Phenethyl Isothiocyanate in Preventing Lung Cancer in Smokers - Full Text View

Purpose

RATIONALE: Chemoprevention is the use of certain drugs to keep cancer from forming. The use of phenethyl isothiocyanate may prevent lung cancer in people who smoke cigarettes.

PURPOSE: This randomized clinical trial is studying phenethyl isothiocyanate to see how well it works in preventing lung cancer in smokers.

Condition	Intervention	Phase
Lung Cancer Tobacco Use Disorder	Drug: phenethyl isothiocyanate Other: placebo	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Prevention
Official Title:	Randomized Trial of PEITC as a Modifier of NNK Metabolism in Smokers

Resource links provided by NLM:

MedlinePlus related topics: Cancer Lung Cancer

U.S. FDA Resources

Further study details as provided by Masonic Cancer Center, University of Minnesota:

Primary Outcome Measures:

Urinary levels of biomarkers of NNK metabolism [ Time Frame: Baseline and Completion of Study Treatment ] [ Designated as safety issue: No ]
Total NNAL, free NNAL, keto acid and hydroxyacids will be measured by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS).

Secondary Outcome Measures:

Effects of GSTM1 genotype on phenethyl isothiocyanate (PEITC)-NNK association and on the metabolism and excretion of PEITC [ Time Frame: Baseline and Completion of Study Treatment ] [ Designated as safety issue: No ]
Measured by high-performance liquid chromatography (HPLC). The aim is to determine the possible differential effects of GSTM1 genotype on PEITC excretion, using the method of Chung et al. The method will result in quantitative recovery of the PEITC-NAC.
Histopathological evaluation of lung lesions [ Time Frame: Baseline and Completion of Study Treatment ] [ Designated as safety issue: No ]
Will use the World Health Organization (WHO) criteria to score all lung biopsies.
Molecular markers of cell proliferation (Ki-67) in bronchial tissue [ Time Frame: Baseline and Completion of Study Treatment ] [ Designated as safety issue: No ]
Ki-67. The proliferation index will be determined by immunohistochemistry (IHC) detection of Ki-67 positive cells.
Molecular markers of apoptosis (caspase-3 and TUNEL) in bronchial tissue [ Time Frame: Baseline and Completion of Study Treatment ] [ Designated as safety issue: No ]
Apoptosis biomarkers: The terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) technique has been extensively used for the detection and quantification of apoptosis in histological tissue sections. We will use the ApopTag in situ hybridization detection kit (Oncor, Gaithersburg, MD) to identify apoptotic cells in tissue sections prepared from study subjects' lung biopsies.
Immunohistochemistry (IHC) Quantitation [ Time Frame: Baseline and Completion of Study Treatment ] [ Designated as safety issue: No ]
Three representative fields per slide will be photographed with a digital camera. The pictures will be analyzed by two trained associates to score IHC slides independently; both scorers will be blinded to the treatment status of the subject. Total number of cells will be determined with ImageProPlus Program for each picture. The percentage of IHC-positive cells over total cells examined will be recorded.

Estimated Enrollment:	120
Study Start Date:	February 2009
Estimated Study Completion Date:	January 2013
Estimated Primary Completion Date:	January 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Arm I (short-term trial) Participants are asked to smoke only deuterated NNK cigarettes (provided by the study) and record the exact number of cigarettes smoked and alcoholic drinks consumed each day for 1 month. Participants receive oral phenethyl isothiocyanate (PEITC) four times daily for 5 days in week 2 and oral placebo four times daily for 5 days in week 4. Participants keep a diary of all food and beverages consumed on the days that PEITC or placebo are taken.	Drug: phenethyl isothiocyanate Given orally Other Name: PEITC Other: placebo Given orally Other Name: Placebo
Experimental: Arm II (short-term trial) Participants receive oral placebo four times daily for 5 days in week 2 and oral PEITC four times daily for 5 days in week 4. Participants are also asked to smoke only deuterated NNK cigarettes, record the number of cigarettes smoked and alcoholic drinks consumed each day, and keep a food and beverage diary as in arm I.	Drug: phenethyl isothiocyanate Given orally Other Name: PEITC Other: placebo Given orally Other Name: Placebo
Experimental: Arm I (long-term trial) Participants receive oral PEITC twice daily for 12 months.	Drug: phenethyl isothiocyanate Given orally Other Name: PEITC
Placebo Comparator: Arm II (long-term trial) Participants receive oral placebo twice daily for 12 months.	Other: placebo Given orally Other Name: Placebo

Detailed Description:

OBJECTIVES:

Primary

To determine whether oral phenethyl isothiocyanate (PEITC) affects urinary levels of biomarkers of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism in current smokers.

Secondary

To determine the effect of GSTM1 genotype on PEITC's impact on urinary biomarkers of NNK metabolism.
To determine the effect of GSTM1 genotype on the metabolism and excretion of PEITC as measured by urinary levels of its major metabolite.
To determine whether oral PEITC affects molecular markers of cell proliferation (Ki-67) and apoptosis (caspase-3 and TUNEL) in bronchial tissue.

