选择性口服 MEK1/2 抑制剂 Pimasertib：晚期实体瘤患者的 I 期临床试验。

Selective Oral MEK1/2 Inhibitor Pimasertib: A Phase I Trial in Patients with Advanced Solid Tumors.

机构信息

Clinical Research Unit, Institut Universitaire du Cancer, Oncopole, Toulouse, France.

Early Phase Trials and Sarcoma Units, Institut Bergonie, Bordeaux, France.

出版信息

Target Oncol. 2021 Jan;16(1):37-46. doi: 10.1007/s11523-020-00768-0.

DOI:10.1007/s11523-020-00768-0

PMID:33170484

Abstract

BACKGROUND

The Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (Ras/Raf/MEK/ERK) signaling cascade is frequently constitutively activated in human cancers. Pimasertib is a selective and potent adenosine triphosphate non-competitive MEK1/2 inhibitor.

OBJECTIVE

Our objectives were to describe the results of a phase I, first-in-human, dose-escalation trial of pimasertib that investigated the maximum tolerated dose, recommended phase II dose, and safety, as well as other endpoints.

PATIENTS AND METHODS

Four dosing schedules of pimasertib (once daily [qd], 5 days on, 2 days off; qd, 15 days on, 6 days off; continuous qd; continuous twice daily [bid]) were evaluated in patients with advanced solid tumors. Each treatment cycle lasted 21 days. The primary objective was to determine the maximum tolerated dose based on dose-limiting toxicities (DLTs) evaluated during cycle 1, and the recommended phase II dose (RP2D). Secondary objectives included safety, pharmacokinetics, pharmacodynamics, and antitumor activity.

RESULTS

Overall, 180 patients received pimasertib (dose range 1-255 mg/day). DLTs were mainly observed at doses ≥ 120 mg/day and included skin rash/acneiform dermatitis and ocular events, such as serous retinal detachment. The most common drug-related adverse events were consistent with class effects, including diarrhea, skin disorders, ocular disorders, asthenia/fatigue, and peripheral edema. The median time to maximum pimasertib concentration was 1.5 h across dosing schedules, and the apparent terminal half-life was 5 h across qd dosing schedules. Pimasertib decreased ERK phosphorylation within 2 h of administration, which was maintained for up to 8 h at higher doses and prolonged with bid dosing.

CONCLUSIONS

Based on the safety profile and efficacy signals, a continuous bid regimen was the preferred dosing schedule and the RP2D was defined as 60 mg bid.

TRIAL REGISTRATION

ClinicalTrials.gov, NCT00982865.

摘要

背景

Ras/Raf/丝裂原活化蛋白激酶激酶/细胞外信号调节激酶（Ras/Raf/MEK/ERK）信号通路在人类癌症中经常被组成性激活。Pimasertib 是一种选择性和有效的三磷酸腺苷非竞争性 MEK1/2 抑制剂。

目的

我们的目的是描述一项 I 期、首次人体、剂量递增试验的结果，该试验研究了 pimasertib 的最大耐受剂量、推荐的 II 期剂量以及安全性和其他终点。

患者和方法

评估了 4 种 pimasertib 给药方案（每日一次 [qd]，连续 5 天，停药 2 天；qd，连续 15 天，停药 6 天；连续 qd；连续每日两次 [bid]）在晚期实体瘤患者中的应用。每个治疗周期持续 21 天。主要目标是根据第 1 周期中评估的剂量限制毒性（DLT）确定最大耐受剂量，以及推荐的 II 期剂量（RP2D）。次要目标包括安全性、药代动力学、药效学和抗肿瘤活性。

结果

总体而言，180 名患者接受了 pimasertib（剂量范围为 1-255mg/天）。剂量≥120mg/天时主要观察到剂量限制毒性，包括皮疹/痤疮样皮炎和眼部事件，如浆液性视网膜脱离。最常见的药物相关不良事件与类效应一致，包括腹泻、皮肤疾病、眼部疾病、乏力/疲劳和外周水肿。在所有给药方案中，pimasertib 达峰时间的中位数为 1.5 小时，qd 给药方案的表观终末半衰期为 5 小时。pimasertib 在给药后 2 小时内降低 ERK 磷酸化，在较高剂量下可维持长达 8 小时，并随着 bid 给药而延长。