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

• ClinicalTrials.gov Identifier: NCT01483144
• Recruitment Status: Completed
• First Posted: December 1, 2011
• Results First Posted: June 8, 2021
• Last Update Posted: June 8, 2021
• Sponsor: Cancer Prevention Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Cancer Prevention Pharmaceuticals, Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Familial Adenomatous Polyposis	Drug: Eflornithine; Drug: Eflornithine Placebo; Drug: Sulindac 150 MG; Drug: Sulindac placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 171 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: October 2013
• Actual Primary Completion Date: November 2018
• Actual Study Completion Date: March 2019

Arms and Interventions

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 Name: CPP-1X; Drug: Sulindac 150 MG; Sulindac [one tablet orally once a day]; Other Name: 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 Name: 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: Eflornithine Placebo; Eflornithine placebo [three tablets orally once a day]; Other Name: CPP-1X placebo; Drug: Sulindac 150 MG; Sulindac [one tablet orally once a day]; Other Name: Clinoril

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Improvement in Investigator Upper GI Assessment [ Time Frame: through month 12 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.
2. Improvement in Investigator Lower GI Assessment [ Time Frame: through month 12 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, California

University of California San Diego

La Jolla, California, United States, 92093

United States, Georgia

Emory University

Atlanta, Georgia, United States, 30322

United States, Massachusetts

Dana Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Michigan

University of Michigan

Ann Arbor, Michigan, United States, 48109

United States, Minnesota

Mayo Clinic

Rochester, Minnesota, United States, 55905

United States, Missouri

Washington University

Saint Louis, Missouri, United States, 63110

United States, Ohio

Cleveland Clinic

Cleveland, Ohio, United States, 44195

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

United States, Texas

MD Anderson Cancer Center

Houston, Texas, United States, 77030

United States, Utah

University of Utah- Huntsman Cancer Institute

Salt Lake City, Utah, United States, 84112

Belgium

UZ Leuven

Leuven, Belgium, 3000

Canada, Ontario

Zane Cohen Centre For Digestive Diseases

Toronto, Ontario, Canada, M5T 3L9

Germany

University Hospital Bonn

Bonn, Germany, 53105

Netherlands

Academic Medical Centre

Amsterdam, Netherlands, 1100 DE

Spain

Institut de Malalties Digestives

Barcelona, Catalonia, Spain, 08036

United Kingdom

Institute of Genetic Medicine

Newcastle Upon Tyne, Tyne And Wear, United Kingdom, NEI 3BZ

Manchester Center for Genomic Medicine

Manchester, United Kingdom, M13 NWL

Sponsors and Collaborators

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

  Study Documents (Full-Text)

Documents provided by Cancer Prevention Pharmaceuticals, Inc.:

Study Protocol  [PDF] January 17, 2019

Statistical Analysis Plan  [PDF] January 25, 2019

More Information

Publications of Results:

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.

Other 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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Cancer Prevention Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01483144
• Other Study ID Numbers: CPP-FAP-310
• First Posted: December 1, 2011
• Results First Posted: June 8, 2021
• Last Update Posted: June 8, 2021
• Last Verified: May 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Cancer Prevention Pharmaceuticals, Inc.:

Familial Adenomatous Polyposis; Eflornithine; Sulindac

Additional relevant MeSH terms:

Colorectal Neoplasms; Nasopharyngeal Neoplasms; Adenomatous Polyposis Coli; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Head and Neck Neoplasms; Nasopharyngeal Diseases; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Adenomatous Polyps; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplastic Syndromes, Hereditary; Intestinal Polyposis; Genetic Diseases, Inborn; Eflornithine; Sulindac; Antineoplastic Agents