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

Primary Purpose

Familial Adenomatous Polyposis

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Eflornithine
Eflornithine Placebo
Sulindac 150 MG
Sulindac placebo
Sponsored by
Cancer Prevention Pharmaceuticals, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Familial Adenomatous Polyposis focused on measuring Familial Adenomatous Polyposis, Eflornithine, Sulindac

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of California San Diego
  • Emory University
  • Dana Farber Cancer Institute
  • University of Michigan
  • Mayo Clinic
  • Washington University
  • Cleveland Clinic
  • University of Pennsylvania
  • MD Anderson Cancer Center
  • University of Utah- Huntsman Cancer Institute
  • UZ Leuven
  • Zane Cohen Centre For Digestive Diseases
  • University Hospital Bonn
  • Academic Medical Centre
  • Institut de Malalties Digestives
  • Institute of Genetic Medicine
  • Manchester Center for Genomic Medicine

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Active Comparator

Arm Label

Eflornithine plus Sulindac

Eflornithine plus Sulindac Placebo

Sulindac plus Eflornithine Placebo

Arm Description

Eflornithine 750 mg and Sulindac 150 mg

Eflornithine 750 mg and Placebo

Sulindac 150 mg and Placebo

Outcomes

Primary Outcome Measures

Number of Subjects With Any FAP-related Event.
Progression of disease by evaluation of FAP-related events over the course of study treatment

Secondary Outcome Measures

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.
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.

Full Information

First Posted
November 21, 2011
Last Updated
May 12, 2021
Sponsor
Cancer Prevention Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01483144
Brief Title
Trial of Eflornithine Plus Sulindac in Patients With Familial Adenomatous Polyposis (FAP)
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 Type
Interventional

2. Study Status

Record Verification Date
May 2021
Overall Recruitment Status
Completed
Study Start Date
October 2013 (undefined)
Primary Completion Date
November 2018 (Actual)
Study Completion Date
March 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Cancer Prevention Pharmaceuticals, Inc.

4. Oversight

Data Monitoring Committee
Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Familial Adenomatous Polyposis
Keywords
Familial Adenomatous Polyposis, Eflornithine, Sulindac

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
171 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Eflornithine plus Sulindac
Arm Type
Experimental
Arm Description
Eflornithine 750 mg and Sulindac 150 mg
Arm Title
Eflornithine plus Sulindac Placebo
Arm Type
Active Comparator
Arm Description
Eflornithine 750 mg and Placebo
Arm Title
Sulindac plus Eflornithine Placebo
Arm Type
Active Comparator
Arm Description
Sulindac 150 mg and Placebo
Intervention Type
Drug
Intervention Name(s)
Eflornithine
Other Intervention Name(s)
CPP-1X
Intervention Description
Eflornithine [250 mg tablet, three tablets (750 mg) orally once a day]
Intervention Type
Drug
Intervention Name(s)
Eflornithine Placebo
Other Intervention Name(s)
CPP-1X placebo
Intervention Description
Eflornithine placebo [three tablets orally once a day]
Intervention Type
Drug
Intervention Name(s)
Sulindac 150 MG
Other Intervention Name(s)
Clinoril
Intervention Description
Sulindac [one tablet orally once a day]
Intervention Type
Drug
Intervention Name(s)
Sulindac placebo
Intervention Description
Sulindac placebo [one tablet orally once a day]
Primary Outcome Measure Information:
Title
Number of Subjects With Any FAP-related Event.
Description
Progression of disease by evaluation of FAP-related events over the course of study treatment
Time Frame
Up to 48 months from the start of treatment
Secondary Outcome Measure Information:
Title
Improvement in Investigator Upper GI Assessment
Description
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.
Time Frame
through month 12 assessment
Title
Improvement in Investigator Lower GI Assessment
Description
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.
Time Frame
through month 12 assessment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis of phenotypic classical FAP with disease involvement of the duodenum and/or colon/rectum/pouch. Genotype: Adenomatous polyposis coli (APC) mutation (with or without family history) required 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: 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.] 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: Current Spigelman Stage 3 or 4. 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): No significant hematologic abnormalities White blood cell count (WBC) at least 3,000/mm3 Platelet count at least 100,000/mm3 Hemoglobin at least 10.0 g/dL No history of clinical coagulopathy Hepatic Status (within 30 days prior to randomization): Bilirubin no greater than 1.5 times ULN Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) no greater than 1.5 times ULN 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Carol Burke, M.D.
Organizational Affiliation
The Cleveland Clinic
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
James Church, M.D.
Organizational Affiliation
The Cleveland Clinic
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Gabriella Möslein, M.D.
Organizational Affiliation
Helios Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California San Diego
City
La Jolla
State/Province
California
ZIP/Postal Code
92093
Country
United States
Facility Name
Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Dana Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
University of Michigan
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Washington University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Cleveland Clinic
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Utah- Huntsman Cancer Institute
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112
Country
United States
Facility Name
UZ Leuven
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
Zane Cohen Centre For Digestive Diseases
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5T 3L9
Country
Canada
Facility Name
University Hospital Bonn
City
Bonn
ZIP/Postal Code
53105
Country
Germany
Facility Name
Academic Medical Centre
City
Amsterdam
ZIP/Postal Code
1100 DE
Country
Netherlands
Facility Name
Institut de Malalties Digestives
City
Barcelona
State/Province
Catalonia
ZIP/Postal Code
08036
Country
Spain
Facility Name
Institute of Genetic Medicine
City
Newcastle Upon Tyne
State/Province
Tyne And Wear
ZIP/Postal Code
NEI 3BZ
Country
United Kingdom
Facility Name
Manchester Center for Genomic Medicine
City
Manchester
ZIP/Postal Code
M13 NWL
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
27480131
Citation
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.
Results Reference
background
PubMed Identifier
32905675
Citation
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.
Results Reference
result
PubMed Identifier
34261858
Citation
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.
Results Reference
derived
Links:
URL
http://canprevent.com/our-work/fap/fap-clinical-trial-for-new-drug/
Description
Related Info

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

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