Abstract
Purpose
Nimotuzumab is a humanized IgG1 monoclonal antibody to the epidermal growth factor receptor (EGFR) and has demonstrated the absence of severe dermatological toxicity commonly caused by other EGFR-targeting antibodies. We conducted a phase I study to assess toxicities, pharmacokinetics, pharmacodynamics, and predictive biomarkers of nimotuzumab administered in Japanese patients with advanced solid tumors.
Methods
Three dose levels, 100, 200, and 400 mg, of weekly i.v. nimotuzumab were given until disease progression or drug intolerability. Four patients with solid tumors were enrolled in each dose level. The expression and gene copy number of EGFR or its downstream transducers were investigated using skin biopsy samples and tumor specimens.
Results
Planned dose escalation was completed without dose-limiting toxicity, and maximum tolerated dose was not reached. No allergic reaction and hypomagnesaemia were observed, and grade 3 or 4 toxicity did not occur. The common toxicity was skin rash (58 %); however, all of them were grade 1 or 2. In skin biopsies, no correlation was shown between doses and the phosphorylation of EGFR or its downstream signal transducers. Of 11 evaluable patients, no objective response was obtained, while 8 patients had stable disease (73 %). Patients with a higher-EGFR gene copy number level measured by FISH showed a longer time to progression.
Conclusions
Nimotuzumab administered weekly was feasible and well tolerated up to 400 mg in Japanese patients. A low dermatological toxicity could be a notable advantage as anti-EGFR mAb, and further evaluation is warranted.
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Acknowledgments
The authors would like to thank all the patients who participated in this study as well as Hiroshi Terakawa, Kenji Hirotani, Yuko Aramaki, Kiyo Nishimoto, Taiga Takagi and Koji Ishizuka in DAIICHI SANKYO CO., LTD. (Tokyo, Japan) for the assistance. This study was supported by DAIICHI SANKYO CO., LTD. which provided study medication and assistance with data collection.
Conflict of interest
Wataru Okamoto, Takayuki Yoshino, Toshiaki Takahashi, Isamu Okamoto, Shinya Ueda, Asuka Tsuya, Narikazu Boku, Kazuto Nishio, Masahiro Fukuoka, Nobuyuki Yamamoto, and Kazuhiko Nakagawa received a research funding for conducting this study from DAIICHI SANKYO CO., LTD. Masahiro Fukuoka and Narikazu Boku received lecture fees from DAIICHI SANKYO CO., LTD.
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Okamoto, W., Yoshino, T., Takahashi, T. et al. A phase I, pharmacokinetic and pharmacodynamic study of nimotuzumab in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 72, 1063–1071 (2013). https://doi.org/10.1007/s00280-013-2277-8
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DOI: https://doi.org/10.1007/s00280-013-2277-8