Aspirin in Preventing Colorectal Cancer in Patients With Colorectal Adenoma

Phase 2

Active, not recruiting

Conditions: Colorectal Adenoma
Colorectal Carcinoma

Interventions: Drug: Aspirin
Procedure: Biospecimen Collection
Other: Questionnaire Administration
Other: Placebo Administration
Procedure: Rectal Biopsy

Registration Number: NCT02965703

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase IIa trial studies how well aspirin works in preventing colorectal cancer in patients with colorectal adenoma. Aspirin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description: PRIMARY OBJECTIVE:

I. To test for the equivalency of the two aspirin schedules.

SECONDARY OBJECTIVES:

I. To evaluate the effects of aspirin treatments on:

Ia. The ratio of cell proliferation (Ki-67)/apoptosis (TUNEL) in rectal biopsies; Ib. The ratio of cell proliferation (Ki-67)/necroptosis (pMLKL) in rectal biopsies; Ic. Fecal occult blood test (measures of adverse events) as measured by stool samples.

EXPLORATORY OBJECTIVES:

I. To evaluate the effects of aspirin treatments on:

Ia. Cyclooxygenase-2 (COX-2) in rectal biopsies; Ib. Bcl-2-like protein 4 (BAX) in rectal biopsies; Ic. Transient receptor potential cation channel subfamily M member (7TRPM7) in rectal biopsies; Id. Joint index of COX-2 with TRPM7 expression in rectal biopsies; Ie. Joint index of TRPM7 with BAX in rectal biopsies; If. Methylation assays using the MethylationEPIC BeadChip to identify methylation biomarkers in genes (i.e. CDKN2A \[cell cycle regulation\], MGMT \[deoxyribonucleic acid (DNA) repair\], DAPK1 \[apoptosis\], CDH1 \[cell invasion\], WNT16 \[Wnt pathway\] and RASSF1 \[RAS signaling\]) involved in colorectal carcinogenesis, and other epigenome-wide methylation biomarkers as measured in rectal biopsies; Ig. Metagenomics analysis to measure abundance of Escherichia coli (E. coli) and Fusobacterium and other microbiota in rectal swabs.

OUTLINE: Patients are randomized to 1 of 3 arms.

ARM I: Patients receive aspirin orally (PO) daily for 12 weeks in the absence of unacceptable toxicity. Patients also undergo collection of blood, urine, stool, rectal swab samples, and rectal biopsies throughout the trial.

ARM II: Patients receive aspirin PO daily at weeks 1-3 and 7-9 and placebo PO daily at weeks 4-6 and 10-12 in the absence of unacceptable toxicity. Patients also undergo collection of blood, urine, stool, rectal swab samples, and rectal biopsies throughout the trial.

ARM III: Patients receive placebo PO daily for 12 weeks in the absence of unacceptable toxicity. Patients also undergo collection of blood, urine, stool, rectal swab samples, and rectal biopsies throughout the trial.

After completion of study, patients are followed up at 1 month.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 81

Inclusion Criteria

Diagnosis of colorectal adenoma of any grade
Age >= 18 years. Because no dosing or adverse event (AE) data are currently available on the use of aspirin in participants < 18 years of age, children are excluded from this study but will be eligible for future pediatric trials, if applicable
Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
Leukocytes >= 3,000/microliter
Absolute neutrophil count >= 1,500/microliter
Platelets >= 150,000/microliter
Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x institutional ULN
Creatinine =< 1.5 x institutional ULN
Blood hemoglobin >= 12.0 g/dL
Alkaline phosphatase =< 1.5 x institutional ULN
Blood urea nitrogen (BUN) =< 40 mg/dL
Estimated glomerular filtration rate (eGFR) >= 45 mL/min
Negative fecal occult blood test
The effects of aspirin on the developing human fetus at the recommended therapeutic dose are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately
Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

Current (within three weeks of randomization) or planned use during the study intervention of the following:
- Aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), or COX-2 inhibitors
- Anticoagulants, anti-platelet agents, or corticosteroids
- Gingko
- Ethanol consumption > 1 standard drinks/day for women, or > 2 standard drinks/day for men
- Methotrexate (MTX)
- Study participants will be instructed to use Tylenol or some other non-excluded agent to treat common ailments (i.e. headache/minor aches and pains)
History of
- Any invasive malignancy within the past 2 years, with the exception of non-melanoma skin cancer
- Chronic renal diseases or liver cirrhosis
- Diseases such as anemia, peptic ulcer, gastrointestinal bleeding, active colitis and inflammatory bowel disease
- Hemorrhagic stroke or uncontrolled hypertension
Participants may not be receiving any other investigational agents
History of allergic reactions or intolerance attributed to aspirin or compounds of similar chemical or biologic composition
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness that would limit compliance with study requirements
Women who are pregnant or breastfeeding; pregnant women are excluded from this study because aspirin has the potential for abortifacient effects; because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with aspirin, breastfeeding should be discontinued if the mother is treated with aspirin

