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HA-1 T TCR T Cell Immunotherapy for the Treating 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 2, 2018
Sponsor:
Collaborators:
Alex's Lemonade Stand Foundation
National Cancer Institute (NCI)
The Leukemia and Lymphoma Society
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
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 Biological: CD8+ and CD4+ Donor Memory T-cells-expressing HA1-Specific TCR Drug: Fludarabine Phosphate Other: Laboratory Biomarker Analysis Phase 1

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.


Study Type : Interventional
Estimated Enrollment : 24 participants
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)
Estimated Study Start Date : June 23, 2018
Estimated Primary Completion Date : December 16, 2019
Estimated Study Completion Date : October 16, 2020


Arm Intervention/treatment
Experimental: Treatment (CD4+ and CD8+ HA-1 TCR T cells)
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 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 Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586

Other: Laboratory Biomarker Analysis
Correlative studies




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.


Secondary Outcome Measures :
  1. 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).

  2. 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.

  3. 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.

  4. 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.

  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 [ Time Frame: 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 [ 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.

  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 [ Time Frame: 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 [ Time Frame: Up to 1 year ]
    Quantified by 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 [ Time Frame: Up to 1 year ]
    Assessed using clinical evaluation and standard clinical GVHD grading criteria (see appendices 28.1 and 28.1).



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 70 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03326921


Locations
United States, Washington
Fred Hutch/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Marie Bleakley    206-667-6572    mbleakle@fredhutch.org   
Principal Investigator: Marie Bleakley         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Alex's Lemonade Stand Foundation
National Cancer Institute (NCI)
The Leukemia and Lymphoma Society
Investigators
Principal Investigator: Marie Bleakley Fred Hutch/University of Washington Cancer Consortium

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT03326921     History of Changes
Other Study ID Numbers: 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 )
First Posted: October 31, 2017    Key Record Dates
Last Update Posted: May 2, 2018
Last Verified: April 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Fred Hutchinson Cancer Research Center:
HA-1
TCR
Immunotherapy
Leukemia

Additional relevant MeSH terms:
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplastic Processes
Pathologic Processes
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Lymphoid
Neoplasm, Residual
Leukemia, Biphenotypic, Acute
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Fludarabine
Fludarabine phosphate
Vidarabine
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents
Anti-Infective Agents