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Phase I study of BGT226, a pan-PI3K and mTOR inhibitor, in Japanese patients with advanced solid cancers

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Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway is a promising therapeutic target for various cancers. BGT226 is a pan-PI3K and mammalian target of rapamycin (mTOR) inhibitor. The tolerability and pharmacokinetics/pharmacodynamics of BGT226 were investigated in a phase I study in Japanese patients with advanced solid cancers. BGT226 was orally administered on days 1, 3, and 5 of each week. The initial dose of 10 mg was subsequently escalated to 20, 40, 80, and 100 mg in a cohort of three patients. Pharmacokinetics and pharmacodynamics were investigated using plasma, normal skin, and tumor samples. A total of 18 patients were enrolled and evaluated. The most frequently reported toxicities were diarrhea, nausea, decreased appetite, vomiting, and fatigue. They were all grade 1 or 2, and no dose-limiting toxicity was observed. However, all six patients treated at 100 mg experienced diarrhea and nausea, while two experienced a dose reduction and/or interruptions during the study. Two of five patients who exhibited stable disease continued the study treatment for ≥ 16 weeks. The absorption of BGT226 was rapid, and systemic exposure increased in a dose-dependent manner. Treatment with BGT226 did not change any of the biomarkers in neither normal skin nor tumor tissues. BGT226 was tolerated up to 100 mg three times a week in Japanese patients with solid cancers, without difference in toxicity profiles and pharmacokinetics compared to Western patients.

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Funding

This study was supported by Novartis Pharma K.K.

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Author notes

  1. Yutaka Fujiwara

    Present address: Department of Respiratory Medicine, Mitsui Memorial Hospital, Tokyo, Japan

Authors and Affiliations

  1. Medical Oncology and Hematology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

    Hironobu Minami & Yutaka Fujiwara

  2. Cancer Center, Kobe University Hospital, Kobe, Japan

    Hironobu Minami & Yutaka Fujiwara

  3. Department of Clinical Oncology and Outpatient Treatment Center, Aichi Cancer Center Hospital, Nagoya, Japan

    Kei Muro

  4. Novartis Pharma K.K, Tokyo, Japan

    Masahiko Sato & Atsuko Moriya

Authors
  1. Hironobu Minami
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  2. Yutaka Fujiwara
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Correspondence to Hironobu Minami.

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Conflict of interest

Hironobu Minami has received research funding from Asahi-Kasei, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eizai, Exelixis, Fuji, Kowa, Kyowa-Kirin, Lilly, Nihon Shinyaku, Novartis, Ono, Otsuka, Pfizer, Sanofi, Shire Japan, Taiho, and Takeda, and speaker honoraria from Bayer, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eizai, Exelixis, Kowa, Kyowa-Kirin, Lilly, Novartis, Ono, Otsuka, Pfizer, Sanofi, Shire Japan, Taiho, and Takeda. Yutaka Fujiwara has received research funding from AbbVie, AstraZeneca, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Incyte, Merck Serono, MSD, and Novartis, and speaker honoraria from Bristol-Myers Squibb, MSD, ONO, and Taiho.

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Minami, H., Fujiwara, Y., Muro, K. et al. Phase I study of BGT226, a pan-PI3K and mTOR inhibitor, in Japanese patients with advanced solid cancers. Cancer Chemother Pharmacol 84, 337–343 (2019). https://doi.org/10.1007/s00280-019-03883-6

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  • DOI: https://doi.org/10.1007/s00280-019-03883-6

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