1203 Pharmacokinetic and pharmacodynamic Phase I trial of ARQ 197 incorporating dynamic contrast-enhanced (DCE) and diffusion weighted (DW) magnetic resonance imaging (MRI) studies investigating the antiangiogenic and antitumor activity of selective c-Met inhibition

Early Clinical Development of ARQ 197, a Selective, Non–ATP-Competitive Inhibitor Targeting MET Tyrosine Kinase for the Treatment of Advanced Cancers

“…Safety of the 360 mg bid dose using the modified formulation was confirmed in an expanded cohort of 20 patients [29,36]. In total, 51 patients experienced 73 drug-related AEs, with gastrointestinal AEs (n ϭ 18; 25%) and fatigue (n ϭ 10; 14%) reported most frequently [33].…”

“…In the 400 mg bid cohort, a DLT of grade 3 febrile neutropenia was observed in each of two patients; in one of these patients, two other grade 3 DLTs were observed (mucosal inflammation and palmar-plantar erythrodysesthesia). All DLTs resolved within 2 weeks of ARQ 197 discontinuation [33]. ARQ 197 300 mg bid was initially identified as the MTD but was subsequently adjusted to 360 mg bid following introduction of a modified commercialgrade formulation and PK studies demonstrating a 5:6 conversion factor [33].…”

“…All DLTs resolved within 2 weeks of ARQ 197 discontinuation [33]. ARQ 197 300 mg bid was initially identified as the MTD but was subsequently adjusted to 360 mg bid following introduction of a modified commercialgrade formulation and PK studies demonstrating a 5:6 conversion factor [33]. Safety of the 360 mg bid dose using the modified formulation was confirmed in an expanded cohort of 20 patients [29,36].…”

Targeting the HGF/c-Met Axis: State of Play

“…Currently, the most selective c-Met inhibitors seem to be MetMAb (OA5D5; Genentech), a c-Met monoclonal antibody and ARQ197 (ArQule, Inc), an oral, non-ATP competitive c-Met inhibitor, with a novel mechanism of action involving the stabilization of an inactive conformation of c-Met (13). Both agents reported impressive preclinical data (14,15), and promising results in phase I studies (16)(17)(18). Both are currently in phase II trials, including independent double-blind randomized phase II studies evaluating their combination with erlotinib (Genentech, OSI Pharmaceuticals) versus placeboerlotinib in patients with NSCLC (19).…”

The c-Met receptor: Implication for targeted therapies in colorectal cancer

“…Tivantinib activity has been determined against c-Met in cellular and enzymatic tests and in xenograft tumor specimens. [115][116][117][118][119] This medication has been studied in phase I trial of advanced cancer patients and another trial appraising the composed effect of EGFR TKI erlotinib and tivantinib. 120 Primary results from another survey have shown that tivantinib is an effective marker in the therapy of patients with tumors associated with microphthalmia transcription factor (MiT) family.…”