Title |
A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor
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Published in |
British Journal of Cancer, February 2017
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DOI | 10.1038/bjc.2017.10 |
Pubmed ID | |
Authors |
Johanna C Bendell, Milind Javle, Tanios S Bekaii-Saab, Richard S Finn, Zev A Wainberg, Daniel A Laheru, Colin D Weekes, Benjamin R Tan, Gazala N Khan, Mark M Zalupski, Jeffrey R Infante, Suzanne Jones, Kyriakos P Papadopoulos, Anthony W Tolcher, Renae E Chavira, Janna L Christy-Bittel, Emma Barrett, Amita Patnaik |
Abstract |
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. 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. 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). 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.British Journal of Cancer advance online publication, 2 February 2017; doi:10.1038/bjc.2017.10 www.bjcancer.com. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United Kingdom | 1 | 20% |
Unknown | 4 | 80% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 3 | 60% |
Science communicators (journalists, bloggers, editors) | 1 | 20% |
Practitioners (doctors, other healthcare professionals) | 1 | 20% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 99 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 14 | 14% |
Student > Bachelor | 11 | 11% |
Student > Ph. D. Student | 10 | 10% |
Other | 9 | 9% |
Student > Master | 9 | 9% |
Other | 14 | 14% |
Unknown | 32 | 32% |
Readers by discipline | Count | As % |
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Medicine and Dentistry | 19 | 19% |
Biochemistry, Genetics and Molecular Biology | 14 | 14% |
Pharmacology, Toxicology and Pharmaceutical Science | 12 | 12% |
Nursing and Health Professions | 5 | 5% |
Agricultural and Biological Sciences | 5 | 5% |
Other | 9 | 9% |
Unknown | 35 | 35% |