Chemotherapy and Radiation Therapy (RT) With or Without Vandetanib in Treating Patients With High-Risk Stage III or Stage IV Head and Neck Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as cisplatin, 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 kill tumor cells. Vandetanib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving chemotherapy together with radiation therapy is more effective with or without vandetanib in treating patients with head and neck cancer. PURPOSE: This randomized phase II trial is studying giving chemotherapy together with radiation therapy to see how well it works compared with giving chemotherapy and radiation therapy together with vandetanib in treating patients with high-risk stage III or stage IV head and neck cancer.

Detailed Description
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OBJECTIVES: Primary To screen for an indication that the addition of vandetanib to chemoradiotherapy may prolong disease-free survival as compared to a combination of chemoradiotherapy in patients with resected, high-risk stage III or IV head and neck squamous cell carcinoma. Secondary To determine whether this treatment regimen can be delivered safely and successfully following surgical resection for advanced head and neck cancer. To estimate the locoregional progression, distant metastasis, and overall survival rates for patients treated with this regimen. To examine the distribution of selected biomarkers that may include but are not limited to EGFR (epidermal growth factor receptor, total and phosphorylated), E-cadherin, pMAPK (phosphorylated mitogen-activated protein kinase), pAKT, Stat-3 (signal transducer and activator of transcription 3), Ki-67, COX-2 (cyclooxygenase 2), and cyclin B1 (G2/mitotic-specific cyclin-B1)expression in this group of patients and to explore the potential correlation between these markers with the ultimate treatment outcome OUTLINE: This is a multicenter study. Patients are stratified according to Zubrod performance status (0 vs 1) and primary site of disease (oral cavity/hypopharynx vs larynx vs oropharynx, HPV+ (human papillomavirus positive) vs oropharynx, HPV- (human papillomavirus negative)). Patients are randomized to 1 of 2 arms. Arm I: Patients undergo radiotherapy 5 times a week for up to 6.5 weeks and receive cisplatin IV over 1 hour on days 1, 22, and 43 of radiotherapy. Arm II: Patients undergo radiotherapy as in arm I and receive cisplatin IV over 1 hour once a week beginning on day 1 of radiotherapy. Patients also receive oral vandetanib once daily beginning 14 days prior to the start of radiotherapy. In both arms, treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Tissue samples from all patients are collected and reviewed. Tissue from patients with oropharyngeal carcinoma is analyzed for human papillomavirus. After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 4 years, and then annually thereafter.

Official Title
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A Randomized Phase II Trial of Chemoradiotherapy Versus Chemoradiotherapy and Vandetanib for High-Risk Postoperative Advanced Squamous Cell Carcinoma of the Head and Neck

Conditions
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Head and Neck Cancer

Intervention / Treatment
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* Drug: cisplatin
* Drug: vandetanib
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed squamous cell carcinoma of the head and neck, including any of the following subtypes: Oral cavity Oropharynx Larynx Hypopharynx Stage III or IV disease (no distant metastases) No cancer of the lip, nasopharynx, or sinuses Must have undergone gross total resection* (with curative intent) within 3-6 weeks of registration, with pathology demonstrating 1 or more of the following risk factors: Histologic extracapsular nodal extension Invasive cancer seen on microscopic evaluation of the resection margin, when all visible tumor has been removed NOTE: *Tonsillar cancer patients who undergo transoral excision of all gross tumor are eligible if the patient has formal neck dissection confirming histologic extracapsular nodal extension PATIENT CHARACTERISTICS: Inclusion criteria: Zubrod performance status 0-1 ANC (absolute neutrophil count) ≥ 2,000/mm³ Platelet count ≥ 100,000/mm³ Hemoglobin ≥ 8.0 g/dL (transfusion or other intervention to achieve this level allowed) Total bilirubin normal AST (aspartate aminotransferase) or ALT (alanine amino transferase) ≤ 2 times upper limit of normal (ULN) Alkaline phosphatase ≤ 2.5 times ULN Serum creatinine ≤ 1.5 mg/dL Creatinine clearance ≥ 60 mL/min Glucose ≥ 40 mg/dL AND ≤ 250 mg/dL Sodium ≥ 130 mmol/L AND ≤ 155 mmol/L Magnesium ≥ 0.9 mg/dL AND ≤ 3 mg/dL (supplementation allowed) Potassium ≥ 4 mmol/L AND ≤ 6 mmol/L (supplementation allowed) Serum calcium (ionized or adjusted for albumin) ≥ 7 mg/dL AND ≤ 12.5 mg/dL (supplementation allowed) QTc (corrected QT interval) interval ≥ 480 msec must have 2 additional EKGs ≥ 24 hrs apart and the average QTc from the 3 screening EKGs must be < 480 msec Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for at least 60 days after completion of study treatment May not donate blood during the study or for 3 months after last dose of vandetanib Exclusion criteria: Other simultaneous primary cancer Prior invasive malignancy (except nonmelanoma skin cancer) unless disease free for a minimum of 3 years with the exception of the following: Carcinoma in situ of the cervix Adequately treated basal cell or squamous cell carcinoma of the skin Untreated or treated low-risk prostate cancer (defined as clinical or pathologic T1c, N0 M0, PSA (prostate-specific antigen) < 10, Gleason < 7, < 50% of the total cores positive for cancer) Severe, active co-morbidity, defined as follows: Clinically significant cardiovascular event (e.g., myocardial infarction, superior vena cava syndrome, or New York Heart Association class II-IV) or presence of cardiac disease that, in the opinion of the investigator, increases the risk of ventricular arrhythmia within the past 3 months Unstable angina and/or congestive heart failure requiring hospitalization within the past 3 months Transmural myocardial infarction within the past 3 months History of arrhythmia (e.g., multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) which is symptomatic or requires treatment (CTCAE [Common Terminology Criteria for Adverse Events] grade 3), or asymptomatic sustained ventricular tachycardia Patients with atrial fibrillation, controlled on medication, are eligible Presence of left bundle branch block Previous history of QTc prolongation as a result from other medication that required discontinuation of that medication Congenital long QTc syndrome or first degree relative with unexplained sudden death under 40 years of age QTc with Bazett's correction that is unmeasurable or ≥ 480 msec on screening EKG Patients who are receiving a drug that has a risk of QTc prolongation are not eligible if QTc is ≥ 460 msec Hypertension (systolic blood pressure [BP] > 160 mm Hg or diastolic BP > 100 mm Hg) not controlled by medical therapy Diarrhea ≥ grade 1 (increase of < 4 stools per day over baseline or mild increase in ostomy output compared to baseline) Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within the past 30 days Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC (Center for Disease Control) definition (no HIV testing is required for study entry) Prior allergic reaction to cisplatin or vandetanib or derivatives similar to these drugs PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior systemic chemotherapy for this disease (prior chemotherapy for a different cancer allowed) No prior radiotherapy to the head and neck area that would result in overlap of radiotherapy fields More than 30 days since prior investigational agents More than 3 weeks since prior major surgery and recovered More than 2 weeks since prior and no concurrent medications that induce Torsades de Pointes More than 2 weeks since prior and no concurrent known potent inducers of CYP3A4 (Cytochrome P450 3A4), including rifampicin, phenytoin, carbamazepine, barbiturates, and Hypericum perforatum (St. John wort) No concurrent medication that may cause QTc prolongation

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: RT + Cisplatin<br>Patients undergo radiotherapy 5 times a week for up to 6.5 weeks and receive cisplatin IV over 1 hour on days 1, 22, and 43 of radiotherapy. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. | Drug: cisplatin<br>* Given IV<br>Radiation: radiation therapy<br>* Patients undergo radiotherapy 5 times a week for up to 6.5 weeks.<br>|
| Experimental: RT + Cisplatin + Vandetanib<br>Patients undergo radiotherapy as in arm I and receive cisplatin IV over 1 hour once a week beginning on day 1 of radiotherapy. Patients also receive oral vandetanib once daily beginning 14 days prior to the start of radiotherapy. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. | Drug: cisplatin<br>* Given IV<br>Drug: vandetanib<br>* Given orally<br>Radiation: radiation therapy<br>* Patients undergo radiotherapy 5 times a week for up to 6.5 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free Survival | This study terminated early with 34 subjects accrued out of 170 planned, therefore no analyses were performed. | From randomization to date of failure (local, regional, or distant progression, or death) or last follow-up. Analysis occurs after 78 failures have been reported. | 

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