Celecoxib With or Without Eflornithine in Preventing Colorectal Cancer in Patients With Familial Adenomatous Polyposis

NCT00033371 | Completed Phase 2 Results DMC

• 9 other identifiers: NCI-2013-00844N01-CN95040CDR0000069278NCI-P02-0219ID00-109P30CA016672MDA-ID-00109N01-CN-95040N01CN95040
• Study Type: interventional
• Target: 205
• Locations: 1 country
• Sites: 1

Brief Summary

This randomized phase II trial studies how well giving celecoxib with or without eflornithine works in preventing colorectal cancer in patients with familial adenomatous polyposis. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of celecoxib and eflornithine may keep cancer from forming in patients with familial adenomatous polyposis.

Conditions

Colorectal Cancer; Familial Adenomatous Polyposis

Outcome Measures

Primary Outcomes (2)

• Percent Change in the Number of Polyps Greater Than or Equal to 2mm in Diameter in Focal Area(s) of the Colorectum

  Differences between average treatment effects of two study arms tested using two-sided type I error rate of 5% in two-sample t-test. If model assumptions not met by data or transformations of data, appropriate nonparametric tests (e.g. Wilcoxon rank sums test) were used to compare treatment arms - Percent change of polyp counts from baseline to 6 months, ie \[(6 months - baseline) x 100\]/baseline (%). For each participant, first were matched polyps between baseline \& 6 months by region and landmark and summed over all matched regions on number of polyps \>2 mm to calculate total number of polyps \>2 mm at baseline \& 6 months, respectively. For participants refusing exit colonoscopy, 0% change entered as primary endpoint. Defined ITT All: All patients; if 6-month polyp counts missing = 0% change; ITT Measurable: All participants with baseline \& 6 month polyp counts; ITT Evaluable: ITT Measurable participants who also took 80% of treatment, both overall as well as during final 60 days.

  Baseline up to 6 months

• Number of Participants With Adverse Events Occurring at a Frequency of 5% or Grade 3 and Higher

  To determine the relative tolerability and safety of celecoxib + DFMO in FAP study participants. Includes only adverse events that occurred in at least 5% of the patients or a patient exhibited at least 1 grade 3 toxicity.

  6 months

Secondary Outcomes (2)

• Percentage Change in Global Colorectal Polyps Burden

  6 months

• Percent Change in the Area of Plaque-like Duodenal Polyps

  6 months

Other Outcomes (2)

• Global Duodenal Polyp Burden

  6 months

• Percent Change in Polyp Size in Focal Area(s) of the Colorectum

  Baseline up to 2 months after completion of study treatment

Study Arms (2)

Arm I: Celecoxib and Placebo

ACTIVE COMPARATOR

Celecoxib 400 mg orally twice daily (PO BID) and Placebo once a day. Treatment continues for 6 months in the absence of disease progression or unacceptable toxicity.

Drug: Celecoxib; Other: Placebo; Other: Laboratory biomarker analysis; Other: Questionnaire administration

Arm II: Celecoxib and Eflornithine

EXPERIMENTAL

Celecoxib 400 mg PO BID and Eflornithine PO daily 0.5 g/m\^2/day rounded down to the nearest 250 mg dose. Treatment continues for 6 months in the absence of disease progression or unacceptable toxicity.

Drug: Celecoxib; Drug: eflornithine; Other: Laboratory biomarker analysis; Other: Questionnaire administration

Interventions

Celecoxib DRUG

Given 400 mg PO twice a day

Also known as: Celebrex, SC-58635

Arm I: Celecoxib and Placebo; Arm II: Celecoxib and Eflornithine

Placebo OTHER

Given PO to match DFMO

Also known as: PLCB

Arm I: Celecoxib and Placebo

eflornithine DRUG

Given PO at 0.5 gm/m\^2/day rounded down to the nearest 250 mg dose (BSA of \< 1.4 = 500 mg/day; BSA of 1.5 - 2.0 = 750 mg/day; BSA of 2.1 - 2.5 = 1000 mg/day; BSA of \> 2.6 = 1,250 mg/day).

Also known as: 2-difluoromethylornithine, DFMO, difluromethylornithine

Arm II: Celecoxib and Eflornithine

Laboratory biomarker analysis OTHER

Correlative studies

Arm I: Celecoxib and Placebo; Arm II: Celecoxib and Eflornithine

Questionnaire administration OTHER

Ancillary studies

Also known as: Survey

Arm I: Celecoxib and Placebo; Arm II: Celecoxib and Eflornithine

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of FAP based on any of the following will be acceptable:
• \> 100 polyps or
• \> 10 polyps and age \< 40 years, or \> 25 polyps and age \> 40 years and characteristic family history (autosomal dominant pattern) including:
• \> 100 polyps in a first degree family member or
• \> 25 polyps in two relatives in two generations, including a first degree family member or
• Genetic diagnosis in a relative or
• Genetic diagnosis by in vitro synthesized protein (IVSP) or similar assay
• Willingness to abstain from use of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, for the duration of the study; a cardio-protective dose of aspirin (\>= 80 mg) may be permitted but must be reviewed/approved by principal investigator (PI)
• If participant is female and of child bearing potential, she agrees to participate in this study by providing written informed consent, has been using adequate contraception (e.g. abstinence, condom, intrauterine device \[IUD\], birth control pill, diaphragm and spermicide gel combination) since her last menses and will use adequate contraception during the study, is not lactating, and agrees to undergo a serum pregnancy test at baseline, month 3 and month 6; sexually active males must agree to use an accepted and effective method of contraception
• Colon polyp status: the participant has an endoscopically assessable colonic and/or rectal segment
• Participant has no clinically significant hearing loss that is defined by the patient reporting that their hearing loss affects their everyday life and/or wears a hearing aide
• Participants whose air conduction pure tone audiogram reveals a deficit that differs from the age specific norm by less than 30 dB when averaged across two contiguous test frequencies in either ear are eligible, as long as no self-reported hearing deficit or tinnitus is present
• Willingness and ability to sign informed consent
• The individual has assessable colonic polyps remaining in the colon or rectum post baseline colonoscopy or flexible sigmoidoscopy
• Potential participants must have the following colonic or rectal polyp burden at the conclusion of the baseline endoscopy:

You may not qualify if:

• Anticipated colectomy within eight months of randomization
• History of hypersensitivity to COX-2 inhibitors, sulfonamides, NSAIDs or salicylates
• Chronic use of NSAIDs, including aspirin or Celebrex, at any dose during the six months prior to study entry will require a three-month washout period prior to eligibility beginning with the time of the patient's last dose; participants must voluntarily agree to be off all NSAIDs for three months prior to study enrollment; a cardio-protective dose of aspirin (\>= 80 mg) may be permitted but must be reviewed/approved by PI
• The use of fluconazole, lithium or chronic use of adrenocorticosteroids
• History in the past year of discrete gastric or duodenal ulcer of size \> 5 mm, except that those with a history of Helicobacter pylori related peptic ulcer disease will become eligible for study upon successfully completing antibiotic treatment of Helicobacter pylori
• History of invasive carcinoma in the past five years other than resected Duke's A/B1 colon cancer or resected non-melanomatous skin cancer
• Partial or complete colectomy within 12 months prior to enrollment
• Inability to return for follow-up tests
• Significant medical or psychiatric problems, (including significant renal, hepatic or hematologic dysfunction) which would make the individual a poor protocol candidate
• Use of any investigational agent within the last 3 months, or at the discretion of the medical monitor
• History of pelvic radiation
• Anticipated colectomy within eight months of randomization; the results of the initial endoscopies, including pathology reports and blood tests will be reviewed by the study endoscopist and surgeon prior to initiation of drug treatment to determine if the patient can remain on study
• Discrete gastric or duodenal ulcer of size \> 5 mm; patients with Helicobacter pylori related peptic ulcers of \> 5 mm at the time of the baseline endoscopy will become eligible upon endoscopically documented successful treatment of Helicobacter pylori and of the ulcer(s).
• Hemoglobin (Hgb) \< 10.0 gm/dl
• Platelet count \< 100,000/ml

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Lynch PM, Burke CA, Phillips R, Morris JS, Slack R, Wang X, Liu J, Patterson S, Sinicrope FA, Rodriguez-Bigas MA, Half E, Bulow S, Latchford A, Clark S, Ross WA, Malone B, Hasson H, Richmond E, Hawk E. An international randomised trial of celecoxib versus celecoxib plus difluoromethylornithine in patients with familial adenomatous polyposis. Gut. 2016 Feb;65(2):286-95. doi: 10.1136/gutjnl-2014-307235. Epub 2015 Mar 19.

  PMID: 25792707 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms; Adenomatous Polyposis Coli

Interventions

Celecoxib; Eflornithine; Surveys and Questionnaires

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Adenomatous Polyps; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplastic Syndromes, Hereditary; Intestinal Polyposis; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Ornithine; Amino Acids, Basic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Diamino; Data Collection; Epidemiologic Methods; Investigative Techniques; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health

Limitations and Caveats

Following reports of COX-2 inhibitor-associated cardiovascular toxicities, trial suspended from December 17, 2004 to March 18, 2005 pending reevaluation of cardiovascular risks, only two sites resumed the trial.

Results Point of Contact

• Title: Patrick Lynch, MD/Professor, Gastroenterology/Hepatology
• Organization: University of Texas (UT) MD Anderson Cancer Center

plynch@mdanderson.org

713-794-5073

Study Officials

• Patrick Lynch

  MD Anderson Cancer Network

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 9, 2002
• First Posted: January 27, 2003
• Study Start: December 13, 2001
• Primary Completion: February 24, 2009
• Study Completion: March 24, 2009
• Last Updated: September 29, 2020
• Results First Posted: February 4, 2015

Record last verified: 2020-09

Locations

US (1)