This is a single-arm, open label, phase 2 study to determine the safety and efficacy of vorinostat without serotherapy as GVHD prophylaxis when combined with either tacrolimus and methotrexate or post-transplant cyclophosphamide, tacrolimus, and mycophenolate in patients aged 1 to 26 years of age with non-malignant disorders undergoing bone marrow transplant following myeloablative conditioning.
The Hypothesis of the trial: The addition of vorinostat to standard GVHD prophylaxis without serotherapy will lead to improved GVHD-free event-free survival (GEFS) at 1-year post-transplant compared to historical serotherapy-containing GVHD prophylaxis regimens in patients with non-malignant disorders (NMD) undergoing Hematopoietic stem cell transplant (HSCT).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
55
For Matched sibling and matched unrelated donor transplant recipients: Vorinostat will be given orally at a dose of 60 milligrams per square meter two times a day (BID) (120 mg/m2/day) from day -10 to day 30 post-transplant. The maximum dose will be 100 mg BID. Haploidentical donor transplant recipients: Vorinostat will be given orally at a dose of 60 mg/m2 BID (120 mg/m2/day) from day +5 (at least 24 hours after completion of the day +4 cyclophosphamide) through day 30 post-transplant. The maximum dose will be 100 mg BID. Dosing may be rounded by +/- 10%. Patients that are able to take capsules and whose calculated dose is ≥91 mg may take 100 mg capsules.
University of Michigan
Ann Arbor, Michigan, United States
RECRUITINGGVHD-free relapse-free Survival
Composite endpoint of 1-year GVHD-free, event free survival (GEFS) with the addition of vorinostat to standard serotherapy-free GVHD prophylaxis. Grade III-IV acute GVHD and chronic GVHD requiring immunosuppression will be considered in this assessment. Events contributing to this endpoint will include death due to any cause, primary or secondary graft failure/rejection, or second HSCT, whichever occurs first.
Time frame: 1 year
Primary graft failure/rejection
Defined as never achieving an absolute neutrophil count (ANC) ≥500/microliters (µL) or never achieving ≥5% donor myeloid chimerism assessed by peripheral blood chimerism assays by day +42 post-Hematopoietic stem cell transplant (HSCT). Second infusion of hematopoietic stem cells is also considered indicative of primary graft failure by day +42 post-HSCT.
Time frame: By day+42 post-Hematopoietic stem cell transplant
Secondary graft failure/rejection
Defined as \<5% donor myeloid chimerism in peripheral blood beyond day +42 post-HSCT in patients with prior documentation of hematopoietic recovery with ≥5% donor cells by day +42 post-HSCT.
Time frame: Beyond day +42 post-HSCT
Secondary graft failure/rejection
Second infusion of hematopoietic stem cells is also considered indicative of primary graft failure by day +42 post-HSCT
Time frame: By day +42 post-HSCT
Overall survival (OS) at day 100, 6-months, and 1-year post-HSCT
This will be measured after HSCT.
Time frame: Day 100, 6-months, and 1-year post-HSCT
Event Free Survival (EFS) at 1-year post-HSCT
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An event will be defined as death due to any cause, graft rejection/failure, or second transplant, whichever occurs first.
Time frame: 1 year post-HSCT
Neutrophil engraftment at day 42
The time to engraftment of neutrophils \>500/microliter (μl) was defined as per Center for International Blood and Marrow Transplant Research (CIBMTR) standards, requiring donor chimerism for neutrophil engraftment.
Time frame: Day 42 post-HSCT
Platelet engraftment at day 100 post-HSCT
Platelet engraftment is defined as independence from platelet transfusion for at least 3 days with a platelet count of more than ≥20 × 10\^9/L.
Time frame: Day 100 post-HSCT
Donor chimerism at day 28, 100, and 1-year post-HSCT
Number of participants with full (95-100%), mixed (5-94%), and no (0-4%) donor cells. Chimerism is reported for unsorted whole blood and T cells.
Time frame: Day 28, 100, and 1-year post-HSCT
Primary graft failure at day 42
Time frame: Day 42 post-HSCT
Secondary graft failure post-HSCT
Time frame: Day 42 post-HSCT
Day 100 grade II-IV and grade III-IV GVHD
Time frame: Day 100 post-HSCT
Chronic GVHD requiring immunosuppressive therapy (IST) at 1-year post-HSCT
Time frame: 1-year post-HSCT
Incidence of grade 4 systemic infections (septicemia) at 1-year post-HSCT
Time frame: 1-year post-HSCT
Incidence of viral reactivation by 1-year post-HSCT
Time frame: 1 year post-HSCT