Evaluation of Cetuximab (ERBITUX) and Concurrent Carboplatin, Paclitaxel & Radiotherapy in the Management of Patients With Advanced Locoregional Squamous Cell Carcinomas of the Head and Neck (GCC 0442)

The purpose of this study is to evaluate the response of the tumor to the treatment regimen that will be used in this study. This study will also test the safety of cetuximab (C225), given with chemotherapy and radiation therapy. We also want to see what effects (good and bad) cetuximab, chemotherapy, and radiation therapy have head \& neck cancer.

C225 has been designed to stop the growth of the tumor by blocking certain chemical pathways that lead to tumor cell growth. In prior studies with head \& neck cancer patients, C225 has delayed tumor growth and provided relief of symptoms in some patients.

Primary Objective- To evaluate whether the addition of Cetuximab (C225) in combination with chemotherapy and radiation can cause an enhanced anti-tumor effect resulting in improving local regional control of patients with locally advanced, unresectable squamous cell carcinoma of head and neck. (SCCHN).

OVERVIEW OF STUDY DESIGN Open label, non-randomized, single arm trial.

P = Paclitaxel will be administered on a weekly schedule at a dose of 40mg/m2 IV by 1-hour infusion prior to cetuximab dose. This will be administered for a total of 8 weeks (from weeks 2-9)

C225 = Cetuximab: 400 mg/m2 IV will be given as the initial OR loading dose in week 1 and then 250 mg/m2 IV weekly will be given for 8 weeks (weeks 2-9).

C = Carboplatin will be given at a dose of AUC=2/week - will be administered as a 30 minute infusion after cetuximab infusion (weeks 2-9)

RT = Radiation therapy will be delivered at 1.8 Gy fraction/day, 5 days a week for a total of 70.2 Gy. RT will be given from weeks 2-9.

Note: Sequence of administration will be paclitaxel followed by cetuximab followed by carboplatin followed by XRT.

Approximately 60 patients from MSGCC/BVAMC will participate in this study. Prior to entering the study the doctor will examine the patient and order blood tests ( which will be done by blood draw, approximately 2 tablespoons) and tests to measure the patients disease (scans). The patient will also be evaluated by a dietician who will follow the patient throughout the course of the therapy to help the patient meet his/her nutritional needs

Eligibility Criteria:
Inclusion Criteria:

1. Histologically proved locally advanced squamous cell carcinoma of the head and neck of all primary sites. The following TNM stages by sites will be eligible.Oral cavity, Pharynx, Larynx, Nasopharynx, paranasal sinuses, Oral cavity, Pharynx, Larynx, Nasopharynx, paranasal sinuses- T4 N0 N1 N2-A,B,C N3, T3 N0 N1 N2-A,B,C N3 Any T N2-A,B,C N3 Unknown primary Tx N2-A,B,C N3 Note: Only clearly unresectable T4 N0 lesions are eligible for study provided the reasons for unresectability are due to extensive anatomic involvement and are outlined by the surgeon
2. Patients must have signed an approved informed consent.
3. Patients with Performance Status 0-2.
4. No evidence of distant metastatic disease.
5. No previous radiation therapy.
6. No previous chemotherapy.
7. Patients must be greater than 18 years of age.
8. Women of child bearing potential (WOCBP) must have a negative pregnancy test within 7 days of treatment. Patients are considered not of child bearing potential if they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal.
9. Pretreatment evaluations include:

   History and physical examination within four weeks prior to study entry Dental evaluation Medical oncology examination to evaluate medical contraindications prior to start of chemotherapy
10. Adequate renal \& bone marrow function determined by the following laboratory parameters:

    ANC greater than or equal to 1500/mm3; platelets greater than or equal to 100,000/mm3; hemoglobin greater than or equal to 8.0 g/dl; Serum Creatinine less than or equal to 2.0 mg/dl, Total bilirubin less than 1.5 X the ULIN; AST/ALT less than 3 times the ULN, Creatinine Clearance greater than or equal to 50 cc/min
11. Evidence of measurable disease.
12. No evidence of concomitant malignancy except for non-melanomatous skin cancer (controlled or controllable) or carcinoma in situ of the cervix.

Exclusion Criteria:

Any of the following criteria will make the patient ineligible to participate in this study:

1. Acute hepatitis or known HIV.
2. Active or uncontrolled infection.
3. Significant history of concomitant life threatening / uncontrolled cardiac disease; i.e., uncontrolled hypertension, unstable angina, recent myocardial infarction (within prior 6 months), uncontrolled congestive heart failure, and known cardiomyopathy with decreased ejection fraction, cardiac arrhythmia
4. Prior therapy which specifically and directly targets the EGFR pathway.
5. Prior severe infusion reaction to a monoclonal antibody.
6. Any concurrent chemotherapy not indicated in the study protocol or any other investigational agent(s).
7. Women of childbearing potential (WOCBP) and male participants who are unwilling or unable to use an effective method to avoid pregnancy for the entire study period
8. Preexisting clinically significant neuropathy.
9. Patients with loco-regional recurrences from any site with no prior radiation therapy and not amenable for salvage surgery are not eligible for study.