A Phase II, single arm, multicenter open label trial to determine the safety and efficacy of tisagenlecleucel in pediatric patients with relapsed or refractory mature B-cell non-Hodgkin lymphoma (NHL) (BIANCA)

Lymphomas most commonly occur during the second decade of life, with a median
age at diagnosis of 10 years 8 months, and is rare in infants (*1 percent). The
incidence increases with age as lymphomas account for approximately 4, 14, 22,
and 25 percent of neoplasms in children 1 to 4, 5 to 9, 10 to 14, and 15 to 19
years of age, respectively.
Non-Hodgkin lymphoma (NHL), a heterogeneous group of lymphoid malignancies, is
the fourth most common malignancy diagnosed in children.
In adults, NHL typically presents as a low or intermediate grade disease,
however, childhood NHL is usually an aggressive, poorly differentiated,
disseminated disease, often invading extra nodal sites, the bone marrow, and
central nervous system in advanced stages. Aggressive mature B-cell NHL
consists mainly of Burkitt lymphoma (BL), diffuse large B-cell lymphoma
(DLBCL), and primary mediastinal large B-cell lymphoma (PMBCL).
Newly diagnosed pediatric B-cell NHL patients are cured in the vast majority of
cases, with rates approaching 80-90%, with standard available therapies.
However, there remains a high unmet medical need for patients with relapsed or
refractory mature B-cell NHL, as salvage therapies including hematopoietic stem
cell transplant, rituximab-based therapies and intensive chemotherapy regimens,
offer limited clinical benefit and no therapies are currently accepted as the
standard of care. Outcomes for this patient population are generally poor, with
5 year survival rates approaching 10-30%.
Tisagenlecleucel, marketed as Kymriah in the US, is a treatment which uses the
body's own T-cells to fight NHL. T-cells from a person with cancer are removed
(leukapheresis), genetically engineered to make a specific T-cell receptor that
reacts to the cancer, and transferred back to the person. The T-cells are
engineered to target a protein called CD19 that is common on B-cells (both the
malignant and the healthy B-cells).
It was invented and initially developed at the University of Pennsylvania.
Novartis completed development and obtained FDA approval in 2017 for the
indications inadequately responding or relapsed B-cell acute lymphoblastic
leukemia in children and young adults and relapsed or refractory diffuse large
B-cell lymphoma in adults. It became the first FDA-approved treatment that
included a gene therapy step in the US. It is administered in a single
treatment.

Primary:
To evaluate the efficacy of tisagenlecleucel therapy as measured by overall
response rate by investigator assessment.
Secondary: Duration of response, event free survival, relapse free survival,
overall survival, safety, kinetics, immunogenicity, % subjects who proceed to
transplant, potential predictive models for cytokine release syndrome.

Single arm, open-label, multi-center, phase II study to determine the efficacy
and safety of tisagenlecleucel in pediatric subjects and young adults (up to
25 years) with CD19-positive relapsed or refractory mature B-cell NHL. The
study will have the following sequential phases: screening phase, pre-treatment
phase, treatment & follow-up phase.
Prior to planned infusion date: lymphodepleting chemotherapy (fludarabine,
cyclophosphamide) (unless the subject has a significant cytopenia), see
protocol section 6.1.5.2 for details.
Leukapheresis, genetic engineering of T-cells and transfer back to patient
(tisagenlecleucel infusion).
After tisagenlecleucel infusion, efficacy will be assessed at Day 29, then
every 3 months for the first year, every 6 months for the second year, then
yearly until the end of study.
The study will end when the last subjects has completed the 2nd study year.
A post-study long term follow-up for lentiviral vector safety is planned via a
separate protocol.
Approx. 35 subjects enrolled.

Treatment with 1 tisagenlecleucel infusion.

Risk: Adverse effects of study treatment.
Burden:
Screening 4 weeks, including leukapheresis
Lymphodepleting chemotherapy: fludarabine I.V. and cyclophosphamide I.V. or
cytarabine I.V. and etoposide I.V.
Treatment: 1 tisagenlecleucel infusion (premedication: acetaminophen or
paracetamol plus antihistaminic).
Study procedures (based on 2 years study duration):
Physical examination: 15.
Blood tests: 17 (5-30 ml).
Bone marrow aspirate: 1.
Lumbar puncture: 1.
Tumor biopsy: 1-2. (in case of Burkitt Leukemia 7)
Pregnancy test (if relevant): 8.
Pulse oximetry: 2.
ECG: 2.
Echocardiography/MUGA: 1.
CT/MRI scan(s): 9.
Tanner staging (up to 18 years of age, up to Tanner stage 5): 4.