Eflornithine and Sulindac in Preventing Colorectal Cancer in Patients With Colon Polyps

Study Overview
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Brief Summary
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This randomized phase III trial is studying eflornithine and sulindac to see how well they work compared to a placebo in preventing colorectal cancer in patients with colon polyps. Chemoprevention is the use of certain drugs to keep cancer from forming, growing, or coming back. The use of eflornithine and sulindac may prevent colorectal cancer. It is not yet known whether eflornithine and sulindac are more effective than a placebo in preventing colorectal cancer

Detailed Description
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PRIMARY OBJECTIVES: I. Compare the rate of new adenomatous polyp formation in patients with a history of adenomatous polyps of the colon treated with eflornithine and sulindac vs placebo. II. Correlate the effects of eflornithine and sulindac on polyamine and prostaglandin content in the flat mucosa with the rate of new adenoma formation in these patients. III. Compare the rate of side effects in patients treated with these regimens. OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to participating center and aspirin use (yes vs no). Patients receive oral double placebo once daily for 4 weeks. Patients who are more than 70% compliant by pill measurement or self reporting are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral double placebo once daily. Arm II: Patients receive oral eflornithine (DFMO) and oral sulindac once daily. In both arms, treatment continues for 36 months in the absence of unacceptable toxicity or the development of an invasive malignancy.

Official Title
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A Phase III Randomized, Double-Blind, Placebo-Controlled Clinical Trial of the Combination of DFMO and Sulindac to Decrease the Rate of Recurrence of Adenomatous Polyps in the Colon

Conditions
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Precancerous Condition

Intervention / Treatment
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* Other: placebo
* Drug: eflornithine
* Drug: sulindac
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Criteria: History of >= 1 surgically resected adenomatous polyp of the colon measuring >= 3 mm within the past 5 years Screening colonoscopy performed within the past 6 months All polyps must have been removed during colonoscopy, pathologically examined, and archived No prior surgical resection removing > 40 cm of the colon No personal or family history of familial polyposis or hereditary non-polyposis colon cancer SWOG 0-1 Bilirubin =< 2.0 mg/dL AST and ALT =< 2 times normal Creatinine =< 1.5 mg/dL Urine protein =<, urine casts 0-3, urine WBC and RBC count 0-5 cells by urinalysis No history of inflammatory bowel disease No gastric or duodenal ulcers within the past 12 months Gastric or duodenal ulcers that were adequately treated > 24 months ago are allowed No symptomatic gastric or duodenal ulcers Not pregnant or nursing Negative pregnancy test Must have regional geographic stability over the next 36 months Pure tone audiometry evaluation normal Patients with >= 20 dB of uncorrectable hearing loss (for age) of any 2 contiguous frequencies are not allowed No invasive malignancy within the past 5 years except adequately treated nonmelanoma skin cancer, level I (or Breslow < 0.76 mm) cutaneous melanoma, Duke's A colon cancer, stage I cervical cancer, or stage 0 chronic lymphocytic leukemia No severe metabolic disorder No other significant acute or chronic disease that would preclude study participation No history of abnormal wound healing or repair No conditions that would confer risk of abnormal wound healing or repair No history of allergy to NSAIDs or eflornithine No concurrent chemotherapy No concurrent corticosteroids on a regular or predictable intermittent basis No concurrent radiotherapy Concurrent calcium supplements (=< 1,000 mg/day) allowed Concurrent lipid-lowering drugs (i.e., high-dose statins) allowed No other concurrent nonsteroidal anti-inflammatory drugs (NSAIDs) on a regular or predictable intermittent basis Concurrent aspirin for cardiovascular prophylaxis (i.e., 81 mg/day) allowed No concurrent anticoagulants on a regular or predictable intermittent basis No concurrent treatment for gastric or duodenal ulcers

