Conditions: Ovarian Cancer Fallopian Tube Cancer Primary Peritoneal Carcinoma
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 46
Healthy volunteers: no

Brief summary:
Phase I study to establish safety and feasibility of intraperitoneally administered lentiviral transduced MOv19-BBz CAR T cells with or without cyclophosphamide + fludarabine as lymphodepleting chemotherapy

Detailed description:
This is a Phase I study evaluating the safety and feasibility of intraperitoneally administered lentiviral transduced MOv19-BBz CAR T cells in 4 cohorts with or without cyclophosphamide + fludarabine in a 3+3 dose escalation design.

The DLT observation period is 28 days post CAR T cell infusion. The Maximum Tolerated Dose (MTD) is defined as the dose at which 0 or 1 DLT occurs in 6 evaluable subjects tested within the dose range of this study.

Cohort 1: (n= 3 to 6 subjects): Single infusion of 1-3x107 /m2 lentivirally transduced MOv19-BBz CAR T cells on day 0 without lymphodepleting chemotherapy.

Cohort 2: (n= 3 to 6 subjects): Single infusion of 1-3x107 /m2 lentivirally transduced MOv19-BBz CAR T cells on day 0 beginning 3 days (+/- 1 day) after lymphodepleting chemotherapy with cyclophosphamide + fludarabine.

Cohort 3: (n=3 to 6 subjects): Single infusion of 1-3x108 lentivirally transduced MOv19-BBz CAR T cells on day 0 beginning 3 days (+/- 1 day) after lymphodepleting chemotherapy with cyclophosphamide + fludarabine.

Cohort -1: (n= 3 to 6 subjects): Single Infusion of 1-3x106 /m2 lentivirally transduced MOv19-BBz CAR T cells on day 0 without lymphodepleting chemotherapy. Up to 6 subjects will be infused in Cohort -1 with ≤ 1 DLT/6 subjects to establish the MTD.

Arms:
arm 1: Cohort 1: (n= 3 to 6 subjects): Single infusion of 1-3x107 /m2 lentivirally transduced MOv19-BBz CAR T cells on day 0 without lymphodepleting chemotherapy. arm 2: Cohort 2: (n= 3 to 6 subjects): Single infusion of 1-3x107 /m2 lentivirally transduced MOv19-BBz CAR T cells on day 0 beginning 3 days (+/- 1 day) after lymphodepleting chemotherapy with cyclophosphamide + fludarabine. arm 3: Cohort 3: (n=3 to 6 subjects): Single infusion of 1-3x108 lentivirally transduced MOv19-BBz CAR T cells on day 0 beginning 3 days (+/- 1 day) after lymphodepleting chemotherapy with cyclophosphamide + fludarabine. arm 4: Cohort -1: (n= 3 to 6 subjects): Single Infusion of 1-3x106 /m2 lentivirally transduced MOv19-BBz CAR T cells on day 0 without lymphodepleting chemotherapy. Up to 6 subjects will be infused in Cohort -1 with ≤ 1 DLT/6 subjects to establish the MTD.

Interventions: intervention 1: MOv19-BBz CAR T cells intervention 2: Alpha Folate Receptor expression test
Intervention descriptions: intervention 1: intraperitoneally administered lentiviral transduced MOv19-BBz CAR T cells with or without cyclophosphamide + fludarabine as lymphodepleting chemotherapy. intervention 2: Patients will first be pre-screened for alpha folate receptor expression. The test for alpha folate receptor expression is a laboratory developed test+, developed and conducted by the Hospital of the University of Pennsylvania Pathology and Laboratory Medicine lab to determine subject eligibility. This test is not an approved FDA device and its use is investigational.

