Cytochlor and Tetrahydrouridine as Radiosensitizers and Cisplatin Combined With Radiation Therapy in Treating Patients With Advanced Squamous Cell Carcinoma of the Oral Cavity (Mouth) or Oropharynx (Throat)

Study Overview
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Brief Summary
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RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. Radiosensitizing drugs, such as cytochlor and tetrahydrouridine, may make tumor cells more sensitive to radiation therapy. 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. Combining radiosensitizers with chemotherapy and radiation therapy may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of cytochlor when given together with tetrahydrouridine, cisplatin and radiation therapy in treating patients with advanced squamous cell carcinoma of the oral cavity (mouth) or oropharynx (throat).

Detailed Description
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OBJECTIVES: Primary Determine the dose range of cytochlor to be used in phase II trials, based on safety, toxicity, and tissue selectivity, in patients with advanced squamous cell carcinoma of the oral cavity or oropharynx. Determine the safety and toxicity profile of cytochlor, tetrahydrouridine, and concurrent radiotherapy followed by radiotherapy alone in these patients. Determine the percentage of cancer cells vs normal cells that incorporate cytochlor in the DNA of patients treated with this regimen. Determine the percentage replacement of thymine by 5-chlorouracil in tumors vs normal tissue of patients treated with this regimen. Secondary Determine the tissue selectivity of this regimen in these patients. Determine the level of cytochlor and its metabolites within the serum and urine of these patients during combination treatment and before radiotherapy alone is initiated. Determine the pharmacokinetics of this regimen in these patients. OUTLINE: This is an open-label, dose-escalation study of cytochlor. Patients receive tetrahydrouridine IV over 5 minutes followed by cytochlor IV for 3 days on week 1 and 5 days a week on weeks 2-4 and cisplatin IV over 30-60 minutes once in weeks 2 and 5. Patients also undergo radiotherapy 5 days a week during weeks 2-7. Treatment continues in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of cytochlor until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 1 of 3 or 3 of 6 patients experience dose-limiting toxicity. Patients are followed at 1 month, monthly for 3 months, every 3 months for up to 1 year, every 4 months for 1 year, every 6 months for 1 year, and then annually thereafter. PROJECTED ACCRUAL: A total of 3-18 patients will be accrued for this study within 2 years.

Official Title
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Translational Phase I Trial of Escalating Doses of 5-Chloro-2'-Deoxycytidine (CldC) With a Fixed Dose of Tetrahydrouridine Combined With a Fixed Dose of Cisplatin Concomitant With Definitive Radiation in Patients With Advanced Squamous Cell Carcinoma of the Oral Cavity and Oropharynx

Conditions
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Head and Neck Cancer

Intervention / Treatment
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* Drug: cisplatin
* Drug: cytochlor
* Drug: tetrahydrouridine
* 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 oral cavity or oropharynx Stage III disease not eligible for surgery Stage IV disease allowed if patient is not eligible for chemotherapy or refused chemotherapy No distant metastasis Previously untreated disease No osteoradionecrosis in patients with tumors involving the maxilla Tumor tissue/normal adjacent tissue (T/N) ratio for dC kinase and dCMP deaminase greater than 2.5 PATIENT CHARACTERISTICS: Age Over 21 Performance status Karnofsky 80-100% OR ECOG 0-1 Life expectancy More than 6 months Hematopoietic Absolute neutrophil count greater than 1,500/mm^3 WBC at least 3,000/mm^3 Platelet count greater than 100,000/mm^3 Hepatic AST/ALT less than 2.5 times upper limit of normal Bilirubin normal Renal Creatinine normal OR Creatinine clearance greater than 60 mL/min Cardiovascular No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia No impending carotid rupture Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 6 months after study treatment HIV negative No other concurrent uncontrolled illness No active or ongoing infection No alcohol dependence No psychiatric illness or social situation that would preclude study compliance No other malignancy within the past 3 years except low-risk, non-melanomatous skin cancer, carcinoma in situ (e.g., breast, cervix, or bladder), or stage T1-2, low-to-moderate grade prostate cancer (Gleason score no greater than 7) PRIOR CONCURRENT THERAPY: Biologic therapy No concurrent immunotherapy Chemotherapy See Disease Characteristics No other concurrent chemotherapy Endocrine therapy No concurrent hormonal therapy except contraceptives or replacement steroids Radiotherapy Not specified Surgery See Disease Characteristics Other No prior therapy for head and neck cancer No other concurrent experimental medications No other concurrent anticancer therapy No concurrent combination antiretroviral therapy for HIV-positive patients

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 120 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: Single Arm<br> | Drug: cisplatin<br> <br> Drug: cytochlor<br> <br> Drug: tetrahydrouridine<br> <br> Radiation: radiation therapy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

 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 lip and oral cavity, stage III squamous cell carcinoma of the oropharynx, stage IV squamous cell carcinoma of the lip and oral cavity, stage IV squamous cell carcinoma of the oropharynx