Entinostat And Imatinib Mesylate In Treating Patients With Relapsed or Refractory Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of entinostat when
given in combination with imatinib. II. To estimate the rate of complete response (CR) for
adults with relapsed/refractory Ph+ ALL treated with a combination of entinostat and
imatinib. SECONDARY OBJECTIVES: I. To estimate the 1 year progression free survival (PFS)
for adults with relapsed/refractory Ph+ ALL treated with a combination of entinostat and
imatinib. II. To describe the comparative pharmacokinetics (PK) and pharmacodynamics (PD) of
entinostat alone vs. entinostat plus imatinib. III. To assess the predictive value of levels
of flow cytometric minimal residual disease (MRD) on duration of progression free survival
for the study population. OUTLINE: This is a phase I, dose-escalation study of entinostat
followed by a phase II study. Patients receive oral entinostat daily on days 1, 8, 15, and
22 and oral imatinib mesylate twice daily on days 1-28 (days 4-28 of course 1). Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity. After
completion of study treatment, patients are followed up for 30 days.Treatment may continue
up to 1 year.

Inclusion Criteria:

- Patients must have histologically confirmed BCR-ABL1 associated (Ph+) acute
lymphoblastic leukemia (ALL) with primary refractory or relapsed disease;
demonstration of BCR-ABL1 in leukemia cells by one or more of the following is
required: t(9;22)(q34;q11.2) cytogenetics; FISH for BCR-ABL1 fusion; RT-PCR for
BCR-ABL1 fusion

- Prior treatment with tyrosine kinase inhibitors (including imatinib, nilotinib and/or
dasatinib) is allowed, although patients must be off any tyrosine kinase inhibitor
for a minimum of 72 hours prior to beginning protocol therapy

- ECOG performance status of 0, 1 or 2

- Total WBC =< 150,000 with no evidence for ongoing or impending leukostasis

- Total bilirubin =< 2.0 mg/dL unless elevated due to Gilbert's, hemolysis or leukemic
infiltration

- Aspartate transaminase (AST)/alanine transaminase (ALT) =< 2.5 × upper limit of
normal (ULN) unless due to leukemic infiltration

- Serum creatinine =< 2.0 mg/dL or creatinine clearance > 50 ml/min

- Left ventricular ejection fraction (LVEF) >= 45% as measured by echocardiogram (ECHO)
or MUGA

- Patients who have undergone stem cell transplantation (SCT), autologous or
allogeneic, are eligible provided that they are > 4 weeks from stem cell infusion,
have no active GVHD, and meet other eligibility criteria

- Patients who fail primary induction therapy or relapse after achieving complete
remission (CR) are eligible if they are > 3 weeks off cytotoxic chemotherapy and > 2
weeks off radiation therapy; patients must be off biologic therapies including
hematopoietic growth factors > 1 week; if using hydroxyurea (HU), steroids, or other
non-cytotoxics for blast count control, patient must be off for > 24 hrs before
starting protocol therapy; patients must have recovered from all acute toxicities
from any previous therapy

- Female patients of childbearing age must have negative pregnancy test; 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 may not be receiving any other investigational agents

- Active CNS leukemia; patients with known previous CNS leukemia may continue to
receive intrathecal therapy with ara-C, methotrexate, and/or thiotepa plus steroids
as prophylaxis against reactivation of previous CNS disease

- Patients may not have received previous treatment with entinostat or other HDAC
inhibitors

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to entinostat or other agents used in study

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
untreated infection, symptomatic congestive heart failure, unstable angina pectoris,
unstable cardiac arrhythmia, or psychiatric illness/social situations that would
limit compliance with study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with entinostat

- HIV-positive patients on combination antiretroviral therapy are ineligible