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Phenethylisothiocyanate

phenethyl isothiocyanate

Leonard Liebes, PhD

RATIONALE: Chemoprevention therapy is the use of certain drugs to try to prevent the development or recurrence of cancer. Phenethyl isothiocyanate may be effective in preventing lung cancer in smokers.

PURPOSE: Phase I trial of phenethyl isothiocyanate in preventing lung cancer in people who smoke.

OBJECTIVES: I. Determine the maximum tolerated dose of oral phenethyl isothiocyanate in smokers. II. Measure the steady state pharmacokinetics of phenethyl isothiocyanate required to maintain a steady state of this substance during the hours of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) exposure in these patients. III. Obtain preliminary data on the perturbation of NNK metabolism by phenethyl isothiocyanate in these patients.

OUTLINE: Patients complete a questionnaire containing a smoking and dietary log to assess cigarette and cruciferous vegetable consumption. Patients receive phenethyl isothiocyanate orally 4 times a day for 30 days. Cohorts of 3-6 patients receive escalating doses of phenethyl isothiocyanate until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose limiting toxicities. Patients are followed on days 35, 36, and 43.

PROJECTED ACCRUAL: A total of 15-27 patients will be accrued for this study over 4-6 months.

Phenethyl Isothiocyanate in Preventing Lung Cancer in People Who Smoke

A Phase I - Part B Multiple Dose Trial of Phenethyl Isothiocyanate

National Cancer Institute (NCI)

NYU Langone Health

Substance Related Disorders

Behaviors and Mental Disorders

Tobacco Use Disorder

Substance-Related Disorders

Chemically-Induced Disorders

Mental Disorders

Psychotic Disorders

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.

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

Dorothy K. Hatsukami, PhD

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.

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.

Phenethyl Isothiocyanate in Preventing Lung Cancer in Smokers

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

Urinary levels of Total ITC and PEITC-NAC by treatment sequence groups and treatment period.

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.

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.

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.

% 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%

University of Minnesota

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

Placebo (Short-term Trial)

Washout

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

PEITC (Short-term Trial)

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 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

Placebo - PEITC (Short-term Trial)

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Body Mass Index

High school or lower

College or higher

Level of Education

Current smoking rate

Years of smoking

Age at starting smoking

Age became regular smokers

Cigarette smoking history

Never

Monthly or less

Greater than monthly

Alcohol drinking

Both present

Present/null

Null/present

Both null

GSTM1 & GSTT1 genotypes

Dr. Dorothy Hatsukami

Period 1 - Total ITC

Period 2 - Total ITC

Period 1 - PEITC-NAC

Period 2 - PEITC-NAC

Participants receive oral phenethyl isothiocyanate (PEITC) four times daily for 5 days in Period 1 and oral placebo four times daily for 5 days in Period 2, with washout period in between. 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.

PEITC-Placebo

Participants receive oral placebo four times daily for 5 days in Period 1 and oral phenethyl isothiocyanate (PEITC) four times daily for 5 days in Period 2, with washout period in between. 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.

Placebo - PEITC

Urinary Levels of Biomarkers of NNK Metabolism

% difference between Placebo and PEITC periods in the ratio of \[pyridine-D4\]Hydroxy acid : \[pyridine-D4\] total NNAL

Total [pyridine-D4]NNAL

[pyridine-D4]Hydroxy acid

[pyridine-D4]Hydroxy acid :[pyridine-D4]total NNAL

Participants receive oral placebo four times daily for 5 days in either Period 1 or Period 2.

Placebo

Participants receive oral phenethyl isothiocyanate (PEITC) four times daily for 5 days in either Period 1 or Period 2.

PEITC

PEITC-NAC

Total ITC

GSTM1 Null: gene for glutathione-S-transferase (GST) M1 (GSTM1), the homozygous deletion of the gene (GSTM1 null), leading to a lack of corresponding enzymatic activity.

GSTM1 Null

GSTM1 Present: gene for glutathione-S-transferase (GST) M1 (GSTM1), present in one or both alleles, leading to a enzymatic activity.

GSTM1 Present

Effects of GSTM1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC

GSTT1 Null: gene for glutathione-S-transferase (GST) T1 (GSTT1), the homozygous deletion of the gene (GSTT1 null), leading to a lack of corresponding enzymatic activity.

GSTT1 Null

GSTT1 Present: gene for glutathione-S-transferase (GST) T1 (GSTT1), present in one or both alleles, leading to a enzymatic activity.

GSTT1 Present

Effects of GSTT1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC

GSTM1 \& GSTT1 Null: genes for glutathione-S-transferase (GST) M1 \& T1, the homozygous deletion of both genes (GSTM1 null and GSTT1 null), leading to a lack of corresponding enzymatic activity.

GSTM1 and GSTT1 Both Genes Null

GSTM1 or GSTT1 Present: at least one allele positive for either the gene for glutathione-S-transferase (GST) M1 or T1, but not or both genes, leading to moderate enzymatic activity.

GSTM1 and GSTT1 Only One Gene Present

GSTM1 and GSTT1 Present: at least one allele positive for both glutathione-S-transferase (GST) M1 and T1, leading to higher enzymatic activity.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phenethyl Isothiocyanate in Preventing Lung Cancer in People Who Smoke	NCT00005883	Lung Cancer	phenethyl isoth...	-	NYU Langone Health
Phenethyl Isothiocyanate in Preventing Lung Cancer in People Who Smoke	NCT00005883	Lung Cancer	phenethyl isoth...	-	NYU Langone Health
Phenethyl Isothiocyanate in Preventing Lung Cancer in Smokers	NCT00691132	Lung Cancer Tobacco Use Dis...	phenethyl isoth... placebo	21 Years - 70 Years	University of Minnesota

Spots Global Cancer Trial Database for phenethyl isothiocyanate