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首页> 外文期刊>British Journal of Cancer >First-in-human study of the PARP/tankyrase inhibitor E7449 in patients with advanced solid tumours and evaluation of a novel drug-response predictor
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First-in-human study of the PARP/tankyrase inhibitor E7449 in patients with advanced solid tumours and evaluation of a novel drug-response predictor

机译：先进实体肿瘤患者的PARP / Tankysase抑制剂E7449的首先进行研究，并进行新药反应预测因子的评价

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Background This phase 1 study examined the safety, maximum-tolerated dose (MTD) and antitumour activity of E7449, a novel PARP 1/2 and tankyrase 1/2 inhibitor. Methods E7449 was orally administered once daily in 28-day cycles to patients with advanced solid tumours (50–800-mg doses). Archival tumour samples from consenting patients were evaluated for the expression of 414 genes in a biomarker panel (2X-121 drug-response predictor [DRP]) found to be predictive of the response to E7449 in cell lines. Results Forty-one patients were enrolled (13 pancreatic, 5 ovarian, 4 each with breast, lung or colorectal cancer and 11 with other tumour types). The most common grade ≥3 treatment-related adverse event was fatigue ( n ?=?7, 17.1%). Five patients experienced a dose-limiting toxicity (fatigue, n ?=?4, 800?mg; anaphylaxis, n ?=?1, 600?mg) for an MTD of 600?mg. E7449 exhibited antitumour activity in solid tumours, including 2 partial responses (PRs), and stable disease (SD) in 13 patients, which was durable (&23 weeks) for 8 patients. In 13 patients, the 2X-121 DRP identified those achieving PR and durable SD. E7449 showed good tolerability, promising antitumour activity and significant concentration-dependent PARP inhibition following 50–800-mg oral dosing. Conclusion The results support further clinical investigation of E7449 and its associated biomarker 2X-121 DRP. Clinical trial registration www.ClinicalTrials.gov code: NCT01618136.
机译：背景技术本阶段1研究了E7449，一种新型PARP 1/2和Tankyrase 1/2抑制剂的安全性，最大耐受剂量（MTD）和抗肿瘤活性。方法将E7449每天在28天的循环中口服给予一次，对先进的实体瘤（50-800mg剂量）。评估患者的归档肿瘤样品在生物标志物面板中的表达414基因（2×121药物 - 反应预测器[DRP]）中发现，发现预测细胞系中E7449的反应。结果40-一名患者注册（13名胰腺，5卵巢，4例，每个乳腺癌，肺或结肠直肠癌和11种带有其他肿瘤类型）。最常见的≥3级治疗相关的不良事件是疲劳（n？=？7,17.1％）。五名患者经历了一种剂量限制毒性（疲劳，N？= 4,800×mg;过敏反应，N？= 1,600×mg），用于600毫克的MTD。 E7449在13名患者中表现出实体肿瘤中的抗肿瘤活性，包括2名部分反应（PRS）和稳定的疾病（SD），其持续（＆ 23周）为8名患者。在13名患者中，2x-121 DRP确定了实现PR和持久SD的DUS。 E7449显示出良好的耐受性，有前途的抗肿瘤活性和50-800mg口服给药后的显着浓度依赖性PARP抑制。结论结果支持E7449及其相关生物标志物2X-121 DRP的进一步临床研究。临床试验登记www.clinicaltrials.gov代码：nct01618136。

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