Clinical Trials /

In Vitro Expanded Allogeneic Epstein-Barr Virus Specific Cytotoxic T-Lymphocytes (EBV-CTLs) Genetically Targeted to the CD19 Antigen in B-cell Malignancies

NCT01430390

Description:

The purpose of this study is to test the safety of giving the patient special cells from a donor called "Modified T-cells". The goal is to find a safe dose of modified T-cells for patients with relapsed B cell leukemia or lymphoma after a blood SCT. The investigators also want to find out what effects these T-cells have on the patient and the disease.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: In Vitro Expanded Allogeneic Epstein-Barr Virus Specific Cytotoxic T-Lymphocytes (EBV-CTLs) Genetically Targeted to the CD19 Antigen in B-cell Malignancies
  • Official Title: A Phase I Dose Escalation Trial Using In Vitro Expanded Allogeneic Epstein-Barr Virus Specific Cytotoxic T-Lymphocytes (EBV-CTLs) Genetically Targeted to the CD19 Antigen in B-cell Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 11-038
  • NCT ID: NCT01430390

Conditions

  • Acute Lymphocytic Leukemia
  • Lymphoma

Interventions

DrugSynonymsArms
Biological/Genetically Modified T cellsBiological/Genetically Modified T cells
Cyclophosphamide-based chemotherapyBiological/Genetically Modified T cells

Purpose

The purpose of this study is to test the safety of giving the patient special cells from a donor called "Modified T-cells". The goal is to find a safe dose of modified T-cells for patients with relapsed B cell leukemia or lymphoma after a blood SCT. The investigators also want to find out what effects these T-cells have on the patient and the disease.

Trial Arms

NameTypeDescriptionInterventions
Biological/Genetically Modified T cellsExperimentalPatients with persistent minimal residual disease (+MRD)/ relapsed/refractory CD19+ malignancy will receive EBV specific cytotoxic T-cells (EBV-CTLs) genetically modified ex vivo to express the CD19-specific 19-28z chimeric artificial receptor.
  • Biological/Genetically Modified T cells
  • Cyclophosphamide-based chemotherapy

Eligibility Criteria

        Inclusion Criteria:

          -  History of CD19+ malignancy with evidence of relapse or persistent MRD following
             autologous or allogenic hematopoietic stem cell transplantation. (cohort 1)

          -  Relapse on this protocol is detection of CD19+ malignancies in bone marrow ≥ 5% or
             extramedullary lesion by morphology cytogenetics, molecular, radiographic and/or flow
             cytometry.

          -  Persistent minimal residual disease after transplantation must be demonstrated by
             morphology karyotype, FISH, flow cytometry or RT-PCR.

          -  History of relapsed or refractory CD19+ malignancies (e.g. Non Hodgkin Lymphoma) who
             have failed prior treatment and require autologous hematopoietic stem cell transplant.
             Evidence of disease not required. (cohort 2)

          -  No age restriction for patients

          -  KPS or Lansky score > or = to 50

          -  Renal function (measured prior to conditioning chemotherapy)

          -  Hepatic function (measured prior to conditioning chemotherapy):

          -  AST ≤ 5 x the institutional ULN Elevation secondary to leukemic involvement is not an
             exclusion criterion. Leukemic involvement will be determined by the presence of
             progressive relapse defined by escalating bone marrow or peripheral blood leukemia
             blasts within the previous month and the absence of initiation of know hepatotoxic
             medication (e.g. azoles).

          -  Total bilirubin ≤ 2.5 x the institutional ULN

          -  Adequate cardiac function (e.g. LVEF ≥ 40%) as assessed by ECHO or MUGA or other
             similar cardia imaging performed within 1 month of treatment.

          -  Pulmonary function (measured prior to treatment):

          -  Oxygen saturation ≥ 90% on room air

        Donor Eligibility:

          -  The patient's HSCT donor, or if HSCT donor is not available a third party donor, must
             consent to a leukapheresis or whole blood donation(s) obtained at one or more
             phlebotomies which, in aggregate, will total approximately 250 ml for adults and no
             more than 5ml/kg per draw from pediatric donors.

          -  Related donors <18 years of age requiring placement of a leukapheresis catheter will
             donate peripheral blood collected by phlebotomy (including a unit of blood if weight
             permits) and shall not undergo catheter placement for leukapheresis as this is
             considered above minimal risk to the donor.

          -  There is no upper age limit for a donors. However, the minimum age for a related donor
             is 7 years as this is the youngest age a person can be considered capable of giving
             assent to participate in a research study.

