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Completed

NCT Number: NCT00084409

Iloprost in Preventing Lung Cancer in Patients at High Risk for This Disease

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

PURPOSE: This randomized phase II trial is studying how well iloprost works in preventing lung cancer in patients who are at high risk for this disease.

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Key information

Conditions

Lung Cancer Bronchial Neoplasms Carcinoma, Bronchogenic Carcinoma, Non-Small-Cell Lung Lung Diseases Lung Neoplasms Neoplasms Neoplasms by Site Precancerous Condition Precancerous Conditions Respiratory Tract Diseases Respiratory Tract Neoplasms Thoracic Neoplasms

Age range

18 year–85 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

University of Colorado Cancer Center at UC Health Sciences Center, Aurora, Colorado, United States

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About this study

OBJECTIVES:

Primary

  • Compare the reversal of premalignant histological changes in the bronchial epithelium of patients at high risk for lung cancer (defined by > 20 pack years of smoking and sputum atypia) treated with iloprost vs placebo.
  • Determine whether this drug modulates Ki-67 proliferation index (Antigen Ki-67) in these patients.
  • Determine whether this drug affects prostaglandin metabolism in these patients.
  • Determine the toxicity profile of this drug in these patients.

Secondary

  • Determine whether this drug modulates a panel of biomarkers, including MCM-2(Minichromosome maintenance protein: forms DNA helicase), EGFR (Epidermal growth factor receptor: cell surface receptor for the epidermal growth factor family of proteins. Mutations in EGFR expression or activity can result in cancer.) , HER2/neu (Human epidermal growth factor receptor 2 HER2 is a member of the EGFR family), RARβ (Retinoic Acic Receptor Beta is a nuclear transcription regulator and a member of the thyroid-steroid hormone receptor superfamily), p53, FHIT (Fragile histidine triad protein is an enzyme involved in purine metabolism and had been demonstrated to be a tumor suppressor), apoptotic index, and microvessel density, in these patients.
  • Determine the genes whose expression is altered by this drug in these patients.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to smoking status (current vs former) and participating center. Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive oral iloprost twice daily.
  • Arm II: Patients receive oral placebo twice daily. In both arms, treatment continues for 6 months in the absence of unacceptable toxicity.

Patients are followed at 1 month and then annually thereafter.

PROJECTED ACCRUAL: A total of 152 patients (76 [38 current smokers and 38 former smokers] per treatment arm) will be accrued for this study within 2 years.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Current or former smoker with ≥ 20 pack-year history of smoking with no tobacco use within the past 6 months
  • Mild atypia or worse on sputum cytology, or
  • Bronchial biopsy with mild or worse dysplasia within the past 12 months
  • Age 18 and over
  • SWOG (Southwest Oncology Group)0-2
  • Life expectancy at least 6 months
  • Granulocyte count > 1,500/mm^3
  • Platelet count > 100,000/mm^3
  • Alkaline phosphatase ≤ 2.5 times upper limit of normal (ULN)
  • Transaminases ≤ 2.5 times ULN
  • Bilirubin ≤ 2.0 mg/dL
  • Albumin ≥ 2.5 g/dL
  • Creatinine ≤ 1.5 mg/dL
  • Well-controlled atrial fibrillation OR rare (< 2 minutes) premature ventricular contractions allowed
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • Able and willing to undergo bronchoscopy

Exclusion criteria

  • Clinically apparent bleeding diathesis
  • Ventricular tachycardia
  • Multifocal premature ventricular contractions or supraventricular tachycardias with rapid ventricular response
  • Pneumonia or acute bronchitis within the past 2 weeks
  • Hypoxemia (< 90% saturation with supplemental oxygen)
  • Pregnant or nursing
  • Malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
  • Serious medical condition that would preclude bronchoscopy or study participation
  • Clinically active coronary artery disease
  • Myocardial infarction within the past 6 weeks
  • Chest pain
  • Congestive heart failure
  • Cardiac dysrhythmia that is potentially life-threatening

Exclusion for PRIOR CONCURRENT THERAPY:

  • Biologic therapy (Not specified)
  • More than 5 years since prior chemotherapy
  • More than 6 weeks since prior inhaled steroids
  • More than 5 years since prior thoracic radiotherapy
  • Surgery (Not specified)
  • No prior prostacyclin

Treatment and study plan

ILOPROST

Drug

Given orally

Placebo

Other

Given orally

Primary outcomes

  1. Change in Average (Follow-up - Baseline) From All Biopsies

    Time frame: Nine years

    This outcome measure is created for each subject as follows:

    From all biopsies scored at the baseline bronchoscopy, the mean WHO score is calculated.

    From all biopsies scored at the follow-up bronchoscopy, the mean WHO score is calculated.Histology on bronchial biopsies pre-treatment and post-treatment will be compared. All biopsies will be graded according to the WHO classification for bronchial epithelium for this outcome, and all the following outcomes.

    WHO Classification Grade Normal 1.0 Reserve Cell Hyperplasia 2.0 Metaplasia 3.0 Mild Dysplasia 4.0 Moderate Dysplasia 5.0 Severe Dysplasia 6.0 Carcinoma in Situ 7.0 Carcinoma 8.0

    The difference (follow-up mean - baseline mean) is used as the outcome measure for each subject.

Secondary outcomes

  1. Change in Dysplasia Index (Follow-up - Baseline) Using All Biopsies

    Time frame: 9 Years

    This outcome measure is created for each subject as follows:

    From all biopsies scored at the baseline bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated (this is the definition of Dysplasia Index (DI)).

    From all biopsies scored at the follow-up bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated.

    The difference (follow-up DI - baseline DI) is used as the outcome measure for each subject.

  2. Change in Average (Follow-up - Baseline) Using Reference Sites

    Time frame: 9 Years

    This outcome measure is created for each subject as follows:

    The biopsies used in this analysis are those from the following 6 anatomical sites pre-specified in the protocol to be biopsied: RUL (Right upper lobe: the superior region of the right lung), RML (Right middle lobe: an anatomic portion of the right lung), RB6 (The carina in the right lower lobe at the entrance to the superior segment), LUL (Left upper lobe: the superior portion of the lung), LUDB (Left upper division bronchus: the carina between the lingular orifice and the left upper lobe), and LB6 (The carina in the left lower lobe at the entrance to the superior segment).

    From these biopsies scored at the baseline bronchoscopy, the mean WHO score is calculated.

    From these biopsies scored at the follow-up bronchoscopy, the mean WHO score is calculated.

    The difference (follow-up mean - baseline mean) is used as the outcome measure for each subject.

  3. Change in Maximum (Follow-up - Baseline) Using Reference Sites

    Time frame: 9 Years

    This outcome measure is created for each subject as follows:

    The biopsies used in this analysis are those from the following 6 anatomical sites pre-specified in the protocol to be biopsied: RUL, RML, RB6, LUL, LUDB, and LB6.

    From these biopsies scored at the baseline bronchoscopy, the maximum WHO score is used.

    From these biopsies scored at the follow-up bronchoscopy, the maximum WHO score is used.

    The difference (follow-up maximum - baseline maximum) is used as the outcome measure for each subject.

  4. Change in Dysplasia Index (Follow-up - Baseline) Using Reference Sites

    Time frame: 9 Years

    This outcome measure is created for each subject as follows:

    The biopsies used in this analysis are those from the following 6 anatomical sites pre-specified in the protocol to be biopsied: RUL, RML, RB6, LUL, LUDB, and LB6.

    From these biopsies scored at the baseline bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated (this is the definition of Dysplasia Index (DI)).

    From these biopsies scored at the follow-up bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated.

    The difference (follow-up DI - baseline DI) is used as the outcome measure for each subject.

  5. Change in Average (Follow-up - Baseline) Using Matched Sites

    Time frame: 9 Years

    This outcome measure is created for each subject as follows:

    The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies, thus creating "pairs" of biopsies.

    From these biopsies scored at the baseline bronchoscopy, the mean WHO score is calculated.

    From these biopsies scored at the follow-up bronchoscopy, the mean WHO score is calculated.

    The difference (follow-up mean - baseline mean) is used as the outcome measure for each subject.

  6. Change in Maximum (Follow-up - Baseline) Using Matched Sites

    Time frame: 9 Years

    This outcome measure is created for each subject as follows:

    The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies.

