S0820, Adenoma and Second Primary Prevention Trial

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Double Blind Placebo-Controlled Trial of Eflornithine and Sulindac to Prevent Recurrence of High Risk Adenomas and Second Primary Colorectal Cancers in Patients With Stage 0-III Colon or Rectal Cancer, Phase III - Preventing Adenomas of the Colon With Eflornithine and Sulindac (PACES)

Conditions
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Colorectal Neoplasms

Intervention / Treatment
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* Drug: Eflornithine placebo & sulindac placebo
* Drug: eflornithine & sulindac placebo
* Drug: Eflornithine placebo & sulindac
* Drug: Eflornithine plus sulindac


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: History of Stage 0-III colon or rectal cancer with primary resection 1 year previously Post-operative colonoscopy and CT scans of chest, abdomen & pelvis showing no evidence of disease Must not have cardiovascular risk factors including unstable angina, history of myocardial infarction, or cerebrovascular accident, coronary artery bypass surgery, or NY Heart Assoc Class III or IV heart failure. Patients must not have known uncontrolled hyperlipidemia (defined as LDL-C >/= 190 mg/dL or triglycerides >/= 500 mg/dL within the past 3 years or uncontrolled high blood pressure (systolic blood pressure > 150 mm Hg) within 28 days prior to registration At least 30 days from completion of adjuvant chemo and RT. Presence of gastroesophageal reflux disease acceptable if controlled with medications Not receiving or planning to receive concomitant intravenous corticosteroids on a regular basis,nonsteroidal anti-inflammatory drugs (NSAIDs), nor anticoagulants on a regular predictable intermittent basis. NSAID use must not exceed 10 days per month; Maximum aspirin dose 100 mg per day or ≤ two 325 mg tablets per week. Inhaled steroids (i.e. for asthma or related conditions) are allowed. Able to swallow oral medications Laboratory: WBC ≥ 4.0 x 1000/mcL, platelets ≥ 100,000/mcL and hemoglobin > 11.0 g/dL. (A total WBC ≥ 3.1 x 1000/mcL is allowed for non-Hispanic black males and total WBC ≥ 3.4 x 1000/mcL for non-Hispanic black females. Serum bilirubin ≤ 2.0 mg/dL and AST (SGOT) or ALT(SGPT) ≤ 2 x IULN. Serum creatinine ≤ 1.5 x IULN Zubrod PS 0-1, 18 years of age or older Will not participate in any other clinical trial for the treatment or prevention of cancer unless off protocol treatment, on follow-up phase only Offered opportunity to participate in blood specimen banking Exclusion Criteria: History of colon resection > 40 cm Mid-low rectal cancer Recurrent or metastatic disease High cardiovascular risk; Uncontrolled hypertension Planned radiation therapy or additional chemotherapy Documented history of gastric/duodenal ulcer within last 12 months and/or current treatment or active symptoms of gastric/duodenal ulcer Known history of familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, or inflammatory bowel disease ≥ 30 dB uncorrectable hearing loss for age of any of the five tested frequencies on prestudy audiogram Known hypersensitivity to sulindac or excipient byproducts. Previous asthma, urticaria, or allergic-type reaction to aspirin or other NSAIDs Significant medical or psychiatric condition that would preclude study completion (8 years) No other prior malignancy except adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for > 5 years Pregnant or nursing women. Women/men of reproductive potential must agree to use effective contraception

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: eflornithine placebo & sulindac placebo<br>Eflornithine placebo 2 tablets, PO, daily for 3 years. Sulindac placebo, 1 tablet, PO, daily for 3 years. | Drug: Eflornithine placebo & sulindac placebo<br>* Eflornithine placebo 2 tablets PO daily for 3 years. Sulindac placebo 1 tablet PO daily for 3 years<br>|
| Experimental: Eflornithine & sulindac placebo<br>Eflornithine two 250 mg tablets PO daily for 3 years. Sulindac placebo one tablet PO daily for 3 years. | Drug: eflornithine & sulindac placebo<br>* Eflornithine two 250 mg tablets PO daily for 3 years. Sulindac placebo 1 tablet PO daily for 3 years.<br>|
| Experimental: Eflornithine placebo & sulindac<br>Eflornithine placebo 2 tablets PO daily for 3 years. Sulindac one 150 mg tablet PO daily for 3 years. | Drug: Eflornithine placebo & sulindac<br>* Eflornithine placebo 2 tablets PO daily for 3 years. Sulindac one 150 mg tablet PO daily for 3 years.<br>|
| Experimental: Eflornithine plus sulindac<br>Eflornithine two 250 mg tablets PO daily for 3 years. Sulindac one 150 mg tablet PO daily for 3 years. | Drug: Eflornithine plus sulindac<br>* Eflornithine two 250 mg tablets PO daily for 3 years. Sulindac one 150 mg tablet PO daily for 3 years.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 3 years after registration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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). | 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. | Up to 8 years | 
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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). | 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. | Up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Eflornithine/sulindac prevention trial