Pediatric and Young Adult Leukemia Adoptive Therapy (PLAT)-02: A Phase 1/2 Feasibility and Safety Study of CD19-CAR T Cell Immunotherapy for CD19+ Leukemia
Phase: PHASE1
Conditions: CD19+ Acute Leukemia
Sponsor: Seattle Children's Hospital

 
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Activated: 01/20/14 
Version Date: 06/04/2020 
Closed: not applicable 
 
 
Seattle Children’s Hospital and Research Institute 
Clinical Research Protocol 
Pediatric and Young Adult Leukemia Adoptive Therapy (PLAT)-02:  A Phase 1/2 Feasibility 
and Safety Study of CD19-CAR T Cell Immunotherapy for CD19+ Leukemia  
Protocol Number: 
PLAT-02 
Investigational Product: 
Defined Composition CD4 and CD8 T Cells Lentivirally 
Transduced to Express a Second Generation 4-1BB:zeta 
CD19 CAR and EGFRt 
IND Number: 
BB IND# 15829 
NCT Number 
NCT02028455 
Development Phase: 
Phase 1/2 
Study Chair: 
Rebecca Gardner, MD 
Seattle Children’s Hospital 
Seattle, WA 98105 
Telephone: 206-469-3300 
 
 
 
 
This study is to be performed in compliance with the protocol, Good Clinical Practice 
(GCP) and applicable regulatory requirements. 
This confidential information about an investigational product is provided for the exclusive use 
of investigators of this product and is subject to recall at any time. Subject to the foregoing, this 
information may be disclosed only to those persons involved in the study who have a need to 
know, with the obligation not to further disseminate this information. 
 
 

 
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SIGNATURE PAGE 
 
Protocol Title:  Pediatric and Young Adult Leukemia Adoptive Therapy (PLAT)-02:  A Phase 
1/2 Feasibility and Safety Study of CD19-CAR T Cell Immunotherapy for CD19+ Leukemia  
Protocol Number:  PLAT-02 
Sponsor Acknowledgement: 
As the Sponsor representative, I confirm that SCRI will comply with all Sponsor obligations as 
detailed in all applicable regulations and guidelines. I will ensure that the investigator is 
informed of all relevant information that becomes available during the conduct of this study.  
 
 
 
 
Rebecca Gardner, MD 
Associate Medical Director, Immunotherapy Coordinating Center 
Seattle Children’s Research Institute 
 
Date 
 
Principal Investigator: 
I have read Protocol, including all appendices, and I agree to conduct the study as detailed in this 
protocol and in compliance with the Declaration of Helsinki, Good Clinical Practices (GCP) and 
all applicable regulatory requirements and guidelines.   
 
 
 
 
Principal Investigator 
 
Date 
 

 
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Signature Page ............................................................................................................................................... 2 
1 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) ........................................................................................ 15 
 
Primary Objectives ....................................................................................................................... 15 
 
Secondary Objectives .................................................................................................................. 15 
2 
BACKGROUND ...................................................................................................................................... 16 
 
Introduction/Rationale for Development.................................................................................... 16 
 
Development of Adoptive Therapy for B-Lineage Malignancies using Chimeric Antigen 
Receptor Re-directed CD19-Specific T Cells ............................................................................................ 17 
2.2.1 
Adoptive Therapy for Viral Infections and Malignant Disease ............................................ 17 
2.2.2 
Barriers to the Clinical Success of AT ................................................................................... 18 
2.2.3 
Redirected Specificity of T Cells Engineered to Express scFvFc:ζ Chimeric Antigen 
Receptors ............................................................................................................................................. 18 
2.2.4 
CD4+ T cell help enhances the function and persistence of CD8+ T cells ............................ 20 
2.2.5 
Enhancing Persistence of Transferred Cells ........................................................................ 20 
 
Clinical trials using CAR modified T cells ...................................................................................... 21 
2.3.1 
1st Generation CARs ............................................................................................................. 21 
2.3.2 
Enhanced persistence and clinical results with second generation CARs ........................... 21 
2.3.3 
CD19 CAR T cell Therapy Experience for Pediatric CD19+ Malignancies ............................. 23 
 
Potential Toxicity Associated with the Infusion of CD19 Specific CAR+ T Cell Lines ................... 24 
 
T Cell Dosing Rationale ................................................................................................................ 26 
3 
ENROLLMENT PROCEDURES AND ELIGIBILITY CRITERIA ..................................................................... 30 
 
Study Enrollment ......................................................................................................................... 30 
3.1.1 
Patient Registration ............................................................................................................. 30 
3.1.2 
Informed Consent/Assent.................................................................................................... 30 
3.1.3 
Study Enrollment ................................................................................................................. 30 
3.1.4 
Dose Assignment ................................................................................................................. 30 
3.1.5 
Timing .................................................................................................................................. 30 
 
Patient Criteria ............................................................................................................................. 30 
3.2.1 
Inclusion Criteria .................................................................................................................. 30 
3.2.2 
Exclusion Criteria ................................................................................................................. 33 

 
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Definitions .................................................................................................................................... 34 
3.3.1 
Definition of CNS status ....................................................................................................... 34 
4 
TREATMENT PROGRAM ....................................................................................................................... 36 
 
Overview of Treatment Plan ........................................................................................................ 36 
4.1.1 
Phase 1 Dosing Regimen (enrollment onto Phase 1 was completed on 11 May 2016)...... 36 
4.1.2 
Phase 2 Dosing and Lymphodepletion Regimen ................................................................. 37 
 
Definition of Toxicity .................................................................................................................... 37 
4.2.1 
Treatment related toxicity ................................................................................................... 37 
 
Treatment Details and Plan ......................................................................................................... 39 
4.3.1 
Apheresis for T cell isolation ................................................................................................ 39 
4.3.2 
Lymphodepletion ................................................................................................................. 40 
4.3.3 
T cell Product Infusion ......................................................................................................... 40 
4.3.4 
T cell Product Infusion Details of Care ................................................................................. 41 
4.3.5 
Retreatment with modified T cells ...................................................................................... 42 
 
General Information .................................................................................................................... 43 
4.4.1 
Hospitalization: .................................................................................................................... 43 
4.4.2 
Central Venous Access ......................................................................................................... 43 
 
Evaluations ................................................................................................................................... 43 
4.5.1 
Clinical Assessments ............................................................................................................ 43 
4.5.2 
Clinical Laboratory Measurements ...................................................................................... 45 
4.5.3 
Correlative Studies ............................................................................................................... 46 
4.5.4 
Long-Term Follow-Up .......................................................................................................... 46 
 
Concomitant Therapy .................................................................................................................. 48 
5 
MANAGEMENT OF TOXICITIES AND COMPLICATIONS ........................................................................ 49 
 
Management of Symptoms Associated with T cell Infusion ....................................................... 49 
 
Management of Acute Adverse Event(s) Attributable to Expansion of the Infused T Cells........ 49 
5.2.1 
Ablation of T cells:................................................................................................................ 51 
6 
DRUG INFORMATION........................................................................................................................... 53 
 
Possible Side Effects of Gene Modified T Cells ............................................................................ 53 
7 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED ............................................................... 54 
 
Required and Recommended Clinical, Laboratory and Disease Evaluations .............................. 54 

 
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Optional Studies........................................................................................................................... 61 
8 
SUPPORTIVE CARE ............................................................................................................................... 62 
 
Central Venous Access ................................................................................................................. 62 
 
Blood Product Support ................................................................................................................ 62 
 
Hospitalization ............................................................................................................................. 62 
 
Antimicrobial Prophylaxis ............................................................................................................ 62 
 
Diet ............................................................................................................................................... 62 
9 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA ............................. 63 
 
Criteria for Removal from Protocol Prescribed Therapy ............................................................. 63 
 
Off Study Criteria ......................................................................................................................... 63 
 
Replacement of Subjects ............................................................................................................. 64 
 
Temporary Suspension of T Cell Infusion .................................................................................... 64 
 
Protocol Violations....................................................................................................................... 64 
10 
STATISTICAL CONSIDERATIONS ....................................................................................................... 66 
 
Primary Objectives ....................................................................................................................... 66 
10.1.1 
Feasibility ............................................................................................................................. 66 
10.1.2 
Safety ................................................................................................................................... 66 
10.1.3 
Persistence ........................................................................................................................... 67 
 
Secondary Objectives .................................................................................................................. 67 
10.2.1 
Duration of overall response-leukemia: .............................................................................. 67 
10.2.2 
Survival ................................................................................................................................. 67 
 
Cohort size and Rules for Cohort Advancement ......................................................................... 68 
10.3.1 
Sample size .......................................................................................................................... 68 
10.3.2 
Cohort advancement rules for phase 1 – applies to dose escalation cohorts .................... 68 
10.3.3 
Definition of MTD and BED, and dose selection for phase 1 extension cohort and phase 2
 
69 
10.3.4 
Statistical design for phase 2 ............................................................................................... 70 
 
Study Analysis Plan ...................................................................................................................... 71 
 
Data and Safety Monitoring ........................................................................................................ 72 
10.5.1 
Quality Assurance ................................................................................................................ 72 
10.5.2 
Weekly Safety Review .......................................................................................................... 72 

 
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10.5.3 
Aggregate and Real-Time Safety Review ............................................................................. 72 
10.5.4 
Data Monitoring Committee ............................................................................................... 72 
10.5.5 
Study Stopping Rules ........................................................................................................... 73 
 
Data Sets Analyzed ...................................................................................................................... 73 
 
Demographics and Baseline Characteristics ................................................................................ 73 
 
Evaluability for Toxicity ................................................................................................................ 73 
 
Evaluability for Efficacy ................................................................................................................ 74 
11 
EVALUATION CRITERIA .................................................................................................................... 75 
 
Common Terminology Criteria for Adverse Events (CTCAE) ....................................................... 75 
 
Disease Response Criteria Leukemia ........................................................................................... 75 
11.2.1 
MRD negative Complete Remission (MRD-CR) ................................................................... 75 
11.2.2 
MRD positive Complete Remission (MRD+CR) .................................................................... 75 
11.2.3 
MRD negative Complete Remission without count recovery (MRD-CRi)............................ 75 
11.2.4 
MRD positive Complete Remission without count recovery (MRD+CRi) ............................ 75 
11.2.5 
Complete Remission, MRD unknown (CR) .......................................................................... 75 
11.2.6 
Complete Remission without count recovery, MRD unknown (CRi)................................... 75 
11.2.7 
Partial Remission (PR) .......................................................................................................... 76 
11.2.8 
Partial Remission Cytolytic (PRCL) ....................................................................................... 76 
11.2.9 
Minimal Response Cytolytic (MRCL) .................................................................................... 76 
11.2.10 
Stable Disease (SD) .......................................................................................................... 76 
11.2.11 
Progressive Disease (PD).................................................................................................. 76 
11.2.12 
Definitions of Relapse ...................................................................................................... 76 
 
Disease Response Criteria Lymphoma......................................................................................... 77 
11.3.1 
CR ......................................................................................................................................... 77 
11.3.2 
CRu ....................................................................................................................................... 77 
11.3.3 
Partial Response (PR) ........................................................................................................... 77 
11.3.4 
Minor Response (MR) .......................................................................................................... 77 
11.3.5 
No Response (NR) ................................................................................................................ 77 
11.3.6 
Progressive Disease (PD)...................................................................................................... 77 
11.3.7 
Definitions of Relapse .......................................................................................................... 77 
12 
ADVERSE EVENT REPORTING REQUIREMENTS ................................................................................ 78 

 
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Purpose ........................................................................................................................................ 78 
 
Definitions .................................................................................................................................... 78 
 
AE Grading and Relationship to Investigation agent ................................................................... 79 
 
Event Collection ........................................................................................................................... 80 
 
Serious Adverse Event Reporting and Study-Specific Reporting ................................................. 81 
13 
RECORDS AND REPORTING .............................................................................................................. 82 
 
Data Collection Instruments ........................................................................................................ 82 
 
Data Management Procedures .................................................................................................... 82 
 
Data Quality Control and Reporting ............................................................................................ 82 
 
Archival of Data............................................................................................................................ 82 
 
Availability and Retention of Investigational Records ................................................................. 83 
 
Subject Confidentiality ................................................................................................................. 83 
14 
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ........................................................ 84 
 
Protocol Amendments ................................................................................................................. 84 
 
Institutional Review Boards and Independent Biosafety Committees ....................................... 84 
 
Informed Consent Form............................................................................................................... 85 
 
Publications .................................................................................................................................. 85 
 
Investigator Responsibilities ........................................................................................................ 85 
15 
RESEARCH PARTICIPANT-SPECIFIC BIOLOGICAL MATERIALS .......................................................... 87 
16 
REFERENCES ..................................................................................................................................... 88 
Appendices .................................................................................................................................................. 99 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES.............................................................................. 100 
APPENDIX II GVHD STAGING, GRADING, AND DIAGNOSIS INFORMATION ............................................... 101 
APPENDIX III: Highly Effective Contraception ............................................................................................ 107 
 
 
 

 
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Abbreviation 
Term 
AE 
Adverse Event 
Allo-HCT 
Allogeneic hematopoietic cell transplantation 
ALP 
Alkaline Phosphatase 
ALT 
Alanine transaminase 
ANC 
Absolute Neutrophil Count 
ALL 
Acute Lymphoblastic Leukemia 
AST 
Aspartate transaminase 
BUN 
Blood Urea Nitrogen 
CAR 
Chimeric antigen receptor 
CBC 
Complete Blood Count 
CLL 
Chronic lymphocytic leukemia 
CMV 
Cytomegalovirus 
CR 
Complete remission 
CRA 
Clinical research associate 
CRF 
Case report form 
CRS 
Cytokine release syndrome 
CXR 
Chest x-ray 
CSF 
Cerebrospinal fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
CSL 
Correlative Studies Laboratory 
CTL 
Cytotoxic T lymphocytes 
DLI 
Donor lymphocyte infusion 
DLT 
Dose-Limiting Toxicity 
DMC 
Data Monitoring Committee 
EBV 
Epstein Barr virus 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EFS 
Event-Free Survival 
FDA 
Food and Drug Administration 
g 
Gram 
GCP 
Good Clinical Practice 
GVHD 
Graft-versus-host disease 

 
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h 
Hour 
HCT 
Hematopoietic Cell Transplant 
HCT 
Hematopoietic Cell Transplant 
IBC 
Institutional Biosafety Committee 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
ITAMs 
Immunoreceptor tyrosine activation motifs 
IVIG 
Intravenous immunoglobulin 
L 
Liter 
LTFU 
Long term follow-up 
m2 
Meters squared 
mg 
Milligram 
MHC 
Major Histocompatibility Complex 
MRD 
Minimal residual disease 
mL 
Milliliter 
mm3 
Millimeter cubed 
MPF 
Multiparameter flow cytometry 
MRD 
Minimal residual disease 
MRD-CR 
Minimal residual disease negative Complete Remission 
MRD+CD 
Minimal residual disease positive Complete Remission 
MRP-CRp 
Minimal residual disease negative Complete Remission without platelet 
recovery 
MRP+CRp 
Minimal residual disease positive Complete Remission without platelet 
recovery 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NHL 
Non-Hodgkin lymphoma 
OS 
Overall survival 
PBMC 
Peripheral Blood Mononuclear Cell 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PR 
Partial Remission 
RCL 
Replication Competent Lentivirus 

 
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rhuIL-2 
Recombinant Human Interleukin-2 
SAE 
Serious Adverse Event 
SCH 
Seattle Children’s Hospital 
SD 
Stable disease 
SIN 
Self-inactivating 
SITE 
Study Implementation Team 
SPRT 
Statistical Probability Ratio Test 
TCM 
Central Memory T Cell 
TE 
Effector T Cell 
Treg 
Regulatory T cell 
TIL 
Tumor infiltrating lymphocytes 
WBC 
White blood cells 
  
 
 

 
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STUDY COMMITTEE 
STUDY CHAIR 
 
STUDY STATISTICIAN 
Rebecca Gardner, MD 
 
Qian (Vicky) Wu, PhD 
Seattle Children’s Hospital 
 
Fred Hutchinson Cancer Research Center 
4800 Sand Point Way NE 
 
1100 Fairview Avenue N 
Seattle, WA 98105 
 
Seattle, WA 98109 
Phone: 206-987-1426 
 
Phone: 206-667-3358 
email: rebecca.gardner@seattlechildrens.org 
 
email: qwu@fredhutch.org 
 
 
 
STUDY COMMITTEE 
 
 
Marie Bleakley, MD, PhD 
 
 
Fred Hutchinson Cancer Research Center 
 
 
1100 Fairview Avenue N 
 
 
Seattle, WA 98109 
 
 
Phone: 206-667-6572 
 
 
email: mbleakle@fhcrc.org 
 
 
 
 
 
Julie Park, MD 
 
 
Seattle Children’s Hospital 
 
 
4800 Sand Point Way NE 
 
 
Seattle, WA 98105 
 
 
Phone: 206-987-2106 
 
 
email: julie.park@seattlechildrens.org 
 
 
 
 
 
K. Scott Baker, MD, MPH 
 
 
Fred Hutchinson Cancer Research Center 
 
 
1100 Fairview Avenue N 
 
 
Seattle, WA 98109 
 
 
Phone: 206-667-5594 
 
 
 
 

 
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ABSTRACT 
This phase 1/2, open-label, non-randomized study will enroll pediatric and young adult research 
participants with relapsed or refractory CD19+ leukemia with and without prior history of 
allogeneic stem cell transplant, to examine the safety, feasibility, and efficacy  of administering 
T cell products derived from patient peripheral blood mononuclear cells (PBMC) that have been 
genetically modified using a self-inactivating SIN lentiviral vector to express a CD19-specific 
chimeric antigen receptor (CAR) and the selection-suicide marker EGFRt. The primary 
objectives of the phase 1 portion of the study will be to determine the feasibility of 
manufacturing the cell product, the safety of the T cell product infusion, and to describe the full 
toxicity profile, including development of clinically significant GVHD.  In the phase 1 cohorts, 
subjects will receive a single dose of T cells within the framework of a 3+3 dose escalation trial 
design. Subjects in the phase 2 portion of the study will receive 1 dose of T cells (the dose that 
has been determined as the maximum tolerated dose during phase 1) and have the additional 
primary objective of evaluating the efficacy of the T cell product on CD19+ disease as measured 
by rates of minimal residual disease complete remissions. Two cohorts of participants will enroll 
in the phase 2, those receiving fludarabine/cyclophosphamide lymphodepletion and those 
receiving alternative lymphodepletion. During the phase 2 portion, CD19+ Non-Hodgkin 
lymphoma patients will also be eligible to enroll in the cohorts but they will be analyzed 
separately for both toxicity and efficacy.  CD4 and CD8 T cell subsets will be isolated from 
apheresis products obtained from the research participant.  The CD4 and CD8 CD19 CAR 
modified T cells will be administered as two separate infusions. Once the patient has recovered 
from any acute toxicity from re-induction/salvage chemotherapy, the T cell product will be 
infused via an indwelling catheter or peripheral IV.  The secondary objectives of this protocol are 
to study the engraftment and in vivo persistence of transferred cells by quantitative polymerase 
chain reaction (PCR) for lentiviral vector-specific sequence, to assess T-cell accumulation in the 
bone marrow and effect on tumor/CD19+ B cell numbers, describe efficacy and toxicity in the 
MRD positive CR patients and in the frank relapse/refractory disease patients separately, and to 
assess the incidence of acute GVHD exacerbation and/or T cell engraftment syndrome. Patients 
who experience significant and potentially life-threatening toxicities (other than clinically 
manageable cytokine storm/engraftment syndrome) will receive infusions of cetuximab to assess 
the ability of the EGFRt transgene to be an effective suicide mechanism for the ablation of 
transferred T cell products. 
 
 

 
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EXPERIMENTAL DESIGN SCHEMA  
 
 
Eligibility Screening/Protocol 
Enrollment 
Chemotherapy per Treating 
Physician Discretion AND 
Lymphodepletion 
T Cell Product Infusion (Day 0) 
Monitoring/Follow up Evaluations 
Apheresis 
T Cell Product 
Manufacturing/Release Testing 
(SCRI TCPC) 
 
 
 
 

 
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Flow-chart depiction of the main dose transition rules of Sections 10.3.2 - 10.3.3. These rules 
apply separately to the transition between levels 1Z-1D in Phase I Escalation, and between levels 
1E1-1E2 in Phase 1 Extension. Moving one dose level up or down might be infeasible or 
disallowed, either due to the lack of such a level, or due to additional safety rules described in 
detail in Section 10.3.2. Rules for whether Phase 1 Escalation continues to its Extension or 
directly to Phase II are found in Section 10.3.3 
 
Treat + Evaluate 3 Patients 
at Current Dose Level 
YES 
PLAT-02 Phase I:  Dose Escalation Rules, Visualized 
Go 1 Dose Level Down  (if 
feasible*); restart flowchart 
with that level as 
“Current”. 
NO, and 0 DLTs 
in latest 3-pt 
group 
Go 1 Dose Level Up (if 
allowed*); restart flowchart 
with that level as “Current” 
NO, and 2-3 
DLTs in latest 3-
pt group 
NO, and 1 
DLT in latest 
3-pt group 
(repeat 
same) 
dose)
Start 
Here

 
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1 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
 Primary Objectives 
• To assess the safety and toxicity of cellular immunotherapy utilizing ex-vivo expanded 
patient-derived CD4+/CD8+ T cells genetically modified to express a CD19-specific 
scFvIgG4hinge: CD28tm/4-1BBζ chimeric antigen receptor (CAR) and EGFRt in children 
and young adults who relapse with CD19+ leukemia. 
• To describe the full toxicity profile. 
• To assess the feasibility of manufacturing and releasing T cell products from pediatric and 
young adult patients who relapse with CD19+ leukemia after both before and after allo-HCT. 
• To estimate the efficacy, defined as a complete remission (CR), minimal residual disease 
(MRD) negative response to ex-vivo expanded patient-derived CD4+/CD8+ T cells 
genetically modified to express a CD19-specific scFvIgG4hinge: CD28tm/4-1BBζ CAR and 
EGFRt in patients with relapsed or refractory CD19+ leukemia. 
• To estimate the rate of persistence of functional CAR+ T cells past day +63. 
 
Secondary Objectives  
• To determine the duration and magnitude of in vivo persistence of adoptively transferred T 
cells in the peripheral blood. 
• To assess the accumulation of transferred T-cells in the bone marrow and cerebrospinal fluid 
(CSF). 
• To quantitate anti-leukemic responses by measuring changes in leukemia burden using multi-
parameter flow cytometry (MPF), IgH deep sequencing and/or induction of CD19+ B-cell 
aplasia. 
• To determine the incidence of recrudescence or development of acute graft-versus-host-
disease (GVHD) in treated patients and its association with the engraftment of transferred T 
cells for the post-allogenic HCT cohort. 
• To assess the efficacy of infusional cetuximab in ablating transferred T cells and 
ameliorating acute toxicities and/or facilitating B cell recovery in treated patients. 
• To separately determine response rates and toxicity rates in the CR, MRD+ group and the 
refractory group. 
• To explore relationships of CD19 antigen load/disease burden and conditioning regimen on 
persistence of CAR+ T cells. 

