Familial Adenomatous Polyposis
Conditions
Keywords
Familial Adenomatous Polyposis, Colorectal Tumors, Molecular Targeting, Celecoxib, Celebrex, SC-58635, Apoptosis Induction, Colon, Rectum, colonoscopy, Biopsy
Brief summary
Primary Objective: * To determine whether celecoxib downregulates GATA-6 expression to upregulate 15-LOX-1 expression and induce apoptosis in human rectal tumors, researchers will measure GATA-6 and 15-LOX-1 expression, 13-S-HODE levels, and apoptosis rates in normal and colorectal polyp epithelial tissues before and after 6 months of celecoxib treatment of patients with familial adenomatous polyposis (FAP).
Detailed description
Celecoxib is a drug that was developed to treat arthritis. However, celecoxib may also help to stop or slow the growth of colon and rectal tumor cells. At the start of the study, you will be asked questions about your medical history, have a complete physical exam, and have around 2 tablespoons of blood drawn for blood tests as part of your routine care for familial adenomatous polyposis. Also, blood tests such as fasting blood glucose and lipid profiling (cholesterol, LDL, HDL and triglyceride) will be assessed to determine eligibility. Women who are able to have children must have a negative blood pregnancy test within 14 days of starting celecoxib. Before your scheduled colonoscopy, you will fill out a form asking about any medications and nutritional supplements that you are taking. In addition, you will be asked to complete a diet history. This will help researchers to evaluate patients' dietary habits. The questionnaire takes about 15 minutes to complete. You will also have around 1 teaspoon of blood drawn to measure the amount of celecoxib in your blood. Then, during your already scheduled colonoscopy procedure, you will have additional tissue biopsies (the size of a pencil tip) of your colon taken. For a colonoscopy procedure, a flexible tube with a light attached to the end is used to look inside your colon/lower gut. The biopsies will be taken through the flexible tube using a special cutting tool. Up to 23 biopsy samples may be taken. The biopsies should take about 20 extra minutes to complete. After the procedure, you will start taking celecoxib by mouth once every 12 hours for 6 months. You will also have around 1 teaspoon of blood drawn to measure the amount of celecoxib in your blood at the completion of month 2 and 4 of celecoxib treatment. At the end of the 6 month treatment period, you will have another colonoscopy procedure. This is an additional procedure performed solely for this study and is not part of your standard of care for the treatment of familial adenomatous polyposis. A second set of biopsies will be taken (23 maximum). These biopsy samples will be studied and compared to the samples taken before treatment with celecoxib. You will also have around 1 teaspoon of blood drawn to measure the amount of celecoxib in your blood. You will be contacted by phone 72 hours after your first dose of celecoxib and then every 2 weeks for the study to check for any side effects you may be experiencing. The maximum amount of time you will remain on this study is 6 months. If at any time, you experience any intolerable side effects, you will be taken off the study. This is an investigational study. Celecoxib is FDA approved and commercially available for familial adenomatous polyposis patients to reduce polyp formation. Up to 40 patients will take part in this study. All will be enrolled at M. D. Anderson.
Interventions
DRUGCelecoxib
400 mg by mouth twice daily x 6 months
PROCEDUREColonoscopy Biopsy
Up to 23 additional colon tissue biopsies (the size of a pencil tip), additional 20 minutes on colonoscopy procedure
Sponsors
National Cancer Institute (NCI)
M.D. Anderson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of familial adenomatous polyposis (patients should have colorectal remnant that can be biopsied. Patients who have had total colorectal surgical resection are not eligible). 2. Adequate bone marrow function (ANC \> 1500 ml, platelet count \> 100,000/ml). Serum creatinine, total bilirubin, and ALT \< 1.5 upper limit normal. 3. Over 16 years of age. 4. Patient is able to give an informed consent. 5. Women of childbearing potential (women are considered to be of childbearing potential unless they are at 2 or more years post-menopausal/or surgically sterile), must: * Not be pregnant or lactating. * use adequate contraceptive measures (abstinence, IUD, birth control pills, or diaphragm or condom with spermicidal gel) starting with last menses and throughout the study duration. * Have a negative serum pregnancy test within 14 days of starting celecoxib.