Ages Eligible for Study
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Minimum Age: 40 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Arm II (placebo)<br>Patients receive oral double placebo once daily. In both arms, treatment continues for 36 months in the absence of unacceptable toxicity or the development of an invasive malignancy. | Other: placebo<br>* Given orally<br>* Other names: PLCB;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Arm I (eflornithine and sulindac)<br>Patients receive oral eflornithine (DFMO) and oral sulindac once daily. In both arms, treatment continues for 36 months in the absence of unacceptable toxicity or the development of an invasive malignancy. | Drug: eflornithine<br>* Given orally<br>* Other names: difluromethylornithine;Drug: sulindac<br>* Given orally<br>* Other names: SULIN;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 |
| --- | --- | --- |
| Detection of Any Adenoma at the End of the Study | Detection of any adenoma at the end of the study. This analysis is based on the participants who had the end-of-study colonscopy procedure done. | Up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Detection of Any Adenoma at the End of the Study Stratified by Baseline Prostaglandin E2 (PGE2) and Treatment | This analysis is based on the participants who had the end-of-study colonscopy procedure done and their baseline PGE2 values are available. The low PGE2 is defined as the values that are below the median PGE2 value in the analysis cohort. The high PGE2 is defined as the values that are above the median PGE2 value in the analysis cohort. | Up to 36 months | 
| Detection of Any Adenoma at the End of the Study Stratified by Baseline Putrescine and Treatment | The low is defined as the values that are below the median putrescine level in the analysis cohort. The high is defined as the values that are above the median putrescine level in the analysis cohort. | Up 36 months | 
| Detection of Any Adenoma at the End of the Study Stratified by Baseline Spermidine-to-spermine Ratio and Treatment | The low is defined as the ratios that are below the median spermidine-to-spermine ratio in the analysis cohort. The high is defined as the ratios that are above the median spermidine-to-spermine ratio in the analysis cohort. In the finalized datasaet, the total number of adnoma detected in the placebo group is 55. The descrepancy in the total number of adnoma detected in placebo group between Outcome Measure 1 and this oucome is due to the revolution of the datatset. The analysis cohort is based on the participants whose data are available and complete. | Up 36 months | 
| Detection of Any Adenoma at the End of the Study Stratified by Prostaglandin E2 (PGE2) Response and Treatment | PGE2 Responder = PGE2 values at 36-month are decreased by >=30% in PGE2 values from baseline PGE2 nonresponder = PGE2 values at 36-month are increased, or decreased by < 30% from baseline The analysis cohort is based on the participants whose data are available and complete. | Up to 36 months | 
| Detection of Any Adenoma at the End of the Study Stratified by Putrescine Response and Treatment | Putrescine responder = Putrescine values at 36-month are decreased by >=30% from baseline Putrescine nonresponder = Putrescine values at 36-month are increased, or decreased by < 30% from baseline The analysis cohort is based on the participants whose data are available and complete. | Up to 36 months | 
| Detection of Any Adenoma at the End of the Study Stratified by Spermidine-to-spermine Ratio Response and Treatment | Spermidine-to-spermine ratio responder = ratios at 36-month are decreased by >=30% from baseline Spermidine-to-spermine ratio nonresponder = ratios at 36-month are increased, or decreased by < 30% from baseline The analysis cohort is based on the participants whose data are available and complete. | Up to 36 months | 
| Adverse Events With a Grade of 3 and Above | Participants reported at least 1 adverse event with a grade of 3 and above, regardless if the event is defined as serious per protocol or other. Per protocol, not all grade 3 events are considered as serious events. | Up to 36 months | 
| Baseline Putrescine by ODC Genotype | ODC genotype is the genotype of single nucleotide polymorphisms (SNP) in the ornithine decarboxylase (ODC) promoter The analysis cohort is based on the participants whose data are available and complete. | Baseline | 
