BACKGROUND The majority of patients with advanced gastrointestinal stromal tumours (GISTs) develop resistance to imatinib and sunitinib, the standard of care for these patients. This study evaluated the combination of buparlisib, an oral phosphoinositide 3-kinase (PI3K) inhibitor, with imatinib in patients with advanced GIST, who have failed prior therapy with imatinib and sunitinib. METHODS This Phase 1b, multicentre, open-label study aimed to determine the maximum tolerated dose (MTD) and/or a recommended Phase 2 dose of buparlisib in combination with 400 mg of imatinib through a dose-escalation part and a dose-expansion part, and also evaluated the clinical profile of the combination. RESULTS Sixty patients were enrolled, including 25 in the dose-escalation part and 35 in the dose-expansion part. In the combination, MTD of buparlisib was established as 80 mg. No partial or complete responses were observed. The estimated median progression-free survival was 3.5 months in the expansion phase. Overall, 98.3% of patients had treatment-related adverse events (AEs), including 45% with grade 3 or 4 AEs. CONCLUSIONS Buparlisib in combination with imatinib provided no additional benefit compared with currently available therapies. Due to the lack of objective responses, further development of this combination was not pursued for third-line/fourth-line advanced/metastatic GIST. TRIAL REGISTRATION NUMBER NCT01468688.

中文翻译：

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伊马替尼联合磷酸肌醇激酶抑制剂buparlisib用于先前使用伊马替尼和舒尼替尼治疗失败的胃肠道间质瘤患者：1b期多中心研究。

背景技术大多数患有晚期胃肠道间质瘤（GIST）的患者对伊马替尼和舒尼替尼具有耐药性，这是这些患者的治疗标准。这项研究评估了口服磷肌苷3激酶（PI3K）抑制剂buparlisib与伊马替尼在晚期GIST的患者中的组合，这些患者先前使用伊马替尼和舒尼替尼治疗均无效。方法这项1b阶段，多中心，开放标签研究旨在通过剂量递增部分和剂量扩大部分确定buparlisib与400 mg伊马替尼组合的最大耐受剂量（MTD）和/或推荐的阶段2剂量，并评估了该组合的临床概况。结果入选患者60例，其中剂量增加部分25例，剂量增加部分35例。结合起来 布巴列布的MTD确定为80 mg。没有观察到部分或全部反应。在扩张期，估计的无进展生存期中位数为3.5个月。总体而言，98.3％的患者患有与治疗相关的不良事件（AE），包括45％的3级或4级AE。结论与当前可用的疗法相比，布帕西布联合伊马替尼没有提供额外的益处。由于缺乏客观的回应，因此对于三线/四线晚期/转移性GIST并未寻求进一步发展。试用注册号NCT01468688。包括4％的3级或4级AE。结论与当前可用的疗法相比，布帕西布联合伊马替尼没有提供额外的益处。由于缺乏客观的回应，因此对于三线/四线晚期/转移性GIST并未寻求进一步发展。试用注册号NCT01468688。包括4％的3级或4级AE。结论与当前可用的疗法相比，布帕西布联合伊马替尼没有提供额外的益处。由于缺乏客观的回应，因此对于三线/四线晚期/转移性GIST，未寻求进一步发展这种组合。试用注册号NCT01468688。