Haploidentical Hematopoietic Cell Transplantation Using TCR Alpha/Beta and CD19 Depletion

Study Overview
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Brief Summary
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Patients with medical conditions requiring allogeneic hematopoietic cell transplantation (allo-HCT) are at risk of developing a condition called graft versus host disease (GvHD) which carries a high morbidity and mortality. This is a phase I/II study that will test the safety and efficacy of hematopoietic cell transplantation (HCT) with ex-vivo T cell receptor Alpha/Beta+ and CD19 depletion to treat patients' underlying condition. This process is expected to substantially decrease the risk of GvHD thus allowing for the elimination of immunosuppressive therapy post-transplant. The study will use blood stem/progenitor cells collected from the peripheral blood of parent or other half-matched (haploidentical) family member donor. The procedure will be performed using CliniMACS® TCRα/β-Biotin System which is considered investigational.

Detailed Description
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This is a phase I/II study of haploidentical HCT (HHCT) with ex vivo TCRαβ+ and CD19+ depletion using the CliniMACS device in patients with hematological malignancies and non-malignant disorders. HHCT will be performed according to current standards of care at the Center for Cell and Gene Therapy (CAGT) within Texas Children's Hospital (TCH) and Houston Methodist Hospital (HMH), including the use of a standard chemotherapy conditioning regimens, supportive care and standard follow-up laboratory assessments. The study will determine efficacy of this strategy in terms of engraftment, and safety in terms of rates of acute and chronic graft versus Host Disease (GvHD), one-year overall survival (OS) and transplant-related mortality (TRM). The peripheral blood hematopoietic cell product will undergo negative selection of TCR αβ following the standardized protocol in the user's manual for the CliniMACS (Miltenyi Biotech, Germany). TCR αβ+ T-cells are labeled by CliniMACS TCR αβ-Biotin (murine anti-TCR αβ monoclonal antibodies conjugated to biotin) which allows the TCR αβ+ T-cells to be magnetically labeled with CliniMACS Anti-Biotin Microbeads (murine anti-biotin monoclonal antibodies conjugated to superparamagnetic iron dextran particles) for depletion. The CD19+ B cells are labeled by CliniMACS CD19 microbeads which allows the CD19+ B cells to be magnetically labeled for depletion. All unlabeled cells are selected as target cells which should contain a minimum amount of TCR αβ+ and CD19+ cells. The microbeads used for labeling are approximately 50 nanometers in diameter and do not require removal prior to patient infusion. In January 2014, the U.S. Food and Drug Administration (FDA) has approved the Miltenyi Biotec's CliniMACS CD34 Reagent System as a Humanitarian Use Device for the prevention of GvHD in patients with acute myeloid leukemia (AML) in first complete remission undergoing allo-HCT from HLA-matched related donor.

Official Title
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T-Cell Receptor Alpha Beta+/CD19+ Depletion in Haploidentical Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) for Adult and Pediatric Patients With Hematological Malignancies and Non-malignant Disorders

Conditions
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Primary Immunodeficiency Diseases, Acute Lymphoblastic Leukemia in Remission, Acute Myeloid Leukemia in Remission, Myelodysplastic Syndromes, Chronic Myeloid Leukemia, Hemophagocytic Lymphohistiocytoses, Hemoglobinopathies, Severe Aplastic Anemia, Cytopenia, Bone Marrow Failure Syndrome, Severe Chronic Active Epstein-Barr Virus Infection

