Trial of Eflornithine Plus Sulindac in Patients With Familial Adenomatous Polyposis (FAP)

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

The purpose of this randomized, double-blind, Phase III trial is to determine if the combination of eflornithine plus sulindac is superior to sulindac or eflornithine as single agents in delaying time to the first occurrence of any FAP-related event. This includes: 1) FAP related disease progression indicating the need for excisional intervention involving the colon, rectum, pouch, duodenum and/or 2) clinically important events which includes progression to more advanced duodenal polyposis, cancer or death.

Study Overview

• Status: Completed
• Conditions: Familial Adenomatous Polyposis
• Intervention / Treatment: Drug: Eflornithine; Drug: Sulindac 150 MG; Drug: Sulindac placebo; Drug: Eflornithine Placebo

• Study Type: Interventional
• Enrollment (Actual): 171
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • UZ Leuven
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5T 3L9
      • Zane Cohen Centre For Digestive Diseases
• Germany
  • Bonn, Germany, 53105
    • University Hospital Bonn
• Netherlands
  • Amsterdam, Netherlands, 1100 DE
    • Academic Medical Centre
• Spain
  • Catalonia
    • Barcelona, Catalonia, Spain, 08036
      • Institut de Malalties Digestives
• United Kingdom
  • Manchester, United Kingdom, M13 NWL
    • Manchester Center for Genomic Medicine
  • Tyne And Wear
    • Newcastle Upon Tyne, Tyne And Wear, United Kingdom, NEI 3BZ
      • Institute of Genetic Medicine
• United States
  • California
    • La Jolla, California, United States, 92093
      • University of California San Diego
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah- Huntsman Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

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 750 mg and Sulindac 150 mg	Drug: Eflornithine; Eflornithine [250 mg tablet, three tablets (750 mg) orally once a day]; Other Names: CPP-1X; Drug: Sulindac 150 MG; Sulindac [one tablet orally once a day]; Other Names: Clinoril
Active Comparator: Eflornithine plus Sulindac Placebo; Eflornithine 750 mg and Placebo	Drug: Eflornithine; Eflornithine [250 mg tablet, three tablets (750 mg) orally once a day]; Other Names: CPP-1X; Drug: Sulindac placebo; Sulindac placebo [one tablet orally once a day]
Active Comparator: Sulindac plus Eflornithine Placebo; Sulindac 150 mg and Placebo	Drug: Sulindac 150 MG; Sulindac [one tablet orally once a day]; Other Names: Clinoril; Drug: Eflornithine Placebo; Eflornithine placebo [three tablets orally once a day]; Other Names: CPP-1X placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With Any FAP-related Event.	Progression of disease by evaluation of FAP-related events over the course of study treatment	Up to 48 months from the start of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in Investigator Upper GI Assessment	Global assessment of change in upper GI polyp burden. These are binary outcomes derived from scores assigned by the investigator during each procedure, using a scale (-2, -1, 0, +1, +2) which corresponds, respectively, to the investigator's overall qualitative assessment of: much worse, worse, no change, improved, much improved. Summarizes the corresponding 6- and 12-month investigator change scores according to whether or not there was any positive improvement at either month 6 (compared to baseline) or at month 12 (compared to baseline or month 6), under the condition that there be no worsening at either timepoint.	through month 12 assessment
Improvement in Investigator Lower GI Assessment	Global assessment of change in lower GI polyp burden. These are binary outcomes derived from scores assigned by the investigator during each procedure, using a scale (-2, -1, 0, +1, +2) which corresponds, respectively, to the investigator's overall qualitative assessment of: much worse, worse, no change, improved, much improved. Summarizes the corresponding 6- and 12-month investigator change scores according to whether or not there was any positive improvement at either month 6 (compared to baseline) or at month 12 (compared to baseline or month 6), under the condition that there be no worsening at either timepoint.	through month 12 assessment

Collaborators and Investigators

• Sponsor: Cancer Prevention Pharmaceuticals, Inc.
• Investigators: Principal Investigator: Carol Burke, M.D., The Cleveland Clinic; Principal Investigator: James Church, M.D., The Cleveland Clinic; Principal Investigator: Gabriella Möslein, M.D., Helios Hospital

Publications and helpful links

General Publications

• Burke CA, Dekker E, Samadder NJ, Stoffel E, Cohen A. Efficacy and safety of eflornithine (CPP-1X)/sulindac combination therapy versus each as monotherapy in patients with familial adenomatous polyposis (FAP): design and rationale of a randomized, double-blind, Phase III trial. BMC Gastroenterol. 2016 Aug 2;16(1):87. doi: 10.1186/s12876-016-0494-4.
• Burke CA, Dekker E, Lynch P, Samadder NJ, Balaguer F, Huneburg R, Burn J, Castells A, Gallinger S, Lim R, Stoffel EM, Gupta S, Henderson A, Kallenberg FG, Kanth P, Roos VH, Ginsberg GG, Sinicrope FA, Strassburg CP, Van Cutsem E, Church J, Lalloo F, Willingham FF, Wise PE, Grady WM, Ford M, Weiss JM, Gryfe R, Rustgi AK, Syngal S, Cohen A. Eflornithine plus Sulindac for Prevention of Progression in Familial Adenomatous Polyposis. N Engl J Med. 2020 Sep 10;383(11):1028-1039. doi: 10.1056/NEJMoa1916063.
• Balaguer F, Stoffel EM, Burke CA, Dekker E, Samadder NJ, Van Cutsem E, Lynch PM, Wise PE, Huneburg R, Lim RM, Boytim ML, Du W, Bruckheimer EM, Cohen A, Church J; FAP-310 Investigators. Combination of Sulindac and Eflornithine Delays the Need for Lower Gastrointestinal Surgery in Patients With Familial Adenomatous Polyposis: Post Hoc Analysis of a Randomized Clinical Trial. Dis Colon Rectum. 2022 Apr 1;65(4):536-545. doi: 10.1097/DCR.0000000000002095.

Study record dates

Study Major Dates

• Study Start: October 1, 2013
• Primary Completion (Actual): November 1, 2018
• Study Completion (Actual): March 1, 2019

Study Registration Dates

• First Submitted: November 21, 2011
• First Submitted That Met QC Criteria: November 30, 2011
• First Posted (Estimate): December 1, 2011

Study Record Updates

• Last Update Posted (Actual): June 8, 2021
• Last Update Submitted That Met QC Criteria: May 12, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Eflornithine; Familial Adenomatous Polyposis; Sulindac
• 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-310

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No