Details

Details

Title A Randomized Phase II Trial to Simultaneously Evaluate Two Schedules of the Histone Deacetylase Inhibitor Entinostat in Combination with 5-Azacytidine (5AC, NSC 102816) in Elderly Patients with Acute Myeloid Leukemia (AML)

IRB CASE2914

CC 15-851

Hospital Main Campus

Phase Phase 2

Disease Leukemia - Acute Myeloid (AML)

Drug Entinostat, Vidaza (Azacitidine)

Description

Description

Primary Objective
  1. To estimate the major response rate (complete and partial responses by the International Working Group (IWG) response criteria) in patients with 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 50mg/m2 subcutaneously/intravenously for 10 days on days 1 - 10 of a 28 day cycle given in combination with entinostat 8 mg (flat dose) administered orally on days 3 and10 of each cycle or (b) the same regimen of 5AC with entinostat given on days 10 and 17.
  2. To estimate the overall response rate (complete, partial, and hematologic improvement- major by IWG criteria) following treatment with two different dose schedules of 5-Azacytidine 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.
Secondary Objective(s)
  1. 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.
  2. To evaluate the effect of entinostat on the induction of hyperacetylation of histones from peripheral blood and/or bone marrow samples.
  3. To evaluate changes in DNA damage in response to combination therapy using gammaH2AX determination by western blotting.
  4. 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.
  5. To evaluate duration of response.
Inclusion Criteria

Inclusion Criteria

  1. One of the following:
    • Untreated AML (de novo or treatment related) in 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
  2. ECOG performance status 0, 1, or 2 (see Appendix A)
  3. Age ≥60 years
  4. Patients must not have untreated active infections at the time of study entry
  5. Normal Organ Function as defined below:
    • Creatinine < 2 mg/dl
    • Total serum bilirubin within institutional limits unless due to hemolysis, Gilbert's Syndrome, or ineffective erythropoiesis
    • AST (SGOT)/ALT (SGPT) ≤ 2.5x institutional upper limit of normal
  6. Life expectancy of at least 3 months
  7. 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.
  8. Declined or ineligible for potentially curative options such as allogenic stem cell transplant
  9. No chemotherapy or study drugs for >3 weeks prior to starting study
  10. 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

Exclusion Criteria

  1. 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 WBC > 30,000/μL (see Section 6.2.1)
    • Diagnosis of APL
    • 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)
  2. Prior therapy with demethylating agents within the last four months.
  3. Clinical evidence of CNS or pulmonary leukostasis, disseminated intravascular coagulation, or CNS leukemia.
  4. Serious or uncontrolled medical conditions.
  5. Concurrent use of any other investigational agents.
  6. Known HIV-positive patients.
  7. Pregnancy or breast feeding
  8. 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.