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Acetylsalicylic Acid and Eflornithine in Treating Patients at High Risk for Colorectal Cancer

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ClinicalTrials.gov Identifier: NCT00983580
Recruitment Status : Completed
First Posted : September 24, 2009
Results First Posted : April 30, 2018
Last Update Posted : September 4, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase II trial is studying how well giving acetylsalicylic acid together with eflornithine works in treating patients at high risk for colorectal cancer. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of acetylsalicylic acid and eflornithine may prevent colorectal cancer.

Condition or disease Intervention/treatment Phase
Adenomatous Polyp Drug: Aspirin Drug: Eflornithine Other: Laboratory Biomarker Analysis Other: Placebo Other: Telephone-Based Intervention Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 107 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: Randomized Phase II Trial of Aspirin and Difluoromethylornithine (DFMO) in Patients at High Risk of Colorectal Cancer
Actual Study Start Date : August 20, 2009
Actual Primary Completion Date : October 7, 2016
Actual Study Completion Date : August 13, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm I (acetylsalicylic acid and eflornithine)
Patients receive acetylsalicylic acid PO once daily and eflornithine PO twice daily on days 1-28.
Drug: Aspirin
Given PO
Other Names:
  • Acetylsalicylic Acid
  • ASA
  • Aspergum
  • Ecotrin
  • Empirin
  • Entericin
  • Extren
  • Measurin

Drug: Eflornithine
Given PO
Other Names:
  • Alpha-Difluoromethylornithine
  • DFMO
  • difluoromethylornithine
  • Difluromethylornithine

Other: Laboratory Biomarker Analysis
Correlative study

Other: Telephone-Based Intervention
Ancillary studies

Placebo Comparator: Arm II (placebo)
Patients receive placebo PO three times daily on days 1-28.
Other: Laboratory Biomarker Analysis
Correlative study

Other: Placebo
Given PO
Other Names:
  • placebo therapy
  • PLCB
  • sham therapy

Other: Telephone-Based Intervention
Ancillary studies




Primary Outcome Measures :
  1. Adenoma Recurrence Rate for the Treatment Arm Relative to Placebo [ Time Frame: At 1 year ]
    The primary endpoint is the proportion of participants with an adenoma recurrence at the 1-year follow-up colonoscopy exam. All eligible, randomized participants who have signed a consent form and received at least one follow-up endoscopy exam will be considered evaluable for the primary endpoint. This adenoma recurrence rate for DFMO + aspirin will be compared to double placebo to see if there is improvement in the adenoma recurrence rate in this patient population. A 1-sided Chi-square test was used to determine if there was a significant difference between treatment arms.


Secondary Outcome Measures :
  1. ACF Characteristics vs Adenoma Recurrence Rate [ Time Frame: At baseline and 1 year ]
    A potential surrogate endpoint biomarker is the aberrant crypt focus (ACF). ACF are the earliest lesions that can be detected in colorectal mucosa and are believed to be precursors of adenomas and cancers. At the 1-year time point, the presence of adenoma recurrence and the number of ACF sites was recorded for each patient. The percent change in ACF number was calculated as the number of ACF present at the 1-year post-intervention exam minus the baseline number of ACF, divided by the number of ACF present at baseline. A negative score represents a loss in the number of sites and a positive number indicates an increase in the number of ACF sites. Therefore, the possible range in percent change cannot be lower than -100% and has no upper bound. A Wilcoxon Rank-sum test was used to assess the relationship between ACF percent change and adenoma recurrence rate. This analysis was only conducted in those participants who had at least 5 rectal ACF at baseline.

  2. Characterization of ACF [ Time Frame: Baseline ]
    A potential surrogate endpoint biomarker is the aberrant crypt focus (ACF). ACF are the earliest lesions that can be detected in colorectal mucosa and are believed to be precursors of adenomas and cancers. The number and total size of ACF sites may serve as risk markers for adenoma/carcinoma development. The median number of ACF sites per patient were collected prior to treatment.

  3. Comparison of the Percent Change in ACF Number Across the 2 Treatment Arms [ Time Frame: At baseline and 12 months ]
    The number of ACF sites per patient was collected at baseline and at 1-year time points. The percent change in ACF number was calculated as the number of ACF present at the 12-month post-intervention exam minus the baseline number of ACF, divided by the number of ACF present at baseline. A negative score represents a loss in the number of sites from baseline to year 1 post-treatment. A positive number indicates an increase in the number of ACF sites. Therefore, the possible range in percent change cannot be lower than -100% and has no upper bound. The percent change in ACF number between arms was compared using a t-test.

  4. Safety, Tolerability, and Adverse Events of Study Treatment [ Time Frame: Up to 48 months from beginning treatment. ]
    The National Cancer Institute (NCI) Common Terminology Criteria (CTC) Version 3.0 was used to grade all adverse events. The number of patients reporting a grade 3 or higher event are tabulated here. A grade 3 event is one categorized as being severe or medically significant but not immediately life-threatening. A grade 4 is considered life-threatening, and a grade 5 is death related to the event. A complete list of all adverse events is given in the Adverse Events section.


