Residual Hypermethylation in Early Stage Non-Small Cell Lung Cancer (NSCLC) As Part of Adjuvant Therapy and Preventive Strategy - Full Text View

Purpose

The trial investigates the feasibility and efficacy of targeting Non-Small Cell Lung Cancer (NSCLC) "driven" by epigenetic changes. The investigators study the impact of 5-azacitidine (Vidaza®, Celgene, Summit, NJ, USA) in combination with conventional cytotoxic chemotherapy in a sequential fashion. The study population consists of all NSCLC patients who undergo "curative" lung cancer resection and whose tumors harbor hypermethylation in any of the protocol-specific genes (samples will be banked for additional molecular testing including other 21 loci which have shown to be important in lung carcinogenesis.

Condition	Intervention
Lung Cancer Non Small Cell Lung Carcinoma Hypermethylation	Drug: Cisplatin Drug: Carboplatin Drug: Paclitaxel Drug: Vidaza Procedure: Tumor Specimen for Methylation Analysis Procedure: Blood Sample for Methylation Analysis Drug: Vinorelbine Drug: Docetaxel Drug: Pemetrexed

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Pilot Study Targeting Residual Hypermethylation in Early Stage Non-Small Cell Lung Cancer As Part of Adjuvant Therapy and Preventive Strategy

Resource links provided by NLM:

MedlinePlus related topics: Cancer Lung Cancer

Drug Information available for: Azacitidine Cisplatin Paclitaxel Carboplatin Vinorelbine Docetaxel Vinorelbine tartrate Pemetrexed Pemetrexed disodium

U.S. FDA Resources

Further study details as provided by University of Miami Sylvester Comprehensive Cancer Center:

Primary Outcome Measures:

To determine the presence of methylated tumor suppressor genes (TSGs) in the tumor tissue and/or serum of patients diagnosed with NSCLC. [ Time Frame: Prior to cycle 1, prior to cycle 3, prior to cycle 6, and every 4 months for the first 2 years post-completion of therapy ] [ Designated as safety issue: No ]
To measure the grade of demethylation induced by 5-azacitidine on specific TSGs by analyzing plasma DNA, and global demethylation by analyzing WBC DNA, and determine the duration of this effect [ Time Frame: Prior to cycle 1, prior to cycle 3, prior to cycle 6, and every 4 months for the first 2 years post-completion of therapy ] [ Designated as safety issue: No ]
This value will be the difference between percentage of hypermethylation at baseline (tumor tissue/serum samples) minus percentage of hypermethylation found at: prior to cycle 1, prior to cycle 3, prior to cycle 6, and every 4 months for the first 2 years post-completion of therapy divided by the percentage of hypermethylation at baseline.

Secondary Outcome Measures:

To obtain preliminary data on methylation "pattern/profile" of silenced genes due to promoter hypermethylation once they have been treated with conventional cytotoxic chemotherapy followed by 5-azacitidine, a demethylating agent. [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
In the event of recurrence, methylation analysis (including gene identification and percentage of hypermethylation) will be performed and compared with original "pattern/profile" of gene methylation.

Estimated Enrollment:	20
Study Start Date:	July 2009
Estimated Primary Completion Date:	July 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Single Arm	Drug: Cisplatin Patients will receive a total of 4 cycles of adjuvant chemotherapy (each cycle given every 21 days). Conventional chemotherapy will be selected at discretion of the treating physicians except on those cases in which pathologic diagnosis indicates non squamous NSCLC. Other Names: Platinol®, cis-diamminedichloroplatinum Drug: Carboplatin Patients will receive a total of 4 cycles of adjuvant chemotherapy (each cycle given every 21 days). Conventional chemotherapy will be selected at discretion of the treating physicians except on those cases in which pathologic diagnosis indicates non squamous NSCLC. Other Name: Paraplatin® Drug: Paclitaxel Patients will receive a total of 4 cycles of adjuvant chemotherapy (each cycle given every 21 days). Conventional chemotherapy will be selected at discretion of the treating physicians except on those cases in which pathologic diagnosis indicates non squamous NSCLC. Other Name: Taxol Drug: Vidaza Patient will receive 5-azacitidine at a dose of 75 mg/m2 intravenously daily on day 1-5 every 28 days for 6 cycles Other Name: 5-azacitidine Procedure: Tumor Specimen for Methylation Analysis Obtained from tissue of resected NSCLC tumor. Procedure: Blood Sample for Methylation Analysis Pre-Surgery, Post-Surgery, Post-Vidaza Therapy and during follow-up. Drug: Vinorelbine Patients will receive a total of 4 cycles of adjuvant chemotherapy (each cycle given every 21 days). Conventional chemotherapy will be selected at discretion of the treating physicians except on those cases in which pathologic diagnosis indicates non squamous NSCLC. Other Name: Navelbine® Drug: Docetaxel Patients will receive a total of 4 cycles of adjuvant chemotherapy (each cycle given every 21 days). Conventional chemotherapy will be selected at discretion of the treating physicians except on those cases in which pathologic diagnosis indicates non squamous NSCLC. Drug: Pemetrexed Patients will receive a total of 4 cycles of adjuvant chemotherapy (each cycle given every 21 days). Conventional chemotherapy will be selected at discretion of the treating physicians except on those cases in which pathologic diagnosis indicates non squamous NSCLC.

Arms

Assigned Interventions

Experimental: Single Arm

Drug: Cisplatin

Patients will receive a total of 4 cycles of adjuvant chemotherapy (each cycle given every 21 days). Conventional chemotherapy will be selected at discretion of the treating physicians except on those cases in which pathologic diagnosis indicates non squamous NSCLC.

