title: Phase I and pharmacokinetics/pharmacodynamics study of the MEK inhibitor RO4987655 in Japanese patients with advanced solid tumors.
abstract: RO4987655 is an oral and selective inhibitor of MEK, a key enzyme of the mitogen-activated protein kinase (MAPK) signaling pathway. This phase I dose-escalation study of RO4987655 in Japanese patients with advanced solid tumors aimed to determine maximum tolerated dose (MTD) and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity. Patients received a single dose of RO4987655 (1, 2, 4, 5, or 6.5 mg) followed by continuous once-daily dosing (1, 2, or 4 mg QD) or twice-daily dosing (4, 5, or 6.5 mg BID) in 28-day cycles. A 3 + 3 dose-escalation design was used. PD was evaluated by pERK inhibition in peripheral blood mononuclear cells (PBMCs). In dose-escalation, 25 patients were enrolled. After the MTD was determined, a further six patients were administered the MTD for further confirmation of safety. MTD was determined as 8 mg/day (4 mg BID) due to a total of four dose-limiting toxicities (DLTs) of grade 3 creatine phosphokinase (CPK) elevation (2 DLTs each in 10 mg/day and 13 mg/day). Most commonly related adverse events included dermatitis acneiform, CPK elevation, and eye disorders. Plasma concentration of RO4987655 appeared to increase in a dose-proportional manner with a plasma half-life of 4.32 to 21.1 h. Following multiple dose administration, a steady-state condition was reached by Cycle 1 Day 8. The inhibitory effects of RO4987655 on pERK in PBMCs increased in a dose-dependent manner. One esophageal cancer patient had confirmed partial response and seven patients showed progression-free survival for longer than 16 weeks. The MTD of RO4987655 for Japanese patients was determined as 8 mg/day (4 mg BID). RO4987655 was tolerated up to the MTD with a favorable PK/PD profile in Japanese patients with advanced solid tumors.
authors: Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan.
authors: Shinji
authors: S
authors: Nakamichi
authors: Hiroshi
authors: H
authors: Nokihara
authors: Noboru
authors: N
authors: Yamamoto
authors: Yasuhide
authors: Y
authors: Yamada
authors: Yutaka
authors: Y
authors: Fujiwara
authors: Yosuke
authors: Y
authors: Tamura
authors: Hiroshi
authors: H
authors: Wakui
authors: Kazunori
authors: K
authors: Honda
authors: Hidenori
authors: H
authors: Mizugaki
authors: Satoru
authors: S
authors: Kitazono
authors: Yuko
authors: Y
authors: Tanabe
authors: Hajime
authors: H
authors: Asahina
authors: Naoya
authors: N
authors: Yamazaki
authors: Shigenobu
authors: S
authors: Suzuki
authors: Mieko
authors: M
authors: Matsuoka
authors: Yoshitaka
authors: Y
authors: Ogita
authors: Tomohide
authors: T
authors: Tamura
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D044466:Asian People; D001549:Benzamides / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010078:Oxazines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D014408:Biomarkers, Tumor; C559138:CH 4987655; D010078:Oxazines; D047428:Protein Kinase Inhibitors; D020929:Mitogen-Activated Protein Kinase Kinases