Randomized Phase II Trial of Aspirin and Difluoromethylornithine (DFMO) in Patients at High Risk of Colorectal Cancer
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.
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
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.
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
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
After completion of study treatment, patients are followed at 6, 12, and 36 months.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention
Adenoma recurrence rate for the treatment arm relative to placebo
At 1 year
United States: Food and Drug Administration
|Mayo Clinic||Rochester, Minnesota 55905|
|University of Chicago||Chicago, Illinois 60637|
|University of Illinois College of Medicine - Chicago||Chicago, Illinois 60612|