Back to resultsEflornithine and Sulindac in Preventing Colorectal Cancer in Patients With Colon Polyps
Primary Purpose
Precancerous Condition
Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
placebo
eflornithine
sulindac
laboratory biomarker analysis
Sponsored by
About this trial
This is an interventional prevention trial for Precancerous Condition
Eligibility Criteria
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
Sites / Locations
- University of California Medical Center At Irvine-Orange Campus
Arms of the Study
Arm 1
Arm 2
Arm Type
Placebo Comparator
Experimental
Arm Label
Arm II (placebo)
Arm I (eflornithine and sulindac)
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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.
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.
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.
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.
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.
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 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 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.
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 - 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 - 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.
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.
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.
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
Biomarker in Adenoma: CEA
carcino-embryonic antigen (CEA) is adenocarcinoma tissue marker that is expressed during adenoma formation.
Biomarker in Adenoma: Sialyl-TN (B72.3)
sialyl-Tn (B72.3) is adenocarcinoma tissue marker that is expressed during adenoma formation.
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.
Biomarker in Adenoma: Bcl-2
bcl-2 is the anti-apoptotic protein BCL2
Full Information
NCT ID
NCT00118365
First Posted
July 8, 2005
Last Updated
January 12, 2015
Sponsor
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT00118365
Brief Title
Eflornithine and Sulindac in Preventing Colorectal Cancer in Patients With Colon Polyps
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
February 2014
Overall Recruitment Status
Completed
Study Start Date
July 1998 (undefined)
Primary Completion Date
August 2008 (Actual)
Study Completion Date
August 2008 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)
4. Oversight
5. Study Description
Brief Summary
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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Precancerous Condition
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
375 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Arm II (placebo)
Arm Type
Placebo Comparator
Arm Description
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.
Arm Title
Arm I (eflornithine and sulindac)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Other
Intervention Name(s)
placebo
Other Intervention Name(s)
PLCB
Intervention Description
Given orally
Intervention Type
Drug
Intervention Name(s)
eflornithine
Other Intervention Name(s)
2-difluoromethylornithine, DFMO, difluromethylornithine
Intervention Description
Given orally
Intervention Type
Drug
Intervention Name(s)
sulindac
Other Intervention Name(s)
Aflodac, Algocetil, Clinoril, SULIN
Intervention Description
Given orally
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Detection of Any Adenoma at the End of the Study
Description
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.
Time Frame
Up to 36 months
Secondary Outcome Measure Information:
Title
Detection of Any Adenoma at the End of the Study Stratified by Baseline Prostaglandin E2 (PGE2) and Treatment
Description
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.
Time Frame
Up to 36 months
Title
Detection of Any Adenoma at the End of the Study Stratified by Baseline Putrescine and Treatment
Description
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.
Time Frame
Up 36 months
Title
Detection of Any Adenoma at the End of the Study Stratified by Baseline Spermidine-to-spermine Ratio and Treatment
Description
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.
Time Frame
Up 36 months
Title
Detection of Any Adenoma at the End of the Study Stratified by Prostaglandin E2 (PGE2) Response and Treatment
Description
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.
Time Frame
Up to 36 months
Title
Detection of Any Adenoma at the End of the Study Stratified by Putrescine Response and Treatment
Description
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.
Time Frame
Up to 36 months
Title
Detection of Any Adenoma at the End of the Study Stratified by Spermidine-to-spermine Ratio Response and Treatment
Description
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.
Time Frame
Up to 36 months
Title
Adverse Events With a Grade of 3 and Above
Description
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.
Time Frame
Up to 36 months
Title
Baseline Putrescine by ODC Genotype
Description
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.
Time Frame
Baseline
Title
Baseline Spermidine by ODC Genotype
Description
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.
Time Frame
Baseline
Title
Baseline Spermine by ODC Genotype
Description
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.
Time Frame
Baseline
Title
At the End of the Study - Putrescine Response by ODC Genotype
Description
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.
Time Frame
At the end of the study
Title
At the End of the Study - Spermidine Response by ODC Genotype
Description
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.
Time Frame
At the end of the study
Title
At the End of the Study - Spermine Response by ODC Genotype
Description
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.
Time Frame
At the end of the study
Title
Number of Participants Have Adenoma Recurrence in Each ODC1 Genotytpe by Treatment Group
Description
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.
Time Frame
Up to 36 months
Title
Biomarker in Adenoma: Apoptosis
Description
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.
Time Frame
At the end of the study
Title
Biomarker in Adenoma - Ki-67
Description
Estimated mean percent of cells staining postivie for the Ki-67 based on the GEE approach with adjustment for covariates
Time Frame
At the end of the study
Title
Biomarker in Adenoma: CEA
Description
carcino-embryonic antigen (CEA) is adenocarcinoma tissue marker that is expressed during adenoma formation.
Time Frame
At the end of the study
Title
Biomarker in Adenoma: Sialyl-TN (B72.3)
Description
sialyl-Tn (B72.3) is adenocarcinoma tissue marker that is expressed during adenoma formation.
Time Frame
At the end of the study
Title
Biomarker in Adenoma - p53
Description
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.
Time Frame
At the end of the study
Title
Biomarker in Adenoma: Bcl-2
Description
bcl-2 is the anti-apoptotic protein BCL2
Time Frame
At the end of the study, up to 3 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Frank Meyskens
Organizational Affiliation
University of California Medical Center At Irvine-Orange Campus
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California Medical Center At Irvine-Orange Campus
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
20538001
Citation
Thompson PA, Wertheim BC, Zell JA, Chen WP, McLaren CE, LaFleur BJ, Meyskens FL, Gerner EW. Levels of rectal mucosal polyamines and prostaglandin E2 predict ability of DFMO and sulindac to prevent colorectal adenoma. Gastroenterology. 2010 Sep;139(3):797-805, 805.e1. doi: 10.1053/j.gastro.2010.06.005. Epub 2010 Jun 9.
Results Reference
derived
Learn more about this trial
Eflornithine and Sulindac in Preventing Colorectal Cancer in Patients With Colon Polyps
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