Haploidentical Donor Hematopoietic Progenitor Cell and NK Cell Transplantation for Hematologic Malignancy

Study Overview
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Brief Summary
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In this study, participants with high-risk hematologic malignancies undergoing hematopoietic cell transplantation (HCT), who do not have a suitable human leukocyte antigen (HLA) matched related/sibling donor (MSD) or matched unrelated donor (MUD) identified, will receive a haploidentical donor HCT with additional natural killer (NK) cells. The investigators anticipate enrollment of 75 donors and 75 recipients. PRIMARY OBJECTIVE: To estimate the rate of successful engraftment at day +42 post-transplant in patients who receive haploidentical donor stem cell plus NK cell transplantation with TLI based conditioning regimen for high risk hematologic malignancy. SECONDARY OBJECTIVES: Estimate the incidence of malignant relapse, event-free survival, and overall survival at one-year post-transplantation. Estimate incidence and severity of acute and chronic (GVHD). Estimate the rate of transplant related mortality (TRM) in the first 100 days after transplantation.

Detailed Description
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Donors will undergo G-CSF mobilization of peripheral blood stem cells (PBSC) prior to undergoing two apheresis collections of hematopoietic progenitor cells (HPC,A) and one apheresis collection of therapeutic cell product of purified natural killer cells (TC-NK). The HPC products will be T-cell depleted (TCD) using the investigational CliniMACS device. CD34+ enrichment and CD45RA depletion will be utilized on sequential HPC grafts. Participants will undergo a preparative regimen of total lymphoid irradiation, fludarabine, cyclophosphamide, granulocyte colony stimulating factor (G-CSF), thiotepa, and melphalan. This is followed by infusions of donor cells that have been prepared using the CliniMACS system: HPC,A (CD34+ selected), HPC,A (CD45RA depleted), and TC-NK.

Official Title
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Haploidentical Donor Hematopoietic Progenitor Cell and Natural Killer Cell Transplantation With a TLI Based Conditioning Regimen in Patients With Hematologic Malignancies

Conditions
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Leukemia, Lymphoma

Intervention / Treatment
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* Radiation: Total Lymphoid Irradiation
* Drug: Fludarabine
* Drug: Cyclophosphamide
* Drug: Thiotepa
* Drug: Melphalan
* Biological: HPC,A Infusion
* Biological: TC-NK Infusion
* Biological: G-CSF
* Drug: Mesna
* Device: CliniMACS
* Drug: Mycophenolate mofetil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria - Transplant Recipients: Age less than or equal to 21 years. Does not have a suitable MSD or volunteer MUD available in the necessary time for stem cell donation. Has a suitable single haplotype matched (≥ 3 of 6) and family member donor. High risk hematologic malignancy. If prior CNS leukemia, it must be treated and in CNS CR Does not have any other active malignancy other than the one for which this HCT is indicated. No prior allogeneic HCT, and no autologous HCT within the previous 12 months. Patient must fulfill pre-transplant evaluation Inclusion Criteria - Haploidentical Donor: At least single haplotype matched (≥ 3 of 6) family member At least 18 years of age. HIV negative. Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment (if female). Not breast feeding. Regarding eligibility, is identified as either: (1) Completed the process of donor eligibility determination as outlined in 21 CFR 1271 and agency guidance; OR (2) Does not meet 21 CFR 1271 eligibility requirements, but has a declaration of urgent medical need completed by the principal investigator or physician sub-investigator per 21 CFR 1271.

