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Vorinostat in Preventing Graft Versus Host Disease in Children, Adolescents, and Young Adults Undergoing Blood and Bone Marrow Transplant

Trial Status: Active

This phase I / II trial studies the side effects and best dose of vorinostat in preventing graft versus host disease in children, adolescents, and young adults who are undergoing unrelated donor blood and bone marrow transplant. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells, called graft-versus-host disease. During this process, chemicals (called cytokines) are released that may damage certain body tissues, including the gut, liver and skin. Vorinostat may be an effective treatment for graft-versus-host disease caused by a bone marrow transplant.

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 central nervous system (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. Highresolution typing is required for all alleles
  • Diagnoses to be included: * 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 * 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 * Myelodysplastic syndrome (MDS) with intermediate or high‐risk International Prognostic Scoring System (IPSS) or equivalent Revised IPSS (IPSSR) score with < 10% blasts in the bone marrow * 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
  • Karnofsky >= 70%
  • Life expectancy of greater than 6 months
  • Total bilirubin =< 2.5 mg % (unless from Gilbert’s disease or disease-related)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 3.0 X institutional upper limit of normal
  • Estimated or actual glomerular filtration rate (GFR)* > 50 mL/min/1.73 m^2 for subjects with creatinine levels above institutional normal * GFR should be corrected for body surface area (BSA)
  • Pulmonary function tests carbon monoxide diffusing capability (DLCO), forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) > 50% DLCO should be corrected for hemoglobin
  • Ejection fraction >= 50%
  • 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 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 principal investigator (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 human immunodeficiency virus (HIV) seropositivity and/or positive polymerase chain reaction (PCR) assay, human T-cell lymphotropic virus (HTLV)1/HTLV2 seropositivity. The safety of allogeneic hematopoietic stem cell transplantation (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 corrected QT interval (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

Michigan

Ann Arbor
University of Michigan Comprehensive Cancer Center
Status: ACTIVE
Contact: Sung Won Choi
Phone: 734-615-5707

PRIMARY OBJECTIVES:

I. To determine the recommended phase 2 dose (RP2D) of vorinostat in children, adolescents and young adults following allogeneic hematopoietic cell transplantation (HCT). (Part A)

II. To determine the incidence of grade 2‐4 acute graft versus host disease (GVHD) by day 100 in subjects who receive vorinostat in addition to standard GVHD prophylaxis after allogeneic bone marrow transplant (BMT). (Part B)

SECONDARY OBJECTIVES:

I. To confirm the pharmacokinetics (PK) of vorinostat and demonstrate safety and feasibility of vorinostat for GVHD prophylaxis in BMT subjects aged 3-21.

II. Determine the incidence of severe grade 3‐4 acute GVHD at day +100, and chronic GVHD, relapse and 1‐year survival in vorinostat‐treated children, adolescents and young adults.

EXPLORATORY OBJECTIVES:

I. To correlate laboratory studies and patient outcomes after histone deacetylase (HDAC) inhibition.

II. To correlate patient cognitive function and patient‐reported quality of life (QOL) outcomes with clinical outcomes.

OUTLINE: This is a phase I, dose-escalation study of vorinostat followed by a phase II study.

Patients receive vorinostat orally (PO) twice daily (BID) on days -10 to 100. Patients may receive fludarabine intravenously (IV) over 30 minutes on days -9 to -6 or -6 to -2, melphalan IV over 30 minutes on days -3 to -2, or busulfan IV over 2 hours or PO on days -5 to -2. Patients also receive tacrolimus IV continuously or PO BID starting on day -3 and taper beginning on day 100 post transplant. Patients then undergo BMT on day 0 and receive methotrexate IV once daily (QD) on days 1, 3, 6, and 11 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 9 months and 1 year.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
University of Michigan Comprehensive Cancer Center

Principal Investigator
Sung Won Choi

  • Primary ID UMCC 2018.081
  • Secondary IDs NCI-2019-04695, HUM00147796
  • Clinicaltrials.gov ID NCT03842696