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.

Trial registration: ClinicalTrials.gov NCT00813384.

Keywords: MET; first-in-human; prostate cancer; small molecule; solid tumors.

Figure 1. Schematic overview of the dose escalation cohorts

Three to nine patients were enrolled into one of the following seven AMG 208 dose cohorts: 25, 50, 100, 150, 200, 300, and 400 mg. A standard 3+3 design was followed in cohorts 1–3, and a modified 3+3+3 design was followed in cohorts 4–7. The protocol was amended to evaluate an intermediate dose level of 150 mg after two DLTs (out of six patients) were observed with 200 mg AMG 208 (red arrow); re-escalation to 200 mg occurred after the 150-mg dose cohort was considered well tolerated (red arrow).

Figure 2. Plasma concentration time profiles of AMG 208 on days 1 and 28 following oral administration on days 1 and 4 to 28 once daily

Data points represent means ± standard deviations.

Figure 3. PlGF mean ratio to baseline by treatment arm

Patients who received ≥1 dose of AMG 208 and had a measurable baseline concentration of PlGF were analyzed. The mean log ratio to baseline and standard error were computed, and the results were anti-logged and presented as mean ratio to baseline. Results from day 64 were excluded due to small sample size.

Figure 4. Antitumor activity of AMG 208

A. The percent change in the sum of the longest diameter (SLD) for the best postdose response is shown. Patients with baseline and ≥1 post-baseline SLD for the target lesion were analyzed. Thirty-seven patients are shown, and 17 were not included because of the following reasons: five patients were evaluated with nontarget lesions only (four prostate and one NSCLC), one patient with NSCLC had progressive disease due to a new lesion, and 11 patients did not have baseline and/or post-baseline scans. B. The percent change in the sum of ¹⁸F-FLT SUV_max (1 cm spot) at week 5 day 29. Only patients with both baseline and week 5 day 29 SUV_max (1 cm spot) are shown. *Prostate cancer. ^†Carcinoma of unknown origin. NSCLC, non-small cell lung cancer; SUV_max, maximum standardized uptake value.

Figure 5

A. Complete response in a 66-year-old patient with prostate cancer treated with 300 mg AMG 208 (bone scans). At baseline, bone metastasis was present at T4 and L1. At week 18, evidence of bone metastasis was not observed. B. Partial response in a 63-year-old patient with prostate cancer treated with 400 mg AMG 208 (¹⁸F-FLT-PET and CT scans).