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TCRαβ-depleted Progenitor Cell Graft With Additional Memory T-cell DLI, Plus Selected Use of Blinatumomab, in Naive T-cell Depleted Haploidentical Donor Hematopoietc Cell Transplantation for Hematologic Malignancies

NCT03849651

Description:

Patients less than or equal to 21 years old with high-risk hematologic malignancies who would likely benefit from allogeneic hematopoietic cell transplantation (HCT). Patients with a suitable HLA matched sibling or unrelated donor identified will be eligible for participation ONLY if the donor is not available in the necessary time. The purpose of the study is to learn more about the effects (good and bad) of transplanting blood cells donated by a family member, and that have been modified in a laboratory to remove the type of T cells known to cause graft-vs.-host disease, to children and young adults with a high risk cancer that is in remission but is at high risk of relapse. This study will give donor cells that have been TCRαβ-depleted. The TCR (T-cell receptor) is a molecule that is found only on T cells. These T-cell receptors are made up of two proteins that are linked together. About 95% of all T-cells have a TCR that is composed of an alpha protein linked to a beta protein, and these will be removed. This leaves only the T cells that have a TCR made up of a gamma protein linked to a delta protein. This donor cell infusion will be followed by an additional infusion of donor memory cells (CD45RA-depleted) after donor cell engraftment. This study will be testing the safety and effects of the chemotherapy and the donor blood cell infusions on the transplant recipient's disease and overall survival.

Related Conditions:
  • Acute Biphenotypic Leukemia
  • Acute Erythroid Leukemia
  • Acute Lymphoblastic Leukemia
  • Acute Megakaryoblastic Leukemia
  • Acute Myeloid Leukemia
  • Acute Undifferentiated Leukemia
  • Chronic Myeloid Leukemia
  • Hodgkin Lymphoma
  • Juvenile Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
  • Myeloid Sarcoma
  • Natural Killer Cell Lymphoblastic Leukemia/Lymphoma
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: TCRαβ-DEPLETED PROGENITOR CELL GRAFT WITH ADDITIONAL MEMORY T-CELL DLI, PLUS SELECTED USE OF BLINATUMOMAB, IN NAÏVE T-CELL DEPLETED HAPLOIDENTICAL DONOR HEMATOPOIEITC CELL TRANSPLANTATION FOR HEMATOLOGIC MALIGNANCIES
  • Official Title: TCRαβ-DEPLETED PROGENITOR CELL GRAFT WITH ADDITIONAL MEMORY T-CELL DLI, PLUS SELECTED USE OF BLINATUMOMAB, IN NAÏVE T-CELL DEPLETED HAPLOIDENTICAL DONOR HEMATOPOIEITC CELL TRANSPLANTATION FOR HEMATOLOGIC MALIGNANCIES

Clinical Trial IDs

  • ORG STUDY ID: HAP2HCT
  • NCT ID: NCT03849651

Conditions

  • Acute Lymphoblastic Leukemia (ALL)
  • Acute Myeloid Leukemia (AML)
  • Myelodysplastic Syndromes (MDS)
  • NK-Cell Leukemia
  • Hodgkin Lymphoma
  • Non Hodgkin Lymphoma (NHL)
  • Juvenile Myelomonocytic Leukemia (JMML)
  • Chronic Myeloid Leukemia (CML)

Interventions

DrugSynonymsArms
CyclophosphamideCytoxanTransplant participants
FludarabineFludaraTransplant participants
ThiotepaThioplexTransplant participants
MelphalanAlkeranTransplant participants
G-csfNeupogen, FilgrastimTransplant participants
MesnaMesnexTransplant participants
ATG (rabbit)ThymoglobulinTransplant participants
BlinatumomabBlincytoTransplant participants
TCRα/β+Transplant participants
CD19+Transplant participants
CD45RA-depleted DLITransplant participants

Purpose

Patients less than or equal to 21 years old with high-risk hematologic malignancies who would likely benefit from allogeneic hematopoietic cell transplantation (HCT). Patients with a suitable HLA matched sibling or unrelated donor identified will be eligible for participation ONLY if the donor is not available in the necessary time. The purpose of the study is to learn more about the effects (good and bad) of transplanting blood cells donated by a family member, and that have been modified in a laboratory to remove the type of T cells known to cause graft-vs.-host disease, to children and young adults with a high risk cancer that is in remission but is at high risk of relapse. This study will give donor cells that have been TCRαβ-depleted. The TCR (T-cell receptor) is a molecule that is found only on T cells. These T-cell receptors are made up of two proteins that are linked together. About 95% of all T-cells have a TCR that is composed of an alpha protein linked to a beta protein, and these will be removed. This leaves only the T cells that have a TCR made up of a gamma protein linked to a delta protein. This donor cell infusion will be followed by an additional infusion of donor memory cells (CD45RA-depleted) after donor cell engraftment. This study will be testing the safety and effects of the chemotherapy and the donor blood cell infusions on the transplant recipient's disease and overall survival.

