Trial to Determine the Efficacy and Safety of JCAR017 in Adult Subjects With Aggressive B-Cell Non-Hodgkin Lymphoma
Trial to Determine the Efficacy and Safety of JCAR017 in Adult Subjects With Aggressive B-Cell Non-Hodgkin Lymphoma
This open-label Phase 2 study will evaluate the safety and efficacy of modified T cells
 (JCAR017) administered to adult patients with aggressive B-cell non-Hodgkin lymphoma (NHL).
 The study will also help determine how long the modified T cells stay in the patient's body.
 Furthermore, changes in the patient's quality of life will be described. Phase 2 (autologous
 T cells expressing anti-CD19 chimeric antigen receptor) (DLBCL NOS [de novo or tFL],
 follicular lymphoma Grade 3B [FL3B], high grade B-cell Lymphoma [HGBL] and primary central
 nervous system lymphoma [PCNSL]).
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