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

BackgroundThis first-in-human study evaluated AMG 208, a small-molecule MET inhibitor, in patients with advanced solid tumors.MethodsThree 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.ResultsFifty-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.ConclusionsIn this study, AMG 208 had manageable toxicities and showed evidence of antitumor activity, particularly in prostate cancer

Pharmacodynamic effect of bempedoic acid and statin combinations: predictions from a dose–response model

Aims Many patients are unable to achieve guideline-recommended LDL cholesterol (LDL-C) targets, despite taking maximally tolerated lipid-lowering therapy. Bempedoic acid, a competitive inhibitor of ATP citrate lyase, significantly lowers LDL-C with or without background statin therapy in diverse populations. Because pharmacodynamic interaction between statins and bempedoic acid is complex, a dose-response model was developed to predict LDL-C pharmacodynamics following administration of statins combined with bempedoic acid. Methods And Results Bempedoic acid and statin dosing and LDL-C data were pooled from 14 phase 1-3 clinical studies. Dose-response models were developed for bempedoic acid monotherapy and bempedoic acid-statin combinations using previously published statin parameters. Simulations were performed using these models to predict change in LDL-C levels following treatment with bempedoic acid combined with clinically relevant doses of atorvastatin, rosuvastatin, simvastatin, and pravastatin. Dose-response models predicted that combining bempedoic acid with the lowest statin dose of commonly used statins would achieve a similar degree of LDL-C lowering as quadrupling that statin dose" for example, the predicted LDL-C lowering was 54% with atorvastatin 80 mg compared with 54% with atorvastatin 20 mg + bempedoic acid 180 mg, and 42% with simvastatin 40 mg compared with 46% with simvastatin 10 mg + bempedoic acid 180 mg. Conclusion These findings suggest bempedoic acid combined with lower statin doses offers similar LDL-C lowering compared with statin monotherapy at higher doses, potentially sparing patients requiring additional lipid-lowering therapies from the adverse events associated with higher statin doses

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

BackgroundThis first-in-human study evaluated AMG 208, a small-molecule MET inhibitor, in patients with advanced solid tumors.MethodsThree 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.ResultsFifty-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.ConclusionsIn this study, AMG 208 had manageable toxicities and showed evidence of antitumor activity, particularly in prostate cancer

First-in-human study of AMG 208, an oral MET inhibitor, in adult patients (pts) with advanced solid tumors.

41 Background: AMG 208 is a small molecule MET inhibitor that suppresses proliferation and induces apoptosis in human tumor xenografts. This first-in-human study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of AMG 208. We report data from the dose escalation part of the study. Methods: Key eligibility criteria: ≥ 18 yr, advanced solid tumors, ECOG ≤ 2, and evaluable/measurable disease. Using a modified Fibonacci design, 3–9 pts were enrolled into 1 of 7 sequential dose cohorts (25, 50, 100, 150, 200, 300, and 400 mg) of AMG 208. Pts received AMG 208 orally on days 1 and 4–28 once daily. If no dose limiting toxicity (DLT) was seen on days 1–28, pts received AMG 208 once daily starting at day 36 provided pts showed no evident disease progression. In cohorts 1–3, a standard 3+3 design was followed. In cohorts 4–7, a modified 3+3+3 design was followed. Results: As of July 16 2012, 54 pts (25 mg [n=6], 50 mg [n=4], 100 mg [n=4], 150 mg [n=3], 200 mg [n=16], 300 mg [n=10], and 400 mg [n =11]) had received ≥ 1 dose of AMG 208. 67% were men; 19% had prostate cancer (PC). Median (range) age: 61 (39–80) yr. ECOG 0/1: 52%/48%. 6 DLTs were seen: a grade (G) 3 increased AST (200 mg), a G3 thrombocytopenia (200 mg), a G4 acute myocardial infarction (300 mg), a G3 prolonged QT (300 mg), and two G3 hypertensions (400 mg). The maximum tolerated dose was not reached. 83% of pts had tx-related adverse events (AE). Tx-related AE occurring in > 10 pts: fatigue (n=24), nausea (n=18), hypertension (n=12), and diarrhea (n=11). 24% of pts had grade ≥ 3 tx-related AE. AMG 208 was orally bioavailable with a 30–35 hr mean half-life in plasma. Exposure increased linearly with dose; accumulation at day 28 was 2.7-fold across cohorts. Of the 42 pts with available tumor response data for site reads, 1 had complete response on bone scan (PC 300 mg) while 2 had partial responses (PR; PC 400 mg and kidney cancer 200 mg; both had -33% tumor shrinkage), and 29 had stable disease (SD); 1 other PC pt had PR after data cutoff. Of the 35 pts with available tumor response data for central reads, 26 had SD. FLT and biomarker data will be presented. Conclusions: AMG 208 up to 400 mg daily had manageable toxicities and showed evidence of antitumor activity, especially in prostate cancer. Clinical trial information: NCT00813384