Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase II, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Adult Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL)
Brief Summary: This is a multi-center, phase II study to determine the efficacy and safety of CTL019 in adult patients with relapsed or refractory DLBCL.


Options:
A: Inclusion Criteria:

* Histologically diagnosed as DLBCL according to the NCCN non-Hodgkin's lymphoma Clinical Practice Guidelines (3rd edition 2016)
* Refractory DLBCL
* All subjects must have received adequate prior therapy including anti-CD20 monoclonal antibody (unless tumor is CD20-negative) and an anthracycline containing chemotherapy regimen. The standardized treatment regimens reference to NCCN non-Hodgkin lymphoma Clinical Practice Guidelines (2016 Version 3)
* At least one measurable lesion per revised IWG Response Criteria (the longest diameter of the tumor ≥ 1.5 cm)
* Age 18-70 years old, male or female
* Expected survival ≥ 12 weeks
* ECOG score 0-1
* Subject's left ventricular ejection fraction (LVEF) is ≥ 50% and no evidence of pericardial effusion as determined by an ECHO
* At least 4 weeks from receiving previous treatment (radiotherapy, chemotherapy, monoclonal antibody therapy or other treatments)
* No contraindications of peripheral blood apheresis
* Female subjects in childbearing age, their serum or urine pregnancy test must be negative, and must agree to take effective contraceptive measures during the trial measures
* Volunteered to participate in this study and signed informed consent

Exclusion Criteria:

* Have a history of allergy to cellular products
* Used any genetically modified T cell therapy
* History of allogeneic hematopoietic stem cell transplantation
* Severe active infection (uncomplicated urinary tract infections, bacterial pharyngitis allowed) or currently receiving intravenous antibiotic therapy and received intravenous antibiotic therapy within one week. Prophylactic antibiotic, antiviral and antifungal treatment is permissible
* Hepatitis B or hepatitis C virus infection (including carriers), as well as acquired, congenital immune deficiency diseases, including but not limited to HIV-infected persons
* Patients with class III and IV heart failure according to the NYHA Heart Failure Classifications
* A history of QT prolongation
* A history of epilepsy or other central nervous system disorders
* The patient had a history of other primary cancers, with the following exceptions: Excisional non-melanoma such as cutaneous basal cell carcinoma; Cured in situ carcinoma such as cervical cancer, bladder cancer or breast cancer
* Subjects with any autoimmune disease or any immune deficiency disease or other disease in need of immunosuppressive therapy
* Used of systemic steroids within two weeks (using inhaled steroids is an exception)
* Women who are pregnant or lactating or have breeding intent in 6 months
* Participated in any other clinical trial within three months
* The investigators believe that any increase in the risk of the subject or interference with the results of the trial
B: Inclusion Criteria:

* Written informed consent must be obtained prior to any screening procedures
* Histologically confirmed DLBCL at last relapse(by central pathology review before enrolment.

  .- Relapsed or refractory disease after ≥2 lines of chemotherapy including rituximab and anthracycline and either having failed autologous Hematopoietic stem cell transplantation (ASCT), or being ineligible for or not consenting to ASCT
* Measurable disease at time of enrollment
* Life expectancy ≥12 weeks
* Eastern Cooperative Oncology Group (ECOG) performance status that is either 0 or 1 at screening
* Adequate organ function:

  * Renal function defined as:

    * A serum creatinine of ≤1.5 x Upper Limit of Normal ULN OR
    * Estimated Glomerular Filtration Rate (eGFR) ≥ 60 mL/min/1.73 m\^2
  * Liver function defined as:

    * Alanine Aminotransferase (ALT) ≤ 5 times the Upper Limit of Normal (ULN) for age
    * Bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert-Meulengracht syndrome; patients with Gilbert-Meulengracht syndrome may be included if their total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN
  * Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygenation \> 91% on room air
  * Hemodynamically stable and Left Ventricle Ejection Fraction (LVEF) ≥ 45% confirmed by echocardiogram or Multigated Radionuclide Angiography (MUGA)
  * Adequate bone marrow reserve without transfusions defined as:

    * Absolute neutrophil count (ANC) \> 1.000/mm\^3
    * Absolute lymphocyte count (ALC) ≥ 300/mm\^3 and absolute number of CD3+ T cells \> 150/mm\^3
    * Platelets ≥ 50.000//mm\^3
    * Hemoglobin \> 8.0 g/dl
  * Must have an apheresis product of non-mobilized cells accepted for manufacturing
  * Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and all male participants must agree to use highly effective methods of contraception for at least 12 months following CTL019 infusion and until CAR T cells are no longer present by PCR on two consecutive tests

Exclusion Criteria:

* Prior treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy
* Treatment with any prior gene therapy product
* Active Central Nervous System (CNS) involvement by malignancy
* Prior allogeneic HSCT
* Eligible for and consenting to HSCT
* Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of infusion
* Investigational medicinal product within the last 30 days prior to screening
* The following medications are excluded:

  * Steroids: Therapeutic doses of steroids must be stopped \>72 hours prior to leukapheresis and \>72 hours prior to CTL019 infusion. However, the following physiological replacement doses of steroids are allowed: \< 12 mg/m\^2/day hydrocortisone or equivalent
  * Immunosuppression: Any other immunosuppressive medication must be stopped ≥2 weeks prior to leukapheresis and ≥ 2 weeks prior to CTL019 infusion. This could include check point inhibitors (monoclonal antibodies and small molecule modulators)
  * Antiproliferative therapies other than lymphodepleting chemotherapy within two weeks of leukapheresis and 2 weeks prior to infusion
* Short acting drugs used to treat leukemia or lymphoma (e.g. tyrosine kinase inhibitors, and hydroxyurea) must be stopped \> 72 hour prior to leukapheresis and \> 72 hours prior to CTL019 infusion
* Other cytotoxic drugs, including low dose daily or weekly maintenance chemotherapy, must not be given within 2 weeks prior to leukapheresis and within 2 weeks prior to CTL019 infusion
* Fludarabine may be associated with prolonged lymphopenia. This should be taken into consideration when evaluating the optimal timing for leukapheresis collection.

  * Antibody use including anti-CD20 therapy within 4 weeks prior to infusion or 5 half-lives of the respected antibody, whichever is longer
  * CNS disease prophylaxis must be stopped \> 1 week prior to CTL019 infusion (e.g. intrathecal methotrexate)
* Prior radiation therapy within 2 weeks of infusion
* Active replication of or prior infection with hepatitis B or active hepatitis C( HCV RNA positive )
* HIV positive patients
* Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours prior to infusion)
* Unstable angina and/or myocardial infarction within 6 months prior to screening
* Previous or concurrent malignancy with the following exceptions:

  * Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry)
  * In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to the study
  * A primary malignancy which has been completely resected and in complete remission for ≥ 5 years
* Pregnant or nursing (lactating) women. NOTE: female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 24 hours before lymphodepletion
* Intolerance to the excipients of the CTL019 cell product
* Cardiac arrhythmia not controlled with medical management
* Prior treatment with any adoptive T cell therapy
* Patients with T-cell rich/histiocyte rich large B-cell lymphoma (THRBCL), primary cutaneous large B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBCL), EBV positive DLBCL of the elderly, Richter's transformation, and Burkitt lymphoma
* Patients with active neurological auto immune or inflammatory disorders (e.g. Guillain Barre Syndrome, Amyptrophic Lateral Sclerosis)
C: Inclusion Criteria

1. Diagnosis of B-cell non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) / small lymphocytic leukemia (SLL): Patients must be aged≥18 years with relapsed, refractory disease and no available curative options that meet clinical criteria to initiate treatment.
2. Patients with B-cell NHL or CLL/SLL must have either CD19 or CD20 positive disease on most recent biopsy performed (a repeat biopsy is not mandatory for this study except as noted below). A minimum of 5% CD19 or CD20 positivity by immunohistochemistry or flow cytometry on prior or repeat biopsy is required.
3. Absolute CD3+ T cell count ≥50/mm\^3.
4. MRI brain and Lumbar Puncture with cerebral spinal fluid (CSF) analysis by cytology and flow cytometry without evidence of central nervous system (CNS) involvement only in patients with history of CNS involvement.
5. Measurable disease must have been documented within 4 weeks of the time of consent defined as the following by disease specific subtype:

   1. B-cell NHL: Active disease defined as nodal lesions greater than 20 mm in the long axis or extranodal lesions \>10 mm in long and short axis or bone marrow involvement that is biopsy proven.
   2. CLL/SLL: Active disease by either bone marrow, peripheral flow cytometry, or CT and/or positron emission tomography (PET) imaging with nodal disease.
6. Patients should have failed at least two lines of a standard treatment and meet disease specific criteria detailed below:

   1. CLL/SLL: measurable disease as defined above that has relapsed after at least one line of chemo-immunotherapy and progressed or intolerant to ibrutinib monotherapy.
   2. CD19 or CD20 positive B cell NHL limited to the following histologies: Advanced Stage III or IV Follicular Lymphoma, Diffuse Large B cell Lymphoma and associated subtypes (e.g. aggressive B-cell lymphoma, T-cell/histocyte rich B-cell lymphoma, primary mediastinal B-cell lymphoma, Epstein Barr virus positive diffuse large B-cell lymphoma, transformed lymphoma such as transformed follicular or marginal zone lymphoma, and Richter's transformation) and Mantle cell lymphoma. Specific criteria include:

      * Patients must have active, measurable disease after two lines of cytotoxic chemotherapy of which one must be anthracycline containing.
      * Must have received Rituximab or another CD20 antibody and at minimum two chemotherapy regimens appropriate for their disease.
      * Either failed autologous transplant or ineligible to receive autologous transplant
7. Karnofsky performance score ≥70. See Appendix A for scales.
8. Normal Baseline Neurological Evaluation: Mini-Mental Status Exam Score 24-30.
9. Adequate hepatic function, defined as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<5 x upper limit of normal (ULN); serum bilirubin and alkaline phosphatase \<5 x ULN, or considered not clinically significant as per the clinical PIs discretion (e.g. Gilbert's or indirect hyperbilirubinemia) or felt to be due to underlying disease.
10. Adequate renal function, defined as creatinine clearance\>60 ml/min
11. Able to provide written informed consent.
12. Agree to practice birth control during the study.
13. Adequate cardiac function as indicated by New York Heart Association (NYHA) classification I or II AND left ventricular ejection fraction of ≥35% (by echocardiogram or MUGA) and adequate pulmonary function as indicated by room air oxygen saturation of ≥92%.
14. Expected survival \>12 weeks.
15. Negative urine or serum pregnancy test in females of child bearing potential at study entry and again within 48 hours' prior lymphodepleting chemotherapy.
16. Patients with prior blinatumomab treatment require repeat biopsy post-blinatumomab treatment that demonstrates CD19 or CD20 positive disease.
17. Meet criteria for regarding fertility and contraception.
18. Central line access will be required for CAR-20/19-T cell infusion.

Exclusion Criteria

1. Positive beta-human chorionic gonadotropin in females of child-bearing potential.
2. Patients with known systemic allergy to bovine or murine products.
3. Known prior positive serology for human anti-mouse antibody (HAMA).
4. Confirmed active human immunodeficiency virus (HIV), Hepatitis B or C infection.
5. History of significant autoimmune disease OR active, uncontrolled autoimmune phenomenon: such as systemic lupus erythematous, Wegner's glomerulonephritis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura (AIHA, ITP) requiring steroid therapy defined as \>20 mg of prednisone or equivalent daily.
6. Presence of ≥grade 3 non-hematologic toxicities as per CTCAE version 5.0 from any previous treatment unless it is felt to be due to underlying disease.
7. Concurrent use of investigational therapeutic agents or enrollment on another therapeutic clinical trial at any institution. Minimum of ≥4 weeks required from administration of any other investigational agents on other clinical trials prior to enrollment on this CAR-T protocol.
8. Refusal to participate in the long-term follow-up protocol.
9. Patients with active CNS involvement by malignancy on MRI or by lumbar puncture.

   a. Patients with prior CNS disease that has been effectively treated will be eligible providing treatment was \>4 weeks before enrollment and a remission documented within 8 weeks of planned CAR-T cell infusion by MRI brain and CSF analysis.
10. Previous recipients of allogeneic hematopoietic stem cell transplantation (AHCT) are excluded if they are \<100 days' post-transplant, have evidence of active graft-versus-host-disease (GVHD) of any grade, or are currently on immunosuppression.
11. Previous CAR-T cell therapy directed at either CD19 or CD20 within 100 days of planned CAR-20/19-T cell infusion (does not include re-enrollment)

    a. Patients with prior CAR-T treatment against CD19 or CD20 must have repeat biopsy confirming a minimum of 5% CD19 or CD20 positivity by immunohistochemistry or flow cytometry.
12. Anti-CD20 antibody treatment within 4 weeks of cell infusion.
13. Anti-CD19 antibody treatment within 4 weeks of cell infusion.
14. Cytotoxic chemotherapy other than lymphodepletion within 14 days of CAR-T cell infusion.
15. Cytotoxic chemotherapy treatment within 14 days or steroid treatment (other than replacement dose steroids) within 7 days prior to apheresis collection for CAR-T cells.
16. Patients post solid organ transplant who develop high grade lymphomas or leukemias.
17. Concurrent active malignancy other than basal or squamous cell carcinomas of the skin.

Special Criteria for regarding Fertility and Contraception

Female subjects of reproductive potential (women who have reached menarche or women who have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 months, or have not undergone a sterilization procedure \[hysterectomy or bilateral oophorectomy\]) must have a negative serum or urine pregnancy test performed as part of eligibility criteria and again within 48 hours of initiation of lymphodepleting chemotherapy.

Due to the high-risk level of this study, while enrolled, all subjects must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization). Additionally, if participating in sexual activity that could lead to pregnancy, the study subject must agree to use reliable and double barrier methods of contraception during the follow-up period of the protocol.

Acceptable birth control includes a combination of two of the following methods:

* Condoms\* (male or female) with or without a spermicidal agent.
* Diaphragm or cervical cap with spermicide
* Intrauterine device (IUD)
* Hormonal-based contraception Subjects who are not of reproductive potential (women who are premenarche or have been post-menopausal for at least 24 consecutive months or have undergone hysterectomy tubal ligation, salpingectomy, and/or bilateral oophorectomy or men who have documented azoospermia) are eligible without requiring the use of contraception.
D: 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

Answer: B