Other Outcome Measures:
  1. Effect of the Study Drugs and Placebo With Respect to Biomarkers [ Time Frame: Baseline and 12 months ]
    For continuous variables, we will use the 2-sample t-test (or nonparametric equivalent) to compare the active arm to the placebo arm. For categorical data, we will explore the relationship between the treatment arms and biomarkers with chi-square or fisher's exact tests. Correlations will be sought between caspase-3 staining, proliferative indices and their ratio, as well as other biomarkers using a chi-square test.

  2. Gene Expression Analysis [ Time Frame: Baseline and 12 months ]
    Differences in log-transformed values among ACF or patient characteristics will be compared using t tests or analysis of variance (ANOVAs).



Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Current or prior advanced adenomas
  • Advanced adenomas are defined as subject with polyps >= 1 cm, tubulovillous adenomas (25-75 percent villous features), villous adenomas (> 75 percent villous), or high-grade dysplasia
  • Prior colon cancer (>= 3 years out from invasive cancer)
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
  • Ability to under and the willingness to sign a written informed consent document
  • Willingness to provide mandatory tissue for research purposes
  • Negative pregnancy test =< 7 days prior to randomization
  • Hemoglobin (Hgb) within normal limits for institution/lab
  • Platelet count >= 100,000/ul
  • White blood cell count (WBC) >= 3,000/ul
  • Alanine aminotransferase (ALT) =< 2 x institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) =< 2 x institutional ULN
  • Total bilirubin =< 1.5 x institutional ULN
  • Serum calcium =< institutional ULN
  • Serum creatinine =< 1.5 x institutional ULN
  • Colonoscopy =< 45 days prior to randomization with removal of all adenomas or polyps >= 2 mm in size

Exclusion Criteria:

  • Any history of current or prior rectal cancer
  • Known diagnosis of colon heritable cancer syndrome (familial adenomatous polyposis [FAP], hereditary nonpolyposis colorectal cancer [HNPCC]) or inflammatory bowel disease (Crohn's disease, ulcerative colitis)
  • Inability to swallow pills
  • Bleeding diathesis
  • New diagnosis of carcinoma
  • History of hypersensitivity to COX-2 inhibitors, sulfonamides, nonsteroidal antiinflammatory drugs (NSAIDs), salicylates, or ursodeoxycholic acid
  • History of gastroduodenal ulcers documented =< 1 year
  • Known inability to participate in the scheduled follow-up tests
  • Significant medical or psychiatric problems which would make the subject a poor protocol candidate, in the opinion of the treating physician
  • Total colectomy
  • Patients with a colostomy
  • History of pelvic or rectal radiation therapy
  • History of invasive carcinoma =< 5 years (except subjects with Dukes A/B1 carcinoma =< 5 years prior to pre-registration or any stage of colon cancer if >= 3 years post surgical resection)
  • Acute liver disease, unexplained transaminase elevations, or elevated serum calcium
  • History of allergic reactions attributed to compounds of similar chemical composition to the study agents
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia
  • Concomitant corticosteroids or anticoagulants needed on a regular or predictable intermittent basis
  • New diagnosis of invasive carcinoma
  • Use of non-study investigational agent(s) =< 3 months prior to randomization
  • Chemotherapy =< 6 months prior to randomization (Note: topical chemotherapy will be assessed on a case-by-case basis)
  • Pregnant women
  • Nursing women
  • Men or women of childbearing potential who are unwilling to employ adequate contraception
  • Regular use of NSAIDs =< 6 weeks prior to randomization, defined as a frequency of 7 consecutive days (1 week) for > 3 weeks (Exception: low dose aspirin [81 mg] for those subjects who are chronic users of aspirin prior to the beginning of the study)

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): NCT00983580


Locations
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United States, Illinois
University of Illinois College of Medicine - Chicago
Chicago, Illinois, United States, 60612
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, United States, 60637
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Frank A Sinicrope Mayo Clinic

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00983580     History of Changes
Obsolete Identifiers: NCT01647126
Other Study ID Numbers: NCI-2009-01192
NCI-2009-01192 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
09-001758
MC054A ( Other Identifier: Mayo Clinic )
R01CA113681 ( U.S. NIH Grant/Contract )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: September 24, 2009    Key Record Dates
Results First Posted: April 30, 2018
Last Update Posted: September 4, 2019
Last Verified: August 2019
Additional relevant MeSH terms:
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Adenomatous Polyps
Neoplasms
Adenoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Aspirin
Eflornithine
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Antipyretics
Antineoplastic Agents
Trypanocidal Agents
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Ornithine Decarboxylase Inhibitors