Clinical Trials /

HA-1 T TCR T Cell Immunotherapy for the Treatment of Patients With Relapsed or Refractory Acute Leukemia After Donor Stem Cell Transplant

NCT03326921

Description:

This phase I trial studies the side effects and best dose of CD4+ and CD8+ HA-1 T cell receptor (TCR) (HA-1 T TCR) T cells in treating patients with acute leukemia that persists, has come back (recurrent) or does not respond to treatment (refractory) following donor stem cell transplant. T cell receptor is a special protein on T cells that helps them recognize proteins on other cells including leukemia. HA-1 is a protein that is present on the surface of some peoples' blood cells, including leukemia. HA-1 T cell immunotherapy enables genes to be added to the donor cells to make them recognize HA-1 markers on leukemia cells.

Related Conditions:
  • Acute Biphenotypic Leukemia
  • Acute Leukemia
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Chronic Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Juvenile Myelomonocytic Leukemia
  • Mixed Phenotype Acute Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: HA-1 T TCR T Cell Immunotherapy for the Treatment of Patients With Relapsed or Refractory Acute Leukemia After Donor Stem Cell Transplant
  • Official Title: Phase I Study of Adoptive Immunotherapy With CD8+ and CD4+ Memory T Cells Transduced to Express an HA-1-Specific T Cell Receptor (TCR) for Children and Adults With Recurrent Acute Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation (HCT)

Clinical Trial IDs

  • ORG STUDY ID: 9716
  • SECONDARY ID: NCI-2017-01054
  • SECONDARY ID: 9716
  • SECONDARY ID: P30CA015704
  • SECONDARY ID: RG9217022
  • NCT ID: NCT03326921

Conditions

  • Juvenile Myelomonocytic Leukemia
  • Recurrent Acute Biphenotypic Leukemia
  • Recurrent Acute Undifferentiated Leukemia
  • Recurrent Childhood Acute Lymphoblastic Leukemia
  • Recurrent Childhood Acute Myeloid Leukemia
  • Refractory Acute Lymphoblastic Leukemia
  • Refractory Adult Acute Lymphoblastic Leukemia
  • Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Recurrent Blastic Plasmacytoid Dendritic Cell Neoplasm
  • Recurrent Myelodysplastic Syndrome
  • Refractory Blastic Plasmacytoid Dendritic Cell Neoplasm
  • Refractory Myelodysplastic Syndrome
  • Acute Undifferentiated Leukemia
  • Mixed Phenotype Acute Leukemia
  • Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Recurrent Acute Lymphoblastic Leukemia
  • Recurrent Acute Myeloid Leukemia
  • Myelodysplastic Syndrome
  • Acute Myeloid Leukemia
  • Acute Lymphoblastic Leukemia
  • Acute Biphenotypic Leukemia
  • Chronic Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Minimal Residual Disease
  • Recurrent Chronic Myelomonocytic Leukemia
  • Recurrent Mixed Phenotype Acute Leukemia
  • Leukemia

Interventions

DrugSynonymsArms
CD8+ and CD4+ Donor Memory T-cells-expressing HA1-Specific TCRCD8+ and CD4+ Donor Memory T-cells-expressing pRRLSIN iC9-HA1 TCR2-RQR-CD8, HA-1 TCR CD8+ and CD4+ Tm Cells, HA-1 TCR T CellsTreatment (CD4+ and CD8+ HA-1 TCR T cells)
FludarabineFluradosa, 2-Fluoro-9-beta-arabinofuranosyladenine, 2-Fluorovidarabine, 21679-14-1, 9-Beta-D-arabinofuranosyl-2-fluoro-9H-purin-6-amine, 9-Beta-D-arabinofuranosyl-2-fluoroadenineTreatment (CD4+ and CD8+ HA-1 TCR T cells)

Purpose

This phase I trial studies the side effects and best dose of CD4+ and CD8+ HA-1 T cell receptor (TCR) (HA-1 T TCR) T cells in treating patients with acute leukemia that persists, has come back (recurrent) or does not respond to treatment (refractory) following donor stem cell transplant. T cell receptor is a special protein on T cells that helps them recognize proteins on other cells including leukemia. HA-1 is a protein that is present on the surface of some peoples' blood cells, including leukemia. HA-1 T cell immunotherapy enables genes to be added to the donor cells to make them recognize HA-1 markers on leukemia cells.

