Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Br J Cancer. 2019 Aug;121(4):318-324. doi: 10.1038/s41416-019-0517-3. Epub 2019 Jul 15.
CFI-400945 is a first-in-class oral inhibitor of polo-like kinase 4 (PLK4) that regulates centriole duplication. Primary objectives of this first-in-human phase 1 trial were to establish the safety and tolerability of CFI-400945 in patients with advanced solid tumours. Secondary objectives included pharmacokinetics, pharmacodynamics, efficacy, and recommended phase 2 dose (RP2D).
Continuous daily oral dosing of CFI-400945 was evaluated using a 3+3 design guided by incidence of dose-limiting toxicities (DLTs) in the first 28-day cycle. Safety was assessed by CTCAE v4.0. ORR and CBR were evaluated using RECIST v1.1.
Forty-three patients were treated in dose escalation from 3 to 96 mg/day, and 9 were treated in 64 mg dose expansion. After DLT occurred at 96 and 72 mg, 64 mg was established as the RP2D. Neutropenia was a common high-grade (19%) treatment-related adverse event at ≥ 64 mg. Half-life of CFI-400945 was 9 h, with C achieved 2-4 h following dosing. One PR (45 cycles, ongoing) and two SD ≥ 6 months were observed (ORR = 2%; CBR = 6%).
CFI-400945 is well tolerated at 64 mg with dose-dependent neutropenia. Favourable pharmacokinetic profiles were achieved with daily dosing. Response rates were low without biomarker pre-selection. Disease-specific and combination studies are ongoing.
Clinical Trials Registration Number - NCT01954316 (Oct 1st, 2013).
CFI-400945 是一种首创的口服 Polo 样激酶 4（PLK4）抑制剂，可调节中心体复制。这项首次人体 I 期试验的主要目的是确定 CFI-400945 在晚期实体瘤患者中的安全性和耐受性。次要目标包括药代动力学、药效学、疗效和推荐的 II 期剂量（RP2D）。
采用 3+3 设计，根据前 28 天周期中剂量限制毒性（DLT）的发生率指导连续每日口服 CFI-400945 给药。使用 CTCAE v4.0 评估安全性。根据 RECIST v1.1 评估 ORR 和 CBR。
43 名患者在剂量递增至 3 至 96mg/天，9 名患者在 64mg 剂量扩展中接受治疗。在 96 和 72mg 时发生 DLT 后，确定 64mg 为 RP2D。≥64mg 时，中性粒细胞减少是一种常见的高级（19%）与治疗相关的不良事件。CFI-400945 的半衰期为 9 小时，给药后 2-4 小时达到 C 最大值。观察到 1 例 PR（45 个周期，持续进行中）和 2 例 SD≥6 个月（ORR=2%；CBR=6%）。
CFI-400945 在 64mg 时耐受良好，剂量依赖性中性粒细胞减少。每日给药可实现有利的药代动力学特征。在没有生物标志物预选择的情况下，反应率较低。正在进行疾病特异性和联合研究。
临床试验注册号-NCT01954316（2013 年 10 月 1 日）。
