Cetuximab, Chemotherapy, and Radiation Therapy for Operable Stage III or IV Head and Neck Cancer

Study Overview
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Brief Summary
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RATIONALE: Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to damage tumor cells. Giving cetuximab with combination chemotherapy and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving cetuximab after surgery may kill any tumor cells that remain. PURPOSE: This phase II trial is studying how well giving cetuximab together with combination chemotherapy and radiation therapy works in treating patients who are undergoing surgery for stage III or stage IV head and neck cancer.

Detailed Description
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OBJECTIVES: Primary Determine the effect of induction therapy comprising cetuximab, paclitaxel, and carboplatin followed by chemoradiotherapy comprising cetuximab, paclitaxel, carboplatin, and radiotherapy and maintenance therapy comprising cetuximab on 1-year event-free survival (freedom from surgery at the primary site and freedom from recurrence and death) in patients with stage III or IV operable squamous cell cancer of the head and neck. Secondary Determine the pathologic antitumor response at the primary site in patients treated with this regimen. Determine disease-free and overall survival of patients treated with this regimen. Determine the toxicity of this regimen in these patients. Determine local/regional and distant failure rates in patients treated with this regimen. Determine the effect of this treatment regimen on selective biologic pathways, total and phosphorylated epidermal growth factor receptor, ERK/MAPK, and P13K/AKT in these patients. OUTLINE: This is a multicenter study. Induction therapy (weeks 1-6): Patients receive cetuximab IV over 1-2 hours, paclitaxel IV over 1 hour, and carboplatin IV over 30 minutes on days 1, 8, 15, 22, 29, and 36. During week 7 or 8, patients undergo biopsy and evaluation of the primary site. Patients then proceed to chemoradiotherapy. Chemoradiotherapy (weeks 9-13): Patients receive cetuximab IV over 1 hour, paclitaxel IV over 1 hour, and carboplatin IV over 15 minutes on days 57, 64, 71, 78, and 85. Patients also undergo radiotherapy once daily, 5 days a week, on weeks 9-13. Patients with a positive biopsy at week 7 or 8 or persistent tumor at the primary site after induction therapy undergo a second biopsy after chemoradiotherapy at week 14. Patients with a negative biopsy at week 7 or 8 who achieve a complete clinical and pathological response at the primary site OR patients whose biopsy becomes negative at week 14 receive an additional 3-weeks of chemoradiotherapy beginning at week 15. Patients receive cetuximab, carboplatin, and paclitaxel as in chemoradiotherapy (as outlined above) on days 99, 106, and 113. Patients also undergo radiotherapy once daily, 5 days a week, for 3 weeks (weeks 15-17). Patients with N1-N3 disease undergo neck dissection in weeks 20-21. Patients with a positive biopsy at week 14 do not receive additional chemoradiotherapy, but rather undergo surgical resection of the primary site in weeks 18-19. Patients with N1-N3 disease also undergo neck dissection at this time. Maintenance therapy: Beginning after completion of surgery and/or chemoradiotherapy, patients receive cetuximab IV over 1 hour once weekly for 6 months in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 2 years and then every 6 months for 3 years. ACTUAL ACCRUAL: A total of 74 patients were accrued for this study.

Official Title
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Phase II Evaluation of Cetuximab (C225) Combined With Induction Paclitaxel and Carboplatin Followed by C225, Paclitaxel, Carboplatin, and Radiation for Stage III/IV Operable Squamous Cancer of the Head and Neck

Conditions
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Head and Neck Cancer

Intervention / Treatment
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* Biological: Cetuximab
* Drug: Carboplatin
* Drug: Paclitaxel
* Radiation: Radiation therapy


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Locally advanced (Stage III/IV), but potentially operable squamous cancer of the head and neck (exclude nasopharynx). Primary site biopsies must have had proven for cancer, nodal status, confirmed by clinical and pathologic exam with fine needle aspiration cytology recommended. ECOG performance status 0 - 1. Adequate laboratory index (ANC > 1500/mm3, platelets > 100,000/mm3, creatinine 1.5mg/dl, bilirubin 1.5mg/dl) completed within 4 weeks prior to registration. Surgical resectability: Included patients with operative stage III/IV disease, high likelihood of achieving R0 resection (complete resection with clean margins indicating NO residual cancer). Measurable disease, biopsy proven at primary site. Patients with clinically palpable cervical nodes were to have evaluation by CT scan and fine needle aspiration (FNA) confirmation of disease. Patients with non-palpable neck nodes had CT determination. In the absence of clinically palpable nodes, radiographic findings were acceptable. At least one objective measurable disease parameter in the primary site or neck. Baseline measurements or evaluations must have had obtained within 4 weeks prior to registration in the study. Age > 18 years. Women of childbearing potential and sexually active males were strongly advised to use an accepted and effective method of contraception. Original diagnostic materials must have had submitted for baseline EGFR assessment by the designated laboratory. EXCLUSION CRITERIA: Patients with fixed nodal metastases to spine or carotid artery, patients with invasion of root of tongue, pharyngeal muscle, post pharynx, or vertebral fascia or invasion of laryngeal cartilage into strap muscles or tracheal (>1cm) invasion. Prior chemotherapy, surgery radiation or immunotherapy for head and neck cancer. Prior malignancies except in situ lobular breast carcinoma, in situ cervical carcinoma, basal cell cancers or previously excised and controlled cutaneous squamous cancer (<200 mm thick) were permitted. Significant history of cardiac disease i.e., uncontrolled hypertension, unstable angina, congestive heart failure, or uncontrolled arrhythmias. Prior anti-epidermal growth factor receptor antibody therapy or therapy with a tyrosine kinase inhibitor including inhibitors targeting EGFR pathway. Prior chimerized or murine monoclonal antibody therapy or known allergy to murine proteins or cremophor EL. Pregnant or breast-feeding women. All females of childbearing potential must have had a blood test or urine study within 72 hours of study entry and must not have had started therapy until 5 days after registration was over to rule out pregnancy.

