Phase II Study of Concurrent C225, Cisplatin and Radiation in Stage IV Squamous Cell Carcinoma of the Head and Neck

Study Overview
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Brief Summary
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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, 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. Cetuximab may make the tumor cells more sensitive to radiation therapy and chemotherapy. Giving monoclonal antibody therapy together with chemoradiotherapy may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving cetuximab and cisplatin together with radiation therapy works in treating patients with locally advanced or regional stage IV head and neck cancer that cannot be removed by surgery.

Detailed Description
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OBJECTIVES: Primary Determine 2-year progression-free survival in patients with unresectable locally advanced or regional stage IV squamous cell or undifferentiated carcinoma of the head and neck treated with cetuximab, cisplatin, and definitive radiotherapy. Secondary Determine response rate and overall survival in patients treated with this regimen. Determine the toxic effects of this regimen in these patients. Correlate epidermal growth factor receptor (EGFR) expression by immunohistochemistry, EGFR phosphorylation, map kinase, Akt, signal transducer and activator of transcription 3 (STAT3), and other tissue and serum tests with toxicity of this regimen and outcomes in these patients. OUTLINE: This is a multicenter study. Patients are stratified according to tumor site (hypopharynx vs. oropharynx vs. oral cavity vs. larynx), primary tumor stage (T1-3 vs. T4), and nodal status (N0 vs. N1 vs. N2-3). Cetuximab therapy: Patients receive an initial loading dose of cetuximab IV over 2 hours on day 1. Patients then receive cetuximab IV over 1 hour on days 8, 15, 22, 29, 36, 43, 50, and 57. Chemoradiotherapy: Beginning on day 15 of cetuximab therapy, patients undergo radiotherapy once daily, 5 days a week, for at least 7 weeks. Patients also receive cisplatin IV over 1-2 hours on days 15, 36, and 57. Cetuximab maintenance therapy: After the completion of chemoradiotherapy, patients continue to receive cetuximab IV over 1 hour once weekly for 6-12 months. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients are followed every 6 months for 10 years. ACCRUAL: A total of 69 patients were accrued for this study.

Official Title
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Phase II Study of C225 (Erbitux or Cetuximab) in Combination With Cisplatin and Definitive Radiation in Unresectable Stage IV Squamous Cell Carcinoma of the Head and Neck

Conditions
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Head and Neck Cancer

Intervention / Treatment
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* Biological: cetuximab C225
* Drug: cisplatin
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed squamous cell or undifferentiated carcinoma of the head and neck (excluding nasopharynx, paranasal sinus, and parotid gland) Unresectable locally advanced or regional stage IV disease No evidence of distant metastases Must have demonstrable primary tumor site Measurable disease Unresectable disease Meets the following criteria for unresectable disease by tumor site: Hypopharynx, meeting 1 of the following criteria: Extension across the midline of the posterior pharyngeal wall Any evidence of fixation to the cervical spine Larynx Direct subglottic extension (>3cm) into surrounding muscle or skin Oral cavity Lesion precluding functional reconstruction Base of tongue, meeting 1 of the following criteria: Extension into the root of the tongue Patient refuses total glossectomy Tonsillar area, meeting 1 of the following criteria: Extension into pterygoid area as manifested by x-ray or trismus Extension across midline of pharyngeal wall Direct extension into soft tissue of the neck Unilateral neck node metastases fixed to carotid artery, mastoid, base of skull, or cervical spine with any of the above tumors Patients requiring total glossectomy are eligible Age>=18 years ECOG Performance status of 0-1 Adequate hematologic, renal, and hepatic function obtained <=4 weeks prior to registration Absolute neutrophil count ≥ 2,000/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 9.0 g/dL Alkaline phosphatase ≤ 3 times normal Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) ≤ 3 times normal Bilirubin ≤ 1.5 mg/dL Creatinine ≤ 1.2 mg/dL OR creatinine clearance ≥ 50 mL/min Able to tolerate fluid load At least 14 days since major surgery (including dental extraction) except percutaneous endoscopic gastrostomy (PEG) placement or mediport placement Exclusion Criteria: Pregnant or nursing Fertile patients do not use effective contraception Patients who refuse surgery but whose tumors are technically resectable OR whose tumors are unresectable for medical reasons are not eligible Disease metastases below the clavicles or elsewhere (M1) or with a postoperative recurrence Prior excisional surgery of head and neck tumor Prior radiotherapy to the head and neck region Prior chemotherapy Prior drugs that target the epidermal growth factor receptor pathway Prior chimerized or murine monoclonal antibody Active systemic infection Known allergy to murine proteins Severe chronic obstructive pulmonary disease requiring ≥ 3 hospitalizations within the past year Myocardial infarction within the past 3 months Uncontrolled congestive heart failure Unstable or uncontrolled angina Clinically apparent jaundice Postoperative recurrence Other malignancy within the past 3 years except resected basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or other in situ tumors

