Vorinostat, Tacrolimus, and Methotrexate in Preventing GVHD After Stem Cell Transplant in Patients With Hematological Malignancies

June 28, 2018 updated by: National Cancer Institute (NCI)

A Pilot Trial of Vorinostat Plus Tacrolimus and Methotrexate to Prevent Graft Versus Host Disease Following Unrelated Donor Hematopoietic Stem Cell Transplantation

This pilot phase II trial studies how well giving vorinostat, tacrolimus, and methotrexate works in preventing graft-versus-host disease (GVHD) after stem cell transplant in patients with hematological malignancies. Vorinostat, tacrolimus, and methotrexate may be an effective treatment for GVHD caused by a bone marrow transplant.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVES:

I. To assess the safety and the feasibility of the addition of vorinostat to tacrolimus and methotrexate GVHD prophylaxis.

SECONDARY OBJECTIVES:

I. To determine day 100 grades 2-4 acute GVHD. II. To determine 1-year overall survival and relapse-free survival. III. To correlate plasma concentrations of inflammatory markers of acute GVHD. IV. To correlate protein acetylation in peripheral blood mononuclear cells before and after administration of vorinostat.

OUTLINE:

Patients receive vorinostat orally (PO) twice daily (BID) on days -10 to 100. Beginning on day -3, patients receive tacrolimus intravenously (IV) continuously or PO BID (or cyclosporine IV continuously or PO in patients unable to tolerate tacrolimus) with taper on days 100-180.Patients also receive methotrexate IV once daily (QD) on days 1, 3, 6, and 11.

After completion of study treatment, patients are followed up periodically for 1 year.

Study Type

Interventional

Enrollment (Actual)

12

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • University of Michigan University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (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 central nervous system (CNS) involvement is eligible if CNS disease is in remission at time of study consideration
  • The donor and recipient must have a human leukocyte antigen (HLA)-8/8 allelic match at the HLA-A, -B, -C, and -DRB1; high-resolution typing is required for all alleles
  • Diagnoses to be included:

  • Acute myelogenous leukemia at the following stages:

    • First remission
    • Second or subsequent remission
    • Complete remission is defined as the absence of blasts in the peripheral circulation at the time of enrollment and < 5% blasts in the bone marrow

  • Chronic myelogenous leukemia at the following stages:

    • First or subsequent chronic phase:

      • Patient refused tyrosine kinase therapy or is otherwise not suited for it
      • Stable, not hematologic remission: blasts present in marrow and/or peripheral blood, but disease does not qualify as accelerated or blast phase
      • Hematologic remission: no blast cells or precursor cells in the blood or marrow
      • Partial cytogenetic remission: Philadelphia chromosome positive (Ph+) metaphases > 0% but < 35%
      • Complete cytogenetic remission: absence of Ph+ metaphases

    • Accelerated phase - any one of the following symptoms:

      • White blood cells (WBC) difficult to control (> 50 x 10^9/L despite therapy)
      • Rapid doubling of WBC (< 5 days)
      • 10% blasts in blood or marrow
      • 20% blasts and/or promyelocytes in blood or marrow
      • 20% basophils and/or eosinophils in blood
      • Anemia or thrombocytopenia unresponsive to standard treatment
      • Persistent thrombocytosis (> 1000 x 10^9/L)
      • Cytogenetic abnormalities in addition to Ph+
      • Increasing splenomegaly
      • Marrow fibrosis

  • Myelodysplastic syndromes at any of the following stages:

    • Refractory anemia
    • Refractory anemia with ringed sideroblasts
    • Refractory cytopenia with multilineage dysplasia
    • Refractory cytopenia with multilineage dysplasia and ringed sideroblasts
    • Refractory anemia with excess blasts-1 (5-10% blasts)
    • Refractory anemia with excess blasts-2 (10-20% blasts)
    • Myelodysplastic syndrome, unclassified
    • Myelodysplastic syndrome (MDS) associated with isolated del (5q)
    • Chronic myelomonocytic leukemia

  • Primary Myelofibrosis

    • Intermediate-2 risk or high risk disease
    • Patients should have extinguished standard of care options prior to being considered for this trial

  • Chronic lymphocytic leukemia

    • Complete remission: the disease is completely absent and no relapse occurred prior to the preparative regimen; requires all of the following:

      • Nodular partial remission: complete response with persistent lymphoid nodules in bone marrow
      • Partial remission: reduction of more than 50% in the disease burden regardless of the number of lines of therapy received

  • Mature B cell malignancies

    • Patients should have extinguished standard of care options prior to being considered eligible for this trial
    • First complete remission (CR1) confirmed: complete disappearance of all known disease; the term "confirmed" is defined as a laboratory and/or pathological or radiographic determination.
    • CR1 unconfirmed (CRU1): complete disappearance of all known disease with the exception of persistent scan abnormalities of unknown significance; the term "unconfirmed" is defined as scan abnormalities of unknown significance that are not biopsied or otherwise evaluated
    • Second or subsequent complete remission (CR2+) confirmed: the recipient relapsed, then achieved complete absence of disease without radiographic evidence of disease
    • CR2+ unconfirmed: the recipient has achieved a second or subsequent complete response but has persistent radiographic abnormalities of unknown significance.
    • Partial remission: reductions of >= 50% in greatest diameter of all sites of known disease and no new sites
  • Karnofsky >= 70%
  • Life expectancy of greater than 6 months
  • Total bilirubin =< 2.5 mg% (unless from Gilbert's disease or disease-related)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 3.0 X institutional upper limit of normal
  • Estimated or actual glomerular filtration rate (GFR) > 50 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal; GFR should be corrected for body surface area (BSA)
  • Diffusing capacity of the lung for carbon monoxide (DLCO) > 50%; DLCO should be corrected for hemoglobin
  • Forced expiratory volume in 1 second (FEV1) > 50%
  • Forced vital capacity (FVC) > 50%
  • Ejection fraction >= 50%
  • 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 and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of vorinostat administration
  • Ability to understand and the willingness to sign a written informed consent document
  • Patients must be able to swallow capsules/tablets

Exclusion Criteria:

  • Patients who are not a candidate for an unrelated donor allogeneic HSCT based on the current institutional bone marrow transplant (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
  • Patients undergoing a total body irradiation (TBI)-based conditioning regimen (TBI 1200 centigray [cGy])
  • Uncontrolled intercurrent 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 Principal Investigator (PI)
  • Pregnant women are excluded from this study because vorinostat is a histone deacetylase inhibitor agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with vorinostat, breastfeeding should be discontinued if the mother is treated with vorinostat
  • Patients with evidence of human immunodeficiency virus (HIV) seropositivity and/or positive polymerase chain reaction (PCR) assay, human T-lymphotropic virus (HTLV)1/HTLV2 seropositivity; the safety of allogeneic HSCT is not yet well-established for this population
  • Patients with evidence of hepatitis B or hepatitis C PCR positivity; hepatitis reactivation following myelosuppressive therapy can lead to fatal complications
  • Patients with a history of prolonged corrected QT interval (QTc) syndrome
  • Patients asking or who have had prior treatment with a drug like vorinostat (i.e., valproic acid) within the last 30 days

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: SUPPORTIVE_CARE
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Supportive care (vorinostat, tacrolimus, methotrexate)
Patients receive vorinostat PO BID on days -10 to 100. Beginning on day -3, patients receive tacrolimus IV continuously or PO BID (or cyclosporine IV continuously or PO in patients unable to tolerate tacrolimus) with taper on days 100-180.Patients also receive methotrexate IV QD on days 1, 3, 6, and 11.
Other: laboratory biomarker analysis
Correlative studies
Drug: methotrexate
Given IV
Other Names:
  • amethopterin
  • Folex
  • methylaminopterin
  • Mexate
  • MTX
Other: pharmacological study
Correlative studies
Other Names:
  • pharmacological studies
Drug: tacrolimus
Given IV or PO
Other Names:
  • Prograf
  • FK 506
Drug: cyclosporine
Given IV or PO
Other Names:
  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
Drug: vorinostat
Given PO
Other Names:
  • SAHA
  • Zolinza
  • L-001079038
  • suberoylanilide hydroxamic acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The Number of Participants That Experience Grade 2-4 Acute GVHD (Graft Versus Host Disease) by Day 100
Time Frame: Day 100

The incidence of grade 2-4 acute GVHD (Graft Versus Host Disease) by day 100

Grade 2 GVHD: Maculopapular rash covering 25-50% of BSA (Body Surface Area), bilirubin between 3.1-6 mg/dl, and/ or adult stool output between 1000-1500 ml/day (child between 20-30 ml/kg/day).

Grade 3 GVHD: Maculopapular rash covering >50% of BSA, bilirubin between 6.1-15 mg/dl, and/ or adult stool output >1500 ml/day (child >30 ml/kg/day).

Grade 4 GVHD: Generalized erythroderma plus bullous formation and desquamation >5% BSA, bilirubin >15 mg/dl, and/ or severe abdominal pain with or without ileus, or grossly bloody stool.
Day 100

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mean Percent of Planned Dose Administered
Time Frame: Up to day 30
The addition of vorinostat to tacrolimus and methotrexate for GVHD prophylaxis will be considered feasible if 60% or more of the planned doses are administered.
Up to day 30
The Percentage of Patients Alive Without GVHD or Use of Steroids
Time Frame: Up to 1 year
The percentage of patients alive without GVHD or use of steroids at 1 year.
Up to 1 year
The Percentage of Patients Alive at 1 Year
Time Frame: Up to 1 year
The percentage of patients alive at 1 year
Up to 1 year
The Percentage of Patients With Relapse at 1 Year
Time Frame: Up to 1 year
Up to 1 year
Median Ac-H3 Levels in Patients Treated With Vorinostat and Patients Not Treated With Vorinostat
Time Frame: Up to day 100
Median Ac-H3 levels ( depicted as a ratio of ac-H2 optical density (OD) and beta actin OD) were compared in patients treated with Vorinostat to patients not treated with Vorinostat. Optical Density is a dimensionless unit.
Up to day 100
Median Plasma Concentration of IL-6 in Patients Treated With Vorinostat and Patients Not Treated With Vorinostat
Time Frame: Up to day 100
Median plasma concentration of IL-6 (Interleukin-6 cytokine) was compared in patients treated with Vorinostat to those not treated with Vorinostat.
Up to day 100

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Pavan Reddy, University of Michigan University Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2013

Primary Completion (ACTUAL)

March 1, 2014

Study Completion (ACTUAL)

March 1, 2014

Study Registration Dates

First Submitted

February 7, 2013

First Submitted That Met QC Criteria

February 7, 2013

First Posted (ESTIMATE)

February 12, 2013

Study Record Updates

Last Update Posted (ACTUAL)

July 24, 2018

Last Update Submitted That Met QC Criteria

June 28, 2018

Last Verified

June 1, 2018

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCI-2013-00355 (REGISTRY: CTRP (Clinical Trial Reporting Program))
  • P30CA046592 (U.S. NIH Grant/Contract)
  • 9330 (OTHER: CTEP)
  • HUM00070080 (Other Identifier: University of Michigan)
  • UMCC 2012.047 (University of Michigan University Hospital)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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