A Trial of Low Dose Sulindac Combined With Eflornithine in Patients With Familial Adenomatous Polyposis (FAP)

A Randomized Phase III Trial of Low Dose Sulindac Combined With Eflornithine in Patients With Familial Adenomatous Polyposis (FAP)

The purpose of this phase III study is to evaluate the safety and efficacy of the combination of eflornithine and sulindac compared to single agent sulindac or eflornithine in reducing the number of polyps in patients with familial adenomatous polyposis (FAP).

Study Overview

• Status: Withdrawn
• Conditions: Familial Adenomatous Polyposis
• Intervention / Treatment: Drug: Eflornithine plus Sulindac; Drug: Eflornithine plus Placebo; Drug: Sulindac plus Placebo

• Study Type: Interventional
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of phenotypic Familial Adenomatous Polyposis (FAP) of the colorectum based on meeting the criteria in one of two groups: Group 1-Greater than 100 adenomatous colorectal polyps prior to age 40. Group 2-Greater than 10 adenomatous polyps and age <40 or greater than 25 polyps and age >40; combined with a dominant family history or genotype: More than 100 polyps in a first-degree relative; More than 25 polyps in 2 relatives in 2 generations, including a first-degree family member; Genetic diagnosis in a relative; Genetic diagnosis by in vitro synthesized truncated protein or similar assay.
• No colorectal surgery or prior colon surgery for polyposis at least 1 year prior (total abdominal colectomy with ileal-rectal anastomosis, or total proctocolectomy with ilea pouch-anal reconstruction.

• Baseline endoscopy

  1. If no prior colorectal surgery, at least 3 polyps in a cluster each ≥ 2 mm in diameter; or
  2. If rectum is in situ and to be assessed, baseline rectal segment endoscopy documenting 3 or more rectal polyps each at least 2 mm in diameter in a defined cluster and/or at least 6 polyps, ≥ 2 mm in diameter, in the distal 10 cm of rectum
  3. If ileal pouch neo-rectum is in place, 3 or more pouch polyps in a cluster ≥ 2 mm in diameter, or at least 6 polyps, ≥ 2 mm in diameter, in the distal 10 cm of pouch.
  4. Clinical/pathological grading of duodenal polyps will utilize the Spigelman Classification.
• Hematopoietic: no significant hematologic dysfunction; WBC ≥3,000/mm3; platelet count ≥100,000/mm3; hemoglobin ≥10g/dL; no known or prior clinical coagulopathy.
• Hepatic: bilirubin ≤ 1.5 times ULN; AST and ALT ≤ 1.5 times ULN; Alkaline phosphatase ≤ 1.5 times ULN.
• Renal: No significant renal dysfunction; creatinine ≤ 1.5 times ULN.
• Hearing: no clinically significant hearing loss that affects everyday life.
• Not pregnant or nursing.
• Negative serum pregnancy test if female of child-bearing potential.
• Absence of gross blood in stool.
• Fertile patients must use effective contraception.
• Stool occult blood either negative or minimal (1+).
• No prior hypersensitivity to cyclooxygenase-2 inhibitors, sulfonamides, NSAIDs, or salicylates; no NSAID associated symptoms of gastritis.
• No discrete gastric or duodenal ulcer greater than 5 mm within the past year except Helicobacter pylori-related peptic ulcer disease treated successfully with antibiotics (as documented by an endoscopy.
• No invasive malignancy within the past 5 years except stage I or II colon or rectal cancer or resected nonmelanomatous skin cancer.
• No other significant medical or psychiatric problems that would preclude study participation.
• No chronic adrenocorticosteroids.
• No prior pelvic irradiation.
• At least 3 months since prior investigational agents.
• Patients may not be receiving or plan to receive corticosteroids.
• Concomitant NSAID use outside this study may not exceed 4 days per month.
• Use of 81 mg daily aspirin or 650 mg aspirin not more than once a week.
• No concurrent warfarin, fluconazole, or lithium.
• Must be willing and able to sign informed consent.

Exclusion Criteria:

• High Risk for cardiovascular disease including clinical diabetes mellitus (Type I or II) requiring glycemic medications; Prior personal history of cardiovascular disease or, two or more of the following - hypertension or use of anti-hypertensive medications, hyperlipidemia or use of lipid-lowering medications or current smoker.
• Hearing loss that affects everyday life and or for which a hearing aid is required.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Eflornithine plus Sulindac; Eflornithine 500 mg and Sulindac 150 mg	Drug: Eflornithine plus Sulindac; Eflornithine, 250 mg tablet, two tablets (500 mg) orally once a day; Sulindac, 150 mg tablet, one tablet orally once a day; Other Names: DFMO
Active Comparator: Elfornithine plus Placebo; Eflornithine 500 mg and Placebo	Drug: Eflornithine plus Placebo; Eflornithine, 250 mg tablet, two tablets (500 mg) orally once a day; Placebo, one tablet orally once a day; Other Names: DFMO
Active Comparator: Sulindac plus Placebo; Sulindac 150 mg and Placebo	Drug: Sulindac plus Placebo; Sulindac, 150 mg tablet, one tablet orally once a day; Placebo, two tablets orally once a day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Efficacy of Eflornithine plus Sulindac compared to Eflornithine alone and Sulindac alone determined by change in the number of polyps 2 mm or greater in a defined focal area of the rectum or pouch at baseline and after completion of the study treatment.	6 months from the start of treatment.

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in number of polyps 2 mm or greater in the distal 10 cm of rectum or pouch.	6 months from the start of treatment.
Qualitative change in overall colon/rectum/pouch polyp burden (number and size).	6 months from the start of treatment.
Presence of high grade dysplasia or villous adenoma in any polyp resected.	6 months from the start of treatment.

Collaborators and Investigators

• Sponsor: Cancer Prevention Pharmaceuticals, Inc.
• Investigators: Study Director: Alfred M. Cohen, M.D., Cancer Prevention Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (Anticipated): May 1, 2013
• Study Completion (Anticipated): June 1, 2013

Study Registration Dates

• First Submitted: November 19, 2010
• First Submitted That Met QC Criteria: November 22, 2010
• First Posted (Estimate): November 23, 2010

Study Record Updates

• Last Update Posted (Estimate): April 24, 2015
• Last Update Submitted That Met QC Criteria: April 23, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Keywords: colon polyps
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Genetic Diseases, Inborn; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Head and Neck Neoplasms; Nasopharyngeal Diseases; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplastic Syndromes, Hereditary; Adenomatous Polyps; Adenoma; Intestinal Polyposis; Nasopharyngeal Neoplasms; Colorectal Neoplasms; Adenomatous Polyposis Coli; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antineoplastic Agents; Antiprotozoal Agents; Antiparasitic Agents; Trypanocidal Agents; Ornithine Decarboxylase Inhibitors; Eflornithine; Sulindac
• Other Study ID Numbers: CPP FAP-301