A phase IB dose-escalation study of the safety and pharmacokinetics of pictilisib in combination with either paclitaxel and carboplatin (with or without bevacizumab) or pemetrexed and cisplatin (with or without bevacizumab) in patients with advanced non-small cell lung cancer.
一项 IB 期剂量递增研究,研究了匹替利司联合紫杉醇和卡铂 (含或不含贝伐单抗) 或培美曲塞和顺铂 (含或不含贝伐单抗) 的安全性和药代动力学。晚期非小细胞肺癌患者。
Bevacizumab Carboplatin Cisplatin First-line NSCLC Front-line NSCLC Metastatic NSCLC Non–small cell lung Paclitaxel Pemetrexed Phosphatidylinositol 3-kinase
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摘要

AIM:The phosphatidylinositol 3-kinase (PI3K) pathway is a potential therapeutic target in non-small cell lung cancer (NSCLC). This study aimed to evaluate the pan-PI3K inhibitor pictilisib in combination with first-line treatment regimens that were the standard of care at the time of study, in patients with NSCLC.
PATIENTS AND METHODS:A 3 + 3 dose-escalation study was performed using a starting daily dose of 60 mg pictilisib on days 1-14 of a 21-day cycle. Depending on bevacizumab eligibility and NSCLC histology, patients also received either paclitaxel + carboplatin or pemetrexed + cisplatin, ± bevacizumab every 3 weeks. The primary objectives of the study were to assess safety and tolerability and to identify dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD) and a recommended phase II dose (RP2D), for each combination.
RESULTS:All 66 treated patients experienced at least one adverse event (AE). Grade ≥III AEs, serious AEs and deaths occurred in 57 (86.4%), 56 (84.8%) and 9 (13.6%) patients, respectively. Three patients reported DLTs across the four arms of the study. The MTD was not reached in any arm and the RP2D of pictilisib was determined to be 330 mg (capsules) or 340 mg (tablets) on a '14 days on, 7 days off' schedule. The best confirmed response was partial response in 29 (43.9%) patients and stable disease in 20 (30.9%) patients.
CONCLUSION:Combining pictilisib with various standard-of-care first-line treatment regimens is feasible from a safety perspective in patients with NSCLC, and encouraging preliminary anti-tumour activity was observed.

译文

目的: 磷脂酰肌醇 3-激酶 (PI3K) 通路是非小细胞肺癌的潜在治疗靶点。本研究旨在评估 pan-PI3K 抑制剂 pictilisib 与一线治疗方案的联合应用,一线治疗方案是研究时的标准治疗方案。
患者和方法: 在 21 天周期的第 1-14 天,使用 60 mg pictilisib 的起始日剂量进行 3 3 剂量递增研究。根据贝伐珠单抗的资格和非小细胞肺癌组织学,患者还每 3 周接受紫杉醇卡铂或培美曲塞顺铂 ± 贝伐珠单抗。该研究的主要目的是评估安全性和耐受性,并确定剂量限制毒性 (DLTs) 、最大耐受剂量 (MTD) 和推荐的第二阶段剂量 (RP2D), 对于每个组合。
结果: 所有 66 名接受治疗的患者都经历了至少一次不良事件 (AE)。分级 ≥ ⅲ 级的不良事件、严重不良事件和死亡分别发生在 57 例 (86.4%) 、 56 例 (84.8%) 和 9 例 (13.6%) 患者中。三名患者报告了研究的四个部分的 DLTs。在任何一个 arm 中都没有达到 MTD,并且在 “14 天,7 天” 的时间表中,pictilisib 的 RP2D 被确定为 330 毫克 (胶囊) 或 340 毫克 (片剂)。最佳确认应答是 29 例 (43.9%) 患者的部分应答和 20 例 (30.9%) 患者的稳定疾病。
结论: 从安全性的角度来看,将 pictilisib 与各种标准护理一线治疗方案相结合在非小细胞肺癌患者中是可行的,并观察到鼓励初步的抗肿瘤活性。

Pemetrexed

肿瘤 恶性胸膜间皮瘤、肺癌 药物
概述  :  

培美曲塞是一种胸苷酸合酶/二氢叶酸还原酶双重抑制剂,由礼来公司作为抗代谢类抗癌药进行开发。该品是一种多靶点抗叶酸制剂,属于抗代谢类药物。通过破坏细胞内叶酸依赖性的正常代谢过程,抑制DNA合成和细胞复制,从而抑制肿瘤增长。 2002年,礼来培美曲塞以孤儿药身份被FDA批准与顺铂联用治疗恶性胸膜间皮瘤,随后又先后于2004年、2008年、2009年获批非鳞状非小细胞肺癌二线治疗、一线治疗以及维持治疗。本品主要成份为培美曲塞二钠,分子量:597.49。性状方面

Pemetrexed

释    义   n. 培美曲塞

例    句   Maintenance therapy with the drug pemetrexed improves the survival of people with non-small-cell lung cancer whose disease has not progressed after chemotherapy, a new study has found. 一项新的研究发现,使用培美曲塞药物进行的保守治疗,可以非小细胞肺癌患者的存活率,且在化疗之后疾病没有进展。

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