Phase 2 Study of CD19-directed Chimeric Antigen Receptor-modified T Cells (CART19) for Adult Patients With Minimal Residual Disease During Upfront Treatment for Acute Lymphoblastic Leukemia
Phase: PHASE2
Conditions: Leukemia, Acute Lymphoblastic
Sponsor: University of Pennsylvania



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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................. 5 
STUDY SUMMARY AND STUDY SCHEMA ..................................................................... 7 
 
INTRODUCTION ......................................................................................................... 9 
1.1. 
Background ........................................................................................................... 9 
1.2. 
Investigational Agent .......................................................................................... 10 
1.3. 
Preclinical Data ................................................................................................... 12 
1.4. 
Previous Clinical Data with CART-19 cells ....................................................... 12 
1.5. 
Dose Rationale and Risk/Benefits ...................................................................... 16 
1.5.1. Dose Rationale ........................................................................................ 16 
 
STUDY OBJECTIVES AND ENDPOINTS ............................................................. 20 
 
STUDY DESIGN ......................................................................................................... 22 
 
PATIENT SELECTION AND WITHDRAWAL ..................................................... 23 
4.1. 
Inclusion Criteria ................................................................................................ 23 
4.2. 
Exclusion Criteria ............................................................................................... 23 
4.3. 
Patient Recruitment and Screening ..................................................................... 24 
4.4. 
Early Withdrawal of Patients .............................................................................. 25 
4.4.1. When and How to Withdraw Patients ..................................................... 25 
 
STUDY DRUG ............................................................................................................. 26 
5.1. 
Description .......................................................................................................... 26 
5.2. 
Subject Eligibility to Receive CART19 Transduced Cells ................................. 26 
5.3. 
Treatment Regimen ............................................................................................. 27 
5.4. 
Preparation and Administration of Study Drug .................................................. 28 
5.5. 
CART19 Product Infusions................................................................................. 29 
5.6. 
Concomitant Therapy .......................................................................................... 29 
 
STUDY PROCEDURES ............................................................................................. 30 
6.1. 
Screening/Enrollment Assessments (~Week -12 to Week -4) ............................ 30 
6.2. 
Subject Enrollment.............................................................................................. 31 
6.3. 
Apheresis (~Week -4 to -3) ................................................................................. 31 
6.4. 
Assessment Types ............................................................................................... 32 
6.4.1. Demographics, Eligibility Verification, Medical History, Historical and 
Concomitant Medications ....................................................................... 32 
6.4.2. Physical Exam ......................................................................................... 32 
6.4.3. Vital Signs ............................................................................................... 32 
6.4.4. ECOG Performance status ...................................................................... 33 

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6.4.5. Cardiac Assessment: ECHO/MUGA ...................................................... 33 
6.4.6. Local Clinical Laboratory Evaluations ................................................... 33 
6.4.7. Hematology, Coagulation and T cell Subsets ......................................... 34 
6.4.8. Chemistry ................................................................................................ 34 
6.4.9. Viral Serology ......................................................................................... 35 
6.4.10. Serum Immunoglobulin Levels............................................................... 35 
6.4.11. Pregnancy Testing ................................................................................... 35 
6.4.12. Research Assessments to Assess Engraftment, Persistence and 
Bioactivity ............................................................................................... 35 
6.4.13. Cytogenetics/FISH .................................................................................. 36 
6.4.14. Cytoreductive chemotherapy .................................................................. 36 
6.4.15. CART19 Infusions .................................................................................. 37 
6.4.16. Day 28: Follow Up.................................................................................. 37 
6.4.17. Monthly Evaluations 2 to 6 Months Post Infusion .................................. 37 
6.4.18. Quarterly Evaluations for up to 1 Year Post Infusion ............................. 37 
6.4.19. Long-term Follow-up .............................................................................. 38 
6.5. 
Efficacy Assessments.......................................................................................... 38 
6.5.1. Physical Exam ......................................................................................... 39 
6.5.2. Bone Marrow Aspirate/Biopsy and Peripheral Blood ............................ 39 
6.5.3. Cerebrospinal Fluid (CSF) Assessment .................................................. 39 
6.5.4. Mediastinal Disease Assessment ............................................................ 39 
6.5.5. Minimal Residual Disease (MRD).......................................................... 40 
6.5.6. BCR-ABL: Ph+ ALL Patients ................................................................ 40 
6.5.7. Evaluation of Transfusion Dependency .................................................. 40 
6.6. 
ALL Response Criteria ....................................................................................... 40 
 
STATISTICAL PLAN ................................................................................................ 42 
7.1. 
Design Overview ................................................................................................ 42 
7.2. 
Sample Size Justification .................................................................................... 42 
7.3. 
Analysis Sets ....................................................................................................... 42 
7.4. 
Analysis of Primary Objective ............................................................................ 43 
7.5. 
Analysis of Secondary Objectives ...................................................................... 43 
7.6. 
Analysis of other secondary objectives............................................................... 45 
 
SAFETY AND ADVERSE EVENTS ......................................................................... 45 
8.1. 
Definitions........................................................................................................... 45 
8.2. 
Recording of Adverse Events ............................................................................. 47 

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8.3. 
Reporting of Serious Adverse Events ................................................................. 50 
8.4. 
Pregnancies ......................................................................................................... 53 
8.5. 
Toxicity Management, Stopping Rules and Study Termination ......................... 54 
8.6. 
Protocol Exceptions and Deviations ................................................................... 58 
8.7. 
Medical Monitoring ............................................................................................ 58 
8.8. 
Independent Data and Safety Monitoring Board ................................................ 59 
 
DATA HANDLING AND RECORDKEEPING ...................................................... 59 
9.1. 
Confidentiality .................................................................................................... 59 
9.2. 
Source Documents .............................................................................................. 59 
9.3. 
Case Report Forms .............................................................................................. 60 
9.4. 
Records Retention ............................................................................................... 60 
 
STUDY MONITORING, AUDITING, AND INSPECTING .................................. 60 
10.1. Study Monitoring Plan ........................................................................................ 60 
10.2. Auditing and Inspecting ...................................................................................... 61 
 
ETHICAL CONSIDERATIONS ............................................................................... 61 
 
STUDY FINANCES .................................................................................................... 61 
12.1. Funding Source ................................................................................................... 61 
12.2. Conflict of Interest .............................................................................................. 61 
12.3. Patient Stipends or Payments .............................................................................. 61 
12.4. Study Discontinuation ......................................................................................... 62 
 
PUBLICATION PLAN ............................................................................................... 62 
 
REFERENCES ............................................................................................................ 63 
Appendix 1:  VISIT EVALUATION SCHEDULE ............................................................ 70 
Appendix 2:  NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL 
CLASSIFICATION .................................................................................................... 77 
 

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LIST OF ABBREVIATIONS 
 
ACC 
Abramson Cancer Center 
ALL 
acute lymphoblastic leukemia 
APC 
antigen presenting cell 
aAPC 
artificial APC 
AE  
adverse event 
B-ALL 
B lineage acute leukemia 
B-cell ALL 
B cell acute lymphoblastic leukemia 
CAR 
chimeric antigen receptor 
CART19 cells 
CD19 redirected autologous T cells 
CHOP 
Children’s Hospital of Philadelphia  
CFR 
code of federal regulations 
CLL 
chronic lymphoblastic leukemia 
CMV 
Cytomegalovirus 
CNS 
central nervous system 
CR 
complete remission 
CRi 
complete remission with incomplete blood count recovery 
CRF 
case report form 
CRP 
C-reactive protein 
CRS 
cytokine release syndrome 
CSF 
cerebral spinal fluid 
CTCAE 
common toxicity criteria of adverse events 
CTRC 
clinical and translational research center 
CT scan 
computed tomography scan 
CTL 
cytotoxic T lymphocyte 
CVPF 
clinical cell and vaccine production facility 
CTL 
cytotoxic T lymphocyte 
CD137 
4-1BB costimulatory molecule 
DFS 
disease free survival 
DOR 
duration of response 
DSMB 
data safety and monitoring board 
DSMC 
data safety and monitoring committee 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
event free survival 
FAS  
full analysis set 
FDA 
food and drug administration 
FISH 
fluorescent in situ hybridization 

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GCP 
good clinical practices 
GMP 
good manufacturing practices 
HAMA 
human anti-murine antibody 
HSCT 
hematopoietic stem cell transplantation 
IBC 
Institutional Biosafety Committee 
IRB 
Institutional Review Board 
MAS 
macrophage activation syndrome 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging  
NCCN 
National Comprehensive Cancer Network 
ORR 
overall remission rate 
OS 
overall survival 
PFS 
Progression free survival 
PBMC 
peripheral blood mononuclear cells 
PDCS 
Product Development and Correlative Studies Laboratory 
PD 
progressive disease  
PK 
pharmacokinetics  
PR 
partial remission  
RAC 
NIH Office of Biotechnology Recombinant DNA Advisory Committee 
RCR/L 
replication competent lentivirus 
RFS 
relapse free survival 
SAE 
serious adverse event 
scFv 
single chain variable fragment 
SCT 
stem cell transplant 
TCR 
T cell receptor 
TCSL 
Translational and Correlative Studies Laboratory 
TLS 
tumor lysis syndrome 
TRM 
treatment related mortality 
UPenn 
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 
WBC 
white blood cell 
 
 
 

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STUDY SUMMARY AND STUDY SCHEMA 
Title 
Phase 2 Study of CD19-directed Chimeric Antigen Receptor-modified T cells 
(CART19) for Adult Patients with Minimal Residual Disease during upfront 
treatment for acute lymphoblastic leukemia (ALL) 
Short Title 
CD19 redirected autologous T cells for MRD positive patients during upfront 
treatment for ALL 
Protocol Numbers 
UPCC # 39416; IRB # 825668; 
 
Phase 
2  
Methodology 
This is a single center, single arm, open-label phase 2 study to determine the 
efficacy of autologous T cells expressing CD19 chimeric antigen receptors 
expressing tandem TCRζ and 4-1BB (TCRζ/4-1BB) co-stimulatory domains 
(referred to as “CART19” cells) in adults with minimal residual disease (MRD) 
during upfront treatment for  CD19+ acute lymphoblastic leukemia. 
Study Duration 
The duration of active protocol intervention is approximately 12-15 months from 
screening visit. The protocol will require approximately 12-18 months to 
complete enrollment. 
Study Center(s) 
Single-center 
Objectives 
Primary Objective: 
Describe the incidence of conversion of minimal residual disease (MRD) to 
<0.01% after CART19 therapy in patients with MRD+ ALL during upfront 
treatment  
 
Secondary Objectives: 
 
Evaluate best overall response rate 
 
Evaluate overall survival, duration of remission, relapse free survival, and 
event free survival 
 
Evaluate manufacturing feasibility of CART19 
 
Assess safety and tolerability of CART19 
 
Exploratory Objectives: 
 
Describe anti-tumor response to CART19 by deep sequencing 
 
Characterize the CART19 pharmacokinetic (PK) profile 
 
Evaluate bioactivity of CART19 cells 
Number of Patients 
24 evaluable subjects 
Diagnosis and Main 
Inclusion Criteria 
Adult patients with MRD+, CD19+ ALL during upfront treatment within 18 
months of initial diagnosis  

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Study Product, Dose, 
Route, Regimen 
CART19 cells transduced with a lentiviral vector to express anti-CD19 scFv 
TCRz:41BB administered by IV infusion.   
 
Subjects will receive 1-5 x 108 transduced CAR T cells as a split dose over three days 
as follows: 
 
Day 1, 10% fraction: 1-5x107 CART19 cells 
 
Day 2, 30% fraction: 3x107-1.5x108 CART19 cells 
 
Day 3, 60% fraction: 6x107-3x108 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.  
Statistical 
Methodology 
For the primary objective, the proportion of subjects that are MRD negative 
(MRD<0.01%) by 28 days along with 90% Clopper-Pearson confidence intervals 
will be estimated. With 24 patients, there will be at least 80% power to detect 
an ORR of 40% or greater against a null rate of 15% using a two-sided exact 
binomial test at 10% type I error. At least 8 out of 24 patients would need to 
achieve MRD— by day 28 (ORR=33%; exact 90% CI [17.8%, 52.1%]) to indicate 
meaningful efficacy of 15% or greater.  If the true MRD— rate were 84%, we have 
more than 80% power to reject a rate of 60% or smaller with 90% confidence. 
The confidence intervals below also provide the precision for 90% confidence 
intervals around adverse events. 
 
Adverse events will be collected and evaluated for all patients during the 
protocol specified AE reporting periods. AEs will be graded for severity using the 
National Cancer Institute (NCI) – Common Toxicity Criteria (v4.03). All adverse 
events will be described and exact 90% confidence intervals will be produced for 
adverse event rates, both overall and within major categories. Results will be 
tabulated and summarized.  
 
Descriptive statistics will be applied to determine the persistence, trafficking of 
CART-19cells, and the change of blast counts in blood and marrow. Data 
regarding the number of CART-19 cells in blood, marrow and the immune cell 
components in the marrow will be presented graphically to explore the pattern 
over time. We will compute 90% confidence intervals for proportions and means. 
 
For the secondary clinical objectives, overall complete response rate (ORR) by 
Day 28 will be computed and summarized by exact 90% confidence intervals. 
Distributions of overall, progression-free, and duration of response will be 
presented graphically using Kaplan-Meier curves. The six-month survival rates 
will be presented.   
 

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 INTRODUCTION 
1.1. Background 
B cell malignancies comprise a heterogeneous group of neoplasms including a vast majority of non-
Hodgkin's lymphomas, as well as acute lymphoblastic leukemias (ALL) and chronic lymphocytic leukemias 
(CLL). An estimated 87,000 new cases of leukemia and non-Hodgkin’s lymphomas are diagnosed in the US 
annually1, and most  of  these  are  of  B  cell  origin.  Current treatments for B cell malignancies include 
chemotherapy, radiation therapy, bone marrow transplantation, monoclonal antibodies and peripheral 
blood stem cell transplantation. Despite these treatment modalities, most patients will remain incurable. 
 
