Adjuvant Cetuximab and Chemoradiotherapy Using Either Cisplatin or Docetaxel in Treating Patients With Resected Stage III or Stage IV Squamous Cell Carcinoma or Lymphoepithelioma of the Head and Neck

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Monoclonal antibodies such as cetuximab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as cisplatin and docetaxel, work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Cisplatin and docetaxel may make the tumor cells more sensitive to radiation therapy. Combining a monoclonal antibody with chemoradiotherapy and giving them after surgery may kill any remaining tumor cells. PURPOSE: This randomized phase II trial is studying adjuvant cetuximab given together with chemoradiotherapy using cisplatin to see how well it works compared to adjuvant cetuximab given together with chemoradiotherapy using docetaxel in treating patients with resected stage III or stage IV squamous cell carcinoma (cancer) or lymphoepithelioma of the head and neck.

Detailed Description
-----------------
OBJECTIVES: Primary Compare disease-free survival of patients with resected stage III or IV squamous cell carcinoma or lymphoepithelioma of the head and neck treated with adjuvant cetuximab in combination with chemoradiotherapy comprising docetaxel vs cisplatin. Secondary Compare the safety and efficacy of these regimens in these patients. Compare locoregional control and overall survival rates in patients treated with these regimens. Correlate epidermal growth factor receptor (total and phosphorylated), pMAPK, pAKT, Stat-3, Ki-67, cyclo-oxygenase-2, and cyclin B1 expression with outcome in patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to Zubrod performance status (0 vs 1), risk category (positive margins vs high risk [i.e., ≥ 2 positive nodes or extracapsular nodal extension]) and use of intensity-modulated radiotherapy (no vs yes). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive cetuximab IV over 2 hours on day 1 (week 1). Patients then receive cetuximab IV over 1 hour and cisplatin IV over 1 hour before radiotherapy on days 8, 15, 22, 29, 36, and 43 (weeks 2-7). Patients undergo radiotherapy once daily, 5 days a week, beginning on day 8 for a total of 6 weeks (weeks 2-7). Arm II: Patients receive cetuximab and undergo radiotherapy as in arm I. Patients also receive docetaxel IV over 30 minutes before radiotherapy on days 8, 15, 22, 29, 36, and 43 (weeks 2-7). Treatment in both arms continues in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 2 years and then every 6 months for 4 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 230 patients (115 per treatment arm) will be accrued for this study within approximately 29 months.

Official Title
-----------------
A Phase II Randomized Trial Of Surgery Followed By Chemoradiotherapy Plus Cetuximab For Advanced Squamous Cell Carcinoma Of The Head and Neck