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (aspirin)	Biospecimen Collection	Patients receive aspirin PO daily for 12 weeks in the absence of unacceptable toxicity. Patients also undergo collection of blood, urine, stool, rectal swab samples, and rectal biopsies throughout the trial.
Arm I (aspirin)	Questionnaire Administration	Patients receive aspirin PO daily for 12 weeks in the absence of unacceptable toxicity. Patients also undergo collection of blood, urine, stool, rectal swab samples, and rectal biopsies throughout the trial.
Arm I (aspirin)	Rectal Biopsy	Patients receive aspirin PO daily for 12 weeks in the absence of unacceptable toxicity. Patients also undergo collection of blood, urine, stool, rectal swab samples, and rectal biopsies throughout the trial.
Arm II (aspirin, placebo)	Biospecimen Collection	Patients receive aspirin PO daily at weeks 1-3 and 7-9 and placebo PO daily at weeks 4-6 and 10-12 in the absence of unacceptable toxicity. Patients also undergo collection of blood, urine, stool, rectal swab samples, and rectal biopsies throughout the trial.
Arm II (aspirin, placebo)	Placebo Administration	Patients receive aspirin PO daily at weeks 1-3 and 7-9 and placebo PO daily at weeks 4-6 and 10-12 in the absence of unacceptable toxicity. Patients also undergo collection of blood, urine, stool, rectal swab samples, and rectal biopsies throughout the trial.
Arm II (aspirin, placebo)	Questionnaire Administration	Patients receive aspirin PO daily at weeks 1-3 and 7-9 and placebo PO daily at weeks 4-6 and 10-12 in the absence of unacceptable toxicity. Patients also undergo collection of blood, urine, stool, rectal swab samples, and rectal biopsies throughout the trial.
Arm II (aspirin, placebo)	Rectal Biopsy	Patients receive aspirin PO daily at weeks 1-3 and 7-9 and placebo PO daily at weeks 4-6 and 10-12 in the absence of unacceptable toxicity. Patients also undergo collection of blood, urine, stool, rectal swab samples, and rectal biopsies throughout the trial.
Arm III (placebo)	Biospecimen Collection	Patients receive placebo PO daily for 12 weeks in the absence of unacceptable toxicity. Patients also undergo collection of blood, urine, stool, rectal swab samples, and rectal biopsies throughout the trial.
Arm III (placebo)	Placebo Administration	Patients receive placebo PO daily for 12 weeks in the absence of unacceptable toxicity. Patients also undergo collection of blood, urine, stool, rectal swab samples, and rectal biopsies throughout the trial.
Arm III (placebo)	Rectal Biopsy	Patients receive placebo PO daily for 12 weeks in the absence of unacceptable toxicity. Patients also undergo collection of blood, urine, stool, rectal swab samples, and rectal biopsies throughout the trial.
Arm III (placebo)	Questionnaire Administration	Patients receive placebo PO daily for 12 weeks in the absence of unacceptable toxicity. Patients also undergo collection of blood, urine, stool, rectal swab samples, and rectal biopsies throughout the trial.
Arm I (aspirin)	Aspirin	Patients receive aspirin PO daily for 12 weeks in the absence of unacceptable toxicity. Patients also undergo collection of blood, urine, stool, rectal swab samples, and rectal biopsies throughout the trial.
Arm II (aspirin, placebo)	Aspirin	Patients receive aspirin PO daily at weeks 1-3 and 7-9 and placebo PO daily at weeks 4-6 and 10-12 in the absence of unacceptable toxicity. Patients also undergo collection of blood, urine, stool, rectal swab samples, and rectal biopsies throughout the trial.

Primary Outcome Measures

Name	Time	Method
Ratio of Cell Proliferation to Apoptosis Biomarkers (Ki67 Index and BAX Index)	Baseline to end of intervention up to 12 weeks	Change in the ratio of proliferation to apoptosis biomarkers (Ki67 density index: BAX density index, measured continuously after IHC staining) in colorectal mucosa of compliant participants

Secondary Outcome Measures

Name	Time	Method
Ratio of Cell Proliferation (Ki-67)/Apoptosis (TdT-mediated dUTP Nick End Labeling [TUNEL]) in Rectal Biopsies	Baseline to end of intervention up to 12 weeks	Change in the ratio of proliferation to apoptosis biomarkers (Ki67 density index: TUNEL density index, measured continuously after IHC staining) in colorectal mucosa of compliant participants.
Ratio of Cell Proliferation (Ki-67)/Necroptosis (MLKL) in Rectal Biopsies	Baseline to end of intervention up to 12 weeks	Change in the ratio of proliferation to necroptosis biomarkers (Ki67 density index: pMLKLdensity index, measured continuously after IHC staining) in colorectal mucosa of compliant participants
Fecal Occult Blood Test (Measures of Adverse Events) as Measured by Stool Samples	Baseline to end of intervention up to 12 weeks.	The number of participants who started intervention and had a positive fecal occult blood test result