A Phase Ib Dose-Escalation Study of the Oral Pan-PI3K Inhibitor Buparlisib (BKM120) in Combination with the Oral MEK1/2 Inhibitor Trametinib (GSK1120212) in Patients with Selected Advanced Solid Tumors
A Phase Ib Dose-Escalation Study of the Oral Pan-PI3K Inhibitor Buparlisib (BKM120) in Combination with the Oral MEK1/2 Inhibitor Trametinib (GSK1120212) in Patients with Selected Advanced Solid Tumors
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DOI：
10.1158/1078-0432.ccr-14-1814
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发表时间：
2015-02-15
影响因子：
11.5
通讯作者：
Sessa, Cristiana
中科院分区：
文献类型：
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作者：
Bedard, Philippe L.;Tabernero, Josep;Sessa, Cristiana
目的：MAPK和PI3K/AKT/mTOR通路在多种肿瘤中发挥重要作用。本研究对布帕利西布（pan类PI3K抑制剂）和曲美替尼（MEK抑制剂）的安全性、抗肿瘤活性和药代动力学进行了评价。实验设计：这项开放标签、剂量发现、Ib期研究包括剂量递增，随后在ras或braf突变的非小细胞肺癌、卵巢癌或胰腺癌患者中进行扩展部分。结果：值得注意的是，有113例患者入组，剂量递增和扩展部分分别为66例和47例。MTD确定为布帕利西布70 mg +曲美替尼1.5 mg /天[5/ 15,33 %的剂量限制性毒性（DLT）患者]和推荐II期剂量（RP2D）布帕利西布60 mg +曲美替尼1.5 mg /天（1/10,10%的DLT患者）。DLTs包括口炎（8/ 103,8%）、腹泻、吞咽困难和肌酸激酶（CK）升高（2/ 103,2%）。73例（65%）患者发生治疗相关的3/4级不良事件（ae）；主要表现为CK升高、口炎、谷草转氨酶/谷丙转氨酶比值升高、皮疹。21例卵巢癌患者中，总缓解率为29%[1例完全缓解，5例部分缓解（PR）]，疾病控制率76%，中位无进展生存期为7个月。在非小细胞肺癌（1/17 PR）和胰腺癌（最佳总缓解为SD）患者中观察到最小的活性。与历史数据相比，布帕利西布暴露增加，曲美替尼暴露略有增加。结论：在RP2D， buparisib 60mg + trametinib 1.5 mg /天对kras突变型卵巢癌患者显示出良好的抗肿瘤活性。由于频繁的剂量中断和毒性降低，RP2D联合用药的长期耐受性具有挑战性。(c) 2014年aacr。
Purpose: MAPK and PI3K/AKT/mTOR pathways play important roles in many tumors. In this study, safety, antitumor activity, and pharmacokinetics of buparlisib (pan class PI3K inhibitor) and trametinib (MEK inhibitor) were evaluated.Experimental Design: This open-label, dose-finding, phase Ib study comprised dose escalation, followed by expansion part in patients with RAS-or BRAF-mutant non-small cell lung, ovarian, or pancreatic cancer.Results: Of note, 113 patients were enrolled, 66 and 47 in dose-escalation and -expansion parts, respectively. MTD was established as buparlisib 70 mg + trametinib 1.5 mg daily [5/15, 33% patients with dose-limiting toxicities (DLT)] and recommended phase II dose (RP2D) buparlisib 60 mg + trametinib 1.5 mg daily (1/10,10% patients with DLTs). DLTs included stomatitis (8/103, 8%), diarrhea, dysphagia, and creatine kinase (CK) increase (2/103, 2% each). Treatment-related grade 3/4 adverse events (AEs) occurred in 73 patients (65%); mainly CK increase, stomatitis, AST/ALT (aspartate aminotransferase/alanine aminotransferase) increase, and rash. For all (21) patients with ovarian cancer, overall response rate was 29% [1 complete response, 5 partial responses (PR)], disease control rate 76%, and median progression-free survival was 7 months. Minimal activity was observed in patients with non-small cell lung cancer (1/17 PR) and pancreatic cancer (best overall response was SD). Relative to historical data, buparlisib exposure increased and trametinib exposure slightly increased with the combination.Conclusions: At RP2D, buparlisib 60 mg + trametinib 1.5 mg daily shows promising antitumor activity for patients with KRAS-mutant ovarian cancer. Long-term tolerability of the combination at RP2D is challenging, due to frequent dose interruptions and reductions for toxicity. (C) 2014 AACR.