Acetylsalicylic Acid and Eflornithine in Treating Patients at High Risk for 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.

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)