CD19 CAR T Cells for B Cell Malignancies After Allogeneic Transplant

Phase 1

Completed

• Conditions: Refractory Chronic Lymphocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Mantle Cell Lymphoma; Philadelphia Chromosome Negative Adult Precursor Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia
• Interventions: Biological: allogeneic cytomegalovirus-specific cytotoxic T lymphocytes

• Registration Number: NCT01475058
• Lead Sponsor: Fred Hutchinson Cancer Center

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.

Study Timeline

• Study First Submitted: 2011-11-10
• Study First Submitted QC: 2011-11-16
• Study First Posted: 2011-11-21
• Study Start: 2012-04
• Primary Completion: 2014-04
• Study Completion: 2014-07
• Disposition First Submitted: 2017-01-31
• Status Verified: 2017-02
• Disposition First Submitted QC: 2017-02-14
• Last Update Submitted: 2017-02-14
• Disposition First Posted: 2017-02-15
• Last Update Posted: 2017-02-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 1

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (T cell therapy)	allogeneic cytomegalovirus-specific cytotoxic T lymphocytes	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.

Primary Outcome Measures

Name	Time	Method
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.
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.

Secondary Outcome Measures

Name	Time	Method
Anti-tumor efficacy and duration of persistence, migration, and function of adoptively transferred bi-specific effector cells	Up to 15 years

Trial Locations

Locations (1)

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium; 🇺🇸 Seattle, Washington, United States