Abstract
Background:Binimetinib (MEK162; ARRY-438162) is a potent and selective oral MEK 1/2 inhibitor. This phase 1 study determined the maximum tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and preliminary anti-tumour activity of binimetinib in patients with advanced solid tumours, with expansion cohorts of patients with biliary cancer or KRAS- or BRAF-mutant colorectal cancer.Methods:Binimetinib was administered twice daily. Expansion cohorts were enroled after MTD determination following a 3+3 dose-escalation design. Pharmacokinetic properties were determined from plasma samples. Tumour samples were assessed for mutations in RAS, RAF, and other relevant genes. Pharmacodynamic properties were evaluated in serum and skin punch biopsy samples.Results:Ninety-three patients received binimetinib (dose-escalation phase, 19; expansion, 74). The MTD was 60 mg twice daily, with dose-limiting adverse events (AEs) of dermatitis acneiform and chorioretinopathy. The dose for expansion patients was subsequently decreased to 45 mg twice daily because of the frequency of treatment-related ocular toxicity at the MTD. Common AEs across all dose levels included rash (81%), nausea (56%), vomiting (52%), diarrhoea (51%), peripheral oedema (46%), and fatigue (43%); most were grade 1/2. Dose-proportional increases in binimetinib exposure were observed and target inhibition was demonstrated in serum and skin punch biopsy samples. Three patients with biliary cancer had objective responses (one complete and two partial).Conclusions:Binimetinib demonstrated a manageable safety profile, target inhibition, and dose-proportional exposure. The 45 mg twice daily dose was identified as the recommended phase 2 dose. The three objective responses in biliary cancer patients are encouraging and support further evaluation in this population.
Highlights
Binimetinib (MEK162; ARRY-438162) is a potent and selective oral MEK 1/2 inhibitor
Growth factor-mediated proliferative signals are transmitted from the extracellular environment to the nucleus through several pathways, including the mitogen-activated protein kinase (MAPK) pathway (Chang et al, 2003b; Schulze et al, 2004; Roberts and Der, 2007)
Activation of this pathway results in a signal cascade leading to sequential phosphorylation and activation of MAPK kinase (MEK) and extracellular signal-regulated kinase (ERK)
Summary
Expansion cohorts were enroled after MTD determination following a 3 þ 3 dose-escalation design. Pharmacokinetic properties were determined from plasma samples. Tumour samples were assessed for mutations in RAS, RAF, and other relevant genes. Pharmacodynamic properties were evaluated in serum and skin punch biopsy samples. This study (NCT00959127) was conducted under all applicable regulatory requirements. The study was approved by the institutional review boards of all participating sites, and patients provided written informed consent before the initiation of study-related treatment or procedures
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