TY - JOUR
T1 - A first-in-human study of AMG 208, an oral MET inhibitor, in adult patients with advanced solid tumors
AU - Hong, David S.
AU - Rosen, Peter
AU - Lockhart, A. Craig
AU - Fu, Siqing
AU - Janku, Filip
AU - Kurzrock, Razelle
AU - Khan, Rabia
AU - Amore, Benny
AU - Caudillo, Isaac
AU - Deng, Hongjie
AU - Hwang, Yuying C.
AU - Loberg, Robert
AU - Ngarmchamnanrith, Gataree
AU - Beaupre, Darrin M.
AU - Lee, Peter
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - First-in-human
KW - MET
KW - Prostate cancer
KW - Small molecule
KW - Solid tumors
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U2 - 10.18632/oncotarget.4472
DO - 10.18632/oncotarget.4472
M3 - Article
C2 - 26155941
AN - SCOPUS:84938800976
SN - 1949-2553
VL - 6
SP - 18693
EP - 18706
JO - Oncotarget
JF - Oncotarget
IS - 21
ER -