Dose Optimization Trial of Autologous T Cells Engineered to Express Anti-CD19 Chimeric Antigen Receptor (CART-19) in Patients With Relapsed or Refractory CD19+ Chronic Lymphocytic Leukemia (CLL)
Phase: PHASE2
Conditions: Adult Patients Who Have Relapsed or Refractory CLL (3rd Line) or SLL
Sponsor: University of Pennsylvania

 
 
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University of Pennsylvania 
 
UPCC03712:  DOSE OPTIMIZATION TRIAL OF AUTOLOGOUS T CELLS 
ENGINEERED TO EXPRESS ANTI-CD19 CHIMERIC ANTIGEN RECEPTOR 
(CART-19) IN PATIENTS WITH RELAPSED OR REFRACTORY  
CD19+ CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)  
 
Principal Investigator: 
Noelle Frey, MD 
Department of Medicine 
Perelman  School of Medicine  
Philadelphia, Pennsylvania 19104 
Sub-Investigators: 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Investigators: 
  
 
Regulatory Sponsor: 
 
 
Perelman  School of Medicine 
 
Philadelphia, PA 19104-
 
 
Funding Organization: 
Novartis Pharmaceuticals Corp 
One Health Plaza 
East Hanover, NJ 07936 
Study Product: 
CD19 redirected autologous T cells (CART-19-T Cells) 
Protocol Numbers: 
IRB 
, UPCC 03712, 
1 
 
 

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transmitted, reproduced, published, or used by other persons without prior written authorization from the 
study sponsor. 
Date: 
Aug 7, 2012 
Sept 28, 2012 
October 24, 2012 
November 20, 2012 
January 21, 2013, January 29, 2013 
March 11, 2013 
May 28, 2013 
September 30, 2013 
March 24, 2014 
July 18, 2014 
November 12, 2014 
March 5, 2015 
 
 
 
Medical Monitor 
 
 
 
STUDY TEAM 
 
Clinical Trial Site - University of Pennsylvania  
 
Principal Investigator 
Noelle Frey, MD 
 
Clinical Team 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Protocol Advisor 
 
 
Statistical Team 
 
 
Quality Assurance for Manufacturing 
  
 
Immune Correlative Studies 
 
 
Sponsor Cell Manufacturing – University of Pennsylvania 
 
 

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STUDY MANAGEMENT 
 
Clinical Management Questions 
For questions concerning entry criteria, toxicity management, concomitant medications, and 
coenrollment, contact 
 
. Include 
the protocol number in the subject line and patient identification number (PID) and a brief relevant 
history in the message. 
 
Laboratory Questions 
For questions specifically related to clinical laboratory tests, contact the Project Managerat 
; for questions related to research laboratory tests, contact the 
Translational Correlative Sciences Laboratory (TCSL) at S
 For 
questions related to cell manufacturing, contact the CVPF Laboratory Director at 
. 
 
Data Management Questions 
For nonclinical questions about inclusion/exclusion criteria, case report forms (CRF), the CRF 
schedule of events, randomization/registration, transfers, delinquencies, and other data 
management issues, contact the Project Manager at t
. For statistical 
questions, contact the Protocol Statistician. Send an e-mail message to Wei-Ting Hwang 
(
). Include the protocol number, PID, and a detailed question.  
 
Protocol Document Questions 
For questions concerning the protocol document, contact the Project Manager at 
. 
 
Copies of the Protocol 
To request hard copies of the protocol contact the Project Manager at t
. 
 
Study Drug/Cell Manufacturing Questions 
For questions related to cell manufacturing, contact the CVPF Laboratory Director at 
. 
 
IND Number or Questions 
Contact the Project Manager at 
. 
 
Adverse Event Reporting/Questions 
Contact the Project Manager at 
.  

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Table of Contents 
CART-19 STUDY SYNOPSIS .................................................................................................................................. 10 
1 
INTRODUCTION ............................................................................................................................................ 17 
1.1 
BACKGROUND ................................................................................................................................................ 17 
1.2 
INVESTIGATIONAL AGENT .............................................................................................................................. 17 
1.3 
PRECLINICAL DATA ....................................................................................................................................... 20 
1.4 
PREVIOUS CLINICAL DATA WITH CART-19 CELLS ........................................................................................ 20 
1.5 
RATIONALE FOR THE STUDY DESIGN .............................................................................................................. 22 
1.6 
RATIONALE FOR DOSE AND REGIMEN SELECTION ........................................................................................... 23 
1.7 
RATIONALE FOR PRE-TREATMENT LYMPHODEPLETION .................................................................................. 24 
1.8 
BENEFIT AND RISK ASSESSMENT ................................................................................................................... 24 
2 
STUDY OBJECTIVES AND ENDPOINTS .................................................................................................. 28 
3 
STUDY DESIGN .............................................................................................................................................. 30 
3.1 
GENERAL DESIGN .......................................................................................................................................... 30 
3.2 
PRIMARY EFFICACY NON-EVALUABLE PATIENTS .......................................................................................... 33 
3.3 
RETREATMENT COHORT ................................................................................................................................ 33 
3.3.1 Overview ................................................................................................................................................... 33 
3.3.2 Retreatment Objectives ............................................................................................................................. 34 
3.3.3 Retreatment Dose ...................................................................................................................................... 35 
4 
SUBJECT SELECTION AND WITHDRAWAL ......................................................................................... 35 
4.1 
INCLUSION CRITERIA ..................................................................................................................................... 35 
4.2 
EXCLUSION CRITERIA .................................................................................................................................... 36 
4.3 
SUBJECT RECRUITMENT AND SCREENING ...................................................................................................... 37 
4.4 
EARLY WITHDRAWAL OF SUBJECTS ............................................................................................................... 38 
4.4.1 
When and How to Withdraw Subjects .................................................................................................. 38 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects ..................................................................... 38 
5 
STUDY DRUG ................................................................................................................................................. 39 
5.1 
DESCRIPTION ................................................................................................................................................. 39 
5.2 
PATIENT ELIGIBILITY TO RECEIVE CART-19 TRANSDUCED T CELLS ............................................................ 39 
5.3 
TREATMENT REGIMEN ................................................................................................................................... 41 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ................................................................................. 41 
5.5 
INFUSION OF CART-19 PRODUCT .................................................................................................................. 42 
5.6 
PRIOR AND CONCOMITANT THERAPY............................................................................................................. 42 
5.7 
SUBJECT COMPLIANCE MONITORING ............................................................................................................. 43 
6 
STUDY PROCEDURES .................................................................................................................................. 43 
6.1 
PRE-ENTRY EVALUATIONS (SCREENING) AND SUBJECT NUMBER ASSIGNMENT (WEEK -8 TO -12) ............... 43 
6.2 
ENROLLMENT AND BASELINE ASSESSMENT (WEEK -6 TO -8) ........................................................................ 44 
6.3 
ENROLLMENT PROCESS .................................................................................................................................. 45 
6.4 
APHERESIS (WEEK -4) .................................................................................................................................... 46 
6.5 
CYTOREDUCTIVE CHEMOTHERAPY (WEEK -1) ............................................................................................... 46 
6.6 
CART-19 PRE-INFUSION (DAY -1) ................................................................................................................ 47 
6.7 
CART-19 INFUSIONS (DAYS 1, 2, AND 3) ...................................................................................................... 47 
6.8 
POST INFUSION LABORATORIES TO ASSESS ENGRAFTMENT, PERSISTENCE AND BIOACTIVITY (DAYS 4, 7, 10, 
14, AND 21) ............................................................................................................................................................. 49 
6.9 
DAY 28/END OF TREATMENT ......................................................................................................................... 49 
6.10 
MONTHLY EVALUATIONS 2 TO 6 MONTHS POST INFUSION (SAFETY FOLLOW-UPS 1 TO 5) .......................... 50 
6.11 
MONTHS 9 (SAFETY FOLLOW-UP 6) AND 12 (END OF STUDY) EVALUATIONS POST INFUSION .................... 50 
6.12 
SECONDARY FOLLOW-UP .......................................................................................................................... 51 
6.13 
LONG-TERM FOLLOW-UP PROTOCOL ......................................................................................................... 51 
6.14 
RETREATMENT COHORT PROCEDURES ...................................................................................................... 51 

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6.14.1 Eligibility for Retreatment ....................................................................................................................... 51 
Retreatment Inclusion Criteria .......................................................................................................................... 51 
Retreatment Exclusion Criteria .......................................................................................................................... 52 
6.13.2  Retreatment Procedures ......................................................................................................................... 52 
7 
RESPONSE ASSESSMENTS ......................................................................................................................... 53 
8 
STATISTICAL CONSIDERATIONS ............................................................................................................ 55 
8.1 
DESIGN OVERVIEW ........................................................................................................................................ 55 
8.2 
SAMPLE SIZE JUSTIFICATION .......................................................................................................................... 56 
8.3 
ANALYSIS POPULATION(S) ............................................................................................................................. 57 
8.4 
PRIMARY OBJECTIVE ...................................................................................................................................... 57 
8.5 
SECONDARY EFFICACY OBJECTIVES .............................................................................................................. 58 
8.6 
SAFETY OBJECTIVES ....................................................................................................................................... 59 
8.7 
MANUFACTURING (DOSE) FEASIBILITY ......................................................................................................... 59 
8.8 
CORRELATIVE RESEARCH SECONDARY AND EXPLORATORY OBJECTIVES ..................................................... 59 
8.9 
RETREATMENT COHORT ANALYSIS ............................................................................................................... 60 
8.10 
PATIENT REPORTED OUTCOMES (PRO) ..................................................................................................... 60 
9 
SAFETY AND ADVERSE EVENTS ............................................................................................................. 61 
9.1 
DEFINITIONS .................................................................................................................................................. 61 
9.2 
RECORDING OF ADVERSE EVENTS ................................................................................................................. 64 
9.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ............................................... 68 
9.3.1 
Sponsor Notification by Investigator ................................................................................................... 68 
9.3.2 
Investigator reporting: notifying the UPenn IRBs ............................................................................... 69 
9.3.3 
Reporting obligations to the DSMC of the Abramson Cancer Center ................................................. 71 
9.3.4 
IBC Notification by Investigator .......................................................................................................... 72 
9.3.5 
FDA Notification by Regulatory Sponsor ............................................................................................ 72 
9.4 
PREGNANCIES ................................................................................................................................................ 73 
9.5 
TOXICITY MANAGEMENT, STOPPING RULES AND STUDY TERMINATION ....................................................... 73 
9.5.1 
Criteria for stopping or pausing the study ........................................................................................... 73 
9.5.2 
Toxicity management considerations ................................................................................................... 74 
9.5.3 
Criteria for discontinuing a subject’s participation in the study: ........................................................ 78 
9.6 
PROTOCOL EXCEPTIONS AND DEVIATIONS..................................................................................................... 78 
9.7 
MEDICAL MONITORING .................................................................................................................................. 80 
9.7.1 
Independent Data and Safety Monitoring Board ................................................................................. 81 
9.7.2 
Clinical Field Monitors ....................................................................................................................... 81 
10 
DATA HANDLING AND RECORD KEEPING .......................................................................................... 83 
10.1 
CONFIDENTIALITY ..................................................................................................................................... 83 
10.2 
SOURCE DOCUMENTS ................................................................................................................................ 84 
10.3 
CASE REPORT FORMS ................................................................................................................................ 84 
11 
STUDY MONITORING, AUDITING, AND INSPECTING ....................................................................... 85 
11.1 
STUDY MONITORING PLAN ....................................................................................................................... 85 
11.2 
AUDITING AND INSPECTING ....................................................................................................................... 85 
12 
ETHICAL CONSIDERATIONS .................................................................................................................... 85 
13 
STUDY FINANCES ......................................................................................................................................... 86 
13.1 
FUNDING SOURCE ..................................................................................................................................... 86 
13.2 
CONFLICT OF INTEREST ............................................................................................................................. 86 
13.3 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................................ 86 
13.4 
STUDY DISCONTINUATION ........................................................................................................................ 86 
14 
PUBLICATION PLAN .................................................................................................................................... 86 
15 
REFERENCES ................................................................................................................................................. 86 

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APPENDIX 1 - SCHEDULE OF STUDY PROCEDURES ................................................................................... 95 
APPENDIX 2 - SCHEDULE OF STUDY PROCEDURES/RETREATMENT COHORT- SINGLE DOSE . 104 
APPENDIX 3.  NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL CLASSIFICATION ........ 120 

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List of Abbreviations 
aAPC 
Artificial APC 
AE 
Adverse event 
ALL 
Acute lymphoblastic leukemia 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
APC 
Antigen presenting cell 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
B-ALL 
B-lineage acute lymphoblastic leukemia 
cAIX 
Carbonic anhydrase IX 
CAR 
Chimeric antigen receptor 
CART-19 cells 
CD19 redirected autologous T cells 
CD137 
4-1BB co-stimulatory molecule 
CFR 
Code of federal regulations 
CHOP 
Children’s Hospital of Philadelphia 
CI 
Confidence Interval 
CIR 
Chimeric immune receptor, interchangeable with CAR 
CLL 
Chronic lymphocytic leukemia 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CR 
Complete Response 
CRi 
Complete Response with incomplete marrow recovery 
CRF 
Case report form 
CRP 
C-Reactive Protein 
CSR 
Clinical study report 
CTC 
Common toxicity criteria 
CTL 
Cytotoxic T lymphocyte 
CTRC 
Clinical and translational research center 
CVPF 
Clinical cell and vaccine production facility 
DFS 
Disease free survival 
DIC 
Disseminated intravascular coagulation  
DMC 
Data monitoring committee  
DOCM 
DSMC 
DSMB 
ACC Department of Compliance and Monitoring 
Data Safety Monitoring Committee 
Data safety and monitoring board 
DSMP 
Data safety monitoring plan 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report forms 
EDC 
Electronic data capture 

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EKG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GMP 
Good Manufacturing Practices 
GVHD 
Graft versus host disease 
HAMA 
Human anti-murine antibody 
HIV 
Human immunodeficiency virus 
HLA 
human leukocyte antigen 
HUP 
Hospital of the University of Pennsylvania 
IBC 
Institutional Biosafety Committee 
Ig 
Immunoglobulin 
IRB 
Institutional Review Board 
IVIG 
Intravenous immunoglobulin 
IWCLL 
International Workshop Group on Chronic lymphocytic leukemia 
MAS 
Macrophage activation syndrome 
MED 
Minimal efficacious dose 
MEDRA 
Medical dictionary for regulatory activities 
MHC 
Major histocompatibility complex 
MOI 
Multiplicity of infection 
MOP 
Manual of procedures 
MRD 
Minimal residual disease 
mTOR 
Mammalian target of Rapamycin 
NHL 
Non-Hodgkin’s Lymphoma 
PBMC 
Peripheral blood mononuclear cells 
PD 
Progressive disease 
PFS 
Progression-free survival 
PHI 
Protected health information 
PID 
Patient identification number 
PLL 
Prolymphocytic leukemia 
PR 
Partial Response 
PRi 
Partial Response with incomplete marrow recovery 
Q-PCR 
Quantitative polymerase chain reaction 
Q-RT-PCR 
Quantitative reverse transcriptase polymerase chain reaction 
RAC 
NIH Office of Biotechnology Recombinant DNA Advisory Committee 
RCR/L 
Replication competent retrovirus/lentivirus 
RIC 
Reduced intensity conditioning 
RSA 
Research Subject Advocate 

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RVP 
Respiratory virus panel 
scFv 
Single chain variable fragment 
SCID 
Severe combined immunodeficiency 
SCT 
Stem cell transplant 
SD 
Stable disease 
SLL 
Small lymphocytic lymphoma 
STR 
Short tandem repeat analysis 
SUSAR  
Suspected unexpected serious adverse reaction 
Tcm 
Central Memory T cells 
TCR 
T cell receptor 
TCRζ 
Signaling domain found in the intracellular region of the TCR zeta, gamma 
and epsilon chains 
TCSL 
Translational Correlative Sciences Laboratory 
Tem 
Effector memory T cells 
TLS 
Tumor lysis syndrome 
Treg 
Regulatory T cells 
UPenn 
University of Pennsylvania 
VSV-G 
Vesicular Stomatitis Virus, Glycoprotein 
Vβ 
A rearranged T cell specific gene that can be used to determine clonality of a 
T cell population 
 
 
 
 

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transmitted, reproduced, published, or used by other persons without prior written authorization from the 
study sponsor. 
CART-19 Study Synopsis 
Title 
DOSE OPTIMIZATION TRIAL OF AUTOLOGOUS T CELLS 
ENGINEERED TO EXPRESS ANTI-CD19 CHIMERIC ANTIGEN 
RECEPTOR (CART-19) IN PATIENTS WITH RELAPSED OR 
REFRACTORY CD19+ CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) 
Short Title 
CD19 redirected autologous T cells 
Protocol Numbers 
, UPCC 03712, 
 
Phase 
2 
Study Population 
Adult patients who have relapsed or refractory CLL or SLL (3rd line)  
Methodology 
This is a randomized, open-label, parallel group study to determine the 
optimal dose of CART-19 cells (autologous T cells expressing CD19 
chimeric antigen receptors expressing tandem TCRζ and 4-1BB 
costimulatory domains) of the two dose levels being assessed (1-5x108 
vs. 1-5x107 CART-19 cells). This trial will be conducted in two 
stages.  
 
In Stage I, subjects will be randomized into one of the two dose 
cohorts with 1:1 ratio as below: 
1) Arm 1: Target dose of 1 x108 to 5x108 CART-19 transduced 
cells  
2) Arm 2: Target dose of 1 x107 to 5x107 CART-19 transduced 
cells  
 
In Stage I, approximately 30 subjects are expected to be randomized 
to ensure a total of 24 subjects (approximately 12 evaluable subjects 
in each arm) are evaluable for primary efficacy analysis. Safety, 
tolerability, and clinical response rates will be evaluated to determine 
a dose cohort for expansion.   Subjects with cell doses less than the 
stated range will receive their cells, but will be scored as 
“manufacturing failures”.  They will be evaluated for safety endpoints 
and followed in the same way as subjects that have received the target 
dose, but will not be evaluable for primary endpoints and will be 
replaced for the purposes of the study. We will target the upper dose 
level but accept the lower dose range as a “successful” manufactured 
product.  Anything below the lower limit will be considered a 
manufacturing failure, will follow the study protocol and will be 
monitored for safety and disease response, but will not be evaluable 
for the other endpoints (other than feasibility) on this protocol.  
Subjects with cell doses less than cell doses above will be replaced for 
analysis. No more than 20% of the total enrollment may be 
manufacturing failures. If this is exceeded a separate modification will 

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be submitted for IRB review. If appropriate, an additional dose level 
may be explored prior to the start of Stage 2. 
 
In Stage 2, the selected dose cohort will be expanded to enroll 
additional subjects, to ensure that a total of 20 evaluable subjects are 
treated at that dose level. Based on the Stage 1 analysis performed in 
November 2014, Arm 1 was chosen for expansion in Stage 2. 
Therefore, the Stage 2 dose will be 1-5x108 transduced CART-19 
cells.  The dose of 1-5 x 108 T-cells in Stage 2 will be administered 
via split dosing: 10% on Day 1 (1-5x107), 30% on Day 2 (3x107-
1.5x108), 60% on Day 3 (6x107-3x108). 
 
Evaluable subjects are defined as those who were able to receive the 
viable product at the intended dose level and have completed at least 3 
months of follow-up after the first infusion, or have discontinued early 
due to disease progression, initiation of a new cancer therapy, or 
death. 
 
This protocol also allows for the retreatment of any subject who had 
an initial response to their 1st infusion, lost detectable CART19 cells, 
and has subsequently relapsed.  The target dose for this retreatment 
cohort is 1-5 x 108 CART19 cells. The minimum acceptable dose for 
infusion is 1 x 107 CART19 cells. Subjects originally treated under 
Stage 1 will receive a single infusion, if sufficient CART19 product 
remains. For patients from Stage 1 who do not have a sufficient dose 
remaining, subjects will be remanufactured under Stage 2 conditions 
and receive the split dose. Subjects originally treated under Stage 2 
will also receive the split dose for retreatment. 
 
 
Study Duration 
Enrollment:  
 Stage 1: Approximately 18 months* 
 Stage 2: Approximately 12 months*  
Follow-up: 12 months 
Total study duration: approximately 42 months 
* Assumes adequate manufacturing and clinic capacity 
 
Safety and clinical response will be assessed every month for the first 
six months, followed by every three months for a total of 12 months. 
Tumor response will be assessed at 1 month post-infusion, and then 
every 3 months for a total of 12 months. The same schedule for 
evaluations will be applied for the retreatment cohort. 
 
Post-study follow-up: annual follow-up for lentiviral vector safety will 
continue under a separate destination protocol for 15 years post 
infusion in accordance with FDA guidelines for retroviral vectors.  

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Study Center(s) 
Single-center 
 
Objectives 
Endpoint 
Primary 
 
 Estimate efficacy of 
each CART 19 cell 
dose level 
 Complete response (including complete response with incomplete 
marrow recovery) within 3 months (in evaluable patients). 
 
Secondary 
 
 Assess safety and 
tolerability profile of 
each dose level 
 Frequency and severity of adverse events and other safety data as 
considered appropriate. 
 Dose 
(Manufacturing) 
Feasibility  
 Number of manufacturing failures due to issues with in vitro (pre-
infusion) cell expansion, T cell and product purity, viability, 
sterility, and tumor contamination.  
 
 Evaluate additional 
efficacy parameters 
and other clinical 
outcomes 
 Best overall response, progression free survival, overall survival, 
time to response, duration of response, time to alternative therapy 
 Characterize CART-
19 cell levels, 
function, and host 
responses 
 
 Fold- and kinetics- of expansion, persistence and homing to 
marrow of infused cells. 
 Development of humoral and /or cellular immunity to CART-19 
cells. 
 
 Follow subjects 
infused with less 
than protocol-
specified doses 
 Exploratory analyses to inform on dose-response activity 
Exploratory 
 
 Understand 
modulation of 
systemic levels of 
soluble immune and 
inflammatory factors 
by CART-19 cells 
 Systemic soluble immune factors in serum before and after  
treatment 
 
 Determine incidence 
of CD19 escape 
mutants  
 Assess residual tumor in peripheral blood, bone marrow and 
lymph node aspirates for CD19 expression, and compared to base 
line tumor samples. 
 Patient Reported 
Outcomes 
 
 EORTC QLQ-C30 and CLL-16 questionnaires at baseline, 
chemotherapy week, end of treatment (day 28), 3, 6, 9, and 12 
months post infusion.  
 Assess safety and 
efficacy of re-
infusion of CART19 
 Frequency and severity of adverse events and other safety data 
 Expansion and persistence of CART19 cells, in comparison to 
their original infusion 

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cells in previously 
treated patients 
 
 Overall response, time to response, duration of response and time 
to alternative therapy, in comparison to their original infusion  
 
Number of Subjects 
Stage 1: Approximately 30 subjects are expected to be randomized to 
ensure a total of 24 subjects (approximately 12 evaluable subjects in 
each arm) are evaluable for primary efficacy analysis.  
 
Stage 2: The arm (Arm 1) identified to have the optimal dose will 
enroll additional patients to ensure that a total of 20 evaluable subjects 
are treated at that dose level.  
 
Retreatment: The number of patients in the retreatment cohort will be 
no more than the number of infused patients in Stage 1 and 2 
combined.  
 
Study Product, Dose, 
Route, Regimen 
CART-19 cells transduced with a lentiviral vector to express anti-
CD19 scFv TCRζ:41BB administered via a single i.v. infusion on 
Study Day 1. A single lot of vector and a single manufacturing site 
will be used for all subjects enrolled into this study. 
 
The two dose levels to be tested are:  
1) Target dose of 1-5x108 CART-19 cells  
2) Target dose of 1-5x107 CART-19 cells  
 
In Stage I, subjects will be randomized into one of these two dose 
cohorts with 1:1 ratio.  In Stage 2, the selected dose cohort will be 
expanded to enroll additional subjects, to ensure that a total of 20 
evaluable subjects are treated at that dose level.   
 
Based on the Stage 1 analysis performed in November 2014, Arm 1 
was chosen for expansion in Stage 2. Therefore, the Stage 2 dose will 
be 1-5x108 transduced CART-19 cells.  The dose of 1-5 x 108 T-cells 
will be administered via split dosing: 10% on Day 1 (1-5x107), 30% 
on Day 2 (3x107-1.5x108), 60% on Day 3 (6x107-3x108). 
 
Dose Rationale 
Manufacturing success rates decline when targeting more than 108 
CART-19 cells. Patients with CLL who have responded to CART-19 
therapy have all received a magnitude of 107 or higher CART-19 cells. 
Therefore, the target dose level ranges of 1-5x108 and 1-5x107 CART-
19 cells have been selected. If appropriate, an additional dose level 
may be explored.  
Duration of 
administration 
Based on the total volume to be infused and the recommended 
infusion rate of 10-20mL per minute 
Reference therapy 
None. This protocol will be given to subjects with unmet medical 
needs for whom there are no effective therapies known at this time. 

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Eligibility Criteria 
 Documented CD19+ CLL or SLL 
 Successful test expansion of T-cells 
 Patients who progress within 2 years after the second or higher 
line of therapy will be eligible. For instance, patients who had 
progressions < 2 years after second or greater line therapy, but 
who have responded to their most recent treatment (3rd line of 
higher) will be eligible.   
 At least 2 prior chemotherapy regimens (not including single agent 
monoclonal antibody (Rituxan) therapy. Single agent of 
ofatumumab will be counted as a regimen.  Patients with high risk 
disease manifested by deletion chromosome 17p will be eligible if 
they fail to achieve a CR to initial therapy or progress within 2 
years of 1 prior regimen 
 Subject has not appropriate candidate for a potentially curative SCT 
due to the state of disease, co-morbid illness, lack of an available 
donor, or patient declines  
 Performance status (ECOG) 0 or 1 
 Age >/= 18 years 
 Adequate organ system function including: 
o Creatinine < 1.6 mg/dl 
o ALT/AST < 3x upper limit of normal 
o Total Bilirubin <2.0 mg/dl 
 Any relapse after prior autologous SCT will make patient eligible 
regardless of other prior therapy 
 Patients with relapsed disease after prior allogeneic SCT 
(myeloablative or nonmyeloablative) will be eligible if they meet 
all other inclusion criteria and: 
o Have no active GVHD and require no immunosuppression 
o Are more than 6 months from transplant 
 No contraindications for leukapheresis 
 Left Ventricular Ejection Fraction >40% 
 Gives voluntary informed consent 
 
Retreatment Cohort: 
 Subjects previously infused with CART19 cells as part of this 
protocol and who experienced an initial response (either CR, CRi 
or PR) to therapy, but have subsequently progressed within 2 years 
of their initial response. 
1. Subjects have undergone the 3 month efficacy endpoint 
evaluation. Subjects who achieve an initial response, but relapse 
prior to this Month 3 timepoint will be eligible. 
2. Subjects have <5% CART19 cells in the CD3+ population by flow 
cytometry on PBMCs 
3. Subjects have recovered from any toxicity attributed to the initial 
CART19 infusion, such as CRS. 
 

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Statistical Methodology  Safety population includes all patients who receive the T cell infusion. 
Safety population will be used to analyze safety-related endpoints. All 
adverse events will be described. 
 
Evaluable patients are defined as those eligible patients who receive 
the T cell infusion at the intended dose level by randomization and 
have completed at least 3 months of follow-up after the first infusion, 
or have discontinued early due to disease progression, initiation of a 
new cancer therapy, or death. This population will be the basis for the 
primary analysis in this study. The primary objective will be evaluated 
by calculating the CR rate by 3 months as the proportion of patients 
who reach CR or CRi within 3 months from the time of the first 
CART-19 infusion among the total evaluable patients. The exact 90% 
confidence interval (CI) will also be computed. Data from the two 
dose groups will be analyzed separately.   All evaluable patients per 
arm will be included for the analysis. If 4 of 12 planned evaluable 
patients achieve CR or CRi within 3 months post infusion (i.e., an 
observed 3-month CR rate of 33%), then the lower bound of the 90% 
CI will exclude 10%. Specifically, the 90% exact CI would be (12%, 
61%). At the end of the expansion cohort, the width of the exact 90% 
CI will be less than 20% based on 20 patients. For an observed 3-
month CR rate of 30% (i.e., 6 out of 20 had CR or CRi), the 90% 
exact CI would be (14%, 51%). 
 
Analysis of other secondary or exploratory endpoints will be 
descriptive and may include summary statistics such as means and 
standard deviations or Kaplan-Meier curves for time-to-event survival 
information if appropriate.   
 
Safety and efficacy analyses for patients in retreatment cohort will be 
exploratory and used to generate hypotheses for future studies. 
Feasibility endpoints will be analyzed using all patients who are 
evaluated for cell expansion.  

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Figure 1a-Dose Finding Study Design Schema – Stage 1 
 
 
 
 
 
 
 
 
Figure 1b-Study Design Schema – Stage 2 
 
 
 
 
       

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1 
Introduction 
1.1 
Background  
CLL is the most common leukemia in Western countries accounting for approximately 30 percent 
of all leukemias in the United States1. CLL is considered to be mainly a disease of the elderly, with 
a median age at diagnosis of 70 years2; however, it is not unusual to make this diagnosis in younger 
individuals from 30 to 39 years of age3. The incidence increases rapidly with increasing age. It is 
estimated that 16,060 new cases of CLL will be diagnosed in 2012, 9490 in males, and 6570 in 
females1. 
 
Patients who have relapsed or refractory CLL represent a population with high unmet need. With 
the exception of allogeneic hematopoietic cell transplantation, treatment options for CLL are 
almost never curative.  About 60% of first-line patients will go on to receive second-line therapy 
including ~ 20% of patients who do not respond to first-line therapy (the refractory pool) and those 
patients who relapse after achieving a response. About one-half of second-line patients will either 
die before receiving the next line of chemotherapy or may be alive and not receive the next line of 
therapy either due to age, comorbidities or lack of available options4.  
 
CLL is a B-cell neoplasm. In most cancers, tumor-specific antigens for targeting are not well 
defined, but in B-cell neoplasms, CD19 is an attractive target. CD19 is a 95kDa glycoprotein 
present on B cells from early development until differentiation into plasma cells5-7. It is a member 
of the immunoglobulin (Ig) superfamily and a component of a cell surface signal transduction 
complex that regulates signal transduction through the B cell receptor7-9. Mice lacking CD19 have 
a decreased number of B cells in peripheral lymphoid tissues, a decreased B cell response to oral 
vaccines and mitogens, and decreased serum Ig levels7, 10.  
 
CD19 is not present on most normal tissues, other than normal B cells, including pluripotent blood 
stem cells11, which makes CD19 a relatively safe target presenting a minimal risk of autoimmune 
disease or irreversible myelotoxicity. Anti-CD19 antibodies and scFvs either native or conjugated 
to radioisotopes or toxins are currently being developed and have demonstrated promise in both 
mouse models12-16 and human and non-human primates17-27.  
1.2 
Investigational Agent 
The investigational agent in this protocol is CART-19 cells.  
CART-19 is the most recent adaptation of adoptive cellular 
immunotherapy that uses the patient’s own peripheral blood 
T cells that have been genetically re-directed to kill CD19+ 
cells. As shown in Figure 2, the CAR approach uses 
genetically programmed, patient-derived lymphocytes 
transfected with chimeric receptor genes to combine the 
effector functions of T lymphocytes with the ability of 
antibodies to recognize predefined surface antigens with 
high specificity in a non-MHC restricted manner28, 29. These 
receptors have the ability to recognize intact membrane 
proteins independent of antigen processing. CARs or T-
bodies typically encode an extracellular domain to bind tumor or virus linked to an intracellular 
 
Fig. 2.  CAR design. Bispecific T cells 
are created by the introduction of 
genes encoding CAR proteins that 
recognize target surface antigens in an 
MHC-independent fashion.  

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signaling domain that mediates T cell activation (reviewed in30, 31). In principle, universal targeting 
vectors can be constructed because the scFv bind to native cell surface epitopes and bypass the 
requirement for MHC restriction. The tumor binding function of CAR is usually accomplished by 
the inclusion of a single chain variable fragment (scFv) antibody, containing the VH and VL chains 
joined by a peptide linker of about 15 residues in length32. First generation CARs contain a minimal 
TCR signaling domain consisting of TCRζ. Second generation CARs contain double costimulatory 
signaling domains either CD28 and TCRζ or 4-1BB and TCRζ. The 3rd generation CARs contain 
further advancements such as triple costimulatory modules comprised of CD28, 4-1BB, and TCRζ. 
See reviews of CARs for details33-35. 
 
Autologous T cells will be engineered using a lentiviral vector to express an extracellular single 
chain antibody (scFv) with specificity for CD19. This will be expected to redirect specificity of 
the transduced T cells for cells that express CD19, a molecule that is restricted in expression on 
the surface of the malignant cells and on normal B cells. In addition to the CD19 scFv, the cells 
will be transduced to express an intracellular tandem signaling domain comprised of 4-1BB and 
TCRζ signaling modules. Clinical grade CD19 TCRζ/4-1BB lentiviral vector will be manufactured 
at the Children’s Hospital of Philadelphia (CHOP) and City of Hope Center for Applied 
Technology Development. The extracellular single chain antibody (scFv) with specificity for 
CD19 was previously reported21. The scFv is derived from a mouse monoclonal antibody using 
hybridoma cell line FMC63 described in Nicholson et al.21. The signaling domains are entirely of 
the native human sequences36, 37. 
 
The CART-19 cells will be manufactured in the Clinical Cell and Vaccine Production Facility at 
the University of Pennsylvania. CART-19/4-1BB cells are resuspended in cryopreservation media 
containing 31.25% Plasmalyte-A, 31.25% Dextrose 5%, 0.45% NaCl, 10% Dextran 40, 20% 
Human Serum Albumin, and 7.5% DMSO. Cells are frozen in bags using a controlled-rate freezer. 
Cryopreserved CART-19 products are stored in a monitored freezer at ≤-130°C.  The target dose 
of CART-19 cells is calculated based on the scFv percent transduction efficiency (see section 5.4 
for unthawing and infusion instructions). 
 
Absorption, distribution and metabolism. Lymphocytes have complex trafficking and survival 
kinetics, and after adoptive transfer several fates have been demonstrated: 1) margination; 2) exit 
from the peripheral blood trafficking to lymphoid tissues; and 3) death by apoptosis. Following an 
intravenous dose, retrovirally modified and adoptively transferred T cells have been shown to 
persist in the circulation for at least 10 years in immunodeficient SCID patients due to the 
replicative competence of T cells71. Human CD8 CTLs have an elimination half life from the 
peripheral blood of about 8 days, and this increases to about 16 days when low doses of IL-2 are 
given72. In patients with HIV infection, we found that the mean half life of lentivirally modified 
CD4 T cells in the circulation of 5 patients following a single infusion was 23.5 (± 7.7) days in 
patients. Adoptively transferred human T cells have been shown to traffic to tumor and secondary 
lymphoid tissues38-41.   
 
Drug interactions. CART-19 cells are expected to retain many of the properties of natural T cells. 
As such, they will be expected to be susceptible to immunosuppressive agents such as 
corticosteroids, immunophilins such as cyclosporine and tacrolimus, methotrexate, mycophenolate 
mofetil, mTOR inhibitors such as rapamycin, alemtuzumab, daclizumab, denileukin difitox, and 

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everolimus. Lymphocytes are especially susceptible to cytotoxic and chemotherapeutic agents that 
are commonly administered for hematologic malignancies such as cyclophosphamide and 
fludarabine. 
 
Immune elimination. An important consideration is that the CAR can be immunogenic, either 
because foreign sequences such as antibiotic selection genes or mouse antibody sequences are 
expressed, or because of novel epitopes that are created at the fusion joint of human signaling 
domains that are not normally juxtaposed. Immunogenicity of the CAR can lead to the rejection 
of the adoptively transferred T cells. The basis for this supposition is that human retrovirally-
modified CTLs expressing a fusion protein consisting of hygromycin:HSV thymidine kinase were 
eliminated by host CTLs in patients with advanced HIV infection42; importantly, this immune 
mediated elimination was not accompanied by adverse effects and required 6 to 8 weeks to occur. 
There is one report where CAR containing a scFv with mouse sequences has been given to cancer 
patients. Following a single dose of CAR T cells (0.6 to 4 x 109 T cells), the CAR T cells were 
detected in circulation from 23, 32, and 53 days after infusion in three patients with renal cell 
carcinoma43. All three patients developed low levels of anti-scFv antibodies between 37 and 100 
days after the CAR T-cell infusion. It is important to note that it is possible the CART-19 T cells 
will be rejected in our patients. We expect the cells to persist for a sufficient period of time to 
determine safety, T cell subset specific persistence, and effects on tumor burden and tumor specific 
immunity at 4 weeks following the first infusion.  
 
Lymphocyte costimulation. Extensive research in the past two decades has documented that 
maximal activation, proliferation and persistence of T cells responding to antigenic stimuli is 
dependent on receipt of two discrete signals mediated by cell surface receptors. The primary 
“activation” signal is generated by ligation of the TCR with antigen (typically in the form of 
peptides presented in the groove of HLA class I molecules) and the second signal by ligation of a 
costimulatory molecule with its cognate ligand. T cell costimulatory molecules which have been 
identified to date include members of the immunoglobulin super-family (CD28), members of the 
tumor necrosis factor (TNF) super-family (e.g. CD40L, CD134 [OX-40], CD137 [4-1BB]44. 
 
One issue that needs to be addressed with CARs is that signaling through the cytosolic domain of 
the usual scFv-TCRζ single chain construct does not fully replicate the multichain TCR signaling 
complex45, 46. Chimeric receptors bearing TCRζ signaling modules are sufficient to trigger 
sustained proliferation in T cell hybridomas and clones but are not sufficient to drive proliferation 
or cytokine production in peripheral T cells45. 4-1BB is a T cell co-stimulatory receptor induced 
by TCR activation, and evokes various T cell responses47. We and others have observed that 4-
1BB signals are critical for long term proliferation of CD8 cells, and that CD28 is essential for 
sustained CD4 cell proliferation48, 49. We have begun to investigate the requirement for 
costimulation in our CD19-CAR by incorporating additional signaling modules in the cytoplasmic 
domain of the chimeric receptor. Our preclinical data are in accordance with the results from other 
laboratories50, 51, and indicate that “bipartite receptors” comprised of TCRζ and either CD28 or 4-
1BB signaling modules substantially improve the function and proliferation of T cells.  The 
coalescence of improved T cell culture methods and lentiviral vector technology have made it 
possible to test this novel CD19 CAR- T cell concept, as we have done so in 3 patients and plan to 
continue to evaluate in this protocol with additional patients.  

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Since CRS mechanistically is a required part of the antitumor mechanism of in vivo CART-19  cell 
expansion and tumor killing, tocilizumab was administered for CRS with worsening respiratory 
distress, including pulmonary infiltrates, increasing oxygen requirement  including high-flow 
oxygen  and/or need for mechanical ventilation or hemodynamic instability despite intravenous 
fluids and moderate vasopressor support or rapid clinical deterioration. Steroids following CART-
19 infusion were avoided and given only under life threatening situations due to the known 
lymphocytic effects. 
 
Historical Clinical Data with CARs 
Completed clinical studies are limited to phase I studies evaluating first generation CARs targeting 
the folate receptor in ovarian cancer65, carbonic anhydrase in renal cancer43, CD20 in lymphoma66, 
and GD2 in neuroblastoma67, 68. According to available literature, the clinical responses have 
overall been very modest, with the exception of one partial response in one of the neuroblastoma 
studies. Immunogenicity of CARs was observed in the first two studies, but not the latter two.  
However, two serious adverse events have recently been reported.  The first occurred in a patient 
with bulky CLL and extensive prior therapies. The patient received autologous T cells modified to 
express a CD19-targeted CAR at a dose of 3x 107 cells/kg after lymphodepletion with high-dose 
cyclophosphamide. This patient developed fever, hypotension, and dyspnea 20 hours after 
infusion, which rapidly progressed. Elevated cytokine levels were seen before the T-cell infusion, 
and an autopsy failed to reveal an obvious cause of death. It was concluded that low grade sepsis, 
which was likely present before the initiation of therapy, was the most likely trigger in this heavily 
pretreated immunosuppressed patient66. The other adverse event occurred in a patient with colon 
cancer who received a high dose (> 1010 ) of CAR T cells modified with a CAR targeting HER2 
containing two costimulatory moieties (CD28 and 4-1BB) after intensive lymphodepletion. The 
subject developed pulmonary toxicity within 15 minutes in association with very high cytokine 
levels, followed by cardiac arrest, and died 4 days later.  This patient is thought to have died from 
an on-target cytokine storm resulting from high numbers of cells localizing in the lung after 
infusion and recognizing low levels of the antigen on lung tissue67. Another example of on-target, 
off-organ toxicity occurred in a clinical trial in which patients were given T cells engineered to 
express a chimeric antigen receptor that was specific for carbonic anhydrase IX (cAIX), a 
transmembrane protein that is overexpressed by cancerous kidney cells67. In all three patients, 
severe liver toxicity ensued within 1 week following infusion of the gene-modified T cells. 
Subsequent investigation revealed that the cAIX protein was also expressed in the biliary tract of 
the liver. These events illustrate the potent effects of engineered lymphocytes and the need to 
carefully select the target. Trials with second generation CARs are just beginning as several 
centers.  
 
CART-19 appears to have greater success than previous CAR constructs, since in vivo these cells 
proliferate more and persistent longer, and retain effector functions, therefore amplifying and 
sustaining effective anti-tumor responses. For recent reviews of CAR T cell trials, see PMID 
22818942, 22308288, 22538493, 22262649, 21358705, 22781680. 
1.5 
Rationale for the study design 
This is a randomized, open-label, parallel group study to determine the optimal dose of CART-19 
cells of the two dose levels being assessed (1-5x108 vs. 1-5x107). This trial will be conducted in 
two stages. In the first stage, approximately 30 patients are expected to be randomized to ensure a 

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total of 24 subjects (approximately 12 evaluable subjects in each arm) are evaluable for primary 
efficacy analysis. Randomization will allow for a greater degree of comparability between the two 
arms than if there were two independent trials. Safety, tolerability, and clinical response rates will 
be evaluated to determine a dose cohort with a minimum of 30% three-month complete response 
(CR) rate for expansion. If appropriate, an additional dose level may be explored.   
 
In the second stage, the selected dose cohort will be expanded to enroll additional subjects to 
ensure that a total of 20 evaluable subjects are treated at that dose level. Having at least 20 
evaluable subjects treated at the same dose level will provide enough confidence in the estimated 
efficacy and safety assumptions that will be used in future trials for patients with refractory or 
relapsed CLL. 
1.6 
Rationale for dose and regimen selection 
Based on the current manufacturing limitations and recent clinical experience from ongoing trials 
(UPCC
, UPCC
 and UPCC
), the target dose levels of 1-5x108 and 1-5x107 
CART-19 cells have been selected for this study.  
 
Patients with heavily pretreated CLL frequently have a significantly lower percentage of CD3+ 
cells in leukapheresis products than subjects with other types of hematologic malignancy.  
Lentiviral transduction and expansion therefore could be limited in the setting of fewer CD3+ cells. 
As was observed in clinical protocol UPCC
, manufacturing success rates declined to 
approximately 50% when targeting 109 or more CART-19 cells. Targeting 108 or fewer cells is not 
anticipated to be an issue from a manufacturing standpoint.  
 
With the first 3 patients with CLL treated with CART-19 in UPCC
, durable clinical activity 
was observed at doses ranging from 1.4x107 to 1.1x109 CART-19 cells. This two-log-fold 
difference did not support an obvious dose response relationship. Unlike standard drugs that are 
metabolized, CAR T cells can have a wide dose response range.  This is most likely because the 
CAR T cells are able to proliferate extensively in the patients, and thus the actual in vivo amount 
of CART-19 T cells after engraftment and expansion will vary from patient to patient.  
 
The upper range of the target dose was chosen because it is anticipated to be safe based on recent 
clinical experience from the ongoing trials as mentioned above, and because it will permit 
sufficient engraftment in order to evaluate the primary and secondary endpoints of this study. 
 
Based on the Stage 1 interim analysis performed in November 2014, Arm 1 (1-5x108 CART-19 
cells) was chosen for expansion in Stage 2. At the beginning of Stage 2 of this trial, IND-approved 
manufacturing changes were instituted.  The first subject treated in Stage 2 (03712-51), 
experienced early CRS within 12 hours of receiving T-cells, and received anti-cytokine therapy 
with tocilizumab and steroids within 24 hours of infusion.  The subject’s clinical status improved 
in response to anti-cytokine therapy.   
 
Based on this clinical experience and efforts to improve subject safety, the subsequent CLL 
subjects enrolled in Stage 2 of this study will be treated with the selected dose of 1-5 x 108 T-cells 
administered via split dosing: 10% on Day 1, 30% on Day 2, 60% on Day 3.  Our initial pilot trial 
of CAR T cells in CLL (UPCC 
) gave a similar dose of T cells split over 3 days. Additionally, 

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in our companion trial for subjects with ALL (UPCC 
), CART-19 cells are being 
administered via split dosing over three days. This reflects an altered schedule of administration 
due to early and severe CRS experienced after single dose administration.   
1.7 
Rationale for pre-treatment lymphodepletion 
Adoptive immunotherapy strategies may be able to capitalize on homeostatic T cell proliferation69, 
a recent finding that naive T cells begin to proliferate and differentiate into memory-like T cells 
when total numbers of naive T cells are reduced below a certain threshold70, 71. Lymphodepletion 
eliminates regulatory T-cells and other competing elements of the immune system that act as 
“cytokine sinks”, enhancing the availability of cytokines such as IL-7 and IL-15 72. This hypothesis 
has been tested clinically in patients with metastatic melanoma refractory of conventional 
treatments39. The patients received a lymphodepleting conditioning regimen consisting of 
cyclophosphamide (60 mg/kg x 2 days) and fludarabine (25 mg/m2 x 5 days) prior to adoptive 
transfer of T cells. We have treated patients with myeloma and lymphopenia after lymphodepleting 
chemotherapy, and observed improved engraftment73, 74.  
 
In this protocol CART-19 cells will be transfused into subjects who are rendered lymphopenic as 
a result of cytotoxic chemotherapy. Recent data indicates that the increased antitumor efficacy of 
adoptive transfer following host conditioning is more than simply “making room” because the 
quantitative recovery of adoptively transferred T cells in mice reveals that in vivo proliferation 
following adoptive transfer is identical in mice with or without previous irradiation.   
1.8 
Benefit and Risk Assessment 
General safety. Participation in this study will expose the patient to genetically engineered 
autologous T cells. The risk of the cells alone is low based on clinical experience. The unknown 
risk is that of the signaling domains in the CAR. T cell proliferation could be uncontrolled; 
however we have not observed this in our pre-clinical models. In this case, corticosteroids and 
chemotherapy would be given to eradicate the CAR cells; this has worked in previous cases43.  
At the University of Pennsylvania we have treated >20 patients with HIV infection with autologous 
T cells modified with lentiviral vector. In the first protocol, each subject received a single i.v. 
infusion of 1x1010 lentiviral modified T cells; in the second protocol, each subject received up to 
6 doses of 0.5-1 x 1010 cells. The lentiviral engineered T cells were well tolerated in all patients, 
with follow up of up to 5 years. Doses of up to 5x1010 autologous ex vivo non-gene modified and 
expanded T cells have been administered in five protocols to 128 patients with hematologic 
malignancies and HIV, and have found this to be well tolerated73-76 95.  
 
Immunogenicity.  It is possible the cells may be immunogenic, and that the patients will have an 
immune response directed against the scFv; this has not had clinical consequences in previous 
trials. If an immune response to the cells occurs, it is possible that the cells will be rejected. Three 
of 3 subjects developed HAMA and loss of T cell engraftment in the Lamers study47, but this has 
generally not been an issue in patients with B cell malignancies.  
 
Immunoglobulin depletion. Transient or permanent host B cell depletion is also a potential risk 
with CART-19 cells, since normal B cells express CD19.  This is expected to resolve when the 
CART-19 cells are cleared. In the meantime, patients may require periodic infusions of 
immunoglobulin.  

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Transformation. There is a risk that people who receive gene transfer may develop new tumors 
derived from their genetically modified cells. This risk is primarily associated with viral gene 
transfer vectors that integrate into the cellular DNA where they may dysregulate genes controlling 
proliferation. Transformation has not been observed following adoptive T cell transfer in hundreds 
of cancer and HIV patients receiving gamma retroviral modified T cells treated on multiple 
protocols at many academic centers34, and in the 21 HIV patients treated with lentiviral modified 
T cells treated at University of Pennsylvania77.    
 
Risk of tumor lysis syndrome (TLS) related to cytoreductive chemotherapy or CAR T cells.  The 
risk of TLS is dependent on the disease and burden of disease, but in most cases, this risk will be 
low. These are not front line CLL patients. Patients will be closely monitored both before and after 
chemotherapy and CART-19 infusions including blood tests for potassium and other relevant 
chemistries.  Patients will receive hydration and allopurinol or rasburicase to minimize any toxicity 
should signs of significant acute tumor lysis begin to occur. 
 
Cytokine release syndrome and Macrophage Activation Syndrome.  Patients treated with CART-
19 may experience a cytokine release syndrome (CRS), which has correlated with disease response.  
Clinical manifestations have included high fevers, fatigue, anorexia, nausea, vomiting, headache, 
rash, hypotension (occasionally requiring pressor support), tachypnea, hypoxia (occasionally 
requiring ventilator support), delirium and confusion (in several patients), evidence of disseminate 
intravascular coagulation as well as macrophage activation syndrome (MAS).  In some cases CRS, 
TLS and hypotension have led to acute kidney injury and several patients have required at least 
transient dialysis.  The CRS has been effectively abrogated with anti-cytokine directed therapy 
including tocilizumab in most patients.  As of July 2014, three patients on another CART-19 trial 
have died of complications related to refractory CRS and intercurrent infections.  It is unclear if 
treating the CRS adversely impacts the anti-tumor response.   
 
Features consistent with MAS or HLH have been observed in patients treated with CART 19, 
coincident with clinical manifestations of the CRS.  MAS appears to be a reaction to immune 
activation that occurs from the CRS, and therefore should be considered a manifestation of CRS.  
 
Macrophage activation syndrome is similar to Hemophagocytic lymphohistiocytosis (HLH); it is a 
reaction to immune stimulation by infection, autoimmune diseases or other precipitants, but is 
distinguished from familial or genetically mediated HLH.  There are no definitive diagnostic criteria 
for MAS, but it is typically diagnosed by meeting HLH criteria. 
 
Some but not all features of MAS are typically observed.  The clinical syndrome of MAS is 
characterized by high grade non-remitting fever, cytopenias affecting at least two of three lineages, 
and hepatosplenomegaly.  It is associated with biochemical abnormalities, such as high circulating 
levels of serum ferritin, soluble interleukin-2 receptor (sCD25), and triglycerides, together with a 
decrease of circulating NK activity.  Other findings include variable levels of transaminases up to 
signs of acute liver failure and coagulopathy with findings consistent with DIC. A pathologic 
feature of MAS is the presence of hemophagocytic CD163+ macrophages (HPC) in bone marrow 
or lymph-node aspirates. 
 

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Diagnosis is based on the fulfillment of criteria established in 200478 for HLH associated with 
autosomal recessive disorders (familial HLH, fHLH).  
 
A diagnosis of non-familial HLH/MAS is made by having 5/8 criteria: 
 Fever 
 Splenomegaly 
 Cytopenias (affecting 2 or more lineages in the peripheral blood; hemoglobin <9 g/dL, 
platelets <100,000/L, Absolute neutrophil count <1000/L) 
 Fasting triglycerides >265 mg/dL , Fibrinogen   < 1.5 g/L 
 Hemophagocytosis in bone marrow or spleen or lymph nodes  
 Low or absent NK-cell activity 
 Ferritin  > 500 g/L 
 Soluble CD25R > 2400 U/L 
Supportive clinical criteria include neurologic symptoms and cerebrospinal ﬂuid pleocytosis, 
conjugated hyperbilirubinemia, and transaminitis, hypoalbuminemia and hyponatremia. Typically  
high fevers, cytopenias, and when performed hemophagocytosis in the bone marrow is observed 
(though marrow specimens at the time of the reaction are not often taken). Soluble CD25R and NK 
cell activity are not standard tests, though samples are taken for retrospective CD25R analysis.  
Therefore, patients may not meet strict definition of HLH/MAS, but given the constellation of 
findings, and the consistent dramatic elevation in Ferritin, this is indeed the reaction associated with 
the CRS.   
 
At this time it is still unknown whether CRS/MAS is beneficial or harmful to the antitumor 
response.  Research monitoring data showed that IL6 levels were extraordinarily high during the 
CRS, prompting us to use an anti-IL6 receptor antibody tocilizumab to treat the CRS/MAS. Four 
adult patients have been treated with tocilizumab for CRS and MAS.  The majority of patients 
treated with tocilizumab for CRS and MAS had rapid (within hours) resolution of dramatic fevers, 
and continuous improvement in hypotension and hypoxia over hours to several days, and showed 
improvement in biochemical evidence of CRS and MAS within 48 hours.  Adult patients were 
treated with tocilizumab 4mg/kg or 8mg/kg.  It is unclear if early treatment will negate the 
antitumor response.  Treatment and timing of treatment of this toxicity will be at the discretion of 
the patient’s physician and the study investigator, and occur in the setting of hemodynamic 
instability.  
 
Pediatric ALL patients treated with CART-19 on CHP9595 have experienced a similar CRS and 
MAS. CHP959-100 experienced a severe CRS and had high fevers, hypotension, acute vascular 
leak syndrome and acute respiratory distress. The patient was treated with etanercept and 
tocilizumab, as described in Grupp et al., NEJM, 2013, and all associated adverse events resolved. 
CHP959-104 and CHP959-105 received the 10% dose only and experienced CRS. CHP959-103 
received the 10% and 30% doses, respectively, and experienced a mild CRS after the 10% dose, 
with no CRS experienced after the 30% dose. None of these patients experienced were severe 
enough CRS (i.e. there were no instances of more than transient oxygen requirements, or 
hypotension requiring pressor support) requiring treatment with steroids or cytokine blockade. 
 

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Fatal SAEs with CARs:  Two studies have reported fatal SAEs following CAR infusion in patients 
with malignancy.  Brentjens et al designed a retrovirally-transduced CAR against the CD19 
molecule for patients with B cell lymphoma. The CD19 CAR was the second generation design 
containing CD28 and CD3ζ signaling domains. A total of 7 subjects have been treated on this 
protocol, 6 without SAE. However, subject four in this study was a 69 year old man with refractory 
CLL and who had a significant past medical history of myocardial infarction, coronary artery 
disease, hypertension, and chronic renal failure. This was the 4th patient in the study and the first 
one on the cohort undergoing lymphodepletion. This subject received pre-T cell conditioning with 
1.5g/m2 of cyclophosphamide followed 2 days later by infusion with genetically modified CD19 
CAR T cells at 1.2-3x107 cells/kg. Twenty hours following T cell infusion, the patient developed 
persistent fever (transient fever was observed in the first 3 subjects on the study too) and 
hypotension that was rapidly followed by respiratory distress despite negative chest x-ray, 
hypoxemic respiratory failure, and acute renal failure. The family decided to remove further life 
sustaining therapies and the patient expired 44h post-T cell infusion. The post-mortem pathology 
report failed to support a diagnosis of tumor lysis syndrome as the primary source of renal failure. 
Analysis of serum cytokines revealed elevated levels of IL-2, IL-7, IL-15, and IL-12 following 
cyclophosphamide therapy which may have been secondary to a prior subacute infection 
exacerbated by the immune suppression associated with cyclophosphamide-mediated 
lymphodepletion.  The authors concluded that concomitant sepsis was the most likely cause of 
death and attributed the etiology of the death as “possibly related” to CAR T cell infusion79.  
 
The second case of a fatal SAE related to CAR T cells was reported by the NCI group (Morgan et 
al. 2010). This study attempted to treat cancer patients with overexpressing ERBB2 tumors with 
an anti-ERBB2 CAR of 3rd generation (containing CD28, 41BB and CD3ζ signaling domains). 
The first subject in the study was a 39-year-old female with colon cancer metastatic to lungs and 
liver. The patient received lymphodepleting regimen (60mg/kg cyclophosphamide daily for 2 days 
followed by fludarabine 25mg/m2 for the next 5 days) followed the next day by retrovirally-
transduced 1010 ERBB2 CAR T cell (transduction efficiency 79%). At 15min post-infusion, the 
patient began to develop dyspnea and hypoxia with pulmonary infiltrates on chest X-ray. The 
patient progressed into hypoxemic respiratory failure requiring mechanical ventilatory support, 
vasopressor-dependent hypotension, and cardiopulmonary arrest. The patient was initially 
resuscitated and started on high dose steroids, but despite aggressive supportive care, the patient 
expired 5 days after infusion. Serum cytokine measurements demonstrated a dramatic rise in pro-
inflammatory cytokines (IFN-γ, TNF-α, IL-6, GM-CSF) within 4 hours of infusion consistent with 
a cytokine storm initiating multi-system organ failure. Dr. Morgan postulates that upon first 
pulmonary circulation passage80, the CAR ERBB2 T cells bound to native low level expression 
pulmonary epithelial cell ERBB2 proteins81, leading to CAR activation and pulmonary 
microvascular injury.  
 
Other fatal SAEs have been reported.  Two events occurred at the Memorial Sloan Kettering 
Cancer Center using CD19 specific CAR redirected T cells. Five fatal events occurred at the 
University of Pennsylvania using CART-19 T-cells (a CD19-specific CAR using a lentiviral 
vector) in patients with acute lymphoblastic leukemia. These SAEs are still under investigation.   
 
Grading of CRS:  The CTC grading system was originally developed to capture a cytokine 
syndrome occurring during infusional therapy; therefore, it is inadequate to capture the delayed 

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The International Workshop Group on CLL (IWCLL) has published a revised version of the 
guidelines for evaluating disease response that were published in 1996 by the National Cancer 
Institute Working Group (NCI/WG)84, 88, 89. Please refer to Section 7 for definitions of complete 
response, partial response, progressive disease, and stable disease. 
3 
Study Design 
3.1 
General Design 
This is a randomized, parallel group study to determine the optimal dose of CART-19 cells of the 
two dose levels being assessed (1-5x108 vs. 1-5x107). This trial will be conducted in two stages.  
 
In Stage I, subjects will be randomized into one of the two dose cohorts with 1:1 ratio as below: 
1) Arm 1: Target dose of 1 x108 to 5x108 CART-19 transduced cells  
2) Arm 2: Target dose of 1 x107 to 5x107 CART-19 transduced cells  
 
In Stage I, approximately 30 patients are expected to be randomized to ensure a total of 24 subjects 
(approximately 12 patients in each arm) are evaluable for primary efficacy endpoint analysis. 
Primary efficacy evaluable patients are those who have received CART-19 cells at the protocol-
specified dose for the Arm they have been randomized to (1-5x108 and 1-5x107 CART-19 cells for 
Arms 1 and 2, respectively). These patients will be evaluable for primary efficacy endpoints. 
Safety, tolerability, and clinical response rates will be evaluated to determine a dose cohort with a 
minimum of 30% three-month complete response (CR) rate for expansion.  
 
Subjects with a manufactured cell dose that is less than the protocol-specified dose will be scored 
as a manufacturing failure. These subjects will receive their cell infusion, provided that the 
manufactured dose is above the CVPF minimum acceptable dose for infusion (2x106 CART-19 
cells) and all other manufacturing release criteria are met. The subjects that are infused with lower 
than the protocol specified dose for their randomized arm are primary efficacy non-evaluable 
patients. They will not be included in the primary efficacy endpoint analysis. However, they will 
be included for secondary efficacy, safety, manufacturing, correlative and exploratory endpoint 
analyses. 
  
For the purposes of the study, primary efficacy non-evaluable patients will be replaced with primary 
efficacy evaluable patients. Both primary efficacy evaluable and non-evaluable patients will be 
followed in the same manner according to the Schedule of Study Procedures for all evaluations, 
including clinical, research (correlative) and safety. 
 
All patients receiving ≥2x106 CART-19 will be assessed for clinical response according to the 
criteria discussed in Section 7.  Again, patients scored as manufacturing failures and receiving 
less than the dose for their randomized arm will not be included in primary efficacy endpoint 
analysis (see Section 8.3). Table 3-1 summarizes nomenclature, endpoint analysis and clinical 
evaluations for all possible CART-19 dose manufacturing and infusion scenarios. 
 
Table 3-1 Subject Dose, Infusion and Endpoint Analysis Summary- Stage 1 
 

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15 years from initial infusion to assess for the diagnosis of long-term health problems, such as 
development of new malignancy.  
3.2 
Primary Efficacy Non-Evaluable Patients 
A primary efficacy non-evaluable patient is defined as any patient who is infused with the CART-
19 cells at less than the protocol-specified dose for which a manufactured product has been 
released. The minimum CART-19 dose for this protocol that will be released from CVPF for 
infusion is 2x106; therefore, this is the lowest dose that will be administered to subjects under this 
protocol. Patients who choose to receive their released CART-19 dose that falls below the 
protocol-specified dose will be clinically followed for safety and efficacy exactly the same as those 
patients who receive their CART-19 dose that falls within the protocol-specified range (i.e. the 
primary efficacy evaluable patients). The only difference between the primary efficacy evaluable 
and non-evaluable patients is that only the primary efficacy evaluable patients will be used for 
primary efficacy endpoint analysis. Both primary efficacy evaluable and non-evaluable patients 
will be used in secondary efficacy, safety, manufacturing feasibility, correlative and exploratory 
analyses. The statistical analysis sets are detailed in Section 8.3. 
3.3 
Retreatment Cohort 
3.3.1 Overview 
Based on available clinical trial data as of February 1, 2014, sustained persistence of CART19 
cells are directly correlated with ongoing response.  Thus, several subjects who have lost detectable 
CART19 cells have subsequently relapsed. Relapsed subjects have been retreated with additional 
CART19 cell infusions and, in some cases, the initial responses were reestablished. Given the 
clinical evidence that will be described in depth below, we would like to allow for the retreatment 
of subjects who had an initial response to their 1st infusion, lost detectable CART19 cells and have 
subsequently relapsed.   
 