Conditions
-----------------
Head and Neck Cancer

Intervention / Treatment
-----------------
* Biological: cetuximab
* Drug: cisplatin
* Drug: docetaxel
* Radiation: radiation therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically confirmed squamous cell carcinoma of the head and neck meeting the following criteria: Site of tumor origin in the oral cavity, oropharynx, larynx, or hypopharynx (excluding lip, nasopharynx, or sinuses) Gross total resection must be completed within 7 weeks of randomization, with pathology demonstrating one or more of the following risk factors: Histologic extracapsular nodal extension Histologic involvement of ≥ 2 regional lymph nodes Invasive cancer seen on microscopic evaluation of the resection margin, with no evidence of gross tumor residual. Tonsillar cancer patients who undergo transoral excision of all gross tumor are eligible provided extracapsular nodal extension or involvement of ≥ 2 regional lymph nodes is histologically confirmed American Joint Committee on Cancer (AJCC) pathological stage III or IV No evidence of distant metastases No synchronous or concurrent head and neck primary tumors PATIENT CHARACTERISTICS: Age 18 and over Performance status Zubrod 0-1 Life expectancy Not specified Hematopoietic Absolute neutrophil count ≥ 2,000/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin > 8.0 g/dL Hepatic Bilirubin ≤ 1.5 times upper limit of normal (ULN) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT), and alkaline phosphatase meeting 1 of the following parameters: Alkaline phosphatase ≤ ULN AND AST or ALT ≤ 5 times ULN Alkaline phosphatase ≤ 2.5 times ULN AND AST or ALT ≤ 1.5 times ULN Alkaline phosphatase ≤ 5 times ULN AND AST or ALT ≤ ULN Renal Creatinine ≤ 1.5 mg/dL Cardiovascular No unstable angina No uncontrolled hypertension No myocardial infarction within the past 6 months (unless successfully treated with coronary artery bypass surgery or percutaneous transluminal coronary angioplasty) No uncontrolled arrhythmia No congestive heart failure No more than 2 heart-related hospitalizations within the past year No other active cardiac disease Pulmonary No more than 2 hospitalizations for chronic obstructive pulmonary disease within the past year Neurologic No pre-existing peripheral neuropathy ≥ grade 2 No uncontrolled seizure disorder No active neurological disease Other No prior severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80 No other invasive malignancy within the past 3 years except nonmelanoma skin cancer Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 3 months after study participation PRIOR CONCURRENT THERAPY: Biologic therapy No prior anti-epidermal growth factor receptor antibody therapy Chemotherapy More than 3 years since prior cytotoxic chemotherapy Endocrine therapy Not specified Radiotherapy No prior head and neck radiotherapy Surgery See Disease Characteristics Other No prior tyrosine kinase inhibitor therapy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RT + cisplatin + cetuximab<br>Loading dose of cetuximab followed by radiation therapy with weekly cisplatin and cetuximab. | Biological: cetuximab<br>* 400 mg/m^2 intravenously over 120 minutes on day 1 (week 1) followed by 250 mg/m^2 intravenously over 60 minutes in weeks 2 through 7.<br>Drug: cisplatin<br>* 30 mg/m^2 intravenously infused over over 60 minutes in weeks 2 through 7.<br>Radiation: radiation therapy<br>* 60 Gy (2 Gy once a day, 5 times a week)<br>|
| Experimental: RT + docetaxel + cetuximab<br>Loading dose of cetuximab followed by radiation therapy (RT) with weekly docetaxel and cetuximab. | Biological: cetuximab<br>* 400 mg/m^2 intravenously over 120 minutes on day 1 (week 1) followed by 250 mg/m^2 intravenously over 60 minutes in weeks 2 through 7.<br>Drug: docetaxel<br>* 15 mg/m^2 intravenously infused over 30 minutes in weeks 2 through 7.<br>Radiation: radiation therapy<br>* 60 Gy (2 Gy once a day, 5 times a week)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free Survival | Two-year rates are shown (Kaplan-Meier estimates). Disease-free survival is defined as the time from randomization to local, regional, or distant progression, second primary, or death (event) or last follow-up (censored). Response criteria as follows: No evidence of disease (NED): All patients must have no measurable tumor following surgery; Local-Regional Relapse: Recurrent cancer in the tumor bed and/or neck not clearly attributable to a second primary neoplasm; biopsy confirmation is necessary; Distant Relapse: Clear evidence of distant metastases (lung, bone, brain, etc.); Biopsy is recommended where possible. A solitary lung mass/nodule is considered a second primary neoplasm unless proven otherwise. | From randomization to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Two-year rates are shown (Kaplan-Meier estimates). Overall survival is defined as the time from randomization to death (event) or last follow-up (censored). | From randomization to 2 years | 
| Treatment Tolerance | Tolerability was defined as having received 90% of the radiation dose, 95% of the cetuximab loading dose, and at least 4 weeks of cetuximab and cisplatin or docetaxel at doses 95% of the protocol prescription. The percentage of patients determined to be tolerant of treatment are shown. | From start of treatment to end of treatment (protocol treatment lasts seven weeks). | 
| Frequency of Toxicity (Grade 5 and Acute Non-hematologic Grade 4) | Each regimen was monitored for excessive acute toxicity (defined as nonhematologic grade 4 toxicity within 90 days of the start of radiation or any grade 5 toxicity). The target rate was based on the observed rate from RTOG-9501/NCT00002670 of 15%. The unacceptable rate was >30%. [RTOG = Radiation Therapy Oncology Group] | From start of treatment to last follow-up. Analysis occurs at the time of the primary analysis. | 
| Frequency of Other Acute and Late Toxicity | Maximum grade toxicity that is definitely, probably, or possibly related to protocol treatment. | From start of treatment to last follow-up. Analysis occurs at the time of the primary endpoint analysis. | 
| Local-regional Control | Two-year rate is shown (cumulative incidence estimate). Local-regional failure is defined as the time from randomization to local-regional recurrence (event), death (competing risk), or last follow-up (censored). | From randomization to 2 years | 
| Correlation of EGFR (Total and Phosphorylated) pMAPK, pAKT, Stat-3, KI-67, COX-2, and Cyclin B1 Expression With Local-regional Control, and Overall and Disease-free Survival |  | From randomization to two years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stage III squamous cell carcinoma of the oropharynx, stage IV squamous cell carcinoma of the oropharynx, stage IV squamous cell carcinoma of the larynx, stage III lymphoepithelioma of the oropharynx, stage IV lymphoepithelioma of the oropharynx, stage III squamous cell carcinoma of the hypopharynx, stage IV squamous cell carcinoma of the hypopharynx, stage III squamous cell carcinoma of the larynx