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

Sponsor
Fred Hutchinson Cancer Research Center (Other)
Overall Status
Recruiting
CT.gov ID
NCT03326921
Collaborator
Alex's Lemonade Stand Foundation (Industry), National Cancer Institute (NCI) (NIH), The Leukemia and Lymphoma Society (Other), HighPass Bio, Inc. (Other)
24
Enrollment
1
Location
1
Arm
88.7
Anticipated Duration (Months)
0.3
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
24 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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)
Actual Study Start Date :
Feb 23, 2018
Anticipated Primary Completion Date :
Oct 16, 2024
Anticipated Study Completion Date :
Jul 16, 2025

Arms and Interventions

ArmIntervention/Treatment
Experimental: Treatment (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 IV over 1 hour.

Biological: CD8+ and CD4+ Donor Memory T-cells-expressing HA1-Specific TCR
Given IV
Other Names:
  • CD8+ 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 Cells
  • Drug: Fludarabine
    Given IV
    Other Names:
  • Fluradosa
  • 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-fluoroadenine
  • Other: Laboratory Biomarker Analysis
    Correlative studies

    Outcome Measures

    Primary Outcome Measures

    1. Feasibility of manufacturing minor H antigen (HA-1) T cell receptor (TCR) CD8+ and CD4+ T cells [At time of T cell infusion (at day 0)]

      Proportion of participants for whom a HA-1 TCR T cell product can be produced.

    2. Feasibility of administering minor H antigen (HA-1) T cell receptor (TCR) CD8+ and CD4+ T cells [At time of T cell infusion (at day 0)]

      Proportion of participants for whom a HA-1 TCR T cell product can be administered.

    3. Incidence of dose-limiting toxicities of HA-1 T cell receptor (TCR) T cells [Up to 12 weeks after T-cell infusion]

      Toxicities will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.

    Secondary Outcome Measures

    1. Duration of in vivo persistence of transferred HA-1 T cell receptor (TCR) CD4+ T cells in peripheral blood [Up to 1 year]

      Evaluated by tetramer and/or molecular tracking e.g. quantitative polymerase chain reaction (qPCR).

    2. Duration of in vivo persistence of transferred HA-1 T cell receptor (TCR) CD8+ T cells in peripheral blood [Up to 1 year]

      Evaluated by tetramer and/or molecular tracking e.g. qPCR.

    3. Presence, proportion and persistence of HA-1 T cell receptor (TCR) CD4+ T cells in the bone marrow [Up to 1 year]

      Evaluated by tetramer and/or molecular tracking e.g. qPCR.

    4. Presence, proportion and persistence of HA-1 T cell receptor (TCR) CD8+ T cells in the bone marrow [Up to 1 year]

      Evaluated by tetramer and/or molecular tracking e.g. qPCR.

    5. 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 [At the time of T cell infusion (at day 0)]

      Assessed by in vitro chromium release assay or equivalent cytotoxicity assay.

    6. 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 [Up to 1 year]

      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.

    7. 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 [Up to 1 year]

      Quantified by flow cytometry to determine percentage of leukemic cells in the marrow.

    8. 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 [Up to 1 year]

      Quantified by variable number tandem repeat (VNTR) to determine percentage of normal recipient and donor cells in the marrow.

    9. Proportion of patients who develop new or recurrent symptoms or signs of graft-versus-host disease [Up to 1 year]

      Assessed using clinical evaluation and standard clinical graft versus host disease (GVHD) grading criteria

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    N/A to 75 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Fred Hutch/University of Washington Cancer ConsortiumSeattleWashingtonUnited States98109

    Sponsors and Collaborators

    • Fred Hutchinson Cancer Research Center
    • Alex's Lemonade Stand Foundation
    • National Cancer Institute (NCI)
    • The Leukemia and Lymphoma Society
    • HighPass Bio, Inc.

    Investigators

    • Principal Investigator: Elizabeth Krakow, Fred Hutch/University of Washington Cancer Consortium

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Fred Hutchinson Cancer Research Center
    ClinicalTrials.gov Identifier:
    NCT03326921
    Other Study ID Numbers:
    • 9716
    • NCI-2017-01054
    • 9716
    • P30CA015704
    • RG9217022
    First Posted:
    Oct 31, 2017
    Last Update Posted:
    Sep 29, 2021
    Last Verified:
    Sep 1, 2021

    Study Results

    No Results Posted as of Sep 29, 2021