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Author Notes:

E-mail Address : dmshin@emory.edu.

We thank Genentech for providing erlotinib for this study.

We also thank Dr. Anthea Hammond for her critical reading of the article and Dana Ray for her administrative support of the study.

There are no disclaimers to report

Subjects:

Research Funding:

This study was supported by grants from the National Institutes of Health (U01 CA101244 and Specialized Programs of Research Excellence in Head and Neck Cancer, P50 CA128613) to DMS and R01CA0983722, P50CA097190 and the American Cancer Society (to JRG).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • GROWTH-FACTOR-RECEPTOR
  • SQUAMOUS-CELL CARCINOMA
  • ORAL PREMALIGNANT LESIONS
  • LUNG-CANCER
  • TUMOR PROGRESSION
  • NATURAL COMPOUNDS
  • TYROSINE KINASE
  • FACTOR-ALPHA
  • CYCLOOXYGENASE-2
  • INHIBITION

Chemoprevention of Head and Neck Cancer with Celecoxib and Erlotinib: Results of a Phase Ib and Pharmacokinetic Study

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Journal Title:

Cancer Prevention Research

Volume:

Volume 7, Number 3

Publisher:

, Pages 283-291

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Epidermal growth factor receptor (EGFR) and COX-2 inhibitors synergistically inhibit head and neck squamous cell carcinoma tumorigenesis in preclinical studies. We conducted a phase I and pharmacokinetic study with the erlotinib and celecoxib combination in patients with advanced premalignant lesions. Thirty-six subjects with oral leukoplakia, mild, moderate, or severe dysplasia, or carcinoma in situ were screened for study participation; 12 consented and received therapy for a median of 5.38 months. Erlotinib was escalated following a standard 3+3 design at 50, 75, and 100 mg orally daily and celecoxib was fixed at 400 mg twice daily for 6 months. Biopsy of lesions and cytobrush of normal mucosa were performed at baseline, 3, 6, and 12 months. Erlotinib pharmacokinetics were analyzed in 10 subjects. The maximum tolerated dose of erlotinib with celecoxib 400 mg BID was 50 mg per day with skin rash being the main observed toxicity. Overall histologic response rate was 63% (complete response, 43%; partial response, 14%; stable disease, 29%; and disease progression, 14%). With median follow-up of 36 months, mean time to progression to higher-grade dysplasia or carcinoma was 25.4 months. Downregulation of EGFR and p-ERK in follow-up biopsies correlated with response to treatment. Larger average erlotinib V/F (approximately 308 L) and CL/F (8.3 L/h) compared with previous studies may be related to relatively large average bodyweights. Average erlotinib t1/2 was 25.6 hours. Encouraging responses to the celecoxib and erlotinib combination correlated with EGFR pathway inhibition. Although erlotinib-related rash was the main limitation to dose escalation, the intervention was well tolerated.

Copyright information:

©2013 AACR.

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