Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 1/2 Multicenter Study Evaluating the Safety and Efficacy of KTE-C19 in Adults With Refractory Aggressive Non-Hodgkin Lymphoma
Brief Summary: This study will be separated into 3 distinct phases designated as the Phase 1 study, Phase 2 pivotal study (Cohort 1 and Cohort 2), and Phase 2 safety management study (Cohort 3 and Cohort 4, Cohort 5 and Cohort 6).

The primary objectives of this study are:

* Phase 1 Study: Evaluate the safety of axicabtagene ciloleucel regimens
* Phase 2 Pivotal Study; Evaluate the efficacy of axicabtagene ciloleucel
* Phase 2 Safety Management Study: Assess the impact of prophylactic regimens or earlier interventions on the rate and severity of cytokine release syndrome (CRS) and neurologic toxicities

Subjects who received an infusion of KTE-C19 will complete the remainder of the 15 year follow-up assessments in a separate long-term follow-up study, KT-US-982-5968.


Options:
A: 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
B: 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))
C: Inclusion Criteria:

* Research participants enrolled are patients with an indication to be considered for HSCT, who are diagnosed with intermediate grade B-cell NHL (e.g., DLBCL, MCL or transformed NHL), and that have either recurrence/progression following prior therapy, or verification of high-risk disease in first remission
* Karnofsky performance status of \>= 70% and a life expectancy \>= 16 weeks at time of enrollment
* Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately
* City of Hope (COH) pathology review confirms that research participant's diagnostic material is consistent with the history of intermediate grade B-cell NHL (e.g., DLBCL, MCL or transformed NHL)
* Negative serum pregnancy test for women of childbearing potential
* Research participant has an indication to be considered for autologous stem cell transplantation
* All patients must have the ability to understand and the willingness to sign a written informed consent

ELIGIBILITY TO UNDERGO AUTOLOGOUS MYELOABLATIVE TRANSPLANTATION WITH HEMATOPOETIC PROGENITOR CELL (HPC)A RESCUE

* Research participant meets all standard clinical parameters for candidates of autologous transplant as described in the current COH Hematopoietic Cell Transplant Standard Operating Policies, Procedures and Protocols
* Patient Evaluation \& Selection or Deferral for hematopoietic cell transplantation (HCT)
* Research participant is scheduled to receive a standard chemotherapy-based conditioning regimen, such as cyclophosphamide, carmustine, etoposide (CBV) or carmustine, etoposide, cytarabine, melphalan (BEAM)
* Research participant has a cryopreserved unselected HPCA product of at least 3 x 10\^6/kg CD34+ cells
* Research participant does not have evidence of disease progression after salvage therapy

ELIGIBILITY CRITERIA AT TIME OF INFUSION OF GENETICALLY MODIFIED AUTOLOGOUS T CELLS

* Research participant has a released cryopreserved T cell product
* Research participant has undergone an autologous HPC(A) procedure
* Not requiring supplemental oxygen or mechanical ventilation, oxygen saturation of 90% or higher on room air
* Not requiring pressor support, not having symptomatic cardiac arrhythmias
* Lack of acute renal failure/requirement for dialysis, as evidenced by creatinine \< 1.6 - Total bilirubin =\< 5.0
* Research participant without clinically significant encephalopathy/new focal deficits
* No clinical evidence of uncontrolled active infections process

Exclusion Criteria:

* Research participants with any uncontrolled illness including ongoing or active infection; research participants with known active hepatitis B or C infection; research participants who are human immunodeficiency virus (HIV) seropositive based on testing performed within 4 weeks of enrollment; research participants with any signs of symptoms of active infection, positive blood cultures or radiological evidence of infections
* Research participants receiving any other investigational agents, or concurrent biological, chemotherapy or radiation therapy
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to cetuximab
* Research participants with known brain metastases (central nervous system \[CNS\] involvement or parenchymal or leptomeningeal involvement)
* Research participants with presence of other malignancy or history of prior malignancy within 5 years of study entry; although patients treated with curative intent within 5 year are eligible; this exclusion rule does not apply to non-melanoma skin tumors and in-situ cervical cancer
* Failure of research participant to understand the basic elements of the protocol and/or the risks/benefits of participating in this phase I/II study; a legal guardian may substitute for the research participant
* History of allogeneic HSCT or prior autologous HSCT
* Any standard contraindications to myeloablative HSCT per standard of care practices at COH
* Dependence on corticosteroids
* Active autoimmune disease requiring systemic immunosuppressive therapy
* Research participants will be excluded, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study
D: Key Inclusion Criteria

1. Histologically confirmed:

   * Diffuse Large B Cell Lymphoma (DLBCL)
   * Primary Mediastinal Large B Cell Lymphoma (PMBCL)
   * Transformation Follicular Lymphoma (TFL)
   * High grade B-cell lymphoma (HGBCL)
2. Chemotherapy-refractory disease, defined as one of more of the following:

   * No response to last line of therapy i. Progressive disease (PD) as best response to most recent therapy regimen ii. Stable disease (SD) as best response to most recent therapy with duration no longer than 6 month from last dose of therapy OR
   * Refractory post-autologous stem cell transplant (ASCT) i. Disease progression or relapsed less than or equal to 12 months of ASCT (must have biopsy proven recurrence in relapsed individuals) ii. If salvage therapy is given post-ASCT, the individual must have had no response to or relapsed after the last line of therapy
3. Individuals must have received adequate prior therapy including at a minimum:

   * Anti-cluster of differentiate 20 (CD20) monoclonal antibody unless investigator determines that tumor is CD20-negative and
   * an anthracycline containing chemotherapy regimen
   * for individual with transformed FL must have chemorefractory disease after transformation to DLBCL.
4. At least one measurable lesion per revised international working group (IWG Response Criteria
5. Eastern cooperative oncology group (ECOG) performance status of 0 or 1
6. Absolute neutrophil count (ANC) ≥ 1000/microliters (uL)
7. Absolute lymphocyte count ≥ 100/uL
8. Platelet count ≥ 75,000/uL
9. Adequate renal, hepatic, pulmonary and cardiac function defined as:

   * Creatinine clearance (as estimated by Cockcroft Gault) \> 60 mL/min
   * Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) \< 2.5 upper limit of normal (ULN)
   * Total bilirubin \< 1.5 mg/dL, except in individuals with Gilbert's syndrome
   * Cardiac ejection fraction \>50%, no evidence of pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant pleural effusion
   * Baseline oxygen saturation \>92% on room air
10. All individuals or legally appointed representatives/caregivers, must personally sign and date the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved consent form before initiating any study specific procedures or activities.
11. Relapsed or refractory large B-cell lymphoma including DLBCL, PMBCL, TFL, and HGBCL after two systemic lines of therapy

Key Exclusion Criteria

1. History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years
2. History of allogeneic stem cell transplantation
3. Prior chimeric antigen receptor (CAR) therapy or other genetically modified T cell therapy
4. Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management. Simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment
5. History of human immunodeficiency virus (HIV) infection or acute or chronic active hepatitis B or C infection. Individuals with history of hepatitis infection must have cleared their infection as determined by standard serological and genetic testing per current Infectious Diseases Society of America (IDSA) guidelines
6. Individuals with detectable cerebrospinal fluid malignant cells, or brain metastases, or with a history of central nervous system (CNS) lymphoma or primary CNS lymphoma, cerebrospinal fluid malignant cells or brain metastases
7. History or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement

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

Answer: D