Phase II Trial of Nelfinavir With Concurrent Chemoradiotherapy in Squamous Cell Carcinoma of the Head and Neck

Study Overview
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Brief Summary
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This is a Phase II trial of definitive chemoradiotherapy (CTRT) given with the protease inhibitor,Nelfinavir (NFV), in patients with locally advanced head and neck. Eligible patients will receive a lead-in period of Nelfinavir (1250 mg po bid) for 7-14 days prior to initiation of CTRT. Nelfinavir will then be given concurrently with platinum-based chemotherapy and radiation therapy (planned total dose of 70 Gy over 7 weeks).

Detailed Description
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This is a single-arm Phase II study of organ-preservation chemoradiotherapy given in combination with the protease inhibitor, Nelfinavir, in patients with stage II, IVa, or IVb (per AJCC version 7) squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx. Patients start treatment with Nelfinvir at a dose of 1250 mg twice daily for 7-14 days, before continuing Nelfinvir at this dose concurrent with chemotherapy and radiation therapy (for a total dose of 70 Gy over a period of 7 weeks).

Official Title
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A Phase II Trial of a Protease Inhibitor, Nelfinavir (NFV), Given With Definitive, Concurrent Chemoradiotherapy (CTRT) in Patients With Locally-Advanced, Human Papilloma Virus (HPV) Negative, Squamous Cell Carcinoma of the Head and Neck

Conditions
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Head and Neck Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: Nelfinavir (Viracept®) 1250 mg
* Other: Chemoradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients ≥ 18 years old. Histologically confirmed diagnosis of squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx stages III, IVa, or IVb, p16-negative on immunohistochemistry Determined by the treating physician to be a candidate for organ preserving, concurrent standard chemotherapy and radiation therapy to the head and neck with definitive intent. ECOG Performance Status 0-2 Patients must sign an informed consent document that indicates they are aware of the investigational nature of the treatment in this protocol as well as the potential risks and benefits. The effects of EF5 on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry, during study, until 1 month after completion of the final FMISO PET/CT scan. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Serum pregnancy testing will be required for women of childbearing potential. Ability to understand and the willingness to sign a written informed consent. Exclusion Criteria Prior radiation therapy to the head and neck Prior chemotherapy within the past 5 years Previous therapy with a human immunodeficiency virus (HIV) protease inhibitor Pregnant or lactating patients. Patients with known HIV disease. These patients have a high probability of treatment with anti-retroviral therapy which may interact with the nelfinavir. Absolute Neutrophil Count ≤ 1500 per mm3 Platelet count ≤ 100,000 per mm3 Serum creatinine > 1.5 times the upper limit of normal Serum AST or ALT > 2 times the upper limit of normal Serum bilirubin > 1.2 mg/dl Weight loss of > 10% over the past 6 months which is due to tumor wasting syndrome Distant metastases Patients receiving the following drugs that are contraindicated with NFV will be excluded: Antiarrhythmics:amiodarone, quinidine, Antimycobacterial: rifampin, Ergot Derivatives:dihydroergotamine, ergonovine, ergotamine, methylergonovine, Herbal Products: St.John's wort (hypericum perforatum), HMG-CoA Reductase Inhibitors: lovastatin,simvastatin, Neuroleptic:pimozide, Proton Pump Inhibitors, Sedative/Hypnotics: midazolam, triazolam, Patients receiving the following drugs will be clinically evaluated as to whether dosage/medication can be changed to permit patient on study: Anti-Convulsants: carbamazepine, Phenobarbital, Anti-Convulsant:phenytoin, Anti-Mycobacterial:rifabutin, PDE5 Inhibitors: sildenafil, vardenafil, tadalafil, HMG-CoA: Reductase Inhibitors: atorvastatin, rosuvastatin, Immuno-suppressants: cyclosporine,tacrolimus, sirolimus, Narcotic Analgesic: methadone, Oral Contraceptive:ethinyl estradiol, Macrolide Antibiotic:azithromycin, Inhaled/nasal steroid fluticasone, Antidepressant: trazodone. Women of childbearing potential who have a positive result on screening urine pregnancy test. Subjects with moderate-severe renal disease. History of allergic reactionsattributed to Flagyl (metronidazole), which has a chemical structure similar to FMISO. Uncontrolled intercurrent illness including, but not limited to symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements.

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: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm Phase 2<br>Single Arm, Phase II study of Nelfinavir Lead-In (Period 1) Followed by Concurrent Chemoradiation with Nelfinavir (Period 2) | Drug: Nelfinavir (Viracept®) 1250 mg<br>* Period 1: Nelfinavir Lead-In (1250 mg bid, 7-14 days).<br>* Other names: Nelfinavir Lead-In;Other: Chemoradiation<br>* Period 2: Concurrent Chemoradiation (70 Gy over 7 weeks) with Nelfinavir (1250 mg bid)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Locoregional Control | locoregional control determined via diagnostic imaging and clinical examination. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Decrease in Hypoxia From Nelfinavir | Decrease in Hypoxia from Nelfinavir was determined by change in uptake and volume as assessed via 18f-FMISO or 18f-EF5 PET/CT pre-Nelfinavir versus post Nelfnavir lead-in | 7-14 days | 
| Change in Glucose Metabolism From Nelfinavir | Change in Glucose Metabolism from Nelfinavir was determined by change in glucose uptake as assessed via FDG-PET/CT pre-Nelfinavir versus post Nelfnavir lead-in | From the initiation of any study procedures to 30 days following the completion of 7 chemoradiation |