CHP 959 - A Phase I/IIA Study of Redirected Autologous T Cells Engineered to Contain Anti-CD19 Attached to TCRzeta and 4-1BB Signaling Domains in Patients With Chemotherapy Resistant Or Refractory CD19+ Leukemia and Lymphoma
Phase: PHASE1
Conditions: B Cell Leukemia, B Cell Lymphoma
Sponsor: University of Pennsylvania

CD19 Lentiviral T body Protocol 
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CONFIDENTIAL 
This document is confidential and the property of the Children’s Hospital and the University of Pennsylvania. 
No part of it may be transmitted, reproduced, published, or used by other persons without prior written 
authorization from the study sponsor. 
CHP959 – A Phase I/IIA Study of Redirected Autologous T Cells Engineered to Contain Anti-
CD19 Attached to TCR zeta and 4-1BB Signaling Domains in Patients with Chemotherapy 
Resistant or Refractory CD19+ Leukemia and Lymphoma  
Principal Investigator 
Stephan Grupp, MD PhD 
Co-Investigators 
Regulatory Sponsor: 
Scientific Advisor: 
Study Product: 
CD19 redirected autologous T cells (CART-19 T Cells) 
Protocol Number: 
CHP-959 
IRB Number: 
Date: 
Amended: 
12/15/2010 
09/05/2011 
03/29/2012 
08/02/2012 
11/10/2012 
11/29/2012 
1/10/13 
2/12/13 
7/7/2013 
3/7/2014 
9/8/2014 
10/6/2014 
05/08/2015 
12/15/2015 
NCT Number:
01626495

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No part of it may be transmitted, reproduced, published, or used by other persons without prior written 
authorization from the study sponsor. 
TABLE OF CONTENTS 
STUDY SUMMARY AND STUDY SCHEMA ......................................................................................................... 6 
STUDY SCHEMA (FIGURE 1) ................................................................................................................................. 7 
 ....................................................................................................................................................................................... 7 
1. 
INTRODUCTION .............................................................................................................................................. 8 
1.1 
BACKGROUND .................................................................................................................................................. 8 
1.2 
INVESTIGATIONAL AGENT.............................................................................................................................. 11 
1.3 
PRECLINICAL DATA ....................................................................................................................................... 14 
1.4     INITIAL CLINICAL DATA ................................................................................................................................. 17 
1.6 
INCLUSION OF CHILDREN IN THE RESEARCH. .................................................................................................. 24 
1.7 
DOSE RATIONALE AND RISK/BENEFITS .......................................................................................................... 25 
2 
STUDY OBJECTIVES .................................................................................................................................... 26 
3 
STUDY DESIGN .............................................................................................................................................. 27 
3.1 
GENERAL DESIGN .......................................................................................................................................... 27 
3.2 
PRIMARY STUDY ENDPOINTS ......................................................................................................................... 28 
3.3 
SECONDARY STUDY ENDPOINTS .................................................................................................................... 29 
3.4 
EXPLORATORY STUDY ENDPOINTS ................................................................................................................ 29 
4 
SUBJECT SELECTION AND WITHDRAWAL.......................................................................................... 29 
4.1 
INCLUSION CRITERIA ..................................................................................................................................... 29 
4.2 
EXCLUSION CRITERIA .................................................................................................................................... 31 
4.3 
SUBJECT RECRUITMENT AND SCREENING ...................................................................................................... 32 
4.4 
EARLY WITHDRAWAL OF SUBJECTS ............................................................................................................... 33 
4.4.1 
When and How to Withdraw Subjects .................................................................................................. 33 
4.4.2 
Data Collection and Follow-up ........................................................................................................... 33 
5 
STUDY DRUG ................................................................................................................................................. 34 
5.1 
DESCRIPTION ................................................................................................................................................. 34 
5.2 
PATIENT ELIGIBILITY TO RECEIVE CART-19 TRANSDUCED T CELLS ............................................................ 34 
5.2.1 
Release criteria for the manufactured T cell product: ......................................................................... 35 
5.3 
TREATMENT REGIMEN ................................................................................................................................... 36 
5.3.1 
Patients 1-72 (infused), including CNS3 cohort .................................................................................. 36 
5.3.2 
Comparison Cohort ............................................................................................................................. 36 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ................................................................................. 36 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................................. 37 
5.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................................................ 37 
5.7 
PACKAGING.................................................................................................................................................... 38 
5.8 
RECEIVING, STORAGE, DISPENSING AND RETURN .......................................................................................... 38 
5.8.1 
Receipt of Drug Supplies ..................................................................................................................... 38 
5.8.2 
Storage ................................................................................................................................................. 38 
5.8.3 
Dispensing of Study Drug .................................................................................................................... 38 
5.8.4 
Return or Destruction of Study Drug ................................................................................................... 38 
6 
STUDY PROCEDURES .................................................................................................................................. 39 
6.1 
PRE-ENTRY EVALUATIONS ............................................................................................................................ 39 
6.2 
ENROLLMENT AND BASELINE ASSESSMENT. .................................................................................................. 39 
6.3 
ENROLLMENT ................................................................................................................................................. 40 
6.4 
APHERESIS ..................................................................................................................................................... 40 
6.4.1 
Cytoreductive chemotherapy ............................................................................................................... 40 
6.5 
RESTAGING ASSESSMENT ............................................................................................................................... 41 
6.6 
CART-19 INFUSION #1 WITH INTRA-PATIENT DOSE ESCALATION ................................................................ 41 

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6.7 
POST INFUSION ASSESSMENTS OF CLINICAL STATUS, ENGRAFTMENT AND PERSISTENCE ................................ 43 
6.8 
CART-19 SUBSEQUENT INFUSIONS ............................................................................................................... 43 
6.9 
DAY 28 EVALUATION..................................................................................................................................... 43 
6.10 
MONTHLY EVALUATIONS 2 TO 6 MONTHS POST INFUSION ......................................................................... 43 
6.11 
QUARTERLY EVALUATIONS FOR UP TO 2 YEARS POST INFUSION ............................................................... 43 
6.12 
SECONDARY FOLLOW-UP PHASE ............................................................................................................... 44 
6.13 
LONG-TERM FOLLOW-UP PROTOCOL ......................................................................................................... 44 
6.14 
TUMOR RESPONSE ASSESSMENTS ............................................................................................................. 44 
7 
STATISTICAL PLAN ..................................................................................................................................... 45 
7.1 
GENERAL DESIGN ISSUES ............................................................................................................................... 45 
7.2 
ENDPOINTS..................................................................................................................................................... 45 
7.2.1 
Primary Endpoints ............................................................................................................................... 45 
7.2.2 
Secondary Endpoints ........................................................................................................................... 46 
7.2.3 
Exploratory Endpoints ......................................................................................................................... 46 
7.3 
SAMPLE SIZE .................................................................................................................................................. 46 
7.4 
SAFETY .......................................................................................................................................................... 47 
7.5 
EFFICACY ....................................................................................................................................................... 47 
7.6 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................................... 47 
7.7 
STATISTICAL ANALYSIS ................................................................................................................................. 48 
8 
SAFETY AND ADVERSE EVENTS ............................................................................................................. 48 
8.1 
DEFINITIONS .................................................................................................................................................. 48 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................................. 51 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ............................................... 51 
8.3.1 
Study Sponsor Notification by Investigator ......................................................................................... 51 
8.3.2 
Investigator reporting: notifying the IRB ............................................................................................. 52 
8.3.3 
Reporting obligations to the ACC DSMC ............................................................................................ 54 
8.3.4 
FDA Notification by Sponsor ............................................................................................................... 54 
8.4 
TOXICITY MANAGEMENT, STOPPING RULES AND STUDY TERMINATION ....................................................... 55 
8.4.1 
Criteria for stopping or pausing the study ........................................................................................... 56 
8.4.2 
Stopping rules related to the CNS3 cohort .......................................................................................... 56 
8.4.3 
General toxicity management considerations ...................................................................................... 57 
8.4.4 
Management of toxicity ........................................................................................................................ 58 
8.4.5 
Criteria for discontinuing a subject’s participation in the study: ........................................................ 61 
8.5 
PROTOCOL EXCEPTIONS AND DEVIATIONS..................................................................................................... 61 
8.6 
MEDICAL MONITORING.................................................................................................................................. 62 
8.6.1 
Independent Data and Safety Monitoring Board ................................................................................. 63 
8.6.2 
Clinical Monitors ................................................................................................................................. 63 
9 
DATA HANDLING AND RECORD KEEPING .......................................................................................... 63 
9.1 
CONFIDENTIALITY .......................................................................................................................................... 63 
9.2 
SOURCE DOCUMENTS ..................................................................................................................................... 64 
9.3 
CASE REPORT FORMS..................................................................................................................................... 64 
9.4 
RECORDS RETENTION .................................................................................................................................... 64 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ....................................................................... 64 
10.1 
STUDY MONITORING PLAN ....................................................................................................................... 64 
10.2 
AUDITING AND INSPECTING ....................................................................................................................... 64 
11 
ETHICAL CONSIDERATIONS .................................................................................................................... 65 
12 
STUDY FINANCES ......................................................................................................................................... 65 
12.1 
FUNDING SOURCE ..................................................................................................................................... 65 
12.2 
CONFLICT OF INTEREST ............................................................................................................................. 65 
12.3 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................................ 65 
12.4 
STUDY DISCONTINUATION ........................................................................................................................ 65 

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13 
PUBLICATION PLAN .................................................................................................................................... 66 
14 
REFERENCES ................................................................................................................................................. 66 
15 
ATTACHMENTS ............................................................................................................................................ 77 
15.1 
SCHEDULE OF STUDY PROCEDURES .......................................................................................................... 78 
15.2 
SUGGESTED LABS ...................................................................................................................................... 82 
15.3 
MONITORING PLAN ................................................................................................................................... 83 
15.4 
 DEFINITION OF CNS LEUKEMIA: ............................................................................................................... 83 
 
 

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LIST OF ABBREVIATIONS 
ACC 
Abramson Cancer Center 
(a)APC 
(artificial) antigen presenting cell 
AE 
adverse event 
CART-19 cells 
CD19-targeted, redirected autologous T cells 
CIR 
chimeric immune receptor 
CFR 
code of federal regulations 
CHOP 
Children’s Hospital of Philadelphia 
CMV 
CRF 
Cytomegalovirus 
case report form 
CTC 
common toxicity criteria 
CRQA 
Clinical Research Quality Assessment Committee 
CRS 
Cytokine Release Syndrome 
CTL 
cytotoxic T lymphocyte 
 
 
CTL 
cytotoxic T lymphocyte 
CD137 
4-1BB costimulatory molecule 
DFS 
disease free survival 
DSMB 
data safety and monitoring board 
FDA 
food and drug administration 
GCP 
good clinical practices 
GMP 
good manufacturing practices 
GVHD 
graft versus host disease 
IBC 
Institutional Biosafety Committee 
IRB 
Institutional Review Board 
MRD 
minimal residual disease 
PBMC 
peripheral blood mononuclear cells 
RAC 
NIH Office of Biotechnology Recombinant DNA Advisory Committee 
RCL 
replication competent lentivirus 
scFv 
single chain Fv fragment 
T-body 
fusion protein expressed in T cells that combines an extracellular antibody 
domain and an intracellular signaling domain. Interchangeable with CIR 
TCR 
T cell receptor 
TCR- 
signaling domain found in the intracellular region of the TCR zeta, gamma 
and epsilon chains 
V 
a rearranged T cell specific gene that can be used to determine clonality of a 
T cell population 
UPENN 
University of Pennsylvania 
 

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STUDY SUMMARY AND STUDY SCHEMA 
Title 
A PHASE I/IIA STUDY OF REDIRECTED AUTOLOGOUS T CELLS 
ENGINEERED TO CONTAIN ANTI-CD19 ATTACHED TO TCR ZETA AND     
4-1BB SIGNALING DOMAINS IN PATIENTS WITH CHEMOTHERAPY 
RESISTANT OR REFRACTORY CD19+ LEUKEMIA AND LYMPHOMA  
Short Title 
CD19 redirected autologous T cells 
Phase 
Phase I/IIa 
Methodology 
Open-label approach 
Study Duration 
Approximately 4-5 years 
Study Center(s) 
CHOP 
 
Objectives 
The primary objective is to determine the safety and survival of the 
redirected autologous T cells transduced with the anti-CD19 lentiviral 
vector (referred to as “CART-19” cells) given in the context of an adult 
and a pediatric protocol targeting CD19+ malignancies. 
Number of Subjects 
72 infused, up to 86 enrolled 
Diagnosis and Main 
Inclusion Criteria 
Inclusion criteria are designed to include pediatric patients aged 1-24 
years with CD19+ B cell malignancies with no available curative 
treatment options (such as autologous or allogeneic stem cell 
transplantation) who have limited prognosis (several months to <2 year 
survival) with currently available therapies. 
Study Product, Dose, 
Route, Regimen 
CART-19 cells transduced with a lentiviral vector to express either anti-
CD19 scFv:TCRor anti-CD19 scFv TCR:41BB, administered by i.v. 
injection using an intra-patient dose escalation approach: 10% on day 0, 
30% on day 1, possibly followed by 60% on day 14 (or later) with a 
total dose goal of ~1.5 x107 – 5 x109 (~0.3x106 - 1.0x108/kg) T cells. 
Duration of 
administration 
Approximately 10-15 minutes; drug is expected to persist at detectable 
levels in circulation for weeks to months. 
Reference therapy 
None. This protocol will be given to subjects with unmet medical needs 
for which there are no current curative therapeutic options. 
Statistical 
Methodology 
The statistical analysis will be primarily descriptive in keeping with the 
exploratory nature of the study.  Descriptive statistics will be applied to 
determine the relative engraftment and persistence. All adverse events 
will be described and exact 95% confidence intervals will be produced 
for adverse event rates, both overall and within major categories.  The 
change in the ratio of CART-19 cells over time will be compared using 
a Wilcoxon signed-rank test for paired data.  This nonparametric test is 
very efficient (>95%) compared to the t-test if the underlying data are 
normally distributed.  Analysis of other secondary endpoints such as 
anti-tumor activity will also be primarily descriptive and may include 
summary statistics such as means and standard deviations or Kaplan-
Meier curves for survival information. 
 
 
 

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STUDY SCHEMA (Figure 1) 
Figure 1: Conduct of study. Initial leukapheresis (week -4) will be a 3-4 volume 
leukapheresis in smaller children.  
 
 
 

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1. INTRODUCTION 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures.  
1.1 
Background 
CD19 positive hematologic malignancies. B cell malignancies comprise a heterogeneous group 
of neoplasms including a vast majority of non-Hodgkin's lymphomas (NHL), as well as acute 
lymphoblastic leukemias (ALL) and chronic lymphocytic leukemias (CLL). An estimated 87,000 
new cases of leukemia and non-Hodgkin’s lymphomas are diagnosed in the US annually1, and 
most of these are of B cell origin. Current treatments for B cell malignancies include 
chemotherapy, radiation therapy, bone marrow transplantation, and peripheral blood stem cell 
transplantation. Despite these treatment modalities, most patients will remain incurable. 
B lineage acute leukemia (B-ALL) is responsive to chemotherapy, however the ability to 
uniformly eradicate the disease has not been achieved, as about 65% of adults and 20% of 
children have disease recurrence 2, 3. Improved response rates have thus far only been achieved 
with intensified cytotoxic chemotherapy, resulting in substantial morbidity. Adoptive 
immunotherapy with allogeneic donor leukocytes has potent anti-leukemic effects, however the 
benefit is confined largely to patients with myeloid leukemias, as B-ALL has a durable remission 
rate of less than 10% 4, and often at the cost of substantial morbidity due to GVHD5, 6. 
 
Adoptive immunotherapy.  Adoptive transfer is a term coined by Medawar7 to study 
allograft rejection, and the term adoptive immunotherapy denotes the transfer of 
immunocompetent cells for the treatment of cancer or infectious disease8. Adoptive 
immunotherapy appears to be the most robust form of immunotherapy for treatment of 
established tumors9. However, several problems remain to be solved before this therapy becomes 
routine; see our reviews for details10, 11. 
 
CD19 as a therapeutic target for leukemia and lymphoma. CD19 is a 95kDa glycoprotein 
present on B cells from early development until differentiation into plasma cells12-14. 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 receptor14-16. 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 levels14, 17. Expression of 
CD19 is restricted to B lineage cells and is not expressed by pluripotent blood stem cells18. CD19 
is also expressed by most B cell lymphomas, mantle cell lymphoma, ALLs, CLLs, hairy cell 
leukemias, and a subset of acute myelogenous leukemias12, 19, 20. CD19 thus represents a highly 
attractive target for immunotherapy18. Furthermore, CD19 is not present on most normal tissues, 
other than normal B cells, including pluripotent blood stem cells18, 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 models21-25 
and human and non-human primates26-36. 
 

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Engineered T cells with redirected specificity: chimeric immune receptors (CIR). The 
daunting task of breaking tolerance to self antigens is the major obstacle facing the field of 
cancer immunotherapy. This can be difficult or impossible if the TCR repertoire has been deleted 
or rendered non functional by various post thymic tolerance mechanisms37, 38. One strategy is to 
identify therapeutically effective T cell clones, clone the heterodimeric TCR, and express it in 
other T cells, creating bispecific T cells with reactivity against the original TCR and the cloned 
TCR (reviewed in39-41). This was first carried out using protoplast fusion to transfer the TCR 
genes from a mouse T cell into another mouse T cell clone with a different specificity42. Other 
labs used cell fusion or electroporation to transfer TCR genes43, 44, and in these cases 
demonstrated that MHC restricted specificity could be transferred. The advent of retroviral 
vectors made it possible to make this process more efficient. The Pease laboratory first used a 
retroviral vector with the LTR directing expression of TCR and an internal CMV promoter 
driving TCR expression in mouse T cells45, 46. In 1999 Clay used a retroviral vector to transfer 
an HLA-A2 restricted TCR with specificity for MART-1, derived from tumor infiltrating 
lymphocytes, from a melanoma patient to T cells from 3 normal donors47. Recently Kessels and 
coworkers demonstrated that redirected mouse T cells were fully functional, could protect 
against tumor challenge, and could treat established metastasis48. The T cells were shown to 
expand dramatically (by more than 3 logs) after in vivo antigen encounter, and they trafficked to 
tumor sites. 
An alternative strategy to produce genetically engineered T cells is the ‘T-body’ or 
chimeric antigen receptor (CAR) approach, which 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 manner49, 50. 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 signaling domain that 
mediates T cell activation (reviewed in41, 51). 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 length52.  
A large number of CARs targeting diverse tumors have been developed41, however, 
clinical pilot tests are just beginning.  
 
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]53. 
One issue that needs to be addressed with CARs is that signaling through the cytosolic 
domain of the usual scFv-TCR single chain construct does not fully replicate the multichain 
TCR signaling complex54, 55. Chimeric receptors bearing TCR signaling modules are sufficient 
to trigger sustained proliferation in T cell hybridomas and clones but are not sufficient to drive 

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proliferation or cytokine production in peripheral T cells 54. 4-1BB is a T cell co-stimulatory 
receptor induced by TCR activation, and evokes various T cell responses56. 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 proliferation 57, 58. 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 laboratories 59, 60, and indicate that “bipartite receptors” comprised of 
TCR and either CD28 or 41BB 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 concept, which is now ready for 
clinical evaluation, and thereby advance the field of cancer gene therapy by adoptive 
immunotherapy. 
 
Rationale for lymphodepletion. Adoptive immunotherapy strategies may be able to 
capitalize on homeostatic T cell proliferation 61, 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 threshold 62, 63. Host lymphodepletion may enhance the effectiveness of 
adoptively transferred T cells61.  Homeostatic T cell proliferation can result in the induction of 
autoimmunity 64, providing a clue to improved antitumor strategies.  T cells can undergo up to 
seven rounds of cell division after being deprived of contact with APC 65, 66. This homeostatic 
response of T cells is directed largely to self antigens 67. 
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 68. This hypothesis has been tested clinically in patients with metastatic melanoma 
refractory of conventional treatments 69. 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 engraftment70, 71. In 
this protocol we propose to transfer RAT-19 T cells into subjects that 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 72.   
 
Competitive repopulation trials. As a secondary endpoint, we propose a competitive 
repopulation strategy for this trial. Competitive repopulation strategies have been used 
previously to test the relative performance of vector constructs.  In a 3 patient pilot trial73, Nabel 
and colleagues tested the utility of a transdominant Rev protein, Rev M10. Autologous T cells 
were separately transfected with either RevM10 or a control protein and were then returned to 
each patient, and toxicity, gene expression, and survival of genetically modified cells assessed.  
The absolute engraftment of the gene marked cells was poor, due to the low transduction 
efficiency and the cell culture process. However, the cells that expressed Rev M10 were more 
resistant to HIV infection than those with Delta Rev M10 in vitro 73, as the Rev M10-transduced 
cells showed preferential in vivo survival compared to Delta Rev M10 controls. More recently, 
Morgan and colleagues have confirmed and extended these findings in 10 subjects with a more 
sophisticated series of anti-HIV vectors74.  

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1.2 
Investigational Agent 
The investigational agent in this protocol is CART-19 cells 
. Autologous T cells will be 
engineered 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 CD19 scFv, the cells will be transduced to express an intracellular signaling 
molecule comprised of either the TCR chain or a tandem signaling domain comprised of 4-1BB 
and TCR signaling modules. The scFv is derived from a mouse monoclonal antibody, and thus 
contains mouse sequences, and the signaling domains are entirely of the native human 
sequences. The CART-19 scFv plasmid was previously reported30 and was generously provided 
. CART-19 T cells are manufactured by isolating the T cells by 
apheresis, and using lentiviral vector technology75-77 to introduce the scFv:TCR into 
CD4 and CD8 T cells. In some patients, a control scFv:TCR will be introduced into a portion 
of the cells for the competitive repopulation experiment described below.  These receptors are 
“universal” in that they bind antigen in an MHC-independent fashion, thus, one receptor 
construct can be used to treat a population of patients with CD19 antigen-positive tumors. 
The CAR constructs were developed at the 
, and the clinical 
grade vector will be manufactured by
 or another facility in accordance with the sponsor’s 
specifications, as outlined in the FDA-approved 
. The CART-19 cells will be 
manufactured in the 
 
 according to the process shown in figure 3. At the end of cell cultures, the cells are 
cryopreserved in infusible cryomedia. The maximium total dose of CART-19 transduced T cells 
will consist of the infusion of 1.5x107-5x109 (0.3x106-1.0x108/kg) total cells.  Each infusion will 
contain an aliquot (volume dependent upon dose) of cryomedia containing the following 
infusible grade reagents: plasmalyte-A, dextrose (5%), NaCl, up to 7.5% DMSO, dextran 40, 
human serum albumin with up to 5x109 autologous T cells per bag. The initial dose will be 
decreased 10-fold, with intra-patient dose escalation (see Section 5.3 for details). 
 
 

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General description of the lentiviral vector (modified from Manilla et al125). The 
lentiviral vector is derived from the NL4-3 clone of wildtype HIV. It is maximally gutted so that 
its backbone is constructed only from conserved regions of HIV (5’ and 3’ long terminal repeats, 
central polypurine tract/central termination sequence, and Rev-responsive element). The final 
transgene constructs were cloned into a SIN vector under the control of the mammalian 
elongation factor 1 promoter. The vector is pseudotyped with a VSV-G envelope coat. The 
VSV-G DNA and the vector DNA are encoded on separate plasmids and are then transfected 
into cells for production of viral vector. The VSV-G envelope facilitates vector attachment to 
cell membranes for efficient vector entry into the cells, and helps to retain the infectivity of the 
viral vector during the stringent purification required for a clinical-grade vector. 
Mechanism of action of transduced T cells. Redirected T cells have been shown in 
experimental models to bind to cells that express the target antigen. Over the past decade, CARs 
directed against a wide variety of tumor antigens have been developed41, 78. In the case of CART-
19 cells, retrovirally transduced primary human T cells containing a TCR cytosolic signaling 
domain were shown to engraft and to eradicate Raji Burkitt lymphoma tumor cells in 
immunodeficient mice34. Human T cells that express the CD19 scFv:TCR or CD19 
scFv:TCR4-1BB can kill B-ALL and lymphoma cells in vitro35, 79-81. There are several 
potential limitations to the CAR T cells: 1) the tumor must express the target antigen on the cell 
surface; 2) large amounts of shed or soluble antigen can inhibit the CAR T cells; 3) the chimeric 
receptor may be immunogenic, resulting in the elimination of the redirected T cells by the host 
immune system.  
Absorption, distribution and metabolism of T cells. 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 cells82. 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 given83. 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 tissues69, 83-85.   
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, ontak. 
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 

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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 infection86; 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 have been 
given to cancer patients. Following a single dose of CAR T cells (0.6 to 4 x 109 T cells), the CIR 
T cells were detected in circulation from 23, 32, and 53 days after infusion in three patients with 
renal cell carcinoma87. All three patients developed low levels of anti-scFv antibodies between 
37 and 100 days after the CIR 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.  
1.3 
Preclinical Data 
An extensive literature supports the use of engineered T cells for tumor immunotherapy in rodent 
tumor models, reviewed40, 41, 88-90. Others have used electroporation or retroviral vectors to create 
CART-19 T cells, and have shown in vivo safety and efficacy of adoptively transferred T cells in 
immunodeficient mouse models34, 35, 80, 91, 92.  The incorporation of signaling modules such as 
CD28 and 4-1BB in T body constructs increases potency of the engineered T cells in pre-clinical 
studies59, 79, 93-97. 
Over the past decade we have developed improved T cell culture systems and T cell 
transduction conditions. The T cell culture systems have been tested in phase I/II trials in patients 
with HIV infection and hematologic malignancies. The culture systems use anti-CD3 and CD28 
costimulation and have proven to be efficient and feasible for large scale manufacturing, thereby 
overcoming a major barrier to adoptive immunotherapy. No significant safety concerns have 
emerged with more than 200 patients treated to date with CD4 and CD8 T cells, with and without 
genetic engineering with retroviral vectors70, 71, 84, 98-103. Our collaborators have used replication 
defective retroviruses for our initial studies to test chimeric receptors in patients with HIV 
infection84, 85, 98. However, HIV-based lentiviral vectors have the potential to be substantially 
more efficient and to be safer from the perspective of insertional mutagenesis for adoptive 
immunotherapy75, 76. Since 2001, we have collaborated with Boro Dropulic at Lentigen Corp. to 
develop lentiviral engineered T cells for adoptive immunotherapy104, 105; the data from our first 
pilot trial to test lentiviral vectors is described in section 1.4 below.  
We have made research use only grade lentiviral vectors to test CART-19 T cells in 
preclinical models. We have found that the various constructs can be efficiently and stably 
expressed in primary human T cells (data not shown).   
 
 
 
 
 
 
   

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1.4     Initial Clinical Data 
CART-19 cells with a 4-1BB:TCRζ have not been previously tested in humans; however a recent 
report testing CART-20 cells with a TCRζ reported safety in patients with mantle cell lymphoma 
106. Results from related approaches testing T bodies / CARs in humans are available from 

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patients with HIV infection and cancer. Human data relevant to CART-19 cells is summarized 
below:  
 
CD4:TCR experience in HIV infection. CD4 is a genetically engineered, MHC–
unrestricted receptor composed of the  subunit of the CD3 T cell receptor, the cytoplasmic 
domain involved in signal transduction, fused to the transmembrane and extracellular domains of 
human CD4, which targets HIV env expressed on the surface of infected cells 107. Upon binding 
to HIV envelope, CD8+ T cells engineered to express the CD4 fusion protein proliferate and 
initiate effector functions such as cytokine secretion and HIV-specific cytolytic activity 108, 109. In 
collaboration with K. Hege at Cell Genesys Inc. and others, we assessed the survival of co-
stimulated gene–marked T cells in 3 published studies 84, 85, 98.  CD4 modified T cells were 
detected by DNA PCR in the peripheral blood of all patients following infusion, and sustained 
mean levels of 1 to 3% of T cells were detected at all time points after infusion.  In extended 
follow-up, CD4 was detected in the blood of 17 of 18 patients 1 year following infusion. In the 
only published phase II HIV gene therapy trial, 40 patients were randomized to receive an 
infusion of CD4–modified T cells or non-transduced costimulated T cells; the treatment was 
found to be safe and associated with treatment-related increases in CD4 T cell counts98.  
Together these clinical results indicate that CD4 CAR anti-HIV vector is safe and has stable 
engraftment and persistence in lymphopenic patients with HIV infection.   
 
G250:TCR experience in renal cell carcinoma. Lamers and colleagues recently reported 
the interim results of a trial testing T bodies in 3 patients with metastatic renal cell carcinoma87, 
110. The T bodies were targeted with an scFv specific for carboxy-anhydrase-IX (the G250 
antigen) that is overexpressed on clear cell RCC and in the biliary tract. The T body was 
expressed in autologous T cells using retroviral transduction. The subjects were treated with a 
dose-escalation scheme of intravenous doses of 2 x 107 T cells at day 1; 2 x 108 T cells at day 2; 
2 x 109 T cells at days 3 through 5 (treatment cycle 1); and 2 x 109 cells at days 17 to 19, in 
combination with human recombinant IL-2, given subcutaneously at 5 x105 U/m2 twice daily 
administered at days 1 to 10 and days 17 to 26. Infusions of these G250 T bodies were initially 
well-tolerated. However, after four to five infusions, liver enzyme disturbances reaching NCI 
CTC grades 2 to 4 developed. These toxicities necessitated the cessation of treatment in subjects 
1 and 3, corticosteroid treatment in patient 1, and reduction of the maximal T-cell dose in 
subjects 2 and 3. All three patients developed low levels of anti-scFv (G250) antibodies between 
37 and 100 days after the start of T-cell therapy. The liver enzyme elevations resolved. The T 
bodies circulated from 32 to 53 days after infusion, and the authors could demonstrate anti-tumor 
activity of the G2550 T body cells in the peripheral blood of the patients after infusion. The 
authors concluded that the liver toxicity was most likely due to the reactivity of G250 T bodies 
against the target antigen expressed on normal tissue, that is, the epithelial cells lining the bile 
ducts. Thus, this is interpreted as a form of “on target, off organ” toxicity.  
 
Anti-CD20 expressing CD8 cells for follicular lymphoma.  Jensen, Press and colleagues 
reported a clinical trial evaluating escalating doses of CD8 T cells modified by electroporation to 
express a chimeric immune receptor targeting the CD20 B cell marker and linked to the CD3zeta 
activation domain for the treatment of refractory follicular lymphoma and mantle cell 
lymphomas 106 106. A total of 7 subjects were enrolled in the trial, and each received 3 infusions 
of escalating doses of CD20 specific CARTs of 108 cell/m2, 109 cell/m2, and 3.3 x 109 cell/m2 
spaced 2 to 5 days apart.  The first three patients had poor persistence of the cells post infusion, 
which was improved in the last 4 patients who received subcutaneous low dose (500,000 IU/m2) 

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IL-2 twice daily for 14 days.  No subjects developed an immune response to the infused cells, 
which was evaluated by chromium release assay against targets expressing the scFv and 
neomycin resistance gene products (for cellular immunity), and by ELISA for antibody 
responses to the anti-CD20 antibody.  Two patients became positive for HAMA 3 and 6 months 
after infusion.  Since the chimeric immune receptor does not contain the murine Fc region, the 
conversion to HAMA positivity may reflect immune reconstitution and response to prior therapy.  
Clinical responses were modest, with no grade 3 or 4 toxicities.  Toxicities were restricted to the 
four patients receiving IL-2, and were attributed to an IL-2 induced flu like syndrome.    
 
Folate Receptor-Fcγ expressing T cells for ovarian cancer.  Kershaw, Hwu and 
colleagues carried out a 14 patient trial with two cohorts evaluating a CIR targeting the folate 
receptor and linked to the Fcγ signaling chain109b.  This trial consisted of two cohorts, the first of 
which received three cycles of escalating doses of T bodies expanded with antiCD3 Ab and IL-2 
for doses of 3 x 109, 1 x 1010 and 3-5 x 1010 respectively, combined with systemic IL-2.  The 
second cohort received 1-2 cycles (depending upon the number of cells available) of cells 
expanded with allogeneic PBMCs and IL-2, followed by allogeneic stimulation in vivo with live 
unirradiated PBMCs. Doses ranged from 4-169 x 109 cells, and two of six patients received 2 
cycles.  Cells were modified using a clinical grade retroviral vector containing the neomycin 
resistance gene, and were selected for using G418 after transduction.  Grade 3 and 4 adverse 
events were observed in cohort 1, but were attributed to IL-2 administration.  No serious adverse 
events were attributed to CIR administration.  Persistence of modified cells was poor and did not 
exceed 3 weeks.  This is likely a result of generation of antibodies to the infused T cells, as 
serum inhibitory factor that could be removed by incubation with protein G was found in patient 
serum post but not pre infusion.  No effect on tumor, as measured by imaging and CA-125 
antigen was observed in patients. 
 
αCD19 redirected T cells with CD28-ζ signaling chain for CLL.  Recently Brentjens, 
Sadelain, Riviere and colleagues initiated a clinical trial evaluating a chimeric immune receptor 
targeting CD19 and linked to the CD28 and CD3ζ signaling chains, for treatment of CLL.   This 
is a two cohort study, with the first cohort receiving a low dose of cells to evaluate safety.  The 
second cohort is designed to better evaluate potential efficacy, and the patients receive 
cytoreductive chemotherapy and a higher dose of cells.  Cells are modified using a retroviral 
vector, and undergo rapid expansion using ClinExVivo beads from Invitrogen.  To date, the 
treatment in cohort 1 has been well tolerated and resulted in transient anti-tumor effects in some 
patients. Results from this ongoing trial have not been published.  
 
Lentiviral vector clinical experience.  Considerable data shows that retroviral vectors are 
safe when expressed in human T cells; however, retroviral vectors appear less safe when used in 
human stem cells111, 112. Lentiviral vectors have the potential to be safer from the perspective of 
insertional mutagenesis, and they have substantially higher efficiency for genetically engineering 
human T cells76, 113, 114. Therefore, we propose to use lentiviral vector technology to introduce the 
CART-19 T body constructs into the T cells. 
 
 
 
  
 
 
  
 

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CD19 immunotoxin experience.  Ideally, the target antigens for T body/CIR anti-tumor 
protocols should be carefully chosen, so as to be expressed only by malignant cells and not by 
normal cells. CD19 expression has been reported to be restricted to the B cell lineage, and thus 
the expectation is that toxicity from CART-19 T cells should be confined to the hematopoietic 
compartment13, 18, 19. Most importantly, CD19 is not expressed on hematopoietic stem cells. 
Empiric clinical data with CD19 antibodies, radiolabeled CD19 antibodies and anti-CD19 
immunotoxins supports this contention28, 115-119, as the infusions have not caused aplasia. 
Furthermore, the widespread clinical use of anti-CD20 (Rituximab), targeting CD20, an antigen 
with a distribution of expression similar to CD19, has shown an acceptable clinical toxicity 
profile that would be expected from B cell depletion120.  Recent clinical trials using chimeric 
immune receptors targeting CD20 and CD19 have also shown that redirected T cell 
immunotherapy appears safe for these targets. 
 
 
Pheresis experience in young children. We have extensive experience over the past 15 
years pheresing young children for therapeutic cells on our high-risk neuroblastoma trials 
(median age 3 years; studies including CHP-594, CHP-667, CCG A3973, COG ANBL00P1 and 
ANBL0532, various NANT studies), as well as a protocol for multiple cycle stem cell transplant 
in young patients with medulloblastoma (COG 99703). The effective lower limit for pheresis is 6 
kg, and the effective lower limit for Medcomp catheter placement (as opposed to a femoral line) 
is 12 kg. Young children will be evaluated for suitability as a pheresis subject using our standard 
apheresis SOPs as approved by FACT.   
 
 
1.5 Initial experience with CD19 redirected T cells and the CART-19 trial in adults at 
UPenn. 
 
 
 
 
 
 
 
 
 
 
 
 
 
   

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UPN 03 received a low dose of CART19 cells (1.5x105 CAR+ T cells/kg divided over 3 days). 
Again, there were no acute infusional toxicities. However, 14 days after his first infusion, he 
began having rigors, fevers, nausea and diarrhea. By day 22 after infusion, tumor lysis syndrome 
was diagnosed requiring hospitalization for treatment. The patient was given rasburicase and IV 
fluids with resolution of biochemical abnormalities.  He had resolution of constitutional 
symptoms, and within 1 month of CART19 infusions, he had clearance of circulating CLL from 
the blood and bone marrow by morphology, flow cytometry, cytogenetic, and FISH analysis. CT 
scans showed resolution of abnormal adenopathy.  His complete remission has been sustained 
beyond 6 months from the initial CART19 cell infusion (Porter, et al. NEJM 2011). 
 

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GVHD risk. The patients in the allo cohort will be pheresed after allo SCT and will have 
some degree of residual donor engraftment, which will include T cells of donor origin. Most 
children who relapse after allo SCT will not have reverted to full recipient chimerism, and would 
be enrolled in the allo cohort. The collection of cells from the patients (as opposed to the donors) 
has 3 potential advantages: 1) many pediatric SCTs use umbilical cord cells as a donor source, in 
which case the donor would not be available; 2) in matched sibling donor SCT, the donor may be 
a minor and pheresing that donor would introduce further complications and potential risks; 3) 
most importantly, the allo cells collected from a subject without GVHD are tolerized and less 
likely to cause GVHD after infusion. There is limited experience with using activated allogeneic 

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cells in this setting. A prior UPENN/CHOP study of “activated DLI” (ex vivo activated cells 
collected from the donor and grown in the same fashion as CART19 but without the CAR 
introduction) did not show high rates of GVHD (2/18 pts with grade 3 GVHD and none with 
grade 4; Porter et al. Blood 2006). A patient recently treated at the NIH with CAR-modified 
“allo” T cells collected from the patient did not experience GVHD (A. Wayne, personal 
communication). While the risk of GVHD still exists, we feel it is low in this setting and the risk-
benefit favors treating this incurable group of ALL patients with CART19 cells. At the same 
time, it must be acknowledged that treatments for GVHD would necessarily limit or destroy 
CART19 cells, so GVHD remains an important risk for these patients. The allo cohort will allow 
us to test CART19 therapy in this group of patients with significant unmet medical need and 
assess the GVHD risk. In 10 post-allo patients treated to date, there has been no GVHD. 
 
Risk of neuropathy. In addition to the toxicities described as part of the CRS, we have also seen 
transient encephalopathy. Several of our patients have experienced confusion and/or aphasia 
lasting 2-3 days, and then recovering over another 2-3 days. For some patients, we have seen 
some confusion or delirium during periods of high fever while on opiates. These patients are 
very difficult to assess as to mental status. However, in 3/14 patients treated to date, we have 
seen this confusion occur at a point when the inflammatory phase was subsiding and the fevers 
were improved or gone. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Although the etiology of this is unclear, it may well be related to the CART19 cells or 
CRS/MAS/HLH in some way. None of these patients have required any treatment, and all of 
them recovered fully in a few days.     
1.6 
Inclusion of children in the research. 
Broadly speaking, we feel inclusion of pediatric patients in phase 1 or pilot protocols at the 
point where we have initial feasibility data from adult trials is appropriate. This is the approach 
that is generally pursued in early phase cancer trials for three reasons: i) to get clinical 
experience in pediatric populations, ii) to learn about issues with dosing or administration that 
might be specific to younger patients, and iii) allow pediatric access to novel therapies earlier in 
the development process. The population of pediatric relapsed/refractory leukemia and 
lymphoma patients targeted for enrollment in this study have no curative options for treatment. 
There is very little available on the horizon, especially for ALL patients, in terms of novel 
therapies at this stage of disease. New and highly innovative approaches are desperately needed 
for this group of pediatric patients. Our initial adult experience suggests a possible signal for 
efficacy. With this, we believe there exists both compelling reasons to include children and 
the prospect of benefit in patients with no curative options. 

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1.7 
Dose Rationale and Risk/Benefits 
The primary objective of this protocol is to test the safety and feasibility of administering 
CART-19 cells to patients with advanced refractory hematologic malignancies. A secondary 
objective of this protocol is to determine which cytosolic signaling domain is superior for 
permitting CIR T cell engraftment and persistence. In this “competitive repopulation” scenario, 
we must administer a dose of cells that is 1) safe and 2) feasible to produce and can be tracked in 
the subject after infusion in order to determine if one T body construct is superior to the other. 
The basis for setting the starting dose was based on 1) Guidance for Industry: S6 Preclinical 
Safety Evaluation of Biotechnology-derived Pharmaceuticals; 2) Joint taskforce report from the 
BioIndustry Association (BIA) and the Association of the British Pharmaceutical Industry 
(ABPI) and 3) the available literature on phase I trials to date conducted with CIR T cells.  The 
FDA guidance on safe starting dose (FDA Guidance for Industry: Estimating the Maximum Safe 
Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers) does not 
apply well for cell and gene therapy, and as such was not used to guide the selection of the 
starting dose for this study.  
We believe that an initial i.v. dose of 1.5x107-5x109 (0.3x106-1.0x108/kg) CART-19 cells 
is optimal for this protocol. Because there are about 1 x 1012 T cells in a healthy adult (equivalent 
to 2x1010 T cells/kg), the proposed total (100%) dose is equivalent to about 0.5% of the total 
body mass of T cells122, 123. Therefore, we expect the initial frequency of cells to be present at 
about 0.5% at baseline following infusion.  In addition, in our animal models, we find that a dose 
of 5 million cells per animal causes a robust antitumor response.  The dose given to animals, 
when scaled, is similar to 5x109 cells in humans. As an additional safety feature 124, the cells will 
be administered using an intrapatient dose escalation approach (see section 6.6). The proposed 
dose in children is also consistent with or less than our prior T cell infusion trial in young 
children (CHP-667).    
Safety. As described above in section 1.2, we propose to insert the scFv CIR constructs 
into T cells using lentiviral vector technology. At the University of Pennsylvania we have treated 
 patients using a related approach for patients with HIV infection with autologous T cells that 
contained a 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. We have given doses of up to 1x1010 autologous ex vivo expanded T 
cells in several trials to patients with hematologic malignancies, HIV, and neuroblastoma and 
have found this to be well tolerated70, 71, 99, 100. The CART-19 cells may eventually be rejected by 
an immune response directed against the mouse scFv sequences. In summary, this dose was 
chosen because it is anticipated to be safe based on previous studies, and because it will permit 
sufficient engraftment in order to evaluate the primary and secondary endpoints of this study. 
Risk of tumor lysis related to cytoreductive chemotherapy.  The risk of tumor lysis 
syndrome (TLS) is dependent on the disease and burden of disease, but in most cases, this risk 
will be very low.  Patients at highest risk for TLS have aggressive lymphomas (Burkitt’s or other 
‘high grade” NHL) and ALL.  The risk of TLS in CLL, follicular lymphoma, mantle cell 
lymphoma and diffuse large cell lymphoma is thought to be low, but may be higher with highly 
effective therapy (Porter et al., NEJM 2011).  Patients will be closely monitored both before and 
after chemotherapy and infusions including blood tests for potassium and uric acid.  Patient-

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subjects will receive hydration and allopurinol to minimize any toxicity should significant acute 
tumor lysis occur. 
Feasibility. The manufacturing feasibility is not expected to be an issue in this protocol, 
as given the combination of ex vivo cell culture and lentiviral vector technologies shown in 
figure 3, we expect to readily exceed the target dose of CART-19 cells that we have chosen.  
Risk/benefits. 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, corticosterioids and 
chemotherapy would be given in an attempt to eradicate the CIR cells; this has worked in 
previous cases87. 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 study, but 
zero of 7 patients in the Press study developed immune responses to their T bodies. It is possible 
that the CART-19 T cells will exert an anti-tumor effect; in a preliminary study, two patients 
treated with T bodies encoding an scFv specific for CD20 had a response that has lasted for a 
year 106.  
 
Transient host B cell depletion is also a likely risk with CART-19 cells, since normal B cells 
express CD19.  This is expected to resolve when the CART-19 cells are cleared.  
 
 
2 
STUDY OBJECTIVES 
Primary objectives:   
1. Determine the safety and feasibility of administration of chimeric antigen receptor T cells 
transduced with the anti-CD19 lentiviral vector (referred to as “CART-19” cells), in 
patients who either: 
a. have not received a prior allogeneic SCT or have 0% residual donor engraftment 
(“no allo” cohort), or 
b. have relapsed after prior allogeneic SCT with any degree of residual donor 
engraftment (“allo” cohort). 
In each case, the cells used will be collected from the subject, not from an allogeneic donor. 
2. Determine duration of in vivo survival of CART-19 cells. RT-PCR analysis of whole 
blood will be used to detect and quantify survival of CART-19 TCR:4-1BB and TCR 
cells over time. 
 
Secondary objectives: 
1. For patients with detectable disease, measure anti-tumor response due to CART-19 cell 
infusions.   
2. To determine if the 4-1BB transgene is superior to the TCR only transgene as measured 
by the relative engraftment levels of CART-19 TCR:4-1BB and TCR cells over time. 
3. For patients with stored or accessible tumor cells (such as patients with active CLL, ALL, 
etc) determine tumor cell killing by CART-19 cells in vitro. 

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4. Determine if cellular or humoral host immunity develops against the murine anti-CD19, 
and assess correlation with loss of detectable CART-19 (loss of engraftment).   
5. Determine the relative subsets of CART-19 T cells (Tcm, Tem, and Treg) 
6. Determine safety and efficacy in a test cohort of patients with CNS3 disease. 
 
Exploratory objectives: 
1. Determine if insufficient in vitro T-cell test expansion in response to CD3/CD28 
costimulation is predictive of manufacturing or clinical outcome. 
 
3 
STUDY DESIGN 
3.1 
General Design 
We have designed a single-arm open-label phase I/IIa study to determine the safety, 
tolerability and engraftment potential of CART-19 T cells in patients with CD19+ hematologic 
malignancies. The general protocol schema is shown above in figure 1 in section 1. All subjects 
will be dosed with CART-19 T cells. In all subjects treated to date, the CART-19 T cells 
contained only the TCR:4-1BB transgene. A total of 72 subjects will be infused across “no 
allo”, “allo”, and CNS-3 cohorts. In order to infuse 72 patients, assuming a 20% drop out rate, 
we would enroll up to 86 patients. 
 
