Clinical trial NCT01483144: 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
Overall status: COMPLETED
Phase: PHASE3
Conditions: Familial Adenomatous Polyposis
Keywords: Familial Adenomatous Polyposis
Eflornithine
Sulindac
Lead sponsor: Cancer Prevention Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2011-12-01
Enrollment: 171
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Number of Subjects With Any FAP-related Event.
timeFrame: Up to 48 months from the start of treatment
Secondary outcomes:
measure: Improvement in Investigator Upper GI Assessment
timeFrame: through month 12 assessment
measure: Improvement in Investigator Lower GI Assessment
timeFrame: through month 12 assessment
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California San Diego
state: California
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah- Huntsman Cancer Institute
state: Utah
city: Leuven
country: Belgium
facility: UZ Leuven
city: Toronto
country: Canada
facility: Zane Cohen Centre For Digestive Diseases
state: Ontario
city: Bonn
country: Germany
facility: University Hospital Bonn
city: Amsterdam
country: Netherlands
facility: Academic Medical Centre
city: Barcelona
country: Spain
facility: Institut de Malalties Digestives
state: Catalonia
city: Newcastle Upon Tyne
country: United Kingdom
facility: Institute of Genetic Medicine
state: Tyne And Wear
city: Manchester
country: United Kingdom
facility: Manchester Center for Genomic Medicine
Study officials:
affiliation: The Cleveland Clinic
name: Carol Burke, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: The Cleveland Clinic
name: James Church, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Helios Hospital
name: Gabriella Möslein, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.