A phase i escalating single-dose and weekly fixed-dose study of cetuximab pharmacokinetics in Japanese patients with solid tumors

Kuniaki Shirao, Takayuki Yoshino, Narikazu Boku, Ken Kato, Tetsuya Hamaguchi, Hisateru Yasui, Nobuyuki Yamamoto, Yusuke Tanigawara, Arno Nolting, Shinichiro Yoshino

Research output: Contribution to journalArticle

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Abstract

Purpose: Cetuximab is a therapeutic immunoglobulin G1 monoclonal antibody that recognizes the epidermal growth factor receptor (EGFR). This phase I dose-escalation study was designed to assess the safety and pharmacokinetics (PK) of cetuximab in Japanese patients with EGFR-expressing, advanced, solid tumors and also to look for evidence of antitumor efficacy. Patients and methods: Thirty patients were enrolled in the study; 29 with colorectal adenocarcinomas and one with an adenocarcinoma of the lung. Patients received an initial/weekly infusion of cetuximab at dose levels of 100/100 (dose level 1), 250/250 (dose level 2), 400/250 (dose level 3), 500/250 (dose level 4) or 400/250 (dose level 5) mg/m2, for 7 or more weeks, with an interval between the initial and second infusion of 1 (dose level 5 representing the standard regimen) or 2 weeks (dose levels 1-4 of the non-standard regimens). Results: No dose-limiting toxicities (DLTs) were observed during the evaluation period. All patients had at least one adverse event (AE). The most common cetuximab-related AEs were skin toxicity (93% of patients), including acneiform dermatitis (83% of patients). Two patients experienced cetuximab-related grade 3 AEs of skin toxicity and diarrhea after DLT evaluation. C max and AUC0-∞ after the initial infusion showed dose-proportional increases. Mean total body clearance (CL) values decreased with dose at the lower dose levels. At doses of ≥400 mg/m2, CL values appeared to level off. Mean trough concentrations for dose level 5 were constant from week 4 (day 29) onward. Two patients (8%) achieved partial response (at 100/100 mg/m2). The overall disease control rate (partial response + stable disease) was 58%. Conclusion: The current study demonstrated that cetuximab PK and safety profiles are similar between Japanese and non-Japanese patient populations. It would appear that the standard dose of an initial 2-h infusion of 400 mg/m2 followed thereafter by weekly 1-h infusions of 250 mg/m2 for non-Japanese patients is feasible for future clinical studies in Japanese patients.

Original languageEnglish
Pages (from-to)557-564
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume64
Issue number3
DOIs
Publication statusPublished - 2009 Jul

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Pharmacokinetics
Tumors
Toxicity
Neoplasms
Epidermal Growth Factor Receptor
Skin
Dermatitis
Disease control
Cetuximab
Immunoglobulins
Monoclonal Antibodies
Safety
Diarrhea
Adenocarcinoma

Keywords

  • Cetuximab
  • Colorectal
  • EGFR
  • Japanese
  • Pharmacokinetics
  • Safety

ASJC Scopus subject areas

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

Cite this

A phase i escalating single-dose and weekly fixed-dose study of cetuximab pharmacokinetics in Japanese patients with solid tumors. / Shirao, Kuniaki; Yoshino, Takayuki; Boku, Narikazu; Kato, Ken; Hamaguchi, Tetsuya; Yasui, Hisateru; Yamamoto, Nobuyuki; Tanigawara, Yusuke; Nolting, Arno; Yoshino, Shinichiro.

In: Cancer Chemotherapy and Pharmacology, Vol. 64, No. 3, 07.2009, p. 557-564.

Research output: Contribution to journalArticle

Shirao, Kuniaki ; Yoshino, Takayuki ; Boku, Narikazu ; Kato, Ken ; Hamaguchi, Tetsuya ; Yasui, Hisateru ; Yamamoto, Nobuyuki ; Tanigawara, Yusuke ; Nolting, Arno ; Yoshino, Shinichiro. / A phase i escalating single-dose and weekly fixed-dose study of cetuximab pharmacokinetics in Japanese patients with solid tumors. In: Cancer Chemotherapy and Pharmacology. 2009 ; Vol. 64, No. 3. pp. 557-564.
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abstract = "Purpose: Cetuximab is a therapeutic immunoglobulin G1 monoclonal antibody that recognizes the epidermal growth factor receptor (EGFR). This phase I dose-escalation study was designed to assess the safety and pharmacokinetics (PK) of cetuximab in Japanese patients with EGFR-expressing, advanced, solid tumors and also to look for evidence of antitumor efficacy. Patients and methods: Thirty patients were enrolled in the study; 29 with colorectal adenocarcinomas and one with an adenocarcinoma of the lung. Patients received an initial/weekly infusion of cetuximab at dose levels of 100/100 (dose level 1), 250/250 (dose level 2), 400/250 (dose level 3), 500/250 (dose level 4) or 400/250 (dose level 5) mg/m2, for 7 or more weeks, with an interval between the initial and second infusion of 1 (dose level 5 representing the standard regimen) or 2 weeks (dose levels 1-4 of the non-standard regimens). Results: No dose-limiting toxicities (DLTs) were observed during the evaluation period. All patients had at least one adverse event (AE). The most common cetuximab-related AEs were skin toxicity (93{\%} of patients), including acneiform dermatitis (83{\%} of patients). Two patients experienced cetuximab-related grade 3 AEs of skin toxicity and diarrhea after DLT evaluation. C max and AUC0-∞ after the initial infusion showed dose-proportional increases. Mean total body clearance (CL) values decreased with dose at the lower dose levels. At doses of ≥400 mg/m2, CL values appeared to level off. Mean trough concentrations for dose level 5 were constant from week 4 (day 29) onward. Two patients (8{\%}) achieved partial response (at 100/100 mg/m2). The overall disease control rate (partial response + stable disease) was 58{\%}. Conclusion: The current study demonstrated that cetuximab PK and safety profiles are similar between Japanese and non-Japanese patient populations. It would appear that the standard dose of an initial 2-h infusion of 400 mg/m2 followed thereafter by weekly 1-h infusions of 250 mg/m2 for non-Japanese patients is feasible for future clinical studies in Japanese patients.",
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author = "Kuniaki Shirao and Takayuki Yoshino and Narikazu Boku and Ken Kato and Tetsuya Hamaguchi and Hisateru Yasui and Nobuyuki Yamamoto and Yusuke Tanigawara and Arno Nolting and Shinichiro Yoshino",
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T1 - A phase i escalating single-dose and weekly fixed-dose study of cetuximab pharmacokinetics in Japanese patients with solid tumors

