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

Randomized Phase II Trial of Aspirin and Difluoromethylornithine (DFMO) in Patients at High Risk of Colorectal Cancer

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.

PRIMARY OBJECTIVES: I. The proportion of subjects with an adenoma recurrence at the 1-year follow-up colonoscopy exam. This adenoma recurrence rate for difluoromethylornithine (DFMO) (eflornithine) + aspirin will be compared to double placebo to see if there is improvement in the adenoma recurrence rate in this patient population. SECONDARY OBJECTIVES: I. To determine the relative tolerability and safety of the treatment regimens administered for 12 months. II. To determine the effect of the study drugs (aspirin [acetylsalicylic acid] + DFMO) and placebo with respect to proliferation (Ki67 labeling index), apoptosis (caspase-3 expression assay), and drug effect markers (COX-1, -2, polyamines, PGE2) from adenomas, aberrant crypt focus (ACF) and normal-appearing mucosa using pre- and 12-month post-intervention tissue biopsy samples. III. To estimate the percentage change in rectal ACF number, as determined by magnifying colonoscopy in subjects treated for 12 months with placebo or study drugs (aspirin +DFMO) by comparing % change in drug versus placebo arms. IV. To characterize ACF based on three criteria (ACF size [crypt number < 50 or >= 50], crypt morphology characteristics, and histology) of ACF and to correlate such characteristics with the intervention (vs placebo). Also, to evaluate the natural history of ACF over 1-year on placebo. V. To correlate the 12-month measurements of ACF size (# crypts/ACF), number, morphology, and histopathology with the adenoma recurrence data at 12 and 36 months; correlate the 12-month % (and actual) change in ACF size and number with the 12- and 36-month adenoma recurrence rate; and correlate the adenoma recurrence data at 1 year with the adenoma recurrence data at 3 years. TERTIARY OBJECTIVES: I. To explore the effects of the study agents on a focused panel of tissue biomarkers in pre- and post-intervention biopsy samples from recurrent adenomas, rectal ACF, and adjacent normal-appearing mucosa among subjects enrolled in the phase II clinical trial. II. To determine if cleaved capase-3 expression can improve the detection of apoptotic cells by recognizing cellular commitment to apoptosis prior to late nuclear morphologic features and correlate with apoptotic regulatory proteins, histology, and treatment response. III. To determine the effects of aspirin on its biochemical targets COX-1, -2, and prostaglandin E2, and polyamine levels in subjects receiving DFMO. IV. To examine COX-2-dependent genes (i.e., Bcl-2 and DR5) in adenomas and ACF that have been shown to regulate the intrinsic mitochondrial and extrinsic death receptor-mediated apoptotic pathways in vitro and in vivo. V. To perform expression profiling of adenomas or ACF and to relate such date to ACF histology, size/morphology, modulation by chemopreventive agents, and subsequent adenoma recurrence rates. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive acetylsalicylic acid orally (PO) once daily and eflornithine PO twice daily on days 1-28. ARM II: Patients receive placebo PO three times daily on days 1-28. Treatment repeats every 28 days for 12 months in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed at 6, 12, and 36 months.

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.

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.

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.

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.

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.

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.

Differences in log-transformed values among ACF or patient characteristics will be compared using t tests or analysis of variance (ANOVAs).

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)