Azacitidine and Entinostat in Treating Patients With Recurrent Advanced Non-Small Cell Lung Cancer
This phase I/II trial is studying the side effects and best dose of azacitidine when given together with entinostat and to see how well they work in treating patients with recurrent advanced non-small cell lung cancer. Azacitidine and entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving azacitidine together with entinostat may kill more tumor cells.
Recurrent Non-small Cell Lung Cancer
Stage IIIA Non-small Cell Lung Cancer
Stage IIIB Non-small Cell Lung Cancer
Stage IV Non-small Cell Lung Cancer
Other: pharmacological study
Other: laboratory biomarker analysis
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I/II Study of Entinostat in Combination With 5-Azacytidine in Patients With Recurrent Advanced Non-Small Cell Lung Cancer|
- Maximum tolerated dose (MTD) of azacitidine when given together with entinostat, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 (phase I) [ Time Frame: Up to 28 days ] [ Designated as safety issue: Yes ]
- Objective response rate after treatment with azacitidine and entinostat using the Response Evaluation Criteria in Solid Tumors (RECIST) (phase II) [ Time Frame: Up to 8 years ] [ Designated as safety issue: No ]
- Effect of entinostat and azacitidine on DNA methylation patterns and gene expression [ Time Frame: Baseline and days 10 and 29 ] [ Designated as safety issue: No ]The frequency of significant demethylation and acetylation will be summarized across dosing cohorts of azacitidine. The difference between the methylation indices post-and pre-treatment will be compared using paired Student's t-test. Similar analyses will be performed for the acetylation index. Relationships between changes in gene re-expression and clinical response will be assessed using Fisher's exact tests.
- Pharmacokinetic profile of entinostat and azacitidine [ Time Frame: Baseline, day 1, 10, 15, 17, and 22 ] [ Designated as safety issue: No ]A Mann-Whitney U test and logistic regression will be used to evaluate the association between azacitidine or entinostat exposure and methylation and acetylation changes expressed as a categorical variable (i.e.: response or no response). The azacitidine exposure parameters explored will be maximum plasma concentrations (Cmax) and area under the concentration-time curve (AUC). The entinostat exposure parameters explored will be Vss.
- Progression-free survival [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]Determined by the method determined by Kaplan and Meier. 95% confidence intervals will be estimated.
- Overall survival [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]Determined by the method determined by Kaplan and Meier. 95% confidence intervals will be estimated.
- Effect of entinostat and azacitidine on enhancing response to subsequent therapy [ Time Frame: Up to 8 years ] [ Designated as safety issue: No ]
|Study Start Date:||August 2006|
|Estimated Primary Completion Date:||July 2014 (Final data collection date for primary outcome measure)|
Experimental: Treatment (azacitidine, entinostat)
Patients receive azacitidine SC on days 1-6 and 8-10 and entinostat PO on days 3 and 10. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Other Names:Drug: azacitidine
Other Names:Other: pharmacological study
Other Name: pharmacological studiesOther: laboratory biomarker analysis
I. To assess safety, characterize toxicities, and determine the maximum tolerated dose of 5-AZA (azacitidine) with a fixed-dose of entinostat in patients with recurrent advanced non-small cell lung cancer (NSCLC). (Phase I) II. To determine the objective response rate of 5-AZA and entinostat in patients with recurrent NSCLC. (Phase II)
I. To determine the pharmacokinetic profile of 5-AZA and entinostat in patients with recurrent NSCLC.
II. To assess the pharmacodynamic effects of 5-AZA and entinostat on deoxyribonucleic acid (DNA) methylation, histone acetylation, and gene re-expression in patients with recurrent NSCLC through analysis of blood, sputum and tissue biopsies.
III. To explore the effect of 5-AZA and entinostat on progression-free and overall survival in patients with recurrent advanced non-small cell lung cancer.
IV. To explore the differing response rates and progression-free survivals of two schedules of 5-AZA and entinostat in patients with recurrent advanced non-small cell lung cancer.
OUTLINE: This is a multicenter, phase I, dose-escalation study of azacitidine followed by an open-label, phase II study.
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 in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months.
|United States, California|
|USC Norris Comprehensive Cancer Center||Recruiting|
|Los Angeles, California, United States, 90033|
|Contact: Barbara J. Gitlitz 323-865-3906 firstname.lastname@example.org|
|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 email@example.com|
|Principal Investigator: Phillip A. Dennis|
|Johns Hopkins University||Recruiting|
|Baltimore, Maryland, United States, 21287-8936|
|Contact: John M. Wrangle 410-955-7161 firstname.lastname@example.org|
|Principal Investigator: John M. Wrangle|
|Principal Investigator:||John Wrangle||Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital|