PMID- 28152546 OWN - NLM STAT- MEDLINE DCOM- 20170523 LR - 20220331 IS - 1532-1827 (Electronic) IS - 0007-0920 (Print) IS - 0007-0920 (Linking) VI - 116 IP - 5 DP - 2017 Feb 28 TI - A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor. PG - 575-583 LID - 10.1038/bjc.2017.10 [doi] AB - 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. FAU - Bendell, Johanna C AU - Bendell JC AD - Drug Development Program, Sarah Cannon Research Institute/Tennessee Oncology, 250 25th Avenue North, Suite 200, Nashville, TN 37203, USA. FAU - Javle, Milind AU - Javle M AD - Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit Number: 426, Room Number: FC10.3062, Houston, TX 77030, USA. FAU - Bekaii-Saab, Tanios S AU - Bekaii-Saab TS AD - Department of Internal Medicine, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA. FAU - Finn, Richard S AU - Finn RS AD - Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, 2825 Santa Monica Boulevard, Suite 200, Santa Monica, CA 90404, USA. FAU - Wainberg, Zev A AU - Wainberg ZA AD - Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, 2825 Santa Monica Boulevard, Suite 200, Santa Monica, CA 90404, USA. FAU - Laheru, Daniel A AU - Laheru DA AD - Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 2825 Santa Monica Boulevard, Baltimore, MD 90404, USA. FAU - Weekes, Colin D AU - Weekes CD AD - Division of Medical Oncology, University of Colorado School of Medicine, 12801 East 17th Avenue, RC1 South, Room 8123, Aurora, CO 80045, USA. FAU - Tan, Benjamin R AU - Tan BR AD - Department of Medicine, Oncology Division, Washington University, School of Medicine, 14th Floor Northwest Tower, Division of Oncology, Campus Box 8056, 660 South Euclid Ave, St Louis, MO 63110, USA. FAU - Khan, Gazala N AU - Khan GN AD - Department of Hematology/Oncology, Henry Ford Health System, 2799 West Grand Boulevard, Detroit, MI 48202, USA. FAU - Zalupski, Mark M AU - Zalupski MM AD - Department of Internal Medicine, University of Michigan, 1500 East Medical Center Drive, SPC 5912, Ann Arbor, MI 48109, USA. FAU - Infante, Jeffrey R AU - Infante JR AD - Drug Development Program, Sarah Cannon Research Institute/Tennessee Oncology, 250 25th Avenue North, Suite 200, Nashville, TN 37203, USA. FAU - Jones, Suzanne AU - Jones S AD - Drug Development Program, Sarah Cannon Research Institute, 3322 West End Avenue, Suite 900, Nashville, TN 37203, USA. FAU - Papadopoulos, Kyriakos P AU - Papadopoulos KP AD - Clinical Research, South Texas Accelerated Research Therapeutics (START), 4383 Medical Drive, San Antonio, TX 78229, USA. FAU - Tolcher, Anthony W AU - Tolcher AW AD - Clinical Research, South Texas Accelerated Research Therapeutics (START), 4383 Medical Drive, San Antonio, TX 78229, USA. FAU - Chavira, Renae E AU - Chavira RE AD - Clinical Development, Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA. FAU - Christy-Bittel, Janna L AU - Christy-Bittel JL AD - Clinical Development, Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA. FAU - Barrett, Emma AU - Barrett E AD - Clinical Development, Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA. FAU - Patnaik, Amita AU - Patnaik A AD - Clinical Research, South Texas Accelerated Research Therapeutics (START), 4383 Medical Drive, San Antonio, TX 78229, USA. LA - eng PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study DEP - 20170202 PL - England TA - Br J Cancer JT - British journal of cancer JID - 0370635 RN - 0 (Benzimidazoles) RN - 181R97MR71 (binimetinib) RN - EC 2.7.1.