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Phase I trial of pimasertib monotherapy in Japanese patients with solid tumors and those with hepatocellular carcinoma

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Abstract

Purpose

This study aimed to confirm the recommended phase II dose (RP2D) of pimasertib in Japanese patients.

Methods

This two-part, phase I dose-escalation and expansion study was conducted in Japanese patients (≥ 18 years old) with advanced solid tumors (ST) including hepatocellular carcinoma (HCC). In Part 1, patients with ST (Arm A) and HCC (Arm B) received escalating doses (3 + 3 design) of oral pimasertib [starting at 45 mg twice daily (BID)] in 21-day cycles, until disease progression or unacceptable toxicity. Dose levels could be escalated/de-escalated depending on tolerance. The primary outcome was the number of patients who experienced ≥ 1 dose-limiting toxicity (DLT). Safety and efficacy were also studied. Part 2 aimed to confirm observations in Part 1.

Results

In total, 26 patients (ST, n = 19; HCC, n = 7) were treated with pimasertib in Part 1: 30 mg (ST, n = 4; HCC, n = 5), 45 mg (ST, n = 9; HCC, n = 2), and 60 mg (ST, n = 6). Four patients reported DLTs [ST: hypokalemia (60 mg), and both stomatitis and muscle weakness (60 mg); HCC: retinal detachment (30 mg) and diarrhea (45 mg)]. All patients had ≥ 1 treatment-related adverse event. Partial response (n = 3) and stable disease (n = 1) were seen in patients with ST (pimasertib 45 mg).

Conclusion

A maximum tolerated dose of pimasertib 45 mg BID was established in Japanese patients with ST, but not established in patients with HCC. The global RP2D of 60 mg BID was not confirmed in Japanese patients. Pimasertib monotherapy in unselected patients with ST may not warrant further investigation; Part 2 was not conducted.

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Acknowledgments

The authors wish to thank the patients and their families, investigators, co-investigators, and the study teams at each of the participating centers. Medical writing assistance was provided by Muchaala Yeboah, PhD, Bioscript Science, Macclesfield, UK and funded by Merck Healthcare KGaA, Darmstadt, Germany. The trial was sponsored by Merck Serono Co., Ltd., Japan (affiliate of Merck Healthcare KGaA, Darmstadt, Germany).

Author information

Authors and Affiliations

  1. Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan

    K. Yamazaki

  2. National Cancer Center Hospital East, Kashiwa, Japan

    T. Doi, M. Ikeda & A. Ohtsu

  3. National Cancer Centre Hospital, Tokyo, Japan

    T. Okusaka

  4. Merck Healthcare KGaA, Darmstadt, Germany

    A. Schueler

  5. Merck Serono Co Ltd, Tokyo, Japan

    M. Watanabe

Authors
  1. K. Yamazaki
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  2. T. Doi
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  3. M. Ikeda
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  4. T. Okusaka
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  5. A. Schueler
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  6. M. Watanabe
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  7. A. Ohtsu
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Corresponding author

Correspondence to K. Yamazaki.

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Conflict of interest

KY has received lecture fees from Merck Serono. TD has received research funding from Taiho, Novartis, Merck Serono, Merck Sharpe and Dohme, Boehringer Ingelheim, Pfizer, Lilly, Sumitomo Dainippon, Kyowa Hakko Kirin, Daiichi Sankyo, Bristol-Myers Sqiibb, Abbvie and Eisai, and has consulted/advised Kyowa Hakko Kirin, Merck Sharpe and Dohme, Amgen, Sumitomo Dainippon, Taiho, Takeda, Abbvie, Novartis and Bayer. MI has received research grants from Bayer Yakuhin, Kyowa Hakko Kirin, Eli Lilly Japan, Eisai, Chugai Pharmaceutical, and Bristol-Myers Sqiibb, and a speaker honorarium from Bayer Yakuhin and Eisai. MI is a member of advisory boards of Bayer Yakuhin and Eisai. AS is an employee of Merck Healthcare KGaA, Darmstadt, Germany. MW is an employee of Merck Serono Co Ltd, Tokyo, Japan. TO and AO declare that they have no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Yamazaki, K., Doi, T., Ikeda, M. et al. Phase I trial of pimasertib monotherapy in Japanese patients with solid tumors and those with hepatocellular carcinoma. Cancer Chemother Pharmacol 84, 1027–1037 (2019). https://doi.org/10.1007/s00280-019-03924-0

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  • DOI: https://doi.org/10.1007/s00280-019-03924-0

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