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

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.

SUBMITTER: Hong DS

PROVIDER: S-EPMC4621921 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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

Hong David S DS Rosen Peter P Lockhart A Craig AC Fu Siqing S Janku Filip F Kurzrock Razelle R Khan Rabia R Amore Benny B Caudillo Isaac I Deng Hongjie H Hwang Yuying C YC Loberg Robert R Ngarmchamnanrith Gataree G Beaupre Darrin M DM Lee Peter P

Oncotarget 20150701 21

<h4>Background</h4>This first-in-human study evaluated AMG 208, a small-molecule MET inhibitor, in patients with advanced solid tumors.<h4>Methods</h4>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.<h4>Results</h4>Fifty-four patient ...[more]

PMID: 26155941

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Project description:Introductionc-MET is an important therapeutic target for various cancers; however, the People's Republic of China currently retails only one specific c-MET inhibitor. Our preclinical study has revealed the high selectivity of HS-10241 to suppress c-MET. This phase 1 study aims to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of the selective c-MET inhibitor (HS-10241) in patients with advanced solid tumors.MethodsPatients with locally advanced or metastatic solid tumors orally received a single or multiple dose of HS-10241 once daily or twice daily for 21 consecutive days, which included the following six regimens: 100 mg once daily, 200 mg once daily, 400 mg once daily, 600 mg once daily, 200 mg twice daily, and 300 mg twice daily. The treatment continued until disease progression, unacceptable toxicity, or treatment termination. The primary end point was the incidence of dose-limiting toxicity and maximal tolerated dose (MTD). Secondary end points included safety, tolerability, pharmacokinetics, and pharmacodynamics.ResultsA total of 27 patients with advanced NSCLC received HS-10241, and dose-limiting toxicity was observed in three patients after 600 mg once-daily HS-10241 treatment. For once-daily dosing, MTD was 400 mg, and for twice-daily dosing, the maximal safe escalated dose was 300 mg, and MTD was not reached. Nausea (48.1%, 13 of 27), fatigue (37.0%, 10 of 27), and anemia (33.3%, 9 of 27) are the three most frequent treatment-emergent adverse events. At 400 mg once daily, Css,max was 5076 ng/mL and steady state area under the curve was 39,998 h × ng/mL. Patients (n = 5) with positive MET (MET exon 14-skipping, MET amplified, and MET immunohistochemistry 3+) had confirmed partial responses (n = 1) or stable disease (n = 3), with a disease control rate of 80.0%.ConclusionsThe selective c-MET inhibitor HS-10241 was well tolerated and had clinical activity in advanced NSCLC, especially in patients with positive MET. Furthermore, this study expounds on the therapeutic potential of HS-10241 in patients with cancer.

Dataset Information

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

Publications

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

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