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Respiratory System Agents

Zileuton

Anti-Inflammatory Agents, Non-Steroidal

Analgesics, Non-Narcotic

Enzyme Inhibitors

Leukotriene Antagonists

Hormones

Hormone Antagonists

zileuton

Omer Kucuk, MD

RATIONALE: Chemoprevention therapy is the use of certain drugs to try to prevent the development or recurrence of cancer. The use of zileuton may be an effective way to prevent lung cancer in patients who have bronchial dysplasia.

PURPOSE: Randomized phase II trial to study the effectiveness of zileuton in preventing lung cancer in patients who have bronchial dysplasia.

OBJECTIVES:

* Determine the efficacy of zileuton, in terms of number of sites and grade of dysplastic lesions in the bronchial epithelium, in patients with documented bronchial dysplasia.
* Correlate the regression of bronchial dysplasia (number and grade) and improvement in sputum cytology with the modulation of molecular biomarkers in patients treated with this drug.
* Determine the overall toxicity of this drug in these patients.
* Determine the 6-month natural history of bronchial dysplasia in patients who are randomized to receive treatment with a placebo.

OUTLINE: This is a randomized, double-blind, placebo-controlled study. Patients are stratified according to smoking status (current vs recently quit smoker), and prior cancer (none vs lung or head and neck). Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive oral zileuton 4 times daily for 6 months in the absence of disease progression or unacceptable toxicity.
* Arm II: Patients receive oral placebo 4 times daily for 6 months in the absence of disease progression or unacceptable toxicity.

Patients are followed at 4 weeks.

PROJECTED ACCRUAL: Approximately 134 patients will be accrued for this study.

Zileuton in Preventing Lung Cancer in Patients With Bronchial Dysplasia

Phase II Trial Of Zileuton In Persons With Bronchial Dysplasia

National Cancer Institute (NCI)

Barbara Ann Karmanos Cancer Institute

Substance Related Disorders

Behaviors and Mental Disorders

Tobacco Use Disorder

Substance-Related Disorders

Chemically-Induced Disorders

Mental Disorders

Psychotic Disorders

Other Dietary Supplements

Celecoxib

Cyclooxygenase 2 Inhibitors

Cyclooxygenase Inhibitors

Arachidonic Acid

Zileuton 1200 mg twice orally twice a day on days 1-6.

Combined Zileuton 1200 mg twice daily plus Celecoxib 200 mg twice daily on days 1-6.

1200 mg twice daily given orally (PO) for 6 days

200 mg twice daily given orally for 6 days

laboratory biomarker analysis

Powel Brown, MD

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

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.

Zileuton With or Without Celecoxib As Chemopreventive Agents in Smokers

Modulation of Arachidonic Acid Metabolism by Chemopreventive Agents in Smokers

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).

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).

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.

Common Toxicity reporting for the study began with Common Toxicity Criteria for Adverse Effects (CTCAE) version 3.0 and completed with CTCAE version 4.0. Reporting has been combined in the provided tables.

Arm I: Zileuton

Arm II: Zileuton and Celecoxib

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Number of cigarette packs smoked annually; Measure includes the 70 compliant participants only.

Smoking (Packs per Year)

Prostaglandin E metabolite (PGE-M) levels via creatinine (Cr) in the urine measured by a chemical assay. Baseline measure includes the 70 compliant study participants only.

Baseline PGE-M (ng/mg Cr)

Leukotriene E4 (LTE4) levels via creatinine (Cr) in the urine measured by a chemical assay. Baseline measure includes the 70 compliant study participants only.

Baseline LTE4 (pg/mg CR)

Female

Male

Measure includes the 70 compliant study participants only.

Gender, Male/Female: Compliant Participants

American Indian or Alaska Native

Asian

Native Hawaiian or Other Pacific Islander

Black or African American

White

Unknown or Not Reported

Baseline measure includes the 70 compliant study participants only.

Race, Compliant Participants

Age, Continuous, Compliant Participants

Of the 80 participants treated three (3) were lost to follow up leaving 77 who completed treatment, and of those reflected as a subset are the 70 compliant participants who completed treatment.

Dr. Powel H. Brown, MD Anderson Phase I/II Prevention Consortium

Pre PGE-M Levels

Post PGE-M Levels

Seventy-seven subjects completed the entire study with seven of those excluded from analysis as non-compliant (study medications were undetectable). Urine of two participants contained interfering substances thus were excluded from PGE-M related analysis.

