Colorectal Adenoma, Colorectal Carcinoma
Conditions
Brief summary
The purpose of this study is to assess how effective celecoxib is in limiting production of a hormone, prostaglandin, in the subject's body. It is felt that this hormone is involved in the evolution of pre-cancerous growths in the colon to cancerous stage or in the progression of an existing cancer. To answer this question, some subjects are given the new investigational drug, and other subjects a placebo. A placebo is a capsule that contains inactive ingredients. Only by comparing the response of two subject groups, one receiving placebo (inactive), and one receiving celecoxib (active), will we be able to know whether or not celecoxib actually works. The outcome we are assessing is the hormone activity before and after celecoxib is given.
Detailed description
We propose to test the hypothesis that celecoxib, a specific inhibitor of cyclooxygenase -2 (COX-2), will effectively inhibit the enzymatic activity in all tissues sampled after oral administration of celecoxib for 7 days preoperatively. One hundred twenty patients (120) undergoing standard surgical resection for the treatment of primary colorectal adenomas or carcinomas would be randomized to celecoxib or placebo given for 7 days prior to operation. Peripheral blood will be drawn prior to drug or placebo administration, and then morning of operation. At the time of definitive resection of the specimen, normal intestinal mucosa and primary tumor would be harvested and immediately snap frozen at -80 degrees. Levels of COX-2 activity (prostaglandin production) as well as expression of COX-2 and other markers (matrix metalloproteinases(MMPs), tissue inhibitors of MMPs (TIMPs), cell adhesion and cell cycle control molecules will be evaluated in normal mucosa and primary tumor compared between celecoxib and placebo treated patients.
Interventions
DRUGCelecoxib
400 mg twice a day for 7 days prior to surgery
DRUGPlacebo
one tablet of placebo will be given for 7 days prior to surgery
Sponsors
Pfizer
Pharmacia
University of Alabama at Birmingham
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
19 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
1. Mass suspicious for carcinoma, clinical diagnosis of adenocarcinoma of the colon (to be histologically confirmed upon study entry) or an adenoma that is not removable by endoscopy. 2. Patient must be undergoing colo-rectal resection 3. age \> 18yrs 4. Karnofsky performance status(KPS) \> 60. 5. Signed and dated informed consent. 6. Complete history and physical examination within 30 days of study entry. 7. Laboratory evaluations within 30 days of study entry to include: Complete Blood Count(CBC) with differential and platelets, Blood Urea Nitrogen(BUN), creatinine, bilirubin, serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase(SGPT), lactate dehydrogenase(LDH), alkaline phosphatase, total protein, albumin and carcinoembryonic antigen(CEA). 8. Chest x-ray within 30 days of study entry. 9. The subject has no other serious medical illness, other than that treated by this study, which would limit the ability of the patient to receive protocol therapy, or psychiatric condition which would prevent informed consent. Absolute
Exclusion criteria
1. severe infection ;White Blood Cell Count(WBC) \> 2 times normal, fever, sepsis) 2. immunosuppression (steroids, transplant patient) 3. emergent operation(perforation, obstruction). 4. Patients with serum bilirubin or creatinine levels greater than two times the normal upper limit would be excluded. 5. Pregnant or lactating women or subjects of child bearing age who do not practice effective means of birth control 6. Sulfonamide allergy 7. Recurrent or previous history of known ischemic heart disease or thrombotic events as well as any angioplasty or cardiac by-pass procedures in the previous 12 months. Relative
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Witha Change (IMPROVEMENT) in Colo-rectal Adenocarcinoma as Measured by Cyclooxygenase-2 Activity After 7 Days of Celecoxib | baseline to 7 days | The Colo-Rectal adenocarcinoma will be measured by cyclooxygenase-2(COX-2) activity at 7 days post baseline. Cox-2 activity is measured by assessing tumors and normal tissue using Electron microscope and Tandem mass Spectrometry methodology though the UAB shared Mass Spectrometry facility. Improvement was measured by 2-fold increase in COX-2 activity from baseline. The methodology used was High Performance Liquid Chromatography(HPLC). additional studies include expression of genes thought to be important in colorectal carcinogenesis: COX-1 and 2, MMP, 2 7, and 9, tissue inhibitor of metalloproteinases(TIMPs) 1 ans 2 and beta-catenin. |
| Subjects With Positive Response 72 Hours After Administration of Study Treatment as Measured by Immunoblot | baseline to 72 hours | At 72 hours after start of treatment, the number of subjects with immunoblot demonstrated a 1.5 to 2 fold increase in 15-LOX-1 protein expression in human colorectal adenocarcinoma cell line with epithelial morphology(HT-29) and dihydrolipoamide dehydrogenase(DLD)-1 cells. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Celecoxib 400 mg BID given for 7 days before surgery | 20 |
| Placebo 1 tablet BID given for 7 days before surgery | 20 |
| Total | 40 |
Baseline characteristics
| Characteristic | Placebo | Celecoxib | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants | 20 Participants | 40 Participants |
| Age, Continuous | 62 years STANDARD_DEVIATION 1 | 62 years STANDARD_DEVIATION 1 | 62 years STANDARD_DEVIATION 1 |
| Region of Enrollment United States | 20 participants | 20 participants | 40 participants |
| Sex: Female, Male Female | 4 Participants | 6 Participants | 10 Participants |
| Sex: Female, Male Male | 16 Participants | 14 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 20 | 0 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
Number of Subjects Witha Change (IMPROVEMENT) in Colo-rectal Adenocarcinoma as Measured by Cyclooxygenase-2 Activity After 7 Days of Celecoxib
The Colo-Rectal adenocarcinoma will be measured by cyclooxygenase-2(COX-2) activity at 7 days post baseline. Cox-2 activity is measured by assessing tumors and normal tissue using Electron microscope and Tandem mass Spectrometry methodology though the UAB shared Mass Spectrometry facility. Improvement was measured by 2-fold increase in COX-2 activity from baseline. The methodology used was High Performance Liquid Chromatography(HPLC). additional studies include expression of genes thought to be important in colorectal carcinogenesis: COX-1 and 2, MMP, 2 7, and 9, tissue inhibitor of metalloproteinases(TIMPs) 1 ans 2 and beta-catenin.
Time frame: baseline to 7 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Celecoxib | Number of Subjects Witha Change (IMPROVEMENT) in Colo-rectal Adenocarcinoma as Measured by Cyclooxygenase-2 Activity After 7 Days of Celecoxib | 2.0 Participant |
| Placebo | Number of Subjects Witha Change (IMPROVEMENT) in Colo-rectal Adenocarcinoma as Measured by Cyclooxygenase-2 Activity After 7 Days of Celecoxib | 2.0 Participant |
Primary
Subjects With Positive Response 72 Hours After Administration of Study Treatment as Measured by Immunoblot
At 72 hours after start of treatment, the number of subjects with immunoblot demonstrated a 1.5 to 2 fold increase in 15-LOX-1 protein expression in human colorectal adenocarcinoma cell line with epithelial morphology(HT-29) and dihydrolipoamide dehydrogenase(DLD)-1 cells.
Time frame: baseline to 72 hours
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Celecoxib | Subjects With Positive Response 72 Hours After Administration of Study Treatment as Measured by Immunoblot | 3.0 Participants | 0.5 |
| Placebo | Subjects With Positive Response 72 Hours After Administration of Study Treatment as Measured by Immunoblot | 0 Participants | 0.5 |