Protocol document:
Prot_SAP_001.pdf: 
University of Pennsylvania 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
PHASE I CLINICAL TRIAL OF ADOPTIVE TRANSFER OF AUTOLOGOUS FOLATE 
RECEPTOR–ALPHA REDIRECTED T CELLS FOR RECURRENT HIGH GRADE 
SEROUS OVARIAN, FALLOPIAN TUBE, OR PRIMARY PERITONEAL CANCER 
Principal Investigator: 
Payal D. Shah, MD 
University of Pennsylvania Health System 
University of Pennsylvania Perelman School of Medicine 
Philadelphia, PA 19104 
Regulatory Sponsor: 
University of Pennsylvania 
Funding Organizations: 
OvaCure 
Alliance for Cancer Gene Therapy 
Ovarian Cancer Alliance of Greater Cincinnati 
Penn Internal Funds 
National Institutes of Health (NIH) 
Sponsor Medical Director: 
University of Pennsylvania Perelman School of Medicine 
Philadelphia, Pennsylvania 19104 
Sponsor Scientific Advisor: 
University of Pennsylvania Perelman School of Medicine 
Philadelphia, Pennsylvania 19104 
Main Investigational Product: 
MOv19-BBz CAR T cells 
Protocol Number: 
UPCC 03818; IRB# 830111 
IND Number: 
Sponsor Cell Manufacturing: 
Clinical Cell and Vaccine Production Facility (CVPF) 
University of Pennsylvania 
Correlative Laboratory: 
TCSL University of Pennsylvania 
Biostatistician: 
Original Protocol Date: 
V1-June 7, 2018 
V2-July 16, 2018 
V3-February 12, 2020 
V4-February 5, 2021 
V5-July 19, 2021 
V6-July 6, 2022 
V7-February 9, 2023 
Date Amended: 
NCT03585764 


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CONFIDENTIAL 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ........................................................................................................ 5 
STUDY SUMMARY ................................................................................................................. 7 
1 
INTRODUCTION ........................................................................................................... 12 
1.1 
Background .............................................................................................................................. 12 
1.1.1 
Epithelial Ovarian Cancer ........................................................................................... 12 
1.1.2 
Adoptive immunotherapy .......................................................................................... 12 
1.1.3 
α Folate Receptor (αFR) ............................................................................................. 14 
1.1.4 
Rationale for using lentivirus vector .......................................................................... 14 
1.1.5 
Lymphodepletion ....................................................................................................... 15 
1.1.6 
Local versus systemic administration of CAR T cells .................................................. 16 
1.2 
Pharmacology of modified T cells ........................................................................................... 17 
1.2.1 
Mechanism of action .................................................................................................. 17 
1.2.2 
Absorption, distribution and metabolism .................................................................. 17 
1.2.3 
Drug interactions ........................................................................................................ 17 
1.2.4 
Immune elimination ................................................................................................... 18 
1.3 
Main Investigational Agent ..................................................................................................... 18 
1.3.1 
Preclinical data ........................................................................................................... 18 
1.3.2 
Clinical data to date .................................................................................................... 28 
1.4 
Toxicities associated with CART cells ...................................................................................... 30 
1.4.1 
Fatal SAEs with CARs .................................................................................................. 30 
1.4.2 
Non-fatal SAEs ............................................................................................................ 31 
1.5 
Trial Rationale .......................................................................................................................... 31 
1.6 
Potential risks and benefits ..................................................................................................... 32 
1.6.1 
Risks of MOv19-BBz CAR T cells ................................................................................. 32 
1.6.2 
Research Procedures .................................................................................................. 40 
1.6.3 
Risks of lymphodepleting chemotherapy ................................................................... 41 
1.6.4 
Potential Benefits ....................................................................................................... 42 
1.7 
Justification of route and dose regimen for Main Investigational Product ............................ 42 
2 
STUDY OBJECTIVES ...................................................................................................... 43 
2.1 
Primary objectives ................................................................................................................... 43 
2.2 
Secondary objectives ............................................................................................................... 43 
3 
STUDY DESIGN ............................................................................................................ 43 
3.1 
General Design ........................................................................................................................ 43 
3.2 
Cohort Assignment/Advancement .......................................................................................... 44 
3.3 
Collection of Research Samples .............................................................................................. 46 
3.4 
Primary Study Endpoints ......................................................................................................... 46 
3.5 
Secondary Study Endpoints ..................................................................................................... 47 
3.5.1 
Clinical Responses ...................................................................................................... 47 
3.5.2 
Research Correlative Studies ...................................................................................... 47 
4 
SUBJECT SELECTION AND WITHDRAWAL ..................................................................... 48 
4.1 
Inclusion Criteria ...................................................................................................................... 48 
4.2 
Exclusion Criteria ..................................................................................................................... 49 


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4.3 
Subject Recruitment ................................................................................................................ 50 
4.4 
Reproductive Status ................................................................................................................ 50 
4.5 
Subject Withdrawal/Discontinuation ...................................................................................... 51 
4.5.1 
Reasons for Subject Discontinuation ......................................................................... 51 
4.5.2 
Data Collection and Follow-up ................................................................................... 52 
4.5.3 
Replacement Subjects ................................................................................................ 52 
5 
INVESTIGATIONAL PRODUCTS ..................................................................................... 52 
5.1 
Description .............................................................................................................................. 52 
5.1.1 
MOv19-BBz CAR T cells............................................................................................... 52 
5.1.2 
Cyclophosphamide and Fludarabine .......................................................................... 52 
5.2 
Treatment Regimen ................................................................................................................. 53 
5.3 
Preparation and Administration of Study Drug(s) ................................................................... 53 
5.3.1 
MOv19-BBz CAR T cells............................................................................................... 53 
5.3.2 
Cyclophosphamide ..................................................................................................... 62 
5.3.3 
Fludarabine ................................................................................................................. 62 
5.4 
Dose-Limiting Toxicity (DLT) and Cohort Progression ............................................................. 63 
5.5 
Subject Compliance Monitoring .............................................................................................. 63 
5.6 
Prior and Concomitant Therapy .............................................................................................. 63 
6 
STUDY PROCEDURES ................................................................................................... 64 
6.1 
Screening ................................................................................................................................. 65 
6.2 
Monitoring Visit for Eligibility .................................................................................................. 66 
6.3 
Leukapheresis .......................................................................................................................... 66 
6.4 
Pre-infusion safety visit (Week -2 to -1) .................................................................................. 67 
6.5 
Lymphodepleting chemotherapy administration (Cohorts 2 and 3 only) ............................... 67 
6.6 
MOv19-BBz CART Product Administration (Day 0) ................................................................. 69 
6.7 
Post-infusion visits and tumor biopsy ..................................................................................... 70 
6.8 
Day 28 (+/- 5 days): Safety and Tumor staging ....................................................................... 70 
6.9 
Month 2 (+/- 5 days): Safety .................................................................................................... 70 
6.10 Month 3 (+/- 5 days): Safety and Tumor staging ..................................................................... 70 
6.11 Month 6 (+/- 5 days): Safety and Tumor staging ..................................................................... 70 
6.12 Quarterly evaluations for up to 2 years post-infusion ............................................................ 70 
6.13 Long-term Follow-up Phase .................................................................................................... 71 
7 
ASSESSMENTS ............................................................................................................. 72 
7.1 
Tumor assessments ................................................................................................................. 72 
7.2 
Research Correlative Studies Assessment ............................................................................... 72 
8 
STATISTICAL PLAN ....................................................................................................... 73 
8.1 
General Design Issues .............................................................................................................. 73 
8.2 
Sample Size Determination ..................................................................................................... 74 
8.3 
Endpoints for Primary Objectives ............................................................................................ 74 
8.4 
Endpoints for Secondary Objectives ....................................................................................... 74 
8.5 
Subject Population(s) for Analysis ........................................................................................... 74 
8.6 
Statistical Analysis of Primary and Secondary Endpoints ........................................................ 75 
9 
SAFETY AND ADVERSE EVENTS .................................................................................... 76 
9.1 
Definitions ............................................................................................................................... 76 
9.1.1 
Adverse Event ............................................................................................................. 76 


