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Phenylalanine

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

Regulatory T-cells

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.

Conventional T-cells

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)

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)

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

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

Anti-thymocyte globulin, rabbit

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.

CliniMACS CD34 Reagent System

Everett H Meyer, MD, PhD

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).

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.

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

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

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).

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.

Assessed as subjects remaining alive 12 months after CD34+ cell infusion (ie, excludes death due to any cause)

Reported as the median overall survival (OS) in months from infusion of the hematopoietic stem cells (HSCT)

Population of participants that received HSCT and T-reg plus T-con, and developed actue, chronic, or any graft vs host disease (GvHD)

Serious infections are reported as the number of participants experienced serious infections.

Doris Duke Charitable Foundation

Everett Meyer

Assistant Professor of Medicine (Blood and Marrow Transplantation)

Adverse events are only reported for those participants that received the allogeneic T-cell Infusion after the stem cell transplant (SCT). Those that did not receive the SCT, or received only the SCT but the T-cell infusion, are not included except in the all-cause mortality data.

Allogeneic, haploidentical hematopoietic stem cell transplant (allo-HSCT) of bone marrow and/or peripheral blood stem cells, followed by infusion of regulatory T-cells (T-reg) plus conventional CD4 and CD8 T-cells (T-con)

Allogeneic T-Cell Infusion After Stem Cell Transplant (SCT)

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Everett H Meyer, MD, PhD; Assistant Professor of Medicine

Includes all participants that received HSCT

Maximum-tolerated Dose (MTD) of Regulatory and Conventional T-cells

Population of participants that received HSCT and T-reg plus T-con

Acute Graft-versus-Host-Disease (aGvHD)

Overall Survival (OS), 1 Year

Median Overall Survival (OS)

Acute GvHD

Chronic GvHD

Any GvHD (actue + chronic)

To Measure the Incidence and Severity of Acute and Chronic GvHD

Serious Infections

Overall Study

Escalating doses of alloreactive NK cells.

Alloreactive NK cells will be purified by a two-step immunomagnetic selection (CD3 depletion followed by CD56 selection) using the CliniMACS device.

Sherif Farag, MD, PhD

The purpose of this study is to determine the maximum tolerated dose of alloreactive NK cells that can be transfused following stem cell transplant.

A Phase I Trial of Alloreactive Cell Infusion Following Transplantation of Haplotype Cells in Patients With Myeloid Malignancies

A PHASE I TRIAL OF ALLOREACTIVE NK CELLS INFUSION FOLLOWING TRANSPLANTATION OF HAPLOTYPE MISMATCHED, KIR MISMATCHED HIGHLY PURIFIED CD34 CELLS IN PATIENTS WITH ADVANCED OR REFRACTORY MYELOID MALIGNANCIES

Indiana University School of Medicine

Bone Marrow Transplantation

Receive CD34-selected peripheral blood stem cells from related or unrelated donors

Peripheral Blood Stem Cell Transplantation

Eneida Nemecek, MD

Eneida R. Nemecek

This expanded access protocol studies bone marrow transplantation using CD34-selected stem cells from related or unrelated donors in treating participants with cancer or other disorders. Stem cells collected from the donor will be processed using a new device called CliniMACS CD34 Reagent System which marks the blood cells collected from the donor with a special protein called "antibody" that tags only the donor stem cells, sorting out other cells of the blood and immune system. This is done to remove, at least partially, some of the T cells. T cells are the cells in the blood that work as scavengers of the immune system deciding what belongs and what does not. These cells can sometimes cause rejection of the donor graft or a condition called graft-versus host disease (GVHD), where the donor cells can attack the body of the recipient. A bone marrow transplantation using CD34-selected stem cells may reduce the risk of these unwanted side effects of transplant as much as possible.

PRIMARY OBJECTIVES:

I. To provide a source of CD34-selected stem cells for patients with malignant and nonmalignant disorders undergoing bone marrow transplantation from haploidentical (human leukocyte antigen \[HLA\]-mismatched) related donors or HLA-compatible unrelated donors

SECONDARY OBJECTIVES:

I. Monitoring the safety of the CD34-selected stem cells for the recipient, as measured by adverse events related to stem cell infusion, incidence of engraftment of neutrophils and platelets, incidence of acute and chronic GVHD, and one year overall survival, disease-free survival, and primary disease recurrence.

OUTLINE:

Donor stem cells undergo CD34 selection ex vivo using the CliniMACS CD34 Reagent System using standard operating procedures (SOPs) from the manufacturer. Recipients undergo standard of care preparative regimen, bone marrow transplantation with CD34-selected peripheral blood stem cells via infusion over 1 to 2 hours on day 0, and then receive standard of care GVHD prophylaxis.

After completion of study treatment, recipients are followed up at least once weekly while inpatient until transplant day 100, every 1-3 months for the first year and yearly thereafter.

Bone Marrow Transplantation Using CD34-Selected Stem Cells From Related or Unrelated Donors in Treating Participants With Cancer or Other Disorders

Institutional Protocol of Bone Marrow Transplantation Using CD34-Selected Peripheral Blood Stem Cells From Related Haploidentical or Unrelated Donors for Treatment of Malignant and Nonmalignant Disorders

Oregon Health and Science University

OHSU Knight Cancer Institute

Principal Investigator

Diseases and Abnormalities at or Before Birth

Nutritional and Metabolic Diseases

Nervous System Diseases

Gland and Hormone Related Diseases

Anemia, Sickle Cell

Anemia

Metabolic Diseases

Thalassemia

Immunologic Deficiency Syndromes

Anemia, Aplastic

Metabolism, Inborn Errors

Adrenoleukodystrophy

Genetic Diseases, Inborn

Sickle Cell Anemia

Aplastic Anemia

X-linked Adrenoleukodystrophy

Adrenomyeloneuropathy

The CliniMACS CD34 Reagent System is a medical device that is used in vitro to select and enrich CD34+ cells from heterogeneous hematologic cell populations for transplantation in cases where this is clinically indicated.

Erin Arbuckle

Joanne Kurtzberg, MD

The objective of this study is to make T-cell depleted stem cells from a family member who is a half match (haplo-identical) available on an expanded access basis to patients receiving one or two unrelated cord blood transplants who are at a higher risk of not engrafting in a safe amount of time. The purpose of the related stem cells is the give the bone marrow a "jump start" towards recovery. Ultimately, the cord blood cells will grow and permanently rescue the bone marrow.

The primary purpose of the study is to provide expanded access of T-cell depleted haplo-identical stem cells for patients receiving allogeneic transplantation from a related haplo-identical donor and an unrelated, umbilical cord blood (UUCB) unit(s) for the treatment of high risk malignancies and non-malignant disorders. The T-cell depleted haplo-identical stems cells are intended to facilitate early, short-term myeloid engraftment with the primary goal of minimizing early infections and other non-relapse mortality while the UUCB cells engraft as the durable and permanent graft. Patients with high risk or refractory malignancies, or non-malignant disorders amenable to stem cell transplantation therapy but lacking conventional related or unrelated donors will be eligible for this protocol.

Expanded Access to T-cell Depleted Haplo-Identical Stem Cells for Patients Receiving Haplo-Identical and Unrelated Cord Blood Transplants

A Compassionate Release Protocol: Expanded Access to T-cell Depleted Haplo-Identical Stem Cells for Patients Receiving Allogeneic Transplantation Using a Related Haplo-Identical Donor and Unrelated, Umbilical Cord Blood Donor(s) for the Treatment of High Risk Malignancies or Non-Malignant Disorders Requiring Allogeneic Transplantation

Duke University

Miltenyi Biotec, Inc.

Antirheumatic Agents

Tacrolimus

Cyclophosphamide

Plerixafor

Lenograstim

Mycophenolic Acid

Adjuvants, Immunologic

Calcineurin Inhibitors

Enzyme Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antitubercular Agents

Anti-HIV Agents

Anti-Retroviral Agents

Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:.

* Fludarabine (160 mg/m2)
* Melphalan (50 mg/m2)
* TBI (4Gy)

All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.

Subjects without an identified matched related or matched unrelated donor will receive a haploidentical transplantation with reduced intensity preparative conditioning:

-. Fludarabine (160 mg/m2)

* Melphalan (100 mg/m2
* TBI (4Gy)

Patients will receive GVHD prophylaxis with post-transplant cyclophosphamide and tacrolimus.

Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:

* Fludarabine (160 mg/m2)
* Thiotepa (10 mg/kg)
* TBI (4Gy)

All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.

Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:

* Fludarabine (160 mg/m2)
* Thiotepa (5 mg/kg)
* TBI (2-3 Gy).

All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.

Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:

* Fludarabine (160 mg/m2)
* Thiotepa (10 mg/kg)
* TBI (4 Gy) All enrolled subjects will receive GVHD prophylaxis with tacrolimus and mycophenolate mofetil (MMF).

Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:

* Fludarabine (160 mg/m2)
* Thiotepa (5 mg/kg)
* TBI (2-3 Gy)

All enrolled subjects will receive GVHD prophylaxis with tacrolimus and ruxolitinib.

Purified regulatory T-cells (Treg) plus CD34+ hematopoietic progenitor cells ("CD34+ HSPC"), followed by conventional T-cells (Tcon) Manufactured at SCTT Laboratory, dose 1x10\^6 cells/ kg to 3x10\^6 cells/kg

Purified regulatory T-cells (Treg) plus CD34+ HSPC

The CliniMACS® CD34 Reagent System is a medical device that is used in vitro to select and enrich specific cell populations is manufactured by Miltenyi Biotec

Single-use vials contain either 300 mcg or 480 mcg filgrastim at a fill volume of 1.0 mL or 1.6 mL

Filgrastim granulocyte colony-stimulating factor (G-CSF) or equivalent

Mycophenolate Mofetil (MMF)

Ruxolitinib

Lindsay Danley

Everett Meyer, MD, PhD

Everett Meyer, MD,PhD

Reduced intensity conditioning (RIC) has emerged and been increasingly adopted as a modality to allow preparative conditioning pre transplant to be tolerated by older adults or those patients that are otherwise unfit for myeloablative conditioning. In this study, we aim to use RIC followed by matched related/unrelated donor, 7/8 matched related/unrelated donor, or haploidentical donor peripheral blood stem cell transplantation. Standard strategies to control the alloreactivity following HCT utilize immunosuppressive or cytotoxic medications. In this study, we explore donor graft engineering to enrich for immmunoregulatory populations to facilitate post transplantation immune reconstitution while minimizing graft versus host disease (GVHD) with post-transplant immunosuppressive agents.

The objectives for the study are listed below:

Primary Objectives

\*Determine the safety, and feasibility of administration of several dose combinations of conventional T-cells (Tcon) and regulatory T-cells (Treg) in subjects undergoing allogeneic hematopoietic cell transplantation (HCT) with related/unrelated HLA-matched or mismatched donors, or haploidentical donors with reduced intensity conditioning preparative regimen.

Secondary Objectives

* To determine the GVHD-free relapse-free survival (GRFS) post-HCT
* To determine the overall survival (OS) post-HCT
* To measure the incidence and severity of acute and chronic GVHD

Exploratory Objectives

* To measure the incidence of serious infections
* To measure the incidence and timing of engraftment
* To measure T cell immunity reconstitution parameters

Reduced Intensity Allogeneic HCT in Advanced Hematologic Malignancies w/T-Cell Depleted Graft

Phase 1 Trial for Patients With Advanced Hematologic Malignancies Undergoing Reduced Intensity Allogeneic HCT With a T-cell Depleted Graft With Infusion of Conventional T-cells and Regulatory T-cells

Neutrophil engraftment is defined as having an ANC ≥ 500 cells/µL for three consecutive days. The first of three days will be designated as the day of engraftment.

Platelet engraftment is defined as achieving a platelet count \> 20,000 cells/µL for three consecutive days without platelet transfusion in the preceding 7 days. The first of three days will be designated as the day of engraftment.

Incidence of serious infections will be measured as event of infections that led to hospitalization or death or required antibiotic treatment. Infections will be graded according to the CTCAE version 5.0

Clinical effect will be assessed as graft vs host disease (GVHD)-free relapse free survival (GRFS), GVHD-free is defined as no GVHD symptoms, and relapse free survival is defined as survival at 12 months without relapse. The outcome will be measured in Arm A only.

Overall survival is measured as number of participants alive. Alive at the time of last observation will be censored.

