LBPO.ET04 · 实验与分子治疗 · Late-Breaking
EP4拮抗剂HTL0039732的药代动力学——一项针对晚期实体瘤患者的CRUK首次人体I期临床试验
Pharmacokinetics of the EP4 antagonist HTL0039732, a CRUK first-in-human phase I trial in patients with advanced solid tumours
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摘要 Abstract
中文摘要
背景：HTL0039732是一种口服给药的EP4拮抗剂。在成功完成临床前研究后，启动了一项HTL0039732的首次人体I期临床试验，包括单药治疗以及与免疫检查点抑制剂联合治疗。我们在此报告该CRUK研究中HTL0039732的药代动力学。
方法：分别有13例和22例晚期实体瘤患者被分配至单药治疗队列和联合治疗队列。在第-7天，单药治疗患者在空腹状态下接受单次口服剂量的HTL0039732（80-640 mg）。从第1天开始，所有患者以21天为一个周期每日给药（80-640 mg）。从第2周期起，联合治疗队列引入阿替利珠单抗（atezolizumab），以1200 mg输注、每21天一次。药代动力学采样在第-7天（仅单药治疗）单次给药后1、2、4、6、10、24、48和72小时进行，并在所有队列的第1周期第1天（至24小时）和第8天（至10小时）进行。80、160和320 mg剂量的单药治疗患者在第1周期第1天接受名义剂量的25%，随后从第2天起恢复至名义剂量，以评估剂量依赖性；而640 mg单药治疗队列则用于评估食物效应。样品采用经过完整验证的LC-MS/MS方法进行分析，定量下限（LLOQ）为10 ng/mL。进行药代动力学分析以确定Cmax、Tmax、曲线下面积（AUC）、血浆半衰期、表观清除率（CL/F）和表观分布容积（Vz/F）。
结果：单次给药HTL0039732后的药代动力学数据见表1（视情况以范围或均值±SD表示）。暴露量总体上与剂量水平成比例（基于Cmax和AUC）。半衰期、CL/F和Vz/F在各剂量水平间一致。未观察到食物效应。
结论：来自HTL0039732首次人体I期临床试验的药代动力学数据显示，药物暴露量随剂量呈依赖性增加。已选定每日一次160 mg剂量水平作为RP2D（推荐的II期剂量）。
表1。第-7天和第1天HTL0039732汇总药代动力学数据摘要 剂量水平（mg） 患者例数 Cmax（µg/mL） AUC 0-24h（µg/mL.h） 半衰期（h） CL/F（L/h） Vz/F（L） 80 7 1.68 - 3.78 28.0 ± 5.76 26.2 ± 14.6 1.54 ± 0.400 52.7 ± 19.8 160 9 2.70 - 7.42 55.6 ± 12.9 26.1 ± 19.7 1.81 ± 1.09 49.3 ± 17.1 320 12 4.76 - 19.2 108 ± 42.9 20.0 ± 12.8 2.26 ± 1.01 53.4 ± 17.8 640 7 11.1 - 31.0 263 ± 53.7 25.2 ± 19.2 1.56 ± 0.790 44.9 ± 19.9
查看英文原文 English abstract
Background: HTL0039732 is an orally administered antagonist of EP4. Following successful preclinical trials, a first-in-human phase I trial of HTL0039732, both as monotherapy and in combination with immune checkpoint inhibition, was initiated. We report the pharmacokinetics of HTL0039732 in this CRUK study.
Methods: 13 and 22 patients with advanced solid tumours were allocated to the monotherapy and combination cohorts, respectively. On Day -7, monotherapy patients received a single oral dose of HTL0039732 (80-640 mg) in a fasted state. From Day 1, all patients received daily administration (80-640 mg) in 21-day cycles. Atezolizumab was introduced to the combination cohort from Cycle 2 onwards as a 1200 mg infusion once every 21 days. Pharmacokinetic sampling took place on Day -7 (monotherapy only), following a single dose at 1, 2, 4, 6, 10, 24, 48 and 72 hours, and in all cohorts on Days 1 (up to 24 hours) and 8 (up to 10 hours) of the first cycle. Monotherapy patients on the 80, 160 and 320 mg doses received 25% of the nominal dose on Day 1 of Cycle 1, followed by a return to the nominal dose from Day 2 onwards to evaluate dose dependency, while the 640 mg monotherapy cohort was used to evaluate food effect. Samples were analysed using a fully validated LC-MS/MS assay with a LLOQ of 10 ng/mL. Pharmacokinetic analysis was performed to determine Cmax, Tmax, area under the curve (AUC), plasma half-life, apparent clearance (CL/F) and apparent volume of distribution (Vz/F).
Results: Pharmacokinetic data following a single dose of HTL0039732 are presented in Table 1 (expressed as range or mean ±SD as appropriate). Exposure was generally proportional to dose level (based on Cmax and AUC). Half-life, CL/F and Vz/F were consistent across dose levels. No food effect was observed.
Conclusion: Pharmacokinetic data generated from a first-in-human phase I trial of HTL0039732 show dose dependent increases in drug exposure. A once daily 160 mg dose level has been selected as the RP2D.
Table 1. Summary of pooled HTL0039732 pharmacokinetic data from Day -7 and Day 1 Dose level (mg) Number of patients Cmax (µg/mL) AUC 0-24h
(µg/mL.h) Half-life
(h) CL/F
(L/h) Vz/F
(L) 80 7 1.68 - 3.78 28.0 ± 5.76 26.2 ± 14.6 1.54 ± 0.400 52.7 ± 19.8 160 9 2.70 - 7.42 55.6 ± 12.9 26.1 ± 19.7 1.81 ± 1.09 49.3 ± 17.1 320 12 4.76 - 19.2 108 ± 42.9 20.0 ± 12.8 2.26 ± 1.01 53.4 ± 17.8 640 7 11.1 - 31.0 263 ± 53.7 25.2 ± 19.2 1.56 ± 0.790 44.9 ± 19.9
利益披露 Disclosure
D. Astley, None..
S. Barnett, None.
B. Basu,
Genmab A/S; Elsai; Roche Other, Advisory Board, I waiver all fees to University of Cambridge via Cambridge Enterprise, the Consultancy arm of the University of Cambridge.
Eisai Europe Limited ).
Roche ).
Cycle Pharma ).
Celgene ).
Incyte ).
Merck ).
Bicycle Therepeutics ).
Exact Therapeutics ).
MiNa Therapeutics ).
Corbus Therapeutics ).
AstraZeneca ), Other, Coordinating PI.
Nxera Pharma UK Ltd Other, Coordinating PI, Chief Investigator.
D. Sarker,
Eisai; Ipsen; Bayer; AAA; AbbVie; Boehringer Ingelheim; AstraZeneca; Incyte; Servier; Pfizer Other, Advisory Board.
MSD; Bayer; AstraZeneca; Eisai; Servier; Incyte; Servier; Ipsen Other, Invited Speaker.
Ipsen; Servier Travel.
UCB; MiNA Therapeutics; Moderna; Relay Therapeutics Other, Coordinating PI.
Eisai; Medivir AB; MSD; Bayer; RedX; GSK; Starpharma; Adaptimmune; Blueprint; H3; Regeneron; Taiho; AstraZeneca; Ipsen; AstraZeneca; Roche Other, Local PI.
Roche; Inspirata; Kinomica ).
N. Cook,
Roche Independent Contractor, ).
Taiho ).
AstraZeneca ).
Avacta ).
Bayer ).
Eisai ).
UCB Pharma ).
Boeringher ).
RedX ).
Orion ).
Starpharma ).
LOXO-Oncology ).
S. N. Symeonides,
Ellipses; Medannex; Eisai; MSD; Pfizer; Merck Serono; Duke Street Bio; Exscientia; Grey Wolf Therapeutics; Roche Other, Advisory Board.
Ipsen; MSD; Roche; Eisai Other, Invited Speaker.
Valley Health; Exscientia; Grey Wolf Therapeutics Other, Independent Data / Safety Monitoring.
MSD; Verastem ).
MSD; BioNTech; Nouscom Other, Coordinating PI.
Roche; Nucana; Sapience Therapeutics; BioLineRx; Boston Pharmaceuticals; Sierra Oncology; Incyte; Scancell; Medannex Other, Steering Committee Member.
S. Svetlik, None..
D. Spencer-Briggs, None.
G. Scarfe,
Nxera Pharma Employment, Stock.
AstraZeneca Stock.
N. Swain,
Nxera Pharma Employment, Stock.
Pfizer Stock.
G. J. Veal, None.