Ages Eligible for Study
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Maximum Age: 21 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: Transplant Recipients<br>Participants undergo a preparative regimen of total lymphoid irradiation, fludarabine, cyclophosphamide, fludarabine, thiotepa, melphalan, and mycophenolate mofetil, followed by HPC,A infusion and TC-NK infusion. They also receive G-CSF and mesna. Cells for infusion are prepared using the CliniMACS System. | Radiation: Total Lymphoid Irradiation<br>* Participants receive total lymphoid irradiation over four doses.<br>* Other names: TLI;Drug: Fludarabine<br>* Given IV.<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* Given IV.<br>* Other names: Cytoxan;Drug: Thiotepa<br>* Given IV.<br>* Other names: TSPA;Drug: Melphalan<br>* Given IV.<br>* Other names: Alkeran(R);Biological: HPC,A Infusion<br>* Participants received infusions of HPC,A (CD34+ selected) and HPC,A (CD45RA depleted).<br>Biological: TC-NK Infusion<br>* Participants receive infusions of TC-NK.<br>Biological: G-CSF<br>* Participants receive G-CSF subcutaneously or intravenously. Donors receive G-CSF subcutaneously during cell mobilization.<br>* Other names: Neupogen(R);Drug: Mesna<br>* Mesna is generally dosed at approximately 25% of the cyclophosphamide dose. It is generally given intravenously prior to and again at 3, 6 and 9 hours following each dose of cyclophosphamide.<br>* Other names: Mesnex;Device: CliniMACS<br>* The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells.<br>* Other names: Cell Selection System;Drug: Mycophenolate mofetil<br>* Given intravenously or orally.<br>* Other names: CellCept®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Transplant Recipients With Successful Engraftment | Neutrophil engraftment will be determined using the parameters put forth by the Center for International Blood and Marrow Registry. Assessments will be made upon review of daily complete blood count and serial chimerism studies. Successful engraftment for the purposes of this objective will be patients who do not experience graft failure. | 42 days post engraftment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Transplant Recipients With Malignant Relapse | Bone marrow studies for disease status evaluation will be performed at 1-year post-transplant. Testing will include a research evaluation for minimal residual disease. | One-year post-transplantation | 
| Event-free Survival | The one-year event free survival is defined by the patient who has neither experienced relapse nor death within one year after post transplantation. And the rate is calculated by computing the ratio between total number of one year event free survival patients and the total number of patients. | One year post-transplantation | 
| Overall Survival | The one-year survival is defined by the patient who has not died within one year after post transplantation. And the rate is calculated by computing the ratio between total number of one year survival patients and the total number of patients. | one year post-transplantation | 
| Number of Transplant Recipients With Acute and/or Chronic Graft Versus Host Disease (GVHD) | Acute and chronic graft-vs.-host disease will be evaluated using the standard grading criteria. The estimate will be the number of recipients who experienced GVHD divided by the total number of patients considered in this group. | 100 days post-transplant for acute GVHD; one year post-transplant for chronic GVHD . | 
| Number of Transplant Recipients With Transplant-related Mortality (TRM) | Estimate the proportion of patients died within 100 days after the transplantation who has not experienced a relapse. The estimate will be the number of TRM divides the total number of patients considered in this group. | In the first 100 days after transplantation | 
| Severity of Acute Graft Versus Host Disease (aGVHD) | Ongoing assessment of toxicity will be done using the NCI CTCAE version 3.0. Acute and chronic graft-vs.-host disease will be evaluated using the standard grading criteria. The severity of acute GvHD and chronic GvHD will be described. The analysis for this objective will be performed when the last evaluable participant has been followed for 100 days post transplant. Acute GvHD is graded from 1-4 with 4 being the worst outcome. | 100 days post-transplant for acute GVHD. | 
| Severity of Chronic Graft Versus Host Disease (cGVHD) | Ongoing assessment of toxicity will be done using the NCI CTCAE version 3.0. Acute and chronic graft-vs.-host disease will be evaluated using the standard grading criteria. The severity of acute GvHD and chronic GvHD will be described. The analysis for this objective will be performed when the last evaluable participant has been followed for 1 year post-transplant. Chronic GvHD is graded as mild, moderate or severe with severe being the worst outcome. | 1 year post-transplant for chronic GVHD . | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NK cell, Haploidentical donor transplantation