Gene Therapy in Preventing Cancer in Patients With Premalignant Carcinoma of the Oral Cavity or Pharynx

Study Overview
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Brief Summary
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This phase I/II trial is studying the side effects and best dose of gene therapy and to see how well it works in preventing cancer in patients with premalignant carcinoma of the oral cavity or pharynx. Inserting the p53 gene into a person's tumor cells may improve the body's ability to kill the tumor cells

Detailed Description
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OBJECTIVES: I. Determine the acute toxic effects of Ad5CMV-p53 gene administered as an oral rinse and as an intramucosal injection in patients with diffuse premalignant carcinoma of the oral cavity or oral pharynx. II. Determine the maximum tolerated dose of this drug in these patients. III. Determine the topical transduction efficiency of adenoviral-mediated wild type p53 gene transfer in patients treated with this drug. IV. Determine the efficacy of this drug in reversing the histology of oral premalignancies in these patients. V. Determine the distribution of transgenic protein within the area of the premalignant lesion in patients treated with this drug. OUTLINE: This is an open-label, dose-escalation study of Ad5CMV-p53 gene administered as an oral rinse. Phase I: Patients receive Ad5CMV-p53 gene by intramucosal injection into the area of the lesion followed at least 2 hours later by Ad5CMV-p53 gene as an oral rinse on day 1. Patients then receive Ad5CMV-p53 gene as an oral rinse twice daily on days 2-5. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of Ad5CMV-p53 gene as an oral rinse until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Phase II: Patients receive treatment with intramucosal Ad5CMV-p53 gene as in phase I and Ad5CMV-p53 gene as an oral rinse at the MTD. Patients are followed every 3 months for 1 year, every 6 months for 1 year, and then annually for 3 years. Patients then receive long-term follow-up annually for an additional 10 years.

Official Title
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Clinical Protocol for Wild Type p53 Gene Induction in Premalignancies of Squamous Epithelium of the Oral Cavity and Oral Pharynx Via an Adenoviral Vector [NCI Supplied Agent Ad-p53, (INGN 201) (Advexin®) NSC 683550, IND# 7135]

Conditions
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Lip and Oral Cavity Cancer, Oropharyngeal Cancer, Stage 0 Lip and Oral Cavity Cancer, Stage 0 Oropharyngeal Cancer, Tongue Cancer

Intervention / Treatment
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* Biological: Ad5CMV-p53 gene
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed mild to moderate dysplasia OR severe dysplasia/carcinoma in situ of the oral cavity or oral pharynx Clinically evident diffuse premalignant disease, defined by 1 of the following mucosal abnormalities: Extension between adjacent organ structures (e.g., lateral tongue, ventral tongue, and the floor of the mouth) Extensive surface area, including the entire ventral tongue or floor of the mouth or buccal mucosa, in a velvety indiscreet pattern Meets 1 of the following criteria: Previously treated with conventional treatment (e.g., radiotherapy or surgery) for a prior head and neck malignancy Failed biochemoprevention approaches for premalignant disease Failed other therapeutic approaches for premalignant disease No active squamous cell carcinoma of the head and neck Performance status - Karnofsky 70-100% Absolute granulocyte count at least 2,000/mm^3 Platelet count at least 100,000/mm^3 Bilirubin no greater than 1.0 mg/dL Creatinine no greater than 1.5 mg/dL No hypertension (baseline blood pressure 140/90 mm Hg or higher) Not pregnant or nursing Negative pregnancy test Fertile patients must use effective barrier contraception during and for 1 year after study participation HIV-1 negative No known contact with former tissue or organ transplantation recipients or individuals with severe immunodeficiency disease (acquired or congenital) during and for 28 days after study treatment No prior malignancy within the past 2 years except nonmelanoma skin cancer or aerodigestive cancer No active systemic viral, bacterial, or fungal infections requiring treatment No serious concurrent illness that would preclude study compliance and follow-up No psychological, familial, sociological, geographical, or other condition that would preclude study compliance and follow-up See Disease Characteristics More than 21 days since prior chemotherapy (42 days for mitomycin and nitrosoureas) No concurrent systemic chemotherapy No concurrent prednisone or the equivalent, including corticosteroids of more than 10 mg/day See Disease Characteristics More than 3 months since prior radiotherapy involving the lesion selected for this study No concurrent radiotherapy See Disease Characteristics More than 8 weeks since prior investigational agents No prior experimental therapy (i.e., oral, systemic, topical, or direct injection) for the lesion selected for treatment in this study No other concurrent immunosuppressive therapy No other concurrent investigational agents No concurrent aspirin dose greater than 175 mg/day

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (Ad5CMV-p53 gene)<br>Phase I: Patients receive Ad5CMV-p53 gene by intramucosal injection into the area of the lesion followed at least 2 hours later by Ad5CMV-p53 gene as an oral rinse on day 1. Patients then receive Ad5CMV-p53 gene as an oral rinse twice daily on days 2-5. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of Ad5CMV-p53 gene as an oral rinse until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Phase II: Patients receive treatment with intramucosal Ad5CMV-p53 gene as in phase I and Ad5CMV-p53 gene as an oral rinse at the MTD. | Biological: Ad5CMV-p53 gene<br>* Given intramucosally or as oral rinse<br>* Other names: INGN-201;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of adverse events |  | Up to 15 years | 
| Severity of adverse events graded using the CTCAE version 3.0 |  | Up to 15 years | 
| Maximum tolerated dose of Ad5CMV-p53 gene | Evaluated by the frequency and relationship of dose-limiting toxicities, if any, experienced by patients during dose escalation. | 6 months | 
| Pharmacodynamics evaluated by examining the injected precancerous lesion for induction of apoptosis and expression of the p53 protein | Presented using descriptive statistics, frequency tabulations, and graphical displays over time by treatment cohort. | 168 days |