Clinical trial NCT01475058: 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
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: 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
Lead sponsor: Fred Hutchinson Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2011-11-21
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Safety and toxicity assessment of study treatment
timeFrame: Up to day 42 after the T cell infusion
measure: Feasibility assessment of study treatment
timeFrame: Up to 5 years
Secondary outcomes:
measure: Anti-tumor efficacy and duration of persistence, migration, and function of adoptively transferred bi-specific effector cells
timeFrame: Up to 15 years
Other outcomes:
Locations:
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
state: Washington
Study officials:
affiliation: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
name: Cameron Turtle
role: PRINCIPAL_INVESTIGATOR
References:
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.