Ex Vivo TCR αβ T Cell Depletion for Graft-Versus-Host Disease Prophylaxis in Mismatched Donor Peripheral Blood Stem Cell Transplantation for Hematologic Malignancies

Study Overview
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Brief Summary
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This research study is studying the removal of a subset of white blood cells (called alpha/beta T cells) from the donor product using a cell separation device before the product is transplanted into the participant. The device used to remove the α/βT cells in this study is: -CliniMACS® TCR α/β Reagent System

Detailed Description
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Patients who receive an allogeneic (using another person as the donor) stem cell transplant (SCT) are at risk for developing graft-versus-host disease (GVHD). The word graft refers to the donor blood cells that you will receive during the transplant. The word host refers to the person receiving the cells. GVHD is a complication of transplantation where the donor graft attacks and damages some of the participant's tissues. GVHD may occur when the T cells (a type of white blood cell that helps protect the body from infection) from the donor react against normal tissues or organs in the body. There are two basic types of GVHD: Acute GVHD often occurs early (generally first 3-6 months after SCT) may affect skin, gastrointestinal tract (stomach and intestines) and liver. Chronic GVHD often occurs later (Usually after 3-6 months after SCT) and may affect many organs and significantly diminish quality of life. To confirm the diagnosis of acute or chronic GVHD, the participant may be asked to have a biopsy (a small sample of the participant's tissue to look at under the microscope) of the skin, gut, or, rarely, the liver. In this research study, the investigator are investigating a pre-transplant intervention aimed to prevent GVHD by processing the donor product with the Miltenyi CliniMACS TCR α/β Reagent System. The Reagent System will remove certain cells (called T-Cell Receptor (TCR) α/β positive T-cells) that are thought to cause GVHD from donor product before it is given to the participant. By selectively removing this specific type of T cells from the donor product, the investigators hope to reduce the risk for GVHD without reducing the efficacy of the transplant. This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. Investigational means that the intervention is being studied. The FDA (the U.S. Food and Drug Administration) has not approved CliniMACS α/β T cell depletion system for use in the US, but this system is approved by the European Medicines Agency (EMA) and used in Europe

Official Title
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A Phase 2 Study of Ex Vivo TCR αβ T Cell Depletion for Graft-Versus-Host Disease (GVHD) Prophylaxis in Mismatched Donor Peripheral Blood Stem Cell Transplantation for Hematologic Malignancies

Conditions
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Hematologic Malignancy

Intervention / Treatment
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* Device: ClinicMACs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnoses and stage at time of transplant admission: Acute leukemia (AML or ALL or MPAL) in first or subsequent remission Myelodysplastic syndromes (MDS) with <10% marrow blasts Myeloproliferative neoplasm (MPN) with <10% marrow blasts CMML with less than 10% marrow blast CML accelerated phase or second or subsequent chronic phase Non-Hodgkin's lymphoma in PR or CR2 or beyond Hodgkin lymphoma in PR or CR2 or beyond Age 18-65 years Patient has a related or unrelated donor who is 8 or 9 out of 10 match at HLA A, B, C, DRB1 and DQB1, based on allele level typing. Patient ECOG performance status 0-2 (Karnofsky ≥60%, see Appendix A) Patient deemed to be appropriate candidate for myeloablative conditioning transplantation. Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Patient with active HIV infection Chronic active hepatitis B infection (HepB surface Ag+ or detectable Hep B viral load) Prior allogeneic hematopoietic stem cell transplantation Impaired cardiac function- ejection fraction < 40% Impaired pulmonary function- pretransplant FEV1, DLCO < 50% Impaired renal function, based on --Serum creatinine > 2.0 mg/dl Impaired liver function unrelated to primary disease, based on --ALT or AST > 3x ULN, or Total Bilirubin > 2.0mg/dl (with exception for known or suspected Gilbert's disease) Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Women who are pregnant or breast feeding. Women of child bearing potential must have a negative serum pregnancy test at study entry. Participants who are receiving any other investigational agents are eligible but such agent must be discontinued before admission for HSCT, and if resumption of investigation agent is planned after HSCT, this must be approved by the study PI. Participants with known active CNS disease. CNS disease that has been treated is eligible

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TCR α/β Reagent System<br>The stem cell apheresis product will be depleted of TCRαβ T cells by negative selection using the automated CliniMACS® Plus device. CD34+ stem cell counts will be obtained before and after processing with the Miltenyi ClinicMACs device | Device: ClinicMACs<br>* The Reagent System will remove certain cells (called T-Cell Receptor (TCR) α/β positive T-cells) that are thought to cause GVHD from donor product before it is given to participants<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Severe Acute GVHD-free Survival | Number of participants with severe acute GVHD-free survival will be assessed at 100 days post-SCT | 100 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Grades II-IV Acute GVHD | Grades II-IV acute GVHD will be assessed at 2 years post-SCT. Grade I GVHD is characterized as mild disease, grade II as moderate, grade III as severe, and grade IV as life-threatening. Higher grades of acute GVHD are associated with worse outcomes. Acute GVHD will be staged by assessment of clinical manifestations in the skin, gastrointestinal tract, and liver. | 2 years | 
| Number of Participants With Chronic GVHD | Number of participants with chronic GVHD will be assessed at 2 years post-SCT. | 2 years | 
| Number of Participants With GVHD and Relapse Free Survival (GRFS) | GRFS will be defined as alive without having experienced grade III-IV acute GVHD, moderate/severe chronic GVHD, or relapse of underlying malignancy. | 2 years | 
| Number of Participants With Immunosuppression-free Survival | Number of participants with immunosuppression-free survival will be assessed at 2 years post-SCT. | 2 years | 
| Number of Participants With Hematologic Recovery | Hematologic recovery will be assessed in participants at 2 years post-SCT. | 2 years | 
| Number of Participants With Immune Reconstitution | Immune reconstitution will be assessed in participants at 2 years post-SCT. | 2 years | 
| Number of Participants With Disease Relapse | Disease relapse will be assessed in participants at 2 years post-SCT. | 2 years | 
| Number of Participants With Transplant-related Mortality | Participant transplant-related mortality will be assessed at 2 years post-SCT. | 2 years | 
| Number of Participants With Organ Toxicity | Participant organ toxicity will be assessed at 2 years post-SCT. | 2 years | 
| Rates of Infections | Participant rate of infections will be assessed at 2 years post-SCT. | 2 years | 
| Number of Participants With Relapse-free and Overall Survival | Number of participants with relapse-free and overall survival will be assessed at 2 years post-SCT. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Graft vs. Host Disease, Hematologic Malignancy