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Azacitidine and Entinostat Before Chemotherapy in Treating Patients With Advanced Non-small Cell Lung Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01935947
First received: September 3, 2013
Last updated: November 21, 2014
Last verified: November 2014
  Purpose

This randomized phase II trial studies how well azacitidine and entinostat before chemotherapy works in treating patients with non-small cell lung cancer that has spread to other places in the body. Drugs used in chemotherapy, such as azacitidine, irinotecan hydrochloride, gemcitabine hydrochloride, docetaxel, and pemetrexed disodium, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving azacitidine and entinostat before chemotherapy may be an effective treatment for non-small cell lung cancer.


Condition Intervention Phase
Recurrent Non-Small Cell Lung Carcinoma
Stage IIIA Non-Small Cell Lung Cancer
Stage IIIB Non-Small Cell Lung Cancer
Stage IV Non-Small Cell Lung Cancer
Drug: Azacitidine
Drug: Entinostat
Drug: Irinotecan Hydrochloride
Drug: Gemcitabine Hydrochloride
Drug: Docetaxel
Drug: Pemetrexed Disodium
Other: Laboratory Biomarker Analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Phase II Trial of Cytotoxic Chemotherapy With or Without Epigenetic Priming in Patients With Advanced Non-small Cell Lung Cancer

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Percentage of patients progression-free at 6 months from the time of randomization [ Time Frame: At 6 months ] [ Designated as safety issue: No ]
    The final analysis will be by Fisher's Exact test, with percentage of patients who have not progressed as the outcome variable. Using Fisher's Exact test for analysis with 55 patients per treatment group will provide 88% power to detect an increase from 40% (chemotherapy alone) to 65% (epigenetic therapy followed by chemotherapy) in the number of patients who are progression free at six months.


Secondary Outcome Measures:
  • PFS [ Time Frame: From the time of randomization until radiologic or clinical progression is noted, assessed up to 2 years ] [ Designated as safety issue: No ]
  • OS [ Time Frame: From the time of enrollment to trial until death, assessed up to 2 years ] [ Designated as safety issue: No ]

Other Outcome Measures:
  • Predictive and prognostic value of the previously defined epigenetic signature, comprised of promoter methylation analysis of 4 target genes [ Time Frame: After 1 month of therapy ] [ Designated as safety issue: No ]
  • Response to therapy compared to genetic and epigenetic factors and tested for association [ Time Frame: After 1 month of therapy ] [ Designated as safety issue: No ]
  • Genome-wide techniques, including expression array and methylation array [ Time Frame: After 1 month of therapy ] [ Designated as safety issue: No ]
    Expression array and methylation array will be compared to response.


Estimated Enrollment: 165
Study Start Date: May 2013
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (azacitidine, entinostat, chemotherapy)
Patients receive azacitidine SC on days 1-6 and 8-10 and entinostat PO on days 3 and 10. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or progressive disease receive chemotherapy of the treating oncologist's choice comprising irinotecan hydrochloride IV on day 1, docetaxel IV on day 1, pemetrexed disodium IV on day 1, or gemcitabine hydrochloride IV on days 1 and 8. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: Azacitidine
Given SC
Other Names:
  • 5-AC
  • 5-AZC
  • U-18496
Drug: Entinostat
Given PO
Other Name: HDAC inhibitor SNDX-275
Drug: Irinotecan Hydrochloride
Given IV
Drug: Gemcitabine Hydrochloride
Given IV
Other Names:
  • dFdC
  • dFdCyd
Drug: Docetaxel
Given IV
Other Name: TXT
Drug: Pemetrexed Disodium
Given IV
Other Names:
  • LY231514
  • MTA
Other: Laboratory Biomarker Analysis
Correlative studies
Experimental: Arm II (azacitidine, entinostat, chemotherapy)
Patients receive azacitidine PO on days 1-21 and entinostat PO on days 3 and 10. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or progressive disease receive chemotherapy of the treating oncologist's choice as in Arm A.
Drug: Azacitidine
Given PO
Other Names:
  • 5-AC
  • 5-AZC
  • U-18496
Drug: Entinostat
Given PO
Other Name: HDAC inhibitor SNDX-275
Drug: Irinotecan Hydrochloride
Given IV
Drug: Gemcitabine Hydrochloride
Given IV
Other Names:
  • dFdC
  • dFdCyd
Drug: Docetaxel
Given IV
Other Name: TXT
Drug: Pemetrexed Disodium
Given IV
Other Names:
  • LY231514
  • MTA
Other: Laboratory Biomarker Analysis
Correlative studies
Active Comparator: Arm III (chemotherapy)
Patients receive chemotherapy of the treating oncologist's choice as in Arm A.
Drug: Irinotecan Hydrochloride
Given IV
Drug: Gemcitabine Hydrochloride
Given IV
Other Names:
  • dFdC
  • dFdCyd
Drug: Docetaxel
Given IV
Other Name: TXT
Drug: Pemetrexed Disodium
Given IV
Other Names:
  • LY231514
  • MTA
Other: Laboratory Biomarker Analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. Percentage of patients progression-free at 6 months from time of randomization.

