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

Study Description

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Colorectal Cancer	Drug: eniluracil; Procedure: conventional colon surgery	Phase 2

Detailed Description:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	28 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Triple (Participant, Care Provider, Investigator)
Primary Purpose:	Treatment
Official Title:	Evaluation of Dihydropyrimidine Dehydrogenase (DPD) Activity in Surgically Resected Primary and Metastatic Colorectal Cancer After 48 hr Pretreatment With Eniluracil
Study Start Date :	September 1998
Actual Primary Completion Date :	October 1999
Actual Study Completion Date :	May 2001

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Oral eniluracil 20 mg twice daily; 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; Will be given to either subject pre-operative and metastatic disease; Other Names: 5 Fu/eniluracil (eli Lilly); 5-fu/eniluracil; 5fu/eniluraci Procedure: conventional colon surgery; Only if the subject is amenable to surgical resections
Placebo Comparator: Placebo; 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; Will be given to either subject pre-operative and metastatic disease; Other Names: 5 Fu/eniluracil (eli Lilly); 5-fu/eniluracil; 5fu/eniluraci Procedure: conventional colon surgery; Only if the subject is amenable to surgical resections

Outcome Measures

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Primary Outcome Measures :

1. Primary Goal to demonstrate that eniluracil at current clinical doses [ Time Frame: Pre-operative and up to 30 days after first dose ]
   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

Secondary Outcome Measures :

1. Evaluate DPD recovery and uracil levels [ Time Frame: pre-operative and up to 30 post first dose ]
   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.

Other Outcome Measures:

1. Specific Aims [ Time Frame: Duriation of trial up to 30 days after first dose ]
   1. Determine the enzymatic activity of DPD in PBMC's normal mucosa or normal liver and in primary and secondary colorectal cancers
   2. Confirm the ability of eniluracil to inactivate DPD in tumors as well as PBMC's and normal tissue
   3. Assess DPD recovery and uracil levels in PBMC's at 5-7,12-16,20-24,and 26-30 days postoperatively

Eligibility Criteria

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Ages Eligible for Study:	19 Years to 80 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion:

1. DISEASE CHARACTERISTICS: Histologically proven or suspicious primary or metastatic colorectal carcinoma undergoing disease resection
2. PATIENT CHARACTERISTICS:A. Age: 19 and over
3. Performance status: Karnofsky 60-100%
4. Not pregnant or nursing Fertile patients must use effective contraception during and for at least 1 month after study
5. PRIOR CONCURRENT THERAPY:
6. Subject has had at least 8 weeks since prior fluorouracil, capecitabine, fluorouracil-uracil, floxuridine, or S-1 Endocrine therapy:
7. No prior or concurrent steroids Radiotherapy:
8. Surgery: No prior emergent surgery (e.g., perforation or obstruction) No prior transplantation
9. At least 8 weeks since any prior drug metabolized by dihydropyrimidine dehydrogenase enzyme At least 8 weeks since prior flucytosine

Exclusion:

1. Severe infection(White Blood Cell Count)WBC>2 times normal
2. Fever
3. Sepsis
4. Subject on immunosuppressives therapy
5. Subjects will serum Bilirubin/Creatinine>2 times normal levels
6. Pregnant /Lactating women
7. Subjects that have received eniluracil or 5-FU(Fluorouracil) within 28 days prior to randomization
8. Subject that have comorbidity illnesses that will increase the likelihood of there death in <5 years

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Sponsors and Collaborators

University of Alabama at Birmingham

National Cancer Institute (NCI)

Glaxo Wellcome

Investigators

Study Chair:	Martin J. Heslin, MD	University of Alabama at Birmingham

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Marty Heslin, Chief of Surgical Oncology, University of Alabama at Birmingham
ClinicalTrials.gov Identifier:	NCT00004195 History of Changes
Other Study ID Numbers:	CDR0000067438; F980826006 ( Other Identifier: University of Alabama at Birmingham IRB )
First Posted:	September 16, 2004
Last Update Posted:	June 15, 2015
Last Verified:	June 2015

Keywords provided by Marty Heslin, University of Alabama at Birmingham:

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

Additional relevant MeSH terms:

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases	Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Eniluracil; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action