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9.1.2 
Serious Adverse Event ................................................................................................ 76 
9.1.3 
Unexpected adverse events ....................................................................................... 76 
9.1.4 
Related adverse events .............................................................................................. 77 
9.1.5 
Unanticipated Adverse Device Effect (UADE) ............................................................ 77 
9.1.6 
Protocol-defined Adverse Events (PDAEs) ................................................................. 77 
9.1.7 
Adverse Event Reporting Period ................................................................................ 77 
9.1.8 
Preexisting Condition/General Physical Examination Findings .................................. 78 
9.1.9 
Abnormal Laboratory Values ...................................................................................... 78 
9.2 
Recording of Adverse Events ................................................................................................... 78 
9.2.1 
Cytokine Release Syndrome Grading System ............................................................. 79 
9.2.2 
Grading System for CAR Neurotoxicity ...................................................................... 81 
9.3 
Reporting of Serious Adverse Events ...................................................................................... 82 
9.3.1 
Investigator Reporting:  Local Regulatory Review Committees ................................. 83 
9.3.2 
Pregnancies ................................................................................................................ 83 
9.4 
Toxicity Management, Stopping Rules and Study Termination .............................................. 83 
9.4.1 
Criteria for stopping or pausing the study ................................................................. 84 
9.4.2 
General toxicity considerations .................................................................................. 84 
9.5 
Protocol Exceptions and Deviations ........................................................................................ 84 
9.6 
Data and Safety Monitoring Board .......................................................................................... 85 
10 
DATA HANDLING AND RECORDKEEPING ...................................................................... 85 
10.1 Confidentiality ......................................................................................................................... 85 
10.2 Source Documents .................................................................................................................. 86 
10.3 Data Management ................................................................................................................... 86 
10.4 Sharing of Study Data .............................................................................................................. 87 
10.5 Future Use of Research Data/Specimens ................................................................................ 87 
10.6 Records Retention ................................................................................................................... 87 
11 
STUDY MONITORING, AUDITING, AND INSPECTING ..................................................... 87 
11.1 Study Monitoring Plan ............................................................................................................. 87 
11.2 Auditing and Inspecting ........................................................................................................... 88 
12 
ETHICAL CONSIDERATIONS .......................................................................................... 88 
13 
STUDY FINANCES......................................................................................................... 88 
13.1 Funding Source ........................................................................................................................ 88 
13.2 Conflict of Interest ................................................................................................................... 88 
13.3 Subject Stipends or Payments ................................................................................................. 89 
14 
PUBLICATION PLAN ..................................................................................................... 89 
15 
REFERENCES ................................................................................................................ 90 
16 
APPENDIX 1 - SCHEDULE OF EVENTS ............................................................................ 97 
17 
APPENDIX 2 - LONG-TERM FOLLOW-UP SURVEY ......................................................... 104 
18 
APPENDIX 3 - EXAMPLE PHYSICIAN LETTER ................................................................. 106 
 
 


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LIST OF ABBREVIATIONS 
AE, adverse event 
aFR, alpha folate receptor 
CAR, chimeric antigen receptor 
CCI, Center for Cellular Immunotherapies 
CD137, 4-1BB costimulatory molecule 
CFR, code of federal regulations 
CRF, case report form 
CRM, Continual Reassessment Method  
CRS, Cytokine Release Syndrome 
CTCAE, common terminology criteria for adverse events 
CTL, cytotoxic T lymphocyte 
CTRC, Clinical Translational Research Center at the University of Pennsylvania 
CVPF, clinical cell and vaccine production facility at the University of Pennsylvania 
CTL, cytotoxic T lymphocyte  
CTX, cyclophosphamide 
DSMB, data and safety monitoring board  
DLT, dose-limiting toxicity 
EOC, epithelial ovarian cancer 
FDA, food and drug administration 
GCP, good clinical practices 
GMP, good manufacturing practices 
HAMA, human anti-mouse antibody 
HACA, human anti-CAR antibody 
IBC, Institutional Biosafety Committee 
i.p., intraperitoneal 
IRB, Institutional Review Board 
irRC, immune related response criteria 
irRECIST, Immune-related Response Evaluation Criteria in Solid Tumors 
MABEL, Minimum Anticipated Biological Effect Level 
MAS, Macrophage Activation Syndrome 
MOv19, alpha folate receptor-specific scFv 
OBD, optimal biologic dose 
PBMC, peripheral blood mononuclear cells 
PDAE, protocol-defined adverse event 
PDCS, Product Development and Correlative Sciences laboratory 
PDSAE, protocol-defined serious adverse event 
RECIST, Response Evaluation Criteria in Solid Tumors 
ROA, route of administration 
SAE, serious adverse event 
SaFRP, soluble alpha folate receptor protein 


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TCR, T cell receptor 
TCSL, Translational and Correlative Studies Laboratory 
UADE, Unanticipated Adverse Device Effect 
UPenn, University of Pennsylvania 
VSV-G, vesicular stomatitis virus 
 
 


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STUDY SUMMARY 
Title 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha 
Redirected T Cells for Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary 
Peritoneal Cancer 
Short Title 
MOv19-BBz CAR T cells in aFR expressing recurrent high grade serous ovarian, fallopian 
tube, or primary peritoneal cancer  
Protocol Number 
UPCC 03818; IRB# 830111 
Phase 
Phase 1 -  Safety and Proof of Concept 
Methodology 
Phase I study to establish safety and feasibility of intraperitoneally administered 
lentiviral transduced MOv19-BBz CAR T cells with or without cyclophosphamide + 
fludarabine as lymphodepleting chemotherapy. 
Study Duration 
The protocol will require approximately 18-24 months to complete enrollment.  Each 
subject will be followed for up to 15 years from their MOv19-BBz CART cell infusion.  
Study Center(s) 
University of Pennsylvania 
Number of Subjects 
9 to 18 evaluable subjects.   
Study Design 
This is a Phase I study evaluating the safety and feasibility of intraperitoneally 
administered lentiviral transduced MOv19-BBz CAR T cells in 4 cohorts with or without 
cyclophosphamide + fludarabine in a 3+3 dose escalation design.   
 
The DLT observation period is 28 days post CAR T cell infusion.  The Maximum 
Tolerated Dose (MTD) is defined as the dose at which 0 or 1 DLT occurs in 6 evaluable 
subjects tested within the dose range of this study.   
 
Evaluable subjects are defined as follows:   
• 
Subjects evaluable for DLT assessment are all those who receive the target 
dose of MOv19-BBz CAR T cell infusion based on cohort.   
• 
Subjects evaluable for safety include all those who receive a MOv19-BBz CAR 
T cell infusion.   
• 
Subjects evaluable for efficacy are all those who receive the target dose of 
MOv19-BBz CAR T cell infusion based on cohort. 
 
• 
Cohort 1: (n= 3 to 6 subjects):  Single infusion of 1-3x107 /m2 lentivirally 
transduced MOv19-BBz CAR T cells on day 0 without lymphodepleting 
chemotherapy.   
o 
If 1 DLT/3 subjects occurs, the study will enroll an additional 3 
subjects at this dose level. If 0 DLT/3 subjects or 1 DLT/6 subjects 
occurs, the study will advance to Cohort 2. If 2 DLT/3 subjects or 2 
DLT/6 subjects occurs, then enrollment in Cohort 1 will be stopped 
and the dose will be de-escalated by 10-fold to 1-3 x 106 cells/m2 
(Cohort -1). 
o 
If the number of manufactured CAR T cells does not meet the 
protocol-specified minimum dose for Cohort 1 subjects of 1 x 107/m2 
cells, but does meet the protocol minimum dose requirement of at 
least 1 x 106/m2 cells, then the subject may receive the cells, but will 
not be included in the DLT assessment for Cohort 1. Thus, the subject 
would be evaluable for safety, but would be replaced in this cohort 
for formal DLT assessment.  If, however, the number of 
manufactured CAR T cells does not meet the minimum acceptable 
dose for infusion, then the cells will not be administered, and the 
subject will be replaced in the study.   


