Lung Cancer, Tobacco Use Disorder
Conditions
Keywords
non-small cell lung cancer, small cell lung cancer, tobacco use disorder
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.
Interventions
Given orally
OTHERplacebo
Given orally
Sponsors
National Cancer Institute (NCI)
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Urinary Levels of Biomarkers of NNK Metabolism | 2 periods, 5 days each on PEITC or Placebo, with washout week between | Urinary levels of Total ITC and PEITC-NAC by treatment sequence groups and treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| 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% |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PEITC - Placebo (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.
phenethyl isothiocyanate: Given orally
placebo: Given orally | 41 |
| Placebo - PEITC (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 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.
phenethyl isothiocyanate: Given orally
placebo: Given orally | 41 |
| Total | 82 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 |
| Overall Study | Withdrawal by Subject | 10 | 10 |
Baseline characteristics
| Characteristic | Placebo - PEITC (Short-term Trial) | PEITC - Placebo (Short-term Trial) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 41 Participants | 41 Participants | 82 Participants |
| Age, Continuous | 41.1 years STANDARD_DEVIATION 9.6 | 40.9 years STANDARD_DEVIATION 10.6 | 41.0 years STANDARD_DEVIATION 10.1 |
| Alcohol drinking Greater than monthly | 11 participants | 12 participants | 23 participants |
| Alcohol drinking Monthly or less | 12 participants | 14 participants | 26 participants |
| Alcohol drinking Never | 17 participants | 14 participants | 31 participants |
| Body Mass Index | 28.0 kg/m^2 STANDARD_DEVIATION 6.3 | 28.0 kg/m^2 STANDARD_DEVIATION 4.8 | 28.0 kg/m^2 STANDARD_DEVIATION 5.6 |
| Cigarette smoking history Age at starting smoking | 15.1 years STANDARD_DEVIATION 4.6 | 15.2 years STANDARD_DEVIATION 4.9 | 15.1 years STANDARD_DEVIATION 4.7 |
| Cigarette smoking history Age became regular smokers | 17.7 years STANDARD_DEVIATION 5.2 | 18.6 years STANDARD_DEVIATION 7.1 | 18.1 years STANDARD_DEVIATION 6.2 |
| Cigarette smoking history Years of smoking | 17.9 years STANDARD_DEVIATION 9.4 | 14.7 years STANDARD_DEVIATION 10.3 | 16.3 years STANDARD_DEVIATION 9.8 |
| Current smoking rate | 19.0 cigarettes/day STANDARD_DEVIATION 6.7 | 19.3 cigarettes/day STANDARD_DEVIATION 6.6 | 19.1 cigarettes/day STANDARD_DEVIATION 6.6 |
| GSTM1 & GSTT1 genotypes Both null | 8 participants | 4 participants | 12 participants |
| GSTM1 & GSTT1 genotypes Both present | 18 participants | 20 participants | 38 participants |
| GSTM1 & GSTT1 genotypes Null/present | 11 participants | 14 participants | 25 participants |
| GSTM1 & GSTT1 genotypes Present/null | 4 participants | 3 participants | 7 participants |
| Level of Education College or higher | 21 participants | 27 participants | 48 participants |
| Level of Education High school or lower | 20 participants | 14 participants | 34 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 8 Participants | 18 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 5 Participants | 9 Participants |
| Race (NIH/OMB) White | 27 Participants | 28 Participants | 55 Participants |
| Region of Enrollment United States | 41 participants | 41 participants | 82 participants |
| Sex: Female, Male Female | 21 Participants | 17 Participants | 38 Participants |
| Sex: Female, Male Male | 20 Participants | 24 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 66 / 107 | 35 / 107 | 107 / 107 |
| serious Total, serious adverse events | 0 / 107 | 0 / 107 | 0 / 107 |
Outcome results
Primary
Urinary Levels of Biomarkers of NNK Metabolism
Urinary levels of Total ITC and PEITC-NAC by treatment sequence groups and treatment period.
Time frame: 2 periods, 5 days each on PEITC or Placebo, with washout week between
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| PEITC-Placebo | Urinary Levels of Biomarkers of NNK Metabolism | Period 1 - Total ITC | 42.8 pmol/mg creatinine |
| PEITC-Placebo | Urinary Levels of Biomarkers of NNK Metabolism | Period 1 - PEITC-NAC | 56.7 pmol/mg creatinine |
| PEITC-Placebo | Urinary Levels of Biomarkers of NNK Metabolism | Period 2 - Total ITC | 0.28 pmol/mg creatinine |
| PEITC-Placebo | Urinary Levels of Biomarkers of NNK Metabolism | Period 2 - PEITC-NAC | 0.36 pmol/mg creatinine |
| Placebo - PEITC | Urinary Levels of Biomarkers of NNK Metabolism | Period 2 - Total ITC | 49.7 pmol/mg creatinine |
| Placebo - PEITC | Urinary Levels of Biomarkers of NNK Metabolism | Period 1 - Total ITC | 0.36 pmol/mg creatinine |
| Placebo - PEITC | Urinary Levels of Biomarkers of NNK Metabolism | Period 2 - PEITC-NAC | 68.1 pmol/mg creatinine |
| Placebo - PEITC | Urinary Levels of Biomarkers of NNK Metabolism | Period 1 - PEITC-NAC | 0.27 pmol/mg creatinine |
Primary
Urinary Levels of Biomarkers of NNK Metabolism
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.