OUTLINE: Patients are stratified according to GST genotypes (GSTM1 null-null genotype vs GSTM1-positive genotype). All participants are initially enrolled in the short-term trial. After the completion of the short-term trial, only those participants meeting certain criteria may proceed to the long-term trial.

Short-term trial: Participants are randomized to 1 of 2 treatment arms.
- Arm I: Participants are asked to smoke only deuterated NNK cigarettes (provided by the study) and record the exact number of cigarettes smoked and alcoholic drinks consumed each day for 1 month. Participants receive oral phenethyl isothiocyanate (PEITC) four times daily for 5 days in week 2 and oral placebo four times daily for 5 days in week 4. Participants keep a diary of all food and beverages consumed on the days that PEITC or placebo are taken.
- Arm II: Participants receive oral placebo four times daily for 5 days in week 2 and oral PEITC four times daily for 5 days in week 4. Participants are also asked to smoke only deuterated NNK cigarettes, record the number of cigarettes smoked and alcoholic drinks consumed each day, and keep a food and beverage diary as in arm I.

After completion of the short-term trial, participants undergo a wash-out period for 1 month in which they are asked to resume smoking regular cigarettes. Participants are offered smoking cessation assistance, if desired. Only those participants meeting certain criteria may proceed to the long-term trial after the 1-month wash-out period.

Long-term trial: Participants are randomized to 1 of 2 treatment arms.
- Arm I: Participants receive oral PEITC twice daily for 12 months.
- Arm II: Participants receive oral placebo twice daily for 12 months. Participants in both arms complete a 3-day food diary monthly for 12 months and a food-frequency questionnaire at baseline and at the completion of study treatment.

All participants undergo blood and urine sample collection periodically for laboratory studies. Participants enrolled in the long-term trial also undergo bronchoscopy and tissue biopsy at baseline and at the completion study treatment. Urine samples are examined by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) for various biomarkers. Tissue samples are examined by IHC for Ki-67, TUNEL, and caspase-3 expression.

Eligibility

Ages Eligible for Study:	21 Years to 70 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion criteria:

Initial from phone interview:

Currently smoking 10-45 cigarettes per day for the past year;
Between the ages of 21 and 70 years;
In apparently good physical health with no unstable medical conditions including seizures or cancer;
In stable and good mental health, i.e., currently do not experience unstable or untreated psychiatric diagnosis, including substance abuse, as determined by the DSM-IV criteria, during the past six months;
Not using any other tobacco or nicotine-containing products;
Not on methadone maintenance or stimulants such as ephedra; not a regular user of street drugs and if uses occasionally, willing to abstain during the study; not taking any drugs known to be P4501A6 substrates such as phenobarbital, rifampicin, dexamethasone, ketoconazole, methoxsalen, pilocarpine, or tranylcypromine due to their role in NNK metabolism;
Does not average more than 21 alcoholic drinks per week;
Willing to perform study activities such as having blood sample drawn, urine collection, multiple clinic visits;
For female subjects of child bearing potential, not known to be pregnant or nursing, or planning to become pregnant within next 12 months.

For enrollment in the Short-Term Trial:

Subjects who are generally healthy with liver enzyme and blood count values within the ranges shown below based on blood samples drawn at the second screening visit. Specifically:
- White blood cells ≥ 3,000/mL
- Total bilirubin ≤ 1.5 x upper limits of normal (ULN)
- AST (SGOT)/ALT (SGPT) ≤ 2.5 x ULN
- BUN and serum creatinine ≤ 1.5 x ULN

For enrollment in the Long-Term Trial:

Participated in the short-term trial and invited to participate in the long-term trial;
Possess the GSTM1 null-null genotype;
Smoke 20 or more cigarettes/day with a cumulative smoking history of 20 or more pack-years (one pack-year equals to smoking a pack of cigarettes a day for one year);
Normal liver enzymes based on blood sample drawn during 1 month wash-out;
Determined to be a good candidate for the bronchoscopy procedure by a primary care physician.

Exclusion Criteria:

Subjects with uncontrolled hypertension, uncontrolled diabetes mellitus, unstable coronary artery disease, history of cancer other than non-melanoma skin cancer, and pregnant or lactating women will not be eligible.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00691132

Locations

United States, Minnesota
Masonic Cancer Center, University of Minnesota	Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Lori Strayer 612-626-8885 swan0156@umn.edu
Principal Investigator: Jian-Min Yuan, MD

Sponsors and Collaborators

Masonic Cancer Center, University of Minnesota

National Cancer Institute (NCI)

Investigators

Principal Investigator:

Jian-Min Yuan, PhD

Masonic Cancer Center, University of Minnesota

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:	NCT00691132 History of Changes
Other Study ID Numbers:	2007NT127, R01CA122244, 0712M22651
Study First Received:	June 4, 2008
Last Updated:	August 29, 2012
Health Authority:	United States: Food and Drug Administration

Keywords provided by Masonic Cancer Center, University of Minnesota:

non-small cell lung cancer
small cell lung cancer
tobacco use disorder

Additional relevant MeSH terms:

Tobacco Use Disorder
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Substance-Related Disorders
Mental Disorders

Phenethyl isothiocyanate
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anticarcinogenic Agents
Protective Agents
Physiological Effects of Drugs
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on June 17, 2013