Activity of preclinical and phase I clinical trial of a novel androgen receptor antagonist GT0918 in metastatic breast cancer
| Autor: | Guohong Song, Jiayang Zhang, Qingqing Zhou, Honghua Yan, Ye Sun, Meiyu Wang, Ruyan Zhang, Qiaoxia Zhou, Hanfang Jiang, Huiping Li, Youzhi Tong, Yaxin Liu, Qianxiang Zhou, Xunwei Dong, Liandong Ma, Ran Ran, Luping Meng |
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| Rok vydání: | 2021 |
| Předmět: |
Oncology
Cancer Research medicine.medical_specialty Anemia Preclinical data Phases of clinical research Breast Neoplasms Mice Breast cancer Androgen receptor antagonist GT0918 Pharmacokinetics Internal medicine Androgen Receptor Antagonists medicine Animals Humans Oxazoles Proxalutamide business.industry Cancer medicine.disease Clinical Trial Metastatic breast cancer Metastasis breast cancer Thiohydantoins Receptors Androgen Phase I clinical trial Absolute neutrophil count Female business |
| Zdroj: | Breast Cancer Research and Treatment |
| ISSN: | 1573-7217 0167-6806 |
| Popis: | Purpose To evaluate GT0918, a 2nd-generation AR antagonist, for its AR down-regulation activity among breast cancer patients. Methods The effect of GT0918 on AR protein expression was evaluated in AR expression breast cancer cells and in breast cancer xenograft model. A 3 + 3 phase I dose-escalation study was launched in Peking University Cancer Hospital. The endpoints included dose finding, safety, pharmacokinetics, and antitumor activity. Results GT0918 was demonstrated to effectively suppress the expression of AR protein and the growth of AR-positive breast cancer tumors in mouse xenograft tumor models. All patients treated with GT0918 were at a QD dose-escalation of five dose levels from 100 to 500 mg. The most common treatment-related AEs of any grade were asthenia, anemia, decreased appetite, increased blood cholesterol, increased blood triglycerides, decreased white blood cell count, and increased low-density lipoprotein. Grade 3 AEs were fatigue (2 of 18, 11.1%), aspartate aminotransferase increase (1 of 18, 5.6%), alanine aminotransferase increase (1 of 18, 5.6%), and neutrophil count decrease (1 of 18, 5.6%). Clinical benefit rate (CBR) in 16 weeks was 23.1% (3/13). Among 7 AR-positive patients, 6 can evaluate efficacy, and 2 completed 23.5- and 25-cycle treatment, respectively (as of 2020/1/20). PK parameters showed a fast absorption profile of GT0918 in the single-dose study. GT0918 and its major metabolite reached steady-state serum concentration levels at day 21 after multiple dosing. Conclusion GT0918 can effectively inhibit AR-positive breast cancer tumor growth. GT0918 was demonstrated well tolerated with a favorable PK profile. The suitable dose of GT0918 was 500 mg QD and may provide clinical benefits for AR-positive mBC. |
| Databáze: | OpenAIRE |
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