A Phase I Study of the Histone Deacetylase Inhibitor Entinostat (SNDX-275, NSC 706995, IND#61198) Plus Clofarabine for Philadelphia Chromosome-Negative, Poor Risk Acute Lymphoblastic Leukemia or Bilineage/Biphenotypic Leukemia in Newly Diagnosed Older Adults or in Adults With Relapsed and Refractory Disease
I. To determine the feasibility, tolerability, toxicities, and maximum tolerated dose (MTD)
of entinostat plus clofarabine for: adult patients age 40 and over with newly diagnosed,
poor-risk Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) or
bilineage/biphenotypic leukemia (ABL) prior to traditional cyclical multi-agent
chemotherapy, and adults age 21 and over with relapsed or refractory ALL/ABL.
II. To determine if entinostat plus clofarabine can induce clinical responses in adults with
newly diagnosed, poor-risk ALL/ABL and in adults with relapsed/refractory ALL/ABL
I. To determine pharmacokinetics (PK) of entinostat alone and in combination with
II. To obtain descriptive preliminary pharmacodynamic (PD) data regarding the effects of
entinostat alone and in combination with clofarabine on histone acetylation and global and
gene specific methylation in leukemic blasts.
III. To obtain descriptive preliminary data regarding the effects of entinostat alone and in
combination with clofarabine on deoxyribonucleic acid (DNA) damage and apoptosis in leukemic
blasts and residual disease monitored by 6-color flow cytometry.
OUTLINE: This is a multicenter, dose-escalation study of entinostat.
Patients receive entinostat orally (PO) on days 1 and 8 and clofarabine intravenously (IV)
over 2 hours on days 3-7. Courses repeat every 21 days in the absence of disease progression
or unacceptable toxicity (only for patients at least 60 years of age with newly diagnosed
acute lymphoblastic leukemia [ALL] or bilineage/biphenotypic leukemia [ABL] who are unable
or unwilling to tolerate standard multi-agent chemotherapy and patients with relapsed or
refractory ALL or ABL).
Patients 40-59 years of age with newly diagnosed ALL receive standard multi-agent induction
chemotherapy beginning on day 11. Patients at least 21 years of age in their first relapse
with sensitive disease begin initiation of allogeneic transplant after one course of
entinostat and clofarabine.
Blood and/or bone marrow samples are collected periodically for pharmacological and
After completion of study treatment, patients are followed up for 30 days.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Feasibility and tolerability
Up to 3 years
Johns Hopkins University
United States: Food and Drug Administration
|Johns Hopkins University||Baltimore, Maryland 21205|
|University of Maryland Greenebaum Cancer Center||Baltimore, Maryland 21201|
|University of Colorado Anschutz Medical Campus||Aurora, Colorado 80045|