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Azacitidine and Entinostat in Treating Patients With Stage I Non-Small Cell Lung Cancer That Has Been Removed By Surgery

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01207726
First received: September 10, 2010
Last updated: October 7, 2013
Last verified: October 2013

September 10, 2010
October 7, 2013
September 2010
May 2013   (final data collection date for primary outcome measure)
Disease-free survival (DFS) [ Time Frame: 3 years ] [ Designated as safety issue: No ]
The DFS hazard rate and 95% confidence interval will be reported. At this time, event time distributions for disease-free survival in the two arms will be estimated with the method of Kaplan and Meier and compared using a stratified Cox-proportional hazards model (stratified for stage IA vs IB) with a two-sided alpha of 10%.
Number of subjects that are alive and disease free after 3 years [ Time Frame: 3 year progression-free survival ] [ Designated as safety issue: No ]
To assess the effect of 5-azacitidine and entinostat on the hazard of 3 year progression-free survival in patients with resected stage I non-small cell lung cancer.
Complete list of historical versions of study NCT01207726 on ClinicalTrials.gov Archive Site
  • Toxicities graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    Simple descriptive statistics will be utilized to display the data.
  • Median disease-free survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Determined by the method determined by Kaplan and Meier. Estimated with 95% confidence intervals. Cox proportional hazard modeling will be used for multivariate analysis.
  • Overall survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Determined by the method determined by Kaplan and Meier. Estimated with 95% confidence intervals. Cox proportional hazard modeling will be used for multivariate analysis.
  • Presence of methylation patterns [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    McNemar's test will be used to compare the change in methylation after treatment in sputum.
  • Number of relapses and deaths per total time of follow-up comparing patients with N2 lymph nodes in terms of methylated and unmethylated [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Kaplan Meier curves will be used.
  • Factors that predict clinical outcome in patients treated with combination epigenetic therapy in terms of epigenomic data generated from the Illumina platform [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
Number of subjects with adverse events as a measure of safety and tolerability [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
To assess the safety, tolerability and toxicity of entinostat and 5-AZA To explore the effect of entinostat and 5-AZA on median disease-free and overall survival To assess the pharmacodynamic effects of 5-AZA and entinostat on DNA methylation and gene re-expression To estimate the effect of entinostat and 5-AZA on progression free survival comparing patients with N2 lymph nodes categorized as methylated pre-treatment with those who are categorized as unmethylated To establish factors that predict clinical outcome in patients treated with combination epigenetic therapy
Not Provided
Not Provided
 
Azacitidine and Entinostat in Treating Patients With Stage I Non-Small Cell Lung Cancer That Has Been Removed By Surgery
Randomized Phase II Trial of Adjuvant Combined Epigenetic Therapy With 5-Azacitidine and Entinostat in Resected Stage I Non-small Cell Lung Cancer Versus Standard Care

This study combines the deoxyribonucleic acid (DNA) methyltransferase inhibitor, 5-azacitidine (5-AZA), with an orally bioavailable histone deacetylase inhibitor, entinostat (SNDX-275), for the adjuvant treatment of patients with resected stage I non-small cell lung cancer (NCSLC).

PRIMARY OBJECTIVES:

I. To assess the effect of 5-azacitidine and entinostat on the hazard of 3 year progression-free survival in patients with resected stage I non-small cell lung cancer.

SECONDARY OBJECTIVES:

I. To assess the safety, tolerability and toxicity of entinostat and 5-azacitidine in patients with resected stage I non-small cell lung cancer.

II. To explore the effect of entinostat and 5-azacitidine on median disease-free and overall survival in patients with resected stage I non-small cell lung cancer.

III. To assess the pharmacodynamic effects of 5-azacitidine and entinostat on DNA methylation and gene re-expression in patients with resected stage I NSCLC through analysis of sputum.

IV. To estimate the effect of entinostat and 5-azacitidine on progression free survival comparing patients with N2 lymph nodes categorized as methylated pre-treatment with those who are categorized as unmethylated.

V. To establish factors that predict clinical outcome in patients treated with combination epigenetic therapy by performing genome-wide analyses on pre-treatment tumor DNA.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive azacitidine subcutaneously (SC) on days 1-5 and 8-10 and entinostat orally (PO) once daily (QD) on days 3 and 10. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive standard of care.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Stage IA Non-small Cell Lung Cancer
  • Stage IB Non-small Cell Lung Cancer
  • Drug: azacitidine
    Given SC
  • Drug: entinostat
    Given PO
  • Other: laboratory biomarker analysis
    Correlative studies
  • Experimental: Arm I (azacitidine, entinostat)
    Patients receive azacitidine SC on days 1-5 and 8-10 and entinostat PO QD on days 3 and 10. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: azacitidine
    • Drug: entinostat
    • Other: laboratory biomarker analysis
  • No Intervention: Arm II (standard of care)
    Patients receive standard of care.
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
258
Not Provided
May 2013   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Patients must be status post complete (R0) surgical resection of pathologically-proven NSCLC (stage IA-IB according to AJCC version 7)
  • Patients must be at least 4 weeks out from completion of surgery
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Absolute neutrophil count >= 1,000/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< 1.5 X institutional upper limit of normal
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
  • Creatinine =< 1.5 X institutional upper limit of normal
  • The effects of entinostat and 5-azacitidine on the developing human fetus at the recommended therapeutic dose are unknown; for this reason, 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 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 must be within 8 weeks of completing surgery
  • Patients who have received prior chemotherapy or radiation for treatment of their current diagnosis of lung cancer
  • Patients with sub-lobar resections (ie: wedge resection or segmentectomy)
  • Patients without mediastinal lymph node specimens from mediastinoscopy or surgery (at least level R4 or 7 for right sided tumors OR at least level 5, 6 or 7 for left sided tumors)
  • Patients may not be receiving any other investigational agents
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to entinostat, 5-azacitidine or other agents used in the study
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic 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 because entinostat and 5-azacitidine are agents with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with entinostat or 5-azacitidine, breastfeeding should be discontinued if the mother is treated on this protocol; these potential risks may also apply to other agents used in this study
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with entinostat or 5-azacitidine; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01207726
NCI-2012-02901, NCI-2012-02901, NA_00038631, J1037, 8311, P30CA006973
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Charles Rudin Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital
National Cancer Institute (NCI)
October 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP