A phase I, pharmacokinetic and pharmacodynamic study of nimotuzumab in Japanese patients with advanced solid tumors

Wataru Okamoto, Takayuki Yoshino, Toshiaki Takahashi, Isamu Okamoto, Shinya Ueda, Asuka Tsuya, Narikazu Boku, Kazuto Nishio, Masahiro Fukuoka, Nobuyuki Yamamoto, Kazuhiko Nakagawa

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1063-1071
Number of pages9
JournalCancer chemotherapy and pharmacology
Volume72
Issue number5
DOIs
Publication statusPublished - Nov 1 2013
Externally publishedYes

Fingerprint

Pharmacodynamics
Pharmacokinetics
Epidermal Growth Factor Receptor
Toxicity
Tumors
Neoplasms
Skin
Gene Dosage
Biopsy
Transducers
Genes
erbB-1 Genes
Antibodies, Monoclonal, Humanized
Phosphorylation
Maximum Tolerated Dose
Biomarkers
Exanthema
Disease Progression
nimotuzumab
Hypersensitivity

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

A phase I, pharmacokinetic and pharmacodynamic study of nimotuzumab in Japanese patients with advanced solid tumors. / Okamoto, Wataru; Yoshino, Takayuki; Takahashi, Toshiaki; Okamoto, Isamu; Ueda, Shinya; Tsuya, Asuka; Boku, Narikazu; Nishio, Kazuto; Fukuoka, Masahiro; Yamamoto, Nobuyuki; Nakagawa, Kazuhiko.

In: Cancer chemotherapy and pharmacology, Vol. 72, No. 5, 01.11.2013, p. 1063-1071.

Research output: Contribution to journalArticle

Okamoto, W, Yoshino, T, Takahashi, T, Okamoto, I, Ueda, S, Tsuya, A, Boku, N, Nishio, K, Fukuoka, M, Yamamoto, N & Nakagawa, K 2013, 'A phase I, pharmacokinetic and pharmacodynamic study of nimotuzumab in Japanese patients with advanced solid tumors', Cancer chemotherapy and pharmacology, vol. 72, no. 5, pp. 1063-1071. https://doi.org/10.1007/s00280-013-2277-8
Okamoto, Wataru ; Yoshino, Takayuki ; Takahashi, Toshiaki ; Okamoto, Isamu ; Ueda, Shinya ; Tsuya, Asuka ; Boku, Narikazu ; Nishio, Kazuto ; Fukuoka, Masahiro ; Yamamoto, Nobuyuki ; Nakagawa, Kazuhiko. / A phase I, pharmacokinetic and pharmacodynamic study of nimotuzumab in Japanese patients with advanced solid tumors. In: Cancer chemotherapy and pharmacology. 2013 ; Vol. 72, No. 5. pp. 1063-1071.
@article{b1fc954978a04939a7fb50fa00118d5a,
title = "A phase I, pharmacokinetic and pharmacodynamic study of nimotuzumab in Japanese patients with advanced solid tumors",
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.",
author = "Wataru Okamoto and Takayuki Yoshino and Toshiaki Takahashi and Isamu Okamoto and Shinya Ueda and Asuka Tsuya and Narikazu Boku and Kazuto Nishio and Masahiro Fukuoka and Nobuyuki Yamamoto and Kazuhiko Nakagawa",
year = "2013",
month = "11",
day = "1",
doi = "10.1007/s00280-013-2277-8",
language = "English",
volume = "72",
pages = "1063--1071",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "5",

}

TY - JOUR

T1 - A phase I, pharmacokinetic and pharmacodynamic study of nimotuzumab in Japanese patients with advanced solid tumors

AU - Okamoto, Wataru

AU - Yoshino, Takayuki

AU - Takahashi, Toshiaki

AU - Okamoto, Isamu

AU - Ueda, Shinya

AU - Tsuya, Asuka

AU - Boku, Narikazu

AU - Nishio, Kazuto

AU - Fukuoka, Masahiro

AU - Yamamoto, Nobuyuki

AU - Nakagawa, Kazuhiko

PY - 2013/11/1

Y1 - 2013/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84887209168&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887209168&partnerID=8YFLogxK

U2 - 10.1007/s00280-013-2277-8

DO - 10.1007/s00280-013-2277-8

M3 - Article

VL - 72

SP - 1063

EP - 1071

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 5

ER -