Clinical trial NCT03743246
Conditions: Precursor Cell Lymphoblastic Leukemia-Lymphoma Lymphoma, Non-Hodgkin
Keywords: Pediatric JCAR017 CAR-T CART CD19 ALL NHL DLBCL BL PMBCL Cell Therapy LisoCell Young Adults Lymphoproliferative disorders Immune system diseases Leukemia Lymphoma lymphatic diseases
Sponsor: Celgene
Start date: 2018-10-17; Completion date: 2024-01-26
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 1/2, open-label, single arm, multicohort study to evaluate the safety and efficacy of JCAR017 in pediatric subjects aged ≤ 25 years with CD19+ r/r B-ALL and B-NHL.

Phase 1 will identify a recommended Phase 2 dose (RP2D). Phase 2 will evaluate the efficacy of JCAR017 RP2D in the following three disease cohorts: Cohort 1 (r/r B-ALL), Cohort 2 (MRD+ B-ALL) and Cohort 3 (r/r B-NHL, \[DLBCL, BL, or PMBCL\]). A Simon's Optimal two-stage study design will be applied to Cohort 1 and 2 in Phase 2.

Detailed description:
This is a Phase 1/2, open-label, single arm, multicohort study incorporating Simon's Optimal two-stage design to evaluate the safety and efficacy of JCAR017 in pediatric subjects aged ≤ 25 years with CD19+ r/r B-ALL and B-NHL.

In the Phase 1, up to 5 dose levels will be of JCAR017 will be evaluated. Enrollment will commence in pediatric subjects with r/r B-ALL at Dose Level 1 (DL1) of 0.05x10\^6 CAR+ T cells/kg (maximum DL1 of 5x10\^6 JCAR017 CAR+ T cells \[non-weight adjusted\]). If this dose is confirmed to be safe and tolerable, additional subjects will be enrolled at higher dose(s) up to 0.75 x10\^6 CAR+ T cells/kg (maximum of 75x10\^6 JCAR017 CAR+ T cells \[non-weight adjusted\]) with the aim to identify the RP2D. Dose escalation/de-escalation will follow a modified toxicity probability interval (mTPI-2) algorithm. A Safety Review Committee (SRC) will recommend the Phase 2 dose (defined as RP2D) based on an integrated assessment of the safety, PK and preliminary efficacy information from at least 10 pediatric subjects treated at the RP2D.

In Phase 2, a minimum of 71 additional subjects (\< 18 years of age) will be enrolled into one of the 3 cohorts listed below. The sample size for Cohorts 1 and 2 is calculated according to Simon's Optimal two-stage design. The 10 or more pediatric subjects treated at the RP2D in Phase 1 will form part of the sample size (ie, Cohort 1 and Cohort 2). Therefore, the protocol intends to treat 81 primary endpoint evaluable pediatric subjects in Phase 2, if warranted by the evaluation of results at the completion of the first stage of the study in each cohort.

* Cohort 1 (r/r B-ALL): 48 evaluable pediatric subjects (13 subjects in Stage 1 and 35 in Stage 2)
* Cohort 2 (MRD+ B-ALL): 23 evaluable pediatric subjects (9 subjects in Stage 1 and 14 subjects in Stage 2)
* Cohort 3 (r/r B-NHL \[DLBCL, BL, or PMBCL\]): 10 evaluable pediatric subjects. Due to the very low incidence rate and therefore expected low subject accrual, there is no formal sample size for this arm.

Up to 20 additional B-ALL subjects between 18 and 25 years of age may be enrolled in Phase 2.

Following treatment with JCAR017 subjects will then enter the post-treatment period for disease progression/relapse, safety, CAR T cell persistence, and survival up to 24 months after administration of JCAR017.

Efficacy will be assessed both locally and by an Independent Review Committee. Response assessments will be based on bone marrow and blood morphologic criteria, physical examination findings, along with laboratory assessments of cerebral spinal fluid (CSF) and bone marrow MRD (B-ALL only) assessments. B-NHL subjects will also have radiographic disease assessment by CT/MRI scans and tumor biopsies, if accessible.

Post-study follow-up for survival, relapse, long-term toxicity, and lentiviral vector safety will continue under a separate long-term follow-up protocol for up to 15 years after the JCAR017 infusion as per health authority regulatory guidelines.

An Independent Data Monitoring Committee will monitor the study conduct.

Arms: arm 1: Subjects will receive Lymphodepleting chemotherapy with intravenous (IV) fludarabine (30 mg/m2/day for 3 days) plus cyclophosphamide IV (300 mg/m2/day for 3 days) (flu/cy) concurrently, followed by JCAR017 cells infusion. Phase 1 will evaluate up to 5 JCAR017 cells dose levels and dose escalation/de-escalation will follow a modified toxicity probability interval (mTPI-2) algorithm. The declared RP2D in Phase 1 will be applied to the subjects enrolled in Phase 2
Interventions: intervention 1: JCAR017 intervention 2: Lymphodepleting intervention 3: Fludarabine intervention 4: Cyclophosphamide
Intervention descriptions: intervention 1: JCAR017 intervention 2: Lymphodepleting intervention 3: Fludarabine intervention 4: Cyclophosphamide

Protocol documents:
Prot_SAP_000.pdf: 
Official Title of Study: 
 
A Phase 1/2, open-label, single arm, multicohort, multicenter trial to evaluate the safety and 
efficacy of JCAR017 in pediatric subjects with relapsed/refractory B-ALL and B-NHL 
(TRANSCEND PEDALL) 
 
NCT Number: NCT03743246 
 
Document Date (Date in which document was last revised): September 10, 2019 


EDMS Doc. Number: 24103106 - 22557341
JCAR017
Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
1
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
TITLE PAGE
A PHASE 1/2, OPEN-LABEL, SINGLE ARM, 
MULTICOHORT, MULTICENTER TRIAL TO 
EVALUATE THE SAFETY AND EFFICACY OF 
JCAR017 IN PEDIATRIC SUBJECTS WITH 
RELAPSED/REFRACTORY B-ALL AND B-NHL
(TRANSCEND PEDALL)
PROTOCOL NUMBER:
JCAR017-BCM-004
DATE FINAL:
29 March 2018
AMENDMENT 1.0 DATE FINAL:
07 January 2019
AMENDMENT 2.0 DATE FINAL: 
10 September 2019
EudraCT NUMBER:
2018-001246-34
IND NUMBER
016506
SPONSOR NAME/ ADDRESS:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or 
consultant for review by you, your staff, and ethics committee/institutional 
review board.  The information contained in this document is regarded as 
confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by 
law or regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.
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JCAR017
Protocol JCAR017-BCM-004
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Confidential and Proprietary
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MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:     
Title:   
Address: 400 Dexter Ave. North, Suite 1200,
                Seattle, WA 98109, USA
Phone:   (Office) 
(Mobile)  
E-mail:   
Contact Information:
Name:     
Title:       
Address: Route de Perreux 1, 2017 Boudry, Switzerland
Phone:    (Office) 
(Mobile) 
E-mail:   
Note: The back-up 24-hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls.
Back-up 24-hour Global Emergency Contact Call Center: 
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Protocol JCAR017-BCM-004
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Confidential and Proprietary
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CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.  
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Protocol JCAR017-BCM-004
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Confidential and Proprietary
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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name:_______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from
Celgene representatives, the Declaration of Helsinki, International Council on 
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.
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JCAR017
Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
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COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:_______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed.
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JCAR017
Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
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PROTOCOL SUMMARY
Study Title
A Phase 1/2, open-label, single arm, multicohort, multicenter trial to evaluate the safety and 
efficacy of JCAR017 in pediatric subjects with relapsed/refractory B-ALL and B-NHL
(TRANSCEND PEDALL). 
Indication
CD19+ relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and B-cell non-
Hodgkin lymphoma (B-NHL) (comprised of diffuse large B-cell lymphoma [DLBCL], Burkitt 
lymphoma [BL] or primary mediastinal large B-cell lymphoma [PMBCL]) in pediatric subjects.
Objectives
Primary Objective
Phase 1:

To identify the recommended Phase 2 dose (RP2D) of JCAR017 in pediatric subjects 
with CD19+ r/r B-ALL. 
Phase 2:
To evaluate the following efficacy endpoints of the JCAR017 RP2D identified in Phase 1, in 
three pediatric disease cohorts:

Cohort 1 (r/r B-ALL): Overall response rate (ORR) defined as proportion of subjects with 
complete response (CR) or complete response with incomplete blood count recovery
(CRi) on Day 28 that must be confirmed on Day 56

Cohort 2 (MRD [minimal residual disease] positive [MRD+] B-ALL): MRD negative 
rate defined as proportion of subjects with a negative MRD response on Day 28 that must 
be confirmed on Day 56

Cohort 3 (r/r B-NHL [DLBCL, BL, or PMBCL]): ORR defined as proportion of subjects 
with a CR or partial response (PR) on Day 28
Study Design
This is a Phase 1/2, open-label, single arm, multicohort study incorporating the mTPI-2 dose 
escalation design in Phase 1 and a Simon’s Optimal two-stage design in Phase 2 to evaluate the 
safety and efficacy of JCAR017 in pediatric subjects with CD19+ r/r B-ALL and B-NHL.
Phase 1
Up to 5 dose levels of JCAR017 will be evaluated.
Enrollment will commence in pediatric subjects with r/r B-ALL at Dose Level 1 (DL1) of 
0.05x106 chimeric antigen receptor (CAR)+ T cells/kg (maximum dose of 5x106 JCAR017 
CAR+ T cells [non-weight adjusted]).  If this dose is confirmed to be safe and tolerable, 
additional subjects will be enrolled at higher dose(s) up to 0.75 x106 CAR+ T cells/kg 
(maximum of 75x106 JCAR017 CAR+ T cells [non-weight adjusted]) with the aim to identify 
the RP2D. Dose escalation/de-escalation will follow a modified toxicity probability interval 
(mTPI-2) algorithm with a target dose limiting toxicity (DLT) rate of 30% and an equivalence 
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Protocol JCAR017-BCM-004
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interval of 25% to 35%. A dose level will be considered unsafe, with no additional pediatric 
subjects enrolled at that dose level, if it has an estimated 95% or more probability of exceeding 
the target DLT rate of 30% (ie, P (DLT > 30%|data) > 95%) with at least 3 pediatric subjects 
treated at that dose level. For a dose level to be declared safe per the mTPI-2 algorithm, at least 
3 DLT-evaluable pediatric subjects must have completed the DLT period and the level estimated 
to be safe.  
Once the RP2D for JCAR017 has been selected, additional subjects will be enrolled until at least 
10 pediatric subjects are treated at the identified RP2D. The final number of pediatric subjects 
enrolled and treated, will depend on the number of dose levels tested and the number of DLTs 
observed within each dose level. Dose finding data from subjects who have become MRD+ or 
MRD negative upon restaging prior to initiation of lymphodepleting therapy will be evaluable 
for the DLT analysis and inform the identification of the RP2D. 
A Safety Review Committee (SRC) will convene regularly during Phase 1 to review DLTs and 
recommend a Phase 2 dose based on an integrated assessment of the safety, pharmacokinetic 
(PK) data and preliminary efficacy information from at least 10 pediatric subjects treated at the 
RP2D.  Analysis of the JCAR017 manufactured product may also be considered.
Phase 2
Up to 71 primary endpoint evaluable pediatric subjects (< 18 years of age) will be treated at the 
RP2D in one of the 3 cohorts listed below. The sample size for Cohorts 1 and 2 is calculated 
according to Simon’s Optimal two-stage design and based on the primary endpoints of ORR 
(Cohorts 1 and 3) and MRD negative rate (Cohort 2).
The 10 or more pediatric subjects treated at the RP2D in Phase 1 will form part of the sample 
size (ie, Cohort 1 and Cohort 2).  Therefore, the protocol intends to treat 81 primary endpoint 
evaluable pediatric subjects in Phase 2, if warranted by the evaluation of results at the 
completion of the first stage of the study in each cohort.

Cohort 1: 48 r/r B-ALL evaluable pediatric subjects (13 subjects in Stage 1 and 35
subjects in Stage 2)

Cohort 2: 23 MRD+ B-ALL evaluable pediatric subjects (9 subjects in Stage 1 and 14 
subjects in Stage 2)

Cohort 3: 10 r/r B-NHL (DLBCL, BL, or PMBCL) evaluable pediatric subjects (due to 
the very low incidence rate and therefore expected low subject accrual, there is no formal 
sample size for this arm).
Celgene may elect to explore the identified RP2D in up to 20 additional B-ALL subjects between 
18 and 25 years of age in an optional cohort in Phase 2, if it is determined that the risk-benefit 
profile is such that exploration is warranted after consultation with the SRC.
Study Flow for Individual Subjects
The study will have the following sequential periods: Pre-Treatment Period (screening and 
leukapheresis and JCAR017 product generation), Treatment Period (lymphodepleting [LD]
chemotherapy followed by infusion of JCAR017) and Post-Treatment Follow-up Period.  Prior 
to initiation of any study procedure (screening), subjects must provide informed consent/assent. 
Once enrolled, subjects will undergo an unstimulated leukapheresis to enable JCAR017 cell 
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Protocol JCAR017-BCM-004
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product generation. Subjects may receive optional bridging chemotherapy and upon successful 
JCAR017 cell product generation, will enter the Treatment Period to receive LD chemotherapy 
followed by infusion of JCAR017.
In Phase 1, subjects will be treated with JCAR017 at a rate of no more than 1 subject per 14 days 
after the prior subject receiving the JCAR017 infusion, regardless of site.  Once the RP2D has 
been identified, additional subjects enrolled in Phase 1 at the selected RP2D will be treated with 
JCAR017 at a rate of no more than 1 subject per site, per week.  
In Phase 2, subjects will be treated with JCAR017 at a rate of no more than 1 subject per site per 
week. 
In addition, a staggered dosing approach will also be utilized for all new sites without prior 
experience of administering CAR T cell therapies as follows:

1st subject infusion, wait 14 days

2nd subject infusion, wait 14 days
Following completion of this site-staggered enrollment approach, the site may proceed with 
subject enrollment as communicated by Celgene.
Following the Treatment Period, subjects will then enter the Post-Treatment Follow-Up Period 
for disease progression/relapse, safety, CAR T cell persistence, second primary malignancies and 
survival follow up for 2 years after administration of JCAR017 unless the subject is lost to 
follow-up. Post-study follow-up for survival, relapse, long-term toxicity, second primary 
malignacies and lentiviral vector safety will continue under a separate long-term follow-up 
(LTFU) protocol for up to 15 years after the JCAR017 infusion as per health authority regulatory 
guidelines.  All subjects who either complete the Post-Treatment Follow-up period or who 
prematurely withdraw after JCAR017 infusion will enroll into the LTFU study at the end of 
study (EOS) visit or at the time of withdrawal, respectively.  
An independent Data Safety Monitoring Board (DSMB) will monitor the study conduct. 
The study will be conducted in compliance with International Council for Harmonisation (ICH) 
Good Clinical Practices (GCPs).
Study Population
Phase 1: Male or female subjects, < 18 years of age, with CD19+ B-ALL who are r/r after ≥ 1 
line of chemotherapy, relapsed after hematopoietic stem cell transplantation (HSCT), or are 
otherwise ineligible for HSCT. 
Phase 2: Male or female subjects, ≤ 25 years of age, with CD19+ B-ALL or B-NHL who are r/r
after ≥ 1 line of chemotherapy, relapsed after HSCT, or are otherwise ineligible for HSCT. Three 
pediatric (< 18 years of age) cohorts of subjects will be enrolled: Cohort 1: r/r B-ALL; Cohort 2: 
MRD+ B-ALL; Cohort 3: r/r B-NHL (DLBCL, BL, or PMBCL). B-ALL subjects between 18 
and 25 years of age may also be enrolled in an optional cohort in Phase 2.
Enrollment and treatment of subjects will be restricted to a weight of ≥ 6 kg.  
B-NHL subjects > 18 years of age will not be eligible for this protocol.  B-NHL subjects with 
secondary central nervous system (CNS) involvement are allowed.  
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Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
9
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
Length of Study
This study will enroll over approximately 
months.
The End of Trial is defined as either the date of the last visit of the last subject completing the 
Post-Treatment Follow-up Period or the date when the last subject enters the LTFU study, or the 
date of receipt of the last data point from the last subject that is required for primary, secondary 
and/or exploratory analysis, as pre-specified in the protocol, whichever is the later date.
Study Treatments
Following enrollment in the study, an unstimulated leukapheresis collection will be performed 
on each subject to obtain a sufficient quantity of 
 
for the production of the JCAR017 investigational product (IP).
If necessary, anticancer treatment (ie, bridging chemotherapy) is allowed for disease control 
while JCAR017 is being manufactured, after leukapheresis but prior to LD chemotherapy. 
Subject must continue to have CD19-positive disease, including measurable disease by computed 
tomography (CT) or magnetic resonance imaging (MRI) for B-NHL subjects, and meet 
eligibility criteria pertaining to adequate organ function, active infections, pregnancy, and 
washout of prior therapy before initiation of LD chemotherapy.
Subjects will receive 3 days of fludarabine intravenously (IV) (30 mg/m2) and cyclophosphamide
IV (300 mg/m2) for LD chemotherapy. Two to 7 days after completion of LD chemotherapy, 
JCAR017 will be administered by IV infusion as a single dose on Day 1. The final JCAR017 
drug product consists of a single infusion of two individually formulated CD4+CAR+ and 
CD8+CAR+ T cell suspensions administered in a 1:1 ratio in a formulation containing dimethyl 
sulfoxide (DMSO).
In Phase 1, up to 5 dose levels of JCAR017 will be evaluated.  The first dose level will be 
0.05x106 CAR+ T cells/kg (maximum dose of 5x106 JCAR017 CAR+ T cells [non-weight
adjusted]). The declared RP2D will be applied in Phase 2. JCAR017 dosing will be capped at 
100kg for all dose levels. 
Overview of Key Efficacy Assessments
In the r/r setting, clinical activity based on the induction of complete responses is commonly 
recognized as a valid endpoint for the evaluation of the activity of a therapy.  The key efficacy 
assessments to be measured include peripheral count, bone marrow (BM) count, cerebrospinal
spinal fluid (CSF), physical examination, evaluation of CNS symptoms, disease specific imaging 
(ie, CT or MRI), and B-symptoms (ie, NHL).  Minimal residual disease in B-ALL subjects will 
be assessed by a validated assay in BM samples. A first response assessment will be performed 
28 days after JCAR017 infusion.
Efficacy response for B-ALL subjects will be assessed using the 2019 National Comprehensive 
Cancer Network (NCCN) response criteria guidelines for pediatric ALL. 
Efficacy response for B-NHL subjects will be assessed using the 2015 international pediatric 
NHL response criteria guidelines. 
An Independent Review Committee (IRC) will review all the efficacy data for each subject and 
confirm the response to therapy. The response assessment for the primary endpoint will be based 
only on the evaluations made by the IRC.
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Minimal residual disease response rate, post-infusion transplant status and time-to-event 
endpoints such as duration of response (DOR), relapse-free survival (RFS), event-free survival 
(EFS), best overall response (BOR) and overall survival (OS) will be assessed as secondary 
efficacy endpoints to ascertain that treatment has a clinically meaningful outcome for these 
subjects at the end-stage of the disease.
Overview of Key Safety Assessments
Adverse events (AEs), serious adverse events (SAEs), and laboratory abnormalities (type, 
frequency, and severity) will be collected. Adverse events of special interest (AESIs) include 
cytokine release syndrome (CRS), neurotoxicity, prolonged cytopenias, infections, tumor lysis 
syndrome (TLS), macrophage activation syndrome, infusion reactions, and 
hypogammaglobulinemia. These events will be carefully monitored during JCAR017 
administration and during follow-up.  The following safety assessments will also be monitored:

The timing and length of inpatient hospitalization

Physical exam and laboratory evaluations to monitor closely for neurologic changes, 
CRS, and fever
 monitoring for 
 vector sequences

Surveillance for second primary malignancies
Subjects will be followed for 2 years after the JCAR017 infusion (unless subject is lost to follow-
up or dies) and will then enter into a separate LTFU study. 
Safety monitoring boundaries based on the incidence of Grade 3 or above JCAR017-related 
AESIs are established using a Bayesian framework (ie, Thall and Simon stopping boundary), to 
help detect safety signals and to assure acceptable risk/benefit ratio during the course of the 
study.  If the safety boundaries are crossed, an ad-hoc DSMB meeting will be held to review the 
data and provide recommendation about the study continuation, as appropriate.
Statistical Methods
A feasibility endpoint will be conducted on the first 10 pediatric subjects enrolled for whom a 
manufacturing process was initiated to assess the percentage of product that is manufactured 
successfully. If product generation is successful for < 70% (< 7/10 subjects), the study will be 
temporarily suspended and reviewed by Celgene/DSMB.
Assuming a 18% enrollment dropout rate, a total of 124 pediatric subjects may be enrolled to 
ensure that approximately 101 primary endpoint evaluable subjects are treated with JCAR017.
Up to 20 additional B-ALL subjects between 18 and 25 years of age may also be treated in Phase 
2.
Primary Endpoint Analysis:
Phase 1:
The target DLT rate is set as 30%. The mTPI-2 method will be used to guide dose escalation and 
the RP2D will be estimated using isotonic regression based on the DLT evaluable analysis set. A 
dose level will be considered unsafe, with no additional pediatric subjects enrolled at that dose 
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Protocol JCAR017-BCM-004
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Confidential and Proprietary
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JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
level, if it has an estimated 95% or more probability of exceeding the target DLT rate of 30% (ie, 
P (DLT > 30%|data) > 95%) with at least 3 pediatric subjects treated at that dose level.  For a 
dose level to be declared safe per the mTPI-2 algorithm, at least 3 DLT-evaluable pediatric 
subjects must have completed the DLT period and the level estimated to be safe.  The DLT 
evaluable analysis set includes all pediatric subjects at a given dose level who have received 
conforming JCAR017 cell product and who have either experienced a DLT or were followed for 
the full DLT evaluation period.  
Phase 2: 
The sample size for Cohorts 1 and 2 is calculated according to Simon’s Optimal two-stage 
design and based on the primary endpoints of ORR (Cohorts 1 and 3) and MRD negative rate 
(Cohort 2).  The 10 or more pediatric subjects treated at the RP2D in Phase 1 will form part of 
the sample size (ie, Cohort 1 and Cohort 2) in Phase 2.
Cohort 1 (r/r B-ALL):  With a 1-sided 5% significance level, 80% power and the boundary to 
reject the null hypothesis of ORR = 75% vs. the boundary to accept the alternative hypothesis of 
ORR = 90%, a total of 48 evaluable subjects are required; 13 subjects in Stage 1 and 35 subjects 
in Stage 2.  At least 11 subjects with a confirmed response are required in Stage 1 to proceed into 
Stage 2 and a total of 41 or more subjects (Stage 1 and 2) are required to have a confirmed 
response to declare the study successful in this cohort (ie, a target ORR of 83%).
Cohort 2 (MRD+ B-ALL): With a 1-sided 5% significance level, 80% power and the boundary 
to reject the null hypothesis of MRD negative rate = 60% vs. the boundary to accept the 
alternative hypothesis of MRD negative rate = 85%, a total of 23 evaluable subjects are required; 
9 subjects in Stage 1 and 14 subjects in Stage 2.  At least 7 subjects with a confirmed MRD
negative response are required in Stage 1 to proceed into Stage 2 and a total of 18 or more 
subjects (Stage 1 and 2) are required to have a confirmed MRD negative response to declare the 
study successful in this cohort (ie, a target MRD response rate of 75%).
Cohort 3 (r/r B-NHL [DLBCL, BL, or PMBCL]): Due to the very low incidence rate and 
therefore expected low subject accrual, there is no formal sample size for this arm; instead, this 
disease indication will act to gain exploratory efficacy data in this population being treated with
JCAR017 at the RP2D. For this reason, the sample size has been set at 10 subjects.
Primary endpoint in Phase 2 will be based on the Efficacy Analysis Population, defined as 
subjects who fulfilled all study eligibility criteria and received a JCAR017 infusion with 
conforming product.  Subjects ineligible for analysis of the primary endpoints will be replaced.
For r/r B-ALL subjects (Cohort 1) with morphologic evidence of leukemia, response rate will be 
measured by the percentage of subjects achieving a CR or CRi on Day 28, confirmed on Day 56.  
Subjects without a response assessment on either Day 28 or Day 56 will be considered a non-
responder for purposes of the primary endpoint. 
For MRD+ patients (Cohort 2), MRD negative rate will be measured by the percentage of 
subjects achieving MRD negative status on Day 28, confirmed on Day 56. Subjects with an 
unknown MRD status on either Day 28 or Day 56 will be considered non-responders for 
purposes of the primary endpoint. 
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Protocol JCAR017-BCM-004
Celgene Corporation
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For r/r B-NHL subjects (Cohort 3), response rate will be measured by the percentage of subjects 
achieving CR or PR on Day 28.  Subjects with an unknown response status on either Day 28 or 
Day 56 will be considered non-responders for the purposes of the primary endpoint. 
 
Safety analysis will be based on the Safety Analysis Population, defined as all subjects receiving 
JCAR017 infusion. Data shall be analyzed according to system organ class and preferred term, 
presented in frequency tables and reported by dose level, disease cohort and in aggregate.
Efficacy data will be analyzed by the non-selected dose levels from Phase 1 and disease cohort 
(Phase 2 subjects and subjects treated at the RP2D in Phase 1).
Efficacy and safety for subjects aged 18 to 25 years shall be fully reported alongside and in 
aggregate with pediatric subjects aged < 18 years of age.  A risk-group sub-analysis with 
descriptive statistics and comparison between groups will be included as part of the overall 
analysis.
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JCAR017
Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
13
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................23
1.1.
Disease Background ...............................................................................................23
1.1.1.
Acute Lymphoblastic Leukemia .............................................................................23
1.1.2.
Non-Hodgkin Lymphoma.......................................................................................25
1.2.
Compound Background ..........................................................................................27
1.2.1.
CD19 as a Therapeutic Target.................................................................................27
1.2.2.
CD19-Targeted Chimeric Antigen Receptors..........................................................27
1.2.3.
JCAR017 Investigational Drug Product ..................................................................27
1.2.4.
Clinical Experience with JCAR017 and Related CAR T Cell Products ...................28
1.3.
Rationale ................................................................................................................29
1.3.1.
Study Rationale and Purpose ..................................................................................29
1.3.2.
Rationale for the Study Design ...............................................................................29
1.3.2.1.
Phase 1 ...................................................................................................................29
1.3.2.2.
Phase 2 ...................................................................................................................30
1.3.3.
Rationale for Dose, Schedule and Regimen Selection .............................................31
1.3.3.1.
Rationale for JCAR017 Dose..................................................................................31
1.3.3.2.
Rationale for Lymphodepleting Chemotherapy Dose..............................................32
32
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................35
3.
OVERALL STUDY DESIGN ................................................................................40
3.1.
Study Design ..........................................................................................................40
3.1.1.
Phase 1 ...................................................................................................................40
3.1.2.
Phase 2:..................................................................................................................41
3.1.3.
Study Flow for Individual Subjects.........................................................................41
3.2.
Stopping Rules .......................................................................................................46
3.2.1.
Criteria for Pausing or Stopping the Study..............................................................46
3.3.
Safety Monitoring Boundaries ................................................................................47
3.4.
Study Duration for Subjects....................................................................................47
3.5.
End of Trial ............................................................................................................47
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JCAR017
Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
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4.
STUDY POPULATION.........................................................................................48
4.1.
Number of Subjects ................................................................................................48
4.2.
Inclusion Criteria....................................................................................................48
4.3.
Exclusion Criteria...................................................................................................52
5.
TABLE OF EVENTS.............................................................................................54
6.
PROCEDURES......................................................................................................62
6.1.
Pre-treatment Period...............................................................................................62
6.1.1.
Screening................................................................................................................62
6.1.2.
Leukapheresis 
.....................63
6.1.3.
Anticancer Treatments Between Leukapheresis and Lymphodepleting 
Chemotherapy ........................................................................................................65
6.1.4.
Pre-Treatment Evaluation (Within 7 days Prior to Lymphodepleting 
Chemotherapy) .......................................................................................................66
6.2.
Treatment and Post-treatment Follow-up Periods....................................................67
6.2.1.
Treatment Period ....................................................................................................67
6.2.1.1.
Criteria for Treatment .............................................................................................67
6.2.1.2.
Lymphodepleting Chemotherapy (Start 5 to 10 Days Prior to JCAR017 
Infusion).................................................................................................................68
6.2.1.3.
JCAR017 Administration – Day 1 ..........................................................................68
6.2.1.4.
Days 2, 3, and 4 (+1 day for Day 4) ........................................................................70
6.2.1.5.
Day 7 (±1 day)........................................................................................................71
6.2.1.6.
Day 10 (±1 day)......................................................................................................71
6.2.1.7.
Days 14, 21, 28, and 56 ..........................................................................................72
6.2.2.
Post-treatment Follow-up Period.............................................................................73
6.3.
Unscheduled Evaluations........................................................................................75
6.4.
Assessments at Time of Death (Subjects Receiving JCAR017)...............................76
6.5.
Early Withdrawal....................................................................................................76
6.6.
Second Primary Malignancies Follow-up Period.....................................................76
6.7.
Survival Status........................................................................................................76
6.8.
Long-Term Follow-up ............................................................................................76
6.9.
Safety Assessments.................................................................................................77
6.9.1.
Physical Examination .............................................................................................77
6.9.2.
Tanner Staging .......................................................................................................77
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6.9.3.
Vital Signs..............................................................................................................77
6.9.4.
Height and Weight..................................................................................................77
6.9.5.
Routine Neurologic Examinations ..........................................................................77
6.9.6.
Cerebrospinal Fluid Assessment and Central Nervous System Symptom 
Assessment.............................................................................................................77
6.9.7.
Performance Status.................................................................................................78
6.9.8.
Echocardiogram/Multi-Gated Acquisition Scan ......................................................78
6.9.9.
Electrocardiogram ..................................................................................................78
78
6.9.11.
Clinical Laboratory Evaluations..............................................................................79
6.10.
Efficacy Assessment...............................................................................................79
6.10.1.
Acute Lymphoblastic Leukemia (B-ALL)...............................................................79
6.10.1.1.
Minimal Residual Disease (MRD) ..........................................................................80
6.10.2.
Non-Hodgkin Lymphoma (B-NHL)........................................................................80
6.10.2.1.
Pseudoprogression..................................................................................................81
6.10.3.
Independent Review Committee .............................................................................81
6.11.
Pharmacokinetics....................................................................................................81
6.11.1.
Viral Vector Sequence Pharmacokinetic Testing.....................................................81
81
81
82
6.13.
Patient-reported Outcomes......................................................................................82
6.14.
Hospital Resource Utilization .................................................................................84
7.
DESCRIPTION OF STUDY TREATMENTS........................................................85
7.1.
Description of Investigational Product ....................................................................85
7.1.1.
JCAR017................................................................................................................85
7.2.
Treatment Administration and Schedule .................................................................85
7.2.1.
Lymphodepleting Chemotherapy............................................................................85
7.2.2.
JCAR017 Premedication.........................................................................................85
7.2.3.
JCAR017 Preparation and Cell Thawing.................................................................86
7.2.4.
JCAR017 Administration........................................................................................86
7.2.5.
JCAR017 Dose Levels and Schedule ......................................................................86
7.2.5.1.
Phase 1 ...................................................................................................................86
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7.2.5.2.
Phase 2 ...................................................................................................................88
7.2.6.
Definition of Dose-limiting Toxicity.......................................................................88
7.2.7.
Overdose ................................................................................................................89
89
89
89
7.3.
Method of Treatment Assignment...........................................................................89
7.4.
Packaging and Labeling..........................................................................................90
7.4.1.
Product Tracking ....................................................................................................90
7.4.1.1.
Lymphodepleting Chemotherapy............................................................................90
7.4.1.2.
JCAR017................................................................................................................90
7.4.2.
Product Packaging and Labeling.............................................................................90
7.4.2.1.
Lymphodepleting Chemotherapy............................................................................90
7.4.2.2.
JCAR017................................................................................................................90
7.4.3.
Cell Product Supply and Storage.............................................................................90
7.5.
Investigational Product Accountability and Disposal ..............................................91
7.5.1.
Accountability Procedures......................................................................................91
7.5.2.
Drug Disposal and Destruction ...............................................................................91
7.6.
Investigational Product Compliance........................................................................91
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................92
8.1.
Permitted Concomitant Medications and Procedures...............................................92
8.1.1.
Anticancer Treatments between Leukapheresis and Lymphodepleting 
Chemotherapy ........................................................................................................93
8.2.
Prohibited Concomitant Medications and Procedures..............................................93
8.3.
Concomitant Medications and Procedures...............................................................94
9.
STATISTICAL CONSIDERATIONS ....................................................................95
9.1.
Overview................................................................................................................95
9.1.1.
Phase 1 ...................................................................................................................95
9.1.2.
Phase 2 ...................................................................................................................95
9.2.
Study Population Definitions ..................................................................................96
9.2.1.
Informed Consent/Assent Population:.....................................................................96
9.2.2.
Pre-treatment Population: .......................................................................................96
9.2.3.
Dose-limiting Toxicity Analysis Population:...........................................................96
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9.2.4.
Efficacy Analysis Population:.................................................................................97
9.2.5.
Safety Analysis Population: ....................................................................................97
9.2.6.
Pre-treatment Safety Analysis Population: ..............................................................97
97
9.2.8.
Pharmacokinetic Analysis Population:....................................................................97
9.2.9.
Patient Reported Outcome Analysis Population ......................................................98
9.3.
Sample Size and Power Considerations...................................................................98
9.3.1.
Phase 1 ...................................................................................................................98
9.3.2.
Phase 2 ...................................................................................................................98
9.3.2.1.
Cohort 1 (r/r B-ALL)..............................................................................................99
9.3.2.2.
Cohort 2 (MRD+ B-ALL).......................................................................................99
9.3.2.3.
Cohort 3 (B-NHL)..................................................................................................99
9.4.
Background and Demographic Characteristics........................................................99
9.5.
Subject Disposition...............................................................................................100
9.6.
Efficacy Analysis..................................................................................................100
9.6.1.
Phase 2 Primary Endpoints ...................................................................................100
9.6.1.1.
Overall Response Rate..........................................................................................100
9.6.1.2.
MRD Negative Rate .............................................................................................100
9.6.2.
Phase 1 and Phase 2 Secondary Endpoints............................................................101
9.6.2.1.
Overall Response Rate..........................................................................................101
9.6.2.2.
MRD Negative Response Rate..............................................................................101
9.6.2.3.
Duration of Response ...........................................................................................102
9.6.2.4.
Relapse-free Survival............................................................................................102
9.6.2.5.
Event-free Survival...............................................................................................102
9.6.2.6.
Overall Survival ...................................................................................................102
9.6.2.7.
Hematopoietic Stem-cell Transplant Rate .............................................................103
9.6.2.8.
Best Overall Response Rate..................................................................................103
9.7.
Safety Analysis.....................................................................................................103
9.7.1.
Phase 1 Primary Endpoint.....................................................................................103
9.7.1.1.
Recommended Phase 2 Dose ................................................................................103
9.7.2.
Phase 1 and Phase 2 Secondary Endpoints............................................................103
9.7.2.1.
Adverse Events.....................................................................................................103
9.7.2.2.
Deaths ..................................................................................................................104
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Protocol JCAR017-BCM-004
Celgene Corporation
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9.7.2.3.
Clinical Laboratories ............................................................................................104
9.7.2.4.
Vital Signs............................................................................................................104
9.8.
Interim Analysis ...................................................................................................104
9.9.
Other Topics.........................................................................................................105
9.9.1.
JCAR017 Manufacturing Feasibility.....................................................................105
9.9.2.
Safety Review Committee (SRC)..........................................................................105
9.9.3.
Data Safety Monitoring Board (DSMB)................................................................105
9.9.4.
Scientific Steering Committee (SSC)....................................................................106
9.9.5.
Exploratory Analysis ............................................................................................106
10.
ADVERSE EVENTS............................................................................................107
10.1.
Monitoring, Recording and Reporting of Adverse Events .....................................107
10.2.
Evaluation of Adverse Events...............................................................................108
10.2.1.
Seriousness...........................................................................................................108
10.2.2.
Severity/Intensity..................................................................................................109
10.2.3.
Causality ..............................................................................................................110
10.2.4.
Duration ...............................................................................................................111
10.2.5.
Action Taken........................................................................................................111
10.2.6.
Outcome...............................................................................................................111
10.3.
Abnormal Laboratory Values................................................................................111
10.4.
Pregnancy.............................................................................................................111
10.4.1.
Female Children of Childbearing Potential/Females of Childbearing 
Potential ...............................................................................................................112
10.4.2.
Male Subjects.......................................................................................................112
10.5.
Reporting of Serious Adverse Events....................................................................112
10.5.1.
Safety Queries ......................................................................................................113
10.5.2.
Death Reports.......................................................................................................113
10.6.
Potential Risks and Management of Treatment Toxicities.....................................113
10.6.1.
Management of Toxicities Associated with JCAR017...........................................113
10.6.1.1.
Cytokine Release Syndrome .................................................................................113
10.6.1.2.
Fever ....................................................................................................................114
10.6.1.3.
Cytopenias............................................................................................................114
10.6.1.4.
Infections..............................................................................................................114
10.6.1.5.
Neurologic Toxicities ...........................................................................................114
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Celgene Corporation
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10.6.1.6.
Macrophage Activation Syndrome........................................................................115
10.6.1.7.
Infusion Reactions ................................................................................................115
10.6.1.8.
Tumor Lysis Syndrome ........................................................................................115
116
10.6.1.10. Graft-Versus-Host Disease ...................................................................................116
10.6.1.11. Uncontrolled T Cell Proliferation..........................................................................116
116
10.6.1.13. Risks Associated with Lymphodepleting Chemotherapy.......................................117
10.6.1.14. Second Primary Malignancies...............................................................................117
10.7.
Expedited Reporting of Adverse Events................................................................117
10.8.
Adverse Event of Special Interest .........................................................................118
11.
DISCONTINUATIONS .......................................................................................119
11.1.
Pre-treatment Period Discontinuation....................................................................119
11.2.
Treatment Period Discontinuation.........................................................................119
11.3.
Study Discontinuation ..........................................................................................119
12.
EMERGENCY PROCEDURES...........................................................................121
12.1.
Emergency Contact...............................................................................................121
12.2.
Emergency Identification of Investigational Products ...........................................121
13.
REGULATORY CONSIDERATIONS.................................................................122
13.1.
Good Clinical Practice..........................................................................................122
13.2.
Investigator Responsibilities .................................................................................122
13.3.
Subject Information and Informed Consent/Assent ...............................................123
13.4.
Confidentiality......................................................................................................123
13.5.
Protocol Amendments...........................................................................................123
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ..............................................................................................................123
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ..............124
13.8.
Termination of the Study ......................................................................................124
14.
DATA HANDLING AND RECORDKEEPING...................................................125
14.1.
Data/Documents ...................................................................................................125
14.2.
Data Management.................................................................................................125
14.3.
Record Retention..................................................................................................125
15.
QUALITY CONTROL AND QUALITY ASSURANCE......................................127
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Protocol JCAR017-BCM-004
Celgene Corporation
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15.1.
Study Monitoring and Source Data Verification....................................................127
15.2.
Audits and Inspections..........................................................................................127
15.3.
Product Quality Complaint ...................................................................................127
16.
PUBLICATIONS .................................................................................................129
17.
REFERENCES.....................................................................................................130
18.
APPENDICES......................................................................................................137
APPENDIX A.
TABLE OF ABBREVIATIONS..................................................................138
APPENDIX B.
RESPONSE CRITERIA FOR ALL..............................................................143
APPENDIX C.
RESPONSE CRITERIA FOR NHL .............................................................144
APPENDIX D.
CLINICAL LABORATORY EVALUATIONS...........................................145
APPENDIX E.
CAIRO-BISHOP DEFINITIONS OF TUMOR LYSIS SYNDROME..........146
APPENDIX F.
MANAGEMENT GUIDELINES FOR CYTOKINE RELEASE 
SYNDROME AND NEUROLOGIC TOXICITIES (PEDIATRICS 
VERSION 2.0) .....................................................................................................148
MANAGEMENT OF TOXICITIES ASSOCIATED WITH JCAR017....................................149
1.
CYTOKINE RELEASE SYNDROME.................................................................150
1.1.
Pathophysiology of Cytokine Release Syndrome ..................................................150
1.2.
Clinical Presentation of Cytokine Release Syndrome............................................150
1.3.
Clinical Management of Cytokine Release Syndrome...........................................151
2.
MACROPHAGE ACTIVATION SYNDROME 
(MAS)/HEMOPHAGOCYTIC LYMPHO-HISTIOCYTOSIS (HLH) ..................154
2.1.
Pathophysiology of HLH/MAS.............................................................................154
2.2.
Clinical Presentation and Diagnosis of HLH/MAS................................................154
2.3.
Clinical Management of HLH/MAS .....................................................................156
3.
NEUROLOGIC TOXICITIES..............................................................................157
3.1.
Pathophysiology of Neurologic Toxicities ............................................................157
3.2.
Clinical Management of Neurologic Toxicities.....................................................157
4.
REFERENCES.....................................................................................................162
APPENDIX G.
MODIFIED TOXICITY PROBABILITY INTERVAL DECISION 
TABLE.................................................................................................................165
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JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
LIST OF TABLES
Table 1:
Study Objectives.....................................................................................................35
Table 2:
Study Endpoints .....................................................................................................36
Table 3:
Table of Events.......................................................................................................54
Table 4:
Washout Periods Prior to Leukapheresis.................................................................64
Table 5:
Administration of Pediatric Quality of Life Inventory Questionnaires.....................83
Table 6:
JCAR017 Dose Levels............................................................................................86
Table 7:
Reporting Periods for Concomitant Medications.....................................................92
Table 8:
Reporting Periods for Adverse Events ..................................................................107
Table 9:
Clinical Laboratory Evaluations............................................................................145
Table 10:
Grading Criteria for Cytokine Release Syndrome .................................................151
Table 11:
High-Dose Vasopressors (all doses required for ≥ 3 hours)...................................152
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Protocol JCAR017-BCM-004
Celgene Corporation
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JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................44
Figure 2:
Study Schematic .....................................................................................................45
Figure 3:
mTPI-2 Dose Escalation Decision Pathway for Dose Level 1 Only.........................87
Figure 4:
JCAR017 Cytokine Release Syndrome Treatment Algorithm ...............................153
Figure 5:
Neurotoxicity Treatment Algorithm......................................................................160
Figure 6:
Cerebral Edema Management Guidelines .............................................................161
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1.
INTRODUCTION 
1.1.
Disease Background 
1.1.1.
Acute Lymphoblastic Leukemia 
Acute lymphoblastic leukemia (ALL) is classified by the World Health Organization 
(WHO) (Vardiman, 2009) as a precursor lymphoid neoplasm of primarily the B-cell type with 
only about 10% to 15% of cases involving T cells (Tasian, 2015).  Precursor B-cell ALL (B-
ALL), defined by the expression of CD79a, CD19, human leukocyte antigen – antigen D related 
(HLA-DR), and other B-cell antigens accounts for 80% to 85% of childhood ALL and about 
30% of all childhood cancers.  Acute lymphoblastic leukemia is the most prevalent cancer 
among children and adolescents in the United States (US), representing 20% of all cancers 
diagnosed in persons aged < 20 years. The overall incidence of pediatric ALL during 2001 to 
2004 was 34.0 cases per 1 million persons. Pediatric ALL has increased during 2001 to 2008 and 
remained stable during 2008 to 2014. During 2001 to 2014, a total of 38,136 new pediatric ALL 
cases were diagnosed in the US (Siegel, 2017). In Europe, the overall incidence of ALL is 11 per 
million per year, but importantly, the incidence peaks in childhood between 2 and 5 years of age 
(53 per million) and again after 50 years of age (Faderl, 2010). The disease is referred to as 
lymphoblastic lymphoma (LBL) if the infiltration of bone marrow (BM) is below 25%, and if the 
BM involvement is > 25% it is leukemia. Immunophenotyping (by flow cytometry) allows the 
differentiation between B and T precursor ALL and reveals the differentiation status of the 
malignant B-cells (pro-B, common, pre-B, and mature B-cell), which is essential for treatment 
selection. 
An aggressive cancer of the blood and BM, ALL is the most common form of precursor B-cell 
neoplasm and is characterized by the proliferation and accumulation of malignant, transformed, 
and immature hematopoietic cells (“blasts”) that accumulate in blood and BM (Gokbuget, 2012).  
Bone marrow analysis, required for diagnosis, reveals the great majority of children presenting 
with ALL have a massive leukemic infiltration of more than 50% blast cells by light microscopy.  
Other lymphatic organs, such as lymph nodes and spleen, can also be affected, as well as non-
lymphatic organs, notably the central nervous system (CNS). Less than 10% of pediatric patients 
have symptomatic CNS involvement, although the frequency is higher in patients with mature B-
ALL (Faderl, 2010).
Risk factors for developing ALL include age, exposure to chemotherapy or radiation therapy, 
and genetic disorders, including Down’s syndrome.  The risk for developing ALL is highest in 
children younger than 5 years of age; the risk declines slowly until the mid-20s, and begins to 
rise again after the age of 50.  Approximately 75% of patients with B-ALL have recurrent 
chromosomal translocations or somatic aneuploidy, many of which have prognostic 
value (Tasian, 2015). Roughly half of patients with childhood ALL have chromosomal 
translocations, many of which are undetectable by conventional cytogenetic analysis, but readily 
detected by fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR).  The 
most common of these is the t(12;21) translocation, resulting in an ETV6-runt-related 
transcription factor 1 fusion that occurs in 20% to 25% of childhood National Cancer Institute 
(NCI) standard-risk B-ALL.  Children with this genetic alteration have an excellent prognosis 
with a > 95% overall survival (OS) rate (Gaynon, 2012).  
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Multidrug chemotherapy is the standard treatment option for newly diagnosed childhood ALL.  
First-line induction therapy for most patients, regardless of presenting features, consists of 
vincristine, dexamethasone (or prednisone), asparaginase, and doxorubicin — the Berlin-
Frankfurt-Münster (BFM) regimen.  More than 95% of children receiving first-line therapy will 
achieve a complete response (CR) within the first 4 weeks of treatment, and 5-year OS rates are 
approaching 90% (Pui, 2015).  For patients presenting with CNS disease, intrathecal triple 
therapy (methotrexate [MTX], cytarabine, and prednisolone) is used during induction therapy 
together with intravenous (IV) high-dose MTX to reduce the risk of systemic relapse.  These 
days, because of the risk of delayed neurocognitive impairment, radiation therapy is rarely a 
component of frontline therapy, but it is used in combination with intrathecal MTX in limited 
situations where there is a particularly high-risk of CNS relapse (Rabin, 2016).
Once a CR has been achieved, standard postinduction treatment options vary depending on risk 
group assignment, but all patients receive some form of intensification therapy after CR and 
before beginning maintenance therapy.  The most commonly used therapy includes 
cyclophosphamide, low-dose cytarabine, and a thiopurine.  Maintenance therapy typically 
consists of mercaptopurine, low-dose MTX, and sometimes vincristine/steroid pulses.  The exact 
therapeutic regimen depends on the risk category of the patient.  There has been an attempt to 
limit exposure to anthracyclines and alkylating agents in children with standard-risk ALL 
because these drugs increase the risk of late toxicity.  
The presence of minimal residual disease (MRD) in these patients, however, necessitates the use 
of these drugs for maintenance therapy. A previous study assessing the prognostic significance of 
MRD in high risk B-ALL found that increased levels of MRD were associated with worsening 
outcomes. MRD > 0.1% at the end of induction is found to be a poor prognostic indicator. 
Additionally, persistence of MRD at 12 weeks was found to be a very poor prognostic factor, 
with 5-year disease-free survival (DFS) of approximately 40% (Borowitz, 2015). A blinded 
prospective study was performed to optimize risk assessment of children with a late isolated, 
combined or an early combined BM relapse of pre-cursor B-ALL. This study found that patients 
with intermediate risk BM relapse of ALL, low MRD after induction is associated with an 
excellent long-term prognosis with conventional chemo-/radiotherapy whereas patients with 
insufficient response have an extremely poor prognosis. The results of this study confirmed that 
the MRD level after induction is the strongest independent prognostic factor for the long-term 
outcome of children with intermediate risk BM relapse of ALL (Eckert, 2011).
Multiple clinical studies with chimeric antigen receptor (CAR) T cells have shown high 
remission rates among children and adults with relapsed B-ALL. For example, a Phase 1 study
was conducted at Memorial Sloan Kettering Cancer Center (MSKCC) involving adults with 
relapsed B-ALL treated with autologous T cells expressing the 19-28z CAR, a CD-19 specific 
CAR T.  A total of 53 subjects received the T cells. After infusion, cytokine release syndrome 
(CRS) occurred in 26% of subjects and 1 subject died. Complete remission was observed in 83% 
of subjects. At a median follow-up of 29 months, the median event-free survival (EFS) was 6.1 
months and median OS was 12.9 months. Subjects with a low disease burden (< 5% BM blasts) 
before treatment had enhanced remission duration and survival. Subjects with a high burden of 
disease (≥ 5% BM blasts or extramedullary disease) had a greater incidence of CRS and 
neurotoxic events with shorter long-term survival (Park, 2018). 
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Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
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The ELIANA clinical study evaluated the recently approved CAR T cell therapy, CTL019 
(Kymriah™), in relapsed/refractory (r/r) pediatric and young adult subjects with B-ALL. The 
ELIANA study was a single-arm, open-label, multicenter Phase 2 registration study that included 
75 subjects aged 3 to 23 years of age who were primary refractory, refractory to chemotherapy 
after their first relapse, relapsed after second-line therapy, or ineligible for an allogeneic stem 
cell transplant (SCT). Subjects in the study received a median of 3 prior lines of therapy, had a 
median marrow blast percentage of 74% at enrollment, and 61% of subjects had a prior SCT. 
This study showed that of 75 subjects who received Kymriah and had at least 3 months of 
follow-up, the overall response rate (ORR) was 81% (60% with CR and 21% with complete 
remission with incomplete blood count recovery [CRi]). Additionally, all subjects with or 
without complete hematologic recovery were MRD negative. The median duration of follow-up 
among subjects who received Kymriah was 13.1 months. The rates of EFS and OS were 73% 
and 90%, respectively, at 6 months and 50% and 76%, respectively, at 12 months. Furthermore, 
47% of subjects experienced grade 3 or 4 CRS within 8 weeks after Kymriah infusion. 
Neurologic events occurred in 30 of 75 subjects (40%) within 8 weeks after infusion. Ten 
subjects (13%) had grade 3 neurologic events; no grade 4 events or cerebral edema were 
reported. Nineteen deaths occurred after Kymriah infusion. Within 30 days after infusion, 1 
subject died from cerebral hemorrhage in the context of coagulopathy and resolving CRS, and 1 
subject died from progressive disease. More than 30 days after infusion, 17 subjects died due to 
various causes (Maude, 2018). 
Until the recent approval of Kymriah in the US, the best therapeutic option capable of achieving 
disease eradication for children with relapsed ALL almost invariably included an allogeneic 
SCT, provided a suitable donor was available and the disease was controlled prior to 
transplant (Bleakley, 2002).  For those who relapse early (< 36 months from diagnosis), the 3-
year post-relapse survival is 30%, whereas those who relapse late (≥ 36 months from diagnosis) 
have a 3-year survival of 57.8% (Freyer, 2011).  
1.1.2.
Non-Hodgkin Lymphoma
Non-Hodgkin lymphoma (NHL) is a heterogeneous group of lymphoproliferative malignancies 
with differing clinical courses and responses to treatment (Pinkerton, 2012).  The WHO 
Lymphoma Classification scheme is commonly used to define specific subtypes of lymphoma 
and subdivides them based on cell of origin (B, T or natural killer [NK]) and the differentiation 
status of the lymphocytes (Vardiman, 2010).  Eighty percent to 90% of NHL are of B-cell origin 
and express CD19 (Pinkerton, 2012). The prognosis of NHL depends on the histologic type 
(indolent versus aggressive), stage, age, and treatment.  The NHL subtypes that occur in adult 
and pediatric populations show both similarities as well as distinct differences. Childhood NHL 
typically displays an aggressive clinical course, while adult NHLs show both indolent and 
aggressive histological forms.  Indolent subtypes of NHL that occur in adults include follicular 
lymphoma (FL), marginal zone lymphoma (MZL), and chronic lymphocytic leukemia (CLL). 
Aggressive B-cell subtypes include diffuse large B-cell lymphoma (DLBCL) and mantle cell 
lymphoma (MCL) (Chao, 2013).  
Many of the NHL types, including FL, CLL, and MCL, that are relatively common in adults 
occur very rarely, if at all, in children (Gerrard, 2008). Pediatric B-cell non-Hodgkin’s 
lymphoma (B-NHL), comprises of 3 main histological subtypes, all of which are classified as 
aggressive:  Burkitt lymphoma (BL), DLBCL, and primary mediastinal large B-cell lymphoma 
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Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
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JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
(PMBCL), in descending order of overall incidence. The majority of LBL cases (≥75%) are T 
cell lineage with the remainder having a pre-B or mature B-cell immunophenotyped (Cairo, 
2016).
The annual incidence per million inhabitants in the US ranges from 5.9 in children younger than 
5 years of age to about 10 in children between 5 and 14 years of age, and 15 in adolescents 
(approximately 150 in adults) (Minard-Colin, 2015). As a group, all forms of NHL combined 
account for approximately 7% of new childhood and adolescent cancer diagnoses in 
Europe (Stiller, 2006); 1436 children and 205 adolescents were diagnosed in Europe between 
1993 and 1997 (Stiller, 2006).  In Europe, the age-adjusted incidence of NHL in children aged 0 
to 14 years is 9.2 per million, and is approximately 2.4-fold higher in males (Stiller, 2006); the 
incidence of NHL and predominant B-cell histologies in Western Europe is comparable to that of
the US.  Data from the US Surveillance, Epidemiology, and End Results (SEER) Program
provides the age-specific incidences of the 3 pediatric B-NHL histologies. The occurrence of 
NHL in infants is very rare, and the incidence in adults increases steeply with age.  Adolescents, 
specifically the 15- to 19-year age group, have a higher mortality rate compared to children in 
the 10- to 14-year age group (Burkhardt, 2012). The most prevalent forms of pediatric B-NHL 
comprise about 60% of all childhood NHL and are detailed below. 
Despite significant progress in treatment, approximately 25% to 30% of children will relapse or 
experience refractory disease with cure rates less than 30% (Jourdain, 2015).  
For both aggressive and indolent subtypes, r/r pediatric B-NHL represents a major treatment 
challenge since there is no standard of care for salvage regimens, with prognosis after relapse 
remaining relatively poor. Salvage treatment typically consists of high-dose chemotherapy 
followed by an intensification phase with either autologous or allogenic hematopoietic SCT 
(HSCT). Given the poor long-term survival in children with r/r B-NHL and the absence of 
potential curative therapies, novel approaches are needed for these patients with no effective 
treatment options.
Diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma accounts for 10% to 20% of B-cell lymphoma in children and 
occurs more frequently in adolescents (Minard-Colin, 2015). Diffuse large B-cell lymphoma is 
the most prevalent form of NHL in children and adolescents combined, occurring with greater 
frequency in adolescents, and comprising up to 37% of all NHL in the 15 to 19 year age 
range (Hochberg, 2016; Minard-Colin, 2015).  With increasing age, the age-specific incidence 
(per million) of DLBCL grows from 2.9 in childhood, 5.8 in adolescence, 43 in adults 25 to 64 
years of age, and peaks at 300 in adults > 65 years of age.  
Burkitt lymphoma
In children ≤ 14 years of age, BL is the most common NHL, comprising 30% to 40% of all NHL 
in North America and Europe (Molyneux, 2012). It generally arises in the abdomen and/or head 
and neck region and presents as advanced-stage disease involving the BM and/or CNS in 
approximately 20% to 25% of patients (Minard-Colin, 2015).  The incidence of BL remains 
relatively constant throughout life, in contrast to other NHL subtypes including DLBCL, which 
typically increase dramatically with age.  Burkitt lymphoma has a distinct epidemiological 
pattern because of its association with Epstein-Barr virus (EBV) and malaria infections that are 
endemic in sub-Saharan Africa.  In this region, the incidence of BL is estimated at 40 to 50 per 
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JCAR017
Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
27
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
million children < 18 years of age and comprises up to 90% of all NHL diagnoses (Molyneux, 
2012).  The sporadic form, found in low-risk areas such as North America and Europe, has a 
much lower incidence of 2 to 4 per million children (Sant, 2010).  The incidence of the sporadic 
form peaks at 6 to 8 years of age and is 3.5 times more common in boys than in girls.  
Primary mediastinal large B-cell lymphoma
Until recently, PMBCL was considered as a form of DLBCL, comprising 10% or fewer of all 
cases (Vitolo, 2016).  It is now recognized as a distinct entity in the WHO classification because 
of its distinct immunophenotype, gene expression profile, and clinical presentation compared to 
other histologies (Dunleavy, 2015).  Owing to the rarity of this form of NHL, data on incidence 
by age are incomplete.  A BFM study group identified a total of 30 children with PMBCL out of 
a large cohort of 1650 pediatric patients with NHL, or 1.8% of all patients diagnosed with NHL, 
during the period from 1986 to 1999 (Seidemann, 2003). This rate equates to approximately 9 to 
16 cases annually in Europe, and is similar to that seen in the US. The incidence of PMBCL 
peaks in the third or fourth decade of life and is more common in women (Cairo, 2016; Vitolo, 
2016).
1.2.
Compound Background 
1.2.1.
CD19 as a Therapeutic Target
CD19 is a 95 kDa glycoprotein present on B-cells from early development until differentiation 
into plasma cells (Stamenkovic, 1988). It is a member of the immunoglobulin superfamily and 
functions as a positive regulator of the B-cell receptor by lowering the signaling threshold for B-
cell activation (Brentjens, 2011; LeBien, 2008; Stamenkovic, 1988). CD19 is an attractive 
therapeutic target because it is expressed by most B-cell malignancies, including B-
NHL (Davila, 2012). Importantly, the CD19 antigen is not expressed on hematopoietic stem cells 
or on any normal tissue apart from those of the B-cell lineage. Additionally, CD19 is not shed in 
the circulation, which limits off-target adverse effects (Shank, 2017). 
1.2.2.
CD19-Targeted Chimeric Antigen Receptors
CD19-specific CARs are generated by the fusion of a single chain variable fragment (scFv), 
derived from an anti-CD19 monoclonal antibody (mAb), to an intracellular signaling domain. 
Expression of the CD19-directed CAR in autologous T cells is achieved by ex vivo transduction 
using a recombinant retroviral or lentiviral vector. The CAR is expressed on the T cell surface 
and redirects the transfected T cells to CD19-expressing lymphoma cells, leading to CD19-
specific tumor cell recognition, lysis, cytokine secretion, and T cell proliferation (Sadelain, 
2013). In clinical studies, CD19-targeted CARs have demonstrated encouraging activity in adult 
and pediatric subjects with r/r B-ALL and B-NHL (Gardner, 2017).
CD19 CAR T cell therapy is an effective adoptive cell treatment and has the potential to 
overcome chemo-refractory B-cell leukemia and lymphoma (Makita, 2017), as demonstrated in 
the ELIANA clinical study and recent approval of Kymriah in the US (Maude, 2018). 
1.2.3.
JCAR017 Investigational Drug Product
The final JCAR017 investigational drug product being evaluated in this study consists of a single 
infusion of two individually formulated CD4+CAR+ and CD8+ CAR+ frozen T cell suspensions 
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EDMS Doc. Number: 24103106 - 22557341
JCAR017
Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
28
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
in media containing dimethyl sulfoxide (DMSO) that are thawed and infused separately. 
JCAR017 is administered by IV infusion.
The CD19-specific CAR and truncated human epidermal growth factor receptor (EGFRt) are 
introduced into autologous CD8+ and CD4+ T cells ex vivo using a replication-incompetent, 
self-inactivating lentiviral vector.  The CD19-specific CAR includes an scFv binding domain 
derived from a murine CD19-specific monoclonal antibody (mAb; FMC63) and 4-1BB and 
CD3ζ chain signaling domains. The EGFRt protein is expressed as a separate cell surface protein 
for purposes of cell tracking.
Refer to the Investigator’s Brochure (IB) for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) profile of 
the investigational product (IP).
1.2.4.
Clinical Experience with JCAR017 and Related CAR T Cell Products
A Phase 1 study of 45 children and young adults with r/r B-ALL was conducted using SCRI-
CAR19v1, a similar CD19 CAR T product of defined CD4/CD8 composition, uniform CAR 
expression, and limited effector differentiation (Study PLAT-02; NCT02028455). The product
met all defined specifications in 93% of enrolled subjects. The maximum tolerated dose (MTD) 
was 1x106 CAR T cells/kilogram (kg), and there were no deaths or instances of cerebral edema 
attributable to product toxicity. The overall intent-to-treat MRD negative remission rate for this 
Phase 1 study was 89%. The MRD negative remission rate was 93% in subjects who received a 
CAR T cell product and 100% in the subset of subjects who received fludarabine and 
cyclophosphamide lymphodepletion (Gardner, 2017). 
JCAR017 is currently being evaluated in adult subjects with relapsed and refractory B-cell NHL
(study 017001 - TRANSCEND NHL001; NCT02631044) (Abramson, 2017). A total of 108 
patients had received JCAR017 at the time of data cutoff (October 9, 2017). Preliminary data 
suggest promising antitumor activity of JCAR017 in these heavily pretreated, poor prognosis 
R/R patients with aggressive NHL (median of 3 prior lines of therapy). In 65 patients with R/R 
DLBCL the best ORR reported was 80% and the complete response rate (CRR) at 6 months 
47%, and an acceptable safety profile. No dose-limiting toxicity (DLT) was observed at Dose 
Level 2 (DL2) (JCAR017 infusion of 1 x 108 viable CAR+ T cells). Pharmacokinetics analyses 
showed that in vivo expansion of JCAR017+ T cells peaks around day 11 after infusion of 
JCAR017. This is consistent with the reported safety with most important toxicities (severe 
cytokine release syndrome [sCRS], neurotoxicity [NT]) occurring within the first 14 days after 
infusion. 
Out of 91 patients evaluable for safety, major safety findings include CRS, NT, and
hematological disorders, including neutropenia, thrombocytopenia, and anemia. The most
significant toxicities reported have been sCRS and NT. Cytokine release syndrome was observed 
in 32 (35%) patients treated, with only 1 patient developing sCRS (Grade 3-4). NT was observed 
in 19% of the patients, of which 12% developed severe NT (Grade 3-4). Median time to onset of 
CRS after JCAR017 infusion was 5 days, median time to onset of NT was 10 days. The median 
time to resolution to grade 1 or better was 5 days for CRS and 10 days for NT. No unexpected 
early or late toxicities were reported. No cerebral edema, fatal CRS or NT were observed, and 
symptoms were reversible and manageable with appropriate treatment intervention and close 
monitoring (Abramson, 2017). 
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JCAR017
Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
29
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
See the JCAR017 IB for further details.
1.3.
Rationale
1.3.1.
Study Rationale and Purpose
The purpose of this Phase 1/2 study is to evaluate the efficacy and safety of JCAR017 in 
pediatric subjects with r/r CD19+ B-ALL and B-NHL. 
The JCAR017 IP is composed of autologous CD8+ and CD4+ T cells that express a CD19-
specific CAR.  CD19 is an attractive therapeutic target because it is expressed in most B-cell 
malignancies.  In clinical studies, CD19-targeted CARs have demonstrated encouraging anti-
leukemic activity in r/r adult and pediatric patients with B-ALL and other B-cell malignancies, as 
seen in the ELIANA clinical study and recent approval of Kymriah in the US (Davila, 2012; Li, 
1993; Li, 1996; Maude, 2018).
JCAR017 differs from other CAR T products in that it is a defined composition product that 
consists of CD4+CAR+ and CD8+CAR+ CD19-targeted T cells. It is known that CD4+ T cells 
enhance CD8+ effector T cell persistence, memory formation, and trafficking to antigen-rich 
tissues. Activated CD8+ T cells have also shown poor survival when CD4+ T cell help is absent, 
and CD4+ T cell help is required during recall expansion of memory CD8+ T cells (Bos, 2010; 
Toes, 1999). Likewise, CD4+CAR+ T cells enhance CD8+CAR+ cytolytic effector T cell 
function both in vitro and in vivo (Adusumilli, 2014). Thus, since JCAR017 has a defined ratio 
of CD4+CAR+ to CD8+CAR+ CD19-targeted T cells, persistence, trafficking to the tumor, and 
antitumor activity may be improved compared with CAR T cell investigational drug products 
without a defined composition.
Post-Treatment follow-up (for 2 years after JCAR017 infusion) will assess subjects for 
progressive disease (PD)/relapse, safety, CAR T cell persistence, second primary malignancies
and survival, while long-term follow-up (LTFU) (up to 15 years after JCAR017 infusion) will 
assess subjects for survival, relapse, long-term toxicity, second primary malignancies and 
lentiviral vector safety. Note: The long-term follow-up may exceed 15 years if the subject does 
not achieve Tanner Stage 5 by the end of the 15-year safety follow-up period.
1.3.2.
Rationale for the Study Design
1.3.2.1.
Phase 1
The dose finding part of this study will utilize the mTPI-2 design (Guo, 2017) to determine the 
recommended Phase 2 dose (RP2D) of JCAR017 in pediatric subjects with CD19+ r/r B-ALL. 
The mTPI-2 design uses a Bayesian statistical framework and a beta/binomial hierarchic model 
to compute the posterior probabilities of three intervals that reflect the relative distance between 
the toxicity rate of each dose level to help identify the RP2D.  Once the RP2D of JCAR017 has 
been selected, additional subjects will be enrolled until at least 10 pediatric subjects are treated at 
the identified RP2D.  The mTPI-2 design will allow to treat a higher percentage of patients at the 
MTD, as well as reaching the MTD sooner than more conventional dose escalation designs.
The Phase 1 will exclusively enroll subjects (< 18 years of age) with morphologically r/r B-ALL 
since these are the subjects with the highest unmet medical need and have few, if any, treatment 
alternatives. Once the RP2D is identified, the Phase 2 (Section 1.3.2.2) will enroll additional 
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Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
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JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
pediatric cohorts, including subjects with a better prognosis and safety profile (eg, MRD+ B-
ALL) who are not expected to receive major bridging chemotherapy.  
Results from the PLAT-02 study showed no significant difference in CAR T related toxicities in 
pediatric subjects with morphological versus MRD+ or MRD negative disease (Gardner 2017). 
Therefore, dose finding data from B-ALL pediatric subjects with morphologic disease as well as 
those with MRD+ or MRD negative disease upon restaging prior to initiation of lymphodepleting 
therapy will be evaluable for the DLT analysis and inform the identification of the RP2D in the 
Phase 1.  Consequently, pediatric subjects with r/r B-ALL (mostly necessitating bridging 
chemotherapy) and MRD+ and MRD negative B-ALL disease (converted following bridging 
chemotherapy; combined incidence expected to be approximately 30% based on PLAT-02 data) 
will be treated in Phase 1 (see Figure 1).  Safety information on B-ALL pediatric subjects with 
both morphologic and MRD+ as well as MRD negative disease will emerge from Phase 1 and 
will be available prior to enrolling pediatric subjects with MRD+ B-ALL disease in Phase 2.
1.3.2.2.
Phase 2
Phase 2 will include pediatric subjects (< 18 years of age) treated at the identified RP2D in the 3 
cohorts listed below:
Cohort 1 (r/r B-ALL): this cohort serves to demonstrate the efficacy and safety of JCAR017 in 
pediatric subjects with r/r B-ALL. 
Cohort 2 (MRD+ B-ALL): this cohort serves to demonstrate the efficacy and safety of 
JCAR017 in pediatric subjects with MRD+ B-ALL. 
Cohort 3 (r/r B-NHL [DLBCL, BL, or PMBCL]): this cohort serves to demonstrate the 
efficacy and safety of JCAR017 in pediatric subjects with r/r B-NHL. 
Cohort 1 and 2 will incorporate Simon’s Optimal two-stage design which accommodates the 
most appropriate endpoint for these diseases in this patient population, response rate. Cohort 3 
will enroll a set number of subjects for the purpose of gaining preliminary efficacy information.
Celgene may elect to explore the identified RP2D in up to 20 additional B-ALL subjects between 
18 and 25 years of age in an optional cohort in Phase 2, if it is determined that the risk-benefit 
profile is such that exploration is warranted after consultation with the SRC.
Recent results from clinical studies have demonstrated promising CR rates, including MRD
negative responses, with the use of CAR T cell products directed against CD19 in r/r pediatric 
ALL (Gardner, 2016). More specifically, early results from an ongoing clinical study of a similar 
CAR T cell product, SCRI-CAR19v1, in pediatric r/r B-ALL (Study PLAT-02) conducted in the 
US has demonstrated exceptionally high response rates of 93%; all responders were MRD 
negative (Gardner, 2017). Overall, the data reveal a reasonably safe, efficacious and durable 
therapy across indications and suggest that CD19-targeted CAR T cells could become one of the 
most effective therapeutic agents for treating r/r B-ALL. 
To optimize safety, Phase 1 subjects will be treated with JCAR017 at a rate of no more than 1 
subject per 14 days after the prior subject receiving the JCAR017 infusion, regardless of site. 
Once the RP2D has been identified, additional subjects enrolled in Phase 1 at the selected RP2D
will be treated with JCAR017 at a rate of no more than 1 subject per site, per week.  In Phase 2, 
subjects will be treated with JCAR017 at a rate of no more than 1 subject per site per week.
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EDMS Doc. Number: 24103106 - 22557341
JCAR017
Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
31
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
In addition, a staggered dosing approach will also be utilized for all new sites without prior 
experience of administering CAR T cell therapies as follows:

1st subject infusion, wait 14 days

2nd subject infusion, wait 14 days
Following completion of this site-staggered enrollment approach, the site may proceed with 
subject enrollment as communicated by Celgene.
1.3.3.
Rationale for Dose, Schedule and Regimen Selection
1.3.3.1.
Rationale for JCAR017 Dose
SCRI-CAR19v1, a CAR T cell product that is similar to JCAR017 has been well tolerated at 
doses from 0.5 x 106 to 1 x 106 CAR+ T cells/kg in pediatric subjects with B-ALL after 
lymphodepleting (LD) chemotherapy with fludarabine and cyclophosphamide in a Phase 1 study
(PLAT-02) of 45 children and young adults. The maximum tolerated (and total) dose of this 
Phase 1 study was 1 x 106 CAR T cells/kg. Overall, 33% of subjects developed reversible severe 
cytokine release syndrome (sCRS) and/or reversible severe neurotoxicity (sNT), toxicities that 
are frequently associated with CAR T cell therapies. There were no deaths or instance of cerebral 
edema attributable to product toxicity (Gardner, 2017). While the PLAT-02 trial demonstrated 
encouraging clinical activity with an overall manageable toxicity profile in pediatric B-ALL, it 
should be noted that process changes are needed to standardize product consistency and process 
robustness are necessary to support the conduct of the trial at multiple clinical sites with a global 
manufacturing process. 
An adverse event (Grade 4 neurotoxicity) observed in the first pediatric subject with B-ALL
dosed in JCAR017-BCM-004 prompted Celgene to re-evaluate the dosing strategy.  Analysis of 
the JCAR017 manufactured product characteristics showed very active cells as a result of the 
necessary process manufacturing modifications, suggesting a lower safe starting dose should be 
identified. Trials using a defined composition product autologous CD8+CAR+ and CD4+CAR+ 
T cells that express a CD19-specific CAR such as JCAR014 (Turtle, 2016b) and SCRI-
CAR19v1 (Gardner, 2017) suggests that a 10-fold dose reduction significantly reduced toxicity 
while preserving efficacy and maintaining a positive risk/benefit. 
Based on these considerations, an initial Phase 1 dose finding with a 10-fold dose reduction to a 
starting dose (Dose Level 1 [DL1]) of 0.05×106 CAR T cells/kg will be pursued.  If this dose is 
confirmed to be safe and tolerable, additional subjects will be enrolled at higher dose(s) up to 
0.75 x106 CAR+ T cells/kg utilizing an mTPI-2 algorithm with the aim to identify the 
Recommend Phase 2 Dose (RP2D).  The concern that DL1 may be non-efficacious in B-ALL 
pediatric subjects with morphologic disease will be addressed with one-time retreatment with 
intra-patient dose-escalation for subjects with no Day 28 response and who have shown no 
severe toxicity at DL1. After Day 28 response assessment, these subjects will receive repeat 
lymphodepletion followed by a single dose of JCAR017 at 0.10×106 CAR T cells/kg (total of 
0.15x106 CAR T cells/kg and equaling DL2).
Additional changes that are designed to support safe administration of JCAR017 in the pediatric 
B-ALL setting include increased frequency of cytokine and PK determinations (to allow 
comprehensive subject data assessment during dose escalation) and modification of the toxicity 
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Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
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JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
management algorithm incorporating the learnings from diagnosis and management of the first 
subject dosed in the study.  
JCAR017 dosing will also be capped at 100 kg at all dose levels to avoid potential overdosing.
Subjects 18 to 25 years of age will receive JCAR017 at the RP2D to be studied.
1.3.3.2.
Rationale for Lymphodepleting Chemotherapy Dose
Lymphodepleting chemotherapy has been shown to be critical to the subsequent anti-CD19 
efficacy of CAR T cells. 
Pre-clinical studies of CAR-modified T cells targeting B-cell malignancies suggest that optimal 
anti-CD19 T cell cytotoxic function and subsequent persistence is enhanced by LD 
chemotherapy prior to adoptive T cell transfer (James, 2009; Kochenderfer, 2010; Pegram, 
2012). 
The Phase 1 PLAT-02 study found that all subjects who received prescribed LD chemotherapy
with fludarabine and cyclophosphamide achieved uniform engraftment of functional CAR T 
cells in blood and subsequent development of B-cell aplasia (BCA) and MRD negative
remission, irrespective of cell dose (Gardner, 2017). The results from the clinical studies 
complement pre-clinical data demonstrating that LD chemotherapy is critical to the subsequent 
anti-CD19 efficacy of CAR T cells.
JCAR017, given as a single flat dose after LD chemotherapy, has been evaluated in the Study 
PLAT-02 and in the Study 017001 (TRANSCEND NHL 001). The TRANSCEND study has 
shown that dose levels 1 and 2 (5 x 107 CAR+ T cells, and 1 x 108 CAR+ T cells, respectively) 
given as a single flat dose after lymphodepletion are safe and have shown preliminary efficacy. 
The lymphodepletion regimen used was cyclophosphamide (300 mg/m2/day x 3 days) combined 
with fludarabine (30 mg/m2/day x 3 days) (flu/cy) (Abramson, 2017).
Based on this data, the LD chemotherapy regimen employed in the current protocol is the same 
as that used in the TRANSCEND study. Subjects will receive fludarabine IV 30 mg/m2 and 
cyclophosphamide IV 300 mg/m2 for 3 days. This regimen was selected to limit toxicity and 
retain anticancer activity, as well as to optimize cellular expansion and anticancer activity after 
treatment with JCAR017. 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number: 24103106 - 22557341
JCAR017
Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
33
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number: 24103106 - 22557341
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Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
34
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
 
 
 
 
 
 
 
 
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JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
2.
STUDY OBJECTIVES AND ENDPOINTS
Table 1:
Study Objectives
Primary Objectives 
The primary objective of Phase 1 is to identify the recommended Phase 2 dose (RP2D) in pediatric 
subjects with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL).
The primary objective of Phase 2 is to evaluate the efficacy of JCAR017 at the RP2D, in the following 
pediatric disease cohorts:

Cohort 1 (r/r B-ALL): Overall response rate (ORR) defined as proportion of subjects with a 
complete response (CR) or complete response with incomplete blood count recovery (CRi) on 
Day 28 that must be confirmed on Day 56

Cohort 2 (minimal residual disease [MRD]+ B-ALL): MRD negative rate defined as 
proportion of subjects with an MRD negative response on Day 28 that must be confirmed on 
Day 56

Cohort 3 (r/r B-cell non-Hodgkin lymphoma [B-NHL] (diffuse large B-cell lymphoma 
[DLBCL], Burkitt lymphoma [BL] or primary mediastinal large B-cell lymphoma [PMBCL]):
ORR defined as proportion of subjects with a CR or partial response (PR) on Day 28
Secondary Objectives
The secondary objectives for Phase 1 and Phase 2 are: 

Evaluate the feasibility of manufacturing JCAR017 measured by the percentage of product 
generated successfully (Phase 1 only)

Evaluate ORR in the non-selected dose levels from Phase 1

Evaluate safety and tolerability assessments during 24 months after JCAR017 infusion

To further evaluate efficacy by assessing the duration of response (DOR), relapse-free survival 
(RFS), event-free survival (EFS), best overall response (BOR) and overall survival (OS) during 
24 months after JCAR017 infusion

Evaluate the percentage of r/r B-ALL subjects who achieve CR or CRi with no MRD detected 
in bone marrow (BM) (below the level of detection [<0.01%] by a validated assay) assessed 
during 24 months after JCAR017 infusion

Assess the percentage of subjects who achieve a response after JCAR017 infusion and then 
proceed to hematopoietic stem cell transplant (HSCT)

Characterize the pharmacokinetic (PK) profile of JCAR017 assessed during 24 months after 
JCAR017 infusion
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Table 1:
Study Objectives (Continued)
Exploratory Objectives
The exploratory objectives apply to both Phase 1 and Phase 2 and are to:

Analyze the best response and ORR by sub-group/risk-group, including cytogenetics/genetic 
sub-group(s)

Analyze impact of prior HSCT on response by comparing ORR in subjects with to those
without prior HSCT
 

Describe the effect of treatments directed at severe cytokine release syndrome (sCRS) and 
neurotoxicity on duration and severity of these events
 
 

Measure Patient Reported Outcomes

Measure hospital resource utilization
Table 2:
Study Endpoints
Endpoint
Name
Description
Timeframe
Phase 1 Primary
Recommended Phase 2 
dose (RP2D) in 
relapsed/refractory (r/r) 
pediatric B-cell acute 
lymphoblastic leukemia 
(B-ALL)
Integral assessment of safety, 
pharmacokinetic (PK), 
preliminary efficacy and 
number of subjects 
experiencing a dose-limiting 
toxicity (DLT) 
28 days after 
JCAR017 infusion
Phase 2 Primary 
Cohort 1 (r/r B-ALL): 
Overall response rate 
(ORR) 
Percentage of subjects 
achieving a confirmed complete 
response (CR) or complete 
response with incomplete blood 
count recovery (CRi)
On Day 28 and 
must be confirmed 
on Day 56 
Cohort 2 (MRD+ B-
ALL): Minimal residual 
disease (MRD) negative 
rate
Percentage of subjects 
achieving a confirmed CR or 
CRi with an MRD negative 
bone marrow (<0.01% tumor 
cells by a validated assay)
On Day 28 and 
must be confirmed 
on Day 56
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Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
Cohort 3 (r/r B-cell non-
Hodgkin lymphoma [B-
NHL]): ORR 
Percentage of subjects 
achieving CR or partial 
response (PR) 
Day 28
Secondary 
Safety
Type, frequency, and severity 
of adverse events (AEs), 
including serious adverse 
events (SAEs) and laboratory 
abnormalities
2 years after 
JCAR017 infusion
Feasibility of 
manufacturing JCAR017 
(Phase 1 only)
Percentage of JCAR017 
product generated successfully
During 
pretreatment period 
(leukapheresis to 
JCAR017 
generation)
Overall response rate 
(ORR) in the non-
selected dose levels from 
Phase 1
Percentage of r/r B-ALL 
subjects achieving a best 
overall response (BOR) of 
confirmed CR or CRi
On Day 28 and 
must be confirmed 
on Day 56 
Duration of response 
(DOR)
Time from first response until 
progressive disease (PD), 
disease relapse, or death from 
any cause, whichever occurs 
first
2 years after 
JCAR017 infusion
Relapse-free survival 
(RFS)
Time from JCAR017 infusion 
to documentation of PD, 
disease relapse, or death due to 
any cause, whichever occurs 
first
2 years after 
JCAR017 infusion
Event-free survival (EFS)
Time from JCAR017 infusion
to PD, disease relapse, start of a 
new anticancer therapy, or 
death from any cause, 
whichever occurs first
2 years after 
JCAR017 infusion
Overall survival (OS)
Time from JCAR017 infusion
to time of death due to any 
cause
2 years after 
JCAR017 infusion
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Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
MRD negative response 
rate (non-selected dose 
levels in Phase 1 and 
Cohort 1 in Phase 2 only)
Percentage of B-ALL subjects 
achieving confirmed CR or CRi 
with an MRD negative BM
(< 0.01% tumor cells by a validated 
assay)
2 years after 
JCAR017 infusion
Best Overall Response 
(BOR)
Percentage of r/r B-NHL subjects 
achieving BOR of CR or PR
2 years after 
JCAR017 infusion
Rate of hematopoietic 
stem cell transplant 
(HSCT) after response to 
JCAR017 infusion
Percentage of subjects who achieve 
a response after JCAR017 infusion 
and then proceed to HSCT
2 years after 
JCAR017 infusion
Pharmacokinetics (PK) by 
ddPCR
Maximum concentration (Cmax), 
time to peak concentration (Tmax), 
area under the curve (AUC)
including maximum expansion and 
duration of persistence of JCAR017
2 years after 
JCAR017 infusion
Exploratory
Response assessment by 
sub-group/risk-group
Sub-group/risk-group analysis of 
best response and overall response 
rate
2 years after 
JCAR017 infusion
Overall response rate with 
and without prior HSCT
Sub-group analysis of overall 
response rate with and without prior 
HSCT
2 years after 
JCAR017 infusion
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Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
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JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
Resolution of severe 
cytokine release syndrome
(sCRS) and/or 
neurotoxicity
Response and time to resolution for 
sCRS and/or neurotoxicity to 
interventions
90 days after
JCAR017 infusion
Patient Reported 
Outcomes
Patient Reported Outcomes
measured by Pediatric Quality of 
Life Inventory (PedsQL) Core 
module, Cancer module, 
Multidimensional Fatigue Scale, 
and Family Impact Module
2 years after
JCAR017 infusion
Hospital resource 
utilization
Number of inpatient intensive care 
unit (ICU) days, and outpatient 
visits
2 years after
JCAR017 infusion
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Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
40
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
3.
OVERALL STUDY DESIGN
3.1.
Study Design
This is a Phase 1/2, open-label, single arm, multicohort study incorporating Simon’s Optimal 
two-stage design to evaluate the safety and efficacy of JCAR017 in pediatric subjects with 
CD19+ r/r B-ALL and B-NHL (Figure 1).
3.1.1.
Phase 1
Up to 5 dose levels of JCAR017 will be evaluated as described in Section 7.2.5. 
Enrollment will commence in pediatric subjects (< 18 years of age) with r/r B-ALL at DL1 of 
0.05x106 CAR+ T cells/kg (maximum dose of 5x106 JCAR017 CAR+ T cells [non-weight 
adjusted]).  If this dose is confirmed to be safe and tolerable additional pediatric subjects will be 
enrolled at higher dose(s) up to 0.75 x106 CAR+ T cells/kg (maximum of 75x106 JCAR017 
CAR+ T cells [non-weight adjusted]) with the aim to identify the pediatric RP2D. Dose
escalation/de-escalation will follow a modified toxicity probability interval (mTPI-2) algorithm 
(Guo, 2017) with a target DLT rate of 30% and an equivalence interval of 25% to 35%
(Appendix G). A dose level will be considered unsafe, with no additional pediatric subjects 
enrolled at that dose level, if it has an estimated 95% or more probability of exceeding the target 
DLT rate of 30% (ie, P (DLT > 30%|data) > 95%) with at least 3 pediatric subjects treated at that 
dose level. For a dose level to be declared safe per the mTPI-2 algorithm, at least 3 DLT-
evaluable pediatric subjects must have completed the DLT period and the level estimated to be 
safe.  Enrollment to the next dose level will be prioritized over the same dose level, if the next 
dose level cohort is open for enrollment. The decision to open a dose level for enrollment will be 
made by Celgene, informed by the Safety Review Committee (SRC), considering results from 
the mTPI-2 algorithm and preliminary efficacy. For the first 5 pediatric subjects treated at a dose 
level, no more than 3 pediatric subjects can be in the DLT period simultaneously at a dose level 
that has not yet been shown to be safe per the mTPI-2 algorithm. Up to 3 additional pediatric 
subjects are allowed to be within the DLT period at lower dose levels that have already been 
shown to be safe.  
Once the RP2D for JCAR017 has been selected, additional subjects will be enrolled until at least 
10 pediatric subjects are treated at the identified RP2D.  Dose finding data from subjects who 
have become MRD+ or MRD negative upon restaging prior to initiation of lymphodepleting
therapy will be evaluable for the DLT analysis and inform the identification of the RP2D in 
Phase 1 (Figure 1).
During Phase 1, the SRC whose members include the medical monitor(s), drug safety physician, 
statistician, and a subset of investigators will recommend the RP2D based on an integrated 
assessment of the safety, pharmacokinetic (PK) and preliminary efficacy information from at 
least 10 pediatric subjects treated at the RP2D. Analysis of the JCAR017 manufactured product 
may also be considered in the RP2D determination.  The SRC may recommend overriding the 
mTPI-2 algorithm’s allocation of a subject or subjects to a particular dose level that is estimated 
to be safe per the mTPI-2 algorithm.
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Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
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JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
3.1.2.
Phase 2: 
Up to 71 primary endpoint evaluable pediatric subjects (< 18 years of age) will be treated in one
of the 3 cohorts listed below.
The sample size for Cohorts 1 and 2 is calculated according to Simon’s Optimal two-stage 
design and based on the primary endpoints of ORR (Cohorts 1 and 3) and MRD negative rate 
(Cohort 2). The 10 or more pediatric subjects treated at the RP2D in Phase 1 will form part of the 
sample size (ie, Cohort 1 and Cohort 2). Therefore, the protocol intends to treat 81 primary 
endpoint evaluable pediatric subjects in Phase 2, if warranted by the evaluation of results at the 
completion of the first stage of the study in each cohort.

