Trial of Eflornithine Plus Sulindac in Patients With Familial Adenomatous Polyposis (FAP)

Inclusion Criteria:

• Diagnosis of phenotypic classical FAP with disease involvement of the duodenum and/orcolon/rectum/pouch.

1. Genotype: Adenomatous polyposis coli (APC) mutation (with or without familyhistory) 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 prophylacticsurgery 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 summarizedas follows: Stage 1: 10-25 polyps, all < 5 mm Stage 2: 10-25 polyps, at least one > 1 cmStage 3: >25 polyps amenable to complete removal, or any incompletely removedsessile polyp, or any evidence of high grade dysplasia, even if completelyremoved. [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 SpigelmanStage 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 greaterthan 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 mustuse 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 exceptHelicobacter pylori-related peptic ulcer disease treated with antibiotics.
• No invasive malignancy within the past 5 years except resected non-melanomatous skincancer, papillary thyroid cancer, or precancerous cervical dysplasia.
• No other significant medical or psychiatric problems that would preclude studyparticipation 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 areeligible.
• No concurrent warfarin, fluconazole, lithium, Pradaxa® or other direct thrombininhibitors, 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 drugtherapy.
• 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 4days 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, fishoil) 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 participationdefined as hearing loss that affects everyday life and/or for which a hearing aid isrequired.
• Colon/rectum/pouch with high grade dysplasia or cancer on biopsy or a large polyp (>1cm) not amenable to complete removal.
• Duodenal cancer on biopsy.
• Intra-abdominal desmoid disease, stage III or IV
• Inability to provide informed consent.