Eniluracil and Surgery in Treating Patients With Primary or Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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RATIONALE: Eniluracil may increase the effectiveness of chemotherapy by blocking tumor enzymes that break down chemotherapy drugs. PURPOSE: Randomized phase II trial to determine the effectiveness of eniluracil followed by surgery in treating patients who have primary or metastatic colorectal cancer.

Detailed Description
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OBJECTIVES: I. Determine the enzymatic activity of dihydropyrimidine dehydrogenase (DPD) in peripheral blood mononuclear cells (PBMC), normal mucosa, or normal liver in patients with primary or metastatic colorectal cancer. II. Evaluate the ability of eniluracil to inactivate DPD in the tumor, PBMCs, and normal tissue in this patient population. III. Assess DPD recovery and uracil levels in PBMCs following surgical resection in these patients. OUTLINE: This is a randomized, placebo controlled study. Patients are stratified according to colorectal tumor (primary vs metastatic). Patients are randomized into one of two treatment arms. Arm I: Patients receive oral eniluracil twice daily on days -2 and -1 followed by surgical resection and tissue harvest on day 0. Arm II: Patients receive an oral placebo as in arm I followed by surgical resection and tissue harvest on day 0. Patients are followed weekly for 1 month. PROJECTED ACCRUAL: A total of 20 patients (10 per treatment arm) will be accrued for this study.

Official Title
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Evaluation of Dihydropyrimidine Dehydrogenase (DPD) Activity in Surgically Resected Primary and Metastatic Colorectal Cancer After 48 hr Pretreatment With Eniluracil

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: eniluracil
* Procedure: conventional colon surgery


Participation Criteria
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Eligibility Criteria
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Inclusion: DISEASE CHARACTERISTICS: Histologically proven or suspicious primary or metastatic colorectal carcinoma undergoing disease resection PATIENT CHARACTERISTICS:A. Age: 19 and over Performance status: Karnofsky 60-100% Not pregnant or nursing Fertile patients must use effective contraception during and for at least 1 month after study PRIOR CONCURRENT THERAPY: Subject has had at least 8 weeks since prior fluorouracil, capecitabine, fluorouracil-uracil, floxuridine, or S-1 Endocrine therapy: No prior or concurrent steroids Radiotherapy: Surgery: No prior emergent surgery (e.g., perforation or obstruction) No prior transplantation At least 8 weeks since any prior drug metabolized by dihydropyrimidine dehydrogenase enzyme At least 8 weeks since prior flucytosine Exclusion: Severe infection(White Blood Cell Count)WBC>2 times normal Fever Sepsis Subject on immunosuppressives therapy Subjects will serum Bilirubin/Creatinine>2 times normal levels Pregnant /Lactating women Subjects that have received eniluracil or 5-FU(Fluorouracil) within 28 days prior to randomization Subject that have comorbidity illnesses that will increase the likelihood of there death in <5 years

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 80 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Oral eniluracil 20 mg twice daily<br>20 mg of eniluracil given twice daily for duration of the study. This subject may have surgery IF tumor is amenable to resection | Drug: eniluracil<br>* Will be given to either subject pre-operative and metastatic disease<br>* Other names: 5fu/eniluraci;Procedure: conventional colon surgery<br>* Only if the subject is amenable to surgical resections<br>|
| Placebo Comparator: Placebo<br>20 mg placebo that will be given for the duration of the study. This subject may have surgery IF tumor is amenable to resection | Drug: eniluracil<br>* Will be given to either subject pre-operative and metastatic disease<br>* Other names: 5fu/eniluraci;Procedure: conventional colon surgery<br>* Only if the subject is amenable to surgical resections<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Goal to demonstrate that eniluracil at current clinical doses | To see if at standard clinical doses are capable of inhibiting DPD in Primary and metastatic colorectal cancer in vivo. Since one of the mechanisms of 5-FU(Fluorouracil) tumor resistance is overexpression of DPD,effective inactivation DPD in tumors by eniluracil in this study will be supportive of the use of eniluracil to overcome this type of 5-FU(Fluorouracil) resistance | Pre-operative and up to 30 days after first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate DPD recovery and uracil levels | To evaluate the recovery of DPD and uracil levels at 4 more times in the range of postoperative days 5-7,12-16,20-24,and 26-30. | pre-operative and up to 30 post first dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I colon cancer, stage II colon cancer, stage III colon cancer, stage IV colon cancer, stage I rectal cancer, stage II rectal cancer, stage III rectal cancer, stage IV rectal cancer, recurrent colon cancer, recurrent rectal cancer