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A phase I/Ib study of trametinib (GSK1120212) alone and in combination with gemcitabine in Japanese patients with advanced solid tumors

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Summary

Background Trametinib is an inhibitor of MEK1/MEK2 activation and kinase activity. In order to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of single-agent trametinib (part 1) and trametinib in combination with gemcitabine (part 2), we undertook the first clinical study of this combination in Japanese patients with cancer and herein report our results. Methods In part 1, 13 patients with advanced solid tumors were enrolled into 3 dose cohorts, receiving trametinib once daily at a dose of 1.0, 2.0, or 3.0 mg. In part 2, 5 patients with pancreatic cancer received trametinib (2.0 mg once daily) in combination with gemcitabine (1000 mg/m2). Results In part 1, a dose-limiting toxicity was observed in a patient in the 2.0-mg dose cohort, but the maximum tolerated dose was not reached at doses up to 3.0 mg daily. The best overall response was a PR in 1 patient, and 6 patients had SD. In part 2, the combination of trametinib and gemcitabine was tolerated for a short period of time. However, serious interstitial lung disease (ILD) was observed in 3 of 5 patients 4 weeks or more after the start of the treatment, including 1 fatal case. Three patients achieved a PR, and 2 patients had SD. The most common adverse event was rash (85 % in part 1 and 100 % in part 2). Conclusions Trametinib monotherapy was tolerable in Japanese patients with cancer. However, the combination of trametinib plus gemcitabine carried a higher risk as compared with monotherapy, during which no ILD was observed. (ClinicalTrials.gov number, NCT01324258.)

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Acknowledgments

We thank the patients who participated in the MEK114784 study and their families, the MEK114784 study investigators, and the nurses, coordinators, and other study staff who contributed to the study. This study was funded by GlaxoSmithKline. Writing/editorial support was provided Anne Marie Corgan at SciMentum and was funded by GlaxoSmithKline.

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Conflicts of interest

Dr. Nakagawa reports research grants to their institution from GlaxoSmithKline K.K., and Eli Lilly Japan K.K., during the conduct of the study; personal fees for speaking engagements from GlaxoSmithKline K.K., outside the submitted work. Dr. Nagashima reports research grants to their institution from GlaxoSmithKline, during the conduct of the study; research grants to their institution from GlaxoSmithKline, Chugai Pharmaceutical Co., Eli Lilly Japan, Bayel Yakuhin, OncoTherapy Science, Novartis Pharma, Yakult Honsha Co., Ono Pharmaceutical Co., Taiho Pharmaceutical Co., Takeda Pharmaceutical Company, Merck Serono Co., Sanofi, Shionogi & Co., Sumitomo Dainippon Pharma Co., Kyowa Hakko Kirin Co, Zeria Pharmaceutical Co, and Daiichi Sankyo Co., personal fees for lectures from Chugai Pharmaceutical Co., Takeda Pharmaceutical Company, Taiho Pharmaceutical Co., and Shionogi & Co., personal fees for consulting from Janssen Pharmaceutical Co., outside the submitted work. Dr. Kurata reports research grants to their institution from GlaxoSmithKline, during the conduct of the study; personal fees for speaking engagements from AstraZeneca, Eli Lilly, Boehringer Ingelheim, Taiho, Chugai, and Pfizer, outside the submitted work. Dr. Fujisaka reports research grants to their institution from GlaxoSmithKline, AstraZeneca K.K., Bristol-Myers Squibb, Novartis Pharma K.K., and MSD K.K., during the conduct of the study; personal fees for lectures from Bayer HealthCare, Chugai Pharmaceutical Co. Ltd, Ono Pharmaceutical Co. Ltd, Taiho Pharmaceutical Co. Ltd, Daiichi Sankyo Co. Ltd, Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd, Eli Lilly Japan K.K., Sanofi K.K., Yakult Honsha Co. Ltd, and Janssen Pharmaceutical K.K., research grants to their institution from AstraZeneca K.K., MSD K.K., Novartis Pharma K.K., and Bristol-Myers Squibb, outside the submitted work. Dr. Okamoto reports research grants to their institution from GlaxoSmithKline, during the conduct of the study. Mr. Nishimura and Mr. Mukaiyama report that they are employees of and stock owners of GlaxoSmithKline. Mr. Matsushita reports that he is an employee of GlaxoSmithKline K.K. Dr. Furuse reports grants from GlaxoSmithKline, during the conduct of the study; grants from Ono pharmaceutical Co., Oncotherapy Science, and Takeda Bio Development Center Ltd, grants and personal fees from Taiho pharmaceutical Co., Eli Lilly Japan, Bayer pharmaceutical Co., and Yakult, personal fees from Chugai pharmaceutical Co., Novartis, Eisai, Kyowa Hakko, and Zeria Pharmaceutical Co., outside the submitted work. Drs. Kitamura and Okamoto report grants to their institutions from GlaxoSmithKline, during the conduct of the study. Drs. Kasuga, Shimizu, Naruge, Nishina, and Takasu have nothing to disclose.

Informed consent

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

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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Authors and Affiliations

  1. Department of Medical Oncology, Kyorin University Hospital, 6-20-2 Shinkawa, 181-8611, Mitaka, Tokyo, Japan

    Akiyoshi Kasuga, Fumio Nagashima, Daisuke Naruge, Hiroshi Kitamura, Atsuko Takasu & Junji Furuse

  2. Department of Medical Oncology, Faculty of Medicine, Kinki University Hospital, 377-2, Ono-Higashi, 577-0818, Osakasayama City, Osaka, Japan

    Kazuhiko Nakagawa, Toshio Shimizu, Shinichi Nishina, Takayasu Kurata, Yasuhito Fujisaka & Wataru Okamoto

  3. Medicines Development, Oncology Therapeutic Area, GlaxoSmithKline K.K., 6-15, Sendagaya 4-chome, 151-8566, Tokyo, Japan

    Yuichiro Nishimura, Akihira Mukaiyama & Hideki Matsushita

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  1. Akiyoshi Kasuga
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  2. Kazuhiko Nakagawa
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  14. Hideki Matsushita
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Correspondence to Junji Furuse.

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Kasuga, A., Nakagawa, K., Nagashima, F. et al. A phase I/Ib study of trametinib (GSK1120212) alone and in combination with gemcitabine in Japanese patients with advanced solid tumors. Invest New Drugs 33, 1058–1067 (2015). https://doi.org/10.1007/s10637-015-0270-2

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