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Phase I and pharmacokinetic/pharmacodynamic study of RO5126766, a first-in-class dual Raf/MEK inhibitor, in Japanese patients with advanced solid tumors

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Abstract

Purpose

RO5126766, a highly selective dual Raf and MEK inhibitor, is a first-in-class tandem mitogen-activated protein kinase signaling pathway inhibitor. The objectives of this phase I study were to determine maximum-tolerated dose (MTD) and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of RO5126766 in Japanese patients with advanced solid tumors.

Methods

Patients received a single oral dose of RO5126766 (0.8, 1.2, 1.8, or 2.25 mg) followed by continuous once-daily dosing at the same dosage in 28-day cycles. A 3 + 3 dose-escalation design was used. PD was evaluated by pMEK and pERK inhibition in peripheral blood mononuclear cells (PBMCs).

Results

A total of 12 patients were enrolled in cohorts of 0.8, 1.2, 1.8, and 2.25 mg/day. In the dose range tested, no dose-limiting toxicity was observed, and therefore, MTD was not defined. Main adverse events included acneiform dermatitis, creatine phosphokinase elevation, and ocular disorders. The plasma exposure of RO5126766 appeared to increase in a dose-proportional manner with a long plasma half-life (t 1/2) of 45.8–93.7 h. Following multiple dose administration, a steady-state condition was reached by Cycle 1 Day 8 (240 h). The inhibitory effects of RO5126766 on both pERK and pMEK in PBMCs increased in a dose-dependent manner. Five out of 12 patients achieved stable diseases, including a melanoma case with over 20 % shrinkage.

Conclusions

RO5126766 has a manageable safety profile up to 2.25 mg/day once daily 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.

Conflict of interest

Tomohide Tamura and Noboru Yamamoto have received honoraria and research funding from Chugai Pharmaceutical Co., Ltd. Hajime Asahina, Yasuhide Yamada, and Naoya Yamazaki have received honoraria from Chugai Pharmaceutical Co., Ltd. Yoshitaka Ogita is an employee of Chugai Pharmaceutical Co., Ltd. All other authors have no conflicts of interest to disclose.

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Authors and Affiliations

  1. Division of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan

    Kazunori Honda, Noboru Yamamoto, Hiroshi Nokihara, Yosuke Tamura, Hajime Asahina & Tomohide Tamura

  2. Division of Gastrointestinal Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan

    Yasuhide Yamada

  3. Division of Ophthalmic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan

    Shigenobu Suzuki

  4. Division of Dermatological Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan

    Naoya Yamazaki

  5. Clinical Research Planning Department, Chugai Pharmaceutical Co., Ltd., 2-1-1 Nihonbashi-Muromachi, Chuo-ku, Tokyo, Japan

    Yoshitaka Ogita

Authors
  1. Kazunori Honda
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  2. Noboru Yamamoto
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  7. Shigenobu Suzuki
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  8. Naoya Yamazaki
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  9. Yoshitaka Ogita
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  10. Tomohide Tamura
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Correspondence to Tomohide Tamura.

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Honda, K., Yamamoto, N., Nokihara, H. et al. Phase I and pharmacokinetic/pharmacodynamic study of RO5126766, a first-in-class dual Raf/MEK inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 72, 577–584 (2013). https://doi.org/10.1007/s00280-013-2228-4

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  • DOI: https://doi.org/10.1007/s00280-013-2228-4

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