A secondary objective is to determine if the 4-1BB transgene is superior to the TCR 
only transgene. To test this, a cohort of 5 patients will be dosed with mixtures of TCR:4-1BB 
and TCR only cells, using a competitive repopulation strategy to determine the optimal signal 
transduction module in the chimeric receptor (figure 13). This cohort will proceed only after the 
2 CARs to be compared are finalized. It is reasonable to assume that engineered T cells 
containing signaling domains that mimic physiologic signaling will function best in vivo, and 
therefore, we think that CART-19:TCR:4-1BB will be superior to CART-19:TCR only. The 
null hypothesis is that they are equivalent.  
At entry, subjects will be staged and the suitability of their T cells for CART-19 
manufacturing will be determined. Subjects in both the no allo and allo cohorts who have 
adequate T cells will be leukapheresed to obtain large numbers of peripheral blood mononuclear 
cells (PBMC) for CART-19 manufacturing. In each cohort, the subject is pheresed; however, in 
the allo cohort, T cells derived from donor engrafted cells may be collected from the subject. The 
T cells will be purified from the PBMC, transduced with CART-19 lentiviral vector, expanded in 
vitro and then frozen for future administration. Chemotherapy will then be given. Following 
tumor burden reassessment, CART-19 cells will be thawed and infused.  
      Subjects will have blood tests to assess safety, and engraftment and persistence of the 
CART-19 cells at regular intervals through week 4 of the study (see table in Appendix 2).  The 
subsets of circulating T-cells that contain the CART-19:TCR:4-1BB and CART-19:TCR only 
lentiviral vector will be assessed at various times after infusion and compared to the baseline 
sample. Following the 6 months of intensive follow-up, subjects will be evaluated quarterly for 
two years with a medical history, a physical examination, and blood tests.  Following completion 
of the primary follow-up phase, subjects will continue to be followed for disease-free survival 
(as applicable) and overall survival every 3 months until they withdraw consent or until two 
years post the last subject infusion, as part of Secondary Follow-up.  Subjects will also be asked 

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to enroll in a 15 year long-term follow-up protocol to evaluate specific long-term adverse events 
related to the study product.  
 
3.2 
Primary Study Endpoints 
This phase I/IIa study is designed to test the safety and relative engraftment of the 
autologous T cells transduced with the anti-CD19 lentiviral vector in patients with relapsed, 
refractory and incurable CD19+ B cell malignancies. 
 
Primary safety, feasibility and engraftment endpoints include: 
1. Occurrence of study related adverse events, defined as NCI CTC > grade 3 
signs/symptoms, laboratory toxicities and clinical events that are possible, likely or 
definitely related to study treatment at any time from the infusion until week 24. This will 
include infusional toxicity and any toxicity possibly related to the CART-19 cells 
including but not limited to: 
a. Fevers 
b. Capillary leak 
c. Rash 
d. Neutropenia, thrombocytopenia, anemia, marrow aplasia 
e. Hepatic dysfunction 
f. Pulmonary infiltrates or other pulmonary toxicity 
g. Hypotension 
h. In the allo cohort only, GVHD 
2. Feasibility to manufacture CART-19 cells from patient apheresis products. The number of 
manufactured products that do not meet release criteria for vector transduction efficiency, 

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T cell purity, viability, sterility and tumor contamination will be determined (defined as 
“manufacturing failures”).   
3. Duration of in vivo survival of CART-19 cells is defined as “engraftment”. The primary 
engraftment endpoint is the # DNA vector copies per ml blood of CART-19 cells on week 
4 after the first infusion. Q-PCR for CART-19 vector sequences will also be performed 
after each infusion, weekly x 4, monthly x 6, and every 3 months thereafter until any 2 
sequential tests are negative documenting loss of CART-19 cells.   
4. New onset secondary malignancies. 
3.3 
Secondary Study Endpoints 
Secondary endpoints include: 
1. Describe anti-tumor responses to CART-19 cell infusions.   
a. For subjects with active disease, typical response criteria for partial response (PR) 
or complete response (CR) will be determined.  Response determination will be 
only “descriptive” given the small number of subjects to be treated. The main 
endpoint for efficacy is Day 28 overall response rate. Other endpoints, including 
duration of remission, best overall response, CR/CRi with MRD negative bone 
marrow, RFS and EFS may also be summarized. 
b. For subjects treated with MRD (identified by PCR analysis of blood or marrow), 
determine elimination of MRD scored as yes/no. 
c. For subjects treated in remission, describe progression-free survival (PFS). 
2. Describe overall survival and cause of death 
3. For patients with stored or accessible tumor cells (such as patients with active CLL or ALL) 
determine if in vitro cell killing assays of CART-19 cells against patient tumor correlates 
with clinical response. 
4. Determine if host immunity develops against the murine anti-CD19 or other elements of the 
transgene or vector such as VSV-G, and assess correlation with loss of detectable CART-19 
(loss of engraftment). 
5. In subjects infused with mixtures of CART-19 TCR and TCR:4-1BB cells, RT-PCR 
analysis of whole blood will be used to detect and quantify relative survival of CART-19 
TCR and TCR:4-1BB cells over time. 
6. Determine the relative subsets of CART-19 T cells (Tcm, Tem, and Treg) 
3.4 
Exploratory Study Endpoints 
Exploratory endpoints include: 
1. Describe the correlation of test expansion results with manufacturing feasibility and clinical 
outcome. 
 
4 
SUBJECT SELECTION AND WITHDRAWAL 
4.1 
Inclusion Criteria 
Inclusion criteria are designed to include a broad spectrum of subjects with documented 
CD19+ hematologic malignancies. Enrollment at CHOP will largely be limited to ALL and high-
grade B cell NHL. Male and female subjects with CD19+ B cell malignancies in patients with no 
available curative treatment options (such as autologous or allogeneic SCT) who have limited 

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prognosis (several months to <2 year survival) with currently available therapies will be 
enrolled:   
1. Eligible diseases: CD19+ leukemia or lymphoma 
a. ALL without curative options for therapy, including those not eligible for allogeneic 
SCT because of: 
 age 
 comorbid disease 
 other contraindications to TBI-based conditioning (required for ALL SCT) 
 lack of suitable donor 
 prior SCT 
 Declines allo SCT (in CR3) as a therapeutic option after documented discussion 
about the role of SCT with a BMT physician not part of the study team (see note 
below). 
Patient may be in any complete response, or patient may have active disease but 
responding or stable after most recent therapy (see 5.2 Patient Eligibility to Receive 
CART-19 Transduced T Cells, below). The intent is not to enroll patients with no degree 
of disease control, or rapidly increasing disease burden between enrollment and cell 
infusion. 
b. Follicular lymphoma, previously identified as CD19+ 
 At least 2 prior combination chemotherapy regimens (not including single agent 
monoclonal antibody (Rituxan) therapy. 
 Stage III-IV disease. 
 Less than 1 year between last chemotherapy and progression (i.e. most recent 
progression free interval <1 year). 
 Disease responding or stable after most recent therapy (chemotherapy, MoAb). 
c. CLL  
 At least 2 prior chemotherapy regimens (not including single agent monoclonal 
antibody (Rituxan) therapy. 
 Less than 1 year between last chemotherapy and progression (i.e. most recent 
progression free interval <1 year). 
 Not eligible or appropriate for conventional allogeneic SCT.   
 Disease responding or stable after most recent therapy (chemotherapy, MoAb) 
d. Mantle cell lymphoma 
 Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate 
for conventional allogeneic or autologous SCT. 
 Disease responding or stable after most recent therapy (chemotherapy, MoAb). 
 Relapsed after prior autologous SCT. 
e. B-cell prolymphocytic leukemia (PLL) with relapsed or residual disease after at least 1 
prior therapy and not eligible for allogeneic SCT. 
f. Diffuse large cell lymphoma or other high-grade NHL, previously identified as CD19+ 
 Residual disease after primary therapy and not eligible for autologous SCT. 
 Relapsed after prior autologous SCT. 
 Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate 
for conventional allogeneic or autologous SCT.   
2. Age 1 to 24 years. Patients ages 22-24 will only be enrolled if they are currently being treated 
at CHOP or another pediatric facility/oncologist. 

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3. Expected survival > 12 weeks 
4. Creatinine < 2.5 mg/dl and less than 2.5x normal for age 
5. ALT <= 5x normal 
6. Bilirubin <2.0 mg/dl 
7. Any relapse after prior SCT will make patient eligible regardless of other prior therapy. 
8. Patients with relapsed disease after prior allogeneic SCT (myeloablative or non-
myeloablative) will be eligible if they meet all other inclusion criteria and  
a. Have no active GVHD and require no immunosuppression 
b. Are more than 4 months from transplant (6 months at infusion; see Section 5.2) 
9. For those patients who require leukapheresis for T cell collection (i.e. no previously collected 
product exists), adequate venous access for apheresis or eligible for appropriate catheter 
placement, and no other contraindications for leukapheresis. 
10. Voluntary informed consent is given. 
11. Patients with CNS3 disease will be eligible if CNS disease is responsive to therapy (at 
infusion, must meet criteria in Section 5.2) (see section 15.5 for definitions of CNS1, CNS2 
and CNS3 disease) 
 
NOTE on 1.a.vi – declines SCT: SCT is performed in patients with ALL in CR3, but the 
outcomes are problematic. Most data suggest about a 30% OS in the highly selected group of 
patients.  A report which places this in context was published in JCO by Saarinen-Pihkala et al., 
looking at the overall (population-based) experience in CR3 ALL. Of 71 pts with ALL in CR3, 
OS after SCT was 30% and EFS 15%. Overall EFS of the 71 patients in CR3 was 7%. These 
numbers indicate that a decision to pursue a therapy other than SCT in CR3 ALL is rational, and 
that CART-19 therapy may offer a benefit to patients in this group.  
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 at the time of cell infusion or cell collection, 
or a condition, in the treating physician's opinion, that is likely to require steroid 
therapy during collection or after infusion. Steroids for disease treatment at times 
other than cell collection or at the time of infusion are permitted. Use of inhaled 
steroids, or hydrocortisone for physiological replacement in patients with adrenal 
insufficiency are permitted as well. 
5. 
Presence of grade 2 4 acute or extensive chronic GVHD. See section 15.2 for 
definition of chronic GVHD.  (NO LONGER APPLICABLE- Retired from V14) 
6. 
Under treatment for GVHD.  (NO LONGER APPLICABLE- Retired from V14) 
7. 
Previous treatment with any gene therapy products.   
8. 
Feasibility assessment during screening shows insufficient expansion in response 
to CD3/CD28 costimulation.(NO LONGER APPLICABLE – Retired from V11)  
9. 
Any uncontrolled active medical disorder that would preclude participation as 
outlined. 
10. 
HIV infection. 

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11. 
  
 
 
 
12. 
CNS3 disease that is progressive on therapy, or with CNS parenchymal lesions 
that might increase the risk of CNS toxicity 
13. 
Acute or chronic GVHD requiring systemic therapy (topical allowed).  
 
 
 
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 investigators will identify patients potentially meeting the 
study eligibility criteria through medical record reviews and the results of tests performed as part 
of routine clinical care. Subjects who are determined to be potentially eligible will be informed 
about the study. If the subject indicates willingness to participate in the study, the consent 
process will begin. Although many screening/eligibility tests are done routinely as part of 
standard oncology care, some are not, and written informed consent will be obtained before any 
non-SOC screening tests are conducted for research purposes. After informed consent has been 
obtained, the subjects will be evaluated for eligibility to ensure all inclusion and exclusion 
criteria are met. Eligible subjects will then be assigned a subject ID and considered enrolled by 
the sponsor. The test expansion (performed for exploratory purposes) will also occur in this 
phase. If and when the patient is eligible and enrolled with the sponsor, pheresis will occur if 
needed, and cell manufacturing begun.     
The test expansion has been used to determine whether the subjects have an adequate 
number of T cells that can be successfully expanded with the anti-CD19 lentivirus vector, as 
determined from a sample of PBMC obtained by phlebotomy or prior apheresis at the first 
screening visit (~week -8).  
Staggered enrollment on the CNS3 cohort: infusion of any subsequent patient on the CNS3 
cohort will be delayed until 21 days after the prior CNS3 patient’s infusion to allow for toxicity 
monitoring.  
          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], or are not <11 years of age or who are not Tanner 1,) 
must have a negative serum or urine pregnancy test performed 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 reliable and double barrier methods of 
contraception during the follow-up period of the protocol. 
    Acceptable birth control includes a combination of two 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 

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      Subjects who are not of reproductive potential (girls<11 years of age or who are Tanner 1, 
women who have been post menopausal for at least 24 consecutive months or have undergone 
hysterectomy, salpingotomy, and/or bilateral oophorectomy or men who have documented 
azoospermia) are eligible without requiring the use of contraception.  Acceptable documentation 
includes written or oral documentation communicated by clinician or clinician’s staff of one of 
the following: 
 
Demographics show age<11 
 
PE indicates Tanner 1 female 
 
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 
 
Laboratory report of azoospermia  
 
Follicle stimulating hormone measurement elevated into the menopausal range 
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 that the patient is too ill to continue. 
3. Pregnancy 
4. 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.   
5. Significant and rapid progression of malignancy, requiring alternative medical, 
radiation or surgical intervention including, but not limited to, the development of CNS 
metastasis. 
6. Grade 3 or 4 toxicity, which is unmanageable, unexpected, unrelated to chemotherapy, 
and attributable to protocol therapy, or a serious adverse event that requires the subject’s 
being withdrawn from the trial.   
7. 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 
criteria outlined in Section 15.3. 
8. Termination of the study by the principal investigator, the sponsor, the study funder, 
the IRB, or the Food and Drug Administration. 
4.4.2 
Data Collection and Follow-up  
Follow-up data collection after 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.  Many patients who respond to 
cell therapy may also have prolonged DFS but are also at risk for late relapse.  Therefore, 

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subjects will continue to be followed for 1) engraftment as long as patients are at risk (until 
evidence of loss of detectable transduced T cells), 2) DFS until there is disease progression or 
they begin a new cancer therapy (except for HSCT); 3) survival until the time of death; or until 
the patient withdraws consent for clinical data collection or until two years after the last subject’s 
infusion. 
 
In the event that a subject cannot return to the study site for follow-up visits because of subject 
preference or geographical concerns, the subject’s primary care physician and/or local oncologist 
may be asked to provide information from the subject’s medical record to the study team at 
protocol defined timepoints (including the results of any routine care examinations and/or 
laboratory assessments), and assist in the collection of protocol required blood samples which 
will be sent to the University of Pennsylvania for protocol required analysis.  The local provider 
will be contacted by a member of the study team to assess any potential toxicity. In numerous 
previous cell therapy trials at the CHOP and UPENN, 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 to further 
evaluate long term adverse events related to the study product.  
  
5 
STUDY DRUG  
5.1 
Description 
CART-19 cells are autologous T cells (collected from the patient) that have been engineered to 
express an extracellular single chain antibody (scFv) with specificity for CD19 linked to an 
intracellular signaling molecule comprised of a tandem signaling domain of the 4-1BB and 
TCR signaling modules. The CART-19 cells are cryopreserved in infusible cryomedia and will 
be administered in either 1 or 2 bags.  Each bag will contain an aliquot (volume dependent upon 
dose) of cryomedia containing the following infusible grade reagents: plasmalyte-A, dextrose, 
NaCl, up to 7.5% DMSO, dextran 40, human serum albumin with up to 5x109 autologous T cells 
per bag. 
 
Expected toxicities associated with infusion of CART-19 cells include transient fever, chills 
nausea, and rigors.  In order to minimize these events, patients will receive premedication as 
instructed below in section 5.4.  Later toxicities (7-21 days post infusion) are likely to be related 
to cytokine release syndrome (CRS), or possibly tumor lysis. Toxicities that could potentially 
occur but are unprecedented are primarily related to the gene transfer and are described in 
Section 8.4.2.  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 
 
Disease response: 

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 
No evidence of high disease burden, that would, in the opinion of 
the treating physician, put the patient at significant potential risk 
for tumor lysis syndrome. 
 
Failure to maintain performance status as indicated in initial eligibility 
criteria 
 
If s/p allogeneic transplant, 6 months from transplant. 
 
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: 
 
Pulmonary: Requirement for supplemental oxygen to keep 
saturation greater than 95% or presence of radiographic 
abnormalities on chest x-ray that are progressive 
 
Cardiac: New cardiac arrhythmia not controlled with medical 
management 
 
Hypotension requiring pressor support 
 
Active Infection: Positive blood cultures for bacteria, fungus, or 
virus within 48 hours. 
 
