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

Precancerous Condition Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00118365
• Other study ID #: NCI-2009-00880
• Secondary ID: UCI 97-05R01CA08
• Status: Completed
• Phase: Phase 3
• First received: July 8, 2005
• Last updated: January 12, 2015
• Start date: July 1998
• Est. completion date: August 2008

Study information

• Verified date: February 2014
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review BoardUnited States: Federal Government
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 375
• Est. completion date: August 2008
• Est. primary completion date: August 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years to 80 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Precancerous Condition
• Precancerous Conditions

Intervention

Other:
• placebo
Given orally

Drug:
• eflornithine
Given orally
• sulindac
Given orally

Other:
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
United States	University of California Medical Center At Irvine-Orange Campus	Orange	California

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	Yes
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Biomarker in Adenoma: CEA	carcino-embryonic antigen (CEA) is adenocarcinoma tissue marker that is expressed during adenoma formation.	At the end of the study	No
Secondary	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	No
Secondary	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	No
Secondary	Biomarker in Adenoma: Bcl-2	bcl-2 is the anti-apoptotic protein BCL2	At the end of the study, up to 3 years	No