Detailed Description

      In this study, participants with high-risk hematologic malignancies undergoing hematopoietic
      cell transplantation (HCT), who lack an available suitable human leukocyte antigen (HLA)
      matched related/sibling donor (MSD) or matched unrelated donor (MUD), will receive a
      TCRαβ-depleted haploidentical donor HCT with additional memory cell DLI. One course of
      blinatumomab will be empirically added for patients with CD19+ malignancy.

      Primary Objectives

        -  Determine the maximum effective dose for prophylactic CD45RA-depleted DLI when given in
           the early post-engraftment period.

        -  Assess the efficacy of TCRαβ-depleted progenitor cell graft with additional memory
           T-cell DLI, plus selected use of blinatumomab, in haploidentical donor hematopoietic
           cell transplantation for hematologic malignancies as measured by 1 year EFS (events =
           relapse, death) Secondary Objectives

        -  Assess the safety and feasibility of the addition of blinatumomab in the early post-
           engraftment period in patients with CD19+ malignancy

        -  Estimate the cumulative incidence of:

        -  neutrophil engraftment at Day +30

        -  platelet engraftment at Day +100

        -  acute GVHD at Day +100

        -  chronic GVHD at 1 year

        -  transplant related mortality (TRM) at Day +100

        -  malignant relapse at 1 year

        -  Estimate 1yr event-free survival per disease subgroups (ALL vs AML)

        -  Estimate 1yr overall survival at one-year post-transplantation. Exploratory Objectives

        -  Record immune reconstitution parameters, including chimerism analysis, quantitative
           lymphocyte subsets, T cell receptor excision circle (TREC) analysis, V-beta
           spectratyping, and lymphocyte phenotype and function. All analysis will be descriptive
           only.

        -  Describe the use of additional CD45RA-depleted DLI for recipients who have severe viral
           infections, disease recurrence or progression, or poor immune reconstitution. Assess and
           record efficacy of CD45RA-depleted DLI for these conditions, and all adverse events that
           are related to CD45RA-depleted DLI. All analysis will be descriptive only.

      Additional Information:

      Blinatumomab will be given to patients with a history of CD19+ malignancy as determined by
      St. Jude hematopathologist review of current and historical specimens and reports.
      Blinatumomab dosing will begin no sooner than 1 week after CD45RA-depleted DLI and no later
      than Day +90. There must be no acute GVHD or it must be quiescent. ALT must be less than 5x
      ULN, bili less than or equal to 1.5x ULN, and creatinine less than or equal to 1.5x ULN.

      If more than one family member donor is suitable, then donor selection will be based on
      several factors including: degree of KIR mismatching, donor-recipient matching of CMV
      serology, donor-recipient red blood cell compatibility, degree of HLA matching, size of the
      potential donor, previous use as a donor, presence of donor-specific antibody, and overall
      health and availability of the potential donor.

      A G-CSF mobilized peripheral blood progenitor cell product (identified as HPC,A) is the
      preferred progenitor cell graft source. Our desired target goal will be 5 x 10^6 CD34+
      cells/kg. This number of cells will be necessary to provide an adequate graft, following the
      various ex vivo manipulations, for prompt reconstitution. More than one collection may be
      needed to achieve this goal. Donors will undergo a standard hematopoietic progenitor cell
      mobilization regimen consisting of 5 days of GSF given subcutaneously at 10
      micrograms/kilogram. The graft will be collected by leukapheresis on day 5 (and 6 if needed)
      of G-CSF. The HPC product will typically be collected and infused fresh, however there may be
      patients or logistical situations that require the HPC product to be collected early,
      processed, and stored frozen.
    

Trial Arms

NameTypeDescriptionInterventions
Transplant participantsExperimentalParticipants receive a conditioning regimen of ATG (rabbit),Cyclophosphamide 60 mg/kg intravenous once daily, mesna, fludarabine, thiotepa, melphalan, followed by HPC,A Infusion(TCRα/β+ and CD19+ depleted),HPC, A infusion (if needed to achieve goal CD34+ cell dose.CD45RA-depleted DLI will be given at least two weeks after engraftment. Blinatumomab will be given at least one week post-DLI, and only to patients with CD19+ malignancies. G-csf 5mcg/kg subcutaneous or intravenous daily until ANC >2000 for 2 consecutive days. Cells for infusion are prepared using the CliniMACS system.
  • Cyclophosphamide
  • Fludarabine
  • Thiotepa
  • Melphalan
  • G-csf
  • Mesna
  • ATG (rabbit)
  • Blinatumomab
  • TCRα/β+
  • CD19+
  • CD45RA-depleted DLI

Eligibility Criteria

        Inclusion Criteria for Transplant Recipient

          -  Age less than or equal to 21 years.

          -  Does not have a suitable HLA-matched sibling donor (MSD) or volunteer 10/10
             HLA-matched unrelated donor (MUD) available in the necessary time for progenitor cell
             donation.

          -  Has a suitable single haplotype matched (≥ 3 of 6) family member donor.

