Drugs in Clinical Pipeline: AMG-208

AMG 208 [4-[(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy]-7-methoxy quinoline] is a potent and highly selective small molecule ATP-competitive MET kinase inhibitor that demonstrates good cellular activity. 

AMG 208 was born using an imaginative skill by the researchers at Amgen. Starting with a binding model of in-house an efficient c-Met inhibitor with a pyrimidinone moiety (1, IC₅₀ = 10 nM) and overlapping with that of triazolopyridazine (2, IC₅₀ = 120 ± 18 nM), researchers at Amgen designed a potent triazolopyridazine quinoline c-Met inhibitor, AMG-208 (IC₅₀ = 9 ± 2 nM) [1]. Furthermore, AMG 208 inhibited HGF-mediated c-Met phosphorylation in PC3 cells with IC₅₀ value of 46 ± 11 nM.

AMG 208 inhibits both ligand-dependent and ligand-independent c-Met cellular growth regulation. Inhibition of c-Met signaling with AMG 208 provides a potential mechanism for blocking tumor growth and survival.

Common Name: AMG-208

Synonyms:  AMG-208; AMG 208;AMG208

IUPAC Name: 4-[(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy]-7-methoxyquinoline

CAS Number: 1002304-34-8

SMILES: COC1=CC2=NC=CC(=C2C=C1)OCC3=NN=C4N3N=C(C=C4)C5=CC=CC=C5

Mechanism of Action: Kinase Inhibitor; MET Kinase Inhibitor

Indication: Various Cancers; Anti-Tumor Therapy

Development Stage: Phase II

Company: Amgen Inc

The receptor tyrosine kinase c-Met and its natural ligand, hepatocyte growth factor (HGF), are involved in cell proliferation, migration, and invasion and are essential for normal embryonic development. Deregulation of c-Met/HGF signaling can lead to tumorigenesis and metastasis and has been implicated in a variety of cancers. Several mechanisms lead to deregulation, including overexpression of c-Met and/or HGF, amplification of the MET gene, or activating mutations of c-Met, all of which have been found in human cancers.

Phase I Study

A phase 1, first-in-human study evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of AMG 208 in adult subjects with advanced solid tumors it was observed that AMG 208 up to 400 mg daily had manageable toxicities and showed evidence of antitumor activity, especially in prostate cancer [2,3].

Methodology

Using a modified Fibonacci design, 3-9 patients (18 yr and above, advanced solid tumors, ECOG = 2, and evaluable/measurable disease) were enrolled into 1 of 7 sequential dose cohorts (25, 50, 100, 150, 200, 300, and 400 mg) of AMG 208. Patients received AMG 208 orally on days 1 and 4-28 once daily. If no dose limiting toxicity (DLT) was seen on days 1-28, patients received AMG 208 once daily starting at day 36 provided patients 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

Fifty four patients (67% were men; 19% had prostate cancer (PC) received dose of AMG 208. Median (range) age was 61 (39-80) year with ECOG 0/1 as 52%/48%. Six 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 patients had tx-related adverse events (AE). Tx-related AE occurring in greater than 10 patients: fatigue (n=24), nausea (n=18), hypertension (n=12), and diarrhea (n=11). 24% of patients 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 patients 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 patient had PR after data cutoff. Of the 35 patients with available tumor response data for central reads, 26 had SD.

References:

1. Albrecht, B. K.; et. al. Discovery and optimization of triazolopyridazines as potent and selective inhibitors of the c-Met kinase. J Med Chem 2008, 51(10), 2879-2882.
2. Hong, D. S.; et. al. First-in-human study of AMG 208, an oral MET inhibitor, in adult patients (pts) with advanced solid tumors. J Clin Oncol 2013, 31(suppl 6; abstr 41).
3. ClinicalTrials.gov A Phase 1 Study of AMG 208 in Subjects With Advanced Solid Tumors. NCT00813384 (retrieved 10-06-2015)