- (MAP2K2 protein, human) RN - EC 2.7.11.1 (BRAF protein, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) RN - EC 2.7.12.2 (MAP Kinase Kinase 1) RN - EC 2.7.12.2 (MAP Kinase Kinase 2) RN - EC 2.7.12.2 (MAP2K1 protein, human) RN - EC 3.6.5.2 (ras Proteins) SB - IM MH - Benzimidazoles/*administration & dosage/adverse effects/pharmacokinetics MH - Drug Administration Schedule MH - Female MH - Humans MH - MAP Kinase Kinase 1/*antagonists & inhibitors MH - MAP Kinase Kinase 2/*antagonists & inhibitors MH - Male MH - Maximum Tolerated Dose MH - Neoplasms/*drug therapy/enzymology/genetics MH - Proto-Oncogene Proteins B-raf/genetics MH - Treatment Outcome MH - ras Proteins/genetics PMC - PMC5344293 COIS- JCB, MJ, TSB-S, DAL, CDW, BRT, GNK, MMZ, JRI, SJ, and KPP have nothing to disclose. RSF serves as a consultant for Bayer, Novartis, Pfizer Inc, and Bristol-Myers Squibb. ZAW serves as a consultant for Array BioPharma Inc. AWT has a leadership role in Symphogen; serves in a consulting or advisory role for Akebia Therapeutics, ArQule, Asana BioSciences, Astex Pharmaceuticals, Bayer Schering Pharma, Bind Therapeutics, Blend Therapeutics, Celator Pharmaceuticals, Dicerna Pharmaceuticals, Endocyte Inc., Genmab, Heron Therapeutics, Janssen Pharmaceuticals, Johnson & Johnson, Mersana Therapeutics, Inc., Merus Labs Inc., Nanobiotix, Pharmacyclics, Pierre Fabre Medicament, Proximagen, Ltd., Symphogen, Valent Technologies, Upsher-Smith Laboratories, Inc.; and receives funding for his research institution from AbbVie Inc., Aeglea Biotherapeutics, Agios Pharmaceuticals, ARMO BioSciences, ArQule, Asana BioSciences, Astex Pharmaceuticals, AVEO Pharmaceuticals, Inc., Corvus Pharmaceuticals, Cerulean Pharma Inc., Daiichi Sankyo, Dicerna Pharmaceuticals, Eisai Inc., Eli Lilly and Company, Endocyte Inc., Five Prime Therapeutics, F-star, Gilead Sciences Inc., GlaxoSmithKline, Jiangsu Hengrui Medicine Co., Pharmacyclics, Incyte Corp, Infinity Pharmaceuticals, MacroGenics, MedImmune, Merck & Co., Millennium Pharmaceuticals, Inc., Otsuka Pharmaceutical Co., Ltd., Onyx Pharmaceuticals Inc., Pfizer Inc, Plexxikon, Regeneron Pharmaceuticals, Inc, Rexahn Pharmaceuticals Inc., Sanofi, Santa Maria Biotherapeutics Inc., TaiRx, Inc. REC, JLC-B, and EB are current or former employees of Array BioPharma Inc. EB owns stock in Array BioPharma Inc. AP receives institutional research funding from Array BioPharma Inc. EDAT- 2017/02/06 06:00 MHDA- 2017/05/24 06:00 PMCR- 2017/02/28 CRDT- 2017/02/03 06:00 PHST- 2016/10/11 00:00 [received] PHST- 2016/12/12 00:00 [revised] PHST- 2017/01/05 00:00 [accepted] PHST- 2017/02/06 06:00 [pubmed] PHST- 2017/05/24 06:00 [medline] PHST- 2017/02/03 06:00 [entrez] PHST- 2017/02/28 00:00 [pmc-release] AID - bjc201710 [pii] AID - 10.1038/bjc.2017.10 [doi] PST - ppublish SO - Br J Cancer. 2017 Feb 28;116(5):575-583. doi: 10.1038/bjc.2017.10. Epub 2017 Feb 2.