CNS3 cohort infusion criteria: 
1) Disease status: 
a. If CNS3 by spinal fluid involvement, stable/responding disease as indicated 
by: 
i. stable or decreasing CSF WBC, and  
ii. total CSF WBC < 100 in a sample obtained within 72 hours of CART-
19 infusion. 
b. If CNS3 by MRI findings, there must be interval stability or improvement on 
MRI within 2 weeks of infusion 
c. If CNS3 by cranial nerve findings, there must be stability or improvement of 
these cranial nerve findings on exam post intervention  
2) At least 21 days since any prior CNS3 patient was infused. 
3) Patients with CNS3 disease requiring radiation therapy must be at least 8 weeks post 
radiation at CART-19 infusion 
4) Patients must have no acute/ongoing neurologic toxicity > Grade 1 with the exception 
of a history of controlled seizures or fixed neurologic deficits that have been 
stable/improving over the past 3 months 
5.2.1 
Release criteria for the manufactured T cell product: 

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5.3 
Treatment Regimen 
5.3.1 
Patients 1-72 (infused), including CNS3 cohort 
CART-19 transduced T cells will be given, up to a total dose of 1.5x107-5x109 (0.3x106-
1.0x108/kg)- total cells transduced with the 41BB-z vector. We will use the following schedule, 
starting with a 10x dose reduction but allowing for intra-patient dose escalation (see section 6.6): 
 
Day 0: 10% of total dose 
 
Day 1: 30% of total dose if patient is clinically stable from prior day’s 
infusion 
See section 6.6 for details on timing and doses of subsequent CART-19 infusions. The toxicities 
that would preclude the next dose of T cells are DLTs or GVHD attributable to the cell infusion, 
and not toxicities attributable to the prior chemotherapy, such as cytopenias. A DLT will prevent 
the infusion of the next dose, even if fully resolved by that time. 
5.3.2 
Comparison Cohort 
NOTE: This cohort is on hold pending redesign of the comparison strategy (i.e., which CAR the 
41-BB CAR will be compared to). Both the protocol and the consent form will require 
modification and IRB approval prior to this cohort being treated. 
 
CART-19 transduced T cells will be given consisting of a mixture of 1.5x107-5x109 (0.3x106-
1.0x108/kg) total cells transduced with either the 41BB-zeta or zeta only vector.  The first patient 
to receive the combined T cell infusion will be an adult, either at PENN on their CART-19 
protocol, or an adult at CHOP. This dose will include 50% of cells of each CART-19-T product, 
which is separately manufactured and released, and then mixed prior to infusion.  Currently, the 
plan is to give the CART-19 cells using the original “split dose” regimen on day 0, 1 and 2, but 
this will be reassessed based on the response in the next patients we treat with the single T cell 
infusions. If we use this schedule, a second dose of CART-19 cells will be planned on day 11 to 
patients, providing they had adequate tolerance of the first dose and sufficient CART-19 cells 
were manufactured. If we proceed with the modified dosing schedule, this day 11 dose will not 
occur. We will clarify this prior to enrolling to this phase of the study.  
5.4 
Preparation and Administration of Study Drug 
Preparation 
The CART-19 T cells are prepared in the 
 as described in Section 1.2, and are not 
released from the 
 until release criteria for the infused cells (e.g., cell purity, sterility, 
average copy number of vectors/cell, etc.)
. Upon 
release, the cells are taken to the CHOP 
.  
 
Cell thawing:  
After logging the cells in the 
, frozen cells will be thawed and transported 
to the subject’s bedside for infusion. 

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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 and Benadryl prior to the 
infusion of CART-19 cells. These medications may be repeated every 4-6 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 
systemic corticosteroids such as hydrocortisone, prednisone, prednisolone or dexamethasone at 
any time, except in the case of a life-threatening emergency, since this may have an adverse 
effect on T cells. 
 
Febrile reaction 
In the unlikely event that the subject develops sepsis or systemic bacteremia following 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 
. 
 
Administration 
The transduced T cells will be administered by slow IV push or IV infusion -targeting an 
infusion time of 10-15 minutes, adjusted as appropriate for smaller children and smaller 
volumes. No more than 10cc/kg of total volume will be delivered to the patient. One or two bags 
of CART-19 modified cells will be delivered. Each infusion bag will have affixed to it a label 
containing the following: “FOR AUTOLOGOUS USE ONLY.” In addition the label will have at 
least two unique identifiers such as the subject’s initials, birth date, and study number. Prior to 
the infusion, two individuals will independently verify all this information and confirm identity 
using the subject’s wristband, and so confirm that the information is correctly matched to the 
participant. 
Emergency medical equipment will be available during the infusion in case the subject 
has an allergic response, or severe hypotensive crisis, or any other reaction to the infusion. Vital 
signs (temperature, respiration rate, pulse, oxygen saturation, and blood pressure) will be taken 
before and after infusion, then every 15 minutes for at least one hour and until these signs are 
satisfactory and stable.  
5.5 
Subject Compliance Monitoring 
Investigator-initiated phase I/II trials at CHOP are subject to routine auditing in accordance with 
the high risk policy of the CRQA.  Ongoing monitoring of each patient-subject is performed by 
the monitor designated by the Sponsor.  
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.  
 
Concomitant medications will be recorded in the medical record and on the appropriate CRF at 
every visit following the Day -1 Pre-Infusion Visit through the End of Study Visit.  Any 
additions, deletions, or changes of these medications will be documented.   
 
 
 

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5.6.1 Anti-neoplastic Therapies 
All prior antineoplastic therapy for the study indication received prior to the start of study 
treatment will be documented and recorded on the appropriate CRF as required per the CRF 
Completion Guidelines.  
 
All antineoplastic therapies for subjects in remission post CART19 T-cell infusion (HSCT and 
non-HSCT therapy for their study disease) will be collected and recorded on the appropriate 
CRF, until the time of disease relapse. 
5.7 
Packaging 
Each infusion bag/syringe will contain 10-50 ml of cells containing up to 5x109 total cells.  
5.8 
Receiving, Storage, Dispensing and Return 
5.8.1 
Receipt of Drug Supplies 
The CART-19 T cells are prepared in the 
 as described in Section 1.2. Upon release, 
the cells are taken to the CHOP 
. Upon receipt of the investigational product 
by the CHOP 
, an inventory must be performed and an Investigational 
Product Accountability log completed.  It is important that the designated study staff counts 
and verifies that the shipment contains all the items noted in the shipment inventory.  Any 
damaged or unusable study drug in a given shipment (active drug or comparator) will be 
documented in the study files.  The investigator must notify study sponsor of any damaged 
or unusable study treatments that were supplied to the investigator’s site. 
5.8.2 
Storage 
Bags (10 to 100 ml capacity) containing CART-19-transduced T cells will be stored under 
blood bank conditions in a monitored -1350C freezer at the University of Pennsylvania 
 until dispensed to the clinical site. Infusion bags will be stored in the freezer until 
needed. 
5.8.3 
Dispensing of Study Drug 
After logging the cells in the CHOP 
, frozen CART-19 cells will be thawed 
and transported for infusion to the subject’s bedside. If the CART-19 T cell product 
appears to be damaged or leaking, or otherwise appears to be compromised, it should not 
be infused, and should be returned to the 
 as specified below. 
5.8.4 
Return or Destruction of Study Drug 
CART-19 T cells may require return to the 
 for a variety of reasons, including but not 
limited to: 1) Mislabeled product; 2) Condition of patient prohibits infusion/injection, and 
3) Subject refuses infusion/injection; any unused product will be returned to the 
 for 
disposal as per 
. 
There is an ongoing reconciliation of drug shipped, drug consumed, and drug 
remaining, performed by the 
.  Final disposition of the investigational product will 
also be documented in the site Investigational Product Accountability logs appropriately. 
This information is submitted on an annual basis to the FDA in annual reports.   
 
 
 

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6 
STUDY PROCEDURES 
Overview 
The study consists of 1) a screening phase, 2) followed by an intervention/treatment phase 
consisting of apheresis, chemotherapy (to be determined according to disease as per section 6.5), 
3) infusions of CART-19 cells, and 4) follow-up. Schedule of evaluations and infusion are 
included in Attachment 2. 
6.1 
Pre-Entry Evaluations 
Subjects will be tested for the Human Immunodeficiency Virus (HIV).  If this was obtained as 
part of the pheresis process, this test result can be used.  The HIV test must be completed no 
more than 8 weeks before the infusion date as per the Schedule of Study Procedures (Section 
15.1).   
6.2 
Enrollment and Baseline Assessment. 
Subjects who have signed an informed consent and have an adequate pre-entry evaluation will 
undergo a routine lymphoma/leukemia staging workup including: 
 
History and Physical Examination (including height, weight, body surface 
area) 
 
CT scans of the Chest, Abdomen, and Pelvis done within 21 days of study 
entry if required for disease evaluation. 
 
Complete Blood Count, Differential. 
 
Chemistry Panel (Glucose, BUN, Creatinine, Sodium, Potassium, Calcium, 
Total Protein, Albumin, Total Bilirubin, Alk Phos, AST, ALT, Mg, Phos, 
LDH, Uric Acid)  
 
Serum pregnancy test for females of child bearing potential 
 
B2 Microglobulin Level if used in disease evaluation 
 
Serum immunoglobulin levels 
 
Performance Status Assessment 
 
GVHD assessment (allo cohort) 
 
Viral serologies (may use Miller-Keystone Autologous Panel) 
 
Autoantibody screen (ANA, ESR) 
 
Bone marrow aspirate, spinal tap (for any patient where spinal fluid 
sampling is part of disease surveillance, such as ALL) and lymph node 
biopsy (if accessible). Samples are sent to hematopathology for MRD 
assessment and CD19 expression. These tests will often already be 
available from prior treatment, in which case they will not be repeated at 
this point unless clinically indicated.   
 
For patients with ALL, CLL, PLL or other malignancy with circulating 
disease, bone marrow assessments will be done if clinically indicated to 
identify disease burden.  If there is circulating disease, blood will be sent 
for flow cytometry to confirm CD19 expression if this has not been done 
in the past 6 months. 
 
An ECHO/MUGA should be performed within 6 weeks of the first 
infusion. 

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6.3 
Enrollment 
To enroll a subject on this study, provide the documents listed below to:  
 
 
Documents required: 
– Enrollment Form 
– Complete screening documentation (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  
 
Upon informed consent completion and receipt of screening and eligibility documentation, the 
Sponsor Monitoring Team will review and provide documentation that the monitoring visit for 
eligibility has been completed.    This documentation must be received prior to cell product 
manufacturing.  
6.4 
Apheresis  
A single large volume apheresis procedure is carried out at the apheresis center. PBMC are 
obtained for CART-19 manufacture during this procedure. From a single leukapheresis, the 
intention is to harvest at up to 50 x 109 (109/kg) 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. The cell product is expected to be ready for release approximately 4 
weeks after beginning manufacturing.  
 
Timing of leukapheresis. Leukapheresis may occur after enrollment or may also occur prior to 
enrollment, in the case of cells collected for another clinical purpose or in anticipation of 
possible immunotherapy, using the cell collection protocol CHP-784, prior to determining 
eligibility for this study. In these cases, cells which were collected under appropriate conditions 
and with adequate number of PBMC available may be used for manufacturing, obviating the 
need for another collection procedure after enrollment.   
6.4.1 
Cytoreductive chemotherapy 
It is anticipated that many patients will have been receiving chemotherapy for relapse or resistant 
disease.  For inclusion, they will have responding or stable disease to the most recent therapy.  
Prior to CART-19 cell infusion and after apheresis, an additional chemotherapy cycle is planned.  
Patients referred with stable disease on no recent therapy will be eligible as well.  The use of 
additional chemotherapy prior to the recommended preinfusion chemotherapy will be at the 
discretion of the investigator and dependent on the patient’s disease burden. 
 
When given, chemotherapy may be started approximately 8-13 days before infusion so that 
CART-19 cells may be given 1-5 days after completion of the chemotherapy.  The timing of 

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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. The chemotherapy may be chosen also to reduce disease tumor 
burden.  The cytoreductive chemotherapy is not part of this investigational protocol and may be 
chosen and administered by the primary/referring oncologists. The choice of chemotherapy will 
depend on the patient’s underlying disease and prior therapies.  Fludarabine (30 mg/m2/day x 4 
days) and cyclophosphamide (500 mg/m2/day x 2 days) are the agents of choice, as there is the 
most experience with the use of these agents in facilitating adoptive immunotherapy.  
6.5 
Restaging assessment 
A limited restaging is done at the completion of chemotherapy in order to provide baseline tumor 
burden measurements. This may include imaging, physical examination, and MRD assessments. 
Subjects will undergo the following for pre-infusion testing: physical exam, documentation of 
adverse events and blood draws for hematology, chemistry and pregnancy testing (if applicable). 
6.6 
CART-19 Infusion #1 With Intra-Patient Dose Escalation 
Infusions may begin a minimum of 1 to 5 days after completion of chemotherapy.  
 
The day of (but prior to) the first infusion, patients will have a CBC with differential, and 
assessment of CD3, CD4 and CD8 counts since chemotherapy is given in part to induce 
lymphopenia. 
 
All patients must undergo a rapid influenza diagnostic test during the flu season months of 
October through May and within 10 days prior to the planned CART-19 infusion. If the patient is 
positive for influenza, oseltamivir phosphate or zanamivir 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 CART-19 infusion 
however if flu-like or respiratory signs and symptoms are present, CART-19 infusion should be 
delayed until the patient is asymptomatic.  
 
CART-19 transduced T cells will be given, up to a total dose of 1.5x107-5x109 (0.3x106-
1.0x108/kg) total cells transduced with the 41BB-z vector. We will use the following schedule, 
starting with a 10x dose reduction but allowing for intra-patient dose escalation: 
 
Day 0: 10% of total dose 
 Day 1: 30% of total dose if patient is stable from prior dose (no significant toxicity such as 
fever from 10% dose). This dose may be given between day 1 and 4 if the patient develops 
transient fever and is subsequently afebrile and clinically stable. If not given on day 1-4, this 
dose will then become available for infusion at day 14 or later (see next paragraph regarding 
timing and subsequent infusions). 
 
Timing and doses of subsequent CART-19 infusions. For patients who have had i) evidence of 
brief B cell aplasia with subsequent B cell recovery (suggesting rapid CAR clearance), or ii) 
fever and other reversible toxicities without evidence of CAR expansion/LGLs or response, or 
iii) no response, or a partial or temporary response to the initial infusion, it may be that the initial 
dose of cells was not adequate to produce a full therapeutic effect, or the cells may not have 
persisted long enough to produce longer-term disease control. In these cases, it may be 

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appropriate to give more CART-19 cells (subsequent infusions). In a recent case, a CLL patient 
at HUP experienced fevers but not CAR expansion after his first (100%) dose of CART-19 cells. 
He then was redosed 4 months later, and subsequently experienced a delayed marrow CR 45 
days after this second infusion (D Porter, personal communication). Patients may receive doses 
of up to 60%, no less than 14 days from any prior infusion (including the first infusion). 
 
It is possible that a subject's cumulative dose could exceed 100% of the dose specified above. 
More than 100% of the cell dose may be given in aliquots to sustain an initial response or 
address rapid CAR clearance (as evidenced by e.g. B cell recovery) if the cells grew well and a 
sufficient number are available. In this scenario, additional doses of 30% (if available) would be 
given at 2 week+ intervals. The rationale for this dosing regimen is that there does not appear to 
be a significant dose-response relationship with the initial dose. We have observed varying and 
significant degrees of cell expansion post infusion, making the amount of the infused cells less 
relevant. Thus, a multiple doses given over time may be more efficacious in sustaining a 
response. In terms of safety, the worst toxicities have been observed with the first infusion. There 
has been minimal toxicity with subsequent infusions in the few patients that have received them. 
Therefore, we consider the potential benefits of administering a greater cell dose over time to 
outweigh the potential risks. However, the cumulative dose will not exceed 1.5 x 108/kg 
administered over time in several doses.  
 
