Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 3, Randomized, Open-Label Study Evaluating the Efficacy of Axicabtagene Ciloleucel Versus Standard of Care Therapy in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma (ZUMA-7)
Brief Summary: The goal of this clinical study is to assess whether axicabtagene ciloleucel therapy improves the clinical outcome compared with standard of care second-line therapy in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).


Options:
A: Inclusion Criteria:

* Adult patients are eligible (\> or = to 18 year old).
* Patients must have B- ALL refractory, relapsed, MRD, or in first CR as described below.
* Complete remission is defined as restoration of normal hematopoiesis with a neutrophil count \> 1,000 x 106/L, a platelet count \> 100,000 x 106/L, and hemoglobin \> 10 g/dL. Blasts should be \< 5% in a post-treatment bone marrow differential. Furthermore, there should be no clinical evidence of leukemia for a minimum of four weeks.
* MRD is defined as patients meeting the criteria for CR above, but with residual disease measured by a quantitative PCR, or by flow or by deep-sequencing of the IgH rearrangements . The assay from blood and/or bone marrow defines MRD by qPCR as a cycle threshold (CT) that is at least 1 CT value \< than the lowest CT value from the background. Outside laboratory tests may suffice for this assessment at the discretion of the Principal Investigator.

Relapsed B-ALL will be defined as patients that meet the above criteria for a CR before developing recurrent disease (increased bone marrow blasts). Refractory patients will be defined as patients that have not achieved a CR after 1 cycle of induction chemotherapy

* Patients must have a diagnosis of B-ALL by flow cytometry, or bone marrow histology, and/or cytogenetics.
* Patients must have CD19+ ALL as confirmed by flow cytometry and/or immunohistochemistry.
* Creatinine \< 2.0 mg/100 ml, bilirubin \< 2.0 mg/100 ml, AST and ALT \< 3x normal, PT and PTT \< 2x normal outside the setting of stable chronic anticoagulation therapy. LFTs (Bilirubin, AST, and/or ALT) may be acceptable if the elevation is secondary to leukemia infiltration or leukemia therapy with tyrosine kinase inhibitors.
* Adequate cardiac function (LVEF ≥ 40%) as assessed by ECHO or MUGA or other similar cardiac imaging performed within 1 month of enrollment.
* Adequate pulmonary function as assessed by ≥ 92% oxygen saturation on room air by pulse oximetry.
* Patients must have adequate access for leukapheresis procedure as assessed by staff from the MSKCC Donor Room.
* Life expectancy \> 3 months

Exclusion Criteria:

* Karnofsky performance status \< 70.
* Active central nervous system (CNS) leukemia, as defined by unequivocal morphologic evidence of lymphoblasts in the cerebrospinal fluid (CSF) or symptomatic CNS leukemia (i.e. cranial nerve palsies or other significant neurologic dysfunction) within 28 days of enrollment. Prophylactic intrathecal medication is not a reason for exclusion.
* Patients previously treated with an allogeneic SCT that is currently complicated by active GVHD requiring T cell suppressive therapy.

Patients with following cardiac conditions will be excluded:

* New York Heart Association (NYHA) stage III or IV congestive heart failure
* Myocardial infarction ≤6 months prior to enrollment
* History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration
* History of severe non-ischemic cardiomyopathy with EF ≤20%

  * Patients with HIV, hepatitis B or hepatitis C infection.
  * Patients with any concurrent active malignancies as defined by malignancies requiring any therapy other than expectant observation.
B: Inclusion Criteria:

* City of Hope (COH) pathology review confirms that research participant's diagnostic material is consistent with history of intermediate grade B-cell NHL (e.g., diffuse B-cell lymphoma, mantle cell lymphoma, transformed follicular lymphoma)
* History of relapse after achieving first remission with primary therapy, or failure to achieve remission with primary therapy
* Life expectancy \> 16 weeks
* Karnofsky performance scale (KPS) \>= 70%
* Negative serum pregnancy test for women of childbearing potential
* Research participant has an indication to be considered for autologous stem cell transplantation

Exclusion Criteria:

* Fails to understand the basic elements of the protocol and/or the risks/benefits of participating in this phase I/II study; evidence of understanding includes passing the Protocol Comprehensive Screening given by the Research Subject Advocate (RSA); a legal guardian may substitute for the research participant
* Any standard contraindications to myeloablative HSCT per standard of care practices at COH
* Dependence on corticosteroids
* Currently enrolled in another investigational therapy protocol
* Human immunodeficiency virus (HIV) seropositive based on testing performed within 4 weeks of enrollment
* History of allogeneic HSCT or prior autologous HSCT
* Active autoimmune disease requiring systemic immunosuppressive therapy
* Research participant(s) who are to receive radioimmunotherapy (Zevalin-based)-based conditioning regimens
* Research participant(s) with known active hepatitis B or C infection
C: Inclusion Criteria:

1. Signed informed consent must be obtained prior to participation in the study
2. Patients must be ≥18 years of age at the time of ICF signature
3. Histologically confirmed DLBCL at last relapse (including DLBCL transformed from follicular lymphoma and double-triple hit lymphoma)
4. Relapsed or refractory disease after at least 2 lines of systemic therapy, including anti-CD20 antibody and an anthracycline, or having failed or being ineligible for autologous HSCT
5. ECOG performance status that is either 0 or 1 at screening
6. Measurable disease at time of enrollment:

   * Nodal lesions greater than 15 mm in the long axis, regardless of the length of the short axis or
   * Extra nodal lesion (outside lymph node or nodal mass, but including liver and spleen) at least 10 mm in long and short axis
7. Adequate organ function
8. Must have a leukapheresis material of non-mobilized cells available for manufacturing

Exclusion Criteria:

1. Prior treatment with anti-CD19 therapy, adoptive T cell therapy, or any prior gene therapy product
2. Primary mediastinal large B-cell lymphoma, EBV+ DLBCL, Richter's transformation, Burkitt lymphoma, primary DLBCL of CNS, T cell / histiocyte rich large B-cell lymphoma, primary cutaneous DLBCL.
3. Eligible for and consenting to autologous HSCT
4. Prior allogeneic SCT
5. Active CNS involvement by disease under study, except if the CNS involvement has been effectively treated (i.e. patient is asymptomatic) and local treatment was greater than 4 weeks before enrollment
6. Active neurological autoimmune or inflammatory disorders (e.g. Guillain-Barre syndrome)
7. Investigational medicinal product within the last 30 days or five half-lives (whichever is longer) prior to screening
D: Key Inclusion Criteria:

* Histologically proven large B-cell lymphoma including the following types defined by World Health Organization (WHO) 2016.

  * Diffuse large B-cell lymphoma (DLBCL) not otherwise specified activated B-cell/ germinal center B-cell (ABC/GCB).
  * High-grade B-cell lymphoma (HGBL) with or without myelocytomatosis oncogene (MYC) and B-cell lymphoma (BCL) 2 and/or BCL6 rearrangement.
  * DLBCL arising from follicular lymphoma (FL).
  * T-cell/histiocyte rich large B-cell lymphoma.
  * DLBCL associated with chronic inflammation.
  * Primary cutaneous DLBCL, leg type.
  * Epstein-Barr virus (EBV) + DLBCL.
* Relapsed or refractory disease after first-line chemoimmunotherapy.

  * Refractory disease defined as no complete remission to first-line therapy; individuals who are intolerant to first-line therapy are excluded.

    * Progressive disease (PD) as best response to first-line therapy.
    * Stable disease (SD) as best response after at least 4 cycles of first-line therapy (eg, 4 cycles of R-CHOP).
    * Partial response (PR) as best response after at least 6 cycles and biopsy-proven residual disease or disease progression ≤ 12 months of therapy.
  * Relapsed disease defined as complete remission to first-line therapy followed by biopsy-proven relapse ≤ 12 months of first-line therapy.
* Individuals must have received adequate first-line therapy including at a minimum:

  * Anti-Cluster of Differentiation antigen (CD) 20 monoclonal antibody unless investigator determines that tumor is CD20 negative, and
  * An anthracycline containing chemotherapy regimen.
* No known history or suspicion of central nervous system involvement by lymphoma.
* Eastern cooperative oncology group (ECOG) performance status of 0 or 1.
* Adequate bone marrow function as evidenced by:

  * Absolute neutrophil count (ANC) ≥ 1000/uL
  * Platelet ≥ 75,000/uL
  * Absolute lymphocyte count ≥ 100/uL
* Adequate renal, hepatic, cardiac, and pulmonary function as evidenced by:

  * Creatinine clearance (Cockcroft Gault) ≥ 60 mL/min.
  * Serum Alanine aminotransferase/Aspartate aminotransferase (ALT/AST) ≤ 2.5 Upper limit of normal (ULN).
  * Total bilirubin ≤ 1.5 mg/dl
  * Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as determined by an Echocardiogram (ECHO), and no clinically significant Electrocardiogram (ECG) findings.
  * No clinically significant pleural effusion.
  * Baseline oxygen saturation \> 92% on room air.

Key Exclusion Criteria:

* History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (eg cervix, bladder, breast) unless disease free for at least 3 years.
* Received more than one line of therapy for DLBCL.
* History of autologous or allogeneic stem cell transplant.
* Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous antimicrobials for management.
* Known history of infection with human immunodeficiency virus (HIV) or hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive). If there is a positive history of treated hepatitis B or hepatitis C, the viral load must be undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing.
* Individuals with detectable cerebrospinal fluid malignant cells or known brain metastases, or with a history of cerebrospinal fluid malignant cells or brain metastases.
* History or presence of non-malignant central nervous system (CNS) disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.
* Presence of any indwelling line or drain. Dedicated central venous access catheter such as a Port-a-Cath or Hickman catheter are permitted.
* History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, New York Heart Association Class II or greater congestive heart failure, or other clinically significant cardiac diseases within 12 months of enrollment.
* History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of enrollment.
* History of autoimmune disease, requiring systemic immunosuppression and/or systemic disease modifying agents within the last 2 years.
* History of anti-CD19 or CAR-T therapy or history of prior randomization in ZUMA-7.

Note: Other protocol defined Inclusion/Exclusion criteria may apply

Answer: D