Angiogenic and EGFR Blockade With Curative Chemoradiation for Advanced Head and Neck Cancer

Study Overview
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Brief Summary
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Radiotherapy (RT) with concurrent chemotherapy represents the state of the art in curative intent treatment for locally advanced squamous carcinoma of the head and neck. Tumor hypoxia and high levels of angiogenesis (blood vessel formation) are associated with treatment failure. Preclinical models reveal that radiotherapy itself may induce tumor secretion of vascular endothelial growth factor (VEGF). Curability may consequently be reduced by multiple mechanisms. Over-expression of epidermal growth factor receptor (EGFR) also occurs commonly and increases the risk of treatment failure. The addition of EGFR blockade to RT alone increases the chance of a cure. Concurrent VEGF and EGFR blockade could be synergistic with one another and improve the effectiveness of concurrent chemoradiation for advanced head and neck cancer. This study will add angiogenic and epidermal growth factor receptor (EGFR) blockade into an established program of curative intent concurrent chemoradiation for locally advanced head and neck cancer. The safety and effectiveness of delivering the drugs bevacizumab and Tarceva in conjunction with twice daily irradiation and concurrent cisplatin (CDDP) chemotherapy will be determined.

Detailed Description
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Pre Radiation Period: Bevacizumab (10 mg/kg) on days -14 and 0, or Tarceva (100 mg) daily from -14-0, or Bevacizumab (10 mg/kg) on days -14 and 0; Tarceva (100 mg) daily from -14-0 Chemoradiation Period: Radiotherapy may be delivered via conventional 2-D, conformal 3-D, or intensity modulated (IMRT) technique as is clinically indicated. Radiotherapy and CDDP doses will be delivered uniformly to all treatment cohorts: RT: 1.25 Gy BID M-F with a 6 hour interfraction interval Treatment break during week 4. Total dose 70 Gy/7 weeks CDDP: 33 mg/m2 M-W on weeks 1 and 5 of RT with standard DUMC hydration and anti-emetic regimens Bevacizumab (10mg/kg): Monday of weeks 1, 3, 5, 7 of RT Tarceva (100 mg): Daily for weeks 1-7 of treatment, except for days receiving CDDP Safety Assessments: Baseline and then weekly assessments of blood pressure and urine protein : creatinine ratios during lead in and chemoRT phases of treatment Baseline carotid Doppler ultrasound evaluation Carotid Doppler ultrasound evaluation 1 month post-chemoRT Efficacy Assessments: MR Imaging/Spectroscopy to be done at baseline, end of lead-in phase, end of week 1 of chemoRT, and end of chemoRT Angiogenic and EGFR related cytokines. Specifically, blood samples will be obtained to assay levels of VEGF, b-FGF, IL-8, D-dimer, EGF, TGF. These samples will be obtained on the same dates as the MR studies with an additional set of samples obtained at the midpoint of the lead in phase of treatment (day -7). Clinical Assessments: All patients will undergo a minimum of once weekly interval history and physical examination including fiberoptic pharyngoscopy/laryngoscopy when indicated in the Department of Radiation Oncology to monitor for side effects and response to treatment as per standard routine for the care of patients with head and neck cancer. Patient compliance with Tarceva administration monitored via diary MRI/MRS (Magnetic Resonance Spectroscopy) DE-MRI

Official Title
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Concurrent Angiogenic and EGFR Blockade in Conjunction With Curative Intent Chemoradiation for Locally Advanced Head and Neck Cancer

Conditions
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Head and Neck Cancer, Pharynx Cancer

Intervention / Treatment
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* Radiation: Chemoradiotherapy
* Drug: Cisplatin
* Drug: Bevacizumab
* Drug: Erlotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Locally advanced squamous carcinoma of the head and neck (AJCC stages II/IV, M0, and excluding T1N1 and T1N2) undergoing curative intent concurrent chemoradiation. Previous treatment of any sort other than a biopsy is not allowed. Eligible anatomic sites: oral cavity oropharynx hypopharynx supraglottic glottic larynx KPS > 60 Exclusion Criteria: Nasopharynx primary History of malignancy other than basal cell skin cancer. History of claudication, bleeding, or thromboembolic disorders. Patients receiving heparin or Coumadin therapy are ineligible. Primary tumor or lymph node encasement of the carotid artery Blood pressure of >150/100 mmHg Unstable angina New York Heart Association (NYHA) Grade II or greater congestive heart failure History of myocardial infarction within 6 months History of stroke within 6 months Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0; anticipation of need for major surgical procedure during the course of the study. Minor surgical procedures, fine needle aspirations, or core biopsies within 7 days prior to Day 0 Pregnant (positive pregnancy test) or lactating Urine protein : creatinine ratio ≥ 1.0 at screening History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 0 Serious, non-healing wound, ulcer, or bone fracture AST, ALT, or bilirubin > 1.5 x normal PT or PTT > 1.5 x normal Platelets < 100,000 WBC < 2000 Hgb < 10 Creatinine clearance < 60 mL/hr Refusal to provide written informed consent

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ChemoRadiotherapy<br>Radiation Therapy concurrent with cisplatin chemotherapy, Avastin and Tarceva | Radiation: Chemoradiotherapy<br>* External beam radiation daily (M-F)<br>Drug: Cisplatin<br>* Cisplatin week 1 and 5 of radiation<br>Drug: Bevacizumab<br>* Bevacizumab (Avastin) day 1 of weeks 1, 3, and 5 of radiation<br>* Other names: Avastin;Drug: Erlotinib<br>* Erlotinib daily during radiation<br>* Other names: Tarceva;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Resolution | Complete response (resolution) of tumor on clinical exam. | Within 30 days of completing RT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local Regional Control |  | 1 yr following chemoradiation | 
| Failure Free Survival |  | 3 yrs | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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upper aerodigestive tract neoplasms, pharynx neoplasms, head and neck cancer, targeted therapy, bevacizumab, erlotinib, Tarceva, radiotherapy, concurrent chemotherapy, pharynx cancer, tonsil cancer, hyperfractionation, angiogenesis, epidermal growth factor, vascular endothelial growth factor, magnetic resonance spectroscopy, cancer of the head and neck