Haploidentical Allogeneic Transplant With Post-transplant Infusion of Regulatory T-cells

Study Overview
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Brief Summary
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Patients with hematologic malignancies will receive myeloablative chemotherapy followed by stem cell rescue with bone marrow or hematopoietic peripheral blood stem cells collected by apheresis from a filgrastim- (G-CSF)-mobilized haploidentical related-donor, ie, hematopoietic peripheral blood stem cell transplant (HSCT).

Detailed Description
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This is dose-escalation study intended to evaluate the use of classification determinant 15-positive (CD15+), CD4+, CD127dim, and FoxP3+ regulatory T-cells (T-reg cells) supplemented by conventional T-cells (T-con cells), to enhance the efficacy of allogeneic (CliniMACS CD34+ selected) hematopoietic stem cell transplantation (allo-HSCT), in the setting of leukemia, lymphoma, and myelodysplastic syndrome (MDS). This study investigates amelioration of the impaired immune recovery and address the significant relapse incidence in the haploidentical HSCT setting. Pre-transplant myeloablative conditioning will be melphalan; thiotepa; fludarabine and rabbit antithymocyte globulin (rATG). Stem cell rescue will be with CD34+ selected cells. The rescue infusion will be supplemented with infusions of regulatory T-cells (T-reg) and conventional T-cells (T-con) from the same donor collection, on Treatment Days 14 and 16 respectively. CD34+ cell infusion day is Treatment Day 0. T-reg cells are those cells enriched by immunomagnetic selection of CD25+ cells, and further purified by flow cytometric cell sorting for the CD15+, CD4+, CD127dim, FoxP3+ cell population. These cells are an enriched but naturally-occurring T-cell population. T-con cells are unseparated/unfractionated cells, ie, as collected by the peripheral blood stem cells apheresis procedure. Post-transplant follow-up is for 5 years.

Official Title
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A Feasibility Trial of Post-Transplant Infusion of Allogeneic Regulatory T Cells and Allogeneic Conventional T Cells in Patients With Hematologic Malignancies Undergoing Allogeneic Myeloablative Hematopoietic Cell Transplantation From Haploidentical-Related Donors

Conditions
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Leukemia, Acute, Chronic Myelogenous Leukemia (CML), Myelodysplastic Syndrome (MDS), Non-Hodgkin Lymphoma (NHL), Chronic Lymphocytic Leukemia (CLL), Acute Myelogenous Leukemia (AML), Acute Lymphoblastic Leukemia (ALL)

Intervention / Treatment
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* Drug: Regulatory T-cells
* Drug: Conventional T-cells
* Drug: Melphalan
* Drug: Thiotepa
* Device: Fludarabine
* Drug: Anti-thymocyte globulin, rabbit
* Drug: CliniMACS CD34 Reagent System


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria RECIPIENT Histopathologically-confirmed: Acute leukemia (in first remission with poor risk factors and molecular prognosis) Acute myelogenous leukemia (AML) with -5,-7, t (6;9), tri8, -11 Acute lymphoblastic leukemia (ALL) with Ph+ t (9;22), t (4;22), (q34;q11) Acute leukemia with refractory disease or > Complete Remission (CR) 1 Chronic myelogenous leukemia (CML) (accelerated, blast or second chronic phase) Myelodysplastic syndrome (in high and high intermediate risk categories) Non-Hodgkin's lymphoma (NHL) with poor risk features and not suitable for autologous transplantation Refractory Chronic lymphocytic leukemia (CLL) At least 21 days from the end of most recent prior therapy to start of the transplant conditioning regimen Must be < 60 years old at time of registration. Karnofsky Performance Status (KPS) > 70% Must have related donor who is: Genotypically human leukocyte antigen (HLA) -A, B,C and DR beta 1 (DRB1), DQ loci haploidentical to the recipient (but differing for 2 to 3 HLA alleles on the unshared haplotype in the graft-versus-host disease (GvHD) direction) No HLA-matched sibling or matched-unrelated donor is identified. Adequate cardiac and pulmonary function (left ventricular ejection fraction (LVEF) > 45%, diffusing capacity of the lungs for carbon monoxide (DLCO) >50% corrected for hemoglobin) Serum creatinine < 1.5 mg/dL OR Creatinine clearance > 50 mL/min for those above serum creatinine at least 1.5 mg/dL Serum bilirubin < 2.0 mg/dL Alanine transaminase (ALT) < 2x upper normal limit (ULN) (unless secondary to disease) No prior myeloablative therapy or hematopoietic cell transplantation DONOR: Age ≤ 70 years Weight ≥ 25 kg. Medical history and physical examination confirm good health status as defined by institutional standards Seronegative for HIV Ag within 30 days of apheresis collection for: Hepatitis B surface antigen (sAg) or polymerase chain reaction (PCR) + Hepatitis C ab or PCR+ Genotypically haploidentical as determined by HLA typing Female donors (child-bearing potential) must have a negative serum or urine beta-human chorionic gonadotropin (HCG) test within 3 weeks of mobilization Capable of undergoing leukapheresis Has adequate venous access Willing to undergo insertion of a central catheter if leukapheresis via peripheral vein is inadequate Capable of agreeing to second donation of peripheral blood progenitor cell (PBPC) (or a bone marrow harvest) should the patient fail to demonstrate sustained engraftment following the transplant Institutional review board (IRB)-approved consent form signed by donor or legal guardian > 18 years of age Donor Selection in the priority order: Recipient's biological mother preferred, if available Other available haploidentical donors will be selected based upon the presence of natural killer (NK) alloreactivity between donor and recipient by high-resolution HLA typing of the C locus. An NK-alloreactive donor will be preferentially chosen. Recipients lacking a killer immunoglobulin-like receptor (KIR)-ligand present in the donor along with the corresponding KIR defines NK alloreactivity. If more than one NK-alloreactive donor is available, preference is to cytomegalovirus (CMV)-seronegative donor Exclusion Criteria RECIPIENT: Suitable candidate for autologous transplantation or allogeneic transplantation with an available matched-related or matched-unrelated donor Seropositive for: HIV ab Hepatitis B sAg or PCR+ Hepatitis C ab or PCR+ History of invasive Aspergillosis Any active, uncontrolled bacterial, viral or fungal infection Uncontrolled central nervous system (CNS) disease involvement Lactating female DONOR: Evidence of active infection or viral hepatitis Factors of increased risk for complications from leukapheresis or granulocyte-colony stimulating factor (G-CSF) therapy Lactating female HIV-positive

