期刊
EUROPEAN JOURNAL OF CANCER
卷 134, 期 -, 页码 29-40出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2020.04.013
关键词
Castration-resistant prostate cancer; Androgen receptor antagonist; GT0918; Phase I
类别
资金
- Shanghai Changhai GCP Platform - National Major Scientific and Technological Special Project for 'Significant New Drugs Development' [2017ZX09304030]
- Shanghai Sailing Program [18YF1422600]
- Second Military Medical University Youth Program [2016QN12]
Purpose: We conducted preclinical experiments and phase I clinical trial to investigate the safety, pharmacokinetics (PK) and antitumour effects of GT0918 in castrationresistant prostate cancer (CRPC). Experimental design: 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. Results: 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. Conclusions: 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. (C) 2020 Elsevier Ltd. All rights reserved.
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