背景: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及其安全性,耐受性,药代动力学,和药效学的I期研究(NCT03685591)。
方法:进行体外和体内临床前研究。患者(年龄≥18岁)接受PF-06952229单药治疗[20-500mg,口服b.i.d.,7天/7天休息,28天周期,部分1A(P1A)]用于晚期/转移性实体瘤和联合治疗[250/375mg与恩杂鲁胺,第1B部分(P1B)]用于转移性去势抗性前列腺癌(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。功效,药代动力学参数,和生物标志物调节进行了评估。
结果:PF-06952229在临床前鼠肿瘤模型中显示活性,包括肿瘤中的pSMAD2调节。该研究(NCT03685591)纳入了49例患者(P1A,n=42;P1B,n=7)。在接受PF-06952229375mg(贫血,颅内肿瘤出血,贫血和高血压,所有3年级,每个n=1)。最常见的3级治疗相关AE(TRAEs)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的暴露剂量在80至375mg之间成比例。药效学研究证实了pSMAD2/3(外周单核细胞)的靶调节。一名接受PF-06952229375mg单一疗法的前列腺癌患者获得了确认的部分反应(反应持续时间为31个月)。共有8名患者(P1A,n=6;P1B,n=2)取得病情稳定。
结论:在临床前研究中观察到PF-06952229的抗肿瘤活性。PF-06952229通常耐受良好,毒性可控;一小群患者获得了持久的反应和/或疾病稳定。
BACKGROUND: 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).
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.