Adenomatous Polyp Clinical Trial
Official title:
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.
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