The investigators hypothesize that the combination of eflornithine and sulindac will be effective in reducing a three-year event rate of adenomas and second primary colorectal cancers in patients previously treated for Stages 0 through III colon or rectal cancer.
The purpose of this study is to assess whether the combination of eflornithine 500 mg and sulindac 150 mg (compared to corresponding placebos) has efficacy against colorectal lesions with respect to high-grade dysplasia, adenomas with villous features, adenomas 1 cm or greater, multiple adenomas, any adenomas \>/= 0.3 cm, total advanced colorectal events, or total colorectal events.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
TRIPLE
Enrollment
354
Eflornithine placebo 2 tablets PO daily for 3 years. Sulindac placebo 1 tablet PO daily for 3 years
Eflornithine two 250 mg tablets PO daily for 3 years. Sulindac placebo 1 tablet PO daily for 3 years.
Eflornithine placebo 2 tablets PO daily for 3 years. Sulindac one 150 mg tablet PO daily for 3 years.
Event rate, defined as rate of high-risk adenoma or second primary colorectal cancer (CRC)
High risk adenoma is defined as either advanced adenoma (villous or tubulovillous histology, size \>= 1 cm, or high grade dysplasia) or multiple adenomas (3 or more each \> 0.3 cm). The primary analysis of the 3-year event rate will be performed using logistic regression, testing the main effect of treatment and adjusting for the baseline stratification factor. A two-arm binomial design without continuity correction will be used.
Time frame: 3 years after registration
Total advanced colorectal event rate, defined as the number of patients with at least one high risk adenoma, second primary CRC, CRC recurrence, or metastasis
The analysis will be performed using logistic regression, testing the main effect of treatment and adjusting for the baseline stratification factor. A time-to-event analysis will be conducted if there is no evidence of differential rates of on-study colonoscopies. To evaluate whether intervention effects are enduring, an analysis of post-treatment follow-up, examining colorectal event rates through year 8 will be performed.
Time frame: Up to 8 years
Colon cancer recurrence
Statistical assessments of association between the biomarker and the recurrence endpoints will be performed after converting the biomarker scores to ranks, which will facilitate detection of monotonic relationship(s).
Time frame: Up to 8 years
High-grade dysplasia
The analysis will be performed using logistic regression, testing the main effect of treatment and adjusting for the baseline stratification factor. A time-to-event analysis will be conducted if there is no evidence of differential rates of on-study colonoscopies. To evaluate whether intervention effects are enduring, an analysis of post-treatment follow-up, examining colorectal event rates through year 8 will be performed.
Time frame: Up to 8 years
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Eflornithine two 250 mg tablets PO daily for 3 years. Sulindac one 150 mg tablet PO daily for 3 years.
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
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Adenomas with villous features, defined as villous histology (villous and tubulovillous adenomas)
The analysis will be performed using logistic regression, testing the main effect of treatment and adjusting for the baseline stratification factor. A time-to-event analysis will be conducted if there is no evidence of differential rates of on-study colonoscopies. To evaluate whether intervention effects are enduring, an analysis of post-treatment follow-up, examining colorectal event rates through year 8 will be performed.
Time frame: Up to 8 years
Adenomas >= 1 cm
The analysis will be performed using logistic regression, testing the main effect of treatment and adjusting for the baseline stratification factor. A time-to-event analysis will be conducted if there is no evidence of differential rates of on-study colonoscopies. To evaluate whether intervention effects are enduring, an analysis of post-treatment follow-up, examining colorectal event rates through year 8 will be performed.
Time frame: Up to 8 years
Multiple adenomas, defined as 3 or more adenomas all measuring > 0.3 cm
The analysis will be performed using logistic regression, testing the main effect of treatment and adjusting for the baseline stratification factor. A time-to-event analysis will be conducted if there is no evidence of differential rates of on-study colonoscopies. To evaluate whether intervention effects are enduring, an analysis of post-treatment follow-up, examining colorectal event rates through year 8 will be performed.
Time frame: Up to 8 years
The number of patients with development of any adenoma > 0.3 cm
The analysis will be performed using logistic regression, testing the main effect of treatment and adjusting for the baseline stratification factor. A time-to-event analysis will be conducted if there is no evidence of differential rates of on-study colonoscopies. To evaluate whether intervention effects are enduring, an analysis of post-treatment follow-up, examining colorectal event rates through year 8 will be performed.
Time frame: Up to 8 years
Total colorectal event rate, defined as the number of patients with at least one colorectal event (advanced colorectal event or adenoma > 0.3 cm)
The analysis will be performed using logistic regression, testing the main effect of treatment and adjusting for the baseline stratification factor. A time-to-event analysis will be conducted if there is no evidence of differential rates of on-study colonoscopies. To evaluate whether intervention effects are enduring, an analysis of post-treatment follow-up, examining colorectal event rates through year 8 will be performed.
Time frame: Up to 8 years
Time to first clinically apparent high-risk adenoma or second primary CRC
The analysis will be performed using logistic regression, testing the main effect of treatment and adjusting for the baseline stratification factor. A time-to-event analysis will be conducted if there is no evidence of differential rates of on-study colonoscopies. To evaluate whether intervention effects are enduring, an analysis of post-treatment follow-up, examining colorectal event rates through year 8 will be performed.
Time frame: From date of registration to date at which high-risk adenoma or second primary CRC is detected, up to 8 years
Toxicity
Qualitative and quantitative assessment of toxicity, collected as CTCAE adverse events. Particular adverse events of interest include thrombotic cardiovascular and ototoxic events at or above a specified grade (e.g., Grade III or worse). All patients who receive any treatment will be included in the analysis of adverse events.
Time frame: Up to 3 years
Baseline statin use
The analysis of the interaction of statin use and the 3-year event rate will be performed using logistic regression.
Time frame: Up to 3 years
Baseline meat consumption
The analysis of the interaction of meat consumption and the 3-year event rate will be performed using logistic regression.
Time frame: Up to 3 years
PK analysis
SNPs with minor allele frequencies greater than 0.20 will be selected for SNP genotyping. The smallest set of SNPs that tag the common variation (frequency \> 0.20) in all of the representative ethnic groups will be used. The genotype data, treatment characteristics and endpoints of interest will be analyzed using the pharmacogenetic-environment interaction approach described by Wacholder and colleagues.
Time frame: Up to 3 years
Biomarker identification based on Integrated Comprehensive Droplet Digital Detection technology
The nature of the relationship between biomarker values identified by Integrated Comprehensive Droplet Digital Detection technology and the aggregate primary endpoint (high-risk adenoma or second primary CRC) will be assessed. Statistical assessments of association between the biomarker and the recurrence endpoints will be performed after converting the biomarker scores to ranks, which will facilitate detection of monotonic relationship(s).
Time frame: Up to 3 years (though the timing of this isn't clear to me)
Cancer type (colorectal vs rectal)
The analysis of the interaction of cancer type (colorectal vs rectal) and the 3-year event rate will be performed using logistic regression.
Time frame: Up to 3 years