Description:
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.
Title
- Brief Title: 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: 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)
Clinical Trial IDs
- ORG STUDY ID:
9716
- SECONDARY ID:
NCI-2017-01054
- SECONDARY ID:
9716
- SECONDARY ID:
P30CA015704
- SECONDARY ID:
RG9217022
- NCT ID:
NCT03326921
Conditions
- 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
Interventions
Drug | Synonyms | Arms |
---|
CD8+ and CD4+ Donor Memory T-cells-expressing HA1-Specific TCR | 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 | Treatment (CD4+ and CD8+ HA-1 TCR T cells) |
Fludarabine | 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 | Treatment (CD4+ and CD8+ HA-1 TCR T cells) |
Purpose
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.
Trial Arms
Name | Type | Description | Interventions |
---|
Treatment (CD4+ and CD8+ HA-1 TCR T cells) | Experimental | 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. | - CD8+ and CD4+ Donor Memory T-cells-expressing HA1-Specific TCR
- Fludarabine
|
Eligibility Criteria
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.
Maximum Eligible Age: | 75 Years |
Minimum Eligible Age: | N/A |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | 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) |
Safety Issue: | |
Description: | Proportion of participants for whom a HA-1 TCR T cell product can be produced. |
Secondary Outcome Measures
Measure: | 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 |
Safety Issue: | |
Description: | Evaluated by tetramer and/or molecular tracking e.g. quantitative polymerase chain reaction (qPCR). |
Measure: | 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 |
Safety Issue: | |
Description: | Evaluated by tetramer and/or molecular tracking e.g. qPCR. |
Measure: | Presence, proportion and persistence of HA-1 T cell receptor (TCR) CD4+ T cells in the bone marrow |
Time Frame: | Up to 1 year |
Safety Issue: | |
Description: | Evaluated by tetramer and/or molecular tracking e.g. qPCR. |
Measure: | Presence, proportion and persistence of HA-1 T cell receptor (TCR) CD8+ T cells in the bone marrow |
Time Frame: | Up to 1 year |
Safety Issue: | |
Description: | Evaluated by tetramer and/or molecular tracking e.g. qPCR. |
Measure: | 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) |
Safety Issue: | |
Description: | Assessed by in vitro chromium release assay or equivalent cytotoxicity assay. |
Measure: | 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 |
Safety Issue: | |
Description: | 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. |
Measure: | 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 |
Safety Issue: | |
Description: | Quantified by flow cytometry to determine percentage of leukemic cells in the marrow. |
Measure: | 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 |
Safety Issue: | |
Description: | Quantified by variable number tandem repeat (VNTR) to determine percentage of normal recipient and donor cells in the marrow. |
Measure: | Proportion of patients who develop new or recurrent symptoms or signs of graft-versus-host disease |
Time Frame: | Up to 1 year |
Safety Issue: | |
Description: | Assessed using clinical evaluation and standard clinical graft versus host disease (GVHD) grading criteria |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Fred Hutchinson Cancer Research Center |
Trial Keywords
- HA-1
- TCR
- Immunotherapy
- Leukemia
Last Updated
July 8, 2021