Ages Eligible for Study
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Maximum Age: 60 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: T-reg Cell Infusion after Allogeneic Stem Cell Transplant<br> | Drug: Regulatory T-cells<br>* To ameliorate the impaired immune recovery and address the significant relapse incidence in the haploidentical setting. Cells will be selected by a tandem selection process and infused on day +14. These are the enriched but naturally-occurring regulatory T cells. Possible dose cohorts and levels are: Cohort 1 T-reg: 1 x 10e5/kg T-con: 3 x10e5/kg Cohort 2 T-reg: 3 x 10e5/kg T-con: 1 x 10e6/kg Cohort 3 T-reg: 1 x 10e6/kg T-con: 3 x 10e6/kg Cohort 4 T-reg: 3 x 10e6/kg T-con: 1 x 10e7/kg<br>* Other names: T-reg cells;Drug: Conventional T-cells<br>* These are conventional (unselected) donor T-cells. Cell dosage of the infusion will be based on the CD3+ cell content and infused on day +16.<br>* Other names: T-con cells;Drug: Melphalan<br>* Anti-cancer chemotherapy drug administered IV at 140 mg/m² on Day -8 prior to HSCT (a component of the conditioning regiment prior to infusion of cells)<br>* Other names: Phenylalanine Mustard;Drug: Thiotepa<br>* Anti-cancer chemotherapy drug administered IV at 10 mg/kg on Day -7 prior to HSCT (a component of the conditioning regiment prior to infusion of cells)<br>* Other names: TSPA;Device: Fludarabine<br>* Anti-cancer chemotherapy drug administered IV at 160mg/m² on Days -6; -5; -4; and -3 prior to HSCT (a component of the conditioning regiment prior to infusion of cells<br>* Other names: Fludara;Drug: Anti-thymocyte globulin, rabbit<br>* Rabbit-derived antibodies against human T-cells used as transplant rejection prophylaxis. Administered at 6 mg/kg IV on Days -6; -5; -4; and -3 prior to HSCT<br>* Other names: rATG;Drug: CliniMACS CD34 Reagent System<br>* An in vitro medical device system that uses antibodies conjugated to magnetic beads to select and enrich for CD34+ blood stem cells from the allogeneic donor apheresis product prior to HSCT, while removing other cells that can cause GvHD. CD34+ cell dosage will be based on the participant's body weight.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum-tolerated Dose (MTD) of Regulatory and Conventional T-cells | The maximum-tolerated dose (MTD) was to be determined based on the safety and feasibility observed for a pre-determined set of cellular dose level combinations of regulatory T-cells (T-reg) and conventional T-cells (T-con). | 30 days after HSCT infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Graft-versus-Host-Disease (aGvHD) | The primary outcome was incidence of grade 3 or 4 acute graft-vs-host-disease (aGvHD), reported as the number of participants developing grade 3 or 4 aGvHD. | 1 year | 
| Overall Survival (OS), 1 Year | Assessed as subjects remaining alive 12 months after CD34+ cell infusion (ie, excludes death due to any cause) | 1 year | 
| Median Overall Survival (OS) | Reported as the median overall survival (OS) in months from infusion of the hematopoietic stem cells (HSCT) | 25 months | 
| To Measure the Incidence and Severity of Acute and Chronic GvHD | Population of participants that received HSCT and T-reg plus T-con, and developed actue, chronic, or any graft vs host disease (GvHD) | 1 year | 
| Serious Infections | Serious infections are reported as the number of participants experienced serious infections. | 1 year |