 
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2 
BACKGROUND  
 
Introduction/Rationale for Development  
Acute Lymphoblastic Leukemia (ALL) is the single most common type of cancer afflicting 
children with a high overall cure rate of >80%. Nevertheless, recurrent disease is a significant 
contributor to childhood cancer morbidity and mortality, with overall survival rates of only 40-
50% [1-3]. The upfront treatment for childhood ALL involves a prolonged course of multidrug 
chemotherapy that is dose and time intensive and is augmented for those patients who are 
identified as high risk [1, 4].  As event free survival (EFS) and overall survival (OS) have greatly 
improved for newly diagnosed patients with ALL, those who relapse after intensive upfront 
therapy are not experiencing improved salvage rates and often have chemo-resistant disease[5]. 
At present, the best therapeutic option capable of achieving disease eradication for children with 
relapsed ALL almost invariably includes an allogeneic hematopoietic cell transplantation (HCT), 
provided a suitable donor is available and the disease is controlled prior to transplant [6-8].  Post 
relapse survival (PRS) is affected by timing of relapse, site of relapse, and age at diagnosis, with 
increasing age portending a worse prognosis. For those who relapse early (< 36 months from 
diagnosis), the 3-yr PRS is 30%, whereas those who relapse late (≥ 36 months from diagnosis) 
have a 3-yr PRS of 57.8% [9].  Additionally, patients who have a marrow relapse, with or 
without extramedullary disease, have the worst outcomes. Additionally, patients who relapse a 
second or greater time, have decreasing rates of responsiveness to chemotherapy, with declining 
rates of CR (44% with 3rd treatment, and 27% with 4th treatment) and OS of <20% [3]. 
Current data indicate that the presence of minimal residual disease (MRD), as defined by greater 
than 0.01% leukemic cell burden in bone marrow by multiparameter flow (MPF), at the time of 
allo-HCT is a significant predictor of post-HCT relapse and poor overall survival.  The 2-year 
disease free survival (DFS) for children with relapsed ALL who achieve a complete remission 
with no detectable disease prior to transplant is 70%, whereas those who have minimal residual 
disease at the time of transplant do much worse, with a 2-year DFS of about 20% [10]. In 
analyzing the patients on the COG relapsed ALL study AALL01P2, MRD was determined at the 
end of each block of chemotherapy [2]. Of the patients who were in CR2 at the end of block 1 
(81%), 62% remained MRD positive, indicative of a worse prognosis. If MRD negative CR is 
the desired response, only 30% of patients achieved that endpoint. The 3-year EFS rate for all 
patients achieving CR at the end of the first month of reinduction who were MRD positive at the 
end of block 1 is roughly 20%.  For patients who were MRD positive, there was a conversion to 
MRD negative after 2 additional cycles of chemotherapy in approximately 20% of the patients. 
What this means is that for relapsed ALL patients who remain MRD positive after re-induction 
chemotherapy, their overall outcome with standard of care, including HCT is substantially 
inferior with an EFS of only 20% or less.  Many transplant centers are now deferring HCT in 
recipients who are MRD positive due to their poor outcomes. Thus, the development of 
therapeutic strategies with augmented anti-ALL activity is warranted to increase the percentage 
of patients who achieve an MRD negative remission prior to allo-HCT, which in turn would be 
expected to increase the proportion of patients who are ultimately cured.   
Relapse following HCT is often not responsive to further chemotherapy and survival is dismal.  
Strategies for the treatment of relapse following HCT includes weaning of immunosuppression 
to invoke a graft versus leukemia (GVL) response, and if feasible, the use of donor lymphocyte 

 
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infusion (DLI).  Unfortunately, ALL is amongst the least responsive hematologic malignancies 
to a GVL effect, and this is demonstrated by the frequent occurrence of relapse despite graft 
versus host (GVH) disease and low response rate to DLI for relapse post HCT [11, 12].   
Therefore alternative strategies are called for in the treatment of relapsed ALL post HCT. 
CD19+ Non Hodgkin Lymphoma (NHL) occurs in pediatrics, most commonly as Burkitt, Diffuse 
Large B cell, and lymphoblastic lymphoma. In general, B cells NHL are highly curable with 
chemotherapy, however with recurrence, they are difficult to salvage and EFS is similar to OS.  
Due to the lack of effective therapies in this group, they will be eligible for this trial as an 
exploratory aim. 
 
Development of Adoptive Therapy for B-Lineage Malignancies using Chimeric 
Antigen Receptor Re-directed CD19-Specific T Cells  
2.2.1 
Adoptive Therapy for Viral Infections and Malignant Disease 
The feasibility of isolating and expanding antigen-specific T cells for adoptive therapy (AT) of 
human disease has been validated in numerous clinical trials [13-17].  Dr. Riddell initially 
studied adoptive T cell therapy with donor-derived CD8+ cytotoxic T-lymphocyte (CTL) clones 
specific for cytomegalovirus (CMV) as a means of reconstituting deficient viral immunity in 
allogeneic HCT recipients; and defined the principles and methodologies for T cell isolation, 
cloning, expansion, and re-infusion[18-20].  A similar approach pioneered by Heslop et al using 
polyclonal EBV-specific T cells has been effective for preventing or treating post-transplant 
EBV-associated lymphoproliferative disease after allogeneic HCT [21, 22].  These studies and 
others have demonstrated that virus-specific T cells derived from donors with established viral 
immunity and expanded in vitro can be transferred with minimal toxicity, mediate virus specific 
effector functions, and control viral replication as well as eradicate virally (EBV) transformed B-
cell immunoblastic lymphoma [23-29]. 
While the adoptive transfer of tumor-specific T cells can result in tumor eradication in a variety 
of animal models [30-41], adoptive T cell therapy for human malignancy has been significantly 
more challenging and less effective than for viral diseases.  Perhaps the most clinically robust 
AT data comes from efforts of the Surgery Branch at the National Cancer Institute (NCI) to treat 
melanoma [42-52]. Their studies demonstrated that administration of lymphodepleting 
chemotherapy followed by the adoptive transfer of polyclonal tumor infiltrating lymphocytes 
(TIL’s) specific for melanocyte lineage antigens/tumor-testis antigens and high-dose 
recombinant human interluckin-2 (rhuIL-2), results in demonstrable tumor regressions in nearly 
one half of treated patients. Of note, the response rate in patients that exhibited high-level 
persistent engraftment of transferred T cells was nearly 90%, while no responders are seen in the 
approximately 50% of patients without T cell engraftment. Interestingly, persisting TILs 
represented only a small subset of the infused product repertoire, suggesting that the capacity for 
engraftment and persistence may be linked to the intrinsic programming of a rare population of T 
cells derived from TIL [51, 52]. The generalization of the NCI group’s AT results for melanoma 
to other tumor types, including hematological malignancies, is the subject of intense ongoing 
investigation. 
 
 

 
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2.2.2 
Barriers to the Clinical Success of AT 
Tumor antigens presented by HLA molecules and recognized by T cells have been identified and 
can originate from processing of normal or over-expressed tissue-specific proteins, aberrantly 
expressed onco-fetal antigens and mutated proteins, or minor histocompatibility (H) antigens in 
the setting of allogeneic HCT [53-58].  However, isolating and expanding high-affinity major 
histocompatibility complex (MHC)-restricted tumor-reactive T cells from tumor-bearing patients 
is technically difficult and even when successful, these T cells often fail to eliminate tumors after 
adoptive transfer [59-61]. Our evolving understandings of the counter-regulatory mechanisms 
that impede successful tumor therapy have been derived largely from murine models [59-61]. 
Because many tumor antigens are self-proteins that are expressed in some normal tissues, 
tolerance mechanisms shape the frequency, avidity, and function of tumor-reactive T cells. 
Additionally, tumors evade immune recognition through a variety of mechanisms including local 
recruitment of regulatory T cells (TREG) and other suppressor cells, loss of antigen expression, 
down-regulation of MHC and co stimulatory molecules, and expression or secretion of inhibitory 
molecules or cytokines [62-74]. Finally, cultured tumor-reactive T cells often exhibit limited 
persistence in vivo after adoptive transfer, even if high doses of rhuIL-2 are administered to 
support their survival [44, 75, 76]. 
2.2.3 
Redirected Specificity of T Cells Engineered to Express scFvFc:ζ Chimeric Antigen 
Receptors 
In order to overcome some of these obstacles, we have focused on T cell genetic engineering 
strategies that serve to equip T cells with tumor specificity through the expression of CARs [77]. 
CARs are engineered to consist of an extracellular single chain antibody fused to the intracellular 
signaling domain of the T cell antigen receptor complex zeta chain, and when expressed in T 
cells, are able to redirect antigen recognition based on the monoclonal antibody’s specificity 
[78]. These chimeric cell-surface molecules have the ability to bind antigen and transduce 
activation signals via immunoreceptor tyrosine activation motifs (ITAMs) present in the CD3-ζ 
cytoplasmic tail [79], or both activation and co-stimulatory signals when CD28 and/or 4-
1BB/OX40 domains are incorporated in series with CD3-ζ [38, 80].  
The design of scFvFc:ζ receptors with target specificities for tumor cell-surface epitopes is a 
conceptually attractive strategy to generate antitumor immune effector cells for adoptive therapy 
as it does not rely on pre-existing anti-tumor immunity.  These receptors are “universal” in that 
they bind antigen in a MHC independent fashion, thus, one receptor construct can be used to 
treat a population of patients with antigen positive tumors.  Several constructs for targeting 
human tumors have been described in the literature including receptors with specificities for 
Her2/Neu, CEA, ERRB-2, CD44v6, and epitopes selectively expressed on renal cell carcinoma 
[29, 81-84].  These epitopes all share the common characteristic of being cell-surface moieties 
accessible to scFv binding by the chimeric T cell receptor.  The function of primary human T 
cells expressing tumor-specific scFvFc:ζ receptors have been evaluated in vitro; these cells 
specifically lyse tumor targets and secrete an array of pro-inflammatory cytokines including IL-
2, TNF-α, IFN-γ, and GM-CSF [85].   
Adoptively transferred CAR-modified T cells can eradicate established tumors in a variety of 
animal models [33, 35, 37, 86-89]. Moreover, T cells expressing second or third generation 

 
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CARs consisting of co-stimulatory signaling domains appear to be more resistant to activation 
induced cell death, exhaustion, and TREG mediated functional energy [33, 38, 80, 90-95].   
2.2.3.1 
CD19 as a target epitope for re-directed T cells 
Efforts to target hematologic malignancies with CAR-modified T cells have focused 
predominantly on cell lineage specific molecules.  Normal and malignant B cells express surface 
molecules that define their lineage commitment and maturation stage, and several are being 
investigated as targets for antibody or cellular therapy. These include CD20, which is present on 
B cell lymphomas and CLL, and has been targeted effectively with rituximab [96-98]. However, 
CD20 is expressed late in B cell development and is often not present on ALL [99]. By contrast, 
CD19 is expressed on all human B cells beginning from the initial lineage commitment until 
terminal differentiation into plasma cells, and is present on the majority of adult and pediatric 
ALL and B cell lymphomas. Genetic studies, in vitro assays, and engraftment assays in 
NOD/SCID mice have indicated that the leukemia repopulating cells in the common forms of 
ALL are CD34+ and CD19+, although a subset of Ph+ ALL may contain CD19- progenitors [100-
103]. Thus, for therapy of ALL and B cell lymphomas, we have constructed a CD19-specific 
CAR.  
2.2.3.2 
Construction of the FMC63scFvIgG4hinge: CD28tm/4-1BBζ-T2A-EGFRt CAR cDNA and 
third generation SIN lentiviral vector. 
We have developed a CAR consisting of tumor targeting single-chain variable fragments 
(scFv’s) specific for CD19 [38, 104-110]. Based on the VH and VL sequences of the CD19-
specific murine IgG1 monoclonal antibody FMC63 published by Nicholson et al, a scFv 
sequence was constructed de novo utilizing PCR [111].  A full length 
CD19scFvIgG4hinge:CD28tm/41BB-T2A-EGFRt cDNA designated ZRX014 and property of 
ZetaRx Biosciences, Inc, encodes for a 2nd generation CD19scFv CAR and was constructed by 
PCR splice overlap extension and consists of the human GM-CSF receptor alpha chain leader 
peptide, FMC63 VL, Gly-Ser linker, FMC63 VH, human IgG4 hinge, human CD28 
transmembrane domain, 4-1BB intracellular cytoplasmic domain (residues 191-232) and CD3ζ 
(residues 31-142).  Further, a truncated human EGFR selection/tracking/suicide construct is co-
expressed with the CAR in constructs designed with T2A cleavable linkers [112].  When 
incorporated into third generation SIN lentiviral vectors, transduced T cells exhibit CD19-
specific tumor cell recognition, lysis, cytokine secretion and proliferation [113]. 
The surface expression of EGFRt in conjunction with the CAR provides for a second cell surface 
marker that allows easy examination of transduction efficiency [112]. Biotinylated Erbitux binds 
to the EGFRt expressed on the cell surface and can be labeled with fluorochrome for analysis 
with flow cytometry. Additionally it can be used for enrichment through selection with anti-
biotin beads to increase the frequency of transduced cells and thus creating a purified population 
of CAR expressing T cells. Because the EGRFt lacks an intracellular domain, it does not have 
any signaling capacity, thus binding of Erbitux to the EGFRt does not affect the cell.  Lastly, it 
has the potential to be used as a suicide gene in the clinical setting with the treatment of Erbitux, 
a clinically available antibody with a low toxicity profile [112, 114].  After binding of Erbitux, 
cells undergo antibody-dependent cellular cytotoxicity in vivo.  Ongoing work is currently taking 
place in a primate model to further evaluate the use of Erbitux as a treatment for ablation of 

 
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transferred T cells and with its success, we anticipate the use of Erbitux as a strategy in which 
cells can be ablated if they are no longer required for efficacy or alternatively, could be used in 
conjunction with glucocorticoids for ablation of T cells due to toxicity. 
2.2.4 
CD4+ T cell help enhances the function and persistence of CD8+ T cells 
CD4+ T cells enhance CD8+ effector T cell persistence, enhance memory formation, and 
trafficking to antigen rich tissues. Without CD4+ help, CD8+ memory cells undergo a transient 
partial exhaustion [115].  Additional work has shown that CD4+ help is required to allow CD8+ 
effector cells entry into infected tissue [116].  Activated CD8+ T cells have shown poor survival 
when CD4 help is absent and CD4 help is required during recall expansion of memory CD8 cells 
[117].  Likewise, CAR+ CD4+ T cells enhance CAR+ CD8+ cytolytic effector function both in 
vitro and in vivo [118]. For these reasons, this protocol will evaluate the use of cell products 
formulated to comprise a 1:1 mix of CD4+ and CD8+ CAR expressing T cells. 
2.2.5 
Enhancing Persistence of Transferred Cells 
While T cell genetic modification can address some of the issues relevant to tumor AT, our 
animal studies, as well as data from initial clinical trials demonstrate that the capacity of gene-
modified CAR+ effector T cells to persist following adoptive transfer is a major obstacle to 
achieving therapeutic responses. However, patient preparation for AT by the induction of 
lymphopenia can enhance the engraftment of adoptively transferred T cells as described below. 
2.2.5.1 
Lymphodepletion prior to T cell transfer 
The size of the T cell pool is subject to homeostatic regulation, and the induction of lymphopenia 
results in the proliferation of residual T cells to restore T cell numbers [119-121]. The 
lymphopenic environment may be more favorable for T cell transfer because of less competition 
for homeostatic cytokines such as IL-15 and IL-7 that promote lymphocyte proliferation and 
survival [122-124], and the elimination of CD4+ CD25+ regulatory T cells [125, 126]. Direct 
evidence that the induction of lymphopenia improves the persistence of transferred tumor-
reactive T cells was provided by studies at the NCI in which melanoma patients were treated 
with fludarabine and cyclophosphamide to induce lymphopenia prior to the transfer of 1010-1011 
polyclonal melanoma-specific T cells. A subset of these patients achieved prolonged high-level 
engraftment of a few clonotypes in the transferred T cell population, and this correlated with 
antitumor efficacy [45, 127, 128]. Studies in murine models subsequently confirmed the human 
data that lymphodepletion can be exploited to improve the antitumor efficacy of transferred T-
effector (TE)cells, and provided evidence that hematopoietic stem cell (HSC) infusion further 
promoted the antitumor activity of T cell transfer [129, 130].  No systematic analysis has been 
done to directly compare various lymphodepletion regimens. 
2.2.5.2 
Lymphopenia post hematopoietic cell transplant 
Prolonged lymphopenia is common following allo-HCT.  If often takes a year or more to obtain 
a full repertoire of lymphocytes assuming that there are no major episodes of chronic GVH 
requiring longer duration of immunosuppression or recurrent infections, particularly CMV 
reactivation.  The CD3+ subset of lymphocytes reaches the 5th percentile of reference range on 
average 2 months post allo-HCT [131].  Helper phenotype (CD3+CD4+) T cells are delayed until 

 
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9 months post-transplant to reach the 5th percentile of reference range, and cytotoxic CD8+ T 
cells recover more quickly and are within normal range by day+60. Naïve T cells begin their 
recovery 6 months following allo-HCT, but typically do not reach normal numbers until 2 years 
post allo-HCT.  We anticipate this patient population will be highly lymphodepleted at the time 
of T cell transfer based on prior allo-HCT and the re-induction/salvage chemotherapy patients 
will receive. 
 
Clinical trials using CAR modified T cells  
Several clinical trials using CAR modified T cells have been published, most recently using 
CD19 CAR specific autologous T cells, and at least a dozen are currently accruing patients.   
2.3.1 
1st Generation CARs  
A study of CD19 and CD20 specific CAR modified T cells in adult patients with recurrent non-
Hodgkin lymphoma (NHL) was recently published from City of Hope [132].  Autologous CD8+ 
T cells were isolated from a leukapheresis product.  A total of 15 infusions (dose range of 108 to 
2x109 cells/m2) were given to four patients with no overt toxicities attributable to the T cell 
product. Noted toxicities include hepatic toxicity, lymphopenia, and eosinophilia.  Also of 
interest, two patients were noted to have a cellular anti-transgene immune rejection response. 
The persistence of the transferred T cells was short lived, lasting between 24 hours and 7 days.  
A similar study was conducted in Seattle using CD20 specific CAR modified T cells for patients 
with relapsed or refractory indolent B-cell lymphoma or mantle cell lymphoma [133].  Of the 
nine patients enrolled, products were generated from seven.  The seven patients received a total 
of 20 T-cell infusions with minimal toxicities (dose range of 108 to 3.3x109 cells/m2).  In this 
group, two patients maintained a previous complete response (CR), while one achieved a partial 
response (PR), and 4 had stable disease (SD).  In this report, no anti-transgene immune rejection 
responses were identified. Of the adverse events (AEs) reported, all grade 2 or lower, they were 
attributed to the concurrent IL-2 treatment rather than the cell product.  In both of these clinical 
trials, there was only a minimal persistence of the transferred T cells, indicating that additional 
modifications needed to be made in order to improve persistence. 
2.3.2 
Enhanced persistence and clinical results with second generation CARs 
Both of the above mentioned trials used first generation CARs, which included CD3ζ as the only 
intracellular signaling domain.  By combining a co-stimulatory signal, from either CD28 or 4-
1BB, enhanced persistence and clinical responses can be demonstrated. A recent clinical trial 
performed by the Baylor group examined the persistence of transferred T cells expressing either 
a first or second generation CD19 specific CAR in the same patient and found that the second 
generation CAR, which contained the co-stimulatory signal from CD28, had better in vivo 
expansion and persistence [134].  Six adult patients with NHL were treated on this trial and had 
two separate T cell products generated over a two-week period with an intra-patient dose 
escalation, resulting in individual doses between 2x107/m2 to 2x108/m2.  The infusions were well 
tolerated, without SAE. The first generation CAR+ T cells failed to expand after transfer and 
were undetectable by 6 weeks, whereas the second generation CAR+ T cells expanded 6.82 fold 
two weeks after transfer and were detectable up to 6 weeks post infusion. These results suggest a 
confirmation of animal studies suggesting that 2nd generation CAR+ T cells have enhanced in-

 
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vivo expansion and persistence. It should be noted that there was no sustained clinical benefit 
noted in any of the six patients. 
The NCI recently reported their findings in a single adult patient with NHL, using autologous 
CD19- specific second generation (CD28 signaling domain) CAR modified autologous T cells 
[135, 136].  The first reported patient received 4X108 total cells divided over 2 days following 
lymphodepletion with cyclophosphamide and fludarabine.  The patient also received IL-2 for 
eight doses following T cell infusion. Acute toxicities included fever for two days, which self-
resolved and the patient demonstrated an impressive partial response to treatment that lasted for 
32 weeks before progression was noted with increased lymphadenopathy. It should be noted that 
the patient experienced prolonged B cell aplasia with resulting decreased serum immunoglobulin 
levels that was clinically not significant and the patient did receive IVIG. In the follow up report, 
6/8 patients with either NHL or CLL have had clinical responses. 
Table 2-1 Published Trial Results with CD19 CAR modified T cells 
NCT 
Site 
Co—
stimu-
lation 
Disease 
Treated 
Pediatric 
patients 
Lympho-
depletion 
Dose 
Range 
Clinical 
Response Reference 
01029366 
U Penn 
41BB 
CLL 
N 
Optional 
145 x 106 
transduced 
T cells 
6/9 
139, 140, 
142 
01626495 
CHOP 
41BB 
ALL 
Y 
Optional 
1.4-12 x106 
transduced 
T cell/kg 
2/2 
143, 144 
00924326 
NCI 
CD28 
NHL, 
CLL 
N 
Y 
3-30 x106 
transduced 
T cell/kg 
6/8 
136 
01593696 
NCI 
CD28 
NHL, 
ALL 
Y 
Y 
1 x106 
transduced 
T cell/kg 
3/4 
144 
00466531 
MSKCC CD28 
CLL 
N 
Y 
4-30 x106 
transduced 
T cell/kg 
3/10 
136, 
Park, JH et 
al. ASH 
abstract 
2012 
01044069 
MSKCC CD28 
ALL 
N 
Y 
1.5-3 x106 
transduced 
T cells/kg 
5/5 
137 
00586391   Baylor 
CD28 
NHL/CLL 
N 
N 
2-20 x 107 
transduced 
cells/m2 
0/6 
134 
CHOP Children’s Hospital of Philadelphia; NCI National Cancer Institute; MSKCC Memorial Sloan 
Kettering Cancer Center; Baylor 
Preliminary results from two trials conducted at Memorial Sloan Kettering have also been 
reported using a CD19-specific CAR with a CD28 costimulatory domain [137, 138].  The ex-
vivo culture time was short; between 11-19 days. This was a dose escalation trial, with starting 
doses of 1.2-3.0x107 CAR+ T-cells/kg initially without lymphodepletion, followed by cohorts 

 
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that were treated with increasing cyclophosphamide doses, first with 1.5gm/m2 followed by 
3gm/m2.  For the patients who did not receive lymphodepletion prior to T cell transfer, there 
were no detectable T cells at one month.  However, there was persistence of the transferred T 
cells for 6 weeks noted in some of the patients who received cyclophosphamide conditioning 
prior to T-cell transfer. There have been 13 reported patients from these trials, 1 of whom was 
enrolled in cohort 2 and had a SAE with subsequent death that has been reported separately and 
discussed below as a potential toxicity of CAR therapy [139]. Following the patient death, the 
next 3 patients received dose level -1 without lymphodepletion, with doses of 0.4-1x107 CAR+ T 
cells/kg.  Among the eight patients who received the T cells, the most common side effects 
included rigors, chills and transient fevers, all occurring within 24 hours of receiving the 
modified T cells infusions.  Most recently, there were five adult patients reported in the trial for 
ALL[138].  Two had frank relapse at the time of enrolling, two were in CR with MRD+ disease, 
and one was MRD -.  All five patients were MRD negative by day 60 following the T cell 
infusion.  One patient relapsed following loss of the modified T cells in vivo after treatment with 
steroids.  Four of the patients went on to an allo-HCT, 3 of whom are alive today with no 
evidence of disease and one died from transplant complications with no disease detectable at the 
time of death.   
Researchers from the University of Pennsylvania have an ongoing trial using modified 
autologous T cells which express a CD19 CAR that has a 4-1BB co-stimulation domain rather 
than CD28 [140, 141].  Polyclonal T cell preparations were generated ex-vivo by PBMC 
stimulation with anti-CD3/CD28 beads over a period of approximately 10-12 days.  The first 
three reported patients had CLL and received between 1.46x105 to 1.6x107 cells/kg.  Infused T 
cells expanded in vivo up to 1000 fold, induced B cell aplasia and in 2 of the 3 patients have 
induced tumor remissions.  A third patient received corticosteroids due to toxicities, which 
blunted the engraftment and anti-tumor response that did not achieve a full regression of CLL 
[140, 141]. This trial was updated at ASH 2012 and at that time a total of 10 patients (9 adults 
with CLL and 1 child with ALL) had been treated, of whom six have had a clinical response, 
including 4 CRs that have been durable.  Maximal T cell response was seen by day+30 following 
T cell infusion in all cases.  See Section 2.4 for full details of toxicities described with these 
trials. 
2.3.3 
CD19 CAR T cell Therapy Experience for Pediatric CD19+ Malignancies 
Two groups, CHOP and NCI have now reported experience treating relapse CD19+ acute 
lymphoblastic leukemia and lymphoma in children both before and following allo-HCT.  Both 
groups reported at the ASH conference 2012.  At that time CHOP had treated two pediatric 
relapsed ALL patients, 1 with no prior allo-HCT, and 1 with a prior allo-HCT [142-144].  Both 
obtained a CR, with the later patient going on to recur with a CD19 negative ALL.  Both subjects 
experienced a cytokine storm, and the first patient required tocilizumab to target elevated IL-6 
levels [145] with more details provided below (Section 2.4).  NCI reported on the treatment of 3 
patients post-allo-HCT with patient-derived CAR modified T cells of donor origin [146].  The 
first patient obtained a CR following T cell infusion with evidence of mild cytokine elevation not 
necessitating intervention. The second two patients had detectable modified T cells (1 in 
peripheral blood and 1 in a malignant pleural effusion) without signs of cytokine elevation and 
did not have a clinical response. See Section 2.4 for full details of toxicities described with these 
trials. 

 
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Potential Toxicity Associated with the Infusion of CD19 Specific CAR+ T Cell 
Lines 
Cytokine Release Syndrome: It is commonly observed that patients receiving therapeutic T cells 
have a mild cytokine release syndrome (CRS) upon infusion of the product, with symptoms of 
fever, chills, rigor, mild hypotension and mild respiratory distress.  These toxicities are typically 
self-resolving within 48 hours of onset and have been reported in the most recent results from 
CD19 CAR specific clinical trials [135, 137]. From the U Penn group, they reported no toxicity 
greater than grade 2 associated with infusion, and NCI and MSKCC reported no infusional 
toxicities in pediatric patients [143, 146].  Unlike these transient and mild infusional side effects, 
emerging clinical data with second generation CAR AT for patients with bulky B-cell 
malignancies has revealed a new toxicity syndrome that occurs in patients who have a robust 
engraftment of T cells (usually occurring two weeks after infusion) and who experience a 
concomitant therapeutic response. The most robust data is from the University of Philadelphia in 
both pediatrics and adults and is described in detail [140, 141, 145].  Several patients required 
corticosteroids for ablation of the cells in addition to tumor lysis therapy (IV fluids and 
allopurinol).  All patients had serum cytokine levels followed and frequently IL-6, INFγ, IL-8, 
IL2Rα and MIP1b were elevated.  Four patients experiencing severe cytokine storm and high 
levels of serum IL-6 received tocilizumab and subsequently experienced rapid resolution of their 
symptoms. One patient required tocilizumab on day D3, and subsequently had no T cell 
proliferation and no disease response, suggesting the early modulation of the immune response 
tempers that efficacy.  It should be noted that the 3 patients who were non responders did not 
have elevated cytokines. Memorial Sloan Kettering and CHOP both also reported acute mental 
status changes during the cytokine surge that are fully reversible [138, 144].   
Deaths on study: Two deaths following CAR therapy have been reported in the literature.  The 
first was a patient with metastatic breast cancer receiving a high dose of third generation CAR 
targeting ErbB2 who had pulmonary toxicity and cytokine release syndrome immediately 
following the infusion of T cells [147]. The patient received a total dose of 1010 cells, and on 
autopsy, was found to have large numbers of transferred T cells present in lung tissue that also 
was heavily seeded with metastatic breast cancer nodules. It has been hypothesized that this was 
due to expression of ErbB2 at low levels on lung epithelial however the impact of tumor 
targeting in the lung cannot be excluded.  The second event occurred in a patient with CLL who 
developed a sepsis like picture following infusion of 1.2-3x107 T cells/kg containing a second 
generation CD19 CAR [139]. Autopsy did not reveal any overt cause of death and the clinical 
investigators have hypothesized that the patient had low-grade sepsis prior to the infusion of T 
cells that was magnified in the context of lymphodepletion and transferred T cell expansion.  
Alloreactive T cell activation:  The use of expanded T cells of donor origin carries the potential 
risk that a portion of the cell product will consist of T cells that have an endogenous TcR that is 
alloreactive and capable of mediating a graft versus host response. In this study, for the post allo-
HCT cohorts, the donor derived T cells are being obtained from the peripheral blood of the 
patient following a prior allo-HCT at a time when GVHD is quiescent, off all 
immunosuppression. Evidence to date that GVHD recrudescence is not a common consequence 
of CAR T cells infusion when the product is derived from post-transplant patient PBMC comes 
from the reports of several patients treated with CD19 directed donor derived T cells that were in 
this setting.  Four total pediatric patients have been reported to date, all of who did not 

 
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experience GVH following in fusion of the cells.  One child treated at CHOP did have an in vivo 
expansion of cells of donor origin CAR+ T cells, accompanied by CRS and a complete remission 
[142, 143, 145].  Likewise, of the reported NCI patients, there has not been GVH reported [146]. 
Additional evidence for GVH immune tolerance that is not reactivated upon T cell activation in 
vivo comes from reports on the use of blinatumomab (a bispecific antibody binding CD3 and 
CD19) in the post allo-HCT setting, including after haploidentical transplantation [148]. In these 
patients there is substantial expansion of CD3 T cells and no GVHD has been observed, 
suggesting that the activation of donor derived T cells, possibly even including T cells with 
alloreactive potential does not necessarily lead to clinical manifestations of GVHD and in fact 
GVHD may occur infrequently or not at all in this context.  
Collectively, these data suggest that the repertoire of donor T cells engrafted in patients who fail 
to flair with GVH following immune suppression withdrawal are not reactivated by their 
inclusion in CAR T cell adoptive therapy products. More experience is required to better define 
the true incidence of this theoretical complication and this trial will seek to carefully assess this 
outcome in treated patients. 
Potential long-term toxicity:  
B cell Aplasia:  A potential long-term toxicity of CD19 directed CAR therapy is prolonged B-
cell aplasia.  Since non-malignant CD19+ B-cells will be subject to recognition by re-directed T 
cells, their long-term persistence of the adoptively transferred CD19-specific CTL has the 
potential to cause B-cell immunodeficiency. In research participants who are predicted to 
succumb to recurrent/progressive ALL, the clinical sequelae of B-cell lymphopenia that can be 
ameliorated by intravenous immunoglobulin (IVIG) therapy is an acceptable side effect of 
CD19-directed immunotherapy, especially since prolonged ablation of normal CD20+ B cells in 
patients receiving rituximab therapy does not appear to result in clinically significant 
complications attributable to depleted numbers of normal B cells.  In fact, this side effect has 
been reported in the literature in adult patients who have received CD19 CAR+ T cell therapy 
with persistence of the transferred T cells and has not been thought to be clinically relevant [135, 
137, 140, 141].  Pediatric ALL patients undergoing chemotherapy are already known to be 
profoundly B cell depleted, so it shouldn’t have a large effect on an already almost absent cell 
population [149].  If the hypogammaglobulinemia becomes clinically significant, then the 
research participant may be given IVIG as replacement therapy until B-cell function returns.  
This trial provides for the intervention of cetuximab infusions to potentially ablate the infused 
CAR T cells that co-express EGFRt and this is an explicit study objective of this protocol for 
patients that achieve a prolonged remission, continued CAR T cell engraftment in the face of B 
cell aplasia and opportunistic infection. 
Secondary Malignancy/Insertional Mutagenesis: A second potential long-term toxicity relates to 
Dr. Alain Fischer’s gene therapy trials at the Necker Children's Hospital in Paris [150, 151].  
Since April 2000, Dr. Fischer’s team has treated approximately 20 patients with a SCID-X 
condition by transducing bone marrow-derived CD34+ cells with a retrovirus encoding the 
common cytokine-receptor -chain gene that forms a T cell growth-factor receptor.  Following 
re-infusion of the transduced stem cells, there is a selective advantage for the survival of T cells 
that bear intact cytokine receptors that is manifested by the emergence of peripheral transduced T 
cells within 6 to 12 weeks of treatment.  However, as of October 2010, five of the children 
treated on this protocol have developed a T cell leukemic disease, resulting in 1 death.  

 
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Preliminary analysis revealed that the retrovirus used for transduction was inserted into a 
hematopoietic precursor that was then differentiated into a T cell having a profound proliferative 
advantage. This adverse event has raised concern that retroviral transduction may have caused 
the lymphoproliferation as the consequence of an insertional mutagenesis event. However, in 19 
patients with ADA deficiency treated with gene therapy, none developed leukemic disease 
suggesting that there may be disease modifiers which predispose to the development of 
leukemia. 
Recently data regarding the risks of gammaretroviral vectors for T cell modification, rather than 
stem cell modification was published [152].  The University of Pennsylvania analyzed 221 
patient samples obtained over a decade from 43 subjects who had been enrolled in T cell trials, in 
which CD4ζ CAR’s where expressed on autologous T cells (CD4 and CD8) through genetic 
modification with gene integration directed by gammaretroviral vectors.  There was durable 
engraftment of the modified T cells in 212 of the samples.  Through whole genome analysis, a 
thorough analysis of the integration sites was evaluated in 11 individuals with high-level 
marking.  A total of 7222 unique integration sites were detected and were enriched for sites near 
the 5’ end of a gene. There did not appear to be any clonality in the samples, and the integration 
sites over time in the same patient varied.  Additionally, there did not appear to be enrichment of 
integration sites near genes involved in clonal expansion or persistence, nor was there 
enrichment of integration sites near the 5’ ends of cancer-related genes.  Overall, this report had 
540 patient-years without integration-mediated toxicity, placing the true adverse event rate at 
less than 0.0068 per person-year. This data suggests that the use of gammaretroviruses for gene-
integration in T cells carries a much safer toxicity profile than when used in hematopoietic stem 
cells and that T cells appear to have an inherent protection to insertional genotoxicity. 
In addition to transducing T cells rather than hematopoietic stem cells, we are using a third 
generation SIN lentiviral vector rather than a gammaretroviral vector.  Additional safety data has 
been published regarding the use of lentiviral vectors in clinical trials.  This report detailed 65 
subjects who received transduced CD4+ cells.  The mean copy number was 2.3 with a range of 
0.2-5.4.  Additionally, all tests for replication competent lentivirus were negative. Previously 
some of these subjects had integration site analysis performed, which showed that there were 
>7000 unique insertion sites without evidence of enrichment near proto-oncogene 5’ ends or 
within tumor suppressor genes[153, 154], suggesting that lentiviral vectors may be safer than 
gammaretroviral vectors in regards to malignant transformation potential. 
In summary, we believe that the potential toxicities associated with the use of CD19-specific T 
cell therapy are outweighed by the need to develop novel treatment for patients with life-
threatening ALL.  
 
T Cell Dosing Rationale 
Phase 1 (enrollment onto Phase 1 completed on 11 May 2016): 
As noted in the above referenced trials using autologous CAR modified T cells, there is 
significant inter-study variability in dosing of T cells.  Doses were determined either on a per kg, 
or a per m2 dose without normalizing to the percentage of T cells in the product that are CAR 
expressing.  The successful study from the University of Pennsylvania had an average dose of 
1.45 (range 0.14-5.9 ) x 108 total transduced cells[143] and in the first 3 reported patients, all of 
whom responded, they received 1.6x107/kg, 1.0 x 107/kg and 1.46 x 105/kg.  Notably, the 1st and 

 
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3rd patients each obtained a CR despite having a 2 log difference in dose, while the 2nd went into 
a PR after requiring glucocorticoids. A pediatric CHOP patient received 1.2 x 107 transduced T 
cells/kg with a second receiving 1.4x106 transduced T cells/kg [144]. The three NCI pediatric 
patients received 1x106/kg transduced T cells.   
There have been no serious infusional toxicities related to CD19 CAR modified T cells and the 
in vivo expansion with resultant cytokine storm appears to not be related to the initial dose of T 
cells but rather the magnitude of the in vivo expansion and size of the antigen load.  These 
toxicities are not predicted based on the infusion dose but rather they are more likely due to both 
culture properties and patient properties. In the U Penn study, all of the patients who obtained a 
CR had between 100-1000 transduced T cells/µl of blood at the time of maximal expansion, PR 
patients had between 10-100 transduced T cells/µl of blood, and NR had <10 transduced T 
cells/µl of blood, stressing the importance of engraftment of the transferred T cells upon 
response [143]. For those patients who were NR, they did not develop toxicities, suggesting that 
only patients who have potential clinical benefit from the product are likely to develop toxicities.   
Therefore, it is difficult to talk about maximum tolerated doses outside of infusional toxicities. 
This study started with a dose of 5x105 CAR+EGFRt+ T cells/kg as there have not been any 
serious adverse events or dose limiting toxicities noted with this dose in prior CD19 CAR T cell 
trials.   
After treating the first six subjects on this study, variability has been seen in the magnitude of 
expansion, as well as ongoing level of T cell persistence accompanied by ongoing B cell aplasia.  
This variability could be attributed to several possible factors.  The modified T cells undergo an 
impressive in-vivo expansion, which may lead to exhaustion and poor persistence.   
Table 2-2 Expansion of persistence of T cells of the subjects treated at dose level 1 
Subject ID 
Peak % Peripheral 
Blood Expansion 
(day) 
Peak 
Absolute/µl 
(day) 
Longest time-point of 
detectable 
105CAR+EGFRt+ T 
cells 
Length of B cell 
aplasia 
14602-S01 
16.6 (d14) 
118 (d14) 
5 months 
5 months 
14602-S02 
93.6 (d10) 
1288 (d10) 
d +35 
d +35 
14602-S03 
78.1 (d14) 
353 (d14) 
Ongoing at 7 months 
Ongoing at 7 months 
14602-S04 
13.4 (d10) 
77 (d10) 
d+35 
d+35 
14602-S05 
25.2 (d8) 
63 (d10) 
d+42 
d +42 
14602-S06 
NR 
NR 
NR 
NR 
NR = non-responder 
Recent data from our group and from the Fred Hutchinson Cancer Research Center (personal 
communication), have shown a potential benefit to enhanced expansion and long-term 
engraftment with the use of fludarabine and cyclophosphamide.  Additionally, the FHCRC group 
has shown superior ability to give repeat infusions of T cells with subsequent engraftment rather 
than rejection.  Subjects 23 and 24 were the first two patients treated on this trial to receive this 
combination of lymphodepletion and both were treated at dose level 3. When compared with the 
other subjects treated at dose level 3 who only received cyclophosphamide, 23 and 24 had 

 
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increased expansion of the T cells in the peripheral blood and bone marrow (Figure 1) but also 
had increased toxicity. Both S23 and S24 had neurotoxicity that met the definition for a DLT.  
Early time points indicate that they may also have enhanced long term persistence.
 
Figure 2-1 Magnitude of engraftment among the subjects treated at dose level 3 with comparison 
of lymphodepletion regimen. 
Table 2-3 Expansion of persistence of T cells of the subjects treated at dose level 3 
Subject ID 
Peak % Peripheral 
Blood Expansion 
(day) 
Peak % in 
Bone Marrow 
(day) 
Longest time-point of 
detectable 
105CAR+EGFRt+ T cells 
Length of B cell aplasia 
14602-S11 
59.79 (d14) 
16 (d21) 
Ongoing at 15 months 
Ongoing at 15 months 
14602-S13 
44( 7) 
30 (d7) 
D+ 42 
D+42 
14602-S14 
30.53 (d7) 
28.9 (d7) 
D+ 14 
D+ 14 
14602-S21 
10.48 (d10) 
17.94 (d7) 
D+14 
D+14 
14602-S23 
74.62 (d10) 
70.82 (d21) 
Ongoing at D+42 
Ongoing at D+42 
14602-S24 
88.0 (d10) 
51.09 (d21) 
Ongoing at D+42, went 
to HSCT 
Ongoing at D+42, went 
to HSCT 
Paramount to the therapeutic efficacy of this investigational cell product is the ability to obtain 
reliable long-term persistence.  In light of the recent data on fludarabine/cyclophosphamide use 
for lymphodepletion, we plan to investigate the uniform use of this specified lymphodepletion 
regimen. Because of the enhanced expansion of T cells with the use of fludarabine, we will begin 
dose escalation again, starting with dose level 1. 
 
 
0
2 0
4 0
6 0
0
2 0
4 0
6 0
8 0
1 0 0
P e rip h e ra l B lo o d
D a y s  P o s t  T  c e lls
%  C A R   T  c e lls /A ll  T  c e lls
0
2 0
4 0
6 0
0
2 0
4 0
6 0
8 0
B o n e   M a rro w
D a y s  P o s t  T  c e lls
%  C A R   T  c e lls /A ll  T  c e lls
C yto xa n
F lu /C y

 
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Phase 2 dosing 
Overall, 43 subjects have been treated on the phase 1 portion of this study to date, and it has been 
well tolerated.  There have been a total of 7 DLT’s across all dose levels.  The phase 1 dose 
escalation demonstrated that with flu/cy lymphodepletion, 0.5x106 CAR+ T cells/kg is a safe 
dose (0/6 subjects developed DLTs) while 1x106 CAR+ T cells/kg is a safe dose after alternative 
lymphodepletion (1/10 subjects developed DLTs).  The phase 2 will open for accrual once the 
safety of 1x106 CAR+ T cells/kg is determined (per Section 10.3.3 if at least 6 patients are treated 
with a <34% DLT rate).  If 1x106 CAR+ T cells/kg is found safe, this will be the RP2D. 
Table 2-4 DLTs with flu/cy lymphodepletion 
Group/Cohort 
DLT description 
Patient ID 
1F1 (n= 6) 
none 
NA 
1F2 (n=6) 
Grade 4 encephalopathy 
14602-S41 
1C (n=2) 
Grade 4 seizure, Grade 2 seizure 
14602-S23, 14602-S24 
For the cohort of patients receiving alternative lymphodepletion, 1x106 CAR+ T cells/kg will be 
the RP2D with a demonstrated DLT rate of 10% (1/10 treated patients). 
Table 2-5 DLTs with non-flu/cy lymphodepletion 
Group/Cohort 
DLT description 
Patient ID 
1A (n=7) 
Grade 4 encephalopathy 
14602-S02 
1B (n=10) 
Grade 4 hydrocephalus 
14602-S12 
1C (n=4) 
NA 
NA 
1D (n=5) 
Grade 3 seizure, Grade 3 left ventricular 
systolic dysfunction 
14602-S19, 14602-
22 

 
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3 
ENROLLMENT PROCEDURES AND ELIGIBILITY CRITERIA 
 
Study Enrollment 
3.1.1 
Patient Registration   
Patients may be enrolled on the study once all eligibility requirements for the study have been 
met. Registered patients that are eligible based on a screening questionnaire will be enrolled on a 
first-come first served selection process based on when the Research Nurse/Protocol Physician is 
first contacted by the referring physician or patient family. 
3.1.2 
Informed Consent/Assent 
The investigational nature and objectives of the trial, the procedures and treatments involved and 
their attendant risks and discomforts, and potential alternative therapies will be carefully 
explained to the patient or the patient’s parents or guardian if the patient is a child, and a signed 
informed consent and assent will be obtained according to institutional guidelines. 
3.1.3 
Study Enrollment 
Upon consent for participation in an SCRI immunotherapy clinical trial, subjects will be entered 
into the Immunotherapy Registration Portal. A unique Registration ID will be assigned to each 
potential study subject, and demographic and general eligibility information will be collected. 
All subjects who are consented will be entered into a study-specific database following review of 
eligibility documentation. 
3.1.4 
Dose Assignment 
Dose and Cohort Assignment will be made at the time of T cell infusion during the phase 1 
portion of the study. Dose assignment will be made at the time of enrollment during the phase 2 
portion of the study and cohort assignment at the time of T cell infusion based on 
lymphodepletion chemotherapy administered. 
3.1.5 
Timing 
Eligibility studies must be performed within 7 days prior to enrollment unless otherwise 
specified. 
The eligibility criteria listed below are interpreted literally and cannot be waived unless the 
protocol PI and IND sponsor petition the Institutional Review Board (IRB) for a planned 
protocol deviation. All clinical and laboratory data required for determining eligibility of a 
patient enrolled on this trial must be available in the patient’s medical or research record which 
will serve as the source document for verification at the time of audit. 
 
