Clinical Trials /

Phase II Study of 5-azacytidine Maintenance After Transplant for AML or MDS

NCT02204020

Description:

Despite improvements in outcomes after Hematopoietic Cell Transplantation (HCT) for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS), the risk of relapse remains high and is the most common cause of mortality after HCT. Moreover, treatment options for relapse after HCT are limited. Strategies to reduce relapse with maintenance therapy in patients who are at high risk are needed to improve survival. 5-aza is a hypomethylating agent that has shown immune modulating properties that may enhance the graft-versus-leukemia (GVL) effect, including upregulation of tumor-associated antigen and costimulatory molecule expression. Moreover, 5-aza has properties that suggest protection against graft-versus-host disease (GVHD) as well. Preliminary data shows that it is well tolerated and effective in clinical use for the treatment of AML or MDS relapse after HCT, as well as for maintenance therapy. This study will evaluate the use of 5-aza for maintenance after HCT in patients with AML or MDS with risk factors that are associated with a high risk for relapse.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Withdrawn

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase II Study of 5-azacytidine Maintenance After Transplant for AML or MDS
  • Official Title: Phase II Study of 5-azacytidine Maintenance After Allogeneic Hematopoietic Cell Transplantation for High-risk Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)

Clinical Trial IDs

  • ORG STUDY ID: UPCI 13-165
  • NCT ID: NCT02204020

Conditions

  • Acute Myeloid Leukemia (AML)
  • Myelodysplastic Syndrome (MDS)

Interventions

DrugSynonymsArms
5-azacytidine (5-aza) maintenance therapy after transplant5-aza5-azacytidine

Purpose

Despite improvements in outcomes after Hematopoietic Cell Transplantation (HCT) for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS), the risk of relapse remains high and is the most common cause of mortality after HCT. Moreover, treatment options for relapse after HCT are limited. Strategies to reduce relapse with maintenance therapy in patients who are at high risk are needed to improve survival. 5-aza is a hypomethylating agent that has shown immune modulating properties that may enhance the graft-versus-leukemia (GVL) effect, including upregulation of tumor-associated antigen and costimulatory molecule expression. Moreover, 5-aza has properties that suggest protection against graft-versus-host disease (GVHD) as well. Preliminary data shows that it is well tolerated and effective in clinical use for the treatment of AML or MDS relapse after HCT, as well as for maintenance therapy. This study will evaluate the use of 5-aza for maintenance after HCT in patients with AML or MDS with risk factors that are associated with a high risk for relapse.

Detailed Description

      Phase II study of 5-aza maintenance after allogeneic Hematopoietic Cell Transplantation (HCT)
      for high-risk Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS). Early studies
      indicate 5-aza is a hypomethylating agent that has shown immune modulating properties that
      may enhance the graft-versus-leukemia (GVL) effect, including upregulation of
      tumor-associated antigen and costimulatory molecule expression. 5-aza also has properties
      that suggest protection against graft-versus-host disease (GVHD). The primary objective is to
      evaluate relapse rate at one year. Secondary objectives will include the incidence of both
      acute and chronic GVHD as well as relapse-free survival, overall survival and toxicity.
      Correlatives will be performed to evaluate the effect of 5-aza maintenance on the immune
      system.

      Subjects must be transplant candidates with MDS or high risk characteristics of AML. Subjects
      are consented, screened, then transplanted. Those showing complete response and no active
      GVHD after transplant can proceed to maintenance with 5-aza. Bone marrow biopsies are
      performed for response assessment after transplant as well as every three cycles (1 cycle=28
      days) while on treatment. Dosing starts at 32mg/m2 and can be increased every 2 cycles
      without a serious adverse event (SAE), or reduced per toxicity for up to 12 cycles.
    

Trial Arms

NameTypeDescriptionInterventions
5-azacytidineExperimental5-aza SC or IV 32mg/m2 - 75mg/m2 (based on dose escalation)
  • 5-azacytidine (5-aza) maintenance therapy after transplant

Eligibility Criteria

        Inclusion Criteria:

          -  Age≥18 with MDS or high-risk AML, morphologically confirmed and based on World Health
             Organization criteria (see below for definition of high-risk AML)*, who are transplant
             candidates with an available human leukocyte antigen (HLA) -matched sibling or
             unrelated donor with at least 8/8 match

             *Definition of high-risk AML:

          -  Age≥60 years

          -  Age<60 years with any of the following:

               -  Secondary AML

               -  Poor risk cytogenetics, which include abnormalities of chromosome 3, 5, or 7,
                  trisomy 8, 11q23 abnormalities, t(6;9), 20q-, and complex karyotype

