Phenethyl Isothiocyanate in Preventing Lung Cancer in Smokers

Lung Cancer Clinical Trial

Official title:

Randomized Trial of PEITC as a Modifier of NNK Metabolism in Smokers

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00691132
• Other study ID #: 2007NT127
• Secondary ID: R01CA1222440712M
• Status: Recruiting
• Phase: Phase 2
• First received: June 4, 2008
• Last updated: August 29, 2012
• Start date: February 2009
• Est. completion date: January 2013

Study information

• Verified date: August 2012
• Source: Masonic Cancer Center, University of Minnesota
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: January 2013
• Est. primary completion date: January 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 21 Years to 70 Years

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• Lung Cancer
• Lung Neoplasms
• Tobacco Use Disorder

Intervention

Drug:
• phenethyl isothiocyanate
Given orally

Other:
• placebo
Given orally

Locations

Country	Name	City	State
United States	Masonic Cancer Center, University of Minnesota	Minneapolis	Minnesota

Sponsors (2)

Lead Sponsor	Collaborator
Masonic Cancer Center, University of Minnesota	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Urinary levels of biomarkers of NNK metabolism	Total NNAL, free NNAL, keto acid and hydroxyacids will be measured by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS).	Baseline and Completion of Study Treatment	No
Secondary	Effects of GSTM1 genotype on phenethyl isothiocyanate (PEITC)-NNK association and on the metabolism and excretion of PEITC	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.	Baseline and Completion of Study Treatment	No
Secondary	Histopathological evaluation of lung lesions	Will use the World Health Organization (WHO) criteria to score all lung biopsies.	Baseline and Completion of Study Treatment	No
Secondary	Molecular markers of cell proliferation (Ki-67) in bronchial tissue	Ki-67. The proliferation index will be determined by immunohistochemistry (IHC) detection of Ki-67 positive cells.	Baseline and Completion of Study Treatment	No
Secondary	Molecular markers of apoptosis (caspase-3 and TUNEL) in bronchial tissue	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.	Baseline and Completion of Study Treatment	No
Secondary	Immunohistochemistry (IHC) Quantitation	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.	Baseline and Completion of Study Treatment	No