 
     
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 

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Taken together, there have been no severe or unexpected toxicities observed in any subject upon 
retreatment with CART19 cells ranging from 2-12 months after the initial infusion(s) retreated 
with CART19 cells as of February 1, 2014. Given the currently available safety data, there is no 
suggestion that retreatment of these targeted subjects will pose risks to the subject greater than that 
of their original infusion. Additionally, 3 of the 7 subjects retreated have experienced clinical 
benefit with few alternative treatment options available. Therefore, retreatment with additional 
CART19 doses carries potential benefit with no observable increased risk associated with the 
current data.  
3.3.2 Retreatment Objectives 
This cohort of subjects will be analyzed separately in order evaluate the following exploratory 
objectives: 
 Assess the frequency and severity of adverse events and other safety data including 
development of cytokine release syndrome 
 Evaluate the expansion and persistence of CART19 cells, in comparison to their original 
infusion 
 Evaluate overall response, time to response, duration of response and time to alternative 
therapy, in comparison to their original infusion. 

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3.3.3 Retreatment Dose 
Three types of subjects will be eligible for retreatment.  
 The first group are subjects initially treated in Stage 1 of this trial (who receive a one-time 
bulk dose infusion), who have previously manufactured cells available and meet criteria 
for retreatment.  These subjects will receive retreatment with a one-time dose of previously 
manufactured cells as described here.   
 The second group of subjects are those treated in Stage 2 on an amended version of the 
protocol (As of Protocol Version 12. 03-05-2015) and will have received split dose 
infusions as described (10% on Day 1; 30% on Day 2; 60% on Day 3), and meet eligibility 
criteria for retreatment.  They will be retreated in the same manner as their initial treatment 
and receive split dose infusions as described.   
 The third group of subjects are subjects initially treated in Stage 1 of this trial (who receive 
a one-time bulk dose infusion), and who meet criteria for retreatment, but do not have 
previously manufactured cells available.  These subjects will undergo a new T-cell 
collection for manufacturing, and will receive cells split dosing fashion (10% on Day 1; 
30% on Day 2; 60% on Day 3). 
 
Up to one retreatment dose (either single or split) will be allowed per eligible subject.   The 
target dose for this retreatment cohort is 1-5 x 108 CART19 cells. The minimum acceptable dose 
for infusion is 1 x 107 CART19 cells.  The target dose corresponds to that of Arm 1 in Stage I of 
this protocol.  Both the target and minimum acceptable dose have been safe and effective in 
ongoing trials evaluating this therapy in patients with both ALL and CLL. Previously 
manufactured cells for this dose level are also readily available in the CVPF for many previously 
enrolled subjects.  
 
All prerequisites for eligibility to receive CART19 outlined in Section 5.2 must be met prior to 
retreatment.  The study drug will be prepared and administered per the guidelines set forth in 
Section 5.    All required pre-medications, prophylaxis monitoring guidelines from the initial 
infusion will apply for retreatment.  
 
Additional information related to retreatment eligibility and procedures, is outlined in Section 
6.13 below.  
4 
Subject Selection and Withdrawal 
 
Patient Population 
4.1 
Inclusion Criteria 
1) Documented CD19+ CLL or SLL 
2) Successful test expansion of T-cells (as described in Section 6.1) 
3) At least 2 prior chemotherapy regimens, not including single agent monoclonal antibody 
(rituxan) therapy. Single agent ofatumumab will be counted as a regimen. Patients with high 
risk disease manifested by deletion chromosome 17p will be eligible if they fail to achieve a 
CR to initial therapy or progress within 2 years of 1 prior regimen. 

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4) Patients who progress within 2 years after the second or higher line of therapy will be 
eligible.  For instance, patients who had progression < 2 years after second or greater line 
therapy, but who have responded to their most recent treatment (3rd line or higher) will be 
eligible.   
5) Subject is not appropriate candidate for a potentially curative allogeneic SCT due to the state 
of disease, co-morbid illness, lack of an available donor, or patient declines 
6) Expected survival > 12 weeksRETIRED FROM PROTOCOL VERSION 12 
7) Performance status (ECOG) 0 or 1 
8) Age >/= 18 years 
9) Adequate organ system function including: 
a. Creatinine < 1.6 mg/dl 
b. ALT/AST < 3x upper limit of normal 
c. Total Bilirubin <2.0 mg/dl 
10) Any relapse after prior autologous SCT will make patient eligible regardless of other prior 
therapy 
11) Patients with relapsed disease after prior allogeneic SCT (myeloablative or 
nonmyeloablative) will be eligible if they meet all other inclusion criteria and: 
a. Have no active GVHD and require no immunosuppression 
b. Are more than 6 months from transplant 
12) No contraindications for leukapheresis 
13) Left Ventricular Ejection fraction >40% 
14) Gives voluntary informed consent 
4.2 
Exclusion Criteria 
1) Pregnant or lactating women.  The safety of this therapy on unborn children is not known. 
Female study participants of reproductive potential must have a negative serum or urine 
pregnancy test performed within 48 hours before infusion. 
2) Uncontrolled active infection 
3) Active hepatitis B or hepatitis C infection 
4) Concurrent use of systemic steroids or chronic use of immunosuppressant medications. Recent 
or current use of inhaled steroids is not exclusionary.  For additional details regarding use of 
steroid and immunosuppressant medications, please see Section 5.6. 
5) Any uncontrolled active medical disorder that would preclude participation as outlined 
6) HIV infection 
7) Patients with active CNS involvement with malignancy.  Patients with prior CNS disease that 
has been effectively treated will be eligible providing treatment was >4 weeks before 
enrollment. 
8) Class III/IV cardiovascular disability according to the New York Heart Association 
Classification (see Appendix 3).  
 
Please see Section 6.13 for eligibility criteria for the Retreatment Cohort. 

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4.3 
Subject Recruitment and Screening 
Subjects will be identified through the clinical practices of the investigator or sub-investigators 
and through referrals from outside hospitals and physicians.  No direct-to-patient advertising will 
be performed.  The clinical trial will be listed on the clinicaltrials.gov website.  
 
To be eligible, the subjects must have an adequate number of T cells that can be successfully 
transduced and expanded with the CD19 TCRζ/4-1BB lentiviral vector (≥ 4-fold expansion 
needed), as determined from a sample of PBMC obtained by phlebotomy at the first screening visit 
(~week -8). The purpose of this screening procedure is to exclude subjects from participation who 
would otherwise undergo a futile apheresis and restaging, without the possibility of having the 
source T cells obtained by apheresis returned as redirected CAR T cells. There will be a minimum 
of 6-8 weeks in between test expansions should the first test expansion fail because of insufficient 
starting T cell numbers, up to a maximum of three test expansions per subject to determine 
eligibility. 
 
Female subjects of reproductive potential (women who have reached menarche or women who 
have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses 
within the preceding 24 months, or have not undergone a sterilization procedure [hysterectomy or 
bilateral oophorectomy]) must have a negative serum or urine pregnancy test within 48 hours prior 
to entry. 
 
Due to the high risk level of this study, while enrolled, all subjects must agree not to participate in 
a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, 
in vitro fertilization). Additionally, if participating in sexual activity that could lead to pregnancy, 
the study subject must agree to use a reliable method of contraception during their participation in 
the study. 
 
Acceptable birth control includes one of the following methods: 
 Condoms* (male or female) with or without a spermicidal agent 
 Diaphragm or cervical cap with spermicide 
 Intrauterine device (IUD) 
 Hormonal-based contraception 
 
Subjects who are not of reproductive potential (women who have been post menopausal for at least 
24 consecutive months or have undergone hysterectomy, salpingectomy, and/or bilateral 
oophorectomy or men who have documented azoospermia) do not require the use of contraception.  
Acceptable documentation of sterilization, azoospermia, and menopause is specified below: 
 
Written documentation by clinician or clinician’s staff through one of the following: 
 Physician report/letter   
 Operative report or other source documentation in the subject record (a laboratory report 
of azoospermia is required to document successful vasectomy)  
 Discharge summary of sterilization procedure or hysterectomy, and/or salpingectomy, 
oophorectomy 
 Laboratory report of azoospermia  
 Follicle stimulating hormone measurement elevated into the menopausal range 

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4.4 
Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Subjects who do not complete the study protocol will be considered to have prematurely 
discontinued the study. The reasons for premature discontinuation (for example, voluntary 
withdrawal, toxicity, death) must be recorded on the case report form. Final study evaluations will 
be completed at the time of discontinuation.   
 
Potential reasons for premature discontinuation include: 
1. The subject is lost to follow-up.   
 
2. The judgment of the principal investigator. 
 
3. Patient noncompliance with study therapy and/or clinic appointments. 
 
4. Pregnancy: Withdraw patient if pregnancy occurs prior to the CART-19 T-cell 
infusion  
 
5. Voluntary withdrawal; a patient may remove himself/herself from the study at any 
time without prejudice. A patient may withdraw from the study at any time they wish 
to withdraw consent.   
 
6. Significant and rapid progression of malignancy, requiring alternative medical, 
radiation or surgical intervention including, but not limited to, the development of 
CNS metastasis if this occurs prior to the CART-19 T-cell infusion. 
 
7.  A serious adverse event that requires the patient’s being withdrawn from the trial if 
the SAE occurs prior to the CART-19 T-cell infusion. 
 
8.  Technical difficulties are encountered in the T cell genetic modification and 
expansion procedure that precludes the generation of clinical cell doses that meet all 
Quality Control release criteria as specified by FDA. 
 
9. Termination of the study by the principal investigator, the sponsor, the study funder, 
the IRB, or the FDA. 
 
Once a subject has received a CART-19 T-cell infusion, subjects should continue to be followed until the 
subject withdraws consent, dies or are lost to follow up. Subjects are encouraged to enroll into a 15 year 
long term follow up protocol to evaluate specific long term adverse events related to the study product.  
 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Follow-up data collection after gene modified cell therapy clinical trials is specified by the FDA.  
As long as patients have detectable cells transduced with the lentiviral vector, they should be 
followed for toxicity, immune reactions, and any long-term adverse events.  Therefore, subjects 
will continue to be followed for 1) engraftment as long as patients are at risk (until evidence of 

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loss of detectable transduced T cells), 2) DFS until there is disease progression or they begin a new 
cancer therapy, and 3) survival until the time of death; until the patient withdraws consent for 
clinical data collection or the end of the study (Last Patient/Last Visit).  
 
Patients who are followed at other institutions or practices, because of preference or geographical 
concerns will have follow-up via notes from their local physician and/or phone interviews with 
periodic study assessments done at HUP.  An example would be a patient referred from out of state 
but cared for at another center.  We will obtain toxicity and other clinical assessments from the 
treating physician, and follow the patient as described in the table in Appendices 1 and 2. In 
numerous previous cell therapy trials at the University of Pennsylvania, loss of follow-up is 
estimated to occur in less than 5% of cases. Every effort will be made to contact subjects who 
appear to be lost to follow-up in order to at least obtain survival data. In the event a subject fails 
to complete the follow-up requirements, documentation of all attempts to contact the subject 
includes at least 3 telephone contacts (on different days and at different times of the day), and a 
certified letter. 
 
After subjects’ complete or prematurely discontinue participation in this study, subjects will also 
be asked to participate in a separate 15 year long-term follow-up destination protocol.  
5 
Study Drug  
5.1 
Description 
CART-19 cells are autologous T cells that have been engineered to express an extracellular single 
chain antibody (scFv) with specificity for CD19 linked to an intracellular signaling molecule 
consisting of a tandem signaling domains comprised of the TCRζ signaling module linked to the 
4-1BB costimulatory domain. The CART-19 cells are cryopreserved in infusible cryomedia and 
will be administered as one bag on Day 1. Each bag will contain an aliquot (volume dependent 
upon dose) of cryomedia containing the following infusible grade reagents (% v/v): 31.25% 
Plasmalyte-A, 31.25% dextrose (5%), 0.45% NaCl, up to 7.5% DMSO, 1% dextran 40, 5% human 
serum albumin.  
 
Expected toxicities associated with infusion of CART-19 cells include transient fever, chills 
nausea, rigors, hypotension, tumor lysis syndrome, and cytokine release syndrome.  In order to 
minimize these events, patients will receive premedication as instructed below.  Toxicities that 
could potentially occur but are unprecedented are primarily related to the gene transfer and are 
described in the Risk and Benefit section (refer to section 1.8).   These include generation of a 
replication competent lentivirus (RCL), insertional oncogenesis, and uncontrolled proliferation of 
the CART-19 cells.  
 
5.2 
Patient Eligibility to Receive CART-19 Transduced T Cells 
Day 1 CART-19 Infusion: 
1. All patients must undergo a Respiratory Virus Panel (RVP) within 10 days prior to 
the first planned CART-19 infusion. If the patient is positive for influenza, Tamiflu® 
or equivalent, should administered for 10 days as preventative treatment.  The patient 
must complete their 10 day preventative treatment course prior to receiving CART-

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19.  The test does not need to be repeated prior to the first CART-19 infusion, 
however if influenza sign and symptoms are present, the CART-19 infusions should 
be delayed until the patient is asymptomatic.  If the patient is positive for another 
virus on the RVP, the CART-19 infusion will be delayed for at least 7 days to be sure 
clinical symptoms of a viral infection do not develop.  If clinical symptoms develop, 
the infusion will be delayed until resolution of these symptoms. 
2. Patient should not experience a significant change in performance status or clinical 
status compared to initial eligibility criteria that would, in the opinion of the treating 
physician, increase the risk of experimental cell infusion. 
3. Patients experiencing laboratory abnormalities after enrollment, that in the opinion of 
the treating investigator or PI may impact subject safety or the subjects’ ability to 
receive CART-19 T-cells, may have their infusion delayed until both the treating 
investigator and PI determine it is clinically appropriate to proceed with the CART-19 
infusion. 
4. Patients experiencing toxicities from their preceding cytoreductive chemotherapy can 
have their infusion schedule delayed until these toxicities have resolved. Note: If 
patients CART-19 infusion is delayed > 4 weeks from cytoreductive chemotherapy, 
the cytoreductive chemotherapy should be repeated. The specific toxicities warranting 
delay of T cell infusions include: 
a. Pulmonary: Requirement for supplemental oxygen to keep saturation greater 
than 95% or presence of radiographic abnormalities on chest x-ray that are 
progressive 
b. Cardiac: New cardiac arrhythmia not controlled with medical management 
c. Hypotension requiring pressor support 
d. Active Infection(s): as evident by positive blood cultures for bacteria, fungus, 
or virus within 48 hours of CART-19 cell infusion. 
 
Day 2 CART-19 Infusion: 
1. Patient should not experience a significant change in performance or clinical 
status compared to their previous study visit that would, in the opinion of the 
treating physician, increase the risk of experimental cell infusion. 
2. Patients experiencing new laboratory abnormalities, that in the opinion of the treating 
investigator or PI may impact subject safety or the subjects’ ability to receive CART-19 
T-cells, may have their infusion delayed until both the treating investigator and PI 
determine it is clinically appropriate to proceed with the CART-19 infusion.  
 
Day 3 CART-19 Infusion: 
1. Patient should not experience a significant change in performance or clinical 
status compared to their previous study visit that would, in the opinion of the 
treating physician, increase the risk of experimental cell infusion. 
2. Patients experiencing new laboratory abnormalities, that in the opinion of the 
treating investigator or PI may impact subject safety or the subjects’ ability to 
receive CART-19 T-cells, may have their infusion delayed until both the 
treating investigator and PI determine it is clinically appropriate to proceed 
with the CART-19 infusion. 

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5.3 
Treatment Regimen 
CART-19 transduced T cells will be administered at a dose of 1-5x108 given via split dosing on 
Days 1, 2 and 3.  The first CART-19 infusion will be scheduled to occur approximately 1 to 4 days 
following lymphodepleting chemotherapy but may be delayed as outlined above (Section 5.2). 
5.4 
Preparation and Administration of Study Drug 
Cell manufacturing is done according to Figure 3 under 
 at the University of 
Pennsylvania Clinical Cell and Vaccine Production Facility (CVPF). The CART-19 T cells are 
prepared in the CVPF and are not released from the CVPF until FDA approved release criteria for 
the infused cells (e.g., cell dose, cell purity, sterility, average copy number of vectors/cell, etc.) are 
met. Upon release, the cells are administered at the bedside.  
 
Cell thawing  
The cells will be transported by CVPF personnel to the subject’s bedside.  The cells will be thawed 
at the bedside or in the CVPF by trained personnel using a water bath maintained at 36C to 38C.  
The bag will be gently massaged until the cells have just thawed.  There should be no frozen 
clumps left in the container by the time it is connected to the I.V. tube. If the CART-19 cell product 
appears to have a damaged or leaking bag, or otherwise appears to be compromised, it should not 
be infused, and should be returned to the CVPF.  
 
Premedication 
Side effects following T cell infusions include transient fever, chills, and/or nausea. It is 
recommended that the subject be pre-medicated with acetaminophen (650 mg) and 
diphenhydramine hydrochloride (25-50 mg IV/PO) at least 30 minutes prior to each infusion of 
CART-19 cells. These medications may be repeated every six hours as needed. A course of non-
steroidal anti-inflammatory medication may be prescribed if the patient continues to have fever 
not relieved by acetaminophen. Patients should not receive systemic corticosteroids such as 
hydrocortisone, prednisone, prednisolone (Solu-Medrol) or dexamethasone (Decadron) at any 
time, except in the case of a life-threatening emergency, since this may have an adverse effect on 
CART-19 cell expansion and function. If corticosteroids are required for an acute infusional 
reaction, an initial dose of hydrocortisone 100 mg is recommended. 
 
Febrile reaction 
In the event of febrile reaction, an evaluation for infection should be initiated, and patients 
managed appropriately with antibiotics, fluids and other supportive care as medically indicated 
and determined by the treating physician. In the event that the patient develops sepsis or systemic 
bacteremia following CAR T cell infusion, appropriate cultures and medical management should 
be initiated. If a contaminated CART-19 T cell product is suspected, the product can be retested 
for sterility using archived samples that are stored in the CVPF. Consideration of a CRS should be 
given.   
 
Additional Safety Procedures prior to Administration 
The on-site pharmacy must confirm that a dose of tocilizumab is on site and available for 
administration in order to manage suspected toxicities prior to infusion. 
 
Emergency medical equipment (i.e., emergency trolley) must be available during the infusion in 

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case the patient has an allergic response, or severe hypotensive crisis, or any other reaction to the 
infusion. Vital signs (temperature, respiration rate, pulse, and blood pressure) will be taken 
before infusion.  
 
Packaging and Labeling 
CART-19 transduced T cells will be administered at a dose of 1-5x108 given via split dosing on Days 
1, 2 and 3.  Each infusion bag will contain an aliquot (volume dependent upon dose) of cryomedia 
containing the following infusible grade reagents (% v/v): 31.25% plasmalyte-A, 31.25% 
dextrose (5%), 0.45% NaCl, up to 7.5% DMSO, 1% dextran 40, 5% human serum albumin. 
 
Each infusion bag will have affixed to it a label containing information regarding the dose, the 
method of manipulation, the vector and “FOR AUTOLOGOUS USE ONLY.”  In addition the 
label will have the following unique identifiers patient name, study ID, and patient birth date. 
Prior to each infusion, two individuals will independently verify all unique identifier 
information in the presence of the patient and to confirm that the information is correctly matched 
to the patient. 
5.5 
Infusion of CART-19 Product 
Trained study staff will administer the CART-19 product via i.v. infusion using precautions for 
immunosuppressed patients. A physician from the research team will be readily available during 
the complete duration of the infusion.  The transduced T cells will be infused at a flow rate of 
approximately 10 to 20 mL per minute through an 18-gauge latex free macrodrip i.v. tubing without 
a leukocyte filter or equivalent. A leukoreduction filter must not be used for the infusion of the 
T cell product. The duration of the infusion will be based on the total volume to be infused and the 
recommended infusion rate.  Vital signs (temperature, respiration rate, pulse, blood pressure, and 
oxygen saturation by pulse oximetry) will be measured within 10 minutes prior, during and within 
10 minutes after the infusion, and then every 15 minutes for the first hour and then every hour for 
the next 2 hours until these signs are satisfactory and stable. In the event that an infusion takes 
longer than 15 minutes, vital signs will be taken every 15 minutes until the infusion is completed.  
If the subject’s vital signs are not satisfactory and stable three hours post-CART-19 infusion, vital 
signs will continued to be monitored at a minimum of every hour or as clinically indicated until 
stable. The subject will be discharged after the physician managing their care on the day of each 
infusion has determined that they are in satisfactory condition. 
5.6 
Prior and Concomitant Therapy 
All prescription and nonprescription medication, vitamins, herbal and nutritional supplements, 
taken by the subject during the 30 days prior to screening will be recorded at the screening visit. 
At every visit following the CART-19 infusions through 1 year, concomitant medications will be 
recorded in the medical record and on the appropriate CRF.  Any additions, deletions, or changes 
of these medications will be documented. The following guidelines must be adhered to during the 
study: 
 GM-CSF should be avoided due to potential to worsen CRS symptoms.  G-CSF would be 
the preferred myeloid growth factor over GM-CSF, if medically indicated. The effects of 
G-CSF are unknown and can be used at the physician’s discretion. 

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 Steroids or other immunosuppressant drugs should NOT be used within 10 days prior to 
the apheresis procedure 
 Steroids or other immunosuppressant drugs should NOT be used within 24 hours prior to 
the CART-19 infusions (refer to Section 5.4) or following CART-19 infusion unless under 
life threatening circumstances or at the physicians’ discretion to manage CRS. 
 Patients with severe signs and symptoms attributable to cytokine release syndrome (i.e. 
CRS) should be managed with administration of tocilizumab or other anti-cytokine 
directed therapies (Refer to Section 9.5.2 for administration details). 
5.7 
Subject Compliance Monitoring 
The investigator-initiated phase I/II trials at the UPenn Abramson Cancer Center (ACC) are 
subject to routine auditing in accordance with their high risk policy.  Ongoing monitoring of each 
patient is performed by the monitor designated by the Sponsor.   
6 
Study Procedures 
The study consists of 1) a screening phase, 2) a randomization and arm assignment stage (Stage 1 
only), 3) an intervention/treatment phase consisting of apheresis, chemotherapy (to be determined 
according) to the investigator and dependent on the patient’s disease burden and histology), 
infusions of CART-19 cells, CT scans and tumor collection by bone marrow aspiration or lymph 
node biopsy (optional, depending on availability), and 4) follow up. Schedule of evaluations and 
infusion are included in Appendix 1. 
6.1 
Pre-Entry Evaluations (Screening) and Subject Number Assignment (Week -8 to -
12) 
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject  
throughout his/her entire participation in the trial. The Subject No. consists of the Center Number 
(Center No.) (as assigned by Sponsor to the investigative site) with a sequential subject number 
suffixed to it, so that each subject is numbered uniquely across the entire database. Upon signing 
the informed consent form, the subject is assigned to the next sequential Subject No. available to 
the investigator. Once assigned, the Subject No. must not be reused for any other subject and the 
Subject No. for that individual must not be changed, even if the subject is re-screened. 
If the subject fails screening for any reason, the reason will be entered into the Screening 
Disposition page. 
 
After informed consent and demographic information are obtained, blood tests to determine 
eligibility are performed, and a blood sample is sent to the CVPF to determine T cell manufacturing 
feasibility.  Adverse events and concomitant medications will be recorded beginning from the time 
the patient’s informed consent has been obtained. In approximately 1 week, the CVPF will return 
a result as to whether the subject’s PBMC are likely to be adequate for large scale CART-19 T cell 
manufacturing process.  At the discretion of the Principal Investigator, subjects who have had a 
successful test expansion of T-cells prior to enrollment in this study may not be required to have a 
second test expansion. During the screening period, inclusion and exclusion criteria will be 
assessed. Also, subjects will be tested for Human Immunodeficiency Virus (HIV). 

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6.2 
Enrollment and Baseline Assessment (Week -6 to -8) 
Eligible subjects who have signed an informed consent and have adequate pre-screening 
evaluation will undergo a routine lymphoma/leukemia staging workup including: 
 
a) Eligibility form and randomization (Stage 1 Subjects Only) 
b) Relevant medical history, current medical conditions, and physical examination 
(including vital signs, height, weight, body surface area) 
c) Concomitant medications 
d) Adverse events 
e) Performance status assessment 
f) CT scans of the chest, abdomen, and pelvis done within 42 days of study entry  
g) Hematology (Complete blood count, differential and platelet count) 
h) Chemistry panel (Glucose, BUN, Creatinine, Sodium, Potassium, Calcium, Total 
Protein, Albumin, Total Bilirubin, Alk Phos, AST, ALT, Mg, Phos, LDH, Ferritin, CRP 
and Uric Acid) 
i) β2 Microglobulin Level 
j) Serum immunoglobulin levels 
k) Serum pregnancy test (qualitative) 
l) Viral serologies (CMV, EBV, Hepatitis B/C). If the HCV antibody is positive, a 
screening HCV RNA by any RT-PCR or bDNA assay must be performed. Eligibility 
will be determined based on the screening value. The test is not required if 
documentation of a negative result of a HCV RNA test performed within 60 days prior 
to screening is provided 
m) Autoimmune screen (ANA, ESR) 
n) Leukapheresis screening (assessment of the suitability of venous access) 
o) Bone marrow biopsy/aspirate and lymph node biopsy (if accessible). Samples are sent 
to hematopathology for MRD assessment, p53 mutation analysis and CD19 expression.  
p) Blood will be sent for flow cytometry to confirm CD19 expression if this has not been 
done in the past 6 months  
q) MUGA/ECHO 
r) Quality of Life Questionnaires (EORTC QLQ-C30 and CLL-16) 
s) Research labs: Molecular (including p53 and VSV-G), cytokine, Immunogenicity 
(HAMA/HACA), and cellular assessments 
 
Correlative Research Labs:  For molecular and cell engraftment studies (Q-PCR and Q-RT-PCR), 
immune phenotyping and functional assays, peripheral blood and marrow samples will be 
collected in Lavender top (K2EDTA) tubes.  For cytokine analyses, such as IL-6 and IL-2, 
peripheral blood and marrow samples will be collected in red top (no additive) tubes.  Samples 
will be collected according to the protocol Schedule of Study Procedures (Appendices 1 and 2).   
Samples will be delivered, processed, and frozen as per SOP to the Translational and Correlative 
Studies Laboratory (TCSL) (University of Pennsylvania).  Samples will be stored in the TCSL at 
the University of Pennsylvania for storage and bulk analyses.  Documentation for sample -receipt, 
-processing, and storage and primary data from the research analyses will be collected and stored 
in the TCSL.   All research analyses will be performed based on principles of Good Clinical 
Laboratory Practice, with assay-specific SOP using qualified and if possible validated assays.   
 

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Translational and Correlative Studies Laboratory 
University of Pennsylvania Perelman School of Medicine 
Translational Research Center, 9-188 
3400 Civic Center Boulevard, Building 421 
Philadelphia, PA 19104-5157 
 
In the event that the time between the above baseline assessments and the Day 1 CART-19 T cell 
infusion exceeds the 8 week Enrollment/Baseline Window, the following clinical tests/procedures 
will be repeated: Physical Examination, Performance Status Assessment, Complete Blood Count, 
Differential and Platelet Count, Chemistry Panel, Pregnancy test, HIV, and Hepatitis B/C. 
6.3 
Enrollment Process 
To enroll a subject on this study, provide the documents listed below to:  
 
Protocol Monitor and Sponsor Project Manager 
Translational Research Program 
Email:
 
Fax: 
 
 
Documents required: 
 Complete Enrollment Form (including patient past medical history, laboratory, radiological 
reports, documentation of consent, physical exam, concomitant medications and any other source 
documentation to support subject meets eligibility criteria and has completed all required screening 
assessments) 
 Copy of signed patient consent and HIPAA form 
 
Upon informed consent completion and receipt of screening and eligibility documentation, the 
Sponsor Protocol Monitor will review and provide documentation that the monitoring visit for 
eligibility has been completed. This documentation must be received prior to cell product 
manufacturing.    
 
For enrollment into Stage 1, randomization assignments will be performed centrally by Novartis 
using Treatment Allocation Cards. A full set of 40 cards will be maintained by the site. Each card 
will have a specific Randomization Number printed on it. The treatment information on each card 
is hidden and will only become visible after it is scratched-off. 
 
When a confirmed eligible patient requires randomization into Stage 1 of the study, designated site 
staff will complete the Randomization Number Request Form and submit it to the Randomization 
Coordinator (NVS).  The Randomization Coordinator will provide the next available 
Randomization Number to the site using the Randomization Number Assignment Form. The site 
will then provide the Treatment Allocation Card corresponding ONLY to the assigned 
Randomization Number to the Investigator/ designee for use in randomizing the eligible patient. 
More details on randomization are available in the study specific Novartis Randomization 
Document. 
 

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All patients will be enrolled into Stage 1 until the dose cohort for Stage 2 has been selected for 
expansion, per section 8.1. After the dose cohort for Stage 2 has been selected, all subsequent 
patients will be enrolled into Stage 2. If deemed appropriate by the Investigator, an additional dose 
level may be explored prior to the start of Stage 2. 
 
No more than 20% of the total enrollment may be manufacturing failures. If this is exceeded, a 
separate modification will be submitted for IRB review. 
6.4 
Apheresis (Week -4) 
Subjects will undergo the additional following assessments: 
 
a) Current medical conditions  
b) Concomitant medications 
c) Adverse events 
d) Leukapheresis (as mentioned below) 
e) Research  labs: Cytokine assessments  
 
A large volume (12-15 liters or ~2-3 blood volumes) apheresis procedure is carried out at the 
apheresis center. PBMC are obtained for CART-19 during this procedure. From a single 
leukapheresis and due to the low percentage of T cells in CLL study subjects, the intention is to 
harvest at least 5 x 109 white blood cells to manufacture CART-19 T cells. Baseline blood 
leukocytes for FDA look-back requirements and for research are also obtained and cryopreserved 
(1 x 108 cells from apheresis to TCSL). The cell product is expected to be ready for release 
approximately 4 weeks later. Baseline cytokines will be measured. If T cells were previously 
collected on another research study, and are acceptable to use to manufacture T cells for this study, 
they may be used in lieu of repeating apheresis.   
6.5 
Cytoreductive chemotherapy (Week -1) 
In preparation for cytoreductive chemotherapy (detailed below), the subjects will undergo the 
following assessments: 
 
a) Current medical conditions   
b) Concomitant medications 
c) Adverse events 
d) Cytoreductive chemotherapy (as mentioned below) 
e) Quality of Life Questionnaires (EORTC QLQ-C30 and CLL-16) 
 
It is anticipated that many patients have been receiving chemotherapy for relapse or resistant 
disease. Patients referred with stable disease on no recent therapy will be eligible.   Prior to the 
first CART-19 cell infusion, an additional chemotherapy cycle for lymphodepletion is planned if 
clinically indicated.  The regimen of chemotherapy will be at the discretion of the investigator and 
dependent on the patient’s disease burden and histology. The preferred chemotherapy and 
lymphodepletion is fludarabine 30 mg per meter squared per day for 3 days and cyclophosphamide 
300 mg per meter squared per day on the same 3 days, as there is the most experience with the use 
of these agents in facilitating adoptive immunotherapy. Rituximab will not to be given. In the 
unusual circumstance that patients have a medical contraindication to either of these drugs, or a 

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failure to respond to previous fludarabine based regimen, bendamustine 90 mg per meter squared 
per day for 2 days will be preferred.  Pentastatin/cyclophosphamide is another acceptable 
alternative if fludarabine cannot be given. 
 
Chemotherapy is started approximately 1 week before the first infusion so that CART-19 cells 
may be given 1-4 days after completion of the chemotherapy.  The timing of chemotherapy 
initiation therefore depends on the length of the regimen. The purpose of the chemotherapy is to 
induce lymphopenia in order to facilitate engraftment and homeostatic expansion of CART-19 
cells.  In addition, chemotherapy can potentiate the ability of T cells to kill tumor cells91, 92. The 
chemotherapy is not investigational and may be given by a patient’s local oncologist within the 
specified time frame. 
 
All patients must undergo a Respiratory Virus Panel (RVP) within 10 days prior to the first planned 
CART-19 infusion. If the patient is positive for influenza, Tamiflu® or equivalent, should 
administered for 10 days as preventative treatment.  The patient must complete their 10 day 
preventative treatment course prior to receiving CART-19.  The test does not need to be repeated 
prior to the first CART-19 infusion, however if influenza sign and symptoms are present, the 
CART-19 infusion should be delayed until the patient is asymptomatic.  If the patient is positive 
for another virus on the RVP, the CART-19 infusion will be delayed for at least 7 days to be sure 
clinical symptoms of a viral infection do not develop.  If clinical symptoms develop, the infusion 
will be delayed until resolution of these symptoms. 
6.6 
CART-19 Pre-Infusion (Day -1) 
Subjects will undergo the following work-up including: 
 
a) Current  medical conditions and physical examination (including vital signs, height, 
weight, body surface area as clinically indicated) 
b) Performance status assessment 
c) Concomitant medications 
d) Adverse events 
e) Hematology (complete blood count, differential and platelet count) 
f) Chemistry panel (Glucose, BUN, Creatinine, Sodium, Potassium, Calcium, Total 
Protein, Albumin, Total Bilirubin, Alk Phos, AST, ALT, Mg, Phos, LDH, Ferritin, CRP 
and Uric Acid) 
g) Urine pregnancy test 
h) Baseline screens for HLH/MAS:  triglycerides and haptoglobin 
i) Baseline screen for coagulation factors:  PT, PTT, INR, fibrinogen, D-dimer 
j) Research labs:  Molecular (including VSV-G), cytokine and cellular assessments   
6.7 
CART-19 Infusions (Days 1, 2, and 3) 
The first CART-19 infusion should begin 1 to 4 days after completion of cytoreductive 
chemotherapy.  The dose will be administered as a split infusion of 1 to 5 x 108 total CART-19 
transduced cells: 10% on Day 1 (1-5x107), 30% on Day 2 (3x107-1.5x108), 60% on Day 3 (6x107-
3x108). Patients will be infused and premedicated as described in Section 5.4. 
 
Prior to each infusion, patients will undergo the following assessments: 

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a) Current medical conditions and physical examination (including vital signs, height, 
weight, body surface area as clinically indicated) 
b) Performance status assessment 
c) Concomitant medications 
d) Adverse events 
e) Hematology (complete blood count, differential and platelet count) 
f) Chemistry panel (Glucose, BUN, Creatinine, Sodium, Potassium, Calcium, Total 
Protein, Albumin, Total Bilirubin, Alk Phos, AST, ALT, Mg, Phos, LDH, Ferritin, CRP 
and Uric Acid). Potassium prior to infusion and 2 hours post infusion. 
g) CD3, CD4 and CD8 lymphocyte counts  
h) CART-19 infusion (as mentioned below) 
i) Research labs:  Molecular, cytokine and cellular assessments (pre & post infusion, as 
below) 
 
The cells are thawed at the patient’s bedside or in the CVPF by trained personnel. The thawed cells 
will be given at an infusion rate as quickly as tolerated so that the duration of the infusion will be 
approximately 2-20 minutes. In order to facilitate mixing, the cells will be administered 
simultaneously using a Y-adapter. Subjects will be infused and premedicated as described in 
Section 5.4. Vital signs (temperature, respiration rate, pulse, blood pressure, and oxygen saturation 
by pulse oximetry) will be measured within 10 minutes prior, during and within 10 minutes after 
the infusion and then every 15 minutes for the first hour and then every hour for the next 2 hours 
until these signs are satisfactory and stable. In the event that an infusion takes longer than 15 
minutes, vital signs will be taken every 15 minutes until the infusion is completed.  If the subject’s 
vital signs are not satisfactory and stable three hours post-CART-19 infusion, vital signs will 
continued to be monitored at a minimum of every hour or as clinically indicated until stable. The 
subject will be discharged after the physician managing their care on the day of the infusion has 
determined that they are in satisfactory condition.  Blood samples for determination of a baseline 
cytokines, molecular persistence and CART-19 levels are obtained any time prior to the first 
infusion.  Additional blood samples are collected 20 minutes to 2 hours post each infusion for 
cytokine assessment and molecular persistence testing (and sent to the TCSL- please refer to 
Section 6.8).  
 
Patients experiencing toxicities from their preceding cytoreductive chemotherapy will have their 
infusion schedule delayed until these toxicities have resolved. The specific toxicities warranting 
delay of T cell infusions include: 1) Pulmonary: Requirement for supplemental oxygen to keep 
saturation greater than 95% or presence of radiographic abnormalities on chest x-ray that are 
progressive; 2) Cardiac: New cardiac arrhythmia not controlled with medical management. 3) 
Hypotension requiring pressor support. 4)  Active Infection: Positive blood cultures for bacteria, 
fungus, or virus within 48-hours of T cell infusion. 
 
A serum sample for potassium will be collected before each infusion (as part of the chemistry 
panel) as well as approximately two hours after each infusion (separate blood sample).  

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6.8 
Post infusion laboratories to assess engraftment, persistence and bioactivity (Days 
4, 7, 10, 14, and 21) 
Subjects will return to the clinic at days 4, 7, 10, 14, and 21 after the CART-19 cell infusions.  At 
these study visits, subjects will undergo the following assessments: 
 
a) Current medical conditions and physical examination (including vital signs, height, 
weight, body surface area as clinically indicated) 
b) Performance status assessment 
c) Concomitant medications 
d) Adverse events 
e) Hematology (complete blood count, differential and platelet count) 
f) Chemistry panel (Glucose, BUN, Creatinine, Sodium, Potassium, Calcium, Total 
Protein, Albumin, Total Bilirubin, Alk Phos, AST, ALT, Mg, Phos, LDH, Ferritin, CRP 
and Uric Acid) 
g) Vital signs 
h) Coagulation factors:  PT, PTT, INR, fibrinogen, D-dimer on Day 14  
i) Research labs: Engraftment and persistence of CART-19 cells,  
j) Research labs:  Molecular, cytokine, and cellular assessments 
6.9 
Day 28/End of Treatment 
 
At this study visit, subjects will undergo the following assessments: 
 
a) Current  medical conditions and physical examination (including vital signs, height, 
weight, body surface area as clinically indicated) 
b) Performance status assessment 
c) Concomitant medications 
d) Adverse events 
e) Hematology (complete blood count, differential and platelet count) 
f) Chemistry panel (Glucose, BUN, Creatinine, Sodium, Potassium, Calcium, Total 
Protein, Albumin, Total Bilirubin, Alk Phos, AST, ALT, Mg, Phos, LDH, Ferritin, 
CRP and Uric Acid) 
g) CT scans of the chest, abdomen, and pelvis  
h) Bone marrow biopsy/aspirate and lymph node biopsy (if accessible)  
i) Serum immunoglobulin levels  
j) HLH/MAS:  triglycerides and haptoglobin  
k) CD3, CD4 and CD8 lymphocyte counts  
l) Research labs: Engraftment and persistence of CART-19 cells,  Molecular, cytokine, 
and cellular assessments  
m) 100mL peripheral blood draw 
n) Quality of Life Questionnaires (EORTC QLQ-C30 and CLL-16) 
 
Restaging is done in order to provide tumor burden measurements.  Restaging testing is determined 
by disease type and may include imaging, MRD assessments by Dr. Bagg (or designee), bone 
marrow aspirate and biopsy and/or optional lymph node biopsy. 

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6.10    Monthly evaluations 2 to 6 months post infusion (Safety follow-ups 1 to 5) 
Subjects will return to the clinic on a monthly basis during months 2 to 6 post CART-19 cell 
infusion.  At these study visits, subjects will undergo the following:   
 
a) Current medical conditions and physical examination (including vital signs, height, 
weight, body surface area as clinically indicated) 
b) Concomitant medications 
c) Adverse events 
d) Hematology (complete blood count, differential and platelet count) 
e) Chemistry panel (Glucose, BUN, Creatinine, Sodium, Potassium, Calcium, Total 
Protein, Albumin, Total Bilirubin, Alk Phos, AST, ALT, Mg, Phos, LDH, Ferritin, CRP 
and Uric Acid) 
f) Performance status assessment 
g) Quality of Life Questionnaires (EORTC QLQ-C30 and CLL-16) (only at months 3 and 
6) 
h) CT scans of the chest, abdomen, and pelvis (only at months 3 and 6) 
i) Bone marrow biopsy/aspirate (only at months 3 and 6) and lymph node biopsy (if 
accessible and as clinically indicated at months 3 and 6 only)  
j) Research labs: Engraftment and persistence of CART-19 cells, Molecular, cytokine, and 
cellular assessments (VSV-G at months 3 and 6 only)   
k) CD3, CD4 and CD8 lymphocyte counts (only at months 3 and 6) 
l) Serum immunoglobulin levels at months 3 and 6 
6.11 Months 9 (Safety follow-up 6) and 12 (End of Study) evaluations post infusion  
Subjects will be evaluated on a quarterly basis until 1 year post infusion (month 12 visit is the end 
of study visit).  At these study visits, subjects will undergo the following assessments: 
 
a) Current medical conditions and physical examination (including vital signs, height, 
weight, body surface area as clinically indicated) 
b) Concomitant medications 
c) Adverse events 
d) Hematology (complete blood count, differential and platelet count) 
e) Chemistry panel (Glucose, BUN, Creatinine, Sodium, Potassium, Calcium, Total 
Protein, Albumin, Total Bilirubin, Alk Phos, AST, ALT, Mg, Phos, LDH, Ferritin, CRP 
and Uric Acid) 
f) Performance status assessment 
g) Quality of Life Questionnaires (EORTC QLQ-C30 and CLL-16 ) 
h) CT scans of the chest, abdomen, and pelvis 
i) Bone marrow biopsy/aspirate and lymph node biopsy (if accessible and as clinically 
indicated)  
j) Serum immunoglobulin levels  
k) CD3, CD4 and CD8 lymphocyte counts (only at month 12) 
l) Research labs: Engraftment and persistence of CART-19 cells, Molecular, 
Immunogenicity (HAMA/HACA), cytokine, and cellular assessments (VSV-G at 
month 12 only) 

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6.12 Secondary Follow-up  
For subjects who complete or prematurely discontinue from study follow-up while in remission, 
follow-up attempts will be made to assess the subject’s relapse and survival status every 3 months 
post CART-19 infusion until the end of the study (Last Patient/Last Visit). Once subjects’ relapse 
or they begin a new cancer therapy, additional follow-up for relapse will not be required, and 
subjects will be followed for survival only.   
6.13 Long-term Follow-up Protocol 
After subjects’ complete or prematurely discontinue participation in this study, subjects will be 
asked to participate in a separate 15 year long-term follow-up destination protocol.  This long-term 
follow-up protocol includes evaluations performed for up to 15 years on all subjects as 
recommended by the FDA for protocols utilizing integrating viral vectors.  Evaluations will 
include:  physical exam and medical history (including concomitant medications and adverse 
events) with careful attention to features possibly related to onco-retroviral diseases such as cancer, 
neurologic disorders or other hematologic disorders. In addition, labs will be drawn to evaluate 
engraftment, CART19 PCR and research labs.  Blood for a VSV-G DNA test will be drawn yearly 
in order to detect RCL. If all VSV-G DNA tests are negative during the study period to the first 
annual evaluation, then future plasma samples may be archived for analysis on an as needed basis.  
6.14 Retreatment Cohort Procedures 
 
6.14.1 Eligibility for Retreatment 
Up to one retreatment dose will be allowed per eligible subject.    
 
1. Subjects previously infused with CART19 cells as part of this protocol and who 
experienced an initial response (either CR, CRi or PR) to therapy, but have 
subsequently progressed within 2 years of their initial response. 
2. Subjects have undergone the 3 month efficacy endpoint evaluation. Subjects who 
achieve an initial response, but relapse prior to this Month 3 timepoint will be 
eligible. 
3. Subjects have <5% CART19 cells in the CD3+ population by flow cytometry on 
PBMCs 
4. Subjects have recovered from any toxicity attributed to the initial CART19 infusion, 
such as CRS. 
 
In addition, subjects must also meet the following: 
 
Retreatment Inclusion Criteria 
1. Performance Status 0-1 
2. Adequate organ system function including: 
o Creatinine < 1.6 mg/dl 
o ALT/AST < 3x upper limit of normal 
o Total Bilirubin < 2.0 mg/dl 
3. Subject is not an appropriate candidate for a potentially curative allogeneic SCT due 
to the state of disease, co-morbid illness, lack of an available donor, or patient 
declines. 

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4. Expected survival > 12 weeks Retired from Protocol Version 12 
5. Left Ventricular Ejection Fraction > 40% 
6. No contraindications for leukapheresis (if required for retreatment)  
7. Gives voluntary informed consent for retreatment 
 
Retreatment Exclusion Criteria 
1. Pregnant or lactating women.  Female study participants must have a negative serum 
or urine pregnancy test performed within 48 hours before infusion. 
2. Uncontrolled active infection 
3. Active hepatitis or hepatitis infection 
4. Concurrent use of systemic steroids.  Recent or current use of inhaled steroids is not 
exclusionary.   
5. Any uncontrolled active medical disorder that would preclude participation as 
outlined. 
6. HIV infection 
7. Patients with active CNS involvement with malignancy.  Patients with prior CNS 
disease that has been effectively treated will be eligible providing treatment was >4 
weeks before enrollment on the retreatment cohort. 
8. Class III/IV cardiovascular disability according to the New York Heart Association 
Classification (see Appendix 3). 
 
6.13.2  Retreatment Procedures 
Subjects eligible for retreatment who consent to participate in this cohort will be enrolled on the 
retreatment cohort.  To enroll a subject on the retreatment cohort, please provide the documents 
listed below to: 
 
Protocol Monitor and Sponsor Project Manager 
Translational Research Program 
Email: t
 
Fax: 
 
 
Documents required: 
 Copy of signed retreatment consent 
 Completed Retreatment Cohort Enrollment Form- including documentation of retreatment 
consent, current physical examination, laboratory and radiological reports, current/past medical 
history and concomitant medications, and any other documentation to support the subjects’ 
enrollment onto the retreatment cohort and has completed all required assessments. 
 
Upon informed consent completion for retreatment and receipt of retreatment screening and 
eligibility documentation, the Sponsor Protocol Monitor will review and provide documentation 
that the monitoring visit for retreatment eligibility has been completed.  This documentation must 
be rec 
 The same Subject Number previously assigned will be used to identify participants.  Enrollment 
on the retreatment cohort will be tracked by adding “r” to the end of this existing subject 
identification number (i.e. 1000-00001R), however the same Subject Number previously assigned 
will be used in the clinical database.  

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Three types of subjects will be eligible for retreatment.  
 The first group are subjects initially treated in Stage 1 of this trial (who receive a one-time 
bulk dose infusion), who have previously manufactured cells available, and who meet 
criteria for retreatment.  These subjects will receive retreatment with a one-time dose of 
previously manufactured cells as described here.   
 The second group of subjects are those treated in Stage 2 on an amended version of the 
protocol (As of Protocol Version 12. 03-05-2015) and will have received split dose 
infusions as described (10% on Day 1; 30% on Day 2; 60% on Day 3), and meet eligibility 
criteria for retreatment.  They will be retreated in the same manner as their initial treatment 
and receive split dose infusions as described.   
 The third group of subjects are subjects initially treated in Stage 1 of this trial (who receive 
a one-time bulk dose infusion), and who meet criteria for retreatment, but who do not have 
previously manufactured cells available.  These subjects will undergo a new T-cell 
collection for manufacturing, and will receive cells split dosing fashion (10% on Day 1; 
30% on Day 2; 60% on Day 3). 
 
The target dose for this cohort is 1-5 x 108 CART19 cells.  All prerequisites for eligibility to receive 
CART19 outlined in Section 5.2 must be met prior to retreatment.  The study drug will be prepared 
and administered per the guidelines set forth in Section 5.  All required pre-medications, 
prophylaxis monitoring guidelines from the initial infusion will apply for retreatment.  
 
Subjects will be required to undergo the same baseline assessments outlined in Section 6.2.  If 
there is an existing sufficient CART19 dose, leukapheresis screening to assess venous access will 
not be performed.  However, if there is either an insufficient manufactured dose or starting material 
available in the CVPF, the subject will be asked to undergo apheresis to collect additional cells to 
manufacturer a sufficient dose for retreatment (per Section 6.4). 
 
All other pre-infusion, on study and follow-up procedures will be completed as outlined in Sections 
6.5 to 6.12 above and the Retreatment Cohort Schedule of Events in Appendix 2, including the 
administration of cytoreductive chemotherapy if clinically indicated.   
 
7 
Response Assessments 
Tumor response assessments will be done according to standard care and practices at baseline 
(within 4 weeks prior to CART-19 infusion), limited assessment after chemotherapy, at day 28 
following the infusion, 3, 6, 9, and 12 months after the first CART-19 cell infusions or until the 
patient requires alternative therapy for their disease.  Tumor assessments will depend on the 
patients underlying disease as follows:  
 
Response Definition After Treatment for CLL 
Parameter 
 
Complete response 
Partial response 
Progressive disease 
Group A 
 
Lymphadenopathy  
 
None > 1.5 cm  
  
Decrease ≥ 50%  
 
Increase ≥ 50% 
 
 
 
 

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Parameter 
 
Complete response 
Partial response 
Progressive disease 
Hepatomegaly 
None by CT 
If enlarged prior to 
therapy, decrease ≥ 
50% by CT 
Increase ≥ 50% 
 
 
Splenomegaly 
 
None by CT 
 
If enlarged prior to 
therapy, decrease ≥ 
50% by CT 
 
Increase ≥ 50% 
 
 
Marrow 
 
 
Normocellular, < 30% 
lymphocytes, no B-
lymphoid nodules, 
Hypocellular marrow 
defines CR with 
incomplete marrow 
recover (Cri) 
50% reduction in 
marrow infiltrate, or 
B-lymphoid nodules 
N/A 
Blood lymphocytes 
< 4000/µ/L 
Decrease ≥ 50% 
over baseline 
Increase ≥ 50% over 
baseline 
Group B 
 
Platelet count without 
growth factors or 
platelet transfusions 
 
>100,000/µ/L 
 
>100,000/µ/L or 
increase ≥ 50% over 
baseline  
 
Decrease ≥ 50% 
over baseline 
secondary to CLL 
Hemoglobin without 
transfusions or 
growth factors 
 
> 11.0 g/dL 
> 11.0 g/dL or 
increase ≥ 50% over 
baseline  
Decrease of > 2 
g/dL from baseline 
secondary to CLL 
Neutrophils without 
growth factors 
> 1500/µ/L 
> 1500/µ/L or > 
50% improvement 
over baseline 
N/A 
The above response criteria are consistent with NCCN Guidelines Version 2.2012 CLL/SLL, 
which is based on the 2008 International Workshop Group on CLL (IWCLL) revisions of the 
original guidelines for evaluating disease response released in 1996 by the National Cancer 
Institute Working Group (NCI/WG)84.  
 
Group A criteria define the tumor load.   Group B criteria define the function of the 
hematopoietic system (or marrow). 
 
Complete response (CR):  all of the criteria must be met, and patients have to lack disease-
related constitutional symptoms attributable to CLL (ie. ≥10 percent unintentional weight loss 
within the previous six months, fatigue that interferes with work or usual activities, fevers greater 
than 100.5ºF (>38ºC) for ≥2 weeks, or night sweats for >1 month). 
 
Complete response with incomplete marrow recovery (CRi): CR in the setting of hypocellular 
marrow. 
 
Partial response (PR): at least two of the criteria of group A plus one of the criteria of group B 
must be met.   

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Partial response with incomplete marrow recovery (PRi):  PR in the setting of hypocellular 
marrow. 
 
Stable disease (SD):  Patients who do not meet the criteria for a complete remission, partial 
remission, or progressive disease, have stable disease. Stable disease is therapeutically equivalent 
to a nonresponse.  
 
Progressive disease (PD): appearance of any new lesions; at least one of the above criteria of 
group A or group B have been met. Includes Richter's transformation (the development of an 
aggressive large-cell lymphoma) as documented by biopsy. Also, cytopenias that occur at least 
three months after the completion of therapy and are accompanied by an infiltrate of clonal CLL 
cells on bone marrow biopsy can be used to define disease progression. Isolated progressive 
lymphocytosis in the setting of reduced lymph node size or organomegaly of improvement in 
hemoglobin/platelets will not be considered PD. 
 
Calculating Tumor Burden: Tumor burden at baseline is calculated as the sum of the volume of 
bone marrow involved with CLL, the peripheral blood CLL burden and the volume of tumor 
masses in spleen and nodal masses as determined in volumetric CT scans. Tumor burden 
reduction is calculated from the tumor assessments done post therapy, and the best overall 
response calculated by the difference from the baseline tumor burden and the residual tumor 
burden after therapy. The estimates of total CLL mass are then converted to total CLL cell 
number using 1 kg = 10 12 cells100. 
8 
Statistical Considerations 
8.1 
Design Overview 
This is a single center, randomized, parallel group study to evaluate two dose levels of CART-19 
cells. This trial will be conducted in two stages.   
 
Stage 1 
In the first stage, subjects will be randomized into one of the two dose levels (ARM 1:  1-5x108 
CART-19 transduced cells vs. ARM 2: 1-5x107 CART-19 transduced cells) with 1:1 
randomization ratio. Approximately twelve (n=12) evaluable subjects will be enrolled into each 
arm.  Safety, tolerability, and rate of complete response by 3 month will be evaluated to determine 
a dose cohort for expansion based on the rule described below.  
 
After the end of the first stage, the lower dose level associated with 3-month CR rate (including 
CRi) of ≥30% and manageable toxicity profile will be expanded to the second stage, unless the 
higher dose level has a 16.7% higher CR rate, or equivalently having ≥2 patients with CR or CRi 
within 3 month out of 12 evaluable subjects, compared to the low dose level and has a comparable 
toxicity profile, then the higher dose level will be expanded.  If none of the dose levels have 
reached an observed 3-month CR rate of ≥30%, the study may be stopped. 
 
Stage 2 
The Stage 1 analysis performed in November 2014 led to choosing Arm 1 for expansion in Stage 
2. Therefore, the Stage 2 dose will be 1-5x108 transduced CART-19 cells. The dose of 1-5 x 108 

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Complete responder (response rate) 
Exact 90% CI (%) 
8 (40%) 
21.7 – 60.6 
7 (35%) 
17.7 – 55.8 
6 (30%) 
14.0 – 50.8 
5 (20%) 
10.4 - 45.6 
Note: the 90% confidence intervals in above table were not adjusted for multiple stages. 
8.3 
Analysis Population(s) 
Evaluable population are defined as all eligible patients who were able to receive the viable T 
cell infusion(s) at the intended dose level and have completed at least 3 months of follow-up after 
the infusion or have discontinued early due to disease progression, initiation of a new cancer 
therapy, or death. Patients receiving a lower than planned dose level due to manufacturing 
limitations will not be considered evaluable.  
 
Full analysis set (FAS) population is defined as all patients who are randomized to each treatment 
arm. In addition, all patients enrolled in the 2nd stage will be included. If an additional arm is 
studied, the FAS will be defined as all patients enrolled at the dose. Sensitivity analysis for efficacy 
endpoints will be performed for FAS population. Patients will be classified by the intended 
treatment arm. Sensitivity analysis for efficacy endpoints will also be performed according to the 
actual dose level received. 
 
Safety population is defined as all patients who were able to receive at least one T cell infusion. 
The safety analyses will be conducted by the actual dose received.  
 
Definitions relevant to the Analysis Sets: 
1) Manufacturing failure – Any patient who has manufactured CART-19 cells that do not 
meet the manufacturing release criteria or the minimum protocol-specified dose for their 
respective stage or randomized arm (as applicable).   
2) Primary efficacy evaluable patient – Any patient who is infused with CART-19 cells at 
the protocol-specified dose for their protocol stage and assigned randomized arm (as 
applicable) and completed the response assessments for the primary efficacy endpoint as 
planned by the protocol. Efficacy evaluable patients also include those with disease 
progression or death prior to the primary efficacy endpoint response assessment. 
3) Primary efficacy non-evaluable patient – Any patient who is infused with CART-19 
cells at a less than the protocol-specified dose. These patients are considered also counted 
as manufacturing failures. 
8.4 
Primary objective 
The primary objective is to assess the 3-month CR rate, which is defined as the proportion of 
patients, whose best overall response by the end of the first 3 months after the first CART-19 
infusion after randomization, is CR among all evaluable patients.  Stage 1 and Stage 2 patients will 
be evaluated independently. The 3-month CR rate will be summarized along with the Exact 
Clopper-Pearson 90% confidence intervals for each dose in evaluable population. As a sensitivity 
analysis, the 3-month CR rate and the respective 90% confidence interval will also be summarized 
for FAS population and safety population by stage, as described above. 

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8.5 
Secondary Efficacy Objectives 
The secondary efficacy objective in this study is to assess each dose with respect to the overall 
response rate, progression free survival (PFS), overall survival, time to response, duration of 
response, and time to alternative therapy. 
If a patient has not had an event of interest at the date of the analysis cut-off or when the patient 
received any further anti-neoplastic therapy, PFS will be censored at the time of the last adequate 
assessment before the cut-off date or the anti-neoplastic therapy start date. 
 
Best overall response rate is defined as the proportion of patients with best overall response either 
complete response [CR, including CRi], or partial response [PR, including PRi].   
 
Best overall response rate will be summarized along with the Clopper-Pearson 90% confidence 
intervals for each dose in evaluable population.  The best overall response rate and its exact 
confidence interval will also be summarized for FAS population and safety population. 
 
Progression free survival (PFS) is defined as the time from the date of the first CART-19 infusion 
to the date of first documented disease progression/relapse or death. If a patient has not had an 
event at the date of the analysis cut-off or when the patient received any further anti-neoplastic 
therapy, PFS will be censored at the time of the last adequate assessment before the cut-off date or 
the anti-neoplastic therapy start date. 
 
Listing of PFS for all patients in each dose will be provided. The distribution function of PFS   
estimated using the Kaplan-Meier method and the median PFS along with 90% confidence 
intervals will be presented for two treatment groups if appropriate.   
 
Overall survival (OS) is defined as the time from date of the first CART-19 infusion to the date of 
death from any cause.  If a patient is not known to have died at the date of analysis cut-off, OS 
will be censored at the last date of contact. 
 
Listing of OS for all patients in each dose will be provided. The distribution function of OS   
estimated using the Kaplan-Meier method and the median OS along with 90% confidence intervals 
will be presented for two treatment groups if appropriate.   
 
Time to response is defined as the time from the date of the first CART-19 infusion to the date 
when the response criteria of PR/PRi/CR/CRi is first met for patients with the best overall response 
of PR/PRi or CR/CRi.   
 
Time to response (CR/CRi or PR/PRi) will be summarized with descriptive statistics for evaluable 
patients in each dose and will also be summarized for FAS population and safety population. 
 
Duration of response is defined as the time from the date when the response criteria of 
PR/PRi/CR/CRi is first met to the date of progression/relapse or death. If a patient has not had an 
event at the date of the analysis cut-off or when the patient received any further anti-neoplastic 
therapy, duration of response will be censored at the time of the last adequate assessment before 
the cut-off date or the new anti-neoplastic therapy start date. A listing of duration of response will 
be provided for all responders.  

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Time to alternative therapy is defined as the time from the date of the first CART-19 infusion to 
the date of alternative therapy. Alternative therapy is defined as any therapy for treatment of CLL 
excluding palliative care. For patients who did not receive any alternative therapy, their time to 
alternative therapy will be censored at the date of analysis cut-off. 
 
A listing of duration of response will be provided for all evaluable population. The distribution 
function of time to alternative therapy estimated using the Kaplan-Meier method and the median 
time to alternative therapy along with 90% confidence intervals will be presented for each dose 
only if appropriate.   
8.6 
Safety objectives 
For all safety analyses, the safety population will be used.  All listings and tables will be presented 
by dose group. 
 
The assessment of safety will be based mainly on the frequency of adverse events.  Other safety 
data will be considered as appropriate.  Vitals and ECGs will be collected as clinically needed. All 
safety data will be listed. 
 
The safety summary tables will include only assessments collected no later than 30 days after study 
treatment discontinuation. 
Adverse Events 
All adverse events (AE) starting on or after study day 1 (i.e. on or after the day of the first infusion) 
and starting no later than 1 year after the end of treatment during the study will be summarized.  
All AEs will be listed.  AEs starting prior to study day 1 and AEs starting later than 30 days after 
the last treatment date will be flagged in the listings. 
 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class, preferred term and maximum toxicity grade (based on CTCAE 
v4.03).  A patient with multiple CTC grades for an AE will be summarized under the maximum 
CTC grade recorded for the event.  The frequency of CTC grade 3 and 4 AEs will be summarized 
separately.  In addition, AEs related to study drug will be presented by primary system organ class, 
preferred term, and maximum CTC grade.  Serious adverse events (SAEs) will be summarized 
separately. 
8.7 
Manufacturing (Dose) Feasibility 
The frequency of manufacture failure will be calculated. Associations between patient 
characteristics and the likelihood of manufacture failure will be evaluated. 
8.8 
Correlative Research Secondary and Exploratory Objectives 
Descriptive statistics will be provided for the correlative endpoints. Correlative secondary 
objectives will focus on the evaluation and quantification of the expansion, homing, persistence, 
phenotype, and functional properties of the infused CART19 cells as assessed by flow cytometry 
and QPCR endpoints. In addition, an assessment of the patient humoral or cellular immune 
response to their CART 19 cells will also be a key correlative secondary objective that informs 

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both efficacy and safety endpoints. These data will help describe the pharmacokinetics of infused 
CART 19 cells and highlight the incidence of CART 19 host immune responses.  
 
Exploratory objectives focus on assessment of serum cytokine levels pre and post CART 19 
infusion(s). In addition, the incidence of CD19 escape mutants will be determined in blood, bone 
marrow and lymph node aspirates by assessing CD19 expression, as compared to base line tumor 
samples. These data will help inform on CART 19 engraftment, cytokine side-effects, and optimal 
patient safety management strategies.  
 
 More detailed characterization of both pre-infusion CART-19 product and the in vivo persisting 
CART-19 cells may be carried out on a per subject basis for research purposes. Specifically, the T 
cell subsets of CART-19 T cells and the relative T cell subset ratio will be determined by flow 
cytometry. In addition, the pre-infusion product and in vivo persisting CART 19 cells may be 
further characterized by transcriptional profiling, flow cytometry-based phenotypic and functional 
assays. These data will help to inform potential predictive markers of CART-19 efficacy but are 
not formal study objectives  
8.9 
Retreatment Cohort Analysis  
Safety and efficacy endpoints for those subjects participating in the retreatment cohort will include 
frequency and severity of adverse events, overall response, time to response, duration of response 
and time to alternative therapy, expansion and persistence of CART19 cells. Definition and 
statistical methods used for those endpoints will be the same as described in Sections 8.4 and 8.5 
but with the start of the observation time as time of the re-infusion. Data analyses for the 
retreatment cohort will be exploratory and performed separately from the analyses for the initial 
infused subjects. In particular, we will use statistical methods appropriate for paired data (e.g., 
paired t-test, McNemar test) to compare endpoints from the same subject between the first and re-
infusion.  Results from these analyses will be used to generate hypotheses for future studies.  
8.10 Patient Reported Outcomes (PRO) 
EORTC QLQ-C30 and CLL16 raw summary scores will be generated by adding up the item 
responses on the questions which make up each domain in accordance with the respective 
scoring manual provided by the developers. Raw scores will be summarized using means and 
medians at each assessment time point and for each domain for each treatment group. Patients 
will be asked to complete the questionnaire at baseline, chemotherapy week, end of treatment 
(day 28), 3, 6, 9, and 12 months after treatment. 
 
EORTC QLQ-C30 
The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire (QLQ-C30) contains 30 questions that incorporates nine multi-item scales: five 
functional scales (physical, role, cognitive, emotional, and social); three symptom scales (fatigue, 
pain, and nausea and vomiting); and a global health and quality-of-life scale. Several single-item 
symptom measures are also included (dyspnea, insomnia, appetite, constipation, diarrhea, and 
financial impact). [Aaronson NK, et al. J Natl Cancer Inst 85: 365-376, 1993]  
 
Chronic Lymphocytic Leukaemia (QLQ- CLL16) 

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This module is designed for patients with stage 0 to stage 4 chronic lymphocytic leukaemia. It is 
comprised of sixteen questions that address five domains of HRQoL important in CLL. There are 
three multi item scales on: - Fatigue (2 items), treatment side effects and disease symptoms 
8  items), infection (4 items) and two single item scales on social activities and future health 
worries. 
 
It was developed using the EORTC recommended guidelines, with additional patient interviews 
based on a grounded theory approach. Pilot testing was performed in England and Germany. The 
module development committee has approved the first three phases of development and a paper 
describing this process is awaiting publication. Phase four international field-testing has yet to be 
agreed 
 
9 
Safety and Adverse Events 
Safety will be assessed by monitoring and recording potential adverse effects of the treatment 
using the Common Toxicity Criteria (CTCAE) version 4.03 at each study visit. Patients will be 
monitored by medical histories, physical examinations, and blood studies to detect potential 
toxicities from the treatment.  If CTCAE grading does not exist for an adverse event, the severity 
of mild, moderate, severe, and life-threatening, corresponding to Grades 1-4, will be used. Subjects 
will be monitored by medical histories, physical examinations, and blood studies to detect potential 
toxicities from the treatment. 
 
To the extent possible, adverse events should be recorded as a diagnosis and symptoms used to 
make the diagnosis recorded within the diagnosis event.  Do not list symptoms if a diagnosis can 
be assigned.  
9.1 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
 Unexpected in nature, severity, or frequency  (i.e. not described in study-related documents 
such as the IRB-approved protocol or consent form, the investigators brochure, etc) 
 Related or possibly related to participation in the research (i.e. possibly related means there 
is a reasonable possibility that the incident experience, or outcome may have been caused 
by the procedures involved in the research) 
 Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm). 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study that occur after the patient has signed the informed consent.  
Intercurrent illnesses or injuries should be regarded as adverse events.  Abnormal laboratory values 
or test results of diagnostic procedures occurring after the informed consent are considered to be 
adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 

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 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
Suspected Adverse Reaction (21 CFR 312.32(a)) 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, "reasonable 
possibility" means there is evidence to suggest a causal relationship between the drug and the 
adverse event. Suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
 
Unexpected Suspected Adverse Reaction (21 CFR 312.32(a))  
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application, as amended. 
For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the investigator brochure referred only to elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of 
greater specificity) if the investigator brochure listed only cerebral vascular accidents. 
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation. 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay, unless hospitalization is for: 
o Routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition, such as preplanned study visits and preplanned 
hospitalizations for study procedures or treatment administration 
o Elective or pre-planned treatment for a pre-existing condition that is unrelated 
to the indication under study and has not worsened since signing the informed 
consent 
o Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
o Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of 
major clinical significance.   They may jeopardize the subject, and may require intervention to 

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prevent one of the other serious outcomes noted above.  For example, drug overdose or abuse, a 
seizure that did not result in patient hospitalization or intensive treatment of bronchospasm in an 
emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.  
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period 
from the time the patient informed consent has been obtained to the end of the study treatment 
follow-up.  For this study, adverse events will be collected until the subject is off study or until the 
end of study visit at 12 months. Events occurring during chemotherapy but prior to CART-19 
infusion will be excluded from the adverse event reporting period. Patients experiencing toxicity 
from their preceding cytoreductive chemotherapy will have their schedule delayed until these 
toxicities have resolved.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the condition 
worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition 
on the medical history eCRF.  During the course of the study if any pre-existing conditions worsen 
or require additional intervention than these should be recorded as adverse events and indicated as 
worsening events.  At the end of the study, any new clinically significant findings/abnormalities 
that meet the definition of an adverse event must also be recorded and documented as an adverse 
event.  
 
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are resolved, 
the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled 
visit, the investigator should instruct each subject to report any subsequent event(s) that the subject, 
or the subject’s personal physician, believes might reasonably be related to participation in this 
study.  The investigator should notify the regulatory sponsor of any death or adverse event 
occurring at any time after a subject has discontinued or terminated study participation that may 
reasonably be related to this study.  The sponsor should also be notified if the investigator should 
become aware of the development of cancer or of a congenital anomaly in a subsequently 
conceived offspring of a subject that has participated in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the 
following conditions is met:  
 The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 

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 The abnormality suggests a disease and/or organ toxicity 
 The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
 
Laboratory abnormalities that meet the criteria for Adverse Events should be followed until they 
have returned to normal or an adequate explanation of the abnormality is found. When an abnormal 
laboratory or test result corresponds to a sign/symptom of an already reported adverse event, it is 
not necessary to separately record the lab/test result as an additional event. Laboratory 
abnormalities, that do not meet the definition of an adverse event, should not be reported as adverse 
events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically indicate a SAE unless 
it meets the definition of serious as defined below and/or as per investigator’s discretion. A dose 
hold or medication for the lab abnormality may be required by the protocol and is still, by 
definition, an adverse event. 
 
Laboratory abnormalities due to underlying disease and chemotherapy regimen are expected and 
will not be reported as adverse events (e.g. abnormal hematology values, mucositis, etc.). 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in this 
protocol.  Any condition responsible for surgery should be documented as an adverse event if the 
condition meets the criteria for and adverse event. As was noted above, events related to the 
cytotoxic chemotherapy will be excluded from adverse event reporting.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  Surgery should not be reported as an outcome 
of an adverse event if the purpose of the surgery was planned, elective or diagnostic and 
the outcome was uneventful. 
 Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study. 
 Hospitalization or prolonged hospitalization for therapy of the target disease of the 
study, unless it is a worsening or increase in frequency of hospital admissions as judged 
by the clinical investigator. 
9.2 
Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by non-
directive questioning and, as appropriate, by examination. Adverse events also may be detected 
when they are volunteered by the subject during the screening process or between visits, or through 
physical examination, laboratory test, or other assessments. Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse event 
module of the case report form (CRF).  All clearly related signs, symptoms, and abnormal 
diagnostic procedures results should recorded in the source document, though should be grouped 
under one diagnosis.  To the extent possible, adverse events should be recorded as a diagnosis and 

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symptoms used to make the diagnosis recorded within the diagnosis event.  Do not list symptoms 
if a diagnosis can be assigned. 
 
All adverse events occurring during the adverse event reporting period (defined in Section 9.1 
above) must be collected, however only the highest grade of the AE will be recorded in the CRF 
if there is a change in grade.  Conditions that were already present at the time of informed consent 
should be recorded in the Medical History CRF.  Any condition listed in a subjects’ Medical 
History for which the severity of the grade increases at the time of, or post CART19 infusion, 
should be captured as an adverse event.  
 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. When a clear 
diagnosis cannot be identified, each sign or symptom should be reported as a separate Adverse 
Event. The clinical course of each event should be followed until resolution, stabilization, or until 
it has been determined that the study treatment or participation is not the cause.   
 
As far as possible, each adverse event should be evaluated to determine: 
1. The severity grade (CTCAE Grade 1-5)- only the highest grade of the AE will be 
recorded in the CRF if there is a change in grade 
2. Its duration (start and end dates) 
3. Its relationship to the study treatment (Is there a reasonable possibility that the AE is 
related to the study treatment: No (unrelated) or Yes).  If yes- is the event possibly, 
probably or definitely related to the investigational treatment (CART-19 T-cells) or the 
non-investigational treatment (i.e. lymphodepleting chemotherapy)?  
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
5. Whether medication or therapy taken (i.e. no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
6. Whether it is serious as defined as in Section 9.1. 
 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.  Once an adverse event 
is detected, it should be followed until its resolution or until it is judged to be permanent, and 
assessment should be made at each visit (or more frequently, if necessary) of any changes in 
severity, the suspected relationship to the study treatment, the interventions required to treat it, and 
the outcome.  Progression of malignancy (including fatal outcomes), documented appropriately in 
the medical records, should not be reported as a serious adverse event. 
 
Adverse events that occur concurrently with the progression of malignancy but that are not related 
to disease progression (i.e. deep vein thrombosis or hemoptysis) will be reported as an adverse 
event as described above.   
 
Serious adverse events that are still ongoing at the end of the adverse event reporting period must 
be followed to determine the final outcome.  Any serious adverse event that occurs after the 
adverse event reporting period and is considered to be possibly related to the study treatment or 
study participation, should be recorded and reported immediately. 

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Modification of CTC Grading scale for Cytokine Release Syndrome (CRS) 
The current CTCAE grading system developed to capture cytokine release syndrome (CRS) relates 
to acute infusional toxicity, within 24 hours. CRS due to CART-19 often occurs 1 or more days 
post-infusion. A proposed CTC grading system specifically to capture toxicity for protocols using 
CART-19 cell is described below (Table 9-1) and should be used to evaluate CRS events.  
 
Recipients of CART-19 cells may develop a CRS. Data from a small number of patients shows 
marked elevations in IL6, IFN-g, and less intensely TNF. Elevations in clinically available markers 
of inflammation including ferritin and CRP have also been observed to correlate with the clinical 
CRS syndrome. 
 
Symptoms usually occur 1-14 days after cell infusion, but the syndrome is not defined by the 
timing of the reaction. Patients developing any symptoms attributable by the investigator as related 
to cytokine release should be reported has having a CRS. Symptoms may include.  
 High fevers 
 Rigors 
 Sweating 
 Nausea 
 Vomiting  
 Anorexia 
 Fatigue 
 Headache 
 Myalgia/arthralgia 
 Hypotension 
 Dyspnea  
 Tachypnea 
 Hypoxia 
 Altered mental status 
 End organ dysfunction 
 Signs of macrophage activation syndrome including hemophagocytosis and 
hemolysis 
For the purposes of reporting and grading on clinical trials using CART-19 cells, the following 
grading system is proposed. The start date of CRS is a retrospective assessment of the date of 
onset of persistent fevers and/or myalgia consistent with CRS and not explained by other 
events (i.e. sepsis). The stop date of CRS is defined as the date when the patient has been 
afebrile for 24 hours and off vasopressors for 24 hours. 
Table 9-1: Amended CTCAE v4 criteria for CRS related to CART-19 infusion 
Modified CRS Toxicity Grading System 
1 
2 
3 
4 
5 
Mild 
reaction: 
Treated with 
supportive 
Moderate reaction 
requiring IV fluids 
or parenteral 
nutrition; some 
More severe reaction: 
Hospitalization required 
for management of 
symptoms related to 
Life-threatening 
complications 
such as 
hypotension 
Death 

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Modified CRS Toxicity Grading System 
1 
2 
3 
4 
5 
care  such as 
anti-pyretics, 
anti-emetics 
signs of organ 
dysfunction (i.e. 
grade 2 creatinine 
or grade 3 liver 
function tests 
([LFTs] related to 
CRS and not 
attributable to any 
other condition).  
Hospitalization for 
management of 
CRS related 
symptoms 
including fevers 
with associated 
neutropenia.  
organ dysfunction 
including grade 4 LFTs 
or grade 3 creatinine 
related to CRS and not 
attributable to any other 
conditions; this 
excludes management 
of fever or myalgias. 
Includes hypotension 
treated with IVFs* or 
low-dose pressors, 
coagulopathy requiring 
fresh frozen plasma 
(FFP) or 
cryoprecipitate, and 
hypoxia requiring 
supplemental oxygen 
(nasal cannula oxygen, 
high flow oxygen, 
Continuous Positive 
Airway Pressure 
[CPAP] or Bilateral 
Positive Airway 
Pressure [BiPAP].).  
Patients admitted for 
management of 
suspected infection due 
to fevers and/or 
neutropenia may have 
grade 2 CRS. 
requiring high-
dose pressors 
(see Table 9-2) 
or hypoxia 
requiring 
mechanical  
ventilation.   
*CRS Grade 3 language clarification: “hypotension treated with intravenous fluids” is further defined as 
hypotension requiring multiple fluid boluses for blood pressure support. 
 
Table 9-2 
High Dose Vasopressor Use 
Definition of “High-Dose” Vasopressors 
Vasopressor 
Dose for ≥ 3 hours 
Norepinephrine monotherapy 
≥ 20 mcg/kg/min 
Dopamine monotherapy 
≥ 10 mcg/kg/min 
Phenylephrine monotherapy 
≥ 200mcg/min 
Epinephrine monotherapy 
≥ 10 mcg/min 

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Definition of “High-Dose” Vasopressors 
If on vasopressin 
High-dose if vaso +  Norepinephrine Equivalent (NE) of >10 
mcg/min (using Vasopressin and Septic Shock Trial 
(VASST) formula) 
If on combination vasopressors 
(not vasopressin) 
Norepinephrine equivalent of ≥ 20 mcg/min (using VASST 
formula) 
Vasopressin and Septic Shock Trial (VASST) Equivalent Equation: 
 
Norepinephrine equivalent dose = [norepinephrine (mcg/min)] + [dopamine (mcg/kg/min) ÷ 2] + [epinephrine 
(mcg/min)] + [phenylephrine (mcg/min) ÷10]  
 
Criteria from Russell et al, 200893. 
9.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
Investigators and the regulatory sponsor must conform to the adverse event reporting timelines, 
formats and requirements of the various entities to which they are responsible, but at a minimum 
those events that must be reported are those that are: 
 related to study participation, 
 unexpected, and  
 serious or involve risks to subjects or others  
(see definitions, section 9.1) 
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring during the 
adverse event reporting period defined in Section 9.1 above must be reported to the sponsor within 
24 hours of learning of its occurrence.  If a subject is taken off study within 30 days of the T-cell 
infusion, all SAEs experienced within 30 days after the T-cell infusion should be reported to the 
sponsor.  SAEs experienced after this 30 days period should only be reported to the sponsor if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode when follow-up information is received. An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one should be reported 
separately as a new event. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and reported per section 9.3.4 below. 
9.3.1 Sponsor Notification by Investigator 
Any study-related unanticipated problem posing risk of harm to subjects or others, and any type 
of serious adverse event, must be reported to the sponsor by email within 24 hours of knowledge 
of the event.   
 
Report serious adverse events by email to: 
 
Attention: Clinical Safety Manager or designee 
Translational Research Program 
University of Pennsylvania 
Fax:  
 
Email: 
 

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At the time of the initial notification, the following information should be provided: 
 Study identifier 
 Subject number 
 A description of the event 
 Date of onset 
 Current status 
 Whether study treatment was 
discontinued 
 The reason the event is classified 
as serious 
 Investigator assessment of the 
association between the event and 
study treatment 
 
Within the following 3 business days, the investigator must provide further information on the 
serious adverse event in the form of a written narrative.  This should include a copy of the 
completed SAE form, and any other diagnostic information that will assist the understanding of 
the event.  The Investigator will keep a copy of this SAE Form on file at the study site.  Significant 
new information on ongoing serious adverse events should be provided promptly to the regulatory 
sponsor. 
 
Follow-up information on SAEs should be reported when received, on a copy of the original SAE 
Form, and should include both the follow-up number and report date.  The follow-up information 
should describe whether the event has resolved or continues, if and how it was treated, and whether 
the patient continued or withdrew from study participation.   
9.3.2 Investigator reporting: notifying the UPenn IRBs 
This section describes the requirements for safety reporting by investigators who are Penn faculty, 
affiliated with a Penn research site, or otherwise responsible for safety reporting to the IRB. The 
IRB requires expedited reporting of those events related to study participation that are unforeseen 
and indicate that participants or others are at increased risk of harm.  The IRB will not acknowledge 
safety reports or bulk adverse event submissions that do not meet the criteria outlined below.  The 
IRB requires researchers to submit reports of the following problems within 10 working days from 
the time the investigator becomes aware of the event: 
 
Any adverse event (regardless of whether the event is serious or non-serious, on-site or off-site) 
that occurs any time during or after the research study, which in the opinion of the principal 
investigator is: 
Unexpected (An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research 
protocol, any applicable investigator brochure, and the current IRB-approved informed 
consent document and other relevant sources of information, such as product labeling 
and package inserts.) 
AND 
Related to the research procedures (An event is “related to the research procedures” if in 
the opinion of the principal investigator or sponsor, the event was more likely than not 
to be caused by the research procedures.) 
 
Reporting Process 

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Unanticipated problems posing risks to subjects or others as noted above will be reported to the 
IRB using the form: “Unanticipated Problems Posing Risks to Subjects or Others Including 
Reportable Adverse Events” or as a written report of the event (including a description of the event 
with information regarding its fulfillment of the above criteria, follow-up/resolution and need for 
revision to consent form and/or other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s study file. 
 
Reporting Deaths:  more rapid reporting requirements 
Concerning deaths that occur during the course of a research study, the following describes the 
more rapid reporting requirement of the Penn IRB for specific situations: 
 Report the event within 72 hours when the death is unforeseen (unexpected) and 
indicates participants or others are at increased risk of harm 
 
For reportable deaths, the initial submission to the IRB may be made by contacting the IRB 
Director or Associate Director. The AE/Unanticipated Problem Form is required as a follow up to 
the initial submission. 
 
Other Reportable events: 
For clinical drug trials, the following events are also reportable to the IRB: 
 Any adverse experience that, even without detailed analysis, represents a serious 
unexpected adverse event that is rare in the absence of drug exposure (such as 
agranulocytosis, hepatic necrosis, Stevens-Johnson syndrome) 
 Any adverse event that would cause the sponsor to modify the investigators brochure, 
protocol or informed consent form, or would prompt other action by the IRB to assure 
protection of human subjects 
 Information that indicates a change to the risks or potential benefits of the research, in 
terms of severity or frequency. For example:  
– An interim analysis indicates that participants have a lower rate of response to 
treatment than initially expected 
– Safety monitoring indicates that a particular side effect is more severe, or more 
frequent than initially expected 
– A paper is published from another study that shows that an arm of your research 
study is of no therapeutic value 
 Change in FDA safety labeling or withdrawal from marketing of a drug, device, or 
biologic used in a research protocol 
 Breach of confidentiality 
 Change to the protocol taken without prior IRB review to eliminate apparent immediate 
hazard to a research participant 
 Incarceration of a participant when the research was not previously approved under 
Subpart C and the investigator believes it is in the best interest of the subject to remain 
on the study 

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 Complaint of a participant when the complaint indicates unexpected risks or the 
complaint cannot be resolved by the research team 
 Protocol violation (meaning an accidental or unintentional deviation from the IRB 
approved protocol) that in the opinion of the investigator placed one or more participants 
at increased risk, or affects the rights or welfare of subjects 
9.3.3 Reporting obligations to the DSMC of the Abramson Cancer Center 
The Abramson Cancer Center (ACC) has developed a detailed data safety and monitoring 
program.  The Clinical Trials Scientific Review and Monitoring Committee (CTSRMC) serves as 
a rigorous scientific peer review mechanism for all cancer protocols conducted within the 
University of Pennsylvania. The CTSRMC’s focus is the scientific merit, priorities, and progress 
of Cancer Center clinical research. The Data Safety and Monitoring Committee (DSMC) is 
responsible for the overall quality control and quality assurance of all cancer related studies 
conducted within the University, including data quality and subject safety monitoring and auditing. 
The guidelines governing both committees have been adapted from the NCI/NIH policies.  
 
All events that meet the DSMC definition of reportable AE’s must be promptly entered into Velos.   
 
The DSMC requires AE/SAE submission as follows:  
 
On-Site subjects (this includes any subjects enrolled at other sites on an in-house study) 
 
 All grade 3 or higher events within 5 business days of knowledge of the adverse event.  
Grade 3 and 4 events that are typical in the disease population, with the exception of 
those that could be symptoms/early indicators of any of the toxicities defined in the 
Toxicity Management section of the protocol, signs/symptoms of an allergic response, 
severe hypotensive crisis or any other reaction to the infusion, do not require DSMC 
reporting. It is important to note that these events must be reported in the absence of a 
diagnosis of a specific toxicity. These events must be reported via e-mail to the 
assigned DOCM study monitor.   
 All unexpected deaths within 24 hours of knowledge 
 All others deaths within 30 days of knowledge (including death of subjects off-study) 
 In the event of a grade 4 or 5 unexpected event regardless of attribution, the DSMC 
and ACC leadership require investigators and the study team to meet or have a 
teleconference within 24 business hours of the event to have a thorough discussion of 
the event. These types of events will not be vetted via e-mail. The sponsor should not 
be involved in discussions about attribution. The PI and Research Coordinator will 
schedule a meeting with the study team to discuss the grade 4 or 5 unexpected event. 
Meeting minutes capturing the review of any ongoing investigations of the grade 4 or 
5 unexpected event, including next steps in the management of the subject and any 
proposed changes to the protocol will be forwarded to the DSMC 

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9.3.4 IBC Notification by Investigator 
Notify the IBC prior to reporting any serious adverse event that meets expedited reporting 
requirements to the FDA and RAC. You must also submit a copy of your FDA cover letter and 
report summary to the IBC should a serious adverse event occur. 
9.3.5 FDA Notification by Regulatory Sponsor 
The regulatory sponsor is required to report certain study events in an expedited fashion to the 
FDA. These written notifications of adverse events are referred to as IND safety reports. The 
regulatory sponsor must report an IND safety reports as described in:   
 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM227351.pdf 
 
The following describes the safety reporting requirements by timeline for reporting and associated 
type of event: 
 Within 7 Calendar Days 
Any study event that is: 
o Unexpected fatal or life-threatening suspected adverse reaction.   
o Expected and unexpected Grade 3 or higher events of cytokine release syndrome 
per the modified CRS grading scale in Table 9-1 
o All fatal events occurring within 30 days of T-cell infusion, regardless of attribution 
and expectedness 
 Within 15 Calendar Days 
Any study event that is: 
o unexpected 
o Suspected adverse reaction that is serious, but not fatal or life-threatening 
-or- 
o a previous adverse event that was not initially deemed reportable but is later found 
to fit the criteria for reporting (reporting within 15 calendar days from when event 
was deemed reportable). 
Any finding from tests in laboratory animals that: 
– suggest a significant risk for human subjects including reports of mutagenicity, 
teratogenicity, or carcinogenicity or reports of significant organ toxicity at or near the 
expected human exposure. 
Increase in rate of occurrence of serious suspected adverse reactions: 
o any clinically important increase in the rate of a serious suspected adverse 
reaction over that listed in the protocol or investigator brochure. 

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Additional Reporting Requirements 
Sponsors are also required to review all adverse events to make a causality determination on the 
basis of information from investigators and report these findings to the FDA in accordance with 
21 CFR 312.32. 
 
If the adverse event does not meet expedited reporting requirements, the regulatory sponsor will 
report the SAE as in the IND Annual Report. 
9.4 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must be 
reported to protocol sponsor within 24 hours of learning of its occurrence. The pregnancy should 
be followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the investigator 
to the protocol sponsor Pregnancy follow-up should be recorded on the same form and should 
include an assessment of the possible relationship to the study drug for any pregnancy outcome. 
Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes should 
be obtained from the mother. 
9.5 
Toxicity Management, Stopping Rules and Study Termination 
It is expected that AEs will occur frequently in this population based on the underlying advanced 
hematologic malignancy and that these can be SAEs. Therefore, there is no specific occurrence of 
SAEs that define a stopping rule, but the review of SAEs will form the basis for potential early 
stopping of the study.  Only unexpected SAEs that are related to the CART-19 cells would define 
a stopping rule. The review of these adverse events, and any decision to prematurely stop subject 
enrollment, will be determined by the DSMB and reviewed by the IRB, Medical Monitor, ACC 
DSMC and FDA. 
 
Premature termination of the clinical trial may occur because of a regulatory authority decision, 
change in opinion of the IRB, the DSMB, Medical Monitor, ACC DSMC, or determination that 
there are problems in the cell product generation or safety at the discretion of the study 
investigators. Additionally, recruitment may be stopped for reasons of particularly low 
recruitment, protocol violations, or inadequate data recording. 
9.5.1 Criteria for stopping or pausing the study 
The study will be stopped if: 
 Any subject develops uncontrolled T cell proliferation that does not respond to 
management. 
 Premature study termination may occur if the Investigator, Study Funder, Sponsor, 
DSMB, Medical Monitor, ACC DSMC or any appropriate independent review board or 
regulatory body decides for any reason that subject safety may be compromised by 
continuing the study. 

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 Premature study termination may occur if the Sponsor or Study Funder decides to 
discontinue the development of the intervention to be used in this study. 
 
The study will be paused if:  
 The protocol will be paused pending submission of the protocol pause to the FDA and 
review by the IRB, ACC DSMC, ACC CTSRMC, Medical Monitor and the DSMB if 
any patient experiences any of the following events within two weeks of the first CART-
19 infusion   
 Life-threatening (grade 4) toxicity attributable to protocol therapy that is 
unmanageable, unexpected and unrelated to chemotherapy and attributable to 
protocol therapy. High fevers, hypotension, possible ICU admission and even 
mechanical ventilation are expected. These side effects can result in grade 4 liver 
toxicity, nephrotoxicity, and other organ involvement 
 Death 
If the study is paused for the reasons above, the PI, members of the study team and Protocol 
Advisor will meet in person or by teleconference within 24 hours of the event to have a thorough 
discussion of the event. These types of events will not be vetted via e-mail. The sponsor should 
not be involved in discussions about attribution. Meeting minutes capturing the review of any 
ongoing investigations, including next steps in the management of subjects and any proposed 
changes to the protocol will be forwarded to the FDA, IRB, ACC DSMC, Medical Monitor, and 
DSMB. If all parties are in agreement as to the event resolution, then the pause will be lifted. 
 
The protocol manufacturing will be paused to review the manufacturing process should there be 
>20% manufacturing failures [i.e. the manufacturing process fails to meet the protocol-specified 
dose range according to the protocol stage and randomized dose arm (as applicable)]. 
If the study is paused for manufacturing reasons, the PI, members of the study team, Protocol 
Advisor, Clinical Operations and Cell Manufacturing will meet to identify manufacturing failure. 
The team will make recommendations for process improvements to be implemented. Pending 
successful completion of a process validation run, the manufacturing pause will be lifted. 
9.5.2 Toxicity management considerations 
Replication-competent lentivirus (RCL) may be generated during the CART-19 manufacturing 
phase or subsequently after introduction of vector transduced cells into the patient. However, an 
RCL resulting from the production phase is highly unlikely since elements are incorporated in the 
design of the vector system that minimize vector recombination and generation of RCL. 
Furthermore, the vector used to transduce the product undergoes sensitive assays for detection of 
RCL before it can be released to a subject. Nevertheless, generation of an RCL following infusion 
of the vector product remains a theoretical possibility. The consequences of such recombination 
events in subjects without a known lentiviral infection are unknown, and therefore subjects with 
coexistent HIV infection are excluded from participation in this study in order to minimize this 
possibility. The development of RCL could pose a risk to both the subject and their close 
contact(s), and therefore, monitoring for RCL will be conducted during the course of the trial. 
 
Regulatory agencies and the gene therapy community have previously discussed measures to be 
taken should an RCL be confirmed in a subject. However, because the probability of developing, 

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and characteristics of an RCL are unknown, no guidelines have been put in place. Nevertheless, 
all agree that the subject must be isolated until an understanding of how to manage the subject 
becomes clear. Some considerations are  
 Intensive follow-up of subject in consultation with gene therapy experts, study 
investigators, FDA and NIH. 
 Inform local public health officials and CDC. 
 Identify sexual partners and provide appropriate counseling and intervention. 
 
RCL will be monitored by a suitable Q-PCR assay for the detection of the lentivirus (VSV-
g DNA). If a positive VSV-g DNA assay result is obtained, the Investigator will be informed 
and the patient rescheduled for a retest for the DNA test.  If the second DNA test is positive, then 
infusions will be temporarily halted.  The patient will undergo a blood draw for isolation of HIV 
from his/her cells.   The virus will be sequenced and compared to sequences of the transfer 
vector and packaging constructs, as well as to available HIV sequences to determine the origin 
of the virus.  Determination of the origin of the virus can be easily performed by evaluation for 
HIV accessory genes such as vif, vpr and vpu which are not present in the packaging constructs. 
If the sequence is derived from wt-HIV then infusions for all patients can resume, and the patient 
will be referred to treatment for HIV.  If an RCL is confirmed, or the virus cannot be isolated 
from the blood draw, the patient will be scheduled for apheresis and will undergo a full 
biological RCR/L testing for detection and/or characterization of the RCRL. 
 