Cohort 1: 48 r/r B-ALL evaluable pediatric subjects (13 subjects in Stage 1 and 35 
subjects in Stage 2)

Cohort 2: 23 MRD+ B-ALL evaluable pediatric subjects (9 subjects in Stage 1 and 14 
subjects in Stage 2).

Cohort 3: 10 r/r B-NHL (DLBCL, BL, or PMBCL) evaluable pediatric subjects (due to 
the very low incidence rate and therefore expected low subject accrual, there is no formal 
sample size for this arm).

Note: B-NHL subjects with secondary CNS lymphoma involvement are eligible; 
however, subject selection must consider clinical risk factors for severe 
neurological AEs and alternative treatment options. Subjects should only be 
enrolled if the Investigator considers the potential benefit outweighs the risk for 
the subject.
Pediatric B-ALL subject enrollment will start with Cohort 1 (morphologic disease only).  
Pediatric subjects with MRD+ B-ALL disease at screening will only be able to be enrolled into 
Cohort 2 after enrollment into Cohort 1 is completed.  However, Cohort 1 subjects who convert 
from morphologic disease to MRD+ B-ALL disease following bridging chemotherapy (and prior 
to LD chemotherapy) will be enrolled into Cohort 2 at any time during Phase 2
Celgene may elect to explore the identified RP2D in up to 20 additional B-ALL subjects between 
18 and 25 years of age in an optional cohort in Phase 2, if it is determined that the risk-benefit 
profile is such that exploration is warranted after consultation with the SRC.
3.1.3.
Study Flow for Individual Subjects
The study will have the following sequential periods: Pre-Treatment Period (screening and 
leukapheresis), Treatment Period and Post-Treatment Follow-up Period (Figure 2). Prior to 
initiation of any study procedures (screening), subjects must provide informed consent/assent. 
Once enrolled, subjects will undergo an unstimulated leukapheresis to enable JCAR017 cell 
product generation. Subjects may receive optional bridging chemotherapy and upon successful 
JCAR017 cell product generation, will enter the Treatment period and receive LD chemotherapy 
followed by infusion of JCAR017. All subjects completing the Pre-treatment Period will be re-
assessed to ensure that inclusion/exclusion criteria are still met prior to receiving LD 
chemotherapy and JCAR017 infusion.

Pre-treatment Period: 
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Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
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JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019

Screening, leukapheresis and JCAR017 product generation. Subjects may receive 
a single cycle of commercially available anticancer treatment (ie, bridging 
chemotherapy) and/or supportive care at the Investigator’s discretion while the 
JCAR017 cell product is being manufactured.  

Treatment and Post-Treatment Follow-up Period:

Treatment Period (LD chemotherapy to Day 56): administration of LD 
chemotherapy followed by a single infusion JCAR017 consisting of two 
individually formulated CD4+CAR+ and CD8+CAR+ T cell at a starting dose of 
0.05x106 CAR+ T cells/kg (2 to 7 days after completion of LD chemotherapy). 
Lymphodepleting chemotherapy will consist of fludarabine/cyclophosphamide. 

Post-treatment Follow-up Period (after Day 56 to end of study [EOS]): subjects 
will be followed for progressive disease (PD)/relapse, safety, CAR T cell 
persistence, second primary malignancies and survival for 2 years after 
administration of JCAR017 unless subject is lost to follow-up.  
In Phase 1, subjects will be treated with JCAR017 at a rate of no more than 1 subject per 14 days 
after the prior subject receiving the JCAR017 infusion, regardless of site.  Once the RP2D has 
been identified, additional subjects enrolled in Phase 1 at the selected RP2D will be treated with 
JCAR017 at a rate of no more than 1 subject per site, per week.  
In Phase 2, subjects will be treated with JCAR017 at a rate of no more than 1 subject per site per 
week. 
In addition, a staggered dosing approach will also be utilized for all new sites without prior 
experience of administering CAR T cell therapies as follows:

1st subject infusion, wait 14 days

2nd subject infusion, wait 14 days
Following completion of this site-staggered enrollment approach, the site may proceed with 
subject enrollment as communicated by Celgene.
The first response assessment will be performed 28 days after JCAR017 infusion.  
One interim analysis is planned for Cohort 1 and Cohort 2, each, and will be based on cleaned 
efficacy data relating to the primary endpoint. In Cohort 1, the interim analysis will be conducted 
once the first 13 subjects eligible for the primary endpoint have all had their efficacy data 
relating to the primary endpoint become available. In Cohort 2, the interim analysis will be 
conducted once the first 9 subjects eligible for the primary endpoint have all had their efficacy 
data relating to the primary endpoint become available.
If at least 11 subjects in Cohort 1 achieve a confirmed response during Stage 1, then Cohort 1 
will proceed to Stage 2; otherwise Cohort 1 shall close to further enrollment. Similarly, if at least 
7 subjects in Cohort 2 achieve a confirmed MRD negative response during Stage 1, then Cohort 
2 will proceed to Stage 2; otherwise Cohort 2 shall close to further enrollment.
During the final analysis, if at least 41 of the 48 subjects in Cohort 1 achieve a confirmed 
response across Stages 1 and 2, it will be concluded that JCAR017 treatment is successful in the 
pediatric r/r B-ALL population. Similarly, during the final analysis, if at least 18 of the 23 
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Protocol JCAR017-BCM-004
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JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
subjects in Cohort 2 achieve a confirmed MRD negative response across Stages 1 and 2, it will 
be concluded that JCAR017 treatment is successful in the pediatric MRD+ B-ALL population.
Post-study follow-up for survival, relapse, long-term toxicity, second primary malignancies and 
lentiviral vector safety will continue under a separate LTFU protocol for up to 15 years after 
JCAR017 infusion as per health authority regulatory guidelines. In addition, details on 
subsequent antineoplastic treatments will be documented for at least 5 years.  Note: The long-
term follow-up may exceed 15 years if the subject does not achieve Tanner Stage 5 by the end of 
the 15-year safety follow-up period.  
All subjects who either complete the Post-Treatment Follow-up period or who prematurely 
withdraw from the study after JCAR017 infusion will enroll into LTFU at the end of study visit 
or at the time of withdrawal, respectively.  Subjects discontinuing the treatment period before 
JCAR017 infusion will complete the EOS visit and then discontinue from the study.  
An independent data safety monitoring board (DSMB) (Section 9.9.3) with multidisciplinary 
representation will evaluate activity of the study treatment and safety data periodically to 
monitor benefit-to-risk of this protocol. The function of the DSMB is to monitor the safety and 
activity of the study treatment and to provide recommendations about the study continuation, as 
appropriate. Details of the DSMB structure, composition, and roles/responsibilities will be 
outlined within a DSMB charter.
The study will be conducted in compliance with the International Council for Harmonisation 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good 
Clinical Practice (GCP) and applicable regulatory requirements.
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Protocol JCAR017-BCM-004
Celgene Corporation
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JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
Figure 1:
Overall Study Design
Abbreviations: B-ALL = B-cell acute lymphoblastic leukemia; MRD = minimal residual disease; NHL = non-Hodgkin lymphoma; RP2D = recommended Phase 
2 dose; r/r = relapsed/refractory.
* Includes subjects from Phase 1 treated at the RP2D.
1 Optional bridging chemotherapy may convert r/r B-ALL into MRD+ and MRD negative B-ALL disease.
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EDMS Doc. Number: 24103106 - 22557341
JCAR017
Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
45
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
Figure 2:
Study Schematic
Abbreviations: Cy = cyclophosphamide; Flu = fludarabine; IV = intravenous.
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Protocol JCAR017-BCM-004
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Confidential and Proprietary
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3.2.
Stopping Rules
Adverse events and serious adverse events (SAEs) are expected to occur frequently in this study
based on the subject population being accrued and on the nature of the advanced hematologic
malignancy under study. As a result, there is no specific incidence rate of SAEs that will define a
stopping rule. Instead, regular systematic review of SAEs will serve as the basis for pausing or
prematurely stopping the study. Unexpected SAEs that are related to JCAR017 will be the
primary criteria for pausing or stopping the study. Review of these SAEs, and any decision to
pause enrollment or terminate the study, will be determined by the Data Safety Monitoring 
Board (DSMB), Celgene and the Medical Monitor. Decisions to pause enrollment or terminate 
the study will be communicated promptly to Investigators, to the Institutional Review Boards 
(IRBs)/Ethics Committees (Ecs), Institutional Biosafety Committees (IBCs) (if applicable), and 
to the appropriate regulatory authorities.
3.2.1.
Criteria for Pausing or Stopping the Study
The study will be paused for enrollment pending notification of the DSMB and appropriate
regulatory authorities if any subject experiences any of the following events within 28 days after
JCAR017 infusion:

Life-threatening (Grade 4) toxicity attributable to protocol therapy (JCAR017 
infusion +/- LD chemotherapy) that is unexpected, unmanageable (ie, does not
resolve to Grade 3 or lower within 7 days), and unrelated to anticancer treatments 
between leukapheresis and LD chemotherapy

Death related to JCAR017 infusion
Expected toxicities are described in the Reference Safety Information (RSI) in the IB. These 
toxicities include but are not limited to: Grade 4 CRS, neurotoxicity (eg, encephalopathy and/or 
seizures), and hypotension. The expected toxicities may also result in secondary toxicities of 
Grade 4 renal toxicity, hepatic toxicity, or other organ involvement. Consistent with the 
Reference Safety Information in the JCAR017 Investigator Brochure all life-threatening or fatal 
events will be considered unexpected for the purpose of reporting suspected unexpected serious 
adverse reactions (SUSARs) to regulatory authorities, and if considered related to JCAR017 
treatment will be reported in an expedited fashion.
The study may be terminated for the following reasons:

Any subject develops uncontrolled JCAR017 proliferation that is unresponsive to
treatment

Any subject develops detectable replication-competent lentivirus (RCL) during the
study

Celgene, IRB/EC, SRC, or DSMB decides that subject safety may be compromised 
by continuing the study

Celgene decides to discontinue/limit the development of JCAR017 in the indications
under evaluation.
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Protocol JCAR017-BCM-004
Celgene Corporation
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JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
3.3.
Safety Monitoring Boundaries
Safety monitoring boundaries based on Bayesian framework (Thall, 1994) have been established
to help detect signals that may occur during the course of the study.  The boundaries are non-
binding and based on the cumulative number of subjects who have received at least one dose of 
JCAR017 and who experienced at least one of the following toxicity events within 30 days of a 
JCAR017 infusion:  

A Grade 3 or above, JCAR017-related, treatment-emergent neurological toxicity

A Grade 4 treatment-emergent AESI that is unmanageable or fails to resolve to Grade 
3 or lower after 7 days
Whenever the safety boundaries are crossed, an ad-hoc DSMB meeting will be held to review the 
data and provide recommendation about the study continuation, as appropriate. The DSMB may 
override the safety stopping boundaries to recommend study continuation based on clinical and 
overall risk benefit considerations.  Additional information will be detailed in the JCAR017-
BCM-004 Statistical Analysis Plan (SAP).
3.4.
Study Duration for Subjects 
This study will enroll over approximately 
months and will consist of 3 periods: 

The Pretreatment Period will consist of screening for eligibility, leukapheresis, 
JCAR017 product generation and a pretreatment evaluation (prior to LD 
chemotherapy).

The Treatment Period will start with LD chemotherapy, followed by JCAR017 
infusion 2 to 7 days after completion of LD chemotherapy and follow-visits through 
Day 56.  The first response evaluation will be performed at approximately 28 days 
after JCAR017 infusion.

The Post-Treatment Follow-up Period will consist of further efficacy and safety 
follow-up visits at approximately 3, 6, 9, 12, 18 and 24 months after JCAR017 
infusion.
The duration of participation for subjects who complete the study will be approximately 26 
months. All subjects who receive JCAR017 will be asked to enroll into the LTFU protocol after 
completion of this study (Section 6.8).
3.5.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject completing the 
Post-Treatment Follow-up period or the date when the last subject enters the LTFU study, or the 
date of receipt of the last data point from the last subject that is required for primary, secondary 
and/or exploratory analysis, as pre-specified in the protocol, whichever is the later date.
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Protocol JCAR017-BCM-004
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JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
4.
STUDY POPULATION
4.1.
Number of Subjects 
This study will enroll and treat approximately up to 101 total pediatric subjects (up to 30 in 
Phase 1 and up to 71 additional subjects in Phase 2) should all dose levels and cohorts enroll the 
maximum number of subjects and assuming no subjects are replaced.  
Up to 20 additional subjects between 18 and 25 years of age may also be enrolled in Phase 2.
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Phase 1: Subject < 18 years of age and weighs ≥ 6 kg at the time of signing the informed 
consent form (ICF)/informed assent form (IAF).
Phase 2: Subject ≤ 25 years of age and weighs ≥ 6 kg at the time of signing the ICF/IAF.
2. Subject (when applicable, parental/legal representative) must understand and voluntarily 
provide permission to the ICF/IAF prior to conducting any study-related 
assessments/procedures.
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. Evidence of CD19 expression via flow cytometry (peripheral blood or bone marrow) or 
immunohistochemistry (bone marrow biopsy)
6. Subject has a Karnofsky score of ≥ 50 (subjects ≥ 16 years of age) or a Lansky score ≥ 50
(subjects < 16 years of age).
7. Diagnosis of B-cell ALL or B-cell NHL as defined below:
Phase 1: Subjects with r/r B-ALL, defined as morphological evidence of disease in BM
(5% or greater lymphoblast by morphology) and either of the following:

First or greater marrow relapse, or 

Any marrow relapse after allogeneic HSCT, or 

Primary refractory defined as not achieving a CR or a CRi after 2 or more 
separate induction regimens (or chemo-refractory as not achieving CR/CRi after 1 
cycle of standard chemotherapy for relapsed leukemia), or 

Ineligible for allogeneic HSCT
Note: Subjects will be included regardless of MRD status.
Phase 2: Subjects with one of the following:

Cohort 1: r/r B-ALL, defined as morphological evidence of disease in BM (5% or 
greater lymphoblast by morphology) and either:

First or greater marrow relapse, or 
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Protocol JCAR017-BCM-004
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Confidential and Proprietary
49
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019

Any marrow relapse after allogeneic HSCT, or 

Primary refractory defined as not achieving a CR or a CRi after 2 or more 
separate induction regimens (or chemo-refractory as not achieving CR/CRi after 1 
cycle of standard chemotherapy for relapsed leukemia), or 

Ineligible for allogeneic HSCT.

Cohort 2: MRD+ B-ALL, defined as: 

< 5% lymphoblasts by morphology with, 

MRD detected by a validated assay at a frequency of 1 x 10-4 or greater in BM 
cells. Subjects eligible for enrollment in Cohort 2 are those with MRD positive 
morphologic CR2 after re-induction when these subjects had previously 
experienced an early relapse (< 36 months) after first-line chemotherapy. Subjects 
who are in MRD+ morphologic CR3 and later, regardless of time to relapse in 
earlier lines, are also eligible.
Subjects who are in morphologic relapse at screening (r/r B-ALL) and become 
MRD+ after bridging chemotherapy are also eligible for treatment in Cohort 2.

Cohort 3: r/r B-NHL (DLBCL, BL or PMBCL), defined as 

Measurable disease after 1 or more lines of chemotherapy and/or having failed 
HSCT or being ineligible for HSCT.
Note: B-NHL subjects with secondary CNS lymphoma involvement are eligible 
however subject selection must consider clinical risk factors for severe
neurological AEs and alternative treatment options. Subjects should only be 
enrolled if the Investigator considers the potential benefit outweighs the risk for 
the subject.
8. Subjects with Philadelphia chromosome positive ALL are eligible if they are intolerant to 
or have failed one or more lines of tyrosine-kinase inhibitor (TKI) therapy or if TKI 
therapy is contraindicated.
9. Adequate organ function, defined as:

Adequate BM function to receive LD chemotherapy as assessed by the Investigator.

Subject with adequate renal function, which is defined as: 

Serum creatinine based on age/gender as described below.  Subjects that do not 
meet the criteria but who have a creatinine clearance or radioisotope glomerular 
filtration rate (GFR) > 70 mL/min/1.73 m2 are eligible.
Approved
930224809
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Approved
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v


EDMS Doc. Number: 24103106 - 22557341
JCAR017
Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
50
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
Creatinine Clearance Estimation Using the Schwartz Formula
Age
Maximum Serum Creatinine (mg/dL)
Male
Female
1 month to < 6 months
0.4
0.4
6 months to < 1 year
0.5
0.5
1 to < 2 years
0.6
0.6
2 to < 6 years
0.8
0.8
6 to < 10 years
1.0
1.0
10 to < 13 years
1.2
1.2
13 to < 16 years
1.5
1.4
≥ 16 years
1.7
1.4
The threshold creatinine values in this table were derived from the Schwartz formula for estimating glomerular 
filtration rate (GFR) (Schwartz, 1976) utilizing child length and stature data published by the Center for Disease 
Control (CDC).

Alanine aminotransferase (ALT) ≤5 x upper limit of normal (ULN) and total 
bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for subjects with Gilbert’s syndrome or 
leukemic/lymphomatous infiltration of the liver).

Adequate pulmonary function, defined as ≤ Grade 1 dyspnea according to Common 
Toxicity Criteria for Adverse Events (CTCAE) and oxygen saturation (SaO2) ≥92% 
on room air.

Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥40% 
as assessed by echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) 
within 4 weeks prior to leukapheresis.
10. Adequate vascular access for leukapheresis procedure.
11. Subjects must agree to not donate blood, organs, sperm or semen, and egg cells for usage 
in other individuals for at least 1 year following LD chemotherapy. There are insufficient 
exposure data to provide any recommendation concerning the duration of refraining from 
tissue donation following treatment with JCAR017.  Therefore, subjects treated with 
JCAR017 should not donate blood, organs, tissues and cells for transplantation.
12. Female children of childbearing potential (FCCBP) and females 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 7 days prior to the first dose of LD
chemotherapy). 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 
Approved
930224809
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Approved
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v


EDMS Doc. Number: 24103106 - 22557341
JCAR017
Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
51
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
contraception from screening until at least 12 months following LD chemotherapy or 
JCAR017 infusion, whichever occurs last.
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 highly effective and additional effective methods of contraception:
Highly effective methods of contraception:

Intrauterine device (IUD)

Hormonal (birth control pill, injections, implants)

Tubal ligation 

Partner’s vasectomy 
Additional effective methods of contraception:

Male condom

Diaphragm

Cervical cap 

Agree to abstain from breastfeeding during study participation and for at least 1 year 
following LD chemotherapy.

There are 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.
NOTE: Female Children of Childbearing Potential (FCCBP) is defined as females who have 
achieved menarche and/or breast development in Tanner Stage 2 or greater and have not 
undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the 
surgical removal of both ovaries). Note: Amenorrhea following cancer therapy does not rule 
out childbearing potential. Female of Childbearing Potential (FCBP) is defined as a sexually 
mature woman who has not undergone a hysterectomy or bilateral oophorectomy, has not 
been naturally postmenopausal (amenorrhea following cancer does not rule out childbearing 
potential) for at least 12 consecutive months without an alternative medical cause.
13. 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 FCBP while participating in the study and until at least 12 months following LD 
chemotherapy even if he has undergone a successful vasectomy.

There are 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.
Approved
930224809
5.0
v
Approved
1.0
v


EDMS Doc. Number: 24103106 - 22557341
JCAR017
Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
52
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
* 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.
4.3.
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 
places the subject at unacceptable risk if he/she were to participate in the study.
3. Subject has any condition that confounds the ability to interpret data from the study.
4. Subject with a history of another primary malignancy that has not been in remission for at 
least 2 years prior to enrollment. 
5. Subjects who have received previous CD19-targeted therapy must have CD19-positive 
disease confirmed since completing the prior CD19-targeted therapy.
6. Prior CAR T cell or other genetically-modified T cell therapy.
7. Subject with a previous history of or active hepatitis B, hepatitis C, or human 
immunodeficiency virus (HIV) infection.
8. 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.
9. Subject has presence of acute or chronic graft-versus-host disease (GVHD).
10. Subject with active autoimmune disease requiring immunosuppressive therapy.
11. Subject has cardiac disorders (CTCAE version 4.03 Grade 3 or 4) within the past 6 
months. 
12. Subject with a concomitant genetic syndrome, with the exception of Down’s syndrome.
13. Subject with active CNS disease and significant neurological deterioration. Subjects with 
CNS-2 or CNS-3 involvement are eligible provided they are asymptomatic and do not 
have significant neurological deterioration and, in the opinion of the study Investigator, 
the CNS disease burden can be controlled until JCAR017 infusion. 
14. Subject with a history or presence of clinically relevant CNS pathology such as epilepsy, 
seizure, paresis, aphasia, stroke, cerebral edema, severe brain injuries, dementia, 
Parkinson’s disease, cerebellar disease, organic brain syndrome, or psychosis.
15. Subject is pregnant or nursing.
16. Subject has used the following:

Therapeutic doses of corticosteroids (defined as > 0.4 mg/kg [maximum 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.
Approved
930224809
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v
Approved
1.0
v


EDMS Doc. Number: 24103106 - 22557341
JCAR017
Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
53
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019

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 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 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 PD in irradiated 
lesions or have additional non-irradiated lesions to be eligible. Radiation to a single 
lesion, if additional non-irradiated, measurable lesions are present, is allowed up to 2 
weeks prior to leukapheresis.

Allogeneic HSCT within 90 days prior to leukapheresis.
17. Tumor invasion of venous or arterial vessels (B-NHL subjects only).
18. Deep Venous Thrombosis (DVT) or Pulmonary Embolism (PE) within 3 months prior to 
leukapheresis. Subjects with DVT or PE that occurred longer than 3 months prior to 
leukapheresis, who still require ongoing therapeutic levels of anti-coagulation therapy, 
are also excluded.
19. Existence of CD19-negative clone(s) of leukemia cells.
Approved
930224809
5.0
v
Approved
1.0
v


EDMS Doc. Number: 24103106 - 22557341
JCAR017
Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
54
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
5.
TABLE OF EVENTS
Table 3:
Table of Events
Pre-treatment Period
Treatment Period
Post-Treatment 
Follow-up Period
Ref. 
Section
Screen-
ingcc
Leuka-
pheresis
Pre-
Treat-
ment 
Evalua-
tion
LD 
Chemo-
therapy
JCAR-
017 
Infu-
sion
Study Month
-
-
-
-
-
-
-
-
-
-
-
-
-
1
2
3
6
9
12
18
24
Study Day
Up to 
14 days 
before
leuka-
pheresis
Within 7 
days 
before LD 
chemo-
therapy
Start 5 to 
10 days 
before
Day 1bb
1bb
2
3
4
7
10
14
21
28
56
90
180
270
365
545
730 
(EOS)
or ET
Visit Window (Days)
-
-
-
-
-
-
-
-
+1
±1
±1
±2
±2
±4
±14
±14
±14
±14
±30
±30
±30
STUDY PROCEDURES FOR BOTH B-ALL AND B-NHL SUBJECTS
Informed consent/assent
6.1
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Eligibility criteria
4.2
x
xa
xa
xa
xa
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
IRT registration
7.3
x
x
x
x
xb
-
-
-
-
-
-
-
-
-
-
-
-
-
-
x
Medical history
6.1
x
x
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Performance score
6.9.7
x
x
x
x
x
-
-
-
x
-
x
x
x
x
x
x
x
x
x
x
Height
6.9.4
x
-
-
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Weight
6.9.4
x
x
x
x
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Physical examination
6.9.1
xc
-
xc
-
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Tanner staging 
6.9.2
x
-
x
-
x
-
-
-
-
-
-
-
x
x
x
x
x
x
x
x
Routine neurologic 
examination
6.9.5
x
-
x
-
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Approved
930224809
5.0
v
Approved
1.0
v


EDMS Doc. Number: 24103106 - 22557341
JCAR017
Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
55
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
Table 3:
Table of Events (Continued)
Pre-treatment Period
Treatment Period
Post-Treatment 
Follow-up Period
Ref. 
Section
Screen-
ingcc
Leuka-
pheresis
Pre-
Treat-
ment 
Evalua-
tion
LD 
Chemo-
therapy
JCAR-
017 
Infu-
sion
Study Month
-
-
-
-
-
-
-
-
-
-
-
-
-
1
2
3
6
9
12
18
24
Study Day
Up to 
14 days 
before
leuka-
pheresis
Within 7 
days 
before LD 
chemo-
therapy
Start 5 to 
10 days 
before
Day 1bb
1bb
2
3
4
7
10
14
21
28
56
90
180
270
365
545
730 
(EOS)
or ET
Visit Window (Days)
-
-
-
-
-
-
-
-
+1
±1
±1
±2
±2
±4
±14
±14
±14
±14
±30
±30
±30
Vital signsd
6.9.3
x
xe
x
xdd
xf
x
x
x
x
x
x
x
x
x
-
-
-
-
-
-
12-lead ECG
6.9.9
x
-
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
MUGA scan/ECHO
6.9.8
xg
-
xo
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Viral serology
Table 9
x
xh
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Serum pregnancy
(FCCBP/FCBP)
Table 9
x
-
xi
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
HLA typing and donor 
chimerismj
6.1
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Hematology
Table 9
x
x
x
xdd
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Coagulation
Table 9
-
-
x
-
x
x
x
x
x
x
x
x
x
x
-
-
-
-
-
-
Chemistry
Table 9
x
x
x
xdd
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Creatinine clearance
4.2
x
-
-
xk
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Peripheral CD3+ count
6.1.2
-
xl
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Leukapheresis
6.1.2
-
xm
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
LD chemotherapy
6.2.1.2
-
-
-
xdd
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
JCAR017 infusion
6.2.1.3
-
-
-
-
xn
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Approved
930224809
5.0
v
Approved
1.0
v


EDMS Doc. Number: 24103106 - 22557341
JCAR017
Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
56
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
Table 3:
Table of Events (Continued)
Pre-treatment Period
Treatment Period
Post-Treatment 
Follow-up Period
Ref. 
Section
Screen-
ingcc
Leuka-
pheresis
Pre-
Treat-
ment 
Evalua-
tion
LD 
Chemo-
therapy
JCAR-
017 
Infu-
sion
Study Month
-
-
-
-
-
-
-
-
-
-
-
-
-
1
2
3
6
9
12
18
24
Study Day
Up to 
14 days 
before
leuka-
pheresis
Within 7 
days 
before LD 
chemo-
therapy
Start 5 to 
10 days 
before
Day 1bb
1bb
2
3
4
7
10
14
21
28
56
90
180
270
365
545
730 
(EOS)
or ET
Visit Window (Days)
-
-
-
-
-
-
-
-
+1
±1
±1
±2
±2
±4
±14
±14
±14
±14
±30
±30
±30
Inflammatory markers
Table 9
-
-
x
-
x
x
x
x
x
x
x
x
xo
xo
-
-
-
-
-
-
Immunoglobulinsp
Table 9
-
-
x
-
-
-
-
-
-
-
x
x
x
x
xq
xq
xq
xq
xq
xq
CSF assessment
Table 9
xr
-
xr
-
-
-
-
-
-
-
-
-
xr
xr
xr
xr
xr
xr
xr
xr
Patient Reported 
Outcomes (PROs)ee
6.13
x
-
x
-
x
-
-
-
-
-
-
-
x
x
x
x
x
x
x
x
Parent/Caregiver Reported 
Outcomesff
6.13
x
-
x
-
x
-
-
-
-
-
-
-
x
x
x
x
x
x
x
x
Hospital resource 
utilization
6.14
-
-
-
Ongoing
Disease therapy since 
study treatment 
discontinuation
6.2.2
-
-
-
Ongoing 
Adverse events and 
concomitant medicationsp
8.0
10.0
AEs related to protocol-
mandated procedures and 
associated concomitant 
medications
All AEs and associated concomitant medications
AEs related to protocol-
mandated procedures or 
JCAR017 and associated 
concomitant medications
Survival status
6.7
-
-
-
Ongoing
Approved
930224809
5.0
v
Approved
1.0
v


EDMS Doc. Number: 24103106 - 22557341
JCAR017
Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
57
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
Table 3:
Table of Events (Continued)
Pre-treatment Period
Treatment Period
Post-Treatment 
Follow-up Period
Ref. 
Section
Screen-
ingcc
Leuka-
pheresis
Pre-
Treat-
ment 
Evalua-
tion
LD 
Chemo-
therapy
JCAR-
017 
Infu-
sion
Study Month
-
-
-
-
-
-
-
-
-
-
-
-
-
1
2
3
6
9
12
18
24
Study Day
Up to 
14 days 
before
leuka-
pheresis
Within 7 
days 
before LD 
chemo-
therapy
Start 5 to 
10 days 
before
Day 1bb
1bb
2
3
4
7
10
14
21
28
56
90
180
270
365
545
730 
(EOS)
or ET
Visit Window (Days)
-
-
-
-
-
-
-
-
+1
±1
±1
±2
±2
±4
±14
±14
±14
±14
±30
±30
±30
STUDY PROCEDURES FOR B-ALL SUBJECTS ONLY
BMA/BMB
6.10.1
x
-
xs
-
-
-
-
-
-
-
-
-
x
x
x
At PD/relapse/as clinically 
indicatedv
Peripheral blood smear 
6.10.1
x
-
xs
-
-
-
-
-
-
-
-
-
x
x
x
At PD/relapse/as clinically 
indicatedv
MRD evaluation 
6.10.1
x
-
xs
-
-
-
-
-
-
-
-
-
x
x
x
At PD/relapse/as clinically 
indicatedv
Efficacy assessment (local 
and IRC)
6.10.1
-
-
-
-
-
-
-
-
-
-
-
-
xt
xt
xt
At PD/relapse/as clinically 
indicatedv
Approved
930224809
5.0
v
Approved
1.0
v


EDMS Doc. Number: 24103106 - 22557341
JCAR017
Protocol JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
58
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
Table 3:
Table of Events (Continued)
Pre-treatment Period
Treatment Period
Post-Treatment 
Follow-up Period
Ref. 
Section
Screen-
ingcc
Leuka-
pheresis
Pre-
Treat-
ment 
Evalua-
tion
LD 
Chemo-
therapy
JCAR-
017 
Infu-
sion
Study Month
-
-
-
-
-
-
-
-
-
-
-
-
-
1
2
3
6
9
12
18
24
Study Day
Up to 
14 days 
before
leuka-
pheresis
Within 7 
days 
before LD 
chemo-
therapy
Start 5 to 
10 days 
before
Day 1bb
1bb
2
3
4
7
10
14
21
28
56
90
180
270
365
545
730 
(EOS)
or ET
Visit Window (Days)
-
-
-
-
-
-
-
-
+1
±1
±1
±2
±2
±4
±14
±14
±14
±14
±30
±30
±30
STUDY PROCEDURES FOR B-NHL SUBJECTS ONLY
BMA/BMB
6.10.2
xw
-
-
-
-
-
-
-
-
-
-
-
xw
At PD/relapse/as clinically indicatedv,w
CT/MRI
6.10.2
xu
-
xu
-
-
-
-
-
-
-
-
-
x
-
x
x
x
xv
Tumor biopsyx 
6.10.2
x
-
-
-
-
-
-
-
-
-
-
-
x
At PD/relapse/as clinically indicatedv
Efficacy assessment (local 
and IRC)
6.10.2
-
-
-
-
-
-
-
-
-
-
-
-
x
-
x
x
x
xv
RESEARCH SAMPLES FOR BOTH B-ALL AND B-NHL SUBJECTS
Peripheral blood for 
JCAR017 PK 
 
6.11.1
x
-
-
x
x
x
-
x
x
x
x
x
x
x
x
x
x
x
xy
xy
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EDMS Doc. Number: 24103106 - 22557341
JCAR017
Protocol JCAR017-BCM-004
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59
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
Table 3:
Table of Events (Continued)
Pre-treatment Period
Treatment Period
Post-Treatment 
Follow-up Period
Ref. 
Section
Screen-
ingcc
Leuka-
pheresis
Pre-
Treat-
ment 
Evalua-
tion
LD 
Chemo-
therapy
JCAR-
017 
Infu-
sion
Study Month
-
-
-
-
-
-
-
-
-
-
-
-
-
1
2
3
6
9
12
18
24
Study Day
Up to 
14 days 
before
leuka-
pheresis
Within 7 
days
before LD 
chemo-
therapy
Start 5 to 
10 days 
before
Day 1bb
1bb
2
3
4
7
10
14
21
28
56
90
180
270
365
545
730 
(EOS)
or ET
Visit Window (Days)
-
-
-
-
-
-
-
-
+1
±1
±1
±2
±2
±4
±14
±14
±14
±14
±30
±30
±30
Abbreviations: AE = adverse event; B-ALL = B-cell acute lymphoblastic leukemia; B-NHL = B-cell non-Hodgkin lymphoma; BM = bone marrow; BMA = bone marrow aspirate; 
BMB = bone marrow biopsy; CNS = central nervous system; eCRF = electronic case report form; CSF = cerebrospinal fluid; CT = computed tomography; ECG = 
electrocardiogram; ECHO = echocardiogram; EOS = end of study; ET = early termination; FCBP = female of child-bearing potential; FCCBP = female children of child-bearing 
potential; FEV1 = forced expiratory volume in one second; GVHD = graft-versus-host disease; HLA = human leukocyte antigen; IRC = Independent Review Committee; IRT = 
interactive response technology; IV = intravenous; LD = lymphodepleting; MRD = minimal residual disease; MRI = magnetic resonance imaging; MUGA = multi-gated 
acquisition scan; 
 PD = progressive disease; PK = pharmacokinetic; PRO = patient reported outcome; 
 
SCT = stem cell transplantation.
a Eligibility criteria: Subjects must be evaluated for evidence of active infections prior to the leukapheresis being started. In case of suspected infection, subject should be treated 
and leukapheresis postponed until the active infection has resolved. The subject must continue to meet pre-treatment eligibility criteria pertaining to adequate organ function, 
active infections, pregnancy, and washout of prior therapy before initiation of LD chemotherapy and JCAR017.  In addition, subjects who receive CD19-targeted therapy as 
anticancer treatment for disease control while JCAR017 is being manufactured, must have CD19-positive disease re-confirmed prior to receiving LD chemotherapy.
b If MRD status is unknown at the time of infusion (Day 1), IRT will be retrospectively updated with the MRD status from the central analytical laboratory.
c Including GVHD assessment (if applicable).
d Subjects who require hospitalization should have vital signs assessed daily. Minimum and maximum values within a 24-hour period should be recorded on the appropriate eCRF.
e Vital signs should be taken before and after leukapheresis.
f Measured within 15 minutes prior to the first JCAR017 administration, within 15 minutes after IV administration, and approximately every 15 minutes thereafter for the first 
hour, and hourly for the next 2 hours.  If the subject’s vital signs are not stable 4 hours following the IV administration, vital signs should be monitored as clinically indicated 
until stable.
g Does not need to be done at screening if one performed within 4 weeks prior to leukapheresis.
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h Infectious disease marker blood sample sent with leukapheresis product and applicable to European sites only. Refer to the MNC collection laboratory manual for further details
on where sample is sent for analysis.
i Within 48 hours prior to starting LD chemotherapy. Female Children of Childbearing Potential is defined as females who have achieved menarche and/or breast development in 
Tanner stage 2 or greater and have not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries). Note: 
Amenorrhea following cancer therapy does not rule out childbearing potential. Female of Childbearing Potential is defined as a sexually mature woman who has not undergone a 
hysterectomy or bilateral oophorectomy, has not been naturally postmenopausal (amenorrhea following cancer does not rule out childbearing potential) for at least 12
consecutive months without an alternative medical cause.
j Required within 3 months prior to enrollment.  Data from local testing will be collected for those subjects with prior allogeneic SCT.  
k First day of LD chemotherapy only.
l Performed within 48 hours prior to leukapheresis to calculate the target whole blood processed volume for the leukapheresis procedure. Refer to the MNC collection laboratory 
manual for further details.
m Should be scheduled as soon as possible after meeting eligibility criteria.
n Administered 2 to 7 days after completion of LD chemotherapy. Prior to dose, it must be confirmed that the subject meets criteria for JCAR017 infusion (refer to 
Section 6.2.1.3).
o If clinically indicated.
p Please refer to Section 10.1  for details on reporting AEs.
q Not required for subjects with documented B-cell recovery without recent use of intravenous immunoglobulin (IVIG).
r Required at screening for subjects with suspected or confirmed CNS involvement. CSF assessment is required to be performed if CNS involvement is suspected at the pre-
treatment evaluation or at any time during the study as clinically indicated.  CNS imaging should be performed as clinically indicated.  CSF assessments are not required for 
subjects in CR/CRi after JCAR017 infusion unless suspicion of CNS relapse.
s For B-ALL subjects, the BM assessment (BMA [BMB only if clinically indicated]) performed at the pre-treatment evaluation will serve as the baseline assessment. Subjects will 
be retrospectively reassigned to the appropriate cohort should their pre-LD chemotherapy disease status show a change from screening. Subjects who demonstrate morphological 
remission and who are MRD negative upon restaging prior to initiation of lymphodepleting therapy will still be treated and followed on study.
t First disease assessment will be performed at 28 days after JCAR017 infusion.  If the subject cannot be assessed for CR/CRi due to hypoplastic marrow, a repeat marrow 
examination should be performed when there is evidence of hematopoietic recovery so that remission can be assessed for the first time. In order for overall response to be 
categorized as CR or CRi, it must be confirmed at a minimum of 4 weeks (28 days) after the initial achievement of CR or CRi.
u If the subject has previous imaging within 14 days of screening that is after the last relapse/progression and no anticancer treatment was given between the imaging and 
screening, those scans can be used as the baseline assessment and do not need to be repeated at screening.  In addition, B-NHL subjects who receive anticancer treatment for 
disease control while JCAR017 is being manufactured will have CT/MRI (chest, neck, abdomen, pelvis) after completion of the intervening anticancer treatment and as close as 
possible to the start of LD chemotherapy (must be within 7 days prior to start) to confirm measurable disease. B-NHL subjects who do not receive anticancer treatment control 
while JCAR017 is being manufactured will have CT/MRI scans repeated (must be within 7 days prior to start of LD chemotherapy), only if no scans were done at screening or 
within 3 weeks prior to the start of LD chemotherapy, to evaluate the tumor load.
v To be performed as clinically indicated and at PD/relapse.
w For B-NHL subjects, BM assessment (BMA [BMB if clinically indicated]) will be performed at screening. If there is BM involvement at screening, then another BM assessment 
should be performed at Day 28 and then as clinically indicated after that and at PD/relapse.  
x To be performed for subjects with accessible disease. Collection of tissue from latest archived tumor biopsy (block or slides) for tumor evaluation at screening.  If archival 
sample is before most recent relapse, a new tumor biopsy is mandated to confirm diagnosis.
y
 
 
 
 
bb All evaluations, research sampling and laboratory assessments must be done prior to administration of lymphodepleting chemotherapy or JCAR017.
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EDMS Doc. Number: 24103106 - 22557341
JCAR017
Protocol JCAR017-BCM-004
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cc Screeningprocedures as standard of care within 30 days prior to signing the ICF/IAF may be used to evaluate study eligibility based on discussion with Celgene Medical 
Monitor.
dd To be done on each day of lymphodepleting chemotherapy. Prior to first dose, it must be confirmed that the subject meets criteria for lymphodepleting chemotherapy as
described in Section 6.2.1.1.
ee PedsQL Generic Core module, PedsQL Cancer module, and PedsQL multidimensional Fatigue Scale. 
ffParent Report PedsQL Generic Core module, Parent Report PedsQL Cancer module, Parent Report PedsQL multidimensional Fatigue Scale, and Parent Report PedsQL Family 
Impact Module.
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EDMS Doc. Number: 24103106 - 22557341
JCAR017
Protocol JCAR017-BCM-004
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6.
PROCEDURES
Any questions regarding the protocol should be directed to the Medical Monitor(s) or designee.
6.1.
Pre-treatment Period
6.1.1.
Screening
Screening may begin once the subject signs the IRB/EC-approved ICF/IAF. Where applicable, 
institutional decision boards (eg, multidisciplinary tumor boards, Réunion de concertation 
pluridisciplinaire [RCP]) should be involved for subject selection. If a subject has had a 
screening procedure as standard of care within 30 days prior to signing the ICF/IAF, it may be 
used to evaluate study eligibility based on discussion with Celgene. The following assessments 
must be performed within 14 days prior to enrollment (unless otherwise specified):

Obtain signed informed consent/assent 

Assess eligibility per inclusion/exclusion criteria. All inclusion/exclusion criteria 
must be met in order for subjects to enroll in the study.