Median Urinary PGE-M Levels (Pre and Post Treatment)

Pre LTE4 levels

Post LTE4 levels

Seventy-seven subjects completed the entire study, three withdrew for personal reasons. Seven of those participants were excluded from analysis as non-compliant (study medications were undetectable).

Median Urinary LTE4 Levels (Pre and Post Treatment)

Analysis includes only number of participants in each treatment arm with post-treatment increase in urinary PGE-M levels as measured from baseline.

Proportion of Cases With a Post-treatment Increase in Urinary PGE-M Levels

Overall Study

Blood and Lymph Conditions

Symptoms and General Pathology

Leukemia

Leukemia, Myeloid

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Myeloproliferative Disorders

Neoplasms by Histologic Type

Hematologic Diseases

Bone Marrow Diseases

Chronic Disease

Disease Attributes

Myeloid Leukemia

Chronic Graft Versus Host Disease

Chronic Myeloid Leukemia

Chronic Myeloproliferative Disorders

Antineoplastic Agents

Imatinib Mesylate

Jan Cerny, MD, PhD

The leukemic stem cells (LSCs) are cells that self- renew and give rise to leukemia. Eradication of LSC is required for cure. In chronic myelogenous leukemia (CML) LSCs are not eradicated by imatinib (Gleevec) alone. Recent discovery by Dr. Shaoguang Li at University of Massachusetts indicates that the LSCs can be targeted by a new drug zileuton (Chen et al. Nature Genetics 2009; 41:783-792). Zileuton (approved for asthma) will be tested in a combination with Gleevec. This combination has not been used previously to treat leukemia.

This is a Phase I study. The goal of this research is to evaluate the safety of the standard anti-cancer drug imatinib and experimental drug zileuton.

More than twenty two thousand people live with chronic myelogenous leukemia in the United States and more than five thousand people are expected to be diagnosed this year. The majority of patients with this disease are diagnosed in what is called the chronic phase. The standard treatment for this phase of the disease is therapy with a medication called imatinib. This treatment can diminish the amount of disease to very low levels that only very sensitive and specialized techniques can measure; it does not, however, provide a cure.

Dr. Shaoguang Li and colleagues at University of Massachusetts have published a unique discovery that the arachidonate 5-lipoxygenase (5-LO) gene (Alox5) is a critical regulator for LSCs in BCR-ABL-induced CML (Chen Y et al. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nature Genetics 41:783-792, 2009). In the absence of Alox5, BCR-ABL failed to induce CML in preclinical studies. While deficiency in Alox5 had no effect on normal hematopoiesis, impairment of the LSCs function through differentiation and cell division of CML LSCs was observed. This defect led to a depletion of LSCs and a failure of CML development. Treatment with a 5-LO inhibitor (zileuton) also impaired the function of LSCs and prolonged survival. These results demonstrate that a specific target gene can be found in cancer stem cells and its inhibition can completely inhibit the function of these stem cells. These findings provide an exciting opportunity to develop the first anti-cancer stem cell therapy for treating CML.

Safety of Zileuton (Zyflo) in Combination With Imatinib Mesylate (Gleevec) in CML.

Phase I Study to Evaluate the Safety of Zileuton (Zyflo) in Combination With Imatinib Mesylate (Gleevec) in Patients With Chronic Myelogenous Leukemia

* Level of 5-lipoxygenase (5-LO) blockade
* The rate of complete hematological response
* The rate of complete cytogenetic response
* The rate of major molecular response

University of Massachusetts, Worcester

Principal Investigator

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Zileuton in Preventing Lung Cancer in Patients With Bronchial Dysplasia	NCT00056004	Head and Neck C... Lung Cancer	zileuton	18 Years -	Barbara Ann Karmanos Cancer Institute
Zileuton With or Without Celecoxib As Chemopreventive Agents in Smokers	NCT01021215	Tobacco Use Dis...	Zileuton Celecoxib laboratory biom...	18 Years -	National Cancer Institute (NCI)
Zileuton With or Without Celecoxib As Chemopreventive Agents in Smokers	NCT01021215	Tobacco Use Dis...	Zileuton Celecoxib laboratory biom...	18 Years -	National Cancer Institute (NCI)
Safety of Zileuton (Zyflo) in Combination With Imatinib Mesylate (Gleevec) in CML.	NCT01130688	Chronic Myeloge...	Zileuton	18 Years -	University of Massachusetts, Worcester

Spots Global Cancer Trial Database for zileuton

Every month we try and update this database with for zileuton cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for zileuton

Every month we try and update this database with for zileuton cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for zileuton cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.