Acute GVHD will be staged and graded per Mount Sinai Acute GvHD International Consortium (MAGIC) Standardization criteria.

Primary graft failure is defined as being alive with donor CD3 chimerism \<5% at day +30 after transplant without recovery of neutrophils (i.e. without achieving an absolute neutrophil count \[ANC\] ≥ 500/mm3 for 3 consecutive days) at Day+28

Defined as a percentage on donor CD3 cells chimerism at day +60 after transplantation.

Clinical effect will be assessed as graft vs host disease (GVHD)-free relapse free survival (GRFS), GVHD-free is defined as no GVHD grade 3 and 4, and relapse free survival is defined as survival at 12 months without relapse.

Secondary graft failure (defined by donor CD3 chimerism \<5% at day +30 after transplant) and neutrophil engraftment followed by subsequent decline in ANC \< 500/mm3 unresponsive to growth factor therapy, by Day +100

TEAEs will be categorized by the System Organ Class and preferred term and will be graded according to the CTCAE version 5.0

Steroid refractory acute GVHD will be defined as per the EBMT-NIH-CIBMTR Task Force position statement

Non-relapse mortality is measured as number of participants died without relapse/ recurrent disease. Subjects without evidence of relapse/progression at last follow-up date or date of death will be censored.

Overall survival is measured as number of participants alive and in remission. Alive in remission at the time of last observation will be censored.

Chronic GVHD will be diagnosed per 2014 International NIH Chronic GVHD Diagnosis and Staging Consensus Working Group criteria (Jagasia 2015). Chronic GVHD scored according to the first day of chronic GVHD onset will be used to calculate cumulative incidence curves. Subjects will be followed for 2 years from the Day 0 (day of CD34+ peripheral blood stem cell infusion) for estimation of cGVHD incidence.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Haploidentical Allogeneic Transplant With Post-transplant Infusion of Regulatory T-cells	NCT01050764	Leukemia, Acute Chronic Myeloge... Myelodysplastic... Non-Hodgkin Lym... Chronic Lymphoc... Acute Myelogeno... Acute Lymphobla...	Regulatory T-ce... Conventional T-... Melphalan Thiotepa Fludarabine Anti-thymocyte ... CliniMACS CD34 ...	- 60 Years	Stanford University
A Phase I Trial of Alloreactive Cell Infusion Following Transplantation of Haplotype Cells in Patients With Myeloid Malignancies	NCT00569179	Leukemia, Myelo... Leukemia, Lymph... Myelodysplastic... Leukemia, Myelo...	CliniMACS CD34 ...	18 Years - 65 Years	Indiana University
Bone Marrow Transplantation Using CD34-Selected Stem Cells From Related or Unrelated Donors in Treating Participants With Cancer or Other Disorders	NCT03626285	Benign Neoplasm Bone Marrow Tra... Hematopoietic C... Malignant Neopl...	Bone Marrow Tra... CliniMACS CD34 ... Peripheral Bloo...	- 70 Years	OHSU Knight Cancer Institute
Expanded Access to T-cell Depleted Haplo-Identical Stem Cells for Patients Receiving Haplo-Identical and Unrelated Cord Blood Transplants	NCT01881334	Hematologic Mal... Inborn Errors o... Immune Deficien...	CliniMACS CD34 ...	- 65 Years	Duke University
A Phase I Trial of Alloreactive Cell Infusion Following Transplantation of Haplotype Cells in Patients With Myeloid Malignancies	NCT00569179	Leukemia, Myelo... Leukemia, Lymph... Myelodysplastic... Leukemia, Myelo...	CliniMACS CD34 ...	18 Years - 65 Years	Indiana University
Reduced Intensity Allogeneic HCT in Advanced Hematologic Malignancies w/T-Cell Depleted Graft	NCT05088356	Allogeneic Hema... Advanced Hemato... Acute Leukemia Chronic Myeloge... Myelodysplastic... Myeloproliferat...	Purified regula... Fludarabine Melphalan CliniMACS CD34 ... Tacrolimus Cyclophosphamid... Plerixafor Filgrastim gran... Thiotepa Mycophenolate M... Ruxolitinib	18 Years - 75 Years	Stanford University

Spots Global Cancer Trial Database for clinimacs cd34 reagent system