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Vorinostat for Graft vs Host Disease Prevention in Children, Adolescents and Young Adults Undergoing Unrelated Donor Blood and Marrow Transplantation

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ClinicalTrials.gov Identifier: NCT03842696
Recruitment Status : Recruiting
First Posted : February 15, 2019
Last Update Posted : November 13, 2019
Sponsor:
Information provided by (Responsible Party):
University of Michigan Rogel Cancer Center

Brief Summary:
The purpose of this study is to determine the recommended phase 2 dose of the drug Vorinostat in children, adolescents and young adults following allogeneic HCT and determine whether the addition of Vorinostat to the standard preventive therapy (tacrolimus / methotrexate) will reduce the incidence of graft versus host disease (GVHD) following unrelated donor, myeloablative transplant in children, adolescents and young adults.

Condition or disease Intervention/treatment Phase
Hematologic Diseases Acute Myeloid Leukemia in Remission Acute Lymphoblastic Leukemia in Remission Chronic Myelogenous Leukemia - Chronic Phase Chronic Myelogenous Leukemia, Accelerated Phase Chronic Myelogenous Leukemia, Blastic Phase Myelodysplastic Syndromes Mantle Cell Lymphoma Follicular Lymphoma Diffuse Large B Cell Lymphoma Non Hodgkin Lymphoma Graft Vs Host Disease Graft-versus-host-disease Drug: Vorinostat Procedure: Blood and Marrow Transplant (BMT) Drug: Tacrolimus Drug: Methotrexate Phase 1 Phase 2

Detailed Description:
All subjects will undergo unrelated donor allogeneic blood and marrow transplant (BMT) according to local site institutional practice. The preparative regimen will depend upon the subject's underlying disease, previous therapy, and comorbidities. GVHD prophylaxis will consist of standard post-transplant immunosuppression, including tacrolimus and methotrexate. Vorinostat will be administered at 30, 45 or 60 mg/m2 BID PO from 10 days prior to transplant (day -10), until day +100 post-transplant (110 total days of dosing).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 49 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: A Phase 1/2 Multi-Center Trial of Vorinostat for Graft vs Host Disease Prevention in Children, Adolescents and Young Adults Undergoing Unrelated Donor Blood and Marrow Transplantation
Estimated Study Start Date : December 2019
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2023


Arm Intervention/treatment
Experimental: Vorinostat Drug: Vorinostat
Vorinostat 30, 45 or 60 mg/m2 BID PO from 10 days prior to transplant (day -10), until day +100 post-transplant (110 total days of dosing).

Procedure: Blood and Marrow Transplant (BMT)
Undergo allogeneic BMT according to local site institutional practice.

Drug: Tacrolimus
Tacrolimus will begin on day -3. Intravenous or oral dosing is permitted.In the absence of GVHD, it is recommended that tacrolimus or cyclosporine tapering begin on day +100 post-transplant as per local site BMT program clinical practice guidelines. In the presence of GVHD, it is recommended that tacrolimus or cyclosporine be continued at therapeutic dosing.

Drug: Methotrexate
Methotrexate will be used in combination with tacrolimus for standard GVHD prophylaxis. It will be given at a dose of 5 mg/m2/dose once daily intravenously on days +1, +3, +6, and +11. Standard criteria for administration will be followed per local site institutional BMT program clinical practice guidelines.




Primary Outcome Measures :
  1. Phase 1 portion: Determine the recommended phase 2 dose (RP2D) of the drug Vorinostat in children, adolescents, and young adults following allogeneic HCT. [ Time Frame: At day +100 ]
    Real time assessment of safety (DLTs), and pharmacokinetic (PK) and pharmacodynamics/histone acetylation (PD) analysis in each dose cohort prior to escalation of dose. Dose de/escalation will be determined using the 3+3 up-or-down algorithm.

  2. Phase 2 portion: Incidence of grade 2-4 acute GVHD within 100 days after transplant [ Time Frame: At day +100 ]
    Cumulative incidence will be determined using the proportional hazards method with a corresponding 95% confidence interval. GVHD severity will be determined clinically and graded by using the institutional BMT program clinical practice guidelines. (Pzrepiorka D, Weisdorf D, Martin P, et al. Consensus conference on acute GVHD grading. Bone Marrow Transplantation 1995; 15:825-8.)


Secondary Outcome Measures :
  1. Incidence of Grade 3-4 acute GVHD within 100 days after transplant [ Time Frame: At day +100 ]
    Cumulative incidence will be determined using the proportional hazards method with a corresponding 95% confidence interval. GVHD severity will be determined clinically and graded by using the institutional BMT program clinical practice guidelines. (Pzrepiorka D, Weisdorf D, Martin P, et al. Consensus conference on acute GVHD grading. Bone Marrow Transplantation 1995; 15:825-8.)

  2. Incidence of chronic GVHD [ Time Frame: At 1 year ]
  3. Incidence of relapse [ Time Frame: At 1 year ]
    Determined using the proportional hazards method with a corresponding 95% confidence interval.

  4. Overall Survival [ Time Frame: At 1 year ]
    The Kaplan-Meier method will be used to estimate overall survival, measured from the date of transplantation to either death from any cause or end of follow-up.

  5. Relapse-free Survival [ Time Frame: At 1 year ]
  6. GVHD-free relapse-free Survival [ Time Frame: At 1 year ]
  7. Number of participants with adverse events of grade 4 or higher that are probably or definitely related to vorinostat. [ Time Frame: Up to day +100 ]
    Graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0

  8. Percentage of participants with engraftment failure [ Time Frame: Up to 28 days post-transplant ]
    Engraftment failure will be defined as the inability to achieve an absolute neutrophil count (ANC) > 500/uL within 28 days post-transplant.

  9. Percentage of participants for whom successful administration of at least 60% of the planned doses occurs between day -1 and day +30 post-transplant [ Time Frame: Up to 30 days post-transplant ]
  10. Maximum concentration (Cmax) of Vorinostat [ Time Frame: At day +1 ]
    Pharmacokinetic (PK) analysis will be performed using blood samples from subjects who have received at least one dose of vorinostat and for whom quantifiable PK samples are available. Pharmacokinetic variables will be summarized with descriptive statistics.

  11. Area under the curve (AUC) of Vorinostat [ Time Frame: At day +1 ]
  12. Clearance (CL) of Vorinostat [ Time Frame: At day +1 ]
  13. Volume (V) of Vorinostat [ Time Frame: At day +1 ]


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Ages Eligible for Study:   3 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • A prospective patient for allogeneic BMT for hematologic conditions, both malignant and nonmalignant. Donor must be unrelated marrow or peripheral blood cells. A patient with history of CNS involvement is eligible if CNS disease is in remission at time of study consideration.
  • The donor and recipient must have an HLA-8/8 allelic match at the HLA-A, -B, -C, and -DRB1. High resolution typing is required for all alleles.
  • Diagnoses to be included:

    1. Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL) in first or second remission. Remission is defined as the absence of blasts in the peripheral circulation at the time of enrollment, < 5% blasts in the bone marrow and absence of extramedullary disease including CNS involvement.
    2. Chronic Myeologenous Leukemia (CML) in first or subsequent chronic phase failing to respond (or intolerant) to at least two different tyrosine kinase inhibitors. CML in accelerated or blast phase (CML-AP/BP) are eligible without requirement to fail tyrosine kinase inhibitor therapy, but must be in remission at time of enrollment. Remission is defined as the absence of blasts in the peripheral circulation at the time of enrollment, <5% blasts in the bone marrow and absence of extramedullary disease including CNS involvement.
    3. Myelodysplastic syndrome (MDS) with intermediate or high-risk IPSS or equivalent IPSSR score with < 10% blasts in the bone marrow.
    4. Mature B Cell Malignancies (including Mantle Cell Lymphoma, Follicular Lymphoma. Diffuse Large B Cell Lymphoma, Non-Hodgkin Lymphoma not otherwise specified).Subjects should have extinguished standard of care options prior to being considered eligible for this trial
  • Subjects aged 3 to 21 years
  • Karnofsky Performance Scale score of 70% or higher
  • Life expectancy of greater than 6 months
  • Subjects must have normal organ and marrow function (as defined in protocol)
  • Ability to take oral medication and be willing to adhere to the vorinostat regimen
  • For females of reproductive potential and men: The effects of vorinostat on the developing human fetus are unknown. For this reason and because histone deacetylase inhibitor agents as well as other therapeutic agents used in this trial (e.g., tacrolimus and methotrexate) are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 4 months after completion of vorinostat administration.
  • Ability to understand and the willingness to sign a written informed consent document
  • Stated willingness to comply with all study procedures and availability for the duration of the Study
  • For the cognitive assessment and patient-reported QOL exploratory correlative portion of the study, subjects must speak, read and understand English. Subjects who do not speak, read and understand English but satisfy all other inclusion criteria may still participate in the study but will not complete the cognitive and QOL portions.

Exclusion Criteria:

  • Subjects who are not a candidate for an unrelated donor allogeneic BMT based on the current local site institutional BMT program clinical practice guidelines. Organ function criteria will be utilized per the current local site institutional BMT program clinical practice guidelines. There will be no restriction to study entry based on hematological parameters.
  • Subjects who are enrolled on another GVHD treatment or prevention trial.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Subjects still under therapy for presumed or proven infection are eligible provided there is clear evidence (radiographic findings and/or culture results) that the infection is well-controlled. Subjects under treatment for infection will be enrolled only after clearance from the PI.
  • Pregnant women are excluded from this study because vorinostat is a histone deacetylase inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with vorinostat, breastfeeding should be discontinued if the mother is treated with vorinostat. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
  • Subjects with evidence of HIV seropositivity and/or positive PCR assay, HTLV1/HTLV2 seropositivity. The safety of allogeneic HSCT is not yet well-established for this population.
  • Subjects with evidence of Hepatitis B or Hepatitis C PCR positivity. Hepatitis reactivation following myelosuppressive therapy can lead to fatal complications.
  • Subjects with a history of prolonged QTc syndrome.
  • Subjects who have had prior treatment with a drug like vorinostat (i.e., valproic acid) within the last 30 days.
  • Subjects with documented evidence of cognitive impairment prior to enrollment on this study (diagnosis of dementia, mild cognitive impairment, or other neurological illnesses that impacts cognition) are excluded from the cognitive assessment portion of the study only.

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 ClinicalTrials.gov identifier (NCT number): NCT03842696


Locations
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United States, Michigan
University of Michigan Health System Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Sung Choi, MD, MS    734-615-5707    sungchoi@med.umich.edu   
Principal Investigator: Sung Choi, MD, MS         
Sponsors and Collaborators
University of Michigan Rogel Cancer Center
Investigators
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Principal Investigator: Sung W Choi, MD, MS University of Michigan

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Responsible Party: University of Michigan Rogel Cancer Center
ClinicalTrials.gov Identifier: NCT03842696     History of Changes
Other Study ID Numbers: UMCC 2018.081
HUM00147796 ( Other Identifier: University of Michigan )
First Posted: February 15, 2019    Key Record Dates
Last Update Posted: November 13, 2019
Last Verified: November 2019
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
Keywords provided by University of Michigan Rogel Cancer Center:
GVHD
Additional relevant MeSH terms:
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Lymphoma
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myeloid
Lymphoma, Mantle-Cell
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Lymphoma, Large B-Cell, Diffuse
Blast Crisis
Leukemia, Myeloid, Chronic-Phase
Leukemia, Myeloid, Accelerated Phase
Myelodysplastic Syndromes
Hematologic Diseases
Graft vs Host Disease
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Bone Marrow Diseases
Leukemia, Lymphoid
Lymphoma, B-Cell
Myeloproliferative Disorders
Cell Transformation, Neoplastic
Carcinogenesis
Neoplastic Processes
Pathologic Processes
Methotrexate
Vorinostat