IRT registration

Obtain medical history, including: Disease diagnosis and history, HSCT history, 
chemotherapy, radiation and surgical history. May include history of toxicities related 
to prior treatments and allergies.

Physical examination, including routine neurologic examination, height, weight, and 
vital signs (blood pressure, body temperature, respirations, heart rate, and oxygen 
saturation via pulse oximetry) and GVHD assessment (if applicable).

Tanner staging

Karnofsky or Lansky performance status assessment 

Cardiac ECHO or MUGA (does not need to be done at screening if one performed 
within 4 weeks prior to leukapheresis) for LVEF

12-lead electrocardiogram (ECG) 

Collection of peripheral blood samples for clinical laboratory evaluations:

Chemistry

Hematology 

Viral serology 

Serum ß-HCG pregnancy test on FCCBP/FCBP

Determination of creatinine clearance

Local laboratory assessments

Human leukocyte antigen (HLA) typing and donor chimerism for subjects who 
had previous allogeneic HSCT (required within 3 months prior to enrollment)
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EDMS Doc. Number: 24103106 - 22557341
JCAR017
Protocol JCAR017-BCM-004
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63
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019

Administration of Pediatric Quality of Life Inventory (PedsQL) questionnaires 
(subject and parent/caregiver as applicable) 

Record all AEs related to protocol-mandated procedures and associated concomitant 
medications

Research peripheral blood samples 
 
: 

JCAR017 PK 

Cerebrospinal fluid assessment is required for subjects with suspected or confirmed 
CNS involvement. CNS imaging should be performed as clinically indicated.

B-ALL subjects ONLY:

Bone marrow morphological assessment (BM aspirate [BM biopsy only if 
clinically indicated]).  

Peripheral blood morphological assessment (PB smear)

Minimal residual disease analysis.  
Minimal residual disease will be assessed by a validated assay in BM samples at a 
central analytical laboratory. Note: Additional BM aspirate may be collected 
unscheduled if required for additional MRD testing. 

B-NHL subjects ONLY:

Bone marrow morphological assessment (BM aspirate [BM biopsy only if 
clinically indicated])

Computer tomography (CT)/magnetic resonance imaging (MRI) (chest, neck, 
abdomen, pelvis): If the subject has previous imaging within 14 days of screening 
that is after the last relapse/progression and no anticancer treatment was given 
between the imaging and screening, these scans can be used as the baseline 
assessment and do not need to be repeated at screening. 

Collection of tissue from latest archived tumor biopsy (block or slides) for tumor 
evaluation. If archival sample is before most recent relapse, a new tumor biopsy is 
mandated to confirm diagnosis.
6.1.2.
Leukapheresis 
Leukapheresis should be scheduled in coordination with Celgene as soon as possible after the 
subject has completed screening and has determined to be eligible and is enrolled in the study.
Venous access is required for leukapheresis and should be determined according to institutional 
practice. Should a technical issue arise during the procedure or in the immediate processing of 
the product such that it cannot be used for JCAR017 production, a second collection procedure 
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EDMS Doc. Number: 24103106 - 22557341
JCAR017
Protocol JCAR017-BCM-004
  Celgene Corporation
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64
JCAR017-BCM-004 Amendment 2 Final: 10 Sep 2019
may be performed. Subjects must continue to meet eligibility requirements for repeat 
leukapheresis.
An unstimulated leukapheresis collection will be performed on each subject to obtain a sufficient 
quantity of 
 for the production of the JCAR017 
investigational product. Please refer to the MNC collection manual for further details.
The following assessments will be conducted prior to leukapheresis: 

Eligibility check: subjects must be evaluated for evidence of active infections prior to 
the leukapheresis being started. In case of suspected infection, leukapheresis should be 
postponed until the active infection has been treated and has resolved.

IRT registration

Medical history 

Karnofsky (subjects 16 ≥ years of age) or Lansky (subjects < 16 years of age) 
performance status assessment

Weight 

Vital signs (performed before and after leukapheresis) 

Viral serology testing – infectious disease markers

Peripheral blood CD3+ count (within 48 hours prior to leukapheresis)

Hematology (CBC with differential within 24 hours prior to leukapheresis and must 
include absolute lymphocyte count [ALC].)

Chemistry

Record all AEs related to protocol-mandated procedures and associated concomitant 
medications
Table 4:
Washout Periods Prior to Leukapheresis 
Treatment
Washout
Systemic Therapy
Alemtuzumab
6 months
Fludarabine
3 months
Cladribine
3 months
Mitoxantrone
6 weeks
Idarubicin
6 weeks
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EDMS Doc. Number: 24103106 - 22557341
JCAR017
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Table 4:
Washout Periods Prior to Leukapheresis (Continued)
Treatment
Washout
Clofarabine
3 months
Arabinoside-C
3 months
Experimental agents (applies only to treatments not listed in 
Table 4)
4 weeks/3 half-lives (whichever is greater)
Lymphotoxic chemotherapeutic agents (eg, 
cyclophosphamide >300 mg/m2, ifosfamide, bendamustine)
2 weeks (with the exception of pegylated 
asparaginase which is 4 weeks)
Therapeutic doses of corticosteroids (defined as > 0.4 mg/kg 
[maximum 20 mg/day] prednisone or equivalent)
7 days
Cytotoxic chemotherapeutic agents not considered 
lymphotoxic (eg, doxorubicin, vincristine, gemcitabine, 
oxaliplatin, carboplatin, etoposide, etc) 
7 days
Intrathecal
Dexamethasone, methotrexate
7 days
Radiation Therapy
Radiation, multiple lesions
6 weeks
Radiation, single lesion, if additional non-irradiated 
measurable lesions are present
2 weeks
6.1.3.
Anticancer Treatments Between Leukapheresis and Lymphodepleting 
Chemotherapy
If necessary, anticancer treatment (ie, bridging chemotherapy) is allowed for disease control 
while JCAR017 is being manufactured (ie, after leukapheresis and prior to LD chemotherapy). 
Chemotherapy is allowed if completed at least 7 days prior to the start of LD chemotherapy. If 
other agents are used, the washout periods noted in the exclusion criteria (see Section 4.3) must 
be met. The use of therapeutic agents with little/no evidence in the scientific literature for B-ALL 
or B-NHL should be discussed with Celgene. For B-NHL subjects, local radiation is allowed to a 
single lesion or subset of lesions. If anticancer treatment is necessary during this time, the pre-
treatment CT/MRI assessments, BM assessment, peripheral blood smear, and other pre-treatment 
study procedures (see Section 6.1.4) must be performed after the anticancer treatment has been 
completed. Subjects must continue to have confirmed disease, including measurable disease by 
CT/MRI for B-NHL subjects, and must meet pre-treatment eligibility criteria pertaining to 
adequate organ function, active infections, pregnancy, and washout of prior therapy before 
initiation of LD chemotherapy.
Note: Subjects who receive CD19-targeted therapy as anticancer treatment for disease control 
while JCAR017 is being manufactured, must have CD19-positive disease re-confirmed prior to 
starting LD chemotherapy. Subjects without confirmed CD19+ disease will not be evaluable for
the primary endpoint analysis however they will still be able to be treated at Investigator 
discretion.
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EDMS Doc. Number: 24103106 - 22557341
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6.1.4.
Pre-Treatment Evaluation (Within 7 days Prior to Lymphodepleting 
Chemotherapy) 
The following assessments will be conducted:

B-ALL subjects ONLY: (regardless if anticancer treatment for disease control was 
given while JCAR017 is being manufactured): 

Bone marrow morphological assessment (BM aspirate [BM biopsy only if 
clinically indicated])  

Peripheral blood morphological assessment (PB smear)

Minimal residual disease analysis 
Minimal residual disease will be assessed by a validated assay in BM samples at a 
central analytical laboratory. 
NOTE: The BM assessment performed at the pre-treatment evaluation will serve as 
the baseline disease assessment. Subjects will be retrospectively reassigned to the 
appropriate cohort should their pre-LD chemotherapy disease status show a change 
from screening.  
Subjects who demonstrate morphologic remission and are MRD negative upon 
restaging prior to initiation of lymphodepleting therapy will continue to be treated and 
followed on study but will not be considered evaluable for MRD response endpoint 
and may be replaced.

B-NHL subjects ONLY: 

For subjects who receive anticancer treatment for disease control while JCAR017 
is being manufactured: 
Restaging CT/MRI (chest, neck, abdomen, pelvis) must be performed after 
completion of the intervening anticancer treatment and as close as possible to the 
start of LD chemotherapy (must be within 7 days prior to start) to confirm 
measurable disease.

For subjects who did not receive anticancer treatment control while JCAR017 is 
being manufactured:
If no scans were done at the study site for screening and within 3 weeks prior to 
the start of LD chemotherapy, CT/MRI scans must be performed (within 7 days 
prior to start of LD chemotherapy).
The following assessments will be conducted in all subjects within 7 days prior to starting LD
chemotherapy and regardless if any anticancer treatment was received for disease control: 

Confirm subject meets study pre-treatment eligibility criteria

IRT registration

Medical history

Physical examination, including routine neurologic examination, weight, vital signs 
and GVHD assessment (if applicable). 
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EDMS Doc. Number: 24103106 - 22557341
JCAR017
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
Tanner staging

Karnofsky (subjects ≥ 16 years of age) or Lansky (subjects < 16 years of age)
performance status assessment 

12-lead ECG

Cardiac ECHO or MUGA for LVEF  (if clinically indicated) 

Collection of peripheral blood samples for clinical laboratory evaluations:

Chemistry

Hematology 

Coagulation 

Inflammatory markers 

Immunoglobulins 

Serum ß-HCG pregnancy test on FCCBP/FCBP (within 7 days prior to starting 
LD chemotherapy)

Cerebrospinal fluid assessment is required to be performed if CNS involvement is 
suspected or has been confirmed at a previous assessment. CNS imaging should be 
performed as clinically indicated. 

Administration of Pediatric Quality of Life Inventory (PedsQL) questionnaires 
(subject and parent/caregiver as applicable)

Record all AEs related to protocol-mandated procedures (see Table 8) and associated 
concomitant medications (see Table 7)
6.2.
Treatment and Post-treatment Follow-up Periods
6.2.1.
Treatment Period
6.2.1.1.
Criteria for Treatment
Subject eligibility criteria must be confirmed immediately prior to starting the first cycle of 
lymphodepleting chemotherapy. Chemotherapy or chemoimmunotherapy given after 
leukapheresis to maintain disease control must be stopped ≥ 7 days prior to lymphodepleting 
chemotherapy, respecting washout periods in Table 4 and the exclusion criteria (see Section 4.3).
Subjects must also be clinically stable and must have recovered from prior organ (non-
hematologic) toxicities to Grade ≤ 2 to receive lymphodepleting chemotherapy and proceed to 
JCAR017 infusion. Neither lymphodepleting chemotherapy nor JCAR017 treatment will be 
administered if there is a worsening of performance status, rapid clinical deterioration, or 
evidence of rapidly progressive disease.  
In the absence of infection, isolated AST and/or ALT elevation that can be linked temporally to 
administration of medication (eg, fungal prophylaxis or bridging chemotherapy) may not 
preclude treatment of subjects (LD chemotherapy and infusion of JCAR017) after discussion 
with Celgene’s Medical Monitor. 
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EDMS Doc. Number: 24103106 - 22557341
JCAR017
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6.2.1.2.
Lymphodepleting Chemotherapy (Start 5 to 10 Days Prior to JCAR017 
Infusion) 
Upon notification from Celgene that JCAR017 will be available, LD chemotherapy should be 
initiated so as to finish 2 to 7 days prior to JCAR017 infusion. Please see Section 7.2.1 for the 
recommended administration. Subjects must be evaluated for evidence of ongoing infections 
prior to the LD chemotherapy. In case of suspicion of infection, subject should be treated 
accordingly, and LD chemotherapy postponed until infection resolution. Delay of 
lymphodepleting chemotherapy of more than 14 days requires discussion with Celgene and may 
require rescreening.
The following assessments will be performed prior to dosing on each day of LD chemotherapy
administration, unless otherwise noted:

IRT registration

Height (only first day of LD chemotherapy) and weight 

Vital signs 

Karnofsky (subjects ≥ 16 years of age) or Lansky (subjects < 16 years of age) 
performance status assessment 

Collection of peripheral blood samples for clinical laboratory evaluations:

Serum creatinine or determination of creatinine clearance (required only on first 
day of LD chemotherapy).
Lymphodepleting chemotherapy should be withheld if serum creatinine is beyond 
the maximum value (see Section 4.2) using the Schwartz formula or radioisotope 
GFR is ≤ 70 mL/min/1.73 m2.  

Chemistry

Hematology 

Research peripheral blood samples 
 

For JCAR017 PK 
 (only first day of LD chemotherapy prior to
dosing)

Record all AEs and associated concomitant medications 

Hospital resource utilization
6.2.1.3.
JCAR017 Administration – Day 1 
Based on the risks of adverse events requiring immediate medical intervention, following 
JCAR017 infusion and prior to discharge from the hospital subjects must meet the following 
criteria:

Have dedicated full-time (24-hour care) caregiver support for the first 30 days after 
JCAR017 infusion
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EDMS Doc. Number: 24103106 - 22557341
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
Stay within a 30-minute transportation ride to the treating clinical trial site for first 30 
days after JCAR017 infusion for close monitoring of fever and other signs of CRS or 
neurotoxicity

Cannot have disease characteristics that, in the Investigator’s clinical judgment, puts 
the subject at higher risk of complications (eg, tumor lysis syndrome, CRS, 
neurotoxicity)

Cannot have a psychosocial condition that puts them at risk for not following 
instructions
After Day 30, subjects can travel further from site only if they are afebrile for 24 hours and signs 
and symptoms of CRS and neurotoxicity have completely resolved. If discharged prior to Day 
30, self-monitoring of fever is required every 6 to 8 hours (while awake) until 30 days following 
JCAR017 infusion. Hospitalization is required if there are any signs of fever (≥38oC/100.4oF), 
or signs or symptoms suggestive of CRS or neurotoxicity for close monitoring of cardiac and 
organ function, including routine neurologic exams.  In addition, febrile subjects need to be 
worked up for infections per institutional guidelines.
Subjects who do not have adequate social support (a full-time caregiver) outside of the hospital 
or do not have reliable transportation to the clinic for scheduled evaluations or emergencies post-
therapy should be considered for hospitalization for the first 30 days following JCAR017 
infusion. 
Subjects should not experience a significant worsening in clinical status compared to initial 
eligibility criteria that would, in the opinion of the treating physician, increase the risk of adverse 
events associated with JCAR017 infusion. Subjects who meet at least one of the following 
criteria on the day of scheduled JCAR017 infusion should have JCAR017 administration 
delayed:

Suspected or active systemic infection

Onset of fever ≥ 38°C/100.4°F, not related to underlying disease

Presence of progressive radiographic abnormalities on chest x-ray, or requirement for 
supplemental oxygen to keep saturation greater than 91% 

Cardiac arrhythmia not controlled with medical management

Hypotension requiring vasopressor support

New onset or worsening of other non-hematologic organ dysfunction ≥Grade 3

Taking any of the prohibited medications as described in Section 8.2
Subjects with active infection must have JCAR017 infusion postponed until the active infection 
has resolved (subjects with suspected/active infection must have negative culture for at least 24 
hours on appropriate antibiotics or negative rapid viral panel). Subjects with non-hematologic
organ toxicities may not receive JCAR017 until the non-hematologic organ toxicities have 
recovered to ≤ Grade 2. In case of a possible delayed infusion, discussion with medical monitor 
must occur regarding decision on delay of treatment and/or repeating of LD chemotherapy.
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In the event that a subject experiences any of the above, Celgene must be contacted and 
discussion regarding delay of treatment must occur.
The following will be performed on Day 1 prior to JCAR017 infusion:

IRT registration

Physical examination 

Tanner staging

Weight

Vital signs (measured within 15 minutes prior to the first JCAR017 administration, 
and approximately every 15 minutes thereafter for the first hour, and hourly for the 
next 2 hours. If the subject’s vital signs are not stable 4 hours following the final IV 
administration, vital signs should be monitored as clinically indicated until stable) 

Karnofsky (subjects ≥ 16 years of age) or Lansky (subjects < 16 years of age)
performance status assessment 

Routine neurologic examination

Record all AEs and associated concomitant medications 

Administration of PedsQL questionnaires (subject and parent/caregiver as applicable) 

Hospital resource utilization

Collection of peripheral blood samples for clinical laboratory evaluations:

Chemistry

Hematology

Coagulation

Inflammatory markers

JCAR017 premedication (see Section 7.2.2)

Research peripheral blood samples 
 

For JCAR017 PK 
6.2.1.4.
Days 2, 3, and 4 (+1 day for Day 4) 

Vital signs 

Routine neurological examination

Physical examination 

Record all AEs and associated concomitant medications 

Hospital resource utilization

Collection of peripheral blood samples for clinical laboratory evaluations:

Chemistry
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
Hematology 

Coagulation 

Inflammatory markers 

Research peripheral blood samples 
 

For JCAR017 PK 
 (Day 2 and Day 4 only)
6.2.1.5.
Day 7 (±1 day) 

Physical examination 

Vital signs 

Karnofsky (subjects ≥ 16 years of age) or Lansky (subjects < 16 years of age) 
performance status assessment

Routine neurological examination

Record all AEs and associated concomitant medications 

Hospital resource utilization

Collection of peripheral blood samples for clinical laboratory evaluations:

Chemistry

Hematology 

Coagulation 

Inflammatory markers 

Research peripheral blood samples 
: 

For JCAR017 PK 
6.2.1.6.
Day 10 (±1 day) 

Vital signs 

Physical examination 

Routine neurologic examination

Record all AEs and associated concomitant medications 

Hospital resource utilization

Collection of peripheral blood samples for clinical laboratory evaluations:

Chemistry

Hematology 

Coagulation 

Inflammatory markers 
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
Research peripheral blood samples 
 

For JCAR017 PK 
6.2.1.7.
Days 14, 21, 28, and 56

Physical examination 

Tanner staging on Days 28 and 56

Vital signs 

Karnofsky (subjects ≥ 16 years of age) or Lansky (subjects < 16 years of age) 
performance status assessment 

Routine neurologic examination

Record all AEs and associated concomitant medications 

Administration of PedsQL questionnaires (subject and parent/caregiver as applicable) 
required on Days 28 and 56

Hospital resource utilization

Collection of peripheral blood samples for clinical laboratory evaluations:

Chemistry

Hematology 

Coagulation 

Inflammatory markers (required on Days 14 and 21; required on Days 28 and 56
if clinically indicated) 

Immunoglobulins 

Cerebrospinal fluid assessment is required for subjects with suspected or confirmed 
CNS involvement (not required after PD/relapse occurs). CNS imaging should be 
performed as clinically indicated.

Research peripheral blood samples 
: 

JCAR017 PK 
required on Days 14, 21, 28, and 56

Response evaluation by local Investigator review and Independent Review 
Committee (IRC) 
B-ALL subjects ONLY (Day 28 and 56):

Bone marrow morphological assessment (BM aspirate [BM biopsy only if 
clinically indicated])  

Peripheral blood morphological assessment (PB smear)
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
Minimal residual disease analysis 
B-NHL subjects ONLY (Day 28): 

CT/MRI 

Tumor biopsy (for subjects with accessible disease)

Bone marrow morphological assessment (BM aspirate [BM biopsy only if 
clinically indicated]) only if previous BM involvement at screening  
Please refer to Section 6.10 for additional details on B-ALL and B-NHL efficacy 
assessments.
6.2.2.
Post-treatment Follow-up Period 
All subjects who received any JCAR017 infusion should complete the Post-Treatment Follow-up
period visits at approximately 3, 6, 9, 12, 18, and 24 months (EOS) after JCAR017 infusion for 
disease status and survival. 
The following assessments will be performed at each of the Post-Treatment Follow-up visits in 
subjects who have not received subsequent anticancer treatment: 

IRT registration (EOS visit)

Physical examination and Tanner staging

Routine neurologic examination

Karnofsky (subjects ≥ 16 years of age) or Lansky (subjects < 16 years of age) 
performance status assessment 

Cerebrospinal fluid assessment is required for subjects with suspected or confirmed 
CNS involvement (not required after PD/relapse occurs). CNS imaging should be 
performed as clinically indicated.

Response evaluation by local Investigator review and IRC – at timepoints indicated in 
Table 3
B-ALL subjects ONLY:

Bone marrow morphological assessment (BM aspirate [BM biopsy only if 
clinically indicated])  

Peripheral blood morphological assessment (PB smear)

Minimal residual disease analysis 
B-NHL subjects ONLY: 

CT/MRI

Tumor biopsy for subjects with accessible disease only required as clinically 
indicated
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
Bone marrow morphological assessment (BM aspirate [BM biopsy only if 
clinically indicated]) required as clinically indicated if BM involvement at 
screening  
Please refer to Section 6.10 for additional details on efficacy assessments. 

Collection of peripheral blood samples for clinical laboratory evaluations:

Chemistry

Hematology

Immunoglobulins (not required if B-cell recovery documented without recent 
administration of intravenous immunoglobulins [IVIG])

Research peripheral blood samples 
 
: 

JCAR017 PK 
 (required at all Post-treatment Follow-up Period 
timepoints). 
 

Record all AEs and associated concomitant medications according to Table 8 and
Table 7, respectively.

Administration of PedsQL questionnaires (subject and parent/caregiver as applicable)

Hospital resource utilization

Survival status
The following assessments will be performed in subjects who have received subsequent 
anticancer treatment: 

Collection of anticancer treatment since JCAR017 infusion

Physical examination at Months 12 and 24

Immunoglobulins per Table 3 (not required if B-cell recovery documented without
recent administration of IVIG)

JCAR017 PK 
 (required at all timepoints).

Survival status
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Note: Subjects who receive HSCT post-JCAR017 (but no other subsequent anticancer treatment) 
should continue to undergo response/efficacy evaluations as described above (B-ALL or B-
NHL), unless they have demonstrated relapse/PD prior to HSCT.  
6.3.
Unscheduled Evaluations 
If the Investigator feels that a subject needs to be evaluated at a time other than the protocol-
specified visits, the subject may be asked to come to the clinic for an unscheduled evaluation. 
The following assessments may be performed, as appropriate: 

Physical examination

Neurological examination

Vital signs 

Karnofsky (subjects ≥ 16 years of age) or Lansky (subjects < 16 years of age) 
performance status assessment

Clinical laboratory evaluations 

CT/MRI scan 

MUGA scan/ECHO

CD19+ status

Tumor biopsy (see the JCAR017-BCM-004 laboratory manual) 

Bone marrow assessment (see the JCAR017- BCM-004 laboratory manual) 

Peripheral blood smear (see the JCAR017-BCM-004 laboratory manual)

Cerebrospinal fluid assessment (see the JCAR017-BCM-004 laboratory manual) 

Research peripheral blood samples 
: 

JCAR017 PK 
 
 
 
Additionally, if the Investigator requests any of the following procedures, research samples will 
be requested: 

Lumbar puncture for CSF assessment

Pleural, peritoneal, or other relevant fluid sampling 

Tissue sampling 
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
Autopsy
6.4.
Assessments at Time of Death (Subjects Receiving JCAR017)
In case an autopsy is performed and if feasible, blood and tissue samples will be collected for 
central analysis of markers related to safety and efficacy of the CAR T cells. See the JCAR017-
BCM-004 laboratory manual for details. 
6.5.
Early Withdrawal 
If a subject voluntarily withdraws prematurely from the study, a visit will be scheduled as soon 
as possible, and all of the assessments listed for the 24-month (EOS) visit will be performed. For 
subjects receiving LD chemotherapy but not JCAR017, all AEs will be collected for 30 days 
following the last dose of LD chemotherapy.
6.6.
Second Primary Malignancies Follow-up Period
Second primary malignancies will be monitored as events of interest and must be reported as 
serious adverse events. This includes any second primary malignancies, regardless of causal 
relationship to JCAR017, occurring throughout the subject’s entire participation in the study. If a 
subject develops a second primary malignancy, Celgene will request that a tumor sample, BM and 
blood samples are collected (refer to JCAR017-BCM-004 laboratory manual).  See also 
 Section 6.11.1.
6.7.
Survival Status
All subjects will be followed for survival for 2 years after JCAR017 infusion in the Post-
Treatment Follow-up Period which starts after Day 56 and continues for 2 years after JCAR017 
infusion. Additional survival follow-up information will be collected in the context of the LTFU 
protocol once a subject (who received JCAR017) is discontinued from the study.
6.8.
Long-Term Follow-up
Because this protocol involves gene transfer, long-term follow-up for lentiviral vector safety, 
disease status for at least 5 years, second primary malignancies and survival will continue after 
EOS under a separate LTFU protocol thereafter for up to 15 years after the JCAR017 
infusion (European Medicines Agency [EMA], 2009; FDA, 2010; FDA, 2006). In addition, 
details on all subsequent anti-neoplastic treatments for at least 5 years must be documented. 
Note: The long-term follow-up may exceed 15 years if the subject does not achieve Tanner Stage 
5 by the end of the 15-year safety follow-up period.
All subjects who either complete the Post-Treatment Follow-up Period specified in this protocol 
or who prematurely withdraw after JCAR017 infusion will be asked to enroll in the LTFU 
protocol at the EOS visit or at the time of withdrawal, respectively. A separate ICF/IAF will be 
provided for the LTFU protocol. Subjects who do not consent to participate in the LTFU 
protocol will be followed for survival through public record, if permitted by local regulations.
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6.9.
Safety Assessments
6.9.1.
Physical Examination
A physical examination will be conducted as specified timepoints indicated in the schedule of 
events (Table 3).  Examinations should include assessments of the following body parts/systems: 
abdomen, extremities, heart, lungs, and neurological.
At screening, pre-treatment and at each visit for response assessment, the physical exam must 
also include an assessment of the presence of extramedullary disease (ie, hepatomegaly, 
splenomegaly, lymph nodes, CNS, skin/gum infiltration, testicular masses and other disease 
manifestations).  
Significant physical exam findings identified during screening should be recorded in the medical 
history CRF. The disease response assessment results, including presence or absence and 
physical location of extramedullary disease, will be recorded in the appropriate eCRF. 
Significant abnormalities that begin or worsen after initiation of study treatment must be 
recorded as AEs, as defined in Section 10.
6.9.2.
Tanner Staging
Growth, development, and sexual maturity assessments will be included in the physical 
examination using the Tanner staging system (Marshal and Tanner, 1969 and 1970).  Once a 
subject reaches an overall Tanner Stage of 5, subsequent Tanner Staging assessments do not 
need to be performed.  If a subject is Tanner Stage 5 at screening, only the screening Tanner 
Staging is required to be performed.  
6.9.3.
Vital Signs
Vital signs include temperature, respiratory rate, heart rate, blood pressure, and oxygen 
saturation via pulse oximetry (SaO2).
6.9.4.
Height and Weight
Height in centimeters (cm) or inches (in) and body weight to the nearest kg.
6.9.5.
Routine Neurologic Examinations
A routine neurologic examination should include, at minimum, a physical examination to assess 
cranial nerves, motor and sensory skills, coordination and balance.
6.9.6.
Cerebrospinal Fluid Assessment and Central Nervous System Symptom 
Assessment
Cerebrospinal fluid assessment is required to be performed for subjects with suspected or 
confirmed CNS involvement at screening. Repeated CSF assessments should be performed if 
CNS involvement is suspected or confirmed at the pre-treatment evaluation or at any time during 
the study as clinically indicated (eg, if new CNS symptoms occur, or if clinical signs or suspicion 
of CNS involvement exist). Cerebrospinal fluid assessments (post JCAR017 infusion) are not 
required for subjects in CR/CRi following JCAR017 administration, unless suspicion of CNS 
relapse. Sampling of CSF will be performed per institution’s clinical guidelines and analyzed for 
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cell count, differential cytology, protein level and for research analysis (see the JCAR017-BCM-
004 laboratory manual for instructions on sending a sample for central JCAR017 testing). 
Cerebrospinal fluid cultures (bacterial, fungal, viral) should be performed as clinically indicated 
for suspicion of infection.
CNS imaging (CT and/or MRI) scans should also be performed as clinically indicated with CAR 
T related neurotoxicity.
The classification of CNS status includes the following (NCCN, 2019):

CNS-1 refers to no lymphoblasts in the CSF regardless of WBC count;

CNS-2 is defined as WBC less than 5/mcL in CSF with presence of lymphoblasts;

CNS-3 is defined as WBC of 5/mcL or greater with presence of lymphoblasts or 
clinical symptoms (ie, cranial nerve palsy, clinical spinal cord compression, or 
isolated intracerebral mass)
CNS remission is defined as achievement of CNS-1 status in a subject with CNS-2 or CNS-3 at 
baseline assessment (prior to LD chemotherapy).
CNS relapse is defined as development of CNS-3 status (if < CNS-3 at baseline) or development 
of clinical signs of CNS leukemia (eg, facial nerve palsy, brain/eye involvement, hypothalamic 
syndrome, etc.). If clinical signs of CNS leukemia/lymphoma exist, it must be confirmed by 
relevant methods (eg, biopsy, lumbar puncture, CNS imaging [CT or MRI of brain], etc.) to 
define CNS relapse.
6.9.7.
Performance Status
The Karnofsky (age ≥ 16 years) or Lansky (age < 16 years) performance status will be used to
evaluate subject eligibility at screening and will be assessed throughout the study.
The same performance status scale used at screening should continue to be assessed during the 
duration of the study, regardless of any age change.
6.9.8.
Echocardiogram/Multi-Gated Acquisition Scan
An assessment of LVEF will be performed by ECHO or MUGA to assess the cardiac function of 
the subject and to confirm study eligibility.
6.9.9.
Electrocardiogram 
A standard 12-lead ECG should be obtained. Electrocardiogram tracings should be labelled with 
the study number, subject number, date, and Investigator’s signature, and kept in the source 
documents at the study site.
 
 
 
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6.9.11.
Clinical Laboratory Evaluations
Screening and other laboratory evaluations will be performed both centrally and locally 
according to Table 3 and Appendix D. Additional assessments should be performed between 
scheduled study visits as clinically required in order to diagnose and monitor AEs/SAEs or 
expected events. Clinical management of study subjects will be based on local assessments.
It is the responsibility of the Investigator to obtain and review laboratory results for subject 
safety and follow up with subjects in a timely manner.
6.10.
Efficacy Assessment
The key efficacy assessments to be measured include peripheral blood count, BM, CSF, physical 
examination, evaluation of CNS symptoms, disease specific imaging (ie, CT or MRI), and B-
symptoms (ie, NHL).  Peripheral blood and BM will be analyzed locally and also sent to a 
central laboratory for morphologic evaluation and determination of MRD status (ie, B-ALL).
Overall response will be evaluated locally by the Investigator and by an Independent Review 
Committee (IRC).  The central laboratory results, imaging and pertinent clinical data will be 
provided to the IRC, who will provide a separate response assessment. Clinical management of 
study subjects will be based upon Investigator’s assessment. Efficacy based endpoints (primary 
and secondary) will be based on the IRC review.  
All components of a disease assessment must be performed within 14 days of each other to 
qualify as the same response evaluation, unless otherwise specified.
6.10.1.
Acute Lymphoblastic Leukemia (B-ALL)
Efficacy assessments for B-ALL subjects will be performed according to the 2019 National 
Comprehensive Cancer Network (NCCN) response criteria guidelines for pediatric ALL 
(Appendix B).  A full response evaluation, including assessments of peripheral blood, BM, 
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CSF/CNS assessment (if applicable), and physical exam including assessment of extramedullary 
disease is required at screening, pre-treatment and at each response assessment. Disease 
assessment at the pre-treatment visit (prior to LD chemotherapy) will serve as the baseline.  
Subjects will be retrospectively reassigned to the appropriate cohort should their pre-LD 
chemotherapy disease status show a change from the screening. 
The first disease assessment will be performed 28 days after JCAR017 infusion.  If the subject 
cannot be assessed for CR/CRi due to hypoplastic marrow, a repeat marrow examination should 
be performed when there is evidence of hematopoietic recovery so that remission can be assessed 
for the first time. Repeat BM examinations and response assessments will be performed at Day 
56, Day 90 and at relapse and/or as clinically indicated. 
In order for the best overall disease response to be categorized as CR or CRi, there must be no 
clinical evidence of relapse as assessed by peripheral blood, BM, CSF and extramedullary 
disease assessment (where applicable) confirmed at a minimum of 4 weeks (28 days) after the 
initial achievement of CR or CRi. Any additional assessments performed for the purpose of 
disease response evaluation must also support a response of remission. 
6.10.1.1.
Minimal Residual Disease (MRD)
Minimal residual disease in B-ALL refers to the presence of leukemic cells below the threshold 
of detection using conventional morphologic methods and will be assessed on all B-ALL BM 
timepoints by a validated assay at a central analytical laboratory. For Cohort 2 in Phase 2, MRD 
results will be used for enrollment and monitoring of subjects for the primary endpoint.  

MRD relapse will be defined as an MRD detection by validated assay at a frequency of 
1 x 10-4 or greater in BM cells following an initial MRD negative (less than 1 x 10-4) 
CR/CRi. 
Subjects who demonstrate morphologic remission and are MRD negative upon restaging prior to 
initiation of lymphodepleting therapy will continue to be treated and followed on study but will 
not be considered evaluable for the MRD response endpoints and may be replaced.
6.10.2.
Non-Hodgkin Lymphoma (B-NHL)
Efficacy assessments will be performed according to the 2015 international pediatric NHL 
response criteria guidelines (Appendix C) based on radiographic tumor evaluation by CT/MRI 
scans (chest, neck, abdomen and pelvis).  Radiographic response determination will be evaluated 
locally at the site and also sent for central radiology review. Bone marrow aspirates/biopsies and 
tumor biopsies will also be performed according to Table 3 to assess involvement by lymphoma 
and will be considered when determining overall response.  Efficacy assessments will be 
performed at Day 28, 90, 180, 270 and at relapse/PD/as clinically indicated.  
B-NHL subjects who do not receive anticancer treatment control while JCAR017 is being 
manufactured will have CT/MRI scans repeated (within 7 days prior to start of LD 
chemotherapy), only if no scans were done at screening or within 3 weeks prior to the start of LD 
chemotherapy, to evaluate the tumor load. If the subject has previous imaging within 14 days of 
screening that is after the last relapse/progression and no anticancer treatment was given between 
the imaging and screening, these scans can be used as the baseline assessment. 
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6.10.2.1.
Pseudoprogression
If a subject with B-NHL demonstrates early tumor progression (defined as occurring prior to/at 1 
month after JCAR017 infusion), the Investigator is responsible for evaluating whether the 
subject is experiencing a possible pseudoprogression (ie, tumor flare, which is a local 
inflammatory reaction indicating early tumor response at sites of disease such as lymph nodes.
6.10.3.
Independent Review Committee
An IRC will be established to review the BMA/BMB, peripheral blood and radiographic data 
provided by the central laboratory as well as pertinent clinical eCRF data listings (as appropriate) 
in order to perform an independent response assessment. Clinical management of study subjects 
will be based upon local Investigator’s assessment. The designation of response for the primary 
and select secondary based endpoints will be based only on the evaluations made by the IRC.
An IRC charter will detail the IRC data flow and review process in alignment with the response 
definitions in Appendix B and Appendix C. Results from the IRC will not be provided to the 
clinical sites. 
6.11.
Pharmacokinetics 
Assessment of JCAR017 PK will be determined by droplet digital polymerase chain reaction 
(ddPCR)
 
Detailed information regarding the collection, handling, and shipment of PK assessment samples 
is provided in the JCAR017-BCM-004 laboratory manual.
6.11.1.
Viral Vector Sequence Pharmacokinetic Testing
Persistence of JCAR017 vector sequences will be monitored. Details regarding sample collection 
and processing are provided in the JCAR017-BCM-004 laboratory manual. 
 
. 
At any time point ≥ 12 months after JCAR017 infusion, if persistence vector sequence is 
detected in ≥ 1% of cells in two consecutive blood samples, the pattern for vector integration 
sites will be analyzed. If integration pattern suggests a predominant integration site, a repeat 
analysis will be conducted within 3 months and further studies including insertion site analysis 
will be performed.
Any observation of clonal outgrowth (clonal dominance), or monoclonality, will be reported as
an SAE within 24 hours.
If a subject develops a second primary malignancy, Celgene will request a sample for assessment 
of viral vector sequence testing. 
  
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6.13.
Patient-reported Outcomes
Patient-reported quality-of-life outcomes will be administered according to Table 3.
The Pediatric Quality of Life (PedsQL) Core module, Cancer module, and Multidimensional 
Fatigue Scale will be used to assess the subject’s health as well as physical, social, emotional, 
and school functioning. The parent versions of the same modules will be administered to the 
parent/caregivers.  The PedsQL Family Impact Module will also be administered to caregivers 
through the EOS (will not be administered in the LTFU protocol). 
In this study, completion of the following questionnaire(s) will be required based on age at study 
entry as described in Table 5:
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Table 5:
Administration of Pediatric Quality of Life Inventory Questionnaires
Age at Study Entry
PedsQL™ 4.0 Version
0 to 1 
Not Donea
2 to 4
Parent/caregiver proxy version onlya
5 to 7
PedsQL (Young Child)
8 to 12
PedsQL (Children)
13 to 17
PedsQL (Teens)
18 to 25
PedsQL (Young Adult)
a Subjects less < 5 years of age will not have self-questionnaires administered.  Only parent/caregiver proxy version 
and Family Impact module will be completed of subjects ages 2 to 4 years of age.
The questionnaire will be completed by the subjects/caregivers before they see the Investigator, 
or any clinical assessments are performed at any given visit. Under extenuating circumstances 
where the questionnaire(s) were not completed at the screening visit, it must be completed before
administration of LD chemotherapy.  
Questionnaires should be completed in the language most familiar to each subject, and 
subjects/caregivers should be given adequate time and space to complete the questionnaires. For 
each visit a questionnaire is to be performed, it is expected to have the subject (self-
administering where applicable), parent-proxy and Family Impact modules completed. If 
possible, the subject/caregiver should first complete the PedsQL Core module and then complete 
any additional modules.  
Parents/caregivers, Children (age 8-12), Teens (age 13-17) and Young Adults (age 18 to 25) may 
self-administer the PedsQL after introductory instructions from the administrator. If the 
administrator determines that the subject is unable to self-administer the PedsQL (eg, due to 
illness, fatigue, reading difficulties), the PedsQL should be read aloud to the subject.  However, 
the administrator and the caregivers should be instructed not to modify or interpret subjects’ 
responses, but to record them exactly as they were produced by the subject.
Age-appropriate versions of the questionnaires will be administered and a 30 day recall 
assessment will be utilized. Administers of the questionnaire should make the decision about age 
appropriateness. If it is felt the subject will or has difficulty understanding the age-appropriate 
version, the preceding age group version may be administered.  However, if the subject presents 
with severe cognitive impairments (as determined by the administrator), the PedsQL may not be 
appropriate.  In such cases, only the Parent-Proxy Report and Family Impact Module should be 
administered to the child’s parent/caregiver and this decision should be source documented.  In 
addition, the parent/caregiver and subject should complete the questionnaires independently of 
one another. The parent/caregiver, subject, and/or other family members should be discouraged 
from consulting with one another during the completion of the questionnaire.  
Subjects/caregivers should be administered the same version of the questionnaires for the first 
year on study, despite a change in age range. After the first year on study, an updated version of 
the questionnaires should be administered to reflect any change in age. Once a subject enrolls 
into the LTFU protocol, an updated version of the questionnaires should be administered based 
on the subject’s age at the time of the assessment. 
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Site personnel should review questionnaires for completeness and ask subjects/caregivers to 
complete any missing responses. Reasons for missing reported outcome questionnaires should 
also be captured so that the appropriate imputation method can be employed to correct for 
missing data in the analysis. If subjects/caregivers refuse to complete all or any part of a 
questionnaire, this will be documented. If the subject withdraws from the study prematurely, all 
attempts should be made to obtain a final quality-of-life questionnaire prior to subject 
discontinuation.
Completed questionnaire(s) and any unsolicited comments should be reviewed and assessed by 
the Investigator for responses which may indicate potential AEs, including SAEs, before any 
clinical study assessments. This assessment should be documented in study source records. If 
AEs or SAEs are confirmed, study investigators should not encourage the subject to change 
responses reported in the completed questionnaires. 
6.14.
Hospital Resource Utilization
Hospital resource utilization will be assessed based on the numbers of hospitalizations, intensive 
care unit (ICU) inpatient days and non-ICU inpatient days in addition to outpatient visits. Dates 
of admission and discharge to the hospital and to the ICU will be collected together with the 
reasons for the hospitalization(s).
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7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Product
7.1.1.
JCAR017
See Section 1.2.3 for a description of JCAR017.
JCAR017 will be supplied by Celgene and labeled appropriately as IP for this study.  See the 
JCAR017 Product Administration Manual for details of packaging and labeling, product request 
and shipment, product preparation and administration, and product disposal and destruction. 
7.2.
Treatment Administration and Schedule
7.2.1.
Lymphodepleting Chemotherapy
Subjects will be treated for 3 days with fludarabine IV (30 mg/m2/day) and cyclophosphamide 
IV (300 mg/m2/day) prior to JCAR017 infusion. Lymphodepleting chemotherapy should be 
initiated so as to be completed 2 to 7 days before JCAR017 infusion.
See Section 1.3.3.2 for a description of the LD chemotherapy dose.
Please refer to local fludarabine and cyclophosphamide prescribing information for more details 
on available formulations, preparation, storage conditions (eg, refrigeration), the approved 
indications, known precautions, warnings, and adverse reactions of fludarabine and 
cyclophosphamide (see current version of Prescribing Information). 
Serum creatinine will be measured on the first day of LD chemotherapy; LD chemotherapy 
should be withheld if serum creatinine is beyond the maximum value (see Section 4.2) using the 
Schwartz formula or radioisotope GFR is ≤ 70 mL/min/1.73 m2. 
Antiemetic therapy may be given prior to LD chemotherapy per institutional practice. Mesna
may be used for subjects with a history of hemorrhagic cystitis per institutional practice.
If side effects from the LD chemotherapy occur, JCAR017 infusion may be delayed for up to 14 
days after LD chemotherapy upon discussion with Celgene. If the delay is more than 14 days, 
some of the screening procedures as well as LD chemotherapy may need to be repeated (Refer to 
Section 6.1). Refer to Section 6.2.1.2  for the assessments that will be performed on each day of 
LD chemotherapy.
7.2.2.
JCAR017 Premedication
Subjects should be premedicated with paracetamol/acetaminophen 12.5 mg/kg (maximum dose 
650 mg) by mouth (per os [PO]) or IV at an equivalent dose and diphenhydramine hydrochloride 
1 milligram (mg)/kg (maximum dose 50 mg) PO or IV 30 to 60 minutes prior to JCAR017 
infusion. If diphenhydramine hydrochloride is not commercially available or a subject cannot 
tolerate diphenhydramine hydrochloride, premedication with an equivalent antihistamine may be 
substituted. Ondansetron 0.15 mg/kg (maximum dose 8 mg) PO or IV may be optionally used 
prior to JCAR017 infusion. 
These medications may be repeated every 6 hours as needed based on the Investigator’s 
assessment of symptoms. Premedication with steroids should be avoided.
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7.2.3.
JCAR017 Preparation and Cell Thawing
See the JCAR017-BCM-004 Product Administration Manual for details.
7.2.4.
JCAR017 Administration
Each JCAR017 dose consists of a single infusion of two individually formulated CD4+CAR+ 
and CD8+CAR+ T cell suspensions administered separately in a 1:1 ratio in a formulation 
containing dimethyl sulfoxide (DMSO). The subject must be continuously monitored during IV 
administration of JCAR017. Vital signs (temperature, respiratory rate, heart rate, blood pressure, 
and SaO2 by pulse oximetry) will be measured within 15 minutes prior to the first JCAR017 
administration, and approximately every 15 minutes thereafter for the first hour, and hourly for 
the next 2 hours. If the subject’s vital signs are not stable 4 hours following the completion of IV 
administration, vital signs should be monitored as clinically indicated until stable.
See the JCAR017 Product Administration Manual for complete information.
7.2.5.
JCAR017 Dose Levels and Schedule
JCAR017 will be given on Day 1 (2 to 7 days after completion of lymphodepleting 
chemotherapy).  
7.2.5.1.
Phase 1
Up to 5 dose levels of JCAR017 will be evaluated (Table 6).  
Enrollment will commence in pediatric subjects at DL1 of 0.05x106 CAR+ T cells/kg (maximum 
dose of 5x106 JCAR017 CAR+ T cells [non-weight adjusted]).  If this dose is confirmed to be 
safe and tolerable, additional pediatric subjects will be enrolled at higher dose(s) up to 0.75 x106
CAR+ T cells/kg (maximum of 75x106 JCAR017 CAR+ T cells [non-weight adjusted]) with the 
aim to identify the RP2D. Dose escalation/de-escalation will follow a modified toxicity 
probability interval (mTPI-2) algorithm (Guo, 2017) as described in Section 3.1. Based on the 
cumulative safety, PK and preliminary efficacy data, a recommended pediatric dose to be further 
tested in the Phase 2 portion of the trial will be selected in consultation with the SRC based on 
data from at least 10 pediatric subjects treated at this RP2D level.  Analysis of the JCAR017 
manufactured product may also be considered.
Table 6:
JCAR017 Dose Levels 
Dose Level
JCAR017 Dose
JCAR017 Maximum Dosea
1b
0.05 x 106 CAR+ T cells/kg
5 x 106 CAR+ T cells
2
0.15 x 106 CAR+ T cells/kg
15 x 106 CAR+ T cells
3
0.30 x 106 CAR+ T cells/kg
30 x 106 CAR+ T cells
4c
0.50 x 106 CAR+ T cells/kg
50 x 106 CAR+ T cells
5c
0.75 x 106 CAR+ T cells/kg
75 x 106 CAR+ T cells
a JCAR017 dosing will be capped at 100kg for all dose levels.
b Dose escalation will proceed as described in Figure 3. 
c Optional based on comprehensive assessment.
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7.2.5.1.1. mTPI-2 Dose Escalation Decision Pathway (Dose Level 1 Only)
Dose de-escalation from DL1 is not currently planned. Therefore, dose escalation from DL1 to 
DL2 will follow a modified mTPI-2 algorithm as described in Figure 3.  Enrollment will be 
temporarily suspended and reviewed by Celgene with input from SRC and only if needed, from 
the DSMB and Study Steering Committee (SSC) when:

> 1 subject with a DLT occurring within the first 3 DLT-evaluable subjects at a 
JCAR017 dose of 0.05x106 CAR+ T cells/kg, or 

> 2 subjects with DLTs occurring across the first 5 total DLT-evaluable subjects at a 
JCAR017 dose of 0.05x106 CAR+ T cells/kg
Figure 3:
mTPI-2 Dose Escalation Decision Pathway for Dose Level 1 Only 
Abbreviations: CAR = chimeric antigen receptor; DLT = dose limiting toxicity
1 Subjects without response are eligible for intra-patient dose escalation.
2 For subjects without DLT at DL1, see Section 7.2.5.1.2.
7.2.5.1.2. Intra-Patient Dose Escalation 
If additional JCAR017 doses are available, a one-time retreatment with intra-patient dose-
escalation of 0.10x106 CAR+ T cells/kg (maximum dose of 10x106 JCAR017 CAR+ T cells 
[non-weight adjusted]) will be allowed for subjects at DL1 who have not experienced severe 
toxicity and have no response on Day 28 after JCAR017 infusion.  The subject must continue to 
meet the eligibility criteria for initial therapy with JCAR017. Data from subjects who are 
retreated with JCAR017 will not be included in the mTPI-2 algorithm to estimate DLT rates at 
DL2. 
Subjects will follow the schedule of assessments for screening (some assessments may not be 
required after discussion with Celgene) and upon meeting eligibility criteria, pre-treatment 
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evaluations will begin. Post-treatment follow-up will occur per the schedule of assessments from 
the time of the last dose of JCAR017and will continue for 2 years after the last dose of 
JCAR017, unless the subject is lost to follow-up. 
Retreatment and/or intra-patient dose escalation of JCAR017 will not be allowed at other dose 
levels.
7.2.5.2.
Phase 2
The identified RP2D from Phase 1, will be applied in Phase 2 (Cohort 1, Cohort 2 and Cohort 3). 
Subjects 18 to 25 years of age may enroll in Phase 2 and will be treated with JCAR017 at the 
RP2D.
7.2.6.
Definition of Dose-limiting Toxicity 
Dose-limiting toxicities will be evaluated for the subjects in Phase 1 during the DLT evaluation 
period of 28 days after JCAR017 infusion.  The severity grading of adverse events will be 
determined according to NCI CTCAE Version 4.03. Cytokine release syndrome is graded as per
Table 10.
A DLT will be defined as below:

Death not related to disease progression

Grade 4 neurotoxicity

Grade 3 neurotoxicity of greater than 7 days’ duration 

Grade 3 neurotoxicity that does not revert to baseline within 28 days of the start date 
of the Grade 3 event

Seizures of any grade that do not resolve within 7 days

Grade 4 CRS that does not resolve to Grade ≤3 within 3 days

Grade 3 CRS that does not resolve to Grade ≤ 2 within 7 days 

Any increase in aspartate aminotransferase (AST) or ALT > 3 × ULN and concurrent 
increase in total bilirubin > 2 × ULN that is unrelated to CRS and has no other 
probable reason to explain the combination of increases 

Any cardiac, dermatologic, gastrointestinal, hepatic, pulmonary, renal/genitourinary, 
or neurologic Grade 3 or 4 event not pre-existing or not due to the underlying 
malignancy

Any other Grade 3 or 4 event deemed unexpected by the Investigator and considered 
a DLT upon evaluation by the SRC
Should a subject experience a suspected DLT, the treating Investigator should contact Celgene’s 
medical monitor prior to declaring the event a DLT. All DLT cases will also be discussed with 
the SRC during regular calls with sites and their respective investigators aiming to review and 
share all safety related events including but not limited to DLTs. 
Please see Section 10 for further details on AE reporting. 
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7.2.7.
Overdose
Overdose, as defined for this protocol, refers to fludarabine, cyclophosphamide or JCAR017. On 
a per-dose basis, an overdose is defined as the following amount over the protocol-specified dose 
of these drug(s) assigned to a given subject, regardless of any associated AEs or sequelae:

IV: 10% over the protocol-specified dose
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency. On an infusion rate basis, an overdose is defined as any 
rate faster or slower than the protocol-specified infusion time reflected as infusion time (± 50%).
Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the electronic case report form 
(eCRF) (see Section 10.1 for the reporting of AEs associated with overdose).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.3.
Method of Treatment Assignment
Interactive response technology (IRT) will be employed to manage cohort assignments. IRT 
registration will be performed according to Table 3.  
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Protocol JCAR017-BCM-004
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7.4.
Packaging and Labeling
7.4.1.
Product Tracking
7.4.1.1.
Lymphodepleting Chemotherapy
Manufacturer details and batch numbers will be used for the products tracking.
7.4.1.2.
JCAR017
The identity of the IP will be checked and verified at each critical step of cell processing as part 
of the chain of identity. Procedures will be in place to address product tracking requirements and 
will encompass all process steps including collection of the leukapheresis product, receipt of the 
leukapheresis product, JCAR017 manufacturing and testing, in-process labeling, and JCAR017 
labeling and packaging for shipment.
7.4.2.
Product Packaging and Labeling
7.4.2.1.
Lymphodepleting Chemotherapy
Fludarabine and cyclophosphamide will be provided by the clinical sites and labeled as per their 
local procedures.
7.4.2.2.
JCAR017
The label(s) for the IP will include, but may not be limited to, Sponsor name, address and 
telephone number, the protocol number, IP name, dosage form and strength (where applicable), 
amount of IP per container, lot number, expiry date (where applicable), medication 
identification/kit number, dosing instructions, storage conditions, and required caution 
statements and/or regulatory statements as applicable. Additional information may be included 
on the label as applicable per local regulations.
These same identifiers are maintained from leukapheresis collection throughout the 
manufacturing process and are used on the final JCAR017 cell product. These unique identifiers 
should be verified per the Chain of Identity procedures listed in the JCAR017 Product 
Administration Manual.
The final JCAR017 cell product is provided cryopreserved and packaged to the study site per the 
dosing regimen specified in the protocol.
Prior to the JCAR017 infusion, two trained individuals will verify all unique identifier 
information in the presence of the subject/guardian(s) to confirm that the information is correctly 
matched to the subject.
7.4.3.
Cell Product Supply and Storage
Detailed instructions on the storage, handling, and preparation of JCAR017 cell product will be 
provided in the JCAR017 Product Administration Manual.
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7.5.
Investigational Product Accountability and Disposal 
7.5.1.
Accountability Procedures
Inventory must be performed, and a product receipt log must be filled out and signed by the 
person accepting the shipment of JCAR017 cell product.
7.5.2.
Drug Disposal and Destruction
Celgene (or designee) will review with the Investigator and relevant site personnel the process 
for IP return, disposal, and/or destruction including responsibilities for the site versus Celgene 
(or designee).
7.6.
Investigational Product Compliance
The administered dosage of JCAR017 will be recorded in source documents. The Investigator(s) 
or designee is responsible for taking an inventory of each shipment of IP received and comparing 
it with the accompanying shipping order/packaging slip.  The Investigator(s) will verify the 
accuracy of the information on the shipping order/packaging slip.  
At the study site, the IP will be stored in a locked, safe area to prevent unauthorized access and 
should be stored as directed on the product label.
An accurate accounting of the dispensing and return of IP for each study subject will be 
maintained in source documents on an ongoing basis by a member of the study site staff.  
Additionally, if any IP is lost or damaged or if the study subject misses a dose, this information 
should be documented in the study subject’s eCRF and source documents.  
Celgene will instruct the Investigator on the return, disposal, and/or destruction of unused IP.
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8.
CONCOMITANT MEDICATIONS AND PROCEDURES
8.1.
Permitted Concomitant Medications and Procedures
Medications and procedures will be recorded as shown in Table 7.  Subjects should be 
discouraged from use of illicit drugs, herbal remedies, self-prescribed drugs, tobacco products, or 
excessive alcohol at any time during the clinical study.
Table 7:
Reporting Periods for Concomitant Medications
Start
End
Required Reporting
Informed Consent 
Initiation of LD 
chemotherapy 
Medications taken by the subject at the time 
of an AE related to protocol-mandated 
procedures or for active medical history
conditions
Start of LD chemotherapy
Day 90, after JCAR017 
infusion
All medications 
Day 91, after JCAR017 
infusion
End of study
Only medications ongoing at the time of 
AEs related to any protocol-mandated 
procedures or JCAR017
For subjects receiving lymphodepleting chemotherapy but not JCAR017, concomitant 
medications associated with AEs/SAEs will be recorded for 30 days following the last dose of 
lymphodepleting chemotherapy.
Due to the large amount of data generated during hospitalizations, a targeted concomitant 
medication collection approach will be utilized for the eCRF. The following medications should 
NOT be entered on the Concomitant Medications eCRF during inpatient and ICU stays (also 
defined in the eCRF Completion Guidelines):

IV fluids (with the exception of IV fluids administered for treatment of hypotension 
associated with CRS, which should be recorded)

Heparin flushes

Stool softeners

Vitamins, minerals, health supplements

Saline flushes

Lotions
The following treatments should be reported during inpatient and ICU stays: 

Vasopressor – enter the maximum infusion rate/day

Oxygen – enter the maximum fraction of inspired oxygen (FiO2) per day

Transfusions

Antibiotics

Growth factors
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
Systemic anticoagulants 
Over the course of this study, additional medications may be required to manage aspects of the 
disease state of the subjects, including side effects from trial treatment or disease progression. 
Supportive care, including, but not limited to antiemetic medications, may be administered at the 
discretion of the Investigator. 
Prophylactic treatment/measures are strongly recommended for subjects at risk for tumor lysis 
syndrome (TLS), per institutional or clinical standards. The use of red blood cells and platelet 
transfusions, and/or colony-stimulating factors is permitted per institutional or clinical standards.
Use of colony-stimulating factors should be avoided in B-ALL subjects before Days 28 and 56 to 
not interfere with the BM interpretation.
The use of prophylactic or empiric anti-infective agents (eg, trimethoprim/sulfamethoxazole for
pneumocystis pneumonia [PCP] prophylaxis, broad spectrum antibiotics, antifungals, or antiviral 
agents for febrile neutropenia) is permitted per institutional standards.
For information regarding other drugs that may interact with JCAR017 and affect its metabolism, 
pharmacokinetics, or excretion, please see the IB and/or local package insert.
Vaccination with a killed vaccine is permitted at any time in consultation with the medical 
monitor.
8.1.1.
Anticancer Treatments between Leukapheresis and Lymphodepleting 
Chemotherapy
If necessary, anticancer treatment is allowed for disease control while JCAR017 is being 
manufactured (ie, after leukapheresis and prior to LD chemotherapy). Chemotherapy is allowed 
if completed at least 7 days prior to the start of LD chemotherapy. If other agents are used, the 
washout periods noted in the exclusion criteria (see Section 4.3) must be met. The use of 
therapeutic agents with little/no evidence in the scientific literature for B-ALL or B-NHL should 
be discussed with Celgene. For B-NHL subjects, local radiation is allowed to a single lesion or 
subset of lesions.
8.2.
Prohibited Concomitant Medications and Procedures
The following medications are prohibited until lack of response, subsequent therapy, or 1 year 
following JCAR017 infusion, whichever comes first: 

Steroids: therapeutic doses (> 0.4 mg/kg [maximum 20 mg/day] of prednisone or 
equivalent) unless used for treatment of CRS. Therapeutic doses may be used in life-
threatening situations and for other medical conditions when indicated, or after loss of 
detectable JCAR017 cells. Pretreatment containing steroids may be given for 
necessary medications (eg, IVIG) after discussion with Celgene. Premedication with 
steroids for JCAR017 infusion is not allowed. Physiologic replacement dosing of 
steroids (≤ 12 mg/m2/day hydrocortisone or equivalent [≤ 3 mg/m2/day prednisone or 
≤ 0.45 mg/m2/day dexamethasone]) is allowed. Topical steroids, inhaled steroids, and 
intrathecal steroids for CNS relapse prophylaxis are permitted.
The following medications are prohibited during the treatment and follow-up periods unless used 
as an anticancer agent after lack of adequate response to JCAR017:
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
Donor lymphocyte infusion (DLI)

Immunosuppressive therapies (eg, calcineurin inhibitors, methotrexate or other 
chemotherapeutics, mycophenolate, rapamycin, thalidomide, immunosuppressive 
antibodies such as anti-TNF, anti-IL-6, or anti-IL-6R), unless needed for GVHD

Non-protocol specified anticancer agents. Lymphocytic cytotoxic chemotherapy may 
be administered as an extraordinary measure to treat AEs of uncontrolled JCAR017 
proliferation, CRS, or neurotoxicity unresponsive to other therapeutic interventions

Cetuximab, or other anti-EGFR treatments, unless indicated for treatment of 
uncontrolled JCAR017 proliferation 

Experimental agents 

Radiation, unless needed for local control of a single tumor lesion 
8.3.
Concomitant Medications and Procedures
Lymphodepleting regimens accompany JCAR017 administration and utilize cyclophosphamide 
and fludarabine. Please refer to the currently approved cyclophosphamide and fludarabine 
phosphate Summary of Product Characteristics (Cyclophosphamide SmPC, 2014; Fludarabine 
SmPC, 2011).
To minimize the risk of infusion reactions, all subjects should be premedicated with 
paracetamol/acetaminophen 12.5 mg/kg (maximum dose 650 mg) PO (or IV at an equivalent 
dose) and diphenhydramine hydrochloride 1 mg/kg (maximum dose 50 mg) PO or IV 30 to 60 
minutes prior to JCAR017 infusion (see Section 7.2.2). If diphenhydramine hydrochloride is not 
commercially available or a subject cannot tolerate diphenhydramine hydrochloride,
premedication with an equivalent antihistamine may be substituted.
Supportive care for the management of CRS is detailed in Appendix F. In some cases, 
tocilizumab, an anti-IL-6R-antibody, may be required to treat toxicities such as sCRS. Please 
refer to the currently approved Actemra®/ RoActemra® package inserts. As per the approved 
European Union (EU) SmPCs for CAR T therapy, the EMA is expecting a minimum of 4 doses 
of tocilizumab to be available prior to infusion for the management of CRS. However, as a 
JCAR017 Investigator, it is important to understand that the JCAR017 Management Guidelines 
for Cytokine Release Syndrome and Neurotoxicity and the recommended use of tocilizumab is 
different from the CRS management algorithms of the approved CAR Ts.  Hence, Celgene 
requires that all JCAR017 global sites (eg, US and EU) must have at least 2 doses of tocilizumab 
available prior to infusion per a given subject. It is recommended to resupply in case tocilizumab 
is given.
The preferred dose to intervene in subjects with CRS is 8 mg/kg. Another anti-IL-6 agent, if 
available in the country, should be considered in the event of sCRS not responding to 
tocilizumab. Dosing of any other anti-IL-6 agent should be per prescribing information.  
In some cases, steroids (eg, dexamethasone) may also be given for the treatment of CRS or NT.
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Protocol JCAR017-BCM-004
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9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
This is a Phase 1/2 open-label, single-arm, multicohort study, to identify a safe and tolerable 
dose and to evaluate the safety and efficacy of JCAR017 in pediatric subjects with r/r B-ALL 
and B-NHL. 
9.1.1.
Phase 1
Up to 5 dose levels of JCAR017 will be evaluated (Table 6) in r/r B-ALL pediatric subjects. 
Dose escalation/de-escalation will follow a modified toxicity probability interval (mTPI-2) 
algorithm (Guo, 2017) as described in Section 3.1 until the RP2D has been identified.  Based on 
the cumulative safety, PK and preliminary efficacy data, a RP2D will be selected in consultation 
with the SRC based on data from at least 10 pediatric subjects treated at the identified RP2D.  
Analysis of the JCAR017 manufactured product may also be considered.
9.1.2.
Phase 2
In Phase 2, pediatric subjects (< 18 years of age) will enroll into one the following disease 
cohorts to further evaluate the efficacy and safety of JCAR017 at the identified RP2D in Phase 1.

Cohort 1: r/r B-ALL

Cohort 2: MRD+ B-ALL

Cohort 3: r/r B-NHL (DLBCL, BL, or PMBCL)
Endpoints which are rate/proportion based shall show the number of subjects eligible for a given 
analysis along with the rate (percentage) and corresponding Clopper-Pearson 95% confidence 
interval (CI), while time-to event data shall be analyzed by Kaplan-Meier curves and the
proportion of subjects remaining event free at given time points presented along with the median 
time. Greenwood 95% Cis shall be given. Descriptive statistics shall also be presented for time-
to-event data such as number of subjects censored or having an event. Safety data will be 
presented by frequency according to the preferred term and system organ class they are 
categorized as. Efficacy based data will be analyzed by the non-selected dose levels from Phase 
1 and by disease cohort (Phase 2 subjects and subjects treated at the RP2D in Phase 1) while 
safety data will be analyzed by the non-selected dose levels from Phase 1, disease cohort (Phase 
2 subjects and subjects treated at the RP2D in Phase 1), and in aggregate across pediatric 
subjects receiving RP2D, and in aggregate of all pediatric subjects regardless of dose level.
All efficacy endpoints shall primarily be analyzed according to the central response assessment
by IRC while the local response assessments shall form part of a select secondary/sensitivity 
analysis.
Full data analysis details will be outlined in the statistical analysis plan (SAP).
A risk-group sub-analysis with descriptive statistics and comparison between groups will be 
included as part of the overall analysis, provided a sufficient number of subjects are within 
certain risk-group categories; further detail will be provided in the SAP. The risk-groups to be 
analyzed, provided sufficient number of subjects are enrolled into the various sub-groups, are:
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
Age at diagnosis

Gender

Race

Prior response status (eg, primary refractory versus relapse to last prior therapy, prior 
HSCT, etc)

Baseline CNS disease

Timing of relapse

Site of relapse

Geography

Stem cell transplant eligibility

Baseline tumor burden and presence/absence of extramedullary disease

Cytogenetics
Up to 20 additional subjects between 18 and 25 years of age may be enrolled in an optional 
cohort in Phase 2 and treated with JCAR017 at the RP2D.  Subjects enrolled that are aged 18 to 
25 years will not be considered for the primary endpoint of Phase 2. Efficacy and safety for 
subjects aged 18 to 25 years shall be fully reported alongside and in aggregate with subjects aged 
< 18 years of age.  
9.2.
Study Population Definitions
9.2.1.
Informed Consent/Assent Population: 
The Informed Consent/Assent Population includes all subjects for whom informed 
consent/assent was provided for this study.
9.2.2.
Pre-treatment Population: 
The Pre-treatment Population will consist of all subjects who are screened successfully into the 
study and either did or did not receive a JCAR017 infusion. The Pre-treatment Population shall 
be used for analysis of the JCAR017 manufacturing feasibility endpoint (where leukapheresis 
took place).
9.2.3.
Dose-limiting Toxicity Analysis Population:  
The DLT Analysis Population will include all Phase 1 enrolled subjects who received a 
JCAR017 infusion and completed 28 days post JCAR017 infusion, the DLT assessment period, 
if having not been observed as having a DLT before this point. The DLT Analysis Population 
will be used for identification of the RP2D as described in Section 3.1. 
 
In addition, pediatric subjects at DL1 who are retreated with JCAR017 
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intra-patient dose escalation in Phase 1 will not be included in the mTPI-2 algorithm to estimate 
DLT rates at DL2. 
Relapsed/refractory B-ALL subjects who demonstrated morphological remission and are MRD+
or MRD negative upon restaging prior to initiation of lymphodepleting therapy will still be 
evaluable for the DLT Analysis Population in Phase 1 if they meet other analysis criteria. 
9.2.4.
Efficacy Analysis Population: 
The Efficacy Analysis Population will include all subjects who fulfill all study eligibility criteria 
(prospectively and retrospectively) and receive JCAR017 infusion in accordance with drug 
product release specifications (ie, conforming JCAR017 product).
 
The Efficacy Analysis Population will be used for analysis of all efficacy-based
endpoints. For the purpose of the primary endpoints, subjects ineligible for the Efficacy Analysis 
Population will be replaced.
Subjects who demonstrate morphological remission and are MRD negative upon restaging prior 
to initiation of lymphodepleting therapy (ie, no baseline disease) will be treated and followed on 
study but will not be considered evaluable for the Efficacy Analysis Population and may be 
replaced. 
9.2.5.
Safety Analysis Population: 
The Safety Analysis Population will include all enrolled subjects who received a JCAR017 
infusion. The Safety Analysis Population shall be used for analysis of the safety-based endpoints, 
and if different from the Efficacy Analysis Population, applied to the analysis of efficacy-based
endpoints as a secondary analysis.
9.2.6.
Pre-treatment Safety Analysis Population:
The Pre-treatment Safety Analysis Population will include all enrolled subjects who receive LD 
chemotherapy regardless of receiving a JCAR017 infusion or not. The Pre-treatment Safety 
Analysis Population shall be used for analysis of the safety data collected during the pre-
treatment period. 
 
 
 
 
9.2.8.
Pharmacokinetic Analysis Population: 
The PK Population will include all subjects who received JCAR017 infusion and have at least 
one measurable JCAR017 concentration.  The evaluable subjects in the PK population will be 
included in the PK data analysis.
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9.2.9.
Patient Reported Outcome Analysis Population
The Patient Reported Outcome (PRO) analysis set will include all subjects who complete their 
baseline (screening or pre-treatment) questionnaires, have received JCAR017 and had at least 
one post-baseline PRO assessment.
9.3.
Sample Size and Power Considerations
Assuming an 18% enrollment dropout rate (defined as subjects enrolled but not eligible for the 
primary endpoint analysis of the respective Phase of the study), a total of 124 subjects may be 
enrolled to ensure that approximately 101 primary endpoint evaluable subjects are treated with 
JCAR017.
Up to 20 additional B-ALL subjects between 18 and 25 years of age may also be enrolled in an 
optional cohort in Phase 2.
9.3.1.
Phase 1 
The Phase 1 portion of the study will utilize the mTPI-2 algorithm to help identify a RP2D in
pediatric r/r B-ALL subjects.
The target DLT rate is set as 30%. Dose escalation/de-escalation will follow a modified toxicity 
probability interval (mTPI-2) algorithm (Guo, 2017) with a target DLT rate of 30% and an 
equivalence interval of 25% to 35%. A dose level will be considered unsafe, with no additional 
pediatric subjects enrolled at that dose level, if it has an estimated 95% or more probability of 
exceeding the target DLT rate of 30% ie, P (DLT > 30%|data) > 95% with at least 3 pediatric 
subjects treated at that dose level. Appendix G provides the decision table of mTPI-2 for each 
dose level. For a dose level to be shown safe per the mTPI-2 algorithm, at least 3 DLT-evaluable 
pediatric subjects must have completed the DLT period and the level estimated to be safe.  The 
RP2D for pediatric subjects will be selected in consultation with the SRC based on data from at 
least 10 pediatric subjects treated at this dose level. The final number of subjects will depend on 
the number of dose levels tested and the number of DLTs observed within each cohort.  Non-
DLT-evaluable subjects will be replaced.
At least 11 DLT-evaluable pediatric (< 18 years of age) subjects will be treated in Phase 1. This 
is the minimum number of pediatric subjects to allow the study to continue to Phase 2.  Up to 30
DLT-evaluable pediatric subjects will be included in Phase 1 to determine the RP2D assuming 
all dose levels enroll/treat the maximum number of subjects and no subjects are replaced. 
9.3.2.
Phase 2
The Phase 2 study population will consist of up to 71 evaluable pediatric subjects (< 18 years of 
age), should all cohorts below enroll the maximum number of subjects and assuming no subjects 
are replaced.  The 10 or more pediatric subjects treated at the RP2D in Phase 1 will form part of 
the sample size (ie, Cohort 1 and Cohort 2), totaling at least 81 evaluable pediatric subjects in 
Phase 2.
Up to 20 subjects between 18 and 25 years of age may be enrolled in Phase 2 and will receive 
JCAR017 at the RP2D.
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9.3.2.1.
Cohort 1 (r/r B-ALL)
Assuming a 1-sided 5% significance level and 80%, along with the boundary to reject the null 
hypothesis or ORR = 75% vs. the boundary to accept the alternative hypothesis of ORR = 90%, a 
total of 48 evaluable subjects for the primary endpoint are required based on Simon’s Optimal 
two-stage design (13 subjects in Stage 1 and a further 35 subjects in Stage 2). For the study 
treatment to be considered successful in this cohort, a total of 41 or more of the 48 subjects are 
required to have achieved a CR or CRi on Day 28, confirmed on Day 56.  Subjects who enroll in 
Cohort 2 but demonstrate morphologic relapse upon restaging prior to initiation of 
lymphodepleting therapy will be included in Cohort 1.  
9.3.2.2.
Cohort 2 (MRD+ B-ALL)
Assuming a 1-sided 5% significance level and 80%, along with the boundary to reject the null 
hypothesis of MRD negative rate = 60% vs. the boundary to accept the alternative hypothesis of 
MRD negative rate = 85%, a total of 23 evaluable subjects for the primary endpoint are required 
based on Simon’s Optimal two-stage design (9 subjects in Stage 1 and a further 14 subjects in 
Stage 2). For the study treatment to be considered successful in this cohort, a total of 18 or more 
of the 23 subjects are required to have a CR or CRi with an MRD negative BM on Day 28, 
confirmed on Day 56. Subjects that enroll in Phase 1 at the RP2D and Cohort 1 in Phase 2, who 
demonstrate morphological remission and are MRD+ upon restaging prior to initiation of 
lymphodepleting therapy will be included in Cohort 2.
9.3.2.3.
Cohort 3 (B-NHL)
There is no formal sample size calculation; however, due to the low anticipated enrollment rate, 
the sample size of 10 pediatric subjects has been considered a feasible number that can be 
enrolled in order to gain preliminary efficacy data regarding the primary endpoint ORR, defined 
as the proportion of subjects achieving a CR or partial response (PR) on Day 28.
Should the required number of subjects achieving a response on Day 28 (Cohort 3), confirmed
on Day 56 (Cohort 1) or MRD negative response on Day 28, confirmed on Day 56 (Cohort 2), be
reached before the total required number of subjects for a given cohort can be enrolled, that
given cohort may stop enrolment and declare the treatment positive in that given cohort with
regard to the primary endpoint. Alternatively, if it is clear that the required number of primary
endpoint responders will not be observed within the specified sample size for a given cohort then
enrollment to that given cohort may be stopped due to lack of efficacy.
9.4.
Background and Demographic Characteristics
The baseline characteristics of subjects will be summarized by dose level and cohort using the 
Safety Analysis Population. The age, weight, height, and other continuous demographic and 
baseline variables will be summarized using descriptive statistics (sample size, mean, standard 
deviation, median, minimum, and maximum). Lansky/Karnofsky performance status, gender, 
rate, and other categorical variables will be summarized with frequency tabulations. Medical 
history data will be summarized using frequency tabulations by system organ class and preferred 
terms or names, wherever applicable. All baseline characteristics and demographics will also be 
displayed in listings.
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9.5.
Subject Disposition
Subject disposition shall be presented by dose level and cohort for subjects in the Pre-treatment 
Safety Analysis Population and the Safety Analysis Population. For the pre-treatment period, 
treatment period and for the Post-Treatment Follow-up Period, the proportion of subjects 
entering, completing or discontinuing, along with the primary reason for discontinuation will be 
summarized using frequency and percentages. A summary of subjects enrolled by site will be 
provided. Protocol deviations will be summarized using frequency tabulations while protocol 
deviation and violations will be presented in a listing.
9.6.
Efficacy Analysis
9.6.1.
Phase 2 Primary Endpoints
9.6.1.1.
Overall Response Rate
The primary endpoint of ORR will be analyzed for subjects in Cohort 1 and Cohort 3 subjects. 
Each cohort shall be analyzed separately. For each ORR calculated, the corresponding Clopper-
Pearson 95% CI will be calculated.
Subjects without a Day 28 (Cohort 1 and Cohort 3) and/or Day 56 response assessment (Cohort 
1) for whatever reason will be considered a non-responder with regard to the ORR. 
Response assessment data collected after start of a new anticancer treatment or HSCT will not be 
considered for the ORR.
9.6.1.1.1. Cohort 1
Overall Response Rate is defined as the proportion of subjects achieving a confirmed CR or Cri 
on Day 28, confirmed on Day 56, divided by the number of subjects included in the analysis.
The first disease assessment will be performed at 28 days after JCAR017 infusion however if the 
subject cannot be assessed for CR/CRi due to hypoplastic marrow, a repeat marrow examination 
should be performed when there is evidence of hematopoietic recovery so that remission can be 
assessed for the first time.
Therefore, in order for the best overall disease response to be categorized as CR or CRi, there 
must be no clinical evidence of relapse as assessed by peripheral blood, BM, CSF and 
extramedullary disease assessment (where applicable) confirmed at a minimum of 4 weeks (28 
days) after the initial achievement of CR or CRi. If additional assessments are performed in the 
same evaluation, they will also need to show remission status.
9.6.1.1.2. Cohort 3
Overall Response Rate is defined as the proportion of pediatric B-NHL subjects achieving a CR 
or PR on Day 28 divided by the number of subjects included in the analysis.
9.6.1.2.
MRD Negative Rate
The primary endpoint of MRD negative rate will be analyzed for subjects in Cohort 2 only.
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The MRD negative rate is defined as the proportion of subjects achieving a CR or CRi with an 
MRD negative BM on Day 28, confirmed on Day 56, divided by the number of subjects included 
in the analysis.
The first disease assessment will be performed at 28 days after JCAR017 infusion however if the
subject cannot be assessed for CR/CRi due to hypoplastic marrow, a repeat marrow examination 
should be performed when there is evidence of hematopoietic recovery so that MRD negative 
remission can be assessed for the first time.
Therefore, in order for the best overall disease response to be categorized as MRD negative CR 
or CRi, there must be no clinical evidence of relapse as assessed by peripheral blood, BM, CSF
and extramedullary disease assessment (where applicable) with no MRD detected in BM (below 
the level of detection [<0.01%] by validated assay at a central analytical laboratory), confirmed 
at a minimum of 4 weeks (28 days) after the initial achievement of MRD negative CR or CRi. If 
additional assessments are performed in the same evaluation, they will also need to show 
remission status.
For each MRD negative rate calculated, the corresponding Clopper-Pearson 95% CI will be 
calculated.
Subjects with an unknown MRD status must be included in the analysis as MRD positive.
Response assessment data collected after start of a new anticancer treatment or HSCT will not be 
considered for the MRD negative rate.
9.6.2.
Phase 1 and Phase 2 Secondary Endpoints 
9.6.2.1.
Overall Response Rate
The ORR will be analyzed for each of the non-selected dose levels in Phase 1. Each cohort shall 
be analyzed separately. For each ORR calculated, the corresponding Clopper-Pearson 95% CI 
will be calculated. Subjects without a Day 28 and/or Day 56 response assessment for whatever 
reason will be considered a non-responder with regard to the ORR.
Response assessment data collected after start of a new anticancer treatment or HSCT will not be 
considered for the ORR.
9.6.2.2.
MRD Negative Response Rate
For B-ALL subjects only, the secondary objective of MRD response rate will be analyzed for the 
non-selected dose levels in Phase 1 and Cohort 1 in Phase 2.
The MRD Response Rate is defined as the proportion of subjects achieving a confirmed CR or 
CRi with no MRD detected in BM (below the level of detection [<0.01%] tumor cells by a 
validated assay), up to 24 months after JCAR017 infusion over the number of subjects available 
for the analysis.
For each Response Rate calculated, the corresponding Clopper-Pearson 95% CI will be 
calculated.
Response assessment data collected after start of a new anticancer treatment or HSCT will not be 
considered for the Response Rate.
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9.6.2.3.
Duration of Response
Duration of response is defined as the time from first observed response until either disease 
progression, or relapsed disease, or death. Only subjects observed with a response shall be 
included in the analysis of DOR. The median DOR time and the proportion of subjects 
remaining with a response at 6, 12, 24 months, and at close of study along with the 
corresponding Greenwood 95% CI will be calculated using Kaplan-Meier methods. Subjects 
who are alive and remain in disease response at the time of analysis will be censored at the time 
of their last adequate disease assessment or at the time of starting a new anticancer therapy, 
whichever is first. Due to the low number of subjects to be included in the analysis, additional 
summary statistics will be presented. Each cohort shall be analyzed separately.  Subjects who 
demonstrate morphological remission and are MRD negative upon restaging prior to initiation of 
lymphodepleting therapy (ie, no baseline disease) will also be considered for DOR (ie, time to 
relapse).
9.6.2.4.
Relapse-free Survival
Relapse-free survival (RFS) is defined as the time from JCAR017 infusion until disease 
progression or disease relapse or death of any cause, whichever occurs first. The median RFS 
time and proportion of subjects remaining relapse-free at 6, 12, 24 months, and at close of study 
as well as the median of subjects within a cohort having an RFS even, along with the 
corresponding Greenwood 95% CI will be calculated using Kaplan-Meier methods. Subjects 
remaining relapse-free at the time of analysis will be censored at the time of their last adequate 
disease assessment. Additionally, subjects will be censored at the time of starting a new 
anticancer therapy if having not had disease progression or disease relapse previously. Due to the 
low number of subjects to be included in the analysis, additional summary statistics will be 
presented. Each cohort shall be analyzed separately.
9.6.2.5.
Event-free Survival
Event-free survival is defined as the time from JCAR017 infusion until either disease 
progression or disease relapse, start of a new anticancer therapy or death of any cause, whichever 
occurs first. The median EFS time and proportion of subjects remaining event-free at 6, 12, 24 
months, and at close of study as well as the median of subjects within a cohort having an EFS 
even, along with the corresponding Greenwood 95% CI will be calculated using Kaplan-Meier 
methods. Subjects remaining event-free at the time of analysis will be censored at the time of 
their last adequate disease assessment. Due to the low number of subjects to be included in the 
analysis, additional summary statistics will be presented. Each cohort shall be analyzed 
separately.
9.6.2.6.
Overall Survival
Overall survival is defined as the time from JCAR017 infusion until death of any cause. The 
median OS time and proportion of subjects remaining alive at 6, 12, 24 months, and at close of 
study, along with the corresponding Greenwood 95% CI, calculated using Kaplan-Meier 
methods will be presented. Subjects remaining alive at the time of analysis will be censored at 
the time they were last known to be alive. Due to the low number of subjects to be included in 
the analysis, additional summary statistics will be presented. Each cohort shall be analyzed 
separately.
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9.6.2.7.
Hematopoietic Stem-cell Transplant Rate 
The HSCT rate is defined as the proportion of subjects who undergo HSCT after receiving a 
JCAR017 infusion and achieving a response divided by the number of subjects available for the 
analysis.  The time of proceeding to HSCT is defined as the time of commencing the 
conditioning regimen as required for HSCT.  
For each HSCT rate calculated, the corresponding Clopper-Pearson 95% CI will be calculated.
Each cohort shall be analyzed separately.
9.6.2.8.
Best Overall Response Rate
Best overall response (BOR) rate is defined as the percentage of B-NHL subjects achieving a 
BOR (either CR or PR) following JCAR017 infusion until disease progression, end of study, the 
start of another anticancer therapy, or HSCT.
Subjects with an unknown or missing response will be included in the analysis counted as non-
responder.
9.7.
Safety Analysis
9.7.1.
Phase 1 Primary Endpoint
9.7.1.1.
Recommended Phase 2 Dose
The Phase 1 portion of the study will utilize the mTPI-2 algorithm to help identify a safe and 
tolerable dose (RP2D) in pediatric subjects as described in Section 9.3.1.
Based on the cumulative safety, PK and preliminary efficacy data, a RP2D will be selected in 
consultation with the SRC based on data from at least 10 pediatric subjects treated at the RP2D.  
Analysis of the JCAR017 manufactured product may also be considered.  
9.7.2.
Phase 1 and Phase 2 Secondary Endpoints
9.7.2.1.
Adverse Events
Adverse Events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) (latest version). This study will utilize the NCI CTCAE (version 4.03 or greater) for 
toxicity grading and performance reporting. All AE data shall be presented by cohort and in 
aggregate.
Treatment-emergent adverse events are defined as any AE occurring or worsening on the day of 
the JCAR017 infusion until 90 days post-treatment (JCAR017 infusion). All treatment-emergent 
adverse events (TEAEs), AEs related to the study treatment, SAEs, and AEs leading to death will 
be summarized as by subject (worse recorded grade) per event type (organ class and preferred 
term) and grade. A summary of AEs with NCI CTCAE (version 4.03 or greater) Grade 3 or 
higher, as well as the most frequent preferred terms, will also be provided by grade and term.
Cross tabulations will be provided to summarize frequencies of abnormalities.
By-subject listings will be provided for all relevant safety data. Graphical displays and figures 
will be provided where useful to assist in the interpretation of results.
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9.7.2.2.
Deaths
Deaths occurring up to 90 days after the JCAR017 infusion, and during the Post-Treatment 
Follow-up ’Period shall be summarized by frequency of occurrence and corresponding 
percentage by primary cause of death per cohort and in aggregate. 
9.7.2.3.
Clinical Laboratories
Clinical laboratory values will be graded according to NCI CTCAE (version 4.03 or greater) for 
applicable tests. Baseline grade and worst grade during treatment for selected laboratory results 
will be summarized. Shift from baseline to the worst grade observed during the treatment for 
selected laboratory results will also be provided. All laboratory data shall be presented by cohort 
and in aggregate.
9.7.2.4.
Vital Signs
For vital signs, shift from baseline to worst during the treatment in below, within, and above the 
normal ranges will be displayed in cross-tabulations. Summary statistics (N, mean, standard 
deviation, median, minimum, and maximum) of observed and change from baseline values will 
be presented. All vital signs data shall be presented by cohort and in aggregate.
9.8.
Interim Analysis
One interim analysis is planned for Cohort 1 and one for Cohort 2.  Interim analyses will be 
based on cleaned efficacy data relating to the primary endpoint and will use the Efficacy 
Analysis Populations using centrally reviewed response assessment data.
In Cohort 1, the interim analysis will be conducted once primary endpoint related efficacy data 
from the first 13 subjects eligible for the primary endpoint is available, ie, up to Day 56 post 
infusion if having a CR or CRi at Day 28, or Day 28 if not having a CR or CRi at that time, and 
earlier still if the subject has a disease progression, disease relapse or discontinues from the study 
prior to Day 28. If the number of subjects observed as having a CR or CRi at Day 28, confirmed 
at Day 56, is 11 or more, then enrollment into Stage 2 will continue as planned; otherwise the 
cohort will be closed to further enrollment and the study treatment in this cohort concluded as 
unpromising. Enrollment will be suspended while assessing Stage 1 for the Stage 2 go/no-go 
decision; if it is clear before reaching the 13th subject that the criteria to move into Stage 2 has 
been met, then enrollment will not be suspended. If it is clear before enrollment of the 13th
subject that the required number of confirmed responses for going into Stage 2 will not be met, 
the cohort will close to enrollment due to futility prior to enrolling the entire 13 subjects.
In Cohort 2, the interim analysis will be conducted once primary endpoint related efficacy data 
from the first 9 subjects eligible for the primary endpoint is available, ie, up to Day 56 post 
infusion if having a MRD negative response at Day 28, or Day 28 if not having a MRD negative 
response at that time, and earlier still if the subject has a disease progression or discontinues 
from the study prior to Day 28. If the number of subjects observed as having a MRD negative 
response at Day 28, confirmed at Day 56, is 7 or more, then enrollment into Stage 2 will 
continue as planned; otherwise the cohort will be closed to further enrollment and the study 
treatment in this cohort concluded unpromising. Enrollment will be suspended while assessing 
Stage 1 for the Stage 2 go/no-go decision; if it is clear before reaching the ninth subject that the 
criteria to move into Stage 2 has been met, then enrollment will not be suspended. If it is clear 
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before enrollment of the ninth subject that the required number of confirmed responses for going 
into Stage 2 will not be met, the cohort will close to enrollment due to futility prior to enrolling 
the entire 9 subjects.
Interim analyses and conclusions will be performed by Celgene and confirmed by the DSMB
and/or the SSC.
9.9.
Other Topics
9.9.1.
JCAR017 Manufacturing Feasibility
Evaluation of the feasibility of manufacturing JCAR017 will be measured by the percentage of 
product generated successfully. Specifically, this feasibility endpoint will be conducted on the 
first 10 pediatric subjects enrolled, regardless of dose; should product generation be successful 
for < 70% (< 7/10) of the subjects, the study will be temporarily suspended pending review by 
Celgene/DSMB. Analysis of this endpoint will be based upon the Pre-treatment Population.
Feasibility endpoint: 
The number and percentage of subjects who are eligible for study treatment but not able to 
successfully generate a JCAR017 cell product, along with the reason(s) for manufacturing 
failure, will be summarized.
Successful product will be defined as: 

