Please select the eligibility criteria that correspond to the clinical trial below.
Title: Phase I/II Study of Anti-CD19 Chimeric Antigen Receptor-Expressing T Cells in Pediatric Patients Affected by Relapsed/refractory CD19+ Acute Lymphoblastic Leukemia and Non Hodgkin Lymphoma
Brief Summary: The primary objective of this phase I study is to evaluate the safety and to establish the recommended dose of CD19-CART01 infused in pediatric patients affected by relapsed/refractory B-ALL or NHL with measurable Bone Marrow (BM) involvement. The phase II extension is aimed at testing the efficacy of the treatment at the optimal dose defined in the phase I.


Options:
A: Inclusion Criteria:

* Confirmation of relapsed or refractory aggressive B-cell non-Hodgkin lymphoma of the following histology at relapse: diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS; de novo or transformed follicular lymphoma \[tFL\]), high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (double/triple hit lymphoma \[DHL/THL\]), and follicular lymphoma Grade 3B per WHO 2016 classification
* Previous treatment must include treatment with a single line of chemoimmunotherapy containing an anthracycline and a CD20-targeted agent
* Subjects must be deemed ineligible for both high-dose chemotherapy and hematopoietic stem cell transplant (based on age, performance status and/or comorbidities) while also having adequate organ function for CAR T cell treatment.
* Positron emission tomography (PET)-positive disease
* Histological confirmation of diagnosis at last relapse. Enough tumor material must be available for central confirmation of diagnosis, otherwise a new tumor biopsy is mandated.
* ECOG performance status of 0, or 1, or 2
* Adequate vascular access for leukapheresis procedure (either peripheral line or surgically-placed line)
* Subjects must agree to use appropriate contraception
* Subjects must agree to not donate blood, organs, semen, and egg cells for usage in other individuals for at least 1 year following lymphodepleting chemotherapy

Exclusion Criteria:

* Subjects with central nervous system (CNS)-only involvement by malignancy (note: subjects with secondary CNS involvement are allowed on study)
* History of another primary malignancy that has not been in remission for at least 2 years.
* Previous treatment with CD19-targeted therapy, with the exception of prior lisocabtagene maraleucel treatment in this protocol for subjects receiving retreatment
* Active hepatitis B or hepatitis C infection at the time of screening
* History of or active human immunodeficiency virus (HIV) infection at the time of screening
* Uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate antibiotics or other treatment at the time of leukapheresis or lisocabtagene maraleucel administration
* History of any one of the following cardiovascular conditions within the past 6 months: Class III or IV heart failure as defined by the New York Heart Association, cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease
* History or presence of clinically relevant CNS pathology
* Pregnant or nursing women
* Subject does not meet protocol-specified washout periods for prior treatments
* Prior hematopoietic stem cell transplant
* Progressive vascular tumor invasion, thrombosis, or embolism
* Venous thrombosis or embolism not managed on stable regimen of anticoagulation
* Uncontrolled medical, psychological, familial, sociological, or geographical conditions
B: Inclusion Criteria:

1. Male and female subjects with CD19 expressing B-cell acute lymphoblastic leukemia (ALL) or Non-Hodgkin Lymphoma (NHL) with BM involvement and one of the following:

   i. Patients in 2nd or subsequent relapse, after at least one standard frontline chemotherapy and one salvage regimen, with BM involvement ii. Relapse after allogeneic HSCT, if at least 100 days post-transplant, if there is no evidence of active GVHD and if the patient is no longer taking immunosuppressive agents for at least 30 days prior to enrollment iii. MRD \> 0.1% after either reinduction therapy or any course of consolidation for relapsed ALL
2. Measurable or evaluable disease at the time of enrollment, which may include any evidence of disease, including MRD detected by flow cytometry, cytogenetics, or polymerase chain reaction (PCR) analysis.
3. Age: 6 months - 25 years.
4. Voluntary informed consent is given. For subjects \< 18 year-old their legal guardian must give informed consent. Pediatric subjects will be included in age-appropriate discussion and verbal assent will be obtained for those greater than or equal to 12 years of age, when appropriate.
5. Clinical performance status: Patients \> 16 years of age: Karnofsky greater than or equal to 60%; Patients \< 16 years of age: Lansky scale greater than or equal to 60%.
6. Patients of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen.
7. Females of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects on the fetus.

Exclusion Criteria:

1. Pregnant or lactating women
2. Severe, uncontrolled active intercurrent infections
3. HIV, or active HCV and/or HBV infection
4. Life-expectancy \< 6 weeks
5. Hepatic function: Inadequate liver function defined as total bilirubin \> 4x upper limit of normal (ULN) or transaminase (ALT and AST) \> 6 x ULN
6. Renal function: serum creatinine \> 3x ULN for age.
7. Blood oxygen saturation \< 90%.
8. Cardiac function: Left ventricular ejection fraction lower than 45% by ECHO.
9. Congestive heart failure, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the PI would pose an unacceptable risk to the subject.
10. BM blasts \> 50% pre-infusion.
11. Hyperleukocytosis (greater than or equal to 20,000 blasts/microliter) or rapidly progressive disease that in the evaluation of the investigator would compromise ability to complete study therapy
12. Active CNS disease as documented by the presence of blasts in the CSF or by MRI. This criterion could be revised once that, after the phase I portion of the study, absence of life-threatening (i.e. grade IV) neurological toxicity will be documented.
13. Presence of active, grade 2-4 acute or extensive chronic GvHD
14. Recurrent or refractory ALL with testicular involvement
15. Concurrent or recent prior therapies, before infusion:

    i. Systemic steroids (at a dose \> 2 mg/kg prednisone) in the 2 weeks before infusion. Recent or current use of inhaled/topical/non-absorbable steroids is not exclusionary.

    ii. Systemic chemotherapy in the 2 weeks preceding infusion. iii. Anti-thymocyte globulin (ATG) or Alemtuzumab (Campath®) in the 4 weeks preceding infusion.

    iv. Immunosuppressive agents in the 2 weeks preceding infusion. v. Radiation therapy must have been completed at least 3 weeks prior to enrollment.

    vi. Other anti-neoplastic investigational agents currently administered or within 30 days prior to infusion (i.e. start of protocol therapy);

    vii. Exceptions:
    1. There is no time restriction with respect to prior intrathecal chemotherapy, provided that there is complete recovery from any acute toxic effects of such;
    2. Patients who relapse while receiving standard ALL maintenance chemotherapy will not be required to have a waiting period before entry onto this study provided that they meet all other eligibility criteria;
    3. Subjects receiving steroid therapy at physiologic replacement doses only are allowed provided that there has been no increase in dose for at least 2 weeks prior to starting apheresis;
16. Patient-derived CD19-CART01 production failure
C: Inclusion Criteria:

1. Subject is ≥ 18 years of age at the time of signing the informed consent form ().
2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
4. Subject must have aggressive B-cell NHL according to "the 2016 revision of the WHO classification of lymphoid neoplasms", histologically confirmed at last relapse by the treating institution, defined as:

   1. Diffuse large B-cell lymphoma (DLBCL) Not otherwise specified (NOS) including transformed indolent Non-Hodgkin lymphoma (NHL)
   2. Follicular lymphoma Grade 3B
   3. T cell/histiocyte-rich large B-cell lymphoma
   4. Epstein-Barr virus (EBV) positive DLBCL, NOS
   5. Primary mediastinal (thymic) large B-cell lymphoma
   6. High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (double/triple-hit lymphoma)
5. Subjects disease must have relapsed or be refractory to at least 2 prior lines of therapy. Previous therapy must have included a CD20-targeted agent and an anthracycline.
6. Subject must have

   1. Positron emission tomography (PET)-positive (Deauville score 4 or 5) and computed tomography (CT) measurable disease as per Lugano Classification
   2. Sum of product of perpendicular diameters (SPD) of up to 6 index lesions ≥ 25 cm2 by CT scan (not applicable to Arm A or B or subjects with Richter's transformation)
7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 at screening
8. Adequate organ function
9. Subjects must agree to not donate blood, organs, sperm or semen, and egg cells for usage in other individuals
10. Participants must agree to use effective contraception

Exclusion Criteria:

1. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study based on investigator´s judgment.
2. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study based on investigator´s judgment.
3. Subject has any condition that confounds the ability to interpret data from the study based on investigator´s judgment.
4. Subjects with prior history of malignancies, other than aggressive R/R NHL, unless the subject has been free of the disease for ≥ 2 years with the exception of the following non-invasive malignancies:

   1. Basal cell carcinoma of the skin
   2. Squamous cell carcinoma of the skin
   3. Carcinoma in situ of the cervix
   4. Carcinoma in situ of the breast
   5. Incidental histologic finding of prostate cancer (T1a or T1b using the TNM \[tumor, nodes, metastasis\] clinical staging system) or prostate cancer that is curative.
   6. Other completely resected stage 1 solid tumor with low risk for recurrence
5. Prior treatment with any prior gene therap y product
6. Prior treatment with any adoptive T cell therapy; prior hematopoietic stem cell transplant (HSCT) is allowed
7. Allogeneic HSCT within 90 days of leukapheresis
8. Prior treatment with the combination agent from the assigned arm:

   1. Anti PD-1 or PD-L1 (Arm A and E)
   2. CC-122 (Arm B)
   3. CC-220 (Arm C)
   4. Prior treatment with ibrutinib is not exclusionary for subjects on any study arm
   5. Anti LAG-3 targeted agent (Arm E)
   6. CC-99282 (Arm F)
9. Presence of acute or chronic graft-versus-host disease (GVHD)
10. Presence of the following:

    1. Active hepatitis B or active hepatitis C infection
    2. History of or active human immunodeficiency virus (HIV) infection
11. Uncontrolled bacterial, viral or fungal infection at the time of leukapheresis, lymphodepleting chemotherapy or JCAR017 infusion
12. Any history of myocarditis (Arm E); history of any one of the following cardiovascular conditions within the past 6 months: Class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease (all arms)
13. History or presence of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis
14. Subjects with active CNS or cerebrospinal fluid (CSF) involvement by malignancy
15. Pregnant or nursing (lactating) women.
16. Subjects with active auto immune disorders/processes or active neurological or inflammatory disorders
17. For subjects to receive oral combination therapy (Arms B, C, D or F): History of a gastrointestinal (GI) condition or procedure that in the opinion of the investigator may affect oral drug absorption.
18. Progressive tumor invasion of venous or arterial vessels.
19. Deep venous thrombosis (DVT)/pulmonary embolism (PE) not managed on a stable regimen of anticoagulation.
D: Inclusion Criteria:

Male or female subjects with CD19+ B cell lymphomas who have a limited prognosis (several months to \<2 year survival) with currently available therapies will be enrolled.

1. 18 to 70 Years Old, Male and female;
2. Expected survival \> 12 weeks;
3. Clinical performance status of ECOG score 0-1;
4. Pathology demonstrated that CD19-positive B-cell non-Hodgkin's lymphoma and who meet one of the following conditions:

   1. Relapsed and refractory CD19-positive Diffuse large B-cell lymphoma and Follicular lymphoma: patients previously received at least first-line and second- line treatment and fail to achieve CR;
   2. Disease recurrence after stem cell transplantation, and at least 1 years after stem cell transplantation.
5. It can establish the venous access required for collection, satisfying hemoglobin ≥ 70 g / L, neutrophils ≥ 1.0 × 10 \^ 9 / L, platelets ≥ 50 × 10 \^ 9 / L. Mononuclear cell collection can be determined by the investigators;
6. At least 1 measurable tumor foci according to the 2014 Lugano treatment response criteria;
7. Liver, kidney and cardiopulmonary functions meet the following requirements:

   1. Serum creatinine ≤ 1.5 × ULN;
   2. Left ventricular ejection fraction \>50%, no pericardial effusion and no pleural effusion (ECHO examination);
   3. Baseline oxygen saturation \> 92%;
   4. Total bilirubin ≤ 1.5 × ULN;
   5. ALT and AST ≤ 3 × ULN.
8. Able to understand and sign the Informed Consent Document.

Exclusion Criteria:

1. In the first 5 years before screening, there are malignant tumors other than diffuse large B-cell lymphoma and follicular lymphoma, except for fully treated cervical carcinoma in situ, basal cell or squamous cell skin cancer, local prostate cancer after radical surgery，and catheter carcinoma in situ after radical surgery;
2. Hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive and peripheral blood HBV DNA titer higher than the upper limit of detection; hepatitis C virus (HCV) antibody positive and peripheral blood HCV RNA positive; human immunodeficiency Viral (HIV) antibody positive; Positive syphilis test;
3. Any unstable systemic disease including, but not limited to, active infection (except for local infection), unstable angina pectoris, cerebrovascular accident or transient cerebral ischemia (within 6 months prior to screening), myocardial infarction (within 6 months prior to screening), congestive heart failure (New York Heart Association \[NYHA\] classification ≥ III), severe arrhythmia , liver, kidney or metabolic disease requiring medication;
4. Any other diseases could affect the outcome of this trial;
5. Any affairs could affect the safety of the subjects or outcome of this trial;
6. Pregnant or lactating women, or planned pregnancy during treatment or within 1 year after treatment, or a male subject whose partner plans pregnancy within 1 year of their cell transfusion;
7. Active or uncontrollable infection requiring systemic therapy within 14 days prior to enrollment;
8. Subjects who are receiving systemic steroid treatment and requiring long-term systemic steroid treatment during the treatment as determined by the investigator before screening (except inhalation or topical use); And subjects treated with systemic steroids (except inhalation or topical use) within 72h prior to cell transfusion;
9. Received CAR-T treatment or other gene therapies before enrollment;
10. Patients with symptoms of central nervous system or brain metastasis or have received treatment for central nervous system or brain metastasis (radiotherapy, surgery or other treatment) within 3 months before enrollment;
11. Subject suffering disease affects the understanding of informed consent or comply with study protocol;
12. The investigators consider other conditions unsuitable for enrollment.

Answer: B