A phase II trial of tisagenlecleucel in first-line high-risk (HR) pediatric and young adult patients with B-cell acute lymphoblastic leukemia (B-ALL) who are minimal residual disease (MRD) positive at the end of consolidation (EOC) therapy

This is a single arm, open-label, multi-center, phase II study to determine the efficacy
and safety of tisagenlecleucel in de novo HR pediatric and young adult B-ALL patients who
received first-line treatment and are EOC MRD positive. The study will have the following
sequential phases: screening, pre-treatment, treatment & follow-up, and survival. After
tisagenlecleucel infusion, patient will have assessments performed more frequently in the
first month and then at Day 29, then every 3 months for the first year, every 6 months
for the second year, then yearly until the end of the study. Efficacy and safety will be
assessed at study visits and as clinically indicated throughout the study. The study is
expected to end in approximately 8 years after first patient first treatment (FPFT). A
post-study long term follow-up safety will continue under a separate protocol per health
authority guidelines.

Inclusion Criteria:

1. CD19 expressing B-cell Acute Lymphoblastic Leukemia

2. De novo NCI HR B-ALL who received first-line treatment and are MRD ≥ 0.01% at EOC.
EOC bone marrow MRD will be collected prior to screening and will be assessed by
multi-parameter flow cytometry using central laboratory analysis.

3. Age 1 to 25 years at the time of screening

4. Lansky (age < 16 years) or Karnofsky (age ≥ 16 years) performance status ≥ 60%

5. Adequate organ function during the screening period:

A. Renal function based on age/gender B. ALT ≤ 5 times ULN for age C. AST ≤ 5 times
ULN for age D. Total bilirubin < 2 mg/dL (for Gilbert's Syndrome subjects total
bilirubin < 4 mg/dL)

E. Adequate pulmonary function defined as:

- no or mild dyspnea (≤ Grade 1)

- oxygen saturation of > 90% on room air F. Adequate cardiac function defined as
LVSF ≥ 28% confirmed by echocardiogram or LVEF ≥ 45% confirmed by
echocardiogram or MUGA within 6 weeks of screening

6. Prior induction and consolidation chemotherapy allowed: 1st line subjects: ≤ 3
blocks of standard chemotherapy for first-line B-ALL, defined as 4-drug induction,
Berlin-Frankfurt-Münster (BFM) consolidation or Phase 1b, and interim maintenance
with high-dose methotrexate.

Exclusion Criteria:

1. M3 marrow at the completion of 1st line induction therapy

2. M2 or M3 marrow or persistent extramedullary disease at the completion of first-line
consolidation therapy or evidence of disease progression in the peripheral blood or
new extramedullary disease prior to enrollment. Patients with previous CNS disease
are eligible if there is no active CNS involvement of leukemia at the time of
screening.

3. Philadelphia chromosome positive ALL

4. Hypodiploid: less than 44 chromosomes and/or DNA index < 0.81, or other clear
evidence of a hypodiploid clone

5. Prior tyrosine kinase inhibitor therapy

6. Subjects with concomitant genetic syndromes associated with bone marrow failure
states: such as subjects with Fanconi anemia, Kostmann syndrome, Shwachman syndrome
or any other known bone marrow failure syndrome. Subjects with Down syndrome will
not be excluded.

7. Subjects with Burkitt's lymphoma/leukemia (i.e. subjects with mature B-ALL, leukemia
with B-cell [sIg positive and kappa or lambda restricted positivity] ALL, with FAB
L3 morphology and /or a MYC translocation)

8. Has had treatment with any prior anti-CD19 therapy 9. Treatment with any prior gene
or engineered T cell therapy

Other protocol-defined inclusion/exclusion may apply.