JCAR017 product was generated and able to be QC released 
 for infusion.  
Unsuccessful product is defined as: 

No JCAR017 product could be generated after two manufacturing attempts using a 
single apheresis product for starting material or 

Product was unable to be QC released for infusion  
9.9.2.
Safety Review Committee (SRC)
During Phase 1, the SRC will be convened to review DLTs and to recommend a Phase 2 dose 
based on an integrated assessment of the safety, PK data and preliminary efficacy information. 
This committee will be composed of the medical monitor, drug safety physician, and statistician 
as well as up to 5 active Investigators. Operational details for the SRC will be detailed in a 
separate SRC charter.
9.9.3.
Data Safety Monitoring Board (DSMB)
An independent data safety monitoring board (DSMB) will review cumulative study data over 
the course of the study to evaluate safety, protocol conduct, and scientific validity and integrity 
of the trial. The DSMB, composed of a statistician and selected physicians with experience in 
hematology/oncology and/or T cell therapy, will be assembled under a dedicated charter 
specifically developed for safety oversight of the study. DSMB members will not be actively 
involved in the study design, conduct, or subject accrual and must not have financial, proprietary, 
professional, or other interests that may affect impartial, independent decision making.
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The DSMB will be convened prior to enrollment of the first subject on the protocol and will 
meet approximately twice a year throughout the trial and as needed to address any safety issues 
that may arise. Subject safety will be evaluated as specified in DSMB charter. The DSMB will 
provide advice to Celgene as outlined in the DSMB charter. The effectiveness of the risk 
mitigation plan will be reviewed by the DSMB at each meeting. Operational details for the 
DSMB will be detailed in the DSMB charter. 
9.9.4.
Scientific Steering Committee (SSC)
The conduct of this trial will be overseen by a Scientific Steering Committee (SSC), comprised 
of Investigators that may or may not be participating in the study.  The SSC will serve in an 
advisory capacity to Celgene.  Operational details for the SSC will be detailed in a separate SSC 
charter.
Note: The SSC is separate from the DSMB.
9.9.5.
Exploratory Analysis
The PK, 
 and the health utilization analyses will be specified 
in separate analysis plans.  The exploratory endpoints of the study are listed in Section 2; details 
of the exploratory analyses are provided in the statistical analysis plan.
Planned exploratory analyses will include:

Best response and ORR by sub-group/risk-group

Prior HSCT impact on response
 

Safety: The effect of treatments directed at sCRS and neurotoxicity on duration and 
severity of sCRS and neurotoxicity

Hospital resource utilization: Number of inpatient days, ICU days, and outpatient 
visits

Patient reported outcomes
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10.
ADVERSE EVENTS
10.1.
Monitoring, Recording and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE.  
Abuse, withdrawal, sensitivity or toxicity to an investigational product should be reported as an 
AE. Overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported on the overdose eCRF. (See Section 7.2.7 for the definition of overdose.) Any sequela 
of an accidental or intentional overdose of an investigational product should be reported as an 
AE on the AE eCRF. If the sequela of an overdose is an SAE, then the sequela must be reported 
on an SAE report form and, on the AE, eCRF. The overdose resulting in the SAE should be 
identified as the cause of the event on the SAE report form and eCRF but should not be reported 
as an SAE itself.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary. There is no known specific antidote for JCAR017, fludarabine 
or cyclophosphamide overdose. Actual treatment should depend on the severity of the clinical 
situation and the judgment and experience of the treating physician. 
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters:  the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or findings from 
other tests and/or procedures.
Adverse events must be recorded as shown in Table 8. If they meet the seriousness criteria, they 
will be reported to Drug Safety as provided in Section 10.5.
Table 8:
Reporting Periods for Adverse Events
Start
End
Required Reporting
Signing of 
informed consent
Start of LD 
chemotherapy 
Only AEs related to any study procedure
Start of LD 
chemotherapy
Day 90, after 
JCAR017 infusion 
All AEs, irrespective of causality, and any toxicity change 
to ongoing AEs will be recorded in the eCRF as a separate 
AE record
Day 91, after 
JCAR017 
infusion
End of study
Only AEs related to any study procedure or JCAR017 will 
be collected; changes in toxicity grade will be recorded as 
a single event with the highest toxicity grade experienced 
at any time during the event recorded
AEs = adverse events; eCRF = electronic case report form; LD = lymphodepleting. 
If a subject receives lymphodepleting therapy but not JCAR017, all AE/SAEs should be 
recorded/reported for 30 days following the last dose of lymphodepleting chemotherapy.  SAEs 
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made known to the Investigator at any time thereafter that are suspected of being related to IP 
will be recorded as well. Documentation must be supported by an entry in the subject’s source 
document.
A diagnosis or syndrome should be recorded on the AE page of the eCRF rather than the 
individual signs or symptoms of the diagnosis or syndrome. In addition to recording CRS and 
neurotoxicity as a diagnosis, the signs and symptoms of CRS and neurotoxicity will be recorded
on separate eCRFs. Any medical condition already present prior to first LD chemotherapy should 
not be reported as an AE unless the medical condition is related to any study procedure and 
increases in severity.  In this case, it should be reported as an AE and indicated as a worsening 
event.
Inpatient or ICU stays, while anticipated, are not scheduled protocol-defined visits. In addition, 
inpatient or ICU admissions can generate large amounts of clinical data (eg, multiple 
concomitant medications, frequent concomitant medication dose changes, laboratory values, and 
vital sign assessments). Therefore, targeted collection of data from inpatient or ICU stays, as 
well as a separate eCRF for detailing specific adverse events of special interest (AESI; ie, signs 
and symptoms of CRS and neurotoxicity), will be utilized for the purpose of adequately 
describing the expected risks of JCAR017 and the recommendations for managing these risks.
Adverse events and SAEs will be recorded on the AE page of the eCRF and in the subject’s 
source documents.  All SAEs meeting the criteria described in Table 8 must be reported to 
Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event by facsimile, 
or other appropriate method, using the SAE Report Form, or approved equivalent form.
10.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all adverse events as to: 
10.2.1.
Seriousness 
An SAE is defined as any AE occurring at any dose that:

Results in death;

Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE);

Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);

Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);

Is a congenital anomaly/birth defect;

Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be 
immediately life-threatening or result in death, hospitalization, or disability, but may 
jeopardize the subject or require medical or surgical intervention to prevent one of the 
other outcomes listed above.  Medical and scientific judgment should be exercised in 
deciding whether such an AE should be considered serious.
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Any confirmed detectable result from 
 testing, as well as any observation of clonal 
outgrowth (clonal dominance), or monoclonality, as a result of the integrated vector will be 
reported as an SAE within 24 hours.
Events not considered to be SAEs are hospitalizations for:

a standard procedure for protocol therapy administration. However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE.

routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.

the administration of blood or platelet transfusion as routine treatment of studied 
indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.

a procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, 
sampling for laboratory tests, BM sampling).  However, hospitalization or prolonged 
hospitalization for a complication of such procedures remains a reportable SAE.

hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.

a procedure that is planned (ie, planned prior to start of treatment on study); must be 
documented in the source document and the eCRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.

an elective treatment of or an elective procedure for a pre-existing condition,
unrelated to the studied indication, that has not worsened from baseline. 

emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the eCRF and the SAE Report Form 
must be completed.
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to the LD chemotherapy and/or JCAR017, action taken regarding LD chemotherapy 
and/or JCAR017, and outcome.
10.2.2.
Severity/Intensity
For both AEs and SAEs, the Investigator must assess the severity/ intensity of the event. 
The severity/intensity of AEs will be graded based upon the subject’s symptoms according to the 
current active minor version of the Common Terminology Criteria for Adverse Events (CTCAE
Version 4.03 or greater); 
Note: Cytokine release syndrome will be graded as per Table 10.
Adverse events that are not defined in the CTCAE should be evaluated for severity/intensity 
according to the following scale:
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
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required

Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required

Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible

Grade 4 = Life-threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable

Grade 5 = Death – the event results in death
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.  
Seriousness, not severity, serves as a guide for defining regulatory obligations.
10.2.3.
Causality
The Investigator must determine the relationship between the administration of LD 
chemotherapy and JCAR017 and the occurrence of an AE/SAE as Not Suspected or Suspected as 
defined below:
Not suspected:
a causal relationship of the adverse event to LD chemotherapy 
or JCAR017 administration is unlikely or remote, or other 
medications, therapeutic interventions, or underlying conditions 
provide a sufficient explanation for the observed event.
Suspected:
there is a reasonable possibility that the administration of LD 
chemotherapy or JCAR017 caused the adverse event.  
‘Reasonable possibility’ means there is evidence to suggest a 
causal relationship between the LD chemotherapy or JCAR017
and the adverse event.
Causality should be assessed and provided for every AE/SAE based on currently available 
information. Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional LD 
chemotherapy that has not been manufactured or provided by Celgene, please provide the name 
of the manufacturer when reporting the event.
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10.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
10.2.5.
Action Taken
The Investigator will report the action taken with investigational products as a result of an AE or 
SAE, as applicable (eg, discontinuation, interruption, or dose reduction of investigational 
products, as appropriate) and report if concomitant and/or additional treatments were given for 
the event.
10.2.6.
Outcome
The Investigator will report the outcome of the event for both AEs and SAEs.
Serious adverse events will be followed until they return to baseline, the event stabilizes or is no 
longer considered clinically significant by the Investigator; the subject dies or withdraws 
consent; or study closure.
10.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:

Results in discontinuation from the study;

Requires treatment, modification/interruption of LD chemotherapy or JCAR017 cell
product dose, or any other therapeutic intervention (including transfusions or growth 
factors); or

Is judged to be of significant clinical importance, eg, one that indicates a new disease 
process and/or organ toxicity, or is an exacerbation or worsening of an existing 
condition.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the eCRF.  If the abnormality was not 
a part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE.
If possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets).
10.4.
Pregnancy
All pregnancies and suspected pregnancies (including elevated βhCG or positive pregnancy test) 
occurring at any time after receipt of lymphodepleting chemotherapy or infusion of JCAR017 in 
either a FCCBP/FCBP or partner of childbearing potential of a male subject are immediately 
reportable events. The pregnancy, suspected pregnancy, or positive pregnancy test must be 
reported to Celgene Drug Safety immediately by email, phone or facsimile, or other appropriate 
method, using the Pregnancy Initial Report Form, or approved equivalent form.
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10.4.1.
Female Children of Childbearing Potential/Females of Childbearing Potential
The Investigator will follow the female subject until completion of the pregnancy and afterwards 
up to 1 year of the newborn baby, and must notify Celgene Drug Safety immediately about the 
outcome of the pregnancy (either normal or abnormal outcome) using the Pregnancy Follow-up 
Report Form, or approved equivalent form.
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the Investigator 
should report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the SAE Report 
Form or approved equivalent form.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in-utero exposure to LD chemotherapy or JCAR017 should also be reported to 
Celgene Drug Safety by facsimile, or other appropriate method, within 24 hours after the 
Investigator’s knowledge of the event using the SAE Report Form, or approved equivalent form.
10.4.2.
Male Subjects
If a female partner of a male subject taking LD chemotherapy and/or JCAR017 becomes 
pregnant, the male subject should notify the Investigator, and the pregnant female partner should 
be advised to call their healthcare provider immediately. The pregnant partner will be asked for 
consent (if permitted by local regulations) for follow-up by the Investigator until completion of 
the pregnancy and afterwards up to 1 year of the newborn baby.
10.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the eCRF. All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event by facsimile, 
or other appropriate method (eg, via email), using the SAE Report Form, or approved equivalent 
form.  This instruction pertains to initial SAE reports as well as any follow-up reports.
The Investigator is required to ensure that the data on these forms is accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to LD chemotherapy or 
JCAR017) recorded in the eCRF as described in Section 10.1.
The SAE report should provide a detailed description of the SAE and include a concise summary 
of hospital records and other relevant documents. If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
Safety as soon as these become available. Any follow-up data should be detailed in a subsequent 
SAE Report Form, or approved equivalent form, and sent to Celgene Drug Safety.
Progressive disease is considered as a study endpoint and will not be reported as an SAE. 
However, any sign, symptom, or manifestation of progressive disease that meet any of the
seriousness criteria will be reported as individual SAE.
Where required by local legislation, the Investigator is responsible for informing the Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
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initial and follow-up information about the event. The Investigator must keep copies of all SAE 
information on file including correspondence with Celgene and the IRB/EC.
10.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail.  The response time is expected to be no more than five (5) business 
days.  Urgent queries (eg, missing causality assessment) may be handled by phone.
10.5.2.
Death Reports
Deaths due to progressive disease will not be reported as an SAE unless considered related to LD 
chemotherapy or JCAR017 (ie, if assessed as lack of efficacy by the Investigator). Any sign, 
symptom, or manifestation of progressive disease that meet any of the seriousness criteria and 
result in death will be reported as individual SAEs. Any other AEs leading to death should be 
reported as an SAE according to Table 8.
10.6.
Potential Risks and Management of Treatment Toxicities
A summary of potential risks and management of treatment toxicity is provided below for the IP. 
See the IB for a complete discussion of potential risks associated with JCAR017.
10.6.1.
Management of Toxicities Associated with JCAR017
Cytokine release syndrome (CRS) and neurologic toxicities (NT) are associated with CAR T cell 
therapies.  Celgene has developed specific toxicity management guidelines (TMG) for CRS and 
NT associated with Celgene cellular products based on current clinical experience across the 
clinical development programs (Appendix F). These recommendations are based on the CRS 
revised grading system (Lee, 2014) and the Common Toxicity Criteria for Adverse Events 
(CTCAE) and need to be used for grading of CRS and NT to guide management in this trial.
If available and adopted as per site standard practice, CRS and NT grading according to the 
American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading 
System (Lee, 2019) should also be recorded in the eCRF to inform future modifications of the 
management guidelines. 
10.6.1.1.
Cytokine Release Syndrome
Administration of JCAR017 is associated with cytokine release syndrome (CRS). Cytokine 
release syndrome is characterized by high fever, fatigue, nausea, headache, dyspnea, tachycardia, 
rigors, hypotension, hypoxia, myalgia/arthralgia, and anorexia. Clinical symptoms and severity 
of CRS are highly variable (Lee, 2014), and management can be complicated by concurrent 
conditions.  With JCAR017, CRS usually occurs within two weeks after infusion (Abramson, 
2017).

Fever, especially high fever (≥38.5°C or ≥101.3°F), is a commonly-observed hallmark of 
CRS, and many features of CRS mimic infection. Hence, infection must be considered in 
all subjects presenting with CRS symptoms and appropriate cultures must be obtained and 
empiric antibiotic therapy initiated per institution standard of care.
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
Less common symptoms associated with CRS include cardiac dysfunction, adult 
respiratory distress syndrome, renal and/or hepatic failure, coagulopathies, disseminated 
intravascular coagulation, and capillary leak syndrome. 

Neurological toxicity has been observed concurrently with CRS.

With other CAR T cell products, CRS has been reported in a few cases to be associated 
with findings of macrophage activation syndrome/hemophagocytoic lymphohistiocytosis
(MAS/HLH), and the physiology of the syndromes may overlap. 
Please refer to Appendix F for detailed description of CRS, grading and treatment 
recommendations.  Note: Cytokine release syndrome will be graded as per Table 10.
10.6.1.2.
Fever
The possibility of CRS should be considered for all subjects with fever (≥38°C or ≥ 100.4°F) 
following JCAR017 treatment. Subjects should be monitored closely for hemodynamic 
instability and changing neurologic status. Febrile subjects, neutropenic or otherwise, should be 
evaluated promptly for infection and managed per institutional or standard clinical practice.
10.6.1.3.
Cytopenias
Severe (Grade ≥ 3) cytopenias, including anemia, leukopenia, neutropenia, and 
thrombocytopenia, can occur with both JCAR017 and lymphodepleting chemotherapy, and 
delayed recovery has been observed. Complete blood counts (CBCs) should be monitored after 
JCAR017 infusion until count recovery.  Institutional guidelines should be followed in the event 
of Grade ≥ 3 cytopenias.
10.6.1.4.
Infections
Life-threatening and fatal infections have been observed. Severe infections may include 
bacterial, fungal (including pneumocystis jirovecii), and viral infections (eg, CMV, HBV, 
respiratory viruses, and other viruses). A high index of suspicion is warranted in the event of 
prolonged or recurrent cytopenias, especially in conjunction with hypogammaglobulinemia, 
severe lymphopenia, and/or recent use of corticosteroids. Viral reactivation and other serious 
opportunistic infections should be considered in these settings, and prophylactic, pre-emptive, or 
symptomatic treatment with antimicrobial, antifungal, anti-pneumocystic, and/or antiviral 
therapies should be considered per local institutional guidelines.
10.6.1.5.
Neurologic Toxicities
CAR T cell therapy is associated with unique neurologic toxicities. Neurologic symptoms may 
include altered mental status, aphasia, altered level of consciousness, and seizures or seizure-like 
activity. With JCAR017, to date, the start of neurologic symptoms has been noted between 3 to 
23 days (median 10 days) (Abramson, 2017) after CAR T cell infusion and in severe cases may 
require admission to the intensive care unit (ICU) for frequent monitoring, respiratory support, or 
intubation for airway protection. The symptoms are variable generally occur as CRS is resolving 
or after CRS resolution. 
Please refer Appendix F for detailed description of neurologic toxicities, grading and treatment 
recommendations. 
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10.6.1.6.
Macrophage Activation Syndrome
Macrophage activation syndrome (MAS) is a serious disorder potentially associated with 
uncontrolled activation and proliferation of CAR T cells and subsequent activation of 
macrophages. Macrophage activation syndrome is typically characterized by high-grade, non-
remitting fever, cytopenias, and hepatosplenomegaly. Laboratory abnormalities found in MAS 
include elevated inflammatory cytokine levels, serum ferritin, soluble IL-2 receptor (sCD25), 
triglycerides, and decreased circulating NK cells. Other findings include variable levels of 
transaminases, signs of acute liver failure, coagulopathy, and disseminated intravascular 
coagulopathy. There are no definitive diagnostic criteria for MAS; it is typically diagnosed using 
published criteria for hemophagocytic lymphohistiocytosis (Schulert, 2015). While there is 
considerable overlap in clinical manifestations and laboratory findings between MAS and CRS, 
other distinguishing MAS physical findings such as hepatosplenomegaly and lymphadenopathy 
are not common in adult subjects treated with activated T cell therapies.
Subjects treated with JCAR017 should be monitored for MAS, and cytokine-directed therapy 
should be considered as clinically indicated (Appendix F).
10.6.1.7.
Infusion Reactions
Administration of JCAR017 may cause infusion reactions, such as fever, rigors, rash, urticaria, 
dyspnea, hypotension, and/or nausea.
To minimize the risk of infusion reactions, all subjects should be pre-medicated with 
acetaminophen and diphenhydramine (see Section 7.2.2). Mild infusion reactions should be 
managed expectantly with antipyretics, antihistamines, and antiemetics. Corticosteroids should 
be avoided because of the potential impact on efficacy of infused JCAR017 cells. Rigors may be 
treated with meperidine.
The following guidelines should be followed for infusion reactions:

Grade 1: administer symptomatic treatment; continue JCAR017 administration of 
both CD8+CAR+ and CD4+CAR+ components at the same dose and rate

Grade 2: stop administration of JCAR017; administer symptomatic treatment, and 
resume JCAR017 administration of both CD8+CAR+ and CD4+CAR+ components 
at a reduced rate of administration only after symptoms resolution

Grade 3: stop administration of JCAR017, administer symptomatic treatment, and 
resume at a reduced rate of administration only after symptoms resolve. If Grade 3 
reaction recurs, discontinue JCAR017 administration; no further CD8+CAR+ or 
CD4+CAR+ components of JCAR017 should be administered

Grade 4: discontinue administration of JCAR017 and administer symptomatic 
treatment as necessary; no further no further CD8+CAR+ or CD4+CAR+
components of JCAR017 should be administered
10.6.1.8.
Tumor Lysis Syndrome
Both LD chemotherapy employed in this protocol and JCAR017 have caused TLS in adult B-
NHL subjects with high disease burden. Subjects should be closely monitored for laboratory 
evidence of TLS (hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia; see
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Appendix E), and subjects at high risk for developing TLS, such as those with high disease 
burden and high cell turnover, should receive prophylactic treatment, including administration of 
allopurinol and hydration, per standard clinical practice.
 
 
 
 
 
10.6.1.10. Graft-Versus-Host Disease
The likelihood of GVHD occurring with CAR T cell therapy is low, but it remains a theoretical 
risk. Subjects who have undergone allogeneic HSCT and who have active, acute or chronic 
GVHD at screening are excluded from enrolling in this protocol. However, due to residual donor 
engraftment, some or all T cells of JCAR017 may be of donor origin. Subjects who received a 
previous allogeneic HSCT will be assessed for donor chimerism at screening and will be 
monitored closely throughout the study for signs of GVHD.
10.6.1.11. Uncontrolled T Cell Proliferation
JCAR017 could theoretically proliferate out of control. If uncontrolled JCAR017 proliferation 
occurs, subjects may be treated with high-dose steroids (eg, methylprednisolone 1 to 3 g/kg/day, 
tapered over 7 days) or LD doses of cyclophosphamide (1 to 3 g/m2 IV). If an Investigator 
suspects uncontrolled JCAR017 proliferation, Celgene should be contacted immediately. In an 
animal model the EGFR antibody cetuximab was used to ablate EGFRt-expressing CAR T cells 
in vivo (Wang, 2011). Currently, there is no data available on efficacy of cetuximab or other 
EGFR-directed antibodies for depletion of JCAR017 CAR T cells in humans.
 
 
 
 
 
 
 
 
 
 
 
 
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10.6.1.13. Risks Associated with Lymphodepleting Chemotherapy
Subjects receiving JCAR017 will receive fludarabine and cyclophosphamide prior to treatment 
with JCAR017 to facilitate lymphodepletion and CAR T cell engraftment. Refer to the package 
inserts or summary of product characteristics for specific details surrounding the risks of 
fludarabine phosphate and cyclophosphamide.
10.6.1.14. Second Primary Malignancies
Second primary malignancies must be reported as SAEs. This includes any second primary 
malignancy, regardless of causal relationship to IP, occurring at any time for the duration of the 
study, from the time of signing the ICF until study end. These events must also be documented in 
the appropriate page(s) of the eCRF and subject’s source documents. Documentation on the 
diagnosis of the second primary malignancy must be provided at the time of reporting as a 
serious adverse event (eg, any confirmatory histology or cytology results, x-rays, CT scans, etc.).
10.7.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to JCAR017 based on the Investigator’s Brochure.
For countries within the European Economic Area (EEA), Celgene or its authorized 
representative will report in an expedited manner to Regulatory Authorities and Ethics 
Committees concerned, SUSARs in accordance with Directive 2001/20/EC and the Detailed 
Guidance on collection, verification and presentation of adverse reaction reports arising from 
clinical trials on Ips for human use (ENTR/CT3) and also in accordance with country-specific 
requirements.
Celgene or its authorized representative shall notify the Investigator of the following 
information:

Any AE suspected of being related to the use of JCAR017 in this study or in other 
studies that is both serious and unexpected (ie, SUSAR);

Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
Where required by local legislation, the Investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects.
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC (see Section 14.3 for record retention 
information).
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Celgene Drug Safety Contact Information:
For Celgene Drug Safety contact information, please refer to the Serious Adverse Event Report 
Form Completion Guidelines or to the Pregnancy Report Form Completion Guidelines.
10.8.
Adverse Event of Special Interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific to
understanding of the Investigational Product and may require close monitoring and rapid
communication by the Investigator to Celgene. An AESI may be serious or nonserious. The rapid 
reporting of AESIs allows ongoing surveillance of these events in order to characterize and
understand them in association with the use of this investigational product.
Adverse events of special interest for JCAR017 include but are not limited to: 

Infusion reaction;

Cytokine release syndrome (CRS);

Neurological toxicity (NT);

Macrophage activation syndrome (MAS);

Tumor lysis syndrome (TLS)

Infections

Prolonged cytopenias

Hypogammaglobulinemia
Further information regarding the list of AESI can be found in the statistical analysis plan (SAP).
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11.
DISCONTINUATIONS
11.1.
Pre-treatment Period Discontinuation 
The following events are considered sufficient reasons for discontinuing a subject from the Pre-
treatment Period who undergoes leukapheresis but does not receive study treatment:

Adverse Event

Withdrawal of consent by subject/guardian

Failure to meet treatment criteria

Study drug manufacturing failure 

Death

Physician decision

Other (to be specified on the eCRF)
11.2.
Treatment Period Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the
Treatment Period:

Adverse Event

Withdrawal of consent by subject/guardian

Death

Lost to follow-up

Physician decision

Other (to be specified on the eCRF)
The reason for discontinuation should be recorded in the eCRF and in the source documents.
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by Celgene.  However, prior to discontinuing a 
subject, the Investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion.
11.3.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
study:

Screen failure

Adverse event

Withdrawal of consent by subject/guardian

Death
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
Lost to follow-up

Unsuccessful manufacturing of JCAR017

Other (to be specified on the eCRF)
The reason for study discontinuation should be recorded in the eCRF and in the source 
documents.
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12.
EMERGENCY PROCEDURES
12.1.
Emergency Contact
In emergency situations, the Investigator should contact the responsible Clinical Research
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page). This global 
Emergency Call Center is available 24 hours a day and 7 days a week. The representatives are 
responsible for obtaining your call-back information and contacting the on-call Celgene/contract 
research organization Medical Monitor, who will then contact you promptly.
Note: The back-up 24-hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls.
12.2.
Emergency Identification of Investigational Products
This is an open-label study; therefore, the IP will be identified on the package labeling.
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13.
REGULATORY CONSIDERATIONS
13.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative, 
and Investigator abide by Good Clinical Practice (GCP), as described in ICH Guideline E6 and 
in accordance with the general ethical principles outlined in the Declaration of Helsinki. The 
study will receive approval from an IRB/EC prior to commencement. The Investigator will 
conduct all aspects of this study in accordance with applicable national, state, and local
regulations of the pertinent regulatory authorities.
13.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations.  Celgene staff or an authorized representative will evaluate and approve all 
Investigators who in turn will select their staff.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of Celgene information. The Investigator should maintain 
a list of Sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an ICF/IAF and are 
screened for entry into the study.  Subjects who fail screening must have the reason(s) recorded 
in the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The Investigator must ensure timely and accurate completion of eCRFs and queries.
The information contained in the protocol and amendments (with the exception of the 
information provided by Celgene on public registry websites) is considered Celgene confidential 
information.  Only information that is previously disclosed by Celgene on a public registry 
website may be freely disclosed by the Investigator or its institution, or as outlined in the Clinical 
Trial Agreement.  Celgene protocol, amendment and IB information is not to be made publicly 
available (for example on the Investigator’s or their institution’s website) without express written 
approval from Celgene.  Information proposed for posting on the Investigator’s or their 
institution’s website must be submitted to Celgene for review and approval, providing at least 5 
business days for review.
At the time results of this study are made available to the public, Celgene will provide 
Investigators with a summary of the results that is written for the lay person. The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.
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13.3.
Subject Information and Informed Consent/Assent
The Investigator must obtain informed consent/assent of a subject and/or a subject’s legal 
representative prior to any study related procedures.
Documentation that informed consent/assent occurred prior to the study subject’s entry into the 
study and of the informed consent process should be recorded in the study subject’s source 
documents including the date.  The original ICF/IAF signed and dated by the study subject and 
by the person consenting the study subject prior to the study subject’s entry into the study, must 
be maintained in the Investigator’s study files and a copy given to the study subject.  In addition, 
if a protocol is amended and it impacts on the content of the informed consent/assent, the 
ICF/IAF must be revised.  Study subjects participating in the study when the amended protocol is 
implemented must be re-consented with the revised version of the ICF/IAF.  The revised 
ICF/IAF signed and dated by the study subject and by the person consenting the study subject 
must be maintained in the Investigator’s study files and a copy given to the study subject.
13.4.
Confidentiality
Celgene affirms the subject’s right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Celgene requires 
the Investigator to permit Celgene’s representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local regulations.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF/IAF, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual.
13.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene Clinical Research 
Physician/Medical Monitor.  Amendments will be submitted to the IRB/EC for written approval.  
Written approval must be obtained before implementation of the amended version occurs.  The 
written signed approval from the IRB/EC should specifically reference the Investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/IEC approval but will be submitted to the IRB/IEC 
for information purposes.
13.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF/IAF, and any other appropriate documents 
will be submitted to the IRB/EC with a cover letter or a form listing the documents submitted, 
their dates of issue, and the site (or region or area of jurisdiction, as applicable) for which 
approval is sought. If applicable, the documents will also be submitted to the authorities in 
accordance with local legal requirements.
IP can only be supplied to an Investigator by Celgene or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
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Celgene or its authorized representative. This documentation must also include a list of the 
members of the IRB/EC and their occupation and qualifications. If the IRB/EC will not disclose 
the names, occupations and qualifications of the committee members, it should be asked to issue 
a statement confirming that the composition of the committee is in accordance with GCP. For 
example, the IRB General Assurance Number may be accepted as a substitute for this list. 
Formal approval by the IRB/EC should mention the protocol title, number, amendment number 
(if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICF/IAF should also be 
revised.
The Investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the Investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and the 
IRB/EC prior to use.  
13.7.
Ongoing Information for Institutional Review Board/ Ethics 
Committee
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC:

Information on serious or unexpected adverse events as soon as possible; 

Periodic reports on the progress of the study;

Deviations from the protocol or anything that may involve added risk to subjects.
13.8.
Termination of the Study
Celgene reserves the right to terminate this study prematurely at any time for reasonable medical 
or administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB/EC, regulatory authorities, etc).
In addition, the Investigator or Celgene has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such as:

Unsatisfactory enrollment;

GCP noncompliance;

Inaccurate or incomplete data collection;

Falsification of records;

Failure to adhere to the study protocol.
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14.
DATA HANDLING AND RECORDKEEPING
14.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the IP are complete, accurate, filed and retained. Examples of source 
documents include: hospital records; clinic and office charts; laboratory notes; memoranda; 
subject’s diaries or evaluation checklists; dispensing records; recorded data from automated 
instruments; copies or transcriptions certified after verification as being accurate copies; 
microfiche; x-ray film and reports; and records kept at the pharmacy, and the laboratories, as 
well as copies of eCRFs or CD-ROM.
14.2.
Data Management
Data will be collected via eCRF and entered into the clinical database per Celgene standard 
operating procedures (SOPs). This data will be electronically verified through use of 
programmed edit checks specified by the clinical team. Discrepancies in the data will be brought 
to the attention of the clinical team, and investigational site personnel, if necessary. Resolutions 
to these issues will be reflected in the database. An audit trail within the system will track all 
changes made to the data.
14.3.
Record Retention
Essential documents must be retained by the Investigator according to the period of time outlined 
in the clinical trial agreement. The Investigator must retain these documents for the time period 
described above or according to local laws or requirements, whichever is longer. Essential 
documents include, but are not limited to, the following:

Signed ICFs for all subjects;

Subject identification code list, screening log (if applicable), and enrollment log;

Record of all communications between the Investigator and the IRB/EC;

Composition of the IRB/EC;

Record of all communications between the Investigator, Celgene, and their authorized 
representative(s);

List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures;

Copies of eCRFs (if paper) and of documentation of corrections for all subjects;

IP accountability records;

Record of any body fluids or tissue samples retained;

All other source documents (subject records, hospital records, laboratory records, 
etc.); 
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
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
The Investigator must notify Celgene if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified period.  
The Investigator must obtain approval in writing from Celgene prior to destruction of any 
records. If the Investigator is unable to meet this obligation, the Investigator must ask Celgene 
for permission to make alternative arrangements. Details of these arrangements should be 
documented. 
All study documents should be made available if required by relevant health authorities. 
Investigator or institution should take measures to prevent accidental or premature destruction of 
these documents.
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15.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative
for compliance with applicable government regulations with respect to current GCP and SOPs.
15.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study. All aspects of the study are reviewed with the Investigator and the staff at a study 
initiation visit and/or at an Investigators’ Meeting. Prior to enrolling subjects into the study, a 
Celgene representative will review the protocol, eCRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the Investigator. Monitoring will 
include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone. During monitoring visits, the facilities, IP
storage area, eCRFs, subject’s source documents, and all other study documentation will be 
inspected/reviewed by the Celgene representative in accordance with the Study Monitoring Plan.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the eCRFs against the appropriate source documentation.  Any resulting 
discrepancies will be reviewed with the Investigator and/or his/her staff.  Any necessary 
corrections will be made directly to the eCRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified.  Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
15.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, eCRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/Ecs, regulatory authorities (eg, Food and Drug Administration 
[FDA], European Medicines Agency [EMA]) and company authorized representatives. The 
Investigator should make every effort to be available for the audits and/or inspections. If the 
Investigator is contacted by any regulatory authority regarding an inspection, he/she should 
contact Celgene immediately.
15.3.
Product Quality Complaint
A Product Quality Complaint (PQC) is any written, electronic, or oral communication that
alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness,
purity, or performance of any drug product manufactured by or on behalf of Celgene Corporation
after it is released for distribution. Product Quality Complaints may reduce the usability of the 
product for its intended function or affect performance of the product and therefore pose a 
significant risk to the patient. Examples of PQCs include (but are not limited to): mixed product, 
mislabeling, lack of effect, seal/packaging breach, product missing/short/overage, contamination, 
suspected falsified, tampered, diverted or stolen material, and general product/packaging 
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damage. If you become aware of a suspected PQC, you are obligated to report the issue 
immediately. You can do so by emailing 
 or by contacting the 
Celgene Customer Care Center 
.
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16.
PUBLICATIONS
As described in Section 13.2, all protocol- and amendment-related information, with the 
exception of the information provided by Celgene on public registry websites, is considered 
Celgene confidential information and is not to be used in any publications.  Celgene protocol-
related information proposed for use in a publication must be submitted to Celgene for review 
and approval, and should not be utilized in a publication without express written approval from 
Celgene, or as described in the Clinical Trial Agreement.
Celgene will ensure Celgene-sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results.  At a minimum, this applies to 
results from all Phase 3 clinical studies, and any other study results of significant medical 
importance.  This also includes results relating to investigational medicines whose development 
programs have been discontinued.
Study results may also be presented at one or more medical congresses, and may be used for 
scientific exchange and teaching purposes.  Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.
Eligibility for external authorship, as well as selection of first authorship, will be based on 
several considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable) and contribution to abstract, presentation and/or publication development.
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17.
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Borowitz MJ, Wood BL, Devidas M, Loh ML, Raetz EA, Salzer WL, et al. Prognostic 
significance of minimal residual disease in high risk B-ALL: a report from Children's Oncology 
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Brentjens RJ, Riviere I, Park JH, Davila ML, Wang X, Stefanski J, et al. Safety and persistence 
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Burkhardt B, Waxman I. Adolescent Non-Hodgkin Lymphoma. 2012:329-47.
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Davila ML, Brentjens R, Wang X, Riviere I, Sadelain M. How do CARs work?: Early insights 
from recent clinical studies targeting CD19. Oncoimmunology. 2012 Dec 01;1(9):1577-83.
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Dunleavy K, Steidl C. Emerging biological insights and novel treatment strategies in primary 
mediastinal large B-cell lymphoma. Seminars in hematology. 2015 Apr;52(2):119-25.
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relapses of acute lymphoblastic leukemia show unexpected changes of clonal markers and high 
heterogeneity in response to initial and relapse treatment. Leukemia. 2011 Aug;25(8):1305-13.
European Medicines Agency. Guideline on follow-up of subjects administered with gene therapy 
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5.jsp&mid=WC0b01ac058002958d.
 
Faderl S, O'Brien S, Pui CH, Stock W, Wetzler M, Hoelzer D, et al. Adult acute lymphoblastic 
leukemia: concepts and strategies. Cancer. 2010 Mar 01;116(5):1165-76.
Food and Drug Administration. Briefing Document — Testing for replication competent 
retrovirus (RCR)/lentivirus (RCL) in retroviral and lentiviral vector based gene therapy products 
— Revisiting current FDA recommendations. Food and Drug Administration. 2010. Available 
from: 
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVacci
nesandOtherBiologics/CellularTissueandGeneTherapiesAdvisoryCommittee/UCM232592.pdf.
Food and Drug Administration. Guidance for industry: supplemental guidance on testing for 
replication competent retrovirus in retroviral vector based gene therapy products and during 
follow-up of patients in clinical trials using retroviral vectors. Food and Drug Administration 
[Internet]. Food and Drug Administration. 2006 Oct. Available from: 
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18.
APPENDICES
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APPENDIX A. TABLE OF ABBREVIATIONS
Abbreviation or Specialist Term
Explanation
AE
Adverse event
AESI
Adverse event of special interest
ALL
Acute lymphoblastic leukemia
ALT
Alanine aminotransferase (SGPT)
AST
Aspartate aminotransferase (SGOT)
B-ALL
B-cell acute lymphoblastic leukemia
B-NHL
B-cell non-Hodgkin lymphoma
BCA
B-cell aplasia
β-hCG
Beta human chorionic gonadotropin 
BFM
Berlin-Frankfurt-Münster
BL
Burkitt lymphoma
BM
Bone marrow
BMA
Bone marrow aspirate
BMB
Bone marrow biopsy
BOR
Best overall response
CAR
Chimeric antigen receptor
CI
Confidence interval
CLL
Chronic lymphocytic leukemia
CNS
Central nervous system
CR
Complete response
eCRF
Electronic case report form
CRi
CR with incomplete blood count recovery
CRP
C-reactive protein
CRS
Cytokine release syndrome
CSF
Cerebrospinal fluid
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ddPCR
Droplet digital polymerase chain reaction
DFS
Disease-free survival
DL
Dose level
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Abbreviation or Specialist Term
Explanation
DLBCL
Diffuse large B-cell lymphoma
DLI
Donor lymphocyte infusions
DLT
Dose-limiting toxicity 
DMSO
Dimethyl sulfoxide
DNA
Deoxyribonucleic acid
DOR
Duration of response
DSMB
Data Safety Monitoring Board
DVT
Deep venous thrombosis 
EBV
Epstein-Barr virus
EC
Ethics Committee
ECG
Electrocardiogram
ECHO
Echocardiogram
EEA
European Economic Area
EEG
Electroencephalogram
EFS
Event-free survival
EGFRt
Truncated human epidermal growth factor receptor
EMA
European Medicines Agency
EOS
End of study
EU
European Union
FCBP
Female of childbearing potential 
FCCBP
Female children of childbearing potential
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in one second
FISH
Fluorescence in situ hybridization
FL
Follicular lymphoma 
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GVHD
Graft-versus-host disease
HIV
Human immunodeficiency virus
HLA
Human leukocyte antigen
HLA-DR
Human leukocyte antigen – antigen D related
HLH
Hemophagocytoic lymphohistiocytosis
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Abbreviation or Specialist Term
Explanation
HSCT
Hematopoietic stem cell transplantation
IAF
Informed assent form
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
ICU
Intensive care unit
IFN
Interferon 
IgG
Immunoglobulin G
IL
Interleukin
IND
Investigational New Drug
IP
Investigational product
IRB
Institutional Review Board
IRC
Independent Review Committee
IRT
Interactive response technology
IUD
Intrauterine device
IV
Intravenous (or intravenously)
IVIG
Intravenous immunoglobulins
kg
kilogram
LBL
Lymphoblastic lymphoma
LD
Lymphodepleting
LDH
Lactate dehydrogenase
LTFU
Long-term follow-up
LTLS
Laboratory tumor lysis syndrome
LVEF
Left ventricular ejection fraction
mAb
Monoclonal antibody
MAS
Macrophage activation syndrome
MCL
Mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
mTPI-2
Modified toxicity probability interval
MRD
Minimal residual disease
MRI
Magnetic resonance imaging
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Abbreviation or Specialist Term
Explanation
MSKCC
Memorial Sloan Kettering Cancer Center
MTD
Maximum tolerated dose
MTX
Methotrexate
MUGA
Multi-gated acquisition scan
MZL
Marginal zone lymphoma 
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NHL
Non-Hodgkin lymphoma
NK
Natural killer
NT
Neurotoxicity 
ORR
Overall response rate
OS
Overall survival
PB 
Peripheral blood
PCP
Pneumocystis pneumonia
PD
Progressive disease
PE
Pulmonary embolism 
PedsQL
Pediatric quality of life
PK
Pharmacokinetic, pharmacokinetics
PMBCL
Primary mediastinal large B-cell lymphoma
PO
Per os, by mouth
PQC
Product Quality Complaint
PR
Partial response
PRO 
Patient reported outcome
ddPCR
Droplet digital polymerase chain reaction
RCL
Replication-competent lentivirus
RFS
Relapse-free survival 
RNA
Ribonucleic acid
RP2D
Recommended Phase 2 dose
r/r
Relapsed/refractory 
RSI
Reference Safety Information
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Abbreviation or Specialist Term
Explanation
SAE
Serious adverse event
SAP 
Statistical analysis plan
SC
Steering committee
scFv
Single chain variable fragment
sCRS
Severe cytokine release syndrome
SCT
Stem cell transplantation
SEER
Surveillance, Epidemiology, and End Results 
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
sNT
Severe neurotoxicity
SOP
Standard operating procedure
SPD
Sum of the product of the perpendicular diameters for multiple 
lesions
SRC
Safety Review Committee
SSC
Scientific Steering Committee
SUSAR
Suspected unexpected serious adverse reaction
TEAE
Treatment-emergent adverse event
TKI
Tyrosine-kinase inhibitor
TLH
Trilineage hematopoiesis
TLS
Tumor lysis syndrome
TMG
Toxicity management guideline
TNF
Tumor necrosis factor
ULN
Upper limit of normal
US
United States
WHO
World Health Organization
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APPENDIX B. RESPONSE CRITERIA FOR ALL
Response
Criteria
Complete response 
(CR)
No circulating blasts in the blood or bone marrow
No extramedullary disease 
No lymphadenopathy, splenomegaly, skin/gum infiltration/testicular 
mass/CNS involvement
Trilineage hematopoiesis (TLH) and < 5%
Absolute neutrophil count (ANC) > 1000/µL
Platelets > 100,000/µL
No recurrence for 4 weeks
Complete response 
with incomplete blood 
count recovery (CRi)
Meets all criteria for CR except platelets < 100,000/µL or ANC is <
1000/µL
Refractory disease
Failure to achieve CR at the end of treatment
Progressive disease 
(PD)
Increase of at least 25% in the absolute number of circulating or bone 
marrow blasts or development of extramedullary disease
Relapsed diseasea
Reappearance of blasts in the blood or bone marrow (> 5%) or > 1% with 
previous/supportive molecular findings or in any extramedullary site after a 
CR
MRD negative 
Complete Response 
(MRD-CR)
CR defined above with no MRD detected (< 0.01% by a validated assay) 
MRD negative 
Complete Response 
with incomplete blood 
count recovery (MRD-
CRi)
CRi defined above with no MRD detected (< 0.01% by a validated assay)
a MRD relapse is defined as an MRD detection by validated assay at a frequency of 1 x 10-4 or greater in BM cells 
following an initial MRD negative (less than 1 x 10-4) CR/CRi.
Abbreviations: ANC = absolute neutrophil count; CNS = central nervous system; CR = complete response; CRi = 
complete response with incomplete blood count recovery; MRD = minimal residual disease; PD = progressive 
disease; TLH = trilineage hematopoiesis; µL = microliter.
Source: NCCN Response Criteria Guidelines for pediatric ALL (NCCN, 2019).
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APPENDIX C. RESPONSE CRITERIA FOR NHL
Response
Criteria
Complete response 
(CR)
CT or MRI reveals no residual disease or new lesions
Resected residual mass that is pathologically (morphologically) negative for 
disease
BM and CSF morphologically free of disease
Partial response (PR)
50% decrease in SPD on CT or MRI
No new lesions and/or PD
Morphologic evidence of disease may be present in BM or CSF if present at 
diagnosis; however, there should be 50% reduction in percentage of 
lymphoma cells
Minor response (MR)
Decrease in SPD > 25% but < 50% on CT or MRI
No new lesions and/or PD
Morphologic evidence of disease may be present in BM or CSF if present at 
diagnosis; however, there should be 25% to 50% reduction in percentage of 
lymphoma cells
No response (NR)
For those who do not meet CR, PR, MR, or PD criteria
Progressive disease 
(PD)
For those with > 25% increase in SPD on CT or MRI, or
Development of new morphologic evidence of disease in BM or CSF
Abbreviations: BM = bone marrow; CR = complete response; CSF = cerebrospinal spinal fluid; CT = computed 
tomography; MR = minor response; MRI = magnetic resonance imaging; NHL = non-Hodgkin lymphoma; NR = no 
response; PD = progressive disease; PR = partial response; SPD = sum of product of greatest perpendicular 
diameters
Source: International Pediatric NHL Response Criteria (2015) (Sandlund, 2015).
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APPENDIX D. CLINICAL LABORATORY EVALUATIONS
Table 9:
Clinical Laboratory Evaluations
Laboratory evaluations will be performed both centrally and locally according to Table 9.
Additional assessments should be performed between scheduled study visits as clinically 
required in order to diagnose and monitor AEs/SAEs or expected events. Clinical management of 
study subjects will be based on local assessments.
It is the responsibility of the Investigator to obtain and review laboratory results for subject 
safety and follow up with subjects in a timely manner.
Laboratory Panel
Analytes
Hematology
CBC with differential
Coagulation
PT, aPTT, INR, fibrinogen, and D-dimer
Chemistry
Glucose, BUN, creatinine, sodium, potassium, chloride, calcium, total protein, 
albumin, total bilirubin, direct bilirubin, alkaline phosphatase, ALT (SGPT), AST 
(SGOT), magnesium, phosphate, bicarbonate, LDH, uric acid, triglycerides 
Immunoglobulins
IgG, IgM, IgA
Viral serologyb
HIV
Hepatitis B (HBsAb, HBsAg, and HBcAb), Hepatitis C (Hep C Ab)
Inflammatory markers 
CRP, ferritin
HLA typinga
HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1
Donor chimerisma
% stem cell donor
Cerebrospinal fluida
RBCs, WBCs with differential including leukemia/lymphoma cells (blasts), 
l
t i
Pregnancya
ß-HCG (serum)
Abbreviations: ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); aPTT = activated 
partial thromboplastin time; AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
BUN = blood urea nitrogen; CBC = complete blood count; CRP = C-reactive protein; HBcAb = Hepatitis B core 
antibody HBsAb = Hepatitis B surface antibody; HBsAg = Hepatitis B surface antibody; HIV= Human 
Immunodeficiency Virus; HLA = Human leukocyte antigen; Ig = immunoglobulin; INR = international normalized 
ratio; LDH = lactate dehydrogenase; PT = prothrombin time; RBC = red blood cell; WBC = white blood cell.
a Local assessment only.
b For the assessment at the leukapheresis visit, refer to the 
 collection laboratory manual for further details on 
where sample is sent for analysis.
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APPENDIX E. CAIRO-BISHOP DEFINITIONS OF TUMOR LYSIS 
SYNDROME
Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome (LTLS)
Laboratory Parameter
Laboratory Result
Urate
≥ 476 μmol/L or 25% increase from baseline
Potassium
≥ 6.0 mmol/L or 25% increase from baseline
Phosphorous
≥ 2.1 mmol/L or 25% increase from baseline
Calcium
≤ 1.75 mmol/L or 25% decrease from baseline
Laboratory tumor lysis syndrome (LTLS) is defined as either a 25% change or level above or 
below normal, as defined above, for any two or more serum values of urate, potassium, 
phosphate, and calcium within 3 days before or 7 days after the initiation of chemotherapy. This 
assessment assumes that a patient has or will receive adequate hydration (± alkalinization) and a 
hypouricaemic agent(s).
Cairo-Bishop Definition of Clinical TLS
The presence of laboratory TLS and one or more of the following criteria:
1. Creatinine: ≥ 1.5 ULN (age > 12 years or age adjusted)
2. Cardiac arrhythmia/sudden deatha
3. Seizurea
Abbreviations: TLS = tumor lysis syndrome; ULN = upper limit of normal.
a Not directly attributable to a therapeutic agent.
Cairo-Bishop Grading System for TLS
Gradeb
LTLS
Creatinine 
Cardiac Arrhythmia 
Seizure
0 
-
≤ 1.5 × ULN
None
None
1 
+ 
1.5 × ULN 
Intervention not indicated
None
2 
+ 
> 1.5 – 3.0 × ULN 
Non-urgent medical 
intervention indicated
One brief generalized 
seizure; seizure(s) well 
controlled or infrequent; 
focal motor seizures not 
interfering with activities 
of daily life (ADL)
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Cairo-Bishop Grading System for TLS (Continued)
Grade 
LTLS
Creatinine 
Cardiac Arrhythmia 
Seizure
3
+
> 3.0 – 6.0 × ULN
Symptomatic and
incompletely controlled
medically or controlled
with device
Seizure in which 
consciousness is altered; 
poorly controlled seizure 
disorder; breakthrough 
generalized seizures 
despite medical 
intervention
4
+
> 6.0 × ULN
Life-threatening
Seizures of any kind that 
are prolonged, repetitive, 
or difficult to control
5
+
Deatha
Deatha
Deatha
Abbreviations: ADL = activities of daily living; LTLS = laboratory tumor lysis syndrome; TLS = tumor lysis 
syndrome; ULN = upper limit of normal.
a Probably or definitely attributable to clinical TLS.
b Clinical tumor lysis syndrome (CTLS) requires one or more clinical manifestations along with criteria for 
laboratory tumor lysis syndrome (LTLS). Maximal CTLS manifestation (renal, cardiac, neuro) defines the grade.
Source: (Cairo, 2004).
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APPENDIX F.
MANAGEMENT GUIDELINES FOR CYTOKINE 
RELEASE SYNDROME AND NEUROLOGIC 
TOXICITIES (PEDIATRICS VERSION 2.0)
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MANAGEMENT OF TOXICITIES ASSOCIATED WITH JCAR017
Cytokine release syndrome (CRS) and neurologic toxicities (NT) are associated with CAR T cell 
therapies.  Celgene has developed the toxicity management guidelines (TMG) for CRS and NT 
associated with Celgene cellular products based on current clinical experience across the clinical 
development programs. These recommendations are based on the CRS revised grading 
system (Lee, 2014) and the Common Toxicity Criteria for Adverse Events (CTCAE) and need to 
be used for grading of CRS and NT to guide management in this trial. 
If available and adopted as per site standard practice, CRS and NT grading according to the 
American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading 
System (Lee, 2019)  should also be recorded in the eCRF to inform future modifications of the 
management guidelines.
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1.
CYTOKINE RELEASE SYNDROME
Administration of cellular products such as chimeric antigen receptor (CAR)-expressing T cells 
can be associated with cytokine-associated toxicity due to systemic production and release of 
various cytokines into the circulation. Cytokine-associated toxicity, also known as cytokine 
release syndrome (CRS), is a toxicity that occurs as a result of immune activation (Gardner, 
2017; Lee, 2014).
1.1.
Pathophysiology of Cytokine Release Syndrome
The hallmark of CRS is immune activation resulting in elevated inflammatory cytokines. 
Cytokine release syndrome clinically manifests when large numbers of lymphocytes (B cells, T 
cells, and/or natural killer cells) and/or myeloid cells (macrophages, dendritic cells, and 
monocytes) become activated and release inflammatory cytokines. Cytokine release syndrome 
has classically been associated with therapeutic monoclonal antibody (mAb) infusions, most 
notably anti-CD3 (OKT3), anti-CD52 (alemtuzumab), anti-CD20 (rituximab), and the CD28 
super-agonist, TGN1412. Cytokine release syndrome is also frequently observed following 
administration of bi-specific T cell engaging antibodies for leukemia, and adoptive cellular 
immunotherapies for cancer, most notably CAR T cells. Incidence, time to onset and severity of 
CRS due to CAR T cells is at least partially dependent on the infused cell dose and tumor 
burden/antigen density, presumably due to more rapid and higher levels of CAR T cell 
activation. Onset of CRS symptoms typically occurs days to occasionally weeks after the CAR T 
cell infusion, usually preceding maximal in vivo T cell expansion. Cytokine release syndrome is 
associated with elevated interferon gamma (IFN-γ), interleukin (IL)-6, and tumor necrosis alpha 
(TNFα) levels, and increases in IL-2, granulocyte macrophage colony-stimulating factor (GM-
CSF), IL-10, IL-8, IL-5, and fractalkine although the pattern of elevated cytokines varies among 
subjects (Davila, 2014; Hay, 2017). Interleukin 6 has been identified as a central mediator of 
toxicity in CRS. Interleukin 6 is a pleiotropic cytokine with anti-inflammatory and 
proinflammatory properties. High levels of IL-6, present in the context of CRS, likely initiates a 
proinflammatory IL-6-mediated signaling cascade.
1.2.
Clinical Presentation of Cytokine Release Syndrome
Cytokine release syndrome is characterized by high fever, fatigue, nausea, headache, dyspnea, 
tachycardia, rigors, hypotension, hypoxia, myalgia/arthralgia, and anorexia. Clinical symptoms 
and severity of CRS are highly variable (Lee, 2014), and management can be complicated by 
concurrent conditions.  In non-Hodgkin lymphoma (NHL) subjects treated with JCAR017, CRS 
usually occurs within two weeks after infusion (Abramson, 2017).

Fever, especially high fever (≥38.5°C or ≥ 101.3°F), is a commonly-observed hallmark of 
CRS, and many features of CRS mimic infection. Hence, infection must be considered in 
all subjects presenting with CRS symptoms, and appropriate cultures must be obtained,
and empiric antibiotic therapy initiated per institution standard of care.

Less common symptoms associated with CRS include cardiac dysfunction, adult 
respiratory distress syndrome, renal and/or hepatic failure, coagulopathies, disseminated 
intravascular coagulation, and capillary leak syndrome. 

Neurologic toxicity has been observed concurrently with CRS; refer to Section 3 below.
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With other CAR T cell products, CRS has been reported in a few cases to be associated 
with findings of macrophage activation syndrome (MAS)/hemophagocytic 
lymphohistiocytosis (HLH), and the physiology of the syndromes may overlap.
1.3.
Clinical Management of Cytokine Release Syndrome
Across various CAR T cell products, early manifestations of CRS can predict more severe 
toxicity for both CRS and neurotoxicity (NT).
Subjects with B-cell acute lymphoblastic leukemia (B-ALL) and high burden of disease are at 
high risk of developing CRS (Frey, 2017). Subjects with NHL who have high baseline tumor 
burden (measured by the sum of product of the perpendicular diameters [SPD] or high serum 
lactate dehydrogenase [LDH; ≥500 U/L prior to the start of lymphodepletion] also have a higher 
risk for developing CRS and/or neurotoxicity (Siddiqi, 2017). 
High baseline levels of other commonly measured inflammatory markers, such as ferritin and C-
reactive protein (CRP), were also associated with CRS. 
It should be noted that, although useful for identifying subjects at higher risk for developing 
CRS, CRP, ferritin, and serum cytokine levels should not be used for CRS clinical 
management/treatment decisions in the absence of other clinical signs and symptoms of CRS; for 
example, a subject with an elevated CRP but no concomitant symptoms may not require 
intervention (Park, 2017). Thus, close observation of these subjects is strongly recommended.
A modification of the Common Toxicity Criteria for Adverse Events (CTCAE) CRS grading 
scale has been established to better reflect CAR T cell-associated CRS, as detailed in Table 10
(Lee, 2014). 
Table 10:
Grading Criteria for Cytokine Release Syndrome
Symptoms/Signs
Cytokine 
Release 
Syndrome 
(CRS) Grade 
1 (mild)
CRS Grade 2 
(moderate)
CRS Grade 3 
(severe)
CRS Grade 4 
(life-
threatening)
CRS grade is defined by the most severe symptom 
(excluding fever)
Vital Signs
Temperature 
≥ 38.5°C/101.3°F
Yes
Any
Any
Any
Systolic blood 
pressure (SBP) < 90 
mm Hg
N/A
Responds to 
intravenous (IV) 
fluids or single 
low-dose 
vasopressor
Needs high-
dosea or multiple 
vasopressors
Life-threatening
Need for oxygen to 
reach oxygen 
saturation (SaO2) > 
90%
N/A
Fraction of 
inspired oxygen 
(FiO2)< 40%
FiO2 ≥ 40%
Needs ventilator 
support 
Organ Toxicity
N/A
Grade 2
Grade 3 or 
transaminitis 
Grade 4
Grade 4 
(excluding 
transaminitis)
a Definition of high-dose vasopressors in Table 11 . 
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Table 11:
High-Dose Vasopressors (all doses required for ≥3 hours)
Vasopressor
Dose
Norepinephrine monotherapy
≥ 0.2 μg/kg/min up to 50 kg, then flat 10 μg/min for > 50 
kg
Dopamine monotherapy
≥ 10 μg/kg/min up to 50 kg, then flat 500 μg/min for > 50 
kg
Phenylephrine monotherapy
4 μg/kg/min up to 50 kg, then flat 200 μg/min for > 50 kg
Epinephrine monotherapy
≥ 0.1 μg/kg/min up to 50 kg, then flat 5 μg/min for > 50 kg
If on vasopressin
Vasopressin + norepinephrine equivalent (NE) of ≥ 0.1 
μg/kg/mina
If on combination vasopressors (not 
vasopressin)
Norepinephrine equivalent of ≥ 20 μg/mina
a VASST Trial Vasopressor Equivalent Equation: Norepinephrine equivalent dose = [norepinephrine (μg/min)] + 
[dopamine (μg/kg/min) ÷ 2] + [epinephrine (μg/min)] + [phenylephrine (μg/min) ÷ 10]
Note: Pediatric weight adjustments should be taken into consideration
Adapted from (Lee, 2014).
Detailed CRS management guidelines are shown in Figure 4.  Treatment should be 
individualized for each subject’s clinical needs (note: For pediatric subjects, please refer to the 
package insert for the appropriate pediatric dosing for treatments outlined in Figure 4). This 
guidance emphasizes the importance of early intervention for Grade 2 CRS, or in the setting of a 
rapid onset or rapid progression of CRS symptoms, to prevent the development of severe (Grade 
3 or greater) CRS and NT.
In some cases, tocilizumab, an anti-IL-6R-antibody, may be required to treat toxicities such as 
severe CRS. Please refer to the currently approved Actemra® prescribing information (US) or 
RoActemra® Summary of Product Characteristics (EU). Actemra® has been approved by the 
Food and Drug Administration (FDA) for the treatment of CAR T cell-induced severe or life-
threatening CRS in adults and pediatric subjects 2 years of age and older. RoActemra® has been 
approved by the European Medicines Agency (EMA) for the treatment of CAR T cell-induced 
severe or life-threatening CRS in adults and pediatric patients 2 years of age and older. The 
preferred dose to intervene in adult subjects with CRS is 8 mg/kg (maximum 800 mg) IV. In 
pediatric subjects above 2 years of age, the recommended dose is 8 mg/kg in subjects weighing 
greater than or equal to 30 kg, or 12 mg/kg in subjects weighing less than 30 kg. If no clinical 
improvement in the signs and symptoms of CRS occurs after the first dose, additional doses of 
tocilizumab may be administered (Please see Figure 4, Actemra® prescribing information [US]
and RoActemra® Summary of Product Characteristics [EU]).
Other anti-IL-6 agents, if available in the country, should be considered in the event of severe 
CRS not responding to tocilizumab and corticosteroids. Dosing of any other anti-IL-6 agent 
should be per prescribing information.
In the most unresponsive severe cases additional treatments with T cell depleting therapies such 
as cyclophosphamide should be considered (Brudno, 2016).
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Figure 4:
JCAR017 Cytokine Release Syndrome Treatment Algorithm
Abbreviations: ANC = absolute neutrophil count; CAR = chimeric antigen receptor; CRP = C-reactive protein; CRS = cytokine release syndrome; EEG = 
electroencephalogram; ICU = intensive care unit; IL-6 = interleukin 6; INR = international normalized ratio; IV = intravenous; NT = neurotoxicity; PTT = partial 
thromboplastin time; q = every; MAS/HLH = macrophage activation syndrome/Hemophagocytic Lympho-histiocytosis.
NOTE 
1.
Tocilizumab dose should be adjusted to 12 mg/kg in subjects weighing < 30 kg.
2.
In pediatric subjects, the recommended dexamethasone dosing is as follows: 10 mg adult equivalent for pediatrics: 0.2 mg/kg up to 50 kg, then flat 10 mg 
thereafter; 20 mg adult equivalent for pediatrics: 0.4 mg/kg up to 50 kg, then flat 20 mg thereafter.
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2.
MACROPHAGE ACTIVATION SYNDROME 
(MAS)/HEMOPHAGOCYTIC LYMPHO-HISTIOCYTOSIS (HLH)
Macrophage Activation Syndrome (MAS) or Hemophagocytic Lympho-histiocytosis (HLH) is a 
rare, potentially fatal immune-mediated disease, caused by impaired natural killer and cytotoxic 
T-cell function. This syndrome has a wide range of causes, symptoms, and outcomes, but all lead 
to a hyperinﬂammatory response (with some characteristics that overlap with Cytokine Release 
Syndrome, CRS) and organ damage (Ramos-Casals, 2014). Cases of HLH have been described 
in patients treated with CAR T therapies.
2.1.
Pathophysiology of HLH/MAS
MAS/HLH is divided into primary (genetic) and secondary (reactive) forms. Secondary 
MAS/HLH is subclassiﬁed as viral, autoimmune, or tumor related. MAS/HLH has both 
infectious and non-infectious triggers (Ramos-Casals, 2014). Viral infection is the most frequent 
trigger, either due to primary infection or after reactivation in immunosuppressed patients.
Bacterial and fungal infections can also trigger MAS/HLH. Macrophage Activation Like 
Syndrome (MALS) is a distinct entity that leads to early death in septic patients and must be 
carefully ruled out in patients who are prone to develop severe infections, including patients 
following CAR T cell therapy (Karakike, 2019). Patients with cancer, mainly those with 
hematological malignancies, and in particular lymphoma, have a higher risk of developing 
MAS/HLH.
A defect in granule-mediated cytotoxicity is the underlying common mechanism in both primary 
and secondary forms of MAS/HLH (Ramos-Casals, 2014; Crayne, 2019). Enhanced antigen 
presentation and repeated interferon γ-dependent stimulation of Toll-like receptors are postulated 
as causal mechanisms of the uncontrolled activation of antigen-presenting cells and T cells 
(Behrens, 2011). This activation produces an overshooting of inﬂammatory response caused by 
hypersecretion of proinﬂammatory cytokines such as interferon γ (IFN-γ), tumor necrosis factor 
α (TNF-α), interleukin 1, interleukin 4, interleukin 6, interleukin 8, interleukin 10 and interleukin 
18. This so-called cytokine storm contributes to tissue damage and progressive systemic organ 
failure (Crayne, 2019).
2.2.
Clinical Presentation and Diagnosis of HLH/MAS
The presentation of secondary MAS/HLH is heterogeneous and characterized by a panoply of 
clinical signs and symptoms. The clinical syndrome can be acute or subacute with non-specific
symptoms appearing over days to week(s) (Ramos-Casals, 2014). The cardinal features are 
continuous high fever (≥38.5 °C) and enlarged lymphohematopoietic organs 
(spleen/hepatomegaly, occasionally accompanied by adenopathy). Pulmonary involvement is 
frequent (42%), symptoms may include cough, dyspnea, and respiratory failure. Neurologic 
presentation (25%) are heterogeneous and may include coma, seizures, meningitis and 
encephalomyelitis. Twenty-five percent of patients also have non-speciﬁc cutaneous 
involvement, including erythematous rashes, edema, petechiae, and/or purpura. Gastrointestinal 
symptoms (18%) include diarrhea, nausea, vomiting and/or abdominal pain.
Laboratory markers associated with MAS/HLH are as follows: 
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
Thrombocytopenia and anemia are identiﬁed in almost 80% of adult cases, and 
leukopenia in 69%. Most of the cases are grade 3 or 4 according to CTCAE v4.03. 

Hyperferritinaemia is a key diagnostic test: 90% of adult patients with MAS/HLH have 
increased concentrations, and 25% may reach very high levels ≥ 22,000 ng/mL. 

Almost 60% of patients have coagulation disorders related to liver dysfunction. 
Hypoﬁbrinogenemia and raised D-dimer levels are reported in 50% of cases. 

Hypertriglyceridemia is identiﬁed in 69% of adults with HLH and has been associated 
with lipoprotein lipase inhibition caused by excess TNF-α.

Nearly 80% of patients have abnormalities in liver function (increased alkaline 
phosphatase and transaminase levels in 71% and 57%, respectively). Increased serum 
lactate dehydrogenase concentrations are reported in 78% of patients. 
Detection of any ongoing infection acting as a trigger for MAS/HLH is critical. Standard tests 
should be used to screen for infections caused by the most common viruses such as herpes, CMV 
and EBV. Other infectious agents (eg, mycobacteria, parasites, and fungi, particularly Candida 
and Mucor) should be ruled out according to speciﬁc clinical or epidemiological features 
(Ramos-Casals, 2014; Lehmberg, 2015).
The abnormal immunological response caused by MAS/HLH can be measured either 
serologically or through functional cellular assays. High serum concentrations of soluble CD25 
(interleukin 2 receptor α) occur in 79% of cases of HLH. Low or absent NK cell cytotoxicity is a 
criterion for diagnosis of MAS/HLH. NK cell function can be assessed with a variety of methods 
(chromium 51 assays, CD107a externalization), though these techniques have not been 
standardized yet (Ramos-Casals, 2014; Lehmberg, 2015).
Bone marrow is the preferred anatomical site for investigation of suspected MAS/HLH, with 
bone marrow aspirates (BMA) in 84% of adult cases showing evidence of hemophagocytosis.
Hemophagocytosis can also occur in the reticuloendothelial organs (lymph nodes, spleen, and 
liver). BMA can be negative at the initial stage of HLH and should be repeated during the 
clinical course if there is a high suspicion of HLH.
The diagnosis of MAS/HLH (according to HLH-2004 consensus criteria, further revised in 2014 
for HLH associated with malignancies) (Lehmberg, 2015) can be established if one of either of 
the criteria below is fulfilled: 
(1) A molecular diagnosis consistent with HLH 
(2) Diagnostic criteria for HLH fulfilled (five out of the eight criteria below):

High persistent fever (≥38.5 °C)

Splenomegaly 

Cytopenias (affecting 2 of 3 lineages in the peripheral blood): Hemoglobin < 90 g/L, 
platelets < 100 x 109/L, neutrophils < 1.0 x 109/L

Triglycerides ≥ 3.0 mmol/L (ie, 265 mg/dL) or fibrinogen ≤ 1.5 g/L

Hemophagocytosis in bone marrow, spleen and/or lymph nodes
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Low or absent NK-cell activity (according to local laboratory reference) 

Ferritin ≥ 500 ng/mL 

Soluble CD25 (ie, soluble IL-2 receptor) ≥ 2,400 U/mL
2.3.
Clinical Management of HLH/MAS
Effective treatment of HLH requires multiple simultaneous approaches (Ramos-Casals, 2014; 
Lehmberg, 2015). 
1. Supportive care is essential because of frequent life-threatening severe manifestations at 
presentation. 
2. The elimination of triggers (particularly infection) is crucial to remove the stimuli that 
initiate the abnormal immune system activation. Appropriate broad-spectrum antiviral, 
antibacterial, antifungal prophylaxis and treatment must be initiated. 
3. Suppression of the inﬂammatory response and cell proliferation by immunosuppressive 
and cytotoxic drugs, respectively, is necessary. First line treatment includes IL-6-
blockade with tocilizumab. Glucocorticoids are also indicated for the initial treatment of 
MAS/HLH, irrespective of the cause (CRS grade 4 algorithm should be followed). IL-1 
blockade with anakinra is suggested as second line treatment or in case of rapidly 
progressing clinical course. Siltuximab might be considered as well as second line 
therapy. The use of cyclosporin, cyclophosphamide, etoposide and/or intrathecal 
methotrexate is not generally indicated in patients who develop MAS/HLH after CAR T 
therapy, but may have to be employed in refractory cases, when prolonged high-dose 
steroid treatment combined with cytokine blockers have previously failed. Newer 
emerging treatments might also be considered (although their value has not yet clearly 
been demonstrated), including lenzilumab (anti-GMCSF antibody) (Sterner, 2019) and 
emapalumab (anti-IFNγ antibody), the latter having been recently approved by FDA for 
the treatment of adult and pediatric patients with primary HLH with refractory, recurrent 
or progressive disease or intolerance to conventional HLH therapy (Benedetti, 2019). 
Platelet transfusions, fresh frozen plasma and/or activated factor VIII might be needed for 
patients with life-threatening acute bleeding. Growth factors such as granulocyte colony 
stimulating factor might be used for severe neutropenia.
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3.
NEUROLOGIC TOXICITIES 
CAR T cell therapy is associated with unique neurologic toxicities. Neurologic symptoms may 
include altered mental status, aphasia, altered level of consciousness, and seizures or seizure-like 
activity. With JCAR017, to date, the start of neurologic symptoms has been noted between 3 to 
23 days (median 10 days) (Abramson, 2017) after CAR T cell infusion and in severe cases may 
require admission to the intensive care unit (ICU) for frequent monitoring, respiratory support, or 
intubation for airway protection. The symptoms are variable and generally occur as CRS is 
resolving or after CRS resolution or can occur in the absence of CRS.
3.1.
Pathophysiology of Neurologic Toxicities
The pathogenesis of neurotoxicity is poorly defined. Analysis of a subset of subjects treated with 
JCAR017 (study 017001 - TRANSCEND NHL001) with NHL who have high baseline tumor 
burden (measured by the sum of product of the perpendicular diameters or high serum LDH 
[≥500 U/L] prior to the start of lymphodepletion) also have a higher risk for developing 
neurotoxicity (Siddiqi, 2017). In addition, severe neurotoxicity has also been reported in subjects 
with B-ALL and higher disease burden at the time of CD19 directed CAR T cell infusion (Gust, 
2017; Park, 2017).
Recent experimental models point to an important role of IL-1 in the initiation of inflammatory 
changes that lead to neurotoxicity (Norelli, 2018; Giavridis, 2018). Peak levels of IL-6, IFN-γ, 
ferritin, and CRP are significantly higher in subjects who develop any grade or Grade 3 or higher 
neurotoxicity (Heipel, 2017; Turtle, 2016a). Protein levels in the cerebrospinal fluid (CSF) are 
usually elevated in patients with neurotoxicity, compared with baseline measurements, 
suggesting disruption of the blood-brain barrier. Other organ dysfunction (hepatic and renal), as 
well as hypoxemia, and infection, might also contribute to the encephalopathy (Neelapu, 2018). 
In another study, it has been reported that evidence for cytokine-mediated endothelial activation 
causes coagulopathy, capillary leak, and blood-brain barrier disruption allowing transit of high 
concentrations of systemic cytokines into the CSF (Gust, 2017).
3.2.
Clinical Management of Neurologic Toxicities
The optimal management of CAR T cell-induced neurotoxicity is unknown at this time. These 
management guidelines represent the current state of knowledge and additional information will 
be provided to Investigators as it becomes available. Medical Monitor should be contacted 
immediately as soon as neurological symptoms occur. Management should follow the guidelines 
provided below and may include additional measures as per institutional or standard clinical 
practice, and as determined by the Investigator or treating physician and/or consulting 
neurologist. A thorough neurologic evaluation should be pursued and additional evaluations, 
including electroencephalogram (EEG), magnetic resonance imaging (MRI) or computer 
tomography (CT) scan of the brain and diagnostic lumbar puncture and frequent monitoring of 
cognitive function (eg, mini mental status exams or handwriting tests) should be considered. 
Treatable causes of neurologic dysfunction, such as infection or hemorrhage should be ruled out. 
Common manifestations of neurotoxicity (eg, confusion, seizure, aphasia), can also be seen with 
infection, electrolyte imbalances, metabolic acidosis, uremia, concomitant medication use (eg, 
narcotics), and other medical conditions. Other causes for such symptoms should be considered.  
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Not all symptoms may be due to CAR T-induced neurotoxicity. For example, headaches are 
common in this population. Headaches alone might suggest the need for imaging but may not need 
to trigger escalating therapy unless there are other findings suggestive of neurotoxicity.
Magnetic resonance imaging and CT scans of the brain are usually negative for any anatomical 
pathology that would account for the neurotoxicity symptoms observed in subjects treated with 
CAR T cell therapy, although rare cases of reversible T2/fluid attenuated inversion recovery 
(FLAIR) MRI hyperintensity involving the thalami, dorsal pons, and medulla, and cerebral 
edema have been reported (Neelapu, 2018).
For subjects who have neurologic toxicity in the presence of CRS, the CRS should be managed 
following the guidelines provided in Figure 4.
Neurotoxicity should be graded per CTCAE v4.03 and managed following the guidelines 
provided in Figure 5. For concurrent CRS and neurotoxicity, the most aggressive intervention 
recommended by either guideline should be employed (if the recommendations for steroid doses 
differ, use the highest dose and/or frequency). For subjects with Grade 4 neurotoxicity with 
cerebral edema, high-dose corticosteroids, hyperventilation and hyperosmolar therapy have been 
recommended (Neelapu, 2018).
Note: Tocilizumab is not recommended for the treatment of neurotoxicity related to CAR T cell 
therapy, unless CRS or MAS/HLH is also present. Results from 2 studies, one of preemptive use 
of tocilizumab shortly after anti-CD19 CAR T cell therapy in relapsed/refractory NHL 
subjects (Locke, 2017), and the other mandatory use of tocilizumab at first fever [> 38.5°C] in 
pediatric ALL patients treated with anti-CD19 CAR T cells (Gardner, 2016), demonstrated that 
early tocilizumab use either increased overall neurotoxicity and Grade ≥3 neurotoxicity rates 
(85% versus 62% overall; 35% versus 26% Grade ≥3) or provided no improvement in 
neurotoxicity rates, respectively.  These findings support the hypothesis that tocilizumab does 
not improve and may worsen isolated neurotoxicity (Locke, 2017).  
Neurotoxicity management guidelines are provided in Figure 5. For pediatric studies, please refer 
to the package insert for the appropriate pediatric dosing for treatments outlined in Figure 5.
If neurotoxicity occurs, anti-seizure prophylaxis should be initiated, and dexamethasone should 
be used as per the NT algorithm in Figure 5. Interventions are guided by timing of preceding 
fever, if any. Early onset of fever within 3 days, particularly if high (> 39°C) (Gust, 2017), will 
trigger shorter intervals between dexamethasone administrations. If no improvement to the 
highest dose of dexamethasone 0.4 mg/kg q6, consider the use of methylprednisolone 2 mg/kg 
loading dose followed by 1 mg/kg q6 per day.
Closely monitor for rapid neurological deterioration, especially if neurotoxicity of Grade 0 or 
Grade 1 is shifting to obtundation within a few hours. In such a situation, high clinical suspicion 
of cerebral edema (CE) is warranted independently of a CT/MRI confirmed diagnosis. The 
subject should immediately be transferred to the ICU and the below recommended measures 
should be instituted (see also Figure 6), after consulting with the Celgene Medical Monitor as 
soon as possible: 
4. Maximal medical support should be given, such as anti-seizure medications, 
mannitol/hypertonic fluids and sedation. 
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5. Appropriate diagnostic measures should be performed as quickly as possible, including 
intracranial pressure (ICP) measurement (neurosurgical consult), lumbar puncture if 
feasible and safe (for cytology, culture, pharmacokinetics [PK] and cytokines), serum PK 
and cytokines, MRI and EEG.
6. Give methylprednisolone IV 20 mg/kg x 1
7. If CRS/MAS present: give anti-cytokine therapy* 
If after 24 hours there is continued clinical suspicion of CE or once CE is documented:
1. Maximal medical support should be continued, including intubation plus 
hyperventilation.
2. Continue methylprednisolone 20-30 mg/kg IV qd and anti-cytokine therapy** until 
improvement, then taper methylprednisolone slowly over 1 week to avoid rebound 
neurotoxicity. 
3. Consider cyclophosphamide 1.5 g/m2 IV as single administration.
*Anakinra 2 mg/kg SQ q8. Also, consider IL-6 blockade with siltuximab 11 mg/kg IV qd. Tocilizumab should NOT 
be used.
**Anakinra higher dosing may be necessary if no response and according to evolution and severity of the clinical 
picture: upon discussion with the Medical Monitor anakinra can be increased up to 10 mg/kg IV or SQ q6. Anakinra 
should be maintained until clear improvement, and, after initiating tapering methylprednisolone, should be 
administered at a standard dose of 2 mg/kg/day SQ and stopped after discontinuation of methylprednisolone. Please 
consider that prolonged use of anakinra at high dosage may increase the risk of concomitant infections.
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Figure 5:
Neurotoxicity Treatment Algorithm
Abbreviations: CAR = chimeric antigen receptor; CE= cerebral edema; CRS = cytokine release syndrome; CT = computed tomography; EEG = 
electroencephalogram; ICP = intracranial pressure; ICU = intensive care unit; IV = intravenous; LP = lumbar puncture; MRI = magnetic resonance imaging; NT 
= neurotoxicity; PK = pharmacokinetics; q = every.
NOTE:
1. In pediatric subjects, the recommended dexamethasone dosing is as follows: 10 mg adult equivalent for pediatrics: 0.2 mg/kg up to 50 kg, then flat 10 
mg thereafter; 20 mg adult equivalent for pediatrics: 0.4 mg/kg up to 50 kg, then flat 20 mg thereafter.
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Figure 6:
Cerebral Edema Management Guidelines 
Abbreviations: CE = cerebral edema; EEG = electroencephalogram; ICP = intracranial pressure; ICU = intensive care unit; IV = intravenous; LP = lumbar 
puncture; MRI = magnetic resonance imaging; PK = pharmacokinetics; qd = every day.
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4.
REFERENCES
Abramson JS, Palomba ML, Gordon LI, Lunning MA, Arnason JE, Wang M, et al. High durable 
CR rates in relapsed/refractory (r/r) aggressive B-NHL treated with the CD19-directed CAR T 
cell product JCAR017 (TRANSCEND NHL 001): defined composition allows for dose-finding 
and definition of pivotal cohort. Blood. 2017 Dec 7;130(1): Abstract No. 581.
Actemra® [Prescribing Information]. South San Francisco, USA: Genentech Inc. Available 
from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125276s092lbl.pdf
Behrens EM, Canna SW, Slade K, et al. Repeated TLR9 stimulation results in macrophage 
activation syndrome-like disease in mice.  J Clin Invest 2011; 121: 2264–77.
Benedetti FD, Brogan P, Grom A, et al. OP0204 Emapalumab, an intrerferon gamma (IFN-Y)-
blocking monoclonal antibody, in patients with macrophage activation syndrome (MAS) 
complicatin systemic juvenile idiopathic arthritis (SJIA). Annals of the Rheumatic Diseases 
2019;78:178.
Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and 
management. Blood. 2016;127(26):3321-30.
Crayne CB, Albeituni S, Nichols KE, Cron RQ.  The Immunology of Macrophage Activation 
Syndrome. Front Immunol. 2019 Feb 1;10:119.
Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al. Efficacy and toxicity 
management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl 
Med. 2014 Feb 19;6(224):224-5.
Frey N. Cytokine release syndrome: Who is at risk and how to treat. Best Pract Res Clin 
Haematol. 2017 Dec;30(4):336-40.
Gardner R, Leger K, Annesley C, Summers C, Rivers, J., Gust J, et al. Decreased Rates of 
Severe CRS seen with early intervention strategies for CD19 CAR-T cell toxicity management. 
Blood. 2016; 128(22): 586. 
Gardner RA, Finney O, Annesley C, Brakke H, Summers C, Leger K, et al. Intent-to-treat 
leukemia remission by CD19 CAR T cells of defined formulation and dose in children and 
young adults. Blood. 2017;129(25):3322-31.
Giavridis T, van der Stegen SJC, Eyquem J, Hamieh M, Piersigilli A, Sadelain M. CAR T cell-
induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. 
Nat Med. 2018 Jun;24(6):731-738.
Gust J, Hay KA, Hanafi LA, Li D, Myerson D, Gonzalez-Cuyar LF, et al. Endothelial activation 
and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 
CAR-T cells. Cancer Discov. 2017 Dec; 7(12):1404-19. 
Hay KA, Hanafi LA, Li D, Gust J, Liles WC, Wurfel MM, et al. Kinetics and biomarkers of 
severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. 
Blood. 2017 Nov 23;130(21):2295-306.
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Heipel M, Smith J, Brown W, Karimi M, Xie B, Li D, et al. Pharmacokinetic, pharmacodynamic 
and blood analytes associated with clinical response and safety in relapsed/refractory aggressive 
B-NHL patients treated with JCAR017. Blood. 2017 Dec 7;130(1): 2835.
Karakike E and Giamarellos-Bourboulis EJ. Macrophage Activation-Like Syndrome: A Distinct 
Entity Leading to Early Death in Sepsis. Front Immunol. 2019 Jan 31;10:55.
Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the 
diagnosis and management of cytokine release syndrome. Blood. 2014 Jul 10;124(2):188-195. 
Erratum in: Blood. 2015;126(8):1048.
Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT 
Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with 
Immune Effector Cells. Biol Blood Marrow Transplant. 2019, Apr;25(4):625-38.
Lehmberg K, Nichols KE, Henter JI, et al. Consensus recommendations for the diagnosis and 
management of hemophagocytic lymphohistiocytosis associated with malignancies. 
Haematologica. 2015 Aug;100(8):997-1004.
Locke FL, Neelapu SS, Bartlett NL, Lekakis LJ, Jabobson CA, Braunschweig I, et al. 
Preliminary results of prophylactic tocilizumab after axicabtagene ciloleucel (axi-cel; KTE-C19) 
treatment for patients with refractory, aggressive non-Hodgkin lymphoma (NHL).  Blood. 2017 
Dec 7;130(1): Abstract 1547.
Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al. Chimeric antigen 
receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. 2018 
Jan;15(1):47-62.
Norelli M, Camisa B, Barbiera G, Falcone L, Purevdorj A, Genua M, et al. Monocyte-derived 
IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to 
CAR T cells. Nat Med. 2018 Jun;24(6):739-748.
Park JH. Managing Cytokine Release Syndrome. Clinical Care Options Oncology [Internet]. 
2017; https://www.clinicaloptions.com/Oncology/Treatment Updates/Managing 
AEs/Modules/Managing_CRS.aspx. 
Ramos-Casals M, Brito-Zerón P, López-Guillermo A, et al. Lancet. Adult haemophagocytic 
syndrome. 2014 Apr 26;383(9927):1503-1516. Erratum in: Lancet. 2014 Apr 
26;383(9927):1464.
Rosalie M. Sterner, Reona Sakemura, et al. GM-CSF inhibition reduces cytokine release 
syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood. 2019 
Feb 14;133(7):697-709.
RoActemra® [Summary of Product Characteristics]. Welwyn Garden City, United Kingdom: 
Roche Products Limited. Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000955/WC500054890.pdf.
Siddiqi T, Abramson JS, Li D, Brown W, Devries T, Dave K, et al. Patient characteristics and 
pre-infusion biomarkers of inflammation correlate with clinical outcomes after treatment with 
the defined composition, CD19-targeted CAR T cell product, JCAR017. Blood. 2017; 130(1): 
Abstract 193.
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Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR–T cells 
of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 
2016;126(6):2123-38.
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APPENDIX G. MODIFIED TOXICITY PROBABILITY INTERVAL DECISION TABLE
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Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
UserName: 
Title:  
Date: Monday, 16 September 2019, 01:23 PM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
 ================================================
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JCAR017
Summary of Changes JCAR017-BCM-004
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JCAR017-BCM-004 Amendment 2 FINAL: 10 Sep 2019
SUMMARY OF CHANGES 
AMENDMENT NO. 2.0
A PHASE 1/2, OPEN-LABEL, SINGLE ARM, MULTICOHORT, 
MULTICENTER TRIAL TO EVALUATE THE SAFETY AND 
EFFICACY OF JCAR017 IN PEDIATRIC SUBJECTS WITH 
RELAPSED/REFRACTORY B-ALL AND B-NHL
(TRANSCEND PEDALL)
INVESTIGATIONAL PRODUCT (IP):
JCAR017
PROTOCOL NUMBER:
JCAR017-BCM-004
ORIGINAL DATE:
29 March 2018
AMENDMENT No. 1.0 DATE:
07 January 2019
AMENDMENT No. 2.0 DATE:
10 September 2019
EudraCT NUMBER:
2018-001246-34
IND NUMBER
016506
Contact Information: 
Name:
Title:
Address: 
400 Dexter Ave. North, Suite 1200, Seattle, WA 98109, USA 
Phone:
E-mail:
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or consultant for 
review by you, your staff, and ethics committee/institutional review board.  The 
information contained in this document is regarded as confidential and, except to the 
extent necessary to obtain informed consent, may not be disclosed to another party unless 
such disclosure is required by law or regulations.  Persons to whom the information is 
disclosed must be informed that the information is confidential and may not be further 
disclosed by them.
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CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this summary of changes and find its 
content to be acceptable.
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Summary of Changes JCAR017-BCM-004
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1.
JUSTIFICATION FOR AMENDMENT
A global protocol Amendment of JCAR017-BCM-004 was prepared primarily to address: 

Commitments made following the initial clinical trial authorization (CTA) review by 
national competent authorities in Europe. 

Revisions made to the Phase 1 study design

Additional details and updates regarding objectives, endpoints, study populations, sample 
size justification and statistical analyses
Significant changes included in this amendment are summarized below:

Revised Phase 1b trial design to Phase 1 dose finding with new starting dose
SCRI-CAR19v1, a chimeric antigen receptor (CAR) T cell product that is similar to 
JCAR017, has been well tolerated at doses from 0.5 x 106 to 1 x 106 CAR+ T cells/kg in 
pediatric subjects with B-cell acute lymphoblastic leukemia (B-ALL) (PLAT-02).  While the 
PLAT-02 trial demonstrated encouraging clinical activity with an overall manageable 
toxicity profile in pediatric B-ALL, it should be noted that manufacturing process changes 
were needed to standardize JCAR017 product consistency and process robustness are 
necessary to support the conduct of the trial at multiple clinical sites with a global 
manufacturing process. 
An adverse event (Grade 4 neurotoxicity) observed in the first pediatric subject with B-ALL 
dosed in JCAR017-BCM-004 prompted Celgene to re-evaluate the dosing strategy.  Analysis 
of the JCAR017 manufactured product characteristics showed very active CAR T+ cells as a 
result of the necessary process manufacturing modifications, suggesting that a lower safe 
starting dose should be identified.  Trials using a defined composition product autologous 
CD8+CAR+ and CD4+CAR+ T cells that express a CD19-specific CAR such as JCAR014 
(Turtle, 2016) and SCRI-CAR19v1 (Gardner, 2017) suggests that a 10-fold dose reduction 
significantly reduced toxicity while preserving efficacy and maintaining a positive 
risk/benefit. 
Based on these considerations, an initial Phase 1 dose finding/escalation with a 10-fold dose 
reduction to starting dose of 0.05×106 CAR T cells/kg will be pursued.  If this dose is 
confirmed to be safe and tolerable, additional subjects will be enrolled at higher dose(s) up to 
0.75 x106 CAR+ T cells/kg utilizing an mTPI-2 algorithm with the aim to identify the 
Recommend Phase 2 Dose (RP2D).  Additional changes that are designed to assure safe 
administration of JCAR017 in the pediatric B-ALL setting are increased frequency of 
cytokine and PK determinations (to allow comprehensive subject data assessment during 
dose escalation) and modification of the toxicity management algorithm incorporating the 
learnings from diagnosis and management of the first subject dosed in the study.
Revised Sections: Title Page; Protocol Summary; Section 1.3.2.1, Phase 1; Section 1.3.3.1
Rational for JCAR017 Dose; Section 3.1.1, Study Design (Phase 1); Figure 1, Overall Study 
Design; Section 4.1, Number of Subjects; Section 7.2.4, JCAR017 Administration; Section 
7.2.5.1, JCAR017 Dose Levels and Schedule (Phase 1); Section 7.2.5.1.1, mTPI-2 Dose 
Escalation Decision Pathway (Dose Level 1); Section 7.2.5.1.2, Intra-Patient Dose 
Escalation; Section 9.1.1, Statistical Considerations Overview (Phase 1); Section 9.2.3, Dose-
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limiting Toxicity Analysis Population; Section 9.3.1, Sample Size and Power Considerations 
(Phase 1); Section 9.7.1.1, Recommended Phase 2 Dose; Appendix G, Modified Toxicity 
Probability Interval Decision Table. 

Best overall response (BOR) was added as a secondary endpoint for B-cell non-Hodgkin 
lymphoma (B-NHL) subjects
To further support the secondary objective to evaluate the efficacy of JCAR017 in B-NHL 
subjects, response assessments were added at Months 3, 6, 9 and as clinically indicated until 
End of Study (EOS). 
Revised Sections: Protocol Summary; Section 2, Table 1 (Study Objectives); Section 2, 
Table 2 (Study Endpoints); Section 5, Table 3; Section 6.10.2, Non-Hodgkin Lymphoma (B-
NHL); Section 9.6.2.8, Best Overall Response Rate.

Eligibility Criteria
Updated lower weight limit to 6 kg for all JCAR017 dose levels 
Revised Sections: Section 4.2, Inclusion Criteria #1
Clarification of the therapeutic setting of minimal residual disease (MRD+) B-ALL, 
defined as:

“< 5% lymphoblasts by morphology with

MRD detected by a validated assay at a frequency of 1 x10-4 or greater in BM cells. 
Subjects eligible for enrollment in Cohort 2 are those with MRD positive morphologic 
CR2 after re-induction when these subjects had previously experienced an early 
relapse (< 36 months) after first-line chemotherapy. Subjects who are in MRD+ 
morphologic CR3 and later, regardless of time to relapse in earlier lines, are also 
eligible.”
Revised Sections: Section 4.2, Inclusion Criteria #7 

A note was added for selection of subjects in Cohort 3 (pediatric relapsed/refractory 
[r/r] B-NHL) with secondary central nervous system (CNS) involvement
“Note: B-NHL subjects with secondary CNS lymphoma involvement are eligible however 
subject selection must consider clinical risk factors for severe neurological AEs and 
alternative treatment options. Subjects should only be enrolled if the Investigator considers 
the potential benefit outweighs the risk for the subject.”
Revised Sections: Section 3.1.2, Study Design (Phase 2); Section 4.2, Inclusion Criteria #7 

Updated Inclusion Criteria #11, #12 and #13 to align with the summary of product 
characteristics (SMPC) and US package insert (USPI) pregnancy guidance for 
cyclophosphamide. In addition, eliminated the exemption from using contraception, 
and abstaining from breastfeeding, based on testing for absence of residual JCAR017 
CAR T cell persistence. 
There is no exposure data to provide a recommendation concerning duration of contraception 
following treatment with JCAR017. The JCAR017 program is excluding pregnant subjects 
from participation and is mandating highly effective contraception to be used. So far, no 
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Summary of Changes JCAR017-BCM-004
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pregnancy occurred in the JCAR017 clinical development program. No animal studies have 
been conducted with JCAR017 to assess whether it can cause fetal harm when administered 
to a pregnant woman. It is not known whether JCAR017 has the potential to be transferred to 
the fetus via the placenta and could cause fetal toxicity, including B-cell lymphocytopenia. 
As the risk for the becoming mother and the fetus/newborn is unknown at this time, and a 
negative qPCR test does not reliably predict complete disappearance of CAR T cells in the 
body, it cannot be used to guide duration of contraception. Therefore, the requirement for 
two subsequent negative qPCR test was removed. 
Revised Sections: Section 4.2, Inclusion Criteria #11, #12 and #13; Section 6.1.4, Pre-
Treatment Evaluation; Section 6.2.2, Post-Treatment Period; Section 10.4, Pregnancy
Subjects must be clinically stable prior to receiving lymphodepleting (LD)
chemotherapy and JCAR017 infusion
To improve subject safety based on observations in other JCAR017 studies, treating 
physicians must evaluate a subject’s medical condition to assess recovery from prior 
toxicities and exclude significant worsening in clinical status when compared to initial 
eligibility criteria at time of LD chemotherapy and of JCAR017 infusion.
In addition, clarified that in the absence of infection, isolated aspartate aminotransferase 
(AST) and/or alanine aminotransferase (ALT) elevation that can be linked temporally to 
administration of medication (eg, fungal prophylaxis or bridging chemotherapy) may not 
preclude treatment of subjects (LD chemotherapy and infusion of JCAR017) after discussion 
with Celgene’s Medical Monitor. 
Revised Sections: Section 6.2.1.1, Criteria for Treatment

Added history or presence of cerebral edema to the list of exclusionary CNS pathologies
Revised Sections: Section 4.3, Exclusion Criteria #14.

Added existence of CD19 negative clone as an exclusionary criterion
Revised Sections: Section 4.3, Exclusion Criteria #19

Added safety monitoring boundaries 
Safety monitoring boundaries that will be used to establish a Bayesian framework (ie, Thall 
and Simon stopping boundaries) have been added to help detect safety signals that may occur 
in the study.  
Revised Sections: Protocol Summary; Section 3.3, Safety Monitoring Boundaries
The amendment also includes several other minor clarifications, changes and corrections:

Revised protocol throughout to align with Celgene protocol template

Revised protocol summary to align with protocol title page

“CD4+” and “CD8+” were replaced with “CD4+CAR+” and “CD8+CAR+”, respectively

Clarified throughout protocol that subjects will be followed “for 2 years” (previously “up 
to 2 years”) after the JCAR017 infusion, unless the subject it lost to follow-up and will 
then enter into a separate long-term follow up (LTFU) study
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Summary of Changes JCAR017-BCM-004
Celgene Corporation
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
Updated length of study enrollment from 
 to 
 months (Protocol Summary) 

Clarified that dose finding data from B-ALL subjects who have become MRD+ or MRD 
negative upon restaging prior to initiation of LD chemotherapy will be evaluable for the 
dose-limiting toxicity (DLT) analysis and be included in the identification of the RP2D in 
the Phase 1 (Protocol Summary, Section 1.3.2.1, Section 3.1.1, Section 9.2.3)

Clarified that the Safety Review Committee (SRC) in Phase 1 will recommend a Phase 2 
dose based on an integrated assessment of the safety, pharmacokinetics (PK) data and 
preliminary efficacy information from at least 10 pediatric subjects treated at the RP2D. 
Analysis of the JCAR017 manufactured product may also be considered (Protocol 
Summary, Section 3.1.1, Section 7.2.5.1, Section 9.1.1, Section 9.3.1, Section 9.7.1.1)

Clarified JCAR017 treatment gating of subjects in Phase 1 and 2 (Protocol Summary, 
Section 1.3.2, Section 3.1.3)

Clarified that the 10 pediatric subjects treated at the RP2D in Phase 1 will be included in, 
and form part of the sample size in Phase 2 (Cohort 1 and 2). The protocol therefore
intends to treat 81 primary endpoint evaluable pediatric subjects in Phase 2, if warranted 
by the evaluation of results at the completion of the first stage of the study in each cohort
(Protocol Summary, Section 3.1.2, Section 9.3.2)

Clarified that Celgene may elect to explore the identified RP2D in up to 20 additional B-
ALL subjects between 18 and 25 years of age in an optional cohort in Phase 2, if it is 
determined that the risk-benefit profile is such that exploration is warranted after 
consultation with the SRC (Protocol Summary, Section 1.3.2.2, Section 3.1.2) 

Part A (leukapheresis and JCAR017 product generation) and Part B (Treatment and Post 
Treatment Period), have been renamed to “Pre-treatment Period” and “Treatment and 
Post-treatment Follow-up Period”, respectively for clarity (change in terminology only)
(Protocol Summary, Section 1.3.1, Table 2, Section 3.1.3, Section 3.4, Section 3.5 , Table 
of Events, Section 6.2, Section 6.2.2, Section 6.8, Section 8.2, Section 9.5, Section 
9.7.2.2)

Clarified that B-NHL subjects > 18 years of age will not be eligible for this protocol
(Protocol Summary)

Clarified JCAR017 dosing will be capped at 100 kg for all dose levels (Protocol 
Summary, Section 1.3.3.1, Section 7.2.5.1)

Clarified subjects, 18 to 25 years of age, will receive JCAR017 at the RP2D to be studied
(previously a flat dose equivalent to 100 kg) (Protocol Summary, Section 1.3.3.1, 
Section 3.1.2, Section 7.2.5.2, Section 9.1.2, Section 9.3.2)

Adverse Events of Special Interest (AESIs) were clarified and hypogammaglobulinemia, 
prolonged cytopenias and surveillance for second primary malignancies were added 
(Protocol Summary, Section 10.10)

Updated the National Comprehensive Cancer Network (NCCN) response criteria 
guidelines for pediatric B-ALL to current version V1.2020 (Protocol Summary, Section 
6.10.1, Appendix B) 
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JCAR017
Summary of Changes JCAR017-BCM-004
Celgene Corporation
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7
JCAR017-BCM-004 Amendment 2 FINAL: 10 Sep 2019

Incorporated an enrollment dropout rate of 18% into the study sample size justification; 
clarified that a total of 124 pediatric subjects may be enrolled to ensure that 
approximately up to 101 primary endpoint evaluable pediatric subjects (up to 30 subjects
in Phase 1 and up to 71 additional subjects in Phase 2) are treated with JCAR017 
(Protocol Summary, Section 3.1, Section 9.3)

Updated the method to be used to determine the presence of the viral vector from 
quantitative polymerase chain reaction (qPCR) to droplet digital polymerase chain 
reaction (ddPCR) (Section 1.3.4, Section 6.11, Section 6.11.1)

Clarified that JCAR017 pharmacokinetics will be assessed by ddPCR for secondary 
endpoint analysis 
 to 
characterize the expansion and persistence of JCAR017 CAR T-cell subsets (Table 2)

Added a one-time retreatment with intra-patient dose-escalation for pediatric subjects at 
Dose Level 1 (DL1) who have not experienced severe toxicity and have no response on 
Day 28 after JCAR017 infusion (Section 1.3.3.1, Section 7.2.5.1.2)

Clarification on the monitoring of vital signs (Table 3, Section 6.2.1.3, Section 7.2.4).

Clarified that subject B-ALL enrollment in Phase 2 will be prioritized to Cohort 1 (r/r B-
ALL) (Section 3.1.2) 

Added reference to Data Safety Monitoring Board (DSMB) and updated the frequency of 
DSMB meetings to occur approximately twice a year (from quarterly) throughout the trial 
and as needed to address any safety issues that may arise (Section 9.9.3)

Clarified that the Karnofsky score will be used for subjects > 16 years of age and Lansky 
score will be used for subjects < 16 years of age (Section 6.1.2, Section 6.2.1.2, Section 
6.2.1.3, Section 6.1.4, Section 6.2.1.5, Section 6.2.1.7, Section 6.2.2, Section 6.3, and 
Section 6.9.7)

Updated figures for Overall Study Design and Study Schematic (Figure 1 and Figure 2) 

Clarified that if the maximum serum creatinine based on age/gender for inclusion is not 
met, subjects with a radioisotope glomerular filtration rate (GFR) > 70 mL/min/1.73 m2
are eligible (Section 4.2)

Removed the requirement of two consecutive negative tests confirming absence of 
JCAR017 T cells (Section 4.2) 

Updated the definition of postmenopausal when determining childbearing potential and 
separated out highly effective and additional effective methods of contraception (Section 
4.2, Table 3)

Examples of low dose chemotherapy and oral anticancer agents were removed (Section 
4.3, Section 6.1.3)

Revised and clarified exclusion criteria of deep vein thrombosis (DVT) or pulmonary 
embolism (PE) within 3 months of leukapheresis (Section 4.3) 

Added timepoints at leukapheresis and pre-treatment evaluation for Medical History to 
align with adverse event (AE) reporting requirements (Table 3)
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EDMS Doc. Number: 24103106 - 23283120
JCAR017
Summary of Changes JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
8
JCAR017-BCM-004 Amendment 2 FINAL: 10 Sep 2019

Removed requirement for subjects to perform pulmonary function test (FEV1) (Table 3, 
Section 6.1.1)

Clarified all evaluations, research sampling and laboratory assessments must be done 
prior to administration of LD chemotherapy or JCAR017 (Table 3)

Clarified that the infectious disease marker blood sample (viral serology) performed at 
the leukapheresis visit is applicable to European sites only (Table 3)

The Screening Period was updated to ”up to 14 days” as all steps can be completed 
during this time, and for consistency with other JCAR017 studies (Table 3, Section 6.1.1)

Extended time windows for assessments performed on Day 28 and Day 56 (Table 3)  

Removed urinalysis assessments (Table 3, Section 6.1.1, Section 6.2.1.3, Appendix D)

Added research sampling timepoints for peripheral blood for JCAR017 PK 
 
 at LD chemotherapy visits, Day 1, 2, 4, 10 and 21 to support the Phase 1 dose 
finding (Table 3, Section 6.2.1.2, Section 6.2.1.3, Section 6.2.1.4, Section 6.2.1.6, Section 
6.2.1.7)
 
 
 

Clarified cerebrospinal fluid (CSF) assessment at screening are for subjects with 
suspected or confirmed CNS involvement; and subsequent assessments are only for 
subjects with confirmed CNS involvement. In addition, clarified CNS imaging should 
only be performed as clinically indicated. (Table 3, Section 6.1.4, Section 6.2.1.7, Section 
6.2.2, Section 6.9.6)

Clarified CSF assessments (post JCAR017 infusion) are not required for subjects in 
CR/CRi following JCAR017 administration, unless suspicion of CNS relapse (Table 3, 
Section 6.9.6)

Added classification of CNS status, definition of CNS remission and CNS relapse 
(Section 6.9.6) 

Clarified that B-ALL subjects will be retrospectively reassigned to the appropriate cohort 
should their pre-LD chemotherapy disease status show a change from screening (Table 3, 
Section 6.1.4, Section 6.10.1)

Added where applicable, institutional decision boards (eg, multidisciplinary tumor 
boards, Réunion de concertation pluridisciplinaire [RCP]) should be involved for subject 
selection (Section 6.1.1)

Clarified donor chimerism and human leukocyte antigen (HLA) typing is not required to 
be repeated if results are available and performed within 3 months prior to screening 
(Table 3, Section 6.1.1)
Approved
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EDMS Doc. Number: 24103106 - 23283120
JCAR017
Summary of Changes JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
9
JCAR017-BCM-004 Amendment 2 FINAL: 10 Sep 2019
 
 
 

Clarified MRD will be assessed by a validated assay in bone marrow (BM) samples at a 
central “analytical” laboratory (Table 3, Section 6.1.1, Section 6.1.4, Section 6.10.1.1)

Updated the name of the “
collection manual” to the “MNC collection manual”
(Table 3, Section 6.1.2)

Clarified that hematology at the leukapheresis visit includes a complete blood count 
(CBC) with differential within 24 hours prior to leukapheresis and must include absolute 
lymphocyte count (ALC) (Section 6.1.2)

Added the washout periods prior to leukapheresis and prior to LD chemotherapy table 
(Table 4)

Clarified anticancer treatment refers to “bridging chemotherapy” for disease control 
while JCAR017 is being manufactured (Protocol Summary, Section 3.1. 3, Section 6.1.3)

Clarified subjects must continue to have confirmed disease, including measurable disease 
by computed tomography/magnetic resonance imaging (CT/MRI) for B-NHL subjects 
(Section 6.1.3)

Clarified that all pretreatment evaluations must be performed within 7 days prior to LD 
chemotherapy regardless of whether the subject has had intervening anticancer therapy, 
unless otherwise noted (Section 6.1.4)

For B-NHL subjects who did not receive intervening anticancer therapy, the time frame 
was updated from 6 weeks to 3 weeks prior to the start of LD chemotherapy for CT/MRI 
scans to be repeated at the Pre-treatment visit (Section 6.1.4)  

Clarified that subjects who demonstrate morphological remission and who are MRD 
negative upon restaging prior to initiation of LD chemotherapy will still be treated and 
followed on study but may be replaced for efficacy analysis (Section 6.1.4, Section 
6.10.1.1, Section 9.2.4, Section 9.6.2.3)

Clarified a delay of LD chemotherapy of more than 14 days requires discussion with 
Celgene and may require rescreening (Section 6.2.1.2)

Clarified assessment of height is only done on first day of LD chemotherapy (Section 
6.2.1.2)

Added criteria subject must meet following JCAR017 infusion and prior to discharge 
from the hospital.  In addition, subjects who do not have adequate social support (a full-
time caregiver) outside of the hospital or do not have reliable transportation to the clinic 
for scheduled evaluations or emergencies post-therapy should be considered for 
hospitalization for the first 30 days (previously 14 days) following JCAR017 infusion. 
(Section 6.2.1.3)
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EDMS Doc. Number: 24103106 - 23283120
JCAR017
Summary of Changes JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
10
JCAR017-BCM-004 Amendment 2 FINAL: 10 Sep 2019

Clarified response evaluation is done be local Investigator review and Independent 
Review Committee (IRC) (Section 6.2.1.7, Section 6.2.2) 

Added clarification that subjects who receive hematopoietic stem cell transplantation 
(HSCT) post-JCAR017 (but no other subsequent anticancer treatment) should continue to 
undergo response/efficacy evaluations, unless they have demonstrated relapse/PD prior to 
HSCT (Section 6.2.2)

Added 
 as an unscheduled assessment in the event a subject develops a 
second primary malignancy (Section 6.3, 
 Section 6.11.1)

Added assessment of second primary malignancies to Post-Treatment Follow-up Period 
and Post-study follow up in LTFU protocol (Protocol Summary, Section 1.3.1) 

Added the “Second Primary Malignancies Follow-up Period” and language that if a 
subject develops a second primary malignancy, Celgene will request a tumor sample, BM 
and blood samples (Section 6.6, 
 and Section 6.11.1)

Clarified that disease status will occur for at least 5 years in the separate LTFU protocol.  
In addition, details on all subsequent anti-neoplastic treatments for at least 5 years must 
be documented (Section 6.8)

Added additional guidance for physical examination assessments (Section 6.9.1) 

Added literature reference to assess Tanner Staging and clarified that once Tanner Stage 
5 is met, subsequent Tanner assessments do not need to be performed (Section 6.9.2) 

Combined pulse oximetry under vital signs (Section 6.9.3)
 

Added guidance for efficacy evaluation and required response assessments to be 
performed for B-ALL and B-NHL subjects (Section 6.10)

Defined MRD relapse (Section 6.10.1.1)

Clarified designation of response for the primary and “select secondary based” endpoints 
will be based on evaluations made by the IRC (Section 6.10.3) 

Clarified that results for IRC will not be provided to clinical sites (Section 6.10.3)

Clarified that any observation of clonal outgrowth (clonal dominance), or monoclonality, 
will be reported as a serious adverse event (SAE) within 24 hours (Section 6.11.1)

Clarifications made for 
 exploratory analysis (Table 1, Table 
2, 
)

“Subject Reported Outcomes” or “Health-related Quality of Life (HRQoL)” were both 
renamed to “Patient Reported Outcomes” for clarity (change in terminology only) (Table 
1, Table 2, Table 3, Section 6.13)

Clarified the age appropriate versions and provided guidance for administration of the 
pediatric quality of life (PedsQL) Patient Reported Outcomes (PRO) questionnaires; 
Parent/Caregiver Reported Outcomes was added to Table of Events; sample copies of all 
Approved
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EDMS Doc. Number: 24103106 - 23283120
JCAR017
Summary of Changes JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
11
JCAR017-BCM-004 Amendment 2 FINAL: 10 Sep 2019
PedsQL questionnaires were removed in the appendices (Table 3, Table 5, Section 6.13, 
Appendix G-J)

Clarified JCAR017 paracetamol/acetaminophen premedication (Section 7.2.2, Section 
8.3) 

Clarified that in case a subject cannot tolerate diphenhydramine hydrochloride (or it’s not 
commercially available), an equivalent antihistamine may be substituted for JCAR017 
premedication (Section 7.2.2, Section 8.3)
 
 
 

Updated list of medications that should be reported during inpatient and intensive care 
unit (ICU) stays (Section 8.1)

Information regarding the reporting period and other details related to concomitant 
medications was moved to table format (Section 8.1)

Clarified the definition of therapeutic doses of corticosteroids for pediatric subjects 
defined as > 0.4 mg/kg (maximum 20 mg/day prednisone) or equivalent (Section 4.3, 
Table 4, Section 8.2)

Updated list of prohibited medications during treatment and follow-up periods (Section 
8.2).

Added reference to the currently approved cyclophosphamide and fludarabine phosphate 
Summary of Product Characteristics (SmPCs) (Section 8.3)

Language was added for sites to have tocilizumab readily available prior to JCAR017 
administration as required for treatment and management of cytokine release syndrome 
(CRS) (Section 8.3)

Additional risk-group sub-analysis were added (Section 9.1)

Modification of the definition of the Dose-limiting Toxicity Analysis Population (Section 
9.2.3)

Modification of the definition of the Efficacy Analysis Population (Section 9.2.4)

Added the Patient Reported Outcome Analysis Population (Section 9.2.9)

Clarified Phase 1 and Phase 2 primary and secondary endpoints (Protocol Summary, 
Section 9.6.1, Section 9.6.2)

Clarified for the analysis of the HSCT rate, the time of proceeding to HSCT is defined as 
the time of commencing the conditioning regimen as required for HSCT (Section 9.6.2.7)

Clarified the JCAR017 manufacturing feasibility secondary endpoint, defining successful 
and unsuccessful JCAR017 product generation (Section 9.9.1)

Clarified that the SRC will include up to 5 active Investigators (Section 9.9.2)
Approved
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EDMS Doc. Number: 24103106 - 23283120
JCAR017
Summary of Changes JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
12
JCAR017-BCM-004 Amendment 2 FINAL: 10 Sep 2019

Independent Review Committee (previously Section 9.9.4) was moved under Efficacy 
(Section 6.10.3)

Clarified the membership of the Scientific Steering Committee (Section 9.9.4)
 

Information regarding the reporting period and other details related to AE/SAEs was 
moved to table format (Section 10.1)

Added guidance that, if available and adopted as per site standard practice, CRS and NT 
grading according to the American Society for Transplantation and Cellular Therapy 
(ASTCT) Consensus Grading System (Lee, 2019) should also be recorded in the eCRF to 
inform future modifications of the management guidelines (Section 10.6.1)

Revised the management of toxicities associated with JCAR017 for tumor lysis syndrome 
(TLS) and uncontrolled T-cell proliferation (Section 10.6.8, Section 10.6.11)

Added events that are considered sufficient reasons for discontinuing a subject who 
undergoes leukapheresis but does not receive study treatment (ie, Pre-Treatment 
discontinuation) (Section 11.1)

References were updated (Section 17)

Table of abbreviations was updated (Appendix A)

Footnotes added to clarify Cairo-Bishop grading system for TLS (Appendix E)

JCAR017 Management Guidelines for Cytokine Release Syndrome and Neurologic 
Toxicities updated to Version 2.0 (Appendix F)

Misspellings, style and formatting
Approved
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EDMS Doc. Number: 23291009 - 23283120
JCAR017
Summary of Changes JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
1
JCAR017-BCM-004 Amendment 1 Final: 07 Jan 2019
TITLE PAGE
SUMMARY OF CHANGES 
AMENDMENT NO. 1.0
A PHASE 1B/2, OPEN-LABEL, SINGLE ARM, 
MULTICOHORT, MULTICENTER TRIAL TO 
EVALUATE THE SAFETY AND EFFICACY OF 
JCAR017 IN PEDIATRIC SUBJECTS WITH 
RELAPSED/REFRACTORY B-ALL AND B-NHL
INVESTIGATIONAL PRODUCT (IP):
JCAR017
PROTOCOL NUMBER:
JCAR017-BCM-004
ORIGINAL DATE:
29 March 2018
AMENDMENT No. 1.0 DATE:
07January 2019
EudraCT NUMBER:
2018-001246-34
IND NUMBER
016506
Contact Information: 
Name:
Title:
Address: 
400 Dexter Ave. North, Suite 1200, Seattle, WA 98109, USA                
Phone:
E-mail:
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or consultant for review by 
you, your staff, and ethics committee/institutional review board.  The information contained in this 
document is regarded as confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by law or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them.
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EDMS Doc. Number: 23291009 - 23283120
JCAR017
Summary of Changes JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
2
JCAR017-BCM-004 Amendment 1 Final: 07 Jan 2019
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this summary of changes and find its 
content to be acceptable.
Approved
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EDMS Doc. Number: 23291009 - 23283120
JCAR017
Summary of Changes JCAR017-BCM-004
Celgene Corporation
Confidential and Proprietary
3
JCAR017-BCM-004 Amendment 1 Final: 07 Jan 2019
1.
JUSTIFICATION FOR AMENDMENT
Following a death (respiratory failure Grade 5) of a subject on 10 December 2018 in study 
JCAR017-BCM-001, a global Phase 1/2 study of JCAR017 in R/R third-line aggressive B-cell 
lymphoma, the program-wide, Data Safety Monitoring Board (DSMB) was convened on 14 
December 2018 to review safety data on all subjects treated with JCAR017 across all studies 
with a ≥ third-line DLBCL patient population.  
The DSMB members recommended continuation of the JCAR017 trials with modifications. The 
modifications are detailed in an Urgent Safety Measure (USM) to modify the inclusion and 
exclusion criteria. 
Significant changes included in this amendment are summarized below:

B-NHL subjects with vascular tumor invasion will not be eligible 
Following the subject’s death and review of the data, the DSMB recommended exclusion of 
B-NHL subjects with vascular tumor invasion.  The following exclusion criteria was 
therefore added:
“Tumor invasion of venous or arterial vessels (B-NHL subjects only)”
Revised Sections: Section 4.3, Exclusion Criteria #17

Subjects with deep venous thrombosis (DVT) and/or pulmonary embolism (PE) will not 
be eligible 
As additional measure, subjects with deep venous thrombosis (DVT) and/or pulmonary 
embolism (PE) will not be eligible. The following exclusion criteria was therefore added: 
“Deep Venous Thrombosis (DVT)/Pulmonary Embolism (PE) within 3 months of ICF 
signature and/or DVT/PE that requires ongoing therapeutic levels of anti-coagulation.” 
Revised Sections: Section 4.3, Exclusion Criteria #18
The amendment also includes several other minor clarifications and corrections:

Update Celgene Medical Monitor’s contact information 

Misspellings, style and formatting

Added potential risks associated with cytopenias and infections (Section 10.6.1).
Approved
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