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Phase 1 study of abemaciclib, an inhibitor of CDK 4 and 6, as a single agent for Japanese patients with advanced cancer

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Abstract

Purpose

To confirm the safety and tolerability, evaluate the pharmacokinetics (PK), and investigate the antitumor activity of abemaciclib in Japanese patients with advanced cancer.

Methods

We conducted a non-randomized, single-arm, open-label, dose-escalation phase 1 study of abemaciclib administered orally every 12 h (Q12H) on a 28-day cycle at doses of 100 mg (Cohort 1, n = 3), 150 mg (Cohort 2, n = 3), or 200 mg [Cohort 3, n = 6, maximum tolerated dose (MTD)]. Dose escalation was based on the frequency of dose-limiting toxicity (DLT). MTD, as established in the previous phase 1 study in non-Japanese patients, was the highest dose level at which <33 % of patients experienced DLT.

Results

Eleven of the 12 patients who received treatment with abemaciclib discontinued: 10 patients due to progressive disease, and 1 due to a DLT (Cohort 3, grade 2 nausea). Diarrhea, the most common treatment-emergent adverse event (AE), was managed supportively and did not require study treatment discontinuation. There were no drug-related serious AEs and no patients with corrected QT (QTc) > 480 ms or QTc change of >60 ms from baseline. The abemaciclib PK profile was characterized by slow absorption and high PK variability after single or repeated doses. Two patients, one with breast cancer and one with neuroendocrine tumor, experienced >30 % decrease in tumor size from baseline.

Conclusions

In Japanese patients with advanced cancer, single-agent abemaciclib has an acceptable safety profile and demonstrates antitumor activity at a dose of 200 mg Q12H. These findings support ongoing development of abemaciclib for diverse populations with advanced cancer.

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Funding support

This study was sponsored by Eli Lilly Japan K.K, manufacturer/licensee of abemaciclib (LY2835219). Medical writing assistance was provided by Mark Snape, MB BS, CMPP and Tania Dickson, PhD of ProScribe—Envision Pharma Group—and was funded by Eli Lilly. ProScribe’s services complied with international guidelines for Good Publication Practice (GPP3).

Other contributors/acknowledgments

The authors would like to thank study participants and their families.

Author information

Authors and Affiliations

  1. Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Yutaka Fujiwara, Kenji Tamura, Shunsuke Kondo, Yuko Tanabe, Satoru Iwasa, Akihiko Shimomura, Shigehisa Kitano & Noboru Yamamoto

  2. Eli Lilly Japan K.K., 7-1-5 Isogamidori, Chuo-Ku, Kobe, 651-0086, Japan

    Ken Ogasawara, Joji Mori & Hiroya Asou

  3. Eli Lilly and Company, S Delaware St, Indianapolis, IN, 46285, USA

    P. Kellie Turner & Edward Michael Chan

Authors
  1. Yutaka Fujiwara
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  2. Kenji Tamura
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  3. Shunsuke Kondo
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  4. Yuko Tanabe
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  6. Akihiko Shimomura
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  7. Shigehisa Kitano
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  8. Ken Ogasawara
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  9. P. Kellie Turner
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  11. Hiroya Asou
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  12. Edward Michael Chan
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  13. Noboru Yamamoto
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Corresponding author

Correspondence to Yutaka Fujiwara.

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Conflict of interest

Kitano, Tanabe, Tamura, and Shimomura have no conflicts of interest to declare. Kondo has received research funding from AstraZeneca, Eli Lilly Japan K.K., and Bayer Yakuhin, Ltd. Yamamoto has received research funding for clinical trials from Chugai Pharmaceutical Co., Ltd, Taiho Pharma, Eisai Co., Ltd, Quintiles, Astellas, Bristol-Myers Squibb, Kyowa-Hakko Kirin, Novartis Pharmaceuticals Japan, Daiichi-Sankyo, Pfizer, and Boehringer Ingelheim. Iwasa has received research funding for clinical trials from Eli Lilly Japan K.K. Fujiwara has served on advisory boards for Novartis Pharmaceuticals Japan and ONO Pharmaceuticals Japan, and received research funding for clinical trials from AstraZeneca, Eli Lilly Japan K.K, Chugai, Eisai Co., Daiichi-Sankyo, and MerckSerono. Ogasawara, Mori, and Asou are current employees of Eli Lilly Japan K.K. Turner and Chan are current employees of and own stock in Eli Lilly and Company.

Role of the sponsor

Eli Lilly Japan K.K. was involved in the study design, data collection, data analysis, and preparation of the manuscript.

Role of contributors

All authors participated in the interpretation of study results, and in the drafting, critical revision, and approval of the final version of the manuscript. KO, PKT, HA, and EMC were involved in the study design and data analyses. S Kitano, S Kondo, NY, KT, YT, SI, AS, and YF were investigators in the study and were involved in data collection. KO and JM conducted the statistical analysis.

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Fujiwara, Y., Tamura, K., Kondo, S. et al. Phase 1 study of abemaciclib, an inhibitor of CDK 4 and 6, as a single agent for Japanese patients with advanced cancer. Cancer Chemother Pharmacol 78, 281–288 (2016). https://doi.org/10.1007/s00280-016-3085-8

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  • DOI: https://doi.org/10.1007/s00280-016-3085-8

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