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Pilot Trial of Vorinostat Plus Tacrolimus & Methotrexate to Prevent Graft Versus Host Disease Following Unrelated Donor Allogeneic Transplant

Phase 2
18 Years
Not Enrolling
Graft vs Host Disease, Hematologic Neoplasms, Non-Neoplastic Hematologic and Lymphocytic Disorder

Thank you

Trial Information

Pilot Trial of Vorinostat Plus Tacrolimus & Methotrexate to Prevent Graft Versus Host Disease Following Unrelated Donor Allogeneic Transplant

This is a prospective pilot trial investigating the use of vorinostat (Merck) to 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 is the inferior outcomes when donors other than HLA-matched siblings are used 1,2.
Compared to matched related donors, recipients of matched unrelated donor transplants are at
a significantly increased risk of death and transplant-related mortality (TRM) 3,4. 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
5-8. 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

- 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 >70%.

- Life expectancy of greater than 6 months.

- Organ and marrow function as defined by the institutional BMT 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

- 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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention

Outcome Measure:

vorinostat, added to tacrolimus and methotrexate treatment regimen

Outcome Description:

If at least 7 of 12 patients can meet the definition of successful study drug administration (≥ 60% of the planned doses) during the period day-10 through day+30 of the study, the regimen is considered tolerable and safe. If no more than 3 subjects are observed with toxicities CTC grade 4 or higher which are considered probably or definitely related to the drug, the regimen is safe.

Outcome Time Frame:

30 days

Safety Issue:


Principal Investigator

Pavan Reddy, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Michigan Cancer Center


United States: Institutional Review Board

Study ID:

umcc 2012.047



Start Date:

April 2013

Completion Date:

July 2018

Related Keywords:

  • Graft Vs Host Disease
  • Hematologic Neoplasms
  • Non-Neoplastic Hematologic and Lymphocytic Disorder
  • Neoplasms
  • Graft vs Host Disease
  • Hematologic Diseases
  • Hematologic Neoplasms



University of Michigan Cancer Center Ann Arbor, Michigan  48109