Chemoprevention of head and neck cancer with celecoxib and erlotinib: results of a phase ib and pharmacokinetic study

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.

Figures

Figure 1

Histologic responses from biopsies of two patients treated with celecoxib and erlotinib. A) Patient 1: baseline severe dysplasia; B) Patient 1: hyperplasia and no dysplasia at 3 months; C) Patient 2: baseline moderate to severe dysplasia; D) Patient 2: mild dysplasia at 3 months; E) Patient 2: hyperplasia and no dysplasia at 6 months; F) Patient 2: hyperkeratosis at 12 months.

Figure 2

Time to progression to higher grade dysplasia or carcinoma. Mean time to progression was 25.4 months. Median time for follow-up was 36 months.

Figure 3

(A) Plasma concentrations of erlotinib and OSI-420 (demethyl erlotinib) versus time. Subjects self-administered 50mg (□, n = 3), 75mg (◯, n = 6) or 100mg erlotinib (Δ, n =1) QD. Closed symbols and solid lines represent erlotinib concentrations, open symbols and dashed lines represent the OSI-420 metabolite. Plasma concentrations of erlotinib were used for PK modeling. (B) Observed versus final model predicted plasma concentrations of erlotinib. The left panel is based on the “typical” prediction without including model variability (IIV), while the right panel is based on the complete model including IIV (post hoc fit). The linear regression coefficients (r2, observed versus predicted) for the respective plots were 0.508 and 0.783, respectively. Inclusion of the error model (post hoc model) decreased the standard errors of prediction of the model from 22 to 15%. (C) Conditioned weighted residuals (CWRES) (39) were plotted versus time and post hoc predicted concentrations. The curvilinear plots depict local regression trend smoother fits to the data. The curvilinear plots in C and D depict local regression trend smoother (R Supersmoother) fits to the data. (D) Model validation by “precision corrected visual predictive check” (40), in which observations are normalized to the median (75mg QD) dosing scheme. One thousand simulations were performed per subject and used to compute percentile ranges (P5, P25, P50, P75 and P95) normalized to median dose and body-weight. Actual observations were also normalized, and superimposed over these ranges for comparison. The shaded area indicates 90% confidence interval; solid lines indicate percentiles: 2.5, 97.5 (red); 5, 95 (blue); 25, 75 (green); 50 (black). Dashed lines indicate percentiles 5, 50, and 95 of observations.

Figure 3

(A) Plasma concentrations of erlotinib and OSI-420 (demethyl erlotinib) versus time. Subjects self-administered 50mg (□, n = 3), 75mg (◯, n = 6) or 100mg erlotinib (Δ, n =1) QD. Closed symbols and solid lines represent erlotinib concentrations, open symbols and dashed lines represent the OSI-420 metabolite. Plasma concentrations of erlotinib were used for PK modeling. (B) Observed versus final model predicted plasma concentrations of erlotinib. The left panel is based on the “typical” prediction without including model variability (IIV), while the right panel is based on the complete model including IIV (post hoc fit). The linear regression coefficients (r2, observed versus predicted) for the respective plots were 0.508 and 0.783, respectively. Inclusion of the error model (post hoc model) decreased the standard errors of prediction of the model from 22 to 15%. (C) Conditioned weighted residuals (CWRES) (39) were plotted versus time and post hoc predicted concentrations. The curvilinear plots depict local regression trend smoother fits to the data. The curvilinear plots in C and D depict local regression trend smoother (R Supersmoother) fits to the data. (D) Model validation by “precision corrected visual predictive check” (40), in which observations are normalized to the median (75mg QD) dosing scheme. One thousand simulations were performed per subject and used to compute percentile ranges (P5, P25, P50, P75 and P95) normalized to median dose and body-weight. Actual observations were also normalized, and superimposed over these ranges for comparison. The shaded area indicates 90% confidence interval; solid lines indicate percentiles: 2.5, 97.5 (red); 5, 95 (blue); 25, 75 (green); 50 (black). Dashed lines indicate percentiles 5, 50, and 95 of observations.