VPA Expanded UCB Transplantation for Treatment of Patients With Hematological Malignancies

Study Overview
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Brief Summary
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In this Phase I study, the study team will evaluate the safety of Valproic Acid (VPA) expanded cord blood stem cells defined by the lack of serious infusion reactions or graft failure in patients with hematological malignancies undergoing umbilical cord blood transplantation. Moreover, the study team will also evaluate time to neutrophil and platelet engraftment as well as transplant related outcomes such as graft versus host disease (GVHD), treatment related mortality (TRM), and overall survival (OS).

Detailed Description
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This is a phase I trial for safety of VPA expanded cord blood stem cells in patients with hematological malignancies undergoing allogeneic stem cell transplantation. The primary endpoint of the study is safety as defined by the incidence of infusion reactions and graft failure, lack of neutrophil engraftment by day +42. The trial will consist of two cohorts. First cohort of 5-7 patients, will undergo double umbilical cord blood (UCB) transplantation. One UCB unit will undergo CD34 selection followed VPA based expansion. CD34 negative portion of that unit will be cryopreserved to be infused later following infusion of the expanded portion. Infusion of the second unmanipulated UCB will follow it. Preparative regimen is Fludarabine 150 mg/m2/Cytoxan 50 mg/m2/Thiotepa 10 mg/m2/TBI 400cGy. Following successful engraftment in the first cohort, second cohort (10 patients) will only receive single manipulated unit. Otherwise, patients will receive standard allogeneic stem cell transplantation care.

Official Title
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Phase I Study of Valproic Acid Expanded Cord Blood Stem Cells as an Allogeneic Donor Source for Adults With Hematological Malignancies

Conditions
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Hematological Malignancy, Acute Leukemia in Remission, Acute Lymphoblastic Leukemia in Remission, Myelodysplastic Syndromes, Non-Hodgkin Lymphoma, Hodgkin Lymphoma

Intervention / Treatment
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* Biological: Cord blood stem cells
* Drug: Valproic Acid
* Drug: Fludarabine
* Drug: cytoxan
* Drug: Thiotepa
* Biological: TBI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Disease criteria: Patients with the following hematological malignancies: Acute Myeloid Leukemia (AML) in complete remission (CR) Acute Lymphoblastic Leukemia (ALL) in complete remission (CR) Myelodysplastic Syndrome (MDS) requiring intensive chemotherapy Non-Hodgkin lymphoma in complete or partial remission Hodgkin lymphoma in complete or partial remission Age Criteria: - 18 years up to 65 years. Organ Function and Performance Status Criteria: - Performance status score: Karnofsky Score ≥60 Adequate major organ function defined as: Left ventricular ejection fraction ≥40% Pulmonary function test demonstrating DLCO ≥50% predicted and corrected for hemoglobin Serum creatinine ≤ 2 mg/dL Transaminases ≤ 3x ULN Bilirubin ≤3x ULN except for in case of Gilbert's syndrome or ongoing hemolysis Ability to understand and the willingness to sign a written informed consent document Donor availability: -Lack of suitable HLA matched related or unrelated donor available within 30 days or less if BMT is urgent in the opinion of the transplant physician. Exclusion Criteria: Progressive, persistent disease or active malignancy Greater than 10% blasts on bone marrow biopsy in patients with MDS Chemotherapy naïve History of myelofibrosis Presence of Bone Marrow Fibrosis grade 2/3 Presence of donor specific anti-HLA antibodies against available UCB units at A, B, C or DR loci, with a mean fluorescence intensity (MFI)>1000 History of prior allogeneic stem cell transplantation Uncontrolled viral, bacterial or fungal infection History of HIV infection Presence of active CNS disease at the time of transplantation Pregnant or breastfeeding female Inability or unwillingness to use effective birth control.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Open label single arm
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VPA expanded cord blood stem cells<br>CD34 selected VPA expanded umbilical cord blood cells used in combination with or without unmanipulated umbilical cord blood for patients with hematological malignancies undergoing allogeneic stem cell transplantation. VPA expanded cord blood stem cells in patients with hematological malignancies undergoing allogeneic stem cell transplantation | Biological: Cord blood stem cells<br>* CD34 selected VPA expanded umbilical cord blood cells used in combination with or without unmanipulated umbilical cord blood .<br>Drug: Valproic Acid<br>* Valproic Acid (VPA) expanded cord blood stem cells<br>* Other names: VPA;Drug: Fludarabine<br>* Fludarabine 150 mg/m2<br>Drug: cytoxan<br>* Cytoxan 50 mg/m2<br>Drug: Thiotepa<br>* Thiotepa 10 mg/m2<br>Biological: TBI<br>* TBI 400cGy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Infusion Reaction | Safety as measured by the incidence of infusion related reactions. | 42 days | 
| Number of Graft Failure | Safety as measured by the incidence of graft failures. | 42 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to neutrophil engraftment | Transplant related outcomes: time to neutrophil engraftment | 1 year | 
| Time to platelets engraftment | Transplant related outcomes: time to platelets engraftment | 1 year | 
| Number of transplant-related mortality (TRM) | Transplant related outcomes: transplant-related mortality (TRM) | 1 year | 
| Number of disease free survivals | Transplant related outcomes: Number of disease free survivals | 1 year | 
| Number of overall survivals | Transplant related outcomes: Number of overall survivals | 1 year | 
| Number of participants at risk of GVHD | Transplant Related Outcomes: risk of GVHD | 1 year | 
| Number of infectious complications | Transplant Related Outcomes: incidence of infectious complications - which is any documented bacterial, viral, or fungal infections. | 1 year | 
| Time to myeloid engraftment | Assess the kinetics of engraftment and immune reconstitution by assessing time to myeloid engraftment | 42 days | 
| Time to lymphoid engraftment | Assess the kinetics of engraftment and immune reconstitution by assessing time to lymphoid engraftment | 42 days | 
| Change in T cell count | Assess the kinetics of engraftment and immune reconstitution by assessing the T cell count at 42 days as compared to baseline | Baseline and 42 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hematological Malignancies, Expanded Umbilical Cord, Allogeneic Stem Cell Transplant, Leukemia, Lymphoma