The purpose of this study is to determine the recommended phase 2 dose of the drug Vorinostat in children, adolescents and young adults following allogeneic blood or marrow transplant (BMT) and determine whether the addition of Vorinostat to the standard graft versus host disease (GVHD) prophylaxis will reduce the incidence of GVHD.
All subjects will undergo allogeneic blood or marrow transplant (BMT) according to local site institutional practice. The preparative regimen will depend upon the subject's underlying disease, type of transplant, previous therapy and comorbidities. Stem cells can be from donors of bone marrow or peripheral blood stem cells.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
PREVENTION
Masking
NONE
Enrollment
43
* HLA-matched BMT recipients: Vorinostat 30, 45 or 60 mg/m2 BID (100 mg/m2 BID maximum) PO from 10 days prior to transplant (day -10), until day +30 post-transplant. * Haploidentical BMT recipients: Vorinostat 30, 45 or 60 mg/m2 BID (100 mg/m2 BID maximum) PO from 5 days after transplant (day +5), until day +30 post-transplant
Undergo allogeneic BMT according to local site institutional practice.
Tacrolimus (or cyclosporine if tacrolimus becomes in shortage during the study period) will begin on day -3. Intravenous or oral dosing is permitted.In the absence of GVHD, it is recommended that tacrolimus or cyclosporine tapering begin on day +100 post-transplant as per local site BMT program clinical practice guidelines. In the presence of GVHD, it is recommended that tacrolimus or cyclosporine be continued at therapeutic dosing.
HLA-matched BMT recipients: Methotrexate will be used in combination with tacrolimus (or cyclosporine) for standard GVHD prophylaxis. It will be given at a dose of 5 mg/m2/dose once daily intravenously on days +1, +3, +6, and +11. Standard criteria for administration will be followed per local site institutional BMT program clinical practice guidelines.
Haploidentical BMT recipients: MMF will be used in combination with post-transplant cyclophosphamide and tacrolimus (or cyclosporine) for standard GVHD prophylaxis. MMF will start on day +5 and discontinue after the last dose on day +35 or may be continued if active GVHD is present. Given intravenously (preferred) or orally at a dose of 15 mg/kg/dose three times a day (based upon adjusted body weight) with the maximum total daily dose not to exceed 3 grams.
Haploidentical BMT recipients: Post-transplant cyclophosphamide (PT-Cy) will be used in combination with MMF and tacrolimus (or cyclosporine) for standard GVHD prophylaxis. PT-Cy (50 mg/kg/dose) given for two days, Days +3 and +4 after transplantation.
University of Colorado
Aurora, Colorado, United States
Emory University
Atlanta, Georgia, United States
Indiana University Melvin and Bren Simon Comprehensive Cancer Center
Indianapolis, Indiana, United States
University of Michigan Health System
Ann Arbor, Michigan, United States
Henry Ford Hospital
Detroit, Michigan, United States
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States
Medical College of Wisconsin
Milwaukee, Wisconsin, United States
Phase 1 portion: Determine the recommended phase 2 dose (RP2D) of the drug Vorinostat in children, adolescents, and young adults following allogeneic blood or marrow transplant (BMT).
Real time assessment of safety (DLTs), and pharmacokinetic (PK) and pharmacodynamics/histone acetylation (PD) analysis in each dose cohort prior to escalation of dose. Dose de/escalation will be determined using the 3+3 up-or-down algorithm.
Time frame: At day +100
Phase 2 portion: Incidence of grade 2-4 acute GVHD within 100 days after transplant
Cumulative incidence will be determined using the proportional hazards method with a corresponding 95% confidence interval. GVHD severity will be determined clinically and graded by using the institutional BMT program clinical practice guidelines. (Pzrepiorka D, Weisdorf D, Martin P, et al. Consensus conference on acute GVHD grading. Bone Marrow Transplantation 1995; 15:825-8.)
Time frame: At day +100
Incidence of Grade 3-4 acute GVHD within 100 days after transplant
Cumulative incidence will be determined using the proportional hazards method with a corresponding 95% confidence interval. GVHD severity will be determined clinically and graded by using the institutional BMT program clinical practice guidelines. (Pzrepiorka D, Weisdorf D, Martin P, et al. Consensus conference on acute GVHD grading. Bone Marrow Transplantation 1995; 15:825-8.)
Time frame: At day +100
Incidence of chronic GVHD
Time frame: At 1 year
Incidence of relapse
Determined using the proportional hazards method with a corresponding 95% confidence interval.
Time frame: At 1 year
Overall Survival
The Kaplan-Meier method will be used to estimate overall survival, measured from the date of transplantation to either death from any cause or end of follow-up.
Time frame: At 1 year
Relapse-free Survival
Time frame: At 1 year
GVHD-free relapse-free Survival
Time frame: At 1 year
Number of participants with adverse events of grade 4 or higher that are probably or definitely related to vorinostat.
Graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
Time frame: Up to day +100
Percentage of participants with engraftment failure
Engraftment failure will be defined as the inability to achieve an absolute neutrophil count (ANC) \> 500/uL within 28 days post-transplant.
Time frame: Up to 28 days post-transplant
Percentage of participants for whom successful administration of at least 60% of the planned doses occurs between day -1 and day +30 post-transplant
Time frame: Up to 30 days post-transplant
Maximum concentration (Cmax) of Vorinostat
Pharmacokinetic (PK) analysis will be performed using blood samples from subjects who have received at least one dose of vorinostat and for whom quantifiable PK samples are available. Pharmacokinetic variables will be summarized with descriptive statistics.
Time frame: At day +1
Area under the curve (AUC) of Vorinostat
Time frame: At day +1
Clearance (CL) of Vorinostat
Time frame: At day +1
Volume (V) of Vorinostat
Time frame: At day +1
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.