Detailed Description

      OUTLINE:

      This is a dose-escalation study of CD4+ and CD8+ HA-1 TCR T cells.

      Patients receive fludarabine for 1-3 doses 3-14 days prior to HA-1 TCR T cell administration.
      Patients then receive CD4+ and CD8+ HA-1 TCR T cells intravenously (IV) over 1 hour.

      After completion of study treatment, patients are followed up closely for 12 weeks and then
      every 6 months for years 1-5, and every year for years 6-15.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (CD4+ and CD8+ HA-1 TCR T cells)ExperimentalPatients receive fludarabine for 1-3 doses 3-14 days prior to HA-1 TCR T cell administration. Patients then receive CD4+ and CD8+ HA-1 TCR T cells IV over 1 hour.
  • CD8+ and CD4+ Donor Memory T-cells-expressing HA1-Specific TCR
  • Fludarabine

Eligibility Criteria

        Inclusion Criteria:

          -  Patient age 0-75 years at the time of enrollment. Initially only patients who are >=
             16 years old will receive HA-1-TCR T cell infusions on the protocol. Younger patients
             may be screened, enrolled in the protocol and monitored for relapse but will not be
             eligible for infusion until at least one patient >=16 years old has been treated and
             discussed with the Food and Drug Administration (FDA)

          -  Patients must express HLA-A*0201

          -  Patients must have the HA-1(H) genotype (RS_1801284: A/G, A/A)

          -  Patients must have an adult donor for HCT who is adequately HLA matched by
             institutional standards (includes HLA-matched related or unrelated donors, and
             HLA-mismatched family donors, including haploidentical donors) and is either:

               -  HLA-A*0201 positive and HA-1(H) negative (RS_1801284: G/G) or

               -  HLA-A*0201 negative

          -  Patients who are currently undergoing or who previously underwent allogeneic HCT for

               -  Acute myeloid leukemia (AML) of any subtype

               -  Acute lymphoid leukemia (ALL) of any subtype

               -  Mixed phenotype/undifferentiated/any other type of acute leukemia, including
                  blastic plasmacytoid dendritic cell neoplasm

               -  Chronic myeloid leukemia with a history of blast crisis and:

                    -  With relapse or refractory disease (>= 5% marrow blasts, or circulating
                       blasts) at any time after HCT

                    -  With persistent rising minimal residual disease (defined as detectable
                       disease by morphology, flow cytometry, molecular or cytogenetic testing but
                       < 5% marrow blasts by morphology, no circulating blasts on >= 2 of two
                       consecutive tests), refractory or ineligible for treatment with tyrosine
                       kinase inhibitors at any time after HCT

               -  Myelodysplastic syndrome (MDS) of any subtype

               -  Chronic myelomonocytic leukemia (CMML)

               -  Juvenile myelomonocytic leukemia (JMML)

          -  Patients must be able to understand and be willing to give informed consent;
             decision-impaired adults may consent with their legally authorized representative;
             parent or legal representative will be asked to consent for patients younger than 18
             years old

          -  Patients must agree to participate in long-term follow-up for up to 15 years if they
             are enrolled in the study and receive T cell infusion

          -  Patients who have relapsed or have MRD after HCT may receive other agents for
             treatment of disease and remain eligible for the protocol

          -  A specific performance status score is not required for enrolling on the protocol; a
             delay in infusion of the HA-1 TCR T cells may be required for patients with low
             performance status

        DONOR SELECTION INCLUSION

          -  Donor age >= 18 years

          -  Donors must be able to give informed consent

          -  Patients must have an adult donor for HCT who is adequately HLA matched by
             institutional standards (includes HLA-matched related or unrelated donors, and
             HLA-mismatched family donors, including haploidentical donors) and is either:

               -  HLA-A*0201 positive and HA-1(H) negative (RS_1801284: G/G) or

               -  HLA-A*0201 negative

        Exclusion Criteria:

          -  Medical or psychological conditions that would make the patient unsuitable candidate
             for cell therapy at the discretion of the principal investigator (PI)

