Phenethyl Isothiocyanate in Preventing Lung Cancer in Smokers

University of Minnesota (UMN)

Status and phase: Completed; Phase 2

Conditions: Tobacco Use Disorder; Lung Cancer

Treatments: Drug: phenethyl isothiocyanate; Other: placebo

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00691132

2007NT127

R01CA122244 (U.S. NIH Grant/Contract)

0712M22651 (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 107 patients

Sex: All

Ages: 21 to 70 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Double Blind

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107 participants in 2 patient groups

PEITC - Placebo (short-term trial)

Experimental group

Description:

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.

Treatment:

Drug: phenethyl isothiocyanate

Other: placebo

Placebo - PEITC (short-term trial)

Experimental group

Description:

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.

Treatment:

Drug: phenethyl isothiocyanate

Other: placebo