Other Names:

Platinol®,
cis-diamminedichloroplatinum

Drug: Carboplatin

Patients will receive a total of 4 cycles of adjuvant chemotherapy (each cycle given every 21 days). Conventional chemotherapy will be selected at discretion of the treating physicians except on those cases in which pathologic diagnosis indicates non squamous NSCLC.

Other Name: Paraplatin®

Drug: Paclitaxel

Patients will receive a total of 4 cycles of adjuvant chemotherapy (each cycle given every 21 days). Conventional chemotherapy will be selected at discretion of the treating physicians except on those cases in which pathologic diagnosis indicates non squamous NSCLC.

Other Name: Taxol

Drug: Vidaza

Patient will receive 5-azacitidine at a dose of 75 mg/m2 intravenously daily on day 1-5 every 28 days for 6 cycles

Other Name: 5-azacitidine

Procedure: Tumor Specimen for Methylation Analysis

Obtained from tissue of resected NSCLC tumor.

Procedure: Blood Sample for Methylation Analysis

Pre-Surgery, Post-Surgery, Post-Vidaza Therapy and during follow-up.

Drug: Vinorelbine

Patients will receive a total of 4 cycles of adjuvant chemotherapy (each cycle given every 21 days). Conventional chemotherapy will be selected at discretion of the treating physicians except on those cases in which pathologic diagnosis indicates non squamous NSCLC.

Other Name: Navelbine®

Drug: Docetaxel

Patients will receive a total of 4 cycles of adjuvant chemotherapy (each cycle given every 21 days). Conventional chemotherapy will be selected at discretion of the treating physicians except on those cases in which pathologic diagnosis indicates non squamous NSCLC.

Drug: Pemetrexed

Patients will receive a total of 4 cycles of adjuvant chemotherapy (each cycle given every 21 days). Conventional chemotherapy will be selected at discretion of the treating physicians except on those cases in which pathologic diagnosis indicates non squamous NSCLC.

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Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Patients must have a pathologic diagnosis of NSCLC.
Patients must have surgical resection for NSCLC (stage I-IIIA) and tumor specimen (ideally) and/or blood sample available for biological correlative studies.
Patient's tumor specimen and/or blood sample must show hypermethylation in at least one (1) of the following genes: DAPK, RASSF1A, CDKN2A (p16INK4a), GATA-4, GATA-5, SPARC, MGMT, APC, and hMLH1.
Patient's age must be 18 years or greater.
Patients must have adequate organ and marrow function prior to be enrolled into the trial, as defined below:
- Absolute neutrophil count (ANC) > 1500/mm3
- Platelets > 100,000/mm3
- Hemoglobin > 8.0 g/dL (with packed red blood cell transfusion or use of erythropoietin stimulating agents allowed)
- Serum creatinine < 2.0 mg/dl.
- Total bilirubin < 2.0 mg/dl.
- AST/ALT < 2 x the upper limits of institutional normal.
ECOG performance status of 0, 1, or 2.
Estimated survival of > 12 months.
Patients must be able to understand and agree to sign an IRB-approved informed consent form, including permission to draw blood sample for correlative studies during active treatment and follow-up.
Women of child-bearing potential and men must agree to use adequate contraceptive method (hormonal or barrier method of birth control) prior to study entry for the duration of study.
Women of childbearing potential must have a negative serum pregnancy test prior to start targeted therapy with 5-azacitidine.
Patients with HIV infection (but not AIDS) are eligible for this trial. Therefore, no HIV testing will be required.

Exclusion Criteria:

Patients who are not candidates for surgical resection.
Patients who have received radiation therapy.
No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, breast DCIS adequately treated, or other cancer for which the subject has been disease-free ≥ 5 years.
Subjects should not have a significant history of cardiac disease (e.g., unstable angina, congestive heart failure, or uncontrolled arrhythmias).
Subjects must not have an uncontrolled seizure disorder, or active neurological disease.
Patients who have significant systemic infections including AIDS.
Pregnant and/or lactating women.
Known or suspected hypersensitivity to azacitidine or mannitol.
Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical illnesses.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01209520

Locations

United States, Florida
University of Miami Sylvester Comprehensive Cancer Center
Miami, Florida, United States, 33136

Sponsors and Collaborators

University of Miami Sylvester Comprehensive Cancer Center

Investigators

Study Chair:

Edgardo Santos, MD

University of Miami Sylvester Comprehensive Cancer Center

More Information

No publications provided

Responsible Party:	University of Miami Sylvester Comprehensive Cancer Center
ClinicalTrials.gov Identifier:	NCT01209520 History of Changes
Other Study ID Numbers:	EPROST-20080779, SCCC-2008045
Study First Received:	September 22, 2010
Last Updated:	January 23, 2013
Health Authority:	United States: Food and Drug Administration

Keywords provided by University of Miami Sylvester Comprehensive Cancer Center:

Lung Cancer
Non-Small Cell Lung Carcinoma
NSCLC
Methylation Analysis

Hypermethylation
Targeted Genes
Tumorigenesis
Tumor Supressor Genes

Additional relevant MeSH terms:

Carcinoma
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Adjuvants, Immunologic
Azacitidine

Pemetrexed
Vinorelbine
Docetaxel
Cisplatin
Carboplatin
Paclitaxel
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors

ClinicalTrials.gov processed this record on June 17, 2013