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• 
Cohort 2: (n= 3 to 6 subjects): Single infusion of 1-3x107 /m2 lentivirally 
transduced MOv19-BBz CAR T cells on day 0 beginning 3 days (+/- 1 day) after 
lymphodepleting chemotherapy with cyclophosphamide + fludarabine.   
o 
If 1 DLT/3 subjects occurs, the study will enroll an additional 3 
subjects at this dose level. If 0 DLT/3 subjects or 1 DLT/6 subjects 
occurs, the study will advance to Cohort 3. If 2 DLT/3 subjects or 2 
DLT/6 subjects occurs, further infusions within this cohort and 
subsequent dose escalation would be halted.  If less than 6 subjects 
were infused in Cohort 1, up to 6 total subjects will be infused in 
Cohort 1 to establish the MTD.  
o 
If the number of manufactured CAR T cells does not meet the 
protocol-specified minimum dose for Cohort 2 subjects of 1 x 107/m2 
cells, but does meet the minimum dose requirement of at least 1 x 
106/m2 cells, then the subject may receive the cells but will not be 
included in the DLT assessment for Cohort 2. Thus, the subject would 
be evaluable for safety, but would be replaced in this cohort for 
formal DLT assessment.  If, however, the number of manufactured 
CAR T cells does not meet the minimum acceptable dose for infusion, 
then the cells will not be administered, and the subject will be 
replaced in the study.   
• 
Cohort 3: (n=3 to 6  subjects): Single infusion of 1-3x108 /m2 lentivirally 
transduced MOv19-BBz CAR T cells on day 0 beginning 3 days (+/- 1 day) after 
lymphodepleting chemotherapy with cyclophosphamide + fludarabine.   
o 
If 0 DLT/3 or 1 DLT/3 subjects occur, the study will enroll an 
additional 3 subjects to confirm tolerability and MTD.  If 2 DLT/3 
subjects or 2 DLT/6 subjects occurs, further infusions within this 
cohort will be halted. If less than 6 subjects were infused in Cohort 2, 
up to 6 total subjects will be infused in Cohort 2 to establish the 
MTD.    
o 
If the number of manufactured CAR T cells does not meet the 
protocol-specified minimum dose for Cohort 2 subjects of 1 x 108/m2 
cells, but does meet the minimum dose requirement of at least 1 x 
106/m2 cells, then the subject may receive the cells but will not be 
included in the DLT assessment for Cohort 3. Thus, the subject would 
be evaluable for safety, but would be replaced in this cohort for 
formal DLT assessment.  If, however, the number of manufactured 
CAR T cells does not meet the minimum acceptable dose for infusion, 
then the cells will not be administered, and the subject will be 
replaced in the study.   
 
In the event that 2 DLTs occur among subjects enrolled in Cohort 1, then enrollment in 
Cohort 1 will be stopped and the dose will be de-escalated by 10-fold to 1-3 x 106 
cells/m2.  This de-escalated cohort will be designated Cohort -1. 
• 
Cohort -1: (n= 3 to 6 subjects): Single Infusion of 1-3x106 /m2 lentivirally 
transduced MOv19-BBz CAR T cells on day 0 without lymphodepleting 
chemotherapy.  Up to 6 subjects will be infused in Cohort -1 with ≤ 1 DLT/6 
subjects to establish the MTD.   
 


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Subjects with accessible lesions will be subjected to a mandatory CT-guided needle 
biopsy of tumors or needle aspiration of malignant effusion pre-infusion and 
approximately Day +14 after T cell administration. 
 
Objectives 
Primary objective: 
Determine the safety and feasibility of intraperitoneal administration of lentivirally 
transduced MOv19-BBz CAR T cells in the target population.  Intraperitoneal 
administration of MOv19-BBz CAR T cells is planned with and without 
cyclophosphamide + fludarabine as lymphodepleting chemotherapy. 
 
Secondary objectives: 
Clinical objectives:  
1. Assess the clinical anti-tumor effect by standard criteria (RECIST 1.1) and 
immune-related response criteria (irRECIST). 
2. Assess overall response rate (ORR), progression-free survival (PFS) and overall 
survival (OS). 
 
