Clinical trial NCT03575351
Conditions: Lymphoma, Non-Hodgkin
Keywords: Non-Hodgkin Lymphomas DLBCL Efficacy Safety JCAR017 Liso-cel High-Risk Relapsed Refractory B-cell NHL
Sponsor: Celgene
Start date: 2018-10-23; Completion date: 2023-10-23
Enrollment: 184 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

This is a randomized, open-label, parallel-group, multi-center trial in adult subjects with Relapsed or refractory (R/R) aggressive Non-Hodgkin lymphoma (NHL) to compare safety and efficacy between the standard of care (SOC) strategy versus JCAR017 (also known as lisocabtagene maraleucel or liso-cel). Subjects will be randomized to either receive SOC (Arm A) or to receive JCAR017 (Arm B).

All subjects randomized to Arm A will receive Standard of care (SOC) salvage therapy (R-DHAP, RICE or R-GDP) as per physician's choice before proceeding to High dose chemotherapy (HDCT) and Hematopoietic stem cell transplant (HSCT).

Subjects from Arm A may be allowed to cross over and receive JCAR017 upon confirmation of an EFS event.

Subjects randomized to Arm B will receive Lymphodepleting (LD) chemotherapy followed by JCAR017 infusion.

Detailed description:

Arms: arm 1: Subjects should receive SOC (R-DHAP, R-ICE or R-GDP) followed by HDCT (BEAM) and HSCT. Standard of care regimen will be administered as per investigator decision. arm 2: 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 infusion.
Interventions: intervention 1: Standard of Care intervention 2: JCAR017
Intervention descriptions: intervention 1: Standard of Care intervention 2: JCAR017

Protocol documents:
Prot_SAP_000.pdf: 
Official Title of Study: 
A Global Randomized Multicenter Phase 3 Trial of JCAR017 Compared to Standard of Care in Adult 
Subjects With High-risk, Second-line, Transplant-eligible Relapsed or Refractory Aggressive B-cell 
Non-Hodgkin Lymphomas (TRANSFORM) 
 
NCT Number: NCT03575351 
Document Date (Date in which document was last revised): 09 December 2019 
 
 
 
 


EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
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TITLE PAGE
A GLOBAL RANDOMIZED MULTICENTER PHASE 
3 TRIAL TO COMPARE THE EFFICACY AND 
SAFETY OF JCAR017 TO STANDARD OF CARE IN 
ADULT SUBJECTS WITH HIGH-RISK, 
TRANSPLANT-ELIGIBLE RELAPSED OR 
REFRACTORY AGGRESSIVE B-CELL NON-
HODGKIN LYMPHOMAS (TRANSFORM)
PROTOCOL NUMBER:
JCAR017-BCM-003
DATE FINAL:
07 Mar 2018
DATE AMENDMENT 1.0:
06 Feb 2019
DATE AMENDMENT 2.0:
09 Dec 2019
EudraCT NUMBER:
2018-000929-32
IND NUMBER:
016506
SPONSOR NAME/ ADDRESS:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901, USA
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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MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION
Contact Information – Ex-US sites:
Name:
Title:
Address: Route de Perreux 1, 2017 Boudry, Switzerland
Phone: (Office)
             (Mobile) 
E-mail:
Medical Monitor email: 
Contact Information – US sites:
Name: 
Title: 
Address: 400 Dexter Ave. North, Suite 1200, Seattle, WA 98109, USA
Phone: (Office)
            (Mobile) 
E-mail: 
Medical Monitor email: 
Note: The back-up 24-hour global emergency contact call center at Celgene 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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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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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 for
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.
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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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Protocol JCAR017-BCM-003
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PROTOCOL SUMMARY
Study Title
A global randomized multicenter Phase 3 trial to compare the efficacy and safety of JCAR017 to 
standard of care in adult subjects with high-risk, transplant-eligible relapsed or refractory 
aggressive B-cell non-Hodgkin lymphomas (TRANSFORM).
Indication
Transplant-eligible relapsed or refractory (R/R) aggressive B-cell non-Hodgkin lymphomas
(NHL) in subjects ≥ 18 and ≤ 75 years.
Objectives
Primary Objective:
To compare the efficacy in subjects treated with JCAR017 versus subjects treated according to 
standard of care (SOC) defined as event-free survival (EFS) 
Key Secondary Objectives:
To compare additional parameters of efficacy in subjects treated with JCAR017 versus subjects 
treated according to SOC defined as complete response rate (CRR), progression-free survival 
(PFS), and overall survival (OS)
Secondary Objectives:

To compare other parameters of efficacy, defined as duration of response (DoR), overall 
response rate (ORR), and PFS on next line of treatment (PFS-2)

To compare efficacy rates (EFS, PFS, OS) at 6, 12, 24 and 36 months after randomization

To compare safety defined as type and frequency of adverse events (AEs), serious 
adverse events (SAEs), and laboratory abnormalities  

To compare the safety and efficacy in clinical, histological and molecular subgroups 

To compare health-related quality of life (HRQoL) using global health/QoL, fatigue,
physical and cognitive functioning subscales of the European Organisation for Research 
and Treatment of Cancer – Quality of Life C30 Questionnaire (EORTC QLQ-C30) and 
the Functional Assessment of Cancer Therapy-Lymphoma “Additional concerns” 
subscale (FACT-Lym)

To compare hospital resource utilization (HRU)

To describe the rate of completion of high dose chemotherapy (HDCT) and
hematopoietic stem cell transplant (HSCT)

To assess the response 3 months after HSCT
Study Design
This is a randomized, open-label, parallel-group, multi-center, Phase 3 study to demonstrate the 
efficacy and safety of JCAR017 (also known as lisocabtagene maraleucel or liso-cel) versus 
SOC salvage therapies in subjects with aggressive B-cell NHL (defined as diffuse large B-cell 
lymphoma [DLBCL] not otherwise specified [NOS], de novo or transformed indolent NHL), 
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high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL 
histology (double-hit lymphoma/ triple-hit lymphoma [DHL/THL]), primary mediastinal 
(thymic) large B-cell lymphoma [PMBCL], T cell/histiocyte-rich large B-cell lymphoma
[THRBCL] or follicular lymphoma Grade 3B [FL3B]) who are refractory to front-line 
immunochemotherapy or have relapsed within 12 months and are eligible for HDCT and HSCT.
The time of relapse is calculated from the date of the first disease assessment confirming a 
complete response (CR) obtained with first-line treatment for disease under study, to the date of 
first assessment demonstrating a relapse.
During screening, a tumor biopsy will be collected for central confirmation of diagnosis. 
During screening, all subjects will undergo an unstimulated leukapheresis to enable JCAR017 
product generation. 
Subjects will be randomized to receive either: 

Arm A (SOC): three cycles of SOC salvage therapy. Responding subjects are 
expected to proceed to HDCT and HSCT

Arm B (JCAR017): lymphodepleting (LD) chemotherapy followed by JCAR017
infusion
Subjects in Arm B may receive bridging therapy with a protocol-defined SOC regimen to 
stabilize their disease during JCAR017 manufacturing. Investigational therapies are not allowed.
Subjects will be followed for safety and efficacy for up to 3 years under this protocol. 
If requested by the investigator, subjects in Arm A may be allowed to receive JCAR017 upon 
central confirmation of one of the following criteria:

Failure to achieve CR or PR by 9 weeks post-randomization (after 3 cycles of SOC)

Progression at any time

Need to start a new antineoplastic therapy due to efficacy concerns after 18 weeks 
post-randomization
Subjects who cross over to JCAR017 will be followed in the study for up to 1 year after the 
JCAR017 infusion. All subjects who received JCAR017 will continue to be monitored for long-
term safety and efficacy after exposure to gene-modified T cells under a separate long-term 
follow-up (LTFU) protocol for up to 15 years after JCAR017 infusion, as per competent 
authority guidelines.
The conduct of the study will be overseen by a scientific steering committee (SSC). 
The study will be conducted in compliance with International Council for Harmonisation (ICH) 
Good Clinical Practices (GCPs).
Study Population
Adult subjects with aggressive B-cell NHL (defined as DLBCL NOS [de novo or transformed 
indolent NHL], high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements 
with DLBCL histology (DHL/THL), PMBCL, THRBCL or FL3B according to WHO 2016
classification) who are refractory to front-line immunochemotherapy or have relapsed within 12 
months and are eligible for HDCT and HSCT.
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Length of Study
The study will last approximately 3 years from the time the last subject is randomized.
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, 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 prespecified in the protocol, whichever is the later date.
Study Treatments
1. Arm A: SOC salvage therapy defined as 3 cycles of either:

R-DHAPab(Rituximab 375 mg/m² - Day 1, dexamethasone 40 mg – Days 1 to 4, 
cytarabine 2 x 2000 mg/m² - Day 2, cisplatin 100 mg/m² – Day 1), or

R-ICEab (Rituximab 375 mg/m² - Day 1, ifosfamide 5000 mg/m² - Day 2, 
etoposide 100 mg/m² - Days 1 to 3, carboplatin area under the curve [AUC] 5 
[maximum dose 800 mg]) – Day 2, or

R-GDPab(Rituximab 375 mg/m² - Day 1, dexamethasone 40 mg – Days 1 to 4, 
gemcitabine 1000 mg/m² - Days 1 and 8, cisplatin 75 mg/m² - Day 1)
and followed by high-dose chemotherapy and HSCT in responding subjects:

BEAMa (Carmustine [BCNU] 300 mg/m² - Day 1, etoposide 200 mg/m² - Days 2
to 5, cytarabine 200 mg/m² - Days 2 to 5, melphalan 140 mg/m² - Day 6), and

HSCT
2. Arm B: LD 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 at 
least 2 days later by JCAR017 infusion (100 x 106 chimeric antigen receptor [CAR]+ T 
cells)
Note: Intrathecal (IT) treatment with methotrexate and/or cytarabine is allowed for prophylaxis and for treatment of 
subjects with secondary CNS involvement. For subjects randomized in Arm B, a minimum of 7 days wash-out 
period after IT treatment is required before start of lymphodepleting chemotherapy.
a Selection of the protocol defined SOC regimen, schedule of the regimen, dose adjustment for toxicities and 
premedication as per site standard, local label and investigator’s decision. In Japan, due to unavailability of 
intravenous BCNU, ranimustine (MCNU) will be used at the same dosage and schedule as BCNU.
b Allowable bridging therapy during manufacturing of JCAR017, if needed for disease control.
Treatment options upon EFS event: 

Arm A: subjects will be treated according to physician’s choice. If requested by the 
investigator, subjects may be allowed to receive JCAR017 upon central confirmation 
of one of above mentioned criteria.

Arm B: subjects will be treated according to physician’s choice, which may include 
HDCT followed by HSCT.
Overview of Key Efficacy Assessments
Efficacy will be assessed according to the Celgene “Guidelines for Efficacy Evaluation in PET-
avid Non-Hodgkin Lymphoma” by an independent review committee (IRC) based on 
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radiographic tumor evaluation by positron emission tomography (PET)/computed tomography
(CT) scans. These guidelines are based on “The Lugano Classification” (Cheson, 2014). Disease 
will be assessed using diagnostic quality CT/ magnetic resonance imaging (MRI) scans (chest,
neck, abdomen, and pelvis) and PET scans. Assessment of bone marrow involvement by 
lymphoma will be done by PET scan only; bone marrow aspirates and biopsies will not be 
required for assessment of disease response. 
The IRC will confirm the response to therapy and the time of progressive disease (PD) for each 
subject.
Overview of Key Safety Assessments
Safety will be monitored continuously. Adverse events (AEs) / serious adverse events (SAEs)
and laboratory abnormalities (type, frequency, and severity) will be collected, graded and 
reported according to common terminology criteria for adverse events (CTCAE). 
Adverse events of special interest (AESI) may include but not limited to:

Infusion-related reaction

Cytokine release syndrome (CRS)

Neurological toxicity (NT)

Macrophage activation syndrome (MAS)

Tumor lysis syndrome (TLS)

Prolonged cytopenias

Hypogammaglobulinemia

Infections

Autoimmune disorders

Second primary malignancy (SPM)
The study data will be regularly reviewed by an independent data safety monitoring board 
(DSMB). 
Statistical Methods
Subjects will be randomized at 1:1 ratio into one of the two arms: Arm A (SOC) or Arm B 
(JCAR017). Randomization will be based on a permuted-blocks randomization method, with the 
following stratification factors: 
1. Best overall response to first-line therapy: refractory (defined as stable disease [SD], 
progressive disease [PD], partial response [PR] or complete response [CR] with relapse 
before 3 months) versus relapse (CR with relapse on or after 3 months)
2. Secondary age adjusted International Prognostic Index (sAAIPI): 0 or 1 versus 2 or 3
The primary efficacy endpoint is event-free survival (EFS), defined as the time from
randomization to death from any cause, progressive disease (PD), failure to achieve complete 
response (CR) or partial response (PR) by 9 weeks post-randomization, or start of new 
antineoplastic therapy due to efficacy concerns, whichever occurs first.
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The key secondary efficacy endpoints are:

Complete response rate (CRR), defined as the proportion of subjects achieving a CR from 
randomization up to 3 years post-randomization. Subjects with unknown or missing 
response will be counted as non-responders in the analysis. Any responses after a start of 
a new antineoplastic therapy will not be considered. Responses after cross over will be 
analyzed descriptively;

Progression-free survival (PFS), defined as the time from randomization to PD or death 
from any cause, whichever occurs first;

Overall survival (OS), defined as the time from randomization to death due to any cause.
A first interim analysis will be conducted when approximately 30 evaluable subjects (~15 
subjects per arm and having received their assigned treatment) have their 9 weeks response 
assessment (after 3 cycles of SOC for Arm A and 5 weeks after the JCAR017 infusion) or have 
been confirmed with disease progression prior to this timepoint. The purpose of this interim 
analysis is to stop for futility. The study may be terminated if the CRR in JCAR017 arm is lower 
than the CRR in the SOC arm. No type I error adjustment is implemented for this futility 
analysis.
A second interim analysis will be performed at approximately 60% information time (ie, at 
around 71 EFS events). The purpose of this interim analysis is to demonstrate superiority of 
JCAR017 versus SOC on EFS. The O’Brien-Fleming method will be used for defining the 
efficacy boundaries. The study will continue as planned regardless of the results at this interim 
analysis unless the experimental arm should be inferior to the reference treatment arm.
Subjects treated with SOC have median EFS of 3 months. Subjects receiving experimental 
treatment JCAR017 are expected to have an increase of ~81% in the median EFS (equivalent to a 
hazard ratio [HR] of 0.55) compared to subjects treated with SOC, bringing the median EFS in 
the experimental group to 5.455 months. Given these assumptions, using a log rank test with 
2.5% one-sided significance level, 119 EFS events will provide at least 90% power to reject the 
null hypothesis of HR greater than or equal to 1. Given a peak randomization rate at about 12 
subjects per month, a 20% drop out rate before first response assessment and a yearly dropout
rate of 10% (30% cumulative), a sample size of 182 subjects is expected to be randomized and 
215 subjects to be screened (screen failure rate of 15%).
If the planned subject randomization rate does not appear adequate to accrue the expected 
number of events within the proposed follow-up period or if lower than expected number of 
events are observed, the sample size may be increased (see Section 9).
The primary analysis of EFS will be conducted based on the intention-to-treat (ITT) population 
(defined as all subjects randomized) when 119 EFS events accumulate from both JCAR017 and 
SOC arms. If null hypothesis on primary endpoint is rejected, hypothesis testing on key 
secondary endpoints will be performed hierarchically (CRR, PFS and subsequently on OS). For 
time to event endpoints, Kaplan-Meier (K-M) survival analyses will be performed. Number and 
percent of subjects experiencing event of interest and censored will be provided. Kaplan-Meier 
product limit method will be used to estimate the survivorship function. Event rates at specific 
time points will be estimated from K-M curves. Medians together with 2-sided 95% confidence 
intervals will be computed using a log-log transformation. Hazard ratio and its confidence 
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interval will be estimated using a stratified Cox-proportional hazards (Cox-PH) model using the 
Efron method for handing ties. In case of violation of the proportional hazard assumption,
piecewise Cox regression model will be used. For categorical endpoints, the Cochran-Mantel-
Haenszel (CMH) test with stratification factors as strata will be used for analysis and calculation 
of p-values. The final analysis will be performed after the last subject randomized has either 
reached an event or been followed for 3 years after randomization.
Sample Size calculation was based on EAST 6.3 software (Cytel Inc.).
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TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
TABLE OF CONTENTS..........................................................................................................12
LIST OF TABLES....................................................................................................................20
LIST OF FIGURES ..................................................................................................................21
1.
INTRODUCTION..................................................................................................22
1.1.
Disease Background ...............................................................................................22
1.2.
Compound Background ..........................................................................................25
1.2.1.
CD19 as a Therapeutic Target.................................................................................25
1.2.2.
CD19–Targeted Chimeric Antigen Receptors .........................................................25
1.2.3.
JCAR017 Investigational Drug Product ..................................................................26
1.2.4.
Clinical Experience with JCAR017.........................................................................26
1.3.
Rationale ................................................................................................................27
1.3.1.
Study Rationale and Purpose ..................................................................................27
1.3.2.
Rationale for the Study Design ...............................................................................28
1.3.3.
Rationale for Dose, Schedule and Regimen Selection .............................................29
1.3.4.
Rationale for Choice of Comparator Compounds....................................................29
29
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................32
3.
OVERALL STUDY DESIGN ................................................................................36
3.1.
Study Design ..........................................................................................................36
3.2.
Study Duration for Subjects....................................................................................38
3.3.
End of Trial ............................................................................................................38
4.
STUDY POPULATION.........................................................................................39
4.1.
Number of Subjects ................................................................................................39
4.2.
Inclusion Criteria....................................................................................................39
4.3.
Exclusion Criteria...................................................................................................41
5.
TABLES OF EVENTS...........................................................................................44
6.
PROCEDURES......................................................................................................56
6.1.
Pre-Treatment Period..............................................................................................56
6.1.1.
Screening................................................................................................................56
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6.2.
Treatment Period ....................................................................................................58
6.2.1.
Day 1 - Randomization (+ 3 days) ..........................................................................58
6.2.1.1.
Arm A ....................................................................................................................59
6.2.1.2.
Arm B ....................................................................................................................59
6.2.2.
Days 8 and 15 (± 2 days) ........................................................................................59
6.2.3.
Day 22 (± 7 days) ...................................................................................................60
6.2.3.1.
Arm A ....................................................................................................................60
6.2.3.2.
Arm B ....................................................................................................................60
6.2.4.
Day 29 (± 7 days) ...................................................................................................61
6.2.4.1.
Arm A ....................................................................................................................61
6.2.4.2.
Arm B ....................................................................................................................62
6.2.5.
Day 31 (±1 day), Day 32 (± 1 day), Day 39 (± 1 day) (Arm B) ...............................64
6.2.6.
Day 36 (± 1 day).....................................................................................................65
6.2.7.
Day 43 (± 6 days) ...................................................................................................66
6.2.7.1.
Arm A ....................................................................................................................66
6.2.8.
Day 50 (± 2 days) ...................................................................................................67
6.2.9.
Day 64 (± 6 days) ...................................................................................................67
6.2.10.
Day 71 (± 6 days) ...................................................................................................68
6.2.10.1.
Arm A ....................................................................................................................69
6.2.11.
Day 85 (± 6 days) ...................................................................................................70
6.2.12.
Day 99 (± 7 days) ...................................................................................................71
6.2.13.
Day 106 (± 7 days) (Arm A)...................................................................................71
6.2.14.
Day 126 (± 7 days) .................................................................................................72
6.3.
Post-Treatment Period ............................................................................................73
6.3.1.
Follow-up...............................................................................................................73
6.3.1.1.
Subjects who Have not Received Subsequent Antineoplastic Treatment .................73
6.3.1.2.
Subjects who Have Received Subsequent Antineoplastic Treatment .......................74
6.3.2.
Assessments for Subjects Crossing Over to JCAR017.............................................75
6.3.3.
Unscheduled Evaluations........................................................................................76
6.3.4.
Assessments at Time of Death (Subjects Receiving JCAR017)...............................77
6.3.5.
Early Withdrawal....................................................................................................77
6.3.6.
Second Primary Malignancy Follow-up Period.......................................................77
6.3.7.
Survival Follow-up.................................................................................................77
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6.3.8.
Long-term Follow-up..............................................................................................77
6.4.
Safety Assessments.................................................................................................78
6.4.1.
Physical Examination .............................................................................................78
6.4.2.
Vital Signs..............................................................................................................78
6.4.3.
Pulse Oximetry.......................................................................................................78
6.4.4.
Height and Weight..................................................................................................78
6.4.5.
Routine Neurologic and Mini Mental State Examinations.......................................78
6.4.6.
Cerebrospinal Fluid Assessment .............................................................................78
6.4.7.
Eastern Cooperative Oncology Group Performance Status......................................78
6.4.8.
Multi-gated Acquisition Scan / Echocardiogram.....................................................79
6.4.9.
Electrocardiogram ..................................................................................................79
6.4.10.
Replication-Competent Lentivirus Testing (Subjects receiving JCAR017)..............79
6.4.11.
Viral Vector Sequence Testing (Subjects receiving JCAR017)................................79
6.4.12.
Clinical Laboratory Evaluations..............................................................................80
6.5.
Efficacy Assessment...............................................................................................80
6.5.1.
Pseudoprogression..................................................................................................80
6.6.
Pharmacokinetics....................................................................................................80
6.6.1.
Pharmacokinetics of JCAR017 ...............................................................................80
6.7.
Biomarkers, 
.............................................80
.80
6.7.2.
Exploratory Biomarkers..........................................................................................81
6.7.3.
Additional and Optional Research...........................................................................81
6.7.3.1.
Additional Research ...............................................................................................82
6.7.3.2.
Optional Research ..................................................................................................82
6.8.
Subject Reported Outcomes or Quality of Life or Health Economics ......................82
6.8.1.
EORTC QLQ-C30..................................................................................................82
82
6.8.3.
FACT-Lym.............................................................................................................83
6.8.4.
Hospital Resource Utilization .................................................................................83
7.
DESCRIPTION OF STUDY TREATMENTS........................................................85
7.1.
Description of Investigational Product(s)................................................................85
7.1.1.
JCAR017................................................................................................................85
7.2.
Lymphodepleting Chemotherapy............................................................................85
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7.3.
Reference therapies.................................................................................................85
7.4.
Treatment Administration and Schedule .................................................................85
7.4.1.
Reference Therapies ...............................................................................................85
7.4.2.
Lymphodepleting Chemotherapy............................................................................86
7.4.3.
JCAR017 Premedication.........................................................................................86
7.4.4.
JCAR017 Preparation and Cell Thawing.................................................................87
7.4.5.
JCAR017 Administration........................................................................................87
7.4.6.
Non-Conforming Product .......................................................................................87
7.4.6.1.
Protocol Product Deviation Plan .............................................................................87
7.4.6.2.
Exception Use of Non-conforming Product.............................................................87
7.4.7.
Overdose ................................................................................................................87
7.5.
Method of Treatment Assignment...........................................................................88
7.6.
Packaging and Labeling..........................................................................................88
7.6.1.
Product Tracking ....................................................................................................88
7.6.1.1.
Reference Therapies ...............................................................................................88
7.6.1.2.
Lymphodepleting Chemotherapy............................................................................88
7.6.1.3.
JCAR017................................................................................................................88
7.6.2.
Product Packaging and Labeling.............................................................................88
7.6.2.1.
Lymphodepleting Chemotherapy............................................................................88
7.6.2.2.
Reference Therapies ...............................................................................................88
7.6.2.3.
JCAR017................................................................................................................89
7.6.3.
Cell Product Supply and Storage.............................................................................89
7.7.
Investigational Product Accountability and Disposal ..............................................89
7.7.1.
Accountability Procedures......................................................................................89
7.7.2.
Drug Disposal and Destruction ...............................................................................89
7.8.
Investigational Product Compliance........................................................................89
7.8.1.
Reference Therapies ...............................................................................................89
7.8.2.
Lymphodepleting Chemotherapy............................................................................89
7.8.3.
JCAR017................................................................................................................90
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................91
8.1.
Permitted Concomitant Medications and Procedures...............................................91
8.1.1.
Bridging Chemotherapy (Subjects Receiving JCAR017) ........................................92
8.2.
Prohibited Concomitant Medications and Procedures..............................................92
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8.2.1.
Subjects Infused with JCAR017..............................................................................93
8.3.
Required Concomitant Medications and Procedures................................................94
9.
STATISTICAL CONSIDERATIONS ....................................................................95
9.1.
Overview................................................................................................................95
9.2.
Study Population Definitions ..................................................................................95
9.2.1.
Screened Analysis Set.............................................................................................95
9.2.2.
Intention-to-Treat Analysis Set ...............................................................................95
9.2.3.
Per-Protocol Analysis Set .......................................................................................95
9.2.4.
Safety Analysis Set.................................................................................................96
9.2.5.
Pharmacokinetic Analysis Set.................................................................................96
9.2.6.
Cross over Analysis Set (Arm A)............................................................................96
9.2.7.
JCAR017-Treated Analysis Set...............................................................................96
9.2.8.
Health-related Quality of Life Analysis Set.............................................................96
9.3.
Sample Size and Power Considerations...................................................................96
9.3.1.
Sample Size Calculation .........................................................................................96
9.3.2.
Sample Size Robustness and Sensitivity .................................................................98
9.4.
Background and Demographic Characteristics........................................................99
9.5.
Subject Disposition.................................................................................................99
9.6.
Efficacy Analysis....................................................................................................99
9.6.1.
Primary Efficacy Analysis ....................................................................................100
9.6.2.
Key Secondary Efficacy Analysis.........................................................................101
9.6.3.
Other Efficacy Analyses .......................................................................................101
9.6.4.
Subgroup Analyses...............................................................................................102
9.7.
Safety Analysis.....................................................................................................102
9.7.1.
Treatment Exposure..............................................................................................102
9.7.2.
Adverse Events.....................................................................................................103
9.7.3.
Laboratory Evaluations.........................................................................................104
9.7.3.1.
Numeric Laboratory Results .................................................................................104
9.7.3.2.
Graded Laboratory Values....................................................................................104
9.7.3.3.
Summaries of Laboratory Abnormalities...............................................................104
9.8.
Interim Analysis ...................................................................................................104
9.8.1.
Futility Interim Analysis.......................................................................................104
9.8.2.
Efficacy Interim Analysis .....................................................................................105
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9.8.3.
Monitoring of EFS Events and Sample Size Increase............................................105
9.9.
Other Topics.........................................................................................................105
9.9.1.
Randomization......................................................................................................105
9.9.2.
Data Safety Monitoring Board..............................................................................105
9.9.3.
Scientific Steering Committee ..............................................................................106
9.9.4.
Independent Review Committee ...........................................................................106
9.9.5.
Exploratory Analysis ............................................................................................106
9.9.6.
Health-Related Quality of Life..............................................................................106
9.9.7.
Hospital Resource Utilization ...............................................................................107
9.9.8.
Pharmacokinetics
..................................................................107
10.
ADVERSE EVENTS............................................................................................108
10.1.
Monitoring, Recording and Reporting of Adverse Events .....................................108
10.2.
Evaluation of Adverse Events...............................................................................110
10.2.1.
Seriousness...........................................................................................................110
10.2.2.
Severity/Intensity..................................................................................................111
10.2.3.
Causality ..............................................................................................................112
10.2.4.
Duration ...............................................................................................................112
10.2.5.
Action Taken........................................................................................................113
10.2.6.
Outcome...............................................................................................................113
10.3.
Abnormal Laboratory Values................................................................................113
10.4.
Pregnancy.............................................................................................................113
10.4.1.
Females of Childbearing Potential: .......................................................................113
10.4.2.
Male Subjects.......................................................................................................114
10.5.
Reporting of Serious Adverse Events....................................................................114
10.5.1.
Safety Queries ......................................................................................................115
10.5.2.
Death Reports.......................................................................................................115
10.6.
Potential Risks and Management of Treatment Toxicities.....................................115
10.6.1.
Management of Toxicities Associated with JCAR017...........................................115
10.6.1.1.
Cytokine Release Syndrome .................................................................................115
10.6.1.2.
Fever ....................................................................................................................116
10.6.1.3.
Neurologic Toxicities ...........................................................................................116
10.6.1.4.
Macrophage Activation Syndrome........................................................................116
10.6.1.5.
Infusion Reactions ................................................................................................117
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10.6.1.6.
Tumor Lysis Syndrome ........................................................................................117
10.6.1.7.
B-cell Aplasia.......................................................................................................117
10.6.1.8.
Uncontrolled T Cell Proliferation..........................................................................117
10.6.1.9.
Replication-Competent Lentivirus, Clonality and Insertional Oncogenesis............118
10.6.1.10. Cytopenias............................................................................................................118
10.6.1.11. Infections..............................................................................................................118
10.6.2.
Risks Associated with Lymphodepleting Chemotherapy.......................................118
10.6.3.
Risks Associated with Reference Therapies ..........................................................119
10.6.4.
Second Primary Malignancies...............................................................................119
10.7.
Expedited Reporting of Adverse Events................................................................119
10.8.
Adverse Events of Special Interest........................................................................120
11.
DISCONTINUATIONS .......................................................................................121
11.1.
Treatment Discontinuation....................................................................................121
11.2.
Study Discontinuation ..........................................................................................121
12.
EMERGENCY PROCEDURES...........................................................................122
12.1.
Emergency Contact...............................................................................................122
12.2.
Emergency Identification of Investigational Products ...........................................122
13.
REGULATORY CONSIDERATIONS.................................................................123
13.1.
Good Clinical Practice..........................................................................................123
13.2.
Investigator Responsibilities .................................................................................123
13.3.
Subject Information and Informed Consent...........................................................124
13.4.
Confidentiality......................................................................................................124
13.5.
Protocol Amendments...........................................................................................124
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ..............................................................................................................124
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ..............125
13.8.
Termination of the Study ......................................................................................125
14.
DATA HANDLING AND RECORDKEEPING...................................................126
14.1.
Data/Documents ...................................................................................................126
14.2.
Data Management.................................................................................................126
14.3.
Record Retention..................................................................................................126
15.
QUALITY CONTROL AND QUALITY ASSURANCE......................................128
15.1.
Study Monitoring and Source Data Verification....................................................128
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15.2.
Audits and Inspections..........................................................................................128
15.3.
Product Quality Complaint ...................................................................................128
16.
PUBLICATIONS .................................................................................................130
17.
REFERENCES.....................................................................................................131
18.
APPENDICES......................................................................................................139
APPENDIX A.
TABLE OF ABBREVIATIONS..................................................................139
APPENDIX B.
PERFORMANCE STATUS BY EASTERN COOPERATIVE 
ONCOLOGY GROUP SCALE ............................................................................145
APPENDIX C.
RECOMMENDATIONS FOR INITIAL EVALUATION, STAGING, 
AND RESPONSE ASSESSMENT OF HODGKIN AND NON-HODGKIN 
LYMPHOMA: THE LUGANO CLASSIFICATION............................................146
APPENDIX D.
COCKCROFT-GAULT EQUATION FOR CALCULATING 
ESTIMATED CREATININE CLEARANCE .......................................................152
APPENDIX E.
CAIRO-BISHOP DEFINITIONS OF TUMOR LYSIS SYNDROME..........153
APPENDIX F.
MINI MENTAL STATE EXAMINATION..................................................155
APPENDIX G.
CLINICAL LABORATORY EVALUATIONS...........................................159
APPENDIX H.
SUBJECT REPORTED OUTCOMES: EORTC QLQ C-30.........................160
162
APPENDIX J.
SUBJECT REPORTED OUTCOMES: FACT-LYM.....................................164
APPENDIX K.
HCT-CI SCORE CALCULATOR ...............................................................165
APPENDIX L.
JCAR017 MANAGEMENT GUIDELINES FOR CYTOKINE 
RELEASE SYNDROME AND NEUROLOGIC TOXICITIES (V3.2).................167
APPENDIX M.
SECONDARY AGE ADJUSTED INTERNATIONAL 
PROGNOSTIC INDEX (SAAIPI)........................................................................179
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LIST OF TABLES
Table 1:
Study Objectives.....................................................................................................32
Table 2:
Study Endpoints .....................................................................................................33
Table 3:
Table of Events.......................................................................................................44
Table 4:
Table of Events for Subjects from Arm A Who Cross Over to JCAR017 ................52
Table 5:
Reporting Periods for Concomitant Medications, Procedures and 
Transfusions ...........................................................................................................91
Table 6:
Power Estimated via Simulation for other HR Assumptions....................................98
Table 7:
Power Estimated via Simulation with Weibull Distribution.....................................99
Table 8:
Recording Periods for Adverse Events..................................................................109
Table 9:
Abbreviations and Specialist Terms......................................................................139
Table 10:
Performance Status by Eastern Cooperative Oncology Group Scale......................145
Table 11:
Criteria for Involvement of Site ............................................................................146
Table 12:
Revised Criteria for Response Assessment............................................................147
Table 13:
Integrated PET+CT Overall Time Point Response ................................................149
Table 14:
PET + CT + CNS Time Point Response................................................................150
Table 15:
Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome (LTLS) ...............153
Table 16:
Cairo-Bishop Definition of Clinical TLS ..............................................................153
Table 17:
Cairo-Bishop Grading System for TLS .................................................................153
Table 18:
Clinical Laboratory Evaluations............................................................................159
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LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................37
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1.
INTRODUCTION 
1.1.
Disease Background 
Non-Hodgkin lymphomas (NHLs) comprise a heterogeneous group of malignancies. Within
Europe, the incidence of NHL is approximately 49,533 new cases annually with 20,347 deaths 
per year (Ferlay, 2015).
In the United States (US), it is estimated that approximately 72,580 new cases of NHL will be
diagnosed and approximately 20,150 subjects will die of their disease per year (Siegel, 2016).
Non-Hodgkin lymphomas are classified according to the current World Health Organization
(WHO) classification (Swerdlow, 2016) into immature lymphoid neoplasms, mature B-cell
neoplasms, T cell and natural killer (NK)-cell neoplasms, and post-transplant
lymphoproliferative disorders. Mature B-cell lymphomas are further classified into indolent
lymphomas (eg, multiple myeloma, chronic lymphocytic leukemia [CLL]) and aggressive
lymphomas (eg, diffuse large B-cell lymphoma [DLBCL]).
Diffuse large B-cell lymphoma is the most frequent lymphoma subtype, representing 
approximately 30% of all NHL, which can develop de novo or secondary to transformation of an 
indolent NHL, eg, from follicular lymphoma. In the United States 27,650 estimated new cases 
were diagnosed in 2016 (Teras, 2016); incidence in Europe is 3 to 4/100,000/year, increasing 
with age from 0.3/100,000/year (35 to 39 years) to 26.6/100,000/year (80 to 84 years) (Tilly, 
2012). About 10,000 deaths per year are due to DLBCL in the United States (US) (National 
Cancer Institute [NCI]). 
Diffuse large B-cell lymphoma is a heterogeneous disease with several histological and
molecular subtypes. The largest subgroup is DLBCL not otherwise specified (NOS). Molecular
profiling by gene expression profiling based on biologic similarity to normal stages of B-cell 
development (cell of origin [COO]) helped to further divide DLBCL into germinal center like
(GCB), activated B-cell-like (ABC) tumors, and primary mediastinal large B-cell lymphoma
(PMBCL) (Lenz, 2008). Immunohistochemistry (IHC) algorithms are clinically used to identify 
the COO and helped to identify ABC DLBCL as a high-risk subtype less likely to respond to 
standard immunochemotherapy. Within the GCB group a specific high-risk group is defined by 
concurrent chromosomal rearrangements of c-MYC and the anti-apoptotic oncogene BCL2, 
referred to as double-hit lymphomas (DHL). In addition, in some cases there is a concurrent 
rearrangement of c-MYC and both antiapoptotic oncogenes BCL2 and BCL6, which are referred 
to as triple-hit lymphoma. Double-hit lymphomas represents approximately 5% of de novo cases 
of DLBCL with very poor overall survival (OS) of ≤ 12 months when treated with rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (Camicia, 2015). Newer 
data suggest negative prognostic impact of p53 mutations or deletions in DLBCL (Schiefer, 
2015). Primary mediastinal (thymic) large B-cell lymphoma (PMBCL), T cell/histiocyte-rich 
large B-cell lymphoma (THRBCL) are considered different histological subtypes in World 
Health Organization 2016 classification (Swerdlow, 2016), but international guidelines 
recommend to use DLBCL treatment algorithm (National Comprehensive Cancer Network 
[NCCN]) (NCCN, 2019), especially for refractory and relapsed disease.
Despite follicular lymphoma being an indolent lymphoma type, follicular lymphoma Grade 3B 
(FL3B) is regarded as an aggressive lymphoma. Clinical behavior is very similar to DLBCL, and 
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follicular lymphoma (FL) frequently undergoes histological transformation into DLBCL. 
Consequently, current guidelines recommend treating FL3B according to the DLBCL treatment 
algorithm (NCCN, 2019; Dreyling 2016; Dreyling, 2017). These patients are generally treated 
with an anthracycline-based chemotherapy combined with rituximab (eg, R-CHOP) and have a 
similar prognosis to that of de novo DLBCL.
Most subjects with localized DLBCL can be cured with conventional combination immuno-
chemo- or combined-modality therapy (Tilly, 2015). For subjects with advanced-stage disease, 
the majority of subjects can be cured with doxorubicin-based combination chemotherapy and 
rituximab (eg, R-CHOP). Prognosis depends on individual risk factors. The International 
Prognostic Index (IPI) for aggressive NHL includes five significant risk factors prognostic of 
OS: Subject age, serum lactate dehydrogenase (LDH) level, Eastern Cooperative Oncology 
Group (ECOG) performance status, disease stage, and extranodal involvement. Subjects with ≥ 2 
risk factors after age-adjustment have a poor prognosis with a 5-year OS-rate of 21% to 46%. 
Age and stage-adjusted modifications are used for younger subjects with localized disease 
(Moller, 2003).
Despite overall improvement in outcomes of DLBCL, approximately one-third of subjects do not 
respond to initial therapy or will relapse (relapsed/refractory [R/R] disease) that remains a major 
cause of mortality. 
The standard of care for patients with R/R DLBCL after initial therapy is salvage therapy with 
platinum-based chemotherapy regimens (ie, rituximab, dexamethasone, cytarabine and cisplatin
[R-DHAP], rituximab, ifosfamide, carboplatin and etoposide [R-ICE], or rituximab, gemcitabine, 
dexamethasone, and cisplatin [R-GDP]) if they are deemed to be eligible for high dose 
chemotherapy (HDCT) and autologous hematopoietic stem cell transplantation (autologous 
HSCT; ASCT) (Tilly, 2015). Patients responding to second line salvage therapy, ie, those with 
chemo-sensitive disease, might proceed to HDCT and ASCT to consolidate their response.  
While approximately 50-60% of patients with R/R DLBCL remain sensitive to conventional 
second line therapy, only roughly 30% will eventually proceed to ASCT (Gisselbrecht, 2010; 
Crump, 2014; van Imhoff, 2016). Yet, only a modest portion of patients undergoing HSCT are 
cured, and patients with high-risk DLBCL, ie, relapsing within a year from first-line treatment, 
obtain a limited survival advantage by undergoing HSCT (Van Den Neste, 2017).
Three large randomized phase 3 trials have compared the efficacy of various 
immunochemotherapy regimens as second line salvage therapy, namely the CORAL trial 
(Collaborative trial in relapsed aggressive lymphoma) (Van Den Neste, 2017), the National 
Cancer Institute of Canada (NCIC) Clinical Trials Group’s LY.12 trial (Crump, 2014), and the 
ORCHARRD (Ofatumumab versus Rituximab Salvage Chemoimmunotherapy) trial (van 
Imhoff, 2016).  
The CORAL trial evaluated the efficacy of standard platinum-based (R-ICE or R-DHAP) second 
line therapy and subsequent consolidation with high dose therapy with ASCT in 396 patients 
who failed R-CHOP or R-CHOP-like therapy (Gisselbrecht, 2010; Van Den Neste, 2016; Van 
Den Neste, 2017). Similar response rates were observed after three cycles of R-ICE (64%) or R-
DHAP (63%). After a median follow-up time of 27 months, the 3-year event-free survival (EFS)
and progression-free survival (PFS) rates were 31% and 37%, respectively, the R-ICE and R-
DHAP arms were not significantly different, and the 3-year OS was 49% with no difference 
between the R-ICE and R-DHAP arms. For patients who underwent ASCT, 3-year PFS was 53% 
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and there was no difference between the numbers of patients who achieved CR and PR just 
before ASCT (Gisselbrecht, 2010). Patients failing salvage therapy or relapsing after ASCT had 
a particularly poor prognosis, with a median OS of 4.4 months and 1- and 2-year OS rates of 
23% and 15.7%, respectively (Van Den Neste, 2016; Van Den Neste, 2017). Median time 
between ASCT and relapse in the CORAL trial was 7.1 months. 
The NCIC-CTG LY.12 trial compared the efficacy of gemcitabine, dexamethasone, and cisplatin 
(GDP) versus dexamethasone, cytarabine, and cisplatin (DHAP) and subsequent consolidation 
by HDCT/ ASCT in 619 patients with R/R aggressive NHLs. Results were very similar to what 
had been observed in the CORAL trial. Overall response rate to GDP was 45% and 44% to 
DHAP with 52% and 49% continuing to ASCT (Crump, 2014). With a median follow-up 
duration of 53 months, 4-year event-free survival was 26% and overall survival 39% in the 
overall patient group with no difference between the two arms. 
The more recent ORCHARRD study in 447 patients relapsing after rituximab-containing 
frontline therapy compared DHAP in combination with either rituximab (R) or the cluster of 
differentiation (CD)20 antibody ofatumumab (O). In contrast to the CORAL and the LY.12 
trials, all patients enrolled in this trial were refractory to, or had relapsed following, first-line 
treatment with rituximab in combination with an anthracycline-containing chemotherapy 
regimen. In this study, response rate for ofatumumab, dexamethasone, high dose cytarabine 
(AraC), and cisplatin (O-DHAP) was 38% (CR 15%) versus 42% (CR 22%) for R-DHAP. Only 
one third of subjects completed ASCT on protocol; 74 patients (33%) in the O-DHAP arm and 
83 patients (37%) in the R-DHAP arm. Progression-free survival (defined as time from random 
assignment until PD, death from any cause, or SD after 2 cycles), EFS, and OS were not 
significantly different between O-DHAP versus R-DHAP: PFS at 2 years was 24% versus 26% 
(hazard ratio [HR], 1.12; 95% confidence interval (CI), 0.89 to 1.42; P 5.33); EFS at 2 years was 
16% versus 18% (HR, 1.10; P 5.35); and OS at 2 years was 41% versus 38% (HR, 0.90; P 5.38).
This study represents the most relevant benchmark for efficacy of salvage therapy in the 
rituximab era. Complete metabolic response (CMR) before ASCT was highly predictive for 
superior outcome (van Imhoff, 2016).
All three trials failed to improve on the standard of care (SOC) and identified early relapse 
(refractory disease or progression within 12 months) as well as secondary age-adjusted elevated 
IPI as poor prognostic factors. The CORAL trial, furthermore, identified prior exposure to 
rituximab as a risk factor. In particular subjects relapsing within 12 months of rituximab-
containing frontline therapy had a very poor prognosis even with ASCT (Gisselbrecht, 2010). 
While prior use of rituximab was not identified as an adverse prognostic factor in the LY.12 and 
ORCHARRD trials, they confirmed the poor prognosis of patients with refractory DLBCL or
patients relapsing within 12 months. 
Recently, the SCHOLAR-1 meta-analysis (n=636) has reported on the very poor outcome of 
patients with DLBCL refractory to anti-CD20 monoclonal antibody- and anthracycline-
containing regimens (Crump, 2017). Chemo-refractoriness was defined as: progressive disease 
(PD) as best response to chemotherapy, or stable disease (SD) as best response to chemotherapy 
(received at least 4 cycles of first-line or 2 cycles of later-line therapy), or relapse within 12 
months from prior autologous HSCT. The median overall response rate (ORR) was 26% (CR 
8%, PR 18%) and the median OS was 6.6 months.
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In summary, while many patients with DLBCL achieve long-term remission after rituximab and 
anthracycline containing first-line immunochemotherapy, there is a high unmet medical need for 
patients with R/R DLBCL. While subjects with chemotherapy sensitive disease (defined as 
relapsing after 12 months of response to first-line therapy) have a relatively good prognosis, the 
majority of subjects with chemotherapy refractory disease (defined as best response of PD, SD or 
relapse within 12 months from response) undergoing second line salvage therapy will not derive 
long term benefit. Thus, novel therapies are urgently needed for this patient population.
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 a 
component of a B-cell surface signal transduction complex that positively regulates signal 
transduction through the B-cell receptor. 
CD19 is an attractive therapeutic target because it is expressed by most B-cell malignancies, 
including B-cell NHL (Li, 1993). Importantly, the CD19 antigen is not expressed on 
hematopoietic stem cells or on any normal tissue apart from those of the B-cell lineage.
1.2.2.
CD19–Targeted Chimeric Antigen Receptors 
CD19-specific chimeric antigen receptors (CARs) are single chain variable fragments (scFv) 
fused to a transmembrane domain and cytoplasmic signaling domains. Expression of CD19-
targeted CARs in autologous T cells typically 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-cell acute lymphoblastic leukemia (ALL) and B-cell NHL (Porter, 
2011; Davila, 2014; Maude, 2014; Kochenderfer, 2015; Lee, 2015; Turtle, 2016a; Turtle, 
2016b). Promising results have been reported for different CD19-directed CARs in the treatment 
of adult (Neelapu, 2017; Schuster, 2017; Turtle, 2016b) and pediatric (Park, 2016) CD19-
positive lymphoid malignancies.
Two CD19-directed CAR T therapies have recently been approved by the US Food and Drug 
Administration (FDA) and the European Medicines Agency (EMA): 

