Vorinostat Dose-escalation After Allogeneic Hematopoietic Cell Transplantation

  • End date
    May 31, 2023
  • participants needed
  • sponsor
    Johns Hopkins All Children's Hospital
Updated on 4 October 2022
graft versus host disease
cell transplantation
transplant conditioning


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.


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.

Condition Acute Myeloid Leukemia, Myelodysplastic Syndromes, Mixed Phenotype Acute Leukemia, Juvenile Myelomonocytic Leukemia
Treatment Vorinostat, Azacitidine Injection
Clinical Study IdentifierNCT03843528
SponsorJohns Hopkins All Children's Hospital
Last Modified on4 October 2022


Yes No Not Sure

Inclusion Criteria

Patient is 1 year to 21 years of age
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
Patient has undergone allogeneic hematopoietic cell transplantation (no restrictions on conditioning regimen, donor or stem cell source, or GVHD prophylaxis regimen)
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
Female patient of childbearing potential has a negative screening pregnancy test (urine or serum, as per local institutional standard)
Female patient with infant(s) agrees not to breastfeed her infant(s) while on study
Patient of child-bearing potential (male and female) agrees to use effective method of contraception during the study

Exclusion Criteria

Patient is enrolled on a clinical trial with investigational post-transplant medications. Note: trials involving defibrotide, post-transplant cyclophosphamide, and Lactobacillus plantarum are permitted. Other trials involving investigational medications that aren't leukemia or GVHD-directed may also be permitted after consultation with the overall PI
Patient has a planned administration of non-protocol chemotherapy, radiation therapy, donor leukocyte infusion, or immunotherapy during the planned study period
Patient has a known allergy to azacitidine or vorinostat
Patient has chronic myelogenous leukemia
Concomitant use of coumarin-derived anticoagulants or valproic acid
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Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

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If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

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Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

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