| Baseline Spermidine by ODC Genotype | ODC genotype is the genotype of single nucleotide polymorphisms (SNP) in the ornithine decarboxylase (ODC) promoter The analysis cohort is based on the participants whose data are available and complete. | Baseline | 
| Baseline Spermine by ODC Genotype | ODC genotype is the genotype of single nucleotide polymorphisms (SNP) in the ornithine decarboxylase (ODC) promoter The analysis cohort is based on the participants whose data are available and complete. | Baseline | 
| At the End of the Study - Putrescine Response by ODC Genotype | Putrescine responder was defined as (tissue putrescine value at baseline - tissue putrescine value at the end of the study)/(tissue putrescine value at baseline) ≥ the threshold. Putrescine non-responder was defined as (tissue putrescine value at baseline - tissue putrescine value at the end of the study)/(tissue putrescine value at baseline) < the threshold. The thresholds range from 0.25 to 0.45 with an increment of 0.5. The below data are shown for the threshold of 0.30. ODC genotype is the genotype of single nucleotide polymorphisms (SNP) in the ornithine decarboxylase (ODC) promoter The analysis cohort is based on the participants whose data are available and complete. | At the end of the study | 
| At the End of the Study - Spermidine Response by ODC Genotype | Spermidine responder was defined as (tissue spermidine value at baseline - tissue spermidine value at the end of the study)/(tissue spermidine value at baseline) ≥ the threshold. Spermidine non-responder was defined as (tissue spermidine value at baseline - tissue spermidine value at the end of the study)/(tissue spermidine value at baseline) < the threshold. The thresholds range from 0.25 to 0.45 with an increment of 0.5. The below data are shown for the threshold of 0.30. ODC genotype is the genotype of single nucleotide polymorphisms (SNP) in the ornithine decarboxylase (ODC) promoter The analysis cohort is based on the participants whose data are available and complete. | At the end of the study | 
| At the End of the Study - Spermine Response by ODC Genotype | Spermine responder was defined as (tissue spermine value at baseline - tissue spermine value at the end of the study)/(tissue spermine value at baseline) ≥ the threshold. Spermine non-responder was defined as (tissue spermine value at baseline - tissue spermine value at the end of the study)/(tissue spermine value at baseline) < the threshold. The thresholds range from 0.25 to 0.45 with an increment of 0.5. The below data are shown for the threshold of 0.30. ODC genotype is the genotype of single nucleotide polymorphisms (SNP) in the ornithine decarboxylase (ODC) promoter The analysis cohort is based on the participants whose data are available and complete. | At the end of the study | 
| Number of Participants Have Adenoma Recurrence in Each ODC1 Genotytpe by Treatment Group | ODC genotype is the genotype of single nucleotide polymorphisms (SNP) in the ornithine decarboxylase (ODC) promoter The analysis cohort is based on the participants whose data are available and complete. | Up to 36 months | 
| Biomarker in Adenoma: Apoptosis | Apoptosis expression was assessed using cytoplasmic staining. The definitions for the category level for the Apoptosis are: 1. focal (less than 10% cells that are positively stained); 2. less than 50% cells are positively stained; 3. more than 50% cells are positively stained. | At the end of the study | 
| Biomarker in Adenoma - Ki-67 | Estimated mean percent of cells staining postivie for the Ki-67 based on the GEE approach with adjustment for covariates | At the end of the study | 
| Biomarker in Adenoma: CEA | carcino-embryonic antigen (CEA) is adenocarcinoma tissue marker that is expressed during adenoma formation. | At the end of the study | 
| Biomarker in Adenoma: Sialyl-TN (B72.3) | sialyl-Tn (B72.3) is adenocarcinoma tissue marker that is expressed during adenoma formation. | At the end of the study | 
| Biomarker in Adenoma - p53 | Estimated mean percent of cells staining postivie for p53 based on GEE approach with adjument for covariates. Tumor protein p53, also known as p53, cellular tumor antigen p53, phosphoprotein p53, or tumor suppressor p53, is a protein that in humans is encoded by the TP53 gene. | At the end of the study | 
| Biomarker in Adenoma: Bcl-2 | bcl-2 is the anti-apoptotic protein BCL2 | At the end of the study, up to 3 years |