Combined T Cell Depleted Haploidentical Peripheral Blood Stem Cell and Unrelated Umbilical Cord Blood Transplantation in Patients With Hematologic Malignancies Using a Total Lymphoid Irradiation Based Preparative Regimen
Condition: Hematological Malignancies
MeSH terms: Neoplasms; Hematologic Neoplasms
Intervention: Cyclophosphamide; Thiotepa; Fludarabine; Melphalan; Mesna; G-CSF; Mycophenolate mofetil; Tacrolimus; Methylprednisolone; Total lymphoid irradiation; Lymphocyte infusions; CliniMACS
Intervention description: Given by intravenous infusion as part of the preparative regimen.; Given by intravenous infusion as part of the preparative regimen.; Given by intravenous infusion as part of the preparative regimen.; Given by intravenous infusion as part of the preparative regimen.; 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.; Given either by intravenous infusion or subcutaneously daily until absolute neutrophil count (ANC) >2000 for 3 consecutive days.; Given either orally or by intravenous infusion as part of the post-transplantation immunosuppression.; Given either orally or by intravenous infusion as part of the post-transplantation immunosuppression.; Given either intravenously or orally, if needed to treat graft-versus-host-disease (GVHD).; TLI will be administered in divided fractions given at a minimum of 6 hours apart.; Donors will undergo haploidentical mobilization with G-CSF. Cells will be collected by leukapheresis over two days, then processed using the investigational CliniMACS device and CD34 Microbead reagent as directed by the manufacturer.; 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.
Intervention MeSH terms: Mycophenolic Acid; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Cyclophosphamide; Melphalan; Mechlorethamine; Thiotepa; Fludarabine; Tacrolimus; Lenograstim; Prednisolone hemisuccinate; Prednisolone phosphate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 24.0
Sex: All
Maximum age: 21 Years
Healthy volunteers: No
Keywords: Cord Blood; Haploidentical; Reduced Intensity Regimen

Summary:

      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), matched unrelated donor (MURD) or killer-immunoglobulin
      receptors (KIR) ligand mismatched haploidentical donor identified, will receive a combined T
      cell depleted (TCD) haploidentical peripheral blood stem cell (PBSC) and unrelated umbilical
      cord blood transplantation (UCBT) using a total lymphoid irradiation (TLI) based preparative
      regimen.

      Primary objective:

        -  To estimate the incidence of donor derived neutrophil engraftment by day +42
           post-transplant for participants with high-risk hematologic malignancies undergoing a
           total lymphoid irradiation (TLI)-based hematopoietic cell transplantation (HCT) using a
           T cell depleted (TCI) haploidentical donor peripheral blood stem cell (PBSC) donor
           combined with an unrelated umbilical cord blood (UCB) donor.

      Secondary objectives:

        -  Estimate the incidence of malignant relapse, event-free survival (EFS), and overall
           survival (OS) at one-year post-transplantation.

        -  Estimate the incidence and severity of acute and chronic graft versus host disease
           (GVHD) in the first 100 days after transplantation.

        -  Estimate the incidence of secondary graft failure transplant related mortality (TRM) and
           transplant related morbidity in the first 100 days after HCT.
    

Eligibility criteria:

        Inclusion Criteria-Transplant Recipient:

          -  Age less than or equal to 21 years old.

          -  Does not have a suitable matched related/sibling donor (MSD) or volunteer matched
             unrelated donor (MUD) available in the necessary time for stem cell donation.

          -  Has a suitable partially human leukocyte antigen (HLA)-matched (≥ 3 of 6) family
             member donor.

          -  Has a partially HLA-matched single umbilical cord blood (UCB) unit (≥ 4 of 6) with
             adequate cell dose. UCB units must fulfill eligibility as outlined in 21 CFR 1271 and
             agency guidance.

          -  High-risk hematologic malignancy.

               -  High risk acute lymphocytic leukemia (ALL) in complete remission-1 (CR)1.
                  [Examples include, but not limited to t(9;22), hypodiploid,, M2 or greater marrow
                  at the end of induction, infants with mixed lineage leukemia (MLL) fusion or
                  t(4;11)].

               -  ALL in High risk CR2. [Examples include but not limited to t(9;22), bone marrow
                  (BM) relapse <36 mo CR1, T-ALL, very early (< 6mo CR1) isolated central nervous
                  system (CNS) relapse.]

               -  ALL in CR3 or subsequent.

               -  Acute myeloid leukemia (AML) in high risk CR1. [Examples include but not limited
                  to preceding MDS, 5q-, -5, -7, FAB M6, FAB M7 not t(1;22), minimal residual
                  disease (MRD) ≥ 5% on day 22 (AML08), M3 marrow after induction 1, M2 marrow
                  after two cycles of induction, FLT3-ITD.]

               -  AML in CR2 or subsequent.

               -  Therapy related AML, with prior malignancy in CR > 12mo

               -  Myelodysplastic syndrome (MDS), primary or secondary

               -  Natural killer (NK) cell, biphenotypic, or undifferentiated leukemia in CR1 or
                  subsequent.

               -  Chronic myeloid leukemia (CML) in accelerated phase, or in chronic phase with
                  persistent molecular positivity or intolerance to tyrosine kinase inhibitor.

               -  Hodgkin lymphoma in CR2 or subsequent after failure of prior autologous
                  hematopoietic cell transplantation (HCT), or unable to mobilize stem cells for
                  autologous HCT.

               -  Non-Hodgkin lymphoma in CR2 or subsequent.

               -  Juvenile myelomonocytic leukemia (JMML).

               -  Refractory hematologic malignancies [ALL, AML, chronic myeloid leukemia (CML) in
                  blast crisis, Hodgkin or non-Hodgkin lymphoma] due to chemoresistant relapse or
                  primary induction failure.

               -  All patients with evidence of CNS leukemia must be treated and be in CNS CR to be
                  eligible for study.

          -  Patient must fulfill pre-transplant evaluation:

               -  Cardiac Function: Left ventricular ejection fraction (LVEF) ≥ 40% or shortening
                  fraction (SF) ≥ 25%.

               -  Creatinine clearance (CrCL) or glomerular filtration rate (GFR) ≥ 50
                  ml/min/1.73m2.

               -  Forced vital capacity (FVC) ≥ 50% of predicted value or pulse oximetry (Pox) ≥
                  92% on room air.

               -  Karnofsky or Lansky performance score ≥ 50.

               -  Bilirubin ≤ 3 times the upper limit of normal for age.

               -  Alanine aminotransferase (ALT) ≤ 5x the upper limit of normal for age.

               -  Aspartate aminotransferase (AST) ≤ 5x the upper limit of normal for age.

        Exclusion Criteria - Transplant Recipient:

          -  Patient has a suitable MSD, volunteer matched unrelated donor (MURD), or
             killer-immunoglobulin receptors (KIR) mismatched haploidentical donor available in the
             necessary time for stem cell donation.

          -  Patient has any other active malignancy other than the one for which HCT is indicated.

          -  Patient is pregnant as confirmed by positive serum or urine pregnancy test within 14
             days prior to enrollment.

          -  Patient is breast feeding.

          -  Patient has Down Syndrome.

          -  Patient has a current uncontrolled bacterial, fungal, or viral infection per the
             judgment of the principal investigator.

        Inclusion criteria - haploidentical donor

          -  At least single haplotype matched (≥ 3 of 6) family member

          -  At least 18 years of age.

          -  Human immunodeficiency virus (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:

               -  Completed the process of donor eligibility determination as outlined in 21 CFR
                  1271 and agency guidance; OR

               -  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.