Phenethyl Isothiocyanate in Preventing Lung Cancer in Smokers

Phase 2

Completed

Conditions: Lung Cancer
Tobacco Use Disorder

Interventions: Drug: phenethyl isothiocyanate
Other: placebo

Registration Number: NCT00691132

Lead Sponsor: University of Minnesota

Brief 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 107

Inclusion Criteria

Not provided

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

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
PEITC - Placebo (short-term trial)	placebo	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.
Placebo - PEITC (short-term trial)	phenethyl isothiocyanate	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.
Placebo - PEITC (short-term trial)	placebo	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.
PEITC - Placebo (short-term trial)	phenethyl isothiocyanate	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.

Primary Outcome Measures

Name	Time	Method
Urinary Levels of Biomarkers of NNK Metabolism	After 5 days of treatment	The ratio of urinary \[pyridine-D4\]hydroxy acid : total \[pyridine-D4\]NNAL will be measured. This ratio is not expected to be influenced by the number of cigarettes smoked per day, or smoking topography.

Secondary Outcome Measures

Name	Time	Method
Urinary Levels of [Pyridine-D4]Hydroxy Acid:Total [Pyridine-D4]NNAL Ratio by GSTM1 and GSTT1 Genotype.	After 5 days of treatment	% Difference in ratio of urinary \[pyridine-D4\]hydroxy acid : total \[pyridine-D4\]NNAL while on PEITC compared to while on Placebo ((PEITC - Placebo) / PEITC) x 100%
Effects of GSTM1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC	After 5 days of PEITC treatment	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.
Effects of GSTT1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC	After 5 days of treatment	Measured by high-performance liquid chromatography (HPLC). The aim is to determine the possible differential effects of GSTT1 genotype on PEITC excretion, using the method of Chung et al. The method will result in quantitative recovery of the PEITC-NAC.
Combined Effects of GSTM1 and GSTT1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC	After 5 days of treatment