The goal is to give 30% aliquots for these subsequent infusions, unless only a 60% aliquot exists 
to be infused. Prior to amendment 10, the 
 has preparing the product in 10%, 30% and 60% 
aliquots, thus, it was not possible to administer less than 60% if that was the only aliquot 
remaining. Going forward, the manufacturing facility will prepare the product in several 30% 
aliquots (if sufficient cells exist), making subsequent administration of 30% doses possible. We 
will not administer several 60% doses over time (i.e. only one 60% dose would be given after the 
initial 10% and 30% doses).  
 
Regardless of timing, toxicities that would preclude a subsequent dose of T cells are DLTs 
(defined in section 8.1) or GVHD attributable to the cell infusion, and not non-DLT toxicities or 
toxicities attributable to the prior chemotherapy, such as cytopenias. A DLT will prevent the 
infusion of the next dose, even if fully resolved by that time. 
 
The cells are thawed by the 
. The thawed cells will be given as a slow IV push or 
infusion rate as quickly as tolerated so that the duration of the infusion will be approximately 10-
15 minutes, adjusted for size of patient and volume of infusion. In subjects 15-20 who receive 
mixtures of CART-19 cells, in order to facilitate mixing, the cells may be administered 
simultaneously using a Y-adapter. Subjects will be infused and premedicated as described in 
section 5.3. Subjects’ vital signs will be assessed and pulse oximetry will be done prior to 
dosing, at the end of the infusion and every 15 minutes thereafter for 1 hour and until these are 
stable and satisfactory. A blood sample for determination of baseline CART-19 level is obtained 
before infusion. 
 
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 

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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. These delay criteria apply to subsequent 
doses of CART-19 cells as well. 
 
A serum sample for potassium and uric acid will be collected before each infusion.   
6.7 
Post infusion assessments of clinical status, engraftment and persistence  
Subjects will return to CHOP twice weekly for 2 weeks after each CART-19 cell infusion to 
undergo the following:  physical exam, documentation of adverse events and blood draws for 
hematology, chemistry, engraftment and persistence of CART-19 cells and research labs. 
Two weeks after all infusions are complete, subjects will then return once a week for three 
weeks to undergo some or all of the following:  physical exam, documentation of adverse events 
and blood draws for hematology, chemistry, engraftment and persistence of CART-19 cells and 
research labs. Subjects will be instructed to call if there are any fevers or other side effects such 
as rigors experienced. These instructions, part of routine Oncology AVS instructions, will be 
reinforced by the study team. 
6.8 
CART-19 Subsequent Infusions 
Subsequent CART-19 infusions are considered in circumstances such as: 1) after disease relapse 
or 2) No response or 3) CART loss/B cell recovery while still in CR. Please refer to Attachment 
15.1 for further details. 
6.9 
Day 28 Evaluation 
PBMC will be obtained by a peripheral blood draw. Subjects will undergo the following:  
physical exam, documentation of adverse events and blood draws for hematology, chemistry, 
engraftment and persistence of CART-19 cells and research labs.  In addition, restaging is done 
in order to provide tumor burden measurements. Restaging testing is determined by disease type 
and may include imaging, MRD assessments, lumbar puncture, bone marrow aspirate and biopsy 
and/or lymph node biopsy – these biopsies will be performed if necessary for determination of 
disease status and not for research. The day 28 evaluation may be repeated 28 days after the last 
infusion if the patient receives subsequent infusions. 
6.10  Monthly evaluations 2 to 6 months post infusion 
Subjects will be monitored on a monthly basis during months 2 to 6 post CART-19 cell infusion.  
At these study visits, subjects will undergo the following:  review of concomitant medications 
and post treatment antineoplastic therapy, physical exam with GVHD assessment if applicable, 
documentation of adverse events and blood draws for hematology, chemistry, engraftment and 
persistence of CART-19 cells and research labs.   
 
An appropriate RCL test (i.e. HIV-gag or VSV-G or similar) will be performed at 3 and 6 
months post the initial CART-19 cell infusion to exclude the presence of detectable RCL. 
6.11 Quarterly evaluations for up to 2 Years Post Infusion 
Subjects will be evaluated on a quarterly basis until 2 years post infusion. At these study visits, 
subjects will undergo the following:  review of concomitant medication and post treatment 

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antineoplastic therapy, physical exam, documentation of adverse events and blood draws for 
hematology, chemistry, engraftment and persistence of CART-19 cells and research labs.   
6.12 Secondary Follow-up Phase 
For subjects who complete or prematurely discontinue from the primary follow-up phase while 
in remission, follow-up attempts will be made to assess the subject’s relapse, post treatment 
antineoplastic therapy, and survival status every 3 months post CART-19 infusion until two 
years post the last subject infusion.  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 that will be performed for up to 15 years on all 
subjects as recommended by the FDA for protocols utilizing integrating viral vectors.  
Evaluations include: physical exam and medical history (including concomitant medications and 
adverse events) with careful attention to features possibly related to oncoretroviral diseases such 
as cancer, neurologic disorders or other hematologic disorders. In addition, labs will be drawn to 
evaluate engraftment, T body PCR and research labs.  Blood for an appropriate RCL test (i.e. 
HIV-gag or VSV-G or similar) will be drawn yearly in order to detect RCL. If all RCL tests are 
negative during the study period to the first annual evaluation, then plasma may be archived for 
analysis on an as needed basis.  
6.14 Tumor Response Assessments 
Tumor response assessments will be done according to standard of care and practices at baseline 
(~21 days prior to CART 19 infusion), a limited reassessment after chemotherapy (see section 
6.5), at the 4 week response evaluation and day 28 after last infusion if the patient receives 
subsequent CART-19 cells, and then every 3 months for 1-2 years after 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: 
 
 
Disease 
Physical 
Exam 
CBC with 
differential 
Bone marrow 
Aspirate +/- 
bx with MRD 
Lymph 
node biopsy 
Lumbar 
puncture 
CT scans 
ALL 
+ 
+ 
+ 
 
+ 
 
CLL/PLL 
+ 
+ 
+/- (If 
clinically 
indicated) 
If clinically 
indicated 
 
+/- 
NHL/ 
Mantle Cell 
+ 
+ 
+/- (If 
clinically 
indicated) 
If clinically 
indicated 
If 
clinically 
indicated 
+ 

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7 
STATISTICAL PLAN 
7.1 
General Design Issues 
This is an open label, phase I/IIa study to evaluate the safety and tolerability, and persistence and 
engraftment of autologous T cells engineered to express a chimeric antigen receptor targeting 
CD19, that is linked to the CD3z-4-1BB signaling chains in the setting of a competitive 
repopulation in patients with chemotherapy resistant or refractory CD19+ leukemia or 
lymphoma. Patients at CHOP will be enrolled on this protocol (including some adults up to age 
24), while patients at UPENN will be enrolled on the UPENN protocol. Inclusion of patients 
ages 22-24 will be limited to patients already being treated at CHOP or another pediatric center. 
The eligibility criteria are similar. The accrual goals at CHOP and UPENN will be separate. 
SAEs will be reported to both IRBs, with CHOP SAEs being reported according to the timing 
below and UPENN SAEs being provided according to the “outside center” reporting rules. 
Events on both the CHOP and UPENN protocols will be evaluated by the same DSMB. Possible 
triggering of pausing and stopping rules on this protocol will reflect events at CHOP only unless 
recommended by the DSMB. 
Failure to complete the study due to the stopping rules being invoked will be the main 
basis for determining safety and feasibility of this study. This study is primarily intended to 
provide data that might allow the investigators to conduct a preliminary assessment of safety and 
feasibility. 
Upon enrollment, patients will undergo leukapheresis (if needed) and an optional bone 
marrow aspirate approximately four weeks prior to dosing.  Between leukapheresis and 
treatment, patients may undergo an additional chemotherapy treatment depending upon their 
disease.  At dosing, patients will receive redirected autologous T cells against CD19 (CART-19 
cells), containing a CD3z-4-1BB intracellular signaling chain.  Patients will be monitored weekly 
for four weeks.  At the end of four weeks, patients will undergo a second evaluation.   
Observation and monitoring of patients will continue on a monthly basis until 24 weeks 
after a cell infusion is given.  In subjects given a mixture of CART-19 cells, the change in the 
ratio of the vector transduced cells to each other between baseline and week four will be 
evaluated.  After two years, annual follow-up for lentiviral vector safety will be carried out under 
a separate destination protocol for 15 years post infusion in accordance with FDA guidelines for 
retroviral vectors.   
72 subjects will be targeted for infusion in this study. We have observed a drop out rate of 
less than 20% or less due to disease progression or clinical deterioration between enrollment and 
initial infusion (this will take about 6-8 weeks for screening-apheresis to dosing).  However, as 
we are eliminating the test expansion, we may increase this dropout rate by 5-15%. Thus, up to 
86 subjects will be initially enrolled to allow our goal of 72 infusions.  
All safety data after initial CART-19 infusion will be summarized regardless of whether 
patient receives subsequent CART-19 infusions or not (Section 6.6). Efficacy data will be 
summarized from initial CART-19 infusion to first documented relapse or end of follow-up, 
whichever occurs first. Additional analyses may be planned as needed. 
7.2 
Endpoints 
7.2.1 
Primary Endpoints 
 Monitor the occurrence of study related adverse events (defined as ≥ Grade 3 
signs/symptoms, laboratory toxicities, and clinical events) that are “possibly”, 

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“likely”, or “definitely” related to study treatment any time from the first day of 
study treatment until week 24.   
 Feasibility to manufacture CART-19 cells from patient apheresis products. The 
number of manufactured products that do not meet release criteria for vector 
transduction efficiency, T cell purity, viability, sterility and tumor contamination 
will be determined (defined as “manufacturing failures”).   
 Duration of in vivo survival of CART-19 cells is defined as “engraftment”. PCR 
for CART-19 vector sequences will also be performed after infusion at 24 hours, 
weekly x 4, monthly x 6, and every 3 months thereafter until any 2 sequential 
tests are negative documenting loss of CART-19 cells.   
 New onset secondary malignancies. 
7.2.2 
Secondary Endpoints 
 Describe anti-tumor responses to CART-19 cell infusions.   
i. For subjects with active disease, typical response criteria for partial 
response (PR) or complete response (CR) will be determined.  Response 
determination will be only “descriptive” given the small number of 
subjects to be treated.  
ii. For subjects treated with MRD (identified by PCR analysis of blood or 
marrow), determine elimination of MRD scored as yes/no. 
iii. For subjects treated in remission, describe progression-free survival (PFS). 
 Describe overall survival and cause of death 
 Rates of grade 2, 3 and 4 GVHD 
 For patients with banked or accessible tumor cells (such as patients with active 
CLL, ALL, etc) determine if in vitro cell killing assays of CART-19 cells against 
patient tumor correlates with clinical response. 
 Determine if host immunity develops against the murine anti-CD19, and assess 
correlation with loss of detectable CART-19 (loss of engraftment). 
 For patients with stored or accessible tumor cells, evaluate the post infusion 
tumor response in comparison to baseline responses prior to cytoreductive 
chemotherapy (week -4), to evaluate the effect on general anti-tumor immunity. 
 In subjects infused with mixtures of CART-19 TCR and TCR:4-1BB cells, 
RT-PCR analysis of whole blood will be used to detect and quantify relative 
survival of CART-19 TCR and TCR:4-1BB cells over time. 
 Determine the relative subsets of CART-19 T cells (Tcm, Tem, and Treg) 
7.2.3 
Exploratory Endpoints 
 Describe the correlation of test expansion results with manufacturing feasibility 
and clinical outcome. 
7.3 
Sample Size  
This is a 86 patient phase I/IIa study with an anticipated dropout rate of 20%.  If this exploratory 
study suggests that one vector persists and engrafts better than the other vector, then a larger 
follow-on trial will be designed that has the statistical power to assess the potential efficacy of 
that vector.   

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7.4 
Safety 
This trial will infuse up to 72 patients. This may require enrollment of more subjects because of 
the dropout rate.  In order to assess the confidence with which we can obtain an initial estimate 
on the toxicity rate in each cohort, the table below presents the exact 95% confidence intervals 
for the toxicity rate based on the first 7 or 10 subjects 
.   
 
n=7 Evaluable Subjects 
n=10 Evaluable Subjects 
Observed 
Toxicity 
Rate 
95% Exact 
Confidence 
Interval 
Observed 
Toxicity 
Rate 
95% Exact 
Confidence 
Interval 
  0% (0/7) 
(0%, 41%) 
  0%  (0/10) 
(0%, 31%) 
14% (1/7) 
(0%, 58%) 
10% (1/10) 
(0%, 45%) 
29% (2/7) 
(4%, 71%) 
20% (2/10) 
(3%, 56%) 
43% (3/7) 
(10%, 82%) 
30% (3/10) 
(7%, 65%) 
 
With 10 subjects and a true underlying toxicity rate of 20%, the probability of failing to observe 
an adverse event is 11%.  The probability decreases to 3% if the true toxicity rate is 30%.  
Taking into account potential drop out due to disease progression either prior to infusion or 
before the planned response assessment is possible, with seven subjects the probability of failing 
to observe an adverse event is 21%, if the true toxicity rate is 20% and decreases to 8% if the 
true toxicity rate is 30%. 
7.5 
Efficacy 
Anti-tumor activity will be assessed as a secondary trial endpoint.  Anti-tumor efficacy of 
CART-19 cells will be determined in a follow-on study. 
Another exploratory endpoint is to test the relative engraftment of CART-19 cells expressing 
TCR or TCR:4-1BB domains. It is recognized that there will be statistical power to detect only 
very large change in the ratio of CART-19 cells.  The results of this study will provide 
information on the expected change in ratios of CART-19 cells from baseline to four weeks post 
dosing to provide guidance on which vector should be considered for a future larger study, as 
well as pilot data to allow determination of required samples sizes for that study.   
 
With a total of 20 evaluable subjects in each cohort, there would be 80% power to detect a 0.76 
standard deviation difference in the ratio between the two different CART-19 cell between just 
post dosing baseline values and values obtained from the week four apheresis, using a paired t-
test at a 0.05 two-sided level of significance.  With a total of seven evaluable subjects in each 
cohort, there would be 80% power to detect a 1.27 standard deviation difference in the CART-19 
ratio under the same conditions.   
7.6 
Subject Population(s) for Analysis 
The subject population to be analyzed for primary and secondary endpoints will include all 
patients infused with CART-19 cells.   
A second population of patients will include all patients enrolled on study but who do not receive 
CART-19 cells.  Reasons patients do not receive cell infusions are likely to include 1) ineffective 

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transduction of autologous T cells; 2) rapid progression, clinical deterioration, and/or death 
between the time of enrollment and infusion; 3) subject withdrawal.  
The number of patients enrolled versus the number of patients infused will be described and is a 
measure of the feasibility of this therapy for patients with various malignancies to be treated. 
7.7 
Statistical Analysis 
The statistical analysis will be primarily descriptive in keeping with the exploratory nature of the 
study.  All adverse events will be described and exact 95% confidence intervals will be produced 
for adverse event rates, both overall and within major categories.  The change in the ratio of 
CART-19 cells over time will be compared using a Wilcoxon signed-rank test for paired data.  
This nonparametric test is very efficient (>95%) compared to the t-test if the underlying data are 
normally distributed.  Analysis of other secondary endpoints such as anti-tumor activity will also 
be primarily descriptive and may include summary statistics such as means and standard 
deviations or Kaplan-Meier curves for survival information. Descriptive statistics may also be 
summarized for the exploratory endpoint. 
8 
SAFETY AND ADVERSE EVENTS 
Safety will be assessed by monitoring and recording potential adverse effects of the treatment 
using the Common Toxicity Criteria version 3.0 at each study visit. Subjects will be monitored 
by medical histories, physical examinations, and blood studies to detect potential toxicities from 
the treatment. 
8.1 
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.  Intercurrent illnesses or injuries should 
be regarded as adverse events.  Abnormal results of diagnostic procedures are considered to 
be adverse events if the abnormality: 
1. results in study withdrawal 
2. is associated with a serious adverse event 
3. is associated with clinical signs or symptoms 
4. leads to additional treatment or to further diagnostic tests 
5. is considered by the investigator to be of clinical significance 
 

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Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE 
that is:  
1. fatal 
2. life-threatening 
3. requires or prolongs hospital stay 
4. results in persistent or significant disability or incapacity 
5. a congenital anomaly or birth defect 
6. 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 prevent one of the other serious outcomes noted above.  For example, drug 
overdose or abuse, a seizure that did not result in 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.  
 
