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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Acute Myeloid Leukemia, Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Recurrent Acute Lymphoblastic Leukemia, Recurrent Acute Myeloid Leukemia, Myelodysplastic Syndrome, Acute Lymphoblastic Leukemia, Leukemia, 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, Acute Biphenotypic Leukemia, Chronic Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Minimal Residual Disease, Recurrent Chronic Myelomonocytic Leukemia, Recurrent Mixed Phenotype Acute Leukemia

Intervention / Treatment
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* Biological: CD8+ and CD4+ Donor Memory T-cells-expressing HA1-Specific TCR
* Drug: Fludarabine
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient age 0-75 years at the time of enrollment. 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.

Ages Eligible for Study
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Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (CD4+ and CD8+ HA-1 TCR T cells)<br>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<br>* Given IV<br>* Other names: HA-1 TCR T Cells;Drug: Fludarabine<br>* Given IV<br>* Other names: 9-Beta-D-arabinofuranosyl-2-fluoroadenine;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of manufacturing minor H antigen (HA-1) T cell receptor (TCR) CD8+ and CD4+ T cells | Proportion of participants for whom a HA-1 TCR T cell product can be produced. | At time of T cell infusion (at day 0) | 
| Feasibility of administering minor H antigen (HA-1) T cell receptor (TCR) CD8+ and CD4+ T cells | Proportion of participants for whom a HA-1 TCR T cell product can be administered. | At time of T cell infusion (at day 0) | 
| Incidence of dose-limiting toxicities of HA-1 T cell receptor (TCR) T cells | Toxicities will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4. | Up to 12 weeks after T-cell infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of in vivo persistence of transferred HA-1 T cell receptor (TCR) CD4+ T cells in peripheral blood | Evaluated by tetramer and/or molecular tracking e.g. quantitative polymerase chain reaction (qPCR). | Up to 1 year | 
| Duration of in vivo persistence of transferred HA-1 T cell receptor (TCR) CD8+ T cells in peripheral blood | Evaluated by tetramer and/or molecular tracking e.g. qPCR. | Up to 1 year | 
| Presence, proportion and persistence of HA-1 T cell receptor (TCR) CD4+ T cells in the bone marrow | Evaluated by tetramer and/or molecular tracking e.g. qPCR. | Up to 1 year | 
| Presence, proportion and persistence of HA-1 T cell receptor (TCR) CD8+ T cells in the bone marrow | Evaluated by tetramer and/or molecular tracking e.g. qPCR. | Up to 1 year | 
| 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 | Assessed by in vitro chromium release assay or equivalent cytotoxicity assay. | At the time of T cell infusion (at day 0) | 
| 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 | 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. | Up to 1 year | 
| 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 | Quantified by flow cytometry to determine percentage of leukemic cells in the marrow. | Up to 1 year | 
| 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 | Quantified by variable number tandem repeat (VNTR) to determine percentage of normal recipient and donor cells in the marrow. | Up to 1 year | 
| Proportion of patients who develop new or recurrent symptoms or signs of graft-versus-host disease | Assessed using clinical evaluation and standard clinical graft versus host disease (GVHD) grading criteria | Up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HA-1, TCR, Immunotherapy, Leukemia