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

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ClinicalTrials.gov Identifier: NCT03326921
Recruitment Status : Recruiting
First Posted : October 31, 2017
Last Update Posted : May 28, 2021
Sponsor:
Collaborators:
Alex's Lemonade Stand Foundation
National Cancer Institute (NCI)
The Leukemia and Lymphoma Society
HighPass Bio, Inc.
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center

Tracking Information
First Submitted Date  ICMJE October 5, 2017
First Posted Date  ICMJE October 31, 2017
Last Update Posted Date May 28, 2021
Actual Study Start Date  ICMJE February 23, 2018
Estimated Primary Completion Date October 16, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 25, 2019)
  • 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) ]
    Proportion of participants for whom a HA-1 TCR T cell product can be produced.
  • Feasibility of administering 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) ]
    Proportion of participants for whom a HA-1 TCR T cell product can be administered.
  • Incidence of dose-limiting toxicities of HA-1 T cell receptor (TCR) T cells [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 25, 2017)
  • 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) ]
    Proportion of participants for whom a HA-1 TCR T cell product can be produced.
  • Feasibility of administering 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) ]
    Proportion of participants for whom a HA-1 TCR T cell product can be administered.
  • Incidence of dose-limiting toxicities of HA-1 T cell receptor (TCR) T cells [ Time Frame: Up to 12 weeks after T-cell infusion ]
    Toxicities will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 7, 2018)
  • 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 ]
    Evaluated by tetramer and/or molecular tracking e.g. quantitative polymerase chain reaction (qPCR).
  • 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 ]
    Evaluated by tetramer and/or molecular tracking e.g. qPCR.
  • Presence, proportion and persistence of HA-1 T cell receptor (TCR) CD4+ T cells in the bone marrow [ Time Frame: Up to 1 year ]
    Evaluated by tetramer and/or molecular tracking e.g. qPCR.
  • Presence, proportion and persistence of HA-1 T cell receptor (TCR) CD8+ T cells in the bone marrow [ Time Frame: Up to 1 year ]
    Evaluated by tetramer and/or molecular tracking e.g. qPCR.
  • 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) ]
    Assessed by in vitro chromium release assay or equivalent cytotoxicity assay.
  • 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 ]
    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.
  • 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 ]
    Quantified by flow cytometry to determine percentage of leukemic cells in the marrow.
  • 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 ]
    Quantified by variable number tandem repeat (VNTR) to determine percentage of normal recipient and donor cells in the marrow.
  • Proportion of patients who develop new or recurrent symptoms or signs of graft-versus-host disease [ Time Frame: Up to 1 year ]
    Assessed using clinical evaluation and standard clinical graft versus host disease (GVHD) grading criteria
Original Secondary Outcome Measures  ICMJE
 (submitted: October 25, 2017)
  • 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 ]
    Evaluated by tetramer and/or molecular tracking e.g. qPCR
  • 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 ]
    Evaluated by tetramer and/or molecular tracking e.g. qPCR
  • Presence, proportion and persistence of HA-1 T cell receptor (TCR) CD4+ T cells in the bone marrow [ Time Frame: Up to 1 year ]
    Evaluated by tetramer and/or molecular tracking e.g. qPCR
  • Presence, proportion and persistence of HA-1 T cell receptor (TCR) CD8+ T cells in the bone marrow [ Time Frame: Up to 1 year ]
    Evaluated by tetramer and/or molecular tracking e.g. qPCR
  • Specific cytolytic activity of HA-1 T cell receptor (TCR) CD8+ and CD4+ TM 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) ]
    Assessed by in vitro chromium release assay or equivalent cytotoxicity assay
  • Specific cytolytic activity of HA-1 T cell receptor (TCR) CD8+ and CD4+ TM cells against HLA-A*0201+ HA-1+ target cells after adoptive T cell transfer [ Time Frame: 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
  • 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 ]
    Quantified by flow cytometry to determine percentage of leukemic cells in the marrow.
  • 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 ]
    Quantified by VNTR to determine percentage of normal recipient and donor cells in the marrow.
  • Proportion of patients who develop new or recurrent symptoms or signs of graft-versus-host disease [ Time Frame: Up to 1 year ]
    Assessed using clinical evaluation and standard clinical GVHD grading criteria (see appendices 28.1 and 28.1).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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)
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • 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
Study Arms  ICMJE 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.
Interventions:
  • Biological: CD8+ and CD4+ Donor Memory T-cells-expressing HA1-Specific TCR
  • Drug: Fludarabine
  • Other: Laboratory Biomarker Analysis
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 25, 2017)
24
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 16, 2025
Estimated Primary Completion Date October 16, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 75 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Elizabeth Krakow 206-667-3410 efkrakow@fredhutch.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03326921
Other Study ID Numbers  ICMJE 9716
NCI-2017-01054 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
9716 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
RG9217022 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Fred Hutchinson Cancer Research Center
Study Sponsor  ICMJE Fred Hutchinson Cancer Research Center
Collaborators  ICMJE
  • Alex's Lemonade Stand Foundation
  • National Cancer Institute (NCI)
  • The Leukemia and Lymphoma Society
  • HighPass Bio, Inc.
Investigators  ICMJE
Principal Investigator: Elizabeth Krakow Fred Hutch/University of Washington Cancer Consortium
PRS Account Fred Hutchinson Cancer Research Center
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP