Faculty Collaboration Database

A first-in-human study of AMG 208, an oral MET inhibitor, in adult patients with advanced solid tumors. Oncotarget 2015 Jul 30;6(21):18693-706

Date

07/15/2015

Pubmed ID

26155941

Pubmed Central ID

PMC4621921

DOI

10.18632/oncotarget.4472

Scopus ID

2-s2.0-84938800976 (requires institutional sign-in at Scopus site)   24 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.

Author List

Hong DS, Rosen P, Lockhart AC, Fu S, Janku F, Kurzrock R, Khan R, Amore B, Caudillo I, Deng H, Hwang YC, Loberg R, Ngarmchamnanrith G, Beaupre DM, Lee P

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Administration, Oral
Adult
Aged
Aged, 80 and over
Area Under Curve
Biomarkers, Tumor
Dose-Response Relationship, Drug
Fatigue
Female
Humans
Hypertension
Immunohistochemistry
In Situ Hybridization, Fluorescence
Male
Metabolic Clearance Rate
Middle Aged
Nausea
Neoplasms
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-met
Pyridazines
Remission Induction
Treatment Outcome
Triazoles