Phase IIa Study of Redirected Autologous T Cells Engineered to Contain Anti-CD19 Attached to TCRz and 4-Signaling Domains in Patients With Chemotherapy Relapsed or Refractory CD19+ Lymphomas
Phase: PHASE2
Conditions: Non-Hodgkins Lymphoma (NHL) Patients, With CD19+B Cell Lymphomas
Sponsor: University of Pennsylvania

CD19 CART-19 Protocol for Lymphoma 
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CONFIDENTIAL 
This document is confidential and the property of the University of Pennsylvania.  No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorization from the 
regulatory sponsor. 
University of Pennsylvania 
PHASE IIA STUDY OF REDIRECTED AUTOLOGOUS T CELLS 
ENGINEERED TO CONTAIN ANTI-CD19 ATTACHED TO TCR AND 4-1BB
SIGNALING DOMAINS IN PATIENTS WITH CHEMOTHERAPY RELAPSED 
OR REFRACTORY CD19+ LYMPHOMAS
Principal Investigator 
Stephen Schuster, MD 
University of Pennsylvania 
Regulatory Sponsor: 
University of Pennsylvania 
Sponsor Medical Director: 
Sponsor Scientific Advisor: 
Clinical Protocol Advisor: 
Funding Organization: 
Novartis Pharmaceuticals 
Study Product: 
CD19 redirected autologous T cells (CART-19; or 
CTL019/CTL119 cells) 
Protocol Number: 
UPCC#13413; IRB# 818607 
IND Number: 
Sponsor Cell Manufacturing – 
University of Pennsylvania: 
Laboratory Team: 
Biostatistician: 
Medical Monitor: 
Date 
07-26-2013
Amended: 
08-22-2013
11-20-2013
07-18-2014
03-05-2015
06-08-2015
10-17-2016
08-07-2017
NCT 02030834

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TABLE OF CONTENTS 
STUDY SUMMARY AND STUDY SCHEMA ......................................................................................................... 5 
1 
INTRODUCTION ............................................................................................................................................ 9 
1.1 
BACKGROUND ........................................................................................................................................... 9 
1.2 
INVESTIGATIONAL AGENT ...................................................................................................................... 11 
1.3 
PRECLINICAL DATA ................................................................................................................................ 12 
1.4 
PREVIOUS CLINICAL DATA WITH CART-19 CELLS ................................................................................. 13 
1.5 
DOSE RATIONALE AND RISK/BENEFITS................................................................................................... 15 
1.5.1 Dose Rationale ............................................................................................................................ 15 
1.5.2 Risk/Benefits ................................................................................................................................ 16 
2 
STUDY OBJECTIVES ................................................................................................................................... 22 
3 
STUDY DESIGN ............................................................................................................................................. 23 
3.1 
GENERAL DESIGN ................................................................................................................................... 23 
3.2 
PRIMARY EFFICACY NON-EVALUABLE PATIENTS ................................................................................... 25 
3.3 
PRIMARY STUDY ENDPOINTS .................................................................................................................. 26 
3.4 
SECONDARY STUDY ENDPOINTS ............................................................................................................. 26 
4 
SUBJECT SELECTION AND WITHDRAWAL ........................................................................................ 27 
4.1 
INCLUSION CRITERIA .............................................................................................................................. 27 
4.2 
EXCLUSION CRITERIA ............................................................................................................................. 29 
4.3 
SUBJECT RECRUITMENT AND SCREENING ............................................................................................... 29 
4.4 
EARLY WITHDRAWAL OF SUBJECTS ....................................................................................................... 30 
4.4.1 When and How to Withdraw Subjects ......................................................................................... 30 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects ............................................................ 31 
5 
STUDY DRUG ................................................................................................................................................ 32 
5.1 
DESCRIPTION .......................................................................................................................................... 32 
5.2 
PATIENT ELIGIBILITY TO RECEIVE CART-19 TRANSDUCED T CELLS ..................................................... 32 
5.3 
TREATMENT REGIMEN ............................................................................................................................ 33 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG .......................................................................... 33 
5.5 
PRIOR AND CONCOMITANT THERAPY ..................................................................................................... 34 
6 
STUDY PROCEDURES ................................................................................................................................ 35 
6.1 
PRE-ENTRY EVALUATIONS ..................................................................................................................... 35 
6.2 
ENROLLMENT AND BASELINE ASSESSMENT. ........................................................................................... 35 
6.3 
ENROLLMENT.......................................................................................................................................... 36 
6.4 
APHERESIS .............................................................................................................................................. 36 
6.5 
CYTOREDUCTIVE CHEMOTHERAPY ......................................................................................................... 37 
6.6 
PRE-INFUSION VISIT ............................................................................................................................... 38 
6.7 
CART-19 INFUSION ................................................................................................................................ 38 
6.8 
POST INFUSION LABORATORIES TO ASSESS ENGRAFTMENT, PERSISTENCE AND BIOACTIVITY .................. 39 
6.9 
DAY 28: ENGRAFTMENT ENDPOINT ........................................................................................................ 39 
6.10 MONTHLY EVALUATIONS 2 TO 6 MONTHS POST INFUSION ....................................................................... 40 
6.11 QUARTERLY EVALUATIONS AFTER 6 MONTHS FOR UP TO 2 YEARS POST INFUSION ................................ 40 
6.12 SECONDARY FOLLOW-UP PHASE ............................................................................................................. 40 
6.13 LONG-TERM FOLLOW-UP PROTOCOL ...................................................................................................... 40 
6.14 TUMOR ASSESSMENTS ............................................................................................................................ 40 
7 
STATISTICAL PLAN .................................................................................................................................... 45 
7.1 
GENERAL DESIGN ISSUES ....................................................................................................................... 45 
7.2 
SAMPLE SIZE ........................................................................................................................................... 46 
7.3 
ACCRUAL ................................................................................................................................................ 47 

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7.4 
SUBJECT POPULATION(S) FOR ANALYSIS ................................................................................................ 47 
7.5 
STATISTICAL ANALYSIS .......................................................................................................................... 48 
8 
SAFETY AND ADVERSE EVENTS ............................................................................................................ 49 
8.1 
DEFINITIONS ........................................................................................................................................... 49 
8.2 
RECORDING OF ADVERSE EVENTS .......................................................................................................... 51 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS ............................................................................................ 54 
8.3.1 Investigator reporting: notifying the Penn IRBs.......................................................................... 55 
8.3.2 Reporting obligations to the DSMC of the ACC .......................................................................... 56 
8.3.3 IBC Notification by Investigator .................................................................................................. 57 
8.3.4 FDA Notification by Sponsor ...................................................................................................... 57 
8.3.5 Pregnancies ................................................................................................................................. 58 
8.4 
TOXICITY MANAGEMENT, STOPPING RULES AND STUDY TERMINATION ................................................ 59 
8.4.1 Criteria for stopping or pausing the study .................................................................................. 59 
8.4.2 General toxicity management considerations.............................................................................. 60 
8.4.3 Criteria for discontinuing a subject’s participation in the study: ............................................... 65 
8.5 
PROTOCOL EXCEPTIONS AND DEVIATIONS ............................................................................................. 65 
8.6 
MEDICAL MONITORING .......................................................................................................................... 66 
8.6.1 Independent Data and Safety Monitoring Board ......................................................................... 67 
9 
DATA HANDLING AND RECORDKEEPING .......................................................................................... 67 
9.1 
CONFIDENTIALITY .................................................................................................................................. 67 
9.2 
SOURCE DOCUMENTS ............................................................................................................................. 68 
9.3 
CASE REPORT FORMS ............................................................................................................................. 68 
9.4 
RECORDS RETENTION ............................................................................................................................. 68 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ...................................................................... 68 
10.1 STUDY MONITORING PLAN ..................................................................................................................... 68 
10.2 AUDITING AND INSPECTING .................................................................................................................... 69 
11 
ETHICAL CONSIDERATIONS ................................................................................................................... 69 
12 
STUDY FINANCES ....................................................................................................................................... 69 
12.1 FUNDING SOURCE ................................................................................................................................... 69 
12.2 CONFLICT OF INTEREST ........................................................................................................................... 70 
12.3 SUBJECT STIPENDS OR PAYMENTS .......................................................................................................... 70 
12.4 STUDY DISCONTINUATION ...................................................................................................................... 70 
13 
PUBLICATION PLAN .................................................................................................................................. 70 
14 
REFERENCES ................................................................................................................................................ 71 
15 
SCHEDULE OF STUDY PROCEDURES ................................................................................................... 81 
APPENDIX 1.  NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL CLASSIFICATION .......... 87 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
APC 
antigen presenting cell 
aAPC 
artificial APC 
AE 
CAR 
adverse event 
chimeric antigen receptor 
CART-19 cells 
CD19 redirected autologous T cells 
CIR 
chimeric immune receptor, interchangeable with CAR 
CFR 
code of federal regulations 
CMV 
Cytomegalovirus 
CRF 
case report form 
CTC 
common toxicity criteria 
CTRC 
clinical and translational research center 
CTL 
cytotoxic T lymphocyte 
CVPF 
clinical cell and vaccine production facility 
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 
RCR/L 
replication competent lentivirus 
RVP 
scFv 
respiratory virus panel 
single chain Fv fragment 
SPD 
the sum of the product of the longest perpendicular dimensions of all 
dominant tumor masses 
TCR 
T cell receptor 
TCR- 
 
UPenn 
signaling domain found in the intracellular region of the TCR zeta, gamma 
and epsilon chains 
University of Pennsylvania 
Vβ 
a rearranged T cell specific gene that can be used to determine clonality of a 
T cell population 
VSV-G 
Vesicular Stomatitis Virus, Glycoprotein 

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STUDY SUMMARY AND STUDY SCHEMA 
Title 
PHASE IIA STUDY OF REDIRECTED AUTOLOGOUS T CELLS ENGINEERED TO 
CONTAIN ANTI-CD19 ATTACHED TO TCR AND 4-1BB SIGNALING DOMAINS 
IN PATIENTS WITH CHEMOTHERAPY RELAPSED OR REFRACTORY CD19+ 
LYMPHOMAS  
 
Short Title 
CD19 redirected autologous T cells 
Protocol Numbers IRB #818607, UPCC #13413, INDs #
  
Phase 
Phase 2a 
Methodology 
Phase IIa study to estimate the efficacy of a single infusion of autologous T 
cells expressing CD19 chimeric antigen receptors expressing tandem TCRζ 
and 4-1BB  (TCRζ /4-1BB) costimulatory domains (referred to as “CART-
19” or “CTL019” cells) in non-Hodgkin’s Lymphoma (NHL) patients.  
Study Duration 
The duration of active protocol intervention is approximately 24 months from 
screening visit. The protocol will require approximately 48 months to 
complete. 
Study Center(s) 
Single-center 
Objectives 
The primary objective is to estimate the efficacy of CART-19 cells in NHL 
patients by measuring the overall response rate (ORR) in evaluable patients at 
3 months. 
1. We will treat a total of 60 patients with either DLBCL, FL or MCL. 
(Cohort A, N=39 NHL treated with murine CART19; Cohort B, N=7 
T cell/histiocyte-rich DLBCL treated with murine CART19; Cohort 
C, N=14 DLBCL treated with humanized CART19). Since there is 
no a priori suggestion that CART-19 cells would be more or less 
effective or safe for any histology, all patients in Cohort A will be 
analyzed together. A subset analysis according to histology will also 
be performed as a secondary objective. Cohorts B and C will be 
analyzed individually to focus on ORR for patients with T 
cell/histiocyte-rich DLBCL and DLBCL subjects treated with 
huCART19, respectively. 
 
Secondary objectives are to: 
1. Determine persistence, trafficking and function of CART-19 cells 
2. Determine the effects of CART-19 infusion on B cells and CD19 
expression in vivo.  
3. Evaluate impact of CART-19 treatment on systemic soluble immune 
factors in patients  
4. Determine if cellular or humoral host immunity develops against 
CART-19 cells.  
5. Characterize the relative subsets of CART-19 T cells (Tcm, Tem, and 
Treg). 
6. Evaluate MRD using molecular technologies 
7. Describe survival and response rates. 

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a. Describe overall response rate (ORR) for each individual 
histology with either murine CART19 or humanized 
CART19, as well as CR, CRu and PR rates. 
b. Describe overall survival (OS) and progression-free survival 
(PFS) for all patients 
c. Describe duration of response (DOR) for responding patients 
8. Assess the safety and tolerability of CART-19 in NHL subjects by 
recording the frequency and severity of adverse events reporting, 
including but not limited to, estimating the frequency of CRS and 
MAS. 
9. Determine the dose manufacturing feasibility. 
10. Follow subjects infused with less than protocol-specified target dose. 
Number of 
Subjects 
A total of 60 evaluable subjects with Follicular Lymphoma (FL), Diffuse 
Large B Cell Lymphoma (DLBCL) and Mantle Cell Lymphoma (MCL) will 
be enrolled on this study in one of three Cohorts. 
  
Cohort A: Will include a total of 39 evaluable subjects; with a minimum of 
20 DLBCL subjects and a minimum of 16 total subjects with either FL or 
MCL histologies (enrolled on a first-come, first-serve basis). All subjects in 
Cohort A will receive murine CART19.  
Cohort B: Will include 7 evaluable DLBCL subjects with T-cell rich disease.  
All subjects in Cohort B will receive murine CART19. 
Cohort C: Will include 14 evaluable DLBCL subjects, without restriction on 
T-cell or non-T-cell rich disease. All subjects in Cohort C will receive 
humanized CART19. 
Diagnosis and 
Main Inclusion 
Criteria 
Inclusion criteria include adult patients age ≥18 with CD19+ B cell 
lymphomas with no available potentially curative treatment options (such as 
autologous or allogeneic stem cell transplantation) who have a limited 
prognosis (several months to <2 year expected survival) with currently 
available therapies. 
Study Product, 
Dose, Route, 
Regimen 
Single infusion of CART-19 cells administered by i.v. injection (total dose of 
1 – 5 x108 CART-19 cells). The dose will be the same for Cohorts A, B and C 
and for subjects receiving either murine or humanized CART19 cells. 
 
Duration of 
administration 
Based on the total volume to be infused and the recommended infusion rate of 
10-20mL per minute  
Reference therapy None. Enrollment in this protocol will be offered to subjects with unmet 
medical needs for which there are no effective therapies known at this time. 
Statistical 
Methodology 
A total of 60 evaluable subjects will be planned for analysis of the primary 
endpoints.  Analyses will be done principally by cohort. For cohort A, if 18 
out of 39 evaluable subjects have partial or complete response at 3 months, 
we will have strong evidence (i.e., 95% confidence) that the true ORR 
following CART-19 infusion is at least above an ORR of 30%. For cohort B 
(N=7), if 0/7 respond, we would be 90% confident that the ORR was less than 
35%.  For cohort C, both the safety and the efficacy are primary interests. For 
Cohort C, with n=14 and treatment limiting toxicity (TLT) defined as 
unexpected >grade 3 non-hematologic toxicity probably related to the CART-

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19 infusion, the probability of observing no (i.e., 0), 1, 2 or 3 treatment 
limiting toxicities (i.e., a TLT rate of 0%, 7%, 14%, and 21%) is 0.7%, 4.1%, 
11.3% and 22.9%, respectively, assuming a maximum acceptable toxicity rate 
of 30%.If 7/14 subjects respond, the 95% CI is (0.23, 0.77). 
 
Descriptive statistics will be computed for all study variables for the 
evaluable populations as whole and within cohorts and histologic subgroups.  
The primary endpoint of overall response will be summarized as overall 
response rate (ORR) and the 95% exact confidence interval will be calculated 
based on binomial distribution. For secondary objectives, all adverse events 
will be described and exact 95% confidence intervals will be produced for 
adverse event rates, both overall and within major categories. Overall 
survival, progression-free survival, and duration of response will be analyzed 
using Kaplan-Meier curves and median survival time will be computed. To 
evaluate the persistence of CART-19 (or its subsets), the within-subject 
change in the ratio of CART-19 cells (or subsets) between two pre-specified 
time points will be compared using a Wilcoxon signed-rank test, or to 
simultaneously analyze multiple times, linear mixed effects model 
methodology will be used.  All other secondary endpoints are measured as 
continuous variable and the effects of CART-19 infusion can be evaluated by 
analyzed the change of various immunity measures from its baseline values 
using the nonparametric Wilcoxon signed-rank test. All the analyses will be 
two-sided and cut-off for statistical significance will be a P-value <0.05. The 
number of patients enrolled versus the number of patients infused and 
proportion of subjects with manufacturing failure will be computed as a 
measure of feasibility. 

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1 INTRODUCTION 
1.1 Background 
CD19 positive hematologic malignancies. B cell malignancies comprise a heterogeneous group 
of neoplasms including multiple non-Hodgkin's lymphomas (NHL), acute lymphoblastic 
leukemias (ALL) and chronic lymphocytic leukemias (CLL). An estimated 87,000 new cases of 
leukemia and NHL are diagnosed in the US annually1. This protocol will evaluate potential of 
CART-19 cells to treat NHL, specifically diffuse large B cell lymphoma (DLBCL), follicular 
lymphoma (FL) and mantle cell lymphoma (MCL),  which account for 31%, 22% and 6%, 
respectively, of the total NHL cases. As mentioned below, current treatments for these B cell 
malignancies include chemotherapy, radiation therapy, or autologous and allogeneic blood and 
bone marrow transplantation. Despite these treatment modalities, many patients remain 
incurable. Taken together, these data demonstrate that there is still a need to develop therapies 
for NHL that is relapsed or refractory to available therapies. 
 
Diffuse Large B Cell Lymphoma: DLBCL has at least several subtypes, including but not limited 
to germinal center B cell (GCB) type, activated B-cell type (ABC) and primary mediastinal 
DLBCL2. The 3-year overall survival (OS) for GCB and ABC subsets of CLBCL in treated 
subjects is 84% and 56%, respectively3. Most DLBCL subjects are cured with conventional 
immunochemotherapy. However, for patients who relapse, while at least 60% of subjects remain 
sensitive to conventional treatment, < 10% have prolonged disease-free survival with second-line 
treatment conventional dose immunochemotherapy regimens4. Patients with relapsed or 
refractory (r/r) DLBCL are treated with chemotherapy (±rituximab) with the goal of subsequent 
high-dose chemotherapy and bone marrow or stem cell transplantation (HSCT), for the subset of 
subjects with chemotherapy-sensitive disease.  Approximately 20-50% of responders to a second 
chemotherapy regimen followed by HSCT maintain their response at 2 years5. Patients with 
relapses within 12 months of rituximab-containing first-line therapy have a particularly poor 
prognosis even with transplantation4. For non-transplant candidates who fail second line therapy 
or who relapse post-transplant, therapy is palliative.  Without transplant, chemotherapy provides 
short-term disease control in r/r DLBCL.  Primary refractory subjects are unlikely to achieve CR 
with a second chemotherapy regimen and following relapse, second remissions are usually not 
durable6.  
 
