CART19 to Treat B-Cell Leukemia or Lymphoma That Are Resistant or Refractory to Chemotherapy
Condition: Hematopoietic/Lymphoid Cancer; Adult Acute Lymphoblastic Leukemia in Remission; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma
MeSH terms: Lymphoma; Leukemia; Lymphoma, Follicular; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Lymphoma, Non-Hodgkin; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Lymphoma, Large B-Cell, Diffuse; Leukemia, Prolymphocytic; Recurrence
Intervention: CART-19
Intervention description: Autologous T cells purified from the peripheral blood mononuclear cells of subjects, transduced with TCR-ζ/4-1BB lentiviral vector, expanded in vitro and then frozen for future administration.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 26.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a Pilot/Phase I, single arm, single center, open label study to determine the safety,
      efficacy and cellular kinetics of CART19 (CTL019) in chemotherapy resistant or refractory
      CD19+ leukemia and lymphoma subjects. The study consists of three Phases:

      1) a Screening Phase, followed by 2) an Intervention/Treatment Phase consisting of apheresis,
      lymphodepleting chemotherapy (determined by the Investigator and based on subject's disease
      burden and histology, as well as on the prior chemotherapy history received), infusions of
      CTL019, tumor collection by bone marrow aspiration or lymph node biopsy (optional, depending
      on availability), and 3) a Follow-up Phase.

      The suitability of subjects' T cells for CTL019 manufacturing was determined at study entry.

      Subjects with adequate T cells were leukapheresed to obtain large numbers of peripheral blood
      mononuclear cells for CTL019 manufacturing. The T cells were purified from the peripheral
      blood mononuclear cells, transduced with TCR-ζ/4-1BB lentiviral vector, expanded in vitro and
      then frozen for future administration. The number of subjects who had inadequate T cell
      collections, expansion or manufacturing compared to the number of subjects who had T cells
      successfully manufactured is a primary measure of feasibility of this study.

      Unless contraindicated and medically not advisable based on previous chemotherapy, subjects
      were given conditioning chemotherapy prior to CTL019 infusion. The chemotherapy was completed
      1 to 4 days before the planned infusion of the first dose of CTL019.

      Up to 20 evaluable subjects with CD19+ leukemia or lymphoma were planned to be dosed with
      CTL019. A single dose of CTL019 (consisting of approximately 5x10^9 total cells, with a
      minimal acceptable dose for infusion of 1.5x10^7 CTL019 cells) was to be given to subjects as
      fractions (10%, 30% and 60% of the total dose) on Day 0, 1 and 2. A second 100% dose of
      CTL019 was initially permitted to be given on Day 11 to 14 to subjects, providing they had
      adequate tolerance to the first dose and sufficient CTL019 was manufactured.
    

Eligibility criteria:

        Inclusion

          -  Male and female subjects with CD19+ B cell malignancies in patients with no available
             curative treatment options (such as autologous or allogeneic SCT) who have limited
             prognosis (several months to < 2 year survival) with currently available therapies
             will be enrolled

          -  CD19+ leukemia or lymphoma

          -  ALL in CR2 or CR3 and not eligible for allogeneic SCT because of age, comorbid
             disease, or lack of available family member or unrelated donor

          -  Follicular lymphoma, previously identified as CD19+:

          -  At least 2 prior combination chemotherapy regimens (not including single agent
             monoclonal antibody (Rituxan) therapy

          -  Stage III-IV disease

          -  Less than 1 year between last chemotherapy and progression (i.e. most recent
             progression free interval < 1 year)

          -  Disease responding or stable after most recent therapy (chemotherapy, MoAb, etc)

          -  CLL:

          -  At least 2 prior chemotherapy regimens (not including single agent monoclonal antibody
             (Rituxan) therapy. Patients with high risk disease manifested by deletion chromosome
             17p will be eligible if they fail to achieve a CR to initial therapy or progress
             within 2 years of 1 prior

          -  Less than 2 years between last chemotherapy and progression (i.e. most recent
             progression free interval < 2 years)

          -  Not eligible or appropriate for conventional allogeneic SCT

          -  Patients who achieve only a partial response to FCR as initial therapy will be
             eligible.

          -  Mantle cell lymphoma:

          -  Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate for
             conventional allogeneic or autologous SCT

          -  Disease responding or stable after most recent therapy (chemotherapy, MoAb, etc...)

          -  Relapsed after prior autologous SCT

          -  B-cell prolymphocytic leukemia (PLL) with relapsed or residual disease after at least
             1 prior therapy and not eligible for allogeneic SCT

          -  Diffuse large cell lymphoma, previously identified as CD19+:

          -  Residual disease after primary therapy and not eligible for autologous SCT

          -  Relapsed after prior autologous SCT

          -  Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate of
             conventional allogeneic or autologous SCT

          -  Expected survival > 12 weeks

          -  Creatinine < 2.5 mg/dl

          -  ALT/AST < 3x normal

          -  Bilirubin < 2.0 mg/dl

          -  Any relapse after prior autologous SCT will make patient eligible regardless of other
             prior therapy

          -  Adequate venous access for apheresis, and no other contraindications for leukapheresis

          -  Voluntary informed consent is given

        Exclusion

          -  Pregnant or lactating women

          -  The safety of this therapy on unborn children is not known

          -  Female study participants of reproductive potential must have a negative serum or
             urine pregnancy test performed within 48 hours before infusion

          -  Uncontrolled active infection

          -  Active hepatitis B or hepatitis C infection

          -  Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not
             exclusionary

          -  Previously treatment with any gene therapy products

          -  Feasibility assessment during screening demonstrates < 30% transduction of target
             lymphocytes, or insufficient expansion (< 5-fold) in response to CD3/CD28
             costimulation

          -  Any uncontrolled active medical disorder that would preclude participation as outlined

          -  HIV infection