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.
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Acknowledgments
The authors thank all the patients who participated in this study, their families, and staff at the National Cancer Center Hospital. This study was sponsored by Chugai Pharmaceutical Co., Ltd., Japan. Quality control of data, data analysis, and statistical analysis was performed at Chugai Pharmaceutical Co., Ltd. Writing assistance was funded by Chugai Pharmaceutical Co., Ltd.
Conflicts of Interest
Tomohide Tamura and Noboru Yamamoto have received honoraria and research funding from Chugai Pharmaceutical Co., Ltd. Hiroshi Nokihara has received research funding from Chugai Pharmaceutical Co., Ltd. Yasuhide Yamada, Hajime Asahina, and Naoya Yamazaki have received honoraria from Chugai Pharmaceutical Co., Ltd. Mieko Matsuoka and Yoshitaka Ogita are employees of Chugai Pharmaceutical Co., Ltd. All other authors declare that they have no conflicts of interest.
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Clinical trial number: JapicCTI-111490
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Fig. 1
Relationship between CPK elevation and pharmacokinetics of RO4987655 at Cycle 1 Day 15 by individual. Maximum value of CPK and corresponding AUC inf (a) or C max (b) of RO4987655 by individual. Closed circles show patients who experienced DLT (grade 3 CPK elevation); open circles show patients who did not experience DLT. CPK: creatine phosphokinase, AUC inf : Area under the concentration—time curve from 0 to infinity, C max : Maximum plasma concentration. (TIF 101 kb)
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Nakamichi, S., Nokihara, H., Yamamoto, N. et al. Phase I and pharmacokinetics/pharmacodynamics study of the MEK inhibitor RO4987655 in Japanese patients with advanced solid tumors. Invest New Drugs 33, 641–651 (2015). https://doi.org/10.1007/s10637-015-0229-3
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DOI: https://doi.org/10.1007/s10637-015-0229-3