Clinical trial NCT00118365: 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
Overall status: COMPLETED
Phase: PHASE3
Conditions: Precancerous Condition
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2005-07-11
Enrollment: 375
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Detection of Any Adenoma at the End of the Study
timeFrame: Up to 36 months
Secondary outcomes:
measure: Detection of Any Adenoma at the End of the Study Stratified by Baseline Prostaglandin E2 (PGE2) and Treatment
timeFrame: Up to 36 months
measure: Detection of Any Adenoma at the End of the Study Stratified by Baseline Putrescine and Treatment
timeFrame: Up 36 months
measure: Detection of Any Adenoma at the End of the Study Stratified by Baseline Spermidine-to-spermine Ratio and Treatment
timeFrame: Up 36 months
measure: Detection of Any Adenoma at the End of the Study Stratified by Prostaglandin E2 (PGE2) Response and Treatment
timeFrame: Up to 36 months
measure: Detection of Any Adenoma at the End of the Study Stratified by Putrescine Response and Treatment
timeFrame: Up to 36 months
measure: Detection of Any Adenoma at the End of the Study Stratified by Spermidine-to-spermine Ratio Response and Treatment
timeFrame: Up to 36 months
measure: Adverse Events With a Grade of 3 and Above
timeFrame: Up to 36 months
measure: Baseline Putrescine by ODC Genotype
timeFrame: Baseline
measure: Baseline Spermidine by ODC Genotype
timeFrame: Baseline
measure: Baseline Spermine by ODC Genotype
timeFrame: Baseline
measure: At the End of the Study - Putrescine Response by ODC Genotype
timeFrame: At the end of the study
measure: At the End of the Study - Spermidine Response by ODC Genotype
timeFrame: At the end of the study
measure: At the End of the Study - Spermine Response by ODC Genotype
timeFrame: At the end of the study
measure: Number of Participants Have Adenoma Recurrence in Each ODC1 Genotytpe by Treatment Group
timeFrame: Up to 36 months
measure: Biomarker in Adenoma: Apoptosis
timeFrame: At the end of the study
measure: Biomarker in Adenoma - Ki-67
timeFrame: At the end of the study
measure: Biomarker in Adenoma: CEA
timeFrame: At the end of the study
measure: Biomarker in Adenoma: Sialyl-TN (B72.3)
timeFrame: At the end of the study
measure: Biomarker in Adenoma - p53
timeFrame: At the end of the study
measure: Biomarker in Adenoma: Bcl-2
timeFrame: At the end of the study, up to 3 years
Other outcomes:
Locations:
city: Orange
country: United States
facility: University of California Medical Center At Irvine-Orange Campus
state: California
Study officials:
affiliation: University of California Medical Center At Irvine-Orange Campus
name: Frank Meyskens
role: PRINCIPAL_INVESTIGATOR
References:
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.