Patient Criteria   
3.2.1 
Inclusion Criteria 
1. Male or female subjects 12 months of age and <27 years of age at the time of study 
enrollment. 
2. Weight 10 kg 

 
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3. Diagnosis of CD19+ leukemia or lymphoma: 
4a. Disease Status for Phase 1 portion (leukemia only) 
If post allogeneic HCT: Confirmed CD19+ leukemia recurrence defined as ≥0.01% disease 
by SCH or UW Pathology Department following allogeneic HCT. 
If Relapse/Refractory status with no prior history of allogeneic HCT (one of the following): 
• 2nd or greater marrow relapse, with or without extramedullary disease 
• 1st marrow relapse at end of 1st month of re-induction with marrow having  ≥0.01% 
blasts by morphology and/or MPF, with or without extramedullary disease 
• Primary Refractory as defined as having M2 or M3 marrow after 2 or more separate 
induction regimens 
• Subject has indication for HCT but has been deemed ineligible 
4b. Disease status for Phase 2 portion: 
Leukemia 
Subject status post allogeneic HCT: 
Recurrent CD19+ leukemia defined as ≥0.01% disease in the marrow or isolated 
extramedullary disease following allogeneic HCT.  
Subject with no prior history of allogeneic HCT (one of the following): 
• 2nd or greater relapse, with or without extramedullary disease (isolated extramedullary 
disease is eligible) 
• 1st marrow relapse at end of 1st month of re-induction with marrow having ≥0.01% blast 
disease, with or without extramedullary disease 
• Primary Refractory as defined as having M2 or M3 marrow after induction 
• Subject has indication for HCT but has been deemed ineligible 
Marrow involvement: 
For those subjects with marrow involvement, the first 15 subjects enrolled after the 
03.28.2017 amendment must have detectable disease at the time of enrollment (this criterion 
was satisfied as of 1 September 2017). 
Lymphoma: 
CD19+ Non-Hodgkin Lymphoma (NHL) refractory or relapsed with no known curative 
therapies available 
5. Patients with CNS involvement are eligible provided that they are asymptomatic and in the 
opinion of the study PI have a reasonable expectation that disease burden can be controlled in 
the interval between enrollment and T cell infusion.  Patients that have a significant 
neurologic deterioration will be not be eligible for T cell infusion until alternate therapies 
result in neurological stabilization. 

 
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6. Lansky performance status score of  50 or a Karnofsky score of  50 for patients    16 years 
of age. Note: Patients who are unable to walk because of paralysis, but who are up in a 
wheelchair, will be considered ambulatory for the purpose of assessing the performance score. 
7. Life expectancy of >8 weeks 
8. All patients must discontinue all anti-cancer agents and radiotherapy, and, in the opinion of the 
study PI, have sufficiently recovered from significant acute toxic effects of all prior 
chemotherapy, immunotherapy, or radiotherapy prior to entering this study.  
a. Chemotherapy:  Must be at least 7 days since last chemotherapy was administered (this 
does not include intrathecal chemotherapy which can be administered at any given time pre 
study or upon enrollment nor does it include maintenance chemotherapy for the subset of 
patients who relapse during maintenance) 
For patients who were previously enrolled on the trial but were removed prior to receiving 
T cell therapy and are re-enrolling on the trial and already have a useable T cell product 
generated during previous enrollment, the duration and chemotherapy agents used is not 
restricted. 
b. Immunotherapy directed at leukemia: No antibodies within 3 half-lives prior to study 
enrollment (applicable to phase 1 only). 
c. Steroids: No systemic corticosteroids (unless physiologic replacement dosing) within 7 
days of enrollment. 
d. Gene-Modified Cells: No prior genetically modified cell therapy that is still detectable or 
virotherapy allowed.  Patients who are otherwise eligible but have detectable circulating 
CAR T cells of <5% will be eligible,but will be evaluated as a separate strata from CAR-
naïve patients in the phase 2 portion of the study. 
9. Adequate organ function as indicated by: 
a. Adequate Renal function defined as: a serum creatinine that is ≤ maximum based on 
age/gender 
Table 3-1 Screening Serum Creatinine 
Maximum Serum Creatinine (mg/dL) 
Age 
Male 
Female 
1 to < 2 years  
0.6 
0.6 
2 years < 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 
 
 

 
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b. Adequate liver function defined as: 
• Total Bilirubin: ≤ 3X upper limit of normal (ULN) for age OR conjugated bilirubin ≤ 
2mg/dl 
• ALT (SGPT): ≤ 5X the ULN.   
c. Adequate cardiac function defined as shortening fraction >28% by echocardiogram or 
Ejection Fraction of >50 % by MUGA 
d. Adequate respiratory function defined as oxygen saturation ≥90% on room air without 
supplemental oxygen or mechanical ventilation. 
10. Laboratory values meet the following criteria: 
a. Adequate Absolute Lymphocyte count defined as ALC ≥ 100 cells/µl 
b. Documented negative HIV antigen and antibody, Hepatitis B surface antigen, and 
Hepatitis C antibody within 3 months prior to enrollment. For patient with positive 
Hepatitis C Ab, negative PCR testing must be documented in order to be eligible. 
c. ONLY APPLICABLE TO THE PHASE 1 cohorts: For the post allo-HCT cohort, 
chimerism analysis must demonstrate >95% either donor or recipient in peripheral 
blood CD3 cells, must be done within 1 month of enrollment (no mixed chimerism are 
eligible) 
11. Able to tolerate apheresis procedure, including placement of temporary apheresis line if 
required. 
12. Willing to participate in long-term follow-up for up to 15 years if enrolled in the study and 
receive T-cell infusion. 
13. Subjects of childbearing/fathering potential must agree to use highly effective contraception 
(Appendix III: Highly Effective Contraception) from the time of initial T cell infusion 
through 12 months following the last T cell infusion. 
3.2.2 
Exclusion Criteria 
1. Presence of active clinically significant CNS dysfunction (including but not limited to such as 
uncontrolled seizure disorder, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe 
brain injuries, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination 
or movement disorder) 
2. Pregnant or breast-feeding 
3. If status post allogeneic HCT, presence of active GVHD or receiving immunosuppressive 
GVHD therapy within 4 weeks prior to enrollment 
4. Presence of an active malignancy other than CD19+ leukemia 
5. Presence of an active severe infection defined as: 
• A positive blood culture within 48 hours of study enrollment 
• A fever above 38.2 C AND clinical signs of infection within 48 hours of study enrollment 

 
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6. Presence of any concurrent medical condition that, in the opinion of the PI or designee, would 
prevent the patient from undergoing protocol-based therapy.  Patients with a primary 
immunodeficiency/ bone marrow failure syndrome are excluded from this trial. 
 
Definitions 
3.3.1 
Definition of CNS status 
CNS status is defined as: 
• CNS 1: In cerebrospinal fluid (CSF), absence of blasts on cytospin preparation, regardless 
of the number of white blood cells (WBCs). 
• CNS 2: In CSF, presence < 5/μL WBCs and cytospin positive for blasts, or >5/μL WBCs 
but negative by Steinherz/Bleyer algorithm: 
o CNS 2a: <10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts 
o CNS 2b: ≥10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts 
o CNS 2c: ≥10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts but negative by 
Steinherz/Bleyer algorithm (see below). 
• CNS 3: In CSF, presence of ≥ 5/μL WBCs and cytospin positive for blasts (in the absence 
of traumatic lumbar puncture) and/or clinical signs of CNS leukemia. 
STEINHERZ/BLEYER ALGORITHM FOR EVALUATING TRAUMATIC LUMBAR PUNCTURES: 
If the patient has leukemic cells in the peripheral blood and the lumbar puncture is 
traumatic and the cytospin contains ≥ 5 WBC/μL with blasts, the following algorithm 
should be used to distinguish between CNS 2 and CNS 3 disease: 
CSF WBC 
> 2 x 
blood WBC 
------------ 
---------------- 
CSF RBC 
blood RBC 
Therefore, a patient with CSF WBC ≥ 5/μL blasts, whose CSF WBC/RBC is 2X greater 
than the blood WBC/RBC ratio, has CNS disease at diagnosis. 
For example, the following patient would be classified as CNS3: 
CSF WBC = 60/μL; CSF RBC = 1500/μL; blood WBC = 46000/μL; blood RBC = 
3.0x106/μL 
60 /µL 
 
 
4600 /µL 
 
----------- 
= 0.4 
> 2x 
----------------- 
= 0.015 
1500 /µL 
 
 
3.0 x 106 /µL 
 
3.3.2 Definition of Bone Marrow Status Morphology 
• M1 Marrow: less than 5% blasts by morphology in bone marrow aspirate 
• M2 marrow: 5-25% blasts by morphology in a bone marrow aspirate 
• M3 marrow: >25% blasts by morphology in a bone marrow aspirate 

 
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Minimal Residual Disease (MRD) 
• MRD negative (MRD-CR): M1 marrow with <0.01% blasts detected by MPF or PCR  
• MRD positive (MRD+CR): M1 marrow with  ≥0.01% blasts detected by MPF or PCR 

 
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4 
TREATMENT PROGRAM 
 
 
 
 
 
 
Overview of Treatment Plan 
This is a single center phase 1/ multi-institutional phase 2 study.  
4.1.1 
Phase 1 Dosing Regimen (enrollment onto Phase 1 was completed on 11 May 2016) 
The primary goal of the phase 1 portion is to evaluate the feasibility and safety of cellular 
immunotherapy that utilizes patient-derived T cells that have been genetically modified to co-
express a second generation CD19-specific CAR and EGFRt for patients with relapsed CD19+ 
acute lymphoblastic leukemia following allogeneic HCT.  The cohort dose levels are as follows: 
Dose Escalation Cohorts: 
1Z Dose Level -1: Target Dose 2.5x105 # of EGFRt+ T cells/kg (range >1x105 to 2.5x105) on 
Day 0 
1A Dose Level 1: Target Dose 5x105 # of EGFRt+ T cells/kg (range >3x105 to 5x105) on Day 0 
1B Dose Level 2: Target Dose 1x106 # of EGFRt+ T cells/kg (range >7.5x105 to 1x106) on Day 0 
1C Dose Level 3: Target Dose 5 x106 # of EGFRt+ T cells/kg (range >3x106 to 5x106) on Day 0 
1D Dose Level 4: Target Dose 1x107 # of EGFRt+ T cells/kg(range >7.5 x106 to 1x 107) on 
Day 0 
Dose Escalation Cohorts with prescribed Fludarabine/Cyclophosphamide Lymphodepletion: 
1F1 Dose Level 1: Target Dose 5x105 # of EGFRt+ T cells/kg (range >3x105 to 5x105) on Day 0 
1F2 Dose Level 2:  Target Dose 1x106 # of EGFRt+ T cells/kg (range >7.5x105 to 1x106) on 
Day 0 
As of 2/29/16 protocol amendment, the Phase 1 extension cohorts are no longer applicable. 
Phase 1 Extension Cohorts – to open if no biologically effective dose (BED – see Section 10.3.3) 
has been identified in the proceeding cohorts and it will enroll a minimum of 6 patients and a 
maximum of 15 patients in order to collect data on long term engraftment strategies. 
The extension cohorts will aim to overcome exhaustion of T cells in order to promote long term 
engraftment.  The timing of the 2nd dose will coincide with the contracting of the 1st dose, as the 
antigen burden has been lowered.  Responding patients are MRD negative by day 21 with <1% 
CD19+ cells in the peripheral blood or bone marrow.  The 2nd dose will begin as the MTD, but 
may escalate to 1 dose level higher, as the higher cell dose in the presence of less antigen should 
be better tolerated with less toxicity. 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on 
established standards of care. Minor unavoidable departures (up to 3 days) from 
protocol directed therapy and/or disease evaluations  for valid clinical, patient and 
family logistical, or facility, procedure and/or anesthesia scheduling issues are 
(except where explicitly prohibited within the protocol) do not constitute failure to 
comply with the protocol prescribed study calendar.

 
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1E1  
Dose 1 (day 0): target dose of MTD from Dose Escalation Cohorts 
 
Dose 2 (day 21): target dose MTD from Dose Escalation Cohorts 
1E2  
Dose 1 (day 0): target dose of MTD from Dose Escalation Cohorts 
 
Dose 2 (day 21): target dose of 1 dose level above MTD from Dose Escalation Cohorts 
If a cell product does not make the target dose but otherwise is releasable, it will still be 
administered to the patient assuming they meet eligibility criteria to undergo T cell infusion.  
However, in the absence of a DLT, they will not be counted towards the evaluable cohort.  
During the phase 1 cohort, the first 3 patients on each dose level will have their T cell infusions 
no sooner than 14 days from the prior subject’s T cell infusion. 
If a subject has a releasable cell product but the trial is currently suspended for T cell infusions 
while awaiting the mandated period in between subjects or the data is under review by the DMC, 
and the patient is not medically stable to wait until the trial is open to cell infusion, subjects may 
receive their T cell product at one dose level below the currently enrolling dose, assuming that 
dose has previously been deemed tolerable.  
4.1.2 
Phase 2 Dosing and Lymphodepletion Regimen 
There will be two separate cohorts of patients:  Those receiving lymphodepletion with 
fludarabine/cyclophosphamide, and those receiving alternative lymphodepletion.  The alternative 
lymphodepletion subjects are those with a contraindication to receiving 
fludarabine/cyclophosphamide combination chemotherapy.  Cohort assignment will be made at 
the time of T cell infusion based on the lymphodepletion chemotherapy administered. The dosing 
in each cohort will be the highest tolerated dose from the Phase 1 portion of the trial. The dose is 
comprised of both CD4+EGFRt+ and CD8+EGFRt+ cells which are infused separately, with the 
intention of providing the total target dose as a 1:1 ratio of the two products. 
Flu/Cy cohort (2A) 
T cell infusion with prescribed Fludarabine/Cyclophosphamide Lymphodepletion 
Target Dose 1x106 # of EGFRt+ T cells/kg (range >7.5x105 to 1x106/kg with a maximum total 
dose of 1 x 108) on Day 0 
Alternative lymphodepletion cohort (2B) 
T cell infusion for patients with contraindications for Fludarabine/Cyclophosphamide 
Lymphodepletion 
Target Dose 1x106 # of EGFRt+ T cells/kg (range >7.5x105 to 1x106/kg with a maximum total 
dose of 1 x 108) on Day 0 
 
Definition of Toxicity 
4.2.1 
Treatment related toxicity 
Treatment related toxicity will be based on toxicities observed following the infusion of T cells 
and based on changes from the patient’s baseline toxicity profile documented within 24 hours 
prior to the T cell infusion. Toxicities will be recorded using the NCI CTCAE 4 (see Section 
12.3). The duration of study subject monitoring for treatment related toxicity is broken up into 

 
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acute (within 60 days following the first T cell infusion) versus late (up to 15 years from time of 
T cell infusion). 
4.2.1.1 
Dose Limiting Toxicity (DLT) (Applicable only to the phase 1 portion with CRS grading 
per the CTCv4): 
Any grade 3 or higher toxicity; and designated as definitely or probably related (level of 
attribution) to the infusion of the T cells; and occurring within 30 days of T-cell infusion except 
for the following: 
Non DLT Toxicities at time of T cell infusion: 
• ≤ Grade 4 Fever for less than 48 hours after completion of the T cell infusion  
• ≤ Grade 3 Chills lasting for less than 24 hours after completion of the T cell infusion  
• ≤ Grade 3 Cough lasting for less than 24 hours after completion of the T cell infusion  
• ≤ Grade 3 Transaminases lasting for less than 7 days after completion of the T cell 
infusion  
• ≤ Grade 3 Hypotension lasting for less than 48 hours after completion of the T cell 
infusion 
• ≤ Grade 3 Cytokine release syndrome lasting for less than 48 hours after completion of 
the T cell infusion 
Non DLT Toxicities at the time of T cell engraftment/in vivo expansion (usually occurring up to 3 
weeks after completion of the T cell infusion): 
• ≤ Grade 4 Fever lasting up to 2 weeks 
• ≤ Grade 3 Chills lasting up to 5 days 
• ≤ Grade 3 Transaminases lasting up to 2 weeks 
• ≤ Grade 4 Hypotension, limited to requiring a single pressor for support, resolving to 
<grade 3 within 72 hours 
• ≤ Grade 4 Cytokine Release Syndrome with hypotension alone limited to requiring a 
single pressor for support (not requiring intubation) resolving to <grade 3 within 72 hours 
• ≤ Grade 4 Lymphopenia lasting up to 4 weeks 
• ≤ Grade 4 Leukopenia lasting up to 4 weeks 
• ≤ Grade 3 Bone pain (the result of T cell expansion in marrow compartments) lasting up 
to 2 weeks 
• ≤ Grade 4 Tumor Lysis Syndrome lasting up to 2 weeks 
• ≤ Grade 3 Encephalopathy lasting up to 72 hours 
OR 

 
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1. Any toxicity requiring the use of steroids and/or cetuximab to ameliorate side effects 
attributable to the infusion of the T cells and occurring within 30 days of T-cell infusion.  
This does not include the use of steroids to prevent toxicity. 
OR 
2. Any grade 3 or greater autoimmune toxicity (with the exception of B cell aplasia). 
Toxicities of any grade normally expected with apheresis or lymphodepletion will not be 
considered a DLT with respect to protocol continuation, or dose escalation/de-escalation of T 
cell dose. 
4.2.1.2 
Apheresis related toxicities: These toxicities are not a determinant of this trial’s safety 
analysis. 
Side effects that can occur during cell collection include nausea, vomiting, fainting or dizziness, 
seizures, skin rash, hives, flushing (redness and warmness of the skin, usually the face), blood 
loss, and infection. Tingling of the lips, muscle cramping and, very rarely, changes in the heart 
rhythm can occur. These can be prevented or made milder by giving calcium supplements, either 
by mouth or IV. Very rarely, (less than 1 in 1,000 procedures), clotting may occur in the 
apheresis machine or in a patient and is potentially life-threatening. To reduce the risk of 
clotting, ACD (acid-citrate-dextrose) and heparin will be given. ACD may increase the risk of 
bleeding and may cause temporary tingling of the lips and limbs, muscle cramping, seizures, or 
changes in the heart rhythm. Heparin may also increase the risk of bleeding.  Transfusions of 
both red blood cells and platelets may be required surrounding the procedure. 
 
Treatment Details and Plan 
The following guidelines are for all patients receiving study therapy.  A treatment course will be 
through Day +63 (Day 0 = T cell infusion day). 
4.3.1 
Apheresis for T cell isolation  
Eligibility Criteria at the time of apheresis: 
• Patients must NOT have an active severe infection defined as: 
A positive blood culture within 48 hours of blood draw OR 
A fever above 38.2° C AND clinical signs of infection within 48 hours of apheresis. 
• On the day of the apheresis, patients will be cared for in either outpatient or inpatient 
unit. Apheresis will be done according to institutional standard operating procedure. 
After undergoing medical clearance, patients will undergo apheresis with a target volume 
of whole blood processed for approximately 3-4 blood volumes and a total cell collection 
target of 1X109 total nucleated cells.   
Between the time of apheresis and T cell product infusion (approximately 28-35 days) subjects 
will be returned to the care of their treating physician and may undergo additional therapy aimed 
at controlling disease burden, as well as, providing lymphodepletion prior to receiving their T 
cell product.  It is also acceptable to not undergo treatment during the time of cell manufacturing 
and this will be a decision made by the treating physician.  

 
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4.3.2 
Lymphodepletion 
Recommendations for lymphodepletion regimens during phase 1 cohorts 1Z-1D and for phase 2 
alternative lymphodepletion cohort 2B: the following are general guidelines for lymphodepleting 
regimens that may be employed immediately prior to T cell therapy.  Lymphodepleting regimens 
not included here may also be used after consulting with the study chair.  If a subject is already 
lymphodeplete (ALC <500) they may opt to not undergo additional lymphodepletion. 
• Single Agent Cyclophosphamide: 
o High Dose Cyclophosphamide (2-4g/m2) with MESNA 
• Fludarabine 
• Fludarabine/Cytarabine  
• Cyclophosphamide/Etoposide 
For subjects on the specified lymphodepletion arm (phase 1 cohorts 1F1, 1F2 and phase 2 cohort 
2A), they will be required to receive fludarabine/cyclophosphamide lymphodepletion as 
prescribed below: 
• Fludarabine 30mg/m2 IV once daily X 4 days (d1-4) 
• Cyclophosphamide 500mg/m2 IV once daily X 2 doses (d3-4) 
4.3.3 
T cell Product Infusion  
Within the two days prior to administering the T cell infusion, the patient will undergo a history 
and physical exam and protocol prescribed testing. Documented verification that the patient is 
eligible to proceed per below listed criteria is required.   
4.3.3.1 
Eligibility Criteria for T-Cell Product Infusion  
• Research participant without clinically significant encephalopathy/new focal neurologic 
deficits. 
• Research participant with no current evidence of active GVHD 
• Subject has been without supra-physiologic dosing of systemic corticosteroids for at least 
7 days prior to planned T cell infusion 
• Adequate respiratory function defined as not requiring supplemental oxygen or 
mechanical ventilation, oxygen saturation 90% or higher on room air.  
• Absolute Lymphocyte Count <500/µl or subject has received lymphodepleting 
chemotherapy administered at least 48 hours prior to T cell infusion.  
• Adequate Renal Function defined as: a serum creatinine that is ≤ maximum based on 
age/gender 
 
 

 
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Table 4-1 Pre-Infusion Serum Creatinine 
Maximum Serum Creatinine (mg/dL) 
Age 
Male 
Female 
1 to < 2 years  
0.6 
0.6 
2 years < 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 
• Adequate Liver function defined as: 
o Total bilirubin: ≤3x ULN for age OR conjugated bilirubin ≤2mg/dL  
o ALT (SGPT): ≤5x ULN 
• Patients must NOT have an active severe infection defined as: 
o A positive blood culture within 48 hours of scheduled T cell infusion OR 
o A fever above 38.2 C AND clinical signs of infection within 48 hours of T cell 
infusion 
• Adequate Cardiac Function: If a patient has received anthracycline chemotherapy after 
enrollment, they must have an echocardiogram to demonstrate shortening fraction >28% 
or MUGA to demonstrate ejection fraction of >50%. The echocardiogram or MUGA can 
be done at any time following the anthracycline (does NOT need to be within 48 hours of 
the T cell infusion) 
4.3.4 
T cell Product Infusion Details of Care 
In addition to institutional guidelines for infusion of cellular products, subjects are to receive the 
therapeutic T cell products according to the following guidelines: 
• Prior to CAR T cell product administration (in instances of documented allergy or 
sensitivity to any of the below pre-medications clinical discretion may be used for 
appropriate substitution):  
o Required: acetaminophen 
▪ Recommended dosing: 12.5 mg/kg (maximum dose 650 mg), PO 
o Required: diphenhydramine  
▪ Recommended dosing: 1 mg/kg (maximum dose 50 mg), IV or PO 
o Optional: ondansetron  
▪ Recommended dosing: 0.15 mg/kg (maximum dose 8 mg), IV or PO 
• Investigational product will be infused as rapidly as tolerated through a central venous 
catheter and should be infused by gravity or syringe push 

 
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• Microaggregate filters and leukodepletion filters must not be used for infusion of 
investigational product 
The principal investigator or co-investigator will be present during the infusion and immediately 
available for 3-4 hours following the infusion. 
4.3.5 
Retreatment with modified T cells 
For subjects who have lost persistence, they may be eligible for additional infusions of T cells if 
the below criteria are met.  The dose of the T cell infusion may be up to the highest dose they 
previously received or at the recommended phase 2 dose, whichever is higher. Retreatment may 
not be given sooner than day +30.  If a patient receives a 2nd dose, that dose is not counted 
towards evaluation of that particular dose level (including toxicity and efficacy). 
Within the two days prior (unless otherwise indicated) to administering the T cell infusion, the 
patient will undergo a history and physical exam and protocol prescribed testing. Documented 
verification that the patient is eligible to proceed per below listed criteria is required.  
Inclusion Criteria 
• Subject has tolerated prior dose of modified T cell infusion without experiencing a dose 
limiting toxicity OR if patient did have a DLT, they have fully recovered back to baseline  
• Subject has modified T cell product available for release 
• Subject has <5 % detectable modified T cells in peripheral blood (can be done at any time 
prior) 
• Subject has evidence of persistence of CD19+ malignant cells OR has CD19+ B cell 
recovery detected within 1 year of initial T cell infusion 
• Research participant without clinically significant encephalopathy/new focal neurologic 
deficits. 
• Oxygen saturation 90% or higher on room air.  
• Adequate Renal Function defined as: a serum creatinine that is ≤ maximum based on 
age/gender 
Table 4-2 Serum Creatinine Prior to Subsequent Infusion 
Maximum Serum Creatinine (mg/dL) 
Age 
Male 
Female 
1 to < 2 years  
0.6 
0.6 
2 years < 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 

 
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•  Adequate Liver function defined as: 
o Total bilirubin: ≤3x ULN for age OR conjugated bilirubin ≤2mg/dL  
o ALT (SGPT): ≤ 5x ULN 
Exclusion Criteria 
• Research participant with current evidence of GVHD 
• Patient requiring supplemental oxygen or mechanical ventilation,  
• Patients has an active severe infection defined as: 
o A positive blood culture within 48 hours of scheduled T cell infusion OR 
o A fever above 38.2 C AND clinical signs of infection within 48 hours of T cell 
infusion 
 
General Information  
See Section 8 for Supportive Care Guidelines 
4.4.1 
Hospitalization: 
Patients will undergo infusion of the T cell product in the outpatient or inpatient setting. When 
clinically prudent, patients may be admitted to the hospital following the T cell infusion for 
careful observation and monitoring should they exhibit any constellation of minor symptoms, 
which, if to worsen, could place the patient at risk of a serious adverse event. 
4.4.2 
Central Venous Access 
All patients should have central venous access line placed prior to the beginning of T cell 
infusion.  Infusion of a DMSO containing cell product may NOT be infused through a peripheral 
IV. 
 
 Evaluations 
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Section 7.1. 
Prior to conducting any study-related activities, written informed consent must be signed and 
dated by the subject or subject’s legal representative.  If appropriate, assent must also be 
obtained prior to conducting any study-related activities.  If during the screening period an 
assessment is performed more than once, the most recent assessment will be the relevant 
assessment used. 
4.5.1 
Clinical Assessments 
4.5.1.1 
Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at Baseline/Screening 
and at the pre-apheresis visit, then again starting from time of pre-T cell infusion through day 
+30. The following medications will not be recorded in the eCRF: contrast for radiologic 
procedures, hydration (unless given in response to an AE), lidocaine given during minor 

 
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procedures, saline and heparin used to flush ports, lines, catheters, and other attached medical 
devices. 
4.5.1.2 
Demographics  
Demographic information (date of birth, gender, race) will be recorded at Screening. 
4.5.1.3 
Medical History  
Relevant medical history, including history of current disease, information regarding other 
underlying medical conditions, and review of signs/symptoms of CTCAE toxicities will be 
recorded at designated intervals. 
4.5.1.4 
Physical Examination 
A complete physical examination will be performed by either the investigator or a designated 
sub-investigator who is a physician at the screening visit and each subsequent evaluation that 
determines eligibility to enroll and proceed with protocol defined interventions. Qualified staff 
(MD, NP, RN, and PA) may complete the abbreviated physical exam at all other visits.  New 
abnormal physical exam findings must be documented and will be followed by a physician or 
other qualified staff at the time of presentation. 
4.5.1.5 
GVHD Assessment 
A complete graft versus host review will occur at the time of regularly scheduled visits indicated 
in Section 7 and will include a history, physical exam and lab work if required.  Please refer to 
APPENDIX II GVHD STAGING, GRADING, AND DIAGNOSIS INFORMATION. 
4.5.1.6 
Neurological Exam 
A complete neurological exam will occur at the designated time points as indicated in Section 7. 
This should include cranial nerve exam, and should note the presence or absence of 
encephalopathy, confusion, dizziness, lethargy, seizures, tremors, and difficulty with speaking, 
purposeful movement, and concentration. 
4.5.1.7 
Bone Marrow Aspiration 
Bone marrow aspiration and biopsy will be performed according to standards of care.  Bone 
marrow specimens will be sent for morphologic evaluation and determination of MRD status as 
detected by MPF or PCR. Where indicated in the study calendar, portions of these aspirates will 
be shipped to the Correlative Studies Laboratory (CSL). If the primary oncology team feels so 
inclined, cytogenetics may also be obtained on bone marrow specimens and the results collected. 
For patients undergoing non-protocol mandated bone marrow evaluations done for clinical 
indications prior to patient undergoing HCT, an additional aliquot (up to 5mL) will be requested 
and if obtained, sent to the CSL. 
4.5.1.8 
Spinal Fluid Assessment 
CSF sampling by lumbar puncture or Omaya accessing will be performed according to standards 
of care. Spinal fluid will be assessed for cell count, glucose, protein and cytology.   If Grade 2 or 
higher CTCAE CNS adverse events occur, a lumbar puncture will be performed. When indicated 

 
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on the evaluations table, an additional 2-3mL aliquot will be taken for central measurement of 
cytokines and presence of CAR T cells in the CSF and shipped to CSL. 
4.5.1.9 
FDG-PET 
FDG-PET scans will be performed in subjects with known active non-CNS extramedullary 
disease and for those with NHL 
4.5.1.10 Cardiac Function Evaluations 
Echocardiograms or MUGA scan to evaluate cardiac function.  The same modality should be 
used at screening and subsequent time points if applicable. 
4.5.1.11 Adverse Events 
The baseline (within 24 hours prior to T cell infusion) and subsequent toxicity status based on 
review of all CTCAE version 4.0 elements will be documented by the research team at least as 
frequently as the medical evaluation schedule set forth in the evaluation table (Section 7).  
Information regarding occurrence of adverse events will be captured following start of the T cell 
infusion. Duration (start and stop dates), severity/grade, and relation to the study drug will be 
recorded on the case report form (CRF).  This study will utilize the CTCAE of the NCI for 
toxicity and performance reporting except for phase 2 for CRS in which study specific grading 
should be used.  The descriptions and grading scales found in the revised CTCAE version 4.03 
will be utilized for reporting.  All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0, which can be downloaded from the CTEP website (http://ctep.cancer.gov). 
Additionally, toxicities are to be reported on the appropriate data collection forms.  Refer to 
Section 12 for reporting of Adverse Events. 
4.5.2 
Clinical Laboratory Measurements  
Please refer to the table in section 7 for timing of when specific labs need to be obtained. 
4.5.2.1 
Hematology 
Complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count, 
white blood cell differential, and platelet count). 
4.5.2.2 
Comprehensive Metabolic Panel 
Serum sodium, potassium, chloride, bicarbonate, calcium, phosphorus, magnesium, BUN, 
creatinine, alanine aminotransferase (ALT/SGPT), total bilirubin, conjugated bilirubin, uric acid, 
and LDH.   
4.5.2.3 
Infectious Disease Studies 
HIV antigen and antibody, hepatitis B surface antigen, Hepatitis C antibody and if applicable 
Hepatitis C quantitative PCR 
4.5.2.4 
Cytokine Release Syndrome Labs 
CRP, LDH, ferritin, d-dimer, fibrinogen, and absolute lymphocyte count 

 
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4.5.2.5 
Serum Immunoglobulin G 
Serum for IgG level 
4.5.2.6 
Ferritin 
Serum ferritin testing. 
4.5.2.7 
Pregnancy Test 
A urine or serum pregnancy test will be obtained during the screening process and sent from 
female subjects who are of childbearing age prior to their enrollment on the study. 
4.5.3 
Correlative Studies 
 Please refer to section 7 for specifics of when these studies should be obtained 
• Up to 1mL/kg (maximum of 40mL) peripheral blood samples and/or up to 5mL bone 
marrow aspirate samples will be sent to the Correlative Studies Laboratory (CSL).  Refer 
to provided study specific lab manual for tube and shipping requirements. Specimens 
may be processed for molecular analysis of T cell persistence and flow cytometric 
analysis based on detection of EGFRt in conjunction with T cell surface markers. These 
samples may also be used to detect the in vitro anti-CD19 activity of the persistent CD19 
CAR+ T cells and for serum cytokine analysis.  Additionally, DNA based testing may be 
done to detect low levels of malignant cells. 
• Up to 2-3mL of CSF will be sent to the Correlative Studies Laboratory (CSL). Refer to 
provided study specific lab manual for tube and shipping requirements. 
• If peripheral blasts are present in the apheresis sample, they may be frozen for use in 
future in vitro or in vivo experiments to evaluate the ability of the modified T cells to 
target the patient’s primary leukemic cells. 
• Any materials in excess of that needed for prescribed correlative studies will be retained 
for potential additional analysis predicated on trial findings that cannot be anticipated in 
advance (see section 15). 
• If patient undergoes a tissue biopsy, additional slides or tissue will be requested by the 
Sponsor and if obtained, sent to CSL to be examined for the presence of CAR modified T 
cells and/or CD19+ cells either using immunohistochemical analysis and/or PCR based 
assays. 
4.5.4 
Long-Term Follow-Up 
Research participants who receive engineered T cells will be required to participate in long-term 
follow-up (LTFU) per the guidelines set forth by the FDA’s Biologic Response Modifiers 
Advisory Committee that apply to gene transfer studies to capture delayed adverse events related 
to the use of lentivirally transduced T cells.   
Screening for Delayed Adverse Events 
For the first 5 years following treatment with CAR T cells, patients will be seen yearly. The visit 
will include an interval medical history, including disease response evaluation if applicable and 

 
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physical exam, specifically eliciting for the development of any new clinical conditions, 
including malignancy, neurologic disorder, rheumatologic or autoimmune disorder, or 
hematologic disorder. Unexpected medical problems that are felt to be related to the CAR T cells 
will be collected.  If patients are not able to be seen at study site, they may be seen by their 
primary physician for a physical exam and a blood draw courier kit will be provided to obtain 
research samples. The physician will be provided with adverse event screening guidelines and 
will be requested to notify the study team of all new malignancies and unexpected illness felt to 
be related to the CAR T cells. 
Adverse Event reporting will be compliant with 21 CRF 312.32. 
Following the first 5 years of LTFU, patients who do not have evidence of persisting gene 
modified T cells will be contacted yearly by phone for an additional 10 years (for a total of 15 
years of LTFU).  For those patients who have continued persistence of transferred T cells, they 
will continue to be seen yearly. For LTFU for at least a total of 15 years, with the expectation 
that more frequent medically monitoring will be conducted to adequately care for patients who 
have B cell aplasia and require immunoglobulin replacement therapy. 
Research Tests 
At time points specified in section 7 LTFU tables, for the first five years after T cell infusion, up 
to 15mL of blood will be collected and then if required, analyzed for persistence of T cells and 
replication-competent lentivirus (RCL) at the CSL according to the guidance from the FDA 
regarding Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse Events. At 
year 5, continued annual blood specimens will be obtained for an additional 10 years only from 
patients with evidence of persistent engraftment of gene modified T cells or a prior positive RCL 
test.   
If a patient receives a repeat CAR T cell infusion on this protocol after beginning LTFU research 
testing, the testing schedule will restart with the most recent infusion. 
If a patient receives a different lentivirus gene therapy product following treatment on PLAT-02, 
they will be expected to have RCL and persistence testing for that product on the subsequent 
gene therapy protocol and will no longer have such specimens collected on PLAT-02. 
Persistence: PCR for the transgene vector sequence and/or flow cytometric analysis may be done 
on circulating mononuclear cells to determine the persistence of transferred T cells. Persistence 
assay testing will be discontinued if patient has had 2 successive negative tests. 
Clonality:  Patients who at any time point in long term follow up have an absolute increase of 
>5% of cells positive for the CAR transduction marker will have a repeat test in 1 month.  If the 
% of cells positive for the CAR transduction marker continues to increase, additional testing for 
clonality will be performed.  Clonality may be measured by either examining integration sites or 
TCR diversity among CAR transduction marker positive cells. If there is evidence of clonality, 
repeat testing will be performed no later than 3 months. 
Replication Competent Lentivirus (RCL): Evidence for RCL will be done using VSVg qPCR at 
each post-infusion time point during the first year (pre-infusion, 3, 6 and 12 months).  If all post-
treatment assays are negative during the first year, no additional samples will be collected.   
Subsequent myeloablative HCT patients 

 
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For the subset of patients that do go on to a subsequent myeloablative allogeneic HCT, the only 
relevant information for delayed adverse event monitoring will be the research tests, given that 
the spectrum of concomitant medical issues common to allo-HCT patients such as graft-versus-
host disease will preclude an accurate attribution to the gene therapy component of this protocol. 
For this reason, HCT patients will only be asked to provide a blood sample for required LTFU 
timepoints. 
If the research participant dies while on study, then an autopsy will be requested. 
 
Concomitant Therapy 
All standard supportive care measures for patients undergoing experimental therapies will be 
used at the discretion of the patient's treating oncologist. 
After undergoing leukapheresis, patients are eligible to receive additional chemotherapy per the 
treating oncologist while their therapeutic cell product is being generated. This includes both 
intrathecal and systemic, although there is not a requirement for either to be given.  Specific 
regimens to be used will be at the discretion of the treating physician and based on patient 
specific considerations.  
The following agents are not allowed while on study through day +30:  
• Supra physiologic dosing of systemic corticosteroids (except as outlined for management 
or prevention of T cell therapy toxicity OR when given during the time of cell generation 
when the patient receives non-study specified chemotherapy and must not be given 
within the 7 days prior to the infusion of the T cell product) 
• CD19 directed immunotherapy (for example- murine monoclonal antibodies or 
derivatives there of; blinatumomab) 
• T cell growth factors (such as IL-2, IL-7 or IL-15) interferons, vaccines, and other 
cellular products), pentoxifylline 
• Other investigational agents.  
• G-CSF is permitted prior to CAR T cell infusion or when delayed neutrophil engraftment 
is encountered beyond d+21 following T cell infusion and at any time for life-threatening 
infections. Pegylated G-CSF and GM-CSF are NOT permitted. 
Active infections due to anti-leukemia chemotherapy that occur after study enrollment will be 
treated according to the clinical standard of care. 
If the T cell product has a positive culture that is discovered after being infused into the patient, 
the treating physician will be immediately notified, blood cultures will be drawn and appropriate 
antibiotic coverage will be initiated. 

 
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5 
MANAGEMENT OF TOXICITIES AND COMPLICATIONS 
 
Management of Symptoms Associated with T cell Infusion 
Mild transient symptoms have been observed with adoptive T cell therapy including fevers, 
chills, rigors, headache, and rarely nausea, vomiting, hypotension and pulmonary toxicity. The 
management of these symptoms is outlined below. 
• Fever, chills and temperature elevations >38.2C will be managed with additional 
acetaminophen as clinically indicated, and 1 mg/kg Demerol I.V. for chills (max 50mg).  
Additional methods such as cooling blankets may be employed for fevers resistant to 
these measures.  All patients who develop fever or chills should have a blood culture 
drawn with an admission for IV antibiotics and supportive care. 
• Headache may be managed with acetaminophen.  If unresponsive to acetaminophen, 
manage with good clinical judgment. 
• Nausea and vomiting may be treated with ondansetron IV or PO as well as additional 
standard anti-emetic treatments per patient preference. 
• Transient hypotension will initially be managed by intravenous fluid administration, 
however, patients with persistent hypotension will require transfer to the intensive care 
unit for definitive medical treatment. 
• If significant hypotension occurs during the infusion, the infusion should be immediately 
suspended.  Significant hypotension is defined as symptomatic and/or systolic blood 
pressure < 80 mm/hg for age >12 years old, <70 mm/hg for age <12 years old, or a 15% 
drop from baseline, whichever value is lower. 
• Treatment algorithm for significant hypotension: begin with normal saline 10mL/kg over 
30 minutes; repeat additional boluses, up to a total of 60ml/kg.  Alternatively, may use 
PRBC in place of normal saline if patient‘s HCT is <25%.  After receiving 40ml/kg, 
consideration of vasopressors should be prioritized. 
• Hypoxemia will be managed with supplemental oxygen and an etiology for hypoxemia 
will be worked up per standard clinical practice.  
• If the T cell infusion is stopped before completion, and the symptoms causing cessation 
of the infusion have returned to baseline within 30 minutes, the T cell infusion may be 
restarted at 50% of the rate it was previously infusing, and all products should be 
completed prior to the expiration date and time listed on the bag label. 
• For any acute toxicity occurring during the infusion for which a decision is made to 
terminate the infusion, the residual T cells should be returned to the TCPC for analysis.  
Investigation of possible causes of observed signs should proceed and, if necessary, 
additional medical treatment will be instituted.    
 
Management of Acute Adverse Event(s) Attributable to Expansion of the Infused 
T Cells  
In managing patients with adverse events during the time of in vivo expansion of genetically 
modified T cells, additional research labs may be requested. All patients for whom there is 

 
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concern of cytokine release syndrome will be admitted to the hospital for observation.  During 
Phase 1 if a patient is suspected of having a cytokine release syndrome, blood samples will be 
requested up to once per day during the time of illness in order to do cytokine analysis as well as 
T cell analysis.  Patients may receive cytokine directed therapy for symptom control including 
but not limited to tocilizumab. The use of steroids may be given in an effort to prevent a more 
serious toxicity. 
Table 5-1 Recommended symptom management of CRS 
Symptom related to CRS 
Suggested Intervention 
Fever of > 38.2°C 
Acetaminophen (12.5mg/kg) PO/IV 
up to every 4 hours 
Persistent fever of ≥ 39°C for 10 hours that is 
unresponsive to acetaminophen 
Tocilizumab (8-12mg/kg) IV 
Persistent fevers ≥ 39°C after Tocilizumab 
Dexamethasone 5-10 mg IV/PO up to 
every 6-12 hours with continued 
fevers 
Recurrence of symptoms 48 hours after initial dose 
of Tocilizumab  
Tocilizumab (8-12mg/kg) IV 
Hypotension 
Fluid bolus, target hematocrit >24% 
Persistent/recurrent hypotension after initial fluid 
bolus (within 6 hours) 
Tocilizumab (8-12mg/kg) IV 
Use of low dose pressors for hypotension for 
longer than 12 hours 
Dexamethasone 5-10 mg IV/PO up to 
every 6 hours with continued use of 
pressors 
Initiation of higher dose pressors or addition of a 
second pressor for hypotension 
Dexamethasone 5-10 mg IV/PO up to 
every 6 hours with continued use of 
pressors 
Initiation of oxygen supplementation 
Tocilizumab (8-12mg/kg) IV 
Increasing respiratory support with concern for 
impending intubation 
Dexamethasone 5-10 mg IV/PO up to 
every 6-12 hours 
Recurrence/Persistence of symptoms for which 
tocilizumab was given ≥ 48 hours after initial dose 
was administered  
Tocilizumab (8-12mg/kg) IV 

 
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5.2.1 
Ablation of T cells: 
Following start of T cell infusions, the following rules for initiation of corticosteroid therapy will 
be applied: 
Research participants experiencing a new grade 3 or higher non –hematologic toxicity with an 
attribution of ≥4 (probable or definite) to the infused T cells that does not meet the definition of 
the exclusion criteria for dose limiting toxicity detailed in Section 4.2.1.1 that last for greater 
than 48 hours and is not controlled by medical intervention (including cytokine directed therapy), 
will commence with corticosteroid treatment outlined below. 
Research participants experiencing a new grade 3 or higher non-hematologic toxicity with an 
attribution of ≥4 (probable or definite) to the infused T cells, regardless of the exclusion criteria 
for dose limiting toxicity detailed in Section 4.2.1.1, that in the opinion of the protocol principal 
investigator or designee, cannot be controlled and puts the research participant in significant risk 
of an untoward outcome if measures are not taken to ameliorate the toxicity, will commence with 
corticosteroid treatment outlined below. 
Table 5-2 Recommended Steroid dose schedule 
Treatment 
Day 
Treatment Type and Dosage 
Day 1 
Intravenous methylprednisolone at 2 mg/kg/day divided q 8hr 
Day 2 
Intravenous methylprednisolone at 1 mg/kg/day divided q 8hr 
Day 3-4 
Prednisone  at 1 mg/kg/day divided q 12 hours (begin wean if 
symptom improvement) 
Day 4-5 
Prednisone at 0.5 mg/kg/day divided q 12 hours  
Day 5-6 
Prednisone at 0.25 mg/kg/day divided q 12 hours  
Day 6-9 
Prednisone at 0.1 mg/kg/day divided q 12 hours 
Methylprednisolone may be substituted for prednisone at an 80% dose equivalent. Alternatively, 
dexamethasone may be given in place of prednisone. All research participants will be 
hospitalized for at least the first 72 hours of receiving corticosteroids. Such steroid treatment 
strategies have been clinically shown to reverse the side effects of adoptively transferred 
cytolytic immune cells such as T cells [155-157].  
Cetuximab will be administered to study subjects under the following circumstances: 
• Subjects who meet the criteria for corticosteroid treatment (5.2.2.1) and who fail to 
improve after 48 hours as outlined in 5.2.2.2 
• Subjects who exhibit clinically significant GVHD that is unresponsive to corticosteroids 
and have evidence of EGFRt+ T cell engraftment 
• Subjects whose molecular studies indicate a lymphoproliferative disorder arising from a 
infused genetically modified T cell 

 
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• Prolonged B cell aplasia in patients with persistence of infused EGFRt+ T cells who 
require chronic IVIG replacement in the setting of a durable complete disease remission 
of >3 years. Remission status must include either multiparameter flow or PCR negative. 
• Subjects preparing to undergo a myeloablative HCT who have evidence of EGFRt+ T 
cell engraftment will receive cetuximab in order to generate additional data as to the 
efficacy of cetuximab to ablate the EGFRt+ T cells. 
Cetuximab shall only be given after conferring with the study PI.  Prior to administering, patients 
will be made aware of potential toxicities associated with the treatment and will be given written 
documentation.   
Dosing recommendations are as follows: 
Subjects Age ≥ 18 years based FDA approved dosing: 
Loading dose of 400mg/m2 IV, followed by 250mg/m2 IV weekly for a total of 4 doses. 
Subjects Age <18 years based on phase I data in children [158]: 
Dose of 250mg/m2 IV administered over 1 hour weekly for a total of 4 doses.   
Pretreatment with IV diphenhydramine is recommended 30-60 minutes before each dose of 
cetuximab.   
For all subjects receiving cetuximab, prior to each subsequent dose, T cell persistence shall be 
determined. Subjects should have up to 15 mL of blood drawn for this research study pre-
ablation and 1, 3, 7, 10, 14, and 28 days after.  If after 2 doses there is no appreciable decrement 
in the genetically modified T cell burden, no further doses should be given.  For research 
subjects that have documented response to cetuximab, up to a total of 4 weekly doses may be 
given.  Any further cetuximab therapy, if deemed necessary by the investigative team will be 
administered only after consultation with the FDA. 
Additional measures may also be taken to resolve the toxicity associated with T cell infusion 
such as, but not limited to, immunosuppressive medications such as ATG and calcineurin 
inhibitors, or chemotherapy agents with immunosuppressive properties the administration of 
other immunosuppressive agents or cytokine directed therapy. 
In managing patients who have evidence of tumor lysis, standard guidelines of care should be 
followed 

 
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6 
DRUG INFORMATION 
T cell product manufacturing will be conducted in the SCRI Therapeutic Cell Production Core 
(TCPC).  At the end of the culture, cells from both expansion bags will be harvested, washed and 
formulated in cryopreservation media, and transferred to cryopreservation storage.  
Cryopreserved cells will be stored in vapor phase in a controlled access LN2 freezer maintained 
in the TCPC facility until released for clinical use. Cell product which does not meet release 
criteria will be reviewed for release on a case-by-case basis by the sponsor representative, study 
chair and principal investigator at a minimum, in collaboration with the relevant regulatory 
bodies. On the day of T cell product re-infusion cryopreserved unit(s) will be thawed at the 
bedside and will be immediately available for infusion. 
 