Exclusion criteria
1. Inflammatory bowel disease. 2. Intake of anti-inflammatory medications (e.g., non-steroidal, aspirin, and sulfasalazine) that cannot be discontinued starting 3 days prior to the enrollment. 3. Chemotherapy or radiation therapy in less than three months from the time of enrollment. 4. Individuals who are taking Coumadin that can not be discontinued starting 7 days prior to the enrollment. 5. Individuals who have received an investigational chemopreventive agent during the month prior to the biopsies. 6. History of bleeding diathesis. 7. History of sulfonamides (sulfa) allergies. 8. History of cardiovascular diseases that might include the following: myocardial infarction, angina, coronary angioplasty, congestive heart failure, stroke, or coronary bypass surgery. 9. Uncontrolled hypertension (\> 135/\> 85 mm Hg on three repeated measurements during the 6 weeks prior to enrollment on the study). 10. Diagnosis of diabetes. 11. Smoking history during the 6 months prior to enrollment on the study. 12. Uncontrolled hypercholesteremia (low-density lipoprotein cholesterol (LDL-C) \> 130). Hypercholesteremia needs to be controlled following the updated the National Cholesterol Education Program Adult Treatment Panel III Guidelines for at least 3 months prior to enrollment on the study. Hypercholesteremia treatment needs to be continued during the enrollment on the protocol. 13. Family history of premature coronary disease (i.e., onset \< 55 years of age). 14. Metabolic syndrome diagnosis in patients who are 30 years or older. (The diagnosis of metabolic syndrome is made when three or more of these risk factors are present): * Waist circumference: Men \> 102 cm (\> 40 in); Women \> 88 cm (\> 35 in). \*Triglycerides = 150 mg/dl (= 1.69 mmol/L). * High-density lipoprotein cholesterol (HDL-C): \[Men \< 40 mg/dl (\< 1.03 mmol/L), Women \<50 mg/dl (\< 1.29 mmol/L)\]. * Blood pressure = 130/= 85 mm Hg. * Fasting glucose = 110 mg/dl (= 6.1 mmol/L). 15. History of deep venous thrombosis, pulmonary embolism, systemic lupus erythematous, family history of protein S or C deficiencies or prior heparin-induced thrombocytopenia.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 13-HODE Colonic Tissue Levels | Baseline to post 6 months of celecoxib treatment | 13-HODE colonic tissue levels measured by Liquid chromatography and tandem mass spectrometry measurements (LC/MS/MS) in colorectal normal and polyp tissues |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PGE2 Colonic Tissue Levels | at the baseline colonoscopy (or sigmoidoscopy in patients who had undergone colectomy) before the initiation of celecoxib, and the follow-up colonoscopy or sigmoidoscopy was performed after celecoxib treatment (month 6) | PGE2 colonic tissue levels measured by Liquid chromatography and tandem mass spectrometry measurements (LC/MS/MS) in colorectal normal and polyp tissues |
Countries
United States
Participant flow
Pre-assignment details
51 participants consented, 4 participants were inevaluable.
Participants by arm
| Arm | Count |
|---|---|
| Celecoxib Celecoxib 400 mg orally twice daily for 6 months. Up to 23 colon tissue biopsies (the size of a pencil tip). | 29 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Ineligible | 15 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Physician Decision | 3 |
Baseline characteristics
| Characteristic | Celecoxib |
|---|---|
| Age, Categorical <=18 years | 7 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants |
| Age, Continuous | 32 years STANDARD_DEVIATION 13.48 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 29 Participants |
| Region of Enrollment United States | 29 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 32 |
| other Total, other adverse events | 24 / 32 |
| serious Total, serious adverse events | 2 / 32 |
Outcome results
Primary
13-HODE Colonic Tissue Levels
13-HODE colonic tissue levels measured by Liquid chromatography and tandem mass spectrometry measurements (LC/MS/MS) in colorectal normal and polyp tissues
Time frame: Baseline to post 6 months of celecoxib treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Celecoxib | 13-HODE Colonic Tissue Levels | polyps after celecoxib treatment | 18.83 ng/mg tissue protein | Standard Deviation 14 |
| Celecoxib | 13-HODE Colonic Tissue Levels | polyps before celecoxib treatment | 14.56 ng/mg tissue protein | Standard Deviation 9.93 |
| Celecoxib | 13-HODE Colonic Tissue Levels | Normal: before celecoxib treatment | 23.02 ng/mg tissue protein | Standard Deviation 18.55 |
| Celecoxib | 13-HODE Colonic Tissue Levels | Normal: after celecoxib treatment | 20.03 ng/mg tissue protein | Standard Deviation 11.7 |
Secondary
PGE2 Colonic Tissue Levels
PGE2 colonic tissue levels measured by Liquid chromatography and tandem mass spectrometry measurements (LC/MS/MS) in colorectal normal and polyp tissues
Time frame: at the baseline colonoscopy (or sigmoidoscopy in patients who had undergone colectomy) before the initiation of celecoxib, and the follow-up colonoscopy or sigmoidoscopy was performed after celecoxib treatment (month 6)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Celecoxib | PGE2 Colonic Tissue Levels | Polyps: before celecoxib treatment | 14.71 ng/mg tissue protein | Standard Deviation 6.95 |
| Celecoxib | PGE2 Colonic Tissue Levels | Polyps: after celecoxib treatment | 20.62 ng/mg tissue protein | Standard Deviation 10.48 |
| Celecoxib | PGE2 Colonic Tissue Levels | Normal: before celecoxib treatment | 21.48 ng/mg tissue protein | Standard Deviation 14.32 |
| Celecoxib | PGE2 Colonic Tissue Levels | Normal: after celecoxib treatment | 24.99 ng/mg tissue protein | Standard Deviation 18.25 |