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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2016 by Case Comprehensive Cancer Center
Sponsor:
Information provided by (Responsible Party):
Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT01305499
First received: February 25, 2011
Last updated: March 7, 2016
Last verified: March 2016
  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.


Condition Intervention Phase
Acute Myeloid Leukemia
Drug: Entinostat days 3, 10
Drug: 5AC
Drug: Entinostat days 10,17
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by Case Comprehensive Cancer Center:

Primary Outcome Measures:
  • 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) ] [ Designated as safety issue: No ]
  • To estimate the overall response rate following treatment 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. [ Time Frame: Up to 15 cycles (420 days) ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • To evaluate duration of response. [ Time Frame: Up to 15 cycles (420 days) ] [ Designated as safety issue: No ]

Estimated Enrollment: 108
Study Start Date: July 2011
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A: 5AC days 1-10 / entinostat days 3, 10
Arm 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.
Drug: Entinostat days 3, 10
Given orally on days 3, 10
Other Name: MS275
Drug: 5AC
Other Name: 5-azacitidine
Experimental: B: 5AC days 1-10 / entinostat days 10,17
In 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.
Drug: 5AC
Other Name: 5-azacitidine
Drug: Entinostat days 10,17
Given orally on days 10, 17
Other Name: MS275

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.
  Eligibility

Ages Eligible for Study:   60 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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

  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 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 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 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01305499

Contacts
Contact: Ivana Gojo, MD 410-502-7726 igojo1@jhmi.edu

Locations
United States, Connecticut
Yale School of Medicine Not yet recruiting
New haven, Connecticut, United States, 06520
Contact: Steven Gore, MD       steven.gore@yale.edu   
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Active, not recruiting
Baltimore, Maryland, United States, 21231
United States, Ohio
Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center Recruiting
Cleveland, Ohio, United States, 44195
Contact: Hetty Carraway, MD, MBA    216-445-5899    carrawh@ccf.org   
Sponsors and Collaborators
Case Comprehensive Cancer Center
Investigators
Principal Investigator: Hetty Carraway, MD Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
  More Information

Responsible Party: Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT01305499     History of Changes
Other Study ID Numbers: CASE2914  J1093 
Study First Received: February 25, 2011
Last Updated: March 7, 2016
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Case Comprehensive Cancer Center:
AML

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms
Neoplasms by Histologic Type
Azacitidine
Entinostat
Histone Deacetylase Inhibitors
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on May 23, 2016