Time frame: After 5 days of treatment
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| PEITC-Placebo | Urinary Levels of Biomarkers of NNK Metabolism | Total [pyridine-D4]NNAL | 0.366 pmol/mg creatinine |
| PEITC-Placebo | Urinary Levels of Biomarkers of NNK Metabolism | [pyridine-D4]Hydroxy acid | 0.150 pmol/mg creatinine |
| PEITC-Placebo | Urinary Levels of Biomarkers of NNK Metabolism | [pyridine-D4]Hydroxy acid :[pyridine-D4]total NNAL | 0.455 pmol/mg creatinine |
| Placebo - PEITC | Urinary Levels of Biomarkers of NNK Metabolism | Total [pyridine-D4]NNAL | 0.366 pmol/mg creatinine |
| Placebo - PEITC | Urinary Levels of Biomarkers of NNK Metabolism | [pyridine-D4]Hydroxy acid | 0.140 pmol/mg creatinine |
| Placebo - PEITC | Urinary Levels of Biomarkers of NNK Metabolism | [pyridine-D4]Hydroxy acid :[pyridine-D4]total NNAL | 0.420 pmol/mg creatinine |
Comparison: % difference between Placebo and PEITC periods in the ratio of \[pyridine-D4\]Hydroxy acid : \[pyridine-D4\] total NNALp-value: 0.02395% CI: [-13.8, -1.2]Mixed Models Analysis
Secondary
Combined Effects of GSTM1 and GSTT1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC
Time frame: After 5 days of treatment
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| PEITC-Placebo | Combined Effects of GSTM1 and GSTT1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC | PEITC-NAC | 85.4 nmol/mg creatinine |
| PEITC-Placebo | Combined Effects of GSTM1 and GSTT1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC | Total ITC | 59.6 nmol/mg creatinine |
| Placebo - PEITC | Combined Effects of GSTM1 and GSTT1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC | PEITC-NAC | 60.5 nmol/mg creatinine |
| Placebo - PEITC | Combined Effects of GSTM1 and GSTT1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC | Total ITC | 47.1 nmol/mg creatinine |
| GSTM1 and GSTT1 Both Genes Present | Combined Effects of GSTM1 and GSTT1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC | PEITC-NAC | 56.9 nmol/mg creatinine |
| GSTM1 and GSTT1 Both Genes Present | Combined Effects of GSTM1 and GSTT1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC | Total ITC | 41.5 nmol/mg creatinine |
Comparison: Total ITCp-value: 0.017ANOVA
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.
Time frame: After 5 days of PEITC treatment
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| PEITC-Placebo | Effects of GSTM1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC | PEITC-NAC | 71.7 nmol/mg creatinine |
| PEITC-Placebo | Effects of GSTM1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC | Total ITC | 53.7 nmol/mg creatinine |
| Placebo - PEITC | Effects of GSTM1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC | PEITC-NAC | 54.8 nmol/mg creatinine |
| Placebo - PEITC | Effects of GSTM1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC | Total ITC | 40.5 nmol/mg creatinine |
Comparison: Total ITCp-value: 0.005ANOVA
Secondary
Effects of GSTT1 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 GSTT1 genotype on PEITC excretion, using the method of Chung et al. The method will result in quantitative recovery of the PEITC-NAC.
Time frame: After 5 days of treatment
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| PEITC-Placebo | Effects of GSTT1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC | PEITC-NAC | 67.1 nmol/mg creatinine |
| PEITC-Placebo | Effects of GSTT1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC | Total ITC | 49.2 nmol/mg creatinine |
| Placebo - PEITC | Effects of GSTT1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC | Total ITC | 45.1 nmol/mg creatinine |
| Placebo - PEITC | Effects of GSTT1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC | PEITC-NAC | 60.4 nmol/mg creatinine |
Secondary
Urinary Levels of [Pyridine-D4]Hydroxy Acid:Total [Pyridine-D4]NNAL Ratio by GSTM1 and GSTT1 Genotype.
% 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%
Time frame: After 5 days of treatment
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| PEITC-Placebo | Urinary Levels of [Pyridine-D4]Hydroxy Acid:Total [Pyridine-D4]NNAL Ratio by GSTM1 and GSTT1 Genotype. | -15.6 percentage of change in ratio |
| Placebo - PEITC | Urinary Levels of [Pyridine-D4]Hydroxy Acid:Total [Pyridine-D4]NNAL Ratio by GSTM1 and GSTT1 Genotype. | -3.1 percentage of change in ratio |
| GSTM1 and GSTT1 Both Genes Present | Urinary Levels of [Pyridine-D4]Hydroxy Acid:Total [Pyridine-D4]NNAL Ratio by GSTM1 and GSTT1 Genotype. | -9.4 percentage of change in ratio |
p-value: 0.039Mixed Models Analysis
p-value: 0.623Mixed Models Analysis
p-value: 0.045Mixed Models Analysis