Phase I dose-escalation study of the c-Met tyrosine kinase inhibitor SAR125844 in Asian patients with advanced solid tumors, including patients with MET-amplified gastric cancer

Abstract

SAR125844 is a potent and selective inhibitor of the c-Met kinase receptor. This was an open-label, phase I, multicenter, dose-escalation, and dose-expansion trial of SAR125844 in Asian patients with solid tumors, a subgroup of whom had gastric cancer and MET amplification (NCT01657214). SAR125844 was administered by intravenous infusion (260–570 mg/m2) on days 1, 8, 15, and 22 of each 28-day cycle. Objectives were to determine the maximum tolerated dose (MTD) and to evaluate SAR125844 safety and pharmacokinetic profile. Antitumor activity was also assessed. Of 38 patients enrolled (median age 64.0 years), 22 had gastric cancer, including 14 with MET amplification. In the dose-escalation cohort (N = 19; unselected population, including three patients with MET-amplification [two with gastric cancer and one with lung cancer]), the MTD was not reached, and the recommended dose was established at 570 mg/m2. Most frequent treatment-emergent adverse events (AEs) were nausea (36.8%), vomiting (34.2%), decreased appetite (28.9%), and fatigue or asthenia, constipation, and abdominal pains (each 21.1%); none appeared to be dose-dependent. Grade ≥ 3 AEs were observed in 39.5% of patients and considered drug-related in 7.9%. SAR125844 exposure increased slightly more than expected by dose proportionality; dose had no significant effect on clearance. No objective responses were observed in the dose-escalation cohort, with seven patients (three gastric cancer, two colorectal cancer, one breast cancer, and one with cancer of unknown primary origin) having stable disease. Modest antitumor activity was observed at 570 mg/m2 in the dose-expansion cohort, comprising patients with MET-amplified tumors (N = 19). Two gastric cancer patients had partial responses, seven patients had stable disease (six gastric cancer and one kidney cancer), and 10 patients had progressive disease. Single-agent SAR125844 administered up to 570 mg/m2 has acceptable tolerability and modest antitumor activity in patients with MET-amplified gastric cancer.

HGF/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers

“…In gastrointestinal tumors, several clinical studies have addressed the predictive role of MET dysregulation as an actionable target. These investigations have tested HGF/MET pathway inhibitors as single agents or in combination with other therapies, and have reported different outcomes [20,47,155]. For instance, when 71 patients with advanced hepatocellular carcinoma were enrolled in a placebo-controlled double-blind phase II study, the results showed that tivantinib was associated with a trend towards improved time to progression (2.7 vs. 1.7 months, p ¼ .03), PFS (2.2 vs. 1.4 months, p ¼ .02), and OS (7.2 vs. 3.8 months, p ¼ .01) in the MET-high patients [44].…”

Differential Inhibitory Actions of Multitargeted Tyrosine Kinase Inhibitors on Different Ionic Current Types in Cardiomyocytes

“…Additionally, there were no significant changes of the heart rate in mice receiving LAP compared with the sham group ( Figure 1B). malignancies are thought to be caused by an aberrant tyrosine kinase function [1][2][3]. However, some TKIs have been reported to cause a significant prolongation of the electrocardiographic QTc interval when used to treat patients with advanced carcinoma [4].…”

“…Lapatinib (LAP) and sorafenib (SOR) represent a unique group of multitargeted, active small-molecule tyrosine kinase inhibitors (TKIs) currently used to treat hematological/oncological malignancies. Planning for dose escalation has been considered for their clinical use, as many malignancies are thought to be caused by an aberrant tyrosine kinase function [1][2][3]. However, some TKIs have been reported to cause a significant prolongation of the electrocardiographic QTc interval when used to treat patients with advanced carcinoma [4].…”

Status of Agents Targeting the HGF/c-Met Axis in Lung Cancer

“…Pharmacokinetics studies were performed and analyzed in several species from mice to dog [ 43 ]. Phase I dose escalation and dose expansion study in patients with advanced tumors showed modest antitumor response in patients with MET amplified gastric cancers at 570 mg/m 2 and was well tolerated [ 44 ]. A first in human phase 1 clinical trial was performed in patients with NSCLC ( Table 1 ).…”