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CD19 CAR T Cells for B Cell Malignancies After Allogeneic Transplant

Primary Purpose

Philadelphia Chromosome Negative Adult Precursor Acute Lymphoblastic Leukemia, Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia, Recurrent Adult Acute Lymphoblastic Leukemia

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
allogeneic cytomegalovirus-specific cytotoxic T lymphocytes
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Philadelphia Chromosome Negative Adult Precursor Acute Lymphoblastic Leukemia

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • 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:

    • Philadelphia chromosome negative acute lymphoblastic leukemia:

      • Beyond first complete remission (CR) at the time of pre-transplant evaluation
      • Required > 1 cycle of induction chemotherapy to achieve CR
      • 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)
      • First CR with poor risk cytogenetics (t(4:11), t(8;14), hypodiploidy, near triploidy or > 5 cytogenetic abnormalities) at diagnosis
      • Planned for or have had a reduced intensity conditioned or non-myeloablative transplant

    • Philadelphia positive acute lymphoblastic leukemia

      • Not in CR at the time of pre-transplant evaluation

      • In CR with the following features:

        • Intolerant or unwilling to use a TKI after HCT
        • Current or previous detection of cytogenetic abnormalities in addition to t(9;22) by conventional karyotyping, FISH or molecular methods

    • Chronic lymphocytic leukemia, or low grade B cell lymphomas:

      • 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

    • Mantle cell lymphoma:

      • Failed or ineligible for autologous transplant AND a lymph node >= 2 cm at the time of pre-transplant evaluation

    • Diffuse large B cell lymphomas, large B cell transformation of an indolent lymphoma or other aggressive B cell lymphomas

      • Failed or ineligible for autologous transplant AND not in CR at the time of pre-transplant evaluation
  • 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
  • The patient has signed the informed consent form for this study
  • DONOR: Genotypic or phenotypic HLA-identical family members

  • DONOR: Express one or more of the following combinations of viral serostatus and HLA allele:

    • CMV seropositive and HLA-A*0101 positive
    • CMV seropositive and HLA-A*0201 positive
    • CMV seropositive and HLA-B*0702 positive
    • CMV seropositive and HLA-B*0801 positive
    • EBV seropositive and HLA-A*0201 positive
    • EBV seropositive and HLA-B*0801 positive
  • DONOR: Hematocrit >= 35% at enrollment
  • DONOR: Age >= 18 years
  • DONOR: The donor has signed the informed consent form for the study

Exclusion Criteria:

  • 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
  • Human immunodeficiency virus (HIV) seropositive
  • Significant medical or psychological conditions that would make them unsuitable candidates for T cell therapy
  • Fertile patients unwilling to use contraception during and for 12 months after protocol enrollment
  • Pregnant or breast-feeding
  • DONOR: G-CSF administered within one month prior to the blood draw for T cell collection
  • DONOR: Unable for any reason to provide a 400 ml blood draw
  • DONOR: Inadequate peripheral veins for blood collection
  • DONOR: HIV-1, HIV-2, human T-lymphotropic virus (HTLV)-1 or HTLV-2 seropositive
  • DONOR: Active hepatitis B or hepatitis C virus infection
  • DONOR: Positive serologic test for syphilis
  • DONOR: Aberrant CD45RA isoform expression on all T cells
  • DONOR: Systolic blood pressure (BP) < 80 or > 200
  • DONOR: Heart rate < 50 or > 120, if considered due to cardiac disease
  • DONOR: Oxygen (O2) saturation < 88% on room air
  • DONOR: Serum creatinine (Cr) > 3.0
  • DONOR: Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 4 x the upper limit of normal
  • DONOR: Unable to provide informed consent to participate
  • DONOR: Significant medical conditions (e.g. immunosuppressive therapy) that would make them unsuitable T cell donors
  • DONOR: Pregnant or nursing

Sites / Locations

  • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (T cell therapy)

Arm Description

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.

Outcomes

Primary Outcome Measures

Safety and toxicity assessment of study treatment
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
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

Full Information

First Posted
November 10, 2011
Last Updated
February 14, 2017
Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01475058
Brief Title
CD19 CAR T Cells for B Cell Malignancies After Allogeneic Transplant
Official Title
A Phase I/II Study of Cellular Immunotherapy With Donor Central Memory-derived Virus-specific CD8+ T-cells Engineered to Target CD19 for CD19+ Malignancies After Allogeneic Hematopoietic Stem Cell Transplant
Study Type
Interventional

2. Study Status

Record Verification Date
February 2017
Overall Recruitment Status
Completed
Study Start Date
April 2012 (undefined)
Primary Completion Date
April 2014 (Actual)
Study Completion Date
July 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. 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.
Detailed Description
PRIMARY OBJECTIVES: I. 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) II. 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: I. To determine the duration of in vivo persistence of adoptively transferred bi-specific CD8+ T cells, and the phenotype of persisting T cells. II. To determine if adoptively transferred bi-specific CD8+ T cells traffic to the bone marrow and function in vivo. III. To determine if adoptively transferred bi-specific CD8+ T cells proliferate in allogeneic HCT recipients that reactivate CMV or EBV. IV. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Philadelphia Chromosome Negative Adult Precursor Acute Lymphoblastic Leukemia, Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Mantle Cell Lymphoma, Refractory Chronic Lymphocytic Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
1 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (T cell therapy)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
allogeneic cytomegalovirus-specific cytotoxic T lymphocytes
Other Intervention Name(s)
allogeneic CMV-specific CTLs
Intervention Description
Allogeneic CD19-specific chimeric antigen receptor-modified CD8+ central memory derived virus-specific T cells. Allogeneic CD19CAR-TCM cells given IV
Primary Outcome Measure Information:
Title
Safety and toxicity assessment of study treatment
Description
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.
Time Frame
Up to day 42 after the T cell infusion
Title
Feasibility assessment of study treatment
Description
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.
Time Frame
Up to 5 years
Secondary Outcome Measure Information:
Title
Anti-tumor efficacy and duration of persistence, migration, and function of adoptively transferred bi-specific effector cells
Time Frame
Up to 15 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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: Philadelphia chromosome negative acute lymphoblastic leukemia: Beyond first complete remission (CR) at the time of pre-transplant evaluation Required > 1 cycle of induction chemotherapy to achieve CR 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) First CR with poor risk cytogenetics (t(4:11), t(8;14), hypodiploidy, near triploidy or > 5 cytogenetic abnormalities) at diagnosis Planned for or have had a reduced intensity conditioned or non-myeloablative transplant Philadelphia positive acute lymphoblastic leukemia Not in CR at the time of pre-transplant evaluation In CR with the following features: Intolerant or unwilling to use a TKI after HCT Current or previous detection of cytogenetic abnormalities in addition to t(9;22) by conventional karyotyping, FISH or molecular methods Chronic lymphocytic leukemia, or low grade B cell lymphomas: 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 Mantle cell lymphoma: Failed or ineligible for autologous transplant AND a lymph node >= 2 cm at the time of pre-transplant evaluation Diffuse large B cell lymphomas, large B cell transformation of an indolent lymphoma or other aggressive B cell lymphomas Failed or ineligible for autologous transplant AND not in CR at the time of pre-transplant evaluation 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 The patient has signed the informed consent form for this study DONOR: Genotypic or phenotypic HLA-identical family members DONOR: Express one or more of the following combinations of viral serostatus and HLA allele: CMV seropositive and HLA-A*0101 positive CMV seropositive and HLA-A*0201 positive CMV seropositive and HLA-B*0702 positive CMV seropositive and HLA-B*0801 positive EBV seropositive and HLA-A*0201 positive EBV seropositive and HLA-B*0801 positive DONOR: Hematocrit >= 35% at enrollment DONOR: Age >= 18 years DONOR: The donor has signed the informed consent form for the study Exclusion Criteria: 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 Human immunodeficiency virus (HIV) seropositive Significant medical or psychological conditions that would make them unsuitable candidates for T cell therapy Fertile patients unwilling to use contraception during and for 12 months after protocol enrollment Pregnant or breast-feeding DONOR: G-CSF administered within one month prior to the blood draw for T cell collection DONOR: Unable for any reason to provide a 400 ml blood draw DONOR: Inadequate peripheral veins for blood collection DONOR: HIV-1, HIV-2, human T-lymphotropic virus (HTLV)-1 or HTLV-2 seropositive DONOR: Active hepatitis B or hepatitis C virus infection DONOR: Positive serologic test for syphilis DONOR: Aberrant CD45RA isoform expression on all T cells DONOR: Systolic blood pressure (BP) < 80 or > 200 DONOR: Heart rate < 50 or > 120, if considered due to cardiac disease DONOR: Oxygen (O2) saturation < 88% on room air DONOR: Serum creatinine (Cr) > 3.0 DONOR: Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 4 x the upper limit of normal DONOR: Unable to provide informed consent to participate DONOR: Significant medical conditions (e.g. immunosuppressive therapy) that would make them unsuitable T cell donors DONOR: Pregnant or nursing
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Cameron Turtle
Organizational Affiliation
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
34515338
Citation
Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.
Results Reference
derived

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CD19 CAR T Cells for B Cell Malignancies After Allogeneic Transplant

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