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

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of Colorado, Denver
ClinicalTrials.gov Identifier:
NCT00084409
First received: June 10, 2004
Last updated: May 5, 2014
Last verified: May 2014
  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

Resource links provided by NLM:


Further study details as provided by University of Colorado, Denver:

Primary Outcome Measures:
  • 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.



Secondary Outcome Measures:
  • 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.



Other Outcome Measures:
  • 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
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00084409

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
Sponsors and Collaborators
University of Colorado, Denver
Investigators
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: May 5, 2014
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 July 29, 2014