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.  
 
“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. 
 
Dose Limiting Toxicity (DLT) 
Dose limiting toxicity is defined as a grade 3 or 4 toxicity as determined by CTC 3.0, 
which is unmanageable, unexpected and unrelated to chemotherapy and attributable to 
protocol therapy. For instance, grade 4 neutropenia or thrombocytopenia related to pre-
infusion chemotherapy would not be related to study drug and would not be considered as a 

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DLT. In addition, if the toxicity is autoimmune or allergic in nature and occurs after repeat 
dosing, a grade 2 toxicity will be considered a DLT. 
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the 
period from the initiation of any study procedures to the end of the study treatment follow-
up.  For this study, adverse events are reported starting on Day 0 until the subject is off 
study or until year 2 end of study visit. The only exception is for patients that are 
discontinued due to an adverse event after enrollment and prior to infusion.  This AE or 
SAE leading to study discontinuation will be recorded in the clinical database. Events 
occurring during chemotherapy, and occurring as a direct result of the cytotoxic 
chemotherapy will not be reported as an adverse event but should be listed under medical 
history.  
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.  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 study 
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:  
1. The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
2. The abnormality suggests a disease and/or organ toxicity 
3. 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. 

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Medical conditions and 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 an 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 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. 
8.2 
Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  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 be recorded in the source document, though should be 
grouped under one diagnosis. 
 
All adverse events occurring during the adverse event reporting period (defined in Section 8.1 
above) must be recorded.  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.  Serious adverse events that are still ongoing at the end of the study period must be 
followed up to determine the final outcome.  Any serious adverse event that occurs after the 
study period and is considered to be possibly related to the study treatment or study participation 
should be reported immediately. 
8.3 
Reporting of Serious Adverse Events and Unanticipated Problems  
8.3.1 
Study Sponsor Notification by Investigator 
All serious adverse events must be reported to the study sponsor by email within 24 hours 
of knowledge of the event.    Report serious adverse events by email to: 

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At the time of the initial notification, the following information should be provided: 
1. Study identifier 
2. Subject number 
3. A description of the event 
4. Date of onset 
5. Current status 
6. Whether study treatment was 
discontinued 
7. The reason the event is classified as 
serious 
8. 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 report.  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 study 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.   
8.3.2 
Investigator reporting: notifying 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, or 
where required by the Sponsor.  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 

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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 
Unanticipated problems posing risks to subjects or others as noted above will be reported 
to the IRB as a written or online 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 IRB for specific situations: 
1. 
Report the event within 24 hours when the death is unforeseen (unexpected) and 
indicates participants or others are at increased risk of harm. 
2. 
Report the event within 72 hours, for all other deaths, regardless of whether the 
death is related to study participation. 
 
For reportable deaths, the initial submission to the IRB may be made through the eIRB 
system. 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: 
1. 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). 
2. 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. 
3. 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. 
4. Change in FDA safety labeling or withdrawal from marketing of a drug, device, or 
biologic used in a research protocol. 
5. Breach of confidentiality 

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6. Change to the protocol taken without prior IRB review to eliminate apparent 
immediate hazard to a research participant. 
7. 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. 
8. Complaint of a participant when the complaint indicates unexpected risks or the 
complaint cannot be resolved by the research team. 
9. 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. 
8.3.3 
Reporting obligations to the ACC DSMC 
The Abramson Cancer Center has developed a detailed data safety and monitoring plan.  
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 while the DSMC’s focus is data quality and 
subject safety monitoring and auditing. The guidelines governing both committees have 
been adapted from the NCI/NIH policies.  
The DSMC requires AE/SAE submission through Velos as follows  
 
All grade 3 or higher events, including GVHD, 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.  
 
All unexpected deaths within 24 hours of knowledge 
 
All other 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 
investigators and the study team must 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.  
8.3.4 
FDA Notification by Sponsor 
The study 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 sponsor 
must report an IND safety reports as described in:   
 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM22735
1.pdf.  
 

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Within 7 calendar days 
 
Any study event that is: 
 Unexpected fatal or life-threatening suspected adverse reaction. 
 Expected and unexpected Grade 3 or higher events of cytokine release syndrome per the 
modified CRS grading scale in Table 8-1 
 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: 
 Serious and unexpected  
 Suspected adverse reaction serious, but not fatal or life-threatening 
-or- 
 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 other studies, findings from animal or in vitro testing:  
 that suggest a significant risk for human subjects including reports of mutagenicity, 
teratogenicity, carcinogenicity or reports of significant organ toxicity at or near the 
expected human exposure. 
 
Increase in rate of occurrence of serious suspected adverse reactions: 
 
any clinically important increase in the rate of a serious suspected adverse reaction 
over that listed in the protocol or investigator brochure  
 
Additional reporting requirements 
Sponsors are also required to identify in IND safety reports all previous reports concerning 
similar adverse events and to analyze the significance of the current event in light of the previous 
reports. 
 
If the adverse event does not meet expedited reporting requirements, the Sponsor will report the SAE 
as in the IND Annual Report. 
 
Reporting Process 
Adverse events may be submitted on FDA Form 3500A or in a narrative format. 
8.4 
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 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. 

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Premature termination of the clinical trial may occur because of a regulatory authority decision, 
change in opinion of the IRB, the DSMB, 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. 
8.4.1 
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. 
 
The Investigator, Study Funder, Sponsor, DSMB, ACC DSMC, or any 
independent review board or regulatory body decides for any reason that 
subject safety may be compromised by continuing the study.  
 
The Sponsor or Study Funder decides to discontinue the development of 
the intervention to be used in this study. 
  
The protocol will be paused pending submission of protocol pause to the FDA and review by the 
IRB and DSMB if any patient experiences any of the following events within two weeks of the 
CART-19 infusion: 
 
Life-threatening (grade 4) toxicity attributable to protocol therapy that is 
unmanageable, unexpected, unrelated to chemotherapy, and attributable to 
protocol therapy. This includes grade 4 GVHD.  In terms of expected 
toxicity, we expect high fevers, hypotension, possible ICU admission and 
even mechanical ventilation.  CRS and MAS can result in grade 4 liver 
toxicity, nephrotoxicity and other organ involvement. In addition, we have 
seen reversible confusion in 3 patients which fully resolved spontaneously 
over 2-4 days without treatment or sequelae. 
 
Death. 
 
If the V analysis pattern of insertion is found to favor a single dominant 
insertion site pattern the clinical trial will be placed on hold for dosing to 
allow evaluation of the subject in consultation with gene therapy experts, 
study investigators, DSMB, FDA and NIH. 
8.4.2 
Stopping rules related to the CNS3 cohort 
Accrual to the CNS3 cohort will be stopped for review if: 
1) Any subject develops a grade 5 neurological toxicity attributable to CART-19 
infusion. 
2) Any subject develops grade 3/4 neurotoxicity or agitation, confusion, delirium, or 
psychosis (psychiatric) toxicity that has not resolved to </= Grade 2 within 4 weeks 
with or without medical intervention (ie: anti-epileptics). 
3) Any non-resolving grade 3 or 4 neuro toxicity or death due to neuro/psychiatric 
toxicity clearly attributable to the CART cells will lead to a hold on any further CNS3 
patients enrolled in this high risk stratum pending subsequent review. 
 

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Note on attribution: Toxicity is attributable to CART-19 infusion if, in the opinion of the 
principal investigator or sponsor, the event was more likely than not to be caused by the CART-
19 cells. In making this determination, the investigator will assess: 
 Timing (most other toxicities, other than cytopenias and hypogammaglobulinema 
are resolved within 28 days of infusion). 
 Predisposing structural CNS lesions, prior strokes, or prior seizure history 
 Neurologic baseline at study entry 
 Events during CRS that may have been predisposing to CNS toxicity (such as 
significant coagulopathy) 
 Infections are most likely attributable to cytopenias due to disease and 
chemotherapy, and are therefore less likely to be due to CART-19 infusion  
8.4.3 
General 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 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 Testing: If a positive RCL assay result is obtained from a subject blood 
specimen, the PI will be informed and the subject rescheduled for a retest for the DNA 
test.  If the second RCL 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 subjects can 

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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 RCL testing for detection and/or 
characterization of the RCL.   
 
– Clonality and insertional oncogenesis: The occurrence of adverse events caused by 
insertional mutagenesis in three patients in a gene therapy trial for X-linked SCID 
following stem cell therapy emphasizes the potential for problems in translating this 
approach to the clinic112. To date, clinically evident insertional mutagenesis has not 
been reported following adoptive of engineered T cells. Lentiviral vectors may have a 
lower risk than oncoretroviral vectors based on several considerations113.  Monitoring 
for T cell clonal outgrowth will be performed by flow cytometric analysis for T-body-
expressing cells, and by CBC count.  If the number of chimeric immune receptor cells 
continues to increase after 6 weeks, a V repertoire analysis will be performed to 
evaluate clonality, or if the CBC analysis reveals abnormal T cell counts, then the V 
analysis will be performed earlier.  If a subject's V repertoire is found to be 
monoclonal or oligoclonal, the subject's T cells will be evaluated for the pattern of 
vector insertion. If the pattern of insertion is found to favor a single dominant insertion 
site pattern the clinical trial will be placed on hold for dosing to allow evaluation of 
the subject in consultation with gene therapy experts, study investigators, DSMB, 
FDA and NIH. Further evaluation of the subject will comprise confirmation of the 
persistence of the clonality within a 3 month period, and monitoring of the subject for 
hematologic malignancies. Optionally, a sequence analysis of the dominant insertion 
site(s) will be performed, in order to locate any association of the insertion sites with 
known human oncogenes. 
 
– Uncontrolled T cell proliferation. CART-19 T 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. Clonal dominance of adoptively 
transferred T cells has been associated with tumor reduction in adoptive transfer 
trials69, 132. If any subject develops excessive CART-19 T cell accumulation, 
corticosteroids will be administered to eradicate the infused cells.  
8.4.4 
Management of toxicity 
Uncontrolled T cell proliferation. Toxicity associated with allogeneic or autologous T cell 
infusions has been managed with a course of pharmacologic immunosuppression. T body 
associated toxicity has been reported to respond to systemic corticosteroids87.  If uncontrolled T 
cell proliferation occurs, subjects will be treated with corticosteroids. Subjects will be treated 
with pulse methylprednisolone (2 mg/kg i.v. divided q6-8 hr x 2 days), followed by a rapid taper.  
 
Recommended treatment of cytokine release/ possible macrophage activation syndromes. Given 
the dramatic clinical improvement of several of the patients treated on this protocol after 
treatment with anti-cytokine therapy, we will prospectively manage potential cytokine toxicities 

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with tocilizumab (anti-IL-6), with or without other agents such as steroids and etanercept (anti-
TNF). This management approach is designed to avoid life-threatening toxicities, while 
attempting to allow the CART-19 cells to establish the proliferative phase that appears to 
correlate with anti-tumor efficacy. Thus, the timing of the interventions below will be 
individualized in close consultation with the admitting service.  
– Subjects will be treated with tocilizumab (CHOP Formulary dose 8 mg/kg, or 
12mg/kg for patients<30kg, as per the package insert) with or without 
corticosteroids if grade 4 toxicity related to CART-19 cells is observed, such as 
hypoxia, respiratory distress, or hypotension. If possible and when used, 
steroids will be rapidly tapered.  
– Subjects who have not responded to tocilizumab may be treated with a single 
dose of etanercept (CHOP Formulary dose 0.8mg/kg) if they have developed 
significant respiratory distress including intubation.  
– Subjects will be treated with a single dose of tocilizumab (as above) if they 
develop hypotension requiring more than low-dose pressor support. 
Events of Cytokine Release Syndrome (CRS) will be reported and graded based on the below 
criteria for all patients that experience CRS moving forward.  Events prior to this amendment 
will be reviewed and retrospectively be graded and reported by the primary investigator per 
source documentation.  The Penn Grading Scale for Cytokine Release Syndrome (PGS-CRS) 
will be used for grading of CRS.  Please see below for details.  
CTL019-Therapy-Associated Grading for Cytokine Release Syndrome: The Penn Grading 
Scale for Cytokine Release Syndrome (PGS-CRS) 
 Marked elevations in IL-6, interferon gamma and less intensely TNF 
 Symptoms occur 1 to 14 days after cell infusion in ALL 
 Symptoms may include: High fevers, rigors, myalgia, arthralgia, nausea, vomiting, anorexia, 
fatigue, headache, hypotension, encephalopathy, dyspnea, tachypnea, and hypoxia 
 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.  
 
 
 
 
 
 
 
 
 
 
 

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Table 8-1 
1 
2 
3 
4 
5 
Mild reaction: Treated 
with supportive care 
such as anti-pyretics 
and anti-emetics. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate reaction: 
Requiring intravenous 
therapies or parenteral 
nutrition; some 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. 
 
 
 
 
 
 
 
 
 
 
 
More severe reaction: 
Hospitalization required for 
management of symptoms 
related to 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 
intravenous fluids* 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. 
Life-threatening 
complications such as 
hypotension requiring 
high dose pressors 
(see Table 8-2) or 
hypoxia requiring 
mechanical 
ventilation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Death 
*Defined as: multiple fluid boluses for blood pressure support. 

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Table 8-2 High Dose Vasopressor Use 
Definition of “High-Dose” Vasopressors 
Vasopressor 
Dose for ≥ 3 hours 
Norepinephrine monotherapy 
≥ 0.2 mcg/kg/min 
Dopamine monotherapy 
≥ 10 mcg/kg/min 
Phenylephrine monotherapy 
≥ 200mcg/min 
Epinephrine monotherapy 
≥ 0.1 mcg/kg/min 
If on vasopressin 
High-dose if vaso + Norepinephrine Equivalent (NE) of ≥0.1 
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 2008. 
Note: Pediatric weight adjustments should be taken into consideration. 
 
B cell depletion. It is likely that B cell depletion and hypogammaglobulinemia will occur in 
CART-19 patients who have a disease response. This is common with anti-CD20 directed 
therapies120. 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. 
8.4.5 
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.  
– For other considerations for premature discontinuation from the study, see Section 
4.4.1. 
8.5 
Protocol Exceptions and Deviations 
Exception:  
A one time, intentional action or process that departs from the 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 approval from the Regulatory Sponsor, and local 
regulatory review committees per institutional guidelines, is required.    

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No exception will 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.   
 
Deviation:  
A one time, unintentional action or process that departs from the 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 Regulatory Sponsor 
within 5 business days and local regulatory review committees per institutional guidelines.   
 
Any departure from the protocol that meets the following criteria should be submitted to the 
Regulatory Sponsor: 
 May have affected subject safety.  
 Impacts the integrity of the study design or outcome 
 Violates eligibility 
 Dose adjustment 
 Stopping criteria 
 Affect sample size (adding more subjects, decreasing number of subjects, changing 
the number of subject in a specific arm/cohort) 
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:  Study 
identifier, subject identifier, description of deviation from protocol or exception request, and 
necessity for exception/deviation.  Ensure all completed exception/deviation forms are signed by 
the Principal Investigator (or co-investigator) and submitted to the Sponsor Project Manager.    
 
