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 (CCTL019G2201J)

1. CD19 expressing (in peripheral blood or bone marrow by flow cytometry)
B-cell Acute
Lymphoblastic Leukemia
2. De novo NCI HR B-ALL who received first-line treatment and are MRD >= 0.01%
at EOC
(HR defined by NCI criteria at the time of initial leukemia presentation as age
>= 10 and/ or
WBC >= 50 x 109 cells/L). 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% at
screening
5. Adequate organ function during the screening period
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. Protocols that are allowed
include
the following: COG AALL0232 ([NCT00075725]), AALL1131 ([NCT02883049])
standard arm, COG AALL1732, European ALLTogether 1st line trial, Dana Farber
Cancer Institute (DFCI) 16-001 (High Risk), Dutch Childhood Oncology Group
(DCOG) ALL-11, European Organization for Research and Treatment of Cancer-
Children*s Leukemia Group (EORTC-CLG) 58081 (variant 1), UKALL2011, or other
comparable protocols if approved by Novartis (See Appendix 4 for approved
regimens).
Additional (augmented) chemotherapy such as clofarabine and ifosfamide added
to induction/consolidation therapybprior to enrollment, leukapheresis and
infusion are not
allowed. Subject should be enrolled (leukapheresis accepted by Novartis
manufacturing)
on study before the initiation of the third dose planned dose of high-dose
methotrexate during interim maintenance therapy
8. Must meet the institutional criteria to undergo leukapheresis
9. Once all other eligibility criteria are confirmed, must have a leukapheresis
product of nonmobilized
cells received and accepted by the manufacturing site.

1. M3 marrow (>= 25% blasts by morphologic criteria) at the completion of
first-line
induction therapy
2. M2 (i.e. >= 5% blasts by morphologic criteria) 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 (defined
as CNS-3 by NCCNv1 2018) at the time of screening.
3. Philadelphia chromosome positive (Ph+) 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. Prior malignancy, except carcinoma in situ of the skin or cervix treated
with curative
intent and with no evidence of active disease
9. Has had treatment with any prior anti-CD19 therapy
10. Treatment with any prior gene or engineered T cell therapy
11. Clinically significant active infection confirmed by clinical evidence,
imaging, or positive
laboratory tests (e.g., blood cultures, PCR for DNA/RNA, etc.)
12. Presence of active hepatitis B or C (for detailed criteria
see Appendix 3).
13. Human Immunodeficiency Virus (HIV) positivity as indicated by serology.
14. Subject had an investigational medicinal product within the last 30 days
prior to screening
NOTE: Investigational therapies must not be used at any time while on study
until the
first relapse following tisagenlecleucel infusion.
15. If subjects are taking any of the following medications, their infusion
(including a second
infusion) must be delayed until the medications have been stopped according to
the
following:
a. Medications to be stopped > 72 hours prior to tisagenlecleucel infusion:
* Therapeutic systemic doses of steroids. However, the following physiological
replacement doses of steroids are allowed: < 12 mg/m2/day hydrocortisone or
equivalent
b. Medications to be stopped at least 1 week prior to tisagenlecleucel infusion:
* 6-thioguanine, asparaginase (non-pegylated), vincristine, 6-mercaptopurine,
and
intrathecal methotrexate
c. Medications to be stopped at least 2 weeks prior to tisagenlecleucel
infusion:
* Anthracyclines and cytarabine
* Intravenous methotrexate.
* Radiotherapy: Non-CNS site of radiation
d. Medications to be stopped at least 4 weeks prior to tisagenlecleucel
infusion:
* Pegylated-asparaginase
e. Medications/Therapy to be stopped at least 8 weeks prior to tisagenlecleucel
infusion:
* Radiotherapy: Cranial radiation (for CNS 3 subjects) therapy
16. Pregnant or nursing (lactating) women.