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A Trial to Evaluate Two Schedules of MS275 in Combination With 5AC in Elderly Patients With Acute Myeloid Leukemia (AML)

NCT01305499

Description:

This research is being done to help us learn how to best use new drugs which may be active against acute myeloid leukemia (AML). Two study drugs will be tested: 5AC (5-azacitidine) and entinostat. 5AC improves blood counts in 50 - 60% of patients with MDS and has also shown promise in AML. Entinostat has undergone early testing in patients with MDS and AML. It has decreased the blast count in some patients' blood and bone marrow and has improved the blood counts in some patients. The combinations of these two classes of drugs are well tolerated and appear to work well together in laboratory tests. A recent study at Johns Hopkins University administered 5AC and entinostat in an overlapping schedule to patients with myelodysplastic syndrome (MDS), Chronic myelomonocytic leukemia (CMMoL), and AML. The impressive results from this study have led to another phase II trial to further examine this drug combination versus 5AC alone in these patients. In this study, we want to see how the timing of when 5AC and entinostat are given affects the magnitude of the disease response.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Trial to Evaluate Two Schedules of MS275 in Combination With 5AC in Elderly Patients With Acute Myeloid Leukemia (AML)
  • Official 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)

Clinical Trial IDs

  • ORG STUDY ID: CASE2914
  • SECONDARY ID: 15-851
  • NCT ID: NCT01305499

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Entinostat days 3, 10MS275A: 5AC days 1-10 / entinostat days 3, 10
5AC5-azacitidineA: 5AC days 1-10 / entinostat days 3, 10
Entinostat days 10,17MS275B: 5AC days 1-10 / entinostat days 10,17

Purpose

This research is being done to help us learn how to best use new drugs which may be active against acute myeloid leukemia (AML). Two study drugs will be tested: 5AC (5-azacitidine) and entinostat. 5AC improves blood counts in 50 - 60% of patients with MDS and has also shown promise in AML. Entinostat has undergone early testing in patients with MDS and AML. It has decreased the blast count in some patients' blood and bone marrow and has improved the blood counts in some patients. The combinations of these two classes of drugs are well tolerated and appear to work well together in laboratory tests. A recent study at Johns Hopkins University administered 5AC and entinostat in an overlapping schedule to patients with myelodysplastic syndrome (MDS), Chronic myelomonocytic leukemia (CMMoL), and AML. The impressive results from this study have led to another phase II trial to further examine this drug combination versus 5AC alone in these patients. In this study, we want to see how the timing of when 5AC and entinostat are given affects the magnitude of the disease response.

Detailed Description

      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.

      The secondary objectives of the study are:

        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.
    

Trial Arms

NameTypeDescriptionInterventions
A: 5AC days 1-10 / entinostat days 3, 10ExperimentalArm A will be given an overlapping schedule of drugs with 5AC given at 50mg/m2 subcutaneously daily for 10 days on days 1 - 10 of a 28 day cycle and entinostat given at a flat dose of 8 mg orally on days 3 and 10.
  • Entinostat days 3, 10
  • 5AC
B: 5AC days 1-10 / entinostat days 10,17ExperimentalIn Arm B the agents will be administered sequentially with 5AC given at 50mg/m2 subcutaneously daily for 10 days on days 1 - 10 of a 28 day cycle followed by entinostat at a 8 mg flat dose on days 10 and 17.
  • 5AC
  • Entinostat days 10,17

Eligibility Criteria

        Inclusion Criteria:

          1. One of the following:

             Untreated AML in (de novo or treatment related) patients 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 who have relapsed despite one prior regimen

          2. ECOG performance status 0, 1, or 2

          3. Patients must not have untreated active infections at the time of study entry.

          4. 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) ≤2.5 X institutional upper limit of normal.

          5. Life expectancy of at least three months.

          6. 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.

          7. Declined or ineligible for potentially curative options such as allogeneic stem cell
             transplant.

          8. No chemotherapy or study drugs for >3 weeks prior to starting study.

          9. 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

          1. Any of the Following:

               -  Treatment for acute myeloid leukemia (AML), including hematopoietic growth
                  factors, < 3 weeks prior to study registration. Exception: Hydroxyurea may be
                  administered to patients with WBC > 30,000/µL

               -  Diagnosis of acute promyelocytic leukemia (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 for leukemia treatment within the last four
             months.

          3. Clinical evidence of CNS or pulmonary leukostasis, disseminated intravascular
             coagulation, or central nervous system 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:60 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To estimate the major response rate 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.
Time Frame:Up to 15 cycles (420 days)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:To identify changes in gene promoter methylation and gene expression in response to combination therapy and compare the dynamics and kinetics of these alterations in promoter methylation and gene re-expression in the two different dosing schedules.
Time Frame:Up to 15 cycles (420 days)
Safety Issue:
Description:
Measure:To evaluate the effect of entinostat on the induction of hyperacetylation of histones from peripheral blood and/or bone marrow samples.
Time Frame:Up to 15 cycles (420 days)
Safety Issue:
Description:
Measure:To evaluate changes in DNA damage in response to combination therapy using gammaH2AX determination by western blotting.
Time Frame:Up to 15 cycles (420 days)
Safety Issue:
Description:
Measure:To evaluate the pharmacodynamics of 5AC and entinostat when given at either dosing schedule and to evaluate these in relation to pharmacokinetic and clinical outcomes.
Time Frame:Up to 15 cycles (420 days)
Safety Issue:
Description:
Measure:To evaluate duration of response.
Time Frame:Up to 15 cycles (420 days)
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hetty Carraway

Trial Keywords

  • AML

Last Updated

December 18, 2019