 
The Sponsor Project Manager will submit the exception request or deviation notification to the 
Regulatory Sponsor for review and approval. Once approval of the exception request or 
acknowledgement of the deviation has been received from the Regulatory Sponsor, the event will 
be submitted by the Investigator to the IRB and other local regulatory review committees as 
required for review and approval. 
8.6 
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-

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monitoring plan (see section 9 Auditing, Monitoring and Inspecting).  Medical monitoring will 
include a regular assessment of the number and type of serious adverse events. 
8.6.1 
Independent Data and Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) comprised of 4-6 individuals including physicians 
with experience in oncology and/or gene transfer therapy will be assembled and will work under 
a charter specifically developed for safety oversight of this study. The DSMB will provide 
advice to the investigators, and consult with Sponsor as necessary. The DSMB will evaluate 
patient-subject safety as specified in the DSMB Charter. 
 
If necessary, additional meetings of the DSMB may be held if safety issues arise in between 
scheduled meetings. 
8.6.2 
Clinical Monitors 
Representatives of the Sponsor will conduct a site initiation visit and periodically audit, at 
mutually convenient times during and after the study, all CRFs 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. 
 
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 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. 
 
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. 
 
9 
DATA HANDLING AND RECORD KEEPING 
9.1 
Confidentiality 
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.  
 

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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. 
9.2 
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. 
9.3 
Case Report Forms 
Electronic case report forms will be used.  
9.4 
Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after 
the last approval of a marketing application in their country and until there are no pending or 
contemplated marketing applications in their country or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period if required by an agreement with the sponsor.  In such an 
instance, it is the responsibility of the sponsor to inform the investigator/institution as to when 
these documents no longer need to be retained.  
 
10 STUDY MONITORING, AUDITING, AND INSPECTING 
10.1 Study Monitoring Plan 
This study will be monitored according to the 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 (e.g. pharmacy, diagnostic laboratory, etc.), and 
has adequate space to conduct the monitoring visit. 
10.2 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.). 
 

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Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
 
11 ETHICAL CONSIDERATIONS 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA 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 sponsor before commencement of this study.  The investigator should provide a list of IRB 
members and their affiliate 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 or legally acceptable surrogate, and the investigator-
designated research professional obtaining the consent.  
 
12 STUDY FINANCES 
12.1 Funding Source 
This study is funded by a Pennsylvania Department of Health CURE grant. The cell 
manufacturing is supported by Novartis Pharmaceuticals. 
12.2 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 study sponsor 
prior to participation in this study.  All University of Pennsylvania investigators will follow the 
University conflict of interest policy. 
12.3 Subject Stipends or Payments 
There is no subject stipend/payment for participation in this protocol. 
12.4 Study Discontinuation 
The study may be discontinued at any time by the IRB, the Sponsor, the ACGT, the FDA, or 
other government agencies as part of their duties to ensure that research subjects are protected. 

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13 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 study sponsor.  Any 
investigator involved with this study is obligated to provide the sponsor with complete test 
results and all data derived from the study. 
 
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the study sponsor 
 101.  Porter DL, Levine BL, Bunin N et al. A phase I trial of donor lymphocyte infusions 
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the study sponsor 
 113.  Sinn PL, Sauter SL, McCray PB, Jr. Gene therapy progress and prospects: development 
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 116.  Uckun FM, Messinger Y, Chen CL et al. Treatment of therapy-refractory B-lineage acute 
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the study sponsor 
 126.  Wang GP, Levine BL, Binder GK et al. Analysis of lentiviral vector integration in HIV+ 
study subjects receiving autologous infusions of gene modified CD4+ T cells. Mol Ther 
2009;17(5):844-850. 
 127.  Cruz CR, Hanley PJ, Liu H et al. Adverse events following infusion of T cells for adoptive 
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 130.  Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report 
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 132.  Dudley ME, Wunderlich JR, Yang JC et al. Adoptive cell transfer therapy following non-
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CONFIDENTIAL 
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the study sponsor 
 
  
  
15 ATTACHMENTS 

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CONFIDENTIAL 
This material is the property of Children’s Hospital and the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor 
 
  
  
15.1 Schedule of Study Procedures  
 
~Week (-) 8 
~ Week  (-) 6 to 8 
~ Week  (-) 4 
~ Week  (-) 1 
~ Day  (-) 1 
Day   0  
Day   + 1 
Day +5 (+/- 3D) 
D 10 §(+/-1D) 
D 14(or later) 
D17(+/-3D)26 
D21(+/-4D) 
D 28(+/-4D) 
D 35 (+/-4D) 
D42 (+/-4D) 
Monthly to 6 mo.  
(+/-2 weeks) 
Quarterly to 
Year 28(+/-1 month) 
 
Secondary 
Follow-up40 
Pre-entry eval/ 
Screening 
Enrollment 
Apheresis 
Chemotherapy1 
Pre Infusion 
Infusion 
Infusion24 
Follow-up 
Follow-up 
Possible 
Infusion23  
Follow-up 
(if dose #3 given) 
Follow-up 
1º endpt. 
 
Follow-up 
Follow-up 
Follow – up 
Secondary   
Follow-up 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recent Med. History  
and PE, PS, GVHD12 
 
X 
 
 
X 
X11 
X11 
X 
X 
X11 
X 
X 
X 
 
 
X 
X 
 
Concomitant Meds. 
 
X 
 
 
X 
X11 
X11 
X 
X 
X11 
X 
X 
X 
 
 
X 
X 
 
Adverse Events 
 
 
 
 
 
X11 
X11 
X 
X 
X11 
X 
X 
X 
 
 
X 
X 
 
Antineoplastic 
Therapies33 
X 
X 
X 
X 
X 
Influenza A and B 
 
 
 
Within 10 days of 
infusion 
 
 
 
 
 
 
 
 
 
 
 
 
HIV  test (1 ml SST) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leukapheresis screening 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC, differential 
(includes atypical 
lymphocytes)  
(5 ml lavender) 
 
X 
 
 
X 
X11 
X11 
X 
X 
X11 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry13 (3 ml SST) 
 
X 
 
 
X 
X11 
X11 
X 
X 
X11 
X 
X 
X 
X 
X 
X 
X 
 
Serum pregnancy test2 (1 
ml SST) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test2 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Autoantibody Panel3 (4 
ml SST and 3ml EDTA) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMV, EBV, Hepatitis B/C   
(5ml)18 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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~Week (-) 8 
~ Week  (-) 6 to 8 
~ Week  (-) 4 
~ Week  (-) 1 
~ Day  (-) 1 
Day   0  
Day   + 1 
Day +5 (+/- 3D) 
D 10 §(+/-1D) 
D 14(or later) 
D17(+/-3D)26 
D21(+/-4D) 
D 28(+/-4D) 
D 35 (+/-4D) 
D42 (+/-4D) 
Monthly to 6 mo.  
(+/-2 weeks) 
Quarterly to 
Year 28(+/-1 month) 
 
Secondary 
Follow-up40 
Pre-entry eval/ 
Screening 
Enrollment 
Apheresis 
Chemotherapy1 
Pre Infusion 
Infusion 
Infusion24 
Follow-up 
Follow-up 
Possible 
Infusion23  
Follow-up 
(if dose #3 given) 
Follow-up 
1º endpt. 
 
Follow-up 
Follow-up 
Follow – up 
Secondary   
Follow-up 
CD3/CD4/CD8 
17 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X9 
 
 
β2 Microglobulin15  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Ig levels16 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemotherapy1 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CART-19 cell infusion 
 
 
 
 
 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
Large volume 
Leukapheresis  
 
 
X22,25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow5 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X27 
 
CSF (assessment by 
lumbar puncture)5 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X10 
 
Lymph Node and other 
tissue Aspirate/Biopsy 
 
As clinically indicated 
Other tumor 
assessments (i.e. CBC, 
physical exam)7 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
CT Scan/MRI4, 7 
 
As clinically indicated28,29 
ECHO/MUGA14 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research chimerism 
(allo cohort only) 
X20 
 
 
 
X21 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relapse and Survival 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X30 
DNA 5cc (Lavender) 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
X 
X 
 
       QPCR  
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
X 
X 
 

CD19 Lentiviral T body Protocol 
 
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~Week (-) 8 
~ Week  (-) 6 to 8 
~ Week  (-) 4 
~ Week  (-) 1 
~ Day  (-) 1 
Day   0  
Day   + 1 
Day +5 (+/- 3D) 
D 10 §(+/-1D) 
D 14(or later) 
D17(+/-3D)26 
D21(+/-4D) 
D 28(+/-4D) 
D 35 (+/-4D) 
D42 (+/-4D) 
Monthly to 6 mo.  
(+/-2 weeks) 
Quarterly to 
Year 28(+/-1 month) 
 
Secondary 
Follow-up40 
Pre-entry eval/ 
Screening 
Enrollment 
Apheresis 
Chemotherapy1 
Pre Infusion 
Infusion 
Infusion24 
Follow-up 
Follow-up 
Possible 
Infusion23  
Follow-up 
(if dose #3 given) 
Follow-up 
1º endpt. 
 
Follow-up 
Follow-up 
Follow – up 
Secondary   
Follow-up 
DNA RCL (VSV-G Q-PCR) 
 
 
 
 
X6 
 
 
 
 
 
 
 
 
 
 
X6 
X6 
 
Serum 2cc (Red)31 
 
 
X 
 
X 
X 
X 
X 
x 
X 
 
X 
X 
 
 
X 
X 
 
       HAMA  
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
HACA 
X32 
 
 
      cytokines 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
- 
- 
 
PBMC 25cc (Lavender)31 
 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
X 
 
 
X9 
X 
 
      Flow  
 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
      Spectra-typing 
 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
Total Research Needs 
 
 
32 
 
32 
7 
32 
32 
32 
7 
 
32 
32 
 
 
32 
32 
 
Total Blood Volume (ml)** 
21 
20 
40 
20 
9 
13 
13 
 
18 
13 
 
38 
44 
 
 
38-
44 
42 
 
Total Blood  
Volume (tbsp) 
1.4 
1.4 
1.4 
1.4 
0.6 
0.9 
0.9 
 
1.2 
0.9 
 
2.6 
3.0 
 
 
2.6-3.0 
2.8 
 
 
 
NOTE: study days may be adjusted as indicated above, and also to avoid weekends. Based on patient status, research blood may be obtained on days other than 
those indicated above. 
** limit blood volume removed to 3cc/kg at any sampling point. All research blood volumes subject to adjustment for size and patient condition. 
1. Chemotherapy. Fludarabine and cyclophosphamide recommended. Timing and regimen as appropriate for disease type as determined by 
treating physician. 
2. Pregnancy test. Females of reproductive potential only (Tanner I and/or <11 years of age excluded) 
3. Autoimmune screen (ANA, ESR) 
4. Disease monitoring: staging scans if appropriate to disease. Should be done within 21 days of study entry if required. 

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5. Bone marrow aspirate and LP (for ALL patients) should be sent as part of standard disease assessment and for research assessments including 
flow/QPCR for CART-19 cell detection. The enrollment marrow and LP can be (and usually are) data from a prior procedure. 
6. The RCL (see protocol for details) test is performed at months 3 and 6 and annually. If all DNA tests during the first year (including the first 
annual visit) are negative, then samples for future annual tests may be archived. 
7.  Tumor response assessments will be done according to standard care and practices every 3 months for 2 years after infusion.  Assessments 
are disease specific and are described in Section 6.11.  
8.  After year 2 or at the time of premature protocol discontinuation, patients will be asked to participate in a destination protocol for evaluation 
for up to 15 years post T cell infusion, to monitor for delayed adverse events associated with the lentiviral vector genetic modification. 
9.  Research blood taken at months 3 and 6 only. CD3/4/8 counts will be collected at month 3 only. 
10. CSF assessments by LP are performed on Day -1, Day 28, and every 3 months up to 1 year after infusion. 
11. Hx, PE, concomitant medications are to be done prior to infusion. Lab results are to be obtained prior to infusion for days 0 & 1 and if 
applicable day 14 based on the intra-patient dose escalation.  
12. GVHD assessment for allo cohort only  
13. Chemistry – Glucose, BUN, Creatinine, Sodium, Potassium, Calcium, Total Protein, Albumin, Total Bilirubin, Alk Phos, AST, ALT, Mg, 
Phos, LDH, Uric Acid 
14. Should be performed within 6 weeks of the 1st infusion 
15. If used for disease evaluation 
16. IgG, IgA, IgM 
17. CD3, CD4, CD8 (absolute and %) 
18. May use Miller-Keystone autologous panel results. 
19. Visit only required if subject received cells on day 28 
20. Preferably at time of pheresis. CD3+ lineage-specific & B cell chimerism preferred.  
21. Send from manufactured product 
22. If a product is not already available 
23. Adjust post infusion follow-up days if third infusion is given at a time other than D14.  Recommended twice weekly follow-up visits x 2-3 
weeks after each infusion. 
24. May delay second dose up to 3d for scheduling reasons or to allow a 72h rule out if cultures drawn. 
25. Test expansion for exploratory purposes is often sent from pheresis product. 
26. Twice weekly follow-ups after each subsequent dose, which may be on D14 or later. The two initial infusion visits will count as the two visit 
days. 
27. Bone marrow assessment (morphology) and MRD assessment on bone marrow are performed on Day -1, Day 28, and every 3 months up to 
1 year after infusion. 
28. For CNS3 cohort only: Brain MRI/CT (MRI preferred) within 2 weeks of enrollment. 
29. For CNS3 cohort only: Brain MRI (same modality as above) within 2 weeks of infusion if known chloromatous disease: otherwise an MRI 
within 6 weeks of infusion 

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30. For subjects who complete or prematurely discontinue from the primary follow-up phase while in remission, follow-up attempts will be 
made to assess the subject’s relapse, post treatment antineoplastic therapy, and survival status every 3 months post CART-19 infusion until 
two years post the last subject infusion. 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. 
31. In the event that something unexpected occurs, additional research sample collection may be done as necessary.   
32. Serum samples may also be used for HACA testing when sufficient samples are available.  
33. All prior antineoplastic therapy for the study indication received prior to the start of study treatment will be documented and recorded on the 
appropriate CRF as required per the CRF Completion Guidelines.  All antineoplastic therapies for subjects in remission post CART19 T-cell 
infusion (HSCT and non-HSCT therapy for their study disease) will be collected and recorded on the appropriate CRF, until the time of 
disease relapse. 
 
Recommended additional labs after subsequent infusions: 
/ 
Recommended disease assessment and visit schedules vary for these additional infusions based on the scenario: 
 After disease relapse from primary infusion:  
o Study labs are performed at Day 3, 7, 10, 14, 28, 42, and then monthly.   
o Bone marrow disease assessments are performed from the point of this additional infusion at Day 28, month 3, month 6, month 9, and 
month 12.   
 No response from primary infusion: 
o Study labs are performed at Day 3, 7, 10, 14, 28, 42, and then monthly.   
o Bone marrow disease assessments are performed from the point of this additional infusion at Day 28, and then continued per the 
original schedule from the primary infusions.   
 CART loss/B cell recovery from primary infusion:  
o Study labs are performed at Day 3, 7, 10, 14, 28, 42, and then monthly. 
o Bone marrow disease assessments are continued per the original schedule from the primary infusions and no additional assessments 
will be added. 
 
15.2 Suggested Labs 
 
Suggested Supportive Care Labs 
Lab test 
Suggested Time Points 
Ferritin, D-dimer 
3x weekly if admitted 
LDH/CRP 
Daily if admitted 
CD19 
Visits D +28 and following 
IgG 
Visits D +28 and following 

CD19 Lentiviral T body Protocol 
 
page 83 
Version 15.12-15-2015 
 
CONFIDENTIAL 
This material is the property of Children’s Hospital and the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor 
 
  
  
15.3 Monitoring Plan 
Please refer to the study Monitoring Plan for details. 
15.4  Definition of CNS leukemia: 
 CNS-1 (no detectable blast cells in a sample of cerebrospinal fluid) 
 CNS-2 (blast cells detected in a sample with <5 WBC/mm3 per cubic millimeter and <10 RBC/mm3) 
 CNS-3 (blast cells detected in a sample with ≥5 WBC/mm3 and <10 RBC/mm3)