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 (BELINDA)

• Histologically confirmed, aggressive B-cell NHL at relapse/progression or PR after front line therapy. Aggressive B-cell NHL is heretofore defined by the following list of subtypes (Swerdlow et al 2016):

‣ DLBCL, NOS,

⁃ FL grade 3B,

⁃ Primary mediastinal large B cell lymphoma (PMBCL),

⁃ T cell rich/histiocyte rich large B cell lymphoma (T/HRBCL),

⁃ DLBCL associated with chronic inflammation,

⁃ Intravascular large B-cell lymphoma,

⁃ ALK+ large B-cell lymphoma,

⁃ B-cell lymphoma, unclassifiable, (with features intermediate between DLBCL and classical Hodgkin's Lymphoma (HL)),

⁃ High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements,

⁃ High-grade B-cell lymphoma, NOS

⁃ HHV8+ DLBCL, NOS

⁃ DLBCL transforming from follicular lymphoma

⁃ DLBCL transforming from marginal zone lymphoma

⁃ DLBCL, leg type

• Relapse or progression within 365 days from last dose of anti CD20 antibody and anthracycline containing first line immunochemotherapy or refractory (have not achieved a CR).

• Patient is considered eligible for autologous HSCT as per local investigator assessment. Note: Intention to transplant and type of high dose chemotherapy (HDCT) regimen will be documented at the time of study entry

• Disease that is both active on PET scan (defined as 5-Deauville scorepoint-scale of 4 or 5) and measurable on CT scan, defined as::

‣ Nodal lesions \>15 mm in the long axis, regardless of the length of the short axis, and/or

⁃ Extranodal lesions (outside lymph node or nodal mass, but including liver and spleen) \>10 mm in long AND short axis

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

• Adequate organ function:

∙ Renal function defined as:

• Serum creatinine of ≤1.5 x upper limit of normal (ULN), OR estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2

∙ Hepatic function defined as:

• Alanine Transaminase (ALT) and Aspartate Transiminase (AST) ≤ 5 × ULN

• Total bilirubin ≤ 1.5 x ULN with the exception of patients with Gilbert syndrome who may be included if their total bilirubin is ≤3.0 × ULN and direct bilirubin ≤1.5 × ULN

∙ Hematologic Function (regardless of transfusions) defined as:

• Absolute neutrophil count (ANC) \>1000/mm3

• Absolute lymphocyte count (ALC) \>300/mm3 OR Absolute number of CD3+ T cells \>150/mm3 (only for patients with non-historical apheresis)

• Platelets ≥50000/mm3

• Hemoglobin \>8.0 g/dl

∙ Adequate pulmonary function defined as:

• No or mild dyspnea (≤ Grade 1)

• Oxygen saturation measured by pulse oximetry \> 90% on room air

• Forced expiratory volume in 1 s (FEV1) ≥ 50% and/or carbon monoxide diffusion test (DLCO) ≥50% of predicted level - Must have a leukapheresis material of non-mobilized cells available for manufacturing.