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.

  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.