SECONDARY OBJECTIVES:

I. Progression-free survival (PFS). II. Overall Survival (OS).

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM A: Patients receive azacitidine subcutaneously (SC) on days 1-6 and 8-10 and entinostat orally (PO) on days 3 and 10. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or progressive disease receive chemotherapy of the treating oncologist's choice comprising irinotecan hydrochloride intravenously (IV) on day 1, docetaxel IV on day 1, pemetrexed disodium IV on day 1, or gemcitabine hydrochloride IV on days 1 and 8. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive azacitidine PO on days 1-21 and entinostat PO on days 3 and 10. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or progressive disease receive chemotherapy of the treating oncologist's choice as in Arm A.

ARM C: Patients receive chemotherapy of the treating oncologist's choice as in Arm A.

After completion of treatment, patients are followed up every 3-6 months for 24 months and then yearly thereafter.

  Eligibility

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

Inclusion Criteria:

  • Patients must have histologically or cytologically proven non-small cell lung cancer; tumor tissue must be available from all patients prior to initiation of protocol therapy, either from original diagnostic biopsy, or biopsy performed prior to initiation of protocol therapy
  • Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
  • Patients must have received one prior therapy, and no more than one prior therapy
  • Patients with epidermal growth factor receptor (EGFR) mutations in exon 19 or 21 and patients with detected anaplastic lymphoma kinase (ALK) translocation may have had two prior therapies if one was a tyrosine kinase inhibitor specific to their mutation
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky >= 70%)
  • Life expectancy of greater than 12 weeks
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin within normal institutional limits
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transferase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transferase [SGPT]) =< 2.5 X institutional upper limit of normal
  • Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
  • Patients who are receiving any other investigational agents
  • Patients with uncontrolled brain metastases; patients with brain metastases must have stable neurologic status following local therapy (surgery or radiation) for at least 4 weeks, and must be without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; patients may be treated with steroids as clinically indicated
  • Patients with liver metastases that replace greater than 30% of the liver parenchyma
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to entinostat, azacitidine, mannitol, irinotecan, docetaxel, pemetrexed, or gemcitabine, or other agents used in the study
  • Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, New York Heart Association (NYHA) class 3-4 congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated on this protocol
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  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: NCT01935947

Locations
United States, California
University of Southern California/Norris Cancer Center Recruiting
Los Angeles, California, United States, 90033
Contact: Barbara J. Gitlitz    323-865-3906    gitlitz@usc.edu   
Principal Investigator: Barbara J. Gitlitz         
United States, Maryland
Johns Hopkins Bayview Medical Center Recruiting
Baltimore, Maryland, United States, 21224
Contact: Phillip A. Dennis    410-550-9250    pdennis@jhmi.edu   
Principal Investigator: Phillip A. Dennis         
Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: Julie R. Brahmer    410-502-7159    brahmju@jhmi.edu   
Principal Investigator: Julie R. Brahmer         
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital Recruiting
Baltimore, Maryland, United States, 21231
Contact: Julie R. Brahmer    410-502-7159    brahmju@jhmi.edu   
Principal Investigator: Julie R. Brahmer         
United States, Pennsylvania
Temple University Hospital Recruiting
Philadelphia, Pennsylvania, United States, 19140
Contact: Deric C. Savior    215-707-2777    deric.savior@tuhs.temple.edu   
Principal Investigator: Deric C. Savior         
United States, South Carolina
Medical University of South Carolina Recruiting
Charleston, South Carolina, United States, 29425
Contact: John M. Wrangle    410-955-8804    wrangle@musc.edu   
Principal Investigator: John M. Wrangle         
Sponsors and Collaborators
Investigators
Principal Investigator: Julie Brahmer Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01935947     History of Changes
Obsolete Identifiers: NCT01846897
Other Study ID Numbers: NCI-2013-00949, NCI-2013-00949, NA_00081948, NA_00081948/J1309, 9253, P30CA006973
Study First Received: September 3, 2013
Last Updated: November 21, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Bronchial Neoplasms
Carcinoma, Bronchogenic
Lung Diseases
Neoplasms
Neoplasms by Site
Respiratory Tract Diseases
Respiratory Tract Neoplasms
Thoracic Neoplasms
Azacitidine
Camptothecin
Docetaxel
Entinostat
Gemcitabine
Irinotecan
Pemetrexed
Anti-Infective Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antimitotic Agents
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Antiviral Agents
Enzyme Inhibitors
Folic Acid Antagonists
Histone Deacetylase Inhibitors
Immunologic Factors
Immunosuppressive Agents
Mitosis Modulators

ClinicalTrials.gov processed this record on November 27, 2014