A Phase I 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
Overview
- Phase
- Phase 1
- Intervention
- Biological/Genetically Modified T cells
- Conditions
- Acute Lymphocytic Leukemia
- Sponsor
- Memorial Sloan Kettering Cancer Center
- Enrollment
- 19
- Locations
- 1
- Primary Endpoint
- Evaluate the safety/persistence of (including GVHD) 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.
- Status
- Active, not recruiting
- Last Updated
- 10 months ago
Overview
Brief Summary
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 assess the toxicities of T-cells for patients with relapsed B cell leukemia or lymphoma after a blood SCT organ SCT or for patients who are at high risk for relapse of their B cell leukemia or lymphoma.
Investigators
Eligibility Criteria
Inclusion Criteria
- •History of CD19+ relapse/refractory (R/R) B cell malignancies occurring after allogeneic/autologous HSCT or solid organ transplant (SOT. (cohort 1)
- •Relapse on this protocol is detection of CD19+ malignancies in bone marrow morphology ≥ 5% any extramedullary lesion (radiographic), or detection of any disease level by cytogenetics, molecular, and/or flow cytometry.
- •History of relapsed or refractory CD19+ malignancies (e.g. Non Hodgkin Lymphoma) or considered high risk for relapse and and require autologous or allogeneic hematopoietic stem cell transplant (HSCT). Evidence of disease not required. (cohort 2 and 3)
- •No age restriction for patients
- •KPS or Lansky score \> or = to 50
- •Renal function (measured prior to conditioning chemotherapy)
- •Creatinine ≤ 2.0mg/dL for patients over 18 years of ≤ 2.5 x institutional ULN for age.
- •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
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.
- •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.
Arms & Interventions
Biological/Genetically Modified T cells
Utilizing our initial trial experience, it was amended to include three (3) expansion cohorts. Cohort 1: patients with CD19+ relapse/refractory (R/R) B cell malignancies occurring after allogeneic/autologous HSCT or solid organ transplant (SOT) infusion occurring following conditioning chemotherapy. Cohort 2:patients with CD10+ high risk B cell malignancies eligible for autologous HSCT followed by 19-28z CRA EBV-CTLs (auto-HSCT preparative regimen serves as conditioning chemotherapy. Cohort 3: patients with CD19+ high risk B cell malignancies eligible for allogeneic HSCT followed by consolidative 19-28z CAR EBV-CTLs (allo-HSCT preparative regimen serves as conditioning chemotherapy) Each expansion cohort has a target accrual of 6 patients treated with fixed CAR EBV-CTL dose (3x106 EBV-CTLs/kg) which has been demonstrated to be the ideal manufacturing dose.
Intervention: Biological/Genetically Modified T cells
Biological/Genetically Modified T cells
Utilizing our initial trial experience, it was amended to include three (3) expansion cohorts. Cohort 1: patients with CD19+ relapse/refractory (R/R) B cell malignancies occurring after allogeneic/autologous HSCT or solid organ transplant (SOT) infusion occurring following conditioning chemotherapy. Cohort 2:patients with CD10+ high risk B cell malignancies eligible for autologous HSCT followed by 19-28z CRA EBV-CTLs (auto-HSCT preparative regimen serves as conditioning chemotherapy. Cohort 3: patients with CD19+ high risk B cell malignancies eligible for allogeneic HSCT followed by consolidative 19-28z CAR EBV-CTLs (allo-HSCT preparative regimen serves as conditioning chemotherapy) Each expansion cohort has a target accrual of 6 patients treated with fixed CAR EBV-CTL dose (3x106 EBV-CTLs/kg) which has been demonstrated to be the ideal manufacturing dose.
Intervention: Cyclophosphamide-based chemotherapy
Outcomes
Primary Outcomes
Evaluate the safety/persistence of (including GVHD) 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
Secondary Outcomes
- To assess the effects of the adoptively transferred CD19 specific T-cells on the progression of leukemia.(3 years)
- To quantitate the number of chimeric antigen receptor (CAR) positive T-cells and donor EBV-CTL in the blood at defined intervals post infusion in order to determine their survival and proliferation in the host.(3 years)
- To assess long-term status of treated patients(15 years)