Colorectal Cancer, Familial Adenomatous Polyposis
Conditions
Brief summary
This randomized phase II trial studies how well giving celecoxib with or without eflornithine works in preventing colorectal cancer in patients with familial adenomatous polyposis. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of celecoxib and eflornithine may keep cancer from forming in patients with familial adenomatous polyposis.
Detailed description
PRIMARY OBJECTIVES: I. To determine the relative efficacy of celecoxib plus eflornithine (DFMO) versus celecoxib plus DFMO placebo in participants with familial adenomatous polyposis (FAP), as evidenced by the percent change from baseline in the number of polyps in focal area(s) of the colorectum in participants having 5 or more \>= 2mm colorectal polyps with or without duodenal polyps at baseline. II. To determine the relative tolerability and safety of celecoxib + DFMO in FAP study participants. SECONDARY OBJECTIVES: I. To determine the percent change in polyp size in focal area(s) of the colorectum II. To determine the change in global colorectal polyp burden III. To determine the percent change in the area of plaque-like duodenal polyps in participants presenting with duodenal disease at baseline. IV. To analyze the effects of these agents on the following panel of mucosal biomarkers: antigen identified by monoclonal antibody Ki-67 (Ki-67), mitotic index (number and spatial distribution of mitoses), phosphorylated histone H3, cyclin-dependent kinase inhibitor 1A (p21/WAF1/Cip1), apoptosis (Terminal deoxynucleotidyl transferase dUTP nick end labeling \[TUNEL\]), apoptotic index, BCL2-associated X protein (Bax), B-cell CLL/lymphoma 2 (Bcl-2) and measurement of drug effects in colonic polyp and normal tissue cyclooxygenase (cyclooxygenase-1 \[COX-1\], cyclooxygenase-2 \[COX-2\]) protein levels, prostaglandin E2 (PGE2), ornithine decarboxylase and polyamines. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive celecoxib orally (PO) twice daily (BID) and placebo PO daily. ARM II: Patients receive celecoxib PO BID and eflornithine PO daily. In both arms, treatment continues for 6 months in the absence of disease progression or unacceptable toxicity. After completion of just treatment, patients are followed up at 1-2 months.
Interventions
DRUGCelecoxib
Given 400 mg PO twice a day
OTHERPlacebo
Given PO to match DFMO
DRUGeflornithine
Given PO at 0.5 gm/m\^2/day rounded down to the nearest 250 mg dose (BSA of \< 1.4 = 500 mg/day; BSA of 1.5 - 2.0 = 750 mg/day; BSA of 2.1 - 2.5 = 1000 mg/day; BSA of \> 2.6 = 1,250 mg/day).
OTHERLaboratory biomarker analysis
Correlative studies
OTHERQuestionnaire administration
Ancillary studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* REGISTRATION INCLUSION CRITERIA: * Diagnosis of FAP based on any of the following will be acceptable: * \> 100 polyps or * \> 10 polyps and age \< 40 years, or \> 25 polyps and age \> 40 years and characteristic family history (autosomal dominant pattern) including: * \> 100 polyps in a first degree family member or * \> 25 polyps in two relatives in two generations, including a first degree family member or * Genetic diagnosis in a relative or * Genetic diagnosis by in vitro synthesized protein (IVSP) or similar assay * Willingness to abstain from use of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, for the duration of the study; a cardio-protective dose of aspirin (\>= 80 mg) may be permitted but must be reviewed/approved by principal investigator (PI) * If participant is female and of child bearing potential, she agrees to participate in this study by providing written informed consent, has been using adequate contraception (e.g. abstinence, condom, intrauterine device \[IUD\], birth control pill, diaphragm and spermicide gel combination) since her last menses and will use adequate contraception during the study, is not lactating, and agrees to undergo a serum pregnancy test at baseline, month 3 and month 6; sexually active males must agree to use an accepted and effective method of contraception * Colon polyp status: the participant has an endoscopically assessable colonic and/or rectal segment * Participant has no clinically significant hearing loss that is defined by the patient reporting that their hearing loss affects their everyday life and/or wears a hearing aide * Participants whose air conduction pure tone audiogram reveals a deficit that differs from the age specific norm by less than 30 dB when averaged across two contiguous test frequencies in either ear are eligible, as long as no self-reported hearing deficit or tinnitus is present * Willingness and ability to sign informed consent * RANDOMIZATION INCLUSION CRITERIA: * The individual has assessable colonic polyps remaining in the colon or rectum post baseline colonoscopy or flexible sigmoidoscopy * Potential participants must have the following colonic or rectal polyp burden at the conclusion of the baseline endoscopy: * Rectum: * Five or more polyps \>= 2 mm diameter * Colon: * Five or more polyps \>= 2 mm diameter including: * Three quantifiable polyps \> 3 mm diameter, or two quantifiable polyps \> 5 mm diameter * In the colon, quantifiable polyps are defined as being within a composite cloverleaf photograph that includes a tattoo, the appendix, or the ileocecal valve
