Clinical Trials /

HA-1 T TCR T Cell Immunotherapy for the Treating 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) T cells in treating patients with acute leukemia that has come back or does not respond to treatment 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
  • Mixed Phenotype Acute Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: HA-1 T TCR T Cell Immunotherapy for the Treating 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
  • NCT ID: NCT03326921

Conditions

  • HLA-A*0201 HA-1 Positive Cells Present
  • Minimal Residual Disease
  • Recurrent Acute Biphenotypic Leukemia
  • Recurrent Acute Undifferentiated Leukemia
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Myeloid Leukemia
  • Recurrent Childhood Acute Lymphoblastic Leukemia
  • Recurrent Childhood Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia
  • Refractory Adult Acute Lymphoblastic Leukemia
  • Refractory Childhood Acute Lymphoblastic 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)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586Treatment (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) T cells in treating patients with acute leukemia that has come back or does not respond to treatment 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

      PRIMARY OBJECTIVES:

      I. To evaluate the feasibility and safety of HA-1 T TCR T cell immunotherapy in approximately
      12 children and adolescents and 12 adults with recurrent acute leukemia after allogeneic
      hematopoietic stem cell transplantation (HCT).

      SECONDARY OBJECTIVES:

      I. To determine the in vivo persistence of transferred HA-1 TCR T cells in peripheral blood.

      II. To determine the ability of HA-1 TCR T cells to migrate to bone marrow.

      III. To evaluate the function of HA-1 TCR T cells before and, if possible, after adoptive T
      cell transfer.

      IV. To observe whether infusion of HA-1 TCR T cells is followed by a reduction of leukemia
      burden.

      V. To observe whether infusion of HA-1 TCR T cells is followed by a reduction of recipient
      hematopoietic chimerism.

      VI. To observe whether infusion of HA-1 TCR T cells is followed by the appearance or
      recurrence of signs or symptoms of graft-versus-host disease (GVHD).

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

      Patients receive fludarabine phosphate for 1-3 doses 7-14 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 5 years, and then annually for up to 10 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (CD4+ and CD8+ HA-1 TCR T cells)ExperimentalPatients receive fludarabine phosphate for 1-3 doses 7-14 days prior to HA-1 TCR T cell administration. Patients then receive CD4+ and CD8+ HA-1 TCR T cells IV over 1 hour.
  • Fludarabine Phosphate

Eligibility Criteria

        Inclusion Criteria:

          -  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 and any of the following:

                    -  With relapse or refractory disease (>= 5% marrow blasts by morphology, or
                       circulating blasts, chloroma or granulocytic sarcoma) at the time of the
                       pre-HCT work-up

                    -  With minimal/measurable residual disease (MRD: defined as detectable disease
                       by morphology, flow cytometry, molecular or cytogenetic testing but < 5%
                       marrow blasts by morphology, no circulating blasts) at the time of the
                       pre-HCT work-up

                    -  With marrow aplasia or marked hypoplasia (bone marrow cellularity =< 10%)
                       following chemotherapy for prior refractory AML at the time of the pre-HCT
                       work-up

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

                    -  With MRD at any time after HCT

               -  Acute lymphoid leukemia (ALL) of any subtype and any of the following:

                    -  With relapse or refractory disease (>= 5% marrow blasts, or circulating
                       blasts) at the time of the pre-HCT work-up

                    -  With MRD at the time of the pre-HCT work-up

                    -  With marrow aplasia or marked hypoplasia (bone marrow cellularity =< 10%)
                       following chemotherapy for prior refractory ALL at the time of the pre-HCT
                       work-up

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

                    -  With MRD at any time after HCT

               -  Biphenotypic/undifferentiated/any other type of acute leukemia and any of the
                  following:

                    -  With relapse or refractory disease (defined as detectable disease by
                       morphology, flow cytometry, molecular or cytogenetic testing but < 5% marrow
                       blasts by morphology, no circulating blasts) at the time of the pre-HCT
                       work-up

                    -  With MRD at the time of the pre-HCT work-up

                    -  With marrow aplasia or marked hypoplasia (bone marrow cellularity =< 10%)
                       following chemotherapy for prior refractory acute leukemia at the time of
                       the pre-HCT work-up

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

                    -  With MRD at any time after HCT

               -  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

          -  Patients must be able to understand and be willing to give informed consent; 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:

          -  Central nervous system (CNS) leukemia (including leukemia detectable in the
             cerebrospinal fluid and/or solid chloromas) refractory to intrathecal chemotherapy
             and/or craniospinal radiation within 15 days prior to enrollment

          -  Human immunodeficiency virus (HIV) seropositive on test obtained within 30 days prior
             to enrollment

          -  Medical or psychological conditions present within 30 days prior to enrollment that
             would make the patient unsuitable candidate for cell therapy at the discretion of the
             principal investigator (PI)

          -  Pregnancy or breast-feeding within 30 days prior to enrollment

          -  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 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)
      
Maximum Eligible Age:70 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 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 GVHD grading criteria (see appendices 28.1 and 28.1).

Details

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

Trial Keywords

  • HA-1
  • TCR
  • Immunotherapy
  • Leukemia

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