A Feasibility Study Using CLINIMACS® for Alpha/Beta T-Cell Depletion in Stem Cell Transplant

A Feasibility Study of Using the CiniMacs® Device for Alpha/Best T-Cell Depletion in Stem Cell Transplant Recipients

Patients in need of an allogeneic hematopoietic cell transplant (HCT) are at risk of developing graft-versus-host-disease (GVHD). In certain clinical situations, the optimal approach to minimize the risk of GVHD is to perform ex vivo alpha-beta T-cell depletion of the donor cells. However, the CliniMACS® Device is FDA-approved only for a narrow indication. All other uses of ex vivo processed cells must be done under a feasibility study protocol.

The original CliniMACS® device (CD34 Reagent System) employs a reagent consisting of an antibody that specifically binds to blood cells that express the CD34+ surface marker (hematopoietic stem cells or blood stem cells). The CD34 antibody is conjugated to an iron-containing particle that is only nanometers in size and safe for infusion. The enrichment of CD34+ cells is accomplished by passing the antibody/magnetically-labeled cell suspension through a magnetic separation column, which is provided as part of a single-use disposable tubing set. Magnetically-labeled CD34+ target cells are retained within the separation column, while the unlabeled cells flow through. Recovery of CD34+ cells is achieved by removing the magnetic field and eluting the targeted CD34+ stem cells into a collection bag. On January 24, 2014, the FDA approved the CliniMACS CD34 Reagent System as a Humanitarian Use Device for the prevention of graft-versus-host disease (GVHD) in patients with acute myeloid leukemia (AML) in first complete remission undergoing allogeneic HCT from a matched related donor. Humanitarian Use Device (HUD) is a device that is intended to benefit patients by treating or diagnosing a disease or condition that affects or is manifested in fewer than 4,000 individuals in the United States per year. The CliniMACS® CD34 Reagent System is now indicated for processing hematopoietic progenitor cells collected by apheresis (PBSC) from an allogeneic, Human Leukocyte Antigen (HLA)-identical matched sibling donor (MSD) to obtain a CD34+ cell-enriched population for hematopoietic reconstitution following a myeloablative preparative regimen without the need for additional GVHD prophylaxis in patients with AML in first morphologic complete remission (CR1). The approval as an HUD, however, asserts that there was sufficient information for the FDA to determine that the device does not pose an unreasonable or significant risk of illness or injury. Furthermore, the clinical data supported the premise of a "probable benefit"; in that the risk to health outweighs the risk of injury or illness from its use, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment.19 The CliniMACS CD34 Reagent System was shown to meet these requirements. Uses of the CliniMACS CD34 Reagent System beyond MSD PBSC HCT for AML in CR1 are currently not FDA approved and therefore considered research, even though CD34-selection is widely considered to be a standard-of-care option for haploidentical HCT. In Europe, the European Medicines Agency (EMA) has made the CliniMACs System components available as Conformité Européene (CE) marked medical devices, and "any clinical application of the target cells is exclusively within the responsibility of the user of a CliniMACS System." The CD34-selection system has been widely used in haploidentical HCTs, with the first patient treated at University of California, San Francisco (UCSF) in 2002. Since then, CD34-selection has facilitated over 70 HCTs at UCSF on 2 successive protocols (#01151 and #10082). However, the removal of almost all cells beyond those which are CD34+ leads to minimal passive transfer of immunity. It is therefore complicated by a slow recovery of immunity, with high rates of life-threatening viral infections, and an appreciable degree of transplant-related mortality (TRM). Beginning in 2014, a new approach to ex vivo processing of stem cells was developed with a goal of mainly replacing the older CD34-selection technology. This technique utilizes negative depletion of the cells thought to be most responsible for the development of aGVHD, the alpha-beta T-cell Receptor positive T-cells. All trials of alpha-beta T-cell depleted have included simultaneous depletion of CD19+ B cells from the donor graft. All references to "alpha-beta T-cell depletion" herein implies simultaneous Cluster of Differentiation antigen (CD)19+ depletion as well.

The test product is a stem cell product which has been alpha-beta T- cell depleted using the CliniMACS system. Alpha-beta T-cell depleted cells are given intravenously over a period of time as dictated by the final volume of the infused product (5 ml/kg/hour). The target dose of CD34+ cells is ≥20x10^6/kg, but a minimum of ≥2.5x10^6/kg is required. The target dose of T-cell receptor (TCR) alpha-beta CD3+ cells is ≤1x10^5/kg.

CliniMACS® CD34 Reagent System is now indicated for processing hematopoietic progenitor cells collected by apheresis (PBSC) from an allogeneic, HLA-identical MSD to obtain a CD34+ cell-enriched population for hematopoietic reconstitution following a myeloablative preparative regimen without the need for additional GVHD prophylaxis in patients with AML in first morphologic complete remission (CR1).

The cumulative incidence of Grade III-IV acute GVHD at Day 100 will be summarized by incidence curves. GVHD evaluations will be performed using standard criteria.37 Patients with graft rejection will be censored.

The cumulative incidence of donor cell engraftment at 30 days will be summarized by incidence curves. Engraftment will be defined as ANC recovery (>500 x 3 days) with evidence of donor myeloid cells on chimerism analysis, OR, for non-myeloablative HCTs, evidence of donor cells on chimerism analysis.

The cumulative incidence of transplant-related mortality at 1-year will be summarized by incidence curves.

The cumulative incidence of systemic steroid-requiring chronic GVHD at 1-year will be summarized by incidence curves. GVHD evaluations will be performed using standard criteria.

180-day incidence of T-cell reconstitution (CD4+ T-cell count >200 and proliferation to PHA >50% control).

The incidence of T-cell reconstitution at Day 180 will be summarized by numbers and percentages of subjects in corresponding categories. T cell reconstitution is defined as a CD4+ T-cell count >200 and Proliferation to PHA >50% control

Inclusion Criteria: Male or female 0-30 years of age at time of transplant admission Documentation of a disease requiring HCT A donor (mismatched related or unrelated) must be located who are healthy and willing, and whom are able to donate bone marrow (BM) or peripheral blood stem cells (PBSC). Matched related donors may be used for patients with Fanconi Anemia. Written informed consent (and assent when applicable) obtained from subject or subject's legal representative and ability for subject to comply with the requirements of the study Exclusion Criteria: Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data Presence of a healthy and willing HLA-identical related donor (except when the patient has Fanconi Anemia). Patient with an anticipated life expectancy of <1 month Patients with known hypersensitivity to murine (mouse) proteins or iron dextran

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