    From these biopsies scored at the baseline bronchoscopy, the maximum WHO score is used.

    From these biopsies scored at the follow-up bronchoscopy, the maximum WHO score is used.

    The difference (follow-up maximum - baseline maximum) is used as the outcome measure for each subject.

  7. Change in Dysplasia Index (Follow-up - Baseline) Using Matched Sites

    Time frame: 9 Years

    This outcome measure is created for each subject as follows:

    The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies.

    From these biopsies scored at the baseline bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated (this is the definition of Dysplasia Index (DI)).

    From these biopsies scored at the follow-up bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated.

    The difference (follow-up DI - baseline DI) is used as the outcome measure for each subject.

  8. Change in Average (Follow-up - Baseline) Using Baseline Non-Normal Pairs

    Time frame: 9 Years

    This outcome measure is created for each subject as follows:

    The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies, thus creating "pairs" of biopsies. Any "pair" for which the baseline WHO score was 1 (i.e. normal tissue) was excluded from the analysis.

    From these biopsies scored at the baseline bronchoscopy, the mean WHO score is calculated.

    From these biopsies scored at the follow-up bronchoscopy, the mean WHO score is calculated.

    The difference (follow-up mean - baseline mean) is used as the outcome measure for each subject.

  9. Change in Maximum (Follow-up - Baseline) Using Baseline Non-Normal Pairs

    Time frame: 9 Years

    This outcome measure is created for each subject as follows:

    The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies, thus creating "pairs" of biopsies. Any "pair" for which the baseline WHO score was 1 (i.e. normal tissue) was excluded from the analysis.

    From these biopsies scored at the baseline bronchoscopy, the maximum WHO score is used.

    From these biopsies scored at the follow-up bronchoscopy, the maximum WHO score is used.

    The difference (follow-up maximum - baseline maximum) is used as the outcome measure for each subject.

  10. Change in Dysplasia Index (Follow-up - Baseline) Using Baseline Non-Normal Pairs

    Time frame: 9 Years

    This outcome measure is created for each subject as follows:

    The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies, thus creating "pairs" of biopsies. Any "pair" for which the baseline WHO score was 1 (i.e. normal tissue) was excluded from the analysis.

    From these biopsies scored at the baseline bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated (this is the definition of Dysplasia Index (DI)).

    From these biopsies scored at the follow-up bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated.

    The difference (follow-up DI - baseline DI) is used as the outcome measure for each subject.

Other outcomes

  1. To Determine if Iloprost Can Modulate K-67 Proliferation Index in Patients at High Risk to Develop Lung Cancer

    Time frame: nine years

  2. To Determine Whether Iloprost Affects Prostaglandin Metabolism by Examining 4 Markers, PGIS, COX-2, PPAR and PPAR.

    Time frame: Nine years

    PGIS (Prostacyclin synthase: an enzyme in the eicosanoid pathway that catalyzes the conversion of prostaglandin H2 to prostaglandin I2 (prostacyclin). PPAR (Peroxisome proliferator-activated receptor: a group of nuclear receptor proteins that act as transcription factors regulating gene expression),

  3. To Determine the Toxicity Profile of Iloprost in Patients at High Risk to Develop Lung Cancer.

    Time frame: Nine Years

  4. Define the Genes Whose Expression is Altered by Iloprost Treatment by Gene Expression Arrays and Quantitative PCR.

    Time frame: Nine Years

  5. To Determine Whether Iloprost Can Modulate a Panel of Biomarkes.

    Time frame: 9 years

    To determine if Iloprost can modulate a panel of biomarkers including MCM-2, EGFR, Her-2/neu, RARβ, p53, FHIT, apoptotic index, and microvessel density.

Sponsors and collaborators

Lead sponsor

University of Colorado, Denver

Other

Collaborators

  • National Cancer Institute (NCI)

Registry information

Official study title

A Randomized Phase II Chemoprevention Study of Iloprost Versus Placebo in Patients at High Risk for Lung Cancer

Important dates

Study start
2001
Primary completion
2009
Study completion
2009
First posted
Jun 11, 2004
Registry last updated
May 14, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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