International Journal of Clinical Oncology

, Volume 7, Issue 3, pp 177–186

Phase I studies of nogitecan hydrochloride for Japanese

  • K. Kobayashi
  • M. Hino
  • M. Fukuoka
  • K. Takeuchi
  • K. Furuse
  • S. Yoneda
  • K. Hasegawa
  • K. Noda
  • H. Kinoshita
  • I. Kimura
  • T. Taguchi
  • R. Kanamaru
  • N. Horikoshi
  • H. Niitani
ORIGINAL ARTICLE

DOI: 10.1007/s101470200026

Cite this article as:
Kobayashi, K., Hino, M., Fukuoka, M. et al. Int J Clin Oncol (2002) 7: 177. doi:10.1007/s101470200026
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Abstract

Background. SmithKline Beecham synthesized camptothecin analogs and identified nogitecan hydrochloride (topotecan) with a broad spectrum of antitumor activity and less toxicity than camptothecin. Because preclinical and overseas clinical data indicated the antitumor effect of nogitecan hydrochloride with a 5-day repeat-dose schedule, we carried out phase I studies in Japan to determine the maximum tolerated dose (MTD), pharmacokinetics, and antitumor effect of nogitecan hydrochloride.

Methods. Phase I studies of nogitecan hydrochloride given by single and 5-day repeat dosing were carried out in patients with various solid tumors at 15 medical institutions in Japan. Pharmacokinetic evaluations were performed for both single and 5-day repeated dosing.

Results. The dose-limiting factor (DLF) was reversible leucopenia, and the maximum tolerated dose (MTD) was higher than 22.5 mg/m2 in the single-dose study. In the 5-day repeat-dose study, the DLF was also reversible leucopenia, and the MTD was estimated to be 1.5 mg/m2 per day. The plasma concentration of nogitecan hydrochloride increased with increasing dose, and the half-life after single dosing ranged from 3 to 5 h. There was no evidence of accumulation or delayed excretion during 5-day repeat dosing.

Conclusion. Based on these results and the finding that there were responders among patients treated at 1.5 mg/m2 per day by 5-day repeat dosing in overseas studies, 5-day repeat dosing of 1.2 mg/m2 per day, one dose level lower than the MTD, was selected for phase II studies in Japan.

Key words Topoisomerase I inhibitorTopotecanPhase I study

Copyright information

© The Japan Society of Clinical Oncology 2002

Authors and Affiliations

  • K. Kobayashi
    • 1
  • M. Hino
    • 2
  • M. Fukuoka
    • 3
  • K. Takeuchi
    • 4
  • K. Furuse
    • 5
  • S. Yoneda
    • 1
  • K. Hasegawa
    • 6
  • K. Noda
    • 7
  • H. Kinoshita
    • 8
  • I. Kimura
    • 9
  • T. Taguchi
    • 10
  • R. Kanamaru
    • 11
  • N. Horikoshi
    • 12
  • H. Niitani
    • 13
  1. 1.Department of Respiratory Medicine, Saitama Cancer Center, 818 Komuro, Inamachi, Saitama 362-0806, Japan Tel. +81-48-722-1111; Fax +81-48-722-1129 e-mail: go1059@cancer-c.pref.saitama.jpJP
  2. 2.Respiratory Center, Nippon Medical School, INBA-HITEC Medical Center, Chiba, JapanJP
  3. 3.Department of Medical Oncology, Kinki University School of Medicine, Osaka, JapanJP
  4. 4.Hyogo Prefecture Health Promotion Association, Hyogo, JapanJP
  5. 5.Osaka Central Hospital, Osaka, JapanJP
  6. 6.Department of Internal Medicine, Tsuboi Hospital, Fukushima, JapanJP
  7. 7.Kinki University, Osaka, JapanJP
  8. 8.Second Department of Surgery, Osaka City University Medical School, Osaka, JapanJP
  9. 9.Okayama University Medical School, Okayama, JapanJP
  10. 10.Japan Society for Cancer Chemotherapy, Osaka, JapanJP
  11. 11.Institute of Development, Aging and Cancer, Tohoku University, Miyagi, JapanJP
  12. 12.Department of Medical Oncology, Cancer Institute Hospital, Tokyo, JapanJP
  13. 13.Tokyo Society for Research of Cancer Chemotherapy, Tokyo, JapanJP