Phase I Dose-Escalation Study of Pilaralisib (SAR245408, XL147), a Pan-Class I PI3K Inhibitor, in CombinationWith Erlotinib in Patients With Solid Tumors
Phase I Dose-Escalation Study of Pilaralisib (SAR245408, XL147), a Pan-Class I PI3K Inhibitor, in CombinationWith Erlotinib in Patients With Solid Tumors
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DOI：
10.1634/theoncologist.2014-0449
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发表时间：
2015-03-01
期刊：
影响因子：
5.8
通讯作者：
Burris, Howard
中科院分区：
文献类型：
--
作者：
Soria, Jean-Charles;LoRusso, Patricia;Burris, Howard
背景资料：这项I期研究评估了pilaralisib的最大耐受剂量（MTD）、安全性、药代动力学（PK）和药效学（SAR 245408），一种口服泛I类磷脂酰肌醇3-激酶（PI 3 K）抑制剂，与厄洛替尼（一种表皮生长因子受体（EGFR）抑制剂）联合。在一项3 + 3剂量递增研究中，晚期实体瘤患者每天接受一次pilaralisib胶囊（21天/28天周期; 50-600 mg）加厄洛替尼片剂每日一次（28天/28天周期; 100或150 mg）。一个MTD扩展队列的非小细胞肺癌患者谁曾接受过治疗与EGFR抑制剂included.Results：35例患者入组。只有1例患者存在EGFR激活突变。报告了1例剂量限制性毒性（4级药物反应或皮疹伴嗜酸性粒细胞增多和全身症状）。MTD为pilaralisib 400 mg+厄洛替尼150 mg。最常报告的治疗相关不良事件为皮疹（62.9%）、腹泻（42.9%）和疲乏（40.0%）。Pilaralisib PK结果与先前的研究一致，表明厄洛替尼对Pilaralisib的药代动力学没有影响。药效学分析表明，中度抑制PI 3 K，丝裂原活化蛋白激酶，EGFR途径。在27例可评价患者中，1例部分缓解（3.7%），14例疾病稳定（51.9%）。结论：匹拉里斯联合厄洛替尼抗肿瘤活性有限。安全性结果与最近单药pilaralisib或其他PI 3 K抑制剂的研究相似。
Background: This phase I study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of pilaralisib (SAR245408), an oral pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, in combination with erlotinib, an epidermal growth factor receptor (EGFR) inhibitor.Methods: In a 3 + 3 dose-escalation study, patients with advanced solid tumors received pilaralisib capsules once daily (21 days per 28-day cycle; 50-600 mg) plus erlotinib tablets once daily (28 days per 28-day cycle; 100 or 150 mg). An MTD expansion cohort of patients with non-small cell lung cancer who had previously received treatment with an EGFR inhibitor was included.Results: Thirty-five patients were enrolled. Only one patient had an EGFR activating mutation. One dose-limiting toxicity was reported (grade 4 drug reaction or rash with eosinophilia and systemic symptoms). MTD was pilaralisib 400 mg plus erlotinib 150 mg. The most commonly reported treatment-related adverse events were rash (62.9%), diarrhea (42.9%), and fatigue (40.0%). Pilaralisib PK findings were consistent with previous studies, suggesting erlotinib had no effect on pilaralisib pharmacokinetics. Pharmacodynamic analyses indicated moderate inhibition of PI3K, mitogen-activated protein kinase, and EGFR pathways. Of 27 evaluable patients, one had a partial response (3.7%) and 14 (51.9%) had stable disease. There was no association between molecular alterations of PI3K pathway components and clinical activity.Conclusion: Pilaralisib plus erlotinib had limited antitumor activity. Safety findings were similar to recent studies of single-agent pilaralisib or other PI3K inhibitors.