A Phase I Trial of BKM120 (Buparlisib) in Combination with Fulvestrant in Postmenopausal Women with Estrogen Receptor-Positive Metastatic Breast Cancer.
A Phase I Trial of BKM120 (Buparlisib) in Combination with Fulvestrant in Postmenopausal Women with Estrogen Receptor-Positive Metastatic Breast Cancer.
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DOI：
10.1158/1078-0432.ccr-15-1745
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发表时间：
2016-04-01
期刊：
影响因子：
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通讯作者：
Ellis MJ
中科院分区：
文献类型：
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作者：
Ma CX;Luo J;Naughton M;Ademuyiwa F;Suresh R;Griffith M;Griffith OL;Skidmore ZL;Spies NC;Ramu A;Trani L;Pluard T;Nagaraj G;Thomas S;Guo Z;Hoog J;Han J;Mardis E;Lockhart C;Ellis MJ
本试验旨在确定buparlisib（一种口服泛I类PI 3 K抑制剂）联合氟维司群治疗转移性雌激素受体阳性乳腺癌（ER+BC）绝经后女性的最大耐受剂量（MTD）和初步疗效。IA期采用3+3设计来确定buparlisib每日加氟维司群的MTD。随后的队列评估了间歇性（7天给药中的5天）和连续性buparlisib（每日100 mg）。在IB期和队列C中，转移性背景下的既往全身治疗不允许超过3次。31例患者入组。MTD定义为buparlisib 100 mg/天+氟维司群。常见不良事件（AE）包括疲乏（38.7%）、转氨酶升高（35.5%）、皮疹（29%）和腹泻（19.4%）。治疗期间C肽显著增加，与buparlisib的靶向效应一致。与间歇给药相比，每日buparlisib与更频繁的早发性AE和更高的buparlisib血浆浓度相关。在29例可评价患者中，临床获益率为58.6%（95%CI 40.7-74.5%）。缓解与PIK 3CA突变或治疗队列无关，然而，PTEN、孕酮受体（PgR）表达或TP 53突变的缺失在耐药病例中更为常见，AKT 1和ESR 1突变并不排除治疗缓解。Buparlisib+氟维司群在转移性ER+BC患者中具有临床活性，AE可管理。buparlisib给药的周末休息降低了毒性。PgR阴性和TP 53突变的患者表现不佳，表明buparlisib+氟维司群可能对具有这些不良预后分子特征的肿瘤无效。
This trial was conducted to determine the maximum tolerated dose (MTD) and preliminary efficacy of buparlisib, an oral pan-class I PI3K inhibitor, plus fulvestrant in postmenopausal women with metastatic estrogen receptor positive breast cancer (ER+BC). Phase IA employed a 3+3 design to determine the MTD of buparlisib daily plus fulvestrant. Subsequent cohorts evaluated intermittent (5 of 7 day dosing) and continuous buparlisib (100mg daily). No more than 3 prior systemic treatments in the metastatic setting were allowed in Phase IB and Cohort C. Thirty one patients were enrolled. MTD was defined as buparlisib 100mg daily plus fulvestrant. Common adverse events (AEs) included fatigue (38.7 %), transaminases elevation (35.5 %), rash (29%), and diarrhea (19.4%). C-peptide was significantly increased during treatment, consistent with on-target effect of buparlisib. Compared to intermittent dosing, daily buparlisib was associated with more frequent early onset AEs and higher buparlisib plasma concentrations. Among the 29 evaluable patients, the clinical benefit rate was 58.6% (95% CI 40.7–74.5%). Response was not associated with PIK3CA mutation or treatment cohort, however loss of PTEN, progesterone receptor (PgR) expression, or mutation in TP53 was commoner in resistant cases and mutations in AKT1 and ESR1 did not exclude treatment response. Buparlisib plus fulvestrant is clinically active with manageable AEs in patients with metastatic ER+BC. Weekend breaks in buparlisib dosing reduced toxicity. Patients with PgR negative and TP53 mutation did poorly, suggesting buparlisib plus fulvestrant may not be adequately effective against tumors with these poor prognostic molecular features.