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

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

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)18693-18706
Number of pages14
JournalOncotarget
Volume6
Issue number21
DOIs
StatePublished - 2015

Keywords

  • First-in-human
  • MET
  • Prostate cancer
  • Small molecule
  • Solid tumors

ASJC Scopus subject areas

  • Oncology

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    Hong, D. S., Rosen, P., Lockhart, A. C., Fu, S., Janku, F., Kurzrock, R., Khan, R., Amore, B., Caudillo, I., Deng, H., Hwang, Y. C., Loberg, R., Ngarmchamnanrith, G., Beaupre, D. M., & Lee, P. (2015). A first-in-human study of AMG 208, an oral MET inhibitor, in adult patients with advanced solid tumors. Oncotarget, 6(21), 18693-18706. https://doi.org/10.18632/oncotarget.4472