Phase III B in Acute Lymphoblastic Leukemia
Condition: Acute Lymphoblastic Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Intervention: CTL019
Intervention description: CTL019 transduced T cells were given as a single dose of 0.2 to 5.0 × 10^6 autologous CTL019 transduced viable T cells per kg body weight (for patients ≤ 50 kg) and 0.1 to 2.5 × 10^8 CTL019 transduced viable T cells (for patients > 50 kg)
Intervention MeSH terms: Tisagenlecleucel
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 69.0
Sex: All
Maximum age: 25 Years
Healthy volunteers: No
Keywords: ALL; Acute Lymphoblastic Leukemia; CTL019; relapsed/refractory pediatric/young adult

Summary:

      This is a single arm, open-label, multi-center, phase III B study to determine the safety and
      efficacy of CTL019 in pediatric/young adult patients with r/r B-cell Acute Lymphoblastic
      Leukemia (ALL).
    

Eligibility criteria:

        Inclusion Criteria:

        Relapsed or refractory B-cell ALL in pediatric or young adult patients:

          1. Second or greater bone marrow relapse.

          2. Any bone marrow relapse after allogeneic SCT and must be ≥ 4 months from SCT at the
             time of CTL019 infusion OR

          3. Primary refractory as defined by not achieving a CR after 2 cycles of a standard
             chemotherapy regimen or chemorefractory as defined by not achieving a CR after 1 cycle
             of standard chemotherapy for relapsed leukemia OR

          4. Patients with Philadelphia chromosome positive (Ph+) ALL are eligible if they are
             intolerant to or have failed 2 lines of tyrosine kinase inhibitor (TKI) therapy, or if
             TKI therapy is contraindicated OR

          5. Ineligible for allogeneic SCT

        For relapsed patients, CD19 tumor expression demonstrated in bone marrow or peripheral
        blood by flow cytometry within 3 months of program entry.For relapsed or refractory
        patients previously treated with blinatumomab, CD19 tumor expression must be demonstrated
        (via flow cytometry) at Screening.

        Adequate organ function defined as:

          1. A serum creatinine based on age/gender as follows: Maximum Serum Creatinine (mg/dL).
             Age Male Female: to < 2 years 0.6 0.6; to < 6 years 0.8 0.8; 6 to < 10 years 1.0 1.0;
             10 to < 13 years 1.2 1.2; 13 to < 16 years 1.5 1.4; ≥ 16 years 1.7 1.4.

          2. ALT ≤ 5 times the upper limit of normal (ULN) for age.

          3. Bilirubin < 2.0 mg/dL.

          4. Minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygenation
             > 91% on room air.

          5. Left Ventricular Shortening Fraction ≥ 28% by echocardiogram, or Left Ventricular
             Ejection Fraction ≥ 45% by echocardiogram or Multiple Uptake Gated Acquisition (MUGA).

        Life expectancy > 12 weeks.

        Age less than 26 at the time of screening.

        Karnofsky (age ≥16 years) or Lansky (age < 16 years) performance status ≥ 50 at screening.

        Patients previously treated with blinatumomab who have detectable leukemia and documented
        CD19+ expression (via flow cytometry) and confirmed absence of CD19- leukemic blasts at
        Screening may be included. In this case, at least 1 week washout period must be applied
        from last dose of blinatumomab to start of leukapheresis. Patients previously treated with
        blinatumomab with no detectable MRD (i.e. MRD negative demonstrated by leukemic blasts <
        0.01%) will be excluded.

        Must have a leukapheresis product of non-mobilized cells received and accepted by the
        manufacturing site.

        Patients with active CNS leukemia involvement defined as CNS-3 by CSF findings only are
        eligible but will have their CTL019 infusion delayed until CNS disease is reduced to CNS-1
        or CNS-2 by CSF findings. Patients with other forms of active CNS-3 leukemic involvement
        such as CNS parenchymal or ocular disease, cranial nerve involvement or significant
        leptomeningeal disease are not eligible. However, such patients with other forms of CNS-3
        leukemic involvement (non-CSF involvement) are eligible if there is documented evidence of
        disease stabilization for at least 3 months prior to CTL019 infusion. Patients must have no
        acute/ongoing neurologic toxicity > Grade 1 with the exception of a history of controlled
        seizures or fixed neurologic deficits that have been stable/improving over the past 3
        months.

        Exclusion criteria Isolated extra-medullary disease relapse. Concomitant genetic syndromes
        associated with bone marrow failure states: Fanconi anemia, Kostmann syndrome, Shwachman
        syndrome or any other known bone marrow failure syndrome. Patients with Down Syndrome will
        not be excluded.

        Patients with Burkitt's lymphoma/leukemia (i.e. patients with mature B-cell ALL, leukemia
        with B-cell surface immunoglobulin (sIg) positive and kappa or lambda restricted positivity
        ALL, with FAB L3 morphology and /or a MYC translocation).

        Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative
        intent and with no evidence of active disease.

        Prior treatment with any gene therapy product. Prior treatment with any anti-CD19/anti-CD3
        therapy, or any other anti-CD19 therapy, except for patients pre-treated with blinatumomab
        Active or latent hepatitis B or active hepatitis C (test within 8 weeks of screening), or
        any uncontrolled infection at screening Human immunodeficiency virus (HIV) positive test
        within 8 weeks of screening. Presence of grade 2 to 4 acute or extensive chronic GVHD.
        Uncontrolled acute life threatening bacterial, viral or fungal infection at Screening
        Investigational medicinal product within the last 30 days prior to screening. Pregnant or
        nursing women.Women of child-bearing potential and all male participants, unless they are
        using highly effective methods of contraception for a period of 1 year after the CTL019
        infusion.

        The following medications are excluded:

          1. Steroids: Therapeutic systemic doses of steroids must be stopped > 72 hours prior to
             CTL019 infusion.

          2. Allogeneic cellular therapy: Any donor lymphocyte infusions must be completed > 6
             weeks prior to CTL019 infusion.

          3. GVHD therapies: Any systemic drug used for GVHD must be stopped > 4 weeks prior to
             CTL019 infusion to confirm that GVHD recurrence is not observed.

          4. Chemotherapy:

               -  TKIs and hydroxyurea must be stopped > 72 hours prior to CTL019 infusion.

               -  must be stopped > 1 week prior to CTL019 infusion: vincristine, 6-mercaptopurine,
                  6-thioguanine, methotrexate < 25 mg/m2, cytosine arabinoside < 100 mg/m2/day,
                  asparaginase (non pegylated).

               -  must be stopped > 2 weeks prior to CTL019 infusion: salvage chemotherapy (e.g.
                  clofarabine, cytosine arabinoside > 100 mg/m2, anthracyclines, cyclophosphamide,
                  methotrexate ≥ 25 mg/m2).

               -  Pegylated-asparaginase must be stopped > 4 weeks prior to CTL019 infusion.

          5. CNS disease prophylaxis: CNS prophylaxis treatment must be stopped > 1 week prior to
             CTL019 infusion (e.g. intrathecal methotrexate).

          6. Radiotherapy

               -  Non-CNS site of radiation must be completed > 2 weeks prior to CTL019 infusion.

               -  CNS directed radiation must be completed > 8 weeks prior to CTL019 infusion.

          7. Anti T-cell antibodies: Administration of any T cell lytic or toxic antibody (e.g.
             alemtuzumab) within 8 weeks prior to CTL019 is prohibited Other protocol-defined
             inclusion/exclusion may apply