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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01789255
First received: February 7, 2013
Last updated: June 30, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Accelerated Phase Chronic Myelogenous Leukemia
Adult Acute Myeloid Leukemia in Remission
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Adult Grade III Lymphomatoid Granulomatosis
B-cell Chronic Lymphocytic Leukemia
Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Chronic Myelomonocytic Leukemia
Chronic Phase Chronic Myelogenous Leukemia
Contiguous Stage II Adult Burkitt Lymphoma
Contiguous Stage II Adult Diffuse Large Cell Lymphoma
Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma
Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma
Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma
Contiguous Stage II Adult Lymphoblastic Lymphoma
Contiguous Stage II Grade 1 Follicular Lymphoma
Contiguous Stage II Grade 2 Follicular Lymphoma
Contiguous Stage II Grade 3 Follicular Lymphoma
Contiguous Stage II Mantle Cell Lymphoma
Contiguous Stage II Marginal Zone Lymphoma
Contiguous Stage II Small Lymphocytic Lymphoma
Cutaneous B-cell Non-Hodgkin Lymphoma
Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
Graft Versus Host Disease
Intraocular Lymphoma
Myelodysplastic Syndrome With Isolated Del(5q)
Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
Nodal Marginal Zone B-cell Lymphoma
Noncontiguous Stage II Adult Burkitt Lymphoma
Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma
Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma
Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma
Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma
Noncontiguous Stage II Adult Lymphoblastic Lymphoma
Noncontiguous Stage II Grade 1 Follicular Lymphoma
Noncontiguous Stage II Grade 2 Follicular Lymphoma
Noncontiguous Stage II Grade 3 Follicular Lymphoma
Noncontiguous Stage II Mantle Cell Lymphoma
Noncontiguous Stage II Marginal Zone Lymphoma
Noncontiguous Stage II Small Lymphocytic Lymphoma
Post-transplant Lymphoproliferative Disorder
Primary Central Nervous System Hodgkin Lymphoma
Primary Central Nervous System Non-Hodgkin Lymphoma
Recurrent Adult Acute Myeloid Leukemia
Recurrent Adult Burkitt Lymphoma
Recurrent Adult Diffuse Large Cell Lymphoma
Recurrent Adult Diffuse Mixed Cell Lymphoma
Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
Recurrent Adult Grade III Lymphomatoid Granulomatosis
Recurrent Adult Hodgkin Lymphoma
Recurrent Adult Immunoblastic Large Cell Lymphoma
Recurrent Adult Lymphoblastic Lymphoma
Recurrent Grade 1 Follicular Lymphoma
Recurrent Grade 2 Follicular Lymphoma
Recurrent Grade 3 Follicular Lymphoma
Recurrent Mantle Cell Lymphoma
Recurrent Marginal Zone Lymphoma
Recurrent Small Lymphocytic Lymphoma
Refractory Anemia
Refractory Anemia With Excess Blasts
Refractory Anemia With Ringed Sideroblasts
Refractory Chronic Lymphocytic Leukemia
Refractory Cytopenia With Multilineage Dysplasia
Refractory Hairy Cell Leukemia
Relapsing Chronic Myelogenous Leukemia
Secondary Central Nervous System Hodgkin Lymphoma
Secondary Central Nervous System Non-Hodgkin Lymphoma
Small Intestine Lymphoma
Splenic Marginal Zone Lymphoma
Stage I Adult Burkitt Lymphoma
Stage I Adult Diffuse Large Cell Lymphoma
Stage I Adult Diffuse Mixed Cell Lymphoma
Stage I Adult Diffuse Small Cleaved Cell Lymphoma
Stage I Adult Hodgkin Lymphoma
Stage I Adult Immunoblastic Large Cell Lymphoma
Stage I Adult Lymphoblastic Lymphoma
Stage I Chronic Lymphocytic Leukemia
Stage I Grade 1 Follicular Lymphoma
Stage I Grade 2 Follicular Lymphoma
Stage I Grade 3 Follicular Lymphoma
Stage I Mantle Cell Lymphoma
Stage I Marginal Zone Lymphoma
Stage I Small Lymphocytic Lymphoma
Stage II Adult Hodgkin Lymphoma
Stage II Chronic Lymphocytic Leukemia
Stage III Adult Burkitt Lymphoma
Stage III Adult Diffuse Large Cell Lymphoma
Stage III Adult Diffuse Mixed Cell Lymphoma
Stage III Adult Diffuse Small Cleaved Cell Lymphoma
Stage III Adult Hodgkin Lymphoma
Stage III Adult Immunoblastic Large Cell Lymphoma
Stage III Adult Lymphoblastic Lymphoma
Stage III Chronic Lymphocytic Leukemia
Stage III Grade 1 Follicular Lymphoma
Stage III Grade 2 Follicular Lymphoma
Stage III Grade 3 Follicular Lymphoma
Stage III Mantle Cell Lymphoma
Stage III Marginal Zone Lymphoma
Stage IV Adult Burkitt Lymphoma
Stage IV Adult Diffuse Large Cell Lymphoma
Stage IV Adult Diffuse Mixed Cell Lymphoma
Stage IV Adult Diffuse Small Cleaved Cell Lymphoma
Stage IV Adult Hodgkin Lymphoma
Stage IV Adult Immunoblastic Large Cell Lymphoma
Stage IV Adult Lymphoblastic Lymphoma
Stage IV Chronic Lymphocytic Leukemia
Stage IV Grade 1 Follicular Lymphoma
Stage IV Grade 2 Follicular Lymphoma
Stage IV Grade 3 Follicular Lymphoma
Stage IV Mantle Cell Lymphoma
Stage IV Marginal Zone Lymphoma
Stage IV Small Lymphocytic Lymphoma
Testicular Lymphoma
Waldenström Macroglobulinemia
Drug: vorinostat
Drug: tacrolimus
Drug: cyclosporine
Drug: methotrexate
Other: laboratory biomarker analysis
Other: pharmacological study
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Supportive Care
Official Title: A Pilot Trial of Vorinostat Plus Tacrolimus and Methotrexate to Prevent Graft Versus Host Disease Following Unrelated Donor Hematopoietic Stem Cell Transplantation

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Incidence of adverse events and toxicity assessments [ Time Frame: Up to day 180 ] [ Designated as safety issue: Yes ]
    The descriptions and grading scales found in the revised National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.

  • Feasibility, defined as successful administration of at least 60% of planned doses for an individual study patient [ Time Frame: Up to day 30 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Incidence of grade 2-4 acute GVHD [ Time Frame: Day 100 ] [ Designated as safety issue: No ]
    Estimated with Kaplan-Meier methods.

  • Steroid-free survival [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Estimated with Kaplan-Meier methods.

  • Overall survival [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Estimated with Kaplan-Meier methods.

  • Relapse [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Estimated with Kaplan-Meier methods.

  • Histone acetylation in peripheral blood stem cells (PBMC) [ Time Frame: Up to day 100 ] [ Designated as safety issue: No ]
    Summarized with means and 95% confidence intervals.

  • Plasma concentrations of inflammatory GVHD markers [ Time Frame: Up to day 100 ] [ Designated as safety issue: No ]
    Summarized with means and 95% confidence intervals.


Estimated Enrollment: 12
Study Start Date: June 2013
Estimated Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: vorinostat
Given PO
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza
Drug: tacrolimus
Given IV or PO
Other Names:
  • FK 506
  • Prograf
Drug: cyclosporine
Given IV or PO
Other Names:
  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
Drug: methotrexate
Given IV
Other Names:
  • amethopterin
  • Folex
  • methylaminopterin
  • Mexate
  • MTX
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01789255

Locations
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
Sponsors and Collaborators
Investigators
Principal Investigator: Pavan Reddy University of Michigan
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01789255     History of Changes
Obsolete Identifiers: NCT01790568
Other Study ID Numbers: NCI-2013-00355, NCI-2013-00355, UMCC 2012.047, 9330, P30CA046592
Study First Received: February 7, 2013
Last Updated: June 30, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Congenital Abnormalities
Anemia
Anemia, Refractory
Anemia, Refractory, with Excess of Blasts
Burkitt Lymphoma
Neoplasms
Graft vs Host Disease
Hodgkin Disease
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Hairy Cell
Leukemia, Lymphoid
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia, Myeloid, Accelerated Phase
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid, Chronic-Phase
Leukemia, Myelomonocytic, Chronic
Lymphoma
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
Lymphomatoid Granulomatosis
Lymphoproliferative Disorders
Waldenstrom Macroglobulinemia
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myelomonocytic, Acute
Myeloproliferative Disorders
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse

ClinicalTrials.gov processed this record on July 24, 2014