Follicular Lymphoma (FL): FL is the second most common non-Hodgkin lymphoma (NHL) and 
comprises approximately 22% of all NHL cases7. The overall incidence of B-cell lymphoid 
neoplasms in the United States (US) is estimated at 26.13/100,000 person years8, with FL 
accounting for 3.18 new cases per 100,000 persons each year in the US. Follicular lymphoma is 
subdivided into 3 grades9, with Grade 3 is often further subdivided into 3a or 3b, with 3b 
considered more aggressive10. Treatment depends on the stage of the disease, symptoms, patient 
age, and comorbidities. When treatment is provided, initial therapy may include rituximab as a 
single agent or rituximab combined with one or more cytotoxic drugs. Alkylating agents such as 
cyclophosphamide or bendamustine, in combination with rituximab, constitute the mainstay of 
combination therapy. The most commonly used alkylating agent-based regimens include BR 
(bendamustine and rituximab), R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, 
and prednisone), or R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone)11. 

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Response rates in excess of 85% are observed with many different combinations in the first-line 
setting12-15. In addition, when rituximab is used as maintenance treatment, both response rate and 
disease-free survival increase16-18. Despite availability of multiple active agents, high response 
rates, and long progression-free survival (PFS) with first line therapy, FL remains an incurable 
disease. Most patients treated will eventually relapse, and subsequent responses and durations of 
responses become increasingly shorter. Patients who become resistant to chemoimmunotherapy, 
clinically defined as relapsed or progressive within 12 months, have no good treatment 
options19,20. In these patients, toxicity commonly outweighs the benefit of treatment with 
chemotherapy20,21. Investigational agents (e.g., ofatumumab, lenalidomide, bortezomib) have 
been used with response rates of 10% to 27% and a median PFS of 4 to 6 months22-24. For a 
select group of eligible patients, radioimmunotherapy achieves a long-term remission in <20%25. 
The Bruton tyrosine kinase inhibitor, ibrutinib, and the PI3 kinase δ isoform inhibitor, idelalisib, 
are promising new agents under investigation in this setting and clinical trials are ongoing. 
 
Mantle Cell Lymphoma (MCL): MCL is a less common, incurable subtype of non-Hodgkin 
lymphoma (NHL). It accounts for about 6% of all NHL cases in the Western world. At the 
molecular level, MCL is uniquely characterized by overexpression of the cell cycle regulatory 
protein cyclin D1. This is due to the chromosomal translocation t(11;14)(q13;q32), which puts 
the cyclin D1 gene, also called the B-cell leukemia/lymphoma 1 (bcl-1) gene, under the control 
of the immunoglobulin heavy chain enhancer with subsequent overexpression of cyclin D126-28. 
In association with overexpression of cyclin D1, cell surface markers such as CD20 and CD5 are 
also evident in MCL.  Current initial therapy for the treatment of MCL includes 
cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or hyperfractionated 
cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate 
and cytarabine (Hyper-CVAD), often in combination with rituximab (R-CHOP or R-Hyper 
CVAD); however, many other chemotherapeutic regimens have been evaluated. Younger 
patients with good performance status are frequently considered for more intensive induction 
therapy with combinations such as R-Hyper CVAD or alternating R-CHOP and rituximab, 
dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) followed by consolidation 
therapy with autologous stem cell transplant (SCT); however, this degree of intensive therapy is 
not an option for most patients with MCL because of their age and comorbidities29,30. Once MCL 
has relapsed after or failed to respond to initial treatment, the prognosis is poor. Following 
relapse, the median survival is around 1 to 2 years29-31. The Bruton tyrosine kinase inhibitor, 
ibrutinib, is a promising new agent under investigation in this setting and clinical trials are 
ongoing  
 
CD19 as target for NHL adoptive immunotherapy. CD19 is a highly attractive target for NHL 
immunotherapy. CD19 is expressed by most B cell lymphomas, mantle cell lymphoma, ALL, 
CLL, hairy cell leukemia, and a subset of acute myelogenous leukemias32-34. CD19 is a 95kDa 
glycoprotein present on the B cell surface from early development until differentiation into 
plasma cells34-36. 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 
receptor36-38. CD19 expression is restricted to B lineage cells and is not expressed by pluripotent 
blood stem cells or on most other normal tissues39. Anti-CD19 antibodies and scFvs, either 
native or conjugated to radioisotopes or toxins, are currently being developed and have 
demonstrated promise in both mouse models40-44 and human and non-human primates45-55. 

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Because of this limited tissue expression profile, targeting CD19 is also favorable due to a 
reduced on-target, off-organ activity toxicity profile.  
 
Engineered T cells with redirected specificity: chimeric 
antigen receptors (CARs). As shown in Figure 2, the CAR 
approach uses genetically programmed, patient-derived 
lymphocytes transfected with chimeric receptor genes to 
combine the effector functions of T lymphocytes with the 
ability of antibodies to recognize predefined surface 
antigens with high specificity in a non-MHC restricted 
manner56,57. 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 in58,59). 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 length60. First generation CARs contain a minimal TCR signaling domain 
consisting of TCRζ. Second generation CARs contain double costimulatory signaling domains 
both CD28 and TCRζ or 4-1BB and TCRζ. The third generation CARs contain further 
advancements such as triple costimulatory modules comprised of CD28, 41-BB, and TCRζ. See 
reviews of CARs for details61-63. 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 could 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.  
1.2 Investigational Agent 
The investigational agent in this protocol is CART-19 cells (also known as CTL019 cells).  
Autologous T cells will be engineered using a lentiviral vector to express an extracellular single 
chain antibody (scFv) with specificity for CD19. This will be expected to redirect specificity of 
the transduced T cells for cells that express CD19, a molecule that is restricted in expression on 
the surface of the malignant cells and on normal B cells. In addition to the CD19 scFv, the cells 
will be transduced to express an intracellular tandem signaling domain comprised of 4-1BB and 
TCRζ signaling modules. Clinical grade CD19 TCRζ/4-1BB lentiviral vector will be 
manufactured by the City of Hope Center for Applied Technology Development, the Indiana 
University Vector Production Facility, The Children’s Hospital Of Philadelphia, or equivalent 
lentiviral vector production facility. The extracellular single chain antibody (scFv) with 
specificity for CD19 was previously reported64. The scFv used will either be derived from a 
mouse monoclonal antibody using hybridoma cell line FMC63 described in Nicholson et al. or a 
humanized version of that sequence developed by Novartis Biomedical Institutes of Research. 
The signaling domains are entirely of the native human sequences65,66. 
 
The CART-19 cells will be manufactured in the Clinical Cell and Vaccine Production Facility at 
the University of Pennsylvania. At the end of cell cultures, the cells are cryopreserved in 
 
 
Fig. 2.  CAR design. Bispecific T cells 
are created by the introduction of 
genes encoding CAR proteins that 
recognize target surface antigens in

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infusible cryomedia. A single dose of CART-19 transduced T cells will consist of the infusion of 
1-5 x 108 CART-19 cells. Each bag will contain an aliquot (volume dependent upon dose) of 
cryomedia containing the following infusible grade reagents (% v/v): 31.25% plasmalyte-A, 
31.25% dextrose (5%), 0.45% NaCl, 7.5% DMSO, 1% dextran 40, 5% human serum albumin.  
 
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 
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 infection67; importantly, this 
immune mediated elimination was not accompanied by adverse effects and required 6 to 8 weeks 
to occur.  It is important to note that it is possible the CART-19 T cells may be rejected in our 
patients.  
 
Rationale for lymphodepletion. Adoptive immunotherapy strategies may be able to capitalize on 
homeostatic T cell proliferation68, 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 threshold69,70. 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-1571. This hypothesis has been tested clinically in patients with 
metastatic melanoma refractory of conventional treatments72. The patients received a 
lymphodepleting conditioning regimen consisting of cyclophosphamide (60mg/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, NHL, and CLL with infusions of ex-vivo co-stimulated and expanded autologous 
T cells after lymphodepleting chemotherapy, and observed improved engraftment73-76. In this 
protocol we propose to transfer CART-19 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. 
1.3 Preclinical Data 
An extensive literature supports the use of engineered T cells for tumor immunotherapy in rodent 
tumor models, reviewed77-81. 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 models48,82-85.  The incorporation of signaling modules such as CD28 

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The most significant SAE seen in adult and pediatric patients treated with CART-19 has been on 
target CRS.  CRS is described in details below (section 1.5.2) but typically begins up to 2 weeks 
after CART-19 infusion. The CRS typically starts with several days of fevers.  In all cases, 
evaluation for infections is done.  Fevers tend to be spiking and can be associated with rigors, 
anorexia, nausea, diarrhea, diaphoresis, capillary leak, hypoxia and hypotension.  In several cases 
ICU level care, ventilator support and pressors have been needed.  Observations have noted 
experimentally very high levels of IL6 during the CRS.  In addition, the reaction typically 
appears to be associated with MAS.  This can be manifested by evidence of hemolysis, 
cytopenias, elevated ferritin, altered mental status, and other complications. 
 
CRS/MAS was managed in 1 patient initially with corticosteroids.  Subsequently, as more data 
became available, it has been successfully managed with supportive care and when needed, 
tocilizumab therapy.  Tocilizumab is an anti-IL6 receptor antibody, and has been administered at 
a single dose of 4 to 8 mg/kg. This may be preferable to systemic immunosuppression with 
corticosteroids. In many cases, the CRS has been severe but reversible. However there have been 
three cases of refractory CRS that resulted in death on UPCC21413.  It is hypothesized this may 
be related to tumor burden, so that treating patients with less tumor burden may result in less 
severe cytokine release syndrome. However, additional contributory patient and CART-19 
related factors cannot be ruled out. 
 
Since CRS mechanistically is a required part of the antitumor mechanism of in vivo CART-19  
cell expansion and tumor killing, tocilizumab was administered for CRS with worsening 
respiratory distress, including pulmonary infiltrates, increasing oxygen requirement  including 
high-flow oxygen  and/or need for mechanical ventilation or hemodynamic instability despite 
intravenous fluids and moderate vasopressor support or rapid clinical deterioration. Steroids 
following CART-19 infusion were avoided and given only under life threatening situations due 
to the known lymphocytic effects.  
1.5 Dose Rationale and Risk/Benefits 
We have chosen to use flat dosing via the intravenous route of administration for this protocol. 
The dose that we have selected for administration is 1-5x108 CART-19 cells. This is the “high 
dose” from our randomized CART-19 dose-finding protocol (UPCC03712) as described in 
Section 1.5.1 (Dose Rationale).  
1.5.1 Dose Rationale 
After treatment of 42 CLL and ALL patients in our ongoing trial UPCC04409 and CHP959, 
respectively, we have observed durable clinical responses at doses ranging from 1.4x107 to 
1.1x109 CART-19 cells. Efficacy across this two-log-fold difference does not support an obvious 
dose relationship. Unlike standard drugs that are metabolized, CAR T cells are able to proliferate 
extensively in the patients, and thus the actual in vivo amount of CART-19 T cells after 
engraftment and expansion will vary from patient to patient. Thus, the administered dose may 
underestimate the in vivo amount of CART-19 T cells.  Based on our recent clinical experience 
we have chosen to use a cell dose, 1-5x108 CART-19 cells, which has been identified as safe and 
effective in patients with CLL in UPCC04409 and ALL patients in CHP959.   
 

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We are currently performing a randomized dose finding study for patients with CLL 
(UPCC03712) comparing responses with 1-5 x 107 and 1-5 x 108 CART-19 cells.  If new 
information regarding an optimal dose level and corresponding clinical response were to become 
available, then this trial will be appropriately modified.   
 
Manufacturing of this target dose is deemed achievable for the majority of patients based on our 
published data for manufactured CD3+/CD28+ costimulated and expanded T cells from patients 
with non-Hodgkin’s lymphoma. Fifteen of the sixteen patients for which T cell products were 
manufactured had DLBCL94. In the event that manufacturing feasibility is not met for a 
particular patient, we will request approval from the FDA to proceed with infusion. These 
patients will be included in the safety evaluable population only. We will continue to accumulate 
data in this regard regarding the relationship of cell dose to toxicity and response.   
1.5.2 Risk/Benefits 
Potential Risks: 
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 or in any CART-19 treated patients thus far. In this case, 
corticosteroids and chemotherapy would be given to eradicate the CAR cells; this has worked in 
previous cases95.  
 
Immunogenicity. Another risk is that the cells may be immunogenic, and that the patients will 
have an immune response directed against the scFv or novel sequences generated by the fusion 
protein; this has not had clinical consequences in previous trials studying lentivirus transduced  
T cells. If an immune response to the cells occurs, it is possible that the cells will be rejected. 
Three of 3 patients in an anti-carbonic anhydrase IX (CAIX) CAR trial developed Human Anti-
Murine Antibody (HAMA) and loss of T cell engraftment96. This has generally not been an 
issue in patients treated with CARs directed towards B cells as temporary or persistent B 
cell aplasia results in reduced antibody formation.  
 
Hypogammaglobulinemia. Persistent B cell aplasia leads to hypogammaglobulinemia and may 
increase the risk of infection. This can be managed with IVIG repletion. In the UPenn and CHOP 
CART19 trials, hypogammaglobulinemic CLL and ALL patients have received IVIG. No 
significant unusual infection patterns have been identified in patients receiving IVIG repletion at 
regular intervals. 
 
Transformation. There is a risk that people who receive gene transfer may develop new tumors 
derived from their genetically modified cells. This risk is primarily associated with viral gene 
transfer vectors that integrate into the cellular DNA where they may dysregulate genes 
controlling proliferation. Transformation has not been observed following adoptive T cell 
transfer in hundreds of cancer and HIV patients receiving gammaretroviral modified T cells 
treated on multiple protocols at many academic centers97, and in the 21 HIV patients treated with 
lentiviral modified T cells treated at Penn98 or any of the 200 patients treated to date with 
CART19.    
 

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General Safety. At the University of Pennsylvania we have treated >20 patients with HIV 
infection with autologous T cells modified with lentiviral vector. In the first protocol, each 
subject received a single i.v. infusion of 1x1010 lentiviral modified T cells; in the second 
protocol, each subject received up to 6 doses of 0.5-1 x 1010 cells. The lentiviral engineered T 
cells were well tolerated in all patients, with follow up of up to 5 years. Doses of up to 5x1010 
autologous ex vivo non-gene modified and expanded T cells have been administered in five 
protocols to 128 patients with hematologic malignancies and HIV, and have found this to be well 
tolerated73,94,99-101.  
 
 
Infusion reactions. Immediately following T cell infusions, reactions could occur and may 
include transient fever, chills, and/or nausea. Patients must be pre-medicated with acetaminophen 
and anti-histamine prior to the infusion of CART19. A review of infusion-related adverse events 
of 381 T cell products administered to 180 recipients, enrolled on 18 studies, over a 10 year 
period was conducted by Cruz et al.94 and found no grade 3-4 infusion reactions during initial 
monitoring or 24-hour follow-up. Grade 1-2 adverse events were observed in 21 patients during 
or shortly after infusion and included nausea, vomiting, fever, and/or chills. A mild infusion 
reaction was recorded in one of more than 20 CLL patients with CART19 infusion.  
 
Intracranial Hemorrhage. As of February 2016, there have been two events of intracranial 
hemorrhage on CART19 trials under IND#
.  One event occurred on UPCC#21413 (adult 
ALL) in the setting of thrombocytopenia (related to prior lymphodepleting chemotherapy and 
underlying leukemia), was determined to be possibly related to the CART19 cell infusion, 
occurred with concurrent Grade 4 CRS, and resulted in death. Another event occurred on the 
CNS3 cohort on CHP959 (pediatric ALL) in the setting of active circulating leukemia, CRS, 
sepsis/bacteremia, and acute renal failure requiring dialysis. The subject died, and intracranial 
hemorrhage (suspected clinically, unconfirmed radiologically) was felt to be the immediate cause 
of death in this critically ill patient. A third event occurred on 16CT022 (pediatric ALL study) in 
February 2017.  A 3-year-old subject with refractory ALL and CNS2 disease experienced severe 
CRS complicated by DIC and multi-organ failure.  While on extracorporeal membrane 
oxygenation, the subject experienced an intracranial hemorrhage, with associated cerebral edema 
as a terminal event. 
 
Cytokine Release Syndrome.  
 
Overview and Clinical Manifestations: Patients treated with CART-19 may experience a 
cytokine release syndrome (CRS), which has correlated with disease response.    Clinical 
manifestations have included   high fevers, fatigue, anorexia, nausea, vomiting, headache, rash, 
hypotension (occasionally requiring pressor support)  tachypnea, hypoxia (occasionally requiring 
ventilator support), altered mental status including delirium and confusion (in several patients), 
word finding difficulties, evidence of disseminated intravascular coagulation, as well as 
macrophage activation syndrome (MAS). Additional symptoms of CRS may also include rigors, 
sweating, dyspnea, and seizures.     In some cases CRS, TLS and hypotension have led to acute 
kidney injury and several patients have required at least transient dialysis.  The CRS has been 
effectively abrogated with anti-cytokine directed therapy including tocilizumab in most patients. 
As of July 2014, three patients on another CART-19 trial have died of complications related to 
refractory CRS and intercurrent infections.  It is unclear if treating the CRS adversely impacts 
the anti-tumor response. 

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Features consistent with MAS or HLH have been observed in patients treated with CART 19, 
coincident with clinical manifestations of the CRS. MAS appears to be a reaction to immune 
activation that occurs from the CRS, and therefore should be considered a manifestation of CRS.  
Macrophage activation syndrome (MAS) is similar to Hemophagocytic lymphohistiocytosis 
(HLH); it is a reaction to immune stimulation by infection, autoimmune diseases or other 
precipitants, but is distinguished from familial or genetically mediated HLH.  There are no 
definitive diagnostic criteria for MAS, but it is typically diagnosed by meeting HLH criteria. 
 
Some but not all features of MAS are typically observed.  The clinical syndrome of MAS is 
characterized by high grade non-remitting fever, cytopenias affecting at least two of three 
lineages, and hepatosplenomegaly.  It is associated with biochemical abnormalities, such as high 
circulating levels of serum ferritin, soluble interleukin-2 receptor (sCD25), and triglycerides, 
together with a decrease of circulating NK activity.  Other findings include variable levels of 
transaminases up to signs of acute liver failure and coagulopathy with findings consistent with 
DIC. A pathologic feature of MAS is the presence of hemophagocytic CD163+ macrophages 
(HPC) in bone marrow or lymph-node aspirates. 
 
