Please select the eligibility criteria that correspond to the clinical trial below.
Title: 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)
Brief Summary: This is a randomized, open label, multicenter phase III trial comparing the efficacy, safety, and tolerability of tisagenlecleucel to Standard Of Care in adult patients with aggressive B-cell Non-Hodgkin Lymphoma after failure of rituximab and anthracycline containing frontline immunochemotherapy.


Options:
A: Transplant eligible patients will be eligible if criteria met per below.

Inclusion Criteria:

* Patients ≥ 18 years of age with aggressive B-cell non-Hodgkin lymphoma subtypes including, relapsed or refractory diffused large B-cell lymphoma (DLBCL), and transformed follicular lymphoma meeting at least one of the following criteria:

  * Bone marrow involvement at the time of relapse or refractory disease and not appropriate for allogeneic transplantation.
  * PET positive disease outside of one radiation port unless single-port disease treated with prior radiotherapy within the port, following \> or = to 2 cycles of salvage chemotherapy, still achieving chemosensitive status 1999 IWG criteria (section 12.2 and 12.383).
* Creatinine ≤ 1.5 mg/100 ml (or measured 24 hour creatinine clearance of ≥ 50 cc/min)
* Bilirubin \<2.0 mg/100 ml, AST and ALT \<3x the upper-limit of normal, PT and PTT \< 2x normal outside the setting of stable chronic anticoagulation therapy,
* Adequate cardiac function (LVEF\>40%) as assessed by ECHO or MUGA scan performed within 1 month of treatment.
* Adequate pulmonary function as assessed by DLCO of \> or = to 45% adjusted for hemoglobin.
* Life expectancy of \> 3 months.

Exclusion Criteria:

* Karnofsky performance status ≤ 70 (see appendix VI).
* Patients with other aggressive B-cell malignancies including, but not limited to: Burkitt lymphoma, transformed CLL/SLL and transformed marginal zone lymphoma that are not included in 6.1 inclusion criteria.
* Patients previously treated with autologous or allogeneic bone marrow or stem cell transplantation are ineligible.
* Other past or current malignancy unless in the opinion of the investigator it does not contraindicate participation in the study.
* Uncontrolled bacterial, viral or fungal infection.
* Patients with HIV, active hepatitis B or hepatitis C infection.
B: Inclusion Criteria:

* Relapsed or refractory CD19+ B-cell lymphoma or leukemia.
* Measurable disease.
* Performance status ECOG 0-2.
* \>18 years old.
* Fertile females/males must consent to use contraceptives during participation of the trial.
* Signed informed consent.

Exclusion Criteria:

* Any significant medical or psychiatric illness that would prevent the patient from giving informed consent or from following the study procedures.
* Patients with primary CNS lymphoma.
* Known human immunodeficiency virus (HIV) infection.
* Active and/or severe infection (e.g. tuberculosis, sepsis and opportunistic infections, active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection).
* Other serious underlying medical conditions, which, in the Investigator's judgment, could impair the ability of the patient.
* Treatment with an investigational product within 30 days prior to enrollment, or at least 5 half lives of that drug, which is longest.
* Patients that do not consent to that tissue and blood samples are stored in a biobank.
* Pregnancy
C: Inclusion Criteria:

* 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.

Exclusion Criteria:

* Prior treatment with anti-CD19 therapy, T cell therapy, or any prior gene therapy product
* Treatment with any systemic lymphoma-directed second line anticancer therapy prior to randomization. Only steroids and local irradiation are permitted for disease control
* Patients with active central nervous system (CNS) involvement by disease under study are excluded, except if the CNS involvement has been effectively treated and local treatment was \>4 weeks before randomization
* Prior allogeneic HSCT
* Clinically significant active infection
* Any of the following cardiovascular conditions:

  * Unstable angina, myocardial infarction, coronary artery bypass graft (CABG), or stroke within 6 months prior to screening,
  * Left ventricle ejection fraction (LVEF) \<45% as determined by echocardiogram (ECHO) or magnetic resonance angiography (MRA) or multigated acquisition (MUGA) at the screening assessment.
  * New York Heart Association (NYHA) functional class III or IV (Chavey et al 2001), within the past 12 months.
  * Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II) and third degree AV block unless adequately controlled by pacemaker implantation.
  * Resting QTcF ≥450 msec (male) or ≥460 msec (female) at screening or inability to determine the QTcF interval
  * Risk factors for Torsades de Pointes (TdP), including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/ symptomatic bradycardia, or any of the following:
  * Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome
  * Concomitant medication(s) with a "Known Risk of Torsades de Pointes" per crediblemeds.org that cannot be discontinued or replaced by safe alternative medication.
* Patients with active neurological autoimmune or inflammatory disorders (e.g., Guillain-Barré Syndrome (GBS), Amyotrophic Lateral Sclerosis (ALS)) and clinically significant active cerebrovascular disorders (e.g. cerebral edema, posterior reversible encephalopathy syndrome (PRES))
D: Key Inclusion Criteria:

* Histologically confirmed large B-cell lymphoma
* Chemotherapy-refractory disease, defined as one or more of the following:

  * No response to first-line therapy (primary refractory disease)
  * No response to second or greater lines of therapy OR
  * Refractory after autologous stem cell transplant (ASCT)
* At least 1 measureable lesion according to the Lugano Classification (Cheson 2014).
* Individuals must have received adequate prior therapy, including at a minimum:

  * Anti-CD20 monoclonal antibody
  * An anthracycline-containing chemotherapy regimen
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Adequate renal, hepatic, pulmonary, and cardiac function

Key Exclusion Criteria:

* Known CD19 negative or CD20 negative tumor
* History of Richter's transformation of Chronic Lymphocytic Leukemia (CLL)
* Prior CAR therapy or other genetically modified T-cell therapy
* Prior organ transplantation including prior allogeneic stem cell transplant (SCT)
* Prior CD19 targeted therapy
* Clinically significant infection or cardiopulmonary disease
* Presence of any in-dwelling lines or drains (dedicated central venous access catheters allowed)
* History or presence of central nervous system (CNS) lymphoma or nonmalignant CNS disorder or cerebrospinal fluid (CSF) malignant cells or brain metastases
* History of autoimmune disease
* History of deep vein thrombosis (DVT) or pulmonary embolism (PE) within the last 6 months

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Answer: C