Iloprost in Preventing Lung Cancer in Patients at High Risk for This Disease
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Lung Cancer Precancerous Condition |
Drug: iloprost Other: placebo |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator) Primary Purpose: Prevention |
| Official Title: | A Randomized Phase II Chemoprevention Study of Iloprost Versus Placebo in Patients at High Risk for Lung Cancer |
- Change in Average (Follow-up - Baseline) From All Biopsies [ Time Frame: Nine years ] [ Designated as safety issue: No ]
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.
- To Determine Whether Iloprost Can Modulate a Panel of Biomarkers Including MCM-1 EGFR Mutations in Egfr Expression or Activity Can Result in Cancer), Her-2/Neu, RAR, p53 FHIT, Apoptotic Index, and Microvessel Density. [ Time Frame: Nine years ] [ Designated as safety issue: No ]MCM (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). RAR (Retinoic Acid Receptor Beta is a nuclear transcription regulator and a member of the thyroid-steroid hormone receptor superfamily).FHIT (Fragile histidine triad protein is an enzyme involved in purine metabolism and had been demonstrated to be a tumor suppressor).
- Change in Maximum (Follow-up - Baseline) Using All Biopsies [ Time Frame: 9 Years ] [ Designated as safety issue: No ]
This outcome measure is created for each subject as follows:
From all biopsies scored at the baseline bronchoscopy, the maximum WHO score is used.
From all 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 [ Time Frame: 9 Years ] [ Designated as safety issue: No ]
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 [ Time Frame: 9 Years ] [ Designated as safety issue: No ]
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 Maximum (Follow-up - Baseline) Using Reference Sites [ Time Frame: 9 Years ] [ Designated as safety issue: No ]
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 Dysplasia Index (Follow-up - Baseline) Using Reference Sites [ Time Frame: 9 Years ] [ Designated as safety issue: No ]
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 Average (Follow-up - Baseline) Using Matched Sites [ Time Frame: 9 Years ] [ Designated as safety issue: No ]
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 Maximum (Follow-up - Baseline) Using Matched Sites [ Time Frame: 9 Years ] [ Designated as safety issue: No ]
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 Matched Sites [ Time Frame: 9 Years ] [ Designated as safety issue: No ]
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 Average (Follow-up - Baseline) Using Baseline Non-Normal Pairs [ Time Frame: 9 Years ] [ Designated as safety issue: No ]
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 Maximum (Follow-up - Baseline) Using Baseline Non-Normal Pairs [ Time Frame: 9 Years ] [ Designated as safety issue: No ]
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 Dysplasia Index (Follow-up - Baseline) Using Baseline Non-Normal Pairs [ Time Frame: 9 Years ] [ Designated as safety issue: No ]
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.
- To Determine if Iloprost Can Modulate K-67 Proliferation Index in Patients at High Risk to Develop Lung Cancer [ Time Frame: nine years ] [ Designated as safety issue: No ]
- To Determine Whether Iloprost Affects Prostaglandin Metabolism by Examining 4 Markers, PGIS, COX-2, PPAR and PPAR. [ Time Frame: Nine years ] [ Designated as safety issue: No ]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),
- To Determine the Toxicity Profile of Iloprost in Patients at High Risk to Develop Lung Cancer. [ Time Frame: Nine Years ] [ Designated as safety issue: Yes ]
- Define the Genes Whose Expression is Altered by Iloprost Treatment by Gene Expression Arrays and Quantitative PCR. [ Time Frame: Nine Years ] [ Designated as safety issue: No ]
| Enrollment: | 152 |
| Study Start Date: | November 2001 |
| Study Completion Date: | January 2009 |
| Primary Completion Date: | January 2009 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Arm I
Patients receive oral iloprost twice daily for 6 months in the absence of unacceptable toxicity.
|
Drug: iloprost
Given orally
|
|
Placebo Comparator: Arm II
Patients receive oral placebo twice daily for 6 months in the absence of unacceptable toxicity.
|
Other: placebo
Given orally
|
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 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.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
DISEASE CHARACTERISTICS:
- Current or former* smoker with ≥ 20 pack-year history of smoking NOTE: *Defined as 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
PATIENT CHARACTERISTICS:
Age
- 18 and over
Performance status
- SWOG (Southwest Oncology Group)0-2
Life expectancy
- At least 6 months
Hematopoietic
- Granulocyte count > 1,500/mm^3
- Platelet count > 100,000/mm^3
- No clinically apparent bleeding diathesis
Hepatic
- 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
Renal
- Creatinine ≤ 1.5 mg/dL
Cardiovascular
- No clinically active coronary artery disease
- No myocardial infarction within the past 6 weeks
- No chest pain
- No congestive heart failure
No cardiac dysrhythmia that is potentially life-threatening
- Well-controlled atrial fibrillation OR rare (< 2 minutes) premature ventricular contractions allowed
- No ventricular tachycardia
- No multifocal premature ventricular contractions or supraventricular tachycardias with rapid ventricular response
Pulmonary
- No pneumonia or acute bronchitis within the past 2 weeks
- No hypoxemia (< 90% saturation with supplemental oxygen)
Other
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- Able and willing to undergo bronchoscopy
- No malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
- No serious medical condition that would preclude bronchoscopy or study participation
PRIOR CONCURRENT THERAPY:
Biologic therapy
- Not specified
Chemotherapy
- More than 5 years since prior chemotherapy
Endocrine therapy
- More than 6 weeks since prior inhaled steroids
Radiotherapy
- More than 5 years since prior thoracic radiotherapy
Surgery
- Not specified
Other
- No prior prostacyclin
Contacts and Locations| United States, Colorado | |
| University of Colorado Cancer Center at UC Health Sciences Center | |
| Aurora, Colorado, United States, 80045 | |
| Veterans Affairs Medical Center - Denver | |
| Denver, Colorado, United States, 80220 | |
| United States, Maryland | |
| Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | |
| Baltimore, Maryland, United States, 21231-2410 | |
| United States, Minnesota | |
| Mayo Clinic Cancer Center | |
| Rochester, Minnesota, United States, 55905 | |
| United States, Pennsylvania | |
| UPMC Cancer Centers | |
| Pittsburgh, Pennsylvania, United States, 15232 | |
| United States, Tennessee | |
| Vanderbilt-Ingram Cancer Center | |
| Nashville, Tennessee, United States, 37232-6838 | |
| Principal Investigator: | Robert Keith, MD | University of Colorado, Denver |
More Information
Additional Information:
No publications provided
| Responsible Party: | University of Colorado, Denver |
| ClinicalTrials.gov Identifier: | NCT00084409 History of Changes |
| Other Study ID Numbers: | 01-0279, National Cancer Institute |
| Study First Received: | June 10, 2004 |
| Results First Received: | November 26, 2012 |
| Last Updated: | February 12, 2013 |
| Health Authority: | United States: Federal Government United States: Food and Drug Administration |
Keywords provided by University of Colorado, Denver:
|
non-small cell lung cancer squamous lung dysplasia |
Additional relevant MeSH terms:
|
Lung Neoplasms Precancerous Conditions Respiratory Tract Neoplasms Thoracic Neoplasms Neoplasms by Site Neoplasms Lung Diseases Respiratory Tract Diseases |
Iloprost Platelet Aggregation Inhibitors Hematologic Agents Therapeutic Uses Pharmacologic Actions Vasodilator Agents Cardiovascular Agents |
ClinicalTrials.gov processed this record on June 17, 2013