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Clin Cancer Res：Zotiraciclib联合替莫唑胺治疗复发性高级别星形细胞瘤

2021-06-13 Nebula MedSci原创

替莫唑胺Zotiraciclib高级别星形细胞瘤
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Zotiraciclib联合替莫唑胺治疗复发性高级别星形细胞瘤的安全性良好。Zotiraciclib引发的中性粒细胞减少症可能很严重，但大多是短暂的，需要密切监测而不是停止治疗。

脑肿瘤的治疗具有挑战性，主要是由于其生物学特征，包括高度异质性和复杂的耐药机制。只有一小部分通过临床试验研究的药物成为既定疗法，强调了临床前研究的重要性，可以研究有前途的候选药物，从而增加成功药物研发的机会。

本研究旨在探索Zotiraciclib联合替莫唑胺用于复发性高级别星形细胞瘤的毒性特征并明确最佳的给药方案。

这是一项两阶段的I期试验，采用贝叶斯最优区间设计以明确Zotiraciclib与剂量密集型 (Arm1) 或节拍型 (Arm2) 替莫唑胺组合的最大耐受剂量（MTD）；然后在随机扩展队列中比较了两组在4个月时的无进展生存率（PFS4）。

每位患者治疗期间ANC的变化（A）和Zotiraciclib的浓度变化（B）

共招募了53位患者，剂量限制性毒性有中性粒细胞减少症、腹泻、肝酶升高和疲劳。在两个治疗臂中，Zotiraciclib的MTD都是250 mg，因此被选用于扩展队列。与节拍型替莫唑胺联合Zotiraciclib治疗相比，剂量密集型替莫唑胺联合Zotiraciclib治疗的患者的4个月无进展生存率更高 (40% vs 25%)。

CYP1A2(rs2470890) 多态性与Zotiraciclib的AUCinf值的相关性

在两个治疗臂中，症状负担均在第二疗程时恶化，又在第四疗程时重获稳定。口服Zotiraciclib后12-24小时，中性粒细胞绝对计数和中性粒细胞活性氧产生显著减少，但均在72小时后恢复。药代动力学/药物基因组学分析表明，CYP1A2_5347 T>C(rs2470890) 多态性与AUCinf值更高相关。

综上所述，Zotiraciclib联合替莫唑胺治疗复发性高级别星形细胞瘤的安全性良好。Zotiraciclib引发的中性粒细胞减少症可能很严重，但大多是短暂的，需要密切监测而不是停止治疗。一旦得到验证，预测药物代谢的多态性可能允许个体化Zotiraciclib给药方案。

原始出处：

Jing Wu, et al. Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas. Clin Cancer Res. June 15 2021 27 (12) 3298-3306; DOI:10.1158/1078-0432.CCR-20-4730

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    2021-12-24 hb2008ye

    #复发性#

    0

  2. [GetPortalCommentsPageByObjectIdResponse(id=1909900, encodeId=4a4c190990095, content=<a href='/topic/show?id=8f1f42518d8' target=_blank style='color:#2F92EE;'>#复发性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=40, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=42518, encryptionId=8f1f42518d8, topicName=复发性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4c37265, createdName=hb2008ye, createdTime=Fri Dec 24 13:37:32 CST 2021, time=2021-12-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=973998, encodeId=54b99e399832, content=<a href='/topic/show?id=c70a5968472' target=_blank style='color:#2F92EE;'>#星形细胞瘤#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=76, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=59684, encryptionId=c70a5968472, topicName=星形细胞瘤)], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20211210/ede9c51184aa4f54ae6c1164cfb8eeac/967dbf3eff2943c7bf3ccfec3a776ab0.JPG, createdBy=a33789389, createdName=病毒猎手, createdTime=Wed Jun 16 08:41:50 CST 2021, time=2021-06-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1476134, encodeId=05f014e613466, content=<a href='/topic/show?id=2bcee797732' target=_blank style='color:#2F92EE;'>#细胞瘤#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77977, encryptionId=2bcee797732, topicName=细胞瘤)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=bf5e7252474, createdName=spoonycyy, createdTime=Tue Jun 15 12:37:32 CST 2021, time=2021-06-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=973392, encodeId=09d19e33923d, content=已读，这真是受益匪浅呀！, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f03a5433387, createdName=ms5000000518166734, createdTime=Mon Jun 14 07:59:16 CST 2021, time=2021-06-14, status=1, ipAttribution=)]
    2021-06-16 病毒猎手

