Phase I trial to study the effectiveness of combining erlotinib with radiation therapy with or without cisplatin in treating patients who have advanced mouth or throat cancer. Erlotinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining erlotinib with radiation therapy with or without cisplatin may kill more tumor cells.
PRIMARY OBJECTIVES: I. Determination of the maximally tolerated dose (MTD) of the combination of daily oral OSI-774 and standard fractionation external beam radiation therapy in patients with oral cavity (OC) or oropharyngeal (OP) squamous cell carcinoma (SCC), stage II and III. II. Determination of the MTD of daily oral OSI-774, low dose daily cisplatin at 6 mg/m\^2/day and standard fractionation external beam radiation therapy in patients with oral cavity or oropharyngeal SCC stage III and IV. III. Determination of the safety of chronic oral dosing of OSI-774 after radiation therapy. SECONDARY OBJECTIVES: I. Determination of biological markers of activity of OSI-774 in tumor biopsy specimens from patients with SCC of OC and OP pre and post therapy. II. Determination of the ability of (18F)-FDG-PET scan to demonstrate biological activity of OSI-774 in previously untreated patients with SCC of the OC and OP and to predict for clinical response. OUTLINE: This is a multicenter, dose-escalation study of erlotinib. Patients are assigned to 1 of 2 regimens according to disease stage. Regimen A (patients with stage II \[T2, N0\] or III \[T1-2, N1\] disease): Patients receive oral erlotinib once daily. Beginning on day 15, patients also undergo intensity-modulated radiotherapy (IMRT) once daily 5 days a week for 7 weeks. Regimen B (patients with stage III \[T3, N0-1\] or IV \[T1-4, N2-3, M0 or T4, N0-1, M0\] disease): Patients receive oral erlotinib and undergo IMRT as in regimen A. Patients also receive cisplatin IV over 20 minutes on each day of radiotherapy. Patients in both regimens continue to receive erlotinib until the last day of IMRT (patients already in the maintenance phase of this study as of 5/11/04 continue to receive erlotinib once daily for up to 2 years) in the absence of disease progression or unacceptable toxicity. In both regimens, cohorts of 3-6 patients receive escalating doses of erlotinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Patients are followed at 30 days and then every 3 months for up to 2 years. PROJECTED ACCRUAL: A total of 24-48 patients (12-24 per regimen) will be accrued for this study within 6-24 months.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
48
Johns Hopkins University
Baltimore, Maryland, United States
Maximum tolerated dose (MTD) of cisplatin, graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) v3.0
Summarized using descriptive statistics.
Time frame: Up to 7 weeks
Time to progression
Time frame: Up to 2 years
Pharmacokinetics in terms of steady state concentration (Css, min)
Relationships between cisplatin and erlotinib hydrochloride steady-state concentrations and toxicity and epidermal growth factor receptor (EGFR) inhibition will be assessed using univariate and multivariate statistical methods.
Time frame: Up to 10 weeks
Percent change in standardized uptake value (SUV) corrected for lean body mass
The pre and post treatment scans will be compared by use of Wilcoxon signed rank test. The relationship between metabolic response and clinical response will be evaluated by use of chi square test or Fisher's exact test as appropriate.
Time frame: Up to 14 days
Biological response for each individual patient as defined by determination of the proportional variation of each biomarker
Both pharmacokinetic and pharmacodynamic parameters will be calculated and their relationship fit with flexible regression models.
Time frame: Up to 2 years
Relationship between time to treatment failure versus variations in the biomarkers
Analyzed by the Kaplan Meier method or Cox regression models, and tested with a logrank test.
Time frame: Up to 2 years
Effect of erlotinib hydrochloride on the EGFR activation and signaling
Descriptive statistics (mean +/- standard deviation \[SD\]) will be used to summarize the data. Differences between pre and post treatment immunohistochemistry (IHC) scored will be compared with a paired-t test.
Time frame: Up to day 120
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