Possible Side Effects of Gene Modified T Cells 
Cytokine release syndrome and symptoms of neurotoxicity have been associated with the death 
of patients receiving CAR modified T cells that recognize the same protein we are targeting, 
CD19. The role of CRS and neurotoxicity as a cause of death has not been ruled out. The risks 
and side effects may be related to the dose given and are unpredictable. The additional risk of 
development of graft versus host disease exists in those patients who are receiving donor T cells. 
For complete safety information please see the SCRI-CAR19v1 Investigator’s Brochure. 

 
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7 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
Required and Recommended Clinical, Laboratory and Disease Evaluations 
 
 
 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on 
established standards of care. Minor unavoidable departures (up to +/- 3 days until Day 
+35, and then a +/- 2 week window) from protocol directed therapy and/or disease 
evaluations for valid clinical, patient and family logistical, or facility, procedure and/or 
anesthesia scheduling issues are permitted (except where explicitly prohibited within the 
protocol). 

 
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Required Evaluations - Phase 1 Table 
 
Screen (must 
be within 7 
days of enroll-
ment)* 
Pre- apheresis 
Pre-T cell 
infusion #1* 
Day 
+1 
Day 
+2 
Day 
+3 
Day 
+4, 
5 
and 
6 
Day  
+7 
Day 
+ 8 
and 
9 
Day 
+10 
Day 
+11,
12, 
and 
13 
Day 
+14 
Day 
+21 
Day 
+28 
** 
Day 
+35 
** 
Day 
+42 
** 
Day 
+63 
** 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Performance status a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History and physical 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Review of medical status and systems  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
 
X 
X 
BSA 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (temp, pulse, BP, resp rate) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Pulse oximetry 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GVHD assessment 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
X 
X 
Neuro exam 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Review pathologic specimens 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echo or MUGA 
X 
 
X b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive metabolic panel d 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Serum IgG 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Serum Ferritin 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
Infectious Disease Testing e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BM Unilateral Aspirate f 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
Lumbar Puncture g 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Correlative Studies Peripheral Blood h 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Continued next page 

 
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Required Evaluations - Phase 1 Table, continued 
 
Screen (must 
be within 7 
days of enroll-
Pre- apheresis 
Pre-T cell 
infusion #1* 
Day 
+1 
Day 
+2 
Day 
+3 
Day 
+4, 5 
and 
6 
Day  
+7 
Day 
+ 8 
and 
9 
Day 
+10 
Day 
+11,
12, 
and 
13 
Day 
+14 
Day 
+21 
Day 
+28*
* 
Day 
+35*
* 
Day 
+42*
* 
Day 
+63*
* 
BM evaluation i 
OBTAINED PER THE TREATING PHYSICIAN’S DISCRETION 
Adverse Events j 
CONTINUOUS  
Concomitant medications 
CONTINUOUS 
* Bone marrow aspirate, lumbar puncture, ECHO/MUGA can be done up to 14 days prior 
** If subject has had no detectable CAR T cells for two successive peripheral blood checks after day +14, only samples necessary for RCL 
detection will continue to be taken. Blood persistence assays will be discontinued; however BM samples will continue to be analyzed. 
a Performance status will be assessed using Karnofsky performance status for patients ≥16 years of age or Lansky score for patients < 16 years of 
age (see Appendix I of the protocol) 
b Echo or MUGA should only be repeated if the patient has received anthracyclines following most recent echocardiogram, can be done up to 2 
weeks prior to time point 
c Complete Blood Count (CBC), Manual Differential and Platelet Count 
d Electrolytes, BUN/urea, creatinine, total and conjugated bilirubin, ALT, LDH, Uric Acid, Calcium, Magnesium, Phosphorus 
e Can be done up to 3 months prior to enrollment to include HIV, Hepatitis B surface antigen and Hepatitis C Antibody and PCR if required 
f Up to 5mL to CSL lab for correlative studies to be sent on all marrow aspirates EXCEPT for the screening marrow; standard morphology and 
multiparameter flow to be done and/or reviewed at UW or SCH; cytogenetics must be done on a marrow pre-enrollment, can be done at any time 
time point over the course of the current relapse and does not need to be repeated for the study 
g Up to 2-3mL to CSL lab for correlative studies; cell count, glucose, protein, and cytology on all specimens performed as a clinical lab. 
h Up to 1mL/kg (not to exceed 40mL) to CSL for correlative studies.  
i Any additional bone marrow evaluations done for clinical indications prior to patients undergoing HCT, would request up to5 mL sent to CSL 
lab for correlative studies 
j CTCAE version 4 

 
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Required Evaluations - For patients who receive additional T cell infusions  
 
Pre-T 
cell 
infusion 
#2 
Day 
+1 
Day 
+3 
Day  
+7 
Day 
+10 
Day 
+14 
Day 
+21 
Day 
+28* 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
History and physical 
X 
X 
X 
X 
X 
X 
X 
X 
Review of medical status and systems 
X 
X 
X 
X 
X 
X 
X 
X 
Height  
X 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
X 
X 
X 
BSA 
X 
 
 
 
 
 
 
 
Vital signs (temp, BP, pulse, resp rate) 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetry 
X 
 
 
 
 
 
 
 
GVHD assessment 
X 
 
 
X 
 
X 
X 
X 
Neuro exam 
X 
 
 
X 
 
X 
 
 
Cardiology (Echo or MUGA) 
Xa 
 
 
 
 
 
 
 
Hematology b 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive metabolic panel c 
X 
X 
X 
X 
X 
X 
X 
X 
Serum immunoglobulin G level 
X 
 
 
 
 
 
X 
 
Serum Ferritin 
X 
 
 
X 
 
X 
 
X 
Bone Marrow Unilateral Aspirated 
 
 
 
X 
 
 
X 
 
Lumbar Puncture e 
 
 
 
 
 
 
X 
 
Correlative Studies Peripheral Blood f 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
CONTINUOUS 
Adverse Events 
 
CONTINUOUS 
Bone marrow evaluation 
 
OBTAINED PER TREATING PHYSICIAN’S DISCRETION 
* If subject has had no detectable CAR T cells for two successive peripheral blood checks after day +14, 
only samples necessary for RCL detection will continue to be taken. Blood persistence assays will be 
discontinued 
a ECHO or MUGA should only be repeated if the patient has received anthracyclines following most 
recent echocardiogram, can be done up to 2 weeks prior to time point 
b Complete Blood Count (CBC), Manual Differential and Platelet Count 
c Electrolytes, BUN/urea, creatinine, total and conjugated bilirubin, ALT, LDH, Uric Acid, Calcium, 
Magnesium, Phosphorus 
d 5mL to CSL lab for correlative studies to be sent on all marrow aspirates EXCEPT for screening 
marrow; standard morphology and multiparameter flow; cytogenetics must be done on a marrow pre-
enrollment, can be done at any timepoint over the course of the current relapse and does not need to be 
repeated for the study 
e Up to 2-3mL to CSL lab for correlative studies; as well as clinical lab testing for cell count, glucose, 
protein, and cytology on all specimens performed as a clinical lab. 
f Up to 1mL/kg (not to exceed 40mL) to CSL lab for correlative studies. 
g Any additional bone marrow evaluations done for clinical indications prior to patients undergoing HCT, 
would request 5 mL sent to CSL lab for correlative labs 
h CTCAE version 4 
 

 
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Required Evaluations - Phase 2 Table 
 
Screen (must 
be within 7 
days of enroll-
ment)* 
Pre- apheresis 
Pre-lympho-
depletion 
Pre-T cell 
infusion #1 
Day 
+1 
Day  
+7 
Day 
+10 
Day 
+14 
Day 
+21 
Day 
+63 
Demography 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
X 
 
 
 
 
 
 
Performance status a 
X 
 
 
 
 
 
 
 
 
 
History and physical 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
Height  
X 
 
 
X 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
BSA 
X 
 
 
X 
 
 
 
 
 
 
Vital signs (temp, BP, pulse, resp rate) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetry 
X 
X 
 
X 
 
 
 
 
 
 
GVHD assessment 
X 
 
 
X 
 
X 
 
X 
X 
X 
Neuro exam 
 
 
 
X 
 
X 
 
X 
X 
 
Cardiology (Echo or MUGA) 
X 
 
X b 
 
 
 
 
 
 
 
Hematologyc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive metabolic panel d 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Serum IgG 
 
 
 
X 
 
 
 
 
X 
X 
Serum Ferritin 
 
 
 
X 
 
X 
 
X 
 
X 
Infectious disease testing e 
X 
 
 
 
 
 
 
 
 
 
Bone Marrow unilateral aspirate f 
X 
 
X 
 
 
 
 
 
X 
X 
Lumbar Puncture g 
X 
 
X 
 
 
 
 
 
X 
 
PET Scan h 
 
 
X 
 
 
 
 
 
X 
X 
Correlative Studies Peripheral Blood i 
 
X 
 
X 
 
 
X 
X 
X 
X 
CRS labs j 
 
 
 
 
Daily when grade 2-4 CRS is occurring 
Concomitant medications 
X 
X 
 
 
CONTINUOUS until Day+ 30 
Adverse Events k 
 
 
 
 
CONTINUOUS until Day +30 
* Bone marrow aspirate, lumbar puncture, ECHO/MUGA can be done up to 14 days prior  
a Performance status will be assessed using Karnofsky performance status for patients ≥16 years of age or 
Lansky score for patients < 16 years of age (see Section 17 Appendix I of the protocol) 
b Echo or MUGA should only be repeated if the patient has received anthracyclines following most recent 
echocardiogram, can be done up to 2 weeks prior to time point 
c Complete Blood Count (CBC), Manual Differential and Platelet Count 
d Electrolytes, BUN/urea, creatinine, total and conjugated bilirubin, ALT, LDH, Uric Acid, Calcium, 
Magnesium, Phosphorus 
e Can be done up to 3 months prior to enrollment to include HIV, Hepatitis B surface antigen and 
Hepatitis C Antibody and PCR if required 
f 5mL to CSL lab for correlative studies to be sent on all marrow aspirates EXCEPT for the screening 
marrow; standard morphology and multiparameter flow required with each marrow 
footnotes continued next page 

 
PLAT-02 
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g up to 2-3mL to CSL lab for correlative studies as well a clinical lab testing for glucose and protein 
except for screening LP; cell count and cytology on all specimens performed as a clinical lab. Refer to 
protocol section 4.5.1.8 for obtaining additional LP if grade 2 or higher neurotoxicity occurs 
h Only for subjects with known extramedullary, non-CNS, non-testicular disease involvement.  Once 
negative, it does not need to be repeated. 
i Up to 1mL/kg (not to exceed 40mL) to CSL lab for correlative studies. See Lab Manual for full details 
j CRS labs include CRP, LDH, d-dimer, fibrinogen, ferritin and absolute lymphocyte count.  
k CTCAE version 4 

 
PLAT-02 
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Required Evaluations - LTFU (Years 1-5)  
Evaluations may occur within a 2 month window 
Time Point after most 
recent T cell infusion 
(months) 
3 
4*, 
5* 
6 
7*, 
8* 
9* 
10* 
11* 
12 
15* 18* 24 
30* 36 
42* 48 
54* 60 
Medical History a 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Physical Exam 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
T cell persistence b ** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
RCL c 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Serum IgG d 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Monitoring e 
CONTINUOUS 
Bone Marrow Aspirate f 
OBTAINED PER TREATING PHYSICIAN’S DISCRETION 
* Only applicable if suspected ongoing T cell persistence at last check or required for confirmation of loss 
of persistence. For subjects with a CD19 negative relapse or a stem cell transplant, samples are required 
at 6 month intervals rather than monthly, and should be done in conjunction with required RCL time 
points when applicable. 
** Persistence assays will be discontinued if patient has had 2 successive negative tests. 
a May be obtained by local physician or treating oncologist. If relevant, records pertaining to disease 
response and/or relapse will be collected. 
b Up to 15mL peripheral blood will be collected at each time point for all research studies (T cell 
persistence, RCL detection).   
c Further time points will be determined by sponsor after review with FDA if RCL testing is positive at 
any of the time during the 1st year. 
d If Serum IgG levels are checked, results will be collected. 
e Adverse Event Monitoring will be continuous for the development of a new malignancy, neurologic 
disorder, rheumatologic or autoimmune disorder or hematologic disorder and the primary physician will 
be requested to notify the study team. 
f Any additional bone marrow evaluations done for clinical indications prior to patients undergoing HCT, 
would request 5 mL sent to CSL lab for correlative studies 
 
 

 
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Required Evaluations - LTFU (Years 6-15) 
Evaluations may occur within a 2 month window 
Time point after most 
recent T cell infusion 
(years) 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Medical History a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
T cell Persistence c * 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum IgG d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Monitoring e 
CONTINUOUS 
* Persistence assays will be discontinued if patient has had 2 successive negative tests. 
a Will be conducted by phone unless subject has evidence of T cell persistence, then may be obtained by 
local physician or treating oncologist. If relevant, records pertaining to disease response and/or relapse 
will be collected. 
b Only required for those patients who have evidence of persistence of transferred T cells 
c If required, up to 15mL peripheral blood will be collected for all research studies (T cell persistence).   
d If Serum IgG levels are checked, results will be collected. 
e Adverse Event Monitoring will be continuous for the development of a new malignancy, neurologic 
disorder, rheumatologic or autoimmune disorder or hematologic disorder and the primary physician will 
be requested to notify the study team. 
 
 
 
Optional Studies 
There is no optional portion of the study. 

 
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8 
SUPPORTIVE CARE 
These are provided for institutional consideration. Investigator discretion should be used, and 
individual considerations made for specific patient situations and institutional practices.  
Necessary supportive measures for optimal medical care will be given throughout the study as 
indicated by the treating physician and the patient’s medical need.  
 
Central Venous Access 
See section 4.4.2 
 
Blood Product Support 
• All blood products should be irradiated, leukoreduced prior to transfusion, additional 
requirements per patient needs 
• Efforts should be made to maintain a platelet count > 50,000 mm3 during periods of 
grade 2-4 CRS unless clinically the patient has a higher threshold 
• Packed RBC transfusions should be used to keep hematocrit level ≥ 25% during periods 
of grade 2-4 CRS, unless clinically the patient has a higher threshold   
 
Hospitalization 
See section 4.4.1   
 
Antimicrobial Prophylaxis 
• PJP prophylaxis should be given according to institutional standards. 
• Prevention of fungal infection should be given according to institutional standards. 
• IVIG or substitute should be administered when quantitative gamma immunoglobulins 
(IgG) are below 400 mg/dL or according to institutional standards. 
 
Diet 
An immunosuppressive diet should be maintained while the patients are on protocol. 

 
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9 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
 
Criteria for Removal from Protocol Prescribed Therapy 
A subject is considered to be receiving protocol prescribed therapy for the duration of time 
during which they have persistence of the CAR T cell product or through Day 63 after the first 
infusion, whichever occurs later.  A subject may be discontinued from study treatment at any 
time if the subject, the investigator, or the Sponsor feels that it is not in the subject’s best interest 
to continue.  All subjects who have received a T cell product per this protocol and subsequently 
lose T cell persistence will still be expected to adhere to long-term follow up guidelines as set 
forth by the FDA and this protocol. 
The following is a list of possible reasons for study treatment discontinuation: 
• The judgment of the principal investigator that the patient is too ill to continue prior to T 
cell infusion. 
• Patient/family noncompliance with study therapy and/or clinic appointments. 
• Pregnancy 
• Voluntary withdrawal; a patient or his/her parents/legal guardians may remove 
himself/herself from the study at any time without prejudice. 
• Significant and rapid progression of leukemia requiring medical interventions or 
treatment for leukemia including chemotherapy and stem cell transplant. 
• Subject is enrolled onto PLAT-03 cohort A 
• Patient is unable to undergo apheresis  
• Technical difficulties are encountered in the T cell genetic modification, cloning, and 
expansion procedure precluding the release of T cell product for infusion. 
• If a patient had successful generation of a therapeutic T cell product but was removed 
from the study prior to receiving the infusion, they will be eligible to re-enroll on the trial 
at a future date if they meet the eligibility criteria and a space is available. 
• Meets off study criteria 
 
All subjects who prematurely discontinue study treatment should come in for an early 
discontinuation visit as soon as possible. All subjects who have received a CAR T cell product 
on this protocol and are subsequently removed from protocol therapy will be required to adhere 
to long-term follow-up adverse event and sample collection requirements for 15 years from the 
time of final CAR T cell product administration, as mandated by the FDA. Subjects who receive 
subsequent lentiviral gene modified cells will only be followed on this trial for survival and 
disease status (see Schedule of Procedures).  
A reasonable attempt will be made by the investigator to provide a reason for subject 
withdrawals; if obtained, the reason for the subject’s withdrawal from the study will be 
documented in the subject’s source documents. 
 
Off Study Criteria 
• Death. 
• Lost to follow-up. 

 
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• Withdrawal of consent for any further data submission.   
• 5 year anniversary of T cell infusion and has been enrolled onto a LFTU protocol for 
gene therapy 
• 15 year anniversary of T cell infusion 
• Never received CAR T cell product 
 
Replacement of Subjects 
Subjects who are removed/withdraw from the study prior to receiving T cell therapy will be 
replaced. 
Subjects who are removed/withdrawn from the study prior to day + 30 for a reason other than 
toxicity, that preclude them from a full toxicity evaluation and who do not meet the definition of 
a DLT, will be replaced.  
Subjects in the Phase 2 cohort who are removed/withdrawn from study prior to Day +63 for 
reason other than disease progression or toxicity, without obtaining MRD negative response, will 
be replaced.   
Subjects in the Phase 2 who received products manufactured with ExpAct Beads will be 
replaced. 
 
Temporary Suspension of T Cell Infusion 
T cell infusions will be immediately halted and not re-initiated until proper consultation with the 
DMC, IRB, IBC, FDA for: 
• Unexpected patient death due to infused T cells 
• If there is unexpected Grade 5 toxicity definitely, probably or possibly attributed to study 
treatment while on study.  
• Lack of Improvement of SAE requiring corticosteroid and/or cetuximab administration. 
• If any research participant receiving systemic corticosteroids and/or cetuximab for 
ablation of T cell-mediated side effects does not show an improvement of the toxicity that 
prompted corticosteroid ablation to a toxicity grade of <3 within 14 days of initiating 
ablation procedures. 
• Leukemia lymphoproliferative syndrome involving gene modified T cells or detection of 
RCL. The occurrence of a malignancy attributed to lentiviral modified T cells or 
detection of RCL would result in termination of the protocol. 
• Study Termination 
The study may be terminated at any time by the Sponsor or the F DA.   
 
Protocol Violations 
When a protocol violation occurs, it will be reported to the IRB either in real time or with the 
annual status report, according to severity and according to institutional policy. 
• A protocol violation occurs when the subject or investigator fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, subject safety and primary 

 
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endpoint criteria.  Protocol violations for this study include, but are not limited to, the 
following: 
• Failure to meet inclusion/exclusion criteria 
• Use of a prohibited concomitant medication 
• Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. The study chair will determine if a protocol violation will result in 
withdrawal of a subject. 

 
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10 STATISTICAL CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will be 
written describing all analyses that will be performed.  The SAP will contain any modifications 
to the analysis plan described below.   
 Primary Objectives 
The primary objectives are to determine the feasibility of deriving a therapeutic cell product, the 
safety of the T cell product infusion and to define the full toxicity profile as well as the response 
rate and persistence of T cell product for the Phase 2 cohorts. 
10.1.1 Feasibility 
Feasibility will be assessed by looking at the number of products successfully manufactured 
versus those that were unsuccessful. 
Feasibility Criteria will be defined as follows:  No therapeutic product could be generated for the 
patient after two attempts using a single apheresis product for starting material. 
 