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cisplatin, C225, Radiation<br>Cetuximab therapy: Patients receive an initial loading dose of cetuximab intravenously (IV) over 2 hours on day 1. Patients then receive cetuximab IV over 1 hour on days 8, 15, 22, 29, 36, 43, 50, and 57. Chemoradiotherapy: Beginning on day 15 of cetuximab therapy, patients undergo radiotherapy once daily, 5 days a week, for at least 7 weeks. Patients also receive cisplatin IV over 1-2 hours on days 15, 36, and 57. Cetuximab maintenance therapy: After the completion of chemoradiotherapy, patients continue to receive cetuximab IV over 1 hour once weekly for 6-12 months. | Biological: cetuximab C225<br>* 400 mg/m^2 IV over 120 minutes on Day 1, 250 mg/m^2 IV over 60 minutes on Day 8, then weekly<br>* Other names: Erbitux;Drug: cisplatin<br>* 75 mg/m^2 IV over 30-60 minutes starting day 15 every 3 weeks * 3 (Days 1, 22, and 43 of radiation therapy (RT))<br>* Other names: cis-Platinum;Radiation: radiation therapy<br>* RT 70 Gy / 35 starting Day 15, 200cGy / d * 7 weeks (35 fractions)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year Progression-free Survival Rate | Two-year progression-free survival rate was defined as the proportion of patients that were alive progression-free two years after registration into the study. Disease progression was assessed per modified RECIST criteria, and defined as at least a 20% increase in the sum of the longest diameters of target lesions, in either primary or nodal lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of new lesions. Kaplan-Meier estimate of 2-year progression-free survival was calculated in the 60 eligible and treated patients. | assessed every 3 months for 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year Overall Survival Rate | Overall survival was defined as time from registration to death from any cause. Patients alive at last follow-up were censored. The 2-year overall survival rate was defined as the percentage of patients that were still alive two years after registration into the study. Kaplan-Meier estimate of 2-year overall survival was calculated in the 60 eligible and treated patients. | assessed very 3 months for 2 years | 
| Overall Response Rate | Response was assessed per Response Evaluation in Solid Tumor (RECIST) criteria by physical assessment and CT. Overall response = complete response (CR) + partial response (PR). CR was defined as the disappearance of all target and non-target lesions. PR was defined as at least a 30% decrease in the sum of the longest diameters of target lesions, along with non-progressive disease of non-target lesions. Overall response rate (i.e., proportion of patients who had CR or PR) and the corresponding 90% confidence intervals were calculated for the 60 eligible and treated patients | assessed after all chemoradiation therapy completed Week 9, then every 3 months on C225 maintenance therapy, and every 3 months for 2 years, every 6 months post-treatment 2 years from study entry | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV squamous cell carcinoma of the hypopharynx, stage IV squamous cell carcinoma of the larynx, stage IV squamous cell carcinoma of the lip and oral cavity, stage IV squamous cell carcinoma of the oropharynx