Dosing targeted and cytotoxic two-drug combinations: Lessons learned from analysis of 24,326 patients reported 2010 through 2013.
Dosing targeted and cytotoxic two-drug combinations: Lessons learned from analysis of 24,326 patients reported 2010 through 2013.
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DOI：
10.1002/ijc.30262
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发表时间：
2016-11-01
影响因子：
6.4
通讯作者：
Kurzrock, Razelle
中科院分区：
文献类型：
--
作者：
Nikanjam, Mina;Liu, Sariah;Kurzrock, Razelle
关键词：
联合用药有可能减弱转移性癌症的耐药性。然而，在临床试验和实践中，缺乏关于新药物组合的适当起始剂量的知识。对372项已发表的研究进行了分析，以确定涉及细胞毒性和靶向药物的双联剂的安全起始剂量。检索了I-III期成人肿瘤临床试验出版物（2010年1月1日至2013年12月31日）（PubMed）。将每种联合使用的药物剂量与单药推荐剂量[FDA批准/推荐2期剂量(RP2D)/最大耐受剂量（MTD）]进行比较。剂量百分比计算为：（联合用药安全剂量/ FDA/RP2D/MTD单药安全剂量）× 100。加性剂量百分比是每种药物的剂量百分比之和。共分析24326例患者（248种药物组合）。在38%的研究中，这两种药物都可以100%达到FDA批准的/RP2D/MTD剂量。以聚ADP核糖聚合酶（PARP）或组蛋白去乙酰化酶抑制剂为靶点的最低安全添加剂量百分比为41%；82%，在没有这些药物的情况下；97%的人在组合中含有抗体。如果一种药物以100%单药剂量给药，第二种药物的最低安全剂量百分比为FDA批准/RP2D/MTD剂量的17%（100%细胞毒性）或36%（100%靶向）。目前的发现有助于在临床试验和实践中为新的两种药物联合（细胞毒性和靶向药物）的安全起始剂量提供信息。有什么新鲜事吗?细胞毒性和靶向癌症药物通过不同的机制起作用，当它们联合使用时，它们可以潜在地增强治疗效果，同时对毒性的影响最小。然而，尽管新的单药治疗的安全起始剂量算法已经建立，但联合治疗的指南却很少。在此，对已发表的I-III期临床试验数据的分析显示，约38%的患者耐受两种药物以全起始剂量联合用药。在大多数患者中，需要显著减少剂量以防止毒性。然而，患者体内剂量的增加是可能的，这可能会增加疗效。
Combining agents has the potential to attenuate resistance in metastatic cancer. However, knowledge of appropriate starting doses for novel drug combinations in clinical trials and practice is lacking. Analysis of 372 published studies was used to ascertain safe starting doses for doublets involving a cytotoxic and targeted agent. Phase I–III adult oncology clinical trial publications (January 1, 2010 to December 31, 2013) were identified (PubMed). The dose of drug used in each combination was compared to the single agent recommended dose [FDA‐approved/recommended phase 2 dose (RP2D)/maximum tolerated dose (MTD)]. Dose percentages were calculated as: (safe dose of drug in combination/dose of drug as single agent at FDA/RP2D/MTD) × 100. Additive dose percentages were the sum of the dose percentage for each drug. A total of 24,326 patients (248 drug combinations) were analyzed. In 38% of studies, both drugs could be administered at 100% of their FDA‐approved/RP2D/MTD dose. The lowest safe additive dose percentage was 41% with poly‐ADP ribose polymerase (PARP) or histone deacetylase inhibitors as the targeted agents; 82%, in the absence of these agents; and 97%, with an antibody in the combination. If one drug was administered at 100% of the single agent dose, the lowest safe dose percentage for the second drug was 17% (cytotoxic at 100%) or 36% (targeted at 100%) of the FDA‐approved/RP2D/MTD dose. The current findings can help inform safe starting doses for novel two‐drug combinations (cytotoxic and targeted agents) in the context of clinical trials and practice. What's new? Cytotoxic and targeted cancer drugs act through distinct mechanisms, and when used in combination they can potentially augment therapeutic effectiveness while minimally impacting toxicity. However, whereas algorithms for safe starting doses for new single‐agent therapies are well established, there are few guidelines for combination therapies. Here, analyses of data from published Phase I–III clinical trials shows that about 38% of patients tolerated combinations in which both drugs were administered at full starting doses. In the majority of patients, significant dose reductions were required to guard against toxicity. Intrapatient dose escalation is possible, however, potentially allowing for increased efficacy.
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影响因子：
3.9
作者：
Borad, Mitesh J.;Curtis, Kelly K.;Von Hoff, Daniel D.
通讯作者：
Von Hoff, Daniel D.
影响因子：
4.3
作者：
Kurzrock, Razelle;Giles, Francis J.
通讯作者：
Giles, Francis J.
影响因子：
11.2
作者：
Wheler J;Lee JJ;Kurzrock R
通讯作者：
Kurzrock R
影响因子：
158.5
作者：
Hurwitz, H;Fehrenbacher, L;Kabbinavar, F
通讯作者：
Kabbinavar, F
DOI：
10.1056/nejmoa1113205
发表时间：
2012-03-08
期刊：
The New England journal of medicine
影响因子：
--
作者：
Gerlinger M;Rowan AJ;Horswell S;Math M;Larkin J;Endesfelder D;Gronroos E;Martinez P;Matthews N;Stewart A;Tarpey P;Varela I;Phillimore B;Begum S;McDonald NQ;Butler A;Jones D;Raine K;Latimer C;Santos CR;Nohadani M;Eklund AC;Spencer-Dene B;Clark G;Pickering L;Stamp G;Gore M;Szallasi Z;Downward J;Futreal PA;Swanton C
通讯作者：
Swanton C