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.

• Authors: Wataru Okamoto, Takayuki Yoshino, Toshiaki Takahashi, Isamu Okamoto, Shinya Ueda, Asuka Tsuya, Narikazu Boku, Kazuto Nishio, Masahiro Fukuoka, Nobuyuki Yamamoto, Kazuhiko Nakagawa
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 72 Issue 5 Pg. 1063-71 (Nov 2013) ISSN: 1432-0843 [Electronic] Germany
• PMID: 24046058 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Biomarkers
• Neoplasm Proteins
• nimotuzumab
• ErbB Receptors

Topics

• Aged
• Antibodies, Monoclonal, Humanized (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Biomarkers (blood, metabolism)
• Disease Progression
• Dose-Response Relationship, Drug
• Drug Eruptions (epidemiology)
• ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
• Female
• Gene Dosage
• Humans
• Incidence
• Japan (epidemiology)
• Male
• Middle Aged
• Neoplasm Proteins (genetics, metabolism)
• Neoplasms (drug therapy, genetics, metabolism, physiopathology)
• Skin (drug effects, metabolism)
• Tumor Burden (drug effects)