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Entinostat and Azacitidine in Treating Older Patients with Acute Myeloid Leukemia

Trial Status: Active

This randomized phase II trial studies how well giving two different schedules of entinostat together with azacitidine works in treating older patients with acute myeloid leukemia. Entinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known which schedule of entinostat is more effective in treating acute myeloid leukemia.

Inclusion Criteria

  • One of the following: * Untreated AML in (de novo or treatment related) patients of age >= 60 years in the following categories: ** Medical conditions that compromise the ability to give cytotoxic chemotherapy as the primary modality ** Patients who decline cytotoxic chemotherapy * Patients with AML of age >= 60 years who have relapsed despite one prior regimen
  • Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
  • Patients must not have untreated active infections at the time of study entry
  • Creatinine < 2 mg/dl
  • Total serum bilirubin within institutional limits unless due to hemolysis, Gilbert’s syndrome, or ineffective erythropoiesis
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
  • Life expectancy of at least 3 months
  • Patients must be informed of the investigational nature of the treatment, results that might be expected, and potential toxicities; they must be able to understand and give informed written consent according to federal and institutional guidelines
  • Declined or ineligible for potentially curative options such as allogeneic stem cell transplant
  • No chemotherapy or study drugs for > 3 weeks prior to starting study
  • Women of childbearing potential should be advised to avoid becoming pregnant and men should be advised to not father a child while receiving treatment; all men and women of childbearing potential must use acceptable methods of birth control throughout the study as described below; females of childbearing potential: recommendation is for 2 effective contraceptive methods during the study; adequate forms of contraception are double-barrier methods (condoms with spermicidal jelly or foam and diaphragm with spermicidal jelly or foam), oral, depo Provera, or injectable contraceptives, intrauterine devices, and tubal ligation; male patients with female partners who are of childbearing potential: recommendation is for male and partner to use at least 2 effective contraceptive methods, as described above, during the study or to abstain

Exclusion Criteria

  • Any of the Following: * Treatment for AML, including hematopoietic growth factors, < 3 weeks prior to study registration; exception: hydroxyurea may be administered to patients with white blood cell (WBC) > 30,000/uL * Radiotherapy < 4 weeks prior to study registration * Failure to recover (to < grade 1) from all adverse events associated with prior therapy * Valproic acid < 2 weeks prior to study registration * Hypersensitivity to azacytidine, deoxyazacytidine, mannitol, entinostat or components of the entinostat tablet * Any advanced malignant hepatic tumor(s)
  • Prior therapy with demethylating agents within the last four months
  • Clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated intravascular coagulation, or CNS leukemia
  • Serious or uncontrolled medical conditions
  • Concurrent use of any other investigational agents
  • Known human immunodeficiency virus- (HIV) positive patients
  • Pregnancy or breast feeding
  • Male and female patients who are fertile who do not agree to use an effective barrier methods of birth control (i.e. abstinence) to avoid pregnancy during the study and for a minimum of 30 days after study treatment


New Haven
Yale University
Status: ACTIVE
Contact: Steven D. Gore
Phone: 203-785-5702


Johns Hopkins University / Sidney Kimmel Cancer Center
Contact: Ivana Gojo
Phone: 410-502-7726


Case Comprehensive Cancer Center
Status: ACTIVE
Contact: Hetty Eileen Carraway
Phone: 866-223-8100


I. To estimate the major response rate (complete and partial responses by the International Working Group [IWG] response criteria) in patients with acute myeloid leukemia (AML) who are >= 60 years old and unable to tolerate or decline cytotoxic chemotherapy or patients who have relapsed despite one prior regimen and are treated with (a) 5AC (azacitidine) 50 mg/m^2 subcutaneously/intravenously for 10 on days 1 – 10 of a 28 day cycle given in combination with entinostat 8 mg (flat dose) administered orally on days 3 and 10 of each cycle or (b) the same regimen of 5AC with entinostat given on days 10 and 17.

II. To estimate the overall response rate (complete, partial, and hematologic improvement- major by IWG criteria) in response to two different dose schedules of 5-azacytidine (azacitidine) and entinostat in patients with AML >= 60 years old who are unable to tolerate or decline cytotoxic chemotherapy or those who have relapsed despite one prior regimen.


I. To identify changes in gene promoter methylation and gene expression in response to combination therapy with 5AC and entinostat and compare the dynamics and kinetics of these alterations in promoter methylation and gene re-expression in the two different dosing schedules.

II. To evaluate the effect of entinostat on the induction of hyperacetylation of histones from peripheral blood and/or bone marrow samples.

III. To evaluate changes in deoxyribonucleic acid (DNA) damage in response to combination therapy using gamma H2A histone family, member X (H2AX) determination by western blotting.

IV. To evaluate immune parameters after exposure to 5AC and entinostat when given at either dosing schedule and to evaluate these in relation to clinical outcomes.

V. To evaluate duration of response.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive azacitidine subcutaneously (SC) or intravenously (IV) daily on days 1-10 and entinostat orally (PO) on days 3 and 10.

ARM B: Patients receive azacitidine as in Arm A and entinostat PO on days 10 and 17.

In both arms, treatment repeats every 28 days for up to 15 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 28 days.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Case Comprehensive Cancer Center

Principal Investigator
Hetty Eileen Carraway

  • Primary ID CASE2914
  • Secondary IDs NCI-2011-03564, NA_00038036, VZ-AML-PI-0157
  • ID NCT01305499