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A Two Arm Phase II Chemoprevention Trial In Adenomatous Polyposis Coli Patients


Phase 2
18 Years
65 Years
Open (Enrolling)
Both
Colorectal Cancer, Precancerous Condition

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Trial Information

A Two Arm Phase II Chemoprevention Trial In Adenomatous Polyposis Coli Patients


OBJECTIVES:

- Compare the relative efficacy of celecoxib with or without eflornithine, as evidenced
by the percentage change from baseline in the number of polyps in focal area(s) of the
colorectum, in participants with familial adenomatous polyposis of the colorectum.

- Compare the tolerability and safety of these preventive regimens in these participants.

- Compare the percentage change in polyp size in a focal area of the colorectum in
participants after receiving these regimens.

- Compare the change in global colorectal polyp burden in participants after receiving
these regimens.

- Compare the percentage change in the area of plaque-like duodenal polyps in
participants with duodenal disease at baseline.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients
are randomized to 1 of 2 arms.

- Arm I: Patients receive oral celecoxib twice daily and oral placebo once daily.

- Arm II: Patients receive celecoxib as in arm I and oral eflornithine once daily.

Treatment in both arms continues for 6 months in the absence of disease progression or
unacceptable toxicity.

Patients are followed at 1-2 months after end of study therapy.

PROJECTED ACCRUAL: A total of 120 patients (60 per arm) will be accrued for this study
within 13 months.


Inclusion Criteria:



1. Registration Inclusion Criteria - Diagnosis of FAP based on any of the following will
be acceptable: a. >100 polyps or b. >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 c. Genetic diagnosis by in vitro synthesized protein (IVSP) or similar
assay.

2. Registration Inclusion Criteria - Age 18-65 years.

3. Registration Inclusion Criteria - Willingness to abstain from use of 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 PI.

4. Registration Inclusion Criteria - 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, 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.

5. Registration Inclusion Criteria - Colon polyp status: The participant has an
endoscopically assessable colonic and/or rectal segment.

6. Registration Inclusion Criteria - 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.

7. Registration Inclusion Criteria - Willingness and ability to sign informed consent.

8. 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. (Cont. criteria #9)

9. Baseline Randomization Inclusion Criteria (continuation Criteria #8) - In the colon,
quantifiable polyps are defined as being within a composite "cloverleaf" photograph
that includes a tattoo, the appendix, or the ileocecal valve.

10. Registration - Inclusion Criteria - 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.

Exclusion Criteria:

1. Registration Exclusion Criteria - Anticipated colectomy within eight months of
randomization.

2. Registration Exclusion Criteria - History of hypersensitivity to COX-2 inhibitors,
sulfonamides, NSAIDs or salicylates.

3. Registration Exclusion Criteria - 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.

4. Registration Exclusion Criteria - The use of fluconazole, lithium or chronic use of
adrenocorticosteroids.

5. Registration Exclusion Criteria - 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.

6. Registration Exclusion Criteria - History of invasive carcinoma in the past five
years other than resected Duke's A/B1 colon cancer or resected non-melanomatous skin
cancer.

7. Registration Exclusion Criteria - Partial or complete colectomy within 12 months
prior to enrollment.

8. Registration Exclusion Criteria - Inability to return for follow-up tests.

9. Registration Exclusion Criteria - Significant medical or psychiatric problems,
(including significant renal, hepatic or hematologic dysfunction) which would make
the individual a poor protocol candidate.

10. Registration Exclusion Criteria - Use of any investigational agent within the last 3
months, or at the discretion of the medical monitor.

11. Registration Exclusion Criteria - History of pelvic radiation

12. Baseline 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.

13. Baseline Randomization Exclusion Criteria - 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).

14. Baseline Randomization Exclusion Criteria - On baseline evaluation: Hgb <10.0 gm/dl,
platelet count <100,000/ml; WBC with differential <3,000/ml; SGPT >1.5 x upper limit
of normal, 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.

15. Baseline Randomization Exclusion Criteria - Has had a positive serum pregnancy test
within 14 days prior to baseline randomization.

16. Baseline Randomization Exclusion Criteria - 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.

17. Baseline Randomization Exclusion Criteria - 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. (cont criteria
19)

18. Baseline Randomization Exclusion Criteria - (cont criteria #18) - Such subjects will
be otherwise evaluated for protocol and randomized if they agree to be monitored for
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 offstudy evaluation, for intention to treat analysis.

19. Baseline Randomization Exclusion Criteria - Family history of premature coronary
disease (i.e. onset <55 years of age)

20. Baseline Randomization Exclusion Criteria - 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.(cont criteria #22)

21. Baseline Randomization Exclusion Criteria - (cont criteria #21) - 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. If, 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 offstudy evaluation, for intention to treat analysis.

22. Baseline Randomization Exclusion Criteria - 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. (cont criteria # 24)

23. Baseline Randomization Exclusion Criteria - (cont criteria # 23) - 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. (Cont criteria # 25)

24. Baseline Randomization Exclusion Criteria - (cont Criteria # 24) - 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 offstudy evaluation, for intention to
treat analysis.

25. Baseline Randomization Exclusion Criteria - Metabolic syndrome diagnosis. The
diagnosis of metabolic syndrome is made when three or more of these risk factors are
present: a.Waist circumference : Men > 102 cm (> 40 in.); Women > 88 cm (> 35 in.),
b.Triglycerides > 150 mg/dl ( >1.69 mmol/L), c.High-density lipoprotein cholesterol
(HDL-C): [Men < 40 mg/dl (<1.03 mmol/L), Women < 50 mg/dl (<1.29 mmol/L)], d. Blood
pressure > 130/85 mm Hg, e. Fasting glucose > 110 mg/dl (>6.1 mmol/L)

26. Baseline Randomization Exclusion Criteria - 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

27. Baseline Randomization Exclusion Criteria - Any indications for ASA

28. Baseline Randomization Exclusion Criteria - Known or prior coagulopathy

29. Baseline Randomization Exclusion Criteria - Elevated CRP (>3.0 mg/dL)

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Prevention

Outcome Measure:

Efficacy of Celecoxib with or without Eflornithine

Outcome Description:

Efficacy of celecoxib with or without eflornithine as measured by the percent change of polyps in a focal area of the colorectum measured at baseline and 6 months after completion of study treatment

Outcome Time Frame:

6 months after completion of study treatment

Safety Issue:

No

Principal Investigator

Patrick M. Lynch, MD, JD

Investigator Role:

Study Chair

Investigator Affiliation:

M.D. Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

ID00-109

NCT ID:

NCT00033371

Start Date:

December 2001

Completion Date:

Related Keywords:

  • Colorectal Cancer
  • Precancerous Condition
  • colon cancer
  • rectal cancer
  • familial adenomatous polyposis
  • FAM
  • precancerous condition
  • Colorectal Neoplasms
  • Adenomatous Polyposis Coli
  • Precancerous Conditions

Name

Location

Cleveland Clinic Taussig Cancer CenterCleveland, Ohio  44195
M. D. Anderson Cancer Center at University of TexasHouston, Texas  77030-4009