AU - Shirao, Kuniaki

AU - Yoshino, Takayuki

AU - Boku, Narikazu

AU - Kato, Ken

AU - Hamaguchi, Tetsuya

AU - Yasui, Hisateru

AU - Yamamoto, Nobuyuki

AU - Tanigawara, Yusuke

AU - Nolting, Arno

AU - Yoshino, Shinichiro

PY - 2009/7

Y1 - 2009/7

N2 - Purpose: Cetuximab is a therapeutic immunoglobulin G1 monoclonal antibody that recognizes the epidermal growth factor receptor (EGFR). This phase I dose-escalation study was designed to assess the safety and pharmacokinetics (PK) of cetuximab in Japanese patients with EGFR-expressing, advanced, solid tumors and also to look for evidence of antitumor efficacy. Patients and methods: Thirty patients were enrolled in the study; 29 with colorectal adenocarcinomas and one with an adenocarcinoma of the lung. Patients received an initial/weekly infusion of cetuximab at dose levels of 100/100 (dose level 1), 250/250 (dose level 2), 400/250 (dose level 3), 500/250 (dose level 4) or 400/250 (dose level 5) mg/m2, for 7 or more weeks, with an interval between the initial and second infusion of 1 (dose level 5 representing the standard regimen) or 2 weeks (dose levels 1-4 of the non-standard regimens). Results: No dose-limiting toxicities (DLTs) were observed during the evaluation period. All patients had at least one adverse event (AE). The most common cetuximab-related AEs were skin toxicity (93% of patients), including acneiform dermatitis (83% of patients). Two patients experienced cetuximab-related grade 3 AEs of skin toxicity and diarrhea after DLT evaluation. C max and AUC0-∞ after the initial infusion showed dose-proportional increases. Mean total body clearance (CL) values decreased with dose at the lower dose levels. At doses of ≥400 mg/m2, CL values appeared to level off. Mean trough concentrations for dose level 5 were constant from week 4 (day 29) onward. Two patients (8%) achieved partial response (at 100/100 mg/m2). The overall disease control rate (partial response + stable disease) was 58%. Conclusion: The current study demonstrated that cetuximab PK and safety profiles are similar between Japanese and non-Japanese patient populations. It would appear that the standard dose of an initial 2-h infusion of 400 mg/m2 followed thereafter by weekly 1-h infusions of 250 mg/m2 for non-Japanese patients is feasible for future clinical studies in Japanese patients.

AB - Purpose: Cetuximab is a therapeutic immunoglobulin G1 monoclonal antibody that recognizes the epidermal growth factor receptor (EGFR). This phase I dose-escalation study was designed to assess the safety and pharmacokinetics (PK) of cetuximab in Japanese patients with EGFR-expressing, advanced, solid tumors and also to look for evidence of antitumor efficacy. Patients and methods: Thirty patients were enrolled in the study; 29 with colorectal adenocarcinomas and one with an adenocarcinoma of the lung. Patients received an initial/weekly infusion of cetuximab at dose levels of 100/100 (dose level 1), 250/250 (dose level 2), 400/250 (dose level 3), 500/250 (dose level 4) or 400/250 (dose level 5) mg/m2, for 7 or more weeks, with an interval between the initial and second infusion of 1 (dose level 5 representing the standard regimen) or 2 weeks (dose levels 1-4 of the non-standard regimens). Results: No dose-limiting toxicities (DLTs) were observed during the evaluation period. All patients had at least one adverse event (AE). The most common cetuximab-related AEs were skin toxicity (93% of patients), including acneiform dermatitis (83% of patients). Two patients experienced cetuximab-related grade 3 AEs of skin toxicity and diarrhea after DLT evaluation. C max and AUC0-∞ after the initial infusion showed dose-proportional increases. Mean total body clearance (CL) values decreased with dose at the lower dose levels. At doses of ≥400 mg/m2, CL values appeared to level off. Mean trough concentrations for dose level 5 were constant from week 4 (day 29) onward. Two patients (8%) achieved partial response (at 100/100 mg/m2). The overall disease control rate (partial response + stable disease) was 58%. Conclusion: The current study demonstrated that cetuximab PK and safety profiles are similar between Japanese and non-Japanese patient populations. It would appear that the standard dose of an initial 2-h infusion of 400 mg/m2 followed thereafter by weekly 1-h infusions of 250 mg/m2 for non-Japanese patients is feasible for future clinical studies in Japanese patients.

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KW - Colorectal

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KW - Pharmacokinetics

KW - Safety

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