Phase III Trial of the Safety and Efficacy of Eflornithine Combined With Sulindac Compared to Eflornithine, Sulindac as Single Agents in Patients With Familial Adenomatous Polyposis
- Diagnosis of phenotypic classical FAP with disease involvement of the duodenum and/or
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
- 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
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 mg daily aspirin or 650 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
- Able to provide informed consent and follow protocol requirements.
- Prior pelvic irradiation.
- Patients receiving 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 650 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 at high cardiovascular disease risk are not eligible for study participation
defined as (a) Clinical diabetes mellitus (Type I or II) requiring glycemic
medications, or; (b)Prior personal history of cardiovascular disease - heart attack,
stroke, transient ischemic attack, or symptomatic peripheral vascular disease, or two
of the following: taking anti-hypertensive medication, taking lipid lowering
medication, and/or current cigarette smoker
- 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
- 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.