Phase I Dose‐Escalation Study of Pilaralisib (SAR245408, XL147), a Pan‐Class I PI3K Inhibitor, in Combination With Erlotinib in Patients With Solid Tumors

• Published in: The oncologist (Dayton, Ohio) Ohio), 2015-03, Vol.20 (3), p.245-246
• Main Authors: Soria, Jean‐Charles, LoRusso, Patricia, Bahleda, Ratislav, Lager, Joanne, Liu, Li, Jiang, Jason, Martini, Jean‐François, Macé, Sandrine, Burris, Howard
• Format: Article
• Language: English
• Subjects: Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Carcinoma, Non-Small-Cell Lung - drug therapy; Clinical Trial Results; Dose-Response Relationship, Drug; Erlotinib Hydrochloride; Female; Humans; Lung Neoplasms - drug therapy; Male; Phosphatidylinositol 3-Kinase - antagonists & inhibitors; Quinazolines - administration & dosage; Quinazolines - pharmacokinetics; Quinoxalines - administration & dosage; Quinoxalines - pharmacokinetics; Sulfonamides - administration & dosage; Sulfonamides - pharmacokinetics; Treatment Outcome
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.2014-0449

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