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Vorinostat Dose-escalation After Allogeneic Hematopoietic Cell Transplantation

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03843528
Recruitment Status : Recruiting
First Posted : February 18, 2019
Last Update Posted : September 9, 2020
Information provided by (Responsible Party):
Benjamin Oshrine, Johns Hopkins All Children's Hospital

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Myelodysplastic Syndromes Mixed Phenotype Acute Leukemia Juvenile Myelomonocytic Leukemia Drug: Vorinostat Drug: Azacitidine Injection Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: 3+3 dose-escalation study
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 1, 2019
Estimated Primary Completion Date : May 1, 2021
Estimated Study Completion Date : December 31, 2021

Arm Intervention/treatment
Experimental: Combined therapy

Patients 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.

Drug: Vorinostat
Vorinostat will be administered concurrent with low-dose azacitidine post-transplant, on days 1-7 and 15-21 of 28 day cycles. This is an oral medication.

Drug: Azacitidine Injection
Azacitidine will be administered on days 1-5 of each 28 day cycle, either by IV or subcutaneous injection. The dose of azacitidine will be fixed, with no dose-escalation.

Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) [ Time Frame: 4 months ]
    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 :
  1. Dose-limiting toxicities [ Time Frame: 4 months ]
    Rates of side effects from vorinostat will be recorded and described.

  2. GVHD [ Time Frame: 1 year ]
    Incidence of GVHD will be recorded and described.

  3. Relapse [ Time Frame: 1 year ]
    Incidence of relapse will be recorded and described

  4. Survival [ Time Frame: 1 year ]
    Duration of survival will be recorded and described

  5. Immune recovery [ Time Frame: 1 year ]
    Immune profile will be measured monthly for the first year post-transplant.

Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03843528

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Contact: Benjamin Oshrine, MD 727-460-9921

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United States, Florida
UF Health Shands Children's Hospital Not yet recruiting
Gainesville, Florida, United States, 32610
Contact: Gigi Moore-Higgs   
Principal Investigator: Paul Castillo Caro, MD         
Johns Hopkins All Children's Hospital Recruiting
Saint Petersburg, Florida, United States, 33701
Contact: Benjamin Oshrine, MD   
Sponsors and Collaborators
Johns Hopkins All Children's Hospital
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Principal Investigator: Benjamin Oshrine, MD Johns Hopkins All Children's Hospital
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Responsible Party: Benjamin Oshrine, Physician, Bone Marrow Transplant, Johns Hopkins All Children's Hospital Identifier: NCT03843528    
Other Study ID Numbers: IRB00202540
First Posted: February 18, 2019    Key Record Dates
Last Update Posted: September 9, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia, Myelomonocytic, Juvenile
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Leukemia, Myeloid
Bone Marrow Diseases
Hematologic Diseases
Myelodysplastic-Myeloproliferative Diseases
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Histone Deacetylase Inhibitors