Tisagenlecleucel for the treatment of:

Patients up to age 25 years with B-cell precursor ALL that is refractory or in 
second or later relapse.

Adult patients with relapsed or refractory (R/R) large B-cell lymphoma after two 
or more lines of systemic therapy.

Axicabtagene ciloleucel to treat adult patients with certain types of large B-cell 
lymphoma who have not responded to or who have relapsed after at least two other kinds 
of treatment. 
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1.2.3.
JCAR017 Investigational Drug Product
The final JCAR017 investigational drug product (also known as lisocabtagene maraleucel or 
liso-cel) includes two individually formulated CD4+CAR+ and CD8+ CAR+ frozen T cell 
suspensions in media containing dimethyl sulfoxide (DMSO) that are thawed and infused 
separately. JCAR017 is administered by intravenous (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.
Please refer to the Investigator’s Brochure for detailed information concerning the available 
pharmacology, toxicology, clinical studies, and adverse event profile of the investigational 
product (IP).
1.2.4.
Clinical Experience with JCAR017 
JCAR017 is currently being evaluated in adult subjects with relapsed and refractory B-cell NHL 
(Study 017001 - TRANSCEND NHL001; ClinicalTrials.gov No. NCT02631044) (Abramson,
2017a). 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 DL2 (JCAR017 infusion of 100 x 106 viable CAR+ T cells). 
Pharmacokinetics (PK) 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 (cytokine release syndrome [CRS], 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 severe CRS (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, 2017a, Maloney, 2017). Ability of CAR cells to cross the 
blood-brain-barrier has been reported (Kochenderfer, 2017) and has been observed in Study
017001 (Abramson, 2019). At time of data analysis, the subjects enrolled and experiencing NT 
had no evidence of central nervous system (CNS) involvement. This supports the rational to 
further investigate CAR T cell therapy in patients with primary CNS or secondary CNS 
involvement. Two patients with secondary CNS involvement by DLBCL were included in Study 
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017001. Both patients experienced complete resolution of their CNS disease with no neurologic 
adverse events observed. 
Study JCAR017-BCM-001 will explore the efficacy of JCAR017 in various aggressive large cell 
lymphomas, including primary CNS lymphoma (PCNSL). One additional trial will evaluate 
JCAR017 in subjects with R/R chronic lymphocytic leukemia (CLL). Another trial, JCAR017-
BCM-002 (NCT03310619) will explore safety and efficacy of JCAR017 in combination with
other agents. 
See the JCAR017 Investigator's Brochure (IB) for further details.
1.3.
Rationale
1.3.1.
Study Rationale and Purpose
Despite an improvement in long-term remissions after first-line therapy for subjects with 
DLBCL, outcomes of subjects who have failed front-line therapy are poor, and additional 
options are needed. 
Although several second-line salvage therapies, such as R-DHAP, R-ICE, or R-GDP, each 
followed by HDCT and autologous stem cell transplant (ASCT), have been the standard of care 
(SOC) for subjects who are refractory to or who relapse following first-line treatment with 
combination immuno-chemotherapy, the clinical outcome of these subjects is disappointing. 
Three and 4-year progression free survival (PFS) and overall survival (OS) rates range between 
30% to 40% and 40% to 50%, respectively (Crump, 2014; Gisselbrecht, 2010). Especially 
subjects whose disease is refractory to standard R-CHOP first-line therapy or are relapsing
within 12 months after diagnosis have a very poor prognosis, with a 3 year PFS rate of 23% 
(Gisselbrecht, 2010).
The most recent randomized clinical trial in second-line, transplant-eligible subjects shows an 
ORR to DHAP-based salvage therapy of 40% with approximately 35% of subjects proceeding to 
HDCT/ASCT (van Imhoff, 2016). The overall 2-year PFS rate was approximately 25%, and the 
2-year OS rate was approximately 40%. In this trial, 71% of the subjects had high-risk poor 
prognostic disease (refractory or relapsing within 12 months to R-CHOP). In this high-risk 
population, the ORR and percentage of subjects that completed HDCT/ASCT were 29% and 
26% compared with 67% and 59% for the subject subgroup with CR of more than 1 year from R-
CHOP, respectively. Median PFS in the high-risk versus standard risk populations was 
approximately 2 months versus 24 months, and median OS was approximately 10 months versus 
not reached (van Imhoff, 2016), clearly showing the urgent need for improved therapeutic 
options in this the high-risk population.
The National Comprehensive Cancer Network (NCCN) guidelines recommend that as a second-
line therapy, subjects should receive salvage chemotherapy followed by HDCT with ASCT for 
subjects in CR. Subjects with SD and PD after salvage chemotherapy should receive next line of 
therapy. Subjects who only achieve PR after salvage chemotherapy are recommended to receive 
either CAR T cells, HDCT with ASCT, be enrolled in a clinical trial, or continue to allogeneic 
HSCT in selected cases (NCCN, 2019). For subjects with PR, relapse or PD after consolidation 
with HDCT and ASCT, the recommendation is to use CAR T cell therapy (if not previously 
given), to enroll in a clinical trial, or to use alternative second-line therapy, if available (NCCN,
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JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
2019). Data from Study 017001 in subjects with aggressive B-cell NHL who have failed two or 
more lines of therapy, including subjects who were refractory to first-line and second-line 
therapies, demonstrate that treatment with JCAR017 results in encouraging efficacy results 
(ORR of 49% at 6 months, CRR of 46% at 6 months, and median OS in responders has not been 
reached with a median follow-up of 12 months) and an acceptable safety profile (Abramson, 
2018). Based on promising early results in later lines of therapy, JCAR017 has the potential to 
improve outcomes in this study population. The purpose of this Phase 3 study is to compare the 
current SOC paradigm for subjects with R/R DLBCL and to demonstrate whether JCAR017,
used in an earlier line of therapy will be superior to the current SOC in high-risk, transplant-
eligible subjects who have failed one previous line of CD20-directed antibody and anthracycline 
containing therapy for aggressive B-cell NHL.  
1.3.2.
Rationale for the Study Design
This is a randomized, open-label, parallel-group, multi-center trial to determine the efficacy and 
safety of JCAR017 in adult subjects with relapsed or refractory aggressive NHL after failure of 
anti-CD20 antibody and anthracycline containing first-line immunochemotherapy compared to
the SOC strategy. Subjects with R/R aggressive NHL eligible for transplant are usually treated 
with a salvage immunochemotherapy followed by HDCT and HSCT. This study is designed to 
compare the current SOC treatment paradigm versus JCAR017 for subjects with high risk 
DLBCL, DHL/THL, PMBCL, THRBCL and FL3B.
Subjects will be randomized to either receive SOC (Arm A) or to receive JCAR017 (Arm B). 
Randomization will be stratified by response to first-line therapy (relapsed versus refractory), 
and secondary age-adjusted International Prognostic Index (sAAIPI) (0 to 1 versus 2 to 3). Both 
stratification factors have been used previously in large randomized Phase 3 trials and shown to 
control for imbalances during the randomization (Gisselbrecht, 2010; Crump, 2014; van Imhoff, 
2016). 
The reference treatment in Arm A corresponds to the SOC in this setting based on the CORAL, 
the LY.12, and the ORCHARRD trials. These consist of the R-DHAP, R-ICE, or R-GDP 
regimen followed by HDCT and HSCT (NCCN, 2019; Tilly, 2015). All subjects randomized to 
Arm A will receive 3 cycles of SOC salvage therapy (R-DHAP, R-ICE or R-GDP) as per 
physician’s choice, during which peripheral blood hematopoietic stem cells for HSCT are 
harvested. After 3 cycles, response will be evaluated by PET-CT. Subjects responding to SOC 
(CR and PR) will proceed to HDCT and HSCT. 
Subjects randomized to Arm B will receive LD chemotherapy followed by JCAR017 infusion. 
Subjects may receive one cycle of SOC salvage therapy to bridge the time between 
randomization and availability of the JCAR017 cell product (manufacturing time). Based on 
promising preliminary results from Study 017001, which show high response rates even in 
subjects with refractory DLBCL (Abramson, 2018), it is expected that subjects in high risk 
second line DLBCL will also derive a meaningful benefit from treatment with JCAR017. 
The primary objective of the study is to compare the efficacy of JCAR017 therapy to SOC 
salvage therapy (immunochemotherapy followed by HDCT and HSCT) with respect to event-
free survival (EFS) in adult subjects with relapsed or refractory DLBCL, DHL/THL, PMBCL, 
THRBCL or FL3B who have received one prior therapy but relapsed within 12 months from 
response to or are refractory to first-line treatment regimen (Hitz, 2015) including an anti-CD20 
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antibody and an anthracycline, based on the Lugano criteria (Cheson, 2014) as determined by an 
independent review committee (IRC). Event-free survival is defined as the time from 
randomization to death from any cause, progression, failure to achieve CR or PR by 9 weeks 
post-randomization or start of new antineoplastic therapy due to efficacy concerns, whichever 
comes first. This definition represents the clinical decision path, where only subjects with CR or 
PR would continue on the SOC paradigm and receive HDCT and HSCT, and non-responding 
subjects being subjected to third line rescue therapy. In contrast, the key secondary endpoint, 
PFS, is defined as the time from randomization to PD or death from any cause, as per IRC 
review, whichever occurs first.
1.3.3.
Rationale for Dose, Schedule and Regimen Selection
The Phase 1 trial (Study 017001- NCT02631044) is evaluating JCAR017 at several dose levels 
after LD chemotherapy with cyclophosphamide (300 mg/m2/day x 3 days) combined with 
fludarabine (30 mg/m2/day x 3 days). The initial dose level evaluated (DL1: 50 x 106 CAR+ T 
cells) was found to be tolerable, the dose was escalated and a dose of 100 x 106 CAR+ T cells 
(DL2) and additional dosing schedules are currently being evaluated (Abramson, 2016). Safety 
and efficacy of 18 subjects treated at DL2 showed good tolerability and efficacy with a single 
JCAR017 infusion. This dose was selected for the pivotal cohort in the Study 017001 as the 
recommended Phase 2 dose and therefore was selected for this Phase 3 trial.
1.3.4.
Rationale for Choice of Comparator Compounds
The current SOC salvage therapies for R/R DLBCL in second line are defined as R-DHAP, R-
ICE or R-GDP.
These regimens are widely used and accepted, backed by large randomized trials and 
recommended by international treatment guidelines (Tilly, 2015; NCCN, 2019). As described in 
Section 1.1, it has been demonstrated that the three regimens are comparable in terms of efficacy 
and safety. The most commonly used high dose chemotherapy in NHL is carmustine (BCNU), 
etoposide, cytarabine, and melphalan (BEAM) and will be used as standard HDCT for this trial. 
In Japan, due to unavailability of intravenous BCNU, ranimustine (MCNU) will be used. 
Ranimustine is in the same class of nitrosourea anticancer agents as BCNU and has shown 
efficacy equivalent outcomes (Sugimoto, 2016). Standard of care regimen, schedule of the 
regimen, dose adjustment for toxicities and premedication will be done as per site standard, local 
label and investigator’s decision. Please see Section 7.3 for further details.
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2.
STUDY OBJECTIVES AND ENDPOINTS
Table 1:
Study Objectives
Primary Objective
The primary objective of the study is to compare the efficacy in subjects treated with JCAR017 versus 
subjects treated according to standard of care (SOC) defined as event-free survival (EFS) 
Key Secondary Objectives
The key secondary objectives are to compare the efficacy in subjects treated with JCAR017 versus 
subjects treated according to SOC defined as complete response rate (CRR), progression-free survival
(PFS) and overall survival (OS)
Secondary Objectives
The secondary objectives are:

To compare other parameters of efficacy, defined as duration of response (DoR), overall 
response rate (ORR), PFS on next line of treatment (PFS-2)

To compare efficacy rates (EFS, PFS, OS) at 6, 12, 24 and 36 months after randomization

To compare the safety defined as type and frequency of adverse events (AEs), serious adverse 
events (SAEs), and laboratory abnormalities  

To compare the safety and efficacy in clinical, histological and molecular subgroups 

To compare health-related quality of life (HRQoL) using the global health/QoL, fatigue,
physical and cognitive functioning subscales of the European Organisation for Research and 
Treatment of Cancer – Quality of Life C30 Questionnaire (EORTC QLQ-C30) and the 
Functional Assessment of Cancer Therapy – Lymphoma “Additional concerns” subscale  
(FACT-Lym)

To compare hospital resource utilization (HRU)

To describe the rate of completion of high dose chemotherapy (HDCT) and hematopoietic 
stem cell transplant (HSCT)

To assess the response 3 months after-HSCT 
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Table 1:
Study Objectives (Continued)
Exploratory Objectives
The exploratory objectives are:

To characterize the pharmacokinetic (PK) profile of JCAR017

To evaluate pharmacodynamic (PD) markers of JCAR017, including B-cell aplasia 
 
 

To describe the effect of treatments directed at severe cytokine release syndrome (sCRS) and 
neurotoxicity on duration and severity of these events and whether these safety features are 
affected by initial SOC treatment for subjects that cross over to JCAR017

To assess the safety and efficacy for subjects who crossed over to JCAR017 

To describe changes in the other domains of HRQoL using the rest of the subscales in 
EORTC QLQ-C30 (ie, those not specified in the secondary objectives)
 
Table 2:
Study Endpoints
Endpoint
Name
Description
Timeframe
Primary
Event-free survival 
(EFS)
Time from randomization to death from 
any cause, progressive disease (PD), 
failure to achieve complete response (CR) 
or partial response (PR) by 9 weeks post-
randomization, or start of new 
antineoplastic therapy due to efficacy 
concerns, whichever occurs first
Up to 3 years post-
randomization
Key 
Secondary
Complete response 
rate (CRR)
Percentage of subjects achieving a 
complete response (CR) 
Up to 3 years post-
randomization
Progression-free 
survival (PFS)
Time from randomization to PD, or death 
from any cause, whichever occurs first
Up to 3 years post-
randomization
Overall survival (OS)
Time from randomization to time of death 
due to any cause
Up to last subject 
last visit
Secondary
Overall response rate 
(ORR)
Percentage of subjects achieving an 
objective response of partial response (PR) 
or better 
Up to 3 years post-
randomization
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Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
Duration of response 
(DoR)
Time from first response to disease 
progression, start of new antineoplastic 
therapy due to efficacy concerns or death 
from any cause
Up to 3 years post-
randomization
PFS on next line of 
treatment (PFS-2)
Time from randomization to second 
objective disease progression or death from 
any cause, whichever occurs first.
Up to 3 years post-
randomization
EFS rate
Percentage of subjects free of any EFS 
event at fixed timepoints
At 6, 12, 24 and 36 
months post-
randomization
PFS rate
Percentage of subjects free of any PFS 
event at fixed timepoints
At 6, 12, 24 and 36 
months post-
randomization
OS rate
Percentage of subjects alive at fixed 
timepoints
At 6, 12, 24 and 36 
months post-
randomization
Secondary
Safety
Type, frequency and severity of adverse 
events (AEs), serious adverse events 
(SAEs), and laboratory abnormalities
(overall and in clinical, histological and 
molecular subgroups)
Up to 3 years post-
randomization
Clinical, histological 
and molecular 
subgroup analyses
Response rate, EFS, PFS, OS in clinical, 
histological and molecular subgroups 
Up to 3 years post-
randomization
Health-related quality 
of life (HRQoL)
(domain of interest)
HRQoL using the global health/QoL, 
fatigue, physical and cognitive functioning 
subscales of the European Organisation for 
Research and Treatment of Cancer –
Quality of Life C30 Questionnaire
(EORTC QLQ-C30) and the Functional 
Assessment of Cancer Therapy-Lymphoma 
“Additional concerns” subscale (FACT-
Lym)
Up to 3 years post-
randomization
Hospital resource
utilization (HRU)
Frequency of hospitalizations, inpatient 
days, intensive care unit (ICU) days, 
outpatient visits and reasons for 
hospitalization
Up to 3 years post-
randomization 
Rate of high dose 
chemotherapy 
(HDCT) completion
Percentage of subjects in Arm A 
completing HDCT
Up to 3 years post-
randomization
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Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
Rate of hematopoietic 
stem cell transplant 
(HSCT) completion
Percentage of subjects in Arm A 
completing HSCT
Up to 3 years post-
randomization
Response rate post-
HSCT
Percentage of subjects in response after 
undergoing HSCT
At 3 months post-
HSCT
Exploratory
Pharmacokinetics
Maximum concentration (Cmax),time to 
maximum concentration (Tmax), area 
under the curve (AUC), and other relevant 
PK parameters of JCAR017 as assessed by 
droplet digital polymerase chain reaction
(ddPCR)
Up to 3 years post-
randomization
Blood biomarker
Analyses of pharmacodynamic (PD)
biomarkers including but not limited to 
 B-cell aplasia; 
 
Up to 1 year post-
randomization
Efficacy analyses for 
subjects who crossed 
over to JCAR017
PFS, EFS, DOR, ORR and CRR for 
subjects from Arm A who crossed over to 
JCAR017 
Up to 1 year post-
JCAR017 infusion
Efficacy analyses for 
subjects who crossed 
over to JCAR017
OS for subjects who crossed over to 
JCAR017 
Up to last subject 
last visit
HRQoL (other)
Other domains of HRQoL (not specified as 
secondary endpoints) measured by the rest 
of subscales of EORTC QLQ-C30
Up to 3 years post-
randomization
Responses will be assessed according to the Celgene “Guidelines for Efficacy Evaluation in PET-avid Non-Hodgkin 
Lymphoma” by an independent review committee (IRC). These guidelines are based on “The Lugano 
Classification” (Cheson, 2014) and will be referred to as the Celgene Lugano Classification guidelines throughout 
this document.
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3.
OVERALL STUDY DESIGN
3.1.
Study Design
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.
This is a randomized, open-label, parallel-group, multi-center trial in adult subjects with R/R
aggressive NHL to compare safety and efficacy between the standard of care (SOC) strategy 
versus JCAR017. Subjects will be randomized to either receive SOC (Arm A) or to receive 
JCAR017 (Arm B). See Figure 1.
Randomization will be stratified by response to first-line therapy (SD, PD, PR or CR with 
relapse before 3 months versus CR with relapse on or after lasting at least 3 months), and sAAIPI 
(0 to 1 versus 2 to 3). 
All subjects randomized to Arm A will receive 3 cycles of SOC salvage therapy (R-DHAP, R-
ICE or R-GDP) as per physician’s choice, during which peripheral blood hematopoietic stem 
cells for HSCT are harvested. If peripheral blood hematopoietic stem cells are available from a 
collection done prior to screening, they may be used and a collection does not need to be 
repeated during the study. After 3 cycles, response will be evaluated by PET-CT. Subjects 
responding to SOC (metabolic CR or metabolic PR, see Table 12) are expected to undergo 
HDCT and HSCT. In case of toxicity or not satisfactory response as per investigator judgment to 
the selected SOC regimen, a switch within the 3 defined SOC regimen will be allowed and will 
not be counted as an EFS event.
Subjects randomized to Arm B will receive LD chemotherapy followed by JCAR017 infusion. 
Subjects may receive one cycle of SOC chemotherapy to bridge the manufacturing time. 
A staggered dosing approach will be utilized for all 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 randomization approach, the site may proceed with 
subject randomization as communicated by Celgene. 
If requested by the investigator, subjects in Arm A may be allowed to receive JCAR017 upon 
central confirmation of one of the following criteria:

Failure to achieve CR or PR by 9 weeks post-randomization (after 3 cycles of SOC)

Progression at any time

Need to start a new antineoplastic therapy due to efficacy concerns after 18 weeks 
post-randomization
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Figure 1:
Overall Study Design
Abbreviations: D = day; HDCT = high dose chemotherapy; HSCT = hematopoietic stem cell transplant; LD = lymphodepleting chemotherapy; M = month;
PET = positron emission tomography; R = randomization; SOC = standard of care. 
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JCAR017-BCM-003 Amendment 2 Final:  09 Dec 2019
3.2.
Study Duration for Subjects 
The duration of participation for subjects who complete the study will be approximately 37 
months. All subjects who receive JCAR017 will be eligible and asked to enroll into a separate
long-term follow-up (LTFU) protocol after completion of this study. Subjects who cross over to 
JCAR017 will be followed in the study for 12 months after the JCAR017 infusion.
3.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, 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 prespecified in the protocol, whichever is the later date.
1.0
Approved
930193545
6.0
v
Approved
1.0
v


EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
39
JCAR017-BCM-003 Amendment 2 Final:  09 Dec 2019
4.
STUDY POPULATION
4.1.
Number of Subjects 
Approximately 182 subjects with R/R aggressive B-cell NHL will be randomized worldwide.
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be randomized in the study:
1. Subject is ≥ 18 years and ≤ 75 years of age at the time of signing the informed consent 
form (ICF). 
2. Subject must understand and voluntarily sign an ICF prior to any study-related 
assessments/procedures being conducted. 
3. Subject is willing and able to adhere to the study visit schedule and other protocol 
requirements.
4. ECOG performance status ≤ 1.
5. Histologically proven diffuse large B-cell lymphoma (DLBCL) NOS (de novo or 
transformed indolent NHL), high grade B-cell lymphoma with MYC and BCL2 and/or 
BCL6 rearrangements with DLBCL histology (double/triple-hit lymphoma [DHL/THL]), 
primary mediastinal (thymic) large B-cell lymphoma (PMBCL), T cell/histiocyte-rich 
large B-cell lymphoma (THRBCL) or follicular lymphoma grade 3B (FL3B). Enough 
tumor material must be available for confirmation by central pathology. If archival 
sample is before most recent relapse or if there is no or insufficient archival sample 
available, a new tumor biopsy is mandated to confirm diagnosis. If the patient is 
refractory to first line of treatment, a tumor biopsy sample from disease diagnosis can be 
used if enough archival material is available.
Note: Subjects with secondary CNS involvement are eligible. Subject selection must 
consider clinical risk factors for severe adverse events (AEs) and alternative treatment 
options. Subjects should only be enrolled if the Investigator assesses that the potential 
benefit outweighs the risk for the subject.
6. Refractory disease (SD, PD, PR or CR with relapse before 3 months) or relapsed disease
(defined as CR with relapse on or after lasting at least 3 months but no more than 12 
months), to CD20 antibody and anthracycline containing first-line therapy for disease 
under study.
Note: The time of relapse is calculated from the date of the first disease assessment 
confirming a CR obtained with first-line treatment for disease under study, to the date of 
first assessment demonstrating a relapse. 
7. [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET) positive lesion 
per Lugano criteria at screening (Deauville score 4 or 5).
8. Adequate organ function, defined as:

Adequate bone marrow function defined as: absolute neutrophil count (ANC) ≥ 1.0 x 
109 cells/L and platelets ≥ 50 x 109 cells/L in absence of bone marrow involvement
1.0
Approved
930193545
6.0
v
Approved
1.0
v


EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
40
JCAR017-BCM-003 Amendment 2 Final:  09 Dec 2019

Serum creatinine < 1.5 x upper limit of normal (ULN) or creatinine clearance > 45
mL/min (estimated by Cockcroft Gault; see Appendix D for calculation)

Alanine aminotransferase (ALT) ≤ 5 x ULN and total bilirubin < 2.0 mg/dL (or < 3.0 
mg/dL for subjects with Gilbert's syndrome or lymphomatous infiltration of the liver)

Adequate pulmonary function, defined as ≤ Grade 1 dyspnea according to Common 
Terminology Criteria for Adverse Events (CTCAE) and oxygen saturation (SaO2) 
≥92% on room air and FEV1 ≥50%

Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥ 40% 
as assessed by echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) 
performed within 4 weeks of randomization
9. Adequate vascular access for leukapheresis.
10. Subjects must agree to not donate blood, organs, sperm or semen, and egg cells for usage 
in other individuals for at least 12 months following lymphodepleting chemotherapy. 
There is 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, sperm or
semen and egg cells for usage in other individuals for at least 12 months following 
lymphodepleting chemotherapy. 
11. Females of childbearing potential (FCBP*) must:

Have a negative pregnancy test (2 for Arm B) as verified by the Investigator prior to 
starting study therapy (one negative serum beta-human chorionic gonadotropin [ß-
hCG] pregnancy test result at screening [Arm A and B], and within 7 days prior to the 
first dose of lymphodepleting chemotherapy [Arm B and cross over]). She must agree 
to ongoing pregnancy testing during the course of the study, and after end of study 
treatment. 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 method of contraception from screening until at least 
12 months after receiving lymphodepleting chemotherapy or until 12 months after the 
last chemotherapy, whichever is later.

Agree to abstain from breastfeeding during study participation and for at least 1 year  
after lymphodepleting chemotherapy.

There is insufficient exposure data to provide any recommendation concerning the 
duration of contraception and the abstaining from breastfeeding following treatment 
with JCAR017. Any decision regarding contraception and breastfeeding after 
JCAR017 infusion should be discussed with the treating physician.
1.0
Approved
930193545
6.0
v
Approved
1.0
v


EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
41
JCAR017-BCM-003 Amendment 2 Final:  09 Dec 2019
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 methods of contraception:

Intrauterine device (IUD)

Hormonal (birth control pill, injections, implants)

Tubal ligation 

Partner's vasectomy 
12. Male subjects must:

Practice true abstinence** (which must be reviewed on a monthly basis) or agree to 
use a condom during sexual contact with a pregnant female or a female of 
childbearing potential while participating in the study, during dose interruptions and 
for 12 months after lymphodepleting chemotherapy and for 12 months after the last 
chemotherapy, whichever is later even if he has undergone a successful vasectomy. 
There is insufficient exposure data to provide any recommendation concerning the 
duration of contraception following treatment with JCAR017. Any decision regarding 
contraception after JCAR017 infusion should be discussed with the treating 
physician.
* A female subject of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some 
point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally 
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 
12 consecutive months (ie, has had menses at any time in the preceding 12 consecutive months).
**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 randomization:
1. Subject has any significant medical condition, laboratory abnormality, or psychiatric 
illness that would prevent the subject from participating in the study based on 
investigator´s judgment.
2. Subject has any condition including the presence of laboratory abnormalities, which 
places the subject at unacceptable risk if he/she were to participate in the study based on 
investigator´s judgment.
3. Subject has any condition that confounds the ability to interpret data from the study based 
on investigator´s judgment.
4. Subjects not eligible for hematopoietic stem cell transplantation (HSCT).
5.
Subjects planned to undergo allogeneic stem cell transplantation.
6. Subjects with primary cutaneous large B-cell lymphoma, EBV (Epstein-Barr virus)
positive DLBCL, Burkitt lymphoma or transformation from chronic lymphocytic 
leukemia/small lymphocytic lymphoma (Richter transformation).
1.0
Approved
930193545
6.0
v
Approved
1.0
v


EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
42
JCAR017-BCM-003 Amendment 2 Final:  09 Dec 2019
7. Subjects with prior history of malignancies, other than aggressive R/R NHL, unless the 
subject has been free of the disease for ≥ 2 years with the exception of the following non-
invasive malignancies:

Basal cell carcinoma of the skin

Squamous cell carcinoma of the skin

Carcinoma in situ of the cervix

Carcinoma in situ of the breast

Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, 
nodes, metastasis] clinical staging system) or prostate cancer that is curative.

Other completely resected stage 1 solid tumor with low risk for recurrence
8. Treatment with any prior gene therapy product.
9. Subjects who have received previous CD19-targeted therapy.
10. Subjects with active hepatitis B, or active hepatitis C are excluded. Subjects with 
negative polymerase chain reaction (PCR) assay for viral load for hepatitis B or C are 
permitted. Subjects positive for hepatitis B surface antigen and/or anti-hepatitis B core 
antibody with negative viral load are eligible and should be considered for prophylactic 
antiviral therapy. Subjects with a history of or active human immunodeficiency virus 
(HIV) are excluded.
11. Subjects with uncontrolled systemic fungal, bacterial, viral or other infection (including 
tuberculosis) despite appropriate antibiotics or other treatment.
12. Active autoimmune disease requiring immunosuppressive therapy.
13. History of any one of the following cardiovascular conditions within the past 6 months
prior to signing the ICF: Class III or IV heart failure as defined by the New York Heart 
Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable 
angina, or other clinically significant cardiac disease.
14. History or presence of clinically relevant central nervous system (CNS) pathology such 
as epilepsy, seizure, aphasia, stroke, cerebral edema, severe brain injuries, dementia, 
Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis.
15. Progressive vascular tumor invasion, thrombosis, or embolism.
16. Venous thrombosis or embolism not managed on a stable regimen of anticoagulation.
17. Pregnant or nursing (lactating) women.
18. Use of the following (see Section 8.2 for full details):

Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or 
equivalent) within 7 days prior to unstimulated leukapheresis. Physiologic 
replacement, topical, and inhaled steroids are permitted. 
1.0
Approved
930193545
6.0
v
Approved
1.0
v


EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
43
JCAR017-BCM-003 Amendment 2 Final:  09 Dec 2019

Cytotoxic chemotherapeutic agents that are not considered lymphotoxic (see below) 
and intrathecal (IT) chemotherapy must be stopped ≥ 7 days prior to unstimulated 
leukapheresis. 

Lymphotoxic chemotherapeutic agents (eg, cyclophosphamide, ifosfamide, 
bendamustine) 2 weeks prior to unstimulated leukapheresis. 

Experimental agents within 4 weeks prior to signing the ICF unless no response or 
progressive disease (PD) is documented on the experimental therapy and at least 3 
half-lives have elapsed prior to unstimulated leukapheresis.

Immunosuppressive therapies within 4 weeks prior to unstimulated leukapheresis (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).

Radiation within 4 weeks prior to signing the ICF. Subjects must have progressive 
disease in irradiated lesions or have additional non-irradiated, PET-positive lesions to 
be eligible. Radiation to a single lesion, if additional non-irradiated, measurable PET-
positive lesions are present, is allowed up to 2 weeks prior to unstimulated 
leukapheresis.

Systemic immunostimulatory agents (including but not limited to interferon and IL-2) 
within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to JCAR017 
infusion. 
19. Known allergy to DMSO or Dextran.
1.0
Approved
930193545
6.0
v
Approved
1.0
v


EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
44
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
5.
TABLES OF EVENTS
Table 3:
Table of Events
Note: If study treatment needs to be postponed (eg, due to adverse event), the visit should be documented as an unscheduled visit. Before the actual study 
treatment, the initially planned study visit needs to be repeated and documented as such (eg, if a subject in Arm A cannot start their 2nd cycle of SOC on Day 22, 
but there were assessments performed on the scheduled visit day, these will be documented as unscheduled. Once the subject can receive their treatment, all 
assessments from Day 22 should be performed and next visits scheduled as per the below table. Same example would apply to Arm B JCAR017 infusion at 
Day 29 and following visits). Please refer to the specified protocol section for further details on each procedure.
Treatment Period
Post-Treatment 
Period
Survival 
Follow-up
Screening Random-
ization
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Follow-up Period
Study Month
-
-
-
-
-
1
-
-
-
-
-
-
-
-
3
-
-
-
6
9, 12, 18, 24
and 36 (EOS
or ET)
-
Study Week
-
-
-
-
3
-
-
-
-
-
6
-
9
-
-
-
-
18
-
-
-
Study Day
-28 to -1
1
8
15
22
29
31b
32b
36
39b
43
50
64
71
85
99
106a
126
-
-
q3m
Visit Window 
(days)
-
+3
± 2
± 2
± 7
± 7
± 1
±1
±1
±1
±6
±2
± 6
± 6
± 6
± 7
± 7
± 7
± 10
± 14
± 30
Obtain consent
xc
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Eligibility criteria 
x
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
IRT registration
x
xj
-
-
x
xb
-
-
-
-
xa
-
-
xa
-
-
-
-
-
x
M36
-
Medical history
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Demographics
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
sAAIPI 
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
ECOG 
xe
x
-
-
xb,h
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
-
HCT-CI
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1.0
Approved
930193545
6.0
v
Approved
1.0
v


EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
45
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
Table 3:
Table of Events (Continued)
Treatment Period
Post-Treatment 
Period
Survival 
Follow-up
Screening Random-
ization
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Follow-up Period
Study Month
-
-
-
-
-
1
-
-
-
-
-
-
-
-
3
-
-
-
6
9, 12, 18, 24
and 36 (EOS 
or ET)
-
Study Week
-
-
-
-
3
-
-
-
-
-
6
-
9
-
-
-
-
18
-
-
-
Study Day
-28 to -1
1
8
15
22
29
31b
32b
36
39b
43
50
64
71
85
99
106a
126
-
-
q3m
Visit Window 
(days)
-
+3
± 2
± 2
± 7
± 7
± 1
±1
±1
±1
±6
±2
± 6
± 6
± 6
± 7
± 7
± 7
± 10
± 14
± 30
Pulmonary 
function test 
(FEV1)
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Height
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Weight
x
x
-
-
x
-
-
-
-
-
xa
-
-
xa
-
-
-
-
-
-
-
Body surface 
calculation
-
x
-
-
x
-
-
-
-
-
xa
-
-
xa
-
-
-
-
-
-
-
Physical 
examination
x
x
-
-
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
-
Routine 
neurologic 
examination
x
x
-
-
-
x
x
x
x
x
-
x
x
-
x
x
-
-
-
-
-
MMSEz
-
x
-
-
-
x
x
x
x
x
-
x
x
-
x
x
-
-
-
-
-
Vital signsd
xe
x
-
-
x
xf
x
x
x
x
x
x
x
x
x
x
x
x
x
x
-
Pulse oximetry
x
x
-
-
x
xf
x
x
x
x
x
x
x
-
-
-
-
-
-
-
-
12-lead ECG
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
MUGA/ECHO
xy
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Viral serology
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1.0
Approved
930193545
6.0
v
Approved
1.0
v


EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
46
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
Table 3:
Table of Events (Continued)
Treatment Period
Post-Treatment 
Period
Survival 
Follow-up
Screening Random-
ization
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Follow-up Period
Study Month
-
-
-
-
-
1
-
-
-
-
-
-
-
-
3
-
-
-
6
9, 12, 18, 24
and 36 (EOS 
or ET)
-
Study Week
-
-
-
-
3
-
-
-
-
-
6
-
9
-
-
-
-
18
-
-
-
Study Day
-28 to -1
1
8
15
22
29
31b
32b
36
39b
43
50
64
71
85
99
106a
126
-
-
q3m
Visit Window 
(days)
-
+3
± 2
± 2
± 7
± 7
± 1
±1
±1
±1
±6
±2
± 6
± 6
± 6
± 7
± 7
± 7
± 10
± 14
± 30
Serum pregnancyg
x
-
-
-
xb,h
-
-
-
-
-
-
-
-
-
-
-
-
xb
x
x
M9b, 12b & 
EOS
-
Urinalysis
x
-
-
-
-
x
-
-
-
-
-
-
-
xa
-
-
-
-
-
-
-
CSF assessmenti
x
As clinically indicated
-
Hematology
xe
x
x
x
xh
x
x
x
x
x
x
x
x
xa
x
x
x
x
x
x
-
Coagulation
x
x
-
-
xh
x
x
x
x
x
x
x
x
xa
-
-
-
-
-
-
-
Chemistry
xe
x
x
x
xh
x
x
x
x
x
x
x
x
xa
x
x
x
x
x
x
-
Creatinine 
clearance
x
-
-
-
xb,h
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Inflammatory 
markers
x
x
x
x
xh
x
x
x
x
x
x
x
x
xa
x
-
-
x
-
-
-
Immunoglobulins
x
-
-
-
-
x
-
-
-
-
-
-
x
-
x
-
-
x
x
x
-
Unstimulated 
leukapheresis
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1.0
Approved
930193545
6.0
v
Approved
1.0
v


EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
47
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
Table 3:
Table of Events (Continued)
Treatment Period
Post-Treatment 
Period
Survival 
Follow-up
Screening Random-
ization
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Follow-up Period
Study Month
-
-
-
-
-
1
-
-
-
-
-
-
-
-
3
-
-
-
6
9, 12, 18, 24
and 36 (EOS 
or ET)
-
Study Week
-
-
-
-
3
-
-
-
-
-
6
-
9
-
-
-
-
18
-
-
-
Study Day
-28 to -1
1
8
15
22
29
31b
32b
36
39b
43
50
64
71
85
99
106a
126
-
-
q3m
Visit Window 
(days)
-
+3
± 2
± 2
± 7
± 7
± 1
±1
±1
±1
±6
±2
± 6
± 6
± 6
± 7
± 7
± 7
± 10
± 14
± 30
Arm A treatment
SOC 
chemotherapy
-
x
-
-
x
-
-
-
-
-
x
-
-
-
-
-
-
-
-
-
-
Stem cell 
collection
-
-
xk
-
-
-
-
-
-
-
-
HDCT/HSCT
-
-
-
-
-
-
-
-
-
-
-
-
-
xl
-
-
-
-
-
-
-
Arm B treatment
Bridging 
chemotherapym
-
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Pre-
lymphodepletion 
evaluation
-
-
-
-
xb
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
LD chemotherapy
(3 days)
-
-
-
-
xb,n
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Pre-JCAR017 
infusion 
evaluation
-
-
-
-
-
xb
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
JCAR017 
administration
-
-
-
-
-
xb,o
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1.0
Approved
930193545
6.0
v
Approved
1.0
v


EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
48
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
Table 3:
Table of Events (Continued)
Treatment Period
Post-Treatment 
Period
Survival 
Follow-up
Screening Random-
ization
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Follow-up Period
Study Month
-
-
-
-
-
1
-
-
-
-
-
-
-
-
3
-
-
-
6
9, 12, 18, 24
and 36 (EOS 
or ET)
-
Study Week
-
-
-
-
3
-
-
-
-
-
6
-
9
-
-
-
-
18
-
-
-
Study Day
-28 to -1
1
8
15
22
29
31b
32b
36
39b
43
50
64
71
85
99
106a
126
-
-
q3m
Visit Window 
(days)
-
+3
± 2
± 2
± 7
± 7
± 1
±1
±1
±1
±6
±2
± 6
± 6
± 6
± 7
± 7
± 7
± 10
± 14
± 30
All arms
PET
xp
-
-
-
xw
-
-
-
-
-
-
-
x
-
-
-
-
x
x
x
-
CT/ MRI
xp
-
-
-
-
-
-
-
-
-
-
-
x
-
-
-
-
x
x
x
-
Brain MRIi
x
As clinically indicated
-
Tumor biopsyq
x
-
-
-
-
-
At progressionr
-
AEs/ Con meds/ 
Con procedures 
(including 
transfusions)
AEs, con 
meds and 
con 
procedures
related to 
protocol 
mandated 
procedures
All AEs, con meds and con procedures until 90 days after last dose of chemotherapy (Arm A) or 90 days after JCAR017 
infusion (Arm B)t, u
AEs, con 
meds and con
procedures 
related to 
study
treatment
-
EORTC QLQ-
C30
-
x
-
-
-
x
-
-
-
-
-
-
x
-
-
-
-
x
x
x
-
FACT-Lym
“Additional 
concerns” 
subscale
-
x
-
-
-
x
-
-
-
-
-
-
x
-
-
-
-
x
x
x
-
1.0
Approved
930193545
6.0
v
Approved
1.0
v


EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
49
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
Table 3:
Table of Events (Continued)
Treatment Period
Post-Treatment 
Period
Survival 
Follow-up
Screening Random-
ization
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Follow-up Period
Study Month
-
-
-
-
-
1
-
-
-
-
-
-
-
-
3
-
-
-
6
9, 12, 18, 24
and 36 (EOS 
or ET)
-
Study Week
-
-
-
-
3
-
-
-
-
-
6
-
9
-
-
-
-
18
-
-
-
Study Day
-28 to -1
1
8
15
22
29
31b
32b
36
39b
43
50
64
71
85
99
106a
126
-
-
q3m
Visit Window 
(days)
-
+3
± 2
± 2
± 7
± 7
± 1
±1
±1
±1
±6
±2
± 6
± 6
± 6
± 7
± 7
± 7
± 10
± 14
± 30
Hospital resource 
utilization
-
Ongoing
-
Disease therapy 
since study 
treatment 
discontinuation
-
x
-
Survival status
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
x
Peripheral blood 
sample for RCL 
testing
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
xb
xb
xb
M12, M18, 
M24, M36
-
1.0
Approved
930193545
6.0
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Approved
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EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
50
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
Table 3:
Table of Events (Continued)
Abbreviations: AE = adverse event; CNS = central nervous system; Con = concomitant; Con meds = concomitant medications; CSF = cerebrospinal fluid; CT =  computed 
tomography; ddPCR = droplet digital polymerase chain reaction; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; EFS = 
Event-free survival; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer – Quality of Life C30 Questionnaire; EOS = end of study; ET = early 
termination; 
FACT-Lym = Functional Assessment of Cancer Therapy-Lymphoma; FEV1 = 
forced expiratory volume in one second; HCT-CI = hematopoietic cell transplantation-specific comorbidity index; HDCT = high dose chemotherapy; HSCT = hematopoietic stem 
cell transplant; IP = investigational product; IRT = interactive response technology; IV = intravenous; LD = lymphodepleting; M = month; MMSE = Mini Mental State 
Examination; MRI= magnetic resonance imaging; MUGA = multi-gated acquisition scan; 
 PET = positron emission tomography; PK 
= pharmacokinetic; q3m= every 3 months; RCL = replication-competent lentivirus; sAAIPI = secondary age-adjusted international prognostic index; SOC = standard of care.
Treatment Period
Post-Treatment 
Period
Survival 
Follow-up
Screening Random-
ization
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Follow-up Period
Study Month
-
-
-
-
-
1
-
-
-
-
-
-
-
-
3
-
-
-
6
9, 12, 18, 24
and 36 (EOS 
or ET)
-
Study Week
-
-
-
-
3
-
-
-
-
-
6
-
9
-
-
-
-
18
-
-
-
Study Day
-28 to -1
1
8
15
22
29
31b
32b
36
39b
43
50
64
71
85
99
106a
126
-
-
q3m
Visit Window 
(days)
-
+3
± 2
± 2
± 7
± 7
± 1
±1
±1
±1
±6
±2
± 6
± 6
± 6
± 7
± 7
± 7
± 10
± 14
± 30
Peripheral blood 
sample for viral 
vector sequence 
PK by ddPCR
x
-
-
-
-
xb,v
-
x
xb
x
xb
xb
xb
xb
xb
-
-
xb
xb
xb
-
Peripheral Blood 
Sample for Flow 
Cytometry (B-cell 
aplasia)
x
-
-
-
-
xb
pre-
infusi
on
-
-
xb
-
xb
xb
xb
-
xb
-
-
xb
xb
xb
M12, M18, 
M24, M36
-
Plasma samples
x
-
-
-
xa
xb,v
-
x
x
x
x
-
x
-
-
-
x
x
-
1.0
Approved
930193545
6.0
v
Approved
1.0
v


EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
51
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
a Only for subject randomized to Arm A.
b Only for subject randomized to Arm B. Day 39 visit is mandatory and cannot be combined with Day 43 visit.
c To be obtained any time before any study related procedure.
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 CRF.
e To be performed at screening visit and at pre leukapheresis. Vital signs need to be done pre and post leukapheresis.
f For Arm B: Measured approximately every 15 minutes starting from 15 minutes prior to the first IV administration until one hour after the last IV administration, and hourly for 
the next 2 hours. If the subject's vital signs are not stable 4 hours following the final administration, vital signs should be monitored as clinically indicated until stable.
g Serum pregnancy test is to be performed 90 days after the last dose of chemotherapy or JCAR017 infusion.
h For Arm B: To be performed once within 24 hours of the start of lymphodepleting chemotherapy.
i If CNS involvement is suspected.
j Allowed time window of +2 days do not apply to IRT registration.
k Peripheral blood hematopoietic stem cells for HSCT are to be harvested during the 3 cycles of SOC. If peripheral blood hematopoietic stem cells are available from a collection
done prior to screening, collection does not need to be repeated.
l HDCT to be followed by HSCT as per site procedures.
m Only if needed for disease control (reason to be recorded in the CRF).
n LD chemotherapy (as described in Section 7.2) should start 5 to 7 days before infusion in order to be completed at least 2 days prior to JCAR017 infusion.
o JCAR017 infusion should be started at least 2 days after the end of the LD chemotherapy.
p Not to be repeated if a positive PET-CT/MRI was performed within 4 weeks from randomization and confirmed available for central reading by the IRC.
q Tissue from latest archived tumor biopsy (block or slides) can be used for tumor evaluation. If archival sample is before most recent relapse or if there is no or insufficient archival 
sample available, a new tumor biopsy is mandated to confirm diagnosis.
r To be performed when feasible.
s To be collected if occurred within 28 days of screening.
t For subjects starting a new antineoplastic therapy, all AEs and associated concomitant medications will be collected through 90 days after the JCAR017 infusion or 90 days after 
last dose of chemotherapy, whichever occurs last.
u For subjects receiving LD chemotherapy but not JCAR017, all AEs and associated concomitant medications will be collected for 30 days following the last dose of LD 
chemotherapy.
v To be performed pre-infusion.
w Only for patients randomized in Arm B receiving bridging chemotherapy to be completed before start of lymphodepleting chemotherapy.
y Not to be repeated if one was performed within 4 weeks of randomization.
z If subjects in Arm B develop neurologic symptoms suspicious of and/or diagnosed as neurologic toxicity, subjects will have daily MMSE exams (see Appendix F) until resolution 
of symptoms, unless the subject is medically incapacitated and/or medically unable to complete the MMSE.
1.0
Approved
930193545
6.0
v
Approved
1.0
v


EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
52
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
Table 4:
Table of Events for Subjects from Arm A Who Cross Over to JCAR017
Treatment Period
Post-Treatment Period
Survival 
Follow-up
Pre-Treat-
ment 
Evalua-
tion
LD 
Chemo-
therapy
JCAR017 
Infusion
Follow-up
Study Month
-
-
-
-
-
-
-
-
-
-
1
2
3
6
9
12
Study Day
Within 7 
Days 
Before LD 
Chemo-
Therapy
Start 5 
to 10 
Days 
Before 
Day 1
1
2
3
4
8
11
15
22
29
-
-
-
-
(EOS or 
ET)
q3m
Visit Window (Days)
-
-
-
-
-
+1
±1
±1
±2
±2
±2
±14
±14
±14
±14
±30
±30
IRT registration
-
x
x
-
-
-
-
-
-
-
-
-
-
-
-
x
-
ECOG
x
x
x
-
-
-
x
-
x
x
x
-
x
x
x
x
-
Weight
x
-
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Physical examination
x
-
x
x
x
x
x
x
x
x
x
xa
xa
xa
xa
x
-
Routine neurologic 
examination
x
-
x
x
x
x
x
x
x
x
x
-
x
xa
xa
xa
-
MMSEm
x
-
x
-
-
x
x
-
x
-
x
-
x
-
-
-
-
Vital signsb
x
x
xc
x
x
x
x
x
x
x
x
-
-
-
-
-
-
12-lead ECG
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
MUGA scan/ECHO
xk
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Viral serology
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Serum pregnancy
x
-
-
-
-
-
-
-
-
-
-
-
x
x
x
x
EOS
-
Urinalysis
-
-
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
LD chemotherapy
-
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
JCAR017 infusion
-
-
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1.0
Approved
930193545
6.0
v
Approved
1.0
v


EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
53
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
Table 4:
Table of Events for Subjects from Arm A Who Cross Over to JCAR017 (Continued)
Treatment Period
Post-Treatment Period
Survival 
Follow-up
Pre-Treat-
ment 
Evalua-
tion
LD 
Chemo-
therapy
JCAR017 
Infusion
Follow-up
Study Month
-
-
-
-
-
-
-
-
-
-
1
2
3
6
9
12
Study Day
Within 7 
Days 
Before LD 
Chemo-
Therapy
Start 5 
to 10 
Days 
Before 
Day 1
1
2
3
4
8
11
15
22
29
-
-
-
-
(EOS or 
ET)
q3m
Visit Window (Days)
-
-
-
-
-
+1
±1
±1
±2
±2
±2
±14
±14
±14
±14
±30
±30
Adverse events, concomitant 
medications and con 
procedures (including 
transfusions)
All AEs, associated concomitant medications and con proceduresd, e
AEs related to JCAR017 
and/or LD chemotherapy and 
associated con meds and con 
procedures
-
Disease therapy since study 
treatment discontinuation
-
x
-
PET-CT/MRI
xf
-
-
-
-
-
-
-
-
-
-
-
x
x
-
-
-
Brain MRI/ CSF assessment
xg
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Hematology
x
xl
x
x
x
x
x
x
x
x
x
x
x
x
x
x
-
Coagulation
x
-
x
x
x
x
x
x
x
x
x
x
-
-
-
-
-
Chemistry
x
xl
x
x
x
x
x
x
x
x
x
x
x
x
x
x
-
Creatinine clearance
-
xl
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Inflammatory markers
x
-
x
x
x
x
x
x
x
xh
xh
-
-
-
-
-
-
Immunoglobulins
x
-
-
-
-
-
-
-
x
x
x
-
xi
xi
xi
xi
-
Peripheral blood sample for 
RCL testing
x
-
-
-
-
-
-
-
-
-
-
-
x
x
x
x
-
1.0
Approved
930193545
6.0
v
Approved
1.0
v


EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
54
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
Table 4:
Table of Events for Subjects from Arm A Who Cross Over to JCAR017 (Continued)
Treatment Period
Post-Treatment Period
Survival 
Follow-up
Pre-Treat-
ment 
Evalua-
tion
LD 
Chemo-
therapy
JCAR017 
Infusion
Follow-up
Study Month
-
-
-
-
-
-
-
-
-
-
1
2
3
6
9
12
Study Day
Within 7 
Days 
Before LD 
Chemo-
Therapy
Start 5 
to 10 
Days 
Before 
Day 1
1
2
3
4
8
11
15
22
29
-
-
-
-
(EOS or 
ET)
q3m
Visit Window (Days)
-
-
-
-
-
+1
±1
±1
±2
±2
±2
±14
±14
±14
±14
±30
±30
Peripheral blood sample for 
viral vector sequence PK by 
ddPCR
x
-
x (pre-
infusion)
x
x
x
x
x
x
x
x
x
x
x
x
-
Peripheral blood sample for 
flow cytometry (B-cell 
aplasia)
x
-
x (pre-
infusion)
-
-
-
x
-
x
x
x
x
x
x
x
x
-
Plasma samples 
x
-
x (pre-
infusion)
-
-
x
x
x
x
x
x
-
x
-
-
x
-
Survival status
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
x
Abbreviations: AE = adverse event; CNS = central nervous system; Con = concomitant; Con meds = concomitant medications; CSF = cerebrospinal fluid; CT = computed 
tomography; ddPCR = droplet digital polymerase chain reaction; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; EFS = 
1.0
Approved
930193545
6.0
v
Approved
1.0
v


EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
55
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
event-free survival; EOS = end of study; ET = early termination; IRT = interactive response technology; IV = intravenous; LD = lymphodepleting; MMSE = Mini Mental State 
Examination; MRI= magnetic resonance imaging; MUGA = multi-gated acquisition scan; 
 PET = positron emission tomography; 
q3m= every 3 months; RCL = replication-competent lentivirus.
a Not required after progressive disease (PD)/relapse or subsequent antineoplastic treatment.
b 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 CRF.
c Measured approximately every 15 minutes starting from 15 minutes prior to the first IV administration until one hour after the last IV administration, 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.
d For subjects starting a new antineoplastic therapy after JCAR017 infusion, all AEs and associated concomitant medications will be collected through 90 days after the JCAR017 
infusion or 30 days after the start of the new antineoplastic therapy, whichever occurs last.
e For subjects receiving LD chemotherapy but not JCAR017, all AEs and associated concomitant medications will be collected for 30 days following the last dose of LD 
chemotherapy.
f PET-CT/MRI to be performed if EFS cross over event not confirmed on PET-CT/MRI scans prior to the start of the LD chemotherapy.
g If CNS involvement suspected.
h If clinically indicated.
i Not required for subjects with documented B-cell recovery without recent use of intravenous immunoglobulin (IVIG).
k Not to be repeated if done within 4 weeks of LD chemo and no chemotherapy received between this assessment and the LD chemo.
l To be performed once within 24 hours of the start of lymphodepleting chemotherapy.
m If subjects develop neurologic symptoms suspicious of and/or diagnosed as neurologic toxicity, subjects will have daily MMSE exams (see Appendix F) until resolution of 
symptoms, unless the subject is medically incapacitated and/or medically unable to complete the MMSE.
1.0
Approved
930193545
6.0
v
Approved
1.0
v


EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
56
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
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 evaluations will be performed for all subjects to determine study eligibility. These 
evaluations should be completed within 4 weeks prior to randomization unless noted otherwise 
below. 
Waivers to the protocol will not be granted during the conduct of this trial, under any 
circumstances.
Screening laboratory values must demonstrate subject eligibility, but may be repeated within the 
screening window, if necessary.
The following assessments are to be performed at screening as specified in the Table of Events 
(see Table 3), after informed consent has been obtained:

Subject should be registered in the interactive response technology (IRT) system

Assess eligibility per inclusion/exclusion criteria. All eligibility criteria must be met 
in order for subjects to be randomized in the study

Obtain medical history, including: disease diagnosis and history, chemotherapy, 
radiation and surgical history, and history of prior gene therapy. May include history 
of toxicities related to prior treatments and allergies 

Demographics 

sAAIPI status (see Appendix M)

ECOG performance status assessment 

HCT-CI (hematopoietic cell transplantation – specific comorbidity index) (Sorror, 
2005; see Appendix K)

FEV1 (forced expiratory volume in one second)

Physical examination, including height, weight, vital signs (see Section 6.4.2), 
oxygen saturation via pulse oximetry 

Prior and concomitant procedures and medications within 1 month before signing the 
ICF, except for those related to the disease

Routine neurologic examination 

12-lead electrocardiogram (ECG)

MUGA scan or cardiac ECHO (not to be repeated if one performed within 4 weeks of 
randomization) for LVEF
1.0
Approved
930193545
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Approved
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v


EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
57
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019

Collection of peripheral blood samples for clinical laboratory evaluations as described 
in Table 18:

Hematology panel 

Chemistry panel 

Coagulation tests

Inflammatory markers

Immunoglobulins

Viral serology 

Creatinine clearance (by Cockcroft-Gault) – see Appendix D

Serum ß-hCG pregnancy test on women of child-bearing potential

Replication-competent lentivirus (RCL) testing

Pharmacokinetics (PK) by ddPCR 
 

Urinalysis 

Research samples (see the JCAR017-BCM-003 laboratory manual for details): 

Plasma samples

Peripheral blood for the detection of B-cell aplasia by flow cytometry

Lumbar puncture or Ommaya reservoir tap for CSF assessment if CNS involvement 
suspected

Brain magnetic resonance imaging (MRI) if CNS involvement suspected

Positron emission tomography (PET) and computed tomography (CT) /MRI scan to 
confirm the presence of PET-positive lymphoma. Not to be repeated if a positive PET
and CT/MRI was performed within 4 weeks before randomization and confirmed 
available and fulfill prerequisite for central reading by the IRC.

Tumor biopsy will be collected for central confirmation of diagnosis. Tissue from 
latest archived tumor biopsy (block or slides) can be used for tumor evaluation. If 
archival sample is before most recent relapse or if there is no or insufficient archival 
sample available, a new tumor biopsy is mandated to confirm diagnosis. If the patient 
is refractory to first line of treatment, a tumor biopsy sample from disease diagnosis 
can be used if enough archival material is available.

Record all AEs, concomitant medications and concomitant procedures related to 
protocol mandated procedures
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Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
58
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019

Record the intention to perform consolidation with radiation therapy after completion 
of the per-protocol treatment.

An unstimulated leukapheresis collection will be performed on each subject to obtain 
a sufficient quantity of 
 for the production of the JCAR017 investigational 
product irrespective of the arm assigned. Please refer to the 
 collection 
laboratory manual for further details.
Should a technical issue arise during the procedure or in the processing of the product such that it 
cannot be used for JCAR017 administration, the subject may have a second collection procedure 
performed. Subjects must continue to meet eligibility requirements for repeat leukapheresis. 
The following assessments are to be performed on the day of but before the unstimulated 
leukapheresis:

Eligibility check: 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.

ECOG performance status assessment

Vital signs (pre and post leukapheresis)

Collection of peripheral blood samples for clinical laboratory evaluations as described 
in Table 18 and leukapheresis preparation:

Hematology panel 

Chemistry panel 

Record AEs, concomitant medications and concomitant procedures related to protocol 
mandated procedures
6.2.
Treatment Period
6.2.1.
Day 1 - Randomization (+ 3 days)
Subjects will be randomized to either Arm A or Arm B per the IRT system.
The following assessments are to be performed once the subject is randomized and prior to 
receiving study treatment:

Eligibility must have been confirmed

ECOG performance status assessment 

Physical examination, including weight 

Body surface calculation

Vital signs (see Section 6.4.2), oxygen saturation via pulse oximetry 

Routine neurologic examination 

Mini Mental State Examination (MMSE) (see Appendix F)
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EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
59
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019

Collection of peripheral blood samples for clinical laboratory evaluations as described 
in Table 18:

Hematology panel 

Chemistry panel 

Coagulation tests

Inflammatory markers

Record all AEs, concomitant medications and concomitant procedures

Quality of life questionnaires: EORTC QLQ-C30,
and FACT-Lym 
“Additional concerns” subscale

Hospital resource utilization assessment
6.2.1.1.
Arm A
Subjects will receive their 1st cycle of SOC salvage therapy according to local practice.
6.2.1.2.
Arm B
Subjects may start bridging therapy (reason to be recorded in the CRF) while JCAR017 is 
manufactured, if needed for disease control.
6.2.2.
Days 8 and 15 (± 2 days)
The following assessments are to be performed:

Collection of peripheral blood samples for clinical laboratory evaluations as described 
in Table 18:

Hematology panel 

Chemistry panel 

Inflammatory markers

Record all AEs, concomitant medications and concomitant procedures

Stem cell collection to be performed before Day 71. If peripheral blood hematopoietic 
stem cells are available from a collection done prior to screening, collection does not 
need to be repeated. 

Hospital resource utilization assessment 
Subjects in Arm A who discontinue treatment should be scheduled as soon as possible for early 
termination (ET) visit and subsequently followed as per Table 3 on Days 29, 36, 50, 64, 71, 85, 
99 and 126. In case subjects received subsequent antineoplastic therapies, new disease therapies 
since study treatment discontinuation should be collected and only the assessments described in 
Section 6.3.1.2 applicable for each visit should be performed.
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EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
60
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
6.2.3.
Day 22 (± 7 days)
6.2.3.1.
Arm A 
The following assessments are to be performed prior to receiving study treatment:

Collection of peripheral blood samples for clinical laboratory evaluations as described 
in Table 18:

Hematology panel 

Chemistry panel 

Coagulation tests 

Inflammatory markers

Research samples:

Plasma samples

Physical examination, including weight

Body surface calculation

Vital signs and pulse oximetry 

Record all AEs, concomitant medications and concomitant procedures

Stem cell collection to be performed before Day 71

Hospital resource utilization assessment
Subjects will receive their 2nd cycle of SOC. This treatment administration will be registered in 
IRT system.
Subjects who discontinue treatment should be scheduled as soon as possible for early termination 
(ET) visit and subsequently followed as per Table 3 on Days 29, 36, 50, 64, 71, 85, 99 and 126.
In case subjects received subsequent antineoplastic therapies, new disease therapies since study 
treatment discontinuation should be collected and only the assessments described in 
Section 6.3.1.2 applicable for this visit should be performed.
6.2.3.2.
Arm B
Upon notification from the Sponsor that JCAR017 will be available, LD chemotherapy should be 
initiated so as to be completed 2 to 7 days prior to JCAR017 infusion. This treatment 
administration will be registered in IRT system. For details on LD chemotherapy refer to 
Section 7.4.2.
Subjects receiving bridging chemotherapy should have a PET prior to the start of LD
chemotherapy. Brain MRI and CFS assessment should also be performed if there is secondary 
CNS involvement. Subjects with secondary CNS involvement who received IT treatment with
methotrexate and/or cytarabine should have a minimum of 7 days wash-out period prior to the 
start of LD chemotherapy.
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EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
61
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
Subjects should not experience a significant worsening in clinical status compared to the initial 
eligibility criteria that would, in the opinion of the treating physician, increase the risk of adverse 
events associated with lymphodepleting chemotherapy or exclude them from treatment with 
JCAR017 (see Section 6.2.4.2).
The following assessments are to be performed on each day before administration of LD
chemotherapy: 

Subjects must be evaluated prior to start of lymphodepletion (pre-lymphodepletion 
evaluation): adequate organ function and no evidence of active infections prior to the 
LD chemotherapy are required. In case of suspected infection, subject should be 
treated accordingly and LD chemotherapy postponed until the active infection has 
resolved. Subjects with rapid deterioration or rapid disease progression should not 
start LD chemotherapy. In the event that a subject experiences any of the above, the 
Sponsor must be contacted and discussion regarding delay of treatment must occur.

Vital signs and pulse oximetry

Physical examination, including weight

Body surface calculation 

ECOG performance status assessment (only once within 24 hours prior to start of LD 
chemotherapy)

Collection of peripheral blood samples for clinical laboratory evaluations (only once 
within 24 hours prior to start of LD chemotherapy) as described in Table 18:

Hematology panel

Chemistry panel

Coagulation tests

Inflammatory markers

Creatinine clearance (by Cockcroft-Gault – see Appendix D)

Serum ß-hCG pregnancy test on women of child-bearing potential

PET (only for subjects receiving bridging chemotherapy - once prior to start of LD 
chemotherapy)

Record all AEs, concomitant medications and concomitant procedures

Hospital resource utilization assessment

Collect new disease therapies since study treatment discontinuation (if applicable)
6.2.4.
Day 29 (± 7 days)
6.2.4.1.
Arm A 
The following assessments are to be performed:

ECOG performance status assessment 
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EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
62
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019

Physical examination

Routine neurologic examination

MMSE (see Appendix F)

Vital signs and pulse oximetry

Urinalysis

Collection of peripheral blood samples for clinical laboratory evaluations as described 
in Table 18:

Hematology panel 

Chemistry panel 

Coagulation tests 

Inflammatory markers

Immunoglobulins 

Record all AEs, concomitant medications and concomitant procedures

Stem cell collection to be performed before Day 71 (if applicable)

Quality of life questionnaires: EORTC QLQ-C30, 
and FACT-Lym 
“Additional concerns” subscale

Hospital resource utilization assessment
Subjects who discontinue treatment should be scheduled as soon as possible for early termination 
(ET) visit and subsequently followed as per Table 3 on Days 36, 50, 64, 71, 85, 99 and 126. In 
case subjects received subsequent antineoplastic therapies, new disease therapies since study 
treatment discontinuation should be collected and only the assessments described in 
Section 6.3.1.2 applicable for this visit should be performed.
6.2.4.2.
Arm B
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 daily evaluations or emergencies post-
therapy should be considered for hospitalization for the first 14 days after JCAR017 infusion.
The following assessments are to be performed prior to the JCAR017 infusion:

Subjects must be evaluated for pre-JCAR017 infusion: 
Subjects should not experience a significant worsening in clinical status compared to 
initial eligibility criteria and/or rapid disease progression 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
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EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
63
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
-
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
-
Progressive vascular tumor invasion, thrombosis, or embolism
-
Venous thrombosis or embolism not managed on a stable regimen of 
anticoagulation
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 organ toxicities may not receive JCAR017 until the organ toxicities 
have recovered to ≤ Grade 2. In case of delayed infusion, lymphodepleting 
chemotherapy may need to be repeated after discussion with the Sponsor (see 
Section 6.2.3.2).
In the event that a subject experiences any of the above, the Sponsor must be 
contacted and discussion regarding delay of treatment must occur.

ECOG performance status assessment 

Physical examination

Routine neurologic examination

MMSE (see Appendix F). If subjects in Arm B develop neurologic symptoms 
suspicious of and/or diagnosed as neurologic toxicity, subjects will have daily MMSE 
exams until resolution of symptoms, unless the subject is medically incapacitated 
and/or medically unable to complete the MMSE (see Section 6.4.5).

Vital signs (temperature, respiratory rate, heart rate, blood pressure, and SaO2 by 
pulse oximetry) will be measured approximately every 15 minutes, starting from 15 
minutes prior to the first IV administration until one hour after the last IV 
administration, and hourly for the next 2 hours (see Section 7.4.5). If the subject’s 
vital signs are not stable 4 hours following the final administration, vital signs should 
be monitored as clinically indicated until stable.

Urinalysis

Collection of peripheral blood samples for clinical laboratory evaluations as described 
in Table 18:

Hematology panel 

Chemistry panel 

Coagulation tests
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EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
64
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019

Inflammatory markers

Immunoglobulins 

PK by ddPCR
 

Research samples:

Plasma samples

Peripheral blood for detection of B-cell aplasia by flow cytometry

Record all AEs, concomitant medications and concomitant procedures

Quality of life questionnaires: EORTC QLQ-C30, 
and FACT-Lym 
“Additional concerns” subscale

Hospital resource utilization assessment 

Collect new disease therapies since study treatment discontinuation (if applicable)
Subjects will receive their JCAR017 infusion. This treatment administration will be registered in 
IRT system.
6.2.5.
Day 31 (±1 day), Day 32 (± 1 day), Day 39 (± 1 day) (Arm B)
These visits and subsequent visits for Arm B subjects should be scheduled based on the actual 
Day 29 visit (JCAR017 infusion) (eg, Day 31, 2 days after the infusion; Day 32, 3 days after the 
infusion).
The following assessments are to be performed:

ECOG performance status assessment 

Physical examination

Routine neurologic examination

MMSE (see Appendix F and Section 6.4.5)

Vital signs and pulse oximetry

Collection of peripheral blood samples for clinical laboratory evaluations as described 
in Table 18:

Hematology panel 

Chemistry panel 

Coagulation tests 

Inflammatory markers

PK on Day 32 by ddPCR 
 
 On Day 39 ddPCR 
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EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
65
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019

Research samples:

Plasma samples (Days 32, 39)

Record all AEs, concomitant medications and concomitant procedures

Hospital resource utilization assessment 

Collect new disease therapies since study treatment discontinuation (if applicable)
6.2.6.
Day 36 (± 1 day)
The following assessments are to be performed:

ECOG performance status assessment 

Physical examination

Routine neurologic examination

MMSE (see Appendix F and Section 6.4.5)

Vital signs and pulse oximetry

Collection of peripheral blood samples for clinical laboratory evaluations as described 
in Table 18:

Hematology panel 

Chemistry panel 

Coagulation tests 

Inflammatory markers

PK (Arm B) by ddPCR 
 

Research samples:

Plasma samples

Peripheral blood for detection of B-cell aplasia by flow cytometry (Arm B)

Record all AEs, concomitant medications and concomitant procedures

Stem cell collection to be performed before Day 71 (if applicable) (Arm A)

Hospital resource utilization assessment 
Subjects in Arm A who discontinue treatment should be scheduled as soon as possible for early 
termination (ET) visit and subsequently followed as per Table 3 on Days 50, 64, 71, 85, 99 and 
126.
In case subjects received subsequent antineoplastic therapies, new disease therapies since study 
treatment discontinuation should be collected and only the assessments described in 
Section 6.3.1.2 applicable for this visit should be performed.
1.0
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EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
66
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
6.2.7.
Day 43 (± 6 days)
The following assessments are to be performed (for subjects in Arm A only, the assessments need 
to be performed prior to the start of the 3rd cycle of SOC):

ECOG performance status assessment 

Physical examination

Weight (Arm A)

Body surface calculation (Arm A)

Vital signs and pulse oximetry

Collection of peripheral blood samples for clinical laboratory evaluations as described 
in Table 18:

Hematology panel 

Chemistry panel 

Coagulation tests 

Inflammatory markers

PK (Arm B) by ddPCR 
 

Research samples:

Plasma samples

Peripheral blood for detection of B-cell aplasia by flow cytometry (Arm B)

Record all AEs, concomitant medications and concomitant procedures

Stem cell collection to be performed before Day 71 (if applicable) (Arm A)

Hospital resource utilization assessment 
In case subjects received subsequent antineoplastic therapies, new disease therapies since study 
treatment discontinuation should be collected and only the assessments described in 
Section 6.3.1.2 applicable for this visit should be performed.
6.2.7.1.
Arm A
Subjects will receive their 3rd cycle of SOC. This treatment administration will be registered in 
IRT system.
Subjects who discontinue treatment should be scheduled as soon as possible for early termination 
(ET) visit and subsequently followed as per Table 3 on Days 50, 64, 71, 85, 99 and 126.
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EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
67
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
6.2.8.
Day 50 (± 2 days)
The following assessments are to be performed:

ECOG performance status assessment 

Physical examination

Routine neurologic examination 

MMSE (see Appendix F and Section 6.4.5) 

Vital signs and pulse oximetry

Collection of peripheral blood samples for clinical laboratory evaluations as described 
in Table 18:

Hematology panel 

Coagulation tests 

Chemistry panel 

Inflammatory markers

PK (Arm B) by ddPCR 
 

Research samples:

Peripheral blood for detection of B-cell aplasia by flow cytometry (Arm B)

Record all AEs, concomitant medications and concomitant procedures

Stem cell collection to be performed before Day 71 (if applicable) (Arm A)

Hospital resource utilization assessment 
Subjects in Arm A who discontinue treatment should be scheduled as soon as possible for early 
termination (ET) visit and subsequently followed as per Table 3 on Days 64, 71, 85, 99 and 126.
In case subjects received subsequent antineoplastic therapies, new disease therapies since study 
treatment discontinuation should be collected and only the assessments described in 
Section 6.3.1.2 applicable for this visit should be performed.
6.2.9.
Day 64 (± 6 days)
The following assessments are to be performed:

ECOG performance status assessment 

Physical examination

Routine neurologic examination 

MMSE (see Appendix F and Section 6.4.5) 

Vital signs and pulse oximetry
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EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
68
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019

Collection of peripheral blood samples for clinical laboratory evaluations as described 
in Table 18:

Hematology panel 

Coagulation tests 

Chemistry panel 

Inflammatory markers

Immunoglobulins 

PK (Arm B) by ddPCR 
 

Response assessments: PET and CT/MRI

Research samples:

Plasma samples

Peripheral blood for detection of B-cell aplasia by flow cytometry (Arm B)

Record all AEs, concomitant medications and concomitant procedures

Stem cell collection to be performed before Day 71 (if applicable) (Arm A)

Quality of life questionnaires: EORTC QLQ-C30, 
and FACT-Lym 
“Additional concerns” subscale

Hospital resource utilization assessment 
Subjects in Arm A who discontinue treatment should be scheduled as soon as possible for early 
termination (ET) visit and subsequently followed as per Table 3 on Days 71, 85, 99 and 126.
In case subjects received subsequent antineoplastic therapies, new disease therapies since study 
treatment discontinuation should be collected and only the assessments described in 
Section 6.3.1.2 applicable for this visit should be performed.
6.2.10.
Day 71 (± 6 days)
The following assessments are to be performed (prior to receiving HDCT for Arm A):

ECOG performance status assessment

Weight (Arm A)

Body surface calculation (Arm A)

Physical examination

Vital signs

Urinalysis (Arm A)
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EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
69
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019

Collection of peripheral blood samples for clinical laboratory evaluations as described 
in Table 18:
Arm A:

Hematology panel

Coagulation tests

Chemistry panel 

Inflammatory markers 
Arm B:

PK by ddPCR

Record all AEs, concomitant medications and concomitant procedures

Hospital resource utilization assessment 
In case subjects received subsequent antineoplastic therapies, new disease therapies since study 
treatment discontinuation should be collected and only the assessments described in 
Section 6.3.1.2 applicable for this visit should be performed.
6.2.10.1.
Arm A
Subjects will undergo HDCT prior to receiving the HSCT. This treatment administration will be 
registered in IRT system.
Record the intention to perform consolidation with radiation therapy after completion of the per-
protocol treatment. Eligibility of subjects to undergo HDCT and HSCT must be evaluated: 
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 HDCT and HSCT. Subjects who meet at least one of the following criteria 
on the day of scheduled HDCT and HSCT should have HDCT and HSCT 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 HDCT and HSCT 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 organ toxicities may 
not receive HDCT and HSCT until the organ toxicities have recovered to ≤ Grade 2. In the event 
1.0
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EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
70
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
that a subject experience any of the above, the Sponsor must be contacted and discussion 
regarding delay of treatment must occur.
Subjects who discontinue treatment should be scheduled as soon as possible for early termination 
(ET) visit and subsequently followed as per Table 3 on Day 85, 99 and 126.
6.2.11.
Day 85 (± 6 days)
The following assessments are to be performed:

ECOG performance status assessment 

Physical examination

Routine neurologic examination 

MMSE (see Appendix F and Section 6.4.5) 

Vital signs 

Collection of peripheral blood samples for clinical laboratory evaluations as described 
in Table 18:

Hematology panel 

Chemistry panel 

Inflammatory markers

Immunoglobulins

PK (Arm B) by ddPCR 
 

Research samples:

Peripheral blood for detection of B-cell aplasia by flow cytometry (Arm B)

Record all AEs, concomitant medications and concomitant procedures

Hospital resource utilization assessment 
Subjects in Arm A who discontinue treatment should be scheduled as soon as possible for early 
termination (ET) visit and subsequently followed as per Table 3 on Day 99 and 126.
In case subjects received subsequent antineoplastic therapies, new disease therapies since study 
treatment discontinuation should be collected and only the assessments described in 
Section 6.3.1.2 applicable for this visit should be performed.
1.0
Approved
930193545
6.0
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Approved
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EDMS Doc. Number: 24298999 - 22342725
JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
71
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
6.2.12.
Day 99 (± 7 days)
The following assessments are to be performed

ECOG performance status assessment 

Physical examination

Routine neurologic examination 

MMSE (see Appendix F and Section 6.4.5) 

Vital signs 

Collection of peripheral blood samples for clinical laboratory evaluations as described 
in Table 18:

Hematology panel 

Chemistry panel 

Record all AEs, concomitant medications and concomitant procedures

Hospital resource utilization assessment 
Subjects in Arm A who discontinue treatment should be scheduled as soon as possible for early 
termination (ET) visit and subsequently followed as per Table 3 on Day 126.
In case subjects received subsequent antineoplastic therapies, new disease therapies since study 
treatment discontinuation should be collected and only the assessments described in 
Section 6.3.1.2 applicable for this visit should be performed.
6.2.13.
Day 106 (± 7 days) (Arm A)
The following assessments are to be performed:

ECOG performance status assessment 

Physical examination

Vital signs 

Collection of peripheral blood samples for clinical laboratory evaluations as described 
in Table 18:

Hematology panel 

Chemistry panel 

Record all AEs, concomitant medications and concomitant procedures

Hospital resource utilization assessment 

Collect new disease therapies since study treatment discontinuation (if applicable)
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6.2.14.
Day 126 (± 7 days)
For Arm A subjects, this visit should be scheduled based on date of the HDCT (Day 71) (ie, 2 
months after).
The following assessments are to be performed:

ECOG performance status assessment 

Physical examination

Vital signs 

Collection of peripheral blood samples for clinical laboratory evaluations as described 
in Table 18:

Hematology panel 

Chemistry panel 

Inflammatory markers

Immunoglobulins 

Serum ß-hCG pregnancy test on women of child-bearing potential 3 months after 
the JCAR017 infusion (Arm B)

RCL testing (Arm B)

PK (Arm B) by ddPCR

Research samples:

Plasma samples

Peripheral blood for detection of B-cell aplasia by flow cytometry (Arm B)

Response assessments: PET and CT/MRI (Week 18)

Record all AEs, concomitant medications and concomitant procedures

Quality of life questionnaires: EORTC QLQ-C30, 
and FACT-Lym 
“Additional concerns” subscale

Hospital resource utilization assessment 
In case subjects received subsequent antineoplastic therapies, new disease therapies since study 
treatment discontinuation should be collected and only the assessments described in 
Section 6.3.1.2 applicable for this visit should be performed.
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6.3.
Post-Treatment Period
6.3.1.
Follow-up
All randomized subjects who received study treatment, including subjects who withdraw from 
treatment period early (early termination [ET]) and those with progressive disease, should 
complete the post-treatment follow-up visits at approximately Months 6 (± 10 days), 9, 12, 18, 24 
and 36 (or end of study [EOS]) ± 14 days after randomization for disease status and survival. 
6.3.1.1.
Subjects who Have not Received Subsequent Antineoplastic Treatment
6.3.1.1.1. Month 6 (± 10 days)
The following assessments are to be performed:

ECOG performance status assessment 

Physical examination

Vital signs 

Collection of peripheral blood samples for clinical laboratory evaluations as described 
in Table 18:

Serum ß-hCG pregnancy test on women of child-bearing potential 

Hematology panel 

Chemistry panel 

Immunoglobulins

RCL testing (Arm B)

PK (Arm B) by ddPCR

Research samples:
 

Peripheral blood for detection of B-cell aplasia by flow cytometry (Arm B)

Response assessments: PET and CT/MRI 

Record all AEs, concomitant medications and concomitant procedures

Quality of life questionnaires: EORTC QLQ-C30, 
and FACT-Lym 
“Additional concerns” subscale

Hospital resource utilization assessment 

Collect new disease therapies since study treatment discontinuation (if applicable)
6.3.1.1.2. Months 9, 12, 18, 24, and 36 (± 14 days)
The following assessments are to be performed:
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
ECOG performance status assessment 

Physical examination

Vital signs 

Serum ß-hCG pregnancy test on women of child-bearing potential (Month 9, 12 [Arm 
B] and Month 36 [Arm A and B])

Collection of peripheral blood samples for clinical laboratory evaluations as described 
in Table 18:

Hematology panel 

Chemistry panel 

Immunoglobulins 

RCL testing (Months 12, 18, 24, 36) (Arm B)

PK (Arm B) by ddPCR

Research samples:

Plasma samples 

Peripheral blood for detection of B-cell aplasia by flow cytometry (Months 12, 
18, 24, 36) (Arm B)

Response assessments: PET and CT/MRI 

Record only AEs, concomitant medications and concomitant procedures related to 
study treatment

Quality of life questionnaires: EORTC QLQ-C30, 
and FACT-Lym 
“Additional concerns” subscale

Hospital resource utilization assessment 

Collect new disease therapies since study treatment discontinuation (if applicable)

The EOS visit will be registered in IRT system (Month 36)
6.3.1.2.
Subjects who Have Received Subsequent Antineoplastic Treatment 
The following assessments are to be performed:

Physical examination required on Months 12, 24 and 36

Immunoglobulins required on Months 6, 9, 12, 18, 24 and 36 

RCL sample collection required on Months 6, 12, 24 and 36 only for subjects who 
received JCAR017
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
Viral vector sequence PK by ddPCR sample collection only for subjects who received 
JCAR017

Record AEs, associated concomitant medications and concomitant procedures
according to Section 10.1

Collect information regarding new disease therapies (eg, start and end date, best 
response) since study treatment discontinuation

The EOS visit will be registered in IRT system (Month 36)

Serum ß-hCG pregnancy test on women of child-bearing potential (Month 36)
6.3.2.
Assessments for Subjects Crossing Over to JCAR017
If requested by the investigator, subjects in Arm A may be allowed to receive JCAR017 upon 
central confirmation of one of the following criteria:

