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

Phase 3

Completed

• Conditions: Familial Adenomatous Polyposis
• Interventions: Drug: Eflornithine; Drug: Eflornithine Placebo; Drug: Sulindac 150 MG; Drug: Sulindac placebo

• Registration Number: NCT01483144
• Lead Sponsor: Cancer Prevention Pharmaceuticals, Inc.

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2011-11-21
• Study First Submitted QC: 2011-11-30
• Study First Posted: 2011-12-01
• Study Start: 2013-10
• Primary Completion: 2018-11
• Study Completion: 2019-03
• Disposition First Submitted: 2020-01-28
• Disposition First Submitted QC: 2020-01-28
• Disposition First Posted: 2020-02-07
• Results First Submitted: 2021-04-20
• Status Verified: 2021-05
• Results First Submitted QC: 2021-05-12
• Last Update Submitted: 2021-05-12
• Results First Posted: 2021-06-08
• Last Update Posted: 2021-06-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 171

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sulindac plus Eflornithine Placebo	Sulindac 150 MG	Sulindac 150 mg and Placebo
Eflornithine plus Sulindac	Eflornithine	Eflornithine 750 mg and Sulindac 150 mg
Eflornithine plus Sulindac Placebo	Sulindac placebo	Eflornithine 750 mg and Placebo
Eflornithine plus Sulindac	Sulindac 150 MG	Eflornithine 750 mg and Sulindac 150 mg
Sulindac plus Eflornithine Placebo	Eflornithine Placebo	Sulindac 150 mg and Placebo
Eflornithine plus Sulindac Placebo	Eflornithine	Eflornithine 750 mg and Placebo

Primary Outcome Measures

Name	Time	Method
Number of Subjects With Any FAP-related Event.	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

Name	Time	Method
Improvement in Investigator Upper GI Assessment	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.
Improvement in Investigator Lower GI Assessment	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.

Trial Locations

Locations (17)

Emory University; 🇺🇸 Atlanta, Georgia, United States

Cleveland Clinic; 🇺🇸 Cleveland, Ohio, United States

University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States

MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Zane Cohen Centre For Digestive Diseases; 🇨🇦 Toronto, Ontario, Canada

University of California San Diego; 🇺🇸 La Jolla, California, United States

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

Washington University; 🇺🇸 Saint Louis, Missouri, United States

University of Utah- Huntsman Cancer Institute; 🇺🇸 Salt Lake City, Utah, United States

UZ Leuven; 🇧🇪 Leuven, Belgium

University Hospital Bonn; 🇩🇪 Bonn, Germany

Academic Medical Centre; 🇳🇱 Amsterdam, Netherlands

Institut de Malalties Digestives; 🇪🇸 Barcelona, Catalonia, Spain

Manchester Center for Genomic Medicine; 🇬🇧 Manchester, United Kingdom

Institute of Genetic Medicine; 🇬🇧 Newcastle Upon Tyne, Tyne And Wear, United Kingdom