Colorectal Adenoma, Colorectal Carcinoma
Conditions
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.
Interventions
DRUGAspirin
Given PO
PROCEDUREBiospecimen Collection
Undergo collection of blood, urine, stool, and rectal swab samples
OTHERPlacebo Administration
Given PO
OTHERQuestionnaire Administration
Ancillary studies
PROCEDURERectal Biopsy
Undergo rectal biopsy
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORQi Dai
Northwestern University
Participant flow
Recruitment details
81 participants were randomized. 70 out of the 81 started study agent.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (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.
Aspirin: Given PO
Biospecimen Collection: Undergo collection of blood, urine, stool, and rectal swab samples
Questionnaire Administration: Ancillary studies
Rectal Biopsy: Undergo rectal biopsy | 36 |
| Arm II (Aspirin, Placebo) 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.
Aspirin: Given PO
Biospecimen Collection: Undergo collection of blood, urine, stool, and rectal swab samples
Placebo Administration: Given PO
Questionnaire Administration: Ancillary studies
Rectal Biopsy: Undergo rectal biopsy | 36 |
| Arm III (Placebo) 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.
Biospecimen Collection: Undergo collection of blood, urine, stool, and rectal swab samples
Placebo Administration: Given PO
Questionnaire Administration: Ancillary studies
Rectal Biopsy: Undergo rectal biopsy | 9 |
| Total | 81 |
Baseline characteristics
| Characteristic | Arm I (Aspirin) | Total | Arm III (Placebo) | Arm II (Aspirin, Placebo) |
|---|---|---|---|---|
| Age, Continuous | 61 years STANDARD_DEVIATION 8 | 60 years STANDARD_DEVIATION 7 | 57 years STANDARD_DEVIATION 6 | 60 years STANDARD_DEVIATION 6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants | 80 Participants | 9 Participants | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 9 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 32 Participants | 72 Participants | 9 Participants | 31 Participants |
| Region of Enrollment United States | 36 participants | 81 participants | 9 participants | 36 participants |
| Sex: Female, Male Female | 17 Participants | 43 Participants | 5 Participants | 21 Participants |
| Sex: Female, Male Male | 19 Participants | 38 Participants | 4 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 33 | 0 / 8 |
| other Total, other adverse events | 7 / 29 | 9 / 33 | 4 / 8 |
| serious Total, serious adverse events | 0 / 29 | 1 / 33 | 1 / 8 |
Outcome results
Primary
Ratio of Cell Proliferation to Apoptosis Biomarkers (Ki67 Index and BAX Index)
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
Time frame: Baseline to end of intervention up to 12 weeks
Population: Participants with pre and post intervention samples available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Aspirin) | Ratio of Cell Proliferation to Apoptosis Biomarkers (Ki67 Index and BAX Index) | -0.11 ratio |
| Arm II (Aspirin, Placebo) | Ratio of Cell Proliferation to Apoptosis Biomarkers (Ki67 Index and BAX Index) | 0.00 ratio |
| Arm III (Placebo) | Ratio of Cell Proliferation to Apoptosis Biomarkers (Ki67 Index and BAX Index) | -0.23 ratio |
Secondary
Fecal Occult Blood Test (Measures of Adverse Events) as Measured by Stool Samples
The number of participants who started intervention and had a positive fecal occult blood test result
Time frame: Baseline to end of intervention up to 12 weeks.
Population: Participants with pre and post intervention samples available.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Aspirin) | Fecal Occult Blood Test (Measures of Adverse Events) as Measured by Stool Samples | 1 Participants |
| Arm II (Aspirin, Placebo) | Fecal Occult Blood Test (Measures of Adverse Events) as Measured by Stool Samples | 2 Participants |
| Arm III (Placebo) | Fecal Occult Blood Test (Measures of Adverse Events) as Measured by Stool Samples | 0 Participants |
Secondary
Ratio of Cell Proliferation (Ki-67)/Apoptosis (TdT-mediated dUTP Nick End Labeling [TUNEL]) in Rectal Biopsies
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.
Time frame: Baseline to end of intervention up to 12 weeks
Population: Participants with pre and post intervention samples available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Aspirin) | Ratio of Cell Proliferation (Ki-67)/Apoptosis (TdT-mediated dUTP Nick End Labeling [TUNEL]) in Rectal Biopsies | -1.27 ratio |
| Arm II (Aspirin, Placebo) | Ratio of Cell Proliferation (Ki-67)/Apoptosis (TdT-mediated dUTP Nick End Labeling [TUNEL]) in Rectal Biopsies | 0.63 ratio |
| Arm III (Placebo) | Ratio of Cell Proliferation (Ki-67)/Apoptosis (TdT-mediated dUTP Nick End Labeling [TUNEL]) in Rectal Biopsies | -0.70 ratio |
Secondary
Ratio of Cell Proliferation (Ki-67)/Necroptosis (MLKL) in Rectal Biopsies
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
Time frame: Baseline to end of intervention up to 12 weeks
Population: Participants with pre and post intervention samples available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Aspirin) | Ratio of Cell Proliferation (Ki-67)/Necroptosis (MLKL) in Rectal Biopsies | 0.58 ratio |
| Arm II (Aspirin, Placebo) | Ratio of Cell Proliferation (Ki-67)/Necroptosis (MLKL) in Rectal Biopsies | -0.02 ratio |
| Arm III (Placebo) | Ratio of Cell Proliferation (Ki-67)/Necroptosis (MLKL) in Rectal Biopsies | -0.32 ratio |