HA-1 T TCR T Cell Immunotherapy for the Treatment of Patients With Relapsed or Refractory Acute Leukemia After Donor Stem Cell Transplant
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
Arms and Interventions
Arm | Intervention/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:
Drug: Fludarabine
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
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Outcome Measures
Primary Outcome Measures
- 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.
- 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.
- 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
- 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).
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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
Inclusion Criteria:
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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)
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Patients must express HLA-A*0201
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Patients must have the HA-1(H) genotype (RS_1801284: A/G, A/A)
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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:
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HLA-A*0201 positive and HA-1(H) negative (RS_1801284: G/G) or
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HLA-A*0201 negative
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Patients who are currently undergoing or who previously underwent allogeneic HCT for
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Acute myeloid leukemia (AML) of any subtype
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Acute lymphoid leukemia (ALL) of any subtype
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Mixed phenotype/undifferentiated/any other type of acute leukemia, including blastic plasmacytoid dendritic cell neoplasm
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Chronic myeloid leukemia with a history of blast crisis and:
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With relapse or refractory disease (>= 5% marrow blasts, or circulating blasts) at any time after HCT
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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
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Myelodysplastic syndrome (MDS) of any subtype
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Chronic myelomonocytic leukemia (CMML)
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Juvenile myelomonocytic leukemia (JMML)
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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
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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
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Patients who have relapsed or have MRD after HCT may receive other agents for treatment of disease and remain eligible for the protocol
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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
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Donor age >= 18 years
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Donors must be able to give informed consent
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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
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HLA-A*0201 negative
Exclusion Criteria:
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Medical or psychological conditions that would make the patient unsuitable candidate for cell therapy at the discretion of the principal investigator (PI)
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Fertile patients unwilling to use contraception during and for 12 months after treatment
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Patients with a life expectancy < 3 months of enrollment from coexisting disease other than leukemia
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Patients who develop grade IV acute GVHD or severe chronic GVHD following most recent transplant prior to enrollment on the protocol
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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
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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
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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
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Fred Hutch/University of Washington Cancer Consortium | Seattle | Washington | United States | 98109 |
Sponsors and Collaborators
- Fred Hutchinson Cancer Center
- 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.- 9716
- NCI-2017-01054
- 9716
- RG9217022