        High risk hematologic malignancy. High risk ALL in CR1. Examples include, but not limited
        to: t(9;22) with persistent or recurrent transcript, hypodiploid cytogenetics, MRD >1% at
        the end of induction, M2 or greater marrow at the end of induction, recurrent or rising MRD
        after induction, Infants with MLL fusion or t(4;11), relapse after prior CART therapy.

        ALL in High risk CR2. Examples include, but not limited to t(9;22), BM relapse <36 mo CR1
        or <6mo after completion of therapy, any T-ALL, very early (< 6mo CR1) isolated CNS
        relapse, late BM relapse with poor response to standard reinduction therapy(e.g. MRD
        positive or recurrence after two blocks), relapse after prior CART therapy.

        ALL in CR3 or subsequent.

        AML in high risk CR1 (diagnosis of AML includes myeloid sarcoma). Examples include but not
        limited to: preceding MDS or MDS-related AML, FAB M0, FAB M6, FAB M7 with high risk
        genetics such as ML not t(1;22), MRD > 0.1% after two cycles of induction, MRD > 1% after
        one cycle of induction, FLT3-ITD in combination with NUP98-NSD1 fusion or WT1 mutation, any
        high risk cytogenetics such as: DEK-NUP214 [t(6;9)], KAT6A-CREBBP [t(8;16)], RUNX1-CBFA2T3
        [t(16;21)], -7, -5, 5q-, KMT2A-MLLT10 [t(6;11)], KMT2A-MLLT4 [t(10;11)], inv(3)(q21q26.2),
        CBFA2T3-GLIS2 [inv(16)(p13.3q24.3)], NUP98-KDM5A [t(11;12)(p15;p13)], ETV6-HLXB
        [t(7;12)(q36;p13)], NUP98-HOXA9 [t(7;11)(p15.4;p15)], NUP98-NSD1.

        AML in CR2 or subsequent.

          -  Therapy related AML, with prior malignancy in CR > 12mo

          -  MDS, primary or secondary

          -  NK cell, biphenotypic, or undifferentiated leukemia in CR1 or subsequent.

          -  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 HCT, or unable
             to mobilize progenitor cells for autologous HCT.

          -  Non-Hodgkin lymphoma in CR2 or subsequent after failure of prior autologous HCT, or
             unable to mobilize progenitor cells for autologous HCT.

          -  JMML

          -  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 organ function criteria:

          -  Left ventricular ejection fraction > 40%, or shortening fraction ≥ 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 ≥ 92% on room
             air if patient is unable to perform pulmonary function testing.

          -  Karnofsky or Lansky (age-dependent) performance score ≥ 50 (See APPENDIX A).

          -  Bilirubin ≤ 3 times the upper limit of normal for age.

          -  Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) ≤ 5 times the upper
             limit of normal for age.

          -  Not pregnant. If female with child bearing potential, must be confirmed by negative
             serum or urine pregnancy test within 14 days prior to enrollment.

          -  Not breast feeding

          -  Does not have current uncontrolled bacterial, fungal, or viral infection.

        Inclusion Criteria for 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 donation 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.

        Exclusion Criteria:
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:2 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum effective dose for prophylactic CD45RA-depleted DLI
Time Frame:90 days after the transplant date of the last enrolled patient.
Safety Issue:
Description:Description: A maximum effective dose of CD45RA-depleted DLI is defined as the maximum value of doses that satisfy the proportion of patients with their memory T cell count measured at week 4 post-DLI more than 300/uL is more than 50% and the toxicity of grade 3-4 aGVHD is less than 20%.

Secondary Outcome Measures

Measure:The number of patients experiencing Blinatumomab permanent discontinuation due to toxicity
Time Frame:120 days after transplant date of the last enrolled patient
Safety Issue:
Description:If the drug is held for more than 2 weeks due to toxicity, it will be permanently discontinued
Measure:The estimate of cumulative incidence of relapse
Time Frame:One year after the transplant date of the last enrolled patient
Safety Issue:
Description:The cumulative incidence of relapse will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The Kaplan-Meier estimates of Overall Survival (OS) and Event Free Survival (EFS) along with their standard errors will be calculated. OS is defined as time from transplantation to death or last follow-up, whichever comes first. EFS is defined as time from transplantation to events including relapse, graft failure, death due to any cause and last follow-up, whichever comes first. The participants are alive at the time of analysis without events will be censored.
Measure:The cumulative incidence of acute and chronic Graft-Versus-Host Disease (GVHD)
Time Frame:One year after the transplant date of the last enrolled patient
Safety Issue:
Description:The cumulative incidence of acute and chronic (GVHD) will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The severity of acute GVHD and chronic GVHD will be described.
Measure:The cumulative incidence of transplant related mortality
Time Frame:100 days after the transplant date of the last enrolled patient
Safety Issue:
Description:The cumulative incidence of transplant related mortality will be estimated using Kalbfleisch-Prentice method. Death before day 100 of other reasons are the competing risk events.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:St. Jude Children's Research Hospital

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