Phase 2 Study of Humanized CD19-directed Chimeric Antigen Receptor-modified T Cells (huCART19) for Very High-Risk Subsets of B Cell Acute Lymphoblastic Leukemia (B-ALL)
Phase: PHASE2
Conditions: Acute Lymphoblastic Leukemia
Sponsor: University of Pennsylvania

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University of Pennsylvania 
Phase 2 Study of Humanized CD19-directed Chimeric Antigen Receptor-modified T cells 
(huCART19) for Very High-Risk Subsets of B cell Acute Lymphoblastic Leukemia (B-ALL) 
Principal Investigator: 
Shannon Maude, MD, PhD 
Children’s Hospital of Philadelphia 
Regulatory Sponsor: 
University of Pennsylvania 
Sponsor Medical Director: 
 
Funding Organization(s): 
CHOP Internal Funds 
Investigational Product: 
Humanized CD19 redirected autologous T cells (huCART19) 
Protocol Numbers: 
18CT014; CHOP IRB#18-015566; Penn IRB #831916; NCT03792633 
IND Number: 
IND# 
 
Sponsor Cell Manufacturing: 
Clinical Cell and Vaccine Production Facility (CVPF) 
University of Pennsylvania 
Cell and Gene Therapy 
Laboratory (CGTL)- Children’s 
Hospital of Philadelphia 
(CHOP): 
 
 
Correlative Laboratory Team: 
Translational and Correlative Studies Laboratory (TCSL) 
University of Pennsylvania 
Biostatistician: 
 
Original Protocol Date: 
Amended: 
V1.09-24-2018 
V2.07-23-2020 
V3.08-19-2021 

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TABLE OF CONTENTS 

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LIST OF ABBREVIATIONS 
 
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; also called CTL019 
CCI 
Center for Cellular Immunotherapies 
CGTL 
Cell and Gene Therapy Laboratory at CHOP 
CHOP 
Children’s Hospital of Philadelphia  
CFR 
code of federal regulations 
CLL 
chronic lymphoblastic leukemia 
CMV 
Cytomegalovirus 
CNS 
central nervous system 
COG 
Children’s Oncology Group 
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 terminology 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 and safety monitoring board 
DSMC 
data and safety monitoring committee 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
event free survival 
FACT 
Foundation for the Accreditation of Cellular Therapy 
FAS  
full analysis set 
FDA 
food and drug administration 
FISH 
fluorescent in situ hybridization 
GCP 
good clinical practices 
GMP 
good manufacturing practices 
GVHD 
graft versus host disease 
HAMA 
human anti-murine antibody 

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HSCT 
hematopoietic stem cell transplantation 
huCART19 cells 
humanized CD19 redirected autologous T cells  
IBC 
Institutional Biosafety Committee 
IRB 
Institutional Review Board 
KM 
Kaplan-Meier 
LGL 
large granular lymphocytes 
MAS 
macrophage activation syndrome 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging  
NCCN 
National Comprehensive Cancer Network 
ORR 
overall remission rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cells 
PD 
progressive disease  
PK 
pharmacokinetics  
PR 
partial remission  
QoL 
quality of life 
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 Fv fragment 
SCT 
stem cell transplant 
TCR 
T cell receptor 
TCSL 
Translational and Correlative Studies Laboratory 
TLS 
tumor lysis syndrome 
UPenn 
University of Pennsylvania 
Vβ 
a rearranged T cell specific gene that can be used to determine clonality of a 
T cell population 
VHR 
very high risk 
VSV-G 
Vesicular Stomatitis Virus, Glycoprotein 
WBC 
white blood cell 
 
 
 

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 STUDY SUMMARY  
Title 
Phase 2 Study of Humanized CD19-directed Chimeric Antigen Receptor-modified T 
cells (huCART19) for Very High-Risk Subsets of B cell Acute Lymphoblastic 
Leukemia (B-ALL) 
Short Title 
Phase 2 study of huCART19 in Pediatric ALL 
Protocol Numbers 
18CT014; CHOP IRB# 18-015566 Penn IRB #831916 
Phase 
Phase 2 
Methodology 
This is a two cohort, open-label, phase 2 study to determine the efficacy of 
huCART19 in pediatric and young adult patients with CD19 expressing relapsed 
and refractory B-cell acute lymphoblastic leukemia.  
Study Duration 
The protocol will require approximately 36 months to complete enrollment.  Each 
subject will be followed for approximately 1 year post-infusion as part of this 
study.  
Study Center(s) 
Children’s Hospital of Philadelphia (CHOP) 
Objectives 
Primary Objective: 
1. To determine efficacy of huCART19 
Secondary Objective: 
1. To describe additional efficacy endpoints 
2. To further evaluate the safety of huCART19 in pediatric ALL 
Please refer to protocol Section 2 for corresponding study endpoints. 
Number of Patients A total of 100 infused subjects is targeted. Approximately 52 subjects will be 
infused in Cohort A (up to 62 subjects enrolled) and approximately 48 subjects will 
be infused in Cohort B (up to 54 subjects enrolled). 
Diagnosis and Main 
Inclusion Criteria 
Inclusion criteria are designed to include pediatric and young adult patients aged 3 
months -29 years with CD19 expressing relapsed/refractory B-cell acute 
lymphoblastic leukemia (ALL).  
Investigational 
Product, Dose, 
Route, Regimen 
huCART19 cells transduced with a lentiviral vector to express humanized 
anti-CD19 scFv:41-BB:TCRζ, administered by IV injection with a planned 
dose of 5x106 huCART19 cells/kg on day 0 with possible subsequent doses 
Duration of 
administration 
The duration of CART19 administration will be based on the total volume to be 
infused and the recommended infusion rate of 10-20mL per minute. The 
transduced T cells will be administered by slow IV push.  
Reference therapy 
None. This protocol will be given to subjects with unmet medical needs for which 
there are no current curative therapeutic options. 

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Statistical 
Methodology 
The primary endpoint is 1-year Event-Free Survival (EFS), with time to event or 
censoring defined as the time from infusion to the first of any of the following events: 
no response, relapse, death due to any cause, or to the last day of follow up if no 
event occurs. All analyses will be performed for cohort A and B separately. Kaplan-
Meier (KM) curves will be generated and one-sample Log-rank test will be used to 
test the 1-year EFS against the historical rate. One-year EFS and its 95% confidence 
interval (CI) will also be estimated based on the KM method. For cohort A, the null 
hypothesis is 40% 1-year EFS and the alternative hypothesis is 60% 1-year EFS. The 
sample size of 52 provides 95% power to test this hypothesis, using a one-sided one-
sample Log-rank test with 10% type I error, assuming 1 year of follow up for each 
subject. For cohort B, the null hypothesis is 15% 1-year EFS and the alternative 
hypothesis is 30% 1-year EFS. The sample size of 48 provides 91% power to test this 
hypothesis, using a one-sided one-sample Log-rank test with 10% type I error, 
assuming 1 year of follow up for each subject. We expect that we could infuse 
approximately 85% of enrolled subjects, so we will enroll approximately 62 subjects 
for cohort A and approximately 54 subjects for cohort B to obtain the targeted 
number of infused subjects. 
 

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INTRODUCTION 
While survival rates in children with de novo B-ALL approach 90%,2 subgroups of patients at very high risk 
(VHR) of relapse are in need of novel therapeutic approaches. Many of these patients can be identified 
early in therapy by poor response to therapy. Refractory ALL poses a therapeutic challenge, with long-
term survival close to 30% for patients who do not achieve remission with induction chemotherapy 
(induction failure).3 Survival rates for children who experience early medullary relapse of B-ALL, defined 
as a marrow relapse within 36 months of diagnosis, are equally poor, with EFS rates <30% reported.4 In 
COG trials, survival rates for these patients have not improved measurably in 30 years.5,6 Even for patients 
who achieve a second remission, those remissions are frequently not sustained,4,7 and with each 
subsequent relapse, achieving remission is harder, and long-term survival is extremely poor.4 
 
Intensive chemotherapy followed by hematopoietic stem cell transplant (HSCT) 8 has been considered a 
standard treatment approach for patients with poor outcomes similar to these subsets.9,10 However, even 
with these intensified approaches, these subgroups have demonstrated suboptimal outcomes; therefore, 
we hypothesize that these leukemias may be chemo-refractory.  
 
Adoptive transfer of T cells engineered to express a chimeric antigen receptor (CAR) has emerged as a 
powerful technology producing dramatic responses in patients with highly refractory malignancies. Our 
group and others have shown complete remission (CR) rates of 70-93% in children and adults with 
relapsed/refractory acute lymphoblastic leukemia (ALL)1,11-15,16,17.  Outcomes using autologous T cells 
expressing a murine CAR directed at CD19 (CART19) in a large multicenter trial of 75 patients (median 
survival not reached) led to the 2017 FDA approval of this agent in pediatric and young adult patients with 
r/r disease17. Remission for some patients with CTL019 have been durable even without a consolidative 
HSCT 16,17. However, a subset of patients do not respond or relapse due to poor CAR T cell expansion and 
persistence. Approximately 20% of patients demonstrate early recovery of CD19-expressing B cells,18 a 
surrogate marker of CD19-directed CAR T cell loss, within 6 months of CART19 infusion. Without further 
therapy, early loss of CAR T cells confers an increased risk of CD19+ relapse. Options for patients who do 
not respond or relapse after prior engineered cell therapy are extremely limited.  
 
We have assessed a humanized version of CART19, called huCART19, in a Phase 1 trial at the Children’s 
Hospital of Philadelphia (CHOP). The 13BT022 trial evaluated huCART19 in CAR-naïve subjects as well as 
subjects who had previously received anti-CD19 CARs, either CTL019 at CHOP or another anti-CD19 CAR 
elsewhere. Clinical success was seen on this trial in both patient subsets.  
 
Based on our previous success and lack of clinical options in patients with very high risk (VHR) ALL, we 
propose to test huCART19 as an alternative treatment approach, in newly diagnosed B-ALL patients 
predicted to have an exceedingly poor outcome with conventional chemotherapy, in high-risk first 
relapse, and in second or greater relapse in this phase 2 trial (Cohort A). In addition, a second cohort 
(Cohort B) will test the efficacy of huCART19 in patients with poor response to prior B cell directed 
engineered cell therapy. 

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Background 
 
Engineered T cells with redirected specificity: chimeric antigen 
receptors (CAR) 
CAR T cells are patient-derived lymphocytes transfected with a gene encoding a chimeric transmembrane 
receptor that enables recognition of target cell-surface antigens with high specificity in a non-MHC 
restricted manner, coupling antigen-binding with intracellular signals that promote T cell effector 
functions19,20. The extracellular component of CARs typically consists of the antigen-binding domains from 
the heavy and light chains of an antibody configured as a single-chain (i.e., a single-chain variable 
fragment, or scFv). The intracellular component typically consists of signaling domains that mediates T 
cell activation (as reviewed21,22). The CAR T cells used in this study are so-called second-generation CARs 
that incorporate the TCRζ and 4-1BB signaling domains and are transduced via lentiviral vector.  
The clinical efficacy of CAR T cells was first reported by Porter et al. using CART19/CTL019 in patients with 
advanced, treatment-refractory CLL23,24. This was followed by additional reports with CART19/CTL019 in 
ALL16,17 and non-Hodgkin’s lymphoma25, along with reports from other centers evaluating anti-CD19 CAR 
T cells (as reviewed 26,27).  
 
Response rates and duration of response to CAR T cell therapies vary considerably, however, even among 
the various CD19+ malignancies treated with anti-CD19 CARs.  Therefore, the design of this study is 
informed by clinical and correlative data from ALL patients treated with CART22 and CART19 in previous 
studies. 
 
CD19 as a therapeutic target for B cell leukemia and lymphoma  
CD19 is a 95kDa glycoprotein present on B cells from early development until differentiation into plasma 
cells28-30. 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 receptor30-32. 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 levels30,33. Expression of CD19 is restricted to B lineage 
cells and is not expressed by pluripotent blood stem cells29. CD19 is also expressed by most B cell 
lymphomas, mantle cell lymphoma, ALLs, CLLs, hairy cell leukemias, and a subset of acute myelogenous 
leukemias28,34,35. CD19 thus represents a highly attractive target for immunotherapy29. Furthermore, CD19 
is not present on most normal tissues, other than normal B cells, including pluripotent blood stem cells29, 
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 models36-40 and human and 
non-human primates22,41-50. 
 