Unsuccessful products will be defined as: 
• Cell product did not meet QC release criteria and could not be released for infusion. 
• Cell product that was not manufactured do to expansion failure 
10.1.2 Safety 
Safety assessment will be analyzed and the following data will be obtained: 
Toxicity Assessment (the evaluation taking place with 24-hrs of the initial T cell infusion will 
serve as baseline measurements) 
• History and physical exams occurring on study after the T cell infusion.  
• Vital signs during and at least weekly x 2 weeks after each infusion 
• Pulse oximetry before and during the infusion 
• Laboratory/radiographic evaluations taking place on study and occurring after the T cell 
infusion 
• B cell reconstitution 
• Serum immunoglobulin levels 
• Graft versus host disease assessment 
• Adverse event reporting 
Response rates will be analyzed with bone marrow aspirates taken at day +7 (phase 1 only), 21, 
42 (phase 1 only), and 63. 
• Endpoint is MRD negative rate by day +63 

 
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•  Bone marrow studies will be evaluated and responses graded per standard ALL criteria 
(see section 11.2) 
• Response rate for NHL patients will be analyzed separately with bone marrow aspirates 
and PET scan taken at day +21 and day +63 and will be evaluated and responses graded 
per standard NHL criteria (see section 11.3) 
10.1.3 Persistence 
Persistence of CAR+ T cells will be analyzed with peripheral blood and bone marrow samples. 
• Endpoint is persistence of CAR+ T cells past day +63 
• Persistence of CAR+ T cells is defined as either detection of the CAR+ T cells by flow or 
PCR above the lower limit of detection, or B cell aplasia (defined as <1% CD19+ cells in 
the lymphocyte subset as determined by flow cytometry) that cannot be attributed to 
other B cell targeting agents. 
 Secondary Objectives 
The secondary objectives are to determine the duration and magnitude of the in vivo persistence 
of the adoptively transferred T cells as well as to assess the accumulation of the transferred T-
cells in the bone marrow and the development/persistence of B cell aplasia.  Additionally the 
efficacy of cetuximab to ablate EGFRt+ T cells will be analyzed: 
• PCR and MPF from bone marrow and peripheral blood as a measure of magnitude and 
presence of transferred T cells. 
• MPF from bone marrow and peripheral blood as a measure of B cell aplasia. 
• The pre and post cetuximab T cell persistence data will be analyzed to measure the 
response rate of EGFRt+ T cells to ablation with the endpoint of absence of detectable 
EGFRt+ T cells 28 days after initiation of cetuximab. 
10.2.1 Duration of overall response-leukemia: 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that treatment failure is objectively 
documented 
10.2.2 Survival 
• Overall:  Defined as time from T cell infusion to death from any cause. If a patient is 
alive at the last evaluation time period, survival time is censored at the time of last 
follow-up. 
• Disease Free:  Defined as the time from T cell infusion to the first observation of disease 
or death from any cause, whichever occurs first. If the patient has not relapsed or died, 
disease-free survival is censored at the time of last follow-up. 
• Non-Relapse Mortality: Defined as time to death event where cause of death is not 
attributable to underlying disease. 

 
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 Cohort size and Rules for Cohort Advancement 
The Phase 1 part of the study will follow a 3-patient cohort up-and-down design, with rules very 
similar to the algorithm known as ‘conventional 3+3’ [159, 160].  Phase 2 will employ a non-
sequential, fixed-dose, fixed-sample size design.   Safety and toxicity will be continually 
monitored during both phases. 
10.3.1 Sample size 
Phase 1 is expected to require 24-36 evaluable patients, however depending upon DLT responses 
and dose de-escalation rules it might require between 5 and 48 evaluable patients. Phase 2 is 
designated for 72 additional patients on Cohort 2A (mandated lymphodepletion) with additional 
patients on cohort 2B (alternative lymphodepletion). Cohort 2B is expected to have <10 patients 
but there is no maximum accrual for this cohort. The inevaluability rate is expected to be about 
10%. Due to replacement of subjects receiving ExpAct beads, total accrual of phase 2 subjects is 
expected to be around 150. 
10.3.2 Cohort advancement rules for phase 1 – applies to dose escalation cohorts 
1. 
During Phase 1, dose-escalation decisions will be based on cohorts of the 3 most 
recent evaluable patients receiving the same dose.  
2. 
Treatment of the first cohort at each new dose level will be staggered by a 
minimum of 14 days between patients. 
3. 
The trial commences at Dose Level 1 (see Section 4.1 for dose level definitions). 
4. 
Each patient’s DLT status will be evaluated on the day specified in Section 4.2, or 
upon the recording of a DLT event, whichever occurs earlier. See Section 4.2 for a 
complete description. 
5. 
Ordinary Dose-Escalation Rules: After each cohort’s DLT status is available, 
dose escalation proceeds according to Table 10-1. These rules will be applied 
separately to govern transition between dose levels in Phase I Escalation, and 
between dose levels in Phase I Extension. 
Table 10-1 Phase 1 ordinary dose escalation rules. 
Current 
Cohort’s DLT 
Count 
Escalation Decision Rule 
0 out of 3 
Escalate: Treat the next 3 patients one dose level higher. 
≥ 2 
De-Escalate: Treat the next 3 patients one dose level lower. If the first 2 
patients both experience DLTs, stop the cohort at 2 patients and de-escalate. 
1 out of 3 
Repeat: Enter 3 more patients at the current dose level, and consult this 
table again based on their DLT count. 
6. 
Dose Re-Escalation: This protocol does allow for one re-escalation to a dose level 
de-escalated from, with the following constraints: 

 
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a. 
In the re-escalation cohort, patients will be staggered by 30 days. 
b. 
If the first patient at the re-escalated cohort experiences a DLT, the dose 
level will be closed to further accrual and the study will de-escalate one 
level down. 
c. 
If a second de-escalation from the dose level is mandated according to Table 
10.1 (i.e., 2 or more DLTs in the current cohort), the dose level and all 
levels above it are closed to further accrual. 
7. 
Boundary Conditions:  
a. 
If the current dose is the highest one currently allowed for accrual, and 
further escalation is mandated, the dose will be repeated for the next 3-
patient cohort.  
b. 
If the current dose is the lowest one and further de-escalation is mandated, 
the dose can be repeated once as a re-escalation, with the second cohort 
staggered and evaluated according to the re-escalation rules above. 
8. 
Stopping Rules: Phase I will stop after 9 patients have been evaluated for DLTs at 
any single dose level. Early stopping will take place: 
a. 
If, at any point, a dose level meets the Biologically Effective Dose (BED) 
criteria (see below for BED criteria). 
b. 
If the lowest dose level (Dose Level -1) is disallowed due to safety, 
according to the dose re-escalation rules above. 
9. 
No prior Allo-HSCT Rules during phase 1: these subjects will not be used in the 
dose escalation calculation, but will be counted towards the dose de-escalation. The 
exclusion of them in the dose escalation calculation is due to the possibility that the 
post Allo-HSCT patients have a higher level of toxicity, therefore it is most 
appropriate to escalate based on the post allo-hsct subjects alone. 
10.3.3 Definition of MTD and BED, and dose selection for phase 1 extension cohort and 
phase 2 
The MTD at the end of Phase 1 dose escalation cohorts is defined as the highest T cell dose, with 
at least 6 toxicity-evaluable patients and a cumulative DLT rate under 34%. See section 4.2 for 
the definition of a DLT, and Section 10.6 for the definition of toxicity-evaluable subjects.  
The Biologically Effective Dose (BED) is the lowest dose with at least 6 patients evaluable for 
both safety and efficacy, and having:  
• A cumulative DLT rate under 34%; 
• Over 80% of patients experiencing persistence of CAR modified T cells in the bone 
marrow at day 63, with no detection of CD19+ cell in the bone marrow at day 63.  
If Phase1 ends with no dose meeting either the BED or the MTD, the DMC will convene to 
consult upon the next steps. (enrollment onto Phase 1 was completed on 11 May 2016) 

 
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10.3.4 Statistical design for phase 2  
After analysis of the first 36 evaluable subjects on the phase 1, there was an improved disease-
free survival (DFS) in pts with ongoing BCA beyond day 63 (HR: 0.25 [95% CI: 0.08, 0.81], P = 
0.01). A complete response does benefit patients, but persistence provides an even greater 
benefit. In order to incorporate this distinction into simple and realistic trial rules, one persistence 
response will be equivalent to two efficacy-without-persistence responses. This will enable 
interpretation and analysis of all trial data within a single self-consistent framework. Therefore, 
the main endpoint of the phase 2 design has 3 levels of efficacy:  
1. 
Incomplete response; 
2. 
Complete response (MRD-CR by Day 63), but no persistence of CAR T cells at day 
63; 
3. 
Complete response and CAR T-cell persistence beyond Day 63 
Phase 2 Efficacy Rules 
Phase 2 is designed as a hypothesis test for efficacy, with a three-level endpoint described above. 
Success is defined as an acceptable combination of efficacy and persistence. The hypothesis is 
composite, involving direct measurement of the persistence rate, as well as a combined efficacy-
persistence score in which efficacy only (level 2 endpoint) responses add 1 point, while 
persistence responses (level 3) add 2 points. The Null hypothesis, representing insufficient 
response, is     
Persistence beyond Day 63 ≤25%, or persistence + efficacy ≤0.95 points per subject 
Successful response rate for Phase II will be declared if the Null is rejected at α<0.05, using a 
one-sided Multinomial test. With n=72 patients, the rejection region is defined as 25 or more 
patients experiencing persistence, and a combined efficacy-persistence score of 83 points or 
more. 
The decision rule is outlined by a bold red line in the diagram below (Figure 2). With 72 
patients, this rule will reject the Null at a power of 80% or greater, for true persistence as low as 
39%, provided that true efficacy is high enough. Given true persistence of 62.5% or higher, the 

 
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Null will be rejected with 80% or more power, regardless of additional efficacy-only outcomes.
 
 
Figure 2:  Phase 2 decision rules with n=72. The x and y axes indicate the true underlying 
proportions of efficacy and persistence responses, respectively. The orange region indicates 
conditions included under the definition of the Null hypothesis. The red line demarcates the 
observed proportions lying on the decision boundary. The purple-blue region consists of 
conditions under which successful trial completion is expected with probability 80% or greater. 
There is no statistical design for cohort 2B, for subjects with <5% circulating CAR+ T cells at 
the time of enrollment or for the NHL patients of cohort 2A and 2B who will be analyzed 
separately. It is anticipated that both groups will be a very small.  These patients will be enrolled 
as necessary with descriptive analysis of persistence and efficacy.   
Subjects treated with products manufactured with ExpAct beads will be analyzed separately and 
reported descriptively with regards to efficacy, persistence, and toxicity. 
 Study Analysis Plan 
The primary goal of the Phase 1 study is to evaluate the toxicity and feasibility results associated 
with cellular immunotherapy that utilizes patient-derived T cells that have been genetically 
modified to express a CD19-specific chimeric immunoreceptor for patients with relapsed CD19+ 
acute lymphoblastic leukemia following allogeneic HCT.  
In addition to safety and feasibility, the primary objective of the Phase 2 study is to evaluate the 
efficacy associated with cellular immunotherapy that utilizes patient-derived T cells that have 
been genetically modified to express a CD19-specific chimeric immunoreceptor for patients with 
relapsed CD19+ acute lymphoblastic leukemia.  
Baseline information (e.g., the extent of prior therapy) and demographic information will be 
summarized using means, standard deviations, ranges, counts and percents. The toxicities 

 
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observed at each dose level will be summarized in terms of type (organ affected or laboratory 
determination such as absolute neutrophil count [ANC]), severity (by NCI CTCAE v4.0 and 
nadir or maximum values for the laboratory measures), date of onset and attribution. Tables will 
be created to summarize these toxicities and side effects by dose level.  
All disease responses will be reported. Objective response for all subjects will be summarized at 
each dose level, and the number and percent responding combined across dose levels. Survival 
and time to relapse/progression or HCT will be summarized both by pooling across dose levels 
and within each dose level. All results for the summary statistics noted above will be tabulated 
and reported. 
 Data and Safety Monitoring  
10.5.1 Quality Assurance 
Quality assurance will be monitored by the sponsor/sponsor designee at a minimum of twice per 
year. The Fred Hutchinson/University of Washington Cancer Consortium Clinical Research 
Support office may collaborate with the sponsor to provide the QA monitor for this program at 
Seattle Children’s Hospital in accordance with the Fred Hutch/University of Washington Cancer 
Consortium Institutional Data and Safety Monitoring Plan (DSMP).  In addition, the sponsor 
may delegate monitoring responsibilities to an external CRO. Under the provisions of this plan, 
Fred Hutch Clinical Research Support (CRS) coordinates with data and compliance monitoring 
conducted by consultants, contract research organizations, or Fred Hutch employees unaffiliated 
with the conduct of the study. Independent monitoring visits occur at specified intervals 
determined by the assessed risk level of the study and the findings of previous visits.  
The trial will comply with the standard guidelines set forth by these regulatory committees and 
other institutional, state and federal guidelines. 
10.5.2 Weekly Safety Review 
The Study Chair, Investigators, study statistician (if needed), Clinical Research Associate 
(CRA), research nurses and other site staff will meet weekly (or as needed when there are active 
participants) to review subject enrollment and conduct patient safety review. The group is 
responsible for monitoring the data and safety of this study, including implementation of the 
stopping rules for safety and efficacy.  The group will review as applicable enrollment, adverse 
events from each participant, DLTs, protocol compliance, CAR T-cell persistence analysis, 
feasibility data and follow-up information for each subject.   
10.5.3 Aggregate and Real-Time Safety Review 
In addition to the weekly safety review, at any time of required or clinically indicated 
observations, the patient will have real-time assessment of toxicity and adverse events.  These 
events will be reported to the Principal Investigator, research nurses and clinical research 
associates for attribution and reporting as applicable (see section 12).  
10.5.4 Data Monitoring Committee  
The study will be monitored by a Data Monitoring Committee (DMC). This is an independent 
committee with no affiliation to the protocol. The DMC will meet prior to the study opening to 

 
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review and approve the study protocol and DMC charter.  The DMC will review all toxicity data 
occurring from start of T cell infusion through day 30 after T-cell infusion after accrual has been 
completed at the open dose level.  The DMC will make recommendations regarding the opening 
of the next dose level. During the phase 2 portion, the DMC will review all toxicity and efficacy 
data approximately every 6 months.  In addition, the DMC will review study conduct including 
accrual, drop-outs, data completeness, any inability to generate T cell product that meets all 
Quality Control criteria, positive bacterial cultures from the T-cell product, subjects not meeting 
eligibility criteria for T-cell infusion, protocol compliance and treatment efficacy measures. 
DMC meetings may be called at any time by the DMC chair or sponsor for additional safety 
review if indicated.   Following any temporary suspension of accrual for a safety event, the DMC 
will be convened and will further review the safety data within 48 hours of notification of the 
event to recommend if continuation of accrual is appropriate.  If the DMC agrees that the study 
treatment is likely to be safe for additional subjects, they may recommend accrual to resume.  
Applicable regulatory agencies will receive copies of the DMC’s recommendations as they 
become available.  
The DMC will meet within 2 weeks of the availability of the report at each review point. Further 
enrollment into the cohort or progression to the next cohort will not occur until receipt of DMC 
recommendations and if necessary, approval from regulatory agencies. 
10.5.5 Study Stopping Rules 
Refer to Section 9.4: Study Closure, and Section 10.1.2: Safety with the addition of below 
criteria: 
• If the feasibility endpoint analysis shows <50% successful product generation after at 
least six patients have been enrolled, the study will be suspended pending a detailed 
review by the Sponsor and DMC. 
• If either success or failure in Phase II response (Section 10.3.4) has been arithmetically 
guaranteed before the full 72-patient sample has been evaluated, the research team will be 
entitled, but not compelled, to end the study early, or to continue in order to examine 
differences in response rates between risk groups identified in Phase I. 
 Data Sets Analyzed  
All eligible patients who enrolled into the study and receive T cell therapy will be included in the 
safety analysis. 
 Demographics and Baseline Characteristics  
The following demographic variables at screening will be summarized by dose level: race, 
gender, age, height and weight.   
  Evaluability for Toxicity 
A patient will be considered evaluable for toxicity if the patient receives the prescribed dose of 
genetically modified T cell product, whether during Phase I or Phase II, and meets at least one 
of the following conditions numbered 1-3: 
1. 
Experiences a DLT within the first 30 days following the infusion regardless of 
whether s/he remains on the trial subsequently;  

 
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2. 
Is still available for follow-up on Day 30 following the infusion, and has not 
received additional infusions or treatment in the meantime 
3. 
Prior to pursing additional treatments prior to day 30, there was absence of 
detectable T cells 
 Evaluability for Efficacy   
A patient will be considered evaluable for disease response if: (1) the patient meets the eligibility 
criteria for pre-infusion criteria; (2) the patient receives the T cell infusion; and (3) the patient is 
under follow-up for a sufficient period to evaluate the disease as defined below.  
All patients who received a specified dose of genetically modified T cell product are efficacy-
evaluable for that dose if they meet at least one of the following conditions: 
1. 
Exited the trial due to a DLT and/or disease progression within the first 63 days 
following infusion; 
2. 
Exited the trial due to efficacy within the first 63 days following infusion; 
3. 
Are still available for follow-up on Day 63 following infusion. 
A patient who dies as a result of toxicity after receiving T cell product will be considered a 
non-responder. For patients who receive a 2nd dose of T cells in the Phase 1 portion before 
obtaining a complete response, the response to dose 1 will be used for the efficacy analysis.   

 
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11 EVALUATION CRITERIA 
 Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize the CTCAE of the NCI for toxicity and performance reporting. The 
descriptions and grading scales found in the revised CTCAE version 4 will be utilized for 
reporting except for CRS on the phase 2 portion of the study, for which study-specific grading 
will be used (Section 12.3 AE Grading and Relationship to Investigation agent). All appropriate 
treatment areas should have access to a copy of the CTCAE version 4, which can be downloaded 
from the CTEP web site (http://ctep.cancer.gov). Additionally, toxicities are to be reported on the 
appropriate data collection forms. 
 Disease Response Criteria Leukemia 
11.2.1 MRD negative Complete Remission (MRD-CR) 
Attainment of M1 marrow with negative MRD (<0.01%) with no evidence of circulating 
leukemic blasts or extramedullary disease and with recovery of peripheral counts (ANC ≥ 
500/μL and PLT count ≥ 50,000 μL). Qualifying marrow and peripheral counts should be 
performed within 1 week of each other. 
11.2.2 MRD positive Complete Remission (MRD+CR) 
Attainment of M1 marrow with positive MRD (≥0.01%) with no evidence of circulating 
leukemic blasts or extramedullary disease and with recovery of peripheral counts (ANC ≥ 
500/μL and PLT count ≥ 50,000 μL). Qualifying marrow and peripheral counts should be 
performed within 1 week of each other. 
11.2.3 MRD negative Complete Remission without count recovery (MRD-CRi)  
Insufficient recovery of platelets (< 50,000/ μL) or ANC (<500/μL) but otherwise meets the 
criteria of MRD-CR. 
11.2.4 MRD positive Complete Remission without count recovery (MRD+CRi)  
Insufficient recovery of platelets (< 50,000/ μL) or ANC (<500/μL) but otherwise meets the 
criteria of MRD+CR. 
11.2.5 Complete Remission, MRD unknown (CR) 
Attainment of M1 marrow with no available MRD results, with no evidence of circulating 
leukemic blasts or extra medullary disease and with recovery of peripheral counts (ANC 
≥500/μL and PLT count ≥50,000 μL). Qualifying marrow and peripheral counts should be 
performed within 1 week of each other. 
11.2.6 Complete Remission without count recovery, MRD unknown (CRi) 
Insufficient recovery of platelets (<50,000/ μL) or ANC (<500/μL) but otherwise meets the 
criteria of CR, MRD unknown.  

 
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11.2.7 Partial Remission (PR) 
This requires a decrease of at least 50% in the percentage of blasts to a post-treatment value of 
5% to 25% in the bone marrow aspirate. (If the pre-treatment blast percentage was 50-100%, this 
must decrease to a value between 5-25%.  If the pre-treatment blast percentage was 20-49%, this 
must decrease by at least half to a value greater than 5%) with recovery of peripheral counts 
(ANC > 500/µL and platelet count> 50,000/µL). 
11.2.8 Partial Remission Cytolytic (PRCL) 
Complete disappearance of circulating blasts and achievement of at least 50% reduction in bone 
marrow blast count from baseline. 
11.2.9 Minimal Response Cytolytic (MRCL) 
≥ 50% reduction in the peripheral blast count from baseline with no increase in peripheral white 
blood cell count. 
11.2.10 Stable Disease (SD) 
This is present when the patient fails to qualify for either MRD-CR, MRD+CR, PR, PRCL, 
MRCL, or progressive disease (PD). 
11.2.11 Progressive Disease (PD) 
An increase of at least 25% in the absolute number of circulating leukemic cells from baseline, 
development of extramedullary disease, or other laboratory or clinical evidence of PD following 
delivery of chemotherapy. 
11.2.12 Definitions of Relapse 
All relapses will be classified as CD19+ or CD19-. 
Bone Marrow Relapse is defined as M3 marrow after previous remission from ALL. 
MRD relapse is defined as an increase in MRD level of at least 1 log. 
CNS Relapse is defined as: 
• At least 5 WBC’s/μL in CSF with blasts present on cytospin. 
or 
• Any number of WBC’s in CSF with immunophenotypic proof of leukemic relapse. 
Immunophenotypic proof of relapse is defined as identifiable blasts plus (for B-lineage) 
TdT or CD-10 positivity on 2 consecutive CSF samples four weeks apart or (for T-
lineage) TdT and CD-7 or TdT positivity alone on 2 consecutive CSF samples four weeks 
apart. 
Testicular Relapse is defined as: 
• Unilateral or bilateral testiculomegaly with biopsy-proven testicular involvement. 
or 

 
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• Unilateral or bilateral testiculomegaly with concurrent relapse in the bone marrow and/or 
CNS. 
An extramedullary relapse will be considered as a relapse event. 
Combined Relapse is defined as relapse at 2 or more of the above sites. 
 Disease Response Criteria Lymphoma 
Complete Remission is defined as: 
11.3.1 CR 
Imaging reveals complete disappearance of all measurable or evaluable lesions (except bone), no 
malignant blasts in the bone marrow nor in the CSF 
11.3.2 CRu 
Residual mass is negative by FDG-PET, BM and CSF morphologically free of disease 
11.3.3 Partial Response (PR) 
50% decrease in SPD (sum of product of greatest perpendicular diameters) on imaging (FDG-
PET may be positive( Deauville score of 4 or 5 with reduced lesional uptake compared to 
baseline, no new and /or PD: morphologic evidence of disease may be present in BM or CSF if 
present at diagnosis, however there should be 50% reduction in the percentage of lymphoma 
cells 
11.3.4 Minor Response (MR) 
>25% but <50% decrease in SPC on imaging; no new and/orPD; morphologic evidence of 
disease may be present in BM or CSF if present at diagnosis, however there should be 50% 
reduction in the percentage of lymphoma cells 
11.3.5 No Response (NR) 
Does not meet CR, PR, MR, or PD 
11.3.6 Progressive Disease (PD) 
>25% increase in SPD on imaging, Deauville score of 4 or 5 on FDG-PET with increase in 
lesional uptake from baseline or development of new morphologic evidence of disease in BM or 
CSF 
11.3.7 Definitions of Relapse 
All relapses will be classified as CD19+ or CD19-. 
Relapse: appearance of new lesions, appearance or reappearance of tumor cells in bone marrow 
or CSF 

 
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12  ADVERSE EVENT REPORTING REQUIREMENTS 
 Purpose 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Certain adverse events must be reported in an expedited 
manner to allow for timelier monitoring of patient safety and care. The following sections 
provide information about expedited reporting. 
The investigative team will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents. Adverse 
events will be recorded in the patient CRF. Adverse events will be described by duration (start 
and stop dates and times), severity, outcome, treatment and relation to study drug. AE’s will be 
reported to all institutional and federal regulatory entities in compliance with current statutes. 
 Definitions 
Adverse Event: An AE is any untoward medical occurrence in a clinical investigation of a 
patient administered a T cell product and that does not necessarily have a causal relationship 
with the treatment. An AE is therefore any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the administration 
of an investigational product, whether or not related to that investigational product.  
 An unexpected AE is one of a type not identified in nature, severity, or frequency in the current 
IRB approved protocol or investigator brochure or of greater severity or frequency than 
expected. The investigator will determine whether it is unexpected according to the 
Investigator’s Brochure, the underlying disease and concomitant treatment and the relationship 
of the investigational drug to all AEs 
A Serious Adverse Event (SAE) is any adverse event (experience) occurring in a patient who is 
administered a T cell product at any dose that results in ANY of the following outcomes:  
• death; 
• life threatening (A life-threatening event is defined as having placed the research 
participant, in the view of an Investigator, at immediate risk of death from the adverse 
event as it occurred.  It does not include an adverse event that had it occurred in a more 
serious form, might have caused death); 
• requires an unanticipated inpatient hospitalization or prolongation of existing 
hospitalization 
• a persistent or significant disability/incapacity; 
• a congenital anomaly/birth defect; 
• secondary malignancy, or 
• any other adverse event that, based upon appropriate medical judgment, may jeopardize 
the subject’s health and may require medical or surgical intervention to prevent one of the 
outcomes listed above (examples of such events include allergic bronchospasm requiring 
intensive treatment in the emergency room or at home, blood dyscrasias or convulsions 

 
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that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse). 
All adverse events that do not meet at least one of the above criteria are defined as non-serious.  
Assessment of the cause of the event will have no bearing on the evaluation of the event’s 
severity. 
Additional events not considered serious are hospitalizations occurring under the following 
circumstances: 
• planned before entry into the clinical study 
• elective treatment of a pre-existing condition  
• occur on an outpatient basis and do not result in overnight hospitalization 
• part of the normal treatment or monitoring of the research participant and not associated 
with any deterioration in condition. 
Additionally, a hospitalization/prolongation of a hospitalization for monitoring patients with 
non-serious adverse events or for management of concomitant medical care issues will not be 
considered an AE for expedited reporting nor be a factor in MTD determination. 
 AE Grading and Relationship to Investigation agent 
CTCAE version 4.0 will be used to evaluate all toxicities except for phase 2 reporting which will 
use study specific CRS grading (see table below). Neurological toxicities should not be reported 
as CRS and should be reported separately for each symptom observed.  Any toxicity reported by 
research participants during the protocol designated time frames for which there is no specific 
CTC designation will be graded on the following scale: Grade 0- no toxicity, Grade 1- mild 
toxicity, usually transient, requiring no special treatment and generally not interfering with usual 
daily activities, Grade 2- moderate toxicity that may be ameliorated by simple therapeutic 
maneuvers, and impairs usual activities, Grade 3- severe toxicity which requires therapeutic 
intervention and interrupts usual activities. Hospitalization may be required or may not be 
required, Grade 4- life-threatening toxicity that requires hospitalization. Attribution will be 
unrelated, unlikely, possible, probably, or definite. 
 
 

 
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Table 12-1: Grading Criteria for CRS for Phase 2 
Grade 
Description of Symptoms 
1: Mild 
Not life-threatening, require only symptomatic treatment such as 
antipyretics and anti-emetics (e.g., fever, nausea, fatigue, headache, 
myalgia, malaise) 
2: Moderate 
Require and respond to moderate intervention: 
Oxygen requirement for nasal cannula or simple face mask, or 
Hypotension responsive to fluids or low dose of a single vasopressor, or 
Grade 2 organ toxicity (by CTCAE v4.0) attributed to CRS 
3: Severe 
Require and respond to aggressive intervention: 
Oxygen requirement for non-rebreather or CPAP/BiPAP, or 
Hypotension requiring high dose of a single vasopressor (e.g., 
norepinephrine ≥ 20 µg/min, dopamine ≥ 10 µg/kg/min, phenylephrine 
≥ 200 µg/min, or epinephrine ≥ 10 µg/min), or 
Hypotension requiring multiple vasopressors (e.g., vasopressin + one of 
the above agents, or combination vasopressors equivalent to ≥ 20 µg/min 
norepinephrine), or 
Grade 3 organ toxicity or Grade 4 transaminitis (by CTCAE v4.0) 
attributed to CRS 
4: Life-
threatening 
Life-threatening: 
Requirement for ventilator support, or 
Grade 4 organ toxicity (excluding transaminitis) 
5: Fatal 
Death 
Adapted from (Lee 2014) 
 Event Collection 
All AE’s that occur following infusion of modified T cells and up to and including 30 days after 
the administration of T cells will be captured and documented.  Phase 2 will only capture and 
document grade ≥2 AEs following infusion of modified T cells and up to and including 30 
days. In addition, grade 1 CRS and grade 1 neurotoxicity are considered AEs of interest 
and will be captured and documented during Phase 2. Any SAE that is designated possibly, 
probably, or definitely related to the modified T cells that occurs greater than 30 days will also 
be captured.  Related SAEs will continue to be reported for as long as the patient is being 
followed for any reason. 
Baseline AEs: Although a pertinent positive finding identified on baseline assessment is not an 
AE, when possible it is to be documented as “Course Zero” using CTCAE terminology and 
grade. An expedited AE report is not required if a patient is entered on a protocol with a pre-
existing condition (e.g., elevated laboratory value, diarrhea). The baseline AE must be re-
assessed throughout the study and reported if it fulfills expedited AE reporting guidelines (12.5). 

 
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• If the pre-existing condition worsens in severity, the investigator must reassess the event 
to determine if an expedited report is required. 
• If the AE resolves and then recurs, the investigator must re-assess the event to determine 
if an expedited report is required. 
• No modification in grading is to be made to account for abnormalities existing at 
baseline. 
 Persistent AE’s: A persistent AE is one that extends continuously, without resolution. 
 
 Serious Adverse Event Reporting and Study-Specific Reporting 
Serious adverse events will be evaluated by the institutional PI and must be reported in the eCRF 
database and the CRO managing the safety database as instructed and according to reporting 
guidelines detailed below. All unexpected and related serious adverse events will be sent to the 
DMC. The institutional PI will report all unanticipated problems to the sponsor, institutional IRB 
and IBC according to federal and local guidelines. If there is a question regarding attribution of 
the SAE, the study chair will submit the relevant data to the DMC for review on an ad hoc basis.   
Written notification of an SAE occurring within 30 days of T cell infusion, regardless of 
attribution, must be sent to the Sponsor or Sponsor’s designee within 24 hours of the site’s 
knowledge of the event. Additionally, SAEs that occur more than 30 days after the last 
administration of investigational agent/intervention and have an attribution of possible, probable, 
or definite require reporting within 24 hours. The following events, if meeting SAE criteria in 
Section 12.2 constitute exceptions and do not require reporting to the Sponsor or Sponsor’s 
representative; however they must be entered into the eCRF database.   
Table 12-2 Exceptions to SAE Reporting Guidelines 
Grade: 
Adverse Event 
≤ 4 
Myelosuppression (includes white blood cell decreased) 
≤ 4 
Anemia 
≤ 4 
Lymphocyte count decreased 
≤ 4 
Neutrophil count decreased 
≤ 4 
Platelet count decreased 
≤ 3 
Catheter-related infection 
≤ 3 
Febrile Neutropenia 
1 
Fever 
The institutional PI is responsible for submitting follow-up reports for all SAEs until the SAE 
has resolved or until the patient’s condition stabilizes (in case of persistent impairment), or the 
patient dies. 
The Study Sponsor along with the CRO is responsible for assessing each SAE that occurs, and 
deciding whether or not that SAE meets the criteria specified for reporting to the Food And Drug 
Administration (in accordance with 21 CRF 312) and NIH-OBA (in accordance with the NIH 
guidelines for research involving recombinant DNA molecules). 

 
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13 RECORDS AND REPORTING 
 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents designed to 
record all observations and other pertinent data for each subject treated with the study drug.   
Study personnel at each site will enter data from source documents corresponding to a subject’s 
visit into the protocol-specific electronic Case Report Form (eCRF) OR paper CRF when the 
information corresponding to that visit is available.  Subjects will not be identified by name in 
the study database or on any study documents to be collected by the Sponsor (or designee), but 
will be identified by a site number, subject number and initials. 
For eCRFs: If a correction is required for an eCRF, the time and date stamps track the person 
entering or updating eCRF data and creates an electronic audit trail.  For paper CRFs:  If a 
correction is made on a CRF, the study staff member will line through the incorrect data, write in 
the correct data and initial and date the change. 
The Investigator is responsible for all information collected on subjects enrolled in this study.  
All data collected during the course of this study must be reviewed and verified for completeness 
and accuracy by the Investigator.  A copy of the CRF will remain at the Investigator’s site at the 
completion of the study. 
 Data Management Procedures 
The data will be entered into a validated database.  The Data Management group will be 
responsible for data processing, in accordance with procedural documentation.  Database lock 
will occur once quality assurance procedures have been completed. 
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting FDA guidelines for the handling and analysis of data for clinical trials. 
 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database on a regular basis. For Electronic Data 
Capture (EDC) studies: Queries are entered, tracked, and resolved through the EDC system 
directly.  For paper studies: Query reports (Data Clarification Requests) pertaining to data 
omissions and discrepancies will be forwarded to the Investigators and study monitors for 
resolution.  The study database will be updated in accordance with the resolved queries.  All 
changes to the study database will be documented. 
 Archival of Data 
The database is safeguarded against unauthorized access by established security procedures; 
appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with any 
updates or changes to the database.   
At critical junctures of the protocol (e.g., production of interim reports and final reports), data for 
analysis is locked and cleaned per established procedures. 

 
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 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., FDA) 
inspectors upon request.  A file for each subject must be maintained that includes the signed 
Informed Consent, HIPAA Authorization and Assent Form and copies of all source 
documentation related to that subject.  The Investigator must ensure the reliability and 
availability of source documents from which the information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study File 
Notebook, etc.) must be kept secured for a period of two years following marketing of the 
investigational product or for two years after centers have been notified that the IND has been 
discontinued.  There may be other circumstances for which the Sponsor is required to maintain 
study records and, therefore, the Sponsor should be contacted prior to removing study records for 
any reason. 
 Subject Confidentiality 
In order to maintain subject confidentiality, only a site number, subject number and subject 
initials will identify all study subjects on CRFs and other documentation submitted to the 
Sponsor.  Additional subject confidentiality issues (if applicable) are covered in the Clinical 
Study Agreement. 

 
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14 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical 
Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other records 
will be identified by a coded number and initials only.  All study records will be kept in a locked 
file cabinet and code sheets linking a patient’s name to a patient identification number will be 
stored separately in another locked file cabinet.  Clinical information will not be released without 
written permission of the subject, except as necessary for monitoring by the FDA.  The 
Investigator must also comply with all applicable privacy regulations (e.g., Health Insurance 
Portability and Accountability Act of 1996, EU Data Protection Directive 95/46/EC). 
 Protocol Amendments 
Any amendment to the protocol will be written by the study chair.  Protocol amendments can not 
be implemented without prior written IRB approval except as necessary to eliminate immediate 
safety hazards to patients.  A protocol amendment intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately, provided the IRB is notified within five 
working days. 
 Institutional Review Boards and Independent Biosafety Committees 
The protocol and consent form will be reviewed and approved by the institutional IRB/IBC prior 
to study initiation.  Serious adverse experiences regardless of causality will be reported to the 
IRB/IBC in accordance with the standard operating procedures and policies of the IRB/IBC, and 
the Investigator will keep the IRB/IBC informed as to the progress of the study.  The Investigator 
will obtain assurance of IRB/IBC compliance with regulations. 
Any documents that the IRB/IBC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning patient 
recruitment, payment or compensation procedures, or other pertinent information) will be 
submitted to the IRB/IBC.  The IRB/IBCs written unconditional approval of the study protocol 
and the informed consent form will be in the possession of the Investigator before the study is 
initiated.   
Protocol and/or informed consent modifications may not be initiated without prior written IRB 
approval except when necessary to eliminate immediate hazard to the patient.  Such 
modifications will be submitted to the IRB and written verification that the modification was 
submitted and subsequently approved should be obtained before implementation.   
The IRB must be informed of revisions to other documents originally submitted for review; 
serious and/or unexpected adverse experiences occurring during the study in accordance with the 
standard operating procedures and policies of the IRB; new information that may affect 
adversely the safety of the patients of the conduct of the study; an annual update and/or request 
for re-approval; and when the study has been completed. 
Research modifications will be submitted to the IBC according to NIH guidelines, standard 
operating procedures and policies of the IBC. 

 
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 Informed Consent Form 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US 
Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, 
and CFR Part 56, Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, 
if applicable), and local regulations. 
The Investigator will prepare the informed consent form (ICF), assent and HIPAA authorization 
and provide the documents to the Sponsor or designee for approval prior to submission to the 
IRB. The consent form generated by the Investigator must be acceptable to the Sponsor and be 
approved by the IRB.  The written consent document will embody the elements of informed 
consent as described in the International Conference on Harmonization and will also comply 
with local regulations. The Investigator will send an IRB-approved copy of the Informed 
Consent Form to the Sponsor (or designee) for the study file. 
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written form and 
subjects (or their legal representatives) must be given ample opportunity to inquire about details 
of the study. If appropriate and required by the local IRB, assent from the subject will also be 
obtained.  If a subject is unable to sign the ICF and the HIPAA authorization, a legal 
representative may sign for the subject.   A copy of the signed consent form (and assent) will be 
given to the subject or legal representative of the subject and the original will be maintained with 
the subject’s records. 
 Publications 
The publication or presentation of any study results shall comply with all applicable privacy 
laws, including, but not limited to, the Health Insurance Portability and Accountability Act of 
1996.  
 Investigator Responsibilities 
 By signing the Investigator Signature Page the Investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes 
after notifying the Sponsor (or designee), except when to protect the safety, 
rights or welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB 
review and approval meet federal guidelines, as stated in § 21 CFR, parts 50 
and 56. 
4. Report to the Sponsor or designee any AE’s that occur in the course of the 
study, in accordance with §21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct 
of the study are informed about their obligations in meeting the above 
commitments. 

 
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6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 
and to make those records available for inspection with the Sponsor (or 
designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 
will be responsible for initial and continuing review and approval of the 
clinical study. 
8. Promptly report to the IRB and the Sponsor (or designee) all changes in the 
research activity and all unanticipated problems involving risks to subjects or 
others (to include amendments and IND safety reports). 
9. Seek IRB approval before any changes are made in the research study, except 
when necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical 
investigators and all other pertinent requirements listed in § 21 CFR part 312. 

 
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15 RESEARCH PARTICIPANT-SPECIFIC BIOLOGICAL MATERIALS 
Unused T cell product, biologic samples and cryopreserved PBMC will not be returned to the 
research participant or their family/families.  They will become property of the Sponsor and may 
be used in non-therapeutic research. 
 

 
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APPENDICES 
Appendix I: Performance Status Scales/Scores 
Appendix II: GVHD Staging and Grading Assessment; Diagnosis of Chronic GVHD 
Appendix III: Highly Effective Contraception 

 
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APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
 
*The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only.  
 
 

 
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APPENDIX II GVHD STAGING, GRADING, AND DIAGNOSIS INFORMATION 
Appendix II, Table 1: Staging of Acute GVHD 
 
 
 

 
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Appendix II, Table 2: Grading of Acute GVHD 
Severity of Individual Organ Involvement 
Skin 
+1 
a maculopapular eruption involving less than 25% of the body 
surface 
+2 
a maculopapular eruption involving 25-50% of the body surface 
+3 
generalized erythroderma involving >50% of the body surface 
+4 
generalized erythroderma with bullous formation and often with 
desquamation 
Liver 
+1 
bilirubin (2.0-2.9 mg/100ml) 
+2 
bilirubin (3-5.9mg/100ml) 
+3 
bilirubin (6-14.9mg/100ml) 
+4 
bilirubin > 15mg/100ml 
Gut 
Diarrhea is graded +1 to +4 in severity. Nausea and vomiting and/or 
anorexia caused by GVHD is assigned as +1 in severity. 
The severity of gut involvement is assigned to the most severe involvement 
noted.  Patients with visible bloody diarrhea are at least stage +2 gut and 
grade +3 overall 
Diarrhea 
+1 
 1000 ml of liquid stool/day* ( 15ml of stool/kg/day)† 
+2 
>1,000 ml of stool/day* (> 15ml of stool/kg/day)† 
+3 
>1,500 ml of stool/day* (> 20ml of stool/kg/day)† 
+4 
2,000 ml of stool/day* ( 25ml of stool/kg/day)† 
*In the absence of infectious/medical cause 
†For pediatric patients 
 
 

 
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Appendix II, Table 2: Grading of Acute GVHD, continued 
Severity of GVHD 
Grade I 
+1 to +2 skin rash 
No gut or liver involvement 
Grade II 
+1 to +3 skin rash and/or 
+1 gastrointestinal involvement and/or +1 liver involvement 
Grade III 
+4 skin involvement and/or 
+2 to +4 gastrointestinal involvement and/or 
+2 to +4 liver involvement with or without a rash 
Grade IV 
Pattern and severity of GVHD similar to grade 3 with extreme 
constitutional symptoms or death 
From “Graft-vs-host disease” Sullivan, Keith M. Hematopoietic Cell Transplantation Ed: D. Thomas, K. Blume, S. 
Forman, Blackwell Sciences; 1999, pages 518-519. 
 
 

 
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Appendix II, Table 3: Diagnosis of chronic GVHD 
Table3a: Classification of manifestations for the clinical diagnosis of chronic GVHD 
Organ or site 
Diagnostic 
sufficient to establish a 
chronic GVHD diagnosis 
Distinctive 
insufficient alone to establish a 
chronic GVHD diagnosis 
Common 
seen with both acute and 
chronic GVHD 
Skin 
Poikiloderma 
Lichen planus-like 
Sclerotic morphea-like 
Lichen sclerosis-like 
Depigmentation 
Erythema 
Maculopapular 
Pruritus 
Nails 
 
Dystrophy 
Longitudinal ridging, splitting or 
brittleness 
Onycholysis 
Pterygium ungus 
Nail loss (usually symmetric and 
affects most nails) 
 
Scalp and 
body hair 
 
New alopecia not due to 
chemoradiotherapy 
Scaling, papulosquamous 
lesions 
 
Mouth 
Lichenoid 
Hyperkeratotic plaques 
Diminished oral cavity 
opening from sclerosis 
Xerostomia 
Mucocele 
Mucosal atrophy 
Pseuodmembranes 1 
Ulcers 1 
Gingivitis 
Mucositis 
Erythema 
Pain 
Eyes 
 
New onset of sicca (dryness, 
gritty or painful 2) 
Cicatricial conjunctivitis 
Keratoconjunctivitis sicca 2 
Confluent areas of punctate 
keratopathy 
 
Genitalia 
Lichen planus-like 
Vaginal scarring / 
stenosis 
Erosions 1 
Fissures 1 
Ulcers 1 
 
continued 
 

 
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Table3a: Classification of manifestations for the clinical diagnosis of chronic GVHD, continued 
Organ or site 
Diagnostic 
sufficient to establish a 
chronic GVHD diagnosis 
Distinctive 
insufficient alone to establish a 
chronic GVHD diagnosis 
Common 
seen with both acute and 
chronic GVHD 
GI tract 
Esophageal web 
Esophageal strictures or 
stenosis in upper to mid 
third 1 
 
Anorexia, nausea, 
vomiting, diarrhea 
Failure to thrive / 
weight loss 
Liver 3 
 
 
Bilirubin > 2x ULN 1 
Alk phos > 2x ULN 1 
AST or ALT >2x ULN1 
Lung 
Bronchiolitis obliterans 4 
(biopsy confirmed) 
Bronchiolitis obliterans 4 
(based on PFTs and CT scan 
imaging) 
Cryptogenic organizing 
pneumonia 
(COP/BOOP) 
Muscles, 
fascia, joints 
Fasciitis 
Joint stiffness or sclerotic 
contractures  
Myositis or polymyositis 2 
 
AIHA: autoimmune hemolytic anemia; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BOOP: 
bronchiolitis obliterans with organizing pneumonia; COP: cryptogenic organizing pneumonia; CT: computerized 
tomography; ITP: immune thrombocytopenia; PFTs: pulmonary function tests; ULN, upper limit or normal 
1 In all cases, infection, drug effects, malignancy, and other cause must be excluded. 
2 Diagnosis of cGVHD requires biopsy or radiographic confirmation (or Schirmer test or slit 
lamp examination for eyes) 
3 Because liver histology in acute and chronic GVHD is not distinguishable the diagnosis of 
cGVHD cannot be made on the basis of biopsy alone and requires a distinctive manifestation in 
at least one other organ system. 
4 Criteria for diagnosing bronchiolitis obliterans: Forced expiratory volume in 1 second/forced 
(or slow) vital capacity ratio <0.7 and forced expiratory volume in 1 second <75% of predicted 
and evidence of air trapping or small airway thickening or bronchiectasis 
 
 

 
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Table 3b: Manifestations acknowledged as chronic GVHD if the diagnosis is already confirmed 
Organ or Site 
Manifestation 
Skin 
Hair 
 
Eyes 
GI tract 
Muscle/Joint 
Hematology 
Immune 
Other 
Sweat impairment, ichthyosis, keratosis pilaris, hypopigmentation, hyperpigmentation 
Thinning scalp hair not otherwise explained (typically patchy, coarse or dull), 
premature graying 
Photophobia, periorbital hyperpigmentation, blepharitis (eyelid erythema with edema) 
Exocrine pancreatic insufficiency 
Edema, muscle cramps, arthralgia or arthritis 
Thrombocytopenia, eosinophilia, lymphopenia 
Hypo-or hyper- gammaglobulinemia, autoantibodies (AIHA, ITP) 
Ascites, pericardial or pleural effusions, peripheral neuropathy, nephrotic syndrome, 
myasthenia gravis, cardiac conduction abnormality, cardiomyopathy 
AIHA: autoimmune hemolytic anemia; ITP: immune thrombocytopenia 
 
 
 

 
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APPENDIX III: HIGHLY EFFECTIVE CONTRACEPTION 
Highly effective contraception is defined as either: 
• Total abstinence: When this is in line with the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception. 
• Sterilization: Patient has had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of 
oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment 
• Male partner sterilization (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate). [For female study patients, the vasectomized male 
partner should be the sole partner for that patient] 
• Use a combination of the following (both a+b): 
a. Hormonal contraception (oral or injected) or placement of an intrauterine device (IUD) or an 
intrauterine system (IUS) 
b. Barrier method of contraception: Condom or Occlusive cap (diaphragm or cervical vault caps) 
with spermicidal foam/gel/film/cream/vaginal suppository. 
Note: Woman are considered post-menopausal and not child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with 
serum FSH levels > 40 mIU/mL and estradiol <20 pg/mL or have had surgical bilateral 
oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment is she considered not of child bearing potential.  
Male patient must use highly effective (double barrier) methods of contraception (e.g., 
spermicidal gel plus condom) A condom is required to be used also by vasectomized men in 
order to prevent delivery of the study treatment via seminal fluid.