Clonality and insertional oncogenesis.  Four of nine treated patients in a gene therapy trial for 
X-linked Severe Combined Immunodeficiency (SCID) developed T cell leukemia 31-68 months 
post-treatment. The T cell leukemias were attributable to clonal expansion conferred by 
gammaretroviral vector integration sites in the CD34+ bone marrow stem cell modification94. This 
represents the most severe adverse event caused by vector integration. However, there is also 
evidence for retroviral vector integration site dominance in a gene therapy trial of -thalassaemia 
without malignancy95. The lentiviral vector used for CART-19 manufacturing is part of a vector 
class that may have a lower risk for integration in or near oncogenic regions than oncoretroviral 
vectors96. As of March 2014, none of the patients treated with CART-19 have developed a new 
malignancy, T cell or otherwise, related to lentiviral vector integration. Subjects will be monitored 
for evidence of unexpected CART-19 expansion by CART-19 transgene quantitation by qPCR 
and clinical monitoring for malignancy by complete blood count (CBC) as part of the study design. 
If an unexpected pattern of CART-19 expansion is observed (i.e. CART-19 expansion in the 
absence of CD19+ target), subjects will be closely monitored clinically for new malignancies, 
particularly T cell, and further studies, including insertion site analysis, will be considered to 
investigate the molecular basis of the expansion. Investigators should consult with the Regulatory 
Sponsor if an unexpected pattern of CART-19 expansion and/or a new malignancy arises. Subjects 
will continue to be similarly monitored for clonality and insertional oncogenesis when enrolled on 
the long term follow-up protocol. 
 
Uncontrolled T cell proliferation. CART-19 cells could proliferate without control of normal 
homeostatic mechanisms. In pre-clinical studies, CART-19 cells have only proliferated in response 
to physiologic signals or upon exposure to CD19. In the context of this protocol it is possible that 
the T cells will proliferate in response to signals from the malignant tumor or normal B cells. This 
could be beneficial or harmful depending on the extent of proliferation. If any subject develops 

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excessive CART-19 cell accumulation, corticosteroids will be administered to eradicate the 
infused cells.  
 
Toxicity associated with allogeneic or autologous T cell infusions has been managed with a course 
of pharmacologic immunosuppression. CAR T cell associated toxicity has been reported to 
respond to systemic corticosteroids43.  If uncontrolled T cell proliferation occurs (grade 3 or 4 
toxicity related to CART-19 cells), subjects will be treated with corticosteroids. Subjects will be 
treated with pulse methylprednisolone (2 mg/kg i.v. divided q8 hr x 2 days), followed by a rapid 
taper.  
 
B cell depletion. It is possible that B cell depletion and hypogammaglobulinemia will occur. This 
is common with anti-CD20 directed therapies97. In the event of clinically significant 
hypogammaglobulinemia (i.e. systemic infections), subjects will be given intravenous 
immunoglobulin (IVIG) by established clinical dosing guidelines to restore normal levels of serum 
immunoglobulin levels, as has been done with Rituximab. 
 
Infusion reaction. Acetaminophen and diphenhydramine hydrochloride may be repeated every 6 
hours as needed. A course of non-steroidal anti-inflammatory medication may be prescribed if the 
patient continues to have fever not relieved by acetaminophen. It is recommended that patients not 
receive corticosteroids at any time, except in the case of a life threatening emergency, since this 
may have an adverse effect on CART-19 cells.  
 
Febrile reaction. In the event of febrile reaction, an evaluation for infection should be initiated, 
and patients managed appropriately with antibiotics, fluids and other supportive care as medically 
indicated and determined by the treating physician.  In the event that the patient develops sepsis or 
systemic bacteremia following CAR T cell   infusion,   appropriate   cultures   and   medical   
management   should   be   initiated.   If   a contaminated CART-19 T cell product is suspected, the 
product can be retested for sterility using archived samples that are stored in the CVPF.  
Consideration of a cytokine release syndrome (see below) should be given.   
 
Cytokine Release Syndrome (CRS) / Macrophage Activation Syndrome (MAS)  
CRS has been observed in patients after treatment with CART-19. Patients with clinical responses 
exhibited some level of CRS that ranged from mild to severe consisting of fevers, hypotension, 
capillary leak, hypoxia or other symptoms (See Section 1.5.2 and 8.2).  All patients who have 
responded to CART-19 cells have experienced a CRS.  
 
Cytokine production is required for the activation, expansion and cytolytic function of T cells and 
for CART-19 T cells.  Therefore some degree of CRS may be a desired clinical outcome. 
Premature or early intervention with anti-cytokine therapy may therefore abrogate the anti-tumor 
efficacy of CART-19. Subsequent to this experience, selective tocilizumab (an anti-IL6-receptor 
antibody), therapy has been utilized (described below) with effective toxicity management and 
successful ongoing CART-19 T cell expansion in patients. Please note, steroids or other 
immunosuppressant drugs should NOT be used as pre-medication for CART-19 therapy but may 
be considered in the management of CRS.  
 

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The moderate to severe cases of CRS observed required intervention with tocilizumab with or 
without high dose corticosteroids, between 2 and 9 days after T cell infusion to date. This resulted 
in rapid reversal of the high persistent fevers and hemodynamic instability associated with CRS in 
most but not all patients. 
 
Given the dramatic clinical improvement of most patients treated with anti-cytokine therapy, 
patients with moderate to severe cytokine toxicities should be first managed with administration 
of tocilizumab. 
  
Tocilizumab should be used as a single, weight-based dose of 8 mg/kg at the time of hemodynamic 
instability. This management approach is designed to avoid life-threatening toxicities, while 
attempting to allow the CART-19 cells to establish a proliferative phase that appears to correlate 
with anti-tumor efficacy. Thus, the timing of the tocilizumab should be individualized, in close 
consultation with the Principal Investigator and/or expert consultants for the trial.  Steroids have 
not always been effective in this setting and may not be necessary given the rapid response to 
tocilizumab. Because steroids will interfere with CART-19 function and efficacy, if used, they 
should be rapidly tapered.  
 
Upon developing the prodrome of high-persistent fevers following CART-19 infusion, patients 
should then be followed closely. Infection and tumor lysis syndrome work up should be 
immediately undertaken.  The pharmacy should be notified of the potential need for tocilizumab.  
Patient management in an intensive care unit may be required and the timing is dependent upon 
local institutional practice. In addition to supportive care, tocilizumab may be administered in 
cases of moderate to severe CRS, especially if the patient exhibits any of the following: 
 Hemodynamic instability despite intravenous fluid challenges and moderate stable 
vasopressor support 
 Worsening respiratory distress, including pulmonary infiltrates, increasing oxygen 
requirement including high-flow O2, and/or need for mechanical ventilation.  
 Any other signs or symptoms of rapid deterioration despite medical management 
 
The recommended dosing for tocilizumab is 8 mg/kg i.v. single dose. Not all Grade 4 CRS 
reactions following CART-19 have been immediately treated with tocilizumab and decisions are, 
in part, based upon the rapidity of the syndrome onset and underlying patient reserve. 
 
Other anti-cytokine therapies, such as repeat administration of tocilizumab or use of siltuximab or 
etanercept, may also be considered if the patient does not respond to the initial dose of tocilizumab.  
If the patient experiences ongoing CRS despite administration of anti-cytokine directed therapies, 
anti T-cell therapies such as cytoxan, ATG, campath may be considered.   
 
CRS has been associated with biochemical and physiologic abnormalities consistent with MAS.  
Moderate to extreme elevations in serum C-reactive protein (CRP) and ferritin have been seen with 
CART-19 associated CRS, however the magnitude and kinetics vary greatly between individual 
patients.  CRS management decisions should be based upon clinical signs and symptoms and 
response to interventions, not these laboratory values per se. 
 

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CTCAE grading of CRS relates to its occurrence with acute infusional toxicities, whereas the CRS 
associated with CART-19 therapy is not acute, but rather delayed. Refer to Section 9.2 and Table 
5 for modified definitions of grading of CART-19 delayed CRS events.  
 
Tumor lysis syndrome. Patients will receive allopurinol prophylactically for 28 days to prevent 
complications from TLS.  TLS resulting in insufficiency, or rapidly rising uric acid, or evidence 
of organ dysfunction will be managed with fluids and rasburicase as clinically indicated and 
determined by the treating physicians. 
 
GVHD: The chance of GVHD occurring is low, but it is a potential risk with CTL019 therapy. A 
prior study of activated donor lymphocyte infusions (ex vivo activated cells collected from the 
donor and grown in the same fashion as CART-19  but without the CAR introduction) did not 
show high rates of GVHD (2/18 patients with grade 3 GVHD and none with grade 4).  Eight ALL 
patients treated to date with autologous CART-19 therapy had prior allogeneic hematopoietic SCT 
with residual donor chimerism. None of these patients have developed GVHD after autologous 
CART-19 infusion 
9.5.3 Criteria for discontinuing a subject’s participation in the study: 
If a subject develops a condition that precludes CART-19 infusion after enrollment but before 
infusion, the subject will be prematurely discontinued. This will be done at the judgment of the PI, 
and could include for example, the occurrence of an intercurrent illness requiring the institution of 
systemic immunosuppression.  
9.6 
Protocol Exceptions and Deviations 
 
 
 
Exception 
A one time, intentional action or process that departs from the IRB and CTSRMC approved study 
protocol, intended for one occurrence. If the action disrupts the study progress, such that the study 
design or outcome (endpoints) may be compromised, or the action compromises the safety and 
welfare of study subjects, advance documented IRB and DSMC approval is required.   
 
No exception would be granted if the action disrupts the study progress, such that the study design 
or outcome (endpoints) may be compromised, or the action compromises the safety and welfare 
of study subjects, advance documented IRB and DSMC approval is required.  
 
Exceptions will be approved by the Medical Monitor and Regulatory Sponsor prior to submission 
to the IRB and ACC DSMC.  Documentation of approval by the Medical Monitor and Regulatory 
Sponsor will be submitted with the initial request for an exception to the IRB and ACC DSMC.  All 
exceptions require advance documented IRB and ACC DSMC approval. 
 
No exceptions to eligibility of any type will be granted for this study. 
 
Deviation 

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A one time, unintentional action or process that departs from the IRB and ACC DSMC approved 
study protocol, involving one incident and identified retrospectively, after the event occurred. If 
the impact on the protocol disrupts the study design, may affect the outcome (endpoints) or 
compromises the safety and welfare of the subjects, the deviation must be reported to the ACC 
DSMC within 5 business days and the IRB within 10 business days.  
 
Any departure from the protocol that meets the following criteria should be submitted to the 
regulatory sponsor, ACC DSMC and IRB: 
 
Impacts subject safety 
 
Impacts the integrity of the study design or outcome 
 
Based on the PI’s judgment is reportable 
Deviations identified retrospectively pertaining to manufacturing, treatment, eligibility or safety 
reporting will result in suspension of enrollment until the DSMC is satisfied with the corrective 
action plan. 
 
Other deviations should be explained in a memo to file (such as a subject missing a visit is not an 
issue unless a critical/important treatment or procedure was missed and must have been done at 
that specific time).  
 
Include the following information on the Sponsor supplied exception/deviation form:  protocol 
number, subject study number, description of the exception/deviation and rationale.  Ensure all 
completed exception/deviation forms are signed by the Principal Investigator (or a sub-
investigator) and submitted to the Sponsor Project Manager and Medical Monitor for review.   
 
Attention: Sponsor Project Manager  
Translational Research Program 
University of Pennsylvania 
Fax 
 
 
Email: 
 
 
The Sponsor Project Manager will submit the exception and/or deviation request to the Regulatory 
Sponsor for review and approval.  Once approval of the exception request or acknowledgement of 
the deviation has been granted by the Regulatory Sponsor and Medical Monitor, the exception or 
deviation will be submitted to the IRB, ACC DSMC and all other applicable committees for review 
and approval. 
 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations.  Under no 
circumstances should the investigator contact the regulatory sponsor or its agents, if any, 
monitoring the study to request a protocol exception, as no authorized exceptions are permitted.  
If the investigator feels a protocol exception would improve the conduct of the study, this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by the Sponsor 
and approved by the IRB/IEC/REB it cannot be implemented.  All significant protocol deviations 
will be recorded and reported in the CSR.   

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Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by the Sponsor, Health Authorities where required, and the IRB/IEC/REB.  Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval.  Notwithstanding the need for approval of formal protocol amendments, the investigator 
is expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol.  In such cases, the Sponsor 
should be notified of this action and the IRB/IEC at the study site should be informed to the local 
regulations (e.g., UK required the notification of urgent safety measures within 3 days) but no later 
than 10 working days.   
9.7 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  
This safety monitoring will include careful assessment and appropriate reporting of adverse events 
as noted above, as well as the construction and implementation of a site data and safety-monitoring 
plan (see section 11 Auditing, Monitoring and Inspecting).  Medical monitoring will include a 
regular assessment of the number and type of serious adverse events. 
 
A protocol-specific independent medical monitor with appropriate expertise and experience has 
been recruited in addition to the DSMB to review subject safety data and ensure the safety of 
participants.  The Medical Monitor will receive real-time reporting of any events that could 
potentially impact subject safety (including dose-limiting toxicities).  The Medical Monitor will 
also receive all of the following: 
 
 All Serious Adverse Events (regardless of expectedness/relatedness).  The SAE will be 
reported to the Medical Monitor within 24 hours of becoming aware of the SAE. 
 Deviations reported to the regulatory sponsor, ACC DSMC and IRB as they occur 
 Exceptions prior to submission to the IRB and ACC DSMC 
 IRB Continuing Review Reports  
 All queries issued by the DSMC (including those related to grading, attribution and 
expectedness of adverse events). 
 
 
The Medical Monitor will correspond via email to communicate: 
 SAE acknowledgement and inquiries 
 Deviation acknowledgement, inquiries, recommendations 
 Exception acknowledgement, inquiries and approval/disapproval 
 Continuing review acknowledgement, inquiries 
 
The Medical Monitor will review and acknowledge the above, and make recommendations 
whether to continue with the study, amend the study, and/or stop/pause the study as needed. In 
addition, the Medical Monitor and Principal Investigator will meet approximately every 3 months 
to review cumulative AE data, the status of all enrolled subjects and the study progress.  
 
Documentation of Medical Monitor review will be maintained in the study regulatory binder and 
sent to the ACC DSMC and Regulatory Sponsor as soon as a response is received from the Medical 

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Monitor. 
9.7.1 Independent Data and Safety Monitoring Board 
An Independent Data and Safety Monitoring Board (DSMB) will be constituted prior to the 
randomization of the first patient. Please note that the DSMB is separate from the DSMC (refer to 
section 9.3.3).  The DSMB will be comprised of a minimum of four individuals including 
physicians with experience in oncology and/or gene transfer therapy and a statistician.  The DSMB 
will be assembled and will work under a charter specifically developed for safety oversight of this 
study. The DSMB will be responsible for reviewing available safety data. The DSMB will provide 
advice to the investigators, and consult with regulatory sponsor as necessary. The DSMB will 
evaluate patient-subject safety as specified in the Data Safety and Monitoring Plan. There will be 
a meeting with the DSMB describing their roles and responsibilities and discussing potential data 
format and process issues prior to the finalization of the interim analysis plan. 
 
The results of the analysis following Stage I will also be presented to the DSMB for review and 
recommendations. The analyses will address efficacy and key safety data. 
 
If necessary, additional meetings of the DSMB may be held if safety issues arise in between 
scheduled meetings. 
 
It is envisioned that the DSMB may make four types of recommendations, namely: 
• No safety or efficacy issues, ethical to continue the study as planned 
• Serious safety concerns precluding further study treatment, regardless of efficacy 
• Overwhelming evidence for futility, recommend stopping the study. 
• Recommendation to continue the study but proposing an amendment to the protocol 
(e.g., incorporate an additional safety assessments) 
 
If the study is recommended to continue by the DSMB, no details about the results of the current 
interim analysis will be revealed prior to the next scheduled analysis.  A Regulatory Sponsor 
representative will submit the DSMB report to the PI for submission to the ACC DSMC and IRB 
within 10 working days of receipt of the approved minutes. 
9.7.2 Clinical Field Monitors 
A representative appointed by the Regulatory Sponsor will be responsible for monitoring and 
reporting on the progress of the investigation for GCP compliance with FDA and ICH 
requirements and 21 CFR Part 11. The clinical field monitor will monitor GCP aspects of the 
study, including completeness and accuracy of the CRFs, eligibility, and informed consent. 
 
Representatives of the regulatory sponsor will conduct a site initiation visit and periodically audit, 
at mutually convenient times during and after the study, all eCRFs and corresponding source 
documents for each subject. At the site initiation visit, monitors will assure that proper study-
related documentation exists, provide training to investigators and other site personnel in study 
procedures and GCP guidelines, and assure that acceptable facilities and adequately trained staff 
are available to conduct the study. 
 

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Key study personnel must be available to assist the field monitor during these visits.  The 
investigator must maintain source documents for each patient in the study, consisting of case and 
visit notes (hospital or clinic medical records) containing demographic and medical information, 
laboratory data, electrocardiograms, and the results of any other tests or assessments. All 
information recorded on eCRFs must be traceable to source documents in the patient's file. The 
investigator must also keep the original signed informed consent form (a signed copy is given to 
the patient). 
 
Periodic monitoring visits throughout the study provide the Sponsor with the opportunity to 
evaluate the progress of the study and inform the Sponsor of potential problems. The clinical field 
monitors will assure that submitted data are accurate and in agreement with source documentation; 
verify that investigational products are properly stored and accounted for, verify that subjects’ 
consent for study participation has been properly obtained and documented, confirm that research 
subjects entered into the study meet inclusion and exclusion criteria, and assure that all essential 
documentation required by Good Clinical Practices (GCP) guidelines are appropriately filed. 
 
The investigator must give the clinical field monitor access to all relevant source documents to 
confirm their consistency with the eCRF entries. The monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the eCRFs 
are performed according to the study-specific monitoring plan. 
 
At the end of the study, monitors will conduct a close-out visit and will advise on storage of study 
records and disposition of unused investigational products.  Further details about clinical 
monitoring can be found in the Sponsor Data Safety Monitoring Plan (DSMP). 
 
 
Data Collection 
A PPD electronic database system will be used for data collection in this study.  The designated 
investigator staff will enter the data required by the protocol into the Electronic Case Report Forms 
(eCRF). The eCRFs have been built using fully validated secure web-enabled software that 
conforms to 21 CFR Part 11 requirements. Investigator site staff will not be given access to the 
EDC system until they have been trained. Automatic validation programs check for data 
discrepancies in the eCRFs and, allow modification or verification of the entered data by the 
investigator staff.  The Principal Investigator is responsible for assuring that the data entered into 
eCRF is complete, accurate, and that entry and updates are performed in a timely manner.   
 
Database management and quality control 
The designated CRO will review the data entered by investigational staff for completeness and 
accuracy. Electronic data queries stating the nature of the problem and requesting clarification will 
be created for discrepancies and missing values and sent to the investigational site via the EDC 
system. Designated investigator site staff is required to respond promptly to queries and to make 
any necessary changes to the data. 
 
Concomitant treatments entered into the database will be coded using the WHO Drug Reference 
List, which employs the Anatomical Therapeutic Chemical classification system. Medical 

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history/current medical conditions and adverse events will be coded using the Medical dictionary 
for regulatory activities (MedDRA) terminology. 
 
Samples and/or data will be processed centrally and the results will be sent electronically to a 
designated CRO. 
 
After database lock, the investigator will receive a CD-ROM or paper copies of the CRFs for 
archiving at the investigational site. 
 
In addition to the CRO created database, subject information will also be entered into the UPenn 
Velos database. The following Velos Forms will be filled out:  Protocol Registration, Subject 
Registration, and Adverse Event/SAE CRF. 
 
10 Data Handling and Recordkeeping 
10.1 Confidentiality 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to the funding sponsor.  Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site.   
 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following: 
  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end 
of their scheduled study period. 
 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned user 
identification codes and passwords, made available only to unauthorized personnel who have 
completed the prerequisite training.  
 
If country rules or ethics committee standards do not permit collection of patient initials and the 
exact date of birth, generic initials will be used and only the year of birth will be collected. 

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10.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are 
contained in source documents   Examples of these original documents, and data records include: 
hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
 
The investigator must maintain source documents for each patient in the study, consisting of case 
and visit notes (hospital or clinical medical records) containing demographic and medical 
information, laboratory data, electrocardiograms and the results of any other tests or assessments. 
All information recorded on the eCRFs must be traceable to source documents in the patient’s file. 
The investigator must also keep the original signed informed consent form, and a signed copy must 
be given to the patient. 
10.3 Case Report Forms 
For studies using electronic data capture (EDC), the designated investigator staff will enter the 
data required by the protocol into the electronic case report form (eCRFs). The eCRFs have been 
built using fully validated secure web-enabled software that conforms to 21 CFR Part 11 
requirements.  Investigator site staff will not be given access to the EDC system until they have 
been fully trained. Automatic validation programs check for data discrepancies in the eCRFs and 
allow modification or verification of the entered data by the investigator staff.  
 
The Principal Investigator is responsible for assuring that the data entered into the eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. The designated 
CRO will review the data entered by investigational staff for completeness and accuracy. 
Electronic data queries stating the mature of the problem and requesting clarification will be 
created for discrepancies and missing values and sent to the investigational site via the EDC 
system. Designated investigator site staff is required to respond promptly to queries and to make 
any necessary changes to the data. 
 
Concomitant treatments entered into the database will be coded using the WHO Drug reference 
list. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedRA) terminology. 
 
At the conclusion of the study the occurrence of any protocol violations will be determined, and 
all unused supplies are to be returned. After this has been completed and the data has been verified 
to be complete and accurate, the database will be declared locked. After database lock, all 
investigators will receive a CD-ROM or paper copies of the patient data for archiving at the 
investigational site. 
 
The following CRFs are required to be completed in the ACC Velos electronic database:  
 Protocol Registration form 
 PRA Form 

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 Subject Registration form (for all subject who have signed the ICF) 
 Adverse Event form.  Information required to be reported to the DSMC (section 9.3.3) 
o All grade 3 or higher events within five business days of knowledge 
All unexpected deaths within 24 hours of knowledge 
All others deaths within 30 days of knowledge 
 
11 Study Monitoring, Auditing, and Inspecting 
11.1 Study Monitoring Plan 
This study will be monitored according to the Sponsor Data and Safety Monitoring Plan.  The 
investigator will allocate adequate time for such monitoring activities.  The Investigator will also 
ensure that the monitor or other compliance or quality assurance reviewer is given access to all the 
above noted study-related documents and study related facilities and has adequate space to conduct 
the monitoring visit. 
11.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, government regulatory bodies, and University compliance and quality assurance groups 
of all study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
12 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical Practice 
(FDA Code of Federal Regulations Title 21 Part 312 and International Conference on 
Harmonization guidelines), applicable government regulations and Institutional research policies 
and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal approval 
of the study conduct.  The decision of the IRB concerning the conduct of the study will be made 
in writing to the investigator and a copy of this decision will be provided to the regulatory sponsor 
before commencement of this study.  The investigator should provide current IRB FWA 
information and any other certifications to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the IRB 
for the study.  The formal consent of a subject, using the IRB-approved consent form, must be 
obtained before that subject is submitted to any study procedure.  This consent form must be signed 
by the subject, and the investigator-designated research professional obtaining the consent.  

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The protocol is listed under clinicaltrials.gov. 
 
13 Study Finances 
13.1 Funding Source 
This study will be funded by Novartis Pharmaceuticals.  
13.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed by a properly constituted Conflict of Interest Committee with a Committee-sanctioned 
conflict management plan that has been reviewed and approved by the regulatory sponsor prior to 
participation in this study.  All University of Pennsylvania investigators will follow the University 
conflict of interest policy. 
13.3 Subject Stipends or Payments 
There is no subject stipend/payment for participation in this protocol. 
13.4 Study Discontinuation 
The study may be discontinued at any time by the IRB, CTSRMC and DSMC, the Sponsor, the 
Study Funder, the FDA, or other government agencies as part of their duties to ensure that research 
subjects are protected. 
 
14 Publication Plan 
Publication of the results of this trial will be governed by University of Pennsylvania policies. 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the sponsor.  Any investigator 
involved with this study is obligated to provide the sponsor with complete test results and all data 
derived from the study. 
 
15 References 
Reference List 
 
 
1.  Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 
2012;62(1):10-29. 
 
2.  Smith A, Howell D, Patmore R, Jack A, Roman E. Incidence of haematological malignancy 
by sub-type: a report from the Haematological Malignancy Research Network. Br J Cancer 
2011;105(11):1684-1692. 

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3.  Hernandez JA, Land KJ, McKenna RW. Leukemias, myeloma, and other lymphoreticular 
neoplasms. Cancer 1995;75(1 Suppl):381-394. 
 
4.  Kantar Health. Treatment Evolution: United States Leukemia, Chronic Lymphocytic.  
2011. Ref Type: Online Source 
 
 
5.  Freedman AS, Boyd AW, Bieber FR et al. Normal cellular counterparts of B cell chronic 
lymphocytic leukemia. Blood 1987;70(2):418-427. 
 
6.  Uckun FM, Ledbetter JA. Immunobiologic differences between normal and leukemic 
human B-cell precursors. Proc Natl Acad Sci U S A 1988;85(22):8603-8607. 
 
7.  Fearon DT, Carroll MC. Regulation of B lymphocyte responses to foreign and self-
antigens by the CD19/CD21 complex. Annu Rev Immunol 2000;18:393-422.:393-422. 
 
8.  Stamenkovic I, Seed B. CD19, the earliest differentiation antigen of the B cell lineage, 
bears three extracellular immunoglobulin-like domains and an Epstein-Barr virus-related 
cytoplasmic tail. J Exp Med 1988;168(3):1205-1210. 
 
9.  Ledbetter JA, Rabinovitch PS, June CH, Song CW, Clark EA, Uckun FM. Antigen-
independent regulation of cytoplasmic calcium in B cells with a 12-kDa B-cell growth 
factor and anti-CD19. Proc Natl Acad Sci U S A 1988;85:1897-1901. 
 10.  Tedder TF, Isaacs CM. Isolation of cDNAs encoding the CD19 antigen of human and 
mouse B lymphocytes. A new member of the immunoglobulin superfamily. J Immunol 
1989;143(2):712-717. 
 11.  Uckun FM, Jaszcz W, Ambrus JL et al. Detailed studies on expression and function of 
CD19 surface determinant by using B43 monoclonal antibody and the clinical potential of 
anti-CD19 immunotoxins. Blood 1988;71(1):13-29. 
 12.  Gunther R, Chelstrom LM, Tuel-Ahlgren L, Simon J, Myers DE, Uckun FM. Biotherapy 
for xenografted human central nervous system leukemia in mice with severe combined 
immunodeficiency using B43 (anti-CD19)-pokeweed antiviral protein immunotoxin. Blood 
1995;85(9):2537-2545. 
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CONFIDENTIAL 
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Appendix 1 - Schedule of Study Procedures 
Week/Day of treatment 
period 
 (-) 8 to 12x 
~ Wk  (-) 6 to 8 x 
~ Wk  (-) 4 x 
(+/- 1 wk)
~ Wk  (-) 1 
(+2 days) 
~ Day  (-) 1§ 
Day 1§ 
Day 2 (+1 day)§ 
Day 3 (+1 day)§ 
Day 4 (+1 day) 
Day 7 
(+/- 1 day) 
Day 10 
(+/- 1 day) 
Day  14,  21 
(+/- 1 day) 
Day 28 
(+/- 3 days) 
Month 2 to 6s 
(+/- 7 days) 
Month 9 
(+/- 7 days) 
Month 12t 
(+/- 7 days) 
Every 3 Months 
(+/- 1 month)bb 
 
Pre-entry 
evaluation 
Enrollment 
Apheresis  
Chemo- 
therapyj 
Pre – 
Infusion 
Infusion #1 
Infusion #2 
Infusion #3 
Post 
Infusion 
Post 
Infusion 
Post 
Infusion 
Post 
Infusion 
End of 
Treatment 
Post 
Infusion 
Post 
Infusion 
End of 
study 
Secondary 
Follow-up 
Visit Name 
Screening 
Week -8 to -12 
Baseline  
Week -6 to -8 
Apheresis   
Week -4  
Chemotherapy  
Week  (-1) 
Pre-infusion  
Day -1§ 
Infusion  #1 
Day 1§ 
Infusion #2 
Day 2 §aa 
Infusion #3 
Day 3 §aa 
Post infusion Day 4   
Post infusion  
Day 7          
Post infusion  
Day 10        
Post infusion  
Day 14        
Post infusion Day 21  
End of Treatment 
Safety follow-up 
1 to 5 
Safety follow-up 6 
End of study 
Secondary Follow-
up 
Visit number 
1 
2 
3 
4 
5 
6 
201 
202 
7 
8 
9 
10,11 
777 
501, 502, 
503, 504, 
505 
506 
778 
601 
Clinical Assessments 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Form/ 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quality of Life 
Questionnaires 
(EORTC QLQ-C30 and 
CLL-16) 
 
X 
 
X 
 
 
 
 
 
 
 
 
X 
Xv 
X 
X 
 
Relevant Medical 
History/Current 
Medical Conditions 
 
X 
X 
X 
X 
Xa 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
 

CD19 CART-19 Protocol 
 
page 96 of 120 
Version 12.03-05-2015 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
Week/Day of treatment 
period 
 (-) 8 to 12x 
~ Wk  (-) 6 to 8 x 
~ Wk  (-) 4 x 
(+/- 1 wk)
~ Wk  (-) 1 
(+2 days) 
~ Day  (-) 1§ 
Day 1§ 
Day 2 (+1 day)§ 
Day 3 (+1 day)§ 
Day 4 (+1 day) 
Day 7 
(+/- 1 day) 
Day 10 
(+/- 1 day) 
Day  14,  21 
(+/- 1 day) 
Day 28 
(+/- 3 days) 
Month 2 to 6s 
(+/- 7 days) 
Month 9 
(+/- 7 days) 
Month 12t 
(+/- 7 days) 
Every 3 Months 
(+/- 1 month)bb 
 
Pre-entry 
evaluation 
Enrollment 
Apheresis  
Chemo- 
therapyj 
Pre – 
Infusion 
Infusion #1 
Infusion #2 
Infusion #3 
Post 
Infusion 
Post 
Infusion 
Post 
Infusion 
Post 
Infusion 
End of 
Treatment 
Post 
Infusion 
Post 
Infusion 
End of 
study 
Secondary 
Follow-up 
Visit Name 
Screening 
Week -8 to -12 
Baseline  
Week -6 to -8 
Apheresis   
Week -4  
Chemotherapy  
Week  (-1) 
Pre-infusion  
Day -1§ 
Infusion  #1 
Day 1§ 
Infusion #2 
Day 2 §aa 
Infusion #3 
Day 3 §aa 
Post infusion Day 4   
Post infusion  
Day 7          
Post infusion  
Day 10        
Post infusion  
Day 14        
Post infusion Day 21  
End of Treatment 
Safety follow-up 
1 to 5 
Safety follow-up 6 
End of study 
Secondary Follow-
up 
Visit number 
1 
2 
3 
4 
5 
6 
201 
202 
7 
8 
9 
10,11 
777 
501, 502, 
503, 504, 
505 
506 
778 
601 
Physical examb 
 
