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

Familial Adenomatous Polyposis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01483144
• Other study ID #: CPP-FAP-310
• Status: Completed
• Phase: Phase 3
• Start date: October 2013
• Est. completion date: March 2019

Study information

• Verified date: May 2021
• Source: Cancer Prevention Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 171
• Est. completion date: March 2019
• Est. primary completion date: November 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Adenomatous Polyposis Coli
• Colorectal Neoplasms
• Familial Adenomatous Polyposis
• Nasopharyngeal Neoplasms

Intervention

Drug:
• Eflornithine
Eflornithine [250 mg tablet, three tablets (750 mg) orally once a day]
• Eflornithine Placebo
Eflornithine placebo [three tablets orally once a day]
• Sulindac 150 MG
Sulindac [one tablet orally once a day]
• Sulindac placebo
Sulindac placebo [one tablet orally once a day]

Locations

Country	Name	City	State
Belgium	UZ Leuven	Leuven
Canada	Zane Cohen Centre For Digestive Diseases	Toronto	Ontario
Germany	University Hospital Bonn	Bonn
Netherlands	Academic Medical Centre	Amsterdam
Spain	Institut de Malalties Digestives	Barcelona	Catalonia
United Kingdom	Manchester Center for Genomic Medicine	Manchester
United Kingdom	Institute of Genetic Medicine	Newcastle Upon Tyne	Tyne And Wear
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Cleveland Clinic	Cleveland	Ohio
United States	MD Anderson Cancer Center	Houston	Texas
United States	University of California San Diego	La Jolla	California
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota
United States	Washington University	Saint Louis	Missouri
United States	University of Utah- Huntsman Cancer Institute	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
Cancer Prevention Pharmaceuticals, Inc.

Countries where clinical trial is conducted

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

References & Publications (2)

Burke CA, Dekker E, Lynch P, Samadder NJ, Balaguer F, Hüneburg 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, Willin — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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

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