Zileuton With or Without Celecoxib As Chemopreventive Agents in Smokers

Modulation of Arachidonic Acid Metabolism by Chemopreventive Agents in Smokers

The goal of this clinical research study is to learn how zileuton alone or the combination of zileuton and celecoxib may affect certain chemicals in the body that may be linked with a risk for smoking-related lung disease. These effects will be measured by a urine test

Study Overview

• Status: Completed
• Conditions: Tobacco Use Disorder
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: Zileuton; Drug: Celecoxib

Detailed Description

PRIMARY OBJECTIVES:

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).

SECONDARY OBJECTIVES:

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.

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10021
      • Weill Cornell Medical College in New York City, Cornell University
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center - Consortium Lead Organzation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky 70-100%)
• Total bilirubin less or equal to 2 * upper limit of normal (ULN)
• Direct bilirubin less or equal to 2 * ULN
• aspartate aminotransferase (AST)/(SGOT) less or equal to 2 * ULN
• alanine aminotransferase (ALT)/(SGPT) less or equal to 2 * ULN
• Alkaline phosphatase less or equal to 2 * 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 Hormone replacement therapy (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 pancreatitis
• The participant has an ongoing or active infection, including but not limited to HIV, pneumonia, urinary tract infection
• The participant has a history of nonsteroidal anti-inflammatory drugs (NSAIDs) 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 intrauterine device (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 entry
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I: Zileuton; Zileuton 1200 mg twice orally twice a day on days 1-6.	Other: laboratory biomarker analysis; Correlative studies; Drug: Zileuton; 1200 mg twice daily given orally (PO) for 6 days; Other Names: Zyflo CR
Experimental: Arm II: Zileuton and Celecoxib; Combined Zileuton 1200 mg twice daily plus Celecoxib 200 mg twice daily on days 1-6.	Other: laboratory biomarker analysis; Correlative studies; Drug: Zileuton; 1200 mg twice daily given orally (PO) for 6 days; Other Names: Zyflo CR; Drug: Celecoxib; 200 mg twice daily given orally for 6 days; Other Names: Celebrex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Urinary PGE-M Levels (Pre and Post Treatment)	Pre and Post treatment differences in urinary PGE-M levels measured in each treatment arm. PGE-M levels reported as median with full range (ng/mg creatinine) for Pre treatment versus Post treatment PGE-M levels among study participants compliant to treatment with evaluable urine samples at both time points (baseline and Day 6 +/- 1 day).	Baseline and Day 6
Median Urinary LTE4 Levels (Pre and Post Treatment)	Pre and Post treatment differences in urinary LTE4 levels measured in each treatment arm compared using paired t-test should the data conform to the normality assumption or one-sample Wilcoxon rank-sum test. LTE4 levels reported as median with full range (pg/mg creatinine) for Pre treatment versus Post treatment LTE4 levels among study participants compliant to treatment with evaluable urine samples at both time points (baseline and Day 6 +/- 1 day).	Baseline and day 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Cases With a Post-treatment Increase in Urinary PGE-M Levels	Proportion of cases with a post-treatment increase in urinary PGE-M levels by comparing those treated with Zileuton and Celecoxib combined therapy compared to those treated with Zileuton alone. Pre/postchange in levels (Increase) derived from baseline level to Day 6 +/- 1 day. Differences in baseline levels between 2 treatment arms were examined using the Wilcoxon rank-sum test.	Baseline to Day 6

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Powel Brown, MD, University of Texas (UT) MD Anderson Cancer Center

Publications and helpful links

Helpful Links

• University of Texas (UT) MD Anderson Cancer Center Official Website

Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (Actual): August 1, 2012
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: November 24, 2009
• First Submitted That Met QC Criteria: November 25, 2009
• First Posted (Estimate): November 26, 2009

Study Record Updates

• Last Update Posted (Estimate): April 2, 2015
• Last Update Submitted That Met QC Criteria: April 1, 2015
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Keywords: Celecoxib; Smoking; Prevention; Cancer Prevention; Celebrex; Zileuton; Smoking-related lung disease; Zyflo CR
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Tobacco Use Disorder; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Leukotriene Antagonists; Hormone Antagonists; Cyclooxygenase 2 Inhibitors; Lipoxygenase Inhibitors; Celecoxib; Zileuton
• Other Study ID Numbers: NCI-2013-00730 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); N01CN35159 (U.S. NIH Grant/Contract); 2009-0804 (Other Identifier: DCP)