A randomized phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent endometrial cancer
A randomized phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent endometrial cancer
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DOI：
10.1016/j.ygyno.2016.04.019
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发表时间：
2016-07-01
影响因子：
4.7
通讯作者：
Oza, Amit
中科院分区：
文献类型：
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作者：
Maria del Campo, Josep;Birrer, Michael;Oza, Amit
客观的。 PF-04691502 和 gedatolisib (PF-05212384) 是有效的双重 PI3K/mTOR 抑制剂。这项 II 期研究 (B1271004) 是在含铂化疗后复发性子宫内膜癌患者中进行的。主要终点是评估用 PF-04691502 或 gedatolisib 治疗后的临床获益反应（完全或部分反应，或疾病稳定 16 周）。方法。主要研究由基于西蒙两阶段设计的四个独立组组成。根据 Stathmin 低或 Stathmin 高肿瘤表达，将患者分别分配至假定的 PI3K 基础组（PF-04691502 或 gedatolisib）或 PI3K 激活组（PF-04691502 或 gedatolisib）。日本患者也被纳入一个单独的导入队列。结果。在第一阶段（主要研究）中，18 名患者被随机分配至 PF-04691502 组，40 名患者被随机分配至 gedatolisib。由于不可接受的毒性（包括肺炎和肺炎），两个 PF-04691502 组提前停产。与 gedatolisib 相关的最常见的治疗相关不良事件是恶心（53%）、粘膜炎症（50%）、食欲下降（40%）、腹泻（38%）、疲劳（35%）以及味觉障碍和呕吐（各 30%）。 gedatolisib/stathmin 低组的临床获益反应率为 53% (10/19)，gedatolisib/stathmin 高组的临床获益反应率为 26% (5/19)。日本导入队列中两种药物的安全性和药代动力学特征与西方人群相当。结论。每周静脉输注给药的 Gedatolisib 在复发性子宫内膜癌患者中表现出可接受的耐受性和中等活性。 PF-04691502每日口服给药的耐受性不佳。仅 gedatolisib/stathmin-low 组符合进入第 2 阶段的临床获益反应标准。 Stathmin 高表达与更高的治疗效果无关。 (C) 2016 年，爱思唯尔公司出版
Objective. PF-04691502 and gedatolisib (PF-05212384) are potent, dual PI3K/mTOR inhibitors. This phase II study (B1271004) was conducted in patients with recurrent endometrial cancer following platinum containing chemotherapy. The primary endpoint was to assess clinical benefit response (complete or partial response, or stable disease for 16 weeks) following treatment with PF-04691502 or gedatolisib.Methods. The main study consisted of four independent arms based on a Simon two-stage design. Patients were assigned to putative PI3K-basal (PF-04691502 or gedatolisib) or PI3K-activated (PF-04691502 or gedatolisib) arms based on stathmin-low or stathmin-high tumor expression, respectively. Japanese patients were also enrolled in a separate lead-in cohort.Results. In stage 1 (main study), eighteen patients were randomized to PF-04691502 and 40 to gedatolisib. The two PF-04691502 arms were discontinued early due to unacceptable toxicity, including pneumonia and pneumonitis. The most common treatment-related adverse events associated with gedatolisib were nausea (53%), mucosal inflammation (50%), decreased appetite (40%), diarrhea (38%), fatigue (35%), and dysgeusia and vomiting (each 30%). Clinical benefit response rate was 53% (10/19) in the gedatolisib/stathmin-low arm and 26% (5/19) in the gedatolisib/stathmin-high arm. Safety profile and pharmacokinetic characteristics of both drugs in the Japanese lead-in cohort were comparable to the Western population.Conclusions. Gedatolisib administered by weekly intravenous infusion demonstrated acceptable tolerability and moderate activity in patients with recurrent endometrial cancer. PF-04691502 daily oral dosing was not well tolerated. Clinical benefit response criteria for proceeding to stage 2 were only met in the gedatolisib/stathmin-low arm. Stathmin-high expression did not correlate with greater treatment efficacy. (C) 2016 Published by Elsevier Inc.