Phase III B in Acute Lymphoblastic Leukemia

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).

This was a single-arm, multi-centeric Phase IIIb study provided pediatric/young adult patients with r/r B-cell ALL the opportunity to be treated with CTL019. The main purpose of this study was to assess the safety of CTL019 for up to 12 months after the CTL019 infusion. The study had the following sequential phases for all patients: Screening including leukapheresis, Pre-Treatment (Cell Product Preparation and Lymphodepleting Chemotherapy), Treatment and Follow-up, and Long-Term Follow-Up (LTFU). The end of study (EOS) was defined as the last patient's last visit, which was the last patient's Month 12 evaluation, or the time of premature withdrawal. All patients were followed in this study for up to 12 months after the CTL019 infusion.

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