Safety and efficacy of imatinib (ST1571) in metastatic gastrointestinal stromal tumours: a phase I study
Safety and efficacy of imatinib (ST1571) in metastatic gastrointestinal stromal tumours: a phase I study
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DOI：
10.1016/s0140-6736(01)06535-7
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发表时间：
2001-10-27
期刊：
影响因子：
168.9
通讯作者：
Nielsen, OS
中科院分区：
文献类型：
--
作者：
van Oosterom, AT;Judson, I;Nielsen, OS
背景胃肠道间质瘤（GIST）是一种罕见的胃肠道肿瘤，其特征是细胞表面表达酪氨酸激酶KIT（CD 117）。没有有效的全身治疗方法。伊马替尼（ST 1571）抑制一种类似的酪氨酸激酶BCR-ABL，导致慢性粒细胞白血病的反应，并已被证明抑制KIT。我们进行了一项I期研究，以确定伊马替尼对包括GIST在内的晚期软组织肉瘤患者的剂量限制性毒性作用。方法40例患者（其中36例患有GIST）接受伊马替尼治疗，剂量为400 mg每日一次、300 mg每日两次、400 mg每日两次或500 mg每日两次。在8周的随访期间，评估了毒性作用和血液学、生化学和放射学测量结果。（18）在一个研究中心，使用氟脱氧葡萄糖正电子使命断层扫描（PET）进行反应评估。结果5名患者服用500 mg伊马替尼，每日两次，出现剂量限制性毒性反应（严重恶心、呕吐、水肿或皮疹）。在除4例GIST患者外的所有患者中均观察到肿瘤生长抑制，导致19例确认的部分缓解和6例尚未确认的部分缓解或超过20%的消退。27例临床症状患者中有24例出现改善，36例患者中有29例在9个月以上后仍在接受治疗。PET扫描反应预测随后的计算机断层扫描respons.Interpretation伊马替尼在400毫克的剂量，每天两次是耐受性良好，在第一个8周，副作用减少与继续治疗，它有显着的活动在晚期GIST患者。我们的研究结果提供了KIT在GIST中发挥作用的证据，并显示了基于癌症中存在的特定分子异常开发抗癌药物的潜力。
Background Gastrointestinal stromal tumours (GISTs) are rare tumours of the gastrointestinal tract characterised by cell-surface expression of the tyrosine kinase KIT (CD117). No effective systemic treatment is available. Imatinib (ST1571) inhibits a similar tyrosine kinase, BCR-ABL, leading to responses in chronic myeloid leukaemia, and has also been shown to inhibit KIT. We did a phase I study to identify the dose-limiting toxic effects of imatinib in patients with advanced soft tissue sarcomas including GISTs.Methods 40 patients (of whom 36 had GISTs) received imatinib at doses of 400 mg once daily, 300 mg twice daily, 400 mg twice daily, or 500 mg twice dally. Toxic effects and haematological, biochemical, and radiological measurements were assessed during 8 weeks of follow-up. (18)Fluorodeoxyglucose positron-e mission tomography (PET) was used for response assessment in one centre.Findings Five patients on 500 mg imatinib twice daily had dose-limiting toxic effects (severe nausea, vomiting, oedema, or rash). Inhibition of tumour growth was seen in all but four patients with GISTs, resulting in 19 confirmed partial responses and six as yet unconfirmed partial responses or more than 20% regressions. 24 of 27 clinically symptomatic patients showed improvement, and 29 of 36 were still on treatment after more than 9 months. PET scan responses predicted subsequent computed tomography responses.Interpretation Imatinib at a dose of 400 mg twice daily is well tolerated during the first 8 weeks, side-effects diminish with continuing treatment, and it has significant activity in patients with advanced GISTs. Our results provide evidence of a role for KIT in GISTs, and show the potential for the development of anticancer drugs based on specific molecular abnormalities present in cancers.