Diagnosis is based on the fulfillment of criteria established in 2004102 for HLH associated with 
autosomal recessive disorders (familial HLH, fHLH).  
 
A diagnosis of non-familial HLH/MAS is made by having 5/8 criteria: 
 Fever 
 Splenomegaly 
 Cytopenias (affecting 2 or more lineages in the peripheral blood; hemoglobin <9 g/dL, 
platelets <100,000/L, Absolute neutrophil count <1000/L) 
 Fasting triglycerides >265 mg/dL, Fibrinogen   < 1.5 g/L 
 Hemophagocytosis in bone marrow or spleen or lymph nodes  
 Low or absent NK-cell activity 
 Ferritin  > 500 g/L 
 Soluble CD25R > 2400 U/L 
 
Supportive clinical criteria include neurologic symptoms and cerebrospinal ﬂuid pleocytosis, 
conjugated hyperbilirubinemia, and transaminitis, hypoalbuminemia and hyponatremia. 
Typically, high fevers, cytopenias, and when performed, hemophagocytosis in the bone marrow 
is observed (though marrow specimens at the time of the reaction are not often taken). Soluble 
CD25R and NK cell activity are not standard tests, though samples are taken for retrospective 
CD25R analysis.  Therefore, patients may not meet strict definition of HLH/MAS, but given the 
constellation of findings, and the consistent dramatic elevation in Ferritin, this is indeed the 
reaction associated with the CRS.   
 
At this time it is still unknown whether CRS/MAS is beneficial or harmful to the antitumor 
response.  Research monitoring data showed that IL6 levels were extraordinarily high during the 
CRS, prompting us to use an anti-IL6 receptor antibody tocilizumab to treat the CRS/MAS.  The 
majority of patients treated with tocilizumab for CRS and MAS had rapid (within hours) 
resolution of dramatic fevers, and continuous improvement in hypotension and hypoxia over 
hours to several days, and showed improvement in biochemical evidence of CRS and MAS 

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within 48 hours.  Adult patients were treated with tocilizumab 4mg/kg or 8mg/kg.  It is unclear if 
early treatment will negate the antitumor response.  Treatment and timing of treatment of this 
toxicity will be at the discretion of the patient’s physician and the study investigator, and occur 
in the setting of hemodynamic instability.  
 
Pediatric ALL patients treated with CART-19 on CHP9595 have experienced a similar CRS and 
MAS. CHP959-100 experienced a severe CRS and had high fevers, hypotension, acute vascular 
leak syndrome and acute respiratory distress. The patient was treated with etanercept and 
tocilizumab, as described in Grupp et al., NEJM, 2013, and all associated adverse events 
resolved. CHP959-104 and CHP959-105 received the 10% dose only and experienced CRS. 
CHP959-103 received the 10% and 30% doses, respectively, and experienced a mild CRS after 
the 10% dose, with no CRS experienced after the 30% dose. None of these patients experienced 
severe enough CRS (i.e. there were no instances of more than transient oxygen requirements, or 
hypotension requiring pressor support) to require treatment with steroids or cytokine blockade. 
 
Grading of CRS: The CTC grading system was originally developed to capture a cytokine 
syndrome occurring during infusional therapy; therefore, it is inadequate to capture the delayed 
CRS that occurs after CART19 infusion.  We propose to modify the CTC grading specifically to 
capture toxicity for protocols using CART-19 cells. MAS/HLH observed signs and symptoms 
are a manifestation of CRS and will therefore not be graded separately (See Table 8-1 in Section 
8.1). 
 
Replication-competent lentivirus (RCL). RCL may   be   generated   during   the   CART19 
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 patient. Nevertheless, 
generation of an RCL following infusion of the vector product remains a theoretical possibility. 
The consequences of such recombination events in patients without a known lentiviral 
infection are unknown, and therefore patients with coexistent HIV infection are excluded from 
participation in this study in order to minimize this possibility. 
 
Clonality and insertional oncogenesis. The  occurrence  of  adverse  events  caused  by 
insertional  mutagenesis  in  five  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 clinic95-98. The T cell leukemias were attributable to clonal expansion conferred by 
gammaretroviral vector integration sites in the CD34+ bone marrow stem cell modification98. 
This represents the most severe adverse event caused by vector integration. However, there is 
also evidence for retroviral vector integration site dominance in a gene therapy trial of 
ß-thalassaemia without malignancy99. The lentiviral vector used for CART19 manufacturing is 
part of a vector class that may have a lower risk for integration in or near oncogenic regions than 
oncoretroviral vectors100. 
 
Uncontrolled T cell proliferation. CART19 cells could proliferate without control of normal 
homeostatic mechanisms. In pre-clinical studies, CART19 cells have only proliferated in 

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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 trials51,101.  
 
Graft versus host disease (GVHD). The chance of GVHD occurring is low, but it is a potential 
risk with CART19 therapy if administered after prior allogeneic transplantation.  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 CAR introduction) did not show high rates of 
GVHD (2/18 patients with grade 3 GVHD and none with Grade 4)102.  
 
Patients with active, acute or chronic GVHD requiring systemic therapy are excluded from 
enrolling in this study.  However, due to the possibility of some degree of residual donor 
engraftment, which will include T cells of donor origin, patients that received a previous HSCT 
at the Hospital of the University of Pennsylvania will be assessed for donor chimerism at 
screening and will be monitored closely throughout the study for signs of GVHD.  To date, no 
patient that had a prior allogeneic HSCT developed GVHD after autologous CART19 
infusion61,87,88 even when “autologous” cell included cells of donor origin94. 
 
B cell aplasia. B cell aplasia has been seen in CART19-treated subjects as well as B cell recovery 
in some subjects who had lost CART1988103103103102[102]102(Maude et al., 2014). Persistent B cell 
aplasia leads to hypogammaglobulinemia and may increase the risk of infection. This is common 
with anti-CD20 directed therapies103. This can be managed with IVIG repletion by established 
clinical dosing guidelines to support IgG levels. In previous CART19 trials, responding CLL and 
ALL patients who are hypogammaglobulinemic have received IVIG.  No significant unusual 
infection patterns have been identified. 
 
Fatal SAEs with CARs:  Two studies have reported fatal SAEs following CAR infusion in pa-
tients with malignancy.  Brentjens et al designed a retrovirally-transduced CAR against the 
CD19 molecule for patients with B cell lymphoma. The CD19 CAR was the second generation 
design containing CD28 and CD3ζ signaling domains. A total of 7 subjects have been treated on 
this protocol, 6 without SAE. However, subject four in this study was a 69 year old man with 
refractory CLL and who had a significant past medical history of myocardial infarction, coronary 
artery disease, hypertension, and chronic renal failure. This was the 4th patient in the study and 
the first one on the cohort undergoing lymphodepletion. This subject received pre-T cell condi-
tioning with 1.5g/m2 of cyclophosphamide followed 2 days later by infusion with genetically 
modified CD19 CAR T cells at 1.2-3x107 cells/kg. Twenty hours following T cell infusion, the 
patient developed persistent fever (transient fever was observed in the first 3 subjects on the 
study too) and hypotension that was rapidly followed by respiratory distress despite negative 
chest x-ray, hypoxemic respiratory failure, and acute renal failure. The family decided to remove 
further life sustaining therapies and the patient expired 44h post-T cell infusion. The post-
mortem pathology report failed to support a diagnosis of tumor lysis syndrome as the primary 
source of renal failure. Analysis of serum cytokines revealed elevated levels of IL-2, IL-7, IL-15, 
and IL-12 following cyclophosphamide therapy which may have been secondary to a prior sub-
acute infection exacerbated by the immune suppression associated with cyclophosphamide-

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mediated lymphodepletion.  The authors concluded that concomitant sepsis was the most likely 
cause of death and attributed the etiology of the death as “possibly related” to CAR T cell infu-
sion104.  
 
The second case of a fatal SAE related to CAR T cells was reported by the NCI group (Morgan 
et al. 2010). This study attempted to treat cancer patients with overexpressing ERBB2 tumors 
with an anti-ERBB2 CAR of 3rd generation (containing CD28, 41BB and CD3ζ signaling do-
mains). The first subject in the study was a 39-year-old female with colon cancer metastatic to 
lungs and liver. The patient received lymphodepleting regimen (60mg/kg cyclophosphamide dai-
ly for 2 days followed by fludarabine 25mg/m2 for the next 5 days) followed the next day by ret-
rovirally-transduced 1010 ERBB2 CAR T cell (transduction efficiency 79%). At 15min post-
infusion, the patient began to develop dyspnea and hypoxia with pulmonary infiltrates on chest 
X-ray. The patient progressed into hypoxemic respiratory failure requiring mechanical ventilato-
ry support, vasopressor-dependent hypotension, and cardiopulmonary arrest. The patient was ini-
tially resuscitated and started on high dose steroids, but despite aggressive supportive care, the 
patient expired 5 days after infusion. Serum cytokine measurements demonstrated a dramatic rise 
in pro-inflammatory cytokines (IFN-γ, TNF-α, IL-6, GM-CSF) within 4 hours of infusion con-
sistent with a cytokine storm initiating multi-system organ failure. Dr. Morgan postulates that 
upon first pulmonary circulation passage105, the CAR ERBB2 T cells bound to native low level 
expression pulmonary epithelial cell ERBB2 proteins106, leading to CAR activation and pulmo-
nary microvascular injury.  
 
Other fatal SAEs using CD19-targeting T cells have been reported, including five fatal events at 
the University of Pennsylvania and two events in April 2014 at the Memorial Sloan Kettering 
Cancer Center. At the University of Pennsylvania, three of the first six adult ALL subjects 
infused on UPCC21413 died as a result of refractory Cytokine Release Syndrome (CRS) in the 
setting of intercurrent infections. Thereafter, the single dose administered in UPCC21413 was 
reduced to 1-5x107 CART19 cells. In the next six adult ALL subjects treated at the de-escalated 
dose, two died from an intracranial bleed and sepsis, respectively.  
 
Risk of tumor lysis syndrome (TLS) related to cytoreductive chemotherapy or CAR T cells.  The 
risk of tumor lysis syndrome (TLS) is dependent on the disease and burden of disease. Several of 
the patients treated with CART19 on this protocol have in fact developed tumor lysis syndrome. 
Therefore, all patients will be closely monitored both before and after chemotherapy and CART-
19 infusions including blood tests for potassium and uric acid.  All patient-subjects will receive 
allopurinol prophylactically. TLS resulting in renal insufficiency, or rapidly rising uric acid, or 
evidence of organ dysfunction will be managed with intravenous fluids and rasburicase as 
needed and determined by the treating physicians. Appropriate clinical therapy will be 
administered should any significant tumor lysis occur. 
  
Unknowns: At this time there are still several unknowns regarding the observed CRS after 
CART19 infusion. It is unknown which patient factors (including type of disease; disease 
burden; prior therapies; genetic predisposition) correlate with severity of CRS.  It is also 
unknown if cell dose correlates with severity of clinical CRS and if the duration and intensity of 
the CRS correlates with disease response.  It is evident that responding patients have had CRS, it 

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remains unknown if abrogating the CRS with anti-cytokine directed therapy abrogates anti-tumor 
responses. 
 
Potential benefits:   
Based on inclusion criteria and published literature107,108, eligible patients will have a median 
anticipated survival of <2 years without allogeneic SCT.  The risks associated with allogeneic 
are high and include a minimum 20% treatment-related mortality (TRM); in many cases TRM 
would be even higher, and many of these patients would not be eligible for allogeneic SCT.  At 
best, RIC allogeneic SCT results in a 50% 2 years DFS for patients with CLL but is also 
associated with extensive morbidity and mortality108,109.  Patients not eligible or appropriate for 
allogeneic SCT will have limited treatment options. It is possible that the CART-19 T cells will 
exert an anti-tumor effect; as demonstrated in our preliminary data for patients with advanced 
CLL, including 8/17 ongoing CRs or very significant PRs.  In the two patients with longest 
follow up, CR has persisted beyond 2 ½ years.   Therefore, we believe the risk:benefit ratio for 
this study is quite favorable. 
 
2 STUDY OBJECTIVES 
Primary objective:   
1. To estimate the efficacy of a single target dose of 1-5 x108 CART-19 cells for patients 
with advanced B cell non-Hodgkin’s lymphoma. 
a. Describe overall response rate for patients with NHL.  We will treat a total of 60 
patients with either DLBCL, FL or MCL. (Cohort A, N=39 NHL treated with 
murine CART19; Cohort B, N=7 T cell/histiocyte-rich DLBCL treated with 
murine CART19; Cohort C, N=14 DLBCL treated with humanized CART19). 
Since there is no a priori suggestion that CART-19 cells would be more or less 
effective or safe for any histology, all patients in Cohort A will be analyzed 
together. A subset analysis according to histology will also be performed as a 
secondary objective. Cohorts B and C will be analyzed individually to focus on 
ORR for patients with T cell/histiocyte-rich DLBCL and DLBCL subjects treated 
with huCART19, respectively. 
 
Secondary objectives: 
1. Determine persistence, trafficking and function of CART-19 cells 
2. Determine the effects of CART-19 infusion on B cells and CD19 expression in vivo.  
3. Evaluate impact of CART-19 treatment on systemic soluble immune factors in patients  
4. Determine if cellular or humoral host immunity develops against CART-19 cells.  
5. Characterize the relative subsets of CART-19 T cells (Tcm, Tem, and Treg). 
6. Evaluate MRD using molecular technologies 
7. Describe survival and response rates. 
a. Describe overall response rate (ORR) for each individual histology with either 
murine CART19 or humanized CART19, as well as CR, CRu and PR rates. 
b. Describe overall survival (OS) and progression-free survival (PFS) for all patients 
c. Describe duration of response (DOR) for responding patients 

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8. Assess the safety and tolerability of CART-19 in NHL subjects by recording the 
frequency and severity of adverse events reporting, including but not limited to, 
estimating the frequency of CRS and MAS. 
9. Determine the dose manufacturing feasibility. 
10. Follow subjects infused with less than protocol-specified target dose. 
 
3 STUDY DESIGN 
3.1 General Design 
This is phase IIa trial to test the central hypothesis that CART-19 cell infusions will result in 
anti-tumor responses for patients with advanced B cell NHL.  The primary objective of the study 
is to estimate the ORR at 3 months in patients with NHL.   We will also insure that patients with 
the most common NHL histologies (DLBCL, MCL, FL) are treated and describe activity 
according to histology. The initial study design included at least 8 subjects with one of three 
histologies to be treated with murine CART19. The remaining 6 subjects would be enrolled 
within any of the 3 NHL histologies on a first-come, first-serve basis. The DLBCL histology 
group in Cohort A has reached full enrollment as of this protocol version.  The 8 subject limit for 
MCL and FL is now removed to allow a total of 16 subjects with MCL or FL to be treated on a 
first-come, first-serve basis. These 30 NHL subjects will all receive murine CART19 and will be 
known as Cohort A (V5.03-05-15). 
 
 
As of protocol Version 5.03-05-15, two additional cohorts are also added: (1) Cohort B; N=7 T-
cell/histiocyte rich DLBCL treated with murine CART19; and, (2) Cohort C; N=14 DLBCL 
treated with humanized CART19. Cohort B will expand upon the two subjects with this 
particularly aggressive sub-type already treated per protocol prior to this amendment and 
included in Cohort A. Cohort C expands upon the treatment experience of the DLBCL subject 
13413-09 with humanized CART19, included in Cohort A per prior protocol version.  
 
As of protocol Version 7.10-17-2016, Cohort A was further expanded to allow for 6 additional 
DLBCL subjects to be enrolled.  Therefore, a total of 57 evaluable subjects will be enrolled on 
this protocol across all three Cohorts.   
 
As of protocol Version 8.08-07-2017, three additional enrollment slots were added to further 
expand Cohort A. A maximum of 60 evaluable subjects will now be enrolled across the three 
cohorts as follows: 
 Cohort A: Will include a total of 39 evaluable subjects; with a minimum of 20 DLBCL 
subjects and a minimum of 16 total subjects with either FL or MCL histologies (enrolled 
on a first-come, first-serve basis). All subjects in Cohort A will receive murine CART19.  
 Cohort B: Will include 7 evaluable DLBCL subjects with T-cell rich disease.  All 
subjects in Cohort B will receive murine CART19. 
 Cohort C: Will include 14 evaluable DLBCL subjects, without restriction on T-cell or 
non-T-cell rich disease. All subjects in Cohort C will receive humanized CART19. 
 

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We will monitor and describe safety, tolerability and engraftment potential of CART-19 T cells 
in all of these patient cohorts. This protocol is an open label study. The general protocol schema 
is shown above in Figure 1.  
 
At entry, subjects will be staged and the suitability of their T cells for CART-19 manufacturing 
will be determined. Subjects who have adequate T cells will be leukapheresed to obtain large 
numbers of peripheral blood mononuclear cells (PBMC) for CART-19 manufacturing. The T 
cells will be purified from the PBMC, transduced with TCRζ/4-1BB lentiviral vector, expanded 
in vitro and then frozen for future administration after passing all release tests.  
 
Unless contraindicated and medically not advisable based on previous chemotherapy, patients 
will be given conditioning chemotherapy prior CART-19 cell infusion.  The chemotherapy will 
be planned so that it completes 1-4 days BEFORE the planned infusion of the first dose of 
CART19 cells.  Each regimen is of different duration so the start day will vary.     
 
We will enroll 57 evaluable patients for the primary efficacy endpoint analysis. Primary efficacy 
evaluable patients are those who have received CART-19 cells at the protocol-specified dose (1-
5x108 CART-19 cells). These patients will be evaluable for primary efficacy endpoints.  
 
Subjects with a manufactured cell dose that is less than the protocol-specified dose will be scored 
as a manufacturing failure. These subjects will receive their cell infusion, provided that the 
manufactured dose is above the CVPF minimum acceptable dose for infusion (2x107 CART-19 
cells) and all other manufacturing release criteria are met. The subjects that are infused with 
≥2x107-≤1x108 CART-19 cells are primary efficacy non-evaluable patients. They will not be 
included in the primary efficacy endpoint analysis. However, they will be included for secondary 
efficacy, safety, manufacturing, correlative and exploratory endpoint analyses. 
 
For the purposes of the study, primary efficacy non-evaluable patients will be replaced with 
primary efficacy evaluable patients. Both primary efficacy evaluable and non-evaluable patients 
will be followed in the same manner according to the Schedule of Study Procedures for all 
evaluations, including clinical, research (correlative) and safety. 
 
All patients receiving >2x107 CART-19 will be assessed for clinical response according to the 
criteria discussed in Sections 6.11 and 6.12.  Again, patients scored as manufacturing failures 
and receiving ≥2x107-<1x108 CART-19 cells (e.g. the primary efficacy non-evaluable patients) 
will not be included in primary efficacy endpoint analysis (see Section 7). Table 3-1 
summarizes nomenclature, endpoint analysis and clinical evaluations for all possible CART-19 
dose manufacturing and infusion scenarios. 
 
All subjects will have blood tests to assess safety, engraftment and persistence of the CART-19 
cells at regular intervals as outlined in the Schedule of Study Procedures (Section 15.1).  
Trafficking of CART-19 cells will be assessed in bone marrow aspirates if performed.  Response 
assessments will also be performed for primary endpoint analysis as described in Section 6.11. 
Patients will be followed weekly for 4 weeks, monthly for 6 months, then quarterly for two years 
with a medical history, physical examination, blood tests and CT scans as outlined.  Following 
this evaluation, subjects will enter a long-term follow-up study for annual follow-up by phone 

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3.3 Primary Study Endpoints 
This phase IIa trial is designed to test the efficacy of autologous T cells transduced with the 
CD19 TCRζ/4-1BB in patients with relapsed, refractory and incurable non-Hodgkin’s 
lymphomas by describing the overall response rate (ORR) at 3 months. Responders will include 
those patients achieving complete response (CR), complete response unconfirmed (CRu) and 
partial response (PR) according to the Tumor Response Assessment defined in Section 6.11. 
3.4 Secondary Study Endpoints 
Secondary endpoints include laboratory measures to evaluate: 
 
1. Engraftment, persistence and trafficking to tumor sites:  These analyses will be performed 
using Q-PCR assays.  The duration of in vivo survival of CART-19 cells is defined as 
“engraftment”. The primary engraftment endpoint is the # DNA vector genomic 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 infusion on day 1, 2, and 3 weekly x 4, 
monthly x 6, and every 3 months thereafter until any 2 sequential tests are negative 
documenting loss of CART-19 cells. 
 
2. The effects of CART-19 infusion on peripheral B cell levels and levels of CD19 antigen 
expression, as well as in marrow and other biopsy tissues.  These analyses will be 
performed using multi-parametric flow cytometry 
 
3. The impact of CART-19 treatment on systemic soluble immune factors will be evaluated 
by measuring systemic changes in soluble immune factors in patients post CART-19 
infusion.  These analyses will be performed using Luminex assays. 
 
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).  These analyses will be performed using multiparametric 
flow cytometry. 
 
5. Determine phenotypic and functional evolution of CART-19 T cells in vivo. These 
analyses will be performed using multiparametric flow cytometry. 
 
6. Evaluate MRD using molecular technologies.  These analyses will be performed on 
nucleic acid isolated from patient samples pre- and post-treatment using quantitative 
molecular approaches. 
 
Secondary safety and feasibility 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. Rash 

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c. Neutropenia, thrombocytopenia, anemia, marrow aplasia 
d. Hepatic dysfunction 
e. Pulmonary infiltrates or other pulmonary toxicity 
f. Cytokine release syndrome (CRS) 
g. Macrophage activation syndrome (MAS) 
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, T cell purity, viability, sterility and tumor contamination will be determined. 
3. New onset secondary malignancies. 
4. Describe anti-tumor responses to CART-19 cell infusions and survival. 
a. Describe overall response rate (ORR) for each individual histology with either 
murine CART19 or humanized CART19, as well as CR, CRu and PR rates. 
b. Describe overall survival (OS) and progression-free survival (PFS) for all patients 
c. Describe duration of response (DOR) for responding patients 
5. Exploratory analyses to inform on dose-response activity, inclusive of subjects infused 
with the less than protocol-specified dose.  
a. For subjects with active disease, consensus response criteria for partial response 
(PR), complete response unconfirmed (CRu), or complete response (CR) will be 
determined.  Response determination will be only “descriptive” given the small 
number of subjects to be treated. Exploratory analyses of available CT, MRI, 
and/or PET imaging datasets may also be performed (e.g., to assess whether there 
are imaging biomarkers that are obtainable from pretreatment scans to predict 
response to therapy). 
b. Describe the overall survival and cause(s) of death 
c. Evaluate MRD by deep sequencing or PCR of patient samples post-treatment 
d. For treated subjects with MRD (identified by analysis of blood or marrow), 
determine elimination of MRD scored as yes/no. 
 
4 SUBJECT SELECTION AND WITHDRAWAL 
No exceptions to eligibility will be granted for this study 
4.1 Inclusion Criteria 
Male or female subjects with CD19+ B cell lymphomas with no available curative treatment 
options (such as autologous or allogeneic SCT) who have a limited prognosis (several months to 
<2 year survival) with currently available therapies will be enrolled. The study will enroll 57 
evaluable subjects as follows: 
1. CD19+ Lymphoma 
Cohort A Subjects: 
a. Follicular lymphoma, previously identified as CD19+ 
i. At least 2 prior chemotherapy or immunochemotherapy regimens (not 
including single agent monoclonal antibody therapy) 
ii. Patients who progress within 2 years after second or higher line of therapy 
will be eligible.  For instance, patients who have progression of lymphoma  
< 2 years after second or greater line therapy, but who have responded to 
their most recent treatment (3rd line or higher) will be eligible. Patients may 

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have progression, stable disease or responding disease at the time of 
enrollment. 
iii. Patients with a history of large cell transformation are eligible. 
b. Mantle cell lymphoma, previously identified as CD19+ 
i. Beyond 1st CR with relapsed disease, progressive disease during first line 
rituximab-chemotherapy combination, or persistent disease after first line 
rituximab-chemotherapy combination and not eligible or appropriate for 
conventional allogeneic or autologous SCT. 
ii. Relapsed after prior autologous SCT. 
 
c. Diffuse large B cell lymphoma, previously identified as CD19+ 
i. Residual disease after primary therapy and not eligible for autologous SCT 
ii. Relapsed or persistent disease after prior autologous SCT 
iii. Beyond 1st CR with relapsed or persistent disease and not eligible or 
appropriate for conventional allogeneic or autologous SCT 
iv. Patients with an antecedent history of follicular lymphoma or CLL/SLL 
are eligible. 
Cohort B Subjects: 
a. Diffuse large B cell lymphoma, previously identified as CD19+ 
i. Residual disease after primary therapy and not eligible for autologous SCT 
ii. Relapsed or persistent disease after prior autologous SCT 
iii. Beyond 1st CR with relapsed or persistent disease and not eligible or 
appropriate for conventional allogeneic or autologous SCT 
iv. Patients with an antecedent history of follicular lymphoma or CLL/SLL 
are eligible. 
v. Patients with T cell/histiocyte-rich disease as confirmed by surgical 
pathology report 
Cohort C Subjects: 
a. Diffuse large B cell lymphoma, previously identified as CD19+ 
i. Residual disease after primary therapy and not eligible for autologous SCT 
ii. Relapsed or persistent disease after prior autologous SCT 
iii. Beyond 1st CR with relapsed or persistent disease and not eligible or 
appropriate for conventional allogeneic or autologous SCT 
iv. Patients with an antecedent history of follicular lymphoma or CLL/SLL 
are eligible. 
2. Age  ≥18 years  
3. Creatinine < 1.6 mg/dL 
4. ALT/AST < 3x upper limit of normal 
5. Bilirubin <2.0 mg/dL, unless subject has Gilbert’s Syndrome (<3.0 mg/dL) 
6. Any relapse after prior autologous SCT will make patient eligible regardless of other prior 
therapy. 
7. 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 6 months from transplant 

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8. Measurable or assessable disease according to the “Revised Response Criteria for 
Malignant Lymphoma” (Cheson et al., J. Clin. Onc., 1999)110. Patients in complete 
remission with no evidence of disease are not eligible. 
9. 
Performance status (ECOG) 0 or 1. 
10. Left Ventricle Ejection Fraction (LVEF) > 40% confirmed by ECHO/MUGA 
11. Written informed consent is given. 
12. Successful T cell test expansion (first 10 subjects, see Section 6.1). 
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 
pregnancy test at enrollment.  A urine pregnancy test will be performed within 48 hours 
before infusion. 
2. Uncontrolled active infection. 
3. Active hepatitis B or hepatitis C infection. 
4. Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not 
exclusionary.  For additional details regarding use of steroids, please see Section 5.5. 
5. Any uncontrolled active medical disorder that would preclude participation as outlined. 
6. Class III/IV cardiovascular disability according to the New York Heart Association 
Classification (see Appendix 1).  
7. HIV infection. 
8. Patients with active CNS involvement by malignancy.  Patients with prior CNS disease 
that has been effectively treated will be eligible providing treatment was >4 weeks before 
enrollment 
9. Patients in complete remission with no assessable disease. 
10. Patients with a known history or prior diagnosis of optic neuritis or other immunologic or 
inflammatory disease affecting the central nervous system.  
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.   
 
To be eligible, the subjects must have an adequate number of T cells that can be successfully 
transduced and expanded with the anti-CD19 lentiviral vector, as determined from a sample of 
PBMCs obtained by phlebotomy at the first screening visit (~week -8) for the first 10 subjects 
only. The purpose of this screening procedure is to exclude subjects from participation who 
would otherwise undergo a futile apheresis and restaging, without the possibility of having the 
source T cells obtained by apheresis returned as redirected CAR T cells. 
 
Female subjects of reproductive potential (women who have reached menarche or women who 
have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses 
within the preceding 24 months, or have not undergone a sterilization procedure [hysterectomy 
or bilateral oophorectomy]) must have a negative serum pregnancy test performed at the time of 
screening and a urine pregnancy test within 48 hours of T cell infusion.  
 

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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 at least one reliable method of contraception 
during their participation in the study (from the time of screening/enrollment through the Month 
24 follow-up visit). 
 
Acceptable birth control includes one of the following methods: 
 Condoms (male or female) with or without a spermicidal agent. 
 Diaphragm or cervical cap with spermicide 
 Intrauterine device (IUD) 
 Hormonal-based contraception 
 
Subjects who are not of reproductive potential (women who have been post menopausal for at 
least 24 consecutive months or have undergone hysterectomy, salpingotomy, and/or bilateral 
oophorectomy or men who have documented azoospermia) do not require use of contraception.  
Acceptable documentation of sterilization, azoospermia, and menopause is specified next: 
Written or oral documentation communicated by clinician or clinician’s staff of one of the 
following: 
 Physician report/letter   
 Operative report or other source documentation in the subject record (a laboratory 
report of azoospermia is required to document successful vasectomy)  
 Discharge summary 
 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 
1. Subjects who enroll but do not receive CART-19 cells will be prematurely discontinued 
from the study, will not be followed, and will be replaced in the study.   Reasons for 
premature discontinuation prior to receipt of CART-19 cells include, but are not limited 
to, the following: The subject is lost to follow-up.   
2. The judgment of the principal investigator that the patient is too ill to continue if this 
occurs prior to the CART-19 T-cell infusion. 
3. Pregnancy: Withdraw patient if pregnancy occurs prior to the CART-19 T-cell infusion. 
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 
if this occurs prior to the CART-19 T-cell infusion. 
6. A serious adverse event that requires the subject’s being withdrawn from the trial if this 
occurs prior to the CART-19 T-cell infusion.   

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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 
release criteria as specified by FDA. 
8. Termination of the study by the principal investigator, the sponsor, the study funder, the 
IRB, or the Food and Drug Administration. 
 
Reasons for discontinuation of subjects after receipt of CART-19 cells include, but are not lim-
ited to, the following: 
1. The subject is lost to follow-up. 
2. Voluntary withdrawal: a subject may remove himself/herself from the study at any time.   
3. Disease progression of targeted malignancy 
4. Receipt of alternative treatment for their targeted disease 
5. Termination of the study by the Principal Investigator, the Sponsor, the Funding Sponsor, 
the IRB, ACC CTSRMC, ACC DSMC, DSMB, or the Food and Drug Administration. 
 
The reasons for discontinuation (for example, voluntary withdrawal, toxicity, death) must be 
recorded on the case report form (CRF). Final study evaluations will be completed at the time of 
discontinuation. 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Follow-up data collection after gene modified cell therapy clinical trials is specified by FDA.  As 
long as patients have detectable cells transduced with the lentiviral vector, they should be 
followed for toxicity, immune reactions, and any long-term adverse events.  Therefore, subjects 
will continue to be followed for: 1) engraftment as long as patients are at risk (until evidence of 
loss of detectable transduced T cells), 2) DFS until there is disease progression or they begin a 
new cancer therapy, and 3) survival until the time of death; or until the patient withdraws consent 
for clinical data collection, enrolls into a 15 year long-term follow-up protocol, or the end of the 
study (Last Subject/Last Visit).   
 
Subjects who complete the 2 year follow-up as part of this protocol, or discontinue participation 
early for any reason, will be encouraged to enroll into a 15 year long term follow-up protocol to 
further evaluate long term adverse events related to the study product.  Once subjects are 
enrolled on the long-term follow-up protocol, all follow-up data collection under this protocol 
will be discontinued. 
 
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 
will be asked to provide information from the subject’s medical record to the study team at 
protocol defined time points (including the results of any routine care examinations and/or 
laboratory assessments), and assist in the collection of protocol required blood samples (if 
applicable) which will be sent to the University of Pennsylvania for protocol required analysis.  
The subject and local provider will also be contacted via telephone by a member of the study 
team to assess any potential toxicity. 
 
In numerous previous cell therapy trials at the University of Pennsylvania, loss of follow-up is 
estimated to occur in less than 5% of cases. Every effort will be made to contact subjects who 

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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 should be maintained 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. 
 
5 STUDY DRUG  
5.1 Description 
CART-19 cells are autologous T cells that have been engineered to express an extracellular 
single chain antibody (scFv) with specificity for CD19 linked to an intracellular signaling 
molecule consisting of a tandem signaling domains comprised of the TCR signaling module 
linked to the 4-1BB costimulatory domain. The CART-19 cells are cryopreserved in infusible 
cryomedia and will be administered as a single infusion.  Each bag will contain an aliquot 
(volume dependent upon dose) of cryomedia containing the following infusible grade reagents 
(% v/v): 31.25% plasmalyte-A, 31.25% dextrose (5%), 0.45% NaCl, up to 7.5% DMSO, 1% 
dextran 40, 5% human serum albumin. 
 
Expected toxicities associated with infusion of CART-19 cells include transient fever, chills 
nausea, and rigors.  In order to minimize these events, patients will receive premedication as 
instructed below in Section 5.4.  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 
1. All patients must undergo a Respiratory Virus Panel (RVP) within 10 days prior to the 
planned CART-19 infusion. If the patient is positive for influenza, Tamiflu® or 
equivalent, should administered per package insert.  The patient must complete treatment 
prior to receiving CART-19.  The test does not need to be repeated prior to CART-19 
infusion, however if influenza sign and symptoms are present, the CART-19 infusion 
should be delayed until the patient is asymptomatic.  If the patient is positive for another 
virus on the RVP, the CART-19 infusion will be delayed for at least 7 days to be sure 
clinical symptoms of a viral infection do not develop.  If clinical symptoms develop, the 
infusion will be delayed until resolution of these symptoms. 
2. Patient should not experience a significant change in performance or clinical status 
compared to initial eligibility criteria that would, in the opinion of the treating physician, 
would increase the risk of experimental cell infusion. 
3. Patients experiencing laboratory abnormalities after enrollment, that in the opinion of the 
treating investigator or PI may impact subject safety or the subjects’ ability to receive 
CART-19 T-cells, may have their infusion delayed until both the treating investigator and 
PI determine it is clinically appropriate to proceed with the CART-19 infusion. 
4. Patients experiencing toxicities from their preceding cytoreductive chemotherapy will 
have their infusion schedule delayed until these toxicities have resolved. The specific 
toxicities warranting delay of T cell infusions include: 

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a. Pulmonary: Requirement for supplemental oxygen to keep saturation greater than 
95% or presence of radiographic abnormalities on chest x-ray that are progressive 
b. Cardiac: New cardiac arrhythmia not controlled with medical management 
c. Hypotension requiring pressor support 
d. Active Infection: Positive blood cultures for bacteria, fungus, or virus. 
5.3 Treatment Regimen 
A single dose of CART-19 transduced T cells will be administered by i.v. infusion consisting of 
1-5 x 108 cells transduced with the CD19 TCRζ/4-1BB vector.  The infusion will be scheduled to 
occur approximately 1 to 4 days following chemotherapy. Cohorts A and B will receive murine 
CART19 and Cohort C will receive humanized CART19. 
5.4 Preparation and Administration of Study Drug 
Cell manufacturing is done according to Figure 3 under INDs 
. The CART-19 T 
cells are prepared in the CVPF and are not released from the CVPF until FDA approved release 
criteria for the infused cells (e.g., cell dose, cell purity, sterility, average copy number of 
vectors/cell, etc.) are met. Upon release, the cells are taken to the bedside for administration.  
 
Package and Labeling 
Each bag will contain an aliquot (volume dependent upon dose) of cryomedia containing the 
following infusible grade reagents (% v/v): 31.25% plasmalyte-A, 31.25% dextrose (5%), 0.45% 
NaCl, up to 7.5% DMSO, 1% dextran 40, 5% human serum albumin. 
 
Each infusion bag will be affixed with a label containing information regarding the dose, the 
method of manipulation, the vector and the following statements “FOR AUTOLOGOUS USE 
ONLY” And “Caution: New Drug- Limited by Federal Law to Investigational Use”.  In addition 
the label will have at least two unique identifiers. Prior to each infusion, two individuals will 
independently verify all unique identifier information in the presence of the patient and to 
confirm that the information is correctly matched to the patient. 
 
Cell thawing  
The frozen cells will be transported in dry ice to the subject’s bedside at the CTRC or Rhoads (or 
elsewhere at the Hospital of the University of Pennsylvania).  The cells will be thawed at the 
bedside using a water bath maintained at 36C to 38C.  The bag will be gently massaged until 
the cells have just thawed.  There should be no frozen clumps left in the container at the time of 
infusion. If the CART-19 cell product appears to have a damaged or leaking bag, or otherwise 
appears to be compromised, it should not be infused, and should be returned to the CVPF as 
specified below.  
 
Premedication 
Side effects following T cell infusions include transient fever, chills, and/or nausea. It is 
recommended that the subject be pre-medicated with 650mg acetaminophen and 25-50mg 
diphenhydramine hydrochloride prior to the infusion of CART-19 cells. These medications may 
be repeated every six hours as needed. A course of non-steroidal anti-inflammatory medication 
may be prescribed if the patient continues to have fever not relieved by acetaminophen. It is 
recommended that patients not receive systemic corticosteroids such as hydrocortisone, 

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prednisone, prednisolone (Solu-Medrol) or dexamethasone (Decadron) at any time, except in the 
case of a life-threatening emergency, since this may have an adverse effect on T cells.  
 
