Tucatinib先进与卡培他滨和曲妥珠单抗her2阳性转移性乳腺癌和无脑转移:non-randomised,非盲、1 b阶段的研究。
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Tucatinib先进与卡培他滨和曲妥珠单抗her2阳性转移性乳腺癌和无脑转移:non-randomised,非盲、1 b阶段的研究。
柳叶刀杂志。2018年7月19日(7):880 - 888。doi: 10.1016 / s1470 30256 - 0 - 2045 (18)。2018年5月24日Epub。
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29804905 (在PubMed]
- 文摘
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背景:Tucatinib是一个强有力的和选择性口服HER2酪氨酸激酶抑制剂,可能提供一个良好的耐受性的新治疗方案的患者疾病进展目前可用的治疗方法。我们旨在确定推荐的第二阶段剂量,安全,药物动力学,tucatinib与卡培他滨相结合的初步活动或曲妥珠单抗her2阳性乳腺癌患者有或没有脑转移。方法:在这个non-randomised,非盲、1 b阶段试验在五个地点在美国,我们招募患者18岁或以上乳腺癌her2阳性进步此前曾有过使用曲妥珠单抗治疗,pertuzumab,曲妥珠单抗emtansine。符合条件的病人需要本地HER2-positivity评估,可评价的损伤定义/响应评估标准在实体肿瘤,1.1版本,和东部合作肿瘤组织性能0或1的状态。Tucatinib是管理一天两次与卡培他滨1000毫克/米(2)口服一天两次的14天21天的周期,曲妥珠单抗6毫克/公斤静脉注射一次21天,或两者兼而有之。修改3 + 3剂量递增设计用来确定推荐的第二阶段剂量,从tucatinib结合卡培他滨和曲妥珠单抗,然后评估三联体的组合。主要终点是建立最大耐受剂量和2剂tucatinib推荐阶段,评估毒性评估。疗效评估在所有患者相比之下身体的CT。分析包括所有患者接受了至少一个剂量的研究治疗。这项研究是在ClinicalTrials.gov注册,NCT02025192数量。 FINDINGS: Between Jan 15, 2014, and Dec 15, 2015, 60 patients were enrolled and treated. The current report is from mature data as of June 30, 2017. The tucatinib recommended phase 2 dose was determined to be 300 mg orally twice a day, equivalent to single-agent maximum tolerated dose. Pharmacokinetic analysis showed that there was no drug-drug interaction with capecitabine. Adverse events seen at the recommended phase 2 dose regardless of causality, grade, and treatment group included diarrhoea (35 [67%] of 52 patients), nausea (31 [60%] patients), palmar-plantar erythrodysaesthesia syndrome (23 [44%] patients), fatigue (20 [38%] patients), and vomiting (20 [38%] patients). In all patients, treatment-related toxicities of grade 3 and worse included fatigue (five [8%] patients), diarrhoea (four [7%] patients), and palmar-plantar erythrodysaesthesia (four [7%] patients). No treatment-related deaths were reported. The proportion of patients with measurable disease achieving objective response was 83% (five of six patients) in the combination of tucatinib with capecitabine, 40% (six of 15 patients) in the combination of tucatinib with trastuzumab, and 61% (14 of 23 patients) in the combination of tucatinib with both capecitabine and trastuzumab. INTERPRETATION: Tucatinib in combination with capecitabine and trastuzumab had acceptable toxicity and showed preliminary anti-tumour activity. Validation of the current study results will be determined in the double-blinded randomised study, HER2CLIMB (ONT-380-206; NCT02614794). FUNDING: Cascadian Therapeutics, a wholly owned subsidiary of Seattle Genetics.
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