Phase 2 single-arm, multi-cohort study to determine the efficacy and safety of JCAR017
(autologous T cells expressing anti-CD19 chimeric antigen receptor) in adult subjects with
aggressive B-NHL (diffuse large B-cell lymphoma (DLBCL) NOS [de novo or transformed
follicular lymphoma (tFL)], double/triple-hit lymphoma [DHL/THL], follicular lymphoma Grade
3B [FL3B], primary central nervous system lymphoma [PCNSL] and Richter's transformation).
This is a single-arm, multi-cohort, multi-center, Phase 2 study to determine the efficacy and
safety of JCAR017 in adult subjects with aggressive B-cell NHL. The study will enroll
subjects in Europe and Japan with DLBCL NOS (de novo or tFL), high-grade B-cell lymphoma with
MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (DHL/THL), FL3B, PCNSL and
Richter's transformation. Subjects with secondary central nervous system (CNS) involvement
Once enrolled subjects will undergo leukapheresis to enable JCAR017 cell product generation.
Upon successful JCAR017 cell product generation, subjects will receive LD followed by
infusion of JCAR017. JCAR017 will be administered at a dose of 1 x 10^8 JCAR017-positive
transfected viable T cells by intravenous infusion.
Subjects 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.
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
assessments/procedures being conducted.
3. Subject is willing and able to adhere to the study visit schedule and other protocol
4. Investigator considers the subject is appropriate for adoptive T cell therapy.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
6. Subjects with one of the following:
- Cohort 1: Subjects with DLBCL NOS (de novo or tFL), high-grade B-cell lymphoma
with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (DHL/THL) and
FL3B per WHO 2016 classification, 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), high
grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL
histology (DHL/THL) and FL3B per WHO 2016 classification, 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. At the very least, subjects have to meet one of the
following criteria: age ≥ 70 years, ECOG performance status ≥ 2, impaired
pulmonary function DLCO ≤ 60%), impaired cardiac function (LVEF < 50%),
impaired renal function (CrCl < 60 mL/min/1.73m2) or impaired hepatic
function (AST/ALT > 2x ULN, bilirubin > 2 mg/dL or cirrhosis Child-Pugh B or
- Cohort 3 (Japan only): Subjects meeting eligibility criteria for either Cohort 1
- Cohort 4: Subjects with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6
rearrangements with DLBCL histology (DHL/THL) who failed first line therapy.
Subjects may be screened at time of initial diagnosis and leukapheresis may be
performed prior to initiation of first line therapy.
- Cohort 5: Subjects with PCNSL after ≥ 1 line of therapy, including high-dose
- Cohort 6: Subjects with Richter's transformation after ≥ 1 line of therapy for
Note: Subjects with secondary DLBCL CNS involvement are eligible (not applicable for
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 subsequent therapies are given after last relapse with SD/PD as
best response, the tissue from that last relapse will be considered adequate to
participate in the trial.
8. For subjects with NHL and Richter's transformed CLL: Subject must have positron
emission tomography (PET)-positive disease as per Lugano Classification.
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, 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
- Serum creatinine < 1.5 x age-adjusted upper limit of normal (ULN) or creatinine
clearance > 30 mL/min (estimated glomerular filtration rate [eGFR] by
- 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
- 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 left ventricular ejection fraction (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 until at least 12 months after the JCAR017 infusion and
until CAR T cells are no longer present by quantitative polymerase chain reaction
(qPCR) on two consecutive tests, whichever occurs last.
13. Female subjects of childbearing potential (FCBP) must:
- 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). Subjects must agree to have another pregnancy
test performed 90 days post JCAR017 infusion. This applies even if the subject
practices true abstinence* from heterosexual contact.
- 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 and 1 additional effective (barrier)
method of contraception from screening until at least 12 months following JCAR017
infusion and until CAR T cells are no longer present by qPCR on two consecutive
tests, whichever occurs last.
- Agree to abstain from breastfeeding during study participation and for at least
90 days after JCAR017 infusion and until CAR T cells are no longer present by
qPCR on two consecutive tests, whichever occurs last.
14. Male subjects must:
- 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 JCAR017 infusion even if he has undergone a
successful vasectomy and until CAR T cells are no longer present by qPCR on two
consecutive tests, whichever occurs last.
- 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.
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 and Burkitt lymphoma.
5. History of another primary malignancy that has not been in remission for at least 2
years prior to enrollment. The following are exempt from the 2-year limit if
- Non-melanoma skin cancer
- Localized prostate cancer
- Cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on PAP
6. Treatment with any prior gene therapy product.
7. Subjects who have received previous CD19-targeted therapy.
8. Previous history of or active hepatitis B, hepatitis C, or human immunodeficiency
virus (HIV) infection.
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
- 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 such as epilepsy, seizure,
paresis, aphasia, stroke, 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:
- 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 (see below)
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, 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
antitumor 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.
- Allogeneic HSCT within 90 days prior to leukapheresis.
17. Prior hematopoietic stem cell transplant (only applicable to Cohort 2).