Correlative objectives: 
1. Evaluate MOv19-BBz CAR T cells engraftment and persistence in peripheral 
blood and body fluids (including peritoneal fluid). 
2. Determine the bioactivity of MOv19-BBz CAR T cells in peripheral blood and 
body fluids (including peritoneal fluid). 
3. Evaluate the development of anti-CART immune responses favoring rejection 
of MOv19-BBz CAR T cells. 
4. Evaluate the development of secondary anti-tumor immune responses as a 
consequence of epitope spreading. 
5. Evaluate potential tumor biomarkers of anti-tumor activity. 
6. Where tumor material or body fluids can be obtained: 
a. Measure trafficking of MOv19-BBz CAR T  
b. Evaluate aFR expression on tumor cells to assess for antigen-escape 
c. 
Analyze tumor microenvironment and cell interactions (if feasible) 
Study Population and 
Main Inclusion Criteria 
Subjects with histologically confirmed persistent or recurrent stage II to IV high grade 
serous epithelial ovarian, fallopian tube or primary peritoneal carcinoma that 
expresses aFR as assessed by immunohistochemistry. Inclusion criteria are designed to 
include subjects 18 years of age and older diagnosed with advanced high grade serous 
ovarian, fallopian tube, or primary peritoneal cancer that is incurable by presently 
available therapy, who have failed two or more prior chemotherapy regimens, and 
with ECOG 0-1 performance status. 
Investigational Agent(s), 
Dose, Route, Regimen 
Investigational Agent(s): 
• 
MOv19-BBz CAR T cells: autologous T cells lentivirally transduced with 
chimeric anti-alpha folate receptor immunoreceptor MOv19 scFv fused to the 
4-1BB and CD3ζ signaling domains. 
• 
Cyclophosphamide and Fludarabine: cytotoxic chemotherapy agents used for 
lymphodepletion prior to MOv19-BBz CAR T cell administration (Cohorts 2 + 3 
only) 
 
Dose: 
• 
MOv19-BBz CAR T cells:  
o 
Cohorts 1 + 2: 1-3x107 MOv19-BBz CAR T cells/m2  
o 
Cohort 3: 1-3x108MOv19-BBz CAR T cells/m2  
o 
Cohort -1: 1-3x106 MOv19-BBz CAR T cells/m2   


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• 
Cyclophosphamide and Fludarabine: Cyclophosphamide 300mg/m2 and 
Fludarabine 30mg/m2 (Cohorts 2 + 3).   Fludarabine doses will be rounded 
down to the nearest 50 mg vial size, if the rounded dose does not differ by > 
10% of the original dose prescribed. 
 
Route of Administration: 
• 
MOv19-BBz CAR T cells: intraperitoneal instillation (all Cohorts) 
• 
Cyclophosphamide and Fludarabine: intravenous infusion (Cohorts 2 + 3) 
 
Regimen: 
• 
MOv19-BBz CAR T cells: single dose on Day 0 (all Cohorts) 
• 
Cyclophosphamide and Fludarabine: given over 3 days; scheduled so that the 
last day of chemotherapy falls 3 days (+/- 1 day) prior to the CAR T cell 
infusion (Day 0).  Cohorts 2 + 3 only.  
Reference Therapy 
None 
Statistical Methodology 
This is a phase I safety and feasibility study.  
 
Adverse events will be collected and evaluated for all subjects during the protocol 
specified adverse event reporting period outlined in Section9.1. AEs will be graded for 
severity using the National Cancer Institute (NCI) – Common Terminology Criteria 
(v5.0). All adverse events will be described and exact 95% confidence intervals will be 
produced for adverse event rates, both overall and within major categories. The data 
will be monitored continuously for evidence of excessive toxicity. Results will be 
tabulated and summarized. 
 
Rates of clinical responses will be summarized in exact 95% confidence intervals. 
Distributions of progression-free and overall survival, and overall response rate will be 
presented graphically using Kaplan-Meier curves. Overall survival rates will also be 
presented. 
 
The statistical analysis will be primarily descriptive in keeping with the exploratory 
nature of the study. Descriptive statistics will be applied to determine the relative 
persistence and trafficking to blood (and optionally tumor) of the MOv19-BBz CAR T 
cells. Data regarding the number of CAR T cells in blood, and the tracking of soluble 
biomarker levels will be presented graphically. Correlations with radiographic and 
other standard measures of tumor burden will be determined. We will compute 95% 
confidence intervals for proportions and means. 
 
