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

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

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

Study Overview

• Status: Completed
• Conditions: Precancerous Condition
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: placebo; Drug: sulindac; Drug: eflornithine

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.

• Study Type: Interventional
• Enrollment (Actual): 375
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Orange, California, United States, 92868
      • University of California Medical Center At Irvine-Orange Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Arm II (placebo); 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: laboratory biomarker analysis; Correlative studies; Other: placebo; Given orally; Other Names: PLCB
Experimental: Arm I (eflornithine and sulindac); 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.	Other: laboratory biomarker analysis; Correlative studies; Drug: sulindac; Given orally; Other Names: Aflodac; Algocetil; Clinoril; SULIN; Drug: eflornithine; Given orally; Other Names: 2-difluoromethylornithine; DFMO; difluromethylornithine

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Frank Meyskens, University of California Medical Center At Irvine-Orange Campus

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: July 1, 1998
• Primary Completion (Actual): August 1, 2008
• Study Completion (Actual): August 1, 2008

Study Registration Dates

• First Submitted: July 8, 2005
• First Submitted That Met QC Criteria: July 8, 2005
• First Posted (Estimate): July 11, 2005

Study Record Updates

• Last Update Posted (Estimate): January 22, 2015
• Last Update Submitted That Met QC Criteria: January 12, 2015
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Precancerous Conditions; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antineoplastic Agents; Antiprotozoal Agents; Antiparasitic Agents; Trypanocidal Agents; Ornithine Decarboxylase Inhibitors; Eflornithine; Sulindac
• Other Study ID Numbers: NCI-2009-00880; UCI 97-05; R01CA088078 (U.S. NIH Grant/Contract)