Febrile reaction 
In the event of febrile reaction, an evaluation for infection should be initiated, and patients 
managed appropriately with antibiotics, fluids and other supportive care as medically indicated 
and determined by the treating physician. In the unlikely event that the subject develops sepsis or 
systemic bacteremia following CAR T cell infusion, appropriate cultures and medical 
management should be initiated. If a contaminated CART-19 T cell product is suspected, the 
product can be retested for sterility using archived samples that are stored in the CVPF. 
Consideration of a CRS should be given. 
 
Administration 
The infusion will take place at the Hospital of the University of Pennsylvania by a licensed 
Registered Nurse using precautions for immunosuppressed patients. The transduced T cells will 
be administered by rapid intravenous infusion at a flow rate of approximately 10mL to 20 ml per 
minute through a latex free Y-type blood set. A leukoreduction filter must not be used for the 
infusion of the T cell product. The duration of the infusion will be based on the total volume to 
be infused and the recommended infusion rate.   
 
Emergency medical equipment (i.e., emergency trolley) 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, blood pressure, and oxygen saturation 
by pulse oximetry) will be measured within 10 minutes prior to the infusion and within 15 
minutes after the infusion.  Thereafter, vital signs will be measured at 30 (+/- 5) minutes, 45 (+/- 
5) minutes, and 60 (+/- 5) minutes after the infusion, and then every hour (+/- 10 minutes) for the 
next 2 hours until these signs are satisfactory and stable.  If the subject’s vital signs are not 
satisfactory and stable three hours post-CART-19 infusion, vital signs will continue to be 
monitored at a minimum of every hour or as clinically indicated until stable. The subject will be 
discharged after the physician managing their care on the day of the infusion has determined that 
they are in satisfactory condition. 
 
Return or Destruction of Study Drug 
CART-19 cells may need to be returned to the CVPF 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. Any unused product will be returned to CVPF by CVPF personnel as 
per CVPF SOP. 
 
There is an ongoing reconciliation of drug shipped, drug consumed, and drug remaining per-
formed by the CVPF. Final disposition of the investigational product will also be documented in 
the site Investigational Product Accountability logs appropriately. 
5.5 Prior and Concomitant Therapy 
All prescription and nonprescription medication, vitamins, herbal and nutritional supplements, 
taken by the subject during the 30 days prior to screening will be recorded at the screening visit. 
At every visit following the first dose up to Week 24 concomitant medications will be recorded 

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in the medical record and on the appropriate CRF.  Any additions, deletions, or changes of these 
medications will be documented. The following guidelines must be adhered to during the study: 
 GM-CSF should be avoided due to potential to worsen CRS symptoms.  G-CSF 
would be the preferred myeloid growth factor over GM-CSF, if medically indicated. 
The effects of G-CSF are unknown and can be used at the physician’s discretion. 
 Steroids or other immunosuppressant drugs should NOT be used within 10 days prior 
to the apheresis procedure. 
 Steroids or other immunosuppressant drugs should NOT be used within 24 hours pri-
or to the CART-19 infusion (refer to Section 5.4) or following CART-19 infusion un-
less under life threatening circumstances or at the physicians’ discretion to manage 
CRS. 
 
6 
STUDY PROCEDURES 
Overview 
The study consists of 1) a screening phase, 2) followed by an intervention/treatment phase 
consisting of apheresis, chemotherapy and infusions of CART-19 cells, 3) tumor collection by 
bone marrow aspiration or lymph node biopsy (optional, depending on availability), and 4) 
follow up. Schedule of evaluations and infusion are included in Section 15.1. 
6.1 Pre-Entry Evaluations 
After informed consent is obtained, blood test for HIV will be performed and a blood sample is 
sent to the CVPF for test expansion to determine T cell manufacturing feasibility. In 
approximately 1 week, the CVPF will provide the test expansion result indication whether the 
subject’s PBMC are likely to be adequate for large scale CART-19 T cell manufacturing process. 
The test expansions will be done for the first 10 subjects enrolled. 
6.2 Enrollment and Baseline Assessment. 
In accordance with section 15.1, eligible subjects who have signed an informed consent and have 
adequate pre-screening evaluation will undergo a routine lymphoma staging workup including: 
a. History and Physical Examination (including vital signs,  height, weight), past and current 
medications, leukapheresis screening 
b. Radiologic imaging (diagnostic CT or MRI scans) of the Chest, Abdomen, and Pelvis 
done within 12 weeks of study entry and after the subjects’ last chemotherapy treatment. 
CT or MRI imaging of neck will be performed if required for disease evaluation. 
c. Complete Blood Count, Differential and Platelet Count. 
d. Chemistry Panel (Glucose, Ca, Mg, Phos, Alk Phos, Albumin, Total Protein, Total 
Bilirubin, K, Na, Cl, BUN, uric acid, Cr, ALT, AST and Lactate Dehydrogenase Level) 
e. PT/INR, PTT 
f. β2 Microglobulin Level, autoantibody panel (ANA and ESR) 
g. Serum immunoglobulin levels 
h. Serum pregnancy test for females of child bearing potential. Follicle stimulating hormone 
(FSH) test may be performed to confirm menopausal status.  
i. ECOG performance status assessment 

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j. Viral serologies (CMV, EBV, Hepatitis B/C). If the HCV antibody is positive, a screening 
HCV RNA by any RT-PCR or bDNA assay must be performed. Eligibility will be 
determined based on the screening value. The test is not required if documentation of a 
negative result of a HCV RNA test performed within 60 days prior to screening is 
provided. 
k. Bone marrow evaluation within 42 days of infusion; and lymph node biopsy (optional) 
l. Documentation of CD19 expression.  
m. A baseline cardiac ECHO/MUGA should be performed within 8 weeks of the first 
infusion. 
6.3 Enrollment. 
To enroll a subject on this study, provide the documents listed below to:  
 
Protocol Monitor and Sponsor Project Manager 
 
 
 
Documents required: 
 Complete Enrollment Form  
 Copy of signed patient consent and HIPAA form 
 Source documentation to confirm enrollment/eligibility 
 
Upon receipt of screening and eligibility documentation, the Sponsor Monitor will review and 
provide documentation that the monitoring visit for eligibility has been completed.  This 
documentation must be received prior to cell product manufacturing.   
6.4 Apheresis 
A 12-15 liters or 4-6 blood volumes or a target of 5x109 apheresis procedure will be performed at 
the apheresis center. PBMC are obtained for CART-19 during this procedure. From a single 
leukapheresis, the intention is to harvest at least 5 x 109 white blood cells to manufacture CART-
19 T cells. If a single apheresis does not yield the adequate number of cells for manufacturing, 
then subjects can undergo an additional apheresis as needed. 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 later. Flow cytometry lymphocyte subset 
quantitation, including CD19 and CD20 B cell determination. 
 
Recommended criteria for apheresis product acceptance to initiate processing for clinical 
manufacturing to meet the dosing requirements includes the following specifications: A 
CBC with automated differential on the apheresis product following completion of collection 
that reports absolute lymphocyte count (ALC) ≥ 500/uL. If the ALC <500/uL in the apheresis 
product, it is recommended that the CD3 cell count should be ≥ 150/uL for acceptance to begin 
processing for clinical manufacturing to achieve the target dose. 
 
Historical Apheresis Sample 
Cryopreserved historical apheresis products collected from the patient prior to study entry are 
usable for CART-19 manufacturing if collected at an appropriately certified apheresis center and 

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the product meets adequate mononuclear cell yields. The 12 week window for the apheresis 
collection does not apply to historical samples (e.g. if an approved apheresis sample has been 
collected outside of the 12 week timeframe, this will not be considered a protocol 
violation/deviation.  If a historical apheresis sample is used, the patient would not have to repeat 
the baseline apheresis. If a historical apheresis product is not available, an apheresis procedure 
(as described above) will be performed for cell procurement after study eligibility has been 
confirmed. 
6.5 Cytoreductive chemotherapy 
It is anticipated that many patients will have been receiving chemotherapy for relapsed or 
resistant lymphoma. Patients referred with stable disease on no recent therapy will also be 
eligible.   For inclusion, patients will have responding or stable disease to their most recent 
therapy.  Prior to CART-19 cell infusion, an additional chemotherapy cycle is planned.  Patients 
referred with stable disease on no recent therapy will be eligible.  The regimen of chemotherapy 
will be at the discretion of the investigator and dependent on the patient’s disease burden, 
histology and past therapies.  
 
Chemotherapy may include cyclophosphamide, fludarabine, bendamustine or any other 
appropriate combination chemotherapy. 
 
The chemotherapy will be planned so that it completes approximately 1-4 days BEFORE the 
planned infusion of the first dose of CART19 cells.  Each regimen is of different duration so the 
start day of chemotherapy will vary.  The purpose of the chemotherapy is to induce lymphopenia 
in order to facilitate engraftment and homeostatic expansion of CART-19 cells.  In addition, 
chemotherapy can potentiate the ability of T cells to kill tumor cells85, 86. The chemotherapy is 
not investigational and may be given by a patient’s local oncologist within the specified time 
frame. 
 
All patients must undergo a Respiratory Virus Panel (RVP) within 10 days prior to the planned 
CART-19 infusion. If the patient is positive for influenza, Tamiflu® or equivalent, should 
administered for 10 days as preventative treatment.  The patient must complete their 10 day 
preventative treatment course prior to receiving CART-19.  The test does not need to be 
repeated prior to CART-19 infusion, however if influenza sign and symptoms are present, the 
CART-19 infusion should be delayed until the patient is asymptomatic.  If the patient is positive 
for another virus on the RVP, the CART-19 infusion will be delayed for at least 7 days to be sure 
clinical symptoms of a viral infection do not develop.  If clinical symptoms develop, the infusion 
will be delayed until resolution of these symptoms. 
 
If it has been greater than 42 days since the subjects’ previous radiologic disease assessment 
(performed for enrollment), a repeat CT/MRI of the chest/abdomen/pelvis is required prior to 
receiving cytoreductive chemotherapy.   If it has been less than 42 days since the subjects’ 
enrollment radiologic disease assessment, but the subject has received additional treatment 
during this time, a repeat CT/MRI of the chest/abdomen/pelvis is also required prior to receiving 
cytoreductive chemotherapy. 

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6.6 Pre-Infusion Visit 
Subjects will undergo the following work-up including: 
 
a) Current  medical conditions and physical examination (including vital signs and  
weight) 
b) ECOG performance status assessment 
c) Concomitant medications 
d) Hematology (complete blood count, differential and platelet count) 
e) Chemistry panel (Glucose, Ca, Mg, Phos, Alk Phos, Albumin, Total Protein, Total 
Bilirubin, K, Na, Cl, BUN, uric acid, Cr, ALT, AST and  Lactate Dehydrogenase Lev-
el) 
f) Urine pregnancy test (Females only) 
g) Baseline screens for HLH/MAS: ferritin, triglycerides, haptoglobin and CRP 
h) Baseline screen for coagulation factors:  PT, PTT, INR, fibrinogen, D-dimer 
i) Research labs:  HAMA and HACA testing, molecular labs (including VSV-G), cyto-
kine and cellular assessments   
6.7 CART-19 Infusion  
Infusion begins approximately 1 to 4 days after completion of chemotherapy.  
 
On day 0 prior to the infusion, patients will have a physical exam, medical history, performance 
status evaluation, CBC with differential, and assessment of CD3, CD4 and CD8 counts since 
chemotherapy is given in part to induce lymphopenia.  If clinically indicated, coagulation labs 
(PT, PTT, INR, fibrinogen, D-dimer) and HLH/MAS labs (including ferritin, triglycerides, 
haptoglobin, and CRP) will be drawn.  
 
Subjects will premedicated and administered the CART-19 T cells as described in section 5.4. 
The CART-19 cell dose will be administered by i.v. infusion.  The cells are thawed at the 
patient’s bedside. The thawed cells will be given at an infusion rate of 10 to 20 mL per minute. 
In order to facilitate mixing, the cells will be administered simultaneously using a Y-adapter or 
equivalent. Subjects’ vital signs will be assessed and pulse oximetry will be measured within 10 
minutes prior to dosing and within 15 minutes after the infusion. Thereafter, vital signs will be 
measured at 30 (+/- 5) minutes, 45 (+/- 5) minutes, and 60 (+/- 5) minutes after the infusion, and 
then every hour (+/- 10 minutes) for the next 2 hours until these signs are satisfactory and stable.   
If the subject’s vital signs are not satisfactory and stable three hours post-CART-19 infusion, 
vital signs will continue to be monitored at a minimum of every hour or as clinically indicated 
until stable.  The subject will be discharged after the physician managing their care on the day of 
the infusion has determined that they are in satisfactory condition. 
 
A blood sample for determination of a baseline CART-19 level is obtained any time prior to the 
infusion and 20 minutes to 2 hours post each infusion (and sent to TCSL). 
 
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:  

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6.10    Monthly evaluations 2 to 6 months post infusion 
Subjects will return to the clinic on a monthly basis during month 2 to 6 post CART-19 cell 
infusion.  At these study visits, subjects will undergo tests and procedures in accordance with the 
Schedule of Study Procedures in Section 15.1.   
6.11 Quarterly evaluations after 6 months for up to 2 Years Post 
Infusion 
After month 6, subjects will be evaluated on a quarterly basis until 2 years post infusion. At these 
study visits, subjects will undergo tests and procedures in accordance with the Schedule of Study 
Procedures in Section 15.1.    
6.12    Secondary Follow-up Phase 
Subjects who complete or prematurely discontinue from the Primary Follow-up Phase, who do 
not enroll in a separate 15 year long-term follow-up protocol, will continue to be followed in the 
Secondary Follow-up Phase of this study until the subject withdraws consent, the subject enrolls 
in a long-term follow-up protocol, or the end of the study (Last Patient/Last Visit), whichever 
occurs first.    
 
Secondary follow-up assessments will be performed every 3 months and consist of the 
following: 
 Progression-free survival (PFS) - in patients who discontinue from Primary Follow-up in 
remission.   Subjects will continue to be followed for PFS until disease progression or 
they begin a new cancer therapy (with the exception of alloSCT). 
 Survival Follow-up Status 
 
Additional research blood may also be collected.  The total amount of extra blood that may be 
collected will not exceed 3 tablespoons of blood twice in one week.  In addition, portions of bone 
marrow aspirates that are performed during Secondary Follow-up for clinical disease monitoring 
may be provided to TCSL for correlative studies.  
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 to further 
evaluate long-term adverse events related to the study product. Once subjects are enrolled on the 
long-term follow-up protocol, all follow-up data collection under this protocol will be 
discontinued.  
6.14 Tumor Assessments 
Baseline and subsequent tumor assessments will be performed according to standard of care 
practice, using anatomic imaging to assess tumor volume by CT or MRI. Tumor measurements 
will be done at the University of Pennsylvania within 12 weeks prior to study entry.  These 
enrollment scans must be performed after the subjects’ last chemotherapy treatment.   In 
addition, if it has been greater than 42 days since the subject’s previous radiologic disease 
assessment (performed for enrollment), a repeat CT/MRI of the chest/abdomen/pelvis is required 
prior to receiving cytoreductive chemotherapy.   If it has been less than 42 days since the 

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subjects’ enrollment radiologic disease assessment, but the subject has received additional 
treatment during this time, a repeat CT/MRI of the chest/abdomen/pelvis is also required prior to 
receiving cytoreductive chemotherapy. Please see Figure 4 below for complete details.  
 
Figure 4: 
 
 
Patients will have imaging assessments for tumor response every 3 months post-infusion for the 
first year, every 6 months during the second year. Functional imaging (18FDG-PET/CT) may be 
used at the discretion of the treating physician if in the opinion of the treating investigator it is 
more clinically appropriate (for example- to assess certain extranodal sites like bone marrow or 
to confirm complete response). Exploratory analyses of available CT, MRI, and/or PET imaging 
datasets may also be performed (e.g., to assess whether there are imaging biomarkers that are 
obtainable from pretreatment scans to predict response to therapy). Tumor response assessments 
will be done by a dedicated independent radiologist and the Principal Investigator. Tumor 
response assessments are based on the patient’s underlying disease anatomy using the following 
response definitions. Measurable disease is defined per Cheson et al., 1999)110.   Final response 
assessments will be based on Cheson 2007 criteria111. 
 
 
 
 
 

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CHESON 2007 RESPONSE DEFINITIONS: 
 
Complete Response (CR): 
 
1.   Complete disappearance of all detectable clinical evidence of disease and disease-related 
symptoms if present before therapy. 
 
2a. Typically FDG-avid lymphoma: in patients with no pretreatment PET scan or when the 
PET scan was positive before therapy, a post-treatment residual mass of any size is per-
mitted as long as it is PET negative. 
 
2b. Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a pretreatment 
PET scan, or if a pretreatment PET scan was negative, all lymph nodes and nodal masses 
must have regressed on CT to normal size (≤ 1.5 cm in their greatest transverse diameter 
for nodes > 1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in 
their long axis and more than 1.0 cm in their short axis before treatment must have de-
creased to ≤ 1.0 cm in their short axis after treatment. 
 
3.   The spleen and/or liver, if considered enlarged before therapy on the basis of a physical 
examination or CT scan, should not be palpable on physical examination and should be 
considered normal size by imaging studies, and nodules related to lymphoma should dis-
appear. However, determination of splenic involvement is not always reliable because a 
spleen considered normal in size may still contain lymphoma, whereas an enlarged spleen 
may reflect variations in anatomy, blood volume, the use of hematopoietic growth fac-
tors, or causes other than lymphoma. 
 
4.   If the bone marrow was involved by lymphoma before treatment, the infiltrate must have 
cleared on repeat bone marrow biopsy. The biopsy sample on which this determination is 
made must be adequate (with a goal of > 20 mm unilateral core). If the sample is inde-
terminate by morphology, it should be negative by immunohistochemistry. A sample that 
is negative by immunohistochemistry but that demonstrates a small population of clonal 
lymphocytes by flow cytometry will be considered a CR until data become available 
demonstrating a clear difference in patient outcome. 
 
Complete Response Unconfirmed (CRu): 
 
The use of the above definition for CR and that below for PR eliminates the category of CRu. 
 
 
Partial Response (PR): 
 
The designation of PR requires all of the following:  
1. At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the 
largest dominant nodes or nodal masses. These nodes or masses should be selected ac-
cording to all of the following: they should be clearly measurable in at least 2 perpen-
dicular dimensions; if possible they should be from disparate regions of the body; and 

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they should include mediastinal and retroperitoneal areas of disease whenever these sites 
are involved. 
2. No increase should be observed in the size of other nodes, liver, or spleen. 
3. Splenic and hepatic nodules must regress by ≥ 50% in their SPD or, for single nodules, in 
the greatest transverse diameter. 
4. With the exception of splenic and hepatic nodules, involvement of other organs is usually 
assessable and no measurable disease should be present. 
5. Bone marrow assessment is irrelevant for determination of a PR if the sample was posi-
tive before treatment. However, if positive, the cell type should be specified (eg, large-
cell lymphoma or small neoplastic B cells). Patients who achieve a CR by the above cri-
teria, but who have persistent morphologic bone marrow involvement will be considered 
partial responders. 
When the bone marrow was involved before therapy and a clinical CR was achieved, but 
with no bone marrow assessment after treatment, patients should be considered partial re-
sponders. 
6. No new sites of disease should be observed. 
7. Typically FDG-avid lymphoma: for patients with no pretreatment PET scan or if the PET 
scan was positive before therapy, the post-treatment PET should be positive in at least 
one previously involved site. 
8. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreat-
ment PET scan, or if a pretreatment PET scan was negative, CT criteria should be used. 
 
In patients with follicular lymphoma or mantle-cell lymphoma, a PET scan is only indicated with 
one or at most two residual masses that have regressed by more than 50% on CT; those with 
more than two residual lesions are unlikely to be PET negative and should be considered partial 
responders. 
 
Stable Disease (SD): 
 
Stable disease (SD) is defined as the following:  
1. A patient is considered to have SD when he or she fails to attain the criteria needed for a 
CR or PR, but does not fulfill those for progressive disease (see Relapsed Disease [after 
CR]/Progressive Disease [after PR, SD]). 
2. Typically FGD-avid lymphomas: the PET should be positive at prior sites of disease with 
no new areas of involvement on the post-treatment CT or PET. 
3. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreat-
ment PET scan or if the pretreatment PET was negative, there must be no change in the 
size of the previous lesions on the post-treatment CT scan. 
 
Relapsed Disease (after CR)/Progressive Disease (after PR, SD): 
 
Lymph nodes should be considered abnormal if the long axis is more than 1.5 cm regardless of 
the short axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered ab-
normal if its short axis is more than 1.0. Lymph nodes ≤ 1.0 × ≤ 1.0 cm will not be considered as 
abnormal for relapse or progressive disease.  

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1. Appearance of any new lesion more than 1.5 cm in any axis during or at the end of thera-
py, even if other lesions are decreasing in size. Increased FDG uptake in a previously un-
affected site should only be considered relapsed or progressive disease after confirmation 
with other modalities. In patients with no prior history of pulmonary lymphoma, new 
lung nodules identified by CT are mostly benign. Thus, a therapeutic decision should not 
be made solely on the basis of the PET without histologic confirmation. 
2. At least a 50% increase from nadir in the SPD of any previously involved nodes, or in a 
single involved node, or the size of other lesions (eg, splenic or hepatic nodules). To be 
considered progressive disease, a lymph node with a diameter of the short axis of less 
than 1.0 cm must increase by ≥ 50% and to a size of 1.5 × 1.5 cm or more than 1.5 cm in 
the long axis. 
3. At least a 50% increase in the longest diameter of any single previously identified node 
more than 1 cm in its short axis. 
4. Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the le-
sion was PET positive before therapy unless the lesion is too small to be detected with 
current PET systems (< 1.5 cm in its long axis by CT). 
 
 
Table 4- Tumor Response Assessment Criteria from Cheson et al., 2007
Response 
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance of 
all evidence of 
disease 
(a) FDG-avid or PET 
positive prior to 
therapy; mass of any 
size permitted if PET 
negative (b) Variably 
FDG-avid or PET 
negative; regression 
to normal size on CT 
Not palpable, 
nodules 
disappeared 
Infiltrate cleared on repeat 
biopsy; if indeterminate 
by morphology, 
immunohistochemistry 
should be negative 
PR 
Regression of 
measuable 
disease and no 
new sites 
≥ 50% decrease in 
SPD of up to 6 largest 
dominant masses; no 
increase in size of 
other nodes (a) FDG-
avid or PET positive 
prior to therapy; one 
or more PET positive 
at previously involved 
site (b) Variably 
FDG-avid or PET 
negative; regression 
on CT 
≥ 50% decrease 
in SPD of 
nodules (for 
single nodule in 
greatest 
transverse 
diameter); no 
increase in size 
of liver or 
spleen 
Irrelevant if positive prior 
to therapy; cell type 
should be specified 
SD 
Failure to attain 
CR/PR or PD 
(a) FDG-avid or PET 
positive prior to 
therapy; PET positive 
at prior sites of 
 
 

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Response 
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
disease and no new 
sites on CT or PET 
 
 
(b) Variably FDG-
avid or PET negative; 
no change in size of 
previous lesions on 
CT 
 
 
Relapsed 
disease or 
PD 
Any new lesion 
or increase by ≥ 
50% of 
previously 
involved sites 
from nadir 
Appearance of a new 
lesion(s) > 1.5 cm in 
any axis, ≥ 50% 
increase in SPD of 
more than one node, 
or ≥ 50% increase in 
longest diameter of a 
previously identifed 
node > 1 cm in short 
axis 
> 50% increase 
from nadir in 
the SPD of any 
previous lesions 
New or recurrent 
involvement 
 
 
Lesions PET positive 
if FDG-avid 
lymphoma or PET 
positive prior to 
therapy 
 
 
7 STATISTICAL PLAN 
7.1 General Design Issues 
This is an open label, Phase IIa study to provide exploratory data on the efficacy of CART-19, in 
patients with chemotherapy relapsed or refractory CD19+ lymphoma. Failure to complete the 
study due to the treatment limiting toxicity being invoked will be the main basis for determining 
safety and feasibility.  
 
Upon enrollment, patients will undergo leukapheresis.  Between leukapheresis and CART-19 
infusion, patients may undergo an additional chemotherapy treatment at the treating physician’s 
discretion.  At dosing, patients will receive CART-19 cells, and will be monitored weekly for 
four weeks.  Observation and monitoring of patients will continue on a monthly basis until week 
24 post dosing. Quarterly evaluations will follow from this point up to two years. 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.   
 
Sixty evaluable subjects will be targeted for this study, with an expected rate of drop out of up to 
20-30% due to disease progression between enrollment and the week twelve post-dosing 
response assessment (this will take about 22-24 weeks for screening-apheresis-dosing-to the final 

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12 week endpoint).  Additionally, we anticipate an approximately 20% screen failure rate due to 
subjects not meeting eligibility criteria (e.g., unsuccessful cell expansion screen test) based on 
our current experience. Thus, approximately 94 subjects will be screened so that sufficient 
subjects will be enrolled to ensure at least 60 subjects evaluable at the week 12 post-dosing 
response assessment.   
7.2 Sample Size  
A total of 60 evaluable subjects will be planned for analysis of the primary endpoints, Subjects 
are enrolled in 3 cohorts.  Sample sizes are determined by practical considerations and to obtain 
useful pilot data with which to estimate safety and efficacy in each of the disease and treatment 
sub-cohorts. Cohort A has 39 evaluable subjects: with a minimum of 20 with diffuse large B cell 
lymphoma (DLBCL) and a minimum of 16 who have either follicular lymphoma (FL) or mantle 
cell lymphoma (MCL) (enrolled on a first come first-served basis). Cohort B has 7 evaluable 
subjects with DLBCL and T cell/histiocyte-rich disease. Cohort C has 14 evaluable subjects with 
DLBCL treated with humanized CART19. 
 
The primary endpoint of this study is overall response (i.e. either complete response or partial 
response) evaluated at three months post infusion. For cohort A, the following table displays the 
exact 95% confidence interval (CI) with various observed ORR. 
Table 7.2-1 Potentially observed Overall response rate (ORR) and exact 95% Confidence 
interval for Cohort A 
 
 
 
 
*one-sided, 97.5% confidence interval 
Based on Table 7.2-1, if 18 out of 39 evaluable subjects have partial or complete response at 3 
month, we will have strong evidence (i.e., 95% confidence) that the true ORR following CART-
19 infusion is at least above an ORR of 30%, which would be considered clinically significant in 
this patient population. In addition, overall response rate for each of the three histology types 
will be analyzed as a secondary objective in an exploratory analysis. There will be a minimum of 
20 evaluable subjects with DLBCL and a minimum of 16 evaluable subjects with either FL or 
MCL. Table 7.2-2 displays the exact 95% confidence interval (CI) with various observed ORR 
among 7, 14, and 20 evaluable subjects, from the different subgroups of interest. For example, if 
Cohort A: N=39 Evaluable Subjects 
Observed ORR 
95% Exact Confidence Interval 
0% (0/39) 
(0%, 9.0%)* 
12.8% (5/39) 
(4.3%,27.45%) 
25.6% (10/39) 
(13.0%,42.1%) 
38.5% (15/39) 
(23.4%,55.4%) 
46.2% (18/39) 
(30.1%,62.8%) 
51.3% (20/39) 
(34.8%,67.7%) 
64.1% (25/39) 
(47.2%,78.8%) 
      76.9% (30/39) 
(60.7%,88.9%) 
89.7% (35/39) 
(75.8%, 97.1%) 
100% (39/39) 
(91.0, 100%)* 

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cells at the intended dose range and completed the response assessments for the 
primary efficacy endpoint as planned by the protocol. Efficacy evaluable patients 
also include those with disease progression or death prior to the primary efficacy 
endpoint response assessment. These are the primary efficacy evaluable patients 
as defined below. The Efficacy Evaluable Set will be used for the primary effica-
cy endpoint analysis.  
 The Full Analysis Set (FAS) comprises all patients who received the CART-19 
cells. This set includes both primary efficacy evaluable and non-evaluable pa-
tients as defined below. The Full Analysis Set will be used for the secondary effi-
cacy, safety and correlative endpoints or other exploratory analyses. 
 
Definitions relevant to the Analysis Sets: 
1) Screening failure - Any patient who fails to meet the inclusion/exclusion criteria speci-
fied by the protocol.   
2) Manufacturing failure – Any patient who has manufactured CART-19 cells that do not 
meet the manufacturing release criteria or the minimum protocol-specified dose (1x108 
CART-19 cells).   
3) Primary efficacy evaluable patient – Any patient who is infused with the CART-19 
cells at the protocol-specified dose (1-5x108) and completed the response assessments for 
the primary efficacy endpoint as planned by the protocol. Efficacy evaluable patients also 
include those with disease progression or death prior to the primary efficacy endpoint re-
sponse assessment. 
4) Primary efficacy non-evaluable patient – Any patient who is infused with the CART-
19 cells at less than the protocol-specified dose. These patients are also counted as manu-
facturing failures. 
7.5 Statistical Analysis 
Descriptive statistics will be computed for all study variables for the evaluable populations as 
whole and within cohort and histology subgroups. Primary endpoint of overall response will be 
summarized as overall response rate (ORR) and 95% exact confidence interval will be calculated 
based on binomial distribution. All adverse events will be described and exact 95% confidence 
intervals will be produced for adverse event rates, both overall and within major categories. 
Overall survival, progression-free survival, and duration of response will be analyzed using 
Kaplan-Meier curves. Median survival time and survival probability at selected time points (e.g., 
3 month) will be computed with associated confidence interval. To evaluate the persistence of 
CART-19 (or its subsets), the within-subject change in the ratio of CART-19 cells (or other 
subsets) between two pre-specified time points will be compared using a Wilcoxon signed-rank 
test, or to simultaneously analyze multiple times, linear mixed effects model methodology will 
be used.  The use of the nonparametric test is very efficient (>95%) compared to the t-test if the 
underlying data are normally distributed.  Other secondary endpoints in this trial are all measured 
as continuous variable and can be analyzed in a similar fashion using nonparametric Wilcoxon 
signed-rank test. All the analyses will be two-sided and cut-off for statistical significance will be 
5%.  
 

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The number of patients enrolled versus the number of patients infused will be described and is a 
measure of the feasibility of this therapy. Proportion of subjects with manufacturing failure will 
be computed.  
 
8 SAFETY AND ADVERSE EVENTS 
8.1 Definitions 
 
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.   
 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that 
is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Note that hospitalizations that meet the following criteria should not be reported as serious 
adverse events: 
 Routine treatment or monitoring of the studied indication, not associated with any deteri-
oration in condition, such as preplanned study visits and preplanned hospitalizations for 
study procedures or treatment administration 
 Elective or pre-planned treatment for a pre-existing condition that is unrelated to the indi-
cation under study and has not worsened since signing the informed consent 
 Social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 
Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above is 
not a serious adverse 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.  
 

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All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.  
 
Unexpected adverse events 
An adverse event is considered unexpected (or unanticipated) if the event severity and/or 
frequency is not described in the investigator brochure and/or protocol (in the absence of an 
Investigator Brochure).  Please refer to the investigator brochure for additional detail related to 
severity and/or frequency of a particular event.  
 
Related adverse events 
An adverse event is considered related to participation in the research if there is a reasonable 
possibility that an event was caused by an investigational product, intervention or research-
required procedures.  For the purposes of this study, "reasonable possibility" means there is 
evidence to suggest a causal relationship.  
 
Treatment Limiting Toxicity (TLT) 
Treatment limiting toxicity is defined as an unexpected grade 3 or 4 non-hematologic toxicity 
probably related to the CART-19 infusion (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 TLT).  
 
Adverse Event Reporting Period 
For this study, collection of adverse events will begin on Day 0 (from the start of the CART-19 
infusion) and continue until the subject is off study or until the year 2 end of study visit. Events 
occurring during chemotherapy but prior to CART-19 infusion will be excluded from the adverse 
event reporting period. Patients experiencing toxicity from their preceding cytoreductive 
chemotherapy will have their schedule delayed until these toxicities have resolved. 
 
If a subject is taken off study within 30 days of the T-cell infusion, all SAEs experienced within 
30 days after the T-cell infusion should be reported to the sponsor. Any SAEs experienced after 
this 30 day period should be reported to the sponsor if the investigator suspects a causal 
relationship to the study treatment. 
 
Preexisting Condition/General Physical Examination Findings 
A preexisting condition is one that is present at the start of the study.   At screening, any 
clinically significant abnormality should be recorded as a preexisting condition on the medical 
history eCRF. During the course 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. Preexisting conditions that improve should also be recorded appropriately. 
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the 
following conditions is met:  
 The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
 The abnormality suggests a disease and/or organ toxicity 

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 The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
 
Laboratory abnormalities that meet the criteria for Adverse Events should be followed until they 
have returned to normal or an adequate explanation of the abnormality is found. When an 
abnormal laboratory or test result corresponds to a sign/symptom of an already reported adverse 
event, it is not necessary to separately record the lab/test result as an additional event. Laboratory 
abnormalities, that do not meet the definition of an adverse event, should not be reported as 
adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically indicate a 
SAE unless it meets the definition of serious as defined above and/or as per investigator’s 
discretion.  Whenever possible, a diagnosis, rather than a symptom should be provided (i.e. 
anemia instead of low hemoglobin). 
8.2 Recording of Adverse Events 
Safety will be assessed by monitoring and recording potential adverse effects of the treatment 
using the Common Toxicity Criteria version 4.03 at each study visit. Subjects will be monitored 
by medical histories, physical examinations, and blood studies to detect potential toxicities from 
the treatment.  If CTCAE grading does not exist for an adverse event, the severity of mild, 
moderate, severe, life-threatening, and death, corresponding to Grades 1-5, will be used whenever 
possible.  
 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Adverse events also may be detected 
when they are volunteered by the subject during the screening process or between visits, or 
through physical examination, laboratory test, or other assessments. Information on all adverse 
events should be recorded in the source documentation. All clearly related signs, symptoms, and 
abnormal diagnostic procedures results should be recorded in the source document, though 
should be grouped under one diagnosis. To the extent possible, adverse events should be 
recorded as a diagnosis and symptoms used to make the diagnosis recorded within the diagnosis 
event.  Do not list symptoms if a diagnosis can be assigned.  
 
All adverse events occurring during the adverse event reporting period (defined in Section 8.1 
above) must be recorded.   
 
As much as possible, each adverse event should be evaluated to determine: 
1. The severity grade (CTCAE Grade 1-5) 
2. Its duration (start and end dates) 
3. Its relationship to the study treatment - [Reasonable possibility that AE is related: No 
(unrelated/ not suspected) or Yes (a suspected adverse reaction)].  If yes (suspected) - 
is the event possibly, probably or definitely related to the investigational treatment?   
4. Expectedness to study treatment- [Unexpected- if the event severity and/or frequency 
is not described in the investigator brochure and protocol (in the absence of an investi-
gator brochure)]. 
5. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 

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6. Whether medication or therapy taken (i.e. no concomitant medication/non-drug thera-
py, concomitant medication/non-drug therapy) 
7. Whether it is serious; as defined in Section 8.1. 
 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded.  Once an adverse event is detected, it should be 
followed until its resolution or until it is judged to be permanent, and assessment should be made 
at each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the study treatment, the interventions required to treat it, and the outcome.   
Adverse events that occur concurrently with the progression of malignancy but that are not 
related to disease progression (i.e. deep vein thrombosis or hemoptysis) will be reported as an 
adverse event as described above.  Progression of malignancy resulting in death should be 
reported as a serious adverse event. 
 
Serious adverse events that are still ongoing at the end of the adverse event reporting period must 
be followed to determine the final outcome.  Any serious adverse event that occurs after the 
adverse event reporting period and is considered to be possibly related to the study treatment or 
study participation, should be recorded and reported. 
 
Grading System for Cytokine Release Syndrome (CRS) 
A protocol specific grading system (Table 8-1) has been developed to capture cytokine release 
syndrome (CRS) in CAR T-cell protocols.  Please refer to section 1.5.2 for additional detail on 
CRS in CAR T-cell therapy.   
 
For the purposes of reporting and grading on clinical trials using CART-19 cells, we will use the 
following grading for CRS Toxicity.  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. For the purposes of defining the CRS start date, a 
fever is defined as a temperature of 100.4°F/38°C. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 8-1 - CRS Toxicity Grading 
1 
2 
3 
4 
5 
Mild 
reaction: 
Treated with 
supportive 
care  such as 
anti-pyretics, 
anti-emetics 
Moderate reaction 
requiring IV fluids 
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 IVFs* or 
low-dose pressors, 
coagulopathy requiring 
fresh frozen plasma 
(FFP) or 
cryoprecipitate, and 
hypoxia requiring 
supplemental oxygen 
(nasal cannula oxygen, 
high flow oxygen, 
Continuous Positive 
Airway Pressure 
[CPAP] or Bilateral 
Positive Airway 
Pressure [BiPAP]).  
Patients admitted for 
management of 
suspected infection due 
to fevers and/or 
neutropenia may have 
grade 2 CRS. 
Life-threatening 
complications 
such as 
hypotension 
requiring high-
dose pressors 
(see Table 8-2) 
or hypoxia 
requiring 
mechanical  
ventilation.   
Death 
*CRS Grade 3 language clarification: “hypotension treated with intravenous fluids” is further defined as hypoten-
sion requiring 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 
or ≥ 20 mcg/min (if institutional practice is to use flat dosing) 
Dopamine monotherapy 
≥ 10 mcg/kg/min 
or ≥ 1000 mcg/min (if institutional practice is to use flat dosing) 
Phenylephrine monotherapy 
≥ 2 mcg/kg/min 
or ≥ 200 mcg/min (if institutional practice is to use flat dosing) 
Epinephrine monotherapy 
≥ 0.1 mcg/kg/min 
or ≥ 10 mcg/min (if institutional practice is to use flat dosing) 
If on vasopressin 
High-dose if vaso +  Norepinephrine Equivalent (NE) of > 0.1 
mcg/kg/min (or >10 mcg/min) (using Vasopressin and Septic 
Shock Trial (VASST) formula) 
If on combination vasopressors 
(not vasopressin) 
Norepinephrine equivalent of ≥ 0.2 mcg/kg/min  
(or ≥ 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, 2008113. 
 
