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

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

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.

Study Overview

• Status: Completed
• Conditions: Hematologic Neoplasms; Graft vs Host Disease; Non-Neoplastic Hematologic and Lymphocytic Disorder
• Intervention / Treatment: Drug: Methotrexate; Drug: Tacrolimus; Drug: Vorinostat

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vorinostat; Vorinostat, in combination with standard of care medications tacrolimus and methotrexate, for GVHD prophylaxis after unrelated donor stem cell transplant.	Drug: Methotrexate; Drug: Tacrolimus; Drug: Vorinostat; 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.; Other Names: Zolinza

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Michigan Rogel Cancer Center
• Investigators: Principal Investigator: Pavan Reddy, MD, University of Michigan Rogel Cancer Center

Publications and helpful links

General Publications

• Choi SW, Braun T, Henig I, Gatza E, Magenau J, Parkin B, Pawarode A, Riwes M, Yanik G, Dinarello CA, Reddy P. Vorinostat plus tacrolimus/methotrexate to prevent GVHD after myeloablative conditioning, unrelated donor HCT. Blood. 2017 Oct 12;130(15):1760-1767. doi: 10.1182/blood-2017-06-790469. Epub 2017 Aug 7.

Study record dates

Study Major Dates

• Study Start: December 1, 2014
• Primary Completion (Actual): January 1, 2017
• Study Completion (Actual): October 31, 2017

Study Registration Dates

• First Submitted: October 2, 2012
• First Submitted That Met QC Criteria: February 11, 2013
• First Posted (Estimate): February 13, 2013

Study Record Updates

• Last Update Posted (Actual): August 13, 2018
• Last Update Submitted That Met QC Criteria: July 13, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms; Neoplasms by Site; Hematologic Neoplasms; Hematologic Diseases; Graft vs Host Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Calcineurin Inhibitors; Histone Deacetylase Inhibitors; Methotrexate; Tacrolimus; Vorinostat
• Other Study ID Numbers: UMCC 2012.047 (University of Michigan University Hospital); HUM00070080 (Other Identifier: University of Michigan)