 
 


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Figure 1- Study Schema 
 
 


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1 
INTRODUCTION 
1.1 Background 
1.1.1 Epithelial Ovarian Cancer 
Subjects with recurrent ovarian cancer have been chosen as the study population here because of the 
frequent expression of the target antigen alpha folate receptor in this malignancy. Ovarian cancer is the 
5th most common cancer in women and, in the United States in 2015, 21,290 women were diagnosed 
with ovarian cancer and 14,180 women died of the disease [1].  Despite efforts studying different cytotoxic 
and targeted agents to treat ovarian cancer, no major improvement in cure rates has been seen [2]. 
Surgery and platinum-based therapies are the current standard of care for ovarian cancer management. 
Thus, new approaches to ovarian cancer treatment are desired. As ovarian tumors have previously been 
shown to be immunogenic [3] immunotherapeutic strategies, including vaccines, adoptive cell transfer, 
and immunomodulatory drugs, have recently been presented as possible methods of combating ovarian 
cancer [4, 5].  
 
Multiple lines of evidence indicate that T cells play a role in the control of ovarian cancer progression. For 
instance, T cell accumulation in ovarian cancer is a positive prognostic factor for ovarian cancer survival 
[3]. In an early T cell transfer trial by Fujita et al., administration of autologous tumor infiltrating 
lymphocytes (TILs) to ovarian cancer patients in the adjuvant setting (after surgical resection and 
subsequent cisplatin-chemotherapy) resulted in a prolonged disease-free survival and increased the 3-
year survival rate, supporting the notion that T cell transfer can actively inhibit ovarian tumor growth [6]. 
Moreover, administration of TILs (alone or in combination with cisplatin-containing chemotherapy) after 
a single dose of cyclophosphamide was shown to induce objective cancer regressions in some patients 
with existent chemotherapy-naïve or recurrent ovarian cancer as well [7]. These reports rationalize the 
use of adoptive T cell therapy as a means to bolster anti-tumor immune responses, and control the 
progression of ovarian cancer.  
1.1.2 Adoptive immunotherapy 
Breaking tolerance to self-antigens is a major obstacle in the application of immunotherapy to solid 
malignancies. Vaccine strategies aimed at harnessing endogenous anti-tumor T cells are limited by the T 
cell receptor (TCR) repertoire which can be deleted within the thymus as part of central tolerance or 
rendered non-functional by post-thymic mechanisms of peripheral tolerance. One approach designed to 
overcome these obstacles is adoptive immunotherapy, a term used to describe the transfer of immune 
cells for the treatment of cancer or infectious disease [8]. This therapeutic approach is already 
demonstrating impressive early clinical results [9-11]. With adoptive immunotherapy, therapeutically 
effective T cells can be engineered to recognize tumors. For example, one strategy is to identify 
therapeutically effective T cell clones and then to clone the heterodimeric TCR and express it in other T 
cells, thereby creating bispecific T cells with reactivity defined by the original TCR and the clone TCR 
(reviewed in[12]). Kessels and coworkers demonstrated the potential of this approach using a mouse 
model of cancer. Mouse T cells engineered to express a defined TCR were shown to be fully functional; 
capable of protecting against tumor challenge; and effective at targeting metastatic lesions. Moreover, 


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the T cells were shown to expand more 
than 1000 fold after in vivo antigen 
encounter and to traffic to tumor sites 
[13]. 
 
An alternative strategy to produce 
genetically engineered T cells involves the 
development of ‘T-bodies’ or chimeric 
antigen receptors (CARs). CARs combine 
the effector functions of T lymphocytes 
with the ability of antibodies to recognize 
distinct surface antigens in a non-MHC 
restricted manner. For example, CARs 
usually encode an extracellular single 
chain variable fragment (scFv) antibody, 
containing the VH and VL chains joined by a 
peptide linker of approximately 15 amino 
acid residues. This extracellular domain is 
then linked to an intracellular signaling 
domain that mediates T cell activation 
(reviewed in[14]). As a result, CARs can be used to redirect T cells to recognize an intact membrane protein 
independent of antigen processing.   
 
The in vivo persistence, expansion, and functional capacity of adoptively transferred engineered T cells is 
dependent on two discrete signals mediated by cell surface receptors. The primary “activation” signal is 
produced by ligation of the TCR with an MHC-peptide complex. The second “costimulatory” signal is 
generated by ligation of a costimulatory molecule on the T cell surface with its cognate ligand on the 
surface of an antigen presenting cell. Several T cell costimulatory molecules have been identified