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S0820, Adenoma and Second Primary Prevention Trial (PACES)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01349881
Recruitment Status : Recruiting
First Posted : May 9, 2011
Last Update Posted : January 26, 2023
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Cancer Prevention Pharmaceuticals, Inc.
Information provided by (Responsible Party):
SWOG Cancer Research Network

Study Description
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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.

Condition or disease Intervention/treatment Phase
Colorectal Neoplasms Drug: Eflornithine placebo & sulindac placebo Drug: eflornithine & sulindac placebo Drug: Eflornithine placebo & sulindac Drug: Eflornithine plus sulindac Phase 3

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1340 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
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)
Actual Study Start Date : March 1, 2013
Estimated Primary Completion Date : February 1, 2027
Estimated Study Completion Date : February 1, 2032

Resource links provided by the National Library of Medicine


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


Outcome Measures
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Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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).

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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).

  15. 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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01349881


Contacts
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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

Locations
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Sponsors and Collaborators
SWOG Cancer Research Network
National Cancer Institute (NCI)
Cancer Prevention Pharmaceuticals, Inc.
Investigators
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Principal Investigator: Jason A. Zell, D.O., MPH University of California, Irvine
More Information
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Responsible Party: SWOG Cancer Research Network
ClinicalTrials.gov Identifier: NCT01349881    
Other Study ID Numbers: S0820
U10CA037429 ( U.S. NIH Grant/Contract )
NCI-2012-02067 ( Other Identifier: NCI )
First Posted: May 9, 2011    Key Record Dates
Last Update Posted: January 26, 2023
Last Verified: January 2023
Keywords provided by SWOG Cancer Research Network:
Eflornithine/sulindac prevention trial
Additional relevant MeSH terms:
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Adenoma
Colorectal Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Eflornithine
 Sulindac
Antineoplastic Agents
Trypanocidal Agents
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Ornithine Decarboxylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs