S0820, Adenoma and Second Primary Prevention Trial (PACES)

• ClinicalTrials.gov Identifier: NCT01349881
• Recruitment Status: Recruiting
• First Posted: May 9, 2011
• Last Update Posted: February 25, 2021
• Sponsor: Southwest Oncology Group
• Collaborators: National Cancer Institute (NCI); Cancer Prevention Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Southwest Oncology Group

Tracking Information

• First Submitted Date: May 5, 2011
• First Posted Date: May 9, 2011
• Last Update Posted Date: February 25, 2021
• Study Start Date: March 2013
• Estimated Primary Completion Date: July 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 19, 2020)

Event rate, defined as rate of high-risk adenoma or second primary colorectal cancer (CRC) [ Time Frame: 3 years after registration ]

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.

Original Primary Outcome Measures (submitted: May 6, 2011)

3-year event rate after registration among Stage 0-III colon cancer patients. (An event is defined as high-risk adenoma or second primary colorectal cancer.) [ Time Frame: 3 years ]

The primary objective is to assess whether elfornithine 500 mg or sulindac 150 mg are effective in reducing the 3-year event rate, defined as high risk adenoma or 2nd primary colorectal cancer, in Stage 0, I, II, and III colon cancer patients.

Current Secondary Outcome Measures (submitted: August 19, 2020)

• 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 [ Time Frame: Up to 8 years ]
  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.
• Colon cancer recurrence [ Time Frame: Up to 8 years ]
  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).
• High-grade dysplasia [ Time Frame: Up to 8 years ]
  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.
• Adenomas with villous features, defined as villous histology (villous and tubulovillous adenomas) [ Time Frame: Up to 8 years ]
  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.
• Adenomas >= 1 cm [ Time Frame: Up to 8 years ]
  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.
• Multiple adenomas, defined as 3 or more adenomas all measuring > 0.3 cm [ Time Frame: Up to 8 years ]
  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.
• The number of patients with development of any adenoma > 0.3 cm [ Time Frame: Up to 8 years ]
  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.
• Total colorectal event rate, defined as the number of patients with at least one colorectal event (advanced colorectal event or adenoma > 0.3 cm) [ Time Frame: Up to 8 years ]
  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 to first clinically apparent high-risk adenoma or second primary CRC [ Time Frame: From date of registration to date at which high-risk adenoma or second primary CRC is detected, up to 8 years ]
  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.
• Toxicity [ Time Frame: Up to 3 years ]
  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.
• Baseline statin use [ Time Frame: Up to 3 years ]
  The analysis of the interaction of statin use and the 3-year event rate will be performed using logistic regression.
• Baseline meat consumption [ Time Frame: Up to 3 years ]
  The analysis of the interaction of meat consumption and the 3-year event rate will be performed using logistic regression.
• PK analysis [ Time Frame: Up to 3 years ]
  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.
• Biomarker identification based on Integrated Comprehensive Droplet Digital Detection technology [ Time Frame: Up to 3 years (though the timing of this isn't clear to me) ]
  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).
• Type of cancer at baseline: colorectal vs rectal [ Time Frame: Up to 3 years ]
  The analysis of the interaction of cancer type and the 3-year event rate will be performed using logistic regression.

Original Secondary Outcome Measures (submitted: May 6, 2011)

• Incidence of colorectal lesions with respect to high-grade dysplasia, adenomas with villous features, adenomas 1 cm or greater, multiple adenomas, polyps >/= 0.3 cm, total advanced colorectal events or total colorectal events at 3 years. [ Time Frame: 3 years and 8 years ]
  Incidence of colorectal lesions with respect to high grade dysplasia, adenomas with villous features, adenomas 1 cm or greater, multiple adenomas, polyps >/= 0.3 cm, total advanced colorectal events (defined as the number of patients with at least one high risk adenoma, 2nd primary colorectal cancer, colorectal cancer recurrence, or metastasis) or total colorectal cancer events (defined as the number of pateints with at least one advanced colorectal event or polyp)at 3 years and 8 years.
• Toxicity by CTCAEv.4.0 at 3 years [ Time Frame: 3 years ]
  Quantitative and qualitative toxicities at 3 years.
• Examine interaction of treatment arm and genotype expression with respect to different outcomes. [ Time Frame: 3 years and 8 years ]
• Interaction of intervention arm and baseline statin use with respect to 3-year event rate. [ Time Frame: 3 year ]
  Interaction of intervention arm and baseline statin use with respect to 3-year event rate will be examined.
• Evaluate SNPs associated with decreased adenoma/second primary CRC risk and AEs [ Time Frame: 3 years and 8 years ]
  Evaluate a minimal set of tagging single nucleotide polymorphisms across multiple genes relevant to eflornithine and sulindac, in order to characterize associations with decreased adenoma/second primary CRC risk and adverse events.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: S0820, Adenoma and Second Primary Prevention Trial
• Official Title: 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)
• Brief Summary: 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: 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
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Factorial Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Prevention
• Condition: Colorectal Neoplasms

Intervention

• Drug: Eflornithine placebo & sulindac placebo
  Eflornithine placebo 2 tablets PO daily for 3 years. Sulindac placebo 1 tablet PO daily for 3 years
• Drug: eflornithine & sulindac placebo
  Eflornithine two 250 mg tablets PO daily for 3 years. Sulindac placebo 1 tablet PO daily for 3 years.
• Drug: Eflornithine placebo & sulindac
  Eflornithine placebo 2 tablets PO daily for 3 years. Sulindac one 150 mg tablet PO daily for 3 years.
• Drug: Eflornithine plus sulindac
  Eflornithine two 250 mg tablets PO daily for 3 years. Sulindac one 150 mg tablet PO daily for 3 years.

Study Arms

• Placebo Comparator: eflornithine placebo & sulindac placebo
  Eflornithine placebo 2 tablets, PO, daily for 3 years. Sulindac placebo, 1 tablet, PO, daily for 3 years.
  Intervention: Drug: Eflornithine placebo & sulindac placebo
• Experimental: Eflornithine & sulindac placebo
  Eflornithine two 250 mg tablets PO daily for 3 years. Sulindac placebo one tablet PO daily for 3 years.
  Intervention: Drug: eflornithine & sulindac placebo
• Experimental: Eflornithine placebo & sulindac
  Eflornithine placebo 2 tablets PO daily for 3 years. Sulindac one 150 mg tablet PO daily for 3 years.
  Intervention: Drug: Eflornithine placebo & sulindac
• Experimental: Eflornithine plus sulindac
  Eflornithine two 250 mg tablets PO daily for 3 years. Sulindac one 150 mg tablet PO daily for 3 years.
  Intervention: Drug: Eflornithine plus sulindac

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 6, 2011): 1340
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: July 2029
• Estimated Primary Completion Date: July 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Patricia N. O'Kane, B.S.; 210-614-8808 ext 1011; pokane@swog.org

Contact: Dana Sparks, MAT; 210-614-8808 ext 1004; dsparks@swog.org

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01349881
• Other Study ID Numbers: S0820; U10CA037429 ( U.S. NIH Grant/Contract ); NCI-2012-02067 ( Other Identifier: NCI )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Southwest Oncology Group
• Study Sponsor: Southwest Oncology Group

Collaborators

• National Cancer Institute (NCI)
• Cancer Prevention Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Jason A. Zell, D.O., MPH; University of California, Irvine

• PRS Account: Southwest Oncology Group
• Verification Date: January 2021