Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China.
Suzhou Kintor Pharmaceuticals, Suzhou, Jiangsu, China.
Eur J Cancer. 2020 Jul;134:29-40. doi: 10.1016/j.ejca.2020.04.013. Epub 2020 May 24.
We conducted preclinical experiments and phase I clinical trial to investigate the safety, pharmacokinetics (PK) and antitumour effects of GT0918 in castration-resistant prostate cancer (CRPC).
An androgen receptor (AR) competitive binding assay was performed, followed by evaluation of GT0918 on AR protein expression. The efficacy of GT0918 was investigated in a castration-resistant xenograft model. A phase I dose-escalation study of GT0918 in CRPC was also carried out to evaluate its safety, PK and antitumour efficacy.
GT0918 was demonstrated to inhibit the binding of androgen to AR more potently than MDV3100, and to effectively reduce the AR protein level. GT0918 inhibited the transcriptional activity of wild-type AR and AR with clinically relevant ligand-binding domain mutations. Furthermore, GT0918 significantly inhibited the growth of prostate cancer. A total of 16 patients was treated with GT0918 at five dose levels. Among these 16 patients, 10 and 2 patients, respectively, completed a three-cycle and six-cycle treatment, in which MTD was not reached. All the treatment-related adverse events were grade I, including hypercholesterolemia, hypertriglyceridemia, fatigue and anaemia. PK parameters showed that drug exposure increased with dose proportionally from 50 to 300 mg and a saturation was observed between 300 and 400 mg. PSA declines of ≥30% and ≥50% were, respectively, observed in six and two cases. All the 12 patients with metastatic soft tissue lesions confirmed stable disease.
GT0918, a full AR antagonist without agonist effect, has high binding affinity to AR with AR protein down-regulation activity. GT0918 is demonstrated to be well tolerated with a favourable PK profile and exhibits promising antitumour activity in CRPC. CLINICALTRIALS: gov identifier CTR20150501.
我们进行了临床前实验和 I 期临床试验，以研究 GT0918 在去势抵抗性前列腺癌（CRPC）中的安全性、药代动力学（PK）和抗肿瘤作用。
进行了雄激素受体（AR）竞争性结合测定，然后评估了 GT0918 对 AR 蛋白表达的影响。在去势抵抗性异种移植模型中研究了 GT0918 的疗效。还进行了 GT0918 在 CRPC 中的 I 期剂量递增研究，以评估其安全性、PK 和抗肿瘤疗效。
GT0918 被证明比 MDV3100 更有效地抑制雄激素与 AR 的结合，并有效地降低 AR 蛋白水平。GT0918 抑制野生型 AR 和具有临床相关配体结合域突变的 AR 的转录活性。此外，GT0918 显著抑制前列腺癌的生长。共 16 例患者在五个剂量水平下接受 GT0918 治疗。在这 16 例患者中，分别有 10 例和 2 例患者完成了三个周期和六个周期的治疗，未达到最大耐受剂量。所有与治疗相关的不良事件均为 1 级，包括高胆固醇血症、高三酰甘油血症、疲劳和贫血。PK 参数显示，药物暴露随剂量呈比例增加，从 50 毫克增加到 300 毫克，300 毫克到 400 毫克之间存在饱和。分别有 6 例和 2 例患者的 PSA 下降≥30%和≥50%。所有 12 例转移性软组织病变患者均确认疾病稳定。
GT0918 是一种完全的 AR 拮抗剂，没有激动剂作用，对 AR 具有高结合亲和力，并具有下调 AR 蛋白的活性。GT0918 具有良好的耐受性、有利的 PK 特征，并在 CRPC 中显示出有希望的抗肿瘤活性。临床试验：gov 标识符 CTR20150501。
