Work

A first-in-human study of AMG 208, an oral MET inhibitor, in adult patients with advanced solid tumors

Year: 2015

Type: article

Abstract: // David S. Hong 1 , Peter Rosen 2 , A. Craig Lockhart 3 , Siqing Fu 1 , Filip Janku 1 , Razelle Kurzrock 1 , Rabia Khan 1 , Benny Amore 4 , Isaac Caudillo 5 , Hongjie Deng 5 , Yuying C. Hwang 5 , Robert Loberg 5 , Gataree Ngarmchamnanrith 5 , Darrin M. Beaupre 5 and Peter Lee 2 1 MD Anderson Cancer Center, Houston, TX, USA 2 Tower Cancer Research Foundation, Beverly Hills, CA, USA 3 Washington University School of Medicine, St. Louis, MO, USA 4 Amgen Inc., Seattle, WA, USA 5 Amgen Inc., Thousand Oaks, CA, USA Correspondence to: David S. Hong, email: // Keywords : MET, first-in-human, solid tumors, prostate cancer, small molecule Received : February 04, 2015 Accepted : May 30, 2015 Published : June 19, 2015 Abstract Background: This first-in-human study evaluated AMG 208, a small-molecule MET inhibitor, in patients with advanced solid tumors. Methods: Three to nine patients were enrolled into one of seven AMG 208 dose cohorts (25, 50, 100, 150, 200, 300, and 400 mg). Patients received AMG 208 orally on days 1 and days 4–28 once daily. The primary objectives were to evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of AMG 208. Results: Fifty-four patients were enrolled. Six dose-limiting toxicities were observed: grade 3 increased aspartate aminotransferase (200 mg), grade 3 thrombocytopenia (200 mg), grade 4 acute myocardial infarction (300 mg), grade 3 prolonged QT (300 mg), and two cases of grade 3 hypertension (400 mg). The MTD was not reached. The most frequent grade ≥3 treatment-related adverse event was anemia ( n = 3) followed by hypertension, prolonged QT, and thrombocytopenia (two patients each). AMG 208 exposure increased linearly with dose; mean plasma half-life estimates were 21.4–68.7 hours. One complete response (prostate cancer) and three partial responses (two in prostate cancer, one in kidney cancer) were observed. Conclusions: In this study, AMG 208 had manageable toxicities and showed evidence of antitumor activity, particularly in prostate cancer.

Source: Oncotarget

DOI: 10.18632/oncotarget.4472