Familial Adenomatous Polyposis
Conditions
Keywords
Familial Adenomatous Polyposis, Eflornithine, Sulindac
Brief summary
The purpose of this randomized, double-blind, Phase III trial is to determine if the combination of eflornithine plus sulindac is superior to sulindac or eflornithine as single agents in delaying time to the first occurrence of any FAP-related event. This includes: 1) FAP related disease progression indicating the need for excisional intervention involving the colon, rectum, pouch, duodenum and/or 2) clinically important events which includes progression to more advanced duodenal polyposis, cancer or death.
Interventions
DRUGEflornithine
Eflornithine \[250 mg tablet, three tablets (750 mg) orally once a day\]
Eflornithine placebo \[three tablets orally once a day\]
DRUGSulindac 150 MG
Sulindac \[one tablet orally once a day\]
DRUGSulindac placebo
Sulindac placebo \[one tablet orally once a day\]
Sponsors
Cancer Prevention Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of phenotypic classical FAP with disease involvement of the duodenum and/or colon/rectum/pouch. 1. Genotype: Adenomatous polyposis coli (APC) mutation (with or without family history) required 2. Classical FAP Phenotype: 100's to 1,000's of colorectal adenomatous polyps, usually appearing in teenage years * Upper gastrointestinal (UGI) endoscopy/ lower gastrointestinal (LGI) endoscopy (proctoscopy/colonoscopy) performed within 30 days of randomization. * Patients with an intact colon/rectum, except for clinical polyposis, and prophylactic surgery is being considered as a stratification site. * Rectal/pouch polyposis as a stratification site as follows: 1. At least three years since colectomy with ileorectal anastamosis (IRA)/proctocolectomy with pouch, and demonstrating polyposis as defined by Stage 1, 2, 3, of the proposed InSiGHT 2011 Staging System (Appendix B) and summarized as follows: Stage 1: 10-25 polyps, all \< 5 mm Stage 2: 10-25 polyps, at least one \> 1 cm Stage 3: \>25 polyps amenable to complete removal, or any incompletely removed sessile polyp, or any evidence of high grade dysplasia, even if completely removed. \[Note: For staging purposes only.\] 2. For all subjects, any rectal/pouch polyps \> 5 mm must be excised at baseline. * Duodenal polyposis as a stratification site; one or more of the following: 1. Current Spigelman Stage 3 or 4. 2. Prior surgical endoscopic intervention within the past six months for Spigelman Stage 3 or 4 that may have been down staged to Spigelman Stage 1 or 2. * Hematopoietic Status (within 30 days prior to randomization): 1. No significant hematologic abnormalities 2. White blood cell count (WBC) at least 3,000/mm3 3. Platelet count at least 100,000/mm3 4. Hemoglobin at least 10.0 g/dL 5. No history of clinical coagulopathy * Hepatic Status (within 30 days prior to randomization): 1. Bilirubin no greater than 1.5 times ULN 2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) no greater than 1.5 times ULN 3. Alkaline phosphatase no greater than 1.5 times ULN * Renal Status (within 30 days prior to randomization): a) Creatinine no greater than 1.5 times ULN * Hearing: a) No clinically significant hearing loss, defined in Section 6.2, number 9. * If female, neither pregnant nor lactating. * Negative pregnancy test if female of child-bearing potential. Fertile patients must use effective contraception\*. * Absence of gross blood in stool; red blood on toilet paper only acceptable. * No discrete gastric or duodenal ulcer greater than 5 mm within the past year except Helicobacter pylori-related peptic ulcer disease treated with antibiotics. * No invasive malignancy within the past 5 years except resected non-melanomatous skin cancer, papillary thyroid cancer, or precancerous cervical dysplasia. * No other significant medical or psychiatric problems that would preclude study participation or interfere with capacity to give informed consent. * Use of 81-100 mg daily aspirin or up to 700 mg aspirin not more than once a week are eligible. * No concurrent warfarin, fluconazole, lithium, Pradaxa® or other direct thrombin inhibitors, Plavix®, cyclosporine, other NSAIDs (such as ibuprofen, aspirin, diflunisal), diuretics (furosemide and thiazides), dimethylsulfoxide (DMSO), methotrexate, probenecid, propoxyphene hydrochloride, Tylenol® (acetaminophen) preparations containing aspirin or cytotoxic chemotherapy drugs. * Willingness to forego concurrent use of supplements containing omega-3 fatty acids, corticosteroids, non-steroidal anti-inflammatory drugs or other FAP directed drug therapy. * Able to provide informed consent and follow protocol requirements.
Exclusion criteria
* Prior pelvic irradiation. * Patients receiving oral corticosteroids within 30 days of enrollment. * Treatment with other investigational agents in the prior 4 weeks. * Use of other non-steroidal anti-inflammatory drugs (such as ibuprofen) exceeding 4 days per month, in the prior 6 weeks. * Regular use of aspirin in excess of 700 mg per week. * Treatment with other FAP directed drug therapy (including sulindac or celecoxib, fish oil) within 12 weeks of study enrollment. * Hypersensitivity to cyclooxygenase-2 inhibitors, sulfonamides, NSAIDs, or salicylates; NSAID associated symptoms of gastritis. * Patients must not have cardiovascular disease risk factors as defined below: * Uncontrolled high blood pressure (systolic blood pressure \> 150 mm Hg * Unstable angina * History of documented myocardial infarction or cerebrovascular accident * New York Heart Association Class III or IV heart failure * Known uncontrolled hyperlipidemia defined as LDL-C \>= 190 mg/dL or triglycerides \>= 500 mg/dL * Patients with significant hearing loss are not eligible for study participation defined as hearing loss that affects everyday life and/or for which a hearing aid is required. * Colon/rectum/pouch with high grade dysplasia or cancer on biopsy or a large polyp (\>1 cm) not amenable to complete removal. * Duodenal cancer on biopsy. * Intra-abdominal desmoid disease, stage III or IV * Inability to provide informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Any FAP-related Event. | Up to 48 months from the start of treatment | Progression of disease by evaluation of FAP-related events over the course of study treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Improvement in Investigator Upper GI Assessment | through month 12 assessment | Global assessment of change in upper GI polyp burden. These are binary outcomes derived from scores assigned by the investigator during each procedure, using a scale (-2, -1, 0, +1, +2) which corresponds, respectively, to the investigator's overall qualitative assessment of: much worse, worse, no change, improved, much improved. Summarizes the corresponding 6- and 12-month investigator change scores according to whether or not there was any positive improvement at either month 6 (compared to baseline) or at month 12 (compared to baseline or month 6), under the condition that there be no worsening at either timepoint. |
| Improvement in Investigator Lower GI Assessment | through month 12 assessment | Global assessment of change in lower GI polyp burden. These are binary outcomes derived from scores assigned by the investigator during each procedure, using a scale (-2, -1, 0, +1, +2) which corresponds, respectively, to the investigator's overall qualitative assessment of: much worse, worse, no change, improved, much improved. Summarizes the corresponding 6- and 12-month investigator change scores according to whether or not there was any positive improvement at either month 6 (compared to baseline) or at month 12 (compared to baseline or month 6), under the condition that there be no worsening at either timepoint. |
Countries
Belgium, Canada, Germany, Netherlands, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Eflornithine Plus Sulindac Eflornithine 750 mg and Sulindac 150 mg
Eflornithine: Eflornithine \[250 mg tablet, three tablets (750 mg) orally once a day\]
Sulindac 150 MG: Sulindac \[one tablet orally once a day\] | 56 |
| Eflornithine Plus Sulindac Placebo Eflornithine 750 mg and Placebo
Eflornithine: Eflornithine \[250 mg tablet, three tablets (750 mg) orally once a day\]
Sulindac placebo: Sulindac placebo \[one tablet orally once a day\] | 57 |
| Sulindac Plus Eflornithine Placebo Sulindac 150 mg and Placebo
Eflornithine Placebo: Eflornithine placebo \[three tablets orally once a day\]
Sulindac 150 MG: Sulindac \[one tablet orally once a day\] | 58 |
| Total | 171 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 9 | 4 | 6 |
| Overall Study | Lost to Follow-up | 2 | 4 | 1 |
| Overall Study | Physician Decision | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 3 | 3 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 5 |
Baseline characteristics
| Characteristic | Eflornithine Plus Sulindac | Total | Sulindac Plus Eflornithine Placebo | Eflornithine Plus Sulindac Placebo |
|---|---|---|---|---|
| Age, Continuous | 37.8 years STANDARD_DEVIATION 13.35 | 38.5 years STANDARD_DEVIATION 13.88 | 38.1 years STANDARD_DEVIATION 13.66 | 39.7 years STANDARD_DEVIATION 14.76 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 13 Participants | 3 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 50 Participants | 154 Participants | 54 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 10 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 2 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 | 2 Participants | 6 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 48 Participants | 152 Participants | 50 Participants | 54 Participants |
| Region of Enrollment Belgium | 1 participants | 4 participants | 0 participants | 3 participants |
| Region of Enrollment Canada | 6 participants | 16 participants | 4 participants | 6 participants |
| Region of Enrollment Germany | 9 participants | 19 participants | 4 participants | 6 participants |
| Region of Enrollment Netherlands | 4 participants | 15 participants | 5 participants | 6 participants |
| Region of Enrollment Spain | 2 participants | 6 participants | 1 participants | 3 participants |
| Region of Enrollment United Kingdom | 3 participants | 8 participants | 2 participants | 3 participants |
| Region of Enrollment United States | 31 participants | 103 participants | 42 participants | 30 participants |
| Sex: Female, Male Female | 22 Participants | 72 Participants | 21 Participants | 29 Participants |
| Sex: Female, Male Male | 34 Participants | 99 Participants | 37 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 56 | 0 / 56 | 0 / 57 |
| other Total, other adverse events | 52 / 56 | 49 / 56 | 50 / 57 |
| serious Total, serious adverse events | 11 / 56 | 14 / 56 | 11 / 57 |
Outcome results
Primary
Number of Subjects With Any FAP-related Event.
