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Phase 1 study of pazopanib alone or combined with lapatinib in Japanese patients with solid tumors

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Abstract

Purpose

A phase 1 study of pazopanib alone or in combination with lapatinib was conducted to assess the safety, tolerability, and pharmacokinetics of these oral tyrosine kinase inhibitors in Japanese patients with solid tumors.

Methods

In part A (monotherapy), 7 patients initially received pazopanib 800 mg/day, the recommended dose for non-Japanese patients. Then, 3 patients received pazopanib 400 mg/day on day 1 followed by 800 mg/day from day 2 onward. Three other patients received pazopanib 1,000 mg/day. In part B (combination therapy), 17 patients received pazopanib plus lapatinib (pazopanib/lapatinib) at once-daily doses of 400/1,000 mg (4 patients), 800/1,000 mg (3 patients), 400/1,500 mg (3 patients), and then 600/1,250 mg (7 patients).

Results

There was no dose-limiting toxicity during the study. In part A, most drug-related adverse events were grade 2 or lower, including neutropenia/neutrophil count decreased, thrombocytopenia/platelet count decreased, diarrhea, hypertension, aspartate aminotransferase increased, and lipase increased. In part B, rash, decreased appetite, and serum thyroid-stimulating hormone increased also occurred. In all dose groups, the plasma concentrations after multiple doses of pazopanib exceeded the target trough concentration for inhibition of vascular endothelial growth factor receptor-2 activity (20 μg/mL).

Conclusions

The pharmacokinetic profiles of pazopanib and lapatinib in Japanese patients were not apparently different from those reported in non-Japanese patients. There were no consistent trends in pharmacokinetic drug interactions between pazopanib and lapatinib. Pazopanib monotherapy at 800 and 1,000 mg once daily and pazopanib plus lapatinib once daily at any doses studied were well tolerated in Japanese patients.

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Acknowledgments

Appreciation is expressed to the patients and their families, as well as the many investigators who participated in the study.

Ethical standards

This study was approved by the appropriate ethics committee(s), was performed in accordance with the Declaration of Helsinki, and complied with the current laws of the country (Japan) in which it was conducted. All patients provided informed consent before inclusion in the study.

Conflict of interest

This study (VEG109693; NCT00516672) was supported by research funding from GlaxoSmithKline Pharmaceuticals. Editorial assistance was provided by ProEd Communications, Inc., Beachwood, Ohio, USA, and was supported by GlaxoSmithKline. Akiko Takekura is employee but not stockholder of GSK. Kazuo is employee and stockholder of GSK. Yasutsuna Sasaki served as a consultant/advisor for Takeda-Bio, Kowa, and GlaxoSmithKline. Yuichi Ando served as a consultant/advisor for GlaxoSmithKline. The other authors have no conflicts of interest to disclose concerning this study.

Author information

Authors and Affiliations

  1. Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan

    Megumi Inada-Inoue, Yuichi Ando, Kenji Kawada, Ayako Mitsuma & Masataka Sawaki

  2. Department of Palliative Medicine, Yokohama Municipal Citizen’s Hospital, 56 Okazawa-cho, Hodogaya-ku, Yokohama-shi, Kanagawa, 240-8555, Japan

    Taro Yokoyama

  3. Department of Internal Medicine, Showa University Northern Yokohama Hospital, 35-1 Chigasaki-chou, Tsuzuki-ku, Yokohama-shi, Kanagawa, 224-8503, Japan

    Yu Sunakawa

  4. Department of Medicine, Showa University Hospital, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666, Japan

    Hiroo Ishida & Yasutsuna Sasaki

  5. Department of Breast Oncology, The Cancer Institute Hospital of JFCR, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan

    Kazuhiro Araki

  6. Kawagoe Gastroenterical Hospital, Senba-machi, Kawagoe-shi, Saitama, 350-0034, Japan

    Keishi Yamashita

  7. Department of Pulmonary Medicine, Graduate School of Medicine and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima-shi, Kagoshima, 890-8544, Japan

    Keiko Mizuno

  8. Department of Internal Medicine, Medical Oncology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo, 181-8611, Japan

    Fumio Nagashima

  9. GlaxoSmithKline K.K., GSK Bldg., 6-15 Sendagaya 4-chome, Shibuya-ku, Tokyo, 151-8566, Japan

    Akiko Takekura & Kazuo Nagamatsu

Authors
  1. Megumi Inada-Inoue
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  2. Yuichi Ando
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  3. Kenji Kawada
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  4. Ayako Mitsuma
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  5. Masataka Sawaki
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  6. Taro Yokoyama
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  7. Yu Sunakawa
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  8. Hiroo Ishida
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  9. Kazuhiro Araki
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  10. Keishi Yamashita
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  11. Keiko Mizuno
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  12. Fumio Nagashima
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  13. Akiko Takekura
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  14. Kazuo Nagamatsu
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  15. Yasutsuna Sasaki
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Corresponding author

Correspondence to Yuichi Ando.

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Inada-Inoue, M., Ando, Y., Kawada, K. et al. Phase 1 study of pazopanib alone or combined with lapatinib in Japanese patients with solid tumors. Cancer Chemother Pharmacol 73, 673–683 (2014). https://doi.org/10.1007/s00280-014-2374-3

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  • DOI: https://doi.org/10.1007/s00280-014-2374-3

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