8.3 Reporting of Serious Adverse Events 
Every SAE, regardless of suspected causality, occurring during the adverse event reporting 
period defined in Section 8.1 above must be reported to the sponsor within 24 hours of learning 
of its occurrence. The original SAE notification may take place by email to meet the 24 hour 
reporting window.  However within 3 business days of knowledge of the event, the investigator 
must submit a complete SAE form to the Sponsor along with 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.   
 
Follow-up information on SAEs should be reported when updates are available, as a follow-up to 
the initial SAE form, and should include both the follow-up number and report date.  New 
information on ongoing serious adverse events should be provided promptly to the sponsor.  The 
follow-up information should describe whether the event has resolved or continues, if there are 
any changes in assessment, if and how it was treated, and whether the patient continued or 
withdrew from study participation.    
  
 

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Report serious adverse events by email to: 
Attention: Sponsor Clinical Safety Manager or designee 
 
 
 
 
At the time of the initial notification, the following information should be provided: 
 Study identifier 
 Subject number 
 A description of the event 
 Date of onset 
 Current status 
 Whether study treatment was discontinued 
 The reason the event is classified as serious 
 Investigator assessment of the association 
between the event and study treatment 
 Expectedness relative to investigational 
product(s) 
8.3.1 Investigator reporting: notifying the Penn IRBs 
This section describes the requirements for safety reporting by investigators who are Penn 
faculty, affiliated with a Penn research site, or otherwise responsible for safety reporting to the 
IRB. The IRB requires expedited reporting of those events related to study participation that are 
unforeseen and indicate that participants or others are at increased risk of harm.  The IRB will 
not acknowledge safety reports or bulk adverse event submissions that do not meet the criteria 
outlined below.  The IRB requires researchers to submit reports of the following problems within 
10 working days from the time the investigator becomes aware of the event: 
 
Any adverse event (regardless of whether the event is serious or non-serious, on-site or off-
site) that occurs any time during or after the research study, which in the opinion of the 
principal investigator is: 
 
Unexpected (An event is “unexpected” when its specificity and severity are not 
accurately reflected in the protocol-related documents, such as the IRB-approved 
research protocol, any applicable investigator brochure, and the current IRB-approved 
informed consent document and other relevant sources of information, such as product 
labeling and package inserts.) 
AND 
Related to the research procedures (An event is “related to the research procedures” if 
in the opinion of the principal investigator or sponsor, the event was more likely than 
not to be caused by the research procedures.) 
 
Reporting Process 
Unanticipated problems posing risks to subjects or others as noted above will be reported to the 
IRB using the form: “Unanticipated Problems Posing Risks to Subjects or Others Including 
Reportable Adverse Events” or as a written report of the event (including a description of the 
event with information regarding its fulfillment of the above criteria, follow-up/resolution and 
need for revision to consent form and/or other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the 
Clinical Investigator’s study file. 

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Reporting Deaths:  more rapid reporting requirements 
Concerning deaths that occur during the course of a research study, the following describes the 
more rapid reporting requirement of the Penn IRB for specific situations: 
 
Report the event within 72 hours, when the death is unforeseen (unexpected) and indicates 
participants or others are at increased risk of harm. 
 
For reportable deaths, the initial submission to the IRB may be made by contacting the IRB 
Director or Associate Director. The AE/Unanticipated Problem Form is required as a follow up 
to the initial submission. 
 
Other Reportable events: 
For clinical drug trials, the following events are also reportable to the IRB: 
 
Any adverse experience that, even without detailed analysis, represents a serious 
unexpected adverse event that is rare in the absence of drug exposure (such as 
agranulocytosis, hepatic necrosis, Stevens-Johnson syndrome). 
 
Any adverse event that would cause the sponsor to modify the investigators brochure, 
protocol or informed consent form, or would prompt other action by the IRB to assure 
protection of human subjects. 
 
Information that indicates a change to the risks or potential benefits of the research, in 
terms of severity or frequency. For example:  
– 
An interim analysis indicates that participants have a lower rate of response to 
treatment than initially expected. 
– 
Safety monitoring indicates that a particular side effect is more severe, or more 
frequent than initially expected. 
– 
A paper is published from another study that shows that an arm of your research 
study is of no therapeutic value. 
 
Change in FDA safety labeling or withdrawal from marketing of a drug, device, or 
biologic used in a research protocol. 
 
Breach of confidentiality 
 
Change to the protocol taken without prior IRB review to eliminate apparent immediate 
hazard to a research participant. 
 
Incarceration of a participant when the research was not previously approved under 
Subpart C and the investigator believes it is in the best interest of the subject to remain on 
the study. 
 
Complaint of a participant when the complaint indicates unexpected risks or the complaint 
cannot be resolved by the research team. 
 
Protocol violation (meaning an accidental or unintentional deviation from the IRB 
approved protocol) that in the opinion of the investigator placed one or more participants 
at increased risk, or affects the rights or welfare of subjects. 
8.3.2 Reporting obligations to the DSMC of the ACC 
All events that meet the DSMC definition of reportable AE’s must be promptly entered into 
Velos.   
 

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The DSMC requires AE/SAE submission as follows:  
 Unless covered by exclusions below, grade 3 or higher events must be reported within 10 
days of knowledge of the adverse event.  
Exceptions:  
o 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.  
o All grade 3 or 4 events that are judged by a study investigator to be clearly unre-
lated to protocol therapy.  
o Grade 3 or 4 events that are probably or definitely related to progression of dis-
ease as judged by the study investigator.  
o Grade 3 or 4 events that are probably or definitely related to an FDA approved 
agent.  
 All unexpected deaths within one business day of knowledge  
 All others deaths within 30 days of knowledge. Deaths of subjects off-study for greater 
than 30 days from the last study treatment/intervention are not reportable unless a longer 
time frame is specified in the protocol.  
In the event of a grade 4 or 5 unexpected event regardless of attribution, the DSMC and ACC 
leadership require investigators and the study team to meet or have a teleconference within 24 
business hours of the event to have a thorough discussion of the event. These types of events will 
not be vetted via e-mail. The sponsor should not be involved in discussions about attribution. 
The PI and Research Coordinator will schedule a meeting with the study team to discuss the 
grade 4 or 5 unexpected event. Meeting minutes capturing the review of any ongoing investiga-
tions of the grade 4 or 5 unexpected event, including next steps in the management of the subject 
and any proposed changes to the protocol will be forwarded to the DSMC. 
8.3.3 IBC Notification by Investigator 
Notify the Institutional Biosafety Committee of serious adverse events according to institutional 
requirements.  
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/UCM227351.pdf 
 
The following describes the safety reporting requirements by timeline for reporting an associated 
type of event: 
 Within 7 Calendar Days 
Any study event that is: 
o Unexpected fatal or life-threatening suspected adverse reaction.   

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o Expected and unexpected Grade 3 or higher events of cytokine release syndrome 
per the modified CRS grading scale in Table 8-1 
o All fatal events occurring within 30 days of T-cell infusion, regardless of 
attribution and expectedness 
 Within 15 Calendar Days 
Any study event that is: 
o unexpected 
o Suspected adverse reaction that is serious, but not fatal or life-threatening 
-or- 
o a previous adverse event that was not initially deemed reportable but is later 
found to fit the criteria for reporting (reporting within 15 calendar days from 
when event was deemed reportable). 
Any finding from tests in laboratory animals that: 
– suggest a significant risk for human subjects including reports of mutagenicity, 
teratogenicity, or carcinogenicity or reports of significant organ toxicity at or near the 
expected human exposure. 
Increase in rate of occurrence of serious suspected adverse reactions: 
o any clinically important increase in the rate of a serious suspected adverse 
reaction over that listed in the protocol or investigator brochure. 
Additional Reporting Requirements 
Sponsors are also required to review all adverse events to make a causality determination on the 
basis of information from investigators and report these findings to the FDA in accordance with 
21 CFR  312.32. 
 
If the adverse event does not meet expedited reporting requirements, the Sponsor will report the 
SAE in the IND Annual Report. 
8.3.5 Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to the 
regulatory sponsor within 24 hours of learning of its occurrence. The pregnancy must be 
followed up to determine outcome, including spontaneous or voluntary termination, details of the 
birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.  
 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
investigator to the regulatory sponsor. Pregnancy follow-up should be recorded on the same form 
and must include an assessment of the possible relationship to the study treatment of any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported on the SAE 
Report Form. 
 

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Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study.  Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.   
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 that these can be SAEs. Therefore, there is no specific occurrence 
of SAEs that define a stopping rule, but the review of SAEs will form the basis for potential 
early stopping of the study. Only unexpected SAEs that are probably related to the CART-19 
cells would define a stopping rule.  
 
 
Premature termination of the clinical trial may occur because of a regulatory authority decision, 
change in opinion of the IRB, the DSMB, Medical Monitor, ACC DSMC, determination that 
there are problems in the cell product generation, as a result of safety concerns, or at the 
discretion of the Sponsor or 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. 
 Premature study termination may occur if the Investigator, Study Funder, Sponsor, 
DSMB, Medical Monitor, ACC DSMC or any independent review board or regulatory 
body decides for any reason that subject safety may be compromised by continuing the 
study. 
 Premature study termination may occur if the Sponsor or Study Funder decides to 
discontinue the development of the intervention to be used in this study. 
 
The study will be paused if:  
 The protocol will be paused pending submission of protocol pause to the FDA and review 
by the IRB, ACC DSMC, ACC CTSRMC, Medical Monitor and the DSMB if any patient 
experiences any of the following events within two weeks of the CART-19 infusion.  
o Life-threatening (grade 4) toxicity attributable to protocol therapy that is 
unmanageable, unexpected and unrelated to chemotherapy and attributable to 
CART-19 infusion.  We expect high fevers, hypotension, possible ICU admission 
and even mechanical ventilation.  These side effects can result in grade 4 liver 
toxicity, nephrotoxicity and other organ involvement.   
o Death. 
If the study is paused for the reasons above, the PI, members of the study team and Protocol 
Advisor will meet in person or by teleconference within 24 hours of the event to have a 
thorough discussion of the event. These types of events will not be vetted via e-mail. The 
sponsor should not be involved in discussions about attribution. Meeting minutes capturing the 
review of any ongoing investigations, including next steps in the management of subjects and 
any proposed changes to the protocol will be forwarded to the FDA, IRB, ACC DSMC, Medical 
Monitor, and DSMB. If all parties are in agreement as to the event resolution and any proposed 

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modifications, then the pause will be lifted. 
 
The protocol manufacturing will be paused to review the manufacturing process should there be 
>33% primary efficacy non-evaluable patients (i.e. the manufacturing process fails to meet the 
protocol-specified dose range of 1-5x108 CART-19 cells). 
 
If the study is paused for manufacturing reasons, the PI, members of the study team, Protocol 
Advisor, Clinical Operations and Cell Manufacturing will meet to identify manufacturing failure. 
The team will make recommendations for process improvements to be implemented. Pending 
successful completion of a process validation run, the manufacturing pause will be lifted. 
8.4.2 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  
o Intensive follow-up of subject in consultation with gene therapy experts, study 
investigators, FDA and NIH. 
o Inform local public health officials and CDC. 
o Identify sexual partners and provide appropriate counseling and intervention. 
 
RCL will be monitored by a suitable Q-PCR DNA assay for detection of the lentivirus (for 
example: HIV gag DNA or VSV-G DNA). If a positive RCL DNA assay result is 
obtained, the PI will be informed and the subject rescheduled for a retest for the DNA test.  
If the second DNA test is positive, then infusions will be temporarily halted.  The patient 
will undergo a blood draw for isolation of HIV from his/her cells.  The virus will be 
sequenced and compared to sequences of the transfer vector and packaging constructs, as 
well as to available HIV sequences to determine the origin of the virus.  Determination of 
the origin of the virus can be easily performed by evaluation for HIV accessory genes 
such as vif, vpr and vpu which are not present in the packaging constructs.  If the 
sequence is derived from wt-HIV then infusions for all subjects can resume, and the 

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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:  
Four of nine treated patients in a gene therapy trial for X-linked Severe Combined Immu-
nodeficiency (SCID) developed T cell leukemia 31-68 months post-treatment. The T cell 
leukemias were attributable to clonal expansion conferred by gammaretroviral vector inte-
gration sites in the CD34+ bone marrow stem cell modification112. This represents the 
most severe adverse event caused by vector integration. However, there is also evidence 
for retroviral vector integration site dominance in a gene therapy trial of -thalassaemia 
without malignancy113. The lentiviral vector used for CART19 manufacturing is part of a 
vector class that may have a lower risk for integration in or near oncogenic regions than 
oncoretroviral vectors114. As of March 2014, none of the patients treated with CART19 
have developed a new malignancy, T cell or otherwise, related to lentiviral vector integra-
tion. Subjects will be monitored for evidence of unexpected CART19 expansion by 
CART19 transgene quantitation by qPCR and clinical monitoring for malignancy by com-
plete blood count (CBC) as part of the study design. If an unexpected pattern of CART19 
expansion is observed (i.e. CART19 expansion in the absence of CD19+ target), subjects 
will be closely monitored clinically for new malignancies, particularly T cell, and further 
studies, including insertion site analysis, will be considered to investigate the molecular 
basis of the expansion. Investigators should consult with the Regulatory Sponsor if an un-
expected pattern of CART19 expansion and/or a new malignancy arises. Subjects will be 
similarly monitored for clonality and insertional oncogenesis when enrolled on the long 
term follow up protocol. 
 
 Uncontrolled T cell proliferation. CART-19 cells could proliferate without control of 
normal homeostatic mechanisms. In pre-clinical studies, CART-19 cells have only 
proliferated in response to physiologic signals or upon exposure to CD19. In the context 
of this protocol it is possible that the T cells will proliferate in response to signals from the 
malignant tumor or normal B cells. This could be beneficial or harmful depending on the 
extent of proliferation. If any subject develops excessive CART-19 cell accumulation, 
corticosteroids will be administered to eradicate the infused cells.  
 
Toxicity associated with allogeneic or autologous T cell infusions has been managed with 
a course of pharmacologic immunosuppression. T body associated toxicity has been 
reported to respond to systemic corticosteroids95.  If uncontrolled T cell proliferation 
occurs (grade 3 or 4 toxicity related to CART-19 cells), subjects may be treated with 
corticosteroids. Subjects will be treated with pulse methylprednisolone (2 mg/kg i.v. 
divided q8 hr x 2 days), followed by a rapid taper.  
 
 B cell depletion. It is possible that B cell depletion and hypogammaglobulinemia will 
occur. This is an expected “on target” effect of the CART-19 cells. B cell depletion is 
common with anti-CD20 directed therapies115. B cell depletion has been observed in CLL 
and ALL patients treated with CART-19 cells. In the event of clinically significant 
hypogammaglobulinemia (i.e. systemic infections), subjects will be given intravenous 

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immunoglobulin (IVIG) by established clinical dosing guidelines to restore normal levels 
of serum immunoglobulin levels, as has been done with Rituximab. 
 Infusion reaction. Acetaminophen and diphenhydramine hydrochloride may be repeated 
every 6 hours as needed. A course of non-steroidal anti-inflammatory medication may be 
prescribed if the patient continues to have fever not relieved by acetaminophen. It is 
recommended that patients not receive corticosteroids at any time, except in the case of a 
life threatening emergency, since this may have an adverse effect on CART-19 cells.  
 
 Febrile reaction. In the event of febrile reaction, an evaluation for infection should be 
initiated, and patients managed appropriately with antibiotics, fluids and other supportive 
care as medically indicated and determined by the treating physician.  In the event that the 
patient develops sepsis or systemic bacteremia following CAR T cell   infusion,   
appropriate   cultures   and   medical   management   should   be   initiated.   If   a 
contaminated CART-19 T cell product is suspected, the product can be retested for 
sterility using archived samples that are stored in the CVPF.  Consideration of a cytokine 
release syndrome (see below) should be given.   
 
 Cytokine Release Syndrome (CRS) / Macrophage Activation Syndrome (MAS)  
CRS has been observed in patients after treatment with CART-19. Patients with clinical 
responses exhibited some level of CRS that ranged from mild to severe consisting of fe-
vers, hypotension, capillary leak, hypoxia or other symptoms (See Section 1.5.2 and 8.2).  
All patients who have responded to CART-19 cells have experienced a CRS.  
 
Cytokine production is required for the activation, expansion and cytolytic function of T 
cells and for CART-19 T cells.  Therefore some degree of CRS may be a desired clinical 
outcome. Premature or early intervention with anti-cytokine therapy may therefore 
abrogate the anti-tumor efficacy of CART-19. Subsequent to this experience, selective 
tocilizumab (an anti-IL6-receptor antibody) therapy has been utilized (described below) 
with effective toxicity management and successful ongoing CART-19 T cell expansion in 
patients. Please note, steroids or other immunosuppressant drugs should NOT be used as 
pre-medication for CART-19 therapy but may be considered in the management of CRS.  
 
The moderate to severe cases of CRS observed required intervention with tocilizumab, 
with or without high dose corticosteroids, between 2 and 9 days after T cell infusion. This 
resulted in rapid reversal of the high persistent fevers associated with CRS in most but 
not all patients. 
 
Given the dramatic clinical improvement of most patients treated with anti-cytokine 
therapy, patients with moderate to severe cytokine toxicities should be first managed with 
administration of tocilizumab. 
  
Tocilizumab should be used as a single, weight-based dose of 8 mg/kg at the time of 
hemodynamic instability. This management approach is designed to avoid life-
threatening toxicities, while attempting to allow the CART-19 cells to establish a 
proliferative phase that appears to correlate with anti-tumor efficacy. Thus, the timing of 
the tocilizumab should be individualized, in close consultation with the Principal 

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Investigator and/or expert consultants for the trial.  Steroids have not always been 
effective in this setting and may not be necessary given the rapid response to tocilizumab. 
Because steroids will interfere with CART-19 function and efficacy, if used, they should 
be rapidly tapered.  
 
