Symptoms and General Pathology

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Micronutrients

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Cyclophosphamide

Methotrexate

Cyclosporine

Cyclosporins

Mycophenolic Acid

Tacrolimus

Vorinostat

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Alkylating Agents

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Folic Acid Antagonists

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Clotrimazole

Miconazole

Antifungal Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antitubercular Agents

Histone Deacetylase Inhibitors

Folinic Acid

Folate

Vitamin B9

* 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.

Blood and Marrow Transplant (BMT)

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.

Tacrolimus (or cyclosporine)

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.

Mycophenolate Mofetil (MMF)

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.

Amy Keating, MD

Amy Keating

Kirsten Williams

Sung Choi, MD, MS

Edward Peres

Carrie Kitko, MD

Julie An Talano

Sung W Choi, MD, MS

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.

Vorinostat for Graft vs Host Disease Prevention in Children, Adolescents and Young Adults Undergoing Allogeneic Blood and Marrow Transplantation

A Phase 1/2 Multi-Center Trial of Vorinostat for Graft vs Host Disease Prevention in Children, Adolescents and Young Adults Undergoing Allogeneic Blood and Marrow Transplantation

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.

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.)

Determined using the proportional hazards method with a corresponding 95% confidence interval.

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.

Graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0

Engraftment failure will be defined as the inability to achieve an absolute neutrophil count (ANC) \> 500/uL within 28 days post-transplant.

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.

National Institutes of Health (NIH)

National Center for Advancing Translational Sciences (NCATS)

University of Michigan Rogel Cancer Center

Spots Global Cancer Trial Database for Vorinostat for Graft vs Host Disease Prevention in Children, Adolescents and Young Adults Undergoing Allogeneic Blood and Marrow Transplantation

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