Vorinostat Plus Tacrolimus & Methotrexate to Prevent Graft vs Host Disease Following Unrelated Stem Cell Transplant

This trial is investigating the use of vorinostat (Merck) for standard graft versus-host
disease (GVHD) prophylaxis after unrelated donor allogeneic hematopoietic cell
transplantation (HCT). A major limitation of the increased utilization of allogeneic HCT
(Hematopoietic Cell Transplantation) is the inferior outcomes when donors other than HLA
(HumanLeukocyte Antigen)-matched siblings are used. Compared to matched related donors,
recipients of matched unrelated donor transplants are at a significantly increased risk of
death and transplant-related mortality (TRM). Acute GVHD remains a significant contributor to
TRM, which develops in approximately 50-70% of recipients receiving these type of grafts
despite standard immunosuppressive prophylaxis. Thus, novel GVHD prophylaxis strategies which
successfully attenuate acute GVHD-related complications without increasing other causes of
TRM or relapse are needed.

The historical experience of day 100 grade 2-4 acute GVHD in 154 comparable patients treated
at the University of Michigan (2005 - 2011) receiving standard GVHD prophylaxis after
unrelated donor allogeneic transplant is 48%. At Washington University, the cumulative
incidence of acute grade 2-4 GVHD in patients following unrelated donor transplant is 62%.

Research data collectively suggests, that reducing lethal acute GVHD should improve long-term
survival for patients undergoing unrelated donor transplant.

Inclusion Criteria:

- A prospective patient for allogeneic HSCT for hematologic conditions, both malignant
and non-malignant. Donor can 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.

- Age between 18-75 years

- The donor and recipient must have an HLA-8/8 allelic match at the HLA-A, -B, -C, and
-DRB1.

- Diagnosis of following diseases (subject to additional complex screening criteria)

- Acute Myelogenous Leukemia:

- First remission (cytogenetic intermediate or high risk)

- Second or subsequent remission

- Chronic Myelogenous Leukemia:

- First, subsequent chronic phases, or atypical

- Accelerated Phase

- Myelodysplastic syndromes

- Chronic Lymphocytic Leukemia

- Primary Myelofibrosis

- Mature B Cell Malignancies (including Mantle Cell Lymphoma, Follicular Lymphoma.
Diffuse Large B Cell Lymphoma, Non-Hodgkin Lymphoma not otherwise specified)

- Karnofsky (Attempt to classify a cancer patients' activities of daily life that runs
from 0 to 100 where 100 represents perfect health and 0 represents death) >70%

- Life expectancy of greater than 6 months.

- Organ and marrow function as defined by the institutional BMT (Bone Marrow Transplant)
program clinical practice guidelines

- 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 and for
the duration of study participation.

- Able to swallow capsules/tablets

Exclusion Criteria:

- Not a candidate for an unrelated donor allogeneic transplant conditioning regimen
based on the current institutional BMT program clinical practice guidelines. Organ
function criteria will be utilized per the current institutional BMT program clinical
practice guidelines. There will be no restriction to study entry based on
hematological parameters.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to vorinostat

- Undergoing a total body irradiation (TBI)-based conditioning regimen (TBI 1200 cGy)

- Uncontrolled 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. Patients 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. Patients under treatment for infection
will be enrolled only after clearance from the PI

- Any medical or psychological comorbidities/conditions that would keep the patient from
complying with the needs of the protocol and/or would markedly increase the risk of
morbidity and mortality.

- Pregnant women or nursing mothers.

- Evidence of HIV seropositivity and/or positive PCR assay, HTLV1 / HTLV2
seropositivity.

- Evidence of Hepatitis B or Hepatitis C PCR positivity.

- Less than 18 years of age.

- A history of prolonged QTc syndrome.

- Taking or have had prior treatment with a drug like vorinostat within the last 30
days.