Upon developing the prodrome of high-persistent fevers following CART-19 infusion, 
patients should then be followed closely. Infection and tumor lysis syndrome work up 
should be immediately undertaken.  The pharmacy should be notified of the potential 
need for tocilizumab.  Patient management in an intensive care unit may be required and 
the timing is dependent upon local institutional practice. In addition to supportive care, 
tocilizumab may be administered in cases of moderate to severe CRS, especially if the 
patient exhibits any of the following: 
 Hemodynamic instability despite intravenous fluid challenges and moderate stable 
vasopressor support 
 Worsening respiratory distress, including pulmonary infiltrates, increasing oxygen re-
quirement including high-flow O2, and/or need for mechanical ventilation.  
 Any other signs or symptoms of rapid deterioration despite medical management 
 
The recommended dosing for tocilizumab is 8 mg/kg i.v. single dose. Not all Grade 4 
CRS reactions following CART-19 have been immediately treated with tocilizumab and 
decisions are, in part, based upon the rapidity of the syndrome onset and underlying 
patient reserve. 
 
Other anti-cytokine therapies, such as repeat administration of tocilizumab or use of 
siltuximab or etanercept, may also be considered if the patient does not respond to the 
initial dose of tocilizumab.  If the patient experiences ongoing CRS despite 
administration of anti-cytokine directed therapies, anti T-cell therapies such as cytoxan, 
ATG, campath may be considered.   
 
CRS has been associated with biochemical and physiologic abnormalities consistent with 
MAS.  Moderate to extreme elevations in serum C-reactive protein (CRP) and ferritin 
have been seen with CART-19 associated CRS, however the magnitude and kinetics vary 
greatly between individual patients.  CRS management decisions should be based upon 
clinical signs and symptoms and response to interventions, not these laboratory values 
per se. Refer to Figure 8-1 below for a CRS Management Algorithm. 
 
CTCAE grading of CRS relates to its occurrence with acute infusional toxicities, whereas 
the CRS associated with CART-19 therapy is not acute, but rather delayed. Refer to 
Section 8.1 and Table 8-1 for modified definitions of grading of CART-19 delayed CRS 
events.  
 
 
 
 
 

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Figure 8-1 
CRS Management Algorithm 
 
 
 
 
 
 
 
 Tumor lysis syndrome. Patients will receive allopurinol for 28 days to prevent 
complications from TLS.  For patients with an allergy to allopurinol, febuxostat may be 
used at the discretion of the treating physician. TLS resulting in renal insufficiency, or 
rapidly rising uric acid level, or evidence of organ dysfunction will be managed with 
fluids and rasburicase as needed and as determined by the treating physicians. 
 GVHD. The chance of GVHD occurring is low, but it is a potential risk with CART-19 
therapy. A prior study of activated donor lymphocyte infusions (ex vivo activated cells 

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collected from the donor and grown in the same fashion as CART-19 but without the 
CAR introduction) did not show high rates of GVHD (2/18 patients with grade 3 GVHD 
and none with grade 4)116. ALL patients treated to date with autologous CART19 therapy 
who had prior allogeneic hematopoietic SCT with residual donor chimerism have 
developed GVHD after autologous CART19 infusion117. Patients treated with CART-19 
post allogeneic SCT will be monitored for GVHD. 
8.4.3 Criteria for discontinuing a subject’s participation in the study: 
If a subject develops a condition that precludes CART-19 infusion after enrollment but before 
infusion, the subject will be prematurely discontinued. This will be done at the judgment of the 
PI, and could include for example, the occurrence of an intercurrent illness requiring the 
institution of systemic immunosuppression.  
8.5 Protocol Exceptions and Deviations 
Exception 
A one time, intentional action or process that departs from the IRB and CTSRMC approved 
study protocol, intended for one occurrence.   If the action disrupts the study progress, such that 
the study design or outcome (endpoints) may be compromised, or the action compromises the 
safety and welfare of study subjects, advance documented approval from the Regulatory 
Sponsor, IRB, ACC DSMC and other local regulatory review committees per institutional 
guidelines is required.  Approval from the Regulatory Sponsor must be received prior to 
submission to the IRB, ACC DSMC and local regulatory review committees for approval. 
 
No exception would be granted if the action disrupts the study progress, such that the study 
design or outcome (endpoints) may be compromised, or the action compromises the safety and 
welfare of study subjects. 
 
No exceptions to eligibility will be granted for this study.  
 
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 and 
ACC DSMC within 5 business days and the IRB within 10 business days of PI knowledge.  
 
Any departure from the protocol that meets the following criteria is a protocol deviation and 
should be submitted to the regulatory sponsor, ACC DSMC and IRB: 
 
Impacts subject safety 
 
Impacts the integrity of the study design or outcome 
 
Based on the PI’s judgment is reportable 
 
Include the following information on the Sponsor supplied exception/deviation form:  protocol 
number, subject study number, description of the exception/deviation and rationale.  Ensure all 

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completed exception/deviation forms are signed by the Principal Investigator (or a sub-
investigator) and submitted to the Sponsor Project Manager and Medical Monitor for review.  
  
Attention: Sponsor Project Manager  
 
 
 
 
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 granted by the Regulatory Sponsor and Medical 
Monitor, the exception or deviation will be submitted to the IRB, ACC DSMC and all other 
applicable committees for review and approval.  
 
Other deviations should be explained in a memo to file (such as a subject missing a visit- unless a 
critical/important treatment or procedure was missed and must have been done at that specific 
time). 
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-
monitoring plan (see section 10 Study Monitoring, Auditing and Inspecting).  Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
 
A protocol-specific independent Medical Monitor with appropriate expertise and experience has 
been recruited in addition to the DSMB to review subject safety data and ensure the safety of 
participants.  The Medical Monitor will receive real-time reporting of any event that could 
potentially impact subject safety (including dose-limiting toxicities).  The Medical Monitor will 
also receive all of the following:   
 All Serious Adverse Events (regardless of expectedness/relatedness).  The SAE will be 
reported to the Medical Monitor within 24 hours of the study team’s awareness. 
 Deviations reported to the regulatory sponsor, ACC DSMC and IRB as they occur 
 Exceptions prior to submission to the IRB and ACC DSMC 
 Continuing Review Reports 
 All queries issued by the DSMC (including those related to grading, attribution and ex-
pectedness of adverse events).  
 
The Medical Monitor will correspond via email to communicate: 
 SAE acknowledgement and inquiries 
 Deviation acknowledgement, inquiries, recommendations 
 Exception acknowledgement, inquiries and approval/disapproval 
 Continuing review acknowledgement, inquiries 
 
The Medical Monitor will review and acknowledge the above, and make recommendations 
whether to continue with the study, amend the study, and/or stop/pause the study as needed.  

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8.6.1 Independent Data and Safety Monitoring Board 
An Independent Data and Safety Monitoring Board (DSMB) comprised of a minimum of four 
individuals including physicians with experience in oncology and/or gene transfer therapy and a 
statistician will be assembled, and will work under a charter specifically developed for safety 
oversight of this study.  The DSMB will provide guidance/advice to the Sponsor.  The DSMB 
will evaluate patient-subject safety as specified in the DSMB Charter.   
 
The DSMB will meet approximately every 4 months.  If necessary, additional meetings of the 
DSMB may be held if safety issues arise in between scheduled meetings. 
 
It is envisioned that the DSMB may make four types of recommendations, namely: 
• 
No safety or efficacy issues, ethical to continue the study as planned 
• 
Serious safety concerns precluding further study treatment, regardless of efficacy 
• 
Overwhelming evidence for futility, recommend stopping the study. 
• 
Recommendation to continue the study but proposing an amendment to the protocol (e.g., 
incorporate an additional safety assessments) 
 
If the study is recommended to continue by the DSMB, no details about the results of the current 
interim analysis will be revealed prior to the next scheduled analysis.  A Regulatory Sponsor 
representative will submit a DSMB outcome letter to the PI via email within 10 business days of 
receipt of the approved minutes, for submission to local regulatory review committees as 
required per institutional policy.  
 
9 DATA HANDLING AND RECORDKEEPING 
9.1 Confidentiality 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to the funding sponsor.  Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site.   
 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at 
the end of their scheduled study period. 

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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 
The study case report form (CRF) is the primary data collection instrument for the study. All 
data requested on the CRF must be recorded. All entries will be entered into an electronic 
data capture system (EDC). The Principal Investigator is responsible for assuring that the data 
entered into eCRF is complete, accurate, and that entry and updates are performed in a timely 
manner. 
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 Sponsor Data and Safety Monitoring Plan.  
 
Interim Monitoring Visits will be conducted during the course of the study. 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 subject 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. 
 
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 

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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.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
 
Please notify the Sponsor in real-time if an audit/inspection notification is received. 
 
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.   
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the IRB 
for the study.  The formal consent of a subject, using the IRB-approved consent form, must be 
obtained before that subject is submitted to any study procedure.  This consent form must be 
signed by the subject, and the investigator-designated research professional obtaining the 
consent.  
 
The protocol is listed under clinicaltrials.gov. 
 
12 STUDY FINANCES 
12.1 Funding Source 
This study will be funded by Novartis Pharmaceuticals. 

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12.2 Conflict of Interest 
 All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy 
on Conflicts of Interest Related to Research.  
12.3 Subject Stipends or Payments 
There is 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 FDA, or other 
government agencies as part of their duties to ensure that research subjects are protected. 
 
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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14 REFERENCES 
Reference List 
 
 
1.  Surveillance, Epidemiology, and End Results (SEER) Program of the NCI.  2006.  
Ref Type: Internet Communication 
 
2.  Gisselbrecht C, Mounier N. Novel Agents for Diffuse Large B-cell Lymphoma.  321. 
2011.  ASCO Education Book.  
Ref Type: Report 
 
3.  Lenz G, Wright GW, Emre NC, Kohlhammer H, Dave SS, Davis RE et al. Molecular 
subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc. Natl. 
Acad. Sci. U. S. A 2008; 105: 13520-13525. 
 
4.  Gisselbrecht C, Glass B, Mounier N, Singh GD, Linch DC, Trneny M et al. Salvage 
regimens with autologous transplantation for relapsed large B-cell lymphoma in the 
rituximab era. J. Clin. Oncol. 2010; 28: 4184-4190. 
 
5.  Cortelazzo S, Rambaldi A, Rossi A, Oldani E, Ghielmini M, Benedetti F et al. 
Intensification of salvage treatment with high-dose sequential chemotherapy improves 
the outcome of patients with refractory or relapsed aggressive non-Hodgkin's lymphoma. 
Br. J. Haematol. 2001; 114: 333-341. 
 
6.  Singer CR, Goldstone AH. Clinical studies of ABMT in non-Hodgkin's lymphoma. Clin. 
Haematol. 1986; 15: 105-150. 
 
7.  Marcus R, Hagenbeek A. The therapeutic use of rituximab in non-Hodgkin's lymphoma. 
Eur. J. Haematol. Suppl 2007: 5-14. 
 
8.  Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma 
incidence patterns by WHO subtype in the United States, 1992-2001. Blood 2006; 107: 
265-276. 
 
9.  . A clinical evaluation of the International Lymphoma Study Group classification of non-
Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 1997; 
89: 3909-3918. 
 10.  Hans CP, Weisenburger DD, Vose JM, Hock LM, Lynch JC, Aoun P et al. A significant 
diffuse component predicts for inferior survival in grade 3 follicular lymphoma, but 
cytologic subtypes do not predict survival. Blood 2003; 101: 2363-2367. 
 11.  Lymphoma Research Foundation. National comprehensive clinical network 
clinical practice guidelines in oncology (NCCN guidelines) Non-Hodgkin's 
Lymphoma.  2011.  
Ref Type: Online Source 

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§ The Investigator will review all pre- and post-infusion lab results to determine that it is appropriate to proceed with the infusion.  
Any abnormal Cr, Ca, K, Phos, uric acid, AND that is a change from the prior value should be reviewed by the PI prior to the 
infusion.  Any new lab abnormalities that are also a change from the prior value will be reviewed by investigators. Additional Blood 
Collection: In the event that something unexpected occurs, the research team may request an additional blood draw be performed to 
collect additional blood samples for research analysis. Samples will be delivered to TCSL. This is being done with the intention of 
evaluating the likely effects from the investigational products received. The total amount of extra blood that will be collected will be 
3 tablespoons of blood twice in one week. Additionally, if clinically indicated, CSF from lumbar punctures can be analyzed for 
CART-19. 
1. Chemotherapy appropriate for disease type. 
2. Pregnancy test-Females of child bearing potential only. Follicle stimulating hormone may be performed to confirm menopausal 
status. 
3. Autoimmune screen (ANA, ESR) 
4. Disease monitoring: Anatomic imaging (CT or MRI) for response assessment will be performed within 12 weeks of study entry and 
after the subjects’ last chemotherapy treatment; at month 3 (to assess the primary study endpoint); and at months 6, 9, 12, 18 and 
24 (to monitor disease).  Functional imaging (18FDG-PET/CT) may be used at the discretion of the treating physician if in the 
opinion of the treating investigator it is more clinically appropriate (for example- to assess certain extranodal sites like bone 
marrow or to confirm complete response). 
5. Bone marrow aspirate for tumor and T body PCR. Lymph node aspirate or biopsy to be performed if tumor accessible and clinically 
appropriate. 
6. The RCL DNA test performed at months 3 and 6 and annually.  If all RCL DNA tests during the first year (including the first 
annual visit) are negative, then samples for future annual tests may be archived. VSV-G or other suitable Q-PCR assay for RCL 
detection will be used. 
7.  Baseline imaging for tumor response assessments will be done within 12 weeks of study entry and after the subjects’ last 
chemotherapy. Imaging for tumor response assessments post-CART-19 infusion will be done every 3 months for first year and 
every 6 months for the second year after infusion.  Tumor response assessment criteria are described in Section 6.12. For subjects 
who achieve a CR or CRu, a confirmatory FDG-PET/CT scan will be performed within 4 weeks of the initial CT/MRI scan.  
8.  Subjects who complete follow-up as part of this study or discontinue participation early for any reason will be encouraged to enroll 
into a separate long-term follow-up protocol to further evaluate the safety of CART-19for up to 15 years post T cell infusion and to 
monitor for delayed adverse events associated with the lentiviral vector genetic modification. 
9.  Blood for CD3, CD4, CD8 Monocytes taken at months 3 and 6 only. 
10. Research blood (5 cc red top) taken prior to infusion and between 20-120 minutes post-infusion. 
11. 12-15 liter apheresis to go to CVPF, 1 x 109 cells to be delivered to TCSL  
12.  To be performed as clinically indicated at months 3, 6, 9, 12, 18, and 24. Lymph node aspirate or biopsy to be performed if tumor 
accessible and clinically appropriate. 

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13. 20mL green top to CVPF. This will be performed for the first 10 subjects.  
14. TCSL has requested labs be delivered to TCSL as soon as drawn. If required to keep research labs after hours, please keep red tops 
upright, lavender tubes should be room temperature on rotating platforms. In the event that something unexpected occurs, research 
sample collection may be done as necessary, not to exceed 3 tablespoons of blood twice in one week time window. This would be 
done at the PI’s discretion. 
15. Medical history, physical exam, and concomitant medications are to be collected prior to infusion on Day 0. Hematology and 
chemistry results are to be obtained prior to infusion on Day 0. Adverse events will be collected from the start of the CART19 
infusion.  
16. Chemistry – Glucose, BUN, Creatinine, Sodium, Potassium, Calcium, Total Protein, Albumin, Total Bilirubin, Alk Phos, AST, 
ALT, Mg, Phos, LDH, Uric Acid, Cl 
17. Should be performed within 8 weeks of infusion. 
19. CART-19 and B cells enumerated by flow cytometry using CD3+/CAR19+ and CD19+ expression respectively 
20. 25 cc lavender top collected prior to infusion and between 20-120 minutes post-infusion. 
21. As clinically appropriate 
22. Additional Blood Collection: In the event that something unexpected occurs, the research team may request an additional blood 
draw be performed to collect additional blood samples for research analysis. Samples will be delivered to TCSL. This is being 
done with the intention of evaluating the likely effects from the investigational products received. The total amount of extra blood 
that will be collected will be 3 tablespoons of blood twice in one week. 
23. To be performed within 42 days of CART-19 infusion.  
24. The intent of these windows is to ensure subjects are infused within 8 weeks of enrollment.  If the subject completes these visits 
within a shorter timeframe than 8 weeks, this will not be considered a protocol violation/deviation (e.g. for subjects with active 
disease, the shorter time frame is actually preferred). For subjects with a previous apheresis on another study, the enrollment 
window will not apply, but subjects must be officially enrolled in the study prior to the chemotherapy visit.  
25. If it has been greater than 42 days since the subjects’ previous radiologic disease assessment, a repeat CT/MRI of the 
chest/abdomen/pelvis is required prior to receiving cytoreductive chemotherapy.   If it has been less than 42 days since the 
subjects’ enrollment radiologic disease assessment, but the subject has received additional treatment during this time, a repeat 
CT/MRI of the chest/abdomen/pelvis is also required prior to receiving cytoreductive chemotherapy. 
26. All patients must undergo a Respiratory Virus Panel (RVP) to test for influenza within 10 days prior to the planned CART-19 
infusion.  The Respiratory Virus Panel includes: Influenza A, Influenza B, Respiratory Syncytial Virus A, Respiratory Syncytial 
Virus B, Parainfluenza Virus Type 1, Parainfluenza Virus Type 2, Parainfluenza Virus Type 3, Adenovirus.  If the patient is 
positive for influenza, oseltamivir phosphate (Tamiflu®) or equivalent should be administered per package insert. The patient must 
complete this course of treatment prior to receiving the CART-19 infusion. If the patient is positive for influenza and is also 
experiencing flu-like symptoms, all clinical symptoms must also be resolved prior to the CART-19 infusion.  If the patient is 
positive for another virus on the RVP, the CART-19 infusion will be delayed for at least 7 days to be sure clinical symptoms of a 
viral infection do not develop.  If clinical symptoms develop, the infusion will be delayed until resolution of these symptoms. 

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27. Subjects who complete or prematurely discontinue from the Primary Follow-up Phase, who do not enroll in a separate 15 year 
long-term follow-up protocol will continue to be followed in the Secondary Follow-up Phase of this study until the subject with-
draws consent, the subject enrolls in a long-term follow-up protocol, or the end of the study (Last Patient/Last Visit), whichever 
occurs first.   See Section 6.12 for complete details.