Progression of disease by evaluation of FAP-related events over the course of study treatment
Time frame: Up to 48 months from the start of treatment
Population: Intent to treat population with 171 subjects. Intent to treat population with lower GI anatomy (ower GI population) to evaluate lower GI FAP related events with 158 subjects.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Eflornithine Plus Sulindac | Number of Subjects With Any FAP-related Event. | Number with FAP-related events | 18 Participants |
| Eflornithine Plus Sulindac | Number of Subjects With Any FAP-related Event. | Number with Lower GI FAP-related events | 2 Participants |
| Eflornithine Plus Sulindac Placebo | Number of Subjects With Any FAP-related Event. | Number with FAP-related events | 23 Participants |
| Eflornithine Plus Sulindac Placebo | Number of Subjects With Any FAP-related Event. | Number with Lower GI FAP-related events | 10 Participants |
| Sulindac Plus Eflornithine Placebo | Number of Subjects With Any FAP-related Event. | Number with FAP-related events | 22 Participants |
| Sulindac Plus Eflornithine Placebo | Number of Subjects With Any FAP-related Event. | Number with Lower GI FAP-related events | 9 Participants |
Comparison: Intent to treat population with all FAP-related eventsp-value: 0.12195% CI: [0.4, 1.3]stratified Cox proportional (Score)
Comparison: Intent to treat population with all FAP-related eventsp-value: 0.107695% CI: [0.4, 1.2]stratified Cox proportional (Score)
Comparison: Lower GI populationp-value: 0.020195% CI: [0, 0.8]stratified Cox proportional (Score)
Comparison: Lower GI populationp-value: 0.010195% CI: [0, 0.7]stratified Cox proportional (Score)
Secondary
Improvement in Investigator Lower GI Assessment
Global assessment of change in lower GI polyp burden. These are binary outcomes derived from scores assigned by the investigator during each procedure, using a scale (-2, -1, 0, +1, +2) which corresponds, respectively, to the investigator's overall qualitative assessment of: much worse, worse, no change, improved, much improved. Summarizes the corresponding 6- and 12-month investigator change scores according to whether or not there was any positive improvement at either month 6 (compared to baseline) or at month 12 (compared to baseline or month 6), under the condition that there be no worsening at either timepoint.
Time frame: through month 12 assessment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Eflornithine Plus Sulindac | Improvement in Investigator Lower GI Assessment | Improved | 22 Participants |
| Eflornithine Plus Sulindac | Improvement in Investigator Lower GI Assessment | Not Improved | 34 Participants |
| Eflornithine Plus Sulindac Placebo | Improvement in Investigator Lower GI Assessment | Improved | 16 Participants |
| Eflornithine Plus Sulindac Placebo | Improvement in Investigator Lower GI Assessment | Not Improved | 41 Participants |
| Sulindac Plus Eflornithine Placebo | Improvement in Investigator Lower GI Assessment | Improved | 22 Participants |
| Sulindac Plus Eflornithine Placebo | Improvement in Investigator Lower GI Assessment | Not Improved | 36 Participants |
p-value: 0.999Mantel Haenszel
p-value: 0.2152Mantel Haenszel
Secondary
Improvement in Investigator Upper GI Assessment
Global assessment of change in upper GI polyp burden. These are binary outcomes derived from scores assigned by the investigator during each procedure, using a scale (-2, -1, 0, +1, +2) which corresponds, respectively, to the investigator's overall qualitative assessment of: much worse, worse, no change, improved, much improved. Summarizes the corresponding 6- and 12-month investigator change scores according to whether or not there was any positive improvement at either month 6 (compared to baseline) or at month 12 (compared to baseline or month 6), under the condition that there be no worsening at either timepoint.
Time frame: through month 12 assessment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Eflornithine Plus Sulindac | Improvement in Investigator Upper GI Assessment | Improved | 11 Participants |
| Eflornithine Plus Sulindac | Improvement in Investigator Upper GI Assessment | Not Improved | 45 Participants |
| Eflornithine Plus Sulindac Placebo | Improvement in Investigator Upper GI Assessment | Improved | 10 Participants |
| Eflornithine Plus Sulindac Placebo | Improvement in Investigator Upper GI Assessment | Not Improved | 47 Participants |
| Sulindac Plus Eflornithine Placebo | Improvement in Investigator Upper GI Assessment | Improved | 10 Participants |
| Sulindac Plus Eflornithine Placebo | Improvement in Investigator Upper GI Assessment | Not Improved | 48 Participants |
p-value: 0.8127Mantel Haenszel
p-value: 0.8133Mantel Haenszel