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

NCT ID: NCT01483144

Last Updated: 2021-06-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 171 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-10-31
• Study Completion Date: 2019-03-31

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.

Conditions

Familial Adenomatous Polyposis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Eflornithine plus Sulindac

Eflornithine 750 mg and Sulindac 150 mg

Group Type: EXPERIMENTAL

Eflornithine

Intervention Type: DRUG

Eflornithine \[250 mg tablet, three tablets (750 mg) orally once a day\]

Sulindac 150 MG

Intervention Type: DRUG

Sulindac \[one tablet orally once a day\]

Eflornithine plus Sulindac Placebo

Eflornithine 750 mg and Placebo

Group Type: ACTIVE_COMPARATOR

Eflornithine

Intervention Type: DRUG

Eflornithine \[250 mg tablet, three tablets (750 mg) orally once a day\]

Sulindac placebo

Intervention Type: DRUG

Sulindac placebo \[one tablet orally once a day\]

Sulindac plus Eflornithine Placebo

Sulindac 150 mg and Placebo

Group Type: ACTIVE_COMPARATOR

Eflornithine Placebo

Intervention Type: DRUG

Eflornithine placebo \[three tablets orally once a day\]

Sulindac 150 MG

Intervention Type: DRUG

Sulindac \[one tablet orally once a day\]

Interventions

Eflornithine

Eflornithine \[250 mg tablet, three tablets (750 mg) orally once a day\]

Intervention Type: DRUG

Eflornithine Placebo

Eflornithine placebo \[three tablets orally once a day\]

Intervention Type: DRUG

Sulindac 150 MG

Sulindac \[one tablet orally once a day\]

Intervention Type: DRUG

Sulindac placebo

Sulindac placebo \[one tablet orally once a day\]

Intervention Type: DRUG

Other Intervention Names

CPP-1X; CPP-1X placebo; Clinoril

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Cancer Prevention Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Carol Burke, M.D.

Role: PRINCIPAL_INVESTIGATOR

The Cleveland Clinic

James Church, M.D.

Role: PRINCIPAL_INVESTIGATOR

The Cleveland Clinic

Gabriella Möslein, M.D.

Role: PRINCIPAL_INVESTIGATOR

Helios Hospital

Locations

University of California San Diego

La Jolla, California, United States

Emory University

Atlanta, Georgia, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

University of Michigan

Ann Arbor, Michigan, United States

Mayo Clinic

Rochester, Minnesota, United States

Washington University

St Louis, Missouri, United States

Cleveland Clinic

Cleveland, Ohio, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

MD Anderson Cancer Center

Houston, Texas, United States

University of Utah- Huntsman Cancer Institute

Salt Lake City, Utah, United States

UZ Leuven

Leuven, , Belgium

Zane Cohen Centre For Digestive Diseases

Toronto, Ontario, Canada

University Hospital Bonn

Bonn, , Germany

Academic Medical Centre

Amsterdam, , Netherlands

Institut de Malalties Digestives

Barcelona, Catalonia, Spain

Institute of Genetic Medicine

Newcastle upon Tyne, Tyne and Wear, United Kingdom

Manchester Center for Genomic Medicine

Manchester, , United Kingdom

Countries

United States; Belgium; Canada; Germany; Netherlands; Spain; United Kingdom

References

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.

Reference Type: BACKGROUND

PMID: 27480131 (View on PubMed)

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.

Reference Type: RESULT

PMID: 32905675 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34261858 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

CPP-FAP-310

Identifier Type: -

Identifier Source: org_study_id