Exclusion criteria
* REGISTRATION
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in the Number of Polyps Greater Than or Equal to 2mm in Diameter in Focal Area(s) of the Colorectum | Baseline up to 6 months | Differences between average treatment effects of two study arms tested using two-sided type I error rate of 5% in two-sample t-test. If model assumptions not met by data or transformations of data, appropriate nonparametric tests (e.g. Wilcoxon rank sums test) were used to compare treatment arms - Percent change of polyp counts from baseline to 6 months, ie \[(6 months - baseline) x 100\]/baseline (%). For each participant, first were matched polyps between baseline & 6 months by region and landmark and summed over all matched regions on number of polyps \>2 mm to calculate total number of polyps \>2 mm at baseline & 6 months, respectively. For participants refusing exit colonoscopy, 0% change entered as primary endpoint. Defined ITT All: All patients; if 6-month polyp counts missing = 0% change; ITT Measurable: All participants with baseline & 6 month polyp counts; ITT Evaluable: ITT Measurable participants who also took 80% of treatment, both overall as well as during final 60 days. |
| Number of Participants With Adverse Events Occurring at a Frequency of 5% or Grade 3 and Higher | 6 months | To determine the relative tolerability and safety of celecoxib + DFMO in FAP study participants. Includes only adverse events that occurred in at least 5% of the patients or a patient exhibited at least 1 grade 3 toxicity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Global Colorectal Polyps Burden | 6 months | Percentage Change in Global Colorectal Polyps burden |
| Percent Change in the Area of Plaque-like Duodenal Polyps | 6 months | — |
Other
| Measure | Time frame |
|---|---|
| Global Duodenal Polyp Burden | 6 months |
| Percent Change in Polyp Size in Focal Area(s) of the Colorectum | Baseline up to 2 months after completion of study treatment |
Countries
United States
Participant flow
Recruitment details
Recruitment Period: December 13, 2001 to October 21, 2008. All recruitment done in medical clinics, with the trial conducted at the University of Texas MD Anderson Cancer, the Cleveland Clinic in Cleveland and St. Mark's Hospital in Harrow, UK.
Pre-assignment details
Of the 205 participants with familial adenomatous polyposis (FAP) recruited, 112 were randomized. The study was closed due to slow recruitment with enrollment target almost met.
Participants by arm
| Arm | Count |
|---|---|
| Arm I: Celecoxib and Placebo Celecoxib 400 mg orally twice daily (PO BID) and Placebo once a day. Treatment continues for 6 months (up to 200 days). | 55 |
| Arm II: Celecoxib and Eflornithine Celecoxib 400 mg PO BID and Eflornithine PO daily 0.5 g/m\^2/day rounded down to the nearest 250 mg dose (body surface area (BSA) of \< 1.4 = 500 mg/day; BSA of 1.5 - 2.0 = 750 mg/day; BSA of 2.1 - 2.5 = 1000 mg/day; BSA of \> 2.6 = 1,250 mg/day). Treatment continues for 6 months (up to 200 days). | 57 |
| Total | 112 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 5 |
| Overall Study | Disease Progression | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Arm II: Celecoxib and Eflornithine | Total | Arm I: Celecoxib and Placebo |
|---|---|---|---|
| Age, Continuous | 38 years | 38 years | 38 years |
| Basis of FAP Diagnosis >100 Polyps | 23 participants | 44 participants | 21 participants |
| Basis of FAP Diagnosis >10 Polyps and age <40 | 23 participants | 51 participants | 28 participants |
| Basis of FAP Diagnosis >25 Polyps and age >40 | 11 participants | 17 participants | 6 participants |
| Colon versus Rectum Colon | 27 participants | 46 participants | 19 participants |
| Colon versus Rectum Rectum Only | 30 participants | 66 participants | 36 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 11 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 50 Participants | 96 Participants | 46 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 5 Participants | 2 Participants |
| Number Landmark Polyps at least 2 mm at Baseline Screen for Evaluable polyps, Evaluable Participants 0-1 | 13 participants | 22 participants | 9 participants |
| Number Landmark Polyps at least 2 mm at Baseline Screen for Evaluable polyps, Evaluable Participants 10 or more | 4 participants | 4 participants | 0 participants |
| Number Landmark Polyps at least 2 mm at Baseline Screen for Evaluable polyps, Evaluable Participants 2-4 | 13 participants | 24 participants | 11 participants |
| Number Landmark Polyps at least 2 mm at Baseline Screen for Evaluable polyps, Evaluable Participants 5-9 | 5 participants | 18 participants | 13 participants |
| Number Landmark Polyps at least 2 mm at Baseline Screen for Evaluable polyps, Evaluable Participants No Baseline Screen | 0 participants | 4 participants | 4 participants |
| Number Landmark Polyps at least 2 mm at Baseline Screen for Evaluable polyps, Evaluable Participants Not Evaulable Participant | 22 participants | 40 participants | 18 participants |
| Number of Landmark Polyps at Baseline Screen 0-1 | 5 participants | 8 participants | 3 participants |
| Number of Landmark Polyps at Baseline Screen 10 or more | 19 participants | 41 participants | 22 participants |
| Number of Landmark Polyps at Baseline Screen 2-4 | 12 participants | 19 participants | 7 participants |
| Number of Landmark Polyps at Baseline Screen 5-9 | 21 participants | 40 participants | 19 participants |
| Number of Landmark Polyps at Baseline Screen No Baseline Screen | 0 participants | 4 participants | 4 participants |
| Number of Landmark Polyps at least 2 mm at Baseline Screen 0-1 | 20 participants | 33 participants | 13 participants |
| Number of Landmark Polyps at least 2 mm at Baseline Screen 10 or more | 6 participants | 10 participants | 4 participants |
| Number of Landmark Polyps at least 2 mm at Baseline Screen 2-4 | 23 participants | 35 participants | 12 participants |
| Number of Landmark Polyps at least 2 mm at Baseline Screen 5-9 | 8 participants | 30 participants | 22 participants |
| Number of Landmark Polyps at least 2 mm at Baseline Screen No Baseline Screen | 0 participants | 4 participants | 4 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) White | 53 Participants | 106 Participants | 53 Participants |
| Region of Enrollment United Kingdom | 14 participants | 27 participants | 13 participants |
| Region of Enrollment United States | 43 participants | 85 participants | 42 participants |
| Sex: Female, Male Female | 27 Participants | 52 Participants | 25 Participants |
| Sex: Female, Male Male | 30 Participants | 60 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 | 53 / 55 | 48 / 57 |
| serious Total, serious adverse events | 0 / 55 | 3 / 57 |
Outcome results
Primary
Number of Participants With Adverse Events Occurring at a Frequency of 5% or Grade 3 and Higher
To determine the relative tolerability and safety of celecoxib + DFMO in FAP study participants. Includes only adverse events that occurred in at least 5% of the patients or a patient exhibited at least 1 grade 3 toxicity.
Time frame: 6 months
Population: Total of 57 participants in Arm II, 1 participant is missing AE data
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I: Celecoxib and Placebo | Number of Participants With Adverse Events Occurring at a Frequency of 5% or Grade 3 and Higher | High-frequency hearing loss | 4 Participants |
| Arm I: Celecoxib and Placebo | Number of Participants With Adverse Events Occurring at a Frequency of 5% or Grade 3 and Higher | Fatigue | 11 Participants |
| Arm I: Celecoxib and Placebo | Number of Participants With Adverse Events Occurring at a Frequency of 5% or Grade 3 and Higher | Diarrhoea | 6 Participants |
| Arm I: Celecoxib and Placebo | Number of Participants With Adverse Events Occurring at a Frequency of 5% or Grade 3 and Higher | Heartburn/dyspepsia | 4 Participants |
| Arm I: Celecoxib and Placebo | Number of Participants With Adverse Events Occurring at a Frequency of 5% or Grade 3 and Higher | Mucositis/stomatitis | 11 Participants |
| Arm I: Celecoxib and Placebo | Number of Participants With Adverse Events Occurring at a Frequency of 5% or Grade 3 and Higher | Nausea/vomiting | 6 Participants |
| Arm I: Celecoxib and Placebo | Number of Participants With Adverse Events Occurring at a Frequency of 5% or Grade 3 and Higher | Gout | 0 Participants |
| Arm I: Celecoxib and Placebo | Number of Participants With Adverse Events Occurring at a Frequency of 5% or Grade 3 and Higher | Headache | 5 Participants |
| Arm II: Celecoxib and Eflornithine | Number of Participants With Adverse Events Occurring at a Frequency of 5% or Grade 3 and Higher | Headache | 1 Participants |
| Arm II: Celecoxib and Eflornithine | Number of Participants With Adverse Events Occurring at a Frequency of 5% or Grade 3 and Higher | High-frequency hearing loss | 7 Participants |
| Arm II: Celecoxib and Eflornithine | Number of Participants With Adverse Events Occurring at a Frequency of 5% or Grade 3 and Higher | Mucositis/stomatitis | 15 Participants |
