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

  • Author(s): Hong, David S
  • Rosen, Peter
  • Lockhart, A Craig
  • Fu, Siqing
  • Janku, Filip
  • Kurzrock, Razelle
  • Khan, Rabia
  • Amore, Benny
  • Caudillo, Isaac
  • Deng, Hongjie
  • Hwang, Yuying C
  • Loberg, Robert
  • Ngarmchamnanrith, Gataree
  • Beaupre, Darrin M
  • Lee, Peter
  • et al.
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.

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