          -  Fertile patients unwilling to use contraception during and for 12 months after
             treatment

          -  Patients with a life expectancy < 3 months of enrollment from coexisting disease other
             than leukemia

          -  Patients who develop grade IV acute GVHD or severe chronic GVHD following most recent
             transplant prior to enrollment on the protocol

          -  The presence of organ toxicities will not necessarily exclude patients from enrolling
             on the protocol at the discretion of the PI; however, a delay in the infusion of HA-1
             TCR T cells may be required

        DONOR SELECTION EXCLUSION

          -  Donors who are HIV-1, HIV-2, human T-lymphotropic virus (HTLV)-1, HTLV-2 seropositive
             or with active hepatitis B or hepatitis C virus infection

          -  Unrelated donor residing outside of the United States of America (USA) unless the
             donor screening, testing and leukapheresis occur at an NMDP-affiliated and qualified
             donor center and are facilitated by the NMDP.
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Feasibility of manufacturing minor H antigen (HA-1) T cell receptor (TCR) CD8+ and CD4+ T cells
Time Frame:At time of T cell infusion (at day 0)
Safety Issue:
Description:Proportion of participants for whom a HA-1 TCR T cell product can be produced.

Secondary Outcome Measures

Measure:Duration of in vivo persistence of transferred HA-1 T cell receptor (TCR) CD4+ T cells in peripheral blood
Time Frame:Up to 1 year
Safety Issue:
Description:Evaluated by tetramer and/or molecular tracking e.g. quantitative polymerase chain reaction (qPCR).
Measure:Duration of in vivo persistence of transferred HA-1 T cell receptor (TCR) CD8+ T cells in peripheral blood
Time Frame:Up to 1 year
Safety Issue:
Description:Evaluated by tetramer and/or molecular tracking e.g. qPCR.
Measure:Presence, proportion and persistence of HA-1 T cell receptor (TCR) CD4+ T cells in the bone marrow
Time Frame:Up to 1 year
Safety Issue:
Description:Evaluated by tetramer and/or molecular tracking e.g. qPCR.
Measure:Presence, proportion and persistence of HA-1 T cell receptor (TCR) CD8+ T cells in the bone marrow
Time Frame:Up to 1 year
Safety Issue:
Description:Evaluated by tetramer and/or molecular tracking e.g. qPCR.
Measure:Specific cytolytic activity of HA-1 T cell receptor (TCR) CD8+ and CD4+ T cells against HLA-A*0201+ HA-1+ target cells before adoptive T cell transfer
Time Frame:At the time of T cell infusion (at day 0)
Safety Issue:
Description:Assessed by in vitro chromium release assay or equivalent cytotoxicity assay.
Measure:Specific cytolytic activity of HA-1 T cell receptor (TCR) CD8+ and CD4+ T cells against HLA-A*0201+ HA-1+ target cells after adoptive T cell transfer
Time Frame:Up to 1 year
Safety Issue:
Description:By in vitro chromium release assay or flow cytometric degranulation assay (CD107a) using samples of peripheral blood and/or bone marrow collected from patients after adoptive T cell transfer.
Measure:Reduction of leukemia in the bone marrow in patients who have measurable leukemia in the marrow prior to HA-1 T cell receptor (TCR) T cell infusion
Time Frame:Up to 1 year
Safety Issue:
Description:Quantified by flow cytometry to determine percentage of leukemic cells in the marrow.
Measure:Reduction of recipient normal hematopoietic cells in the bone marrow in patients who have measurable recipient normal hematopoietic cells in the marrow prior to HA-1 T cell receptor (TCR) T cell infusion
Time Frame:Up to 1 year
Safety Issue:
Description:Quantified by variable number tandem repeat (VNTR) to determine percentage of normal recipient and donor cells in the marrow.
Measure:Proportion of patients who develop new or recurrent symptoms or signs of graft-versus-host disease
Time Frame:Up to 1 year
Safety Issue:
Description:Assessed using clinical evaluation and standard clinical graft versus host disease (GVHD) grading criteria

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

Trial Keywords

  • HA-1
  • TCR
  • Immunotherapy
  • Leukemia

Last Updated

July 8, 2021