| Arm II: Celecoxib and Eflornithine | Number of Participants With Adverse Events Occurring at a Frequency of 5% or Grade 3 and Higher | Fatigue | 3 Participants |
| Arm II: Celecoxib and Eflornithine | Number of Participants With Adverse Events Occurring at a Frequency of 5% or Grade 3 and Higher | Gout | 1 Participants |
| Arm II: Celecoxib and Eflornithine | Number of Participants With Adverse Events Occurring at a Frequency of 5% or Grade 3 and Higher | Diarrhoea | 4 Participants |
| Arm II: Celecoxib and Eflornithine | Number of Participants With Adverse Events Occurring at a Frequency of 5% or Grade 3 and Higher | Nausea/vomiting | 7 Participants |
| Arm II: Celecoxib and Eflornithine | Number of Participants With Adverse Events Occurring at a Frequency of 5% or Grade 3 and Higher | Heartburn/dyspepsia | 2 Participants |
Primary
Percent Change in the Number of Polyps Greater Than or Equal to 2mm in Diameter in Focal Area(s) of the Colorectum
Differences between average treatment effects of two study arms tested using two-sided type I error rate of 5% in two-sample t-test. If model assumptions not met by data or transformations of data, appropriate nonparametric tests (e.g. Wilcoxon rank sums test) were used to compare treatment arms - Percent change of polyp counts from baseline to 6 months, ie \[(6 months - baseline) x 100\]/baseline (%). For each participant, first were matched polyps between baseline & 6 months by region and landmark and summed over all matched regions on number of polyps \>2 mm to calculate total number of polyps \>2 mm at baseline & 6 months, respectively. For participants refusing exit colonoscopy, 0% change entered as primary endpoint. Defined ITT All: All patients; if 6-month polyp counts missing = 0% change; ITT Measurable: All participants with baseline & 6 month polyp counts; ITT Evaluable: ITT Measurable participants who also took 80% of treatment, both overall as well as during final 60 days.
Time frame: Baseline up to 6 months
Population: 112 patients were randomized to the study. Analysis was by intent to treat (ITT) with a total of 89 ITT participants measurable by having complete polyp information.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I: Celecoxib and Placebo | Percent Change in the Number of Polyps Greater Than or Equal to 2mm in Diameter in Focal Area(s) of the Colorectum | ITT All | -1 percentage change in polyp count | Standard Error 0.11 |
| Arm I: Celecoxib and Placebo | Percent Change in the Number of Polyps Greater Than or Equal to 2mm in Diameter in Focal Area(s) of the Colorectum | ITT Measurable | -1 percentage change in polyp count | Standard Error 0.14 |
| Arm I: Celecoxib and Placebo | Percent Change in the Number of Polyps Greater Than or Equal to 2mm in Diameter in Focal Area(s) of the Colorectum | ITT Evaluable | 10 percentage change in polyp count | Standard Error 0.18 |
| Arm II: Celecoxib and Eflornithine | Percent Change in the Number of Polyps Greater Than or Equal to 2mm in Diameter in Focal Area(s) of the Colorectum | ITT All | -11 percentage change in polyp count | Standard Error 0.08 |
| Arm II: Celecoxib and Eflornithine | Percent Change in the Number of Polyps Greater Than or Equal to 2mm in Diameter in Focal Area(s) of the Colorectum | ITT Measurable | -13 percentage change in polyp count | Standard Error 0.1 |
| Arm II: Celecoxib and Eflornithine | Percent Change in the Number of Polyps Greater Than or Equal to 2mm in Diameter in Focal Area(s) of the Colorectum | ITT Evaluable | -8 percentage change in polyp count | Standard Error 0.12 |
Secondary
Percentage Change in Global Colorectal Polyps Burden
Percentage Change in Global Colorectal Polyps burden
Time frame: 6 months
Population: A total of 89 participants had complete polyp information at baseline and 6 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I: Celecoxib and Placebo | Percentage Change in Global Colorectal Polyps Burden | -27 percentage change of total Polyps burden | Standard Error 6 |
| Arm II: Celecoxib and Eflornithine | Percentage Change in Global Colorectal Polyps Burden | -40 percentage change of total Polyps burden | Standard Error 6 |
Secondary
Percent Change in the Area of Plaque-like Duodenal Polyps
Time frame: 6 months
Population: The data was inevaluable to determine the percent change in the area of plaque-like duodenal polyps
Other Pre-specified
Global Duodenal Polyp Burden
Time frame: 6 months
Population: The data was inevaluable to determine the global duodenal polyp burden
Other Pre-specified
Percent Change in Polyp Size in Focal Area(s) of the Colorectum
Time frame: Baseline up to 2 months after completion of study treatment
Population: No data collected to determine the percentage change in polyp size in focal area(s) of the colorectum.