Clinical trial NCT00691132: Phenethyl Isothiocyanate in Preventing Lung Cancer in Smokers
Official title: Randomized Trial of PEITC as a Modifier of NNK Metabolism in Smokers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Lung Cancer
Tobacco Use Disorder
Keywords: non-small cell lung cancer
small cell lung cancer
tobacco use disorder
Lead sponsor: University of Minnesota
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2008-06-05
Enrollment: 107
Sex: ALL
Minimum age (years): 21
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: PREVENTION

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.

Eligibility 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.

Primary outcomes:
measure: Urinary Levels of Biomarkers of NNK Metabolism
timeFrame: 2 periods, 5 days each on PEITC or Placebo, with washout week between
measure: Urinary Levels of Biomarkers of NNK Metabolism
timeFrame: After 5 days of treatment
Secondary outcomes:
measure: Effects of GSTM1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC
timeFrame: After 5 days of PEITC treatment
measure: Effects of GSTT1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC
timeFrame: After 5 days of treatment
measure: Combined Effects of GSTM1 and GSTT1 Genotype on Phenethyl Isothiocyanate (PEITC)-NNK Association and on the Metabolism and Excretion of PEITC
timeFrame: After 5 days of treatment
measure: Urinary Levels of [Pyridine-D4]Hydroxy Acid:Total [Pyridine-D4]NNAL Ratio by GSTM1 and GSTT1 Genotype.
timeFrame: After 5 days of treatment
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: Masonic Cancer Center, University of Minnesota
state: Minnesota
Study officials:
affiliation: Masonic Cancer Center, University of Minnesota
name: Dorothy K. Hatsukami, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Yuan JM, Stepanov I, Murphy SE, Wang R, Allen S, Jensen J, Strayer L, Adams-Haduch J, Upadhyaya P, Le C, Kurzer MS, Nelson HH, Yu MC, Hatsukami D, Hecht SS. Clinical Trial of 2-Phenethyl Isothiocyanate as an Inhibitor of Metabolic Activation of a Tobacco-Specific Lung Carcinogen in Cigarette Smokers. Cancer Prev Res (Phila). 2016 May;9(5):396-405. doi: 10.1158/1940-6207.CAPR-15-0380. Epub 2016 Mar 7.
citation: Dinh TN, Parat MO, Ong YS, Khaw KY. Anticancer activities of dietary benzyl isothiocyanate: A comprehensive review. Pharmacol Res. 2021 Jul;169:105666. doi: 10.1016/j.phrs.2021.105666. Epub 2021 May 12.