Lymphodepleting chemotherapy  
Adoptive immunotherapy are designed to capitalize on homeostatic T cell proliferation51,52, the 
phenomenon whereby naive T cells proliferate and differentiate into memory-like T cells when the total 
numbers of naive T cells in the host are reduced to low levels51,53.  This lymphodepletion also eliminates 
regulatory T-cells and other competing elements of the immune system that act as “cytokine sinks”, 
enhancing the availability of cytokines such as IL-7 and IL-15 that are important for T cell proliferation and 
survival54. This concept was initially demonstrated clinically using ex-vivo-expanded tumor-infiltrating 
lymphocytes in patients with metastatic melanoma; in these patients, pre-treatment with 

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cyclophosphamide (60mg/kg x 2 days) and fludarabine (25 mg/m2 x 5 days) enabled in vivo engraftment 
and clinical activity55.  
 
Lymphodepleting chemotherapy has become standard for CAR T cell treatment. While initial studies 
allowed investigators to choose among chemotherapy regimens based on patients’ prior treatment 
histories, more recent studies have been more prescriptive with the recognition that the lymphodepletion 
regimen affects clinical activity and toxicity. For example, Turtle et al. compared results obtained in 
sequential cohorts of non-Hodgkin lymphoma patients treated with a CD28-based second-generation 
anti-CD19 CAR following cyclophosphamide with or without fludarabine (Cy vs Cy/Flu)56. Subjects 
receiving Cy/Flu were more likely to have a complete response (50% vs 8%) and exhibited more robust in 
vivo proliferation and more durable in vivo persistence. As might be expected with increased proliferation, 
Cy/Flu was also associated with higher frequency of severe CRS and neurotoxicity, though this toxicity 
agent differential was only apparent in the highest cell-dose cohort. These data suggest that fludarabine 
contributes to in vivo CAR T cell expansion and persistence, leading to increased efficacy but also perhaps 
increased toxicity. However, fludarabine is likely just one of many factors (e.g., cell dose, CAR design 
specifications, target antigen expression, disease burden, pre-manufacturing T cell phenotype) 
contributing to efficacy and toxicity profile of CAR T cell treatment regimens. The optimal 
lymphodepletion regimen likely varies by CAR T cell product and disease and will need to be determined 
empirically through clinical investigation.  
 
The “flu/cy” regimen has developed into one of the standard regimens for lymphodepletion prior to CAR 
T cell administration. In fact, the prescribed lymphodepleting chemotherapy regimen for use with the 
FDA-approved CTL019 therapy in ALL consists of fludarabine (30 mg/m2/day x 4 days) and 
cyclophosphamide (500 mg/m2/day x 2 days, starting with fludarabine).  
 
Phase 1 trial of huCART19 in pediatric ALL patients – 13BT022 
In a Phase 1 trial in children and young adults with relapsed/refractory B-ALL at CHOP (13BT022, 
NCT02374333), 62 subjects have been infused with huCART19 as of April 2018. Infused subjects received 
a single dose of huCART19 (median 6x106 huCART19 cells/kg; range 5.03x105 – 1.38x107 huCART19 
cells/kg) at Day 0, post-lymphodepleting chemotherapy. The huCART19 cells have been well tolerated in 
this population as grade 1-2 cytokine release syndrome have been the most commonly observed related 
adverse events (57%). We observed that huCART19 can induce durable remissions without further 
therapy in this clinical setting. An interval data analysis showed a 100% CR rate (22 out of 22 subjects) in 
patients with no prior CAR T cell exposure, with a 12 month RFS of 82%. In addition, in patients with a 
prior poor or transient response to murine CD19-directed CAR T cells, 56% (9 out of 16 subjects) achieved 
CR with B cell aplasia. A 56% RFS at 12 months was observed in the retreatment cohort57. The safety and 
efficacy on this trial encouraged us to expand our experience with huCART19 in pediatric ALL patients in 
a Phase 2 study that will enroll patients with VHR ALL (Cohort A) and patients with poor response to prior 
B cell-directed cell therapy (Cohort B). 
 
Investigational Agent 
The investigational agent in this protocol is humanized CART19 cells (huCART19). The huCART19 cells will 
be manufactured in the CVPF at UPenn. huCART19 cells will be administered as a single infusion of 2 - 5 x 
106 huCART19 cells/kg. 
 
See the huCART19 Investigator Brochure for additional details.  

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Drug interactions  
huCART19 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. 
 
Preclinical Data 
The preclinical assessment and evaluation of the huCART19 is detailed in the huCART19 Investigator 
Brochure.  
 
Briefly, huCART19 was evaluated for equivalency to murine CART19 in vitro and in vivo. Based on all 
studies performed, huCART19 was determined to be equivalent to murine CART19 in all tests performed 
including killing assays, T cell proliferation assays, cytokine induction and potency assays, as well as in an 
NSG mouse model.  
 
Therefore, based on these preclinical data, huCART19 was believed to be equally potent and safe when 
compared to murine CART19 in a clinical environment.  To date, the clinical data supports this theory as 
no significant safety concerns related to viral transduction or ex vivo expansion have emerged in more 
than 300 pediatric and adult subjects treated with various CARs [mostly murine CART19 but also 
huCART19] at CHOP and Penn.  
 
Previous Clinical Data  
Prior clinical experience and the safety data collected from prior studies are available in the current 
version of the huCART19 Investigator Brochure.  
 
 
Inclusion of children in the research 
Broadly speaking, we feel inclusion of pediatric patients in this pilot protocol where we have initial 
feasibility data is appropriate. This is the approach that is generally pursued in early phase cancer trials 
for three reasons: i) to get clinical experience in pediatric populations, ii) to learn about issues with dosing 
or administration that might be specific to younger patients, and iii) allow pediatric access to novel 
therapies earlier in the development process. The population of pediatric relapsed/refractory leukemia 
patients targeted for enrollment in this study have no curative options for treatment. New and highly 
innovative approaches are desperately needed for this group of pediatric patients. Our initial pediatric 
experience with huCART19 cells demonstrates a powerful signal for potential efficacy, with a 100% CR 
rate and 82% RFS at 1 year in children with relapsed/refractory B-ALL and a 56% CR rate with B cell aplasia 
and 56% RFS at 1 year in children with poor response to prior B cell directed engineered cell therapy57. 
With this, we believe there exist both compelling reasons to include children and the prospect of benefit 
in patients with no curative options. 

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Dose Rationale and Risk/Benefits 
 
Dose Rationale 
The huCART19 transduced cell dose will be targeted at 5x106 huCART19 cells/kg (acceptable dose range 
2x105/kg – 5x105/kg) with a maximum total huCART19 cell dose of 2.5x108 huCART19 cells. These doses 
are based on the global phase 2 trial of CTL019 (NCT02228096). Because there are about 1 x 1012 T cells in 
a healthy adult (equivalent to 2x1010 T cells/kg), assuming a transduction efficiency of 10%, the total cell 
dose is equivalent to about 0.25% of the total body mass of T cells85,86. Therefore, we expect the initial 
frequency of cells to be present at about 0.25% at baseline following infusion.  In addition, in our animal 
models, we find that a dose of 5 million cells per animal causes a robust antitumor response.  The dose 
given to animals, when scaled, is similar to 5x109 cells in humans.    
 
Potential Risks 
Please refer to the current version of the huCART19 Investigator Brochure for expected adverse events. 
 
Potential benefits 
Outcome remains poor for pediatric patients with r/r B cell ALL. Treatment options include further 
treatment with salvage chemotherapy, allogeneic hematopoietic stem cell transplantation (HSCT) or 
supportive care. 
 
Based on inclusion criteria, patients have poor outcomes with standard available therapies. Furthermore, 
most patients will not be eligible for allogeneic transplant.  For ALL patients, there is little benefit from 
allogeneic SCT with relapsed and active disease and pediatric centers do not offer SCT to patients in this 
situation because of futility. Therefore, any benefit that may be seen with CART19 cells will have a major 
impact for patients.  
 
For patients who relapse after allogeneic transplant, treatment options are even more limited and 
outcomes dismal. Conventional chemotherapy is not curative and often highly toxic and ineffective. 
Second allogeneic transplant is associated with extensive morbidity, mortality, high relapse rate, and is 
ineffective for the majority of patients. Donor lymphocyte infusions result in response rates between 0-
13% and there are very few long-term survivors. 
 
Ongoing clinical trials with murine and humanized CART19 cells expressing the second generation CAR 
with an anti-CD19 scFv and 4-1BB and TCR signaling domains, in patients with B-cell ALL and CLL (both 
CD19 expressing B cell malignancies) described above, show that CART19 therapy has potent anti-tumor 
activity in pediatric and adult ALL patients97, 98, 101 (described in detail in Section 1.4). Therefore, the risk 
benefit ratio for huCART19 potential to induce remission in the ALL populations to be studied here is quite 
favorable.  

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(PBMC) for this purpose. As is currently our practice, cells will be transduced with the anti-CD19 TCRζ/4-
1BB lentiviral vector, expanded in vitro and then frozen for future administration. Cryopreserved historical 
apheresis products collected from the patient prior to study entry are usable for huCART19 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 will be scheduled for 
cell procurement after study entry. 
 
Unless contraindicated and medically not advisable based on previous chemotherapy, patients will be 
given conditioning chemotherapy prior to huCART19 cell infusion with the intent of lymphodepletion.  
Additionally, if the patient’s white blood cell (WBC) count is ≤1,000 /µL, conditioning/lymphodepleting 
chemotherapy may be held at investigator discretion. The chemotherapy will be planned so that the last 
dose is completed 2-5 days BEFORE the planned infusion of huCART19 cells.  The chemotherapy start date 
will vary based on the duration of the selected chemotherapy regimen. If the period from chemotherapy 
to huCART19 infusion is delayed for 4 weeks or more, the patient will need to be re-treated with 
lymphodepleting chemotherapy prior to huCART19 infusion.  
 
Two study cohorts are planned: 
1. Cohort A: Patients with newly diagnosed VHR B-ALL or high-risk relapse of B-ALL  
2. Cohort B: Patients with poor response to prior B cell directed engineered cell therapy  
 
Regardless of Cohort assignment, subjects will be followed according to the same schedule.  
 
Additional huCART19 infusions may also be administered in accordance with Section 6.13.  
 
After completing follow-up on this study, subjects will be offered participation on a separate long-term 
protocol for fifteen years post-receipt of huCART19 cells to monitor for safety assessments per the FDA 
guidelines. 
 

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PATIENT SELECTION AND WITHDRAWAL 
 
Inclusion Criteria  
1. Signed informed consent form must be obtained.  
2. Relapsed or refractory B-cell ALL:    
a. Cohort A: Patients with newly diagnosed VHR B-ALL or high-risk relapse of B-ALL who meet 
one of the following criteria: 
i. Newly diagnosed NCI HR B-ALL with induction failure: M3 marrow (>25% blasts) 
at end of induction OR 
ii. First marrow relapse of B-ALL at < 36 months from diagnosis OR 
iii. 2nd or greater relapse OR 
iv. Any relapse after allogeneic HSCT and ≥ 4 months from SCT at enrollment OR 
 
Figure 3-1:  Study Schema 
*If required
**Re-treatment subjects undergo quarterly follow-up 
through one year post-re-treatment
Screening
Apheresis
Manufacturing
Enrollment
Lymphodepleting 
Chemotherapy*
huCART19 infusion
Day 0
Monthly observation/monitoring
Month 2 - Month 6 post-infusion
Tumor response assessment
Day 28
Safety
Research
Quarterly observation/monitoring
up to 1 years post-infusion**
Re-treatment

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v. Refractory disease defined as having not achieved an MRD-negative and/or CSF-
negative CR after ≥ 2 chemotherapy regimens/cycles of frontline therapy or 1 
cycle of reinduction therapy for patients in first relapse OR 
vi. Ineligible for allogeneic SCT because of: 
1. Comorbid disease 
2. Other contraindications to allogeneic SCT conditioning regimen 
3. Lack of suitable donor 
4. Prior SCT 
5. Declines allogeneic SCT as the therapeutic option after documented 
discussion, with expected outcomes, about the role of SCT with a BMT 
physician not part of the study team 
b. Cohort B:  Patients previously treated with B cell directed engineered cell therapy who meet 
one of the following criteria: 
i. partial response or no response to prior cell therapy 
ii. CD19+ relapse after prior cell therapy 
iii. demonstrated early (≤6 months from infusion) B cell recovery suggesting loss of 
engineered cells 
c. Patients with prior or current history of CNS3 disease will be eligible if CNS disease is 
responsive to therapy (at infusion, must meet criteria in Section 5.3) 
3. Documentation of CD19 tumor expression in bone marrow, peripheral blood, CSF, or tumor 
tissue by flow cytometry at relapse (or a recent sample in the case of refractory disease). If the 
patient has received CD19-directed therapy, then the flow cytometry should be obtained after 
this therapy to show CD19 expression. 
4. Adequate organ function defined as: 
a. A serum creatinine based on age/gender as follows:   
 
 
Maximum Serum Creatinine (mg/dL) 
Age 
Male 
Female 
3 months to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1.0 
1.0 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
b. ALT≤ 500 U/L 
c. Bilirubin ≤2.0 mg/dl  
d. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea, < Grade 3 
hypoxia; DLCO ≥ 40% (corrected for anemia) if PFTs are clinically appropriate as determined 
by the treating investigator  
e. Left Ventricular Shortening Fraction (LVSF) ≥ 28% or Ejection Fraction (LVEF) ≥ 
45% confirmed by ECHO, or adequate ventricular function documented by a scan or a 
cardiologist.  
5. Age 3 months to 29 years.   
6. Adequate performance status (Lansky or Karnofsky score ≥50). 
7. Subjects of reproductive potential must agree to use acceptable birth control methods, as 
described in protocol Section 4.3. 

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Exclusion Criteria  
1. Active hepatitis B or active hepatitis C.  
2. HIV Infection. 
3. Active acute or chronic graft-versus-host disease (GVHD) requiring systemic therapy. 
4. Concurrent use of systemic steroids or immunosuppression at the time of cell infusion or cell 
collection, or a condition, in the treating physician's opinion, that is likely to require steroid 
therapy or immunosuppression during collection or after infusion. Steroids for disease treatment 
at times other than cell collection or at the time of infusion are permitted. Use of physiologic 
replacement hydrocortisone or inhaled steroids is permitted as well. 
5. CNS3 disease that is progressive on therapy, or with CNS parenchymal lesions that might increase 
the risk of CNS toxicity.  
6. Pregnant or nursing (lactating) women. 
7. Uncontrolled active infection. 
8. Active medical disorder that, in the opinion of the investigator, would substantially increase the 
risk of uncontrollable CRS or neurotoxicity. 
 
Please refer to the Concomitant Therapy Section 5.7 for windows related to apheresis and huCART19 
infusion. 
 
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.  
 
Female patients of reproductive potential (women who have reached menarche and have not 
experienced treatment-related premature ovarian failure) must have negative serum pregnancy test 
performed at the time of screening and a negative urine pregnancy test within 48 hours of T cell infusion. 
 
 Due to the unknown risks of the CAR T cells with respect to pregnancy, as well as risks associated with 
lymphodepleting chemotherapy, it is recommended that all subjects of reproductive potential use at least 
one medically acceptable form of contraception for at least 1 year after their last infusion of CAR T cells.  
Investigators shall counsel subjects on the importance of pregnancy prevention and the implications of 
an unexpected pregnancy.  
Medically acceptable birth control includes one of the following methods: 
• 
Condoms (male or female) with or without a spermicidal agent 
• 
Diaphragm or cervical cap with spermicide 
• 
Intrauterine device (IUD) 
• 
Hormonal-based contraception 
 
Patients who are not of reproductive potential (females who are pre-menarchal or have experienced 
treatment-related premature ovarian failure or males who have documented azoospermia) do not require 
the use of contraception.  Acceptable documentation of sterilization, azoospermia, and premature 
ovarian failure is specified below: 
 

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Written documentation by clinician or clinician’s staff through one of the following: 
1. Tanner I or age <11 
2. Physician report/letter 
3. Operative report or other source documentation in the patient record (a laboratory report of 
azoospermia is required to document successful vasectomy) 
4. Discharge summary of the sterilization procedure or hysterectomy, and/or salpingectomy, 
oophorectomy 
5. Laboratory report of azoospermia 
6. Follicle stimulating hormone measurement elevated into the menopausal range 
 
Withdrawal of Subjects 
 
When and How to Withdraw Patients 
Subjects who enroll but do not receive huCART19 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 judgment of the principal investigator. 
3. Patient non-compliance with the study therapy and/or clinic appointments.  
4. Pregnancy:  Withdraw subject if pregnancy occurs prior to the huCART19 infusion.  If pregnancy 
occurs after the subject has received huCART19 cells, they will be kept active in the study for 
safety and pregnancy follow-up and outcome.  No subsequent huCART19 infusions will be 
administered.   
5. 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. 
6. Progression of malignancy requiring alternative medical, radiation or surgical intervention. 
7. A serious adverse event that requires the subject be withdrawn from the trial if the SAE occurs 
prior to the huCART19 T cell infusion. 
8. Failure to produce a product that meets the release criteria (other than dose). 
9. Termination of the study 
 
Reasons for discontinuation of subjects after receipt of huCART19 cells include, but are not limited to, the 
below.  Subjects may not be discontinued from primary follow-up prior to the Day 28 safety follow-up visit 
for reasons other than subject withdrawal of study consent or death. 
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. Completion of study follow-up 
6. Termination of the study  
 
Subjects who do not complete the study protocol will be considered to have prematurely discontinued 
the study. The reasons for discontinuation (for example, voluntary withdrawal, toxicity, death) must be 
recorded on the case report form. Final study evaluations will be completed at the time of discontinuation. 

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Data Collection and Follow-up 
Follow-up data collection after gene modified cell therapy clinical trials is specified by the FDA.   
 
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 for protocol 
required analyses.   
 
Every effort will be made to contact patients who appear to be lost to follow-up in order to obtain survival 
data at minimum. 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.  
 
Subjects who complete follow-up as part of this protocol or discontinue participation early for any reason 
(per Section 4.4.1 above), will be encouraged to enroll in a separate 15 year long term follow-up protocol 
to further evaluate long term adverse events related to the investigational product and survival.   
 
Replacement of Subjects 
All subjects who receive huCART19 cells as part of this study will be considered evaluable.  Subjects who 
enroll but do not receive a huCART19 cell infusion will be removed from the study and replaced.   
 
INVESTIGATIONAL PRODUCT 
 
Description 
Humanized CART19 (huCART19) cells are autologous T cells (collected from the patient) that have been 
engineered to express an extracellular single chain antibody (scFv) with specificity for CD19 linked to an 
intracellular signaling molecule comprised of a tandem signaling domain of the 4-1BB and TCRζ signaling 
modules.  
 
Possible toxicities associated with the administration of huCART19 cells include transient fever, chills, 
nausea, and rigors.  In order to minimize these events, subjects will receive premedication as instructed 
below in Section 5.5.  Later toxicities (7-21 days post infusion) are likely to be related to CRS, or possibly 
tumor lysis. Toxicities that could potentially occur but are unprecedented are primarily related to the gene 
transfer are discussed in greater detail in the huCART19 Investigator Brochure. In addition, management 
of such toxicities is described in Section 8.5.   
 
Cohort Assignment  
Cohort assignment will occur at enrollment: 
• 
Cohort A: Patients with newly diagnosed VHR B-ALL or high-risk relapse of B-ALL 
• 
Cohort B: Patients with poor response to prior B cell directed engineered cell therapy  

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Subject Eligibility to Receive huCART19 Transduced Cells 
For Day 0 Infusion: 
1. Disease response: No evidence of high/accelerating disease burden that would, in the opinion 
of the treating physician, put the subject at significant potential risk for uncontrollable CRS or 
neurotoxicity. 
2. All subjects must undergo influenza testing within 10 days prior to the first planned huCART19 
infusion during the October-May influenza season.  The test does not need to be repeated 
prior to subsequent huCART19 infusions. If the subject is positive for influenza, oseltamivir 
phosphate (Tamiflu®) or equivalent should be administered per package insert.  The subject 
must complete treatment prior to receiving the huCART19 infusion.  The test does not need 
to be repeated after treatment, however if influenza signs and symptoms are present, the 
huCART19 infusion should be delayed until the subject is asymptomatic. 
3. Ability to maintain performance status as indicated in initial eligibility criteria. 
4. If s/p allogeneic transplant, > 6 months from transplant. 
5. At least 2 weeks from other investigational treatments. 
6. Subjects experiencing toxicities prior to huCART19 infusion will have their infusion schedule 
delayed until these toxicities have resolved. The specific toxicities warranting delay of T cell 
infusions include: 
a. Pulmonary: Grade 3 or greater hypoxia or presence of radiographic abnormalities 
that are progressive  
b. Cardiac: New cardiac arrhythmia not controlled with medical management 
c. Hypotension requiring pressor support 
d. Neurologic: acute/ongoing neurologic toxicity > Grade 1 with the exception of 
controlled seizures or fixed neurologic deficits that have been stable/improving over 
the prior 3 months 
e. Uncontrolled active Infection 
 
Subjects with CNS3 Disease - Additional Infusion Criteria: 
1. Disease status: 
a. If CNS3 by spinal fluid involvement, stable/responding disease as indicated by: 
i. 
stable or decreasing CSF WBC, and  
ii. 
total CSF WBC < 100 in a sample obtained within 5 days of huCART19 infusion. 
b. If CNS3 by MRI findings, there must be interval stability or improvement on MRI 
within 2 weeks of infusion 
c. If CNS3 by cranial nerve findings, there must be stability or improvement of these 
cranial nerve findings on exam post intervention  
2. Subjects with CNS3 disease requiring radiation therapy must be at least 8 weeks post cranial 
radiation at huCART19 infusion 
3. Subjects must have no acute/ongoing neurologic toxicity > Grade 1 with the exception of a 
history of controlled seizures or fixed neurologic deficits that have been stable/improving 
over the past 3 months 
 
Reinfusion:  
1. Subjects 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.  Fever may delay or preclude infusion. 

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2. Subjects experiencing new laboratory abnormalities that in the opinion of the treating 
investigator or PI feels may impact subject safety or the subjects’ ability to receive huCART19 
T-cells, may have their infusion delayed until both the treating investigator and PI determine 
it is clinically appropriate to proceed with the infusion.  
 
Retreatment Infusion:  
1. Subjects 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.  Fever may delay or preclude infusion. 
2. Subjects experiencing new laboratory abnormalities that in the opinion of the treating 
investigator or PI feels may impact subject safety or the subjects’ ability to receive huCART19 
T-cells, may have their infusion delayed until both the treating investigator and PI determine 
it is clinically appropriate to proceed with the infusion.  
3. All subjects must undergo influenza testing within 10 days prior to their huCART19 
retreatment infusion during the October-May influenza season.  The test does not need to 
be repeated prior to subsequent huCART19 infusions. If the subject is positive for influenza, 
oseltamivir phosphate (Tamiflu®) or equivalent should be administered per package insert.  
The subject must complete treatment prior to receiving their huCART19 infusion.  The test 
does not need to be repeated after treatment, however if influenza signs and symptoms are 
present, the huCART19 infusion should be delayed until the subject is asymptomatic. 
 
huCART19 Treatment Regimen 
Subjects will receive a single dose of huCART19 cells on Study Day 0. A cell dose of 5x106 huCART19 cells/kg 
will be targeted. The acceptable target dose range is 2x105 – 5x106 huCART19 cells/kg, with the maximum 
single dose of huCART19 cells to be administered is 2.5x108. We will use the following schedule: 
 
If the minimum target dose is not achieved in manufacturing, a product that meets all release criteria may 
be infused at the investigator’s discretion. 
 
Timing of additional huCART19 infusions is described in Section 6.13. The same dosing parameters listed 
above for huCART19 will apply for reinfusion/retreatment doses.  
 
Preparation and Administration of huCART19 
In addition to the language below, please see the Investigational Product Handling Manual for further 
details on product thawing, transport, and labeling. 
 
Manufacturing 
huCART19 cell manufacturing is performed at the University of Pennsylvania Clinical Cell and Vaccine 
Production Facility (CVPF) and transported to the Cell and Gene Therapy Laboratory (CGTL) at CHOP.  
 
Transport and CHOP Cell and Gene Therapy Laboratory Activities 
The investigational product is transported in dry ice from the CVPF to the CGTL at CHOP.  The frozen cells 
will be thawed at the CGTL at CHOP, the bag will be washed to recover all remaining volume with 5% HSA, 
the resulting volume will be drawn into a syringe with a new label affixed that includes the investigational 
product name, participant (denoted as DONOR or RECEIPIENT) ID number, expiration date and time, 

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“Caution: New Drug-Limited by Federal Law to Investigational Use”, “For Autologous Use Only”, and “Not 
Evaluated for Infectious Substances”. 
 
Additionally, an aliquot of the reconstituted product is sent for additional sterility testing. Sterility testing 
is not available in real-time prior to subject administration.  If a positive sterility test is reported, the CGTL 
at CHOP will notify the Sponsor Medical Director and PI immediately. 
 
The syringe is then transported to the subject’s bedside for infusion. The final volume transported to 
subject’s bedside will be recorded at the CHOP CGTL. The investigator must notify the Sponsor of any 
damaged or unusable cell products that were supplied to the investigator’s site by the CGTL at CHOP. 
 
Premedication 
Side effects following T cell infusions include transient fever, chills, and/or nausea. It is recommended that 
the subject be pre-medicated with acetaminophen and an antihistamine prior to each CART19 cell 
infusion. Subjects should not receive systemic corticosteroids such as hydrocortisone, prednisone, 
methylprednisolone or dexamethasone at any time, except physiologic doses of hydrocortisone for 
adrenal support or in the case of a life-threatening emergency, since this may have an adverse effect on 
CART19 cell expansion and function.   
 
Additional Safety Procedures Prior to Administration 
Emergency medical equipment must be available during the infusion in case the subject has an allergic 
reaction, or severe hypotensive crisis, or any other reaction to the infusion. Vital signs (temperature, 
respiration rate, pulse, and blood pressure) will be taken before infusion.  
 
huCART19 Product Infusions 
Prior to each infusion, two individuals will independently verify all unique identifier information in the 
presence of the subject and confirm that the information on the product label is correctly matched to the 
participant.  The product will then be checked to the subject per hospital standards. 
 
Trained study staff will administer the huCART19 product by slow IV push via i.v. or central line, prior to 
the expiration date/time identified on the product label.  A leukoreduction filter must not be used for the 
infusion of the CART cell product. The duration of CART19 administration will be based on the total 
volume to be infused and the recommended infusion rate of 10-20mL per minute.  
 
Vital signs (temperature, respiration rate, pulse, blood pressure, and oxygen saturation as clinically 
indicated) will be measured within 10 minutes prior to the infusion and within 15 minutes after the 
infusion. Vital signs will also be measured 15 (+/- 5) minutes, 30 (+/- 5) minutes, 45 (+/- 5) minutes, and 
60 (+/- 5) minutes after the infusion.  If the subject’s vital signs are not satisfactory and stable one hour 
post-CART19 infusion, vital signs will continue to be monitored as clinically indicated until stable.   The 
subject will be discharged when medically stable and in accordance with hospital policy.   
 
Febrile reaction 
In the event of febrile reaction, an evaluation for infection should be initiated, and subjects managed 
appropriately with antibiotics, fluids and other supportive care as medically indicated and determined by 
the treating physician. In the event that the subject develops sepsis or systemic bacteremia following the 
CAR T cell infusion, appropriate cultures and medical management should be initiated.  If a contaminated 

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huCART19 T cell product is suspected, the product can be retested for sterility using archived samples that 
are stored in the CVPF.  Consideration of CRS as the most likely etiology should be given. 
 
Concomitant Therapy 
All prescription and nonprescription medication, vitamins, herbal and nutritional supplements, taken by 
the patient during the 30 days prior to screening/enrollment will be recorded. At every visit following the 
huCART19 infusions and until the subject 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: 
• 
Granulocyte macrophage colony stimulating factor (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. 
• 
Steroids or other immunosuppressant drugs should NOT be used within 48-72 hours (preferably 
7 days) prior to the apheresis procedure. 
• 
Steroids or other immunosuppressant drugs should NOT be used within 48 hours prior to or at 
any time 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. The 
following physiological replacement doses of steroids are allowed: 6-12 mg/m2/day 
hydrocortisone or equivalent.  
• 
Subjects with severe signs and symptoms attributable to CRS should be managed with the 
administration of tocilizumab or other anti-cytokine therapies (Section 8.5.2) for administration 
details. 
• 
Neutropenic subjects will be administered broad-spectrum antibiotics at the start of fever and 
managed as per institutional SOPs. 
 
STUDY PROCEDURES 
Overview 
The schedule of evaluations and study procedures are described in the Schedule of Evaluations 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.  
 
Screening (~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 Schedule of Evaluations 
(Appendix 1). Values obtained in routine clinical care prior to informed consent can also be used for 
screening purposes. 
• 
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 
childbearing status  
• 
Documentation of historical and concomitant medications and significant non-drug therapies 

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• 
Review of prior antineoplastic medications 
• 
Physical exam and measurement of vital signs (height, weight, blood pressure, body 
temperature, respiration rate, and heart rate, and oxygen saturation via pulse oximetry as 
clinically indicated) 
• 
Lansky or Karnofsky performance status 
• 
ECHO  
• 
Blood will be taken for Hematology, Coagulation, and Biochemistry analysis. Viral serologies 
(HIV, Hepatitis B/C). If the HCV antibody is positive, a screening HCV RNA by any RT-PCR or 
bDNA assay must be performed. Eligibility will be determined based on the screening value. 
The test is not required if documentation of a negative result of a HCV RNA test performed 
within 60 days prior to screening is provided. 
• 
Serum pregnancy test for females of child bearing potential 
• 
Serum IgG level 
• 
Pulmonary function Test (DLCO)- if clinically appropriate as determined by the treating 
investigator 
• 
BCR-ABL PCR (Ph+ ALL patients only; as clinically indicated) 
• 
Bone marrow aspirate for disease as described in Appendix 1. If the results of recent testing 
(obtained at the time of the patient’s most recent relapse) are available, these do not need to 
be repeated for enrollment. 
• 
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. If the 
results of a historical lumbar puncture (obtained at the time of the patient’s most recent 
relapse) are available, this does not need to be repeated for enrollment. 
 
In the event that the time between the screening visit and the infusion of huCART19 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.  An ECHO must be performed within 8 weeks prior to the huCART19 infusion if not 
performed earlier. 
 
Subject Enrollment 
Assignment of subject numbers will occur at consent, will be in ascending order (18CT014-01, 18CT014-
02, etc.) and no numbers will be omitted. Subject numbers will be used on all study documentation. 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. 
 
At the time a subject consents to participate in this study, a Consent Notification Form should be 
completed.  Once required screening tests have been completed and the subject has been determined 
eligible by the physician-investigator, provide the documents listed below to:  
 
Protocol Monitor and Sponsor Project Manager 
Center for Cellular Immunotherapies (CCI) 
 
Documents required:  
1. Completed Enrollment Form  
2. Redacted copy of signed patient consent and HIPAA authorization 

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3. Redacted source documentation to confirm enrollment/eligibility (including patient past medical 
history, laboratory, radiological reports, physical exam, concomitant medications and any other 
documentation to support subject met eligibility criteria and has completed all required screening 
assessments).  
 
Upon informed consent completion and receipt of screening and eligibility documentation, a Sponsor 
Monitor will review and provide documentation that monitoring of eligibility has been completed. This 
documentation must be received prior to cell product manufacturing.  
 
Apheresis (~Week -4 to -3)  
After the monitoring visit for eligibility has been completed, a single large volume apheresis procedure 
may be carried out at a FACT-accredited apheresis center. PBMC are obtained for huCART19 
manufacturing during this procedure. From a single leukapheresis, the intention is to harvest up to 50 x 
109 (recommended 2-10x108/kg) cells to manufacture huCART19 T cells. Baseline samples for FDA look-
back requirements and for research are also obtained and cryopreserved. The cell product is expected to 
be ready for release at least 4 weeks after beginning manufacturing.  
 
Historical Apheresis Sample  
Cryopreserved historical apheresis products collected from the patient prior to study entry are usable for 
huCART19 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/µL. If the ALC <500/µL in the apheresis product, it is 
recommended that the CD3 cell count should be ≥ 150/µl for acceptance to begin processing for clinical 
manufacturing to achieve the target dose. 
 
Assessment Types 
 
Demographics, Eligibility Verification, Medical History, Historical and 
Concomitant Medications 
Patient demographics will be recorded on the demography source documents. A physician-investigator 
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 enrollment) 
concomitant medications. 
 
Physical Exam 
A complete physical examination will be performed 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. Statements of “normal or WNL” will indicate lack of involvement. Height 
will be measured in centimeters and weight will be measured in kilograms.  
 
Significant findings that are present prior to receipt of the investigational product must be included on 

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Additional Assessment of Laboratory Parameters for CRS  
Hematology, coagulation and chemistry safety assessments will be performed at study visits according to 
Appendix 1.  
 
As noted, side effects following CART19 cell infusions can induce high fevers and should be expected. If 
fevers are observed following huCART19 infusion, it is recommended that ferritin and CRP levels be 
monitored daily until resolution of the fever. Other chemistry parameters should be monitored per 
Appendix 1 or as clinically indicated if CRS is suspected.  
 
Viral Serology 
Blood will be taken for HIV, Hepatitis B, and Hepatitis C at baseline.  If the HCV antibody is positive, a 
screening HCV RNA by any RT-PCR or bDNA assay must be performed. Eligibility will be determined based 
on the screening value. The test is not required if documentation of a negative result of a HCV RNA test 
performed within 60 days prior to screening is provided. 
 
Serum Immunoglobulin Levels 
Peripheral blood will be sampled at screening and according to Appendix 1, for analysis of serum 
immunoglobulin.  
 Pregnancy Testing 
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, 
must use an effective contraception (see Section 4.3 for details).  For women of childbearing potential, a 
serum pregnancy test (β-HCG) will be performed at screening according to Appendix 1.  During treatment, 
an additional pregnancy test will be performed within 48 hours prior to the first huCART19 infusion. 
Subjects should be instructed to inform their doctor 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 huCART19 T cell infusion, subjects must be withdrawn from 
the study. 
 Research Assessments to Assess Engraftment, Persistence and 
Bioactivity 
The following assessments will be performed according to Appendix 1 and will be analyzed at the 
Translational and Correlative Studies Laboratory (TCSL). These tests may include:  
• 
Serum Cytokines  
• 
DNA qPCR for huCART19 persistence 
• 
Flow cytometry for huCART19 
 
RCL VSV-G testing will not be routinely performed as of Protocol V2.  Blood samples will be collected and 
banked at pre-infusion and post-infusion at Months 3, 6, and 12.  These samples may be used for future 
RCL VSV-G testing if indicated.  
 
Sample Handling 
Samples will be delivered, processed, and frozen as per SOP to the TCSL at the University of 
Pennsylvania. Samples will be stored for banking and bulk analyses.  Documentation for sample receipt, 
processing, and storage and primary data from the research analyses will be collected and stored.  
 

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Translational and Correlative Studies Laboratory, 
University of Pennsylvania 
 
 
 
Unscheduled Research Sample Collections 
Beyond the research sample collections scheduled for specific time points, up to 45 mL (3 tablespoons) of 
additional peripheral blood may be drawn twice per week to better characterize correlates of clinical 
events such as cytokine release syndrome. Marrow/LN collections would not exceed more than one 
procedure per month at physician’s discretion. In addition, samples obtained during procedures 
performed for standard clinical indications (e.g., bone marrow samples, etc.) may be diverted for research 
use if such diversion does not substantially increase the risk of the procedure or compromise standard 
clinical diagnostic studies.   
 
Cytoreductive/Lymphodepleting Chemotherapy 
Prior to huCART19 cell infusion, an additional chemotherapy cycle is planned. While the choice of 
chemotherapy will be at the investigator’s discretion depending on the patient’s underlying disease and 
prior therapies, fludarabine (30 mg/m2/day x 4 days) and cyclophosphamide (500 mg/m2/day x 2 days) 
are the preferred agents, as there is the most experience with the use of these agents in facilitating 
adoptive immunotherapy on completed and ongoing pediatric CART19 trials. In addition, this is the 
lymphodepleting chemotherapy regimen prescribed with the FDA-approved CART19 therapy in ALL, 
Tisangenlecleucel (Kymriah™).  
 
**Note, the lymphodepleting chemotherapy prior to huCART19 cell infusion is NOT required if patient’s 
WBC ≤ 1,000 /µL. Additionally, if the period between chemotherapy and huCART19 infusion is delayed 4 
or more weeks, the patient may need to be re-treated with lymphodepleting chemotherapy prior to 
huCART19 infusion. 
 
The chemotherapy will be planned so that the last dose is completed approximately 2-5 days BEFORE the 
planned infusion of huCART19 cells. The purpose of the chemotherapy is to induce lymphopenia in order 
to facilitate the engraftment and homeostatic expansion of huCART19 cells.  In addition, chemotherapy is 
intended to control the ALL. The chemotherapy is not investigational and may be given by a patient’s local 
oncologist within the specified time frame. 
 
All patients must undergo influenza testing within 10 days prior to the first planned huCART19 infusion 
during the October-May flu season. If the patient is positive for influenza, oseltamivir phosphate or 
equivalent should be administered per package insert.  The patient must complete this course of 
treatment prior to receiving huCART19.  The test does not need to be repeated after treatment, however 
if influenza signs and symptoms are present, the huCART19 infusions should be delayed until the patient 
is asymptomatic.     
 
Pre-Infusion Evaluation (Day -1) 
Subjects will undergo a Pre-Infusion Evaluation on Day -1 prior to their huCART19 infusion as outlined in 
the Schedule of Evaluations in Appendix 1.  

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huCART19 Infusion (Day 0) 
Subject infusions are to begin 2 to 5 days after completion of chemotherapy as indicated in Section 6.5.  
Subjects will undergo tests and procedures in accordance with the Schedule of Evaluations 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. Subjects 
will be pre-medicated as described in Section 5.5. huCART19 cells will be infused as described in Section 
5.4. 
 
Post-Infusion Follow-up Visits  
Subjects will return to the clinic for safety follow-up and to have blood drawn for evaluation of the safety 
endpoints and secondary endpoints as outlined in the Schedule of Evaluations in Appendix 1.  
 
Additional blood work for research evaluation may be requested at any time at the investigators’ 
discretion, and is especially encouraged whenever there is a clinical concern for a potential toxicity related 
to CAR T cells.  
 
Day 28: Follow Up 
At the Day 28 visit, subjects will undergo tests and procedures in accordance with the Schedule of 
Evaluations in Appendix 1.  Tumor response assessments will be done according to National 
Comprehensive Cancer Network (NCCN) v1 2013 guidelines (Section 6.15). 
 Monthly Evaluations 2 to 6 Months Post Infusion 
Subjects will follow-up with a study doctor or their primary oncologist on a monthly basis during months 
2 to 6 post huCART19 cell infusion.  At these study visits, subjects will undergo tests and procedures in 
accordance with the Schedule of Evaluations in Appendix 1.  Tumor response will be measured according 
to Sections 6.14 and 6.15 at Months 3 and Month 6. 
 Quarterly Evaluations for Up to 1 Year Post Infusion 
Thereafter, subjects will be evaluated on a quarterly basis until 1 years post infusion. At these study visits, 
subjects will undergo tests and procedures in accordance with the Schedule of Evaluations in Appendix 1. 
Tumor response will be measured according to Sections 6.14 and 6.15 at Months 9 and 12. 
 Long-term Follow-up 
All subjects who receive CAR T cells will be encouraged to enroll in a separate 15 year long term follow-
up protocol to further evaluate long term adverse events related to the investigational product at the 
time of discontinuation from the parent study and disease status/overall survival. Long-term follow-up 
includes evaluations that will be performed for up to 15 years on all subjects as recommended by the FDA 
for protocols utilizing integrating viral vectors.  
 Additional huCART19 Infusions 
Timing and doses of additional CART19 infusions 
For patients who have had i) evidence of brief B cell aplasia with subsequent B cell recovery (suggesting 
rapid CAR clearance), or ii) fever and other reversible toxicities without evidence of CAR expansion/LGLs, 
or iii) a partial or temporary response to the initial infusion, it may be that the initial dose of cells was not 

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adequate to produce a full therapeutic effect, or the cells may not have persisted long enough to produce 
longer-term disease control. In these cases, it may be appropriate to give more huCART19 cells. Additional 
huCART19 cells may be given no earlier than Day 14 and no less than 14 days from a prior infusion.  
Additional infusions will be administered as outlined below. 
 Reinfusions 
Subjects in continued remission may receive additional huCART19 infusion(s) at the physician-
investigator’s discretion.  Subjects must be evaluated by a physician-investigator for eligibility to receive 
additional huCART19 infusions according to criteria in Section 5.3.  If performed, these additional infusions 
will be defined as “reinfusions’.  For the purposes of study timepoint identification and reporting, each 
reinfusion will be considered  a new treatment number (i.e. the first huCART19 infusion on Day 0 will be 
Treatment #1, the first reinfusion post Day 0 will be Treatment #2, the second reinfusion post Day 0 will 
be Treatment #3, etc).   
 
If reinfusions are administered, additional safety follow-up visits are required.  While all study visits will 
continue to be calculated based on the date of the initial huCART19 cell infusion (Day 0), subjects will also 
enter into a Reinfusion Section of the Schedule of Evaluations at the time reinfusion of huCART19 cells is 
initiated.  Where Reinfusion Study Visits may overlap with existing study timepoints (i.e. Reinfusion Day 0 
may overlap with the Month 3 study timepoint), all study tests/procedures required for both visits should 
be completed per protocol requirements but will not be duplicated.  When post-reinfusion follow-up is 
completed per protocol. The subject will resume the study follow-up timepoints per the Primary Schedule 
of Evaluations.  Additional follow-up post reinfusion may also be performed per physician-investigator 
discretion. 
   
Both study visit identifiers will be used for data collection/reporting purposes (i.e. continuous study visit 
day and reinfusion visit timepoint).  Please refer to the Schedule of Evaluations in Appendix 1.  
 Retreatment 
Subjects who relapse post huCART19 infusion may also receive additional huCART19 infusions post-
relapse at the physician-investigator’s discretion.  Subjects must be evaluated by a physician-investigator 
for eligibility to receive additional huCART19 infusions according to criteria in Section 5.3.  If performed, 
additional infusions administered post-relapse will be defined as “retreatment”.   
 
If a decision is made to retreat a subject post-relapse, the subject will officially discontinue the Primary 
Schedule of Evaluations (Appendix 1) at the time of their first retreatment study visit/procedure (i.e. 
lymphodepleting chemotherapy) and enter the Retreatment Schedule of Evaluations (Appendix 2). 
Retreatment study visit timepoints will be distinguished from the primary Schedule of Evaluations by a “-
R” identifier (i.e. Day 0-R, Day 1-R, etc). Follow-up will continue under the Retreatment Schedule of 
Evaluations for up to 12 months post retreatment. 
 
Subjects in continued remission post-retreatment may also receive additional huCART19 infusions at the 
physician-investigator’s discretion. Subjects must be evaluated by a physician-investigator for eligibility to 
receive additional CART19 cell infusions according to criteria in Section 5.3. If performed, these additional 
infusions post-retreatment will be defined as “reinfusions”. For the purposes of study timepoint 
identification and reporting, each reinfusion post-retreatment will be considered a new treatment 
number under the Retreatment Schedule of Evaluations (i.e. the first huCART19 retreatment infusion on 

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Day 0-R will be Treatment #1, the first reinfusion post Day 0-R will be Treatment #2, the second reinfusion 
post Day 0-R will be Treatment #3, etc).  
 
If reinfusions are administered, additional safety follow-up visits are required. While all study visits will 
continue to be calculated based on the date of the retreatment CART19 cell infusion (Day 0-R), subjects 
will also enter into a Reinfusion Section of the Retreatment Schedule of Evaluations at the time reinfusion 
of CART19 cells is initiated. Where Reinfusion Study Visits may overlap with existing study timepoints (i.e. 
Reinfusion Day 0 may overlap with the Month 3-R study timepoint), all study tests/procedures required 
for both visits should be completed per protocol requirements but will not be duplicated. When post-
reinfusion follow-up is completed per protocol, the subject will resume the study follow-up timepoints 
per the Retreatment Schedule of Evaluations.   Additional follow-up post reinfusion may also be 
performed per physician-investigator discretion.   
 
Both study visit identifiers will be used for data collection/reporting purposes (i.e. continuous retreatment 
study visit day and reinfusion visit timepoint). Please refer to the Retreatment Schedule of Evaluations in 
Appendix 2 for additional information. 
 Efficacy Assessments  
Tumor response assessments will be done at baseline (prior to huCART19 infusion) and then at Day 28 
and Months 3, 6, 9 and 12 after huCART19 cell infusion or until the patient requires alternative therapy 
for their disease. Assessments will be made as clinically indicated by physical exam, chest x-ray (if clinically 
indicated), 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 (assessments are all standard of care) 
Procedure 
Pre-Infusion 
Assessments 
Post Infusion Assessments 
Bone marrow aspirate and biopsy 
for blast cell counts 
~Day -5 to Day -1 (and after 
start of LD chemotherapy) 
Day 28, Months 3, 6, 9 and 12 
Peripheral Blood for blast, 
neutrophil and platelet cell counts 
Mandated 
Day 28, Months 3, 6, 9 and 12 
CNS Evaluation2  
If clinically indicated at 
Screening/Enrollment1; 
Mandated at Day -1 
Mandated at Day 28; then as clinically 
indicated at subsequent evaluations 
Physical Exam for extramedullary 
disease 
~Day -5 to Day -1 (and after 
start of LD chemotherapy) 
If clinically indicated 
MRD assessment of bone marrow 
by flow cytometry (every patient) 
~Day -5 to Day -1 (and after 
start of LD chemotherapy) 
Day 28, Months 3, 6, 9 and 12 
BCR-ABL assay of blood and bone 
marrow aspirate for patients with 
Ph+  ALL 
As clinically indicated 
Day 28, Months 3, 6, 9 and 12- as 
clinically indicated 
**Lymph node aspirate performed as clinically indicated. 

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1- 
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. If the results of a historical lumbar puncture (obtained at the time of the 
patient’s most recent relapse) are available, this does not need to be repeated for enrollment. 
2- 
If CNS symptoms are present, additional testing may be required as per clinical discretion.  This may include a lumbar 
puncture and brain imaging by MRI/CT. 
 Physical Exam 
A physical examination will be used to assess evidence of extramedullary disease in the liver, spleen, 
lymph node, skin, gum infiltration, testicular involvement and other sites if applicable. The scope of 
assessments performed as part of this evaluation is based on the physician’s clinical discretion. 
Extramedullary involvement is to be assessed pre-infusion and will be followed as clinically appropriate. 
 Bone Marrow Aspirate/Biopsy and Peripheral Blood 
Bone marrow biopsies and aspirate will be measured for tumor evaluations and efficacy analysis per 
Appendix 1.  
 Cerebrospinal Fluid (CSF) Assessment  
If CNS symptoms are present at Screening/Enrollment, a lumbar puncture will be performed to assess CNS 
leukemic involvement. CNS evaluations will also be performed at baseline (Day -1) and on Day 28. If CNS 
symptoms are identified at these timepoints, additional testing may be performed as per clinical 
discretion. Subsequent CNS evaluations and CSF assessments will be performed as clinically indicated (i.e. 
if CSF involvement previously confirmed or by the presence of neurologic symptoms). Additionally, CSF 
may be assessed as clinically indicated during the height of CRS.  
 
CSF will be analyzed for cell count and differential, cytology, and for the presence of huCART19 cells. 
 Extramedullary Disease 
If extramedullary disease is present prior to treatment, this will be followed as clinically appropriate. 
 Minimal Residual Disease (MRD)  
All patients will have multiparameter flow cytometry on bone marrow aspirate for MRD status at each 
time point a bone marrow aspirate is performed (Appendices 1 + 2).  
 Quantitative BCR-ABL: Ph+ ALL Patients 
If clinically indicated, bone marrow aspirates sampled at the time points for tumor assessments will 
additionally be analyzed for quantitative BCR-ABL levels for Ph positive ALL patients only.   
 ALL Response Criteria 
The response criteria will be evaluated accordingly 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) and the International Working Group (IWG) guideline for acute myeloid leukemia (AML). 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. 
 

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Efficacy assessments (Section 6.14) will be performed based on bone marrow and blood morphologic 
criteria, physical examination findings, and imaging (as clinically indicated), 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% leukemic blasts by morphology 
(confirmed by flow cytometry) 
Peripheral blood 
Neutrophils > 1.0 x 109/L, and 
Platelets > 100 x 109/L, and 
Circulating leukemic blasts  < 1% by morphology (if blasts present, must be 
confirmed by flow cytometry) 
Extramedullary disease 
No evidence of extramedullary disease (no CNS disease, mediastinal 
disease, 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 
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 leukemic blasts in the blood (≥ 1% by morphology, must 
be confirmed by flow cytometry), or  
Reappearance of leukemic blasts in bone marrow (≥ 5% by morphology, 
confirmed by flow cytometry), or 
(Re-)appearance of any extramedullary disease after CR 
Note: 

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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)94 
guideline. The difference between PD and “No response” in ALL is not believed to be clinical meaningful. 
 
B cell aplasia status: In addition to disease response defined above, all patients will be evaluated for B cell 
aplasia status at pre-infusion and each response assessment time point thereafter.  In particular, 
achievement of B cell aplasia will be the key biologic response endpoint for subjects who are enrolled in 
continued remission but have demonstrated B cell recovery after prior therapy with engineered T cells. B 
cell aplasia is defined as less than 3% of peripheral blood lymphocytes are CD19+ or an absolute CD19+ 
lymphocyte count of less than 50/µL. 
 
STATISTICAL PLAN 
 
Design Overview  
This is a two cohort, open-label, phase 2 study to determine the efficacy of huCART19 in pediatric and 
young adult patients with CD19-expressing relapsed and refractory B-cell acute lymphoblastic leukemia. 
 
Sample Size Justification  
This is a phase 2 study of huCART19 to determine the efficacy of huCART19 in relapsed/refractory B-ALL. 
The primary endpoint of 1-year EFS will be determined in 2 cohorts based on exposure to prior B cell 
directed engineered cell therapy. 
 
A total of 100 infused subjects is targeted. Cohort A will enroll up to approximately 62 patients with newly 
diagnosed VHR B-ALL or high-risk relapse of B-ALL to achieve a sample size of 52 infused patients for the 
primary endpoint; Cohort B will enroll up to approximately 54 patients with poor response to prior B cell 
directed engineered cell therapy to achieve a samples size of 48 infused patients. For cohort A, the null 
hypothesis is 40% 1-year EFS and the alternative hypothesis is 60% 1-year EFS. The sample size of 52 
provides 95% power to test this hypothesis, using a one-sided one-sample Log-rank test with 10% type I 
error, assuming 1 year of follow up for each patient95. For cohort B, the null hypothesis is 15% 1-year EFS 
and the alternative hypothesis is 30% 1-year EFS. The sample size of 48 provides 91% power to test this 
hypothesis, using a one-sided one-sample Log-rank test with 10% type I error, assuming 1 year of follow 
up for each patient. We expect that we could infuse approximately 85% of enrolled patients, so we will 
enroll approximately 62 patients for cohort A and approximately 54 patients for cohort B to obtain the 
targeted number of infused patients. 
 
Analysis Sets 
• 
The Enrolled Set comprises all subjects who sign an informed consent form and are confirmed 
eligible for the study (i.e. excluding screen failure patients). 
• 
The Full Analysis Set (FAS) comprises all subjects who received the huCART19 cells. The FAS will 
be used for all the analyses, including the primary, secondary, and exploratory analyses. 
 
Definitions relevant to the Analysis Sets: 
1) Screen failure - Any patient who fails to meet the inclusion/exclusion criteria specified by the 
protocol.   

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2) Manufacturing failure – Any patient who has manufactured huCART19 cells that do not meet 
the manufacturing release criteria.   
 
Analysis of Primary Objective  
The primary endpoint is the 1-year Event-Free Survival in patients with newly diagnosed VHR B-ALL or 
high-risk relapse of B-ALL (cohort A) and in patients with poor response to prior B cell directed 
engineered cell therapy (cohort B). Time to event or censoring is defined as the time from infusion to 
the first of any of the following events: no response, relapse, death due to any cause, or to the last day 
of follow up if no event occurs. All analyses will be performed for cohort A and B separately. Kaplan-
Meier (KM) curves will be generated and one-sample Log-rank test will be used to test the 1-year EFS 
against the historical rate. One-year EFS and its 95% confidence interval (CI) will also be estimated based 
on the KM method. 
 
Analysis of Secondary Objectives  
• 
Overall remission rate is determined by the response at day 28, computed as the proportion of 
subjects with CR or CRi according to the response criterion described in Section 6.15. The 
proportion and its 95% CI will be calculated. 
• 
2-year EFS with 95% CI will estimated based on the KM method. 
• 
Relapse-free Survival (RFS) is defined as the time from achievement of remission (CR or Cri) to 
the date of relapse or death due to ALL, or censored at the last day of follow-up. Relapse-free 
Survival will be assessed only in subjects with the best overall response of CR or CRi. KM curves 
will be generated and 2-year relapse-free survival with its 95% CI will be estimated. 
 
All adverse events, CRS, and neurotoxicity will be summarized based on the incidence rate as the main 
source to characterize the safety profile of huCART19 administration.  After completing post-infusion 
follow-up on this study, subjects will be asked to participate in a separate destination long-term follow-
up study for up to 15 years after their first huCART19 infusion.  Response data from this study may be 
used to support analysis of the 2-year EFS and RFS secondary objectives above. 
 
Analysis of Exploratory Objectives 
A nonlinear mixed effect model describing huCART19 expansion followed by biphasic decline will be fit to 
the qPCR cellular kinetic data.  Descriptive statistics will be calculated for change over time as absolute 
values or fold change. Summary statistics will also be provided for measures of anti-CAR antibodies and 
cellular immunogenicity, and measures of checkpoint pathways (e.g. PD-1, CTLA-4, Tim-3, LAG-3) at time 
points before and after infusion. 
 
SAFETY AND ADVERSE EVENTS 
 
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.  
 

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Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• 
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: Treatment on an emergency outpatient basis that does not result in hospital admission and involves 
an event not fulfilling any of the definitions of a SAE given above is not a serious adverse event.   
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.  They may jeopardize the 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, and severity and/or frequency of the event, is 
not consistent with the risk information described in the investigator brochure or protocol.  Please refer 
to the huCART19 Investigator Brochure for complete details.    
 
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. Related adverse events will be classified as possibly related, probably related, and definitely 
related:  
• 
Possibly Related: There is some evidence to suggest a causal relationship, however other factors 
may have contributed to the event.  
• 
Probably Related: There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely.  

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• 
Definitely Related: There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out.  
 
Adverse Event Reporting Period 
Collection of adverse events will begin at the time of apheresis and will continue until the subject is off-
study.  For subjects who do not undergo apheresis on this study (i.e. historical apheresis product is 
available), adverse event reporting will begin on Day 0 (from the start of the first huCART19 infusion) until 
the subject is off-study.   
 
If a subject is taken off study within 30 days of the T-cell infusion, all SAEs experienced within 30 days 
after the T-cell infusion should be reported to the sponsor. Any SAEs experienced after this 30 day period 
should be reported to the sponsor if the investigator suspects a causal relationship to the study treatment.  
 
Preexisting Condition/General Physical Examination Findings 
A preexisting condition is one that is present at the start of the Adverse Event Reporting Period.  All 
clinically significant abnormalities 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 
or test result corresponds to a sign/symptom of an already reported adverse event, it is not necessary to 
separately record the lab/test result as an additional event. Laboratory abnormalities, that do not meet 
the definition of an adverse event, should not be reported as adverse events. A Grade 3 or 4 event (severe) 
as per CTCAE does not automatically indicate a SAE unless it meets the definition of serious as defined 
above and/or as per investigator’s discretion. Whenever possible, a diagnosis, rather than a symptom 
should be provided (i.e. anemia instead of low hemoglobin).   
 
Recording of Adverse Events 
Safety will be assessed by monitoring and recording potential adverse effects of the treatment using the 
Common Terminology Criteria version 5.0 (CTCAE v5.0) 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 

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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 separately if a diagnosis can be 
assigned. The safety team may require events be reported separately if they occur as SAEs (or in the context 
of a SAE) even if they can also be considered a constituent of another AE such as CRS. 
 
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/unsuspected) or Yes (a suspected adverse reaction)].  If yes (suspected) - is the event 
possibly, probably or definitely related to the investigational treatment?  
4. Expectedness to study treatment- [Unexpected- if the event severity and/or frequency is not 
described in the investigator brochure and protocol (in the absence of an investigator 
brochure)]. 
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.  
 
Progression of malignancy, documented appropriately in the medical records, should not be reported as 
a serious adverse event.  Adverse events that occur concurrently with the progression of malignancy but 
that are not related to disease progression (i.e. deep vein thrombosis or hemoptysis) will be reported as 
an adverse event as described above.  Progression of malignancy resulting in death should be reported as 
a serious adverse event. 
 
Serious adverse events that are still ongoing at the end of the adverse event reporting period must be 
followed to determine the final outcome.  Any serious adverse event that occurs after the adverse event 
reporting period and is considered to be possibly related to the study treatment or study participation, 
should be recorded and reported. 
 
Grading System of Cytokine Release Syndrome (CRS)  
A protocol specific grading system (Table 8-1) has been developed to capture cytokine release syndrome 
in CAR T-cell protocols.  Please refer to the current version of the huCART19 Investigator Brochure for 
additional detail on CRS in CAR T-cell therapy.   

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Follow-up information should be submitted as an amendment to the initial SAE form, and should include 
both the follow-up number and report date.  The follow-up information should describe whether the 
event has resolved or continues, if there are any changes in assessment, if and how it was treated, and 
whether the patient continued or withdrew from study participation.  
 
Report serious adverse events by email to: 
Attention: Clinical Safety Manager or designee 
Center for Cellular Immunotherapies (CCI) 
University of Pennsylvania 
 
At the time of the initial notification, the following information should be provided: 
• 
Study identifier 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current subject status 
• 
Whether study treatment was discontinued 
• 
The reason the event is classified as serious 
• 
Investigator assessment of the association 
between the event and study treatment 
• 
Expectedness relative to investigational 
product(s) 
 
Investigator Reporting:  Notifying Local Regulatory Committees 
Notify the local site regulatory review committees as per institutional requirements.  
 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must be 
reported to protocol sponsor within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of the birth, 
and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. If a pregnancy occurs on study, this will be reported as an SAE using 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. 
 
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 huCART19 cells would define a stopping rule. The 
review of these adverse events, and any decision to prematurely stop subject enrollment, will be 
determined by the Sponsor. 
 
In addition to the above, premature termination of the clinical trial may occur because of a regulatory 
authority decision, change in opinion of the DSMB or local regulatory review committees, 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. 

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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. 
• 
Grade 5 CRS is observed in 2 out of the first 3 subjects, 3 out of the first 8 subjects, 4 out of the 
first 14 and 5 at any time. 
• 
Grade 4 neurotoxicity that does not resolve to Grade 1 within two weeks, observed in 2 out of 
the first 3 subjects, 3 out of the first 8 subjects, 4 out of the first 14, and 5 at any time. 
• 
Grade 4 GVHD is observed in 2 out of the first 3 subjects, 3 out of the first 8 subjects, 4 out of 
the first 14 and 5 at any time. 
• 
Premature study termination may occur if the Investigator, Sponsor, DSMB, ACC 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 decides to discontinue the development 
of the intervention to be used in this study.  
 
The stopping rules for CRS, neurotoxicity and GVHD were calculated based on the lower limit of the 90% 
confidence interval exceeding 10%.  
 
General Toxicity Management Considerations 
Replication-competent lentivirus (RCL). 
RCL may in theory be generated during the CAR T cell manufacturing phase or subsequently after 
introduction of vector transduced cells into the subject. 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 to confirm that the vector is RCL negative before it can be released for use in 
product manufacture. Though theoretical, development of RCL could pose a risk to both the subject and 
their close contact(s), and therefore, samples will be archived during the course of the trial. In the event 
of a suspected RCL, measures to detect RCL will be followed as per the recent FDA guidance, Testing of 
Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During 
Product Manufacture and Patient Follow-up.    
 
Clonality and insertional oncogenesis   
Monitoring for T cell clonal outgrowth will be performed by qPCR for huCART19 and by CBC count.   
huCART19 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. 
 
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. 

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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 corticosteroids97.  If uncontrolled T cell proliferation occurs (grade 3 or 4 toxicity related to CAR T 
cells), subjects may be treated with corticosteroids. Subjects will be treated with pulse methylprednisolone 
(2mg/kg i.v. divided q12 hr x 2 days), followed by a rapid taper. 
 
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. 
 
Infusion reaction  
Acetaminophen and an antihistamine may be repeated every 6 hours as needed. It is recommended that 
patients not receive treatment-dose corticosteroids at any time, except as per the CRS algorithm, since 
this may have an adverse effect on huCART19 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 
huCART19 T cell product is suspected, the product can be retested for sterility using archived samples that 
are stored in the CVPF.  Consideration of CRS (see below) should be given.   
 
Cytokine Release Syndrome (CRS)/Macrophage Activation Syndrome (MAS)  
Tocilizumab should be used as a single, weight-based dose of 8-12 mg/kg at the time of hemodynamic 
instability (as per Tocilizumab package insert).  This management approach is designed to avoid life-
threatening toxicities, so 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 huCART19 function and efficacy, if 
used, they should be rapidly tapered.  
 
Upon developing the prodrome of high-persistent fevers following huCART19 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 
 

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Not all Grade 4 CRS reactions following CD19-targeting CAR T cells have been immediately treated with 
tocilizumab and decisions are, in part, based upon the rapidity of the syndrome onset and underlying 
patient reserve. 
 
Please refer to Table 8-4 below for the CRS Treatment Algorithm. 
 
CRS has been associated with biochemical and physiologic abnormalities consistent with MAS.  Moderate 
to extreme elevations in serum C-reactive protein (CRP) and ferritin have been seen with CART19 
associated CRS, however the magnitude and kinetics vary greatly between individual patients.  CRS 
management decisions should be based upon clinical signs and symptoms and response to interventions, 
not these laboratory values per se. 
 
CTCAE grading of CRS relates to its occurrence with acute infusional toxicities, whereas the CRS associated 
with CART19 therapy is not acute, but rather delayed. Refer to Section 8.2 and Table 8-1 for modified 
definitions of grading of huCART19 delayed CRS events.  
 
Table 8-4:  CRS Treatment Algorithm  
Pretreatment 
 
Acetaminophen/paracetamol and diphenhydramine /H1 anti-histamine 
 
Prophylaxis for complications of TLS as appropriate 
CART19 infusion 
 Prodromal syndrome: low grade fevers, fatigue, anorexia (hours to days) 
 
Observation, rule out infection (surveillance cultures) 
 
Antibiotics per local guidelines (febrile neutropenia) 
 
Symptomatic support 
 Symptom progression: High fevers, hypoxia, mild hypotension 
 1st Line Management: 
 
Oxygen, fluids, low dose vasopressor support, antipyretics 
 
Monitor/manage complications of TLS 
 Further symptom progression: 
• 
Hemodynamic instability despite intravenous fluids and moderate to “high dose” vasopressor support OR 
• 
Worsening respiratory distress, including pulmonary infiltrates increasing oxygen requirement including 
high-flow Oxygen (O2) and/or need for mechanical ventilation OR 
• 
Rapid clinical deterioration 
 2nd Line Management: 
 Tocilizumab: IV infusion over 1 hour 
• 
Patient weight < 30 kg: 12 mg/kg i.v. 
• 
Patient weight ≥ 30 kg: 8 mg/kg i.v. (max dose 800 mg) 
 
Hemodynamic and respiratory support 
 Lack of clinical improvement while awaiting tocilizumab response 
 3rd Line Management: 
     Consider other diagnosis causing clinical deterioration (i.e. sepsis, adrenal insufficiency) 
 
If no improvement with 1st dose of tocilizumab within 12 to 18 hours, consider steroids (plan rapid taper after 
        hemodynamic normalization): 
 
2 mg/kg methylprednisolone as an initial dose, then 2 mg/kg per day. As steroids are tapered quickly, 
         monitor for adrenal insufficiency and need for hydrocortisone replacement 
 
If no response to steroids within 24 hours, consider 2nd dose of Tocilizumab (dosed as above) 
 
Hemodynamic and respiratory support 

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 Lack of clinical improvement while awaiting response to 3rd line management 
 4th Line Management: 
 
Consider other diagnosis causing clinical deterioration (i.e. sepsis, adrenal insufficiency) 
 
If no response to steroids and 2nd dose of tocilizumab within 24 hours or further clinical deterioration, consider   
        siltuximab 11 mg/kg IV over 1 hour 
 
Hemodynamic and respiratory support 
 
Lack of clinical improvement while awaiting response to 4th line management 
 
5th Line Management: 
 
Consider other diagnosis causing clinical deterioration (i.e. sepsis, adrenal insufficiency) 
 
In ongoing CRS despite prior therapy, consider anti-T cell therapies such as cyclophosphamide, 
 
anti-thymocyte globulin, or alemtuzumab 
 
Hemodynamic and respiratory support 
 
Neurologic Toxicity 
Guidelines for grading and management of neurologic toxicity are described in Table 8-3 and Table 8-5, 
respectively. The mechanism underlying neurotoxicity after CAR T cell administration is poorly 
understood. Anecdotal evidence suggests that anti-IL6 therapies, which are effective for CRS, do not 
prevent or reverse neurotoxicity. Neurotoxicity can be asynchronous with cytokine release syndrome, 
often reaching its maximum intensity later than CRS or even arising after resolution of CRS. The following 
principles guide the recommended management of neurotoxicity: 
– Most instances of neurologic toxicity are self-limited, but life-threatening complications such 
as cerebral edema develop in some cases of patients treated with other CAR products, such as 
JCAR01598 . This has not been seen in children treated with huCART19 or murine CART19 
(CTL019) at CHOP or on the multisite trials. Corticosteroid therapy has not been necessary in 
any pediatric patient with moderate (grade 2-3) neurotoxicity. The efficacy of corticosteroids 
is unproven, and corticosteroids may adversely affect CAR T cell efficacy, so a risk-benefit 
determination must be made by the CAR team and treating physician. In exceptional 
circumstances, cytotoxic chemotherapy could be considered in grade 4 cases based on a report 
that cerebral edema improved promptly after cyclophosphamide chemotherapy in one case99. 
– Consultation with a neurologist is helpful for properly documenting and tracking neurologic 
abnormalities, evaluating for other potential etiologies of neurologic abnormalities, and 
managing neurologic emergencies such as seizure or elevated intracranial pressure.  
– Coagulopathy and thrombocytopenia should be aggressively managed. Both coagulopathy and 
thrombocytopenia often develop with CRS. Intracranial hemorrhage has been observed in 
conjunction with severe neurotoxicity. In addition, a recent report suggests that 
thrombocytopenia is an independent risk factor for CAR-related neurotoxicity, and platelets 
may serve as a source of mediators that stabilize the endothelium and counteract destabilizing 
effects of cytokines elaborated during CAR T cell proliferation93. 
 
CRS should be managed concurrently with neurotoxicity according to guidelines enumerated above. It is 
difficult to distinguish delirium secondary to CRS from mild/early CAR-related neurotoxicity (and these 
phenomena may not be distinct pathophysiologically).   
 

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Protocol Exceptions and Deviations 
Exception: 
A one time, intentional action or process that departs from the approved study protocol, intended for 
one occurrence. If the action disrupts the study progress, such that the study design or outcome 
(endpoints) may be compromised, or the action compromises the safety and welfare of study subjects, 
advance documented approval from the Regulatory Sponsor and local regulatory review committees per 
institutional guidelines is required.  Approval from the Regulatory Sponsor must be received prior to 
submission to the IRB and local regulatory review committees for approval. 
 
 
Deviation: 
A one time, unintentional action or process that departs from the approved study protocol, involving one 
incident and identified retrospectively, after the event occurred. If the impact on the protocol disrupts the 
study design, may affect the outcome (endpoints) or compromises the safety and welfare of the subjects, 
the deviation must be reported to the Regulatory Sponsor within 10 business days of PI knowledge, and to 
local regulatory review committees per institutional guidelines.  Acknowledgement from the Regulatory 
Sponsor must be received prior to submission to local regulatory review committees.  
 
Other deviations should be appropriately documented (such as a subject missing a visit unless 
critical/important treatment or procedure was missed and must have been done at that specific time) 
per site policies/procedures.  
 
Include the following information on the Sponsor supplied exception/deviation form:  protocol number, 
subject study number, comprehensive description of the exception/deviation from the protocol, 
rationale, and corrective and preventative action plan (deviations only).  Ensure all completed 
exception/deviation forms are signed by the Principal Investigator (or physician sub-investigator) and 
submitted to the Sponsor Project Manager for review. 
 
Attention:  Sponsor Project Manager 
Center for Cellular Immunotherapies (CCI) 
University of Pennsylvania 
 
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 all applicable committees for review 
and approval/acknowledgement as per institutional guidelines.  
 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above. Medical monitoring will include a regular assessment of the number and type of serious adverse 
events. 
 
Independent Data and Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) comprised of four individuals including physicians with 
experience in oncology and/or gene transfer therapy will be assembled and will work under a charter 

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developed for safety oversight of this study. The DSMB will provide guidance/advice to the Regulatory 
Sponsor and Clinical Investigators. The DSMB will evaluate subject safety as specified in the DSMB Charter. 
 
A DSMB meeting will occur approximately every 6 months. If necessary, additional meetings of the DSMB 
may be held if safety issues arise in between scheduled meetings.  
 
 
It is envisioned that the DSMB may make four types of recommendations, namely: 
• 
No safety or efficacy issues, ethical to continue the study as planned. 
• 
Serious safety concerns precluding further study treatment, regardless of efficacy. 
• 
Overwhelming evidence for futility, recommend stopping the study. 
• 
Recommendation to continue the study but proposing an amendment to the protocol (e.g., 
incorporate an additional safety assessments). 
 
A sponsor representative will share the outcome of the DSMB meeting with the PI via email, for 
submission to local regulatory review committees as required per institutional policy. 
 
DATA HANDLING AND RECORDKEEPING 
 
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 patients in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research patient to revoke their authorization for use of their PHI. 
 
In the event that a patient 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 
patients 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 patient is alive) at the end of their scheduled study 
period. 
 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in 
source documents. Examples of these original documents, and data records include:  hospital  records,  
clinical  and  office  charts,  laboratory notes,  memoranda,  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 patient in the study, consisting of case and 
visit notes (hospital or clinical medical records) containing demographic and medical information, 
laboratory data, electrocardiograms and the results of any other tests or assessments. All information 

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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 
and/or legally acceptable surrogate. 
 
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.  
 
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 
 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 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. 
 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the sponsor, and 
government regulatory bodies. 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 offices. 
 

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The Principal Investigator must notify the Sponsor in real-time if an audit/inspection notification is 
received. 
 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.   
 
Per local requirements, all subjects for this study will be provided a consent form describing this study 
and providing sufficient information for subjects to make an informed decision about their participation 
in this study.  This consent form will be submitted with the protocol for review and approval by the IRB 
for the study.   The formal consent of a subject, using the IRB-approved consent form, must be obtained 
before that subject is submitted to any study procedure.  This consent form must be signed by the subject 
or legally acceptable surrogate, and the investigator obtaining the consent. 
 
The protocol is listed on clinicaltrials.gov. 
 STUDY FINANCES 
 Funding Source 
This study will be funded through CHOP internal funds. 
 Conflict of Interest 
All Investigators will follow their Institutional Policy on Conflicts of Interest Related to Research. 
 Patient Stipends or Payments 
There is no patient stipend/payment for participation in this protocol. 
 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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 REFERENCE LIST 
 
1. 
Surveillance, Epidemiology, and End Results (SEER) Program of the NCI. 2006. 
2. 
Hunger SP, Lu X, Devidas M, et al. Improved survival for children and adolescents with acute 
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3. 
Schrappe M, Hunger SP, Pui C-H, et al. Outcomes after Induction Failure in Childhood Acute 
Lymphoblastic Leukemia. N Engl J Med 2012;366:1371-81. 
4. 
Raetz EA, Bhatla T. Where do we stand in the treatment of relapsed acute lymphoblastic leukemia? 
Hematology Am Soc Hematol Educ Program 2012;2012:129-36. 
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Nguyen K, Devidas M, Cheng SC, et al. Factors influencing survival after relapse from acute 
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Raetz EA, Cairo MS, Borowitz MJ, et al. Re-induction chemoimmunotherapy with epratuzumab in 
relapsed acute lymphoblastic leukemia (ALL): Phase II results from Children's Oncology Group (COG) 
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Bhojwani D, Pui C-H. Relapsed childhood acute lymphoblastic leukaemia. Lancet Oncol 
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Gribben JG, Hosing C, Maloney DG. Stem cell transplantation for indolent lymphoma and chronic 
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11. Pui CH, Campana D, Evans WE. Childhood acute lymphoblastic leukaemia--current status and future 
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12. Verma A, Stock W. Management of adult acute lymphoblastic leukemia: moving toward a risk-
adapted approach. Curr Opin Oncol 2001;13:14-20. 
13. Kolb HJ, Schattenberg A, Goldman JM, et al. Graft-versus-leukemia effect of donor lymphocyte 
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14. Appelbaum FR. Haematopoietic cell transplantation as immunotherapy. Nature 2001;411:385-9. 
15. Sullivan KM, Storb R, Buckner CD, et al. Graft-versus-host disease as adoptive immunotherapy in 
patients with advanced hematologic neoplasms. N Engl J Med 1989;320:828-34. 
16. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in 
leukemia. N Engl J Med 2014;371:1507-17. 
17. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in Children and Young Adults with B-Cell 
Lymphoblastic Leukemia. N Engl J Med 2018;378:439-48. 
18. Maude SL, Barrett DM, Rheingold SR, et al. Efficacy of Humanized CD19-targeted Chimeric Antigen 
Receptor (CAR)-Modified T Cells in Children with Relapsed ALL. J Clin Oncol 2016;34 suppl:abstr 3007. 