    #星形细胞瘤#

    0

  3. [GetPortalCommentsPageByObjectIdResponse(id=1909900, encodeId=4a4c190990095, content=<a href='/topic/show?id=8f1f42518d8' target=_blank style='color:#2F92EE;'>#复发性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=40, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=42518, encryptionId=8f1f42518d8, topicName=复发性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4c37265, createdName=hb2008ye, createdTime=Fri Dec 24 13:37:32 CST 2021, time=2021-12-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=973998, encodeId=54b99e399832, content=<a href='/topic/show?id=c70a5968472' target=_blank style='color:#2F92EE;'>#星形细胞瘤#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=76, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=59684, encryptionId=c70a5968472, topicName=星形细胞瘤)], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20211210/ede9c51184aa4f54ae6c1164cfb8eeac/967dbf3eff2943c7bf3ccfec3a776ab0.JPG, createdBy=a33789389, createdName=病毒猎手, createdTime=Wed Jun 16 08:41:50 CST 2021, time=2021-06-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1476134, encodeId=05f014e613466, content=<a href='/topic/show?id=2bcee797732' target=_blank style='color:#2F92EE;'>#细胞瘤#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77977, encryptionId=2bcee797732, topicName=细胞瘤)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=bf5e7252474, createdName=spoonycyy, createdTime=Tue Jun 15 12:37:32 CST 2021, time=2021-06-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=973392, encodeId=09d19e33923d, content=已读，这真是受益匪浅呀！, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f03a5433387, createdName=ms5000000518166734, createdTime=Mon Jun 14 07:59:16 CST 2021, time=2021-06-14, status=1, ipAttribution=)]
    2021-06-15 spoonycyy

    #细胞瘤#

    0

  4. [GetPortalCommentsPageByObjectIdResponse(id=1909900, encodeId=4a4c190990095, content=<a href='/topic/show?id=8f1f42518d8' target=_blank style='color:#2F92EE;'>#复发性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=40, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=42518, encryptionId=8f1f42518d8, topicName=复发性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4c37265, createdName=hb2008ye, createdTime=Fri Dec 24 13:37:32 CST 2021, time=2021-12-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=973998, encodeId=54b99e399832, content=<a href='/topic/show?id=c70a5968472' target=_blank style='color:#2F92EE;'>#星形细胞瘤#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=76, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=59684, encryptionId=c70a5968472, topicName=星形细胞瘤)], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20211210/ede9c51184aa4f54ae6c1164cfb8eeac/967dbf3eff2943c7bf3ccfec3a776ab0.JPG, createdBy=a33789389, createdName=病毒猎手, createdTime=Wed Jun 16 08:41:50 CST 2021, time=2021-06-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1476134, encodeId=05f014e613466, content=<a href='/topic/show?id=2bcee797732' target=_blank style='color:#2F92EE;'>#细胞瘤#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77977, encryptionId=2bcee797732, topicName=细胞瘤)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=bf5e7252474, createdName=spoonycyy, createdTime=Tue Jun 15 12:37:32 CST 2021, time=2021-06-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=973392, encodeId=09d19e33923d, content=已读，这真是受益匪浅呀！, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f03a5433387, createdName=ms5000000518166734, createdTime=Mon Jun 14 07:59:16 CST 2021, time=2021-06-14, status=1, ipAttribution=)]
    2021-06-14 ms5000000518166734

    已读，这真是受益匪浅呀！

    0

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