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Vorinostat Dose-escalation After Allogeneic Hematopoietic Cell Transplantation

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ClinicalTrials.gov Identifier: NCT03843528
Recruitment Status : Recruiting
First Posted : February 18, 2019
Last Update Posted : July 11, 2019
Sponsor:
Information provided by (Responsible Party):
Benjamin Oshrine, Johns Hopkins All Children's Hospital

Tracking Information
First Submitted Date  ICMJE January 24, 2019
First Posted Date  ICMJE February 18, 2019
Last Update Posted Date July 11, 2019
Actual Study Start Date  ICMJE May 1, 2019
Estimated Primary Completion Date May 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 14, 2019)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03843528 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 14, 2019)
  • Dose-limiting toxicities [ Time Frame: 4 months ]
    Rates of side effects from vorinostat will be recorded and described.
  • GVHD [ Time Frame: 1 year ]
    Incidence of GVHD will be recorded and described.
  • Relapse [ Time Frame: 1 year ]
    Incidence of relapse will be recorded and described
  • Survival [ Time Frame: 1 year ]
    Duration of survival will be recorded and described
  • Immune recovery [ Time Frame: 1 year ]
    Immune profile will be measured monthly for the first year post-transplant.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Vorinostat Dose-escalation After Allogeneic Hematopoietic Cell Transplantation
Official Title  ICMJE 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
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.
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Intervention Model Description:
3+3 dose-escalation study
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
  • Mixed Phenotype Acute Leukemia
  • Juvenile Myelomonocytic Leukemia
Intervention  ICMJE
  • 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.
Study Arms  ICMJE 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.

Interventions:
  • Drug: Vorinostat
  • Drug: Azacitidine Injection
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 14, 2019)
15
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2021
Estimated Primary Completion Date May 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

    -

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Benjamin Oshrine, MD 727-460-9921 benjamin.oshrine@jhmi.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03843528
Other Study ID Numbers  ICMJE IRB00202540
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Benjamin Oshrine, Johns Hopkins All Children's Hospital
Study Sponsor  ICMJE Johns Hopkins All Children's Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Benjamin Oshrine, MD Johns Hopkins All Children's Hospital
PRS Account Johns Hopkins All Children's Hospital
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP