Azacitidine and Entinostat in Treating Patients With Recurrent Advanced Non-Small Cell Lung Cancer
|ClinicalTrials.gov Identifier: NCT00387465|
Recruitment Status : Completed
First Posted : October 13, 2006
Last Update Posted : May 1, 2015
|Condition or disease||Intervention/treatment||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 Other: Laboratory Biomarker Analysis Other: Pharmacological Study||Phase 1 Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||162 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I/II Study of Entinostat in Combination With 5-Azacytidine in Patients With Recurrent Advanced Non-Small Cell Lung Cancer|
|Study Start Date :||August 2006|
|Actual Primary Completion Date :||July 2014|
|Actual Study Completion Date :||November 2014|
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: Laboratory Biomarker Analysis
Other: Pharmacological Study
- 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 ]
- 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 ]
- Effect of entinostat and azacitidine on DNA methylation patterns and gene expression [ Time Frame: Baseline and days 10 and 29 ]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.
- Effect of entinostat and azacitidine on enhancing response to subsequent therapy [ Time Frame: Up to 8 years ]
- Overall survival [ Time Frame: Up to 1 year ]Determined by the method determined by Kaplan and Meier. 95% confidence intervals will be estimated.
- Pharmacokinetic profile of entinostat and azacitidine [ Time Frame: Baseline, day 1, 10, 15, 17, and 22 ]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 ]Determined by the method determined by Kaplan and Meier. 95% confidence intervals will be estimated.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00387465
|United States, California|
|USC Norris Comprehensive Cancer Center|
|Los Angeles, California, United States, 90033|
|Sidney Kimmel Cancer Center|
|San Diego, California, United States, 92121|
|United States, Maryland|
|Johns Hopkins Bayview Medical Center|
|Baltimore, Maryland, United States, 21224|
|Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital|
|Baltimore, Maryland, United States, 21231|
|Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center|
|Baltimore, Maryland, United States, 21287|
|Principal Investigator:||John Wrangle||Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital|