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

Study Overview
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Brief Summary
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This protocol, UMCC 2012.047, was a pilot study initially intended for 12 subjects. After completing enrollment of the planned 12 subjects, we are extending the study to an additional 25 subjects. The trial will examine the safety and efficacy of the addition of vorinostat, the study drug, to standard medications to try to prevent or lower the risk of graft versus-host disease (GVHD) for recipients of unrelated (matched) donor, blood or marrow stem cell transplants. The transplant regimens, chosen according to current institutional policy, will depend upon the recipients underlying disease (their blood cancer or other blood disorder), previous therapy, and current health issues. GVHD prophylaxis (preventive drug intervention) will be the local institutional standard for post-transplant immunosuppression, including tacrolimus and methotrexate, plus vorinostat. Vorinostat will be given twice daily orally beginning 10 days prior to the recipient's transplant and continue for up to 100 days after transplant.

Detailed Description
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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.

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

Conditions
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Graft vs Host Disease, Hematologic Neoplasms, Non-Neoplastic Hematologic and Lymphocytic Disorder

Intervention / Treatment
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* Drug: Vorinostat
* Drug: Tacrolimus
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vorinostat<br>Vorinostat, in combination with standard of care medications tacrolimus and methotrexate, for GVHD prophylaxis after unrelated donor stem cell transplant. | Drug: Vorinostat<br>* administered at a dose of 100 mg orally, twice daily starting on day -10 in order to achieve steady-state prior to beginning the conditioning chemotherapy, and continued after transplant (day 0) until day +100.<br>* Other names: Zolinza;Drug: Tacrolimus<br> <br> Drug: Methotrexate<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients That Experience Grade 2-4 GVHD Within 100 Days of Transplant | GVHD Staging: Grade 2: (Skin) Maculopapular rash 25-50% BSA, (Liver) bilirubin 3.1-6mg/dl, (Gut) 1000-1500 ml/day for adult and 20-30ml/kg/day for child. Grade 3: (Skin) Maculopapular rash >50% BSA, (Liver) 6.1-15mg/dl, (Gut) >1500mg/day for adult and >30ml/kg/day for child. Grade 4: (Skin) Generalized erythroderma plus bullous formation and desquamation >5% BSA, (Liver) >15mg/dl, (Gut) Severe abdominal pain with or without ileus, or grossly bloody stool. | 100 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Alive at 1 Year | Overall survival at 1 Year. | 1 Year | 
| Non-Relapse Mortality Incidence |  | 1 year |