Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 1/2 Multi-center Study Evaluating the Safety and Efficacy of Axicabtagene Ciloleucel in Combination With Utomilumab in Subjects With Relapsed/Refractory Large B-Cell Lymphoma
Brief Summary: The primary objectives of this study are:

Phase 1: To evaluate the safety of axicabtagene ciloleucel in combination with utomilumab and to identify the most appropriate dose and timing of utomilumab to carry forward into Phase 2

Phase 2: To evaluate the efficacy of axicabtagene ciloleucel and utomilumab as measured by complete response rate in participants with refractory large B-cell lymphoma


Options:
A: * INCLUSION CRITERIA:
* Malignancy criteria:

  * Patients with the following malignancies are potentially eligible: any B-cell lymphoma, and chronic lymphocytic leukemia (CLL). Patients with indolent malignancies that have transformed to diffuse large B-cell lymphoma are eligible.
  * Clear cluster of differentiation 19 (CD19) expression must be uniformly detected on 75% or more of malignant cells from either bone marrow or a leukemia or lymphoma mass by flow cytometry or immunohistochemistry. These assays must be performed at the National Institutes of Health. It is preferable but not required that the specimen used for CD19 determination comes from a sample that was obtained after the patient's most recent treatment. If paraffin embedded unstained samples of bone marrow involved with malignancy or a lymphoma mass are available, these can be shipped to the National Institutes of Health (NIH) for CD19 staining; otherwise, new biopsies will need to be performed for determination of CD19 expression.
  * Diffuse large B-cell lymphoma (DLBCL) patients must have received at least two prior chemotherapy-containing regimens at least one of which must have contained doxorubicin and a monoclonal antibody. Follicular lymphoma patients must have received at least 2 prior regimens including at least 1 regimen with chemotherapy. All other lymphoma and leukemia patients must have had at least 1 prior chemotherapy-containing regimen. All patients with CLL or small lymphocytic lymphoma must have had prior treatment with ibrutinib or another signal transduction inhibitor.
  * Patients must have measurable malignancy as defined by at least one of the criteria below.

    * Lymphoma or leukemia masses that are measurable (minimum 1.5 cm in largest diameter) by computed tomography (CT) scan is required for all diagnoses except CLL. All masses must be less than 10 cm in the largest diameter.
    * For a lymphoma mass to count as measurable malignancy, it must have abnormally increased metabolic activity when assessed by positron emission tomography (PET) scan.
    * For CLL and lymphoma with only bone marrow involvement no mass is necessary, but if a mass is not present, bone marrow malignancy must be detectable by flow cytometry in lymphoma and CLL.
* Other inclusion criteria:

  * Greater than or equal to 18 years of age and less than or equal to age 73.
  * Able to understand and sign the Informed Consent Document.
  * Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0-1
  * Room air oxygen saturation of 92% or greater
  * Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen.
  * Women of child bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the preparative chemotherapy on the fetus. Women of child-bearing potential are defined as all women except women who are post-menopausal or who have had a hysterectomy. Postmenopausal will be defined as women over the age of 55 who have not had a menstrual period in at least 1 year.
  * Seronegative for human immunodeficiency virus (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.)
  * Patients with a known history of hepatitis B or hepatitis C are not eligible due to the risk of re-activation of hepatitis after prolonged B-cell depletion due to anti-CD19 CAR T cells.
  * Seronegative for hepatitis B antigen, positive hepatitis B tests can be further evaluated by confirmatory tests, and if confirmatory tests are negative, the patient can be enrolled. Patients with a known history of hepatitis B are not eligible.
  * Seronegative for hepatitis C antibody unless antigen negative. If hepatitis C antibody test is positive, then patients must be tested for the presence of ribonucleic acid (RNA) by reverse transcription polymerase chain reaction (RT-PCR) and be hepatitis C virus (HCV) RNA negative. Patients with a known history of hepatitis C are not eligible.
  * Absolute neutrophil count greater than or equal to 1000/mm(3) without the support of filgrastim or other growth factors.
  * Platelet count greater than or equal to 45,000/mm(3) without transfusion support
  * Hemoglobin greater than 8.0 g/dl.
  * Less than 5% malignant cells in the peripheral blood leukocytes
  * Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less or equal to 3 times the upper limit of the institutional normal unless liver involvement by malignancy is demonstrated.
  * Serum creatinine less than or equal to 1.4 mg/dL.
  * Total bilirubin less than or equal to 2.0 mg/dl.
  * At least 14 days must have elapsed since any prior systemic therapy prior to apheresis and prior to the initiation of chemotherapy (including systemic corticosteroids at any dose). Because this protocol requires collection of autologous blood cells by leukapheresis in order to prepare CAR T cells, systemic anti-malignancy therapy including systemic corticosteroid therapy of any dose are not allowed within 14 days prior to the required leukapheresis. NOTE: Because of the long half-life and potential to affect CAR T cells, 60 days must elapse from the time of administration of anti-Programmed cell death protein 1 (PD-1) or anti-Programmed death-ligand 1 (PD-L1) antibodies or other agents that in the opinion of the PI can stimulate immune activity and infusion of CAR T cells.
  * Normal cardiac ejection fraction (greater than or equal to 55% by echocardiography) and no evidence of hemodynamically significant pericardial effusion as determined by an echocardiogram within 4 weeks of the start of the treatment protocol.
  * Patients must not take corticosteroids including prednisone, dexamethasone or any other corticosteroid for 14 days before apheresis and CAR T-cell infusion. Patients must also not take corticosteroids at doses higher than 5 mg/day of prednisone or equivalent at any time after the CAR T cell infusion.
  * Patients who have been treated on other protocols of genetically-modified T cells at the NIH only are potentially eligible under these conditions:

    * At least 6 months have elapsed since the last genetically-modified T-cell therapy that the patient received and there is no evidence of replication-competent retroviruses (evidence must be provided from prior NIH gene-therapy protocol Principal Investigator) and persisting genetically-modified T cells are not detectable in the patient's blood (evidence must be provided by prior NIH gene-therapy protocol Principal Investigator).

EXCLUSION CRITERIA:

* Patients that require urgent therapy due to tumor mass effects or spinal cord compression.
* Patients that have active hemolytic anemia.
* Patients with second malignancies in addition to their B-cell malignancy are not eligible if the second malignancy has required treatment (including maintenance therapy) within the past 4 years or is not in complete remission. There are two exceptions to this criterion: successfully treated non-metastatic basal cell or squamous cell skin carcinoma.
* Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
* Active uncontrolled systemic infections (defined as infections causing fevers and infections requiring intravenous antibiotics when intravenous antibiotics have been administered for less than 72 hours), active coagulation disorders or other major uncontrolled medical illnesses of the cardiovascular, respiratory, endocrine, renal, gastrointestinal, genitourinary or immune system, history of myocardial infarction, history of ventricular tachycardia or ventricular fibrillation, active cardiac arrhythmias (active atrial fibrillation is not allowed, resolved atrial fibrillation not requiring current treatment is allowed (anticoagulants count as current treatment) ), active obstructive or restrictive pulmonary disease, active autoimmune diseases such as rheumatoid arthritis.
* Patients will not be seen for screening appointments or enrolled on the protocol if they have been hospitalized within the 7 days prior to the screening appointment or the date of protocol enrollment.
* Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
* Systemic corticosteroid steroid therapy of any dose is not allowed within 14 days prior to the required leukapheresis, or the initiation of the conditioning chemotherapy regimen. Corticosteroid creams, ointments, and eye drops are allowed.
* History of severe immediate hypersensitivity reaction to any of the agents used in this study.
* Patients with current central nervous system (CNS) involvement by malignancy (either by imaging or cerebrospinal fluid involvement or biopsy-proven).
B: Inclusion Criteria:

* Adult patients are eligible (\> or = to 18 year old).
* Patients must have B- ALL refractory, relapsed, MRD, or in first CR as described below.
* Complete remission is defined as restoration of normal hematopoiesis with a neutrophil count \> 1,000 x 106/L, a platelet count \> 100,000 x 106/L, and hemoglobin \> 10 g/dL. Blasts should be \< 5% in a post-treatment bone marrow differential. Furthermore, there should be no clinical evidence of leukemia for a minimum of four weeks.
* MRD is defined as patients meeting the criteria for CR above, but with residual disease measured by a quantitative PCR, or by flow or by deep-sequencing of the IgH rearrangements . The assay from blood and/or bone marrow defines MRD by qPCR as a cycle threshold (CT) that is at least 1 CT value \< than the lowest CT value from the background. Outside laboratory tests may suffice for this assessment at the discretion of the Principal Investigator.

