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Phase Ia/Ib study of the pan-class I PI3K inhibitor pictilisib (GDC-0941) administered as a single agent in Japanese patients with solid tumors and in combination in Japanese patients with non-squamous non-small cell lung cancer

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Summary

Pictilisib (GDC-0941) is an oral class I phosphatidylinositol-3-phosphate kinase inhibitor. This phase Ia/Ib study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of pictilisib in monotherapy or in combination with carboplatin-paclitaxel and bevacizumab (CP + BEV) in Japanese patients with advanced solid tumors or non-squamous non-small cell lung cancer. A standard 3 + 3 dose escalation design was applied. In stage 1, 140, 260, or 340 mg/day of pictilisib was administered once daily to 12 patients with advanced solid tumors. In stage 2, 260 or 340 mg/day of pictilisib was administered in combination with CP + BEV to 7 patients with advanced non-squamous non-small cell lung cancer. In stage 1, 1 of 6 patients in the 340 mg/day cohort exhibited dose limiting toxicity (DLT) of grade 3 maculopapular rash. The maximum plasma concentration and area under the curve of pictilisib were dose-dependent. A reduction in phosphorylated AKT in platelet rich plasma was observed. No patient had an objective anti-tumor response. In stage 2, DLT was observed in 1 of 3 patients in the 260 mg/day cohort (grade 3 febrile neutropenia), and 2 of 4 patients in the 340 mg/day cohort (1 each of grade 3 febrile neutropenia and grade 3 febrile neutropenia/erythema multiforme). Partial responses were observed in 3 out of 7 patients. In conclusion, pictilisib was shown to have good safety and tolerability in Japanese patients with advanced solid tumors. A recommended dose of pictilisib in monotherapy was determined to be 340 mg once daily. For combination with CP + BEV, tolerability up to 260 mg/day was confirmed.

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Authors and Affiliations

  1. Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan

    Noboru Yamamoto, Yutaka Fujiwara, Kenji Tamura, Shunsuke Kondo, Satoru Iwasa & Yuko Tanabe

  2. Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan

    Atsushi Horiike, Noriko Yanagitani, Satoru Kitazono & Makoto Nishio

  3. Chugai Pharmaceutical Co., Ltd., Tokyo, Japan

    Michiyasu Inatani & Jun Tanaka

Authors
  1. Noboru Yamamoto
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  2. Yutaka Fujiwara
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  3. Kenji Tamura
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  4. Shunsuke Kondo
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  5. Satoru Iwasa
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  6. Yuko Tanabe
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  7. Atsushi Horiike
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  8. Noriko Yanagitani
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  10. Michiyasu Inatani
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  11. Jun Tanaka
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  12. Makoto Nishio
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Corresponding author

Correspondence to Noboru Yamamoto.

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Funding

This study was supported by Chugai Pharmaceutical Co., Ltd. (Tokyo, Japan). Medical writing assistance and editing was provided by Macmillan Medical Communications (Tokyo, Japan), and funded by Chugai Pharmaceutical Co., Ltd.

Conflict of interest

Noboru Yamamoto has received research grants from Chugai Pharmaceutical, Eli Lilly, Taiho, Eisai, Quintiles, Astellas Pharma, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, Boehringer-Ingelheim, Kyowa-Hakko Kirin, and Bayer.

Yutaka Fujiwara has received research grants from AstraZeneca, Daiichi Sankyo, Chugai Pharmaceutical, Eisai, Eli Lilly, MSD, and Merck Serono.

Kenji Tamura has received research grants from Chugai Pharmaceutical, AstraZeneca, Daiichi Sankyo, Eisai, MSD, Eli Lilly, Pfizer, AbbVie and Byer.

Shunsuke Kondo has received research grants from Bayer, AstraZeneca, and Eli Lilly.

Satoru Iwasa has no conflicts of interest to declare.

Yuko Tanabe has no conflicts of interest to declare.

Atsushi Horiike has no conflicts of interest to declare.

Noriko Yanagitani is an advisory board member of Chugai Pharmaceutical.

Satoru Kitazono has no conflicts of interest to declare.

Michiyasu Inatani and Jun Tanaka are employee of Chugai Pharmaceutical.

Makoto Nishio has received research grants from Novartis, Ono Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, Taiho Pharmaceutical, Eli Lilly, Pfizer, Astellas Pharma, and AstraZeneca, and honoraria from Pfizer, Bristol-Myers Squibb, Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, and AstraZeneca.

Human and animal rights

The study was conducted in accordance with the Declaration of Helsinki, the Pharmaceutical Affairs Law, and Good Clinical Practice. The study protocol was approved by the Institutional Review Boards of the participating institutions.

Informed consent

Written informed consent was obtained from all patients included in the study.

Additional information

This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-132162.

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Yamamoto, N., Fujiwara, Y., Tamura, K. et al. Phase Ia/Ib study of the pan-class I PI3K inhibitor pictilisib (GDC-0941) administered as a single agent in Japanese patients with solid tumors and in combination in Japanese patients with non-squamous non-small cell lung cancer. Invest New Drugs 35, 37–46 (2017). https://doi.org/10.1007/s10637-016-0382-3

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  • DOI: https://doi.org/10.1007/s10637-016-0382-3

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