PMID- 27071922 OWN - NLM STAT- MEDLINE DCOM- 20170207 LR - 20220331 IS - 1432-0843 (Electronic) IS - 0344-5704 (Linking) VI - 77 IP - 6 DP - 2016 Jun TI - A phase I study of binimetinib (MEK162) in Japanese patients with advanced solid tumors. PG - 1157-64 LID - 10.1007/s00280-016-3019-5 [doi] AB - PURPOSE: Binimetinib is a potent, selective MEK1/2 inhibitor with demonstrated efficacy against BRAF- and RAS-mutant tumors. Retinal adverse events associated with MEK inhibitors have been reported in some cases. The aim of this study was to assess single-agent binimetinib, with detailed ophthalmologic monitoring, in Japanese patients with advanced solid tumors. METHODS: This was an open-label phase I dose-escalation and dose-expansion study (NCT01469130). Adult patients with histologically confirmed, evaluable, advanced solid tumors were enrolled and treated with binimetinib 30 or 45 mg twice daily (BID). The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of single-agent binimetinib in Japanese patients. RESULTS: Twenty-one patients were enrolled; 3 and 8 patients had documented BRAF and KRAS mutations, respectively. Two of 6 patients (33 %) receiving binimetinib 45 mg BID in dose-escalation experienced recurrent grade 2 retinal adverse events (AEs) which were reversible, and this dose was declared the MTD and RP2D. All patients experienced >/=1 AE suspected to be treatment related; the most common (>50 %) were blood creatine phosphokinase increase (76 %), retinal detachment and aspartate aminotransferase increase (62 % each), and diarrhea (52 %). There were no complete or partial responses; 14 patients (67 %) had stable disease, which lasted >180 days in 5 patients. Expression of phospho-ERK decreased in the skin following binimetinib treatment at both dose levels, indicating target inhibition. CONCLUSIONS: Binimetinib demonstrated efficacy and acceptable safety in Japanese patients with solid tumors, supporting the 45 mg BID dose of binimetinib as the RP2D. FAU - Watanabe, K AU - Watanabe K AD - Department of Medical Oncology, Kouseiren Tsurumi Hospital, 4333 Ooaza Tsurumi, Beppu, Oita, 879-5593, Japan. kwata@me.com. AD - Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Oita, Japan. kwata@me.com. FAU - Otsu, S AU - Otsu S AD - Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Oita, Japan. FAU - Hirashima, Y AU - Hirashima Y AD - Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Oita, Japan. FAU - Morinaga, R AU - Morinaga R AD - Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Oita, Japan. FAU - Nishikawa, K AU - Nishikawa K AD - Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Oita, Japan. FAU - Hisamatsu, Y AU - Hisamatsu Y AD - Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Oita, Japan. FAU - Shimokata, T AU - Shimokata T AD - Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Aichi, Japan. FAU - Inada-Inoue, M AU - Inada-Inoue M AD - Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Aichi, Japan. FAU - Shibata, T AU - Shibata T AD - Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Aichi, Japan. FAU - Takeuchi, H AU - Takeuchi H AD - Oncology Early Clinical Trial Management Department, Novartis Pharma KK, Tokyo, Japan. FAU - Watanabe, T AU - Watanabe T AD - Medical Science Liaison Group, Novartis Pharma KK, Tokyo, Japan. FAU - Tokushige, K AU - Tokushige K AD - Integrated Science and Operations Department, Novartis Pharma KK, Tokyo, Japan. FAU - Maacke, H AU - Maacke H AD - Translational Clinical Oncology, Novartis Pharma AG, Basel, Switzerland. FAU - Shiaro, K AU - Shiaro K AD - Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Oita, Japan. FAU - Ando, Y AU - Ando Y AD - Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Aichi, Japan. LA - eng PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160412 PL - Germany TA - Cancer Chemother Pharmacol JT - Cancer chemotherapy and pharmacology JID - 7806519 RN - 0 (Antineoplastic Agents) RN - 0 (Benzimidazoles) RN - 0 (KRAS protein, human) RN - 181R97MR71 (binimetinib) 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 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) SB - IM MH - Adult MH - Aged MH - Antineoplastic Agents/*administration & dosage/adverse effects/therapeutic use MH - Benzimidazoles/*administration & dosage/adverse effects/therapeutic use MH - Dose-Response Relationship, Drug MH - Drug Administration Schedule MH - Female MH - Humans MH - Japan MH - MAP Kinase Kinase 1/*antagonists & inhibitors MH - MAP Kinase Kinase 2/*antagonists & inhibitors MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Mutation MH - Neoplasms/*drug therapy/enzymology/genetics/pathology MH - Proto-Oncogene Proteins B-raf/genetics MH - Proto-Oncogene Proteins p21(ras)/genetics MH - Retinal Detachment/chemically induced OTO - NOTNLM OT - Binimetinib OT - Japanese OT - MEK inhibitor OT - MEK162 OT - Phase I OT - Solid tumors EDAT- 2016/04/14 06:00 MHDA- 2017/02/09 06:00 CRDT- 2016/04/14 06:00 PHST- 2016/01/14 00:00 [received] PHST- 2016/03/24 00:00 [accepted] PHST- 2016/04/14 06:00 [entrez] PHST- 2016/04/14 06:00 [pubmed] PHST- 2017/02/09 06:00 [medline] AID - 10.1007/s00280-016-3019-5 [pii] AID - 10.1007/s00280-016-3019-5 [doi] PST - ppublish SO - Cancer Chemother Pharmacol. 2016 Jun;77(6):1157-64. doi: 10.1007/s00280-016-3019-5. Epub 2016 Apr 12.