Failure to achieve CR or PR by 9 weeks post-randomization

Progression at any time

Need to start a new antineoplastic therapy due to efficacy concerns after 18 weeks 
post-randomization
Reasons for cross over of a subject will be recorded in the CRF. JCAR017 delivery and 
administration will be coordinated with the Sponsor once the Investigator confirms the request 
for a cross over and the sponsor approves and documents the request based on the IRC 
confirmation. In case the cross over at time of EFS event is not requested by the Investigator, the 
unstimulated leukapheresis collected at screening and stored at the manufacturing site will be 
destroyed. Subjects must meet the criteria for LD chemotherapy as well as for starting JCAR017 
in addition to the confirmation of an EFS event. Please refer to Table 4 for the schedule of 
assessments for subjects randomized to Arm A that cross over to JCAR017 treatment. For 
detailed procedures please refer to the procedures described for Arm B visit, noting that not all 
Arm B assessments are required, with the below correspondence:
Visit for patients crossing over to JCAR017
Section for Reference
Pre-Treatment Evaluation 
Section 6.1.1
LD Chemotherapy
Section 6.2.3.2
JCAR017 infusion – Day 1
Section 6.2.4.2
Days 2, 3, 4, 11
Section 6.2.5
Day 8
Section 6.2.6
Day 15
Section 6.2.7
Day 22
Section 6.2.8
Day 29 – Month 1
Section 6.2.9
Month 2
Section 6.2.11
Month 3
Section 6.2.14
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Visit for patients crossing over to JCAR017
Section for Reference
Month 6
Section 6.3.1.1.1 (Month 6) or Section 6.3.1.2
Month 9
Section 6.3.1.1.2 (Month 12) or Section 6.3.1.2
Month 12
Section 6.3.1.1.2 (Month 24)
Survival Follow-up
Section 6.3.7
6.3.3.
Unscheduled Evaluations 
If the Investigator feels that a subject needs to be evaluated at a time other than the protocol-
specified visit, the subject may be asked to come in to the clinic for an unscheduled evaluation. 
The following assessments may be performed, as appropriate: 

Physical examination 

Neurological examination

MMSE

Vital signs 

ECOG performance status assessment 

Clinical laboratory evaluations 

PET scan 

CT/MRI scan 

Tumor biopsy (see the JCAR017-BCM-003 laboratory manual) 

Bone marrow aspirate and biopsy (see the JCAR017-BCM-003 laboratory manual) 

Electroencephalogram

CSF assessment 

Brain imaging

RCL peripheral blood

PK by ddPCR 

Research samples (see the JCAR017-BCM-003 laboratory manual): 

Plasma samples

Peripheral blood for detection of B-cell aplasia by flow cytometry (Arm B)

Leukapheresis
Additionally, if the Investigator requests any of the following procedures, research samples may
be requested: 

Lumbar puncture or Ommaya reservoir tap for CSF assessment
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
Fluid sampling 

Tissue sampling 

Autopsy 
6.3.4.
Assessments at Time of Death (Subjects Receiving JCAR017)
In case an autopsy is performed, blood and tissue samples may be collected if feasible for central 
analysis of markers related to safety and efficacy of the CAR T cells. 
6.3.5.
Early Withdrawal
If a subject voluntarily withdraws prematurely from the study, a visit will be scheduled as soon 
as possible, and all the assessments listed for the Month 36 (EOS) visit (Table 3) will be 
performed. Subjects from Arm A who cross over to JCAR017 and subsequently voluntarily 
withdraw prematurely from the study, will have a visit scheduled as soon as possible, and all the 
assessments listed for the Month 12 (EOS) visit (Table 4) will be performed.
6.3.6.
Second Primary Malignancy Follow-up Period
Second primary malignancies will be monitored as events of interest and must be reported as 
serious adverse events regardless of the treatment arm and cohort the subject was in. This 
includes any new malignancies, regardless of causal relationship to IP(s), occurring throughout 
the subject’s entire participation in the study. If a subject develops a second primary malignancy, 
the Sponsor will request a tumor sample (refer to JCAR017-BCM-003 laboratory manual) and 
blood samples (See also Section 6.4.10 and Section 6.4.11) for further testing.
6.3.7.
Survival Follow-up
After EOS visit, all subjects will be followed for survival every 3 months (± 30 days) until last 
subject last visit. Additional follow-up information will be collected in the context of the LTFU 
protocol for all subjects who received JCAR017. 
6.3.8.
Long-term Follow-up 
Because this protocol involves gene transfer, long-term follow-up for lentiviral vector safety, 
disease status, 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). 
All subjects who either complete the 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 informed consent form 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.
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6.4.
Safety Assessments
6.4.1.
Physical Examination
A physical examination should include assessments of the following body parts/systems: 
abdomen, extremities, heart, lungs, and neurological (as detailed in Section 6.4.5). In addition, 
symptom-directed exams should be performed.
6.4.2.
Vital Signs
Vital signs include temperature, respiratory rate, heart rate, blood pressure. On the day of 
JCAR017 administration, special monitoring is to be performed, refer to Section 7.4.5 for the 
details.
6.4.3.
Pulse Oximetry
Oxygen saturation (SaO2) will be assessed by pulse oximetry as per Table 3 and Table 4.
6.4.4.
Height and Weight
Height in centimeters (cm) or inches (in) and body weight to the nearest kilogram (kg) or pound 
(lb) in indoor clothing, but without shoes will be measured according to Table 3 and Table 4.
6.4.5.
Routine Neurologic and Mini Mental State Examinations
A routine neurologic examination should include, at minimum, a physical exam to assess cranial 
nerves, motor and sensory skills, coordination and balance, and the Mini Mental State 
Examination (MMSE; see Appendix F). The MMSE may be administered by an appropriately 
trained provider as per investigator judgment (ie, physician, nurse); a neurologist is not required. 
Efforts should be made to have the same provider perform the MMSE on a given subject to 
maintain consistency of assessment. If subjects in Arm B develop neurologic symptoms 
suspicious of and/or diagnosed as neurologic toxicity, subjects will have daily MMSE exams 
until resolution of symptoms, unless the subject is medically incapacitated and/or medically 
unable to complete the MMSE.
6.4.6.
Cerebrospinal Fluid Assessment
Cerebrospinal fluid (CSF) assessment and CNS imaging should be performed if CNS 
involvement is suspected at screening or at any time during the study as clinically indicated (eg, 
if new CNS symptoms occur, or if clinical signs or suspicion of CNS lymphoma exist). 
Cerebrospinal fluid will be analyzed for cell count, differential cytology, glucose and protein 
levels. Cerebrospinal fluid cultures (bacterial, fungal, viral) should be performed as clinically 
indicated for suspicion of infection.
6.4.7.
Eastern Cooperative Oncology Group Performance Status
Eastern Cooperative Oncology Group (ECOG) performance status (see Appendix B) will be used 
to evaluate subject eligibility at screening and will be assessed throughout the study at time 
points specified in Table 3 and Table 4.
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6.4.8.
Multi-gated Acquisition Scan / Echocardiogram
An assessment of LVEF will be performed by ECHO or MUGA to assess the cardiac function of 
the subject and to confirm study eligibility.
6.4.9.
Electrocardiogram 
A standard 12-lead ECG should be obtained. ECG 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.
6.4.10.
Replication-Competent Lentivirus Testing (Subjects receiving JCAR017)
Replication-competent lentivirus (RCL) testing will be performed on genomic DNA obtained by 
a peripheral blood draw, and if positive, confirmed on 
 Details regarding sample 
collection and processing are provided in the JCAR017-BCM-003 laboratory manual. Testing for 
RCL will utilize a polymerase chain reaction based assay.
Samples for RCL testing will be collected at timepoints indicated in Table 3 and Table 4. If all 
samples collected within the first year after the dose of JCAR017 are negative, subsequent 
samples will be collected and archived. 
 
 
 
Samples will be archived with appropriate safeguards to ensure long-term stability and an 
efficient system for the prompt linkage and retrieval of the stored samples with the subject’s 
study records and the production lot records. Archived samples will be destroyed as outlined in 
the LTFU protocol.
If a subject develops a second primary malignancy, the Sponsor will request a sample for 
assessment of RCL.
6.4.11.
Viral Vector Sequence Testing (Subjects receiving JCAR017)
Persistence of JCAR017 vector sequences will be monitored at timepoints indicated in Table 3
and Table 4. Details regarding sample collection and processing are provided in the JCAR017-
BCM-003 laboratory manual. The presence of vector HIV gag DNA sequences will be 
determined by evaluation of blood samples by ddPCR.
 
 
 
 
 
If a subject develops a second primary malignancy, the Sponsor will request a sample for 
assessment of viral vector sequence testing.
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6.4.12.
Clinical Laboratory Evaluations
Screening and other laboratory evaluations (see Appendix G) will be performed according to
Table 3 and Table 4. Additional assessments should be performed between scheduled study visits 
as clinically required in order to diagnose and monitor AEs/SAEs or expected events. A central 
laboratory will be used; however, clinical management of study subjects will be based on local 
assessments.
6.5.
Efficacy Assessment 
Efficacy will be assessed according to the Celgene Lugano Classification guidelines based on 
radiographic tumor evaluation by diagnostic quality CT/MRI scans (chest, neck, abdomen, and 
pelvis) and PET scans (see Appendix C). These guidelines are based on the “Recommendations 
for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin 
Lymphoma: The Lugano Classification” (Cheson, 2014). Assessment of bone marrow 
involvement by lymphoma will be performed by PET scan only; bone marrow aspirates and 
biopsies will not be required for assessment of disease response. Efficacy assessments will be 
performed at Weeks 9 (after 3 cycles of SOC for Arm A and 5 weeks after JCAR017 infusion for 
Arm B) and 18 (8 weeks after the start of HDCT for Arm A and 14 weeks after JCAR017 
infusion for Arm B) and Months 6, 9, 12, 18, 24 and 36. 
Subjects in Arm B who received bridging chemotherapy should have a PET performed prior to 
start of lymphodepleting chemotherapy. This assessment will be only used for evaluation of PET 
disease status, not counted as a formal efficacy assessment.
6.5.1.
Pseudoprogression 
If a subject demonstrates early tumor progression (defined as occurring prior to 3 months after 
JCAR017 infusion), the investigator is responsible for evaluating whether the subject is 
experiencing a possible pseudoprogression (ie, tumor flare, which is local inflammatory reaction 
indicating early tumor response at sites of disease such as lymph nodes) (Cheson, 2016).  
6.6.
Pharmacokinetics 
6.6.1.
Pharmacokinetics of JCAR017
Assessment of JCAR017 PK will be determined by ddPCR to detect vector HIV gag DNA 
sequences
. 
 Peripheral blood will be 
collected as indicated in Table 3 and Table 4.
Detailed information regarding the collection, handling, and shipment of PK assessment samples 
is provided in the JCAR017-BCM-003 laboratory manual.
6.7.
Biomarkers, 
 
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6.7.2.
Exploratory Biomarkers
 
efficacy and severity 
of CRS and neurotoxicity. 

Plasma may be analyzed for presence of cell-free DNA (cfDNA) as a surrogate for 
tumor burden and correlated with clinical efficacy. 
6.7.3.
Additional and Optional Research
Additional and optional research as described below may be performed using left-over samples
originally collected for another test required in this study or using samples collected specifically
for 
 testing. The research may involve genetic tests using DNA or RNA and may lead
to the development of new diagnostic tests.
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6.7.3.1.
Additional Research
Additional research related to the study drug and/or disease may be performed. The results of
this additional research could help to improve the diagnosis and/or the treatment of this disease
in the future.
6.7.3.2.
Optional Research
Optional research not related to the study drug or the subject’s disease may be performed. The
subject’s decision to participate in this optional research will not impact their ability to
participate in the main study.
6.8.
Subject Reported Outcomes or Quality of Life or Health Economics
Subject-reported quality-of-life outcomes will be administered according to Table 3.
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. 
EORTC QLQ-C30 
and FACT-Lym “Additional concerns” subscale will be used to assess the subject’s health as 
well as physical, social, emotional, and functional well-being. Reasons for missing subject 
reported outcomes questionnaires should also be captured so that the appropriate imputation 
method can be employed to correct for missing data in the analysis.
The questionnaire will be completed by the subjects before any clinical assessments are 
performed and treatments administered at any given visit. If subjects refuse to complete all or 
any part of a questionnaire, this will be documented. Questionnaires should be completed in the 
language most familiar to each subject, and subjects should be given adequate time and space to 
complete the questionnaire. Site personnel should review questionnaires for completeness and 
ask subjects to complete any missing responses.
6.8.1.
EORTC QLQ-C30
The European Organization for Research and Treatment of Cancer – Quality of Life C30 
Questionnaire (EORTC QLQ-C30) questionnaire will be used as a measure of health-related 
quality of life. The EORTC QLQ-C30 is composed of both multi-item scales and single item 
measures. These include five functional scales (physical, role, emotional, cognitive and social), 
three symptom scales (fatigue, nausea/vomiting, and pain), a global health status/health-related 
quality of life (HRQoL) scale, and six single items (dyspnea, insomnia, appetite loss, 
constipation, diarrhea, and financial difficulties). Each of the multi-item scales includes a 
different set of items – no item occurs in more than one scale.
The EORTC QLQ-C30 employs a week recall period for all items and a 4-point scale for the 
functional and symptom scales/items with response categories “Not at all”, “A little”, “Quite a 
bit” and “Very much”. The two items assessing global health status/ HRQoL utilize a 7-point 
scale ranging from 1(“Very Poor”) to 7 (“Excellent”) (Aaronson, 1993). See Appendix H.
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6.8.3.
FACT-Lym
The Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) that consists of the 
FACT-General scale and a 15-item lymphoma-specific additional concerns subscale (LYM). 
This scale addresses symptoms and functional limitations that are important to lymphoma 
patients. Only the LYM subscale will be administered in this study because the topics covered by 
these subscales are instead assessed by the EORTC QLQ C30 items and subscales. The LYM 
items are scored on a 0 (“Not at all”) to 4 (“Very much”) response scale. Items are aggregated to 
a single score on a 0-60 scale. See Appendix J.
6.8.4.
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 
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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(s)
7.1.1.
JCAR017
See Section 1.2 for JCAR017 description.
JCAR017 will be supplied by the Sponsor and labeled appropriately as investigational product 
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.
Lymphodepleting Chemotherapy
Fludarabine and cyclophosphamide will be sourced locally by the clinical site. 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). The fludarabine and cyclophosphamide dosing schedule and 
dose adjustments to be followed for this study are described in Section 7.4.2.
7.3.
Reference therapies
Standard of care regimen defined as R-DHAP, R-ICE and R-GDP followed by HDCT will be 
sourced locally by the clinical site. Please refer to local SOC and HDCT components prescribing 
information for more details on available formulations, preparation, storage conditions (eg, 
refrigeration), the approved indications, known precautions, warnings, and adverse reactions of 
the SOC and HDCT components (see current version of Prescribing Information). The SOC and 
HDCT dosing schedule to be followed for this study are described in Section 7.4.1.
7.4.
Treatment Administration and Schedule
7.4.1.
Reference Therapies
Standard of care regimen will be administered as per investigator decision. Subjects should 
receive 3 cycles of SOC followed by HDCT and an HSCT.
1. R-DHAP: Rituximab 375 mg/m² - Day 1, dexamethasone 40 mg – Days 1 to 4, 
cytarabine 2 x 2000 mg/m² - Day 2, cisplatin 100 mg/m² - Day 1
2. R-ICE: Rituximab 375 mg/m² - Day 1, ifosfamide 5000 mg/m² - Day 2, etoposide 100 
mg/m² - Days 1 to 3, carboplatin area under the curve (AUC) 5 (maximum dose 800 mg)
– Day 2
3. R-GDP: Rituximab 375 mg/m² - Day 1, dexamethasone 40 mg – Days 1 to 4, 
gemcitabine 1000 mg/m² - Days 1 and 8, cisplatin 75 mg/m² - Day 1
The standard HDCT to be used in this study prior to the HSCT is BEAM defined as carmustine 
(BCNU) 300 mg/m² - Day 1, etoposide 200 mg/m² - Days 2 to 5, cytarabine 200 mg/m² - Days 2
to 5, melphalan 140 mg/m² - Day 6.
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Standard of care regimen, schedule of the regimen, dose adjustment for toxicities and 
premedication will be done as per site standard, local label and investigator’s decision. In Japan, 
due to unavailability of intravenous BCNU, ranimustine (MCNU) will be used at the same 
dosage and schedule as BCNU.
7.4.2.
Lymphodepleting Chemotherapy
Subjects will be treated with fludarabine IV (30 mg/m2/day for 3 days) and cyclophosphamide 
IV (300 mg/m2/day for 3 days) prior to JCAR017 infusion. Refer to the most recent package 
inserts for further details on administration of these agents.
Lymphodepleting chemotherapy can start 5 to 7 days before JCAR017 infusion and must be 
completed at least 2 days before JCAR017 infusion. If side effects from the LD chemotherapy 
occur, JCAR017 infusion may be delayed for up to 7 days after LD chemotherapy upon 
discussion with Celgene. Refer to Section 6.2.3.2 for the assessments that will be performed on 
each day of LD chemotherapy.
Serum creatinine will be measured on the first day of LD chemotherapy; LD chemotherapy 
should be withheld if serum creatinine is > 1.5 times upper limit of normal (ULN) OR calculated 
creatinine clearance (by Cockcroft-Gault, see Appendix D) is ≤ 30 mL/min. 
The recommended administration is as follows: 

The IV hydration is 1 L of 0.9% sodium chloride (NaCl) given at 500 mL/hr starting 
2 hours prior to cyclophosphamide

Fludarabine IV 30 mg/m2 over 30 minutes

If creatinine clearance (CrCl) is between 50 to 70 mL/min: Reduce dose by 20%
for each daily dose

If CrCl is between 30 to 49 mL/min: Reduce dose by 40% for each daily dose

If CrCl < 30 mL/min: Do not administer fludarabine

Cyclophosphamide IV 300 mg/m2 over 60 minutes

Additional 1 L of 0.9% NaCl given at 500 mL/hr
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.
7.4.3.
JCAR017 Premedication
Subjects should be premedicated with 500 to 650 mg paracetamol/acetaminophen per os (PO) 
and 25 to 50 mg diphenhydramine hydrochloride (PO or IV) 30 to 60 minutes prior to JCAR017 
infusion. In case the diphenhydramine is not available in a country, it is acceptable to use another 
H1 antihistamine.
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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7.4.4.
JCAR017 Preparation and Cell Thawing
See the JCAR017 Product administration manual for details.
7.4.5.
JCAR017 Administration
JCAR017 will be infused at a dose of 100 x 106 JCAR017-positive viable transduced T cells 
(CAR+ T cells) on Day 29 (2 to 7 days after completion of LD chemotherapy) for subjects 
randomized in Arm B. For subjects from Arm A crossing over to JCAR017, refer to the schedule 
on Table 4. Each JCAR017 dose includes CD4+ CAR+ T cells and CD8+ CAR+ T cells. The 
subject must be continuously monitored during each administration of JCAR017. Vital signs 
(temperature, respiratory rate, heart rate, blood pressure, and SaO2 by pulse oximetry) will be 
measured approximately every 15 minutes, starting from 15 minutes prior to the first IV 
administration until one hour after the last IV administration, and hourly for the next 2 hours. If 
the subject’s vital signs are not stable 4 hours following the final administration, vital signs 
should be monitored as clinically indicated until stable.
See the JCAR017 Product Administration Manual for complete information.
7.4.6.
Non-Conforming Product
7.4.6.1.
Protocol Product Deviation Plan 
The JCAR017 Protocol Product Deviation Plan (PPDP) defines an assessment and decision-
making process, which could result in a recommendation to treat a subject with a drug product 
that does not meet the specification for certain non-safety related attributes (non-conforming 
JCAR017). In this process, the Medical Monitor and the Primary Investigator at the clinical site 
agree that the health of the subject and the risk/benefit profile is acceptable for the subject to 
receive treatment. Quality Assurance then assesses the recommendation and is ultimately 
responsible for the drug product lot disposition. Documentation of the non-conforming drug 
product is submitted to local health authorities and is provided to the Investigator to submit per 
institutional review board/ ethics committee (IRB/EC) requirements. The JCAR017 PPDP is a 
stand alone document.
7.4.6.2.
Exception Use of Non-conforming Product
Once a decision is made for the exception use of non-conforming JCAR017, country-specific 
requirements will be followed for the release of a non-conforming JCAR017 product to treat a 
subject enrolled in a JCAR017 clinical trial.  For example, approval from local health authorities 
and/or IRBs/ECs will be obtained where required.  In the European Union (EU), requirements 
provided in Section 11.54 of the EU Guideline on good manufacturing practice specific to 
advanced therapy medicinal products will be followed. Any subject will need to provide consent 
prior to receiving the non-conforming JCAR017 product. Please refer to Section 9 for the details 
regarding analyses of these subjects.
7.4.7.
Overdose
Overdose, as defined for this protocol, refers to SOC regimen and HDCT, fludarabine (IV), 
cyclophosphamide (IV) or JCAR017 (IV). On a per-dose basis, an overdose is defined as the 
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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

PO: Any amount 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 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 case report form (CRF)
(see Section 10 for the reporting of AEs associated with overdose).
7.5.
Method of Treatment Assignment
At Day 1, subjects will be randomized via an IRT system to one of the 2 arms (Arm A or Arm 
B). Details of the use of the IRT system are found in the IRT user manual.
7.6.
Packaging and Labeling
7.6.1.
Product Tracking
7.6.1.1.
Reference Therapies 
Manufacturer details and batch numbers will be used for the reference therapies components
tracking.
7.6.1.2.
Lymphodepleting Chemotherapy
Manufacturer details and batch numbers will be used for the products tracking.
7.6.1.3.
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.
7.6.2.
Product Packaging and Labeling
7.6.2.1.
Lymphodepleting Chemotherapy
Fludarabine and cyclophosphamide will be provided by the clinical sites and labeled as per their 
local procedures.
7.6.2.2.
Reference Therapies
Standard of care regimen and HDCT components will be provided by the clinical sites and 
labeled as per their local procedures. 
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7.6.2.3.
JCAR017
The label(s) for 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.
7.6.3.
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.
7.7.
Investigational Product Accountability and Disposal
7.7.1.
Accountability Procedures
An inventory must be performed and a product receipt log filled out and signed by the person 
accepting the shipment of JCAR017 cell product.
7.7.2.
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).
7.8.
Investigational Product Compliance
7.8.1.
Reference Therapies
For the SOC and HDCT regimen, the administered dosage of the different components will be 
recorded in the source documents and on the appropriate CRFs. Additionally, if the study subject 
misses a dose, this information should be documented in the study subject’s CRF and source 
documents.  
Where provided by Celgene Corporation an accurate accounting of the dispensing and return for 
each study subject will be maintained in the source documents on an ongoing basis by a member 
of the study site staff. Disposal and/or destruction of unused or remaining reference therapies 
will be performed as per local procedures.
7.8.2.
Lymphodepleting Chemotherapy
For the LD chemotherapy, the administered dosage of the different components will be recorded 
in the source documents and on the appropriate CRFs. Additionally, if the study subject misses a 
dose, this information should be documented in the study subject’s CRF and source documents.  
Where provided by Celgene Corporation an accurate accounting of the dispensing and return for 
each study subject will be maintained in the source documents on an ongoing basis by a member 
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of the study site staff. Disposal, and/or destruction of unused or remaining Fludarabine and/or 
Cyclophosphamide will be performed as per local procedures.
7.8.3.
JCAR017
The administered dosage of JCAR017 will be recorded in source documents and on the 
appropriate CRFs. The investigator(s) or designee is responsible for taking an inventory of each 
shipment of investigational product 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 CRF 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 taken by the subject at the time of an AE related to protocol-mandated procedures 
will be recorded from informed consent until randomization. All medications will be recorded 
from the randomization and until 90 days after JCAR017 or 90 days after last dose of 
chemotherapy. From 91 days after JCAR017 or 91 days after last dose of chemotherapy until the 
EOS visit, concomitant medications given for AEs related to the study treatment or any protocol-
mandated procedures will be recorded. For subjects receiving LD chemotherapy but not 
JCAR017, concomitant medications associated with AEs will be recorded for 30 days following 
the last dose of LD chemotherapy. 
Table 5:
Reporting Periods for Concomitant Medications, Procedures and 
Transfusions 
Arm
Start
End
Required Reporting
Arm A and B Informed Consent
Randomization
Medications given, procedures and 
transfusions performed for a clinically 
significant condition related to 
protocol-mandated procedures or for 
active medical history conditions 
should be reported as described in the 
CRF completion guidelines
Arm A
Randomization
90 days after last dose 
of chemotherapy 
All medications, procedures and 
transfusions
Arm B and 
cross over
Randomization (Arm 
B) and
Pre-treatment 
evaluation (cross over)
90 days after 
JCAR017 infusion 
Arm A, B 
and cross 
over
End of previous period
End of study
Only medications, procedures and 
transfusions ongoing at the time of 
AEs related to any protocol-mandated 
procedures, SOC/HDCT or JCAR017
Abbreviations: AEs = adverse events, CRF = case report form, HDCT = high-dose chemotherapy, SOC = standard 
of care.
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.
Due to the large amount of data generated during hospitalizations, a targeted concomitant 
medication collection approach will be utilized for the CRF. The medications which should NOT 
be entered in the Concomitant Medications CRF during inpatient and ICU stays are defined in 
the CRF Completion Guidelines.
Over the course of this study, additional medications may be required to manage aspects of the 
disease state of the subjects (refer to Section 8.1.1), including side effects from trial treatments or 
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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 granulocyte colony-stimulating factors is permitted per institutional or 
clinical standards. Prophylactic anticoagulation to prevent thromboembolic events is permitted as 
per institutional or clinical standards.
All concomitant treatments, including blood and blood products, used from 30 days prior to first 
dose of any IP until 30 days after the last dose of IP, must be reported on the CRF. 
Intrathecal treatment (IT) with methotrexate and/or cytarabine is allowed for prophylaxis and for 
treatment of subjects with secondary CNS involvement. Subjects with secondary CNS 
involvement who received IT treatment with methotrexate and/or cytarabine should have a 
minimum of 7 days wash-out period prior to the start of lymphodepleting chemotherapy.
Local radiation is allowed to a single lesion or subset of lesions if other non-irradiated PET-
positive lesions are present and if completed at least 7 days prior to the start of lymphodepleting 
chemotherapy.
Radiotherapy is allowed after completion of per protocol treatment in both arms to sites of 
previous PET positive disease.
For information regarding other drugs that may interact with any study treatment 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.
Bridging Chemotherapy (Subjects Receiving JCAR017)
In Arm B, bridging chemotherapy with one of the protocol-defined SOC regimen (Section 7.4.1)
is allowed for disease control while JCAR017 is being manufactured if deemed necessary by the 
investigator (ie, after leukapheresis and prior to lymphodepleting chemotherapy). Bridging 
therapy given after leukapheresis to maintain disease control must be stopped at least 7 days 
prior to LD chemotherapy.
For subjects from Arm A who cross over to JCAR017, bridging with non-investigational therapy 
is allowed if completed at least 7 days prior to the start of lymphodepleting chemotherapy. 
Local radiation is allowed to a single lesion or subset of lesions if other non-irradiated PET-
positive lesions are present and if completed at least 7 days prior to the start of lymphodepleting 
chemotherapy.
8.2.
Prohibited Concomitant Medications and Procedures
The following medications are considered exclusionary or should be used with caution during 
the study. The sponsor must be notified if a subject receives any of these during the study.

Any investigational antineoplastic therapy
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
Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for 
cancer treatment (except IT prophylaxis and treatment for secondary CNS 
involvement);

Concurrent use of hormones for non-cancer-related conditions (eg, insulin for 
diabetes and hormone replacement therapy) is acceptable;

Immunosuppressive medications including, but not limited to systemic corticosteroids 
at doses exceeding 20 mg/day of prednisone or equivalent, methotrexate, 
azathioprine, and tumor necrosis factor alpha (TNF-α) blockers;
Note: Use of immunosuppressive medications for the management of IP-related AEs or in 
subjects with contrast allergies is acceptable. In addition, use of inhaled and intranasal 
corticosteroids is permitted; therapeutic doses of steroids may be used in life-threatening 
situations and for other medical conditions when indicated.
8.2.1.
Subjects Infused with JCAR017
The following medications are prohibited until lack of response, subsequent therapy for 
lymphoma, or 1 year following JCAR017 treatment, whichever comes first: 

Steroids: therapeutic doses (> 20 mg/day of prednisone or equivalent) unless used for 
treatment of CRS and NT. Therapeutic doses may be used in life-threatening 
situations and for other medical conditions when indicated, or after loss of detectable 
JCAR017 cells. Pre-treatment containing steroids may be given for necessary 
medications (eg, intravenous immunoglobulin [IVIG]) after discussion with the 
Sponsor. Pre-medication with steroids for JCAR017 administration is not allowed. 
Physiologic replacement dosing of steroids 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 antineoplastic agent after lack of adequate response to study treatment or progression of 
lymphoma: 

Immunosuppressive therapies (eg, calcineurin inhibitors, methotrexate or other 
chemotherapeutics, mycophenolate, rapamycin, thalidomide, immunosuppressive 
antibodies such as anti-TNF, anti-IL6, or anti-IL6R) 

Non-protocol-specified antineoplastic agents, excluding IT prophylaxis and treatment 
for secondary CNS involvement. Lymphodepleting chemotherapy may be 
administered as an extraordinary measure to treat AEs of uncontrolled JCAR017 
proliferation, or CRS or neurotoxicity unresponsive to other therapeutic interventions

Cetuximab, or other anti- epidermal growth factor receptor (EGFR) targeted 
treatments, unless intended for treatment of uncontrolled JCAR017 proliferation 

Experimental agents 
The Sponsor must be notified if a subject receives any of these medications during the study.
Please refer to the locally approved fludarabine and cyclophosphamide labels for the list of
medications which should be avoided from concomitant use.
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8.3.
Required Concomitant Medications and Procedures
To minimize the risk of infusion reactions, all subjects should be premedicated with 
acetaminophen and diphenhydramine prior to JCAR017 infusion (see Section 7.4.3).
Supportive care for the management of CRS is detailed in Appendix L. In some cases, 
tocilizumab, an anti-IL-6R-antibody, may be required to treat toxicities such as CRS. Please refer 
to the currently approved Actemra®/ RoActemra® package insert. As per label, up to 4 doses of 
tocilizumab can be given for treatment of CRS. The recommendation is to follow the local 
labeled guidance. However, for JCAR017 investigators, 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, EU, Japan) 
must have at least 2 doses of tocilizumab available prior to infusion per a given patient and 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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9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
This is a global randomized multicenter phase 3 trial evaluating the efficacy and safety of 
JCAR017 versus SOC in subjects with high-risk, second-line, transplant-eligible 
relapse/refractory aggressive B-cells NHL.
The primary objective is to demonstrate that subjects treated with JCAR017 have a larger benefit 
on EFS than subjects treated with SOC salvage strategies. Key secondary objectives are to 
demonstrate hierarchically additional efficacy benefit on CRR, PFS and OS.
The ORCHARRD trial (van Imhoff, 2016) reports a median PFS (with failure to achieve a 
response after 2 cycles included as an event) in the overall population of approximately 3 
months, with a median OS of approximately 13.5 months, with significantly shorter PFS and OS 
in high risk subjects of approximately 2 months median PFS and 11 months median OS. Event-
free survival at 2 years for the R-DHAP and O-DHAP arms were 18% and 16%, respectively.
Date of randomization will be defined as Day 1. Baseline value will be defined as the last value 
on the randomization date (+3 days) or before the date/time of randomization (date if date/time 
not collected). If multiple values of the same variable are eligible for the baseline, the average of 
these values will be used as the baseline. For subjects who are not randomized, the baseline will 
be the last available value. For subjects crossing over to receive JCAR017, secondary baseline is 
defined as the last value on or before the date/time of start of LD chemotherapy (date if date/time 
not collected).
9.2.
Study Population Definitions
In this study, the following analysis sets will be defined for the analysis and presentation of the 
data.
9.2.1.
Screened Analysis Set
All subjects who signed informed consent form.
9.2.2.
Intention-to-Treat Analysis Set
All subjects randomized to a treatment arm. Reporting on the Intention-to-Treat (ITT) analysis 
set will be done against the planned treatment.
9.2.3.
Per-Protocol Analysis Set
All subjects of the ITT analysis set characterized by:
-
Having a minimal exposure to treatment:

Arm A: one cycle of SOC (consisting on the administration of all the medications 
of the reference therapy);

Arm B: per protocol dose (CD8+ and CD4+) of conforming JCAR017;
-
Having a baseline assessment and at least one post-baseline response assessment;
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-
Without important protocol deviations.
Reporting on the per-protocol (PP) analysis set will be done against the actual treatment 
received.
9.2.4.
Safety Analysis Set
All subjects who take at least one dose of study treatment. Reporting done on safety analysis set
will be done against actual treatment received.
9.2.5.
Pharmacokinetic Analysis Set
All subjects who take conforming JCAR017 who have both pre-infusion and at least one post-
infusion PK measurement.
9.2.6.
Cross over Analysis Set (Arm A)
All subjects of the ITT analysis set randomized in Arm A who cross over to JCAR017 treatment.
9.2.7.
JCAR017-Treated Analysis Set
The JCAR017-treated analysis set will include all subjects who have received JCAR017 
conforming cell product.
9.2.8.
Health-related Quality of Life Analysis Set
The health-related quality of life (HRQoL) analysis set for each instrument, will include all 
subjects from the ITT population who completed a baseline and at least one post-baseline
HRQoL assessment. A subject will be considered compliant on each instrument based on the 
manual of this instrument. 
Reporting on HRQoL analysis set will be done against actual treatment received.
9.3.
Sample Size and Power Considerations
Sample size calculation, robustness and sensitivity is based on EAST 6.3 software (Cytel Inc.).
9.3.1.
Sample Size Calculation
It is hypothesized that subjects treated with SOC have median EFS of 3 months. Subjects 
receiving experimental treatment JCAR017 are expected to have an increase of ~ 81% in the 
median EFS (equivalent to a hazard ratio of 0.55 under the exponential distribution assumption) 
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compared to subjects treated with SOC, bringing the median EFS in the experimental group to 
5.455 months.
An interim analysis for superiority of JCAR017 over SOC on EFS will be performed at 60% 
information time (approximately 71 EFS events). O’Brien-Fleming boundary alpha spending 
function is used.
Given these assumptions, using a log rank test with 2.5% one-sided significance level, 119 EFS 
events will provide at least 90% power to reject the null hypothesis of HR greater than or equal 
to 1.
The null hypothesis will be rejected if the p-value associated to the test is smaller than or equal to 
0.004 at the time of the interim analysis for efficacy (ie, when 71 EFS events are observed) or 
smaller than or equal to 0.024 at the time of the primary efficacy analysis (ie., when 119 EFS 
events are observed). The significance thresholds will be adjusted based on the actual number of 
EFS events observed at the time of each efficacy analysis in order to ensure the nominal 
significance level is maintained.
Given an expected randomization rate of up to 12 subjects per month (2, 4, 6, 8 and 10 subjects 
randomized during 1st, 2nd, 3rd, 4th, 5th month and 12 subjects per months after 6th month) and 
a 20% drop out rate before first response assessment and a yearly dropout rate of 10% (30% 
cumulative), a sample size of 182 subjects is expected to be randomized and 215 subjects to be 
screened (screen failure rate of 15%). The estimated accrual duration is 17.6 months, which is 
the midpoint between the estimated minimal accrual time (15.1 months) and the suggested 
maximum (20 months); minimal and suggested maximum accrual times are estimated by the 
sample size software and are based on the assumptions described above. Interim analysis for 
efficacy is expected to be performed at around 14.7 months after study start and final analysis at 
around 21.4 months after study start. The approximated time for the interim analysis for efficacy 
and for the final analysis are based on the assumptions for alpha, power, HR (or improvement in 
median survival), interim looks, accrual models and drop-out rates and are estimated by the 
sample size software.  
If null hypothesis of HR equal to 1 is rejected for EFS, hypothesis testing on CRR (and 
subsequently on PFS and OS) will be performed hierarchically; the hierarchical testing strategy 
is used in order to control the overall type I error rate. If the null hypothesis can be rejected for 
the primary endpoint but at least one null hypothesis for key secondary endpoint cannot be 
rejected at the interim analysis for efficacy, then hypothesis testing on all key secondary 
endpoints will be re-evaluated at the primary efficacy analysis (Glimm, 2010). 
Considered independently, performed at the same time of the primary efficacy analysis and with 
the same randomization and dropout model, expected power will be respectively over 98% for 
CRR assuming a rate of 22% in Arm A and 51% in Arm B, over 96% for PFS assuming a 
median of 3 months in Arm A and 6 months in Arm B (HR = 0.5), and approximatively 37% for 
OS assuming a rate at 2 years of 41% in Arm A and 56% in Arm B (HR = 0.65).
In addition, an interim analysis for futility will be conducted when ~30 evaluable subjects (~15 
subjects per arm and having received their assigned treatment) have their 9 weeks response 
assessment (after 3 cycles of SOC for Arm A and 5 weeks after the JCAR017 infusion) or have 
been confirmed with disease progression prior to this timepoint. No formal statistical test will be 
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performed for this interim analysis, and therefore no type I error adjustment is implemented in 
the sample size calculation.
9.3.2.
Sample Size Robustness and Sensitivity
The robustness and the sensitivity of the proposed sample size has been evaluated under several 
conditions via simulations. Power extracted out of the simulations were rounded up to the next 
integer. Please note that number of subjects randomized is set to 182 and that maximum number 
of EFS events at primary efficacy analysis is set to 119.
If the HR is below the expected value and median EFS in Arm A is set to 3 months, power at the 
primary efficacy analysis is above 90% (see Table 6). If the HR is above the expected value but 
on or below 0.6 and median EFS in Arm A is set to 3 months, power at the primary efficacy 
analysis is at an acceptable level (see Table 6). If expected HR is strictly above 0.6 with median 
EFS in Arm A set to 3 months, power at the primary efficacy analysis (ie, when 182 subjects are 
randomized and 119 events are observed) is below acceptable levels, indicating that the number 
of EFS events triggering the primary efficacy analysis is insufficient to reject the null hypothesis 
with a high likelihood.
When EFS events are not distributed according to an exponential distribution but according to a 
Weibull distribution (with shape parameter set at the same value in Arm A and Arm B, ensuring 
proportional hazard assumption is maintained), targeting the same absolute clinical benefit 
(median EFS at 3 months in Arm A and median EFS at 5.455 months in Arm B) underpowered 
and overpowered situations may occur. In case the shape parameter is above 1 (indicating that 
hazards in both arms are increasing with time but with constant hazard ratio), HR is below the 
expected value and power at the primary efficacy analysis is above 90% (see Table 7). In case 
the shape parameter is below 1 (indicating that hazards in both arms are decreasing with time but 
with hazard ratio constant), power is at an acceptable level as long as shape parameter is strictly
above 0.75 (see Table 7).
Table 6:
Power Estimated via Simulation for other HR Assumptions
Hazard Ratio
Median EFS in 
Arm A
Median EFS in 
Arm B
Events at 
Interim/Primary 
Efficacy Analysis
Power at 
Primary Efficacy 
Analysis
0.5
3 months
6 months
71 / 119
96%
0.525
3 months
~5.7 months
71 / 119
93%
0.575
3 months
~5.2 months
71 / 119
84%
0.6
3 months
5 months
71 / 119
78%
0.65
3 months
~4.6 months
71 / 119
64%
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Table 7:
Power Estimated via Simulation with Weibull Distribution
Shape Parameter
Median EFS in 
Arm A
Median EFS in 
Arm B
Events at 
Interim/Primary 
Efficacy Analysis
Power at 
Primary Efficacy 
Analysis
1.25
3 months
5.455 months
71 / 119
98%
1.1
3 months
5.455 months
71 / 119
94%
0.9
3 months
5.455 months
71 / 119
82%
0.8
3 months
5.455 months
71 / 119
73%
0.75
3 months
5.455 months
71 / 119
68%
9.4.
Background and Demographic Characteristics
Subject’s age, height, weight, and continuous baseline variables will be summarized using 
descriptive statistics (number of non-missing values, mean, median, standard deviation, 
interquartile range, range), while sex, race and other categorical variables will be provided using 
frequency tabulations for the ITT, PP and safety analysis set for each arm and as per histology. 
Medical history data, including prior cancer therapies will be summarized using frequency 
tabulations by Medical Dictionary for Regulatory Activities (MedDRA) system organ class 
(SOC) and preferred term (PT) for the ITT, PP and safety analysis set for each arm and as per 
histology.
9.5.
Subject Disposition
Subject disposition will be summarized using frequency and percent in the screened, ITT, PP and 
safety analysis set for screening, treatment and follow-up period. Summary of subjects 
randomized by site will be provided. Summary of subjects with protocol deviations and 
important protocol deviations will be provided per arm. Summary of subjects who are 
randomized for study treatment but not able to successfully generate a JCAR017 cell product, 
along with the reason(s) for manufacturing failure, will be summarized.
9.6.
Efficacy Analysis
Primary analysis will be based on the ITT analysis set. Per-protocol and safety analysis set will 
be used for supportive analyses when required.
For time-to-event endpoints such as EFS, PFS, DOR, and OS, the K-M product limit method will 
be used to extract summary information about survivorship. At least medians together with two-
sided 95% confidence intervals will be reported and it will be calculated and extracted from K-M 
curves.
In addition, the event rates at specific time-points will be computed, along with the standard 
errors and associated two-side 95% confidence intervals (Greenwood’s formula; Klein, 1997).
The rank preserving structural failure time (RPSFT), the inverse probability of censoring 
weighting (IPCW) and the 2-stage Weibull approaches, will be considered for PFS and OS in 
order to adjust for cross over bias (Colleoni, 2011; Ishak, 2014; Jin, 2012; Korhonen, 2012; 
Motzer, 2010; Sternberg, 2013; Latimer, 2014).
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The RPSFT approach, relies on a simple model for survival times that assumes that the effect of 
treatment is multiplicative on time, that it conveys benefit immediately, and that the size of the 
benefit is the same regardless of whether subjects were randomized or crossed over to treatment 
(Ishak, 2014).
The IPCW approach reweights the influence of subjects who could have crossed over but did 
not, despite being otherwise similar to those who did cross over (ie, omits survival time after 
cross over from analyses by censoring subjects at the time of the treatment switch). The method 
usually relies on using time-dependent (and possibly time-fixed) risk factors to determine 
subjects’ probability of cross over which serve as weights. It assumes that there are sufficient 
numbers of subjects who did and did not cross over in all risk factor profiles where cross over 
occurred (Ishak, 2014).
In the 2-stage Weibull approach, the EFS event can be used as a secondary baseline and patients 
in Arm A are treated as an observational dataset. Treatment effect received by subjects in Arm A
who switched compared subjects who did not switch will be estimated by fitting a Weibull 
model (excluding patients in Arm B) with covariates measured at the secondary baseline and a 
time-varying covariate indicating treatment switch from Arm A to JCAR017.
For binary endpoints such as CRR and ORR, the frequency distribution (n, %) will be provided 
as summary information. The point estimate together with two-sided exact 95% confidence 
intervals (CI) will be provided. Cochran-Mantel-Haenszel (CMH) test with stratification factors 
as strata will be used for analysis and calculation of p-values.
9.6.1.
Primary Efficacy Analysis
The primary endpoint is EFS, defined as the time from randomization to death due to any cause, 
PD, failure to achieve CR or PR by 9 weeks post-randomization, or start of a new antineoplastic
therapy due to efficacy concerns, whichever occurs first.
Start of a new antineoplastic therapy due to efficacy concerns will be based on investigator’s 
assessment and related data will be collected in the electronic case report form (eCRF). Start of a 
new antineoplastic therapy will be captured from time of randomization to date of imaging (or 
other objective finding) that serves as the basis of starting a new antineoplastic therapy.
Primary response assessment will be based on central assessment performed by the IRC and 
supportive response assessment will be based on investigator assessment. Response assessment 
will be evaluated primarily per the Celgene Lugano Classification guidelines based on “The 
Lugano Classification” (Cheson, 2014).
Event-free survival will be analyzed with a stratified Cox-PH model if the proportional hazards
assumption hold (unstratified Cox-PH model as supportive analysis). The stratification factors to 
be used in the Cox-PH model correspond to the stratification at the time of randomization; in 
addition, the model will include treatment as the only covariate for analysis. If the proportional 
hazards assumption is not fulfilled, piecewise Cox-PH model will be used. Details on the 
evaluation of HR assumption and application of the Cox-PH model will be described in the 
statistical analysis plan (SAP).
Full set of censoring rules for EFS will be detailed in the SAP.
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9.6.2.
Key Secondary Efficacy Analysis
For CRR, CMH test with stratification factors as strata will be used for analysis and calculation 
of p-values. For PFS and OS, similar analysis strategy than for EFS will be used. However, as 
subjects from Arm A have the possibility to cross over to JCAR017, RPSFT method, IPCW 
method and 2-stage Weibull approach will be used for the analysis of these time-to-event data.

Complete response rate (CRR) is defined as the proportion of subjects achieving a CR 
from randomization up to 3 years post-randomization. Subjects with unknown or 
missing response will be counted as non-responder in the analysis. Any responses 
after a start of a new antineoplastic therapy will not be considered. Response after 
cross over will be analyzed descriptively on the cross over population.

Progression free survival (PFS) is defined as the time from randomization to PD or 
death from any cause, whichever occurs first.

Overall survival (OS) is defined as the time from randomization to death due to any 
cause.
Full set of censoring rules for PFS and OS will be detailed in the SAP.
9.6.3.
Other Efficacy Analyses

Overall response rate is defined as the proportion of subjects achieving an objective 
response of PR or CR according to the Lugano Classification during the treatment 
period. Subjects with unknown or missing response will be counted as non-responder 
in the analysis. Any responses after a start of a new antineoplastic therapy will not be 
considered. Response after cross over from Arm A to JCAR017 will be analyzed 
descriptively on the cross over population.

Duration of response (DoR) is defined as the time from first response to disease 
progression, start of new antineoplastic therapy or death and will be summarized 
using K-M estimates. In case a subject does not have PD, start of a new antineoplastic 
therapy or death prior to data cutoff date, DOR will be censored at the date of the last 
adequate response assessment.

Progression-free survival on the next line of treatment (PFS-2) is defined as time 
from randomization to objective tumor progression on next-line treatment or death 
from any cause. Subjects alive and for whom a second objective disease progression 
has not been observed will be censored at the last time known to be alive and without 
second objective disease progression. Recurrent event approach based on a Prentice, 
Williams and Peterson model will be used for the analysis of PFS-2.

Subjects receiving HSCT up to 3 years post-randomization will be summarized via 
counts and percents. Subjects receiving HSCT, response rates will be summarized at 
3 months post-HSCT.

For subjects who cross over from Arm A to JCAR017, descriptive statistics of EFS, 
OS, PFS, DoR, CRR, ORR will be provided.
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9.6.4.
Subgroup Analyses
Efficacy subgroup analyses will be performed on at least the flowing variables:

Secondary age-adjusted International Prognostic Index (sAAIPI) status: 0 or 1 versus 
2 or 3

Prior response status: refractory versus relapse to last prior therapy. The status is 
refractory if a subject achieved PD, SD, PR or CR with relapse within 3 months to 
last prior therapy; otherwise the status is relapsed

Age: < 40, ≥ 40 to < 65, ≥ 65 to < 75 and ≥75 years at the time of randomization

Sex: male versus female

Ethnicity: Hispanic or Latino versus not Hispanic or Latino

Region: Europe, US and Japan

Race: white versus other races

ECOG performance status at screening: 0 and 1

Prior chemotherapy response status: chemorefractory versus chemosensitive to last 
therapy. The status is chemorefractory if a subject achieved SD or PD to last 
chemotherapy-containing regimen; otherwise the status is chemosensitive

Central nervous system (CNS) disease status: known as CNS disease versus no 
known CNS disease at the time of randomization

Histological and molecular subtype: 

NHL type: DLBCL, FL3B, high grade B-cell lymphoma with DLBCL histology, 
PMBCL or THRBCL

DLBCL subtype: DLBCL NOS de novo or DLBCL from transformed indolent 
NHL

DLBCL subtype based on cell of origin: GCB or ABC, non-GCB

Bridging therapy status: impact of bridging therapy treatment effect versus SOC will 
be evaluated in subjects receiving bridging
Subgroup analyses will only be performed if there are enough subjects in each subgroup (more 
than 10 subjects in each subgroup). Some grouping of classes will be considered if there are too 
few subjects in some subgroups. Other subgroup analyses may be performed if deemed 
appropriate. 
9.7.
Safety Analysis
Safety analysis will include all subjects in the Safety analysis set.
9.7.1.
Treatment Exposure
Study treatment and extent of exposure summaries will be provided on the safety population. 
Descriptive statistics will be provided for treatment exposure and duration, cumulative dose, 
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number of days dosed, average daily dose, dose intensity, treatment compliance, relative dose 
intensity per treatment arms, per regimen and agent when relevant. Dose modification will be 
summarized per arm.
9.7.2.
Adverse Events
Adverse events will be coded using MedDRA SOC and preferred term (PT).
The severity of each adverse event will be graded by the Investigator using Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 or higher, unless otherwise 
specified in the protocol. 
Related AEs are those for which the Investigator selects “Related” to JCAR017 or SOC on the 
AE reported in CRF. Adverse events will be identified and captured as SAEs if they meet the 
definition for SAE.
Treatment-emergent adverse events (TEAEs) are defined as AEs occurring or worsening on or 
after the date of randomization and within 90 days after last dose of chemotherapy (Arm A), or 
within 90 days after the infusion of JCAR017 (Arm B or subjects in Arm A crossing over to 
JCAR017) or start of new antineoplastic therapy, whichever occurs first as well as those AEs 
made known to the investigator at any time thereafter that are suspected of being related to study 
treatment. Adverse event summaries will provide the number and percentage of subjects with at 
least one TEAEs by SOC and PT for:

TEAEs

TEAEs by severity grade

Grade 3 or more TEAEs

Grade 5 TEAEs

TEAEs by maximum CTCAE grade

TEAEs suspected to be related to JCAR017 or SOC

Grade 3 or more TEAEs suspected to be related to JCAR017 or SOC

SAEs

SAEs suspected to be related to JCAR017 or SOC

AEs leading to treatment discontinuation, study discontinuation or death

Adverse events of special interest (AESI)

Grade 3 or more AESI
Adverse events will be summarized and listed first by SOC in descending order of incidence and 
then by PT (within each SOC), also in descending order of incidence overall. In summaries by 
severity grade, the most severe grade will be used for those AEs that occur more than once in an 
individual subject during the study. AEs will be summarized in clinical, histological and 
molecular subgroups of interest.
Corresponding supportive subject-level listing will be provided.
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9.7.3.
Laboratory Evaluations
9.7.3.1.
Numeric Laboratory Results
Summaries of numeric laboratory data will be based on central assessment and will be reported 
using conventional units for hematological tests, serum chemistry tests and for other laboratory 
tests including coagulation, inflammatory markers and immunoglobulins. Baseline, raw values, 
and changes from baseline will be summarized per arm using descriptive statistics for each 
laboratory test specified in the study protocol.
9.7.3.2.
Graded Laboratory Values
Central laboratory data will be graded according to NCI CTCAE, Version 4.03 (or higher)
severity grade: mild (Grade 1), moderate (Grade 2), severe (Grade 3), or life threatening (Grade 
4). Grade 0 includes all non-missing values that do not meet criteria for an abnormality of at least 
Grade 1. Summary data (count and percent) within each grade will be provided per arm. Cross-
tabulation table of post-baseline grade and worst post baseline grade versus baseline grade will 
be provided for selected hematology, serum chemistry and coagulation parameters per arm.
9.7.3.3.
Summaries of Laboratory Abnormalities
Laboratory results will be programmatically classified as below normal range, within normal 
range and above normal range if the numeric laboratory result is below the lower limit of normal 
range, within normal range or above the upper limit of normal range. Shift tables per treatment 
arm will be presented for selected hematology, serum chemistry and coagulation parameters 
showing change in results from the baseline value (below normal range, within normal range, 
and above normal range) to each post-baseline visit and to the worst post-baseline value (below 
normal range, within normal range, and above normal range).
9.8.
Interim Analysis
Two interim analyses, one for futility and one for efficacy, will be performed. In addition, the 
rate of EFS events will be monitored during the course of the study at predefined timepoints to 
potentially increase the sample size, if required. In order to prevent bias being introduced into the 
study conduct and analyses, an independent and external statistical group will be responsible for
performing these interim analyses and monitoring of EFS events for sample size increase. A data 
safety monitoring board (DSMB) will be responsible of reviewing such analyses and provide 
recommendation to the sponsor.
9.8.1.
Futility Interim Analysis
The purpose of the first interim analysis is to stop for futility in case of no efficacy signal on 
CRR at 9 weeks after randomization (after 3 cycles of SOC for Arm A and 5 weeks after the 
JCAR017 infusion) for JCAR017 treated subject compared to SOC. The futility interim analysis 
will be conducted when ~30 evaluable subjects (~15 subjects per arm and having received their 
assigned treatment) have their 9 weeks response assessment (after 3 cycles of SOC for Arm A 
and 5 weeks after the JCAR017 infusion) or have been confirmed with disease progression prior 
to this timepoint. Screening and treatment will continue while this interim analysis is being 
conducted. The study may be terminated if the CRR in JCAR017 arm is lower than the CRR in 
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the SOC arm. No formal statistical test will be performed, and no type I error adjustment is 
implemented for this futility interim analysis.
9.8.2.
Efficacy Interim Analysis
A second interim analysis will be performed at 60% information time (ie, at around 71 EFS 
events). The purpose of this interim analysis is to demonstrate superiority of JCAR017 versus 
SOC on EFS. O’Brien-Fleming boundary are used for defining the efficacy boundaries. The null 
hypothesis will be rejected if the p-value associated to the test is smaller than or equal to 0.004. 
Screening and randomization will continue while this interim analysis is being conducted. In 
case of efficacy demonstrated on primary endpoint, recruitment of subjects will continue.
9.8.3.
Monitoring of EFS Events and Sample Size Increase
Monitoring of EFS events will be performed in an aggregate manner during the study course at 
predefined timepoint (at 100 subjects randomized and at the time of the efficacy interim 
analysis). Predictive probability of observing the required 119 EFS events or more at the 
expected primary analysis (ie, at around 21.4 months) will be computed at these predefined 
timepoint. In case this predictive probability is too low (below 50% at first monitoring and below 
80% at second monitoring of the EFS events), then sample size will be increased with a limit of 
up to 40 additional subjects (with a 1:1 ratio). 
Additional information on the estimation of the EFS probability curve and computation of the 
predictive distribution for the EFS events will be mentioned in the SAP.
9.9.
Other Topics
9.9.1.
Randomization
Subjects will be randomized at 1:1 ratio into one of the two arms: Arm A or Arm B. 
Randomization will be based on a permuted-blocks randomization method, with the following 
stratification factors:
1. Best overall response to first-line therapy: refractory (defined as SD, PD, PR or CR with 
relapse before 3 months) versus relapse (CR with relapse on or after lasting at least 3 
months);
2. Secondary age adjusted International Prognostic Index (sAAIPI): 0 or 1 versus 2 or 3.
9.9.2.
Data Safety Monitoring Board
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.
The DSMB will be convened prior to screening of the first subject on the protocol and will meet 
approximately quarterly throughout the trial and as needed to address any safety issues that may 
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arise. Subject safety will be evaluated as specified in DSMB charter. The DSMB will provide 
advice to the Sponsor 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.
9.9.3.
Scientific Steering Committee 
The conduct of this trial will be overseen by a scientific steering committee (SSC), presided over 
by the coordinating Principal Investigator and if possible the representative Regional 
Investigators from countries participating in this study. The SSC will serve in an advisory 
capacity to the Sponsor. Operational details for the SSC will be detailed in a separate SSC 
charter.
Note: The SSC is separate from the DSMB
9.9.4.
Independent Review Committee
An independent review committee (IRC) will be established to review data related to disease
response assessments during the study and determine remission and relapse for the primary
analysis. An IRC charter will detail the IRC data flow and review process in alignment with the 
response definitions in Appendix C. Subject management will be based upon local investigator 
assessments. The designation of remission and relapse for the primary analysis and other related 
key secondary and secondary efficacy endpoints will be based only on the evaluations made by
the IRC. Operational details for the IRC will be detailed in the IRC charter agreed upon between 
Celgene and the IRC before initiation of any IRC review.
9.9.5.
Exploratory Analysis
 pharmacokinetic
 for JCAR017

The effect of treatments directed at sCRS and neurotoxicity on duration and severity 
of sCRS and neurotoxicity

Safety: Detection of RCL
9.9.6.
Health-Related Quality of Life
All HRQoL analyses will be conducted on the HRQoL analysis set. The PRO/QoL compliance 
rate (%) will be calculated for each instrument in two ways: as the number of subjects compliant 
at each visit over the number of expected subjects (alive and on study) at that particular visit and 
over the ITT population. As the power for the study was calculated based on the primary 
endpoint, all PRO analyses should be interpreted as descriptive. Missing values will be addressed 
according to questionnaire guidelines. Reasons for missing questionnaires will be captured so 
that the appropriate imputation method can be applied according to questionnaire guidelines. For 
those domains, the analyses will be conducted as detailed in the SAP.
The primary domains of interest for the HRQoL analysis are global health/quality of life 
(GH/QoL), fatigue, physical functioning and cognitive functioning and FACT-Lym “Additional 
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Concerns” subscale (FACT-Lym).
9.9.7.
Hospital Resource Utilization
Hospital resource utilization (HRU) will be summarized per arm using number and duration of 
hospitalizations, reasons for hospitalization, unit of admission, intensive care unit (ICU) inpatient 
stay, non-ICU inpatient stay and number of outpatient visits. Intensive care unit and non-ICU 
inpatient stay is defined as the sum of duration of all ICU and non-ICU stays respectively.
A supportive by-subject listing will be provided.
9.9.8.
Pharmacokinetics
Description of the statistical analysis for PK 
 will be specified in the 
SAP.
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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 CRF (see Section 7.4.7 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 CRF. If the sequela of an overdose is an SAE, then the sequela must be reported on an 
SAE report form and on the AE CRF. The overdose resulting in the SAE should be identified as 
the cause of the event on the SAE report form and CRF 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 
and cyclophosphamide (flu/cy) and SOC (R-DHAP, R-ICE, R-GDP) 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.
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Table 8:
Recording Periods for Adverse Events
Start
End
Required Recording
Arm A 
and B
Signing of informed consent
Randomization AEs related to any protocol mandated
procedure*
Each AE with a change in toxicity 
grade will be recorded in the CRF as a 
separate AE record
Arm B and 
cross over
Randomization (Arm B) and
Pre-treatment evaluation 
(cross over)
90 days after 
JCAR017 
infusion 
All AEs
Each AE with a change in toxicity 
grade will be recorded in the eCRF as a 
separate AE record
Arm A
Randomization
90 days after 
last dose of 
chemotherapy 
Arm A, B
and cross
over
End of previous period
End of study
Only AEs related to any study 
procedure or JCAR017 or SOC/HDCT
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
Arm A, B 
and cross 
over
Randomization
End of study
The following conditions should be 
reported as SAEs, regardless of 
relationship to study drug: 

Second primary malignancies

New onset or exacerbation of a 
pre-existing neurologic disorder

New onset of a rheumatologic or 
other autoimmune disorder

New onset of a hematologic 
disorder

Rare and unexpected disorders with 
an unknown etiology (eg, Guillain-
Barré, Stevens-Johnson syndrome).
Abbreviations: AEs = adverse events, eCRF = electronic case report form, HDCT = high-dose chemotherapy, 
SAEs = serious adverse events, SOC = standard of care.
* Any clinically significant conditions/events unrelated to study procedures should be reported either in the medical 
history or as an adverse event as described in the CRF completion guidelines (CCGs).
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.
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Serious adverse events 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 CRF rather than the 
individual signs or symptoms of the diagnosis or syndrome.
For CRS and neurotoxicity reporting requirements in the CRF, please refer to the CRF 
completion guidelines (CCGs).
Any medical condition already present prior to randomization 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 CRF 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.
AEs and SAEs will be recorded on the AE page of the CRF 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 
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considered serious. Any confirmed detectable result from RCL testing or any result from a 
second primary malignancy that suggest malignant transformation due to insertional oncogenesis
will be reported as an SAE within 24 hours of the investigator being notified of the positive 
result.
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, bone marrow 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 CRF. 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 CRF and the SAE Report Form 
must be completed.
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to LD chemotherapy, JCAR017 and SOC/HDCT and HSCT, action taken regarding 
LD chemotherapy, JCAR017 and SOC/HDCT and HSCT, and outcome.
10.2.2.
Severity/Intensity
For both AEs and SAEs, the Investigator must assess the severity/ intensity of the event. CRS 
must be graded using the modified CRS grading scale (Appendix L).
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 higher); 
AEs 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 the LD 
chemotherapy, JCAR017 or the SOC regimen 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 IP 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 IP 
caused the adverse event. ‘Reasonable possibility’ means there 
is evidence to suggest a causal relationship between the IP 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 IP 
that has not been manufactured or provided by Celgene, please provide the name of the 
manufacturer when reporting the event.
10.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
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10.2.5.
Action Taken
The Investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(eg, discontinuation, interruption, or dose reduction of IP, 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.
SAEs 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 IP 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 CRF. 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, infusion of JCAR017 or 
SOC/HDCT in either a female subject of childbearing potential or a female partner 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.  
10.4.1.
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.
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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 the IP should also be reported 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.
10.4.2.
Male Subjects
If a female partner of a male subject taking IP becomes pregnant, the male subject taking IP 
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 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 CRF. 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 or 
SOC/HDCT and HSCT) recorded in the CRF 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 a serious 
adverse event (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 
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.
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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 IP 
(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 respective 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 L). These recommendations are based on the CRS 
revised grading system (Lee, 2014) and the Common Terminology 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, 
2017b).

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. 
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
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/hemophagocytic lymphohistiocytosis 
(MAS/HLH), and the physiology of the syndromes may overlap. 
Please refer to Appendix L for detailed description of CRS, grading and treatment 
recommendations. Note: Cetuximab is not indicated for the treatment of CRS.
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.
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, 2017b) 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 to Appendix L for detailed description of neurologic toxicities, grading and 
treatment recommendations. Note: Cetuximab is not indicated for the treatment of neurologic 
toxicities.
10.6.1.4.
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. MAS 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.
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10.6.1.5.
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 7.4.3). Mild infusion reactions should be 
managed expectantly with antipyretics, antihistamines, and anti-emetics. 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+ and CD4+ components at the same dose and rate

Grade 2: stop administration of JCAR017; administer symptomatic treatment, and 
resume JCAR017 administration of both CD8+ and CD4+ 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+ or CD4+ 
components of JCAR017 should be administered

Grade 4: discontinue administration of JCAR017 and administer symptomatic 
treatment as necessary; no further CD8+ or CD4+ components of JCAR017 should be 
administered
10.6.1.6.
Tumor Lysis Syndrome
Both lymphodepleting chemotherapy and JCAR017 may cause tumor lysis syndrome (TLS) in 
subjects with high disease burden. Subjects should be closely monitored for laboratory evidence 
of TLS (hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia) (see
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. 
10.6.1.7.
B-cell Aplasia
B-cell aplasia is an expected potential off-tumor, on-target toxicity. Prolonged B-cell aplasia has 
been observed in other CD19-directed CAR T cell programs (Davila, 2013; Grupp, 2013). Serum 
immunoglobulin levels will be obtained from all subjects prior to and at various time points 
following JCAR017 treatment. Hypogammaglobulinemic subjects (serum immunoglobulin G 
(IgG) < 500 mg/dL) should be considered for intravenous immunoglobulin replacement therapy 
per institutional guidelines.
10.6.1.8.
Uncontrolled T Cell Proliferation
JCAR017 T cells could theoretically proliferate out of control. If uncontrolled JCAR017 T cell 
proliferation occurs, subjects may be treated with high dose steroids (eg, methylprednisolone 1 to 
3 g/day, tapered over 7 days) or lymphodepleting doses of cyclophosphamide (1 to 3 g/m2 IV). If 
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an Investigator suspects uncontrolled JCAR017 proliferation, the Sponsor 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 use of 
cetuximab or other EGFR-directed antibodies for depletion of JCAR017 CAR T cells in humans.
10.6.1.9.
Replication-Competent Lentivirus, Clonality and Insertional Oncogenesis
Lentiviral vectors used in gene transfer are engineered to be replication-defective; however, 
generation of replication-competent lentiviruses (RCLs) during manufacturing is still a 
possibility. Modern vector production systems have been improved to reduce the risk of RCL 
generation. To date, there have been no reports of RCL generated during lentiviral vector 
manufacturing, which may be due, at least in part, to the use of self-inactivating vectors such as 
the lentiviral vector used in the production of JCAR017 (Rothe, 2013). 
Concerns for possible vector integration into the host genome have arisen due to preclinical 
studies that have shown retrovirus-mediated malignant transformation in mice (Li, 2002; 
Modlich, 2005) and monkeys (Donahue, 1992), and a single clinical study reporting 
development of leukemia in subjects with X-linked severe combined immunodeficiency who 
received retroviral-modified CD34+ hematopoietic stem cells (Hacein-Bey-Abina, 2003), 
including one subject who died (Couzin, 2005). Of note, no instances of RCL generation during 
production or lentivirus-mediated malignant transformation in animals or subjects have been 
reported to date. 
Data has recently been published on the integration sites of retroviral and lentiviral vectors used 
for T cell modification in clinical trials (Wang, 2009; Scholler, 2012; McGarrity, 2013). No 
clonality of integration sites was observed. In addition, there did not appear to be enrichment of 
integration sites near genes involved in clonal expansion or persistence. 
10.6.1.10. Cytopenias
Severe cytopenias, including anemia, leukopenia, neutropenia, and thrombocytopenia, can occur 
with both JCAR017 and lymphodepleting chemotherapy, and delayed recovery has been 
observed. Complete blood counts should be monitored after JCAR017 infusion until count 
recovery. Institutional guidelines should be followed in the event of Grade ≥ 3 cytopenias.
10.6.1.11. 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.
10.6.2.
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 
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inserts or summary of product characteristics for specific details surrounding the risks of 
fludarabine and cyclophosphamide.
10.6.3.
Risks Associated with Reference Therapies
Subjects randomized to Arm A will receive reference therapy as defined in Section 7.3. 
Management of toxicities related to the reference therapies should be performed as per local 
institution practice. 
10.6.4.
Second Primary Malignancies
New malignancies must be reported as SAEs. This includes any second primary malignancy,
regardless of the treatment arm the subject is in. This includes any second primary malignancy, 
regardless of causal relationship to IP (study drug[s]), occurring at any time for the duration of 
the study, from randomization until study end. These events must also be documented in the 
appropriate page(s) of the CRF and subject’s source documents. Documentation on the diagnosis 
of the new 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.). In the event a subject 
develops a second primary malignancy, the Sponsor may request a sample for detection of CAR 
T cell sequence, where applicable (refer to Section 6.3.6).
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 Brochure.
In the United States, all suspected unexpected serious adverse reactions (SUSARs) will be 
reported in an expedited manner in accordance with 21 CFR 312.32.
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, suspected unexpected serious adverse reactions (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 investigational products 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; In Japan, 
Celgene KK shall notify the Heads of the Institutes in addition to the Investigators:

Any AE suspected of being related to the use of IP 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.

In Japan, measures taken in foreign countries to ensure subject safety, study reports 
that indicate potential risk of cancer, etc., or biannual SAE report according to the 
local regulations.
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.
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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).
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 Events 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 the Sponsor. 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-related reaction;

Cytokine release syndrome (CRS);

Neurological toxicity (NT);

Macrophage activation syndrome (MAS);

Tumor lysis syndrome (TLS)

Prolonged cytopenias

Hypogammaglobulinemia

Infections

Autoimmune disorders

Second primary malignancy (SPM)
Further information regarding the list of AESI can be found in the SAP.
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11.
DISCONTINUATIONS
11.1.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product(s):

Adverse Event

Withdrawal by subject

Death

Lost to follow-up

Physician decision

Other (to be specified on the CRF)
The reason for discontinuation of treatment should be recorded in the CRF 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 the Sponsor. However, prior to discontinuing 
a subject, the Investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion.
11.2.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
study:

Screen failure

Adverse event

Manufacturing failure

Withdrawal by subject

Death

Lost to follow-up

Other (to be specified on the CRF)
The reason for study discontinuation should be recorded in the CRF 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, 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 International Council for
Harmonisation (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 laws 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 informed consent 
form (ICF) 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 CRFs 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
The Investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures.
Documentation that informed consent 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 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, the ICF 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. The revised ICF 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 laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF, 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/EC approval but will be submitted to the IRB/EC for 
information purposes.
13.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF, 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 consented 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 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 screening and randomization;

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 investigational product 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 CRFs or CD-ROM.
14.2.
Data Management
Data will be collected via CRF 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 
screening/randomization 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 CRFs (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 screening subjects into the study, a 
Celgene representative will review the protocol, CRFs, 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, 
investigational product storage area, CRFs, 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 CRFs 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 CRFs 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, CRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (eg, FDA, EMA, Health Canada) 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.
REFERENCES
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Abramson JS, Palomba ML, Gordon L, Lunning MA, Arnason JE, Wang M, et al. High CR rates 
in relapsed/refractory (r/r) aggressive B-NHL treated with the CD19-directed CAR T cell 
product JCAR017 (TRANSCEND NHL 001). Hematological Oncology. 2017a May;35(S2):138.
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 
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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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Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J 
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Cheson BD, Ansell S, Schwartz L, Gordon LI, Advani R, Jacene HA, et al. Refinement of the 
Lugano Classification lymphoma response criteria in the era of immunomodulatory therapy. 
Blood. 2016 Nov 24;128(21):2489-96.
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Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-
Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014 Sep 20;32(27):3059-68.
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response criteria for malignant lymphoma. J Clin Oncol. 2007 Feb 10;25(5):579-86.
 
 
 
 
Colleoni M, Giobbie-Hurder A, Regan MM, Thürlimann B, Mouridsen H, Mauriac L, et al. 
Analyses adjusting for selective cross over show improved overall survival with adjuvant 
letrozole compared with tamoxifen in the BIG 1-98 Study. J Clin Oncol. 2011 Mar 20; 29(9): 
1117–1124.
Couzin J, Kaiser J. Gene therapy. As Gelsinger case ends, gene therapy suffers another blow. 
Science. 2005 Feb 18;307(5712):1028.
Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, et al. Outcomes in 
refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study.
Blood. 2017 Oct 19; 130(16):1800-8.
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18.
APPENDICES
APPENDIX A. TABLE OF ABBREVIATIONS
Table 9:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
ABC
Activated B-cell like
AE
Adverse event
AESI
Adverse event of special interest
ALL
Acute lymphoblastic leukemia
ALT
Alanine aminotransferase (SGPT)
AraC
Cytarabine
ASCT
Autologous stem cell transplant
ASTCT
American Society for Transplantation and Cellular Therapy
AUC
Area under the curve
AST
Aspartate aminotransferase (SGOT)
BCNU
Carmustine
BEAM
Carmustine, etoposide, cytarabine, melphalan
β-hCG
Beta-human chorionic gonadotropin
CAR
Chimeric antigen receptor
CD
Cluster of differentiation
cfDNA
Cell-free DNA
CI
Confidence intervals
CLL
Chronic lymphocytic leukemia
CMH
Cochran-Mantel-Haenszel
CMR
Complete metabolic response
CNS
Central nervous system
COO
Cell of origin
CORAL
Collaborative trial in relapsed aggressive lymphoma
Cox-PH
Cox-proportional hazards
CR
Complete response
CRF
Case report form
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Table 9:
Abbreviations and Specialist Terms  (Continued)
Abbreviation or 
Specialist Term
Explanation
CRP
C-reactive protein
CRR
Complete response rate
CRS
Cytokine release syndrome
CSF
Cerebrospinal fluid
CT
Computed tomography
CTCAE
Common terminology criteria for adverse events
ddPCR
Droplet digital polymerase chain reaction
DHAP
Dexamethasone, cytarabine, and cisplatin
DHL
Double-hit lymphoma
DL
Dose level
DLBCL
Diffuse large B-cell lymphoma 
DLT
Dose-limiting toxicity
DMSO
Dimethyl sulfoxide
DNA
Deoxyribonucleic acid
DOR
Duration of response
DSMB
Data safety monitoring board
EBV
Epstein-Barr virus
EC
Ethics Committee
eCRF
Electronic case report form
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EEA
European Economic Area
EEG
Electroencephalogram
EFS
Event-free survival
EGFRt
Truncated human epidermal growth factor receptor
EMA
European Medicines Agency
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer – Quality of 
Life C30 Questionnaire
EOS
End of study
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Table 9:
Abbreviations and Specialist Terms  (Continued)
Abbreviation or 
Specialist Term
Explanation
ET
Early termination
EU
European Union
FACT-Lym
Functional Assessment of Cancer Therapy-Lymphoma
FCBP
Female of child bearing potential
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
FL
Follicular lymphoma
FL3B
Follicular lymphoma Grade 3B
flu/cy
Fludarabine and cyclophosphamide 
gagDNA
Glycosaminoglycan Deoxyribonucleic acid
GCB
Germinal center-like
GCP
Good Clinical Practice
GDP
Gemcitabine, dexamethasone, and cisplatin 
GH
Global health
HBcAB
Hepatitis B core antibody
HBsAb
Hepatitis B surface antibody
HBsAg
Hepatitis B surface antigen
HCT-CI
Hematopoietic cell transplantation – specific comorbidity index
HDCT
High dose chemotherapy
HIV
Human immunodeficiency virus
HR
Hazard ratio
HRQoL
Health-related quality of life
HRU
Hospital resource utilization
HSCT
Hematopoietic stem cell transplant
IB
Investigator’s brochure
ICF
Informed consent form
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Table 9:
Abbreviations and Specialist Terms  (Continued)
Abbreviation or 
Specialist Term
Explanation
ICH
International Council for Harmonisation
ICU
Intensive care unit
IFN
Interferon 
IHC
Immunohistochemistry
Ig
Immunoglobulin
IND
Investigational New Drug
IP
Investigational product
IPCW
Inverse probability of censoring weighting
IPI
International index prognostic
IRB
Institutional review board
IRC
Independent review committee
IRT
Interactive response technology
IT
Intrathecal
ITT
Intended-to-treat
IUD
Intrauterine device
IV
Intravenous
IVIG
Intravenous immunoglobulins
K-M
Kaplan-Meier
LD
Lymphodepleting
LDH
Lactate dehydrogenase
LTFU
Long-term follow-up
LVEF
Left ventricular ejection fraction
mAb
Monoclonal antibody
MAS
Macrophage activation syndrome
MCNU
Ranimustine
MedDRA
Medical Dictionary for Regulatory Activities
MMSE
Mini Mental State Examination
MRI
Magnetic resonance imaging
MUGA
Multi-gated acquisition scan
NaCl
Sodium chloride
NCCN
National Comprehensive Cancer Network
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Table 9:
Abbreviations and Specialist Terms  (Continued)
Abbreviation or 
Specialist Term
Explanation
NCI
National Cancer Institute
NCIC
National Cancer Institute of Canada
NHL
Non-Hodgkin lymphoma
NK
Natural killer
NOS
Not otherwise specified
NT
Neurotoxicity
O-DHAP
Ofatumumab, dexamethasone, high dose cytarabine, and cisplatin
ORCHARRD
Ofatumumab versus rituximab salvage chemoimmunotherapy
ORR
Overall response rate
OS
Overall survival
PCR
Polymerase chain reaction
PD
Progressive disease
PET
Positron emission tomography
PFS
Progression-free survival
PFS-2
PFS on next line of treatment
PK
Pharmacokinetics
PMBCL
Primary mediastinal large B-cell lymphoma
PO
Per os (oral)
PP
Per protocol
PPDP
Protocol Product Deviation Plan
PR
Partial response
PRO
Patient reported outcome
PT
Preferred term
R-CHOP
Rituximab- cyclophosphamide, doxorubicin hydrochloride, vincristine 
sulfate and prednisone
R-DHAP
Rituximab- dexamethasone, high dose cytarabine (AraC), and cisplatin
R-GDP
Rituximab- gemcitabine, dexamethasone, and cisplatin
R-ICE
Rituximab- ifosfamide, carboplatin, and etoposide
RCL
Replication-competent lentivirus
RNA
Ribonucleic acid
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Table 9:
Abbreviations and Specialist Terms  (Continued)
Abbreviation or 
Specialist Term
Explanation
RPFST
Rank preserving structural failure time
R/R
Relapsed or refractory
SAE
Serious adverse event
sAAIPI
Secondary age-adjusted International Prognostic Index
SaO2
Oxygen saturation
SAP
Statistical analysis plan
SSC
Scientific steering committee
scFv
Single chain variable fragments
sCRS
Severe cytokine release syndrome
SD
Stable disease
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SOC
Standard of care
SOC
System organ class
SOP
Standard operating procedure
SPM
Second primary malignancy
SSC
Scientific steering committee
SUSAR
Suspected unexpected serious adverse reaction
TEAE
Treatment-emergent adverse events
THL
Triple-hit lymphoma
THRBCL
T cell rich/histiocyte rich large B-cell lymphoma
TLS
Tumor lysis syndrome
TMG
Toxicity management guidelines
TNF
Tumor necrosis factor
TNM
Tumor, nodes, metastasis
ULN
Upper limit of normal
UK
United Kingdom
US/ USA
United States/ United States of America
WHO
World Health Organization
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APPENDIX B. PERFORMANCE STATUS BY EASTERN 
COOPERATIVE ONCOLOGY GROUP SCALE
Table 10:
Performance Status by Eastern Cooperative Oncology Group Scale 
Score
Description
0
Fully active, able to carry on all predisease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light housework, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead.
(Oken, 1982).
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APPENDIX C. RECOMMENDATIONS FOR INITIAL EVALUATION, 
STAGING, AND RESPONSE ASSESSMENT OF 
HODGKIN AND NON-HODGKIN LYMPHOMA: THE 
LUGANO CLASSIFICATION
The guidelines for Recommendations for Initial Evaluation, Staging, and Response Assessment 
of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification are outlined in a report 
(Cheson, 2014).
Table 11:
Criteria for Involvement of Site
Tissue Site
Clinical
FDG Avidity
Test
Positive Finding
Lymph nodes
Palpable
FDG-avid 
histologies
PET-CT
Increase FDG uptake
Nonavid disease
CT
Unexplained node 
enlargement
Spleen
Palpable
FDG-avid 
histologies
PET-CT
Diffuse uptake, solitary 
mass, miliary lesions, 
nodules 
Nonavid disease
CT
> 13 cm in vertical length, 
mass, nodules
Liver
Palpable
FDG-avid 
histologies
PET-CT
Diffuse uptake, mass 
Nonavid disease
CT
Nodules
CNS
Signs, symptoms
CT
Mass lesion(s)
MRI
Leptomeningeal 
infiltration, mass lesions
CSF 
assessment
Cytology, flow cytometry
Other (eg, skin, 
lung, GI tract, 
bone, bone 
marrow)
Site dependent
PET-CTa, 
biopsy
Lymphoma involvement
Abbreviations: CNS = central nervous system; CSF = cerebrospinal fluid; CT = computed tomography; FDG = 
fluorodeoxyglucose; GI = gastrointestinal; MRI = magnetic resonance imaging; PET = positron emission 
tomography.
a PET-CT is adequate for determination of bone marrow involvement and can be considered highly suggestive for 
involvement of other extralymphatic sites. Biopsy confirmation of those sites can be considered if necessary.
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Table 12:
Revised Criteria for Response Assessment
Response and Site
PET-CT Based Response
CT-Based Response
Complete
Complete Metabolic Response
Complete Radiologic Response 
(All of the Following)
Lymph nodes and 
extralymphatic sites
Score 1, 2, or 3a with or without a residual 
mass on 5PSb
It is recognized that in Waldeyer's ring or 
extranodal sites with high physiologic uptake 
or with activation within spleen or marrow (eg, 
with chemotherapy or myeloid colony-
stimulating factors), uptake may be greater 
than normal mediastinum and/or liver. In this 
circumstance, complete metabolic response 
may be inferred if uptake at sites of initial 
involvement is no greater than surrounding 
normal tissue even if the tissue has high 
physiologic uptake
Target nodes/nodal masses must regress 
to ≤ 1.5 cm in LDi
No extralymphatic sites of disease
Nonmeasured lesion
Not applicable
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in marrow
Normal by morphology; if 
indeterminate, IHC negative
Partial
Partial Metabolic Response
Partial Response 
(All of the Following)
Lymph nodes and 
extralymphatic sites
Score 4 or 5b with reduced uptake compared 
with baseline and residual mass(es) of any size
At interim, these findings suggest responding 
disease
At end of treatment, these findings indicate 
residual disease
≥ 50% decrease in sum of perpendicular 
diameters (SPD) of up to 6 target 
measurable nodes and extranodal sites 
When a lesion is too small to measure 
on CT, assign 5 mm × 5 mm as the 
default value
When no longer visible, 0 × 0 mm
For a node > 5 mm × 5 mm, but smaller 
than normal, use actual measurement 
for calculation
Nonmeasured lesion
Not applicable
Absent/normal, regressed, but no 
increase
Organ enlargement
Not applicable
Spleen must have regressed > 50% in 
length beyond normal
New lesions
None
None
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Table 12:
Revised Criteria for Response Assessment (Continued)
Response and Site
PET-CT Based Response
CT-Based Response
Bone marrow
Residual uptake higher than uptake in normal 
marrow but reduced compared with baseline 
(diffuse uptake compatible with reactive 
changes from chemotherapy allowed). If there 
are persistent focal changes in the marrow in 
the context of a nodal response, consideration 
should be given to further evaluation with MRI 
or biopsy or an interval scan
Not applicable
No Response or 
Stable Disease
No Metabolic Response
Stable Disease
Target nodes/nodal 
masses, extranodal 
lesions
Score 4 or 5b with no significant change in 
FDG uptake from baseline at interim or end of 
treatment
< 50% decrease from baseline in SPD 
of up to 6 dominant measurable nodes 
and extranodal sites; no criteria for 
progressive disease are met
Nonmeasured lesion
Not applicable
No increase consistent with progression
Organ enlargement
Not applicable
No increase consistent with progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable
Progressive 
Disease
Progressive Metabolic Disease
Progressive Disease Requires at 
Least 1 of the Following
Individual target 
nodes/nodal masses
Score 4 or 5b with an increase in intensity of 
uptake from baseline and/or
PPD progression:
Extranodal lesions
New FDG-avid foci consistent with lymphoma 
at interim or end-of-treatment assessment
An individual node/lesion must be 
abnormal with:
LDi > 1.5 cm and 
Increase by ≥ 50% from PPD nadir and 
An increase in LDi or SDi from nadir
0.5 cm for lesions ≤ 2 cm
1.0 cm for lesions > 2 cm
In the setting of splenomegaly, the 
splenic length must increase by > 50% 
of the extent of its prior increase 
beyond baseline (eg, a 15 cm spleen 
must increase to > 16 cm). If no prior 
splenomegaly, must increase by at least 
2 cm from baseline
New or recurrent splenomegaly
Nonmeasured 
lesions
None
New or clear progression of preexisting 
nonmeasured lesions
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Table 12:
Revised Criteria for Response Assessment (Continued)
Response and site
PET-CT based response
CT-based response
New lesions
New FDG-avid foci consistent with lymphoma 
rather than another etiology (eg, infection, 
inflammation). If uncertain regarding etiology 
of new lesions, biopsy or interval scan may be 
considered
Regrowth of previously resolved lesions
A new node > 1.5 cm in any axis
A new extranodal site > 1.0 cm in any 
axis, if < 1.0 cm in any axis, its 
presence must be unequivocal and must 
be attributable to lymphoma
Assessable disease of any size 
unequivocally attributable to lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
Abbreviations: 5PS = 5-point scale; CT = computed tomography; FDG = fluorodeoxyglucose; GI = gastrointestinal; 
IHC = immunohistochemistry; LDi = longest transverse diameter of a lesion; MRI = magnetic resonance imaging; 
PET = positron emission tomography; PPD = cross product of the LDi and perpendicular diameter; SDi = shortest 
axis perpendicular to the LDi; SPD = sum of the product of the perpendicular diameters for multiple lesions.
a A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an 
interim scan. However, in trials involving PET where deescalation is investigated, it may be preferable to consider 
a score of 3 as inadequate response (to avoid undertreatment). For the purpose of this trial, while score 3 might 
represent an early response 1 or 3 months after JCAR017 infusion, it likely reflects remaining active disease at 
later time points. 
Measured dominant lesions: Up to 6 of the largest dominant nodes, nodal masses, and extranodal lesions selected 
to be clearly measurable in two diameters. Nodes should preferably be from disparate regions of the body and 
should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid 
organs (eg, liver, spleen, kidneys, and lungs), GI involvement, cutaneous lesions, or those noted on palpation. 
Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly assessable disease should 
be considered not measured. These sites include any nodes, nodal masses, and extranodal sites not selected as 
dominant or measurable or that do not meet the requirements for measurability but are still considered abnormal, 
as well as truly assessable disease, which is any site of suspected disease that would be difficult to follow 
quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, 
abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In Waldeyer’s ring or in 
extranodal sites (eg, GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with 
complete metabolic response, but should be no higher than surrounding normal physiologic uptake (eg, with 
marrow activation as a result of chemotherapy or myeloid growth factors).
b PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, 
uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake 
unlikely to be related to lymphoma.
(Cheson, 2014).
The integrated response assessment will be performed by the IRC as described in Table 13 and 
Table 14. Please refer to the Celgene “Guidelines for Efficacy Evaluation in PET-avid Non-
Hodgkin Lymphoma” (based on the Lugano classification 2014) for the comprehensive 
interpretation used by the IRC. This is a stand-alone document.
Table 13:
Integrated PET+CT Overall Time Point Response
PET-Staging 
Overall Response
CT-Staging
Overall Response
PET + CT
Overall TPR
CMR
CR/PR/SD/NE/PD
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Table 13:
Integrated PET+CT Overall Time Point Response (Continued)
PET-Staging 
Overall Response
CT-Staging
Overall Response
PET + CT
Overall TPR
PMR
CR/PR/SD/NE/PD
PR
NMR
CR/PR/SD/NE/PD
SD
NE1
CR/PR/SD + prior PET response of CMR2
CR3
NE1
CR/PR/SD/NE + prior PET response of non-CMR2
NE
NA/NE1
PD
PD
PMD
CR/PR/SD/NE/PD
PD
NA
NE4
NE
Abbreviations: CMR = complete metabolic response, CR = complete response, CT = computed tomography, 
NA = not applicable, NE = not evaluable, NMR = non metabolic response, PD = progressive disease, PET = 
positron emission tomography, PMD = progressive metabolic response, PMR = partial metabolic response, PR = 
partial response, SD = stable disease, TPR = time point response, UNK= unknown.
1 Non-evaluable PET or missing PET (the terms NE and UNK are equivalent).
2 “Prior PET response” refers to the latest evaluable PET TPR not equivalent to NE. PET responses may be carried 
forward over multiple time points.
3 CR may be carried forward until CT shows progression or is assessed as NE.
4 No disease present.
Table 14:
PET + CT + CNS Time Point Response
PET+CT TPR1
CNS TPR
CT + PET + CNS TPR
CR
CR
CR
CR
SD
PR
PR
CR
PR
PR
SD
PR
SD
CR
SD
SD
SD
SD
Any
SD
PD
PD
Any
PD
CR/PR/SD
NA3/NE4
CR/PR/SD
NE4
CR/SD
NE
NE2
CR/SD
CR/SD
NE2,4
NA2/NE4
NE
Abbreviations: CNS = central nervous system, CR = complete response, CT = computed tomography, NA = not 
applicable, NE = not evaluable, PET = positron emission tomography, PD = progressive disease, PR = partial 
response, SD = stable disease, TPR = time point response.
1 Integrated PET and CT-staging TPR (see Table 13).
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2 No disease was identified. 
3 NA is used of an exam is not submitted for any timepoint or no disease is identified.
4 At least one (1)  lesion or area of disease cannot be adequately evaluated, or exam is missing but was previously 
received.
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APPENDIX D. COCKCROFT-GAULT EQUATION FOR CALCULATING
ESTIMATED CREATININE CLEARANCE
Serum creatinine 
units
Gender
Estimated Creatinine Clearance (mL/min)
mg/dL
Male
(140 − subject age [years]) × subject weight (kg)
72 × subject serum creatinine (mg/dL)
Female
(140 − subject age [years]) × subject weight (kg) × 0.85
72 × subject serum creatinine (mg/dL)
μM/dL
Male
(140 − subject age [years]) × subject weight (kg) × 1.23
Subject serum creatinine (μM/dL)
Female
(140 − subject age [years]) × subject weight (kg) × 1.04
Subject serum creatinine (μM/dL)
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APPENDIX E. CAIRO-BISHOP DEFINITIONS OF TUMOR LYSIS
SYNDROME
Table 15:
Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome (LTLS)
Laboratory 
Parameter
Laboratory Result
Uric acid
≥ 476 μmol/L(≥ 8.0 mg/dL) or 25% increase from baseline
Potassium
≥ 6.0 mmol/L (≥ 6.0 mEq/L) or 25% increase from baseline
Phosphorous
≥1.45 mmol/L (≥ 4.5 mg/dL) or 25% increase from baseline
Calcium
≤ 1.75 mmol/L(≤ 7.0 mg/dL) 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 uric acid, 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 
hypouricemic agent(s).
Table 16:
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.
Table 17:
Cairo-Bishop Grading System for TLS
Grade 
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 ADL
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Table 17:
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.
(Cairo, 2004).
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E D M S D oc. N u m b er: 2 4 2 9 8 9 9 9 - 2 2 3 4 2 7 2 5
J C A R 0 1 7
Pr ot oc ol  J C A R 0 1 7-B C M -0 0 3
C elge ne C or p orati o n
C o nfi de nt ial a n d Pr o priet ar y
1 5 5
J C A R 0 1 7-B C M -0 0 3 A me n d me nt 2 Fi nal: 0 9 D e c 2 0 1 9
A P P E N DI X F.
M I NI M E N TA L S T A T E E X A MI N A TI O N
1 . 0
A p p r o v e d
9 3 0 1 9 3 5 4 5
6 . 0
v
A p p r o v e d
1 . 0
v


E D M S D oc. N u m b er: 2 4 2 9 8 9 9 9 - 2 2 3 4 2 7 2 5
J C A R 0 1 7
Pr ot oc ol  J C A R 0 1 7-B C M -0 0 3
C elge ne C or p orati o n
C o nfi de nt ial a n d Pr o priet ar y
1 5 6
J C A R 0 1 7-B C M -0 0 3 A me n d me nt 2 Fi nal: 0 9 D e c 2 0 1 9
1 . 0
A p p r o v e d
9 3 0 1 9 3 5 4 5
6 . 0
v
A p p r o v e d
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v


E D M S D oc. N u m b er: 2 4 2 9 8 9 9 9 - 2 2 3 4 2 7 2 5
J C A R 0 1 7
Pr ot oc ol  J C A R 0 1 7-B C M -0 0 3
C elge ne C or p orati o n
C o nfi de nt ial a n d Pr o priet ar y
1 5 7
J C A R 0 1 7-B C M -0 0 3 A me n d me nt 2 Fi nal: 0 9 D e c 2 0 1 9
1 . 0
A p p r o v e d
9 3 0 1 9 3 5 4 5
6 . 0
v
A p p r o v e d
1 . 0
v


E D M S D oc. N u m b er: 2 4 2 9 8 9 9 9 - 2 2 3 4 2 7 2 5
J C A R 0 1 7
Pr ot oc ol  J C A R 0 1 7-B C M -0 0 3
C elge ne C or p orati o n
C o nfi de nt ial a n d Pr o priet ar y
1 5 8
J C A R 0 1 7-B C M -0 0 3 A me n d me nt 2 Fi nal: 0 9 D e c 2 0 1 9
1 . 0
A p p r o v e d
9 3 0 1 9 3 5 4 5
6 . 0
v
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APPENDIX G. CLINICAL LABORATORY EVALUATIONS
Table 18:
Clinical Laboratory Evaluations
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, β2-microglobulin, uric acid, 
triglycerides 
Immunoglobulins
IgG, IgM, IgA
Viral serology
HIV
Hepatitis B (HBsAb, HBsAg, and HBcAb), Hepatitis C (Hep C Ab)
Inflammatory markers 
CRP, ferritin
Disease characterization
Histology, cell of origin, immunochemistry, cytogenetics, molecular sub-typing
Cerebrospinal fluid*
RBCs, WBCs with differential, glucose, protein
Urinalysis*
Appearance, pH, specific gravity, protein
Glucose, ketones, RBCs, WBCs
Casts, crystals, or other components
Pregnancy*
ß-HCG (serum)
* Local assessment only.
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; FISH = fluorescence in situ 
hybridization; 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.
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APPENDIX H. SUBJECT REPORTED OUTCOMES: EORTC QLQ C-30 
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APPENDIX J.
SUBJECT REPORTED OUTCOMES: FACT-LYM
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APPENDIX K. HCT-CI SCORE CALCULATOR
Co-morbidity
Definition
Yes
Score
Arrhythmia
Atrial fibrillationa or
1
Atrial fluttera or
Sick sinus syndromea or
Ventricular arrhythmiaa
Cardiovascular
Coronary artery diseasea or
1
Congestive heart failurea or
Myocardial infarctiona or
Ejection fraction ≤ 50%b
Inflammatory bowel disease Crohn’s diseasea or
1
Ulcerative colitisa or
Diabetes
Treated with insulin or oral hypoglycemic drugsb
1
Cerebro-vascular
Transient ischemic attacksa or
1
Cerebro-vascular ischemic or hemorrhagic strokea
Depression/anxiety
Requiring psychological consultation and/or specific
treatmentsb
1
Hepatic - mild
Chronic hepatitisb AND
1
Bilirubin > ULN - 1.5 x ULNb or
AST/ALT > ULN - 2.5 x ULNb
Obesity
Body mass index >35 (adults)b or
1
Body mass index-for-age ≥ 95% percentile (children)b
Infection
Requiring anti-microbial treatment before, during, and after 
the start of conditioningb
1
Rheumatologic
Requiring Treatmenta
2
Peptic ulcer
Confirmed by endoscopy and requiring treatmenta
2
Renal
Serum creatinine > 2 mg/dl (or > 177 µmol/L)b or
2
On dialysisb or
Prior renal transplantationa
Pulmonary - Moderate 
Dlco corrected for hemoglobin 66-80% of predictedb and/or
2
FEV1 66-80% of predictedb or
Dyspnea on slight activityb
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Co-morbidity
Definition
Yes
Score
Pulmonary - Severe 
Dlco corrected for hemoglobin ≤ 65% of predictedb and/or
3
FEV1 ≤ 65% of predictedb or
Dyspnea at rest or requiring oxygen therapyb
Heart valve disease
Except asymptomatic mitral valve prolapse
3
Prior solid malignancy
Treated with surgery, chemotherapy, and/or radiotherapy, 
excluding non-melanoma skin cancera
3
Hepatic - moderate/severe
Liver cirrhosisb AND
3
Bilirubin > 1.5 x ULNb or
AST/ALT > 2.5 x ULNb
Total Score
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; Dlco = diffusion capacity of 
carbon monoxide; FEV1 = forced expiratory volume in one second; ULN = upper limit of normal.
a Diagnosed at any time in the patient’s past history.
b Detected at the time of pretransplant assessment.
(Sorror, 2005).
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APPENDIX L. JCAR017 MANAGEMENT GUIDELINES FOR 
CYTOKINE RELEASE SYNDROME AND NEUROLOGIC
TOXICITIES (V3.2)
1. MANAGEMENT OF TOXICITIES ASSOCIATED WITH JCAR017
Cytokine release syndrome (CRS) and neurologic toxicities (NT) are associated with chimeric 
antigen receptor (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 electronic case report form (eCRF) to inform 
future modifications of the management guidelines.
2. 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 (Lee, 2014; Gardner,
2017). 
2.1.
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 (TNF-α) 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). IL-6 has been identified as a central mediator of toxicity in CRS. IL-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.
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2.2.
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 2.

CRS has been reported in some cases to be associated with findings of macrophage 
activation syndrome (MAS)/ hemophagocytic lymphohistiocytosis (HLH), and the 
physiology of the syndromes may overlap; refer to Section 3. 
2.3.
Clinical Management of Cytokine Release Syndrome
Across various CD19 CAR T cell products, early manifestations of CRS can predict more severe 
toxicity for both CRS and NT. 
Subjects with B-cell acute lymphoblastic leukemia (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 CTCAE CRS grading scale has been established to better reflect CAR T 
cell-associated CRS, as detailed in Table 1 (Lee, 2014).
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Table 1:
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 
vasopressora
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 2.
Table 2:
High Dose Vasopressors (all doses required for ≥3 hours)
Vasopressor
Dose
Norepinephrine monotherapy
≥20 μg/min
Dopamine monotherapy
≥10 μg/kg/min
Phenylephrine monotherapy
≥200 μg/min
Epinephrine monotherapy
≥10 μg/min
If on vasopressin
Vasopressin + norepinephrine equivalent (NE) of ≥10 
μg/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].
Adapted from (Lee, 2014).
Detailed CRS management guidelines are shown in Figure 1. Treatment should be individualized 
for each subject’s clinical needs. 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 
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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. 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. The preferred dose 
to intervene in adult subjects with CRS is 8 mg/kg (maximum 800 mg) IV. 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 1, 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 1:
JCAR017 Cytokine Release Syndrome Treatment Algorithm
Abbreviations: ANC = absolute neutrophil count; BMA = bone marrow aspirate; CAR = chimeric antigen receptor; CRP = C-reactive protein; CRS = cytokine 
release syndrome; EEG = electroencephalogram; HLH = hemophagocytic lymphohistiocytosis; ICU = intensive care unit; IL-6 = interleukin 6; INR = 
international normalized ratio; IV = intravenous; MAS = macrophage activation syndrome; NT = neurotoxicity; PTT = partial thromboplastin time; q = every.
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3. MACROPHAGE ACTIVATION SYNDROME /HEMOPHAGOCYTIC 
LYMPHOHISTIOCYTOSIS
Macrophage activation syndrome (MAS) or HLH is a rare, potentially fatal immune-mediated 
disease, which is 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 CRS and organ damage (Ramos-Casals,
2014). Cases of MAS/HLH have been described in patients treated with CAR T cell 
therapies (Neelapu, 2017). 
3.1. Pathophysiology of Macrophage Activation Syndrome/Hemophagocytic 
Lymphohistiocytosis
Macrophage activation syndrome/hemophagocytic lymphohistiocytosis 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 hematological malignancies, in particular lymphoma, have a higher risk of 
developing MAS/HLH.
3.2.
Clinical Presentation and Diagnosis of Macrophage Activation 
Syndrome/Hemophagocytic Lymphohistiocytosis
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 few days to 4 week(s) (Ramos-Casals, 2014). The cardinal features are 
continuous high fever (≥38.5 °C) and enlarged lymphohematopoietic organs 
(spleno/hepatomegaly, occasionally accompanied by adenopathy). Pulmonary, neurologic, 
cutaneous and gastrointestinal involvement may also be present.
Laboratory markers associated with MAS/HLH include pancytopenia, hyperferritinemia, 
hypoﬁbrinogenemia and raised D-dimer levels, hypertriglyceridemia, and abnormalities in liver
function. 
Detection of any ongoing infection acting as a trigger for MAS/HLH is critical (Figure 1). 
Standard tests should be used to screen for infections caused by the most common viruses such 
as herpes, cytomegalovirus (CMV) and Epstein-Barr virus (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).
Bone marrow is the preferred anatomical site for investigation of suspected MAS/HLH. Bone 
marrow aspirate can be negative at the initial stage of MAS/HLH and should be repeated during 
the clinical course if there is a high suspicion of MAS/HLH.
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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 either of the two 
criteria below is fulfilled: 
1. A molecular diagnosis consistent with MAS/HLH 
2. Diagnostic criteria for MAS/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

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
3.3.
Clinical Management of Macrophage Activation Syndrome/Hemophagocytic 
Lymphohistiocytosis
Effective treatment of MAS/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 treatment recommendations should 
be followed). IL-1 blockade with anakinra is suggested as second line treatment or in 
case of rapidly progressing clinical course. Anti-IL-6 antibody 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 cell therapy, but may have to be employed in refractory 
cases. 
Newer emerging treatments include emapalumab (anti IFN-gamma antibody), which has 
been approved by FDA for the treatment of primary refractory or recurrent MAS/HLH 
(Benedetti, 2019).
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4. 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.
4.1.
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-cell 
ALL and higher disease burden at the time of CD19 directed CAR T cell infusion (Park, 2017; 
Gust, 2017).
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 (Turtle, 2016; Heipel, 2017). 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).
4.2.
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. Management should also be guided as per 
institutional or standard clinical practice, and as determined by the Investigator or treating 
physician and/or consulting neurologist. A thorough neurologic evaluation, 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.
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). 
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For subjects who have neurologic toxicity in the presence of CRS, the CRS should be managed 
following the guidelines provided in Figure 1. 
Neurotoxicity should be evaluated following the guidelines provided in Figure 2. 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 has 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, 2017), demonstrated that early 
tocilizumab use either increased overall neurotoxicity and Grade ≥3 neurotoxicity rates (85% vs 
62% overall; 35% vs 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 2.
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Figure 2: Neurotoxicity Treatment Algorithm
Abbreviations: CAR = chimeric antigen receptor; CRS = cytokine release syndrome; CT = computed tomography; EEG = electroencephalogram; ICU = 
intensive care unit; LP = lumbar puncture; MRI = magnetic resonance imaging; NT = neurotoxicity; q = every.
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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.
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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JCAR017
Protocol JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
179
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
APPENDIX M. SECONDARY AGE ADJUSTED INTERNATIONAL 
PROGNOSTIC INDEX (SAAIPI)
Assessments
Score
Serum Lactate Dehydrogenase (LDH)
Score 0 if LDH ≤ ULN mg/dL
Score 1 if LDH >ULN mg/dL
Ann Arbor Stage
Score 0 if Stage I/II 
Score 1 if Stage III/IV
Karnofsky Performance Status (KPS)
Score 0 if KPS ≥ 80%
Score 1 if KPS < 80%
sAAIPI score
sAAIPI groups are low risk with score zero, low-intermediate risk with score 1, high-
intermediate risk with score 2, and high risk with score 3.
Adapted from Hamlin, 2003.
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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: Thursday, 12 December 2019, 11:31 AM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
 ================================================
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EDMS Doc. Number: 24298999 - 23503775
JCAR017
Summary of Changes JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
1
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
TITLE PAGE
– SUMMARY OF CHANGES –
AMENDMENT NO. 2.0
A GLOBAL RANDOMIZED MULTICENTER PHASE 3 TRIAL 
TO COMPARE THE EFFICACY AND SAFETY OF JCAR017 TO 
STANDARD OF CARE IN ADULT SUBJECTS WITH HIGH-
RISK, TRANSPLANT-ELIGIBLE RELAPSED OR
REFRACTORY AGGRESSIVE B-CELL NON-HODGKIN 
LYMPHOMAS (TRANSFORM)
INVESTIGATIONAL PRODUCT (IP):
JCAR017
PROTOCOL NUMBER:
JCAR017-BCM-003
ORIGINAL DATE:
07 Mar 2018
AMENDMENT No. 1.0 DATE:
06 Feb 2019
AMENDMENT No. 2.0 DATE:
09 Dec 2019
EudraCT NUMBER:
2018-000929-32
Contact Information – Ex-US sites:
Contact Information – US sites:
Name: 
Title: 
 
Address: Route de Perreux 1, 2017 Boudry, 
Switzerland
Phone: (Office) 
             (Mobile) 
E-mail: 
Name: 
Title: 
 
Address: 400 Dexter Ave. North, Suite 1200, Seattle, WA 
98109, USA
Phone: (Office) 
            (Mobile) 
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: 24298999 - 23503775
JCAR017
Summary of Changes JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
2
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 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. 
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EDMS Doc. Number: 24298999 - 23503775
JCAR017
Summary of Changes JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
3
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
1.
JUSTIFICATION FOR AMENDMENT
A global protocol amendment was generated for Study JCAR017-BCM-003 
 
 
The updates introduced with this protocol amendment remain consistent with the scientific 
advice received
 
 in December 2017.
Significant changes included in this amendment are summarized below:

Inclusion and exclusion criteria and pregnancy risk section updated with information 
on blood and tissue donation, contraception and breastfeeding following exposure to 
lymphodepletion, combination agent and/or JCAR017
There is no exposure data to provide a recommendation concerning duration of contraception 
following treatment with JCAR017. The JCAR017 program excludes pregnant subjects from 
participation and mandates that subjects use highly effective contraception. So far, no 
pregnancy has occurred in the JCAR017 clinical development program. No animal studies 
have been conducted with JCAR017 to assess whether it could 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 cause fetal toxicity, including B-cell 
lymphocytopenia. As the risk for the mother and fetus or newborn is unknown at this time, 
and negative CAR T quantitative polymerase chain reaction (qPCR) tests do not reliably 
predict complete disappearance of CAR T cells from the body, this test cannot be used to 
guide duration of contraception. Therefore, the indication that contraception may be changed 
or breastfeeding may be resumed following two subsequent negative CAR T qPCR tests was 
removed from the inclusion criteria.
Inclusion criterion #10 was updated to align with the summary of product characteristics 
(SmPC) and the United States (US) package insert (USPI) pregnancy guidance for 
cyclophosphamide.
Revised Sections: 4.2. Inclusion Criteria (criteria #10 to #12), 5. Table of Events (Tables 3 
and 4), 6.3.1.1.1. Month 6 (± 10 days), Section 6.3.1.1.2. Months 9, 12, 18, 24, and 36 (± 14 
days), 10.4 Pregnancy

Exclusion criterion for known allergy to dimethyl sulfoxide (DMSO) or Dextran was 
added
Revised Section: 4.3. Exclusion Criteria (criterion #19)
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EDMS Doc. Number: 24298999 - 23503775
JCAR017
Summary of Changes JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
4
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019

Toxicity Management Guidelines were updated to provide information on diagnosis 
and management of macrophage activation syndrome / hemophagocytic 
lymphohistiocytosis (MAS/HLH)
Cases of MAS/HLH have been described in patients treated with CAR T cell therapies. 
Guidelines on the background, diagnosis and management of MAS/HLH are provided.
Revised Section: Appendix L

Exclusion of subjects with deep venous thrombosis (DVT) and/or pulmonary embolism 
(PE) within 3 months of leukapheresis and/or DVT or PE that requires ongoing 
therapeutic levels of anticoagulation and tumor invasion or venous or arterial vessels 
were updated
Revised Sections: Section 4.3 Exclusion Criteria (criteria #15 and #16), Section 6.2.3.2 
Arm B, Section 6.2.4.2 Arm B
This amendment includes the following minor changes that are not specific to the above 
major changes:

Medical Monitor/Emergency Contact information updated – Medical Monitor/Emergency 
Contact information section

European Organisation for Research and Treatment of Cancer – Quality of Life C30 
(EORTC QLQ-C30) subscales split between secondary objectives/endpoints and exploratory 
objectives/endpoints – Protocol Summary, Section 2 (Table 1 and Table 2)
 
 

Addition made regarding the calculation of time of relapse for consistency with the note in 
Section 4.2 inclusion criterion #6 – Protocol Summary

Update wording from enrollment to screening – Protocol Summary, Section 9.8.2, Section 
9.9.2, Section 13.8, Section 14.3, Section 15.1
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EDMS Doc. Number: 24298999 - 23503775
JCAR017
Summary of Changes JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
5
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019

Clarification made regarding the expected schedule for ifosfamide for R-ICE regimen -
Protocol Summary, Section 7.4.1

Update of the dose levels of JCAR017 to be displayed in 106 as per program decision –
Protocol Summary, Section 1.2.4, Section 1.3.3, Section 7.4.5

Clarification made that the efficacy assessments performed for the study by the independent 
review committee (IRC) will be done as per the Celgene “Guidelines for Efficacy Evaluation 
in PET-avid Non-Hodgkin Lymphoma” which is based on “The Lugano Classification” –
Protocol Summary, Section 2 (Table 2), Section 6.5, Section 9.6.1

Update of the list of adverse events of special interest – Protocol Summary, Section 10.8

Update wording from enrollment to randomization/randomized – Protocol Summary, Section 
3.1, Section 4.2, Section 4.3, Section 9.3.1, Section 9.8.2, Section 13.8, Section 14.3

Number of subjects for the SCHOLAR-1 meta-analysis updated from 635 to 636 – Section 
1.1

Update made regarding the approvals of CD19-directed CAR T-cell therapies – Section 1.2.2

Reference updated with latest data – Section 1.2.4

Update made to have pharmacokinetic profile of JCAR017 its own objective – Section 2 
(Table 1)

Update made to clarify that stem cell collection in Arm A is not only to be performed in 
responding patients and that a prior collection can be used for the study – Section 3.1, 
Section 5 (Table 3), Section 6.2.2

Overall study design figure updated to show “LD” in the black box – Section 3.1 (Figure 1)

Clarification made to the inclusion criterion #5 regarding the tumor biopsy requirement for 
refractory subjects – Section 4.2 and Section 6.1.1

Clarification made to the inclusion criterion #6 regarding the definition of refractory disease 
and relapsed disease – Section 4.2

Clarification made to the inclusion criterion #7 regarding required Deauville score – Section 
4.2  

Clarification made to the exclusion criterion #6 to clarify that subjects with transformation 
from chronic lymphocytic leukemia/small lymphocytic lymphoma (Richter transformation) 
are not allowed in the study – Section 4.3  

Update made to exclusion criterion #10 to clarify the virology results which exclude subjects
from being eligible to the study – Section 4.3  

Screening period was extended from 21 to 28 days and randomization window was extended 
from 2 to 3 days – Section 5 (Table 3), Section 6.1.1, Section 6.2.1  
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EDMS Doc. Number: 24298999 - 23503775
JCAR017
Summary of Changes JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
6
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019
 
 

Addition of peripheral blood sample for detection of B-cell aplasia by flow cytometry –
Section 5 (Tables 3 and 4), Section 6  

Update made to have body surface calculation done for Arm A as well at randomization –
Section 5 (Table 3), Section 6.2.1

Requirement added for daily MMSE for Arm B subjects in case of neurologic symptoms as 
supported by the investigator letter dated 11 Jul 2019 – Section 5 (Tables 3 and 4), Section 
6.2, Section 6.4.5

Clarification made regarding how visits are to be scheduled for Arm B subjects after Day 29 
– Section 5 (Table 3), Section 6.2.5
 
 

Clarification made on how Day 126 is to be scheduled for Arm A subjects – Section 6.2.14

Removal of Month 5 from the list of visits as per Protocol Amendment 1.0 this visit was 
removed from the table of event – Section 6.3.1

Removal of Month 5 from the list of visits as per Protocol Amendment 1.0 this visit was 
removed from the table of event – Section 6.3.1

Update made regarding the replication-competent lentivirus (RCL) and viral vector collection 
- Section 6.3.1.2
 

Update done to the list of the unscheduled evaluations – Section 6.3.3

Update wording from new malignancies to second primary malignancies – Section 6.3.6, 
Section 6.4.10, Section 6.4.11, Section 10.2.1, Section 10.6.4   

Update done to the analysis performed on the cerebrospinal fluid for alignment with 
Appendix G - Section 6.4.6

Clarification made about the use of a central laboratory for the study – Section 6.4.12

Addition of sections about additional and optional research – Section 6.7.3

Addition of details regarding the exception use of non-conforming product – Section 7.4.6.2

Clarification made about the requirements for concomitant medication and procedures 
reporting align within the other JCAR017 studies – Section 8.1 and Table 5

Clarification provided regarding the allowed local radiation and timing prior to 
lymphodepleting chemotherapy– Section 8.1
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EDMS Doc. Number: 24298999 - 23503775
JCAR017
Summary of Changes JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
7
JCAR017-BCM-003 Amendment 2 Final: 09 Dec 2019

Clarification provided regarding the allowed steroid doses – Section 8.2

Clarification about the prohibited concomitant medications for subjects infused with 
JCAR017 – Section 8.2.1

Clarification made regarding the baseline definition for statistical analysis – Section 9.1

Update made to the per-protocol analysis set to further define the selected elements – Section 
9.2.3
 

Addition of 2 new analysis set: JCAR017-Treated Analysis Set and Health-related Quality of 
Life Analysis Set – respectively Section 9.2.7 and Section 9.2.8

Minor rewording of the sample size calculation and sample size robustness and sensitivity 
description – Section 9.3, Section 17

Clarifications made on the subgroup analyses – Section 9.6.4

Minor rewording of the treatment exposure description – Section 9.7.1

Clarifications made regarding the laboratory evaluations and how they will be used for the 
analyses – Section 9.7.3

Clarifications made regarding the 2 different interim analyses – Section 9.8

Update made to specify pharmacokinetic as part of the exploratory analysis – Section 9.9.5

Clarifications added to the statistical analysis of patient reported outcomes – Section 9.9.6

Clarifications added to the statistical analysis of hospital resource utilization – Section 9.9.7

Addition of conditions to be reported as SAEs regardless of relationship to study drug –
Section 10.1 (Table 8)

Clarification of management of toxicities associated with JCAR017 – Section 10.6.1

Some literature references were updated and added – Protocol body, Section 17

Update to include the integrated positron emission tomography (PET) and computed 
tomography (CT) response assessment performed by IRC based on heath authority’s 
requirement – Appendix C (Tables 13 and 14)

New abbreviations added – Section 18, Appendix A

Typographical errors corrected

Style and formatting updated
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EDMS Doc. Number: 23504168 - 23503775
JCAR017
Summary of Changes JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
1
JCAR017-BCM-003 Amendment 1 Final: 06 Feb 2019
TITLE PAGE
– SUMMARY OF CHANGES –
AMENDMENT NO. 1.0
A GLOBAL RANDOMIZED MULTICENTER PHASE 3 TRIAL 
TO COMPARE THE EFFICACY AND SAFETY OF JCAR017 TO 
STANDARD OF CARE IN ADULT SUBJECTS WITH HIGH-
RISK, TRANSPLANT-ELIGIBLE RELAPSED OR
REFRACTORY AGGRESSIVE B-CELL NON-HODGKIN 
LYMPHOMAS (TRANSFORM)
INVESTIGATIONAL PRODUCT (IP):
JCAR017
PROTOCOL NUMBER:
JCAR017-BCM-003
ORIGINAL DATE:
07 Mar 2018
AMENDMENT No. 1.0 DATE:
06 Feb 2019
EudraCT NUMBER:
2018-000929-32
Contact Information – Ex-US sites: Contact Information – US sites:
Contact Information – US sites:
Name: 
Name: 
Name: 
Title: 
Title: 
Title: 
Address: Route de Perreux 1, 2017 
Boudry, Switzerland
Address: 400 Dexter Ave. North,
Suite 1200, Seattle WA 98109, USA
Address : 400 Dexter Ave. North, 
Suite 1200, Seattle, WA 98109, USA
Phone: (Office) 
             (Mobile) 
Phone: (Office) 
             (Mobile) 
Phone: (Office) 
            (Mobile) 
E-mail: 
E-mail: 
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: 23504168 - 23503775
JCAR017
Summary of Changes JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
2
JCAR017-BCM-003 Amendment 1 Final: 06 Feb 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: 23504168 - 23503775
JCAR017
Summary of Changes JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
3
JCAR017-BCM-003 Amendment 1 Final: 06 Feb 2019
1.
JUSTIFICATION FOR AMENDMENT
A global protocol amendment was generated for Study JCAR017-BCM-003 
 
 
 
 
The updates introduced with this protocol amendment remain consistent with the scientific 
advice received 
 in December 2017.
Significant changes included in this amendment are summarized below:

Eligibility broadened to include additional subtypes of relapsed/refractory (R/R) 
aggressive non-Hodgkin lymphomas
The addition of primary mediastinal (thymic) large B-cell lymphoma [PMBCL], T 
cell/histiocyte-rich large B-cell lymphoma [THRBCL] is based on the fact that these histologies 
have similar biological behavior, are treated according to the DLBCL treatment algorithm, and 
supporting preliminary data are available from Study 017001.
Revised Sections: Protocol Summary, Section 1.1 Disease Background, Section 1.3.2 Rationale 
for the Study Design, Section 4.2 Inclusion Criteria and Section 4.3 Exclusion Criteria

Event-free survival (EFS) and progression-free survival (PFS) definitions were 
modified
“Event-free survival (EFS): Time from randomization to death from any cause, progressive 
disease (PD), failure to achieve complete response (CR) or partial response (PR) by 9 weeks 
post-randomization, or start of new antineoplastic therapy due to efficacy concerns, whichever 
occurs first”
“Progression-free survival (PFS): Time from randomization to PD or death from any cause, 
whichever occurs first”
Revised Sections: Protocol Summary, Section 2 Study Objectives and Endpoints, Section 9.6 
Efficacy Analysis

Study Design was updated
In Arm A standard of care (SOC), subjects will receive 3 cycles and the cycle time has been 
updated from 28 days to 21 days that is in line with clinical practice. Accordingly start of high 
dose chemotherapy (HDCT) has been moved from Day 85 to Day 71. The first efficacy 
assessment has been moved from Day 57 to Day 64; the second efficacy assessment has been 
moved from Day 113 to Day 126. Table of events was updated accordingly; main additional 
changes are listed below:
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EDMS Doc. Number: 23504168 - 23503775
JCAR017
Summary of Changes JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
4
JCAR017-BCM-003 Amendment 1 Final: 06 Feb 2019

Study Day 106 replaced by Day 102 

PET added for Arm B at Day 22 and PET and CT/MRI removed at Month 3 for Arm A. 

Month 5 visit has been removed

Visit windows adjusted
Revised Sections: Protocol Summary, Section 3.1 Study Design, Section 5 Table of Events, 
Section 6 Procedures, Section 7.4.1 Reference Therapies

Crossover criteria were updated 
In order to ensure patients who responded to salvage chemotherapy will receive HDCT and 
HSCT and to reflect the new definition of EFS, cross over rules have been modified. Crossing 
over is now allowed after failure to achieve CR or PR by 9 weeks post-randomization, 
progression at any time, and start of a new antineoplastic therapy due to efficacy concerns after 
18 weeks post- randomization.
Revised Sections: Protocol Summary, Section 3.1 Study Design, Section 6.3.2 Assessments for 
Subjects Crossing Over to JCAR017

Recommendation for the selection of subjects with secondary central nervous system 
(CNS) involvement was added. In addition, intrathecal (IT) treatment is now allowed 
for these patients. 
Existing note in inclusion criteria 5 was further detailed to clarify that the selection of subjects 
with primary or secondary CNS involvement must consider risk factors for severe adverse events 
and alternative treatment options. Subjects should only be enrolled if the potential benefit 
outweighs the risk for the subject, as considered by the Investigator. Details regarding IT 
administration was added.
Revised Section: Protocol Summary, Section 4.2 Inclusion Criteria, Section 4.3 Exclusion 
Criteria, Section 6.2.3.2 Arm B, Section 8.1 Permitted Concomitant Medications and Procedures, 
Section 8.2 Prohibited Concomitant Medications and Procedures

Definition of adequate organ function in inclusion criteria 8 was updated to ensure that 
subjects will be able to complete salvage chemotherapy followed by high dose 
chemotherapy (HDCT) and hematopoietic stem cell transplant (HSCT)
Adequate bone marrow function was defined as absolute neutrophil count (ANC) ≥ 1.0 x 109
cells/L and platelets ≥ 50 x 109 cells/L in absence of bone marrow involvement. Creatinine 
clearance must be >45 mL/min and FEV1 ≥ 50%.
Revised Section: Section 4.2 Inclusion Criteria

Use of systemic immunostimulatory agents added to the list of excluded medications in 
the exclusion criteria
Revised Section: Section 4.3 Exclusion Criteria

Additional eligibility checklist prior to administration of HDCT/HSCT was added
Revised Section: Section 6.2.10.1 Arm A
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EDMS Doc. Number: 23504168 - 23503775
JCAR017
Summary of Changes JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
5
JCAR017-BCM-003 Amendment 1 Final: 06 Feb 2019

Change to allow radiotherapy after completion of per protocol treatment in both arms 
to sites of previous PET positive disease
Revised Sections: Section 8.1 Permitted Concomitant Medications and Procedures, Section 8.2 
Prohibited Concomitant Medications and Procedures. 

Clarification was done on the methodology used for sample size calculation
Revised Section: Section 9.3.1 Sample Size Calculation

Clarification was added that cetuximab is not indicated for the treatment of cytokine 
release syndrome (CRS) or neurotoxicity
Revised Sections: Section 10.6.1.1 Cytokine Release Syndrome and Section 10.6.1.3 Neurologic 
Toxicities

Inclusion criterion 4 was restricted to Eastern Cooperative Oncology Group (ECOG) 
performance status ≤ 1
Revised Sections: Section 4.2 Inclusion Criteria

Subjects with deep venous thrombosis (DVT) and/or pulmonary embolism (PE); and 
vascular tumor invasion will not be eligible
 
Revised Section: Section 4.3 Exclusion Criteria and Section 8.1 Permitted Concomitant 
Medications and Procedures
This amendment includes the following minor changes that are not specific to the above 
major changes:

IND number added – Cover page

Medical monitor added – Medical Monitor/Emergency Contact information section

Addition made for consistency with Section 9.6.1 to indicate that hazard ratio and its 
confidence interval will be estimated using a stratified Cox-proportional hazard – Protocol 
summary

Update wording from enrolled to consented –Section 13.6

Addition of 36 months after randomization timepoint to compare efficacy rates (EFS, PFS, 
OS) – Protocol Summary, Section 2

Clarification made on how to calculate time of relapse for inclusion criteria 6 – Section 4.2 

Exclusion criterion 14 revised to include cerebral edema and remove paresis – Section 4.3 
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EDMS Doc. Number: 23504168 - 23503775
JCAR017
Summary of Changes JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
6
JCAR017-BCM-003 Amendment 1 Final: 06 Feb 2019

Update of 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). 
 Detection of vector 
sequence in two consecutive visits will result in additional analysis on the pattern for vector 
integration sites –
 Section 5 Table of Events, Section 6.1.1, Section 6.2.4.2, 
Section 6.2.5, Section 6.2.6, Section 6.2.7, Section 6.2.8, Section 6.2.9, Section 6.2.10, 
Section 6.2.11, Section 6.3.1, Section 6.3.3, Section 6.4.11 and Section 6.6.1

Clarification made that assessments required at randomization must be done prior to 
receiving study treatment – Section 6.2.1

Criteria for start of LD chemotherapy and infusion of JCAR017 has been updated to exclude 
patients with rapid disease progression – Section 6.2.3.2 and Section 6.2.4.2

Clarification added in regard to vital signs for alignment with Section 7.4.5 JCAR017 
Administration – Section 6.2.4.2

Addition of pregnancy tests at Month 36 or end of study (EOS) – Section 5, Section 6.3.1.1.2 
and Section 6.3.1.2 

Follow-up in case of disease recurrence or new malignancy was further detailed - Section 
6.3.6 and Section 6.4.11

The definition of timing of pseudoprogression was updated – Section 6.5.1 

Clarification added to explain that only the subscale of the Functional Assessment of Cancer 
Treatment-Lymphoma (FACT-Lym) questionnaire will be administered in the study because
other topics are covered by the EORTC QLQ-C30 – Section 6.8.3

Corrections done in the scheduling of R-ICE standard of care (SOC) regimen and HDCT –
Protocol Summary, Section 7.4.1 

Clarification in regard to the standard of care scheduling and dose adjustment for toxicities 
that it will be done as per local label – Protocol Summary and Section 7.4.1 

Update from ASCT to HSCT – Section 7.4.1 and Section 9.6.3

Deletion of radioisotope glomerular filtration rate (GFR) assessment as a criterion for 
withholding LD chemotherapy – Section 7.4.2 

Changes made to the recommendations for dose adjustment of fludarabine – Section 7.4.2 
 
 

Editorial change for the use of cetuximab from ‘indicated’ to ‘intended’ – Section 8.2

Language was added for sites to have tocilizumab readily available prior to JCAR017
administration as required for treatment and management of CRS – Section 8.3
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EDMS Doc. Number: 23504168 - 23503775
JCAR017
Summary of Changes JCAR017-BCM-003
Celgene Corporation
Confidential and Proprietary
7
JCAR017-BCM-003 Amendment 1 Final: 06 Feb 2019

Modification of definition of the Pharmacokinetic Analysis Set – Section 9.2.5 

Update of wording from enrolled to randomized – Protocol Summary, Section 9.3.1, Section 
9.5 and Section 9.8.3

Additional clarifications made in the analysis of adverse events– Section 9.7.2

Correction of wording from blinded to aggregate – Section 9.8.3

Clarification added to explain that additional information on the estimation of the EFS 
probability curve and computation of the predictive distribution for the EFS events will be 
mentioned in the Statistical Analysis Plan (SAP) – Section 9.8.3 

Adverse Event section modified to ease the reading – Section 10

Management of Toxicities associated with JCAR017 section was updated: Tumor lysis 
syndrome and uncontrolled T cell proliferation were updated, cytopenias and infections were 
added - Section 10.6.1

JCAR017 Management Guidelines for Cytokine Release Syndrome and Neurologic 
Toxicities updated from version 2.3 to version 3.1 – Section 18, Appendix L   

Some literature references were updated and added – Protocol body, Section 17

New abbreviations added – Section 18, Appendix A

New appendix added for the calculation of secondary age adjusted international prognostic 
index (sAAIPI) – Section 18, Appendix M

Style and formatting updated
Approved
1.0
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