Azacitidine and Entinostat in Treating Patients With Stage I Non-Small Cell Lung Cancer That Has Been Removed By Surgery
This study is currently recruiting participants.
Verified January 2013 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01207726
First received: September 10, 2010
Last updated: January 11, 2013
Last verified: January 2013
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Purpose
This study combines the 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
| Condition | Intervention | Phase |
|---|---|---|
|
Stage IA Non-small Cell Lung Cancer Stage IB Non-small Cell Lung Cancer |
Drug: azacitidine Drug: entinostat 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: | 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 |
Resource links provided by NLM:
Further study details as provided by National Cancer Institute (NCI):
Primary Outcome Measures:
- 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%.
Secondary Outcome Measures:
- 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 ]
| Estimated Enrollment: | 258 |
| Study Start Date: | September 2010 |
| Estimated Primary Completion Date: | September 2015 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
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.
|
Drug: azacitidine
Given SC
Other Names:
Drug: entinostat
Given PO
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
No Intervention: Arm II (standard of care)
Patients receive standard of care.
|
Detailed Description:
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.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Criteria
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
- ECOG performance status =< 2
- Absolute neutrophil count >= 1,000/mcL
- Platelets >= 100,000/mcL
- Total bilirubin =< 1.5 X institutional upper limit of normal
- AST(SGOT)/ALT(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
- 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
Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01207726
Locations
| United States, Florida | |
| H. Lee Moffitt Cancer Center and Research Institute | Recruiting |
| Tampa, Florida, United States, 33612 | |
| Contact: Jhanelle E. Gray 813-745-3050 jhanelle.gray@moffitt.org | |
| Principal Investigator: Jhanelle E. Gray | |
| United States, Maryland | |
| Anne Arundel Medical Center | Recruiting |
| Annapolis, Maryland, United States, 21401 | |
| Contact: Peter R. Graze 410-573-5300 pgraze@aahs.org | |
| Principal Investigator: Peter R. Graze | |
| Johns Hopkins University | Recruiting |
| Baltimore, Maryland, United States, 21287-8936 | |
| Contact: Charles M. Rudin 410-502-0678 rudin@jhmi.edu | |
| Principal Investigator: Charles M. Rudin | |
| United States, Pennsylvania | |
| University of Pittsburgh Cancer Institute | Recruiting |
| Pittsburgh, Pennsylvania, United States, 15232 | |
| Contact: James D. Luketich 412-647-2911 luketichjd@upmc.edu | |
| Principal Investigator: James D. Luketich | |
| United States, Tennessee | |
| Vanderbilt University | Recruiting |
| Nashville, Tennessee, United States, 37232 | |
| Contact: Leora Horn 615-322-4967 leora.horn@vanderbilt.edu | |
| Principal Investigator: Leora Horn | |
| United States, Texas | |
| University of Texas Southwestern Medical Center | Recruiting |
| Dallas, Texas, United States, 75390 | |
| Contact: Joan H. Schiller 214-648-4180 joan.schiller@utsouthwestern.edu | |
| Principal Investigator: Joan H. Schiller | |
Sponsors and Collaborators
Investigators
| Principal Investigator: | Charles Rudin | Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital |
More Information
No publications provided
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT01207726 History of Changes |
| Other Study ID Numbers: | NCI-2012-02901, J1037 |
| Study First Received: | September 10, 2010 |
| Last Updated: | January 11, 2013 |
| Health Authority: | United States: Food and Drug Administration |
Additional relevant MeSH terms:
|
Carcinoma, Non-Small-Cell Lung Lung Neoplasms Carcinoma, Bronchogenic Bronchial Neoplasms Respiratory Tract Neoplasms Thoracic Neoplasms Neoplasms by Site Neoplasms Lung Diseases Respiratory Tract Diseases |
Azacitidine Histone Deacetylase Inhibitors Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Antineoplastic Agents Therapeutic Uses Enzyme Inhibitors |
ClinicalTrials.gov processed this record on June 17, 2013