ALK靶点药物特点

二师兄 发表于 2014-5-26 21:23
戴先生的聊天记录总结
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1.ap耐药吃3922，ALICE SHAW医生那里现在又十几人在排队。（shaw医生是这颗星球上 ...

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Zykadia(ceritinib,LDK378)胶囊使用说明书2014年第一版.pdf (423.74 KB, 下载次数: 226)

2014-5-28 08:24 上传

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LDK378的说明书

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PF06463922的世界专利

1 v: u4 t0 y9 o2 F, Zhttp://www.google.com/patents/WO2013132376A1?cl=en

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Updated efficacy and safety of the ALK inhibitor AP26113 in patients (pts) with advanced malignancies, including ALK+ non-small cell lung cancer (NSCLC).
更新的有效性和安全性的ALK抑制剂AP26113(pts)晚期恶性肿瘤患者,包括ALK+非小细胞肺癌(NSCLC)。
8 f- t  C2 }  A8 tAbstract No:
8047
# r1 z" s0 _" v: t3 Y8 p, NAuthor(s): Scott N. Gettinger, Lyudmila Bazhenova, Ravi Salgia, Corey J. Langer, Kathryn A. Gold, Rafael Rosell, Alice Tsang Shaw, Glen J. Weiss, Narayana I. Narasimhan, David J. Dorer, Victor M. Rivera, Tim Clackson, Frank G. Haluska, D. Ross Camidge; Yale University, New Haven, CT; UC San Diego Moores Cancer Center, La Jolla, CA; The University of Chicago, Chicago, IL; Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA; Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; Catalan Institute of Oncology, Barcelona, Spain; Massachusetts General Hospital Cancer Center, Boston, MA; Cancer Treatment Centers of America, Goodyear, AZ; ARIAD Pharmaceuticals, Inc., Cambridge, MA; University of Colorado Cancer Center, Aurora, CO
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1 R2 \0 ^$ W5 QAbstract Disclosures

Abstract:
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1 b+ I8 ?2 c; q; c3 G$ R3 mBackground: AP26113 is a novel orally-active tyrosine kinase inhibitor with preclinical activity against ALK and all 9 clinically-identified crizotinib-resistant mutants tested.
  n3 o6 w. c, N2 J/ U. h. r6 [背景:AP26113是新型口服有效的酪氨酸激酶抑制剂在临床前活动对ALK和所有9 种已知的克唑替尼耐药突变体进行测试。
Methods: The Phase (Ph) 2 portion of a Ph1/2 single arm, multicenter study in pts with advanced malignancies is underway. We report updated safety for all treated pts and efficacy data for ALK+ NSCLC pts previously treated with crizotinib. NCT01449461.
0 r) P6 N6 L/ m4 z+ E方法:第2阶段部分Ph1/2单臂,多中心研究分晚期恶性肿瘤正在进行中。我们报告更新安全治疗得分数和ALK+非小细胞肺癌疗效数据得分数，以前经过治疗crizotinib。NCT01449461.
' a, h# m% W4 C! U% k6 zResults: As of 16 Dec 2013, 114 pts were enrolled: 65 in Ph1 (30-300 mg) and 49 in Ph2 (180 mg). Baseline characteristics: 59% female, median age 57 yr;
结果:截止2013年12月16日,114个录取:65人在第一阶段(30 - 300毫克)和49 人在第二阶段(180毫克)。基线特征:59%为女性,平均年龄57岁,
9 y$ r% p5 v! R( e, e2 Bdiagnoses: NSCLC n=106, other n=8. 66 pts remain on study; median follow-up for all pts is 3.6 mo (max= 21.4 mo, ongoing).
( v- X4 ~( W4 r诊断:非小细胞肺癌n = 106,其他n = 8。66继续研究,平均随访3.6(max = 21.4正在进行)。
The most common treatment-emergent AEs (≥20%) were nausea (38%), diarrhea (31%), fatigue (31%), cough (23%), and headache (20%), which were generally grade 1/2 in severity. 最常见治疗诱发的副作用(≥20%)恶心(38%)、腹泻(31%)、疲劳(31%)、咳嗽(23%)、头痛(20%),通常是1/2级的严重性。Early onset of pulmonary symptoms (dyspnea with hypoxia and/or findings on imaging) observed in 6/45 (13%) pts at 180mg QD. 肺部早期症状(呼吸困难和缺氧和/或发现影像)有6/45(13%)在180 mg每日一次。These symptoms, requiring immediate medical attention, were not observed at 90mg QD (n=8) or in the lead-in dose cohort (n=19; initiated at 90mg QD, escalated to 180mg QD after 1 wk). 有这些症状,需要立即就医,没有观察到90 mg QD(n = 8)或引导剂量组(n = 19;在90 mg 每日一次,一周后升级到180 mg 每日一次)。Pts continue to be enrolled with this dose escalation scheme, and an additional cohort of 90mg QD without escalation will be added. 继续参加这个剂量升级方案,和一个额外的90 mg 每日一次没有升级将被添加。Among 38 evaluable ALK+ NSCLC pts with prior crizotinib, 24 (63%) responded (23 partial response, 1 complete response). 在38个可评价的ALK+非小细胞肺癌之前接受克唑替尼 24(63%)回应(23部分反应,1完整的响应)。Duration of response was 1.6 - 14.7 mo (ongoing). 15 pts had confirmed responses; 5 await confirmation, 4 are unconfirmed. Among 42 evaluable pts with ALK+ NSCLC, median progression free survival is 47 wk. 响应时间为1.6 - 14.7周(正在进行)。15个已证实反应;5等待确认,4是未经证实的。42中可评价的ALK+非小细胞肺癌,PFS是47周。Independent radiological review conducted on 10 pts enrolled with untreated or progressing brain metastases showed 6/10 pts with response in brain, including 4 with undetectable brain metastases following AP26113; 2 pts had stable disease, 2 pts progressed; 8/10 remain on study (range 5-17 mo). 独立的放射学检查进行10个录取与未经处理的或进展大脑脑转移显示6/10响应,包括4个察觉脑转移后AP26113;2个稳定,2个进展;8/10仍在研究。
Conclusions: AP26113 has promising anti-tumor activity in pts with crizotinib-resistant ALK+ NSCLC, including pts with brain metastases. A randomized Ph2 trial evaluating 90 mg QD vs. 90mg QD escalating to 180mg QD in crizotinib-resistant ALK+ NSCLC will begin shortly. Clinical trial information: NCT01449461.
4 T5 U- h6 C7 [' W4 p6 w结论:AP26113有前途的抗克唑替尼耐药的ALK+非小细胞肺癌,包括脑转移。随机第二阶段试验评估90 mg QD vs 90 mg QD升级到180 mg QD对克唑替尼耐药的ALK+非小细胞肺癌将很快开始。临床试验信息:NCT01449461。

资料来自美国临床肿瘤学会，仅供参考：
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Per Dr. Shaw 在论坛上讲道：
一些对药物alectinib产生耐药性的病人可能在重新活检中发现，ALK突变变体会对ALK抑制剂ceritinib敏感。这一现象已经有一个案例。幻灯片显示出领先的第二代ALK抑制剂似乎产生了一点作用，其中对ALK突变变体是非常有效的。
从延迟对所有ALK抑制剂产生耐药性的变体出现的角度来说，目前还没有数据表明是否可以更好地以第二代甚至第三代ALK抑制剂预先开始向前按顺序走两到三步。我们也许可以得到一些重复的数据：从XALKORI (crizotinib)胶囊或从另几个数据尚未公布的实验。
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祝好。

知道索坦的半衰期是40─60，有知道多吉美的半衰期是多少吗？希望有人告诉我，谢谢！

AP26113-ASCO_2014_FINAL.pdf (914.88 KB, 下载次数: 155)

2014-6-6 15:29 上传

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二师兄 发表于 2014-5-25 17:39
我EGFR的不太懂

学习了，顶起

前沿有你们真好，，大赞

与ALK靶点LDK378可以联合的有LBH589—针对HDAC，CGM097—HDM2/P53，AUY922—HSP90，BYL719—PI3K，LEE011—CDK4/6
其中HDAC是白血病的，CDK4/6是乳腺癌的，P53凋亡基因可以考虑啊，HSP90的可以选择2代的STA9090，PI3K可以用BKM120你懂的{:soso_e113:}