医学
耐受性
药效学
不利影响
药理学
联合疗法
毒性
药代动力学
内科学
乳腺癌
肺癌
胃肠病学
癌症
作者
Nuria Kotecki,Perrine Vuagnat,Bert H. O’Neil,Shadia I. Jalal,Sylvie Rottey,Hans Prenen,Karim A. Benhadji,Meng Xia,Anna M. Szpurka,Abhijoy Saha,Johan Wallin,Subha Suriyapperuma,Violeta Régnier Galvão,Sandaruwan Geeganage,Thompson N. Doman,Leena Gandhi,Xiaojian Xu,Johanna C. Bendell
出处
期刊:Journal of Immunotherapy
[Ovid Technologies (Wolters Kluwer)]
日期:2021-04-27
卷期号:44 (7): 264-275
被引量:14
标识
DOI:10.1097/cji.0000000000000368
摘要
LY3381916 is an orally available, highly selective, potent inhibitor of indoleamine 2,3-dioxygenase 1. This study explored the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of LY3381916 monotherapy and in combination with a programmed death-ligand 1 (PD-L1) inhibitor (LY3300054) in patients with advanced solid tumors. During dose escalation, patients received escalating doses of LY3381916 at 60–600 mg once daily (qd) and 240 mg twice daily in monotherapy (n=21) and in combination with PD-L1 inhibitor at 700 mg every 2 weeks (n=21). A modified toxicity probability interval method was used to guide dose escalation. Dose-limiting toxicities occurred in 3 patients; 1 at LY3381916 240 mg twice daily (alanine aminotransferase/aspartate aminotransferase increase and systemic inflammatory response syndrome) and 2 at LY3381916 240 mg qd in combination with PD-L1 inhibitor (fatigue and immune-related hepatitis). LY3381916, at the recommended phase II dose, 240 mg qd, in combination with PD-L1 inhibitor, produced maximal inhibition of indoleamine 2,3-dioxygenase 1 activity in plasma and tumor tissue, and led to an increase of CD8 T cells in tumor tissue. In the combination dose expansion cohorts, 14 triple-negative breast cancer and 4 non–small cell lung cancer patients were enrolled. Treatment-related liver toxicity (grade ≥2 alanine aminotransferase/aspartate aminotransferase increase or immune-related hepatitis) was the most prominent adverse event in triple-negative breast cancer patients (n=5, 35.7%). Best response was stable disease. These preliminary data suggest an alternative dose level of LY3381916 is needed for the combination with PD-L1 inhibitor. The combination clinical activity was limited in this study.
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