Phase II study of the PI3K inhibitor BKM120 in patients with advanced or recurrent endometrial carcinoma: a stratified type I-type II study from the GINECO group.
Phase II study of the PI3K inhibitor BKM120 in patients with advanced or recurrent endometrial carcinoma: a stratified type I-type II study from the GINECO group.
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DOI：
10.1038/bjc.2016.430
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发表时间：
2017-01
影响因子：
8.8
通讯作者：
Ray-Coquard I
中科院分区：
文献类型：
--
作者：
Heudel PE;Fabbro M;Roemer-Becuwe C;Kaminsky MC;Arnaud A;Joly F;Roche-Forestier S;Meunier J;Foa C;You B;Priou F;Tazi Y;Floquet A;Selle F;Berton-Rigaud D;Lesoin A;Kalbacher E;Lortholary A;Favier L;Treilleux I;Ray-Coquard I
转移性子宫内膜癌患者预后较差，PIK3CA突变和扩增在这些癌症中很常见。本研究评价了纯PI3K抑制剂BKM120治疗晚期或复发子宫内膜癌的疗效和安全性。这项II期多中心、单臂、双层(组织学低级别(LG)或高级别(HG))开放标签研究纳入了组织学证实的晚期或复发子宫内膜癌患者，这些患者以前接受过不超过一种化疗方案。患者最初服用BKM120100 mg片剂，每日一次。主要终点是2个月(HG STRAL)或3个月(LG STRATA)无进展的患者比例、客观反应率(ORR)和安全性。共40例患者入选，其中16例患者接受BKM120100 mg治疗。由于高毒副作用(皮疹(54%)、抑郁事件(47%)和焦虑(40%))，IDMC建议停止招募100 mg，并继续进行较低剂量的临床试验，每天60 mg。此外，新入选的24例患者(中位年龄67岁)(14例在LG层，10例在HG层)。HG组2个月无进展率为70%，LG组3个月无进展率为60%。所有患者的中位无进展生存期(PFS)为4.5个月(CI 95%2.8-6.1)，LG组的中位无进展生存期为8.3个月，而HG组为3.8个月。没有任何回应的报道。每天服用60 毫克时，最常见的治疗相关不良事件(AEs)是高血糖(58%)、认知(31%)、消化(28%)、肝功能(26%)和皮疹(23%)。最常见的与治疗相关的⩾3级不良反应是HTA(17%)、高血糖(17%)和丙氨酸氨基转移酶升高(24%)。5名患者(21%)因毒性而停用BKM120。在晚期或复发子宫内膜癌的单一治疗中，BKM120与不良的安全性和最低的抗肿瘤活性有关。临床试验在毒性征集结束前停止。
Patients with metastatic endometrial carcinoma have a poor prognosis and PIK3CA mutations and amplifications are common in these cancers. This study evaluated the efficacy and safety of the pure PI3K inhibitor BKM120 in advanced or recurrent endometrial carcinoma. This phase II, multicentre, single-arm, double strata (histological low grade (LG) or high grade (HG)) open-label study enrolled patients with histologically confirmed advanced or recurrent endometrial carcinoma who had received not more than one prior chemotherapy regimen. Patients received initially BKM120 100 mg tablets once daily. Primary end points were proportion of patients free of progression at 2 months (HG strata) or at 3 months (LG strata), objective response rate (ORR), and safety. A total of 40 patients were enrolled, of whom 16 patients had received BKM120 at 100 mg. Because of high toxicities (cutaneous rash (54%), depressive events (47%), and anxiety (40%), the IDMC has proposed to stop recruitment at 100 mg and to continue the clinical trial with a lower dose of 60 mg per day. In addition, 24 patients (median age 67 years old) were newly enrolled (14 in the LG strata and 10 in the HG strata). Rate of nonprogression at 2 months in the HG strata was 70% and at 3 months was 60% in the LG strata. Median progression-free survival (PFS) for all patients is 4.5 months (CI 95% 2.8–6.1), and the median PFS for LG strata is 8.3 months compared with 3.8 months for the HG strata. No response was reported. At 60 mg per day, the most commonly reported treatment-related adverse events (AEs) were hyperglycaemia (58%), cognitive (31%), digestive (28%), hepatic liver functions (26%), and rash (23%). The most commonly reported treatment-related grade ⩾3 AEs were HTA (17%), hyperglycaemia (17%), and increased alanine aminotransferase (24%). Five patients (21%) stopped BKM120 for toxicity. The BKM120 was associated with an unfavourable safety profile and minimal antitumour activity in monotherapy in advanced or recurrent endometrial carcinoma. The clinical trial was stopped before end of recruitment for toxicity.