019-12-08 whmdzju

    #方案设计#

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    2019-11-01 ms4964546379600229

    #联合用药#

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    2019-11-01 zhu_jun9843

    #抗肿瘤药#

    0

  5. [GetPortalCommentsPageByObjectIdResponse(id=2016231, encodeId=4dc520162315c, content=<a href='/topic/show?id=5fc458e751c' target=_blank style='color:#2F92EE;'>#方案设计#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=57, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=58775, encryptionId=5fc458e751c, topicName=方案设计)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=3860283, createdName=whmdzju, createdTime=Sun Dec 08 15:46:00 CST 2019, time=2019-12-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1514299, encodeId=bd771514299ba, content=<a href='/topic/show?id=9d7c80e14b3' target=_blank style='color:#2F92EE;'>#联合用药#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=76, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=80714, encryptionId=9d7c80e14b3, topicName=联合用药)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=36f510649899, createdName=ms4964546379600229, createdTime=Fri Nov 01 08:46:00 CST 2019, time=2019-11-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1537730, encodeId=3aca153e730fd, content=<a href='/topic/show?id=1f9983082fa' target=_blank style='color:#2F92EE;'>#肿瘤药#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=50, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=83082, encryptionId=1f9983082fa, topicName=肿瘤药)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=ed1012894470, createdName=30397608, createdTime=Fri Nov 01 08:46:00 CST 2019, time=2019-11-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1593708, encodeId=8c2f1593e08a8, content=<a href='/topic/show?id=ff895565586' target=_blank style='color:#2F92EE;'>#抗肿瘤药#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=68, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=55655, encryptionId=ff895565586, topicName=抗肿瘤药)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=aa5e18156549, createdName=zhu_jun9843, createdTime=Fri Nov 01 08:46:00 CST 2019, time=2019-11-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=374604, encodeId=d0e83e46044e, content=学习了谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=93, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20160304/IMG56D94856B1B5D6405.jpg, createdBy=27931687771, createdName=一个字-牛, createdTime=Wed Oct 30 19:53:43 CST 2019, time=2019-10-30, status=1, ipAttribution=)]
    2019-10-30 一个字-牛

    学习了谢谢分享

    0

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