CD19 CAR T Cells for B Cell Malignancies After Allogeneic Transplant
Study Details
Study Description
Brief Summary
This phase I/II trial studies the safety and toxicity of post-transplant treatment with donor T cells engineered to express a chimeric antigen receptor (CAR) targeting CD19 in patients who have had a matched related allogeneic hematopoietic stem cell transplant for a CD19+ B cell malignancy.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1/Phase 2 |
Detailed Description
PRIMARY OBJECTIVES:
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To assess the safety and feasibility of pre-emptive adoptive T cell therapy using ex vivo expanded cytomegalovirus (CMV)- or Epstein-Barr virus (EBV)-specific T cells derived from donor CD62L+ central memory (TCM) cells and genetically modified to express a CD19-specific chimeric antigen receptor (CAR) in patients in complete remission after human leukocyte antigen (HLA)-matched related donor hematopoietic stem cell transplantation (HCT) for CD19+ B cell malignancies at high risk of post-HCT relapse. (Cohort A)
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To assess the safety and feasibility of adoptive T cell therapy using ex vivo expanded CMV- or EBV-specific T cells derived from donor CD62L+ TCM cells and genetically modified to express a CD19-specific CAR in patients with persistent, progressive or relapsed disease after HLA-matched related donor HCT for CD19+ B cell malignancies. (Cohort B)
SECONDARY OBJECTIVES:
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To determine the duration of in vivo persistence of adoptively transferred bi-specific CD8+ T cells, and the phenotype of persisting T cells.
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To determine if adoptively transferred bi-specific CD8+ T cells traffic to the bone marrow and function in vivo.
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To determine if adoptively transferred bi-specific CD8+ T cells proliferate in allogeneic HCT recipients that reactivate CMV or EBV.
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To determine if the adoptive transfer of bi-specific CD8+ T cells eliminates CD19+ tumor cells in the subset of patients with a measurable tumor burden prior to T cell transfer.
OUTLINE:
At least 30 days after HCT, patients will receive one intravenous (IV) infusion of CMV/CD19 or EBV/CD19 bi-specific CD8+ T cells.
After completion of study treatment, patients are followed up periodically for 15 years.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Treatment (T cell therapy) Patients undergo one IV infusion of donor-derived CD8+ central memory-derived CMV/CD19 or EBV/CD19 bi-specific T cells, at least 30 days after HCT. |
Biological: allogeneic cytomegalovirus-specific cytotoxic T lymphocytes
Allogeneic CD19-specific chimeric antigen receptor-modified CD8+ central memory derived virus-specific T cells. Allogeneic CD19CAR-TCM cells given IV
Other Names:
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Outcome Measures
Primary Outcome Measures
- Safety and toxicity assessment of study treatment [Up to day 42 after the T cell infusion]
Incidence of grade >= 3 toxicity, as defined by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 occurring from the T cell infusion through day 42 after the T cell infusion. Analysis will be performed separately in patients in complete remission (cohort A) or with detectable disease (cohort B) at day 28 post-transplant (prior to the T cell infusion). Incidence of acute GVHD occurring from the T cell infusion through day 42 after the T cell infusion will be assessed.
- Feasibility assessment of study treatment [Up to 5 years]
If the prescribed T cell dose is delivered in more than 50% of the patients, this approach will be considered feasible for further study to reduce relapse after allogeneic HCT.
