Phase I dose-escalation study of pilaralisib (SAR245408, XL147), a pan-class I PI3K inhibitor, in combination with erlotinib in patients with solid tumors

Oncologist. 2015 Mar;20(3):245-6. doi: 10.1634/theoncologist.2014-0449. Epub 2015 Feb 10.

Abstract

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.

摘要

背景. 本项I期研究评估了口服泛I型磷脂酰肌醇3-激酶(PI3K)抑制剂Pilaralisib(SAR245408)联合表皮生长因子受体(EGFR)抑制剂厄洛替尼的最大耐受剂量(MTD)、安全性、药代动力学(PK)以及药效动力学特征。

方法. 采取3 + 3剂量递增设计,对晚期实体瘤患者给予pilaralisib胶囊每日1次(用药21天,每28天为1周期;50 ∼ 600 mg)联合厄洛替尼片剂每日1次(用药28天,每28天为1周期;100或150 mg)治疗。既往接受过EGFR抑制剂的非小细胞肺癌患者纳入MTD扩大队列。

结果. 入组35例患者。仅1例患者携带EGFR激活突变。报告了1例剂量限制性毒性反应(4级;药物反应或皮疹伴嗜酸性粒细胞增多以及全身症状)。MTD为Pilaralisib 400 mg联合厄洛替尼150 mg。最常报告的治疗相关不良事件包括皮疹(62.9%)、腹泻(42.9%)以及乏力(40.0%)。Pilaralisib PK结果与既往研究一致,提示厄洛替尼对pilaralisib药代动力学无影响。药效动力学分析表明对PI3K、促丝裂原活化蛋白激酶以及EGFR通路有中度抑制。27例可评估患者中,1例(3.7%)部分缓解,14例(51.9%)疾病稳定。PI3K通路分子改变与临床活性之间无相关性。

结论. Pilaralisib联合厄洛替尼抗肿瘤活性有限。安全性结果与最近pilaralisib或其他PI3K抑制剂单药研究结果类似。The Oncologist 2015; 20:245–246

Trial registration: ClinicalTrials.gov NCT00692640.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Dose-Response Relationship, Drug
  • Erlotinib Hydrochloride
  • Female
  • Humans
  • Lung Neoplasms / drug therapy*
  • Male
  • Phosphoinositide-3 Kinase Inhibitors*
  • Quinazolines / administration & dosage*
  • Quinazolines / pharmacokinetics
  • Quinoxalines / administration & dosage*
  • Quinoxalines / pharmacokinetics
  • Sulfonamides / administration & dosage*
  • Sulfonamides / pharmacokinetics
  • Treatment Outcome

Substances

  • Phosphoinositide-3 Kinase Inhibitors
  • Quinazolines
  • Quinoxalines
  • Sulfonamides
  • XL147
  • Erlotinib Hydrochloride

Associated data

  • ClinicalTrials.gov/NCT00692640