          -  Evidence of prior sensitization to EBV by EBV serology testing (seropositive)

          -  Donor's high resolution HLA typing must be available for review

          -  CBC within one week of donation. Results of tests must be within a range that would
             not preclude donating blood or undergoing leukapheresis.

          -  Serologic testing for transmissible diseases will be performed as per institutional
             guidelines adopted from extant NMDP and FACT guidelines. Donors should be considered
             eligible to donate leukapheresis or blood based on these guidelines (i.e. blood
             donation guidelines)

        Exclusion Criteria:

          -  Patients with active HIV, hepatitis B or hepatitis C infection.

          -  Patients with any concurrent active malignancies as defined by malignancies requiring
             any therapy other than expectant observation.

          -  Females who are pregnant.

          -  Patients will be excluded if they have isolated extra-medullary relapse of ALL.

          -  Previous infusion of CD19 CAR T cells at another institution

          -  Patients with active (grade 2-4) acute graft versus host disease (GVHD), chronic GVHD
             or an overt autoimmune disease (e.g. hemolytic anemia) requiring glucocorticosteroid
             treatment (>0.5 mg/kg/day prednisone or its equivalent) as treatment

          -  Active central nervous system (CNS) leukemia, as defined by unequivocal morphologic
             evidence of lymphoblasts in the cerebrospinal fluid (CSF) or symptomatic CNS leukemia
             (i.e. cranial nerve palsies or other significant neurologic dysfunction) within 28
             days of treatment. Prophylactic intrathecal medication is not a reason for exclusion.

          -  Adult patients (≥18 years old) with the following cardiac conditions will be excluded:

          -  New York Heart Association (NYHA) stage III or IV congestive heart failure

          -  Myocardial infarction ≤ 6months prior to enrollment

          -  History of clinically significant ventricular arrhythmia or unexplained syncope, not
             believed to be vasovagal in nature or due to dehydration.

          -  History of severe non-ischemic cardiomyopathy with EF ≤20%

          -  Uncontrolled, symptomatic, intercurrent illness including but not limited to
             infection, psychiatric illness, or social situations that would limit compliance with
             study requirements or in the opinion of the treating investigator would pose an
             unacceptable risk to the subject.

          -  Prior neurologic toxicity to previous immunotherapy

          -  Preceding and/or ongoing organ dysfunction or other co-morbidity including but not
             limited to uncontrolled infection that would impair the patient's ability to endure
             known side effects of cytokine release syndrome or neurological toxicity

          -  Recent prior therapy: Systematic chemotherapy less than 2 weeks prior to infusion.

          -  Recent prior therapy: Systematic chemotherapy less than 2 weeks prior to infusion.
             Exceptions:

               -  There is no time restriction in regard to prior intrathecal chemotherapy provided
                  tere is complete recovery from any acute toxic effects of such.

               -  Subjects receiving hydroxyurea or oral maintenance chemotherapy may be enrolled
                  provided there has been no increase in dose for at least 2 weeks prior to
                  starting apheresis or treatment

               -  Subjects receiving steroid therapy at physiological replacement doses only are
                  allowed provided there has been no increase in dose for at least 2 weeks prior to
                  subject starting apheresis or treatment.

               -  Subjects must have recovered from the acute side effects of their prior therapy,
                  such that eligibility criteria are met. Cytopenias deemed to be disease-related
                  and not therapy-related are exempt from this exclusion.

          -  Rapidly progressive disease that in the estimation of the treating physician would
             compromise ability to complete study therapy.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Evaluate the safety/persistence of escalating doses of allogeneic EBV specific CTL modified to express artificial T cell receptors targeting CD19 molecule given for persistence or relapse of B-Cell ALL post allogeneic HSCT.
Time Frame:3 years
Safety Issue:
Description:

Secondary Outcome Measures

Measure:To assess the effects of the adoptively transferred CD19 specific T-cells on the progression of leukemia.
Time Frame:3 years
Safety Issue:
Description:
Measure:To quantitate the number of chimeric antigen receptor (CAR) positive T-cells in the blood at defined intervals post infusion in order to determine their survival and proliferation in the host.
Time Frame:3 years
Safety Issue:
Description:
Measure:To assess long-term status of treated patients
Time Frame:15 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial Keywords

  • In Vitro Expanded Allogeneic Epstein-Barr Virus Specific Cytotoxic
  • T-Lymphocytes (EBV-CTLs)
  • CD19 specific T-cells
  • 11-038

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