PF-06952229 是转化生长因子-β (TGF-β) 受体 1 的选择性小分子抑制剂。我们在临床前研究中评估了其抗肿瘤活性，并在 I 期研究中评估了其安全性、耐受性、药代动力学和药效学 (NCT03685591) .进行了体外和体内临床前研究。患者（年龄≥18岁）接受PF-06952229单药治疗[20-500毫克，口服b.i.d.，7天用药/7天停药，28天周期，第1A部分（P1A）]用于晚期/转移性实体瘤和联合治疗[ 250/375 mg 与恩杂鲁胺，第 1B 部分 (P1B)] 用于治疗转移性去势抵抗性前列腺癌 (mCRPC)。主要终点是剂量限制性毒性（DLT）、不良事件（AE）和实验室异常。评估了功效、药代动力学参数和生物标志物调节。PF-06952229 在临床前小鼠肿瘤模型中显示出活性，包括肿瘤中的 pSMAD2 调节。该研究 (NCT03685591) 招募了 49 名患者（P1A，n = 42；P1B，n = 7）。接受 PF-06952229 375 mg 治疗的 P1A 患者中有 3/35 (8.6%) 报告出现 DLT（贫血、颅内肿瘤出血、贫血和高血压，均为 3 级，各 n = 1）。最常见的 3 级治疗相关 AE (TRAE) 是丙氨酸转氨酶升高和贫血（各 9.5%）。没有 4-5 级 TRAE。血浆 PF-06952229 暴露量与 80 至 375 mg 之间的剂量成比例。药效学研究证实了 pSMAD2/3（外周单核细胞）的靶向调节。一名接受 PF-06952229 375 mg 单药治疗的 P1A 前列腺癌患者取得了确认的部分缓解（缓解持续时间为 31 个月）。共有 8 名患者（P1A，n = 6；P1B，n = 2）病情稳定。在临床前研究中观察到 PF-06952229 的抗肿瘤活性。 PF-06952229 总体耐受性良好，毒性可控；一小部分患者取得了持久的缓解和/或疾病稳定。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

PF-06952229 is a selective small-molecule inhibitor of transforming growth factor-β (TGF-β) receptor 1. We evaluated its antitumor activity in preclinical studies and its safety, tolerability, pharmacokinetics, and pharmacodynamics in a phase I study (NCT03685591).In vitro and in vivo preclinical studies were conducted. Patients (aged ≥18 years) received PF-06952229 monotherapy [20-500 mg, oral b.i.d., 7 days on/7 days off, 28-day cycles, Part 1A (P1A)] for advanced/metastatic solid tumors and combination therapy [250/375 mg with enzalutamide, Part 1B (P1B)] for metastatic castration-resistant prostate cancer (mCRPC). Primary endpoints were dose-limiting toxicity (DLT), adverse events (AEs), and laboratory abnormalities. Efficacy, pharmacokinetic parameters, and biomarker modulation were assessed.PF-06952229 showed activity in preclinical murine tumor models including pSMAD2 modulation in tumors. The study (NCT03685591) enrolled 49 patients (P1A, n = 42; P1B, n = 7). DLTs were reported in 3/35 (8.6%) P1A patients receiving PF-06952229 375 mg (anemia, intracranial tumor hemorrhage, and anemia and hypertension, all grade 3, n = 1 each). The most frequent grade 3 treatment-related AEs (TRAEs) were alanine aminotransferase increased and anemia (9.5% each). There were no grade 4-5 TRAEs. Plasma PF-06952229 exposures were dose proportional between 80 and 375 mg. Pharmacodynamic studies confirmed target modulation of pSMAD2/3 (peripheral monocytes). One P1A patient with prostate cancer receiving PF-06952229 375 mg monotherapy achieved confirmed partial response (31-month duration of response). A total of 8 patients (P1A, n = 6; P1B, n = 2) achieved stable disease.Antitumor activity of PF-06952229 was observed in preclinical studies. PF-06952229 was generally well tolerated with manageable toxicity; a small group of patients achieved durable responses and/or disease stabilization.Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.