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: Cetuximab/Paclitaxel/Carboplatin<br>Induction: Cetuximab (C225) 400 mg/m2 at wk 1 then 250 mg/m2 for 5 weeks. Paclitaxel (P) 90 mg/m2 IV and carboplatin (C) AUC = 2 IV were given weekly. Restaging biopsy of primary site scheduled at wk 7. Concurrent chemoradiation: Radiation therapy at 200cGy/d/5 wks for a total of 50Gy and C225 at 250 mg/m2/wk. P following C225 at 30 mg/m2/wk and C following P at AUC = 1/week. Patients with a negative biopsy continued concurrent therapy to complete radiation (68-72Gy). Restaging biopsy of primary site: Patients with positive biopsy at wk 7 or patients without a clinical complete response at the primary site after induction therapy had re-biopsy at wk 14. If the biopsy was negative, the patients continued concurrent therapy to complete radiation (68-72 Gy). If positive, resection of the primary site was done. Additional concurrent chemoradiation: C225 at 250mg/m2/wk IV followed by P 30mg/m2/wk IV followed by C AUC = 1/wk and RT for 3 wks. | Biological: Cetuximab<br>* Induction: An initial dose of cetuximab (C225) 400 mg/m2 (over 2 hours) was given week 1 only. Then, C225 was administered at dose of 250 mg/m2 (over 1 hour) weekly for 5 weeks. Concurrent Chemoradiation (Weeks 9-13): C225 was administered at 250 mg/m2/wk (over 1 hour). Restaging Biopsy of Primary Site (Week 14): Patients with positive biopsy of the primary site at week 7 or patients without a clinical complete response at the primary site after induction therapy were scheduled for re-biopsy of the primary site at week 14 after concurrent therapy (50 Gy). If the biopsy were negative after concurrent therapy, the patients were scheduled to continue concurrent therapy to complete radiation (68-72 Gy). Additional Concurrent Chemoradiation (weeks 15, 16 and 17): Concurrent therapy was consisted of C225 at 250mg/m2/week IV over 1 hour followed by paclitaxel 30mg/m2/week IV over 1 hour followed by carboplatin AUC = 1/week over 15 minutes and RT for three weeks.<br>* Other names: Erbitux;Drug: Carboplatin<br>* Induction Therapy (Week 1-6): The induction chemotherapy starting at week 1 included paclitaxel 90 mg/m2 IV over 1 hour weekly and carboplatin AUC = 2 IV over 30 minutes weekly. The paclitaxel and carboplatin doses were given on the same day, 1 hour after C225 dose was administered. For paclitaxel and carboplatin therapy, rounding of doses (to next decimal if above 0.5 and to lower decimal if below 0.5) was permitted. Concurrent Chemoradiation (Weeks 9-13): Concurrent chemotherapy was consisted of paclitaxel following cetuximab at 30 mg/m2/wk (over 1 hour) and carboplatin following paclitaxel at AUC = 1/week (over 15 minutes). Additional Concurrent Chemoradiation (weeks 15, 16 and 17): Concurrent therapy was consisted of C225 at 250mg/m2/week IV over 1 hour followed by paclitaxel 30mg/m2/week IV over 1 hour followed by carboplatin AUC = 1/week over 15 minutes and RT for three weeks.<br>* Other names: Paraplatin-AQ;Drug: Paclitaxel<br>* Induction Therapy (Week 1-6): The induction chemotherapy starting at week 1 included paclitaxel 90 mg/m2 IV over 1 hour weekly and carboplatin AUC = 2 IV over 30 minutes weekly. The paclitaxel and carboplatin doses were given on the same day, 1 hour after C225 dose was administered. For paclitaxel and carboplatin therapy, rounding of doses (to next decimal if above 0.5 and to lower decimal if below 0.5) was permitted. Concurrent Chemoradiation (Weeks 9-13): Concurrent chemotherapy was consisted of paclitaxel following cetuximab at 30 mg/m2/wk (over 1 hour) and carboplatin following paclitaxel at AUC = 1/week (over 15 minutes). Additional Concurrent Chemoradiation (weeks 15, 16 and 17): Concurrent therapy was consisted of C225 at 250mg/m2/week IV over 1 hour followed by paclitaxel 30mg/m2/week IV over 1 hour followed by carboplatin AUC = 1/week over 15 minutes and RT for three weeks.<br>* Other names: Taxol;Radiation: Radiation therapy<br>* Concurrent Chemoradiation (Weeks 9-13): Radiation was given at 200cGy/d/5 weeks for a total dose of 50Gy (5000 cGy). Patients with a negative initial biopsy at week 7 were scheduled to continue concurrent therapy to complete radiation (68-72Gy). If the biopsy was negative after concurrent therapy, the patients were scheduled to continue concurrent therapy to complete radiation (68-72 Gy). Additional Concurrent Chemoradiation (weeks 15, 16 and 17): Concurrent therapy was consisted of C225 at 250mg/m2/week IV over 1 hour followed by paclitaxel 30mg/m2/week IV over 1 hour followed by carboplatin AUC = 1/week over 15 minutes and RT for three weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival Rate at 1 Year | Event-free survival rate at 1 year was defined as the proportion of patients who did not have disease progression, primary site surgery, or death after being followed for 1 year. | Assessed at 1 year. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients With Objective Response by RECIST | Per RECIST criteria, Complete response (CR)= disappearance of all target and nontarget lesions Partial response (PR)= >=30% decrease in the sum of the longest diameters of target lesions from baseline, and persistence of one or more non-target lesion(s) and/or the maintenance of tumor marker level above the normal limits. Objective response = CR + PR. | Assessed at weeks 7, 14, 18, 20, and then every every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry | 
| Progression-free Survival | Progression-free survival was defined as the time from registration to documented progression or death without progression. Progression is defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s) or unequivocal progression of existing nontarget lesions. | Assessed at weeks 7, 14, 18, 20, and then every every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry | 
| Overall Survival | Overall survival is defined as the time from registration to death of any causes. | Weekly during treatment, and then every every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stage III head and neck cancer, Stage IV head and neck cancer, Cetuximab, Paclitaxel, Carboplatin