RATIONALE: Biological therapies such as gefitinib may interfere with the growth of tumor cells and slow the growth of cancer. 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 gefitinib and radiation therapy with cisplatin may kill more tumor cells.

PURPOSE: Phase I trial to study the effectiveness of combining gefitinib and radiation therapy with or without cisplatin in treating patients who have stage III or stage IV head and neck cancer.

Condition	Treatment or Intervention	Phase
Hypopharyngeal Cancer Laryngeal Cancer lip and oral cavity cancer Oropharyngeal Cancer	Drug: cisplatin  Drug: gefitinib  Procedure: adjuvant therapy  Procedure: chemotherapy  Procedure: enzyme inhibitor therapy  Procedure: protein tyrosine kinase inhibitor therapy  Procedure: radiation therapy	Phase I

OBJECTIVES:

• Determine the maximum tolerated dose of gefitinib in combination with radiotherapy with or without cisplatin in patients with previously untreated, locally advanced squamous cell carcinoma of the head and neck.
• Determine the dose-dependent local and/or systemic toxic effects of these regimens in these patients.
• Determine the feasibility and toxicity profile of protracted continuous daily dosing of gefitinib after completion of radiotherapy in these patients.
• Determine the response rate, relapse-free survival rate, and overall survival rate in patients treated with these regimens.

OUTLINE: This is a multicenter, dose-escalation study of gefitinib.

All patients receive oral gefitinib once daily beginning at least 7 days before and continuing throughout radiotherapy or chemoradiotherapy in the absence of disease progression or unacceptable toxicity. Patients are entered into 1 of 5 levels.

• Level I: Patients undergo concurrent boost radiotherapy 5 days per week comprising once daily radiotherapy for 3.5 weeks followed by twice daily radiotherapy for 2.5 weeks.
• Level II: Patients receive escalated dose of gefitinib and undergo radiotherapy as in level I.
• Level III: Patients receive original dose of gefitinib, undergo standard fractionation radiotherapy comprising once daily radiotherapy 5 days per week for 7 weeks, and receive cisplatin IV over 30-60 minutes at the beginning of each week of radiotherapy.
• Level IV: Patients receive escalated dose of gefitinib as in level II and undergo radiotherapy and chemotherapy as in level III.
• Level V: Patients receive the maximum tolerated dose (MTD) of gefitinib, radiotherapy as in level I, and chemotherapy as in level III. Patients with clinical or radiologic evidence of residual disease are required to undergo neck dissection approximately 8 weeks after completion of radiotherapy or chemoradiotherapy.

Patients resume oral gefitinib daily beginning 8 weeks after the completion of radiotherapy or chemoradiotherapy (12 weeks for patients who undergo neck dissection) and continuing for 2 years in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients are enrolled sequentially beginning at level I until the MTD of gefitinib is determined. The MTD is the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity.

Twelve additional patients receive the MTD of gefitinib in combination with radiotherapy with or without cisplatin.

Patients are followed every 6 months for 3 years.

PROJECTED ACCRUAL: A total of 18-30 patients will be accrued for this study within 16 months.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed locally advanced squamous cell carcinoma of the head and neck involving the oral cavity, oropharynx, hypopharynx, or supraglottic or glottic larynx
• Stage III or IV
• No distant metastases
• Only patients with intermediate stage disease (T1-2, N1-N2a or T3, N0-1) are eligible for radiotherapy alone with gefitinib

PATIENT CHARACTERISTICS: Age:

• 18 and over

Performance status:

• ECOG 0-2 OR
• Karnofsky 60-100%

Life expectancy:

• More than 6 months

Hematopoietic:

• WBC at least 3,000/mm^3
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin at least 9 g/dL

Hepatic:

• Bilirubin normal
• AST and ALT no greater than 2.5 times upper limit of normal

Renal:

• Creatinine normal OR
• Creatinine clearance at least 60 mL/min

Cardiac:

• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Medically suitable to withstand a course of definitive radiotherapy
• No ongoing or active infection
• No other malignancy within the past 3 years except basal cell skin cancer or carcinoma in situ of the cervix
• No prior allergic reactions to compounds of similar chemical or biological composition to gefitinib or other study agents
• No uncontrolled concurrent medical or psychiatric illness or social situation that would preclude study participation

PRIOR CONCURRENT THERAPY: Biologic therapy:

• No prior monoclonal antibodies with potential epidermal growth factor receptor (EGFR) binding therapy

Chemotherapy:

• No prior chemotherapy for head and neck cancer

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy to the head and neck region

Surgery:

• No prior surgery to the head and neck region except biopsy

Other:

• No prior anti-EGFR therapy including prior tyrosine kinase inhibitors
• No concurrent combination anti-retroviral therapy for HIV-positive patients
• No other concurrent investigational agents
• No other concurrent commercial or investigational agents or therapies intended to treat the malignancy

Colorado
      University of Colorado Cancer Center at University of Colorado Health Sciences Center, Aurora,  Colorado,  80010-0510,  United States; Recruiting
New Jersey
      Monmouth Medical Center, Long Branch,  New Jersey,  07740-6395,  United States; Recruiting
New York
      St. Luke's-Roosevelt Hospital Center - Roosevelt Division, New York,  New York,  10025,  United States; Recruiting
Pennsylvania
      Abramson Cancer Center at University of Pennsylvania Medical Center, Philadelphia,  Pennsylvania,  19104-4283,  United States; Recruiting

Study chairs or principal investigators

David Raben, MD,  Study Chair,  University of Colorado Cancer Center   

Study ID Numbers:  CDR0000069284; UCHSC-01460; NCI-4551
Record last reviewed:  February 2003
Record first received:  April 9, 2002
ClinicalTrials.gov Identifier:  NCT00033449
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2004-11-17