Celecoxib With or Without Eflornithine in Preventing Colorectal Cancer in Patients With Familial Adenomatous Polyposis
Condition: Colorectal Cancer; Familial Adenomatous Polyposis
MeSH terms: Colorectal Neoplasms; Nasopharyngeal Neoplasms; Adenomatous Polyposis Coli
Intervention: Celecoxib; Placebo; eflornithine; Laboratory biomarker analysis; Questionnaire administration
Intervention description: Given 400 mg PO twice a day; Given PO to match DFMO; 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).; Correlative studies; Ancillary studies
Intervention MeSH terms: Eflornithine; Celecoxib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 205.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  REGISTRATION INCLUSION CRITERIA:

          -  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

          -  RANDOMIZATION INCLUSION CRITERIA:

          -  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:

               -  Rectum:

                    -  Five or more polyps >= 2 mm diameter

               -  Colon:

                    -  Five or more polyps >= 2 mm diameter including:

                         -  Three quantifiable polyps > 3 mm diameter, or two quantifiable polyps >
                            5 mm diameter

                         -  In the colon, quantifiable polyps are defined as being within a
                            composite "cloverleaf" photograph that includes a tattoo, the appendix,
                            or the ileocecal valve

        Exclusion Criteria:

          -  REGISTRATION EXCLUSION CRITERIA:

          -  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

          -  RANDOMIZATION EXCLUSION CRITERIA:

          -  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

          -  White blood cell (WBC) with differential < 3,000/ml

          -  Serum glutamate pyruvate transaminase (SGPT) > 1.5 x upper limit of normal, serum
             glutamic oxaloacetic transaminase (SGOT) > 1.5 upper limit of normal

          -  Alkaline phosphatase > 1.5 x upper limit of normal

          -  Bilirubin > 2 x upper limit of normal

          -  Creatinine > 1.5 x upper limit of normal

          -  Has had a positive serum pregnancy test within 14 days prior to baseline randomization

          -  Known or prior coagulopathy

          -  Elevated C-reactive protein (CRP) (> 3.0 mg/L)

          -  History of cardiovascular diseases or risk factors that might include one of the
             following: myocardial infarction, angina, coronary angioplasty, congestive heart
             failure, stroke, or coronary bypass surgery

          -  Uncontrolled hypertension (> 135/> 85 mm Hg on three repeated measurements during the
             6 weeks prior to enrollment on the study); this pertains to subjects with known
             diagnosis of hypertension; such subjects will have been invited to participate in the
             trial following successful treatment of their known hypertension; subjects with
             diagnosis of hypertension established at study entry will be considered cases of
             potential "white coat" hypertension; such subjects will be otherwise evaluated for
             protocol and randomized if they agree to be monitored for blood pressure (BP); if BP
             remains persistently elevated, subjects will be allowed to remain on-study for three
             months while undergoing antihypertensive therapy and monitoring; if, at the end of 3
             months, subjects cannot demonstrate successful BP control as measured and documented
             locally, dosing will be suspended; such subjects will nevertheless be urged to
             complete 6-month off study evaluation, for intention to treat analysis

          -  Family history of premature coronary disease (i.e. onset < 55 years of age)

          -  Uncontrolled diabetes; subjects with preexisting diagnosis of diabetes will be
             eligible to participate in the trial if able to document acceptable management by
             their treating physician; subjects with diagnosis of diabetes established at study
             entry will be considered cases of new onset disease; such subjects will be otherwise
             evaluated for protocol and randomized if they agree to blood sugar monitoring; if
             glucose remains persistently elevated, subjects will be allowed to remain on-study for
             three months while undergoing therapy and monitoring; of, at the end of 3 months,
             subjects cannot demonstrate successful glucose control as measured and documented
             locally, dosing will be suspended; such subjects will nevertheless be urged to
             complete 6-month off study evaluation, for intention to treat analysis

          -  Uncontrolled hypercholesteremia (low-density lipoprotein cholesterol [LDL-C] > 130);
             hypercholesteremia needs to be controlled following the updated National Cholesterol
             Education Program Adult Treatment Panel III Guidelines for at least 3 months prior to
             enrollment on the study; hypercholesteremia treatment should continue during the
             entire period of Celecoxib treatment on the protocol; this pertains to subjects with
             known diagnosis of hypercholesterolemia; such subjects will have been invited to
             participate in the trial following successful treatment of their elevated cholesterol;
             subjects with diagnosis of hypercholesterolemia established at study entry will be
             considered cases of new onset disease; such subjects will be otherwise evaluated for
             protocol and randomized if they agree to cholesterol treatment and monitoring;
             subjects will be allowed to remain on-study for three months while undergoing therapy
             and monitoring; if, at the end of 3 months, subjects cannot demonstrate successful
             cholesterol control as measured and documented locally, dosing will be suspended; such
             subjects will nevertheless be urged to complete 6-month off study evaluation, for
             intention to treat analysis

          -  Metabolic syndrome diagnosis; the diagnosis of metabolic syndrome is made when three
             or more of these risk factors are present:

               -  Waist circumference: Men > 102 cm (> 40 in.); women > 88 cm (> 35 in.)

               -  Triglycerides > 150 mg/dl ( > 1.69 mmol/L)

               -  High-density lipoprotein cholesterol (HDL-C): Men < 40 mg/dl (< 1.03 mmol/L),
                  women < 50 mg/dl (< 1.29 mmol/L)

               -  Blood pressure > 130/85 mm Hg

               -  Fasting glucose > 110 mg/dl (> 6.1 mmol/L)

          -  History of deep venous thrombosis, pulmonary embolism, systemic lupus erythematous,
             family history of protein S or C deficiencies, prior heparin-induced thrombocytopenia,
             Factor V Leiden deficiencies or high homocysteine levels

          -  Any indications for acetylsalicylic acid (ASA)