A Pilot Trial of Vorinostat Plus Tacrolimus and Methotrexate to Prevent Graft Versus Host Disease Following Unrelated Donor Hematopoietic Stem Cell Transplantation
Overview
- Phase
- Phase 2
- Intervention
- vorinostat
- Conditions
- Accelerated Phase Chronic Myelogenous Leukemia
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 12
- Locations
- 1
- Primary Endpoint
- The Number of Participants That Experience Grade 2-4 Acute GVHD (Graft Versus Host Disease) by Day 100
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
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.
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.
Investigators
Eligibility 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
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
Arms & Interventions
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.
Intervention: vorinostat
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.
Intervention: tacrolimus
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.
Intervention: cyclosporine
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.
Intervention: methotrexate
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.
Intervention: laboratory biomarker analysis
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.
Intervention: pharmacological study
Outcomes
Primary Outcomes
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.
Secondary Outcomes
- Mean Percent of Planned Dose Administered(Up to day 30)
- The Percentage of Patients Alive Without GVHD or Use of Steroids(Up to 1 year)
- The Percentage of Patients Alive at 1 Year(Up to 1 year)
- Median Ac-H3 Levels in Patients Treated With Vorinostat and Patients Not Treated With Vorinostat(Up to day 100)
- The Percentage of Patients With Relapse at 1 Year(Up to 1 year)
- Median Plasma Concentration of IL-6 in Patients Treated With Vorinostat and Patients Not Treated With Vorinostat(Up to day 100)