Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 1b Study of JCAR014, Autologous T Cells Engineered to Express a CD19-Specific Chimeric Antigen Receptor, in Combination With Durvalumab (MEDI4736) for Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma
Brief Summary: This phase Ib trial studies whether anti-CD19-chimeric antigen receptor (CAR) lentiviral vector-transduced autologous T cells (JCAR014) and durvalumab are safe in combination and can work together in treating patients with non-Hodgkin lymphoma that has returned after a period of improvement (relapsed) or has not responded to previous treatment (refractory). JCAR014 is made of each patient's immune cells (T cells) that have a new gene added to them in a laboratory, which programs them to kill lymphoma cells. Durvalumab is a type of drug called a monoclonal antibody, targeted to PD-L1 that may help immune cells attack cancer cells more effectively and thus help JCAR014 work better.


Options:
A: Inclusion Criteria:

INCLUSION CRITERIA FOR SCREENING:

* Relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS); high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements; primary mediastinal B-cell lymphoma (PMBCL); or DLBCL transformed from indolent histology with one of the following:

  * Persistent disease after first-line chemo-immunotherapy
  * Relapse after first-line chemo-immunotherapy and not eligible for autologous hematopoietic stem cell transplant (HCT)
  * Relapse or persistent disease after at least two lines of therapy or after autologous HCT
* Ability to understand and provide informed consent

INCLUSION CRITERIA FOR LEUKAPHERESIS AND PRE-THERAPY EVALUATION:

* Screening evaluation appropriate for leukapheresis and T-cell collection
* Evidence of CD19 expression on any prior or current tumor specimen or a high likelihood of CD19 expression based on disease histology

INCLUSION CRITERIA FOR LYMPHODEPLETION CHEMOTHERAPY, JCAR014 AND DURVALUMAB:

* Successful collection of T cells for JCAR014 manufacturing
* Documentation of CD19 expression on any prior or current tumor biopsy
* Internal review of histology
* Detectable positron emission tomography (PET)-positive disease
* Karnofsky performance status \>= 60%
* Assessed by the investigator to have adequate bone marrow function to receive lymphodepleting conditioning chemotherapy
* Serum creatinine \< 1.5 x age-adjusted upper limit of normal (ULN)
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 3 x ULN and total bilirubin =\< 2 x ULN
* Adequate pulmonary function, defined as Common Terminology Criteria for Adverse Events (CTCAE) grade =\< 1 dyspnea and oxygen saturation (SaO2) \>= 92% on room air; patients with clinically significant pulmonary dysfunction, as determined by medical history and physical exam should undergo pulmonary function testing and must have a forced expiratory volume in 1 second (FEV1) \>= 50% of predicted value or diffusing capacity of the lung for carbon monoxide (DLCO; corrected) \>= 40% of predicted value
* Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) \>= 35% as assessed by echocardiogram (ECHO) or multiple uptake gated acquisition (MUGA)
* Women of reproductive potential (defined as all women physiologically capable of becoming pregnant) must agree to use suitable methods of contraception for 90 days after the last dose of study therapy (durvalumab or JCAR014)
* Males who have partners of reproductive potential must agree to use an effective barrier contraceptive method for 90 days after the last dose of study therapy (durvalumab or JCAR014)

Exclusion Criteria:

EXCLUSION CRITERIA FOR SCREENING:

* Subjects with known active central nervous system (CNS) involvement by malignancy; subjects with prior CNS disease that has been effectively treated will be eligible if treatment was completed at least 3 months prior to enrollment and there is no evidence of disease or stable abnormalities on repeat imaging
* Planned use of corticosteroids (\> 10 mg/day prednisone or equivalent) or other systemic immunosuppression within 4 days prior to leukapheresis; topical and/or inhaled steroids are permitted
* Prior treatment with any CD19 CAR T-cell therapy
* Prior allogeneic HCT
* Known active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection
* Pregnant or breastfeeding women
* Known exclusion criteria for leukapheresis, JCAR014, or durvalumab therapy

EXCLUSION CRITERIA FOR LEUKAPHERESIS AND PRE-THERAPY EVALUATION:

* Subjects with known active central nervous system (CNS) involvement by malignancy; subjects with prior CNS disease that has been effectively treated will be eligible if treatment was completed at least 3 months prior to enrollment and there is no evidence of disease or stable abnormalities on repeat imaging
* Prior treatment with programmed cell death (PD)-1, PD-ligand (L)1, cytotoxic T lymphocyte-associated protein 4 (CTLA 4) targeted therapy, or tumor necrosis factor receptor superfamily (TNFRSF) agonists including CD134 (OX40), CD27, CD137 (4-1BB), and CD357 (glucocorticoid-induced tumor necrosis factor receptor family-related protein \[GITR\])
* Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., ulcerative colitis, Crohn's disease\], celiac disease, or other serious chronic gastrointestinal conditions associated with diarrhea; autoimmune vasculitis; systemic lupus erythematosus; Wegener syndrome \[granulomatosis with polyangiitis\]; myasthenia gravis; Graves' disease; rheumatoid arthritis, hypophysitis, uveitis, etc.) within 3 years prior to the planned start of treatment; the following are exceptions to this criterion:

  * Vitiligo
  * Alopecia
  * Hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
  * Psoriasis not requiring systemic treatment
  * Other conditions considered to be low risk of serious deterioration by the principal investigator (PI)
* 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, or unstable angina; history of other clinically significant cardiac disease that, in the opinion of the PI or designee, is a contraindication to lymphodepleting chemotherapy, JCAR014 infusion, or durvalumab infusion is also excluded
* History or presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, or psychosis; history of other organic brain syndrome that in the opinion of the PI or designee is a contraindication to lymphodepleting chemotherapy, JCAR014 infusion or durvalumab infusion
* History of solid organ transplantation

EXCLUSION CRITERIA FOR LYMPHODEPLETION CHEMOTHERAPY, JCAR014 AND DURVALUMAB:

* For lymphodepletion chemotherapy, JCAR014 and durvalumab: Subjects with known active CNS involvement by malignancy; subjects with prior CNS disease that has been effectively treated will be eligible if treatment was completed at least 3 months prior to enrollment and there is no evidence of disease or stable abnormalities on repeat imaging
* Uncontrolled infection
* Receipt of live, attenuated vaccine within 28 days prior to the first dose of durvalumab (Note: enrolled patients should not receive live vaccine during the study and for 180 days after the last dose of durvalumab)
* Planned use of corticosteroids (\> 10 mg/day prednisone or equivalent) or other systemic immunosuppression is not permitted within 72 hours prior to JCAR014 infusion; topical and/or inhaled steroids are permitted.
B: 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
C: Inclusion Criteria:

INCLUSIONS FOR SCREENING AND LEUKAPHERESIS

* Patients with CD19 expressing acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma (NHL)
* Ability to understand and provide informed consent
* Not human immunodeficiency virus (HIV) infected

INCLUSIONS FOR CAR-T CELL THERAPY

* Patients with:

  * CLL who are beyond first remission and who have failed combination chemoimmunotherapy with regimens containing a purine analogue and anti-CD20 antibody or who were not eligible for such therapy; patients with CLL for whom ibrutinib is now standard first line therapy, must have progressed on ibrutinib; patients with fludarabine refractory disease are eligible; patients may be treated following allogeneic hematopoietic cell transplant (HCT); for the concurrent ibrutinib cohort, patients must agree to continue on or be restarted on ibrutinib and must not have had prior intolerance to ibrutinib that would prevent this; patients managed with prior dose reductions for toxicity will continue at the reduced dose for the remainder of this study
  * Indolent NHL or mantle cell NHL who are beyond first remission and previously treated with chemoimmunotherapy or who were not eligible for such therapy; patients who have relapsed following autologous or allogeneic HCT are eligible
  * Aggressive NHL such as diffuse large B-cell lymphoma (DLBCL), who have relapsed or have residual disease following treatment with curative intent; patients should have relapsed following, or not be eligible for high-dose therapy and autologous HCT; patients with chemotherapy refractory disease or marrow involvement or comorbidities precluding successful autologous HCT are eligible; patients may be treated following allogeneic HCT
  * Patients with CD19 expressing, relapsed or refractory ALL
  * Patients with one of the above diagnoses whose disease state does not qualify but who have prognostic indicators that suggest a high risk of progression of disease may be screened and undergo leukapheresis; enrollment for T cell therapy would require meeting the full disease state eligibility
* Confirmation of diagnosis
* Evidence of CD19 expression by immunohistochemistry or flow cytometry on any prior or current tumor specimen or high likelihood of CD19 expression based on disease histology
* Karnofsky performance status \>= 60%
* All patients of childbearing potential must be willing to use a contraceptive method before, during, and for at least two months after the T cell infusion
* Ability to understand and provide informed consent

Exclusion Criteria:

EXCLUSIONS FOR CAR-T CELL THERAPY

* Patients requiring ongoing daily corticosteroid therapy at a dose of \> 15 mg of prednisone per day (or equivalent); pulsed corticosteroid use for disease control is acceptable
* Active autoimmune disease requiring immunosuppressive therapy is excluded unless discussed with the Principal Investigator (PI)
* Serum creatinine \> 2.5 mg/dL
* Serum glutamic oxaloacetic transaminase (SGOT) \> 5 x upper limit of normal
* Bilirubin \> 3.0 mg/dL
* Patients with clinically significant pulmonary dysfunction, as determined by medical history and physical exam should undergo pulmonary function testing; those with a forced expiratory volume in one second (FEV1) of \< 50 % of predicted will be excluded
* Diffusing capacity of the lung for carbon monoxide (DLCO) (corrected) \< 40% will be excluded
* Significant cardiovascular abnormalities as defined by any one of the following: New York Heart Association (NYHA) class III or IV congestive heart failure, clinically significant hypotension, uncontrolled symptomatic coronary artery disease, or a documented ejection fraction of \< 35%
* Uncontrolled active infection
D: Inclusion Criteria:

* •Male and female subjects with CD20+ B cell malignancies in patients with no available curative treatment options (such as autologous or allogeneic SCT) who have limited prognosis (several months to \< 2 year survival) with currently available therapies will be enrolled

  * CD20+ leukemia or lymphoma
  * ALL in CR2 or CR3 and not eligible for allogeneic SCT because of age, comorbid disease, or lack of available family member or unrelated donor
  * Follicular lymphoma, previously identified as CD20+:
  * At least 2 prior combination chemotherapy regimens (not including single agent monoclonal antibody (Rituxan) therapy
  * Stage III-IV disease
  * Less than 1 year between last chemotherapy and progression (i.e. most recent progression free interval \< 1 year)
  * Disease responding or stable after most recent therapy (chemotherapy, MoAb, etc)
  * CLL:
  * At least 2 prior chemotherapy regimens (not including single agent monoclonal antibody (Rituxan) therapy. Patients with high risk disease manifested by deletion chromosome 17p will be eligible if they fail to achieve a CR to initial therapy or progress within 2 years of 1 prior
  * Less than 2 years between last chemotherapy and progression (i.e. most recent progression free interval \< 2 years)
  * Not eligible or appropriate for conventional allogeneic SCT
  * Patients who achieve only a partial response to FCR as initial therapy will be eligible.
  * Mantle cell lymphoma:
  * Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate for conventional allogeneic or autologous SCT
  * Disease responding or stable after most recent therapy (chemotherapy, MoAb, etc...)
  * Relapsed after prior autologous SCT
  * B-cell prolymphocytic leukemia (PLL) with relapsed or residual disease after at least 1 prior therapy and not eligible for allogeneic SCT
  * Diffuse large cell lymphoma, previously identified as CD20+:
  * Residual disease after primary therapy and not eligible for autologous SCT
  * Relapsed after prior autologous SCT
  * Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate of conventional allogeneic or autologous SCT
  * Expected survival \> 12 weeks
  * Creatinine \< 2.5 mg/dl
  * ALT/AST \< 3x normal
  * Bilirubin \< 2.0 mg/dl
  * Any relapse after prior autologous SCT will make patient eligible regardless of other prior therapy
  * Adequate venous access for apheresis, and no other contraindications for leukapheresis
  * Voluntary informed consent is given

Exclusion Criteria:

* •Pregnant or lactating women

  * The safety of this therapy on unborn children is not known
  * Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion
  * Uncontrolled active infection
  * Active hepatitis B or hepatitis C infection
  * Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not exclusionary
  * Previously treatment with any gene therapy products
  * Feasibility assessment during screening demonstrates \< 30% transduction of target lymphocytes, or insufficient expansion (\< 5-fold) in response to CD3/CD28 costimulation
  * Any uncontrolled active medical disorder that would preclude participation as outlined
  * HIV infection

Answer: A