Secondary Outcome Measures
- Anti-tumor efficacy and duration of persistence, migration, and function of adoptively transferred bi-specific effector cells [Up to 15 years]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Patients with CD19+ B cell malignancy who have persistent, relapsed or progressive disease after hematopoietic stem cell transplant from an human leukocyte antigen (HLA)-matched related donor OR patients with CD19+ B cell malignancy who are planned for or have had a hematopoietic stem cell transplant from an HLA-matched related donor and are at risk of relapse after HCT defined by any one of the disease-specific criteria listed below:
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Philadelphia chromosome negative acute lymphoblastic leukemia:
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Beyond first complete remission (CR) at the time of pre-transplant evaluation
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Required > 1 cycle of induction chemotherapy to achieve CR
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First morphologic CR but with evidence of minimal residual disease by flow cytometry, conventional cytogenetics, fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR)
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First CR with poor risk cytogenetics (t(4:11), t(8;14), hypodiploidy, near triploidy or > 5 cytogenetic abnormalities) at diagnosis
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Planned for or have had a reduced intensity conditioned or non-myeloablative transplant
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Philadelphia positive acute lymphoblastic leukemia
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Not in CR at the time of pre-transplant evaluation
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In CR with the following features:
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Intolerant or unwilling to use a TKI after HCT
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Current or previous detection of cytogenetic abnormalities in addition to t(9;22) by conventional karyotyping, FISH or molecular methods
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Chronic lymphocytic leukemia, or low grade B cell lymphomas:
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Failed or ineligible for prior immunochemotherapy that included a purine analog and anti-CD20 monoclonal antibody AND a lymph node >= 5 cm at the time of pre-transplant evaluation
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Mantle cell lymphoma:
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Failed or ineligible for autologous transplant AND a lymph node >= 2 cm at the time of pre-transplant evaluation
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Diffuse large B cell lymphomas, large B cell transformation of an indolent lymphoma or other aggressive B cell lymphomas
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Failed or ineligible for autologous transplant AND not in CR at the time of pre-transplant evaluation
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Confirmation of tumor diagnosis and expression of CD19 after review by University of Washington Medical Center (UWMC) or Seattle Cancer Care Alliance (SCCA) pathology services
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The patient has signed the informed consent form for this study
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DONOR: Genotypic or phenotypic HLA-identical family members
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DONOR: Express one or more of the following combinations of viral serostatus and HLA allele:
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CMV seropositive and HLA-A*0101 positive
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CMV seropositive and HLA-A*0201 positive
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CMV seropositive and HLA-B*0702 positive
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CMV seropositive and HLA-B*0801 positive
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EBV seropositive and HLA-A*0201 positive
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EBV seropositive and HLA-B*0801 positive
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DONOR: Hematocrit >= 35% at enrollment
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DONOR: Age >= 18 years
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DONOR: The donor has signed the informed consent form for the study
Exclusion Criteria:
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Known central nervous system (CNS) tumor (CNS2 or CNS3) that is refractory to intrathecal chemotherapy and/or cranio-spinal radiation; patients with a history of CNS disease that has been effectively treated to CNS1 or lower evidence of disease will be eligible
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Human immunodeficiency virus (HIV) seropositive
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Significant medical or psychological conditions that would make them unsuitable candidates for T cell therapy
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Fertile patients unwilling to use contraception during and for 12 months after protocol enrollment
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Pregnant or breast-feeding
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DONOR: G-CSF administered within one month prior to the blood draw for T cell collection
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DONOR: Unable for any reason to provide a 400 ml blood draw
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DONOR: Inadequate peripheral veins for blood collection
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DONOR: HIV-1, HIV-2, human T-lymphotropic virus (HTLV)-1 or HTLV-2 seropositive
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DONOR: Active hepatitis B or hepatitis C virus infection
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DONOR: Positive serologic test for syphilis
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DONOR: Aberrant CD45RA isoform expression on all T cells
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DONOR: Systolic blood pressure (BP) < 80 or > 200
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DONOR: Heart rate < 50 or > 120, if considered due to cardiac disease
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DONOR: Oxygen (O2) saturation < 88% on room air
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DONOR: Serum creatinine (Cr) > 3.0
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DONOR: Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 4 x the upper limit of normal
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DONOR: Unable to provide informed consent to participate
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DONOR: Significant medical conditions (e.g. immunosuppressive therapy) that would make them unsuitable T cell donors
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DONOR: Pregnant or nursing
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium | Seattle | Washington | United States | 98109 |
Sponsors and Collaborators
- Fred Hutchinson Cancer Center
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Cameron Turtle, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 2494.00
- NCI-2011-01819
- 2494.00
- P30CA015704
- R01CA136551