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: 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

- UGI endoscopy/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 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. (Refer to Appendix A for Modified Spigelman Score
and Classification table).

2. Prior surgical endoscopic intervention within the past six months for Spigelman
Stage 3 or 4 that may have been down staged to Spigelman 1 or 2.

- Hematopoietic Status (within 30 days prior to randomization):

1. No significant hematologic abnormalities

2. 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. AST and 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), 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.