Please select the eligibility criteria that correspond to the clinical trial below.
Title: Randomized Intergroup Trial of First Line Treatment for Patients With Diffuse Large B-Cell Non-Hodgkin's Lymphoma With a CHOP-Like Chemotherapy Regimen With or Without the Anti-CD20 Antibody Rituximab
Brief Summary: RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. It is not yet known whether combination chemotherapy is more effective with or without rituximab in treating patients with non-Hodgkin's lymphoma.

PURPOSE: This randomized phase III trial is studying four different combination chemotherapy regimens and rituximab to see how well they work compared to four different combination chemotherapy regimens alone in treating patients with non-Hodgkin's lymphoma.


Options:
A: Inclusion Criteria:

1. Age ≥18 years
2. Relapsed or refractory B-cell NHL, including

   1. DLBCL cohort (no longer enrolling): DLBCL, not otherwise specified (NOS; includes transformed DLBCL from indolent histology \[tDLBCL\]), high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (Swerdlow 2016), primary mediastinal B-cell lymphoma (PMBCL), and follicular lymphoma Grade 3B. Subjects must have been treated with an anthracycline and rituximab (or other CD20-targeted agent) and have relapsed or refractory disease after at least 2 lines of systemic therapy or after auto-HSCT.
   2. MCL cohort: MCL (diagnosis must be confirmed with cyclin D1 expression or evidence of t(11;14) by cytogenetics, fluorescent in situ hybridization \[FISH\], or PCR) with relapsed or refractory disease after at least 2 prior lines of systemic MCL therapy. Subjects must have been treated with an alkylating agent, Bruton's tyrosine kinase inhibitor (BTKi), and rituximab (or other CD20-targeted agent).
3. PET-positive disease by Lugano classification
4. Archived tumor biopsy tissue available from the last relapse and corresponding pathology report available or, if at least one tumor-involved site is deemed accessible at time of screening, willing to undergo pre-treatment biopsy (excisional when possible) for disease confirmation. If a subject has never had a complete response, a sample from the most recent biopsy is acceptable.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
6. Adequate bone marrow, renal, hepatic, pulmonary, and cardiac function
7. Adequate vascular access for leukapheresis procedure
8. Participants who have received previous CD19-targeted therapy must have CD19-positive lymphoma confirmed on a biopsy since completing the prior CD19-targeted therapy.
9. Participants must agree to use appropriate contraception.

Exclusion Criteria:

1. Active central nervous system (CNS)-only involvement by malignancy (note: participants with secondary CNS involvement are allowed on study)
2. History of other primary malignancy not in remission for at least 2 years (The following are exempt from the 2-year limit: nonmelanoma skin cancer, definitively treated stage 1 solid tumor with low risk for recurrence, curatively treated localized prostate cancer, and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Pap smear)
3. Treatment with alemtuzumab within 6 months of leukapheresis or fludarabine or cladribine within 3 months of leukapheresis
4. Active hepatitis B, hepatitis C, or Subjects with a history of or active human immunodeficiency virus (HIV) infectionare excluded. Subjects with active hepatitis B, or active hepatitis C are also excluded. Subjects with a negative PCR assay for viral load for hepatitis B or C are permitted. Subjects positive for hepatitis B surface antigen and/or anti-hepatitis B core antibody with negative viral load are eligible and should be considered for prophylactic antiviral therapy
5. Uncontrolled systemic fungal, bacterial, viral, or other infection
6. Presence of graft-vs-host disease (GVHD)
7. History of cardiovascular disease
8. History or presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis
9. Pregnant or nursing women
10. Use of the following:

    * Therapeutic doses of corticosteroids (defined as \>20 mg/day prednisone or equivalent) within 7 days of leukapheresis or 72 hours prior to JCAR017 administration. Physiologic replacement, topical, and inhaled steroids are permitted.
    * Low dose chemotherapy (e.g., vincristine, rituximab, cyclophosphamide ≤300 mg/m2) given after leukapheresis to maintain disease control must be stopped ≥7 days prior to lymphodepleting chemotherapy.
    * Cytotoxic chemotherapeutic agents that are not considered lymphotoxic (see below) within 1 week of leukapheresis. Oral chemotherapeutic agents, including lenalidomide and ibrutinib, are allowed if at least 3 half-lives have elapsed prior to leukapheresis.
    * Lymphotoxic chemotherapeutic agents (e.g., cyclophosphamide, ifosfamide, bendamustine) within 2 weeks of leukapheresis.
    * Experimental agents within 4 weeks of leukapheresis unless no response or disease progression is documented on the experimental therapy and at least 3 half-lives have elapsed prior to leukapheresis
    * Immunosuppressive therapies within 4 weeks of leukapheresis and JCAR017 administration (e.g., calcineurin inhibitors, methotrexate or other chemotherapeutics, mycophenolyate, rapamycin, thalidomide, immunosuppressive antibodies such as anti-TNF, anti IL6, or anti-IL6R)
    * Donor lymphocyte infusions (DLI) within 6 weeks of JCAR017 administration
    * Radiation within 6 weeks of leukapheresis. Subjects must have progressive disease in irradiated lesions or have additional non-irradiated, PET-positive lesions to be eligible. Radiation to a single lesion, if additional non-irradiated PET-positive lesions are present, is allowed up to 2 weeks prior to leukapheresis.
    * Allo-HSCT within 90 days of leukapheresis
11. Prior CAR T-cell or other genetically-modified T-cell therapy, with the exception of prior JCAR017 treatment in this protocol for subjects receiving retreatment
12. Progressive vascular tumor invasion, thrombosis, or embolism
13. Venous thrombosis or embolism not managed on a stable regimen of anticoagulation
B: DISEASE CHARACTERISTICS:

* Histologically confirmed diffuse large B-cell non-Hodgkin's lymphoma according to REAL classification

  * Diagnosed within the past 6 weeks
  * CD20+ disease
  * Ann Arbor stage II, III, or IV disease or stage I bulky disease
* International Prognostic Index (IPI) score of 0 or 1

  * Score 0 defined by all of the following:

    * Stage I or II disease
    * ECOG performance status of 0 or 1
    * Lactic dehydrogenase (LDH) no greater than upper limit of normal (ULN)
  * Score 1 defined by 1 of the following:

    * Stage I or II disease; ECOG performance status of 0 or 1; and LDH greater than ULN
    * Stage I or II disease; ECOG performance status 2 or 3; and LDH no greater than ULN
    * Stage III or IV disease; ECOG performance status 0 or 1; and LDH no greater than ULN
* Previously untreated disease
* Mediastinal B-cell lymphoma allowed
* No secondary lymphoma after prior chemotherapy or radiotherapy for other malignancies
* No transformed lymphoma
* No primary CNS lymphoma
* No primary gastrointestinal (MALT) lymphoma
* No post-transplant lymphoproliferative disorder

PATIENT CHARACTERISTICS:

Age

* 18 to 60

Performance status

* See Disease Characteristics
* ECOG 0-3

Life expectancy

* At least 3 months

Hematopoietic

* Not specified

Hepatic

* Bilirubin no greater than 2.0 mg/dL\*
* Transaminases no greater than 3 times normal\*
* No active chronic hepatitis B or C infection NOTE: \*Unless related to lymphoma

Renal

* Creatinine no greater than 2 times normal\* NOTE: \*Unless related to lymphoma

Cardiovascular

* No myocardial infarction within the past 6 months
* No uncompensated heart failure
* No dilatative cardiomyopathy
* No coronary heart disease with ST segment depression on ECG
* No severe uncompensated hypertension

Pulmonary

* No chronic lung disease with hypoxemia

Other

* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* HIV negative
* No known allergic reactions against foreign proteins
* No other prior malignancy except basal cell skin cancer or carcinoma in situ of the cervix
* No concurrent disease that would preclude study treatment
* No active infections requiring systemic antibiotics or antiviral medications
* No severe uncompensated diabetes mellitus
* No clinical signs of cerebral dysfunction
* No severe psychiatric disease

PRIOR CONCURRENT THERAPY:

Biologic therapy

* No prior murine antibodies

Chemotherapy

* No other concurrent anticancer chemotherapy

Endocrine therapy

* Not specified

Radiotherapy

* No concurrent response-adapted (slow response or unconfirmed complete response) radiotherapy

Surgery

* Not specified

Other

* No prior lymphoma-specific treatment
* More than 12 weeks since prior participation in another clinical trial
* No prior participation in this study
* No other concurrent study medication
C: 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
D: Inclusion Criteria:

* Age ≥18 years, male and female,
* Confirmed as CD19-positive B cell lymphoma/leukemia by immunohistochemistry or flow cytometry
* No effective treatment
* Patients must have a measurable or evaluable disease at the time of enrollment.
* Adequate organ system function including:

  * ALT/AST \< 3 upper limit of normal; Total Bilirubin \< 2.5 upper limit of normal
  * Creatinine \< 2 upper limit of normal
  * Oxygen saturation ≥ 95%
  * Left ventricular ejection fraction ≥ 40%
  * Number of neutrophil ≥ 0.75×10\^9/L, number of platelet ≥ 50×10\^9/L
* 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. All patients must agree to take effective contraceptive measures during the trial measures
* ECOG score 0-2, expected survival ≥ 12 weeks

Exclusion Criteria:

* Women who are pregnant or lactating. Patients have breeding intent in 12 months or cannot take effective contraceptive measures during the trial measures
* Uncontrollable active infection within four week. Prophylactic antibiotic, antiviral and antifungal treatment is permissible. Active hepatitis B or hepatitis C virus infection, as well as acquired, congenital immune deficiency diseases, including but not limited to HIV-infected persons
* Subjects with any autoimmune disease or any immune deficiency disease
* Have a history of allergy to antibodies or cellular products
* Participated in any other clinical trial within four weeks
* Used of systemic steroids within four weeks (using inhaled steroids or ≤ 20mg/d prednison are exceptions)
* Have mental diseases
* Have history of drug addiction
* The investigators believe that any increase in the risk of the subject or interference with the results of the trial

Answer: B