A Phase 2, Single-arm, Multi-center Trial to Determine the Efficacy and Safety of JCAR017 in Subjects With Relapsed or Refractory Diffuse Large B-Cell Lymphoma or With Other Aggressive B-Cell Malignancies

This is a single-arm, multi-cohort, multi-center, Phase 2 study to determine the efficacy and safety of JCAR017 in adult patients with aggressive B-cell NHL. The study will enroll patients in Europe and Japan with 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 (HGBL), follicular lymphoma Grade 3B (FL3B), and primary central nervous system lymphoma (PCNSL). Patients with secondary central nervous system (CNS) involvement are allowed.

Once enrolled, patients will undergo leukapheresis to enable JCAR017 cell product generation. Upon successful JCAR017 cell product generation, patients will receive lymphodepleting chemotherapy followed by infusion of JCAR017. JCAR017 will be administered at a dose of 100 x 10^6 JCAR017-positive transfected viable T cells by intravenous infusion. Patients will be followed for approximately 2 years after their JCAR017 infusion for safety, disease status, survival and health-related quality of life.

Delayed adverse events following exposure to gene modified T cells will be assessed and long-term persistence of these modified T cells will continue to be monitored under a separate long-term follow-up protocol for up to 15 years after JCAR017 infusion as per competent authority guidelines.

Inclusion Criteria:

Subjects must satisfy the following criteria to be enrolled in the study:

1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF)
2. Subject must understand and voluntarily sign an ICF prior to any study-related ssessments/procedures being conducted
3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements
4. Investigator considers the subject is appropriate for adoptive T cell therapy
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Subjects not eligible for transplant (TNE) in Cohorts 2 and 3 and subjects in Cohort 5 may be enrolled with ECOG of 2 only if they meet all other inclusion/exclusion criteria.
6. Subjects with one of the following:

   Cohort 1: Subjects with DLBCL NOS (de novo or tFL), HGBL and FL3B per WHO 2016 classification (Swerdlow, 2016), after ≥ 2 lines of therapy*, including an anthracycline and rituximab (or other CD20-targeted agent) Cohort 2: Transplant not eligible subjects with DLBCL NOS (de novo or tFL), HGBL and FL3B per WHO 2016 classification (Swerdlow, 2016), who failed first line therapy*, including an anthracycline and rituximab (or other CD20-targeted agent)

   • Transplant not eligible subjects will include those who are deemed ineligible for high-dose chemotherapy and HSCT due to age, performance status or comorbidity, while also having adequate organ function for CAR T cell treatment. At the very least, subjects have to meet one of the following criteria:
     1. Age ≥ 70 years
     2. ECOG performance status ≥ 2
     3. Impaired pulmonary function (DLCO ≤ 60%, adjusted for hemoglobin concentration using the Dinakara equation)
     4. Impaired cardiac function (LVEF < 50%)
     5. Impaired renal function (CrCl < 60 mL/min)
     6. Impaired hepatic function (AST/ALT > 2 x ULN, bilirubin ≥ 2 mg/dL or cirrhosis Child-Pugh B or C)
   • Subjects must fulfil all other in- and exclusion criteria Cohort 3 (Japan only): Subjects meeting eligibility criteria for either Cohort 1 or 2 Cohort 4: Subjects with newly diagnosed HGBL. Subjects must be eligible for anthracycline and rituximab (or other CD20-targeted agent) containing regimen as induction prior to consolidation with JCAR017** Cohort 5: Subjects with PCNSL who failed first line therapy with HDCT and ASCT Cohort 6: (REMOVED) Cohort 7: Subjects meeting eligibility criteria for Cohort 1 and suitable for outpatient treatment***
     • For subjects with transformed disease, the subject should have had at least 2 lines of systemic therapy for his/her transformed disease (ie, DLBCL) for Cohort 1 and 1 line for Cohort 2 to be eligible. Lines of therapy do not include those given for a previously indolent condition (ie, follicular lymphoma). Subjects do NOT have to have anthracycline for their DLBCL if received for indolent disease.
       • For subjects already undergoing anthracycline and rituximab containing regimen, eligibility is to be discussed with Medical Monitor. Subjects with complete metabolic response after 2 cycles of induction will proceed with JCAR017 infusion only at time of relapse, if applicable.
         • Subjects must meet the conditions for outpatient treatment and monitoring as outlined in the Outpatient Administration and Monitoring Guidance for Lisocabtagene Maraleucel.

