Please select the eligibility criteria that correspond to the clinical trial below.
Title: An Exploratory Phase 1/2 Trial To Evaluate The Safety And Efficacy Of JCAR017 Combinations In Subjects With Relapsed/Refractory B-Cell Malignancies (PLATFORM)
Brief Summary: This is a global, open-label, multi-arm, parallel multi-cohort, multi-center, Phase 1/2 study to determine the safety, tolerability, PK, efficacy and patient-reported quality of life of JCAR017 in combination with various agents. This protocol is intended to evaluate various drug combinations with JCAR017, as separate arms, over the life of the protocol, using the same objectives. Each combination will be evaluated separately (ie, the intention is not to compare between combinations) for the purposes of the objectives, trial design, and statistical analysis. The following combinations will be tested:

Arm A: JCAR017 in combination with durvalumab Arm B: JCAR017 in combination with CC-122 (avadomide) Arm C: JCAR017 in combination with CC-220 (iberdomide) Arm D: JCAR017 in combination with ibrutinib Arm E: JCAR017 in combination with relatlimab and/or nivolumab Arm F: JCAR017 in combination with CC-99282 Additional arms will be added by way of amendment once combination agents have been selected.

The study will consist of 2 parts: dose finding (Phase 1) and dose expansion (Phase 2). Dose expansion may occur in one or more arms.


Options:
A: Inclusion Criteria:

* Age 16 to 75 years (inclusive)
* Biopsy-proven relapsed or treatment refractory aggressive B-cell non-Hodgkin lymphoma of the following subtypes per World Health Organisation (WHO) classification: DLBCL and its variants, PMBCL, tFL, FL, MCL
* Requirement for treatment in the opinion of the investigator
* Presence of measurable disease as per Lugano 2014 Criteria
* No other curative treatments available, or not suitable due to patient or disease characteristics or lack of stem cell donor
* Malignancy documented to express CD19 based on flow cytometric or immunohistochemical staining
* Provision of written informed consent for this study
* Lymphoma-related life expectancy at least 12 weeks, and life-expectancy from non-lymphoma related causes of \> 12 months
* European Cooperative Oncology Group (ECOG) performance status of 0 to 2 inclusive
* Adequate haematologic function, defined by neutrophils ≥ 1.0 × 10\^9/L and platelets ≥ 50 × 10\^9/L
* No serious cardiac, pulmonary, hepatic or renal disease.

  * Serum bilirubin \< 2.5 times Upper limit of normal (ULN)
  * Estimated creatinine clearance (CrCl) ≥ 50 mL/min using the modified Cockroft Gault estimation or as assessed by direct measurement
  * Cardiac Ejection Fraction ≥ 50% as determined by Echocardiogram or MUGA Scan
  * Oxygen saturations \> 92% on room air
  * Diffuse Capacity of the lungs for carbon monoxide (DLCO) or Carbon monoxide transfer coefficient (KCO), Forced expiratory volume in one second (FEV1) and Forced Vital Capacity (FVC) are all ≥ 50% of predicted by spirometry after correcting for haemoglobin and/or volume on lung function testing.

Exclusion Criteria:

* Confirmed active or prior central nervous system (CNS) involvement by lymphoma. In patients with a clinical suspicion of CNS disease, lumbar puncture and MRI brain must be performed
* Active CNS pathology including: epilepsy, seizure within the preceding year, aphasia, paresis, stroke, dementia, psychosis within the preceding year, severe brain injury, Parkinson disease, or cerebellar disease
* Richter Syndrome
* Active autoimmune disease requiring systemic immunosuppression
* Prior solid organ transplantation
* Allogeneic stem cell transplantation within the preceding three months or still requiring systemic immunosuppression
* Current grade II - IV acute graft versus host disease (GVHD), any prior grade IV acute GVHD, or current moderate or severe chronic GVHD
* Systemic corticosteroids at doses of ≥ 20mg prednisone daily or equivalent within 7 days of enrolment
* Peripheral blood lymphocytes \< 0.3 x 10\^9/L as assessed by complete blood count
* Peripheral blood CD3+ T cells \< 150/μL as assessed by lymphocyte subset analysis
* Pregnant or lactating female
* Women of child-bearing potential who are not willing to use highly effective methods of contraception during study participation and for at least 1 year after WZTL-002 administration
* Men who are not willing to use highly effective methods of contraception during study participation and for at least 1 year after WZTL-002 administration
* Men who have a pregnant partner and are not willing to use a condom while performing sexual activity during study participation and for at least 3 months after WZTL-002 administration
* Participants with known sensitivity to immunoglobulin or to components of the investigational product (IP)
* History of active malignancy other than B-cell malignancy within two years prior to enrolment, with the exception of: adequately treated in situ carcinoma of the cervix; adequately treated basal cell carcinoma (BCC) or localized squamous cell carcinoma (SCC) of the skin; other localised malignancy surgically resected (or radically treated with another treatment modality) with curative intent
* Current or prior human immunodeficiency virus (HIV) infection
* Vaccination with a live virus within the preceding four weeks
* Treatment with a purine analogue within the preceding four weeks
* Treatment with alemtuzumab within the preceding 12 weeks
* Cytotoxic chemotherapy, radiotherapy or monoclonal antibody therapy (other than alemtuzumab) within 2 weeks of enrolment
* Prior gene therapy, including prior anti-CD19 chimeric antigen receptor T-cell therapy
* Receipt of an investigational medicine within another clinical trial within the preceding four weeks
* Inadequately controlled systemic infection
* Serologic status reflecting active viral hepatitis B or any history of hepatitis C infection as follows:

  * Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable (\< 20 IU), and if they are willing to receive appropriate anti-viral prophylaxis.
  * Presence of hepatitis C virus (HCV) antibody
* Presence of New York Heart Association (NYHA) class 2 or higher cardiac symptoms not related to lymphoma
* Significant concomitant illnesses which would in the investigator's opinion make the patient an unsuitable candidate for the trial
* Participants who have diminished capacity or any circumstance that would prohibit them from understanding and providing informed consent in accordance with ICH-GCP (International Conference on Harmonisation, Good Clinical Practice)
* Participant does not provide consent to enrol onto International Cellular Therapy Registry
B: 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.
C: Inclusion Criteria:

* Signed written informed consent obtained prior to study procedures
* Histologically-confirmed relapsed or refractory CD20+ B-cell lymphoma of one of the following types, with documented disease progression or recurrence following the immediate prior therapy:

  * DLBCL, regardless of cell of origin or underlying molecular genetics
  * MCL
  * PMBCL
  * Gr3b-FL
  * TH-FL
* Biopsy-confirmed CD20+ expression of the underlying malignancy by immunohistochemical staining or flow cytometry between the most recent dose of an anti-CD20 monoclonal antibody (mAb) and study enrollment
* At least 1 measurable lesion on imaging. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy
* Must have received adequate prior therapy for the underlying CD20+ B-cell lymphoma, defined as an anti-CD20 mAb in combination with an anthracycline-containing chemotherapy regimen (i.e. chemo-immunotherapy) and at least one of the following:

  * biopsy-proven refractory disease after frontline chemo-immunotherapy
  * relapse within 1 year from frontline chemo-immunotherapy and ineligible for autologous hematopoietic stem cell transplant (auto-HSCT)
  * For subjects with DLBCL, PMBCL, and Gr3b-FL: relapsed or refractory disease following at least 2 prior regimens or following an auto-HSCT
  * For subjects with TH-FL: relapsed or refractory disease following at least 2 prior regimens or following an auto-HSCT. At least 1 prior regimen with an anti-CD20 mAb in combination with chemotherapy is required following documented transformation
  * For subjects with MCL (confirmed with cyclin D1 expression or evidence of t(11;14) by cytogenetics, fluorescent in situ hybridization (FISH) or PCR): relapsed or refractory disease after at least 1 prior regimen with chemo-immunotherapy (prior auto-HSCT is allowable)
* Karnofsky performance scale ≥ 60%
* Life expectancy of at least 6 months
* ANC \> 1000/µL
* Platelet count \> 50,000/µL
* For women of childbearing potential (defined as physiologically capable of becoming pregnant), agreement to use of highly effective contraception for at least 1 year following ACTR087 infusion. For men with partners of childbearing potential, agreement to use effective barrier contraception for at least 1 year following ACTR087 infusion

Exclusion Criteria:

* Known active central nervous system (CNS) involvement by malignancy. Subjects with prior CNS involvement with their lymphoma must have completed effective treatment of their CNS disease at least 3 months prior to enrollment with no evidence of disease clinically and at least stable findings on relevant CNS imaging
* Prior treatment as follows:

  * alemtuzumab within 6 months of enrollment
  * fludarabine, cladribine, or clofarabine within 3 months of enrollment
  * external beam radiation within 2 weeks of enrollment
  * mAb (including rituximab) within 2 weeks of enrollment
  * other lymphotoxic chemotherapy (including steroids except as below) within 2 weeks of enrollment
  * experimental agents within 3 half-lives prior to enrollment, unless progression is documented on therapy
* Serum creatinine ≥ 1.5 X age-adjusted upper limits of normal (ULN)
* Pulse oximetry \< 92% on room air
* Direct bilirubin ≥ 3.0 mg/dL (50 mmol/L)
* Alanine transaminase (ALT) ≥ 3 times the ULN, unless determined to be directly due to lymphoma.
* Aspartate transaminase (AST) ≥ 3 times the ULN, unless determined to be directly due to lymphoma
* Class III or IV heart failure as defined by the New York Heart Association (NYHA), history of cardiac angioplasty or stenting, documented myocardial infarction or unstable angina within 6 months prior to enrollment, cardiac ejection fraction of \< 45%, or other clinically significant cardiac disease
* Clinical history of, prior diagnosis of, or overt evidence of autoimmune disease, regardless of severity
* Clinically significant active infection, in the judgment of the investigator
* Pregnancy (negative serum pregnancy test to be obtained within 6 days prior to enrollment for subjects of childbearing potential)
* Breastfeeding
* Primary immunodeficiency
* Seropositive for Human Immunodeficiency Virus (HIV) 1 or HIV 2, or positive hepatitis B surface antigen (HBsAg) or hepatitis C antibody
* Will need or has needed active treatment of a second malignancy within the prior 3 years before enrollment, other than FL, non-melanoma skin cancers, localized prostate cancer treated with curative intent, or cervical carcinoma in situ
* Is unable to receive any of the agents used in this study due a history of severe immediate hypersensitivity reaction (e.g. hypersensitivity to dimethyl sulfoxide (DMSO))
* History of prior allogeneic HSCT
* History of Richter's transformation from CLL
* Prior infusion of a genetically modified therapy
D: Inclusion Criteria:

1. Patients must have a diagnosis of relapsed or refractory B-cell NHL:

   * DLBCL, Mantle Cell, Follicular Lymphoma, Lymphoplasmacytic lymphoma, Small Lymphocytic Lymphoma, Primary Mediastinal B-Cell Lymphoma, Burkitt Lymphoma, transformed lymphoma.

     * Subjects with small lymphocytic lymphoma (SLL) must have progressed after at least 2 prior therapies and prior treatment with or intolerance of both ibrutinib and venetoclax.
     * Subjects with DLBCL, primary mediastinal B- Cell lymphoma, Burkitt lymphoma and transformed lymphoma must have relapsed or failed to respond to \>= 2 prior lines of multiagent chemoimmunotherapy with prior exposure to both an anti-CD20 antibody agent and an anthracycline.
     * Subjects with indolent lymphomas ((nodal or extranodal marginal zone lymphoma, follicular lymphoma and lymphoplasmacytic lymphoma) must have relapsed after or been refractory to \>=2 prior lines of multi-agent chemoimmunotherapy including prior exposure to rituximab and at least 2 other chemotherapy agents.
     * For subjects with Mantle cell lymphoma, previous lines of therapy may include multiagent chemotherapy including alkylating agent or anthracycline and anti CD20 antibody therapy and Bruton's tyrosine kinase (BTK) inhibitor therapy.
   * Positron Emission Tomography (PET) -positive disease according to "Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification"
   * At least one of the following:

     * Primary refractory or early relapse (first remission \< 12 months) and not eligible for stem cell transplant
     * Relapsed or refractory disease after two or more lines of systemic therapy
   * No significant circulating disease, defined as an elevated total lymphocyte count above the ULN due to the presence of malignant cells.
2. CD19 positive by either immunohistochemistry or flow cytometry analysis on any biopsy. If prior anti-CD19 therapy has been administered, CD19 positivity has to be re-established on the most recent biopsy.
3. Age \>=18 years at the time of consent
4. Absolute lymphocyte count \> 100/ (microliter)
5. Eastern Cooperative Oncology Group (ECOG) performance status \< 2
6. Adequate organ function, defined as:

   * Adequate bone marrow function for apheresis and lymphodepleting chemotherapy

     * Hemoglobin (Hgb) \>8 grams per deciliter (gm/dl) (transfusions allowed)
     * Platelets \>50,000/microliter (uL) (transfusions allowed)
     * Absolute Neutrophil Count (ANC) \> 500/uL
   * Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) \< 3 x institutional upper limit of normal (ULN) and Total bilirubin \< 1.5 mg/dl x institutional ULN, except with Gilbert's syndrome
   * Serum Creatinine \< 2 x the institutional ULN
   * Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) \> 40% as assessed by echocardiogram or multiple uptake gated acquisition (MUGA) within 3 months of screening. Repeat testing may occur at Investigator's discretion.
7. Adequate vascular access for leukapheresis procedure (either peripheral line or surgically placed line).
8. Women of childbearing potential (defined as all women physiologically capable of becoming pregnant) must have a negative serum or urine pregnancy test AND agree to use highly effective methods of contraception for 1 year after the last dose of anti-CD19 CAR-T cells
9. Males who have partners of childbearing potential must agree to use an effective barrier contraceptive method
10. Ability to understand a written informed consent document, and the willingness to sign it.

Exclusion Criteria:

1. Autologous transplant within 6 weeks of planned CAR-T cell infusion
2. Recipient of prior CAR-T cell therapy targeting CD19 outside of this protocol
3. Active other malignancy, other than non-melanoma skin cancer, carcinoma in situ (e.g., cervix, bladder, or breast).
4. HIV seropositivity
5. Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded.)
6. Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations that would limit compliance with study requirements.
7. Pregnant or breastfeeding women are excluded from this study because CAR-T cell therapy may be associated with the potential for teratogenic or abortifacient effects. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with CAR-T cells, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study. NOTE: Women of childbearing potential must have a negative serum or urine pregnancy test.
8. Patients with history of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia and Parkinson's disease.
9. History of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus) with requirement of immunosuppressive medication within 6 months.
10. Body weight \<40 kilograms(kg)

Eligibility for Infusion of Investigational Product:

Subjects will undergo an evaluation of eligibility on day 1 prior to infusion of anti-CD19 CAR-T cell product. This eligibility criterion will include the inclusion and exclusion criteria required for enrollment with the following exceptions and additions:

1. No significant laboratory abnormalities. Laboratory result abnormalities that are considered not clinically significant by the principal investigator AND are not the result of a demonstrated active infection or an active central nervous system condition.
2. ECOG performance status \< 2
3. No evidence of uncontrolled intercurrent illness including, but not limited to ongoing or active infection, inflammatory response, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations.
4. No new neurologic symptoms suggestive of an active central nervous system condition, or uncontrolled CNS involvement by lymphoma.
5. No corticosteroid use within 7 days prior to infusion (with exception of agents used for prevention of emesis during lymphodepletive chemotherapy).

Answer: B