Clinical trial NCT00503035: Molecular Targeting of 15-Lipoxygenase-1 (15-LOX-1) for Apoptosis Induction in Human Colorectal Cancers
Official title: Molecular Targeting of 15-LOX-1 for Apoptosis Induction in Human Colorectal Cancers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Familial Adenomatous Polyposis
Keywords: Familial Adenomatous Polyposis
Colorectal Tumors
Molecular Targeting
Celecoxib
Celebrex
SC-58635
Apoptosis Induction
Colon
Rectum
colonoscopy
Biopsy
Lead sponsor: M.D. Anderson Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-07-18
Enrollment: 51
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 13-HODE Colonic Tissue Levels
timeFrame: Baseline to post 6 months of celecoxib treatment
Secondary outcomes:
measure: PGE2 Colonic Tissue Levels
timeFrame: 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)
Other outcomes:
Locations:
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Imad Shureiqi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: M.D. Anderson Cancer Center
name: Robert S. Bresalier, MD
role: STUDY_CHAIR
affiliation: M.D. Anderson Cancer Center
name: Patrick Lynch, MD, JD
role: STUDY_CHAIR
References:
citation: Lynch PM, Morris JS, Ross WA, Rodriguez-Bigas MA, Posadas J, Khalaf R, Weber DM, Sepeda VO, Levin B, Shureiqi I. Global quantitative assessment of the colorectal polyp burden in familial adenomatous polyposis by using a web-based tool. Gastrointest Endosc. 2013 Mar;77(3):455-63. doi: 10.1016/j.gie.2012.11.038. Epub 2013 Jan 18.
citation: Yang P, Zuo X, Advani S, Wei B, Malek J, Day RS, Shureiqi I. Celecoxib Colorectal Bioavailability and Chemopreventive Response in Patients with Familial Adenomatous Polyposis. Cancer Prev Res (Phila). 2022 Apr 1;15(4):217-223. doi: 10.1158/1940-6207.CAPR-21-0066.