   Note: Subjects with secondary CNS lymphoma involvement may enroll in Cohorts 1 to 4 and 7; subjects with PCNSL are eligible for Cohort 5. Subject selection must consider clinical risk factors for severe adverse events (AEs) and alternative treatment options. Subjects should only be enrolled if the Investigator considers the potential benefit outweighs the risk for the subject. For Cohort 5 and to not compromise safety, subject selection has been restricted to those fit enough to HDCT and ASCT as their prior therapy.

7. 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.

   Note: If the subject did not experience CR since last biopsy, the most recent biopsy will be considered adequate to participate in the trial. For subjects with PCNSL, at a minimum, corresponding pathology report is required if archival tumor material is not available and repeated biopsy not feasible.

8. (REMOVED) For subjects with NHL and Richter's transformed CLL
9. For subjects with PCNSL: Subjects must have disease that is objectively measurable by International Workshop to Standardize Baseline Evaluation and Response Criteria in Primary Central Nervous System (CNS) Lymphoma (Abrey, 2005), cerebrospinal fluid (CSF) cytology (in case of leptomeningeal only disease), or vitreal aspiration cytology and/or retinal photographs (in case of ocular lymphoma if clinically indicated)
10. Adequate organ function, defined as:
    • Adequate bone marrow function to receive LD chemotherapy as assessed by the Investigator
    • Serum creatinine < 1.5 x ULN or creatinine clearance > 30 mL/min (estimated glomerular filtration rate [eGFR] by Cockroft Gault)
    • Alanine aminotransferase (ALT) ≤ 5 x ULN and total bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for subjects with Gilbert's syndrome or lymphomatous infiltration of the liver) Adequate pulmonary function, defined as ≤ Grade 1 dyspnea according to Common Toxicity Criteria for Adverse Events (CTCAE) and SaO2 ≥ 92% on room air
    • Adequate cardiac function, defined as LVEF ≥ 40% as assessed by echocardiogram or multigated acquisition (MUGA) scan performed within 4 weeks prior to leukapheresis
11. Adequate vascular access for leukapheresis procedure
12. Subjects must agree to not donate blood, organs, sperm or semen, and egg cells for usage in other individuals after the JCAR017 infusion
13. Female subjects of childbearing potential (FCBP) must:
    1. Have two negative pregnancy tests as verified by the Investigator (one negative serum beta human chorionic gonadotropin [ß-hCG] pregnancy test result at screening and one negative serum pregnancy test within 48 hours prior to the first dose of LD chemotherapy). This applies even if the subject practices true abstinence* from heterosexual contact
    2. Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, effective contraception without interruption. Contraception methods must include 1 highly effective (barrier) method of contraception from screening until at least 12 months following LD chemotherapy

Note: Highly effective methods are defined as those that result in a low failure rate (ie, less than 1% per year) when used consistently and correctly. The following are examples of contraception:

• Highly effective methods:
• Intrauterine device (IUD)
• Hormonal (birth control pill, injections, implants)
• Tubal ligation
• Partner's vasectomy c) Agree to abstain from breastfeeding during study participation and for at least 12 months following LD chemotherapy d) There is insufficient exposure data to provide any recommendation concerning the duration of contraception and the abstaining from breastfeeding following treatment with JCAR017. Any decision regarding contraception and breastfeeding after JCAR017 infusion should be discussed with the treating physician 14. Male subjects must:
  1. Practice true abstinence* (which must be reviewed on a monthly basis and source documented) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study and until at least 12 months following LD chemotherapy even if he has undergone a successful vasectomy
  2. There is insufficient exposure data to provide any recommendation concerning the duration of contraception following treatment with JCAR017. Any decision regarding contraception after JCAR017 infusion should be discussed with the treating physician * True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. In contrast, periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

Exclusion Criteria:

The presence of any of the following will exclude a subject from enrollment:

1. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
2. Subject has any condition including the presence of laboratory abnormalities, which would place the subject at unacceptable risk if participating in the study
3. Subject has any condition that confounds the ability to interpret data from the study
4. Subjects with T cell rich/histiocyte rich large B-cell lymphoma (THRBCL), primary cutaneous large B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBCL), EBV positive DLBCL of the elderly, Burkitt lymphoma, and intraocular lymphoma
5. Subjects with prior history of malignancies, other than aggressive r/r NHL, unless the subject has been in remission for ≥ 2 years with the exception of the following non-invasive malignancies:
   • Basal cell carcinoma of the skin
   • Squamous cell carcinoma of the skin
   • Carcinoma in situ of the cervix
   • Carcinoma in situ of the breast
   • Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that is curative
   • Other completely resected stage 1 solid tumor with low risk for recurrence
6. Treatment with any prior gene therapy product
7. Subjects who have received previous CD19-targeted therapy
8. Human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C:
   • Subjects with a history of or active HIV are excluded
   • Subjects with active hepatitis B, or active hepatitis C are 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
9. Subjects with uncontrolled systemic fungal, bacterial, viral or other infection (including tuberculosis) despite appropriate antibiotics or other treatment at the time of leukapheresis or JCAR017 infusion
10. Presence of acute or chronic graft-versus-host disease (GVHD)
11. Active autoimmune disease requiring immunosuppressive therapy
12. History of any one of the following cardiovascular conditions within the past 6 months:
    • Heart failure class III or IV as defined by the New York Heart Association (NYHA)
    • Cardiac angioplasty or stenting
    • Myocardial infarction
    • Unstable angina
    • Other clinically significant cardiac disease
13. History or presence of clinically relevant CNS pathology not related to disease under study such as epilepsy, seizure, aphasia, stroke, cerebral edema, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis
14. Pregnant or nursing women
15. Treatment with alemtuzumab within 6 months of leukapheresis, or treatment with fludarabine or cladribine within 3 months of leukapheresis
16. Use of the following (see Section 8.2 for full details):
    • Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 7 days prior to leukapheresis or 72 hours prior to JCAR017 infusion. Physiologic replacement, topical, and inhaled steroids are permitted.
    • Low-dose chemotherapy (eg, vincristine, rituximab, cyclophosphamide ≤ 300 mg/m2) given after leukapheresis to maintain disease control must be stopped ≥ 7 days prior to LD chemotherapy
    • Cytotoxic chemotherapeutic agents that are not considered lymphotoxic within 1 week prior to leukapheresis. Oral anticancer agents, including lenalidomide and ibrutinib, are allowed if at least 3 half-lives have elapsed prior to leukapheresis
    • Lymphotoxic chemotherapeutic agents (eg, cyclophosphamide > 300 mg/m2, ifosfamide, bendamustine) within 2 weeks prior to leukapheresis
    • Experimental agents within 4 weeks prior to leukapheresis unless no response or progressive disease (PD) is documented on the experimental therapy and at least 3 half-lives have elapsed prior to leukapheresis
    • Immunosuppressive therapies within 4 weeks prior to leukapheresis and JCAR017 infusion (eg, calcineurin inhibitors, methotrexate or other chemotherapeutics, mycophenolate, rapamycin, thalidomide, immunosuppressive antibodies such as anti-tumor necrosis factor [TNF], anti-IL-6, or anti-IL-6R)
    • Donor lymphocyte infusions (DLI) within 6 weeks prior to JCAR017 infusion
    • Radiation within 6 weeks prior to 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, measurable PET-positive lesions are present, is allowed up to 2 weeks prior to leukapheresis. Prior WBRT for subjects enrolled in Cohort 5 is not allowed
    • Allogeneic HSCT within 90 days prior to leukapheresis
    • Prior hematopoietic stem cell transplant (only applicable to Cohort 2) Systemic immunostimulatory agents (including but not limited to interferon and IL-2) within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to JCAR017 infusion
17. Progressive vascular tumor invasion, thrombosis, or embolism
18. Venous thrombosis or embolism not managed on a stable regimen of anticoagulation
19. Known severe hypersensitivity to DMSO or Dextran