B cell lineage acute lymphoblastic leukemia (B-ALL) is responsive to chemotherapy, however the ability to 
uniformly eradicate the disease has not been achieved as about 65% of adults and 20% of children have 
disease recurrence2,3. The standard upfront treatment approach for patients with newly diagnosed B-ALL 
is 2-3 years of chemotherapy. Cycles are often described as Induction, Consolidation, Intensification then 
Maintenance and consist of multiple chemotherapy agents.  Minimal residual disease (MRD) as assessed 
by flow cytometry powerfully predicts outcome in both adults and children with ALL.  The presence and 
persistence of MRD during upfront treatment (from Induction through Maintenance) is the most 
important adverse prognostic factor for patients with B-ALL and identifies patients who have 
chemotherapy refractory disease4-6. The clinical significance and medical decision-making based upon 
MRD results is less well-established as it relates to surveillance and decisions related to proceeding with 
allogeneic stem cell transplantation, particularly in adults. The median time to overt morphologic relapse 
after testing MRD+ is 4-5 months7.  The only standard option for cure in this situation is allogeneic stem 
cell transplantation but outcome is suboptimal due to high risk of treatment related morbidity and 
mortality and risks of relapse. Clinical decision-making on the basis of MRD status is at the discretion of 
the investigator. Given the overall uncertainty and rapidly evolving evidence in the field, non-
chemotherapy based treatment options for patients with MRD+ disease is needed.  The benefit of this 
approach has been shown with the T cell engaging, bispecific single-chain (BiTE) antibody blinatumomab. 
In a Phase 2 study, 20 patients with MRD+ ALL during upfront treatment were given blinatumomab with 
60% relapse free survival at 33 months follow up 8.  
 
In most cancers, tumor-specific antigens for targeting are not well defined, but in B-cell neoplasms such 
as B-ALL, CD19 is an attractive target. CD19 is a 95kDa glycoprotein present on B cells from early 
development until differentiation into plasma cells9-11. 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 receptor10-12. Mice lacking CD19 have a decreased number of B cells in 
peripheral lymphoid tissues, a decreased B cell response to oral vaccines and mitogens, and decreased 
serum Ig levels11,13.  
 
CD19 is not present on most normal tissues, other than normal B cells, including pluripotent blood stem 
cells14, which makes CD19 a relatively safe target presenting a minimal risk of autoimmune disease or 
irreversible myelotoxicity. Anti-CD19 antibodies and scFvs either native or conjugated to radioisotopes or 
toxins are currently being developed and have demonstrated promise in both mouse models15-19 and 
human and non-human primates 17,20-29. Outcomes using anti-CD19 CAR T cells, including CTL019, for 
patients with relapsed or refractory ALL have been outstanding 30-32. The most significant treatment 
related adverse event with this line of therapy is cytokine release syndrome (CRS). It is known that a 
significant risk factor for severe CRS from anti-CD19 CAR T cells is baseline disease burden31,32. We 

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hypothesize that patients with MRD+ B-ALL treated on this study 
will therefore have minimal toxicity from CRS. 
 
Adoptive immunotherapy   
Adoptive transfer is a term coined by Medawar33 to study allograft 
rejection, and the term adoptive immunotherapy denotes the 
transfer of immunocompetent cells for the treatment of cancer or 
infectious disease34. Adoptive immunotherapy appears to be the 
most robust form of immunotherapy for treatment of established 
tumors35, as powerful effects have been noted in patients with 
metastatic melanoma after the adoptive transfer of tumor 
infiltrating lymphocytes  and  gene  modified  peripheral  blood  T  
cells36.  However, several problems remain to be solved before this 
therapy becomes routine37. 
 
Engineered T cells with redirected specificity: chimeric antigen 
receptors (CARs)  
As shown in Figure 1-1, the CAR approach uses genetically programmed, patient-derived lymphocytes 
transfected with chimeric receptor genes to combine the effector functions of T lymphocytes with the 
high specificity antibody recognition of predefined surface antigens in a non-MHC restricted manner38,39. 
In principle, universal targeting vectors can be constructed because the CAR’s scFv region binds to native 
cell surface epitopes and bypasses the need for specific antigen processing. The scFv region is engineered 
for tumor binding function and contains the VH and VL chains joined by a peptide linker of about 15 
residues in length40. First generation CARs contain a minimal T cell receptor (TCR) signaling domain 
consisting of TCRζ. Second generation CARs contain double costimulatory signaling domains such as CD28 
and TCRζ or 4-1BB and TCRζ. Third generation CARs contain triple costimulatory modules comprised of 
CD28, 4-1BB, and TCRζ. See reviews of CARs for details41-46.  
1.2. Investigational Agent 
The investigational agent in this protocol is CART19 cells, also referred to as CTL019.  CART19 is the most 
recent adaptation of adoptive cellular immunotherapy that uses the patient’s own peripheral blood T cells 
that have been genetically re-directed to kill CD19+ cells. As shown in Figure 1-1, the CAR approach uses 
genetically programmed, patient-derived lymphocytes transduced 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 manner38,39. 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 in42,45). 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 length40. 
First generation CARs contain a minimal TCR signaling domain consisting of TCRζ. Second generation CARs 
contain double stimulatory signaling domains either CD28 and TCRζ or 4-1BB and TCRζ. The 3rd generation 
CARs contains further advancements such as triple stimulatory modules comprised of CD28, 4-1BB, and 
TCRζ. See reviews of CARs for details43,44,47. 
 
 
Fig. 1-1.  CAR design. Bispecific T 
cells are created by the introduction of 
genes encoding CAR proteins that 
recognize target surface antigens in an 
MHC-independent fashion. 
 

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Autologous T cells will be engineered using a clinical-grade 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 series with the CD19 scFv, the transduced cells will express 
an intracellular tandem signaling domain comprised of 4-1BB and TCRζ signaling modules. The 
extracellular single chain antibody (scFv) with specificity for CD19 was previously reported23. The scFv is 
derived from a mouse monoclonal antibody using hybridoma cell line FMC63 described in Nicholson et 
al.23. The signaling domains are entirely of the native human sequences48,49. 
 
The CART19 cells will be manufactured in the Clinical Cell and Vaccine Production Facility (CVPF) at the 
 At the end of cell cultures, the cells are cryopreserved in infusible cryomedia 
for administration as split dose fractions. The split dose infusion will be administered as a 10%, 30% and 
60% fraction of 1-5 x 108 CART19 transduced cells. The target dose of CART19 cells is calculated based on 
the scFv percent transduction efficiency. The infusion bag(s) 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.  
 
Mechanism of action  
Redirected T cells have been shown in experimental models to bind to cells that express the target 
antigen. Over the past decade, CARs directed against a wide variety of tumor antigens have been 
developed45,50. There are several potential limitations to the CAR T cells: 1) the target antigen must be 
expressed on the cell surface; 2) large amounts of shed or soluble antigen may inhibit the CAR T cells; 3) 
the chimeric receptor may be immunogenic, resulting in the elimination of the redirected T cells by the 
host immune system. 
 
Absorption, distribution and metabolism  
Lymphocytes have complex trafficking and survival kinetics, and after adoptive transfer several fates 
have been demonstrated: 1) margination; 2) exit from the peripheral blood trafficking to lymphoid 
tissues; and 3) death by apoptosis. Following an intravenous dose, retrovirally modified and adoptively 
transferred T cells have been shown to persist in the circulation for at least 10 years in immunodeficient 
SCID patients due to the replicative competence of T cells51. Human CD8 CTLs have an elimination half-
life from the peripheral blood of about 8 days, and this increases to about 16 days when low doses of IL-
2 are given52. In patients with HIV infection, it was determined that the mean half-life of lentivirally 
modified CD4 T cells in the circulation of 5 patients following a single infusion was 23.5 (± 7.7) days in 
patients.  Adoptively  transferred  human  T  cells  have  been  shown  to  traffic  to  tumor  and secondary 
lymphoid tissues52-55. 
 
Drug interactions  
CART19 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 are 
expressed, or because of novel epitopes that are created at the fusion joint of human signaling domains 

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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 infection56; importantly, this immune mediated elimination was not accompanied by 
adverse effects and required 6 to 8 weeks to occur.  There has been one case of immune-based CART19 
rejection at the National Cancer Institute31. Other CART studies at UPENN using a CAR construct in which 
the scFv is of murine origin suggest that a humoral anti-mouse immune response develops following CART 
infusion which may contribute to the limited persistence of the CART cells.  
 
Rationale for lymphodepletion  
Adoptive immunotherapy strategies may be able to capitalize on homeostatic T cell proliferation57, 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 threshold58,59. 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-1560. This hypothesis has been tested clinically in patients with metastatic 
melanoma refractory of conventional treatments53. 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. Patients with myeloma, NHL, CLL and ALL have been treated with infusions of ex-
vivo co-stimulated and expanded autologous T cells after lymphodepleting chemotherapy, and observed 
improved engraftment 61-66. In this protocol, we will transfer CART19 cells into subjects that are given 
lymphodepleting chemotherapy.  This approach has been taken with previous recipients of CART19 cells 
(Section 1.4).  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 
Extensive literature supports the use of engineered T cells for tumor immunotherapy in rodent tumor 
models45,67-70. Others have used electroporation or retroviral vectors to create CART19 T cells, and have 
shown in vivo safety and efficacy of adoptively transferred T cells in immunodeficient mouse models27,28,71-
73.  The incorporation of signaling modules such as CD28 and 4-1BB in 2nd generation CARs increases 
potency of the engineered T cells in pre-clinical studies48,74-79. The pre-clinical data supporting CART19 has 
been published80-82.  
1.4. Previous Clinical Data with CART-19 cells 
 
 
 
 
  
 
 
 
 
 

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 for 
children. ≤ 10cc/kg of total volume 
Dose 1 (10%), Dose 2 (30%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 

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Historical Clinical Data with CART19 
CART19 appears to have greater success than previous CAR constructs, since in vivo these cells proliferate 
more, persist longer, and retain effector functions, therefore amplifying and sustaining effective anti-
tumor responses. Please see recent reviews of CAR T cell trials44,46,83-90. 
 
UPCC04409 was the first-in-human adult CLL and ALL clinical protocol where 1.5x107-5x108 CART19 cells 
are infused in a split dosing regimen (10%, 30% and 60%) on Day 0, 1 and 2. Only one patient 04409-03 
received the optional Day 11 dose (1.5x107-5x108 CART19). Response rate in the ALL cohort was 80% (5/6). 
The main toxicity that was observed was CRS, but was managed clinically in all cases. Results from five of 
the six subjects have been published 32. Based on encouraging response rates and manageable toxicity 
profile, a phase 2 study in ALL, UPCC21413, was opened. The dosing regimen in UPCC21413 has been 
adjusted (as described in Section 1.5.1) to maximize safety after five patient deaths early in the study and 
improve efficacy
   
 
CART19 has also been used in other disease indications at UPenn and CHOP, including CLL 63 66, non-
hodgkin’s lymphoma, multiple myeloma 89 and pediatric ALL 32 91. CART19 is well tolerated in these disease 
indications, with the main toxicity being clinically manageable CRS. In the setting of pediatric ALL, a very 
high response rate of 92% (55/60) has been observed. In addition, the first pediatric patient treated, 
CHP959-100, remains in complete remission as of her 48 month follow-up visit.   
 
CRS has been the most significant SAE seen in adult and pediatric patients treated with CART19.  CRS is 
described in detail below (section 1.5.2) but typically begins within 2 weeks of 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 manifest by evidence of hemolysis, cytopenias, 
elevated ferritin, altered mental status, and other complications. 
 
Teachey and colleagues (2016) reported that, while there have been three cases of refractory CRS which 
resulted in death in the adult ALL population at the University of Pennsylvania, nine out of 12 CRS cases 
observed in this population were severe but reversible.  It is hypothesized that CRS severity may be related 
to tumor burden, so that patients with high tumor burden may develop more severe CRS compared to 
patients with low tumor burden. In ALL patients, high grade CRS is mechanistically linked to the antitumor 
effect of CART19 in patients with high baseline tumor burden92. However, additional patient and CART19-
related factors may also contribute to such an anti-tumor effect. 
 
CRS/MAS was initially managed in one patient with corticosteroids.  Since then, as more data have become 
available, a CRS management algorithm has been developed and is described in detail in Section 8.5.2 and 
outlined in Figure 8-1. Briefly, CRS is managed with supportive care and with anti-cytokine therapy, when 
appropriate.  Specifically, tocilizumab is an anti-IL6 receptor antibody that has been 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. Systemic 
immunosuppression with corticosteroids following CART19 infusion is avoided and corticosteroids are 
given only under life threatening situations due to their known lympholytic effects. 

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1.5. Dose Rationale and Risk/Benefits 
1.5.1. Dose Rationale 
Based on the clinical experience with adult ALL patients treated with CART19 as part of the UPenn protocol 
UPCC21413 and UPCC04409, subjects will receive 1-5x108 CART19 cells as a 10%, 30% and 60% fraction 
administered over 3 days.  
 
The first 6 ALL patients treated on UPCC21413, received a dose of 1-5 x 108 CART19 cells administered as a 
single infusion. Based on three patient deaths at this dose level, the dose was reduced to 1-5 x 107 CART19 
cells administered as a single infusion. This change was implemented in response to three patient deaths 
that were possibly related, in part, to refractory cytokine release syndrome, an expected toxicity of CART19. 
At this reduced, single CART19 dose, an additional two deaths occurred. As a measure to enhance subject 
safety, the CART19 dose schedule was changed from a single infusion back to the well-tolerated split dose 
administration (10% on Day 1, 30% on Day 2 and 60% on Day 3) used in the first CART19 adult ALL study, 
UPCC04409. Three adult subjects were then treated on with 1-5 x 107 CART19 cells as a split dose.  Two of 
the three subjects developed and recovered from CRS after treatment with anti-cytokine therapy, 
demonstrating safety of the split dose approach. However, efficacy was diminished compared to the 
original split dose of 1-5x108 CART19 cells seen for the adult ALL subjects on UPCC04409; only one of the 
two evaluable subjects had a response (CR).  Therefore, the dose was increased back to the well-tolerated 
split dose administration of 1-5x108 CART19 cells that had a 100% Day 28 CR rate on the original CART19 
adult ALL study, UPCC04409. As of December 2015, six subjects have been treated with 1-5 x 108 CART19 
cells as fractionated doses, which has been well tolerated and has resulted in CR at Day 28 in four of the six 
subjects.  
 
Additionally, the spilt dose administration schedule has been well tolerated in multiple adult patients with 
CLL (UPCC04409, UPCC03712 and UPCC18415) as well as pediatric ALL subjects (CHP959).  
Clinical responses at doses ranging from 1.4x107 to 1.1x109 CART-19 cells have been observed and CRS 
events have been clinically manageable under the split dosing strategy. Unlike standard drugs that are 
metabolized, CART cells are able to proliferate extensively in the patients. Thus, the administered dose may 
underestimate the CART19 T cells in vivo following engraftment and expansion and will vary from patient 
to patient.  
1.5.2. Risks/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 in treating nearly 200 adults and children with CART19 cells in our clinical trials as of December 
2015. In this case, corticosteroids and chemotherapy would be given to eradicate the CART19 cells; this 
has worked in previous cases93.  
 
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 engraftment93. This 

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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. 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-modified cells 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 and/or survival. 
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 
centers43, and in the 21 HIV patients treated with lentiviral modified T cells treated at Penn94 or any of the 
nearly 200 patients treated to date on CTL019/CART19.   
 
Risk of tumor lysis syndrome 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 have developed delayed TLS presumably due to T cell proliferation and 
tumor cell killing at that time. Therefore, all patients will be closely monitored both before and after 
chemotherapy and CART19 infusions including blood tests for potassium and uric acid.  All patients will 
receive allopurinol prophylactically for 30 days after infusion and appropriate clinical therapy will be 
administered should any significant tumor lysis occur. 
 
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 an 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.95 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 CART-19 infusion.  
 
Intracranial Hemorrhage  
As of February 2017, there have been three events of intracranial hemorrhage on CART19 trials under 
.  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 CART-19 T-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. 
 

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Cytokine Release Syndrome (CRS) / Macrophage Activation Syndrome (MAS):   
 
Overview and Clinical Manifestations  
Patients treated with CART19 may experience a cytokine release syndrome (CRS), which has correlated 
with disease response.  Clinical manifestations have included high fevers, fatigue, anorexia, nausea, 
vomiting, diarrhea, myalgias, arthralgias, 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 cytokine-directed therapy, typically tocilizumab, in most patients requiring 
therapy. As of December 2015, five adult ALL patients treated with CART19 have died of complications 
related to refractory CRS and intercurrent infections.  In addition, it is unclear if treating the CRS with 
cytokine-directed therapy adversely impacts the anti-tumor response. 
 
Features consistent with MAS or HLH have been observed in patients treated with CART19, coincident with 
clinical manifestations of the CRS.  MAS appears to be a reaction to immune activation that occurs from 
the CRS. Macrophage activation syndrome can also be referred to as 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. 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 (prominent feature of CART19-associated 
MAS), 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. 
D-dimer is nearly universally elevated in CART19 patients, with no evidence of bleeding, but very low 
fibrinogen has been associated with bleeding. 
 
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).  
 
At this time it is still unknown whether CRS/MAS are required for the anti-tumor response.  Research 
monitoring data showed that IL6 levels were extraordinarily high during the CRS, prompting the use of 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 within 48 hours. 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 CART19 on CHP959 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 tocilizumab, as described in Grupp et al., NEJM, 201391, 
and all associated adverse events resolved.  
 

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Replication-competent lentivirus   
Replication-competent lentivirus (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 clinic96-99. The T cell leukemias were attributable to clonal expansion 
conferred by gammaretroviral vector integration sites in the CD34+ bone marrow stem cell modification97. 
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 
malignancy100. 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 vectors101. 
 
Uncontrolled T cell proliferation  
CART19 cells could proliferate without control of normal homeostatic mechanisms. In pre-clinical studies, 
CART19 cells have only proliferated in response to physiologic signals or upon exposure to CD19. In the 
context of this protocol it is possible that the T cells will proliferate in response to signals from the 
malignant tumor or normal B cells. This could be beneficial or harmful depending on the extent of 
proliferation. Clonal dominance of adoptively transferred T cells has been associated with tumor 
reduction in adoptive transfer trials53,102.  
 
B cell aplasia  
Transient or permanent host B cell depletion is also a potential risk with CART19 cells, since B cells express 
CD19. This is expected to resolve when the CART19 cells are cleared. B cell aplasia has been seen in 
CART19-treated subjects as well as B cell recovery in some subjects who had lost CART19 32. Persistent B 
cell aplasia leads to hypogammaglobulinemia and may increase the risk of infection. This is common with 
anti-CD20 directed therapies104. 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 
There have been instances of fatal SAEs following CD19-directed CAR T cell infusion in patients with B cell 
malignancies. In one study, Brentjens et al utilized a second generation, retrovirally transduced anti-CD19 
CAR, containing CD28 and CD3ζ, in patients with CLL. Of the 7 subjects treated on this protocol at the time 
of the study report, 6 infusions proceeded without SAE while one subject experienced complications 
leading to death approximately four days after anti-CD19 CAR infusion. This subject received 
lymphodepleting chemotherapy with 1.5g/m2 of cyclophosphamide two days prior to infusion with 
genetically modified anti-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 

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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 all other manufacturing 
release criteria are met, however these subjects will be considered non-evaluable for the primary endpoint.  
 
All patients will have blood tests to assess CART19 safety, engraftment and persistence at regular intervals 
throughout the study (Visit Evaluation Schedule in Appendix 1).  Circulating CART19 T cells subsets will be 
assessed at various times after infusion. CART19 trafficking will be assessed in bone marrow aspirates, 
and other tissues, if available. Follow up is planned at a minimum of weekly for 4 weeks, monthly for 6 
months, then quarterly for the remainder of the year to obtain a medical history, undergo a physical 
examination, and blood tests. Additional sample collections and assessments between schedule visits 
after CART19 cell infusion will be performed as clinically indicated.  
 
Following these evaluations, patients will enter a long-term follow-up study for long term follow-up for 
up to an additional fourteen years to assess for safety assessments per the FDA guidelines. 
 
 PATIENT SELECTION AND WITHDRAWAL 
Exceptions to eligibility will not be granted for this study. 
4.1. Inclusion Criteria 
1. Patients with CD19+, B cell Acute Lymphoblastic Leukemia (B-ALL) who have 
0.01%≤MRD<10% during upfront treatment 
2. Patients must be within 18 months of initial ALL diagnosis 
3. Age ≥18 years 
4. Adequate organ function defined as: 
a. Creatinine ≤ grade 2  
b. ALT/AST ≤3x upper limit of normal range for age 
c. Direct bilirubin ≤2.0 mg/dl  
d. Adequate pulmonary function defined as ≤ grade 2 dyspnea and ≤ grade 2 hypoxia  
e. Cardiac Left Ventricle Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO/MUGA 
5. Patients with CNS3 disease will be eligible if CNS disease is responsive to therapy. [At infusion- 
must meet criteria in Section 5.2]. 
6. Expression 
of 
CD19 
on 
leukemic 
blasts 
demonstrated 
by 
flow 
cytometry 
or 
immunohistochemistry of bone marrow or peripheral blood 
7. Adequate performance status defined as ECOG Performance Status 0 or 1 
8. Provides written informed consent 
9. Subjects of reproductive potential must agree to use acceptable birth control methods, as 
described in protocol Section 4.3. 
4.2. Exclusion Criteria 
1. Active, uncontrolled infection  
2. Active hepatitis B or hepatitis C  
3. HIV Infection 

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4. Class III/IV cardiovascular disability according to the New York Heart Association Classification 
(see Appendix 2) 
5. Subjects with clinically apparent arrhythmia or arrhythmias who are not stable on medical 
management within two weeks of enrollment. 
6. Pregnant or nursing (lactating) women 
7. Patients with a known history or prior diagnosis of optic neuritis or other immunologic or 
inflammatory disease affecting the central nervous system, and unrelated to leukemia or 
previous leukemia treatment. 
 
Note: For the purposes of this study, enrollment is defined as the date the Investigator confirms subject 
eligibility. 
 
Please refer to the Concomitant Therapy Section 5.6 for windows for related to apheresis and CART19 
infusion. 
4.3. Patient Recruitment and Screening 
Patients will be identified through the clinical practices of the investigator or sub-investigators and 
through referrals from outside hospitals and physicians.  The study will be posted on clinicaltrials.gov, 
and publicized via University of Pennsylvania or Abramson Cancer Center press releases. No direct-to-
patient advertising will be performed. 
 
Female patients 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 negative serum pregnancy test performed at the time of enrollment and 
a negative urine pregnancy test within 72 hours of T cell infusion. 
 
Patients 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 patient must agree to use at least one reliable method of 
contraception during their participation in the study. 
 
Acceptable birth control includes one of the following methods: 
 
Total abstinence (no sexual relations) 
 
Female sterilization- surgical removal of both ovaries (woman's reproductive system that stores 
and releases eggs for fertilization and produces female sex hormones), or tubal ligation (having 
your “tubes tied”) at least six weeks prior to signing this consent.  
 
Male sterilization (i.e. vasectomy) 
 
Condoms (male or female) with or without a spermicidal agent 
 
Diaphragm or cervical cap with spermicide 
 
Intrauterine device (IUD) 
 
Hormonal-based contraception 
 
Patients who are not of reproductive potential (women who have been post-menopausal for at least 24 
consecutive months or have undergone hysterectomy, salpingectomy, and/or bilateral oophorectomy 
or men who have documented azoospermia) do not require the use of contraception.  Acceptable 

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documentation of sterilization, azoospermia, and menopause is specified below: 
 
Written documentation by clinician or clinician’s staff through one of the following: 
1. Physician report/letter 
2. Operative report or other source documentation in the patient record (a laboratory report of 
azoospermia is required to document successful vasectomy) 
3. Discharge summary of sterilization procedure or hysterectomy, and/or salpingectomy, 
oophorectomy 
4. Laboratory report of azoospermia 
5. Follicle stimulating hormone measurement elevated into the menopausal range 
4.4. Early Withdrawal of Patients 
4.4.1. When and How to Withdraw Patients 
Subjects who enroll but do not receive CART19 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 CART19 cells include, but are not limited to, the following: 
 
1. The subject is lost to follow-up. 
2. The principal investigator judges that the subject, prior to CART19 infusion, is too ill to continue. 
3. Pregnancy is documented prior to CART19 infusion.  If pregnancy occurs after the subject has 
received CART19 cells, she will be kept active in the study for safety follow-up and pregnancy 
outcome.  
4. Voluntary withdrawal: a subject may remove himself/herself from the study at any time 
without prejudice. A subject 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 prior to CART19 infusion. 
6. A serious adverse event that requires the subject withdrawn from the trial prior to the CART19 
T cell infusion. 
7. Technical difficulties are encountered in the T cell genetic modification and expansion procedure 
that precludes the generation of clinical cells doses that meet all Quality Control release criteria 
as specified by FDA. 
8. 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. 
 
Reasons for discontinuation of subjects after receipt of CART19 cells include, but are not limited 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. 
 

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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 
Follow-up data collection after gene modified cell therapy clinical trials is specified by FDA.  As long as 
subjects 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) Disease Free Survival (DFS) until there is disease progression, 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 follow-up as 
part of this protocol or discontinue participation early for any reason, will be encouraged to enroll in 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. 
 
Every effort will be made to contact patients who appear to be lost to follow-up in order to at least obtain 
survival data. In the event a patient fails to complete the follow-up requirements, documentation of all 
attempts to contact the patient includes at least 3 telephone contacts - on different days and at different 
times of the day - and a certified letter.  
 
 STUDY DRUG 
5.1. Description 
CART19 cells are autologous T cells that have been engineered to express an extracellular single 
chain antibody (scFv) with specificity for CD19 linked to an intracellular signaling molecule consisting of 
a tandem signaling domains comprised of the TCRζ signaling module linked to the 4-1BB costimulatory 
domain. The CART19 cells are cryopreserved in infusible cryomedia (volume dependent upon dose). 
5.2. Subject Eligibility to Receive CART19 Transduced Cells 
For Day 1 infusion:  
1. All subjects must undergo a Respiratory Virus Panel (RVP) within 10 days prior to the first planned 
CART19 infusion. If the subject is positive for influenza, Tamiflu® or equivalent, should 
administered per package insert.  The subject must complete treatment prior to receiving 
CART19.  The test does not need to be repeated prior to the first CART19 infusion, however if 
influenza sign and symptoms are present, the CART19 infusions should be delayed until the 
subject is asymptomatic.  If the subject is positive for another virus on the RVP, the CART19 

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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. Subject 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, increase the risk of 
experimental cell infusion. 
3. Subjects should not be experiencing signs/symptoms of an active infection.  
4. Subject 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 CART19 T 
cells, may have their infusion delayed until both the treating investigator and PI determine it is 
clinically appropriate to proceed with the CART19 infusion.  
5. Subjects experiencing toxicities from their preceding cytoreductive chemotherapy can have their 
infusion schedule delayed until these toxicities have resolved. Note: If subjects’ CART19 infusion 
is delayed > 4 weeks from cytoreductive chemotherapy, the cytoreductive chemotherapy should 
be repeated. The specific toxicities warranting delay of T cell infusions include: 
a. Pulmonary: Requirement for supplemental oxygen to keep saturation greater than 92% 
or presence of radiographic abnormalities on chest x-ray that are progressive 
b. Cardiac: New cardiac arrhythmia not controlled with medical management 
c. Hypotension requiring pressor support 
d. Active Infection(s) as evidenced by positive blood cultures for bacteria or fungus within 
48 hours of CART19 cell infusion 
6. For subjects with CNS3 disease, it must be > 8 weeks from radiation therapy (if used) and stable 
or improving CNS disease by the following criteria as applicable: 
a. If CNS3 by spinal fluid involvement, CSF WBC count stable or decreasing and <100 by 
lumbar puncture within 72 hours of infusion 
b. If CNS3 by MRI findings, improvement in MRI findings within 2 weeks of infusion  
c. If CNS3 by cranial nerve findings, stable or improving cranial nerve exam 
7. Subjects must not have received any investigational therapy within 4 weeks of CART19 cell 
infusion.  Please refer to Section 5.6 for other concomitant therapy washout requirements.  
 
For Subsequent CART19 infusions: 
1. Subject should not experience a significant change in performance or clinical status compared to 
their previous study visit that would, in the opinion of the treating physician, increase the risk of 
experimental cell infusion. 
2. Subjects should not be experiencing signs/symptoms of an active infection.  
3. Subject experiencing new laboratory abnormalities that, in the opinion of the treating 
investigator or PI, may impact subject safety or the subjects’ ability to receive CART19 cells, may 
have their infusion delayed until both the treating investigator and PI determine it is clinically 
appropriate to proceed with the CART19 infusion.  
5.3. Treatment Regimen 
The infusion will be scheduled to occur approximately 1 to 4 days following lymphodepleting chemotherapy 
but may be delayed as outlined above (Section 5.2). CART19 cells will be given on Days 1, 2 and 3.  
 
Subjects will receive 1 to 5 x 108 transduced CAR T cells as a split dose over three days as follows: 
 
Day 1, 10% fraction: 1-5x107 CART19cells 
 
Day 2, 30% fraction: 3x107-1.5x108 CART19 cells 

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 
Day 3, 60% fraction: 6x107-3x108 CART19 cells 
 
Note: Doses less than the goal range will be released and infused if all release criteria are met.  
5.4. Preparation and Administration of Study Drug 
Cell manufacturing is performed at the University of Pennsylvania Clinical Cell and Vaccine Production 
Facility (CVPF). The CART19 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. The CART19 dose is formulated according to transduced cell dose 
(flow cytometry testing) in cryobags.  
  
The total cell number and volume depends on the transduction efficiency. Each bag will contain an aliquot 
of cryomedia (volume dependent upon dose). 
 
Package and Labeling 
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 cells will be transported to the subject’s bedside on the day of infusion. The cells will be thawed by 
trained personnel using a water bath maintained between 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 CART19 cell product appears to have a damaged or leaking bag, or otherwise 
appears to be compromised, it should not be infused, and should be returned to the CVPF. 
 
Premedication 
Side effects following T cell infusions include transient fever, chills, and/or nausea. It is recommended 
that the patient be pre-medicated with 650mg acetaminophen and an antihistamine prior to each 
CART19 cell infusion. These medications may be repeated every six hours as needed. A course of non-
steroidal anti-inflammatory medication may be prescribed if the patient continues to have fever not 
relieved by acetaminophen. Patients should not receive systemic corticosteroids such as hydrocortisone, 
prednisone, prednisolone (Solu-Medrol) or dexamethasone (Decadron) at any time, except in the case of 
a life-threatening emergency, since this may have an adverse effect on CART19 cell expansion and 
function.   
 
Neutropenic subjects will be administered preventive antibiotics treatment starting on the day of infusion. 
Broad-spectrum antibiotics will be administered orally until recovery of neutrophil counts, or until judged 
by the investigator to no longer be at increased risk of infection. 
 
Return or Destruction of Study Drug 
CART19 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. 

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There is an ongoing reconciliation of drug shipped, drug consumed, and drug remaining performed by the 
CVPF. Final disposition of the investigational product will also be documented in the site Investigational 
Product Accountability logs appropriately. 
5.5. CART19 Product Infusions 
CART19 will be administered via i.v. infusion at the 
 by a licensed 
Registered Nurse. The investigational CART cell products should be infused into the subject immediately 
after they are thawed. There should be no frozen clumps left in the bag prior to infusion. The CART19 cells 
will be infused into an intravenous catheter, either through a peripheral vein (preferred) or central vein.  A 
macrodrip intravenous tubing will be used to infuse the CART cells by gravity (i.e., no infusion pump).  The 
macrodrip intravenous tubing will be connected to a “Y” adapter with one end of the adapter spiked to the 
CART cell product bag(s) and the other to a normal saline solution bag. A leukoreduction filter must not 
be used for the infusion of the CART cell product. The duration of the infusion will be based on the total 
volume to be infused (on the order of 1-10 minutes). 
 
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-CART19 
infusion, vital signs will continued to be monitored at a minimum of every hour or as clinically indicated 
until stable. If the infusion is administered in the outpatient setting, the subject will be discharged after the 
physician managing their care on the day of each infusion has determined that they are in satisfactory 
condition. 
 
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 
CART19 T cell product is suspected, the product can be retested for sterility using archived samples that 
are stored in the CVPF.  Consideration of a CRS should be given. 
 
Additional Safety Procedures Prior to Administration 
The on-site pharmacy must confirm that a dose of tocilizumab is on site prior to infusion and available for 
administration in order to manage suspected toxicities. 
 
Emergency medical equipment (i.e., emergency trolley) must be available during the infusion in case the 
patient has an allergic response, or severe hypotensive crisis, or any other reaction to the infusion. 
5.6. Concomitant Therapy 
All prescription and nonprescription medication, vitamins, herbal and nutritional supplements, taken by 
the patient during the 30 days prior to screening will be recorded. At every visit following the CART19 
infusions and until the patient has completed or has been discontinued from participation in the study, 
concomitant medications will be recorded in the medical record and on the appropriate CRF. Any 
additions, deletions, or changes of these medications will be documented. The following guidelines must 
be adhered to during the study: 

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 
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 on 
CRS symptoms are unknown and can be used at the physician’s discretion. 
 
Chemotherapy, including corticosteroids and tyrosine kinase inhibitors, or immunosuppressive 
medications should NOT be used within one week prior to the apheresis procedure. 
 
Steroids or other immunosuppressant drugs should NOT be used within 24 hours prior to (refer 
to Section 5.4) or following CART19 infusion unless under life threatening circumstances or at 
the physicians’ discretion for CRS management. 
 
Recent or current use of inhaled steroids or physiologic replacement with hydrocortisone is 
allowed. Therapeutic doses of steroids must be stopped >48 hours prior to CART19 infusion. 
However, the following physiological replacement doses of steroids are allowed: 6-12 
mg/m2/day hydrocortisone or equivalent 
 
Patients with severe signs and symptoms attributable to cytokine release syndrome (i.e. CRS) 
should be managed with administration of tocilizumab or other anti-cytokine directed therapies 
(Refer to Section 8.5.2 for administration details). 
 
Neutropenic subjects will be administered broad-spectrum antibiotics on the day of infusion. 
 
 STUDY PROCEDURES 
Overview 
The schedule of evaluations and study procedures are described in Visit Evaluation Schedule located in 
Appendix 1. Also, refer to Sections 6.1 to 6.13 for further details of the schedule of each assessment, 
analysis and processing/handling of samples.  
6.1. Screening/Enrollment Assessments (~Week -12 to Week -4) 
Informed consent must be obtained before the patient can undergo any research related procedures.  
Screening/enrollment assessments are described in this section and in the Visit Evaluation Schedule 
(Appendix 1).  For the purposes of this study, enrollment is defined as the date the Investigator confirms 
subject eligibility. 
 
Verification of inclusion and exclusion criteria 
 
Demography including date of birth, sex, race, and ethnicity  
 
Documentation of medical history including prior and current medical conditions, and child 
bearing status  
 
Documentation of historical and concomitant medications and significant non-drug therapies 
 
Review of prior antineoplastic medications 
 
Physical exam and measurement of vital signs (height, weight, BSA, blood pressure, body 
temperature, heart rate and oxygen saturation via pulse oximetry) 
 
ECOG performance status 
 
ECHO/MUGA-performed within 12 weeks of enrollment and after last treatment with 
induction chemotherapy (excluding maintenance chemotherapy)  
 
Electrocardiogram (EKG) 
 
Complete blood count and differential, comprehensive metabolic panel, and coagulation 
panel.  See Table 6-2 for complete details.  
 
Viral serologies - including HIV, Hepatitis B surface antigen (HBsAg), Hepatitis B surface 
antibody, Hepatitis B core antibody, and Hepatitis C Antibody.  If the HCV antibody is positive, 
a screening HCV RNA by any RT-PCR or bDNA assay must be performed. Eligibility will be 

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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 enrollment is provided. 
 
Serum pregnancy test for females of child bearing potential 
 
Serum immunoglobulin levels 
 
Bone marrow aspirate for disease and MRD assessment as described in Appendix 1 within 4 
weeks of enrollment  
 
Chest X-ray for mediastinal disease assessment- performed only if clinically indicated.  
 
CNS evaluation- If CNS symptoms are present at Screening/Enrollment then a lumbar puncture 
and brain imaging by MRI/CT will be performed to assess CNS leukemic involvement. 
 
In the event that the time between the screening visit and the infusion of CART19 T cells exceeds the 12 
week Screening/Enrollment Window the following will be repeated: Physical Examination, Performance 
Status Assessment, Complete Blood Count with differential and Platelet Count, Chemistry Panel, 
Pregnancy test, and HIV and Hepatitis B/C tests.  An ECHO/MUGA scan must be performed within 6 
months prior to the CART19 infusion. 
6.2. Subject Enrollment  
At the time a subject consents to participate in this study, a Consent Notification Form should be 
completed.  When eligibility of the subject is confirmed by a Study Investigator, and follow-up on this trial 
commences, an Enrollment Notification should be completed.  Both completed forms should be emailed 
in real-time to:  
 
Protocol Monitor and Sponsor Project Manager 
 
 
 
Once subject eligibility has been confirmed by an investigator, the subject may undergo the apheresis 
procedure and CART19 manufacturing may commence.  
 
Each Subject is identified in the study by a Subject Number that is assigned when the subject is first 
consented and is retained as the primary identifier for the subject throughout his/her entire participation 
in the trial. The Subject Number consists of the Protocol Number with a sequential subject number 
suffixed to it, so that each subject is numbered uniquely across the entire database.  Once assigned, the 
Subject Number must not be reused for any other subject and the Subject Number for that individual must 
not be changed, even if the subject is re-screened. If the subject fails screening for any reason, the reason 
will be entered into the End of Study eCRF. 
6.3. Apheresis (~Week -4 to -3)  
After the patient has been enrolled, patients will be scheduled for apheresis (leukapheresed) to obtain a 
target of 5x109 PBMCs for CART19 manufacturing.  Apheresis can occur any time after the subject is 
enrolled and up to 3 weeks prior to CART19 infusion.  Baseline blood leukocytes for FDA look-back 
requirements and for research are also obtained and cryopreserved (1 x 108 cells from apheresis to TCSL 
and 1-2 x 109 to PDL, if available after cells required for manufacturing are obtained). Apheresis should be 
scheduled prior to any planned chemotherapy administration. The cell product is expected to be released 
approximately 3-4 weeks after manufacturing has commenced.  
 

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Historical Apheresis Sample 
Cryopreserved historical apheresis products collected from the patient prior to study entry are usable for 
CART19 manufacturing if collected at an appropriately certified apheresis center and the product meets 
adequate mononuclear cell yields. 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.  
 
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/l for acceptance to begin processing for clinical manufacturing to 
achieve the target dose. 
6.4. Assessment Types 
6.4.1. Demographics, Eligibility Verification, Medical History, Historical and 
Concomitant Medications 
Patient demographics will be recorded on the demography source documents. The Investigator or 
designated staff will review inclusion/exclusion criteria to verify eligibility. A detailed medical history will 
be taken and recorded on the medical history CRF as well as current and prior (within 30 days of pre-entry) 
concomitant medications. 
6.4.2. Physical Exam 
A complete physical examination will be performed by the investigator according to Appendix 1.  Physical 
examination will also be used to assess evidence of disease in the liver, spleen, and lymph node, skin, gum 
infiltration, and testicular involvement in males.  
 
Significant findings that are present prior to the administration of the investigational product must be 
recorded as part of the subjects’ medical history. All findings made after the start of investigational 
product which meet the definition of an Adverse Event must be recorded and reported appropriately. 
Please see Section 8 for additional details.  
6.4.3. Vital Signs 
Blood pressure, body temperature, oxygen saturation by pulse oximetry, and heart rate will be measured 
as indicated in Appendix 1.  
 
On infusion days, 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-
CART19 infusion, vital signs will continued to be monitored at a minimum of every hour or as clinically 
indicated until stable.   
 
If high fevers ( ≥ 101.5o F / 38.6o C)  occur in the days to weeks following CART19 infusion, additional 
assessments are required to more closely monitor the patient until resolution of the fever (below   101.5o 

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F / 38.6o C).  
6.4.4. ECOG Performance status 
At Visits according to Appendix 1, the ECOG performance scale index will be used to evaluate the 
performance status of the patients. 
 
Table 6-1: ECOG Performance status grade 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
6.4.5. Cardiac Assessment: ECHO/MUGA 
An ECHO/MUGA scan is required to confirm protocol eligibility.  This needs to be completed within 12 
weeks of enrollment and after last treatment with induction chemotherapy (excluding maintenance 
chemotherapy).  Patients must have a LVEF ≥40% to be included into the study. An ECHO/MUGA scan will 
need to be repeated prior to CART19 infusion if has been greater than 6 months since this scan was 
performed.  
6.4.6. Local Clinical Laboratory Evaluations 
Screening/enrollment and other laboratory assessments will be performed accordingly to Appendix 1.  
Note: Additional assessments should be performed between visits as clinically required to follow AEs or 
CART19 expected events.  For all laboratory assessments that occur on Infusion Days (Day 1, 2 or 3) these 
should be performed prior to CART19 infusion unless indicated otherwise.  
 
The Investigator will evaluate the clinical significance of each applicable laboratory value outside of the 
reference range. This decision shall be based upon the nature and degree of the observed abnormality. 
Values which are considered clinically significant and/or study related to CART19 will be noted.  The 
Investigator may choose to repeat any abnormal result once, in order to rule out laboratory error.  Further 
details on recording abnormal laboratory values as AEs are described in Section 8.1. 
 

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Table 6-2   Local Clinical laboratory parameters collection plan 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Platelets, White blood cells with a complete differential, 
including lymphoblasts 
Chemistry 
Glucose, BUN, Creatinine, Sodium, Potassium, Calcium, Total Protein, Albumin, Total 
Bilirubin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Magnesium, Phosphate, LDH, 
Uric Acid; Direct bilirubin (to be performed at screening only) 
HLH/MAS and CRS 
screen – repeated 
if clinically 
indicated 
Ferritin, CRP, Haptoglobin, triglycerides, LDH 
Coagulation 
Prothrombin time (PT), International normalized ratio (INR), Partial thromboplastin 
time (PTT), fibrinogen, D-dimer 
Viral Serologies 
HIV, Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody, Hepatitis B core 
antibody, and Hepatitis C Antibody.   
 
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 enrollment is provided. 
Respiratory 
Virus 
Panel (RVP)  
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 
T-Cell Subsets 
CD4, CD3, CD8 
Donor chimerism 
Whole blood (minimum required) and CD3+ lineage-specific chimerism preferred 
Additional 
Assessments 
Serum immunoglobulin levels, Serum and Urine Pregnancy Test 
6.4.7. Hematology, Coagulation and T cell Subsets 
Hematology & Coagulation safety assessments will be performed at screening, pre-infusion (Day-1), prior 
to CART19 infusions on Days 1, 2 and 3, and at each study visit according to Appendix 1. Assessments will 
include WBC (total) with differential count including % lymphoblasts, hematocrit, hemoglobin, platelets, 
prothrombin time, INR, PTT, Fibrinogen and d-dimer. 
 
T-cell subsets analysis (CD3, CD4 and CD8) will be performed prior to the first CART19 infusion on Day 1 
and again on Day 28, and Months 2, 3, 4, 5 and 6.  
6.4.8. Chemistry 
Biochemical safety assessments will be performed at screening, pre-infusion (Day-1), prior to CART19 
infusions on Days 1, 2 and 3, and at each study visit according to Appendix 1. Assessments will include 
Glucose, BUN, Creatinine, Sodium, Potassium, Calcium, Total Protein, Albumin, Total Bilirubin, Alkaline 
phosphatase, ALT (SGPT), AST (SGOT), Magnesium, Phosphate, LDH, Uric Acid.  Direct bilirubin will be 
performed at Screening only. 

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Additional assessment of Ferritin, LDH and CRP levels for CRS:  
As noted, side effects following CART19 cell infusions can induce high fevers and should be expected. If 
high fevers (≥ 101.5o F / 38.6o C) occur following CART19 infusion, every attempt will be made to monitor 
additional Ferritin, LDH and CRP levels daily at fever onset and until resolution of the fever (below 101.5o 
F / 38.6o C). Other chemistries should be monitored per Appendix 1 or as clinically indicated if CRS is 
suspected.  
 
Additional assessments of Haptoglobin and Triglycerides for HLH/MAS screen 
Haptoglobin and triglycerides will be assessed at pre-infusion106 and should be monitored per Appendix 
1 or as clinically indicated if HLH/MAS is suspected. 
6.4.9. Viral Serology 
Blood will be taken for HIV, Hepatitis B, and Hepatitis C at Screening per Table 6-2 above.  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 enrollment is provided. 
6.4.10.  Serum Immunoglobulin Levels 
Peripheral blood will be sampled at screening and accordingly to Appendix 1, for analysis of serum 
immunoglobulin.  
6.4.11.  Pregnancy Testing 
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, 
must use effective contraception (see Section 4.3 for details).  For women of childbearing potential, a 
serum pregnancy test (β-HCG) will be performed according to Appendix 1 at screening.  During treatment, 
an additional pregnancy test will be performed prior to (within 72 hours) the first CART19 infusion and 
again at the end of study (Month 12).  Patients should be instructed to inform site of any positive urine 
pregnancy results not conducted at the clinic. Repeat serum pregnancy testing will be performed for 
confirmation of a positive urine pregnancy test. In case of pregnancy prior to CART19 T cell infusion, 
patients must be withdrawn from the study. 
6.4.12.  Research Assessments to Assess Engraftment, Persistence and Bioactivity 
The following assessments will be collected according to Appendix 1 and will be analyzed as described 
below at the TCSL.  These tests may include: 
 
Serum Cytokines 
 
DNA Q-PCR CART19 persistence  
 
DNA RCL (VSV-G Q-PCR) 
 
CART19 Immune phenotyping 
 
MRD by deep sequencing 
 
For molecular studies (Q-PCR and deep sequencing), immune phenotyping and functional assays, 
peripheral blood and marrow samples will be collected in Lavender top (K2EDTA) tubes. For cytokine 
analyses peripheral blood and marrow samples will be collected in red top (no additive) tubes. For all 
subjects, deep sequencing will be performed on marrow samples collected pre-infusion (~Day -1) and 
at Day 28; for subjects experiencing a morphological response, deep sequencing will also be performed 
on marrow samples collected at months 3 and 12. Samples will be delivered, processed, and frozen as 

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8. ICE (ifosphamide, carboplatin, etoposide) 
9.  Daunorubicin /AraC 
 
The chemotherapy will be planned so that the last dose is completed ~1-4 days BEFORE the planned 
infusion of CART19 cells for ALL.  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 CART19 cells.  In addition, chemotherapy can potentiate the ability of T 
cells to kill tumor cells. The chemotherapy is not investigational and may be given by a patient’s local 
oncologist within the specified time frame. 
 
All subjects must undergo a Respiratory Virus Panel (RVP) within 10 days prior to the first planned CART19 
infusion. If the subject is positive for influenza, Tamiflu® or equivalent, should be administered per package 
insert.  The subject must complete treatment prior to receiving CART19.  The test does not need to be 
repeated prior to the first CART19 infusion, however if influenza sign and symptoms are present, the 
CART19 infusions should be delayed until the subject is asymptomatic.  If the subject is positive for another 
virus on the RVP, the CART19 infusion will be delayed for at least 7 days to be sure clinical symptoms of a 
viral infection do not develop.  If clinical symptoms develop, the infusion will be delayed until resolution of 
these symptoms. 
6.4.15. CART19 Infusions 
Subject infusions are to begin 1 to 4 days after completion of chemotherapy (if administered) as indicated 
in Section 6.4.15. Subjects will undergo tests and procedures in accordance with the Visit Evaluation 
Schedule in Appendix 1.  This includes a CBC with differential prior to each infusion, as well as an 
assessment of CD3, CD4 and CD8 counts prior to the 1st infusion since chemotherapy is given in part to 
induce lymphopenia.  
 
Patients will be infused and premedicated as described in Section 5.4.  
6.4.16. Day 28: Follow Up 
At the Day 28 visit, subjects will undergo tests and procedures in accordance with the Visit Evaluation 
Schedule in Appendix 1. Tumor response assessments will be done according to National Comprehensive 
Cancer Network (NCCN) v1 2013 guidelines (See Sections 6.5 and 6.6) 
6.4.17. Monthly Evaluations 2 to 6 Months Post Infusion 
Subjects will return to the clinic on a monthly basis during months 2 to 6 post CART19 cell infusion.  At 
these study visits, subjects will undergo tests and procedures in accordance with the Visit Evaluation 
Schedule in Appendix 1. Tumor response will be measured accordingly to Sections 6.5 and 6.6 at Months 
3 and Month 6. 
6.4.18. Quarterly Evaluations for up to 1 Year Post Infusion 
Subjects will be evaluated on a quarterly basis until 1 year post infusion. At these study visits, subjects will 
undergo tests and procedures in accordance with the Visit Evaluation Schedule in Appendix 1. Tumor 
response will be measured accordingly to Sections 6.5 and 6.6 at Months 9 and 12. 

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6.4.19. Long-term Follow-up 
Subjects who complete follow-up as part of this protocol or discontinue participation early for any reason 
will be encouraged to enroll in 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. 
6.5. Efficacy Assessments  
Tumor response assessments will be done at Screening/Enrollment, Pre-infusion (prior to CART19 
infusions), and then at Day 28 and Months 3, 6, 9 and 12 after CART19 cell infusions or until the patient 
requires alternative therapy for their disease. Assessments will be made as clinically indicated by physical 
exam, chest x-ray, CSF evaluation, hematology blood panel, and bone marrow biopsy and aspirate.  
 
Disease assessment collection plan is detailed in Table 6-3. 
Table 6-3:  Disease Assessment Collection Plan  
Procedure 
Pre-Infusion Assessments 
Post Infusion Assessments 
Bone marrow aspirate and 
biopsy for blast cell counts 
Mandated 
Mandated: Day 28, Months 3, 6, 9 and 12 
Peripheral Blood for blast, 
neutrophil and platelet cell 
counts 
Mandated 
Mandated: Day 28, Months 3, 6, 9 and 12 
Lymph node biopsy 
Optional; Performed if 
accessible and/or as 
clinically indicated 
Optional; performed if accessible and/or 
as clinically indicated at Day 28 and 
Months 3, 6, 9, and 12 
CSF Assessment for CNS disease  
Mandated- within 4 weeks 
of the first CART19 
infusion.  
Mandated Day 28 and then as clinically 
indicated by the presence of neurologic 
symptoms 
CNS Brain Imaging (MRI/CT) 
As clinically indicated 
As clinically indicated 
Chest x-ray for mediastinal 
disease 
If clinically indicated 
If clinically indicated 
Chest CT/MRI scan for 
mediastinal disease 
Required if the screening 
chest x-ray suggests 
mediastinal enlargement 
Mandated only if mediastinal 
enlargement confirmed at or before 
screening:  Day 28 and Month 3  
Physical exam for 
extramedullary disease 
Mandated 
Mandated Day 28 and Months 3, 6, 9, and 
12 
BCR-ABL PCR of blood and bone 
marrow aspirate for patients 
with Ph+ ALL 
Mandated 
Mandated Day 28 and Months 3, 6, 9, and 
12 
MRD assessment of bone 
marrow by flow cytometry 
(every patient) 
Mandated  
Mandated Day 28, Months 3, 6, 9 and 12 

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Table 6-3:  Disease Assessment Collection Plan  
Procedure 
Pre-Infusion Assessments 
Post Infusion Assessments 
Transfusion dates 
Assess dependency 
Record as needed during the course of 
the trial 
6.5.1. Physical Exam 
A physical examination will be used to assess evidence extramedullary disease as clinically appropriate in 
the liver, spleen, lymph node, skin, gum infiltration, testicular involvement and other sites as applicable. 
Extramedullary involvement is to be assessed at screening and at each response assessment visit. 
6.5.2. Bone Marrow Aspirate/Biopsy and Peripheral Blood 
Bone marrow biopsies and aspirate will be measured for tumor evaluations and efficacy analysis per 
Appendix 1.   When aspirate smear and differential is not interpretable by the pathologist (e.g., 
hemodilute or dry tap) response assessment as evaluated by bone marrow biopsy may substitute for bone 
marrow response. 
6.5.3. Cerebrospinal Fluid (CSF) Assessment  
If CNS symptoms are present at Screening/Enrollment, a lumbar puncture and brain imaging by MRI/CT 
will be performed to assess CNS leukemic involvement. All subjects will have cerebrospinal fluid (CSF) 
evaluations performed at baseline (within 4 weeks of the first CART19 infusion) and at Day 28. Subsequent 
CSF assessments will be performed as clinically indicated (i.e. when new neurological symptoms are 
present). Subjects without baseline CNS involvement who do not have a day 28 evaluation will still be 
considered evaluable for response. CSF will be analyzed for cell count and differential, cytology, and for 
the presence of CART19 cells. Additionally, CSF may be assessed during the height of cytokine release 
syndrome (CRS).  
6.5.4. 
Mediastinal Disease Assessment 
A chest x-ray will be performed at screening.  If the chest x-ray reveals mediastinal widening/enlargement, 
then a CT/MRI scan is required at baseline to confirm the presence of mediastinal disease and subsequent 
visits are required at Day 28 and at Month 3. If the screening chest x-ray suggests no mediastinal disease 
then no further chest imaging is required.  
 
 
If at any time point, mediastinal disease is present by CT/MRI assessment, then follow-up CT/MRI is 
required to document the absence of mediastinal involvement whenever the patient meets all other 
criteria for complete response. Two evaluations at least 28 days apart are needed to confirm a response 
in mediastinal disease. The timing of the CT/MRI must be within the required time window of the other 
disease response components (Table 6-3). 
 
For optimal evaluation of patients, the same imaging method of assessment (i.e. CT or MRI) and technique 
(i.e. with or without contrast) should be used to characterize each identified and reported lesion at 
baseline and during follow-up. A change in methodology can be defined as either a change in contrast use 
(e.g. keeping the same technique, like CT, but switching from intravenous contrast use to non-contrast 

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enhanced CT, regardless of the justification for the change) or a change in technique (e.g. from CT to MRI, 
or vice-versa). 
6.5.5.  Minimal Residual Disease (MRD)  
All patients will have multi-parameter flow cytometry on bone marrow aspirate for MRD status at each 
time point a bone marrow aspirate is collected (Appendix 1).  
MRD testing will be performed at the University of Washington using a multicolor flow measurement that 
has been validated and reproducible (see http://www.fda.gov/downloads/drugs/newsevents/ucm300749.pdf). The 
sensitivity of the test is 0.01%. 
6.5.6. BCR-ABL: Ph+ ALL Patients 
Bone marrow aspirates sampled at the time points for tumor assessments will additionally be analyzed 
for BCR-ABL for Ph positive ALL patients only. Where applicable, peripheral blood testing for quantitative 
BCR-ABL levels should be sent concurrently. 
6.5.7. Evaluation of Transfusion Dependency 
Information on transfusion dependency will be assessed at screening as well as during the course of the 
trial for all patients. Transfusion of blood products will be recorded in a separate module of the eCRF. The 
type of transfusion, start and end date as well as the number of units will be captured at each visit with 
hematologic assessment. 
 
A period of at least one week without any transfusion has been taken as a convention to define the status 
of transfusion independence to assess a CR vs. CRi response107. Any sample of peripheral blood which was 
taken less than seven days after a transfusion will be considered as taken while the patient is transfusion 
dependent. 
6.6.  ALL Response Criteria 
The response criteria will be evaluated according to Table 6-4.  The definitions are primarily based on the 
standardized response criteria defined by National Comprehensive Cancer Network (NCCN) Guidelines 
(NCCN, 2013 v.1) and further supported by the workshop report from American Society of Hematology 
(ASH)108 and the International Working Group (IWG) guideline for acute myeloid leukemia (AML)39,109. The 
Cheson IWG guideline and Appelbaum ASH report were used in recent drug approvals (e.g. Marqibo) in 
ALL, prior to the NCCN guideline availability. The NCCN guidance is a more recently published updated US 
based guideline for ALL. 
 
Efficacy assessments (Section 6.5) will be performed based on bone marrow and blood morphologic 
criteria, physical examination findings, along with laboratory assessments of CSF and bone MRD 
assessment. The overall disease response is determined at a given evaluation using the criteria described 
in Table 6-4.  
 
Table 6-4: Overall disease response classification at a given evaluation time 
Response category 
Definition 
Complete remission (CR) 
All the following criteria are met: 
Bone marrow 
Trilineage Hematopoiesis (TLH) and < 5% blasts 

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Table 6-4: Overall disease response classification at a given evaluation time 
Response category 
Definition 
Peripheral blood 
Neutrophils > 1.0 x 109/L, and 
Platelets > 100 x 109/L, and 
 Circulating blasts  < 1%  
Extramedullary disease 
No evidence of extramedullary disease (no CNS disease, mediastinal disease CR, no 
other extramedullary sites involvement) 
Transfusion independency 
No platelet and/or neutrophil transfusions within 1 week before peripheral blood 
sample for disease assessment 
Complete remission with 
incomplete blood count 
recovery (CRi) 
All criteria for CR as defined above are met, except that the following exist:  
Neutrophils ≤ 1.0 x 109/L, or  
Platelets ≤ 100 x 109/L, or 
Platelet and/or neutrophil transfusions within week before peripheral blood sample 
for disease assessment 
Complete remission (CR) 
with residual mediastinal 
disease  
All criteria for CR or CRi as defined above are met, except that mediastinal disease as 
defined by CRu or PR is observed: 
No response (Treatment 
failure) 
Failure to attain the criteria needed for any response categories  
Relapsed Disease 
Only in patients with a CR or CRi: 
Reappearance of blasts in the blood (≥ 1%), or  
Reappearance of blasts in bone marrow (≥ 5%), or 
(Re-)appearance of any extramedullary disease after CR 
Unknown 
In case the response assessment was not done, the baseline assessment was not 
done, the assessment was incomplete or was not done within the respective time 
frame. If there is evidence of relapse, the overall response will assessed as relapse 
with the relapsed component alone. 
Note: 
The NCCN guideline has defined mediastinal response criteria including CRu and PR. In the case a patient 
achieves CR or CRi at all other non-mediastinal disease sites, and has residual mediastinal disease 110, a 
category for of overall disease response of CR or CRi with residual mediastinal disease has been included 
in this document, which is not part of the NCCN guidance.  
 
The NCCN guidance has defined a progressive disease (PD) category. In this document, PD is considered 
the same as “No response” or “Treatment failure”, which is consistent with the Cheson et al. (2003) 109 
guideline. The difference between PD and “No response” in ALL is not believed to be clinical meaningful. 

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 STATISTICAL PLAN 
7.1. Design Overview  
This is a single center, single arm, open-label phase 2 study to determine the efficacy of autologous T cells 
expressing CD19 chimeric antigen receptors expressing tandem TCRζ and 4-1BB (TCRζ/4-1BB) 
co-stimulatory domains (referred to as “CART19” cells) in adults with minimal residual disease (MRD) 
during upfront treatment for CD19+ acute lymphoblastic leukemia. 
7.2. Sample Size Justification  
The study will enroll 24 evaluable subjects with MRD positive ALL. The primary endpoint is conversion to 
MRD— (MRD< 0.01%) by day 28. The table below provides 90% exact Clopper-Pearson confidence intervals 
for different possible event (conversion) rates. For example, if 21 out of 24 evaluable subjects (87.5%) are 
observed to convert to MRD— (<0.01%), then the observed rate 90% confidence interval is (70.8%, 96.5%). 
With 24 patients, there will be at least 80% power to detect an ORR of 40% or greater against a null rate of 
15% using a two-sided exact binomial test at 10% type I error. At least 8 out of 24 patients would need to 
achieve MRD— by day 28 (ORR=33%; exact 90% CI [17.8%, 52.1%]) to indicate meaningful efficacy of 15% 
or greater.  If the true MRD— rate were 84%, we have more than 80% power to reject a rate of 60% or 
smaller with 90% confidence. The confidence intervals below also provide the precision for 90% confidence 
intervals around adverse events. 
 
90% Clopper-Pearson confidence intervals for different possible observed event rates seen in 24 evaluable 
subjects. 
Observed rate (%) 
90% Confidence Interval (%) 
0/24 (0) 
(0.0, 11.7) 
1/24 (4.2) 
(0.2, 18.3) 
2/24 (8.3) 
(1.5, 24.0) 
3/24 (12.5) 
(3.5, 29.2) 
6/24 (25.0) 
(11.5, 43.5) 
9/24 (37.5) 
(21.2, 56.3) 
12/24 (50.0) 
(31.9, 68.1) 
15/24 (62.5) 
 
 (43.7, 78.8) 
18/24 (75.0) 
(56.5, 88.5) 
21/24 (87.5) 
(70.8, 96.5) 
24/24 (100) 
(88.3, 98.0) 
7.3. Analysis Sets 
 
The Enrolled Set comprises all patients who sign an informed consent form and are enrolled in 
the study, excluding screen failure patients. 
 
The Primary Evaluable Set comprises all patients who receive the CART19 cells at the intended 
dose range and completed the response assessments for the primary endpoint as planned by the 
protocol. Primary evaluable patients also include those with disease progression or death prior to 
the primary endpoint response assessment. These are the primary evaluable patients as defined 
below. The Primary Evaluable Set will be used for the primary endpoint analysis.  
 
The Full Analysis Set (FAS) comprises all patients who received the CART19 cells. This set includes 
both primary efficacy evaluable and non-evaluable patients as defined below. The Full Analysis 

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Set will be used for the secondary efficacy, 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 specified 
by the protocol.   
2) Manufacturing failure – Any patient who has manufactured CART19 cells that do not meet 
the manufacturing release criteria.   
3) Primary evaluable patient – Any patient who is infused with at least 1-5x107 CART19 cells 
and completed the response assessments for the primary efficacy endpoint as planned by 
the protocol. Primary evaluable patients also include those with disease progression or 
death prior to the primary endpoint response assessment. 
4) Primary non-evaluable patient – Any patient who is infused with the CART19 cells at less 
than the protocol-specified dose. These patients are also counted as manufacturing failures.  
Patients who are infused and drop out before the Day 28 assessment due to reasons other 
than disease progression or death are also considered non-evaluable.  
7.4. Analysis of Primary Objective  
The primary endpoint is efficacy as measured by the incidence of MRD conversion to < 0.01% (MRD—) at 
Day 28 post-CART19 in patients with MRD+ ALL during upfront treatment.   
7.5. Analysis of Secondary Objectives  
Efficacy will also be determined as the overall complete remission rate (ORR) at day 28, computed as the 
proportion of subjects with CR or CRi according to the response criterion described in Section 6.12.  The 
two-sided exact Clopper-Pearson 90% confidence intervals for Day 28 ORR will be computed. For the 
secondary efficacy objectives for this study, the proportion of subjects will be computed with a best overall 
disease response of CR or CRi, where the best overall disease response is defined as the best disease 
response recorded from the start of the treatment until death, last follow up, relapse or start of new 
anticancer therapy, whichever comes first. Proportion of subjects achieving CR or CRi before or at Month 
6 (prior to receiving other anticancer therapy if any), and the proportion of subjects with a minimal residual 
disease (MRD) negative bone marrow as determined according to Section 6.13 will also be computed. Two-
sided exact Clopper-Pearson 90% confidence intervals for the proportions will be provided.  
 
Secondary efficacy objectives for this study also include the evaluation of the following time to event 
endpoints: overall survival (OS), duration of remission (DOR), relapse free survival (RFS), and event free 
survival (EFS). Definitions for each of the endpoints are described below. The survival function of those 
endpoints using the Kaplan-Meier method will be estimated. 90% confidence interval for the survival 
probability at a specific time point (e.g., 3-month overall survival) will be computed based on the log-log 
transformation. Median survival time along with the associated 90% confidence intervals will be presented 
if appropriated. Overall survival (OS) is defined as the time from the date of the first CART19 infusion to 
the date of death due to any reason. In case a subject is alive at the date of last contact on or before the 
date of data cutoff, OS is censored at the date of last contact. Cause of death will be described when 
applicable. Duration of remission (DOR) is defined as the duration from the date when the response 
criteria of CR or CRi is first met to the date of relapse or death due to ALL. DOR will be assessed only in 
subjects with the best overall response of CR or CRi. 
 

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In case a subject does not relapse or die due to ALL prior to the date of data cutoff, DOR will be censored 
at the date of the last adequate assessment on or prior to the earliest censoring event. The censoring event 
could be:  
 
Lost to follow-up 
 
Withdrew consent 
 
Death due to reason other than ALL  
 
New anticancer therapy (including HSCT when performed in CR or CRi) 
 
Event after at least two missing scheduled disease assessment 
 
Although subjects in remission might choose to receive HSCT, data on relapse, survival, and response status 
after HSCT will not be used for the calculation of DOR. This is because HSCT procedure could affect 
remission duration independent of CART19 therapy; in addition it is likely to remove any remaining CART19 
cells in the subject thus outcomes after HSCT cannot be solely attributed to the CART19 treatment. If a 
substantial number of subject choose to receive HSCT while in CR or CRi, sensitivity analysis will be 
performed in which subjects who receive HSCT while in CR or CRi are not censored at time of HSCT; an 
analysis with HSCT regarded as a competing risk to the event of interest (e.g., relapse after CART19 
treatment) may also be considered. In a competing risk analysis, the cumulative incidence function (CIF) 
would be computed to estimate the probability of relapse in the presence of the competing risk due to 
HSCT.   Analyses that treat death for reasons unrelated to ALL as a competing risk will also be considered.  
 
Relapse free survival (RFS) is defined as the duration between the date when the response criteria of CR 
or CRi is first met to the date of relapse or death due to any cause. RFS will be assessed only in subjects 
with the best overall response of CR or CRi. 
 
In case a subject does not relapse or die due to any cause prior to the date of data cutoff, RFS will be 
censored at the date of the last adequate assessment on or prior to the earliest censoring event. The 
censoring event could be:  
 
Lost to follow-up 
 
Withdrew consent 
 
New anticancer therapy (including HSCT when performed in CR or CRi) 
 
Event after at least two missing scheduled disease assessment 
 
Sensitivity analyses similar to those described for the analysis DOR will be performed.   
Event free survival (EFS) is defined as the time from start of the first CART19 infusion to the earliest of the 
following:  
 
Death from any cause 
 
Relapse  
 
Treatment failure: Defined as no response in the study and discontinuation from the study due to 
any of the following reasons: 
o Adverse event(s) 
o Abnormal laboratory value(s) 
o Abnormal test procedure results 
o New cancer therapy (excluding HSCT when performed in CR or CRi) 
 
In case a subject does not experience an event of interest prior to the date of data cutoff, EFS is censored 
at the last adequate response assessment date on or prior to the date of data cutoff. 
 

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All secondary efficacy endpoints will be assessed using the FAS. 
7.6. Analysis of other secondary objectives 
Descriptive statistics will be calculated for correlative endpoints and patient reported outcomes. For 
continuous variables, mean, median, standard deviation, inter-quartile range will be provided. For discrete 
variables, frequency and proportions will be used. The correlation between measures of immunogenicity 
and the loss of CART19 engraftment will be evaluated using Pearson’s correlation coefficient or the 
nonparametric equivalent of Spearman rank correlation. When endpoints of interest are obtained from 
the same patient at multiple time points (e.g., CART19 in vivo survival is measured by Q-PCR weekly for the 
first month, monthly until Month 6 and every three months until Month 12), statistical methods 
appropriate for longitudinal data will be implemented. To evaluate manufacturing feasibility, the 
proportion of manufacturing products that do not meet release criteria for vector transduction efficiency, 
T cell product purity, viability, sterility or due to tumor contamination will be computed using patients in 
the enrolled set. 90% confidence interval appropriate for each statistic will be used. 
 SAFETY AND ADVERSE EVENTS 
8.1. Definitions 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  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  
 
leads to a persistent or significant disability or incapacity or substantial disruption of the ability to 
conduct normal life functions 
 
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 deterioration 
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 indication 
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 

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major clinical significance.  They may jeopardize the patient, 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 patient hospitalization, or intensive treatment of bronchospasm in an emergency department 
would typically be considered serious. 
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events. 
 
Unexpected adverse events 
An adverse event is considered unexpected if the event severity and/or frequency is not described in the 
investigator brochure or protocol. 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.  
 
Adverse Event Reporting Period 
For this study, adverse events are reported starting on Day 1 (from the start of the first CART19 infusion) 
until the subject is off study or until the 1 year end of study visit. Events not related to apheresis procedure 
which occurs after enrollment but before CART19 infusion will be excluded from the adverse event 
reporting period.  
 
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. After 30 days, any SAE that the investigators 
become aware of should be reported to the sponsor if the investigator suspects the event may reasonably 
be related 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.  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 
 
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 

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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 
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. Patients will be monitored by medical histories, 
physical examinations, and blood studies to detect potential toxicities from the treatment.  If CTCAE grading 
does not exist for an adverse event, the severity of mild, moderate, severe, 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 non-
directive questioning and, as appropriate, by examination. Adverse events also may be detected when they 
are volunteered by the subject during the screening process or between visits, or through physical 
examination, laboratory test, or other assessments. Information on all adverse events should be recorded 
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 (if applicable) or protocol]. 
5. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
6. Whether medication or therapy taken (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
7. Whether it is serious, where a serious adverse event (SAE) is defined as 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.   
 

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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 cause of the event was deemed probably or definitely related to 
the investigational product or procedure that was performed for the purposes of the research.) 
 
Reporting Process 
Unanticipated problems posing risks to patients or others as noted above will be reported to the IRB. This 
will include a written report of the event (including a description of the event with information regarding 
its fulfillment of the above criteria, follow-up/resolution and need for revision to consent form and/or 
other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s study file. 
 
Reporting Deaths:  more rapid reporting requirements 
Concerning deaths that occur during the course of a research study, the following describes the more 
rapid reporting requirement of the Penn IRB for specific situations: 
 
Report the event within 
 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.  
 
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 a granulocytosis, 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 patients. 
 
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 

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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 patient 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 patients. 
8.3.2. Investigator Reporting: Notifying the DSMC of the Abramson Cancer Center 
(ACC) 
All events that meet the ACC DSMC definition of reportable AE’s must be promptly entered into Velos.   
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 unrelated 
to protocol therapy.   
o Grade 3 or 4 events that are probably or definitely related to progression of disease as 
judged by a 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 study team must meet or 
have a teleconference within 
 hours of knowledge of the event to have a thorough discussion 
of the event. These types of events will not be vetted via e-mail. The sponsor should not be involved in 
discussions about attribution. The PI and Research Coordinator will schedule a meeting with the study 
team to discuss the grade 4 or 5 unexpected event. Meeting minutes capturing the review of any ongoing 
investigations of the grade 4 or 5 unexpected event, including next steps in the management of the subject 
and any proposed changes to the protocol will be documented appropriately.  
8.3.3. IBC Notification by Investigator 
Notify the Institutional Biosafety Committee of serious adverse events according to institutional 
requirements.  

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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/UCM227
351.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  
o Expected and unexpected Grade 3 or higher events of cytokine release syndrome (CRS) 
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: 
o 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. 
 
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. 
8.4. Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must be 
reported to protocol sponsor within 
 of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of the birth, 

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and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. 
 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the investigator to the 
protocol sponsor Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the study drug for any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
 
Pregnancy outcomes must be collected for the female partners of any males who took study treatment in 
this study. Consent to report information regarding these pregnancy outcomes should be obtained from 
the mother. 
8.5. Toxicity Management, Stopping Rules and Study Termination 
It is expected that AEs will occur frequently in this population based on the underlying advanced 
hematologic malignancy and that these can be SAEs. Therefore, there is no specific occurrence of SAEs 
that define a stopping rule, but the review of SAEs will form the basis for potential early stopping of the 
study. Only unexpected SAEs that are related to the CART19 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, ACC DSMC, the DSMB, 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. 
8.5.1. Criteria for stopping or pausing treatment on the study 
 The study will be stopped if: 
 
Any  patient  develops  uncontrolled  T  cell  proliferation  that  does  not  respond  to 
management. 
 
Premature  study  termination  may  occur  if  the  Investigator,  Study  Funder,  Sponsor, DSMB, 
DSMC or any appropriate independent review board or regulatory body decides for any reason 
that patient 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 to the FDA and review by IRB, DSMC, CTSRMC 
and the DSMB if any patient experiences any of the following events within two weeks of the first 
CART19 infusion: 
o Life-threatening (grade 4) occurring within two weeks of the first CART19 infusion that is 
unmanageable, unexpected and unrelated to chemotherapy and attributable to protocol 
therapy.  High fevers, hypotension, possible ICU admission and even mechanical 
ventilation are expected.  These side effects can result in grade IV liver toxicity, 
nephrotoxicity and other organ involvement. 
o Death within 100 days of the first CART19 infusion which is not attributable to the 
subject’s leukemia. 
 
If all parties are in agreement as to the event resolution and any proposed modifications (if applicable), 

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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 1-5x107 CART19 cells).   
 
If the study is paused for manufacturing reasons, required team members will meet to identify the 
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. 
8.5.2. General Toxicity Management Considerations 
RCL will be monitored by a suitable Q-PCR assay for the detection of the lentivirus (VSV-g DNA)  
If a positive VSV-g DNA assay or suitable alternative result is obtained, the Investigator will be informed 
and the patient rescheduled for a retest for the DNA test.  If the second DNA test is positive, then infusions 
will be temporarily halted.  The patient will undergo a blood draw for isolation of HIV from his/her cells.   
The virus will be sequenced and compared to sequences of the transfer vector and packaging constructs, 
as well as to available HIV sequences to determine the origin of the virus.  Determination of the origin of 
the virus can be easily performed by evaluation for HIV accessory genes such as vif, vpr and vpu which are 
not present in the packaging constructs. If the sequence is derived from wt-HIV then infusions for all 
patients can resume, and the patient will be referred to treatment for HIV.  If an RCL is confirmed, or the 
virus cannot be isolated from the blood draw, the patient will be scheduled for apheresis and will undergo 
a full biological RCL testing for detection and/or characterization of the RCL. 
 
Clonality and insertional oncogenesis   
Monitoring for T cell clonal outgrowth will be performed by qPCR for CART19 and by CBC count. CART19 
levels that continue to rise in a manner inconsistent with observed kinetics (i.e. initial expansion after 
infusion) will be examined to determine if these are expected due to subject’s clinical course 
(reappearance of disease) or other cause. If clonal expansion is suspected, the patient's T cells will be 
evaluated for the pattern of vector insertion. 
 
If integration site analysis reveals mono- or oligoclonality and/or integration at or near an oncogenic locus, 
a monitoring plan, including follow-up molecular analyses, will be developed in collaboration between the 
PI and Regulatory Sponsor of the original study that is specific for the health care risks that are anticipated 
given the nature of the integration site and vector target cell type. 
 
A summary of integration site analyses will be presented in the annual report to the FDA.  If oligo- or 
monoclonality of a vector integration site is observed, this data will be reported as an information 
amendment to the IND with best efforts made to submit this amendment within 30 days of data 
confirmation. 
 
Uncontrolled T cell proliferation  
Toxicity associated with allogeneic or autologous T cell infusions has been managed with a course of 
pharmacologic immunosuppression. CAR T cell associated toxicity has been reported to respond to 
systemic corticosteroids93.  If uncontrolled T cell proliferation occurs (grade 3 or 4 toxicity related to 
CART19 cells), patients may be treated with corticosteroids. Patients will be treated with pulse 
methylprednisolone (2 mg/kg i.v. divided q12 hr x 2 days), followed by a rapid taper. 
 

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B cell depletion 
In the event of clinically significant hypogammaglobulinemia (i.e. systemic infections), patients may be 
given intravenous immunoglobulin (IVIG) by established clinical dosing guidelines to restore normal levels 
of serum immunoglobulin levels, as has been done with Rituximab. 
 
Infusion reaction  
Acetaminophen and an antihistamine may be repeated every 6 hours as needed. 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 CART19 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 CART19 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)  
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 (initial dose of tocilizumab within one hour of ordering drug is highly recommended). This 
management approach is designed to avoid life-threatening toxicities, while attempting to allow the 
CART19 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 study team.  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 CART19 function and efficacy, if used, they should be 
rapidly tapered.  
 
Upon developing the prodrome of high-persistent fevers following CART19 infusion, patients should then 
be followed closely. Infection and tumor lysis syndrome work up should be immediately undertaken.  The 
pharmacy should be notified of the potential need for tocilizumab.  Patient management in an intensive 
care unit may be required and the timing is dependent upon local institutional practice. In addition to 
supportive care, tocilizumab may be administered in cases of moderate to severe CRS, especially if the 
patient exhibits any of the following: 
 
Hemodynamic instability despite intravenous fluid challenges and moderate stable vasopressor 
support 
 
Worsening respiratory distress, including pulmonary infiltrates, increasing oxygen requirement 
including high-flow O2, and/or need for mechanical ventilation.  
 
Any other signs or symptoms of rapid deterioration despite medical management 
 
The recommended dosing for tocilizumab is 8 mg/kg i.v. single dose. Not all Grade 4 CRS reactions 
following CART19 have been immediately treated with tocilizumab and decisions are, in part, based upon 
the rapidity of the syndrome onset and underlying patient reserve. 

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8.6. Protocol Exceptions and Deviations 
Exception: 
A one time, intentional action or process that departs from the approved study protocol, intended for 
one occurrence. If the action disrupts the study progress, such that the study design or outcome 
(endpoints) may be compromised, or the action compromises the safety and welfare of study subjects, 
advance documented approval from the Regulatory Sponsor, local 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 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 should be submitted: 
 
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:  Study identifier, 
subject study number, description of the exception/deviation and rationale.  Ensure all completed 
exception/deviation forms are signed by the Principal Investigator (or sub-investigator) and submitted to 
the Sponsor Project Manager for review. 
 
Attention: Sponsor Project Manager 
 
  
 
 
The Sponsor Project Manager will submit the exception/deviation form 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, 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 protocol deviation form (such as a patient missing a visit) is not 
an issue unless a critical/important treatment or procedure was missed and must have been done at that 
specific time. 
8.7. Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 

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above.  Medical monitoring will include a regular assessment of the number and type of serious adverse 
events. 
8.8. 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 meeting 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). 
 
A sponsor representative will share the outcome of the DSMB meeting with the PI via email  for submission 
to the IRB and other local regulatory review committees per institutional requirements. 
 
 DATA HANDLING AND RECORDKEEPING 
9.1. Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed subject authorization informing the subject of the following: 
 
 
What protected health information (PHI) will be collected from subjects in this study 
 
Who will have access to that information and why 
 
Who will use or disclose that information 
 
The rights of a research subject to revoke their authorization for use of their PHI. 
 
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 patient authorization.   For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
9.2. Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in 

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source documents. Examples of these original documents, and data records include:  hospital  records,  
clinical  and  office  charts,  laboratory notes,  memoranda,  patients’ 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, patient files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. 
 
The investigator must maintain source documents for each subject in the study, consisting of case and 
visit notes (hospital or clinical medical records) containing demographic and medical information, 
laboratory data, and the results of any other tests or assessments. All information recorded on the eCRFs 
must be traceable to source documents in the patient’s file. The investigator must also keep the original 
signed informed consent form, and a signed copy must be given to the patient. 
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.  
 
 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 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. 

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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. 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. 
 
 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. A HIPAA 
authorization has been integrated into this consent and therefore a combined consent-authorization 
document will be used. 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 on clinicaltrials.gov. 
 
 STUDY FINANCES 
12.1. Funding Source 
This study is funded by Novartis Pharmaceuticals Corp and the Leukemia and Lymphoma Society (LLS). 
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. Patient Stipends or Payments 
There is no patient stipend/payment for participation in this protocol.  However subjects will be 
reimbursed for some of the cost for travel and lodging to the research study site during their participation 
in this research study.  

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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. 
 
 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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 REFERENCES 
 
1. 
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Pui CH, Campana D, Evans WE: Childhood acute lymphoblastic leukaemia--
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Bassan R, Spinelli O, Oldani E, et al: Improved risk classification for risk-specific 
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Tedder TF, Isaacs CM: Isolation of cDNAs encoding the CD19 antigen of human 
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Gunther R, Chelstrom LM, Tuel-Ahlgren L, et al: Biotherapy for xenografted 
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Messinger Y, Yanishevski Y, Avramis VI, et al: Treatment of human B-cell 
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Appendix 1:  VISIT EVALUATION SCHEDULE 
 
Screening and 
Enrollment 
Apheresis 
Chemo-
Therapy 
Pre-Infusion 
Infusion #1 
Infusion #2 
Infusion #3 
Follow-Up 
Follow-Up 
Follow-Up 
Follow-Up 
Follow-Up 
Follow-Up 
Monthly 
Follow-Up 
Quarterly 
Follow-Up 
 
~-12W 
to       
 -4W 
~-4W 
to      
-3W 
~ -1W 
~ -1D 
D1 
D2 
 (+) 
1d 
D3 (+) 
1d 
D4 
 (+) 
1d 
D7 
(+/-) 
2d 
D11 
(+/-) 
1d 
D14 
(+/-) 
2d 
D21 
(+/-) 
3d 
D28 
(+/-) 
3d 
M2 M3 
M4 M5 
M6      
(+/-) 7d 
M9 M12 
(+/-)14d 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interventions 
Apheresis6 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphodepleting 
Chemotherapy4 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
CART19 Infusion24 
 
 
 
 
x 
x 
x 
 
 
 
 
 
 
 
 
Patient History/Clinical 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant medical 
history/current medical 
conditions  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis and extent of 
cancer 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior antineoplastic therapy 
X7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
X 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical examination 
X 
 
 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
Performance status (ECOG) 
X 
 
 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 

39416 CART19 in Adult ALL 
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CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
 
Screening and 
Enrollment 
Apheresis 
Chemo-
Therapy 
Pre-Infusion 
Infusion #1 
Infusion #2 
Infusion #3 
Follow-Up 
Follow-Up 
Follow-Up 
Follow-Up 
Follow-Up 
Follow-Up 
Monthly 
Follow-Up 
Quarterly 
Follow-Up 
 
~-12W 
to       
 -4W 
~-4W 
to      
-3W 
~ -1W 
~ -1D 
D1 
D2 
 (+) 
1d 
D3 (+) 
1d 
D4 
 (+) 
1d 
D7 
(+/-) 
2d 
D11 
(+/-) 
1d 
D14 
(+/-) 
2d 
D21 
(+/-) 
3d 
D28 
(+/-) 
3d 
M2 M3 
M4 M5 
M6      
(+/-) 7d 
M9 M12 
(+/-)14d 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
Vital signs25 
x 
 
 
x 
x12 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Laboratory assessments27 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology (5 ml lavender 
top, EDTA) 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry (3 ml SST) 
x17 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
Coagulation  [PT, PTT, INR, 
fibrinogen, D-dimer] (4.5 ml 
blue top citrate) 
X 
 
 
x 
x 
x 
x 
x13 
x 
x13 
x 
x 
x 
x 
x 
Serum Pregnancy Test11 (1 ml 
SST) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test11 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
HIV Test (1ml SST) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral Serology (Hepatitis B 
and C) (5ml red top, serum) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Immunoglobulin levels 
(1ml SST) IgG only 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
HLH/MAS (triglycerides, 
haptoglobin)(4mL SST; 2.5mL 
lavender top, EDTA) 
 
 
 
X8 
 
 
 
 
 
 
 
 
 
 
 
Ferritin, LDH and CRP for 
Cytokine Release Syndrome 
 
 
 
X8 
 
 
 
 
 
 
 
 
 
 
 

39416 CART19 in Adult ALL 
Page 72 of 77 
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CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
 
Screening and 
Enrollment 
Apheresis 
Chemo-
Therapy 
Pre-Infusion 
Infusion #1 
Infusion #2 
Infusion #3 
Follow-Up 
Follow-Up 
Follow-Up 
Follow-Up 
Follow-Up 
Follow-Up 
Monthly 
Follow-Up 
Quarterly 
Follow-Up 
 
~-12W 
to       
 -4W 
~-4W 
to      
-3W 
~ -1W 
~ -1D 
D1 
D2 
 (+) 
1d 
D3 (+) 
1d 
D4 
 (+) 
1d 
D7 
(+/-) 
2d 
D11 
(+/-) 
1d 
D14 
(+/-) 
2d 
D21 
(+/-) 
3d 
D28 
(+/-) 
3d 
M2 M3 
M4 M5 
M6      
(+/-) 7d 
M9 M12 
(+/-)14d 
Respiratory Virus Panel (RVP) 
 
 
x18 
 
 
 
 
 
 
 
 
 
 
 
 
T cell Subsets-CD3, CD4, CD8 
(4mL lavender top, EDTA) 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Research Analyses2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum ~6cc (Red top) 
 
 
 
x 
x19 
x19 
x19 
x 
x 
x 
x 
x 
x 
x5 
 
Cytokines 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x5 
 
PBMC ~25cc (purple, EDTA) 
 
 
 
x 
 
 
 
 
x 
x 
x 
X 
x 
x 
x 
Additional 30cc for research 
blood sample (Lavender, 
EDTA) 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
DNA (Q-PCR CART19 
persistence) 
 
 
 
x 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
DNA RCL (VSV-G Q-PCR) 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x3 
x3 
CART19 Immune-
phenotyping, CART19) and B 
cell enumeration, functional 
assays 
 
 
 
x 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
Bone Marrow/LN aspirate22 
(5 cc lavender top, EDTA) 
x26  
 
x23 
x14 
 
 
 
 
 
 
 
 
x1 
x1 
x1 
DNA (Q-PCR CART19 homing) 
x 
 
x 
x 
 
 
 
 
 
 
 
 
x1 
x1 
x1 

39416 CART19 in Adult ALL 
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Version 4.03-15-2017  
 
 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
 
Screening and 
Enrollment 
Apheresis 
Chemo-
Therapy 
Pre-Infusion 
Infusion #1 
Infusion #2 
Infusion #3 
Follow-Up 
Follow-Up 
Follow-Up 
Follow-Up 
Follow-Up 
Follow-Up 
Monthly 
Follow-Up 
Quarterly 
Follow-Up 
 
~-12W 
to       
 -4W 
~-4W 
to      
-3W 
~ -1W 
~ -1D 
D1 
D2 
 (+) 
1d 
D3 (+) 
1d 
D4 
 (+) 
1d 
D7 
(+/-) 
2d 
D11 
(+/-) 
1d 
D14 
(+/-) 
2d 
D21 
(+/-) 
3d 
D28 
(+/-) 
3d 
M2 M3 
M4 M5 
M6      
(+/-) 7d 
M9 M12 
(+/-)14d 
CART19 and B cell 
enumeration, 
immunophenotyping 
x 
 
x 
x 
 
 
 
 
 
 
 
 
x1 
x1 
x1 
MRD by deep sequencing 
 
 
 
x15 
 
 
 
 
 
 
 
 
x15 
x15 
x15 
Marrow Serum (2 cc red top) 
x 
 
x 
x 
 
 
 
 
 
 
 
 
x1 
x1 
x1 
Cytokines 
X 
 
x 
x 
 
 
 
 
 
 
 
 
x1 
x1 
x1 
Disease Monitoring20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor response assessments 
 
 
 
x 
 
 
 
 
 
 
 
 
x1 
x1 
x1 
Physical exam 
(extramedullary disease)16 
X 
 
 
x 
 
 
 
 
 
 
 
 
x1 
x1 
x1 
Bone marrow aspirate/biopsy 
(cytogenetics/FISH if 
appropriate) 
x26  
 
x23 
x14 
 
 
 
 
 
 
 
 
x1 
x1 
x1 
Lymph node biopsy22 
x 
 
 
X 
 
 
 
 
 
 
 
 
x1 
x1 
x1 
CSF evaluation9 
x 
x 
 
 
 
 
 
 
 
 
 
 
x 
As clinically 
indicated 
Mediastinal disease 
assessment (Chest X-ray 
 CT/MRI scan)16 
x 
 
 
 
 
 
 
 
 
 
 
 
x16 
x16 
 
MRD by flow cytometry  
x 
 
 
x 
 
 
 
 
 
 
 
 
x 
x1 
x1 
BCR-ABL (Ph+ patients only)28 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
x1 
x1 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 

39416 CART19 in Adult ALL 
Page 74 of 77 
Version 4.03-15-2017  
 
 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
 
Screening and 
Enrollment 
Apheresis 
Chemo-
Therapy 
Pre-Infusion 
Infusion #1 
Infusion #2 
Infusion #3 
Follow-Up 
Follow-Up 
Follow-Up 
Follow-Up 
Follow-Up 
Follow-Up 
Monthly 
Follow-Up 
Quarterly 
Follow-Up 
 
~-12W 
to       
 -4W 
~-4W 
to      
-3W 
~ -1W 
~ -1D 
D1 
D2 
 (+) 
1d 
D3 (+) 
1d 
D4 
 (+) 
1d 
D7 
(+/-) 
2d 
D11 
(+/-) 
1d 
D14 
(+/-) 
2d 
D21 
(+/-) 
3d 
D28 
(+/-) 
3d 
M2 M3 
M4 M5 
M6      
(+/-) 7d 
M9 M12 
(+/-)14d 
ECHO/MUGA 
x21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram (EKG) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total clinical blood draw 
(mL) 
27 
0 
0 
19 
12.5 
12.5 
12.5 
12.5 
12.5 
12.5 
12.5 
12.5 
16.5 
16.5 
16.5 
Total research blood draw 
(mL) 
0 
0 
0 
30 
5 
0 
0 
0 
30 
30 
60 
30 
60 
30 
30 
Total blood draw (mL) 
27.0 
0 
0 
49 
17.5 
12.5 
12.5 
12.5 
42.5 
42.5 
72.5 
42.5 
76.5 
46.5 
46.5 
Total blood draw (Tbsp.; 
approximately) 
2 
0 
0 
3 
1 
1 
1 
1 
3 
3 
5 
3 
5 
3 
3 
1 Tumor response assessments will be performed at Day 28, Months 3, 6, 9 and 12 after CART19 cell infusions (Refer to Sections 6.5 and 6.6 for further 
details and frequency) 
2 Translational and Correlative Studies Laboratory (TCSL) has requested lab samples for research be sent to TCSL as soon as collected. If required to keep 
research labs after hours, please keep red tops upright, lavender tubes should be room temperature on rotating platforms. In the event that something 
unexpected occurs, additional research sample collection may be done as necessary. Blood collects are not to exceed 3 tablespoons of blood twice in 
one week time window. Marrow/LN collections would not exceed more than one procedure per month. This would be at the PI’s discretion. 
3 Months 3, 6 and 12 only 
4 Lymphodepleting chemotherapy prior to CART19 cell infusion is NOT required if WBC ≤ 1,000 /uL. The infusion will be scheduled to occur 
approximately 1 to 4 days following lymphodepleting chemotherapy.  Please refer to Section 6.4.11 for complete details.  
5 Month 2 only.  
6 Apheresis will be performed to obtain a target of 5x109 PBMCs for CART19 manufacturing.   Apheresis can occur any time after the subject is enrolled 
and up to 3 weeks prior to CART19 infusion.  Cryopreserved historical apheresis products collected from the patient prior to study entry are usable for 

39416 CART19 in Adult ALL 
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Version 4.03-15-2017  
 
 
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CART19 manufacturing if collected at an appropriately certified apheresis center and the product meets adequate mononuclear cell yields. Please see 
Section 6.3 for additional details. 
7 Prior antineoplastic therapy to be collected up through the lymphodepleting chemotherapy prior to CART19 cell infusion.  
8 Repeated as clinically indicated or if HLH/MAS or CRS is suspected.  If high fevers (≥ 101.5o F / 38.6o C) occur following CART19 infusion, every attempt 
will be made to monitor additional Ferritin, LDH and CRP levels daily at fever onset and until resolution of the fever (below 101.5o F / 38.6o C). 
9 If CNS symptoms are present at Screening/Enrollment then a lumbar puncture and brain imaging by MRI/CT will be performed to assess CNS leukemic 
involvement. CNS evaluations will be performed in all patients within 4 weeks of the first CART19 infusion and at Day 28, and will be repeated 
thereafter as clinically indicated by the presence of neurologic symptoms. 
10 Months 3, 6, 9 and 12 
11 Pregnancy test (quantitative) for females of childbearing potential only.  Pre-infusion pregnancy test to be performed within 48 hours prior to the first 
CART19 infusion. End of Study pregnancy test to be performed at the Month 12 visit or at the time of study discontinuation.  
12 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. 
13 D-dimer required on Days 4 and 11.   
14 Bone marrow biopsy/aspirate to be performed within 48 hours prior to the CART19 infusion. The results of this baseline bone marrow are not required 
prior to infusion.  
15 For all subjects, deep sequencing for MRD detection will be performed on marrow samples collected pre-infusion (~Day -1) and at Day 28; for subjects 
experiencing a morphological response, deep sequencing will also be performed on marrow samples collected at months 3 and 12. 
16 A chest x-ray for mediastinal disease will be performed at Screening/Enrollment if clinically indicated.  Chest CT/MRI required pre-infusion and post-
infusion on Day 28 and Month 3 if chest x-ray suggests mediastinal enlargement.   
– If extramedullary disease is present prior to treatment, this will be followed  at each response assessment visit.   
17 Direct bilirubin will be performed at screening only 
18 All subjects must undergo a Respiratory Virus Panel within 10 days prior to the planned CART19 infusion.  If the subject is positive for influenza, 
oseltamivir phosphate (Tamiflu®) or equivalent should be administered per package insert (see Tamiflu® package insert for dosing information). The 
patient must complete treatment prior to receiving the CART19 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 CART19 infusion.  If the subject is positive for another virus on the RVP, the CART19 
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. 
19 Research blood (~6 cc red top) to be taken between 20-120 minutes post-CART19 infusion. 
20 Please refer to Table 6-3 for details regarding Disease Monitoring requirements. 

39416 CART19 in Adult ALL 
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21 ECHO/MUGA must be performed within 12 weeks prior to enrollment (after last treatment with induction chemotherapy, excluding maintenance 
chemotherapy) and within 6 months of CART19 infusion.  
22 Lymph node biopsy is optional and performed if accessible and/or as clinically indicated  
23 If subjects receive treatment for their ALL after study eligibility is confirmed, a repeat bone marrow should be performed prior to lymphodepleting 
chemotherapy (if administered) and within 4 weeks prior to the CART19 infusion. If lymphodepleting chemotherapy is not administered, the pre-
infusion bone marrow (to be performed within 48 hours prior to the CART19 infusion) is sufficient. 
24 Neutropenic subjects will be administered preventive antibiotics treatment starting on the day of infusion. Broad-spectrum antibiotics will be 
administered orally until recovery of neutrophil counts, or until judged by the investigator to no longer be at increased risk of infection.  All patients 
will receive allopurinol prophylactically for 30 days after infusion and appropriate clinical therapy will be administered should any significant tumor 
lysis occur. The Investigator will review all labs to determine that it is appropriate to proceed with the infusion.  See Section 5.2 regarding criteria to 
proceed with CART19 infusion each day.    
25 Vital sign assessments include blood pressure, body temperature, heart rate and oxygen saturation via pulse oximetry. 
26 Bone marrow performed for disease and MRD assessment. Must be performed within 4 weeks of enrollment.  
27 Please refer to Table 6-2 for additional details. 
28 Bone marrow aspirates will be analyzed for BCR-ABL for Ph+ ALL patients only.  Where applicable, peripheral blood testing for quantitative BCR-ABL 
levels should be sent concurrently.