Intervention / Treatment
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* Device: CliniMACS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Lack of suitable conventional donor (10/10 HLA matched related or unrelated donor) or presence of rapidly progressive disease not permitting time to identify an HLA-matched unrelated donor. This does not include cord blood unit (CBU) availability. Lansky/Karnofsky score > 50 Signed written informed consent Diagnosis of one of the following: Patient with life threatening hematological malignancy including high-risk ALL in first complete remission (CR1); ALL in second or subsequent remission (greater than or equal to CR2); high-risk AML in CR1; AML in second or subsequent CR; myelodysplastic syndromes (MDS); non-Hodgkin's lymphomas (NHL) in second or subsequent remission (greater than or equal to CR2); CML Hemophagocytic Lymphohistiocytosis (HLH) including familial HLH, relapsed HLH or central nervous system (CNS) HLH Primary Immunodeficiency Disorders (PID) Hemoglobinopathies including thalassemia or sickle cell disease (SCD) Severe aplastic anemia (SAA) not responding to immune suppressive therapy Congenital/hereditary cytopenias including Fanconi anemia (FA) without malignant clonal evolution (MDA, AML) Other inherited bone marrow failure syndromes (IBMFS) Sever chronic active Epstein Barr virus infection (SCAEBV) with predilection for T-or NK-cell malignancy NOTE: 'High risk' ALL or AML refers to those acute leukemias identified by the presence of specific biologic features, which predict high likelihood of failure to conventional chemotherapy. As biologic features of high-risk disease evolve with improvement of conventional chemotherapy, it is not practical to define this indication with any further specificity. Therefore, high risk AML/ALL will be determined by the primary physician. Exclusion Criteria: Life expectancy of less than or equal to 6 weeks Greater than grade II acute graft versus host disease (GVHD) or chronic extensive GVHD due to a previous allograft at the time of inclusion Subject receiving an immunosuppressive treatment for GVHD treatment due to a previous allograft at the time of inclusion Symptomatic cardiac disease or left ventricular shortening fraction less than 25% or ejection fraction < 40% Severe renal disease, with creatinine clearance < 40cc/1.73m2 Pre-existing severe restrictive pulmonary disease, FVC < 40% of predicted Severe Hepatic Disease with ALT/AST ≥ x 2.5 upper limit of normal or bilirubin level ≥ x 1.5 upper limit of normal Serious concurrent uncontrolled medical disorder or mental illness Pregnant or breastfeeding female subject Current active infectious disease including viral and fungal diseases at the time of enrollment; that on evaluation of PI precludes ablative chemotherapy or successful transplantation Active HIV infection Severe personality disorder or mental illness that would preclude compliance with the study

Ages Eligible for Study
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Maximum Age: 55 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alpha beta+ T cell depleted CD34+ stem cells<br>The patient will be receiving a donor stem cell transplant with a preceding conditioning regimen (chemotherapy with, or without, radiation). The investigators will be specially treating the donor's blood cells used for the stem cell transplant. | Device: CliniMACS<br>* Peripheral blood stem cells from closely matched unrelated donors will be processed using the CliniMACS device to remove TCRalpha/beta (alpha beta+) T cells and B cells, in accordance with the Investigator Brochure and Technical Manual following the laboratory standard operating procedures (SOPs) and using aseptic technique<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of neutrophil engraftment | Neutrophil engraftment defined as the first of 3 consecutive days with a peripheral blood absolute neutrophil count of ≥ 0.5x10^9/L | 42 days post-HCT | 
| Rate of platelet engraftment | Platelet engraftment defined as the first day with platelet count of ≥ 20 x10^9/L without transfusion support for 7 consecutive days | 42 days post-HCT | 
| Rate of acute graft versus host disease (GvHD) by grades | Number of patients who developed grade III or higher aGvHD among patients who achieve engraftment will be reported as rate of acute GvHD and its associated 95% confidence interval | 100 days post-HCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of transplant-related mortality (TRM) | Defined as death due to any transplantation-related cause, other than disease | 100 days and 365 days post-HCT | 
| Overall survival (OS) | The length of time from the day of transplant to death | Up to one year post-HCT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Myeloid Leukemia, Hemophagocytic Lymphohistiocytoses, Non-Hodgkins Lymphoma, Primary Immunodeficiency Diseases, Hemoglobinopathies, Severe Aplastic Anemia, Congenital/hereditary cytopenias including Fanconi Anemia, Bone Marrow Failure Syndrome, Severe Chronic active Epstein-Barr Virus Infections, Stem Cell Transplant, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Myelodysplastic Syndromes