Tisagenlecleucel versus standard of care in adult patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma: A randomized, open label, phase III trial

Non-Hodgkin Lymphomas (NHL) comprise a heterogeneous group of malignancies.
Estimated new cases are 72,240 and deaths are 20,140 in the United States (US)
for 2017 (Siegel et al 2017). In Europe, for 2012, there were an estimated
93,500 new cases and 37,800 deaths due to NHL (Ferlay et al 2015).

Tisagenlecleucel (CART-19, CTL019) is a second generation CAR-T cell product
that uses autologous peripheral blood T cells that have been genetically
modified ex vivo to target CD19 on the surface of B cells.

Recent clinical trials of tisagenlecleucel in r/r CLL, r/r ALL, and r/r B-cell
lymphomas have shown promising and durable anti-tumor efficacy (Porter et al
2011, Grupp et al 2013, Maude et al 2014, Schuster et al 2017). Consequently,
tisagenlecleucel appears to be a therapeutic alternative for patients with B
cell malignancies (including DLBCL) refractory to the current therapies.

This study has been transitioned to CTIS with ID 2023-508343-48-00 check the CTIS register for the current data.

To compare tisagenlecleucel treatment strategy to SOC treatment strategy with
respect to delaying the composite event of disease progression / stable disease
at or after the week 12 assessment; or death at any time.

This is a randomized, open label, multicenter phase III trial comparing the
efficacy, safety, and tolerability of tisagenlecleucel treatment strategy to
SOC treatment strategy in adult patients with aggressive B-cell NHL after
failure of rituximab and anthracycline containing first line
immunochemotherapy. Failure of frontline therapy is defined as refractoriness
(lack of response or progression during therapy) or relapse/progression within
365 days of last dose of first line therapy (in patients who achieved CR on
first line therapy). Screened patients may undergo non-mobilized leukapheresis
for autologous T cell collection after obtaining informed consent (unless
historical product is to be used). There is a cross-over possibillity to arm A
for patients in arm B who have a Stable or Progressive disease response at or
after week 12.

Patients in Arm A receive tisagenlecleucel, and patients in Arm B are treated
according to Standard of Care. The physicians can choose between the following
treatments: R-ICE, R-DHAP, R-GDP, R-GemOx.

For patients randomized to Arm B (SOC therapy), a change in immunochemotherapy
is required if the patient achieves a response which is not sufficientto allow
HSCT, and change in treatment is in the best interest of the patient.
Investigators should choose one of the four regimens above in an effort to
achieve a response that allows the patient to proceed to transplant. Patients
who are deemed no longer eligible for HSCT (e.g. adverse event, poor tolerance
to immunochemotherapy, worsening of performance status) after two cycles of
immunochemotherapy may proceed to treatment with ibrutinib or lenalidomide.

Subjects with Complete Response (CR) or Partial Response (PR) after the 2
cycles (SOC 1) of salvage therapy and adequate stem cell collection may receive
an optional 3rd cycle of salvage therapy before transplant, or may proceed
directly to transplant after 2 cycles. At the investigator*s discretion,
patients in PR may change to one of the other 4 regimens. Every effort should
be attempted to have SOC patients proceed to transplant, if deemed in the best
interest of the patient. Patients should receive high dose chemotherapy
approximately 4-6 weeks after the last cycle of salvage therapy.

Risks: Side effects may occur after tisagenlecleucel infusion, after the
leukapheresis procedure, chemotherapy, autologues stemcell therapy,
chemotherapy to reduce lymphocytes, and after examination procedures such as
bone marrow puncture, PET-CT scan, MUGA, blood collection, tumor biopsy, and
lumbar puncture.

Burden Arm A: Leukapheresis, possible bridging chemotherapy, chemotherapy to
increase lymphocytes, single infusion of tisagenlecleucel, possible
hospitalization D1 - D21 (depending on medical condition), 8 controls in the
first 28 days after tisagenlecleucel infusion, and 12 visits thereafter.
Physical examination: 12x
Blood test: average blooddraw of 45ml, maximum 67.5 ml per visit.
Chemo to reduce lymphocytes in the patient: 1 time (3 to 7 days prior to
infusion tisagenlecleucel)
CT / MRI: month 9, month 12, month 18, month 24, month 36, month 48, month 60.
CT / MRI brain: if clinically indicated
PET-CT: screening, week 6, week 12 and month 6
MUGA / Echo: screening and and if clinically indicated
ECG: screening, day of tisagenlecleucel infusion and if clinically indicated
Bone marrow biopsy: randomization, week 8, month 4 and afterwards if a complete
response is achieved and the disease is in the bone marrow
Lumbar puncture: screening and then if clinically indicated
Tumor biopsy: screening, week 12 and afterwards if clinically indicated
Questionnaires: 13x
Optional use of body material (blood and tissues) and anonymous data for future
research.

Burden Arm B: Leukapheresis, standard of care chemotherapy, patients who
respond receive a high dose of chemotherapy, followed by a stem cell transplant
(if this is in the best interest of the patient), 16 hospital visits in total.
Physical examination: 20x
Blood test: average 45 ml, maximum 67.5 ml per visit.
CT / MRI: month 9, month 12, month 18, month 24, month 36, month 48, month 60.
CT / MRI brain: if clinically indicated
PET-CT: screening, week 6 week 12 and month 6
MUGA / Echo: screening, thereafter as clinically indicated and at crossover
visit
ECG: screening, thereafter as clinically indicated and at crossover visit
Bone marrow biopsy: screening and afterwards if a complete response is achieved
and the disease is in the bone marrow
Lumbar puncture: screening and then if clinically indicated
Tumor biopsy: screening
Questionnaires: 12x
Optional use of body material (blood and tissues) and anonymous data for future
research.