               -  Fms-like tyrosine kinase 3 (FLT3) mutation

               -  Disease status ≥ second complete remission (CR2) at time of HCT

               -  Detectable disease at time of HCT

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2

          -  Adequate major organ function, as defined by AST and ALT < 2 x upper limit of normal,
             total serum bilirubin < 2 x upper limit of normal (unless due to hemolysis or
             Gilbert's syndrome, then no upper limit), creatinine < 2 x upper limit of normal,
             unless there is known chronic kidney disease (creatinine must be at baseline for
             subjects with chronic kidney disease)

          -  In agreement to use an effective barrier method of birth control to avoid pregnancy
             during the study and for a minimum of 30 days after study treatment, for all male and
             female patients who are fertile

        Exclusion Criteria:

          -  Uncontrolled, life-threatening infection that is not responding to antimicrobial
             therapy

          -  Serum creatinine > 2 x upper limit of normal, unless there is known chronic kidney
             disease (creatinine must be at baseline for subjects with chronic kidney disease),
             aspartate aminotransferase (AST),alanine aminotransferase (ALT), or total bilirubin >
             2x upper limit of normal

          -  History of psychiatric disorder which may compromise compliance with the protocol or
             which does not allow for appropriate informed consent

          -  Patient may not be receiving any other antineoplastic agents

          -  Pregnancy

          -  Concurrent use of any other investigational agents on a clinical trial

          -  Prior allogeneic stem cell transplant

          -  Known hypersensitivity to 5-azacytidine * Prior treatment with 5-azacytidine is
             allowed

        Post-transplant eligibility and exclusion criteria

        Patients will have to meet the following post-transplant eligibility criteria to initiate
        treatment:

          -  In complete response (including complete remission with incomplete blood count
             recovery and marrow complete response) on bone marrow biopsy for response assessment
             after HCT (typically day +30)

          -  Patient is within 30-100 days after HCT

          -  Absolute neutrophil count (ANC) ≥ 1000/µL, platelet count ≥ 20,000/µL

          -  ECOG performance status 0-2

          -  Adequate major organ function, as defined by AST and ALT < 2 x upper limit of normal,
             total serum bilirubin < 2 x upper limit of normal (unless due to hemolysis or
             Gilbert's syndrome, then no upper limit), creatinine < 2 x upper limit of normal
             unless there is known chronic kidney disease (creatinine must be at baseline for
             subjects with chronic kidney disease)

          -  In agreement to use an effective barrier method of birth control to avoid pregnancy
             during the study and for a minimum of 30 days after study treatment, for all male and
             female patients who are fertile

        Patients may not have any of the following post-transplant exclusion criteria:

          -  Active grade II-IV acute GVHD, for example requiring treatment with steroids at a dose
             equivalent to prednisone 1mg/kg daily or higher

          -  Uncontrolled, life-threatening infection that is not responding to antimicrobial
             therapy

          -  Serum creatinine > 2 x upper limit of normal unless there is known chronic kidney
             disease (creatinine must be at baseline for subjects with chronic kidney disease),
             aspartate aminotransferase (AST),alanine aminotransferase (ALT), or total bilirubin >
             2x upper limit of normal

          -  History of psychiatric disorder which may compromise compliance with the protocol or
             which does not allow for appropriate informed consent

          -  Pregnancy

          -  Concurrent use of any other investigational agents on a clinical trial

          -  Known hypersensitivity to 5-azacytidine * Prior treatment with 5-azacytidine is
             allowed
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Relapse rate at 1 year
Time Frame:3 years
Safety Issue:
Description:Study will evaluate the relapse rate associated with 5-azacytidine (5-aza) as maintenance therapy after HCT in patients with high-risk AML or MDS.

Secondary Outcome Measures

Measure:Safety of Toxicity Requiring Treatment Discontinuation (TRTD)
Time Frame:3 years
Safety Issue:
Description:
Measure:Overall survival
Time Frame:3 years
Safety Issue:
Description:
Measure:Incidence of acute GVHD
Time Frame:3 years
Safety Issue:
Description:
Measure:Percentage of Toxicity Requiring Treatment Discontinuation (TRTD)
Time Frame:3 years
Safety Issue:
Description:
Measure:relapse-free survival
Time Frame:3 years
Safety Issue:
Description:
Measure:Incidence of chronic GVHD
Time Frame:3 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Withdrawn
Lead Sponsor:University of Pittsburgh

Trial Keywords

  • Acute Myeloid Leukemia (AML)
  • Myelodysplastic Syndrome (MDS)
  • allogeneic
  • 5-azacytidine (5-aza)
  • hematopoietic
  • transplantation
  • transplant
  • graft-versus-tumor
  • graft-versus-host disease (GVHD)
  • epigenetic
  • maintenance
  • hypomethylation
  • relapse

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