Clinical Trials /

Vorinostat Dose-escalation After Allogeneic Hematopoietic Cell Transplantation

NCT03843528

Description:

The objective of this study is to evaluate the maximum tolerated (MTD) of vorinostat used in combination with low-dose azacitidine after allogeneic hematopoietic cell transplantation (alloHCT) for prevention of relapse of childhood myeloid malignancies.

Related Conditions:
  • Acute Myeloid Leukemia
  • Juvenile Myelomonocytic Leukemia
  • Mixed Phenotype Acute Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Vorinostat Dose-escalation After Allogeneic Hematopoietic Cell Transplantation
  • Official Title: Epigenetic Modification for Relapse Prevention: a Dose-finding Study of Vorinostat Used in Combination With Low-dose Azacitidine in Children Undergoing Allogeneic Hematopoietic Cell Transplantation for Myeloid Malignancies

Clinical Trial IDs

  • ORG STUDY ID: IRB00202540
  • NCT ID: NCT03843528

Conditions

  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
  • Mixed Phenotype Acute Leukemia
  • Juvenile Myelomonocytic Leukemia

Interventions

DrugSynonymsArms
VorinostatCombined therapy
Azacitidine InjectionCombined therapy

Purpose

The objective of this study is to evaluate the maximum tolerated (MTD) of vorinostat used in combination with low-dose azacitidine after allogeneic hematopoietic cell transplantation (alloHCT) for prevention of relapse of childhood myeloid malignancies.

Detailed Description

      Children and adolescents ages 1 to 21 years of age who are undergoing allogeneic
      hematopoietic cell transplantation for a myeloid malignancy (AML, MDS, JMML, MPAL) will be
      eligible. There are no restrictions on donor type, conditioning, stem cell source, of GVHD
      prophylaxis approach.

      All participants will be treated on a single arm, and will initially receive 2 cycles of
      standard post-transplant azacitidine at a dose of 32mg/m2/dose IV/subcutnaeous for 5 days, in
      28 day cycles. This is considered standard of care.

      After tolerance of 2 cycles of azacitidine has been established, patients will be assigned to
      receive vorinostat orally at different dose levels, depending on the stage of the study. The
      dose level assignments will be conducted on a standard 3+3 design, whereby dose-escalation is
      peformed if previous patients tolerated the dose without dose-limiting toxicities, and
      dose-reduction is performed if dose-limiting toxicities are seen. The starting dose will be
      100mg/m2/dose on days 1-7 and 15-21 of each 28 day cycles. This will be in addition to
      receiving azacitidine at the fixed dose above. In order to start each cycle, participants
      will be required to meet specific clinical parameters to ensure safety.

      The dose of vorinostat between patients will be escalated or de-escalated until criteria for
      finding the maximum tolerated dose (MTD) is reached, and this will complete the study.
      Participants will continue to receive the prescribed dose of vorinostat for up to 7 cycles (9
      total cycles of azacitidine).

      Participants are followed for dose-limiting toxicities primarily during the first two course
      of combined therapy (cycles 3 and 4), but are continued to be tracked until the completion of
      all potential combined treatment (1 year or 7 combined cycles, whichever is earlier).

      Principal aims:

      1. To evaluate the maximum tolerated dose (MTD) of vorinostat used in combination with
      low-dose azacitidine after allogeneic hematopoietic cell transplantation (alloHCT) for
      childhood myeloid malignancies.

      Secondary aims:

        1. To describe the dose-limiting toxicities (DLT) of the vorinostat used in combination
           with low-dose azacitidine.

        2. To describe rates of relapse, transplant related mortality, graft-versus-host disease,
           and overall survival.

        3. To describe the effect of epigenetic modification on lymphocyte reconstitution in the
           post-alloHCT setting.
    

Trial Arms

NameTypeDescriptionInterventions
Combined therapyExperimentalPatients will be enrolled in blocks of 3, with vorinostat dose-escalation according to 3+3 study design. Low-dose azacitidine will be administered in a fixed dose to all patients, for days 1-5 of each 28 day cycle.
  • Vorinostat
  • Azacitidine Injection

Eligibility Criteria

        Inclusion Criteria:

          1. Patient is 1 year to 21 years of age.

          2. Patient has a diagnosis of AML, MDS, MDS/AML, MPAL, or JMML. Note: patients are
             allowed to have received a HMA or HDACi prior to undergoing alloHCT.

          3. Patient has undergone allogeneic hematopoietic cell transplantation (no restrictions
             on conditioning regimen, donor or stem cell source, or GVHD prophylaxis regimen).

          4. Patient and/or parent(s) or legal guardian(s) are capable of understanding the study,
             including potential benefits and risks, and sign written informed consent.
             Age-appropriate assent will be obtained.

          5. Female patient of childbearing potential has a negative screening pregnancy test
             (urine or serum, as per local institutional standard).

          6. Female patient with infant(s) agrees not to breastfeed her infant(s) while on study.

          7. Patient of child-bearing potential (male and female) agrees to use effective method of
             contraception during the study.

        Exclusion Criteria:

          1. Patient is enrolled on a clinical trial with investigational post-transplant
             medications. Note: trials involving defibrotide and post-transplant cyclophosphamide
             are permitted.

          2. Patient has a planned administration of non-protocol chemotherapy, radiation therapy,
             donor leukocyte infusion, or immunotherapy during the planned study period.

          3. Patient has a known allergy to azacitidine or vorinostat.

          4. Patient has chronic myelogenous leukemia.

          5. Concomitant use of coumarin-derived anticoagulants or valproic acid.

             -
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD)
Time Frame:4 months
Safety Issue:
Description:The primary outcome of this study is to determine the MTD of vorinostat in combination with low-dose azacitidine, using dose-escalation methodology. This is based on toxicities developed by participants enrolled on the study.

Secondary Outcome Measures

Measure:Dose-limiting toxicities
Time Frame:4 months
Safety Issue:
Description:Rates of side effects from vorinostat will be recorded and described.
Measure:GVHD
Time Frame:1 year
Safety Issue:
Description:Incidence of GVHD will be recorded and described.
Measure:Relapse
Time Frame:1 year
Safety Issue:
Description:Incidence of relapse will be recorded and described
Measure:Survival
Time Frame:1 year
Safety Issue:
Description:Duration of survival will be recorded and described
Measure:Immune recovery
Time Frame:1 year
Safety Issue:
Description:Immune profile will be measured monthly for the first year post-transplant.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Johns Hopkins All Children's Hospital

Last Updated

July 9, 2019