Relapsed B-ALL will be defined as patients that meet the above criteria for a CR before developing recurrent disease (increased bone marrow blasts). Refractory patients will be defined as patients that have not achieved a CR after 1 cycle of induction chemotherapy

* Patients must have a diagnosis of B-ALL by flow cytometry, or bone marrow histology, and/or cytogenetics.
* Patients must have CD19+ ALL as confirmed by flow cytometry and/or immunohistochemistry.
* Creatinine \< 2.0 mg/100 ml, bilirubin \< 2.0 mg/100 ml, AST and ALT \< 3x normal, PT and PTT \< 2x normal outside the setting of stable chronic anticoagulation therapy. LFTs (Bilirubin, AST, and/or ALT) may be acceptable if the elevation is secondary to leukemia infiltration or leukemia therapy with tyrosine kinase inhibitors.
* Adequate cardiac function (LVEF ≥ 40%) as assessed by ECHO or MUGA or other similar cardiac imaging performed within 1 month of enrollment.
* Adequate pulmonary function as assessed by ≥ 92% oxygen saturation on room air by pulse oximetry.
* Patients must have adequate access for leukapheresis procedure as assessed by staff from the MSKCC Donor Room.
* Life expectancy \> 3 months

Exclusion Criteria:

* Karnofsky performance status \< 70.
* Active central nervous system (CNS) leukemia, as defined by unequivocal morphologic evidence of lymphoblasts in the cerebrospinal fluid (CSF) or symptomatic CNS leukemia (i.e. cranial nerve palsies or other significant neurologic dysfunction) within 28 days of enrollment. Prophylactic intrathecal medication is not a reason for exclusion.
* Patients previously treated with an allogeneic SCT that is currently complicated by active GVHD requiring T cell suppressive therapy.

Patients with following cardiac conditions will be excluded:

* New York Heart Association (NYHA) stage III or IV congestive heart failure
* Myocardial infarction ≤6 months prior to enrollment
* History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration
* History of severe non-ischemic cardiomyopathy with EF ≤20%

  * Patients with HIV, hepatitis B or hepatitis C infection.
  * Patients with any concurrent active malignancies as defined by malignancies requiring any therapy other than expectant observation.
C: * INCLUSION CRITERIA:

  1. Patient must have a cluster of differentiation 19 (CD19)-expressing B-cell lymphoma. Patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and diffuse large B-cell lymphoma transformed from follicular lymphoma must have measurable disease after at least two prior chemotherapy regimens one of which must have contained doxorubicin and rituximab.
  2. Confirmation of diagnosis of B-cell malignancy and positivity for CD19 confirmed by the Laboratory of Pathology of the National Cancer Institute (NCI). The choice of whether to use flow cytometry or immunohistochemistry will be determined by what is the most easily available tissue sample in each patient. Immunohistochemistry will be used for lymph node biopsies, flow cytometry will be used for peripheral blood, fine needle aspirates and bone marrow samples.
  3. Patients must have indications for treatment for their B-cell malignancy at the time of enrollment on this trial.
  4. Greater than or equal to 18 years of age and less than or equal to age 70.
  5. Willing to sign a durable power of attorney.
  6. Able to understand and sign the Informed Consent Document.
  7. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.
  8. Life expectancy of greater than three months.
  9. Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for four months after treatment.
  10. Women of child bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
  11. Serology:

      * Seronegative for human immunodeficiency virus (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 be less responsive to the experimental treatment and more susceptible to its toxicities.).
      * Seronegative for hepatitis B antigen and hepatitis C antibody unless antigen negative. If hepatitis C antibody test is positive. Then patients must be tested for the presence of antigen by reverse transcription-polymerase chain reaction (RT-PCR) and be hepatitis C virus ribonucleic acid (HCV RNA) negative.
  12. Hematology:

      * Absolute neutrophil count greater than or equal to 1000/mm\^3 without the support of filgrastim.
      * Platelet count greater than or equal to 50,000/mm\^3.
      * Hemoglobin greater than 8.0 g/dl.
      * Lymphocyte count less than or equal to 4,000/ mm\^3
  13. Chemistry:

      * Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less or equal to 5 times the upper limit of normal.
      * Serum creatinine less than or equal to 1.6 mg/dl
      * Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl
  14. More than three weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patient toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo).
  15. Normal cardiac ejection fraction and no evidence of pericardial effusion as determined by an echocardiogram.

EXCLUSION CRITERIA:

1. Patients that require urgent therapy due to tumor mass effects such as bowel obstruction or blood vessel compression.
2. Patients that have active hemolytic anemia.
3. Patients with active brain metastases, or with a history of any central nervous system (CNS) metastases or cerebrospinal fluid malignant cells.

   Note: patients who are asymptomatic but are found to have malignant cells in the cerebrospinal fluid (CSF) on lumbar puncture prior to treatment will be considered eligible.
4. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
5. Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
6. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
7. Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities).
8. Concurrent systemic steroid therapy.
9. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
10. History of allogeneic stem cell transplantation
11. Patients with cardiac atrial or cardiac ventricular lymphoma involvement.

Screening Evaluation:

Within 4 weeks prior to starting the chemotherapy regimen:

1. Complete history and physical examination, including, weight and vital signs, noting in detail the exact size and location of any lesions that exist. (Note: patient history may be obtained within 8 weeks.)
2. Chest x-ray
3. Electrocardiography (EKG)
4. Baseline computed tomography (CT) of the chest, abdomen and pelvis, positron emission tomography (PET) scan, and brain magnetic resonance imaging (MRI) to evaluate the status of disease. Additional scans and x-rays may be performed if clinically indicated based on patient signs and symptoms.
5. HIV antibody titer and Hepatitis B surface antigen (HbsAG) determination, and anti HCV, (Note: May be performed within 3 months of the chemotherapy start date).
6. Anti cytomegalovirus (CMV) antibody titer, herpes simplex virus (HSV) serology, and Epstein-Barr virus (EBV) panel (Note: patients who are known to be positive for any of the above do not need to be retested; may be performed within 3 months of chemotherapy start date)
7. Patients with a left ventricular ejection fraction (LVEF) of less than or equal to 55% will not proceed to treatment (Note: may be performed within 8 weeks of treatment).
8. Cluster of differentiation 19 (CD19) staining of malignant cells by immunohistochemistry or flow cytometry (testing is permitted to be conducted at any time prior to this point).
9. All patients must have a T cells, B cells, and natural killer cells (TBNK) for Peripheral blood cluster of differentiation 3 (CD3) count and CD19#.
10. Patients with a history of leptomeningeal disease, or signs/symptoms suggestive of leptomeningeal involvement, or with symptoms of central nervous system malignancy such as new onset severe headaches, neck stiffness, or any focal neurologic findings on physical exam will have lumbar puncture for examination of cerebral spinal fluid.
11. Patients may undergo lumbar puncture (LP) for flow cytometry of the CSF in order to assess the presence of CD19 positive lymphocytes for potential correlation with neurologic toxicity. Patients who have no neurologic symptoms at the time of LP will be eligible for enrollment regardless of the results of the flow cytometry.

    Within 14 days prior to starting the chemotherapy regimen:
12. Chem 20: (Sodium (Na), Potassium (K), Chloride (Cl), Total carbon dioxide (CO2) (bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total (Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/glutamic pyruvic transaminase (GPT), AST/glutamic oxaloacetic (GOT), Total Bilirubin, Direct Bilirubin, lactate hydrogenase (LD), Total Protein, Total creatine kinase (CK), Uric Acid)
13. Thyroid panel
14. Complete blood count (CBC) with differential and platelet count
15. Prothrombin time (PT)/partial thromboplastin time (PTT)
16. Urinalysis and culture, if indicated

    Within 7 days prior to starting the chemotherapy regimen:
17. Beta-human chorionic gonadotropin (βHCG) pregnancy test (serum or urine) on all women of child-bearing potential
18. ECOG performance status of 0 or 1
D: Key Inclusion Criteria:

* Histologically proven large B-cell lymphoma including the following types:

  * Diffuse large B cell lymphoma (DLBCL) not otherwise specified Activated B cell / Germinal center B cell (ABC/GCB).
  * High grade B-cell lymphoma (HGBCL) with or without MYC and BCL2 and/or BCL6 rearrangement.
  * DLBCL arising from follicular lymphoma.
  * T cell/histiocyte rich large B-cell lymphoma.
  * DLBCL associated with chronic inflammation.
  * Primary cutaneous DLBCL, leg type.
  * Epstein-Barr virus (EBV) + DLBCL
* Relapsed or chemotherapy-refractory disease, defined as one or more of the following:

  * No response to first-line therapy (primary refractory disease); individuals who are intolerant to first-line systemic chemotherapy are excluded

    * Progressive disease (PD) as best response to first-line therapy.
    * Stable disease (SD) as best response after at least 4 cycles of first-line therapy (eg, 4 cycles of R-CHOP) with SD duration no longer than 6 months from last dose of therapy.
  * No response to second or greater lines of therapy.

    * PD as best response to most recent therapy regimen.
    * SD as best response after at least 2 cycles of last line of therapy with SD duration no longer than 6 months from last dose of therapy OR
  * Refractory post-autologous stem cell transplant (ASCT).

    * Disease progression or relapsed 12 months after ASCT (must have biopsy proven recurrence in relapsed individual).
    * if salvage therapy is given post-ASCT, the individual must have had no response to or relapsed after the last line of therapy .
  * Relapsed or refractory LBCL including DLBCL, Transformed follicular lymphoma (TFL), and HGBCL after 2 or more lines of systemic therapy that is defined by and aligns with currently approved indication:

    * Relapsed disease after 2 or more lines of systemic therapy.
    * Best response that is less than a complete response to second or greater line of systemic therapy.
* At least 1 measurable lesion according to the Lugano Classification. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy.
* Individual must have received adequate prior therapy including at a minimum:

  * Anti-cluster of differentiation (CD) 20 monoclonal antibody unless investigator determines that tumor is CD20-negative, and
  * An anthracycline containing chemotherapy regimen.
* No radiographic evidence, suspicion and/or history of central nervous system (CNS) involvement of lymphoma.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Absolute neutrophil count (ANC) ≥ 1000/μL.
* Platelet count ≥ 75,000/μL.
* Absolute lymphocyte count ≥ 100/μL.
* Adequate renal, hepatic, pulmonary, and cardiac function defined as:

  * Creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 mL/min.
  * Serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) ≤ 2.5 upper limit of normal (ULN).
  * Total bilirubin ≤ 1.5 mg/dL, except in individuals with Gilbert's syndrome.
  * Cardiac ejection fraction ≥ 50% and no evidence of pericardial effusion within 180 days provided the individual did not receive an anthracycline-based treatment or experience a cardiac event or change in performance status.
  * No clinically significant pleural effusion.
  * Baseline oxygen saturation \> 92% on room air.

Key Exclusion Criteria:

* Histologically proven primary mediastinal B-cell lymphoma (PMBCL).
* History of Richter's transformation of chronic lymphocytic lymphoma (CLL).
* Prior chimeric antigen receptor therapy or other genetically modified T-cell therapy.
* History of severe, immediate hypersensitivity reaction attributed to aminoglycosides.
* History of human immunodeficiency virus (HIV) infection or acute or chronic active hepatitis B or C infection. Individuals with history of hepatitis infection must have cleared their infection as determined by standard serological and genetic testing per current Infectious Diseases Society of America (IDSA) guidelines or applicable country guidelines.
* Individuals with detectable cerebrospinal fluid malignant cells, brain metastases, or a history of CNS lymphoma.
* History or presence of CNS disorder, such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.
* Individuals with cardiac atrial or cardiac ventricular lymphoma involvement.
* History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment.
* Requirement for urgent therapy due to tumor mass effects (eg, blood vessel compression, bowel obstruction, or transmural gastric involvement.
* Primary immunodeficiency.
* History of autoimmune disease (eg, Crohn's, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years. Individuals with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone and individuals with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible for this study.
* History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of enrollment
* Any medical condition likely to interfere with assessment of safety or efficacy of study treatment
* Autologous stem cell transplant within 6 weeks of planned enrollment
* Prior organ transplantation including prior allogeneic stem cell transplant (SCT)
* Use of any standard or experimental anti-cancer therapy within 2 weeks prior to enrollment, including cytoreductive therapy and radiotherapy, immunotherapy, or cytokine therapy (except for erythropoietin) Prior treatment with PD-L1 inhibitor, PD-1 inhibitor, anti-CTLA4, anti-CD137 (4-1BB), anti-OX40 or other immune checkpoint blockade or activator therapy
* History of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest computed tomography (CT) scan at screening. History of radiation pneumonitis in the radiation field (fibrosis) is allowed.
* In the investigator's judgment, the individual is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Answer: D