This is a single arm, open-label, multi-center, phase II study to determine the safety and efficacy of CTL019 in pediatric/young adult patients with r/r B-cell ALL. The study will have the following sequential phases: Screening, Pre-Treatment (Cell Product Preparation & Lymphodepleting Chemotherapy), Treatment and Follow-up. The total duration of the study is 1 year from CTL019 cell infusion.
2 to 5 x 10(6) autologous CTL019 transduced cells per kg body weight, with a maximum dose of 2.5 x 10(8) autologous CTL019 transduced cells via intravenous infusion.
1. Relapsed or refractory B-cell ALL in pediatric or young adult patients: 1. Second or greater bone marrow relapse OR 2. Any bone marrow relapse after allogeneic SCT and must be ≥ 6 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
2. For relapsed patients, CD19 tumor expression demonstrated in bone marrow or peripheral blood by flow cytometry within 3 months of program entry
3. 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).
4. Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening.
5. Life expectancy > 12 weeks.
6. Age 3 years at the time of screening to age 21 years at the time of initial diagnosis.
7. Karnofsky (age ≥16 years) or Lansky (age < 16 years) performance status ≥ 50 at screening.
8. Must have a leukapheresis product of non-mobilized cells received and accepted by the manufacturing site.
1. Isolated extra-medullary disease relapse.
2. 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.
3. 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).
4. Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease.
5. Prior gene therapy product.
6. Prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy.
7. Active or latent hepatitis B or active hepatitis C, or any uncontrolled infection.
8. Human immunodeficiency virus positive test.
9. Presence of grade 2 to 4 acute or extensive chronic GVHD.
10. Active central nervous system involvement by malignancy, defined as CNS-3 per NCCN guidelines.
11. Investigational medicinal product within the last 30 days prior to screening.
12. Pregnant or nursing women.
13. 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.
14. 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
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