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

Phase 2

Completed

Conditions: Lung Cancer
Precancerous Condition

Interventions: Other: placebo
Drug: iloprost

Registration Number: NCT00084409

Lead Sponsor: University of Colorado, Denver

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 152

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm II	placebo	Patients receive oral placebo twice daily for 6 months in the absence of unacceptable toxicity.
Arm I	iloprost	Patients receive oral iloprost twice daily for 6 months in the absence of unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Change in Average (Follow-up - Baseline) From All Biopsies	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 Outcome Measures

Name	Time	Method
Change in Maximum (Follow-up - Baseline) Using Reference Sites	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.
Change in Average (Follow-up - Baseline) Using Matched Sites	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.
Change in Dysplasia Index (Follow-up - Baseline) Using Matched Sites	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.
Change in Maximum (Follow-up - Baseline) Using Matched Sites	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.
Change in Dysplasia Index (Follow-up - Baseline) Using All Biopsies	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.
Change in Average (Follow-up - Baseline) Using Reference Sites	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.
Change in Dysplasia Index (Follow-up - Baseline) Using Reference Sites	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.
Change in Maximum (Follow-up - Baseline) Using Baseline Non-Normal Pairs	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.
Change in Average (Follow-up - Baseline) Using Baseline Non-Normal Pairs	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.
Change in Dysplasia Index (Follow-up - Baseline) Using Baseline Non-Normal Pairs	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.

Trial Locations

Locations (6): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
🇺🇸
Baltimore, Maryland, United States
Mayo Clinic Cancer Center
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Rochester, Minnesota, United States
University of Colorado Cancer Center at UC Health Sciences Center
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Aurora, Colorado, United States
Veterans Affairs Medical Center - Denver
🇺🇸
Denver, Colorado, United States
UPMC Cancer Centers
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Pittsburgh, Pennsylvania, United States
Vanderbilt-Ingram Cancer Center
🇺🇸
Nashville, Tennessee, United States