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/or colon/rectum/pouch.

• Genotype: Adenomatous polyposis coli (APC) mutation (with or without family history) required
• 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:

• 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.]

• 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:

• Current Spigelman Stage 3 or 4.
• 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):

• No significant hematologic abnormalities
• White blood cell count (WBC) at least 3,000/mm3
• Platelet count at least 100,000/mm3
• Hemoglobin at least 10.0 g/dL
• No history of clinical coagulopathy
• Hepatic Status (within 30 days prior to randomization):

• Bilirubin no greater than 1.5 times ULN
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) no greater than 1.5 times ULN
• 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.