X 
 
 
X 
Xa 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
 
Performance Status 
Assessment 
 
X 
 
 
X 
Xa 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Meds 
X 
X 
X 
X 
X 
Xa 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Eventsc 
X 
X 
X 
X 
X 
Xa 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
 
HIV  test  
(1 ml SST) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
p53 Mutation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leukapheresis 
screening 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT scan of chest, 
abdomen, pelvisd 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Xv 
X 
X 
 
Bone marrow 
biopsy/aspirateo 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Xv 
X 
X 
 
Lymph Node biopsy 
 
Xe 
 
 
 
 
 
 
 
 
 
 
Xe 
Xv,e 
Xe 
Xe 
 
ECHO/MUGAf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Respiratory Virus Panel 
(RVP) 
 
 
 
Xy 
 
 
 
 
 
 
 
 
 
 
 
 
 

CD19 CART-19 Protocol 
 
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Version 12.03-05-2015 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
Week/Day of treatment 
period 
 (-) 8 to 12x 
~ Wk  (-) 6 to 8 x 
~ Wk  (-) 4 x 
(+/- 1 wk)
~ Wk  (-) 1 
(+2 days) 
~ Day  (-) 1§ 
Day 1§ 
Day 2 (+1 day)§ 
Day 3 (+1 day)§ 
Day 4 (+1 day) 
Day 7 
(+/- 1 day) 
Day 10 
(+/- 1 day) 
Day  14,  21 
(+/- 1 day) 
Day 28 
(+/- 3 days) 
Month 2 to 6s 
(+/- 7 days) 
Month 9 
(+/- 7 days) 
Month 12t 
(+/- 7 days) 
Every 3 Months 
(+/- 1 month)bb 
 
Pre-entry 
evaluation 
Enrollment 
Apheresis  
Chemo- 
therapyj 
Pre – 
Infusion 
Infusion #1 
Infusion #2 
Infusion #3 
Post 
Infusion 
Post 
Infusion 
Post 
Infusion 
Post 
Infusion 
End of 
Treatment 
Post 
Infusion 
Post 
Infusion 
End of 
study 
Secondary 
Follow-up 
Visit Name 
Screening 
Week -8 to -12 
Baseline  
Week -6 to -8 
Apheresis   
Week -4  
Chemotherapy  
Week  (-1) 
Pre-infusion  
Day -1§ 
Infusion  #1 
Day 1§ 
Infusion #2 
Day 2 §aa 
Infusion #3 
Day 3 §aa 
Post infusion Day 4   
Post infusion  
Day 7          
Post infusion  
Day 10        
Post infusion  
Day 14        
Post infusion Day 21  
End of Treatment 
Safety follow-up 
1 to 5 
Safety follow-up 6 
End of study 
Secondary Follow-
up 
Visit number 
1 
2 
3 
4 
5 
6 
201 
202 
7 
8 
9 
10,11 
777 
501, 502, 
503, 504, 
505 
506 
778 
601 
Blood Draws 
Hematology 
(CBC, differential, platelet 
count)  
(5 ml lavender top, 
EDTA)a 
 
X 
 
 
X 
Xa 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry (3 ml SST) 
 
X 
 
 
X 
Xa 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum pregnancy testg  
(1 ml SST) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testg 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CD3, CD4, CD8 Mon  
(4 ml lavender top, EDTA) 
 
 
 
 
 
X 
X 
X 
 
 
 
 
X 
Xh 
 
X 
 
Autoimmune Screeni  
(ANA, ESR) (4 ml SST ; 3ml 
lavender top EDTA) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral Serologyj  
(CMV, EBV, Hepatitis B/C)  
(5ml red top, serum) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CD19 CART-19 Protocol 
 
page 98 of 120 
Version 12.03-05-2015 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
Week/Day of treatment 
period 
 (-) 8 to 12x 
~ Wk  (-) 6 to 8 x 
~ Wk  (-) 4 x 
(+/- 1 wk)
~ Wk  (-) 1 
(+2 days) 
~ Day  (-) 1§ 
Day 1§ 
Day 2 (+1 day)§ 
Day 3 (+1 day)§ 
Day 4 (+1 day) 
Day 7 
(+/- 1 day) 
Day 10 
(+/- 1 day) 
Day  14,  21 
(+/- 1 day) 
Day 28 
(+/- 3 days) 
Month 2 to 6s 
(+/- 7 days) 
Month 9 
(+/- 7 days) 
Month 12t 
(+/- 7 days) 
Every 3 Months 
(+/- 1 month)bb 
 
Pre-entry 
evaluation 
Enrollment 
Apheresis  
Chemo- 
therapyj 
Pre – 
Infusion 
Infusion #1 
Infusion #2 
Infusion #3 
Post 
Infusion 
Post 
Infusion 
Post 
Infusion 
Post 
Infusion 
End of 
Treatment 
Post 
Infusion 
Post 
Infusion 
End of 
study 
Secondary 
Follow-up 
Visit Name 
Screening 
Week -8 to -12 
Baseline  
Week -6 to -8 
Apheresis   
Week -4  
Chemotherapy  
Week  (-1) 
Pre-infusion  
Day -1§ 
Infusion  #1 
Day 1§ 
Infusion #2 
Day 2 §aa 
Infusion #3 
Day 3 §aa 
Post infusion Day 4   
Post infusion  
Day 7          
Post infusion  
Day 10        
Post infusion  
Day 14        
Post infusion Day 21  
End of Treatment 
Safety follow-up 
1 to 5 
Safety follow-up 6 
End of study 
Secondary Follow-
up 
Visit number 
1 
2 
3 
4 
5 
6 
201 
202 
7 
8 
9 
10,11 
777 
501, 502, 
503, 504, 
505 
506 
778 
601 
β2 Microglobulin  
(1ml SST) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation factors  
(PT, PTT, INR, fibrinogen, 
D-dimer) (4.5 ml blue top 
citrate) 
 
 
 
 
X 
 
 
 
 
 
 
Xr 
 
 
 
 
 
HLH/MAS, 
(triglycerides, 
haptoglobin) 
(4 ml SST; 2.5 ml lavender 
top, EDTA) 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Serum immunoglobulin 
levels  
( 1ml SST)k 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Xk 
X k 
X k 
 
Immunoglobulin Heavy 
Chain  
(4ml lavender; 0.5-1ml 
BM) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CD19 CART-19 Protocol 
 
page 99 of 120 
Version 12.03-05-2015 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
Week/Day of treatment 
period 
 (-) 8 to 12x 
~ Wk  (-) 6 to 8 x 
~ Wk  (-) 4 x 
(+/- 1 wk)
~ Wk  (-) 1 
(+2 days) 
~ Day  (-) 1§ 
Day 1§ 
Day 2 (+1 day)§ 
Day 3 (+1 day)§ 
Day 4 (+1 day) 
Day 7 
(+/- 1 day) 
Day 10 
(+/- 1 day) 
Day  14,  21 
(+/- 1 day) 
Day 28 
(+/- 3 days) 
Month 2 to 6s 
(+/- 7 days) 
Month 9 
(+/- 7 days) 
Month 12t 
(+/- 7 days) 
Every 3 Months 
(+/- 1 month)bb 
 
Pre-entry 
evaluation 
Enrollment 
Apheresis  
Chemo- 
therapyj 
Pre – 
Infusion 
Infusion #1 
Infusion #2 
Infusion #3 
Post 
Infusion 
Post 
Infusion 
Post 
Infusion 
Post 
Infusion 
End of 
Treatment 
Post 
Infusion 
Post 
Infusion 
End of 
study 
Secondary 
Follow-up 
Visit Name 
Screening 
Week -8 to -12 
Baseline  
Week -6 to -8 
Apheresis   
Week -4  
Chemotherapy  
Week  (-1) 
Pre-infusion  
Day -1§ 
Infusion  #1 
Day 1§ 
Infusion #2 
Day 2 §aa 
Infusion #3 
Day 3 §aa 
Post infusion Day 4   
Post infusion  
Day 7          
Post infusion  
Day 10        
Post infusion  
Day 14        
Post infusion Day 21  
End of Treatment 
Safety follow-up 
1 to 5 
Safety follow-up 6 
End of study 
Secondary Follow-
up 
Visit number 
1 
2 
3 
4 
5 
6 
201 
202 
7 
8 
9 
10,11 
777 
501, 502, 
503, 504, 
505 
506 
778 
601 
Relapse and Survival 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xz 
Intervention 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemotherapyl, e 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CART-19 cell infusion 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Leukapheresis 
 
 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Labso   
Research blood  to 
CVPF for expansion 
screen  
(Two 10 ml green tops, 
Heparin)p 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Large Volume 
Peripheral Blood 
Draw (100mL) 
 
 
 
 
 
 
 
 
 
 
 
 
Xn 
 
 
 
 
Serum 5ml (Red top) 
 
X 
X 
 
X 
Xq 
Xq 
Xq 
X 
X 
X 
X 
X 
X 
X 
X 
 
Immunogenicity 
(HAMA/HACA) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 

CD19 CART-19 Protocol 
 
page 100 of 120 
Version 12.03-05-2015 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
Week/Day of treatment 
period 
 (-) 8 to 12x 
~ Wk  (-) 6 to 8 x 
~ Wk  (-) 4 x 
(+/- 1 wk)
~ Wk  (-) 1 
(+2 days) 
~ Day  (-) 1§ 
Day 1§ 
Day 2 (+1 day)§ 
Day 3 (+1 day)§ 
Day 4 (+1 day) 
Day 7 
(+/- 1 day) 
Day 10 
(+/- 1 day) 
Day  14,  21 
(+/- 1 day) 
Day 28 
(+/- 3 days) 
Month 2 to 6s 
(+/- 7 days) 
Month 9 
(+/- 7 days) 
Month 12t 
(+/- 7 days) 
Every 3 Months 
(+/- 1 month)bb 
 
Pre-entry 
evaluation 
Enrollment 
Apheresis  
Chemo- 
therapyj 
Pre – 
Infusion 
Infusion #1 
Infusion #2 
Infusion #3 
Post 
Infusion 
Post 
Infusion 
Post 
Infusion 
Post 
Infusion 
End of 
Treatment 
Post 
Infusion 
Post 
Infusion 
End of 
study 
Secondary 
Follow-up 
Visit Name 
Screening 
Week -8 to -12 
Baseline  
Week -6 to -8 
Apheresis   
Week -4  
Chemotherapy  
Week  (-1) 
Pre-infusion  
Day -1§ 
Infusion  #1 
Day 1§ 
Infusion #2 
Day 2 §aa 
Infusion #3 
Day 3 §aa 
Post infusion Day 4   
Post infusion  
Day 7          
Post infusion  
Day 10        
Post infusion  
Day 14        
Post infusion Day 21  
End of Treatment 
Safety follow-up 
1 to 5 
Safety follow-up 6 
End of study 
Secondary Follow-
up 
Visit number 
1 
2 
3 
4 
5 
6 
201 
202 
7 
8 
9 
10,11 
777 
501, 502, 
503, 504, 
505 
506 
778 
601 
Multiplex cytokine 
 
x 
x 
 
X 
Xq 
Xq 
Xq 
X 
X 
X 
X 
X 
X 
X 
x 
 
PBMC 25ml  
(Lavender, EDTA) 
 
X 
 
 
X 
Xq 
Xq 
Xq 
X 
X 
X 
X 
X 
X 
X 
X 
 
p53 Mutation Analysis 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DNA (Q-PCR persistence)  
 
x 
 
 
X 
Xq 
Xq 
Xq 
X 
X 
X 
X 
X 
X 
X 
X 
 
DNA  RCL (VSV-G Q-PCR) 
 
x 
 
 
X 
 
 
 
 
 
 
 
 
Xv 
 
X 
 
PBMC (functional assays, 
immunophenotyping, CART-
19 and B cell enumerationw) 
 
x 
 
 
X 
Xq 
Xq 
Xq 
Xq 
X 
X 
X 
X 
X 
X 
X 
 
Bone marrow /  
LN aspirate  
(5 ml lavender top, EDTA) 
 
X 
 
 
 
 
 
 
 
 
 
 
Xu 
Xu 
Xu 
Xu 
 
DNA (Q-PCR homing) 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Xu 
X 
X 
 
MMC (CART19 and B cell 
enumeration, 
immunophenotyping) 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Xu 
X 
X 
 
Marrow Serum (2  ml 
red top) 
 
X 
 
 
 
 
 
 
 
 
 
 
Xu 
Xu 
Xu 
Xu 
 
Multiplex cytokine 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Xu 
X 
X 
 

CD19 CART-19 Protocol 
 
page 101 of 120 
Version 12.03-05-2015 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
Week/Day of treatment 
period 
 (-) 8 to 12x 
~ Wk  (-) 6 to 8 x 
~ Wk  (-) 4 x 
(+/- 1 wk)
~ Wk  (-) 1 
(+2 days) 
~ Day  (-) 1§ 
Day 1§ 
Day 2 (+1 day)§ 
Day 3 (+1 day)§ 
Day 4 (+1 day) 
Day 7 
(+/- 1 day) 
Day 10 
(+/- 1 day) 
Day  14,  21 
(+/- 1 day) 
Day 28 
(+/- 3 days) 
Month 2 to 6s 
(+/- 7 days) 
Month 9 
(+/- 7 days) 
Month 12t 
(+/- 7 days) 
Every 3 Months 
(+/- 1 month)bb 
 
Pre-entry 
evaluation 
Enrollment 
Apheresis  
Chemo- 
therapyj 
Pre – 
Infusion 
Infusion #1 
Infusion #2 
Infusion #3 
Post 
Infusion 
Post 
Infusion 
Post 
Infusion 
Post 
Infusion 
End of 
Treatment 
Post 
Infusion 
Post 
Infusion 
End of 
study 
Secondary 
Follow-up 
Visit Name 
Screening 
Week -8 to -12 
Baseline  
Week -6 to -8 
Apheresis   
Week -4  
Chemotherapy  
Week  (-1) 
Pre-infusion  
Day -1§ 
Infusion  #1 
Day 1§ 
Infusion #2 
Day 2 §aa 
Infusion #3 
Day 3 §aa 
Post infusion Day 4   
Post infusion  
Day 7          
Post infusion  
Day 10        
Post infusion  
Day 14        
Post infusion Day 21  
End of Treatment 
Safety follow-up 
1 to 5 
Safety follow-up 6 
End of study 
Secondary Follow-
up 
Visit number 
1 
2 
3 
4 
5 
6 
201 
202 
7 
8 
9 
10,11 
777 
501, 502, 
503, 504, 
505 
506 
778 
601 
Total research blood 
needs 
20 
ml 
32 
ml 
5 
ml 
0 
ml 
30 
ml 
36 
ml 
36 
ml 
36 
ml 
30 
ml 
30 
ml 
30 
ml 
30 
ml 
130 
ml 
30 
ml 
30 
ml 
30 
ml 
N/A 
TOTAL BLOOD DRAW 
21 
ml 
60 
ml 
5 
ml 
0 
ml 
49-
56 
ml 
45-
56 
ml 
45-
56 
ml 
45-
56 
ml 
38-50 
ml 
38-
50 
ml 
38-
50 
ml 
49-61  
ml 
143-
161 
ml 
42-61 
ml 
38-
57 
ml 
42-
61 
ml 
N/A 
 

CD19 CART-19 Protocol 
 
page 102 of 120 
Version 12.03-05-2015 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
§ 
Lab tests specified on the infusion day will be drawn prior to infusion.  A blood draw for potassium will be drawn 2 hours post infusion. The 
Investigator will review all pre-infusion lab (day -1) results to determine that it is appropriate to proceed with the infusion.  Any abnormal Cr, Ca, K, 
Phos or uric acid result that is a change from the prior value should be reviewed by the PI prior to the infusion.  Any new lab abnormalities that are 
also a change from the prior value will be reviewed by investigators. Additional Research Sample Collection: In the event something unexpected 
occurs the protocol, the research team may request an additional sample collection be performed to collect additional blood or marrow/LN samples 
for research analysis. This is being done with the intention of evaluating the likely effects from the investigational products received. The total 
amount of extra blood that will be collected will be 3 tablespoons of blood twice in one week.  The total amount of extra bone marrow or lymph node 
biopsies collected from you will be up to 1 extra procedure per month. 
 
 
a. Medical history, physical exam, documentation of adverse events and concomitant medications are to be done prior to infusion. 
Hematology and chemistry results are to be obtained prior to each infusion.  Hematology includes CBC, differential, and platelet count.  
Chemistry will include Glucose, BUN, Creatinine, Sodium, Potassium, Calcium, Total Protein, Albumin, Total Bilirubin, Alk Phos, 
AST, ALT, Mg, Phos, LDH, Ferritin, CRP and Uric Acid.  A separate sample for serum K+ is taken approximately 2 hours post-infusion.   
b. Physical exam includes vital signs.  Height, weight, body surface area at enrollment and as clinically indicated. 
c. Adverse events must be reported from the time the patient’s informed consent has been obtained to end of the study. 
d. CT scans should be performed within 42 days of study entry for disease evaluation and as clinically indicated for disease monitoring. 
e. As clinically needed. 
f. Should be performed within 6 weeks of the first CART-19 infusion, but does not need to be performed on the same day as apheresis. 
g. Pregnancy test (quantitative) for female only. 
h. Blood for CD3, CD4, CD8 Lymphocytes taken at months 3 and 6 only. 
i. Autoimmune screen (ANA, ESR) 
j. Viral Serology includes CMV, EBV, and Hepatitis B and C 
k. Serum immunoglobulins will be collected at months 3, 6, 9 and 12 and as clinically indicated. 
l. Chemotherapy as appropriate for disease type. See section 6.5 
m. 12-15 liter apheresis to go to CVPF. 1 x 108 cells to be delivered to TCSL. 
n. 100 mL peripheral blood draw (Lavender EDTA 10mL tubes) to be delivered to TCSL.  
o. TCSL has requested labs samples for research be sent to TCSL as soon as collected. If required to keep research labs after hours, please 
keep red tops upright,   lavender tubes should be room temperature on rotating platforms.  In the event that something unexpected occurs, 
additional research sample collection may be done as necessary. Blood collects are not to exceed 3 tablespoons of blood twice in one 
week time window. Marrow/LN collections would not exceed more than one procedure per month.  This would be at PI discretion. 
p. Two 10 ml green tops to CVPF  
q. The research blood collection is split on infusion days:  20 mL EDTA (lavender) and 2 mL serum (red) are collected pre-infusion for 
cytokines, qPCR and cellular assessments; 5 mL EDTA (lavender) and 2 mL serum (red) are collected 20-120min post-infusion for 
cytokines and qPCR only (cellular assessments only done pre-infusion).  
r. Required on Day 14 and as clinically needed on Day 21. 
s. Post infusion assessments will be performed monthly from month 2 to month 6. 

CD19 CART-19 Protocol 
 
page 104 of 120 
Version 12.03-05-2015 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
Appendix 2 - Schedule of Study Procedures/Retreatment Cohort- Single Dose 
Week/Day of treatment period 
~ Wk  (-) 1 to 6  
~ Wk  (-) 4 to 6  
(+/- 1 wk)m 
~ Wk  (-) 1 
(+2 days) 
~ Day  (-) 1§ 
Day 1§ 
Day 2 
(+1 day)  
Day 7 
(+/- 1 day) 
Day 10 
(+/- 1 day) 
Day  14,  21 
(+/- 1 day) 
Day 28 
(+/- 3 days) 
Month 2 to 6r 
(+/- 7 days) 
Month 9 
(+/- 7 days) 
Month 12s 
(+/- 7 days) 
Every 3 Months 
(+/- 1 month) 
 
Screening/ 
Baseline 
Apheresis #1 
Chemo- 
therapyj 
Pre – 
Infusion 
Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
End of 
Treatment 
Post Infusion 
Post Infusion 
End of study 
Secondary 
Follow-up 
Visit Name 
Screening/Baseline  
Week -1 to -6 
Apheresis #1  
Week -4 to -6m 
Chemotherapy  
Week  (-1) 
Pre-infusion  
Day -1§ 
Infusion  
Day 1§ 
Post infusion  
Day 2         
Post infusion  
Day 7          
Post infusion  
Day 10        
Post infusion  
Day 14        
Post infusion Day 21  
End of Treatment 
Safety follow-up 
1 to 5 
Safety follow-up 6 
End of study 
Secondary Follow-up 
Visit number 
101  
 102 
 103 
 104 
 105  
 106 
 107 
 108 
 109, 110 
 779 
551, 552, 
553, 554, 
555 
556 
780 
602 
Clinical Assessments 
Retreatment Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Retreatment Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quality of Life Questionnaires 
(EORTC QLQ-C30 and CLL-16) 
X 
 
X 
 
 
 
 
 
 
X 
Xu 
X 
X 
 
Interim Treatment History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Current Medical Conditions 
X 
X 
X 
X 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical examb 
X 
 
 
X 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
 
Performance Status Assessment 
X 
 
 
X 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Meds 
X 
X 
X 
X 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Eventsc 
X 
X 
X 
X 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
 
HIV  test (1 ml SST) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
p53 Mutation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 

CD19 CART-19 Protocol 
 
page 105 of 120 
Version 12.03-05-2015 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
Week/Day of treatment period 
~ Wk  (-) 1 to 6  
~ Wk  (-) 4 to 6  
(+/- 1 wk)m 
~ Wk  (-) 1 
(+2 days) 
~ Day  (-) 1§ 
Day 1§ 
Day 2 
(+1 day)  
Day 7 
(+/- 1 day) 
Day 10 
(+/- 1 day) 
Day  14,  21 
(+/- 1 day) 
Day 28 
(+/- 3 days) 
Month 2 to 6r 
(+/- 7 days) 
Month 9 
(+/- 7 days) 
Month 12s 
(+/- 7 days) 
Every 3 Months 
(+/- 1 month) 
 
Screening/ 
Baseline 
Apheresis #1 
Chemo- 
therapyj 
Pre – 
Infusion 
Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
End of 
Treatment 
Post Infusion 
Post Infusion 
End of study 
Secondary 
Follow-up 
Visit Name 
Screening/Baseline  
Week -1 to -6 
Apheresis #1  
Week -4 to -6m 
Chemotherapy  
Week  (-1) 
Pre-infusion  
Day -1§ 
Infusion  
Day 1§ 
Post infusion  
Day 2         
Post infusion  
Day 7          
Post infusion  
Day 10        
Post infusion  
Day 14        
Post infusion Day 21  
End of Treatment 
Safety follow-up 
1 to 5 
Safety follow-up 6 
End of study 
Secondary Follow-up 
Visit number 
101  
 102 
 103 
 104 
 105  
 106 
 107 
 108 
 109, 110 
 779 
551, 552, 
553, 554, 
555 
556 
780 
602 
Leukapheresis screening 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT scan of chest, abdomen, pelvisd 
X 
 
 
 
 
 
 
 
 
X 
Xu 
X 
X 
 
Bone marrow biopsy/aspirateo 
X 
 
 
 
 
 
 
 
 
X 
Xu 
X 
X 
 
Lymph Node biopsy 
Xe 
 
 
 
 
 
 
 
 
Xe 
Xu,e 
Xe 
Xe 
 
ECHO/MUGAf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Respiratory Virus Panel (RVP) 
 
 
Xw 
 
 
 
 
 
 
 
 
 
 
 
Blood Draws 
Hematology (CBC, differential, 
platelet count)  
(5 ml lavender top, EDTA)a 
X 
 
 
X 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry (3 ml SST) 
X 
 
 
X 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum pregnancy testg  
(1 ml SST) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testg 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
CD3, CD4, CD8 Mon (4 ml 
lavender top, EDTA) 
 
 
 
 
X 
 
 
 
 
X 
Xh 
 
X 
 

CD19 CART-19 Protocol 
 
page 106 of 120 
Version 12.03-05-2015 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
Week/Day of treatment period 
~ Wk  (-) 1 to 6  
~ Wk  (-) 4 to 6  
(+/- 1 wk)m 
~ Wk  (-) 1 
(+2 days) 
~ Day  (-) 1§ 
Day 1§ 
Day 2 
(+1 day)  
Day 7 
(+/- 1 day) 
Day 10 
(+/- 1 day) 
Day  14,  21 
(+/- 1 day) 
Day 28 
(+/- 3 days) 
Month 2 to 6r 
(+/- 7 days) 
Month 9 
(+/- 7 days) 
Month 12s 
(+/- 7 days) 
Every 3 Months 
(+/- 1 month) 
 
Screening/ 
Baseline 
Apheresis #1 
Chemo- 
therapyj 
Pre – 
Infusion 
Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
End of 
Treatment 
Post Infusion 
Post Infusion 
End of study 
Secondary 
Follow-up 
Visit Name 
Screening/Baseline  
Week -1 to -6 
Apheresis #1  
Week -4 to -6m 
Chemotherapy  
Week  (-1) 
Pre-infusion  
Day -1§ 
Infusion  
Day 1§ 
Post infusion  
Day 2         
Post infusion  
Day 7          
Post infusion  
Day 10        
Post infusion  
Day 14        
Post infusion Day 21  
End of Treatment 
Safety follow-up 
1 to 5 
Safety follow-up 6 
End of study 
Secondary Follow-up 
Visit number 
101  
 102 
 103 
 104 
 105  
 106 
 107 
 108 
 109, 110 
 779 
551, 552, 
553, 554, 
555 
556 
780 
602 
Autoimmune Screeni  (ANA, ESR) 
(4 ml SST ; 3ml lavender top 
EDTA) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral Serologyj (CMV, EBV, 
Hepatitis B/C)  (5ml red top, 
serum) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
β2 Microglobulin (1ml SST) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation factors (PT, PTT, INR, 
fibrinogen, D-dimer) (4.5 ml blue 
top citrate) 
 
 
 
X 
 
 
 
 
Xq 
 
 
 
 
 
HLH/MAS (triglycerides, 
haptoglobin 
(4 ml SST; 2.5 ml lavender top, 
EDTA) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Serum immunoglobulin levels  
( 1ml SST)k 
X 
 
 
 
 
 
 
 
 
X 
Xk 
Xk 
Xk 
 

CD19 CART-19 Protocol 
 
page 107 of 120 
Version 12.03-05-2015 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
Week/Day of treatment period 
~ Wk  (-) 1 to 6  
~ Wk  (-) 4 to 6  
(+/- 1 wk)m 
~ Wk  (-) 1 
(+2 days) 
~ Day  (-) 1§ 
Day 1§ 
Day 2 
(+1 day)  
Day 7 
(+/- 1 day) 
Day 10 
(+/- 1 day) 
Day  14,  21 
(+/- 1 day) 
Day 28 
(+/- 3 days) 
Month 2 to 6r 
(+/- 7 days) 
Month 9 
(+/- 7 days) 
Month 12s 
(+/- 7 days) 
Every 3 Months 
(+/- 1 month) 
 
Screening/ 
Baseline 
Apheresis #1 
Chemo- 
therapyj 
Pre – 
Infusion 
Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
End of 
Treatment 
Post Infusion 
Post Infusion 
End of study 
Secondary 
Follow-up 
Visit Name 
Screening/Baseline  
Week -1 to -6 
Apheresis #1  
Week -4 to -6m 
Chemotherapy  
Week  (-1) 
Pre-infusion  
Day -1§ 
Infusion  
Day 1§ 
Post infusion  
Day 2         
Post infusion  
Day 7          
Post infusion  
Day 10        
Post infusion  
Day 14        
Post infusion Day 21  
End of Treatment 
Safety follow-up 
1 to 5 
Safety follow-up 6 
End of study 
Secondary Follow-up 
Visit number 
101  
 102 
 103 
 104 
 105  
 106 
 107 
 108 
 109, 110 
 779 
551, 552, 
553, 554, 
555 
556 
780 
602 
Immunoglobulin Heavy Chain 
(4ml lavender; 0.5-1ml BM) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relapse and Survival Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xx 
Intervention 
Chemotherapyl, e 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
CART-19 cell infusion 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Leukapheresis 
 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
Research Labso   
Large Volume Peripheral Blood 
Draw (100mL) 
 
 
 
 
 
 
 
 
 
Xn 
 
 
 
 
Serum 5ml (Red top) 
X 
X 
 
X 
Xp 
X 
X 
X 
X 
X 
X 
X 
X 
 
HAMA 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
HACA 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Multiplex cytokine 
X 
X 
 
X 
Xp 
X 
X 
X 
X 
X 
X 
X 
x 
 
PBMC 25ml (Lavender, EDTA) 
X 
 
 
X 
Xp 
X 
X 
X 
X 
X 
X 
X 
X 
 

CD19 CART-19 Protocol 
 
page 108 of 120 
Version 12.03-05-2015 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
Week/Day of treatment period 
~ Wk  (-) 1 to 6  
~ Wk  (-) 4 to 6  
(+/- 1 wk)m 
~ Wk  (-) 1 
(+2 days) 
~ Day  (-) 1§ 
Day 1§ 
Day 2 
(+1 day)  
Day 7 
(+/- 1 day) 
Day 10 
(+/- 1 day) 
Day  14,  21 
(+/- 1 day) 
Day 28 
(+/- 3 days) 
Month 2 to 6r 
(+/- 7 days) 
Month 9 
(+/- 7 days) 
Month 12s 
(+/- 7 days) 
Every 3 Months 
(+/- 1 month) 
 
Screening/ 
Baseline 
Apheresis #1 
Chemo- 
therapyj 
Pre – 
Infusion 
Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
End of 
Treatment 
Post Infusion 
Post Infusion 
End of study 
Secondary 
Follow-up 
Visit Name 
Screening/Baseline  
Week -1 to -6 
Apheresis #1  
Week -4 to -6m 
Chemotherapy  
Week  (-1) 
Pre-infusion  
Day -1§ 
Infusion  
Day 1§ 
Post infusion  
Day 2         
Post infusion  
Day 7          
Post infusion  
Day 10        
Post infusion  
Day 14        
Post infusion Day 21  
End of Treatment 
Safety follow-up 
1 to 5 
Safety follow-up 6 
End of study 
Secondary Follow-up 
Visit number 
101  
 102 
 103 
 104 
 105  
 106 
 107 
 108 
 109, 110 
 779 
551, 552, 
553, 554, 
555 
556 
780 
602 
p53 Mutation Analysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
DNA (Q-PCR persistence)  
X 
 
 
X 
Xp 
X 
X 
X 
X 
X 
X 
X 
X 
 
DNA  RCL (VSV-G Q-PCR) 
X 
 
 
X 
 
 
 
 
 
 
Xu 
 
X 
 
PBMC (functional assays, 
immunophenotyping, CART-19 and B cell 
enumerationv) 
X 
 
 
X 
Xp 
Xq 
X 
X 
X 
X 
X 
X 
X 
 
Bone marrow / LN aspirate  
(5 ml lavender top, EDTA) 
X 
 
 
 
 
 
 
 
 
Xt 
Xt 
Xt 
Xt 
 
DNA (Q-PCR homing) 
X 
 
 
 
 
 
 
 
 
X 
Xt 
X 
X 
 
MMC (CART19 and B cell enumeration, 
immunophenotyping) 
X 
 
 
 
 
 
 
 
 
X 
Xt 
X 
X 
 
Marrow Serum (2  ml red top) 
X 
 
 
 
 
 
 
 
 
Xt 
Xt 
Xt 
Xt 
 
Multiplex cytokine 
X 
 
 
 
 
 
 
 
 
X 
Xt 
X 
X 
 
Total research blood needs 
32 
ml 
5 
ml 
0 
ml 
30 
ml 
36 
ml 
30 
ml 
30 
ml 
30 
ml 
30 
ml 
130 
ml 
30 
ml 
30 
ml 
30 
ml 
N/A 

CD19 CART-19 Protocol 
 
page 109 of 120 
Version 12.03-05-2015 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
Week/Day of treatment period 
~ Wk  (-) 1 to 6  
~ Wk  (-) 4 to 6  
(+/- 1 wk)m 
~ Wk  (-) 1 
(+2 days) 
~ Day  (-) 1§ 
Day 1§ 
Day 2 
(+1 day)  
Day 7 
(+/- 1 day) 
Day 10 
(+/- 1 day) 
Day  14,  21 
(+/- 1 day) 
Day 28 
(+/- 3 days) 
Month 2 to 6r 
(+/- 7 days) 
Month 9 
(+/- 7 days) 
Month 12s 
(+/- 7 days) 
Every 3 Months 
(+/- 1 month) 
 
Screening/ 
Baseline 
Apheresis #1 
Chemo- 
therapyj 
Pre – 
Infusion 
Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
End of 
Treatment 
Post Infusion 
Post Infusion 
End of study 
Secondary 
Follow-up 
Visit Name 
Screening/Baseline  
Week -1 to -6 
Apheresis #1  
Week -4 to -6m 
Chemotherapy  
Week  (-1) 
Pre-infusion  
Day -1§ 
Infusion  
Day 1§ 
Post infusion  
Day 2         
Post infusion  
Day 7          
Post infusion  
Day 10        
Post infusion  
Day 14        
Post infusion Day 21  
End of Treatment 
Safety follow-up 
1 to 5 
Safety follow-up 6 
End of study 
Secondary Follow-up 
Visit number 
101  
 102 
 103 
 104 
 105  
 106 
 107 
 108 
 109, 110 
 779 
551, 552, 
553, 554, 
555 
556 
780 
602 
TOTAL BLOOD DRAW 
60 
ml 
5 
ml 
0 
ml 
49-
56 
ml 
45-
56 
ml 
38-
50 
ml 
38-
50 
ml 
38-
50 
ml 
49-61  
ml 
143-
161 
ml 
42-61 
ml 
38-
57 
ml 
42-61 
ml 
N/A 
 
 
 
§ 
Lab tests specified on the infusion day will be drawn prior to infusion.  A blood draw for potassium will be drawn 2 hours post infusion. The 
Investigator will review all pre-infusion lab (day -1) results to determine that it is appropriate to proceed with the infusion.  Any abnormal Cr, Ca, K, 
Phos or uric acid result that is a change from the prior value should be reviewed by the PI prior to the infusion.  Any new lab abnormalities that are 
also a change from the prior value will be reviewed by investigators. Additional Research Sample Collection: In the event something unexpected occurs 
the protocol, the research team may request an additional sample collection be performed to collect additional blood or marrow/LN samples for research 
analysis. This is being done with the intention of evaluating the likely effects from the investigational products received. The total amount of extra 
blood that will be collected will be 3 tablespoons of blood twice in one week.  The total amount of extra bone marrow or lymph node biopsies collected 
from you will be up to 1 extra procedure per month. 
 
 
a. Medical history, physical exam, documentation of adverse events and concomitant medications are to be done prior to infusion. 
Hematology and chemistry results are to be obtained prior to infusion for day 1.  Hematology includes CBC, differential, and platelet 

CD19 CART-19 Protocol 
 
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Version 12.03-05-2015 
CONFIDENTIAL 
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count.  Chemistry will include Glucose, BUN, Creatinine, Sodium, Potassium, Calcium, Total Protein, Albumin, Total Bilirubin, Alk 
Phos, AST, ALT, Mg, Phos, LDH, Ferritin, CRP and Uric Acid.  A separate sample for serum K+ is taken approximately 2 hours post-
infusion.   
b. Physical exam includes vital signs.  Height, weight, body surface area at enrollment and as clinically indicated. 
c. Adverse events must be reported from the time the patient signs the retreatment consent until the end of the study. 
d. CT scans should be performed within 42 days of study entry for disease evaluation and as clinically indicated for disease monitoring. 
e. As clinically needed at baseline and throughout the study. 
f. Should be performed within 6 weeks of infusion, but does not need to be performed on the same day as apheresis. 
g. Pregnancy test (quantitative) for female only. 
h. Blood for CD3, CD4, CD8 Lymphocytes taken at months 3 and 6 only. 
i. Autoimmune screen (ANA, ESR) 
j. Viral Serology includes CMV, EBV, and Hepatitis B and C 
k. Serum immunoglobulins will be collected at months 3, 6, 9 and 12, and as clinically indicated. 
l. Chemotherapy as appropriate for disease type. See section 6.5 
m. If there is an existing sufficient CART19 dose, leukapheresis screening to assess venous access will not be performed.  However, if there 
is either an insufficient manufactured dose or starting material available in the CVPF, the subject will be asked to undergo apheresis to 
collect additional cells to manufacturer a sufficient dose for retreatment, and CART19 T cells will be administered via split dosing based 
on the Retreatment Cohort Schedule of Events for Split Dosing Administration below.   
n.  100mL peripheral blood draw (lavender EDTA 10mL tubes) to be delivered to the TCSL. 
o. TCSL has requested labs samples for research be sent to TCSL as soon as collected. If required to keep research labs after hours, please 
keep red tops upright,   lavender tubes should be room temperature on rotating platforms.  In the event that something unexpected occurs, 
additional research sample collection may be done as necessary. Blood collects are not to exceed 3 tablespoons of blood twice in one 
week time window. Marrow/LN collections would not exceed more than one procedure per month.  This would be at PI discretion. 
p. The research blood collection is split on infusion day:  20 mL EDTA (lavender) and 2 mL serum (red) are collected pre-infusion for 
cytokines, qPCR and cellular assessments; 5 mL EDTA (lavender) and 2 mL serum (red) are collected 20-120min post-infusion for 
cytokines and qPCR only (cellular assessments only done pre-infusion).  
q. Required on Day 14 and as clinically needed on Day 21. 
r. Post infusion assessments will be performed monthly from month 2 to month 6. 
s. After year 1, patients will be enrolled into a destination protocol (IRB#
/UPCC 
) for follow-up by phone or mail for up to 
15 years post first T cell infusion, to monitor for delayed adverse events associated with the lentiviral vector genetic modification. 
t. Concomitant with clinical draw, and also at months 1, 3, 6, 9 and 12 post-infusion.  5 ml in lavender top (DNA) and 2 ml in red top 
(serum) to be delivered to TCSL. 
u. At months 3 and 6 only. 
v. CART19 , tumor, and B cells enumerated by flow cytometry following pre-gating using CD3+/CAR19+, CD5,CD19/kappa or lambda 
and CD19+ expression respectively. 
w. All patients must undergo a Respiratory Virus Panel (RVP) to test for influenza within 10 days prior to the planned CART-19 infusion.  
The Respiratory Virus Panel includes: Influenza A, Influenza B, Respiratory Syncytial Virus A, Respiratory Syncytial Virus B, 

CD19 CART-19 Protocol 
 
page 111 of 120 
Version 12.03-05-2015 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
Parainfluenza Virus Type 1, Parainfluenza Virus Type 2, Parainfluenza Virus Type 3, Adenovirus.  If the patient is positive for influenza, 
oseltamivir phosphate (Tamiflu®) or equivalent should be administered for 10 days as preventative treatment (see Tamiflu® package 
insert for dosing information). The patient must complete this course of preventative treatment prior to receiving the CART-19 infusion. If 
the patient is positive for influenza and is also experiencing flu-like symptoms, all clinical symptoms must also be resolved prior to the 
CART-19 infusion.  If the patient is positive for another virus on the RVP, the CART-19 infusion will be delayed for at least 7 days to be 
sure clinical symptoms of a viral infection do not develop.  If clinical symptoms develop, the infusion will be delayed until resolution of 
these symptoms. 
x. For subjects who complete or prematurely discontinue from study follow-up while in remission, follow-up attempts will be made to 
assess subject’s relapse and survival status every 3 months post CART-19 infusion until the end of the study (Last Patient/Last Visit).  
Once subjects’ relapse or they begin a new cancer therapy, additional follow-up for relapse will not be required, and subjects will be 
followed for survival only. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CD19 CART-19 Protocol 
 
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Version 12.03-05-2015 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
Schedule of Study Procedures/Retreatment Cohort- Split Dosing Administration 
 
Week/Day of treatment period 
~ Wk  (-) 1 to 6  
~ Wk  (-) 4 to 6  
(+/- 1 wk)m 
~ Wk  (-) 1 
(+2 days) 
~ Day  (-) 1§ 
Day 1§ 
Day 2 (+1 day)§ 
Day 3 (+1 day)§ 
Day 4 
 (+1 day)  
Day 7 
(+/- 1 day) 
Day 10 
(+/- 1 day) 
Day  14,  21 
(+/- 1 day) 
Day 28 
(+/- 3 days) 
Month 2 to 6r 
(+/- 7 days) 
Month 9 
(+/- 7 days) 
Month 12s 
(+/- 7 days) 
Every 3 Months 
(+/- 1 month)y 
 
Screening/ 
Baseline 
Apheresis 
Chemo- 
therapyj 
Pre – 
Infusion 
Infusion 
Infusion 
Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
End of 
Treatment 
Post Infusion 
Post Infusion 
End of study 
Secondary 
Follow-up 
Visit Name 
Screening/Baseline  
Week -1 to -6 
Apheresis  
Week -4 to -6m 
Chemotherapy  
Week  (-1) 
Pre-infusion  
Day -1§ 
Infusion  
Day 1§ 
Infusion #2 
Day 2 § 
Infusion #3 
Day 3 § 
Post infusion 
 Day 4        
Post infusion  
Day 7          
Post infusion  
Day 10        
Post infusion  
Day 14        
End of Treatment 
Safety follow-up 
1 to 5 
Safety follow-up 6 
End of study 
Secondary Follow-up 
Visit number 
101   102 
 103 
 104 
 105  
203 
204 
106 
107 
108 
109, 
110 
 779 
551, 
552, 
553, 
554, 
555 
556 
780 
602 
Clinical Assessments 
Retreatment Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Retreatment Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quality of Life Questionnaires 
(EORTC QLQ-C30 and CLL-16) 
X 
 
X 
 
 
 
 
 
 
 
 
X 
Xu 
X 
X 
 
Interim Treatment History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Current Medical Conditions 
X 
X 
X 
X 
Xa 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical examb 
X 
 
 
X 
Xa 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
 
Performance Status Assessment 
X 
 
 
X 
Xa 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Meds 
X 
X 
X 
X 
Xa 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Eventsc 
X 
X 
X 
X 
Xa 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
 
HIV  test (1 ml SST) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CD19 CART-19 Protocol 
 
page 113 of 120 
Version 12.03-05-2015 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
Week/Day of treatment period 
~ Wk  (-) 1 to 6  
~ Wk  (-) 4 to 6  
(+/- 1 wk)m 
~ Wk  (-) 1 
(+2 days) 
~ Day  (-) 1§ 
Day 1§ 
Day 2 (+1 day)§ 
Day 3 (+1 day)§ 
Day 4 
 (+1 day)  
Day 7 
(+/- 1 day) 
Day 10 
(+/- 1 day) 
Day  14,  21 
(+/- 1 day) 
Day 28 
(+/- 3 days) 
Month 2 to 6r 
(+/- 7 days) 
Month 9 
(+/- 7 days) 
Month 12s 
(+/- 7 days) 
Every 3 Months 
(+/- 1 month)y 
 
Screening/ 
Baseline 
Apheresis 
Chemo- 
therapyj 
Pre – 
Infusion 
Infusion 
Infusion 
Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
End of 
Treatment 
Post Infusion 
Post Infusion 
End of study 
Secondary 
Follow-up 
Visit Name 
Screening/Baseline  
Week -1 to -6 
Apheresis  
Week -4 to -6m 
Chemotherapy  
Week  (-1) 
Pre-infusion  
Day -1§ 
Infusion  
Day 1§ 
Infusion #2 
Day 2 § 
Infusion #3 
Day 3 § 
Post infusion 
 Day 4        
Post infusion  
Day 7          
Post infusion  
Day 10        
Post infusion  
Day 14        
End of Treatment 
Safety follow-up 
1 to 5 
Safety follow-up 6 
End of study 
Secondary Follow-up 
Visit number 
101   102 
 103 
 104 
 105  
203 
204 
106 
107 
108 
109, 
110 
 779 
551, 
552, 
553, 
554, 
555 
556 
780 
602 
p53 Mutation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leukapheresis screening 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT scan of chest, abdomen, pelvisd 
X 
 
 
 
 
 
 
 
 
 
 
X 
Xu 
X 
X 
 
Bone marrow biopsy/aspirateo 
X 
 
 
 
 
 
 
 
 
 
 
X 
Xu 
X 
X 
 
Lymph Node biopsy 
Xe 
 
 
 
 
 
 
 
 
 
 
Xe 
Xu,e 
Xe 
Xe 
 
ECHO/MUGAf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Respiratory Virus Panel (RVP) 
 
 
Xw 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Draws 
Hematology (CBC, differential, 
platelet count)  
(5 ml lavender top, EDTA)a 
X 
 
 
X 
Xa 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry (3 ml SST) 
X 
 
 
X 
Xa 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum pregnancy testg  
(1 ml SST) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CD19 CART-19 Protocol 
 
page 114 of 120 
Version 12.03-05-2015 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
Week/Day of treatment period 
~ Wk  (-) 1 to 6  
~ Wk  (-) 4 to 6  
(+/- 1 wk)m 
~ Wk  (-) 1 
(+2 days) 
~ Day  (-) 1§ 
Day 1§ 
Day 2 (+1 day)§ 
Day 3 (+1 day)§ 
Day 4 
 (+1 day)  
Day 7 
(+/- 1 day) 
Day 10 
(+/- 1 day) 
Day  14,  21 
(+/- 1 day) 
Day 28 
(+/- 3 days) 
Month 2 to 6r 
(+/- 7 days) 
Month 9 
(+/- 7 days) 
Month 12s 
(+/- 7 days) 
Every 3 Months 
(+/- 1 month)y 
 
Screening/ 
Baseline 
Apheresis 
Chemo- 
therapyj 
Pre – 
Infusion 
Infusion 
Infusion 
Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
End of 
Treatment 
Post Infusion 
Post Infusion 
End of study 
Secondary 
Follow-up 
Visit Name 
Screening/Baseline  
Week -1 to -6 
Apheresis  
Week -4 to -6m 
Chemotherapy  
Week  (-1) 
Pre-infusion  
Day -1§ 
Infusion  
Day 1§ 
Infusion #2 
Day 2 § 
Infusion #3 
Day 3 § 
Post infusion 
 Day 4        
Post infusion  
Day 7          
Post infusion  
Day 10        
Post infusion  
Day 14        
End of Treatment 
Safety follow-up 
1 to 5 
Safety follow-up 6 
End of study 
Secondary Follow-up 
Visit number 
101   102 
 103 
 104 
 105  
203 
204 
106 
107 
108 
109, 
110 
 779 
551, 
552, 
553, 
554, 
555 
556 
780 
602 
Urine pregnancy testg 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CD3, CD4, CD8 Mon (4 ml 
lavender top, EDTA) 
 
 
 
 
X 
 
 
 
 
 
 
X 
Xh 
 
X 
 
Autoimmune Screeni  (ANA, ESR) 
(4 ml SST ; 3ml lavender top 
EDTA) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral Serologyj (CMV, EBV, 
Hepatitis B/C)  (5ml red top, 
serum) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
β2 Microglobulin (1ml SST) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation factors (PT, PTT, INR, 
fibrinogen, D-dimer) (4.5 ml blue 
top citrate) 
 
 
 
X 
 
 
 
 
 
 
Xq 
 
 
 
 
 

CD19 CART-19 Protocol 
 
page 115 of 120 
Version 12.03-05-2015 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
Week/Day of treatment period 
~ Wk  (-) 1 to 6  
~ Wk  (-) 4 to 6  
(+/- 1 wk)m 
~ Wk  (-) 1 
(+2 days) 
~ Day  (-) 1§ 
Day 1§ 
Day 2 (+1 day)§ 
Day 3 (+1 day)§ 
Day 4 
 (+1 day)  
Day 7 
(+/- 1 day) 
Day 10 
(+/- 1 day) 
Day  14,  21 
(+/- 1 day) 
Day 28 
(+/- 3 days) 
Month 2 to 6r 
(+/- 7 days) 
Month 9 
(+/- 7 days) 
Month 12s 
(+/- 7 days) 
Every 3 Months 
(+/- 1 month)y 
 
Screening/ 
Baseline 
Apheresis 
Chemo- 
therapyj 
Pre – 
Infusion 
Infusion 
Infusion 
Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
End of 
Treatment 
Post Infusion 
Post Infusion 
End of study 
Secondary 
Follow-up 
Visit Name 
Screening/Baseline  
Week -1 to -6 
Apheresis  
Week -4 to -6m 
Chemotherapy  
Week  (-1) 
Pre-infusion  
Day -1§ 
Infusion  
Day 1§ 
Infusion #2 
Day 2 § 
Infusion #3 
Day 3 § 
Post infusion 
 Day 4        
Post infusion  
Day 7          
Post infusion  
Day 10        
Post infusion  
Day 14        
End of Treatment 
Safety follow-up 
1 to 5 
Safety follow-up 6 
End of study 
Secondary Follow-up 
Visit number 
101   102 
 103 
 104 
 105  
203 
204 
106 
107 
108 
109, 
110 
 779 
551, 
552, 
553, 
554, 
555 
556 
780 
602 
HLH/MAS (triglycerides, 
haptoglobin 
(4 ml SST; 2.5 ml lavender top, 
EDTA) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Serum immunoglobulin levels  
( 1ml SST)k 
X 
 
 
 
 
 
 
 
 
 
 
X 
Xk 
Xk 
Xk 
 
Immunoglobulin Heavy Chain 
(4ml lavender; 0.5-1ml BM) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relapse and Survival Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xx 
Intervention 
Chemotherapyl, e 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CART-19 cell infusion 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Leukapheresis 
 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Labso   

CD19 CART-19 Protocol 
 
page 116 of 120 
Version 12.03-05-2015 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
Week/Day of treatment period 
~ Wk  (-) 1 to 6  
~ Wk  (-) 4 to 6  
(+/- 1 wk)m 
~ Wk  (-) 1 
(+2 days) 
~ Day  (-) 1§ 
Day 1§ 
Day 2 (+1 day)§ 
Day 3 (+1 day)§ 
Day 4 
 (+1 day)  
Day 7 
(+/- 1 day) 
Day 10 
(+/- 1 day) 
Day  14,  21 
(+/- 1 day) 
Day 28 
(+/- 3 days) 
Month 2 to 6r 
(+/- 7 days) 
Month 9 
(+/- 7 days) 
Month 12s 
(+/- 7 days) 
Every 3 Months 
(+/- 1 month)y 
 
Screening/ 
Baseline 
Apheresis 
Chemo- 
therapyj 
Pre – 
Infusion 
Infusion 
Infusion 
Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
End of 
Treatment 
Post Infusion 
Post Infusion 
End of study 
Secondary 
Follow-up 
Visit Name 
Screening/Baseline  
Week -1 to -6 
Apheresis  
Week -4 to -6m 
Chemotherapy  
Week  (-1) 
Pre-infusion  
Day -1§ 
Infusion  
Day 1§ 
Infusion #2 
Day 2 § 
Infusion #3 
Day 3 § 
Post infusion 
 Day 4        
Post infusion  
Day 7          
Post infusion  
Day 10        
Post infusion  
Day 14        
End of Treatment 
Safety follow-up 
1 to 5 
Safety follow-up 6 
End of study 
Secondary Follow-up 
Visit number 
101   102 
 103 
 104 
 105  
203 
204 
106 
107 
108 
109, 
110 
 779 
551, 
552, 
553, 
554, 
555 
556 
780 
602 
Large Volume Peripheral Blood 
Draw (100mL) 
 
 
 
 
 
 
 
 
 
Xn 
 
 
 
 
Serum 5ml (Red top) 
X 
X 
 
X 
Xp 
X 
X 
X 
X 
X 
X 
X 
X 
 
HAMA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
HACA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Multiplex cytokine 
X 
X 
 
X 
Xp 
Xp 
Xp 
X 
X 
X 
X 
X 
X 
X 
x 
 
PBMC 25ml (Lavender, EDTA) 
X 
 
 
X 
Xp 
Xp 
Xp 
X 
X 
X 
X 
X 
X 
X 
X 
 
p53 Mutation Analysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DNA (Q-PCR persistence)  
X 
 
 
X 
Xp 
Xp 
Xp 
X 
X 
X 
X 
X 
X 
X 
X 
 
DNA  RCL (VSV-G Q-PCR) 
X 
 
 
X 
 
 
 
 
 
 
 
 
Xu 
 
X 
 
PBMC (functional assays, 
immunophenotyping, CART-19 and B cell 
enumerationv) 
X 
 
 
X 
Xp 
Xp 
Xp 
Xq 
X 
X 
X 
X 
X 
X 
X 
 
Bone marrow / LN aspirate  
(5 ml lavender top, EDTA) 
X 
 
 
 
 
 
 
 
 
 
 
Xt 
Xt 
Xt 
Xt 
 

CD19 CART-19 Protocol 
 
page 117 of 120 
Version 12.03-05-2015 
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This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
Week/Day of treatment period 
~ Wk  (-) 1 to 6  
~ Wk  (-) 4 to 6  
(+/- 1 wk)m 
~ Wk  (-) 1 
(+2 days) 
~ Day  (-) 1§ 
Day 1§ 
Day 2 (+1 day)§ 
Day 3 (+1 day)§ 
Day 4 
 (+1 day)  
Day 7 
(+/- 1 day) 
Day 10 
(+/- 1 day) 
Day  14,  21 
(+/- 1 day) 
Day 28 
(+/- 3 days) 
Month 2 to 6r 
(+/- 7 days) 
Month 9 
(+/- 7 days) 
Month 12s 
(+/- 7 days) 
Every 3 Months 
(+/- 1 month)y 
 
Screening/ 
Baseline 
Apheresis 
Chemo- 
therapyj 
Pre – 
Infusion 
Infusion 
Infusion 
Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
Post Infusion 
End of 
Treatment 
Post Infusion 
Post Infusion 
End of study 
Secondary 
Follow-up 
Visit Name 
Screening/Baseline  
Week -1 to -6 
Apheresis  
Week -4 to -6m 
Chemotherapy  
Week  (-1) 
Pre-infusion  
Day -1§ 
Infusion  
Day 1§ 
Infusion #2 
Day 2 § 
Infusion #3 
Day 3 § 
Post infusion 
 Day 4        
Post infusion  
Day 7          
Post infusion  
Day 10        
Post infusion  
Day 14        
End of Treatment 
Safety follow-up 
1 to 5 
Safety follow-up 6 
End of study 
Secondary Follow-up 
Visit number 
101   102 
 103 
 104 
 105  
203 
204 
106 
107 
108 
109, 
110 
 779 
551, 
552, 
553, 
554, 
555 
556 
780 
602 
DNA (Q-PCR homing) 
X 
 
 
 
 
 
 
 
 
 
 
X 
Xt 
X 
X 
 
MMC (CART19 and B cell enumeration, 
immunophenotyping) 
X 
 
 
 
 
 
 
 
 
 
 
X 
Xt 
X 
X 
 
Marrow Serum (2  ml red top) 
X 
 
 
 
 
 
 
 
 
 
 
Xt 
Xt 
Xt 
Xt 
 
Multiplex cytokine 
X 
 
 
 
 
 
 
 
 
 
 
X 
Xt 
X 
X 
 
Total research blood needs 
32 
ml 
5 
ml 
0 
ml 
30 
ml 
36 
ml 
36 
ml 
36 
ml 
30 
ml 
30 
ml 
30 
ml 
30 
ml 
130 
ml 
30 
ml 
30 
ml 
30 
ml 
N/A 
TOTAL BLOOD DRAW 
60 
ml 
5 
ml 
0 
ml 
49-
56 
ml 
45-
56 
ml 
45-
56 
ml 
45-
56 
ml 
38-
50 
ml 
38-
50 
ml 
38-
50 
ml 
49-
61  
ml 
143-
161 
ml 
42-61 
ml 
38-
57 
ml 
42-61 
ml 
N/A 
 
 
§ 
Lab tests specified on the infusion day will be drawn prior to infusion.  A blood draw for potassium will be drawn 2 hours post infusion. The 
Investigator will review all pre-infusion lab (day -1) results to determine that it is appropriate to proceed with the infusion.  Any abnormal Cr, Ca, K, 
Phos or uric acid result that is a change from the prior value should be reviewed by the PI prior to the infusion.  Any new lab abnormalities that are 
also a change from the prior value will be reviewed by investigators. Additional Research Sample Collection: In the event something unexpected occurs 

CD19 CART-19 Protocol 
 
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This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
the protocol, the research team may request an additional sample collection be performed to collect additional blood or marrow/LN samples for research 
analysis. This is being done with the intention of evaluating the likely effects from the investigational products received. The total amount of extra 
blood that will be collected will be 3 tablespoons of blood twice in one week.  The total amount of extra bone marrow or lymph node biopsies collected 
from you will be up to 1 extra procedure per month. 
 
 
a. Medical history, physical exam, documentation of adverse events and concomitant medications are to be done prior to each infusion. 
Hematology and chemistry results are to be obtained prior to infusion.  Hematology includes CBC, differential, and platelet count.  
Chemistry will include Glucose, BUN, Creatinine, Sodium, Potassium, Calcium, Total Protein, Albumin, Total Bilirubin, Alk Phos, 
AST, ALT, Mg, Phos, LDH, Ferritin, CRP and Uric Acid.  A separate sample for serum K+ is taken approximately 2 hours post-infusion.   
b. Physical exam includes vital signs.  Height, weight, body surface area at enrollment and as clinically indicated. 
c. Adverse events must be reported from the time the patient signs the retreatment consent until the end of the study. 
d. CT scans should be performed within 42 days of study entry for disease evaluation and as clinically indicated for disease monitoring. 
e. As clinically needed at baseline and throughout the study. 
f. Should be performed within 6 weeks of the first CART19 infusion, but does not need to be performed on the same day as apheresis. 
g. Pregnancy test (quantitative) for female only. 
h. Blood for CD3, CD4, CD8 Lymphocytes taken at months 3 and 6 only. 
i. Autoimmune screen (ANA, ESR) 
j. Viral Serology includes CMV, EBV, and Hepatitis B and C 
k. Serum immunoglobulins will be collected at months 3, 6, 9 and 12, and as clinically indicated. 
l. Chemotherapy as appropriate for disease type. See section 6.5 
m. If there is an existing sufficient CART19 dose, leukapheresis screening to assess venous access will not be performed.  However, if there 
is either an insufficient manufactured dose or starting material available in the CVPF, the subject will be asked to undergo apheresis to 
collect additional cells to manufacturer a sufficient dose for retreatment.  If apheresis is required: 12-15 liter apheresis to go to CVPF. 1 x 
108 cells to be delivered to TCSL. 
n. 100 mL peripheral blood draw (Lavender EDTA 10mL tubes) to be delivered to the TCSL.   
o. TCSL has requested labs samples for research be sent to TCSL as soon as collected. If required to keep research labs after hours, please 
keep red tops upright,   lavender tubes should be room temperature on rotating platforms.  In the event that something unexpected occurs, 
additional research sample collection may be done as necessary. Blood collects are not to exceed 3 tablespoons of blood twice in one 
week time window. Marrow/LN collections would not exceed more than one procedure per month.  This would be at PI discretion. 
p. The research blood collection is split on infusion day:  20 mL EDTA (lavender) and 2 mL serum (red) are collected pre-infusion for 
cytokines, qPCR and cellular assessments; 5 mL EDTA (lavender) and 2 mL serum (red) are collected 20-120min post-infusion for 
cytokines and qPCR only (cellular assessments only done pre-infusion).  
q. Required on Day 14 and as clinically needed on Day 21. 
r. Post infusion assessments will be performed monthly from month 2 to month 6. 
s. After year 1, patients will be enrolled into a destination protocol (IRB# 
/UPCC 
) for follow-up by phone or mail for up to 
15 years post first T cell infusion, to monitor for delayed adverse events associated with the lentiviral vector genetic modification. 

CD19 CART-19 Protocol 
 
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Version 12.03-05-2015 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
t. Concomitant with clinical draw, and also at months 1, 3, 6, 9 and 12 post-infusion.  5 ml in lavender top (DNA) and 2 ml in red top 
(serum) to be delivered to TCSL. 
u. At months 3 and 6 only. 
v. CART19 , tumor, and B cells enumerated by flow cytometry following pre-gating using CD3+/CAR19+, CD5,CD19/kappa or lambda 
and CD19+ expression respectively. 
w. All patients must undergo a Respiratory Virus Panel (RVP) to test for influenza within 10 days prior to the first planned CART-19 
infusion.  The Respiratory Virus Panel includes: Influenza A, Influenza B, Respiratory Syncytial Virus A, Respiratory Syncytial Virus B, 
Parainfluenza Virus Type 1, Parainfluenza Virus Type 2, Parainfluenza Virus Type 3, Adenovirus.  If the patient is positive for influenza, 
oseltamivir phosphate (Tamiflu®) or equivalent should be administered for 10 days as preventative treatment (see Tamiflu® package 
insert for dosing information). The patient must complete this course of preventative treatment prior to receiving the first CART-19 
infusion. If the patient is positive for influenza and is also experiencing flu-like symptoms, all clinical symptoms must also be resolved 
prior to the first CART-19 infusion.  If the patient is positive for another virus on the RVP, the CART-19 infusion will be delayed for at 
least 7 days to be sure clinical symptoms of a viral infection do not develop.  If clinical symptoms develop, the infusion will be delayed 
until resolution of these symptoms. 
x. For subjects who complete or prematurely discontinue from study follow-up while in remission, follow-up attempts will be made to 
assess subject’s relapse and survival status every 3 months post CART-19 infusion until the end of the study (Last Patient/Last Visit).  
Once subjects’ relapse or they begin a new cancer therapy, additional follow-up for relapse will not be required, and subjects will be 
followed for survival only. 
y. Secondary follow-up will take place in Stage 2 only.