Cetuximab and Radiation Therapy in Laryngeal Cancer Patients Who Have Responded to One Cycle of Chemotherapy (SPORE)

Study Overview
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Brief Summary
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The purpose of this study is to learn how to identify early which patients will respond to chemotherapy plus radiation therapy in order to reduce the number of subjects who require surgery (followed by radiation therapy).

Detailed Description
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In this study one cycle of chemotherapy will be administered and then those subjects who respond well to that cycle will be started on radiation therapy along with chemotherapy and those that don't respond well to the initial cycle of chemotherapy, will undergo a total laryngectomy (surgery to remove the voice box) followed by radiation therapy. The initial cycle of chemotherapy consists of the drugs Taxotere, Cisplatin, and 5-Fluorouracil (this combination is known as TPF). Then on Day 20 of the study, the subjects will be administered another chemotherapy agent called cetuximab (a.k.a. C-225). It will then be determined if the patient's response to the chemotherapy was favorable by examining the patient's tumor with an endoscopy. If the response is determined to be good, then the patient will continue with a chemotherapy regimen with the addition of radiation therapy combination. If the patient's response to the chemotherapy is determined to be less than favorable, then the patient will be advised to undergo salvage surgery (a.k.a. laryngectomy) to remove their voice box and then undergo radiation therapy treatment. Additionally, tumor tissue samples and blood will be studied to see if there are special molecular markers that help predict when a tumor will respond to chemotherapy and radiation treatment.

Official Title
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A Phase II Organ Preservation Trial Using Cetuximab and Radiation Therapy in Advanced Laryngeal Cancer Patients Who Have Responded to One Cycle of Induction Chemotherapy With Taxotere, Cisplatin, 5-Fluorouracil (TPF), and Cetuximab

Conditions
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Cancer of Larynx

Intervention / Treatment
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* Drug: Cisplatin
* Drug: Cetuximab
* Drug: 5-Fluorouracil
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have pathologically confirmed, previously untreated, resectable, squamous cell carcinoma of the larynx. Disease must be Stage III or IV. Tumor must be potentially surgically resectable and curable with conventional surgery and radiation therapy. Patients must undergo pre-treatment endoscopic tumor staging and CT scanning. ECOG Performance status 0-2 Pre-treatment laboratory criteria: WBC > or = to 3500/ul, granulocyte > or = to 1500/ul. Platelet count > or equal to 100,000/ul. Calculated or measured creatinine clearance > or = to 60 cc/min. Total Bilirubin < or = to 1.5 X ULN. AST and ALT < or = to 2.5 X ULN. Patients must give documented informed consent to participate in this study. Exclusion Criteria: Prior head and neck malignancy or history of other prior non-head and neck malignancy within the past 3 years. Prior head and neck radiation or prior chemotherapy. Documented evidence of distant metastases. Active infection. Pregnancy or lactation. Patients must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry, for the duration of study participation and for 3 months after discontinuing therapy. Any medical or psychiatric illness which in the opinion of the principal investigator would compromise the patients ability to tolerate this treatment. Patients residing in prison. Age < 18 years. Patients with psychiatric/social situations that would limit compliance with study requirements are not eligible. Patients with prior radiation to the head and neck. Patients with prior anti-epidermal growth-factor receptor antibody therapy or therapy with a tyrosine-kinase inhibitor. Patients with Grade > 2 peripheral neuropathy. Any history of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80.

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: Chemotherapy/Radiation/Surgery<br>Patients will undergo induction chemotherapy with (TPF): Docetaxel (Taxotere) 75 mg/m2 and cisplatin 100 mg/m2 on day 1, and 5-FU 750 mg/m2 days 1-4. On day 20 patients will receive a single dose of cetuximab (C-225) 400 mg/m2. Depending upon disease response, patients will undergo salvage laryngectomy followed by radiation therapy and chemotherapy. | Drug: Cisplatin<br>* 1. Day 1: 100 mg/m2, administered as an i.v. infusion will run over one hour. 2. Day #23: Subjects with a < 50% response (NR) to induction chemotherapy will undergo salvage laryngectomy followed by RT. Cisplatin will be added to radiation for patients whose surgical pathology reveals high-risk features (i.e. extracapsular spread, > 2 positive lymph nodes, perineural invasion, or positive margins). Cisplatin will either be dosed a 100 mg/m2 every 21 days or 40 mg/m2 weekly at the discretion of the prescribing physician.<br>* Other names: Platinol®-AQ;Drug: Cetuximab<br>* 1. Cetuximab will be administered at 400 mg/m2 on Day 20 (2 hour administration). 2. Cetuximab will be administered in combination with radiation therapy to those subjects who had a Partial or Complete response after the first cycle of the chemotherapy regimen is administered. The dosage for these administrations is 250 mg/m2 over sixty minutes and it will be administered for six weeks.<br>* Other names: Erbitux®;Drug: 5-Fluorouracil<br>* 5-FU will be administered 750 mg/m2 in 0.9% normal saline as a 24-hour continuous infusion, days #1-4.<br>* Other names: FU;Drug: Docetaxel<br>* 75 mg/m2 by I.V. over one hour on Day # 1 only<br>* Other names: Taxotere®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Achieving Histologic Complete Response | The proportion of patients treated with radiation+cetuximab achieving histologic CR will be estimated, along with 95% exact confidence intervals. Histologic Complete Response (CR) will be defined as primary tumors exhibiting a clinical CR or at least a 90% PR (Partial Response) along with a negative post-treatment biopsy. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Difference, From Baseline, in EGFR, for Tumor Biopsies Taken After the Administration of Cetuximab Following TPF. | To determine tumor EGFR degradation, as well as other markers of down-stream EGFR inhibition, observed in tumor biopsies taken shortly after the administration of cetuximab following TPF, compared with pre-treatment biopsies. | Day 23 | 
| The Change in Overall Quality of Life Score During Radiation Therapy and at 6, 12, and 24 Months Post Treatment. | To evaluate the quality of life (QOL). | 24 months | 
| Overall Survival Time | To determine the overall survival rates compared to the overall survival rates of historical controls. | 3 years | 
| The Number of Patients That Experience Grade 3 and 4 Mucositis or Dysphagia | To determine and compare toxicities, most notably mucositis and dysphagia, in patients on this treatment regimen as compared to historical controls. | 3 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer of Larynx