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69. Imai C, Mihara K, Andreansky M, et al. Chimeric receptors with 4-1BB signaling capacity provoke 
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70. Friedmann-Morvinski D, Bendavid A, Waks T, Schindler D, Eshhar Z. Redirected primary T cells 
harboring a chimeric receptor require costimulation for their antigen-specific activation. Blood 
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72. Finney HM, Akbar AN, Lawson ADG. Activation of resting human primary T cells with chimeric 
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86. Macallan DC, Asquith B, Irvine AJ, et al. Measurement and modeling of human T cell kinetics. Eur J 
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87. Wang GP, Levine BL, Binder GK, et al. Analysis of lentiviral vector integration in HIV+ study subjects 
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5 Bone marrow performed for disease and MRD assessment.  If the results of a historical marrow or tissue biopsy (obtained at the time of the 
patient’s most recent relapse) are available, this does not need to be repeated for enrollment.  
6 Apheresis will be performed to obtain a target of 50 x 109 (109/kg) white blood cells to manufacture huCART19 T cells. Apheresis can occur any 
time after the monitoring visit for eligibility is completed.  Cryopreserved historical apheresis products collected from the patient prior to study 
entry are usable for huCART19 manufacturing if collected at an appropriately certified apheresis center and the product meets adequate 
mononuclear cell yields.  
7 Prior antineoplastic therapy to be collected up through the lymphodepleting chemotherapy prior to huCART19 cell infusion.  
8 Repeated as clinically indicated or if HLH/MAS or CRS is suspected.  If fevers are observed following huCART19 infusion, every attempt will be 
made to monitor additional Ferritin and CRP levels daily at fever onset and until resolution of the fever. 
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. If the results of a historical lumbar puncture (obtained at the time of the patient’s most recent relapse) are available, 
this does not need to be repeated for enrollment.  CNS evaluations will also be performed at Day -1 and Day 28.  If CNS symptoms are identified 
at these timepoints, additional testing may be performed as per clinical discretion.   If CSF involvement was confirmed at Enrollment, then lumbar 
punctures will be repeated thereafter as clinically indicated.   Please refer to Section 6.14.3 for complete details.  
10 Months 3, 6, 9 and 12 
11 Pregnancy test for females of childbearing potential only.  Pre-infusion pregnancy test to be performed within 48 hours prior to the huCART19 
infusion.  
12 Vital signs will be measured within 10 minutes prior to the infusion and within 15 minutes after the infusion. Vital signs will also be measured 
at 30 (+/- 5) minutes, 45 (+/- 5) minutes, and 60 (+/- 5) minutes after the infusion.  If the subject’s vital signs are not satisfactory and stable one 
hour post-huCART19 infusion, vital signs will continue to be monitored as clinically indicated until stable.    
13 D-dimer required on Days 3 and 10.   
14 Bone marrow biopsy/aspirate to be performed between initiation of LD chemo and huCART19 T-cell infusion.  
15 DLCO > 40% (if PFTs are clinically appropriate as determined by the treating investigator); Pulse Oxygen > 92% on room air 
16 A chest x-ray for mediastinal disease will be performed at Screening/Enrollment if clinically indicated.  If extramedullary disease is present prior 
to treatment, this will be followed as clinically appropriate. 
17 Visit windows have been incorporated to allow for flexibility in scheduling however these visits cannot overlap and all individual follow-up visits 
must be performed.  
18 All subjects must undergo influenza testing within 10 days prior to the first planned huCART19 infusion during the October-May flu season. If the 
subject is positive for influenza, oseltamivir phosphate (Tamiflu®) or equivalent should be administered per package insert.  The subject must 
complete this course treatment prior to receiving huCART19.  The test does not need to be repeated prior to the initial huCART19 infusion, 
however if influenza symptoms are present, the huCART19 infusions should be delayed until the subject is asymptomatic.   

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19 Research blood (5 cc red top) to be taken between 20-120 minutes post-huCART19 infusion. 
20 Please refer to Table 6-3 for details regarding Disease Monitoring requirements. 
21 ECHO must be performed within 8 weeks prior to the huCART19 infusion. 
22 Testing for huCART19 persistence by qPCR will continue until any 2 sequential tests are negative documenting loss of CAR T cells. 
23 See Section 5.3 regarding criteria to proceed with huCART19 infusion.    
24 Vital sign assessments include blood pressure, body temperature, respiration rate, and heart rate, and oxygen saturation via pulse oximetry as 
clinically indicated. 
25 Subjects in continued remission may receive additional huCART19 infusions at the physician-investigator’s discretion.  Subjects must be 
evaluated by a physician-investigator for eligibility to receive additional huCART19 infusions according to criteria in Section 5.3.  If performed, 
these additional infusions will be defined as “reinfusions”.  If reinfusions are administered, additional safety follow-up visits are required.  While 
all study visits will continue to be calculated based on the date of the initial huCART19 infusion (Day 0), subjects will also enter into a Reinfusion 
Section of the Schedule of Evaluations at the time reinfusion of huCART19 cells is initiated.  When Reinfusion Study Visits may overlap with 
existing study timepoints (i.e. Reinfusion Day 0 may overlap with the Month 3 study timepoint), all study tests/procedures required for both 
visits should still be completed per protocol requirements but will not be duplicated.  When post-reinfusion follow-up is completed per protocol, 
the subject will resume the study follow-up per the primary Schedule of Evaluations. Additional follow-up post reinfusion may also be 
performed per physician-investigator discretion. Please refer to Section 6.13 for additional information.  Please refer to the Retreatment 
Schedule of Evaluations (Appendix 2) for retreatment with huCART19 post-relapse.   
26 Collection of adverse events will begin at the time of apheresis and will continue until the subject is off-study.  For subjects who do not undergo 
apheresis on this study (i.e. historical apheresis product is available), adverse event reporting will begin on Day 0 (from the start of the first 
huCART19 infusion) until the subject is off-study.   
27 If LN aspirate performed as per clinical discretion.   
28 Disease assessments may be performed prior to reinfusion of huCART19 cells per clinical discretion. If a bone marrow aspirate is performed, a 
portion of this sample may also be used for research purposes.   
29 qPCR persistence testing performed post reinfusion on Days +7, +10, and +14 only. 
30 Lymphodepleting chemotherapy may be repeated prior to huCART19 reinfusions per clinical discretion.  Please refer to Section 6.5 for 
additional information. 
31 Additional follow-up post-reinfusion may also be performed per physician-investigator discretion.  
32  Research samples to be collected pre-infusion. 
 
 
 

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1 Tumor response assessments will be performed at Day 28, Months 3, 6, 9 and 12 after huCART19 cell infusion (Refer to Section 6.14 for further 
details and frequency). 
2 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 collections 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  RCL VSV-G testing will not be routinely performed as of Protocol V2.  Blood samples will be collected and banked at pre-infusion and post-
infusion at Months 3, 6, and 12.  These samples will be used for future RCL VSV-G testing if indicated. 
4 Lymphodepleting chemotherapy prior to huCART19 cell infusion is NOT required if WBC ≤ 1,000/uL. The chemotherapy will be planned so that 
the last dose is completed approximately 2-5 days BEFORE the planned infusion of huCART19 cells. Please refer to Section 6.5 for complete 
details.  
5 Testing for huCART19 persistence by qPCR will continue until any 2 sequential tests are negative documenting loss of CAR T cells. 
6 Collection of adverse events during retreatment will be continuous from the primary Schedule of Evaluations and will continue until the subject 
is off-study.   
7 Vital sign assessments include blood pressure, body temperature, respiration rate, and heart rate, and oxygen saturation via pulse oximetry as 
clinically indicated. 
8 Repeated as clinically indicated or if HLH/MAS or CRS is suspected.  If fevers are observed following huCART19 infusion, every attempt will be 
made to monitor additional Ferritin and CRP levels daily at fever onset and until resolution of the fever. 
9 CNS evaluations will then be performed at Day -1 and Day 28. If CNS symptoms are identified at these timepoints, additional testing may be 
performed as per clinical discretion.   
10 Months 3, 6, 9 and 12 
11 Pregnancy test for females of childbearing potential only.  Pre-infusion pregnancy test to be performed within 48 hours prior to the huCART19 
retreatment infusion (Day 0-R).  
12 Vital signs will be measured within 10 minutes prior to the infusion and within 15 minutes after the infusion. Vital signs will also be measured 
at 30 (+/- 5) minutes, 45 (+/- 5) minutes, and 60 (+/- 5) minutes after the infusion.  If the subject’s vital signs are not satisfactory and stable one 
hour post-huCART19 infusion, vital signs will continue to be monitored as clinically indicated until stable.    
13 D-dimer required on Days 3 and 10.   
14 Bone marrow biopsy/aspirate to be performed between initiation of LD chemo and huCART19 T-cell infusion.  
15 See Section 5.3 regarding criteria to proceed with huCART19 infusion.    
16 If extramedullary disease is present prior to treatment, this will be followed as clinically appropriate (including chest x-ray). 

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This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
 
17 Visit windows have been incorporated to allow for flexibility in scheduling however these visits cannot overlap and all individual follow-up visits 
must be performed.  
18 All subjects must undergo influenza testing within 10 days prior to the  huCART19 retreatment infusion during the October-May flu season. If the 
subject is positive for influenza, oseltamivir phosphate (Tamiflu®) or equivalent should be administered per package insert.  The subject must 
complete this course treatment prior to receiving huCART19.  The test does not need to be repeated prior to the huCART19 infusion, however if 
influenza symptoms are present, the huCART19 infusion should be delayed until the subject is asymptomatic.   
19 Research blood (5 cc red top) to be taken between 20-120 minutes post-huCART19 infusion. 
20 Please refer to Table 6-3 for details regarding Disease Monitoring requirements. 
21 Subjects in continued remission post-retreatment may also receive additional huCART19 infusions at the physician-investigator’s discretion. 
Subjects must be evaluated by a physician-investigator for eligibility to receive additional CART19 cell infusions according to criteria in Section 
5.3. If performed, these additional infusions post-retreatment will be defined as “reinfusions”. For the purposes of study timepoint 
identification and reporting, each reinfusion post-retreatment will be considered a new treatment number under the Retreatment Schedule 
of Evaluations (i.e. the first huCART19 retreatment infusion on Day 0-R will be Treatment #1, the first reinfusion post Day 0-R will be 
Treatment #2, the second reinfusion post Day 0-R will be Treatment #3, etc).  If reinfusions are administered, additional safety follow-up visits 
are required. While all study visits will continue to be calculated based on the date of the retreatment CART19 cell infusion (Day 0-R), subjects 
will also enter into a Reinfusion Section of the Retreatment Schedule of Evaluations at the time reinfusion of CART19 cells is initiated. Where 
Reinfusion Study Visits may overlap with existing study timepoints (i.e. Reinfusion Day 0 may overlap with the Month 3-R study timepoint), all 
study tests/procedures required for both visits should be completed per protocol requirements. When post-reinfusion follow-up is completed 
per protocol, the subject will resume the study follow-up timepoints per the Retreatment Schedule of Evaluations.   Additional follow-up post 
reinfusion may also be performed per physician-investigator discretion.  Please refer to Section 6.13 for additional information. 
22 Testing for huCART19 persistence by qPCR will continue until any 2 sequential tests are negative documenting loss of CAR T cells. 
23 If LN aspirate performed as per clinical discretion.  
24 Subjects who relapse post huCART19 infusion may also receive additional huCART19 infusions post-relapse at the physician-investigator’s 
discretion.  Subjects must be evaluated by a physician-investigator for eligibility to receive additional huCART19 infusions according to criteria 
in Section 5.3.  If performed, additional infusions administered post-relapse will be defined as “retreatment”.  If a decision is made to retreat a 
subject post-relapse, the subject will officially discontinue the Primary Schedule of Evaluations (Appendix 1) at the time of their first 
retreatment study visit/procedure (i.e. lymphodepleting chemotherapy) and enter the Retreatment Schedule of Evaluations (Appendix 2). 
Retreatment study visit timepoints will be distinguished from the primary Schedule of Evaluations by a “-R” identifier (i.e. Day 0-R, Day 1-R, 
etc). Follow-up will continue under the Retreatment Schedule of Evaluations for up to 12 months post retreatment.  Please refer to Section 
6.13 for additional information.  
25 Lymphodepleting chemotherapy may be repeated prior to huCART19 reinfusions per clinical discretion.  Please refer to Section 6.5 for 
additional information. 

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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. 
 
26 qPCR persistence testing performed post reinfusion on Days +7, +10, and +14 only. 
27 Disease assessments may be performed prior to reinfusion of huCART19 cells per clinical discretion.  If a bone marrow aspirate is performed, a 
portion of this sample may also be used for research purposes.  
28   Additional follow-up post-reinfusion may also be performed per physician-investigator discretion.  
29  Research samples to be collected pre-infusion.