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Modulation of Arachidonic Acid Metabolism by Chemopreventive Agents in Smokers

Phase 1/Phase 2
18 Years
Not Enrolling
Tobacco Use Disorder

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Trial Information

Modulation of Arachidonic Acid Metabolism by Chemopreventive Agents in Smokers


I. To determine whether short-term administration of zileuton, a 5-lipoxygenase (5-LO)
inhibitor, in current smokers will suppress the formation of urinary leukotriene E4 (LTE4)
and shunt arachidonic acid into the cyclooxygenase (COX) pathway, resulting in elevated
urinary prostaglandin E-metabolite (PGE-M).


I. To determine whether short-term co-administration of celecoxib, a selective COX-2
inhibitor, and zileuton suppresses levels of both urinary LTE4 and PGE-M in current smokers.

II. To evaluate the association between baseline levels of urinary LTE4 and magnitude of the
arachidonic acid shunt induced by zileuton.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive zileuton orally (PO) twice daily (BID) on days 1-6.

ARM II: Patients receive zileuton as in Arm I and celecoxib PO BID on days 1-6.

Inclusion Criteria:

- Male or female current tobacco smokers with more or equal to 10 pack years of
self-reported smoking exposure and an average of more or equal to 10 cigarettes/day

- ECOG performance status 0 or 1 (Karnofsky 70-100%)

- Total bilirubin less or equal to 2 X ULN

- Direct bilirubin less or equal to 2 X ULN

- AST (SGOT) less or equal to 2 X ULN

- ALT (SGPT) less or equal to 2 X ULN

- Alkaline phosphatase less or equal to 2 X ULN

- If the participant is female, of childbearing potential and not lactating, she has a
documented negative serum pregnancy test within 14 days prior to randomization

Exclusion Criteria:

- The participant has active cancer (excluding non-melanoma skin cancer)

- The participant has a history of curatively treated cancer with surgical therapy
finished within 6 months prior to the Screening visit; or has had chemotherapy,
cancer-related immunotherapy, hormonal therapy (other than HRT for menopause), or
radiation therapy within 12 months of the screening visit

- The participant has a chronic inflammatory condition, including but not limited to,
ulcerative colitis, Crohn's disease, rheumatoid arthritis, psoriasis, gout and

- The participant has an ongoing or active infection, including but not limited to HIV,
pneumonia, urinary tract infection

- The participant has a history of NSAID use, including aspirin (low-dose aspirin also
prohibited) and selective COX-2 inhibitors within the previous 4 weeks

- The participant has used zileuton or a leukotriene receptor antagonist within the
previous 4 weeks

- The participant has a history of corticosteroid use (excluding topical nasal sprays
and dermal application) within the last 6 weeks

- The participant has an acute or chronic kidney disorder

- The participant exhibits clinical evidence of active liver disease or history of
chronic liver disease

- The participant has active cardiac disease, or a history of myocardial infarction,
angina or coronary artery disease within the past 6 months

- The participant has a history of a cerebrovascular accident (CVA) or transient
ischemic attack (TIA)

- The participant has a bleeding history

- The participant is taking drugs known to interact with zileuton or celecoxib,
including theophylline, warfarin, propranolol, fluconazole or lithium

- The participant has received any investigational medication within 30 days of the
screening visit or is scheduled to receive an investigational agent during the study

- The participant is pregnant or nursing; women must not be pregnant or lactating

- The participant is a female of child-bearing potential (women are considered not of
childbearing potential if they are at least two years postmenopausal and/or
surgically sterile) who has not used adequate contraception (abstinence; barrier
methods such as IUD, diaphragm with spermicidal gel, condom, or others; and hormonal
methods such as birth control pills or others) since her last menses prior to study

- The participant is a female of child-bearing potential or male who does not agree to
use adequate contraception for the duration of study participation; should a woman
become pregnant or suspect she is pregnant while participating in this study, she
should inform her study physician immediately

- The participant has participated in the study previously and was withdrawn

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant or nursing participants or those who are HIV-positive will be excluded from
the study

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Outcome Measure:

Change in urinary LTE4 and PGE-M levels

Outcome Description:

Pre- and post- treatment differences in biomarker values measured in each treatment arm will be compared using the paired t-test should the data conform to the normality assumption or one-sample Wilcoxon rank-sum test.

Outcome Time Frame:

Baseline and day 6

Safety Issue:


Principal Investigator

Powel Brown

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

May 2010

Completion Date:

Related Keywords:

  • Tobacco Use Disorder
  • Tobacco Use Disorder



M D Anderson Cancer Center Houston, Texas  77030