A Phase I/II Study of Entinostat in Combination With 5-Azacytidine in Patients With Recurrent Advanced Non-Small Cell Lung Cancer
I. Determine the maximum tolerated dose (MTD) of azacitidine when given together with MS-275
in patients with recurrent advanced non-small cell lung cancer. (Phase I) II. Determine the
safety and toxicity of this regimen in these patients. (Phase I) III. Determine the
objective response rate in patients treated with this regimen. (Phase II)
I. Determine the pharmacokinetic profile of azacitidine and MS-275 in these patients.
II. Assess the pharmacodynamic effects of azacitidine and MS-275 on DNA methylation, histone
acetylation, and gene re-expression by blood and sputum analysis (and tissue biopsies from
III. Assess the effect of azacitidine and MS-275 on progression-free survival and overall
survival of these patients.
OUTLINE: This is a multicenter, phase I, dose-escalation study of azacitidine followed by an
open-label, phase II study.
PHASE I: Patients receive azacitidine subcutaneously (SC) on days 1-6 and 8-10 and MS-275
orally (PO) on days 3 and 10. Treatment repeats every 28 days in the absence of disease
progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of
azacitidine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the
dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
PHASE II: Patients receive azacitidine as in phase I at the MTD determined in phase I and
MS-275 as in phase I.
Patients undergo plasma sample collection for pharmacokinetic evaluation before beginning
treatment and then at days 1, 10, and 17. Patients also undergo blood and sputum collection
to evaluate the pharmacodynamic effects of azacitidine and MS-275 on deoxyribonucleic acid
(DNA) methylation before beginning treatment and then at days 10 and 29.
After completion of study treatment, patients are followed periodically for 4 weeks.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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)
Up to 28 days
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital
United States: Food and Drug Administration
|Johns Hopkins University||Baltimore, Maryland 21205|
|USC Norris Comprehensive Cancer Center||Los Angeles, California 90089|
|M D Anderson Cancer Center||Houston, Texas 77030|
|Johns Hopkins Bayview Medical Center||Baltimore, Maryland 21224|