Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 2 Study of Lisocabtagene Maraleucel (JCAR017) as Second-Line Therapy in Adult Patients With Aggressive B-cell NHL (017006)
Brief Summary: This is a Phase 2, open-label, multicenter study to determine the efficacy and safety of lisocabtagene maraleucel (JCAR017) in adult subjects who have relapsed from, or are refractory to, a single line of immunochemotherapy for aggressive B-cell non-Hodgkin lymphoma (NHL) and are ineligible for hematopoietic stem cell transplant (based on age, performance status, and/or comorbidities). Subjects will receive treatment with lisocabtagene maraleucel and will be followed for 2 years for safety, pharmacokinetics and biomarkers, disease status, quality of life, and survival.


Options:
A: For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

* Have received at least 3 prior lines of therapy, including a proteasome inhibitor \[PI\] and an immunomodulatory agent \[IMiD\] OR have disease that is double refractory to a PI and IMiD
* More than 12 weeks post-transplant of your own blood forming stem cells (autologous transplant)
* Have detectable disease measured by a specific protein in your blood and/or urine
* Must consent to bone marrow aspirate or biopsy.

Exclusion Criteria:

* Solitary bone or extramedullary plasmacytoma as the only evidence of plasma cell dyscrasia, or monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), primary amyloidosis, Waldenstrom's macroglobulinemia, POEMS syndrome or active plasma cell leukemia
* Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti CTLA 4, or anti-CD38 antibody, or allogeneic stem cell transplantation
* Seropositive for human immunodeficiency virus (HIV), Hepatitis B surface antigen or Hepatitis C antibody positive (except if HCV-RNA negative), or history of active chronic hepatitis B or C
* History of central nervous system involvement or symptoms suggestive of central nervous system involvement by multiple myeloma

Other protocol defined inclusion/exclusion criteria could apply
B: * INCLUSION CRITERIA:

Inclusion Criteria: Recipient

1. Recipients (patients with B-cell malignancy) must have received an HLA-identical or 9/10 matched sibling allogeneic hematopoietic stem cell transplant, a 1-antigen mismatched related transplant, or a greater than or equal to 9/10-matched unrelated donor (URD) alloHSCT for any CD19+ B-cell malignancy. Patients with any CD19+ B-cell malignancy that is persistent or relapsed after all of the following interventions are eligible:

   1. Donor T cell engraftment after alloHSCT (\>50% donor chimerism of the T cell compartment and a peripheral blood T cell number from the NIH, CC clinical lab of at least 50 CD3+ cells/uL).
   2. A trial of withdrawal of immunosuppressive therapy.

   Exception: Prior (DCI) DLI is not an eligibility requirement for patients with ALL, Burkitt lyphoma, ALL like high-grade lymphomas, or diffuse large B-cell lymphoma.

   At least 28 days weeks must have elapsed since the latest trial of withdraw of immunosuppression or DLI until the patient can be deemed to have persistent disease.
2. CD19 expression must be detected on the majority of the malignant cells by immunohistochemistry or by flow cytometry in the Laboratory of Pathology, CCR, NCI, NIH. Definition of which cells are malignant must be determined for each patient by the Laboratory of Pathology using techniques to demonstrate monoclonality such as kappa/lambda restriction (other techniques can be used to determine monoclonality at the discretion of the Laboratory of Pathology). The choice of whether to use flow cytometry or immuohistochemistry will be determined by what is the most easily available tissue sample in each patient. Immunohistochemistry will be used for lymph node biopsies and bone marrow biopsies. Flow cytometry will be used for peripheral blood, fine needle aspirate, and bone marrow aspirate samples.
3. Patients must be 18-75 years of age.
4. Performance status: ECOG less than or equal to 2
5. Either no evidence of GVHD or minimal clinical evidence of acute GVHD and chronic GVHD while off of systemic immunosuppressive therapy for at least 28 days. Minimal clinical evidence of acute GVHD is defined as grade 0 to I acute GVHD. Minimal evidence of chronic GVHD is defined as chronic GVHD with no organ site with a score exceeding 1, except for the skin, for which a score of 1 or 2 will be allowable (as defined by the 2005 NIH consensus project) or no chronic GVHD. Subjects with disease that is controlled to stage I acute GVHD or chronic GVHD meeting the above criteria with local therapy only, e.g., topical cutaneous steroids, will be eligible for enrollment.
6. Ability to give informed consent.
7. Prior Therapy: Therapy with monoclonal antibodies and/or chemotherapy must be stopped at least 7 days prior to anti-CD19 CAR-transduced T cell infusion, and recovery of treatment-associated toxicity to less than or equal to grade 2 is required prior to infusion of cells. For patients that have received prior DLI, the last dose must be at least 28 days prior to anti-CD19 CAR-transduced T cell administration. Note that patients can be enrolled on this study at any time after or during therapy, but at least 14 days must elapse from the time of prior monoclonal antibody administration or chemotherapy until anti-CD19 CAR-transduced T cells are infused, and at least 28 days must elapse from the time of withdraw of immunosuppression, or DLI, or other immunomodulatory therapies such as lenalidomide until anti-CD19 CAR-transduced T cells are infused. Systemic immunosuppression given for graft versus host disease must be stopped at least 28 days prior to protocol entry. There is no time restriction in regard to prior intrathecal chemotherapy provided there is complete recovery from any acute toxic effects of such.
8. Recipients of unrelated donor transplants from a National Marrow Donor Program (NMDP) Center must sign a release of information form to authorize NMDP transfer of information to the NIH.
9. Previous allogeneic donor must be willing and available to donate again.
10. Patients of childbearing or child-fathering potential must be willing use an effective method of contraception while being treated on this study and for 4 months after the last cell infusion.
11. Normal left ventricular function as evaluated by echocardiograph within 4 weeks of anti- CD19-CAR-transduced T cell infusion

Inclusion Criteria: Donor

1. Donors greater than or equal to 18 years of age must be the same individual whose cells were used as the source for the patient s original stem cell transplant.
2. Adequate venous access for peripheral leukapheresis, or consent to use a temporary central venous catheter for leukapheresis.
3. Donors must be HIV negative, hepatitis B surface antigen negative, and hepatitis C antibody negative.
4. Ability to give informed consent.
5. Donor selection will be in accordance with NIH/CC Department of Transfusion Medicine (DTM) criteria and, in the case of an unrelated donor from a Transplant Center, the National Marrow Donor Program (NMDP) standards. When a potentially eligible recipient of an unrelated donor product from an NMDP Center is identified, the recipient will complete an NMDP search transfer request to allow NIH NMDP staff to contact the NMDP Coordinating Center, who will, in turn, contact the donor s prior Donor Center. The NMDP Policy for Subsequent Donation Requests will be followed and the appropriate forms (Subsequent Donation Request form) and Therapeutic T Cell Collection Prescription will be submitted as required.

EXCLUSION CRITERIA:

Exclusion Criteria: Recipients

1. Active infection that is not responding to antimicrobial therapy.
2. Sero positive for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune -competence and thus are less responsive to the experimental treatment and more susceptible to its toxicities.)
3. Sero positive for hepatitis B antigen, positive hepatitis B tests can be further evaluated by confirmatory tests (HBV DNA), and if confirmatory tests are negative, the patient can be enrolled.
4. Sero positive for hepatitis C antibody unless antigen negative. If hepatitis C antibody test is positive, then patients must be tested for the presence of RNA by RT-PCR and be HCV RNA negative.
5. Active psychiatric disorder which may compromise compliance with the treatment protocol, or which does not allow for appropriate informed consent (as determined by Principal Investigator and/or his designee).
6. Pregnant or lactating. The effects of the immunosuppressive medications that could be required to treat GHVD are likely to be harmful to a fetus. The effects upon breast milk are also unknown and may be harmful to an infant.
7. Serum total bilirubin \> 2.5 mg/dl, serum ALT and AST values greater than or equal to 2.5 times the upper limit of normal based on age-specific normal values. If the abnormal liver function is attributable to liver involvement by malignancy, patients may be eligible with serum total bilirubin up to 5.0 mg/dl, and serum ALT and AST values up to 5.0 times the upper limit of normal, provided the patient has no evidence of impending hepatic failure (encephalopathy or prothrombin time \>2 times the upper limit of normal).
8. Serum creatinine greater than 1.6 mg/dL
9. Absolute neutrophil count of less than 1000 cells/microL unless low neutrophil count is thought to be due to malignancy in the bone marrow and malignancy is documented in the bone marrow.
10. Active cerebrospinal fluid involvement with malignancy or brain metastasis.
11. Platelet count less than 30,000/microL unless low platelet count is thought to be due to malignancy in the bone marrow and malignancy is documented in the bone marrow.
12. Hemoglobin less than 8.0 g/dL.
13. Receiving systemic corticosteroids including prednisone, dexamethasone or any other corticosteroid at doses of higher than 5 mg/day of prednisone within 28 days prior to anti-CD19-CAR-transduced T cell administration. Corticosteroid creams, ointments, and eye drops are allowed.
14. Blood blast percentage higher than 5%.

Exclusion Criteria: Donors

1. History of psychiatric disorder which may compromise compliance with this protocol or which does not allow for appropriate informed consent.
2. History of hypertension that is not controlled by medication, stroke, or severe heart disease (donors with symptomatic angina will be excluded). Donors with a history of coronary artery bypass grafting or angioplasty who are symptom free will receive a cardiology evaluation and be considered on a case-by-case basis.
3. Donors must not be pregnant.
4. Anemia (Hb \< 11 gm/dl) or thrombocytopenia (platelets \< 100,000 per microL). However, potential donors with Hb levels \< 11 gm/dl that is due to iron deficiency will be eligible as long as the donor is initiated on iron replacement therapy. The NIH Clinical Center, Department of Transfusion Medicine/NMDP physicians will determine the appropriateness of individuals as donors.
C: 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
D: Inclusion Criteria:

* Patient with relapsed or refractory B-cell malignancy
* Age 1-50 years
* CD19 expression shown by flow cytometry or immunohistochemistry on at least 70% of leukemic blasts / lymphoma cells
* Adequate CD3 count (above 250 CD3+ cells per microliter blood)
* Clinical performance status: Patients \> 10 years of age: Karnofsky ≥ 50%; Patients ≤ 10 years of age: Lansky scale ≥ 50%. Exception for neurologic symptoms (e.g. paralysis) that are explained by the malignancy.
* Females of child-bearing potential must have a negative pregnancy test
* Cardiac function: Left ventricular ejection fraction \>45% or shortening fraction \>28%
* For patients following allogeneic bone marrow transplantation - at least 100 days post BMT with no signs or symptoms of active graft-versus-host disease.

Key Exclusion Criteria:

* Hyperleukocytosis (WBC\>50,000) or rapidly progressive disease
* Pregnant or breast-feeding females
* Hepatic dysfunction, defined as bilirubin \> x2 upper normal limit (except when explained by hemolysis or Gilbert) or serum glutamate oxaloacetate transaminase \> x25 upper normal limit.
* Hepatitis B, Hepatitis C or HIV infection.
* Anti-neoplastic treatment given in the 2 weeks prior to apheresis, with the exception of intrathecal chemotherapy.
* Active immunosuppressive therapy

Answer: C