Summary

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.

Objectives

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.

Eligibility

1. 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
2. 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
3. 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
4. Karnofsky >= 70%
5. Life expectancy of greater than 6 months
6. Total bilirubin =< 2.5 mg % (unless from Gilbert’s disease or disease-related)
7. Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 3.0 X institutional upper limit of normal
8. 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)
9. 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
10. Ejection fraction >= 50%
11. Ability to take oral medication and be willing to adhere to the vorinostat regimen
12. 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
13. Ability to understand and the willingness to sign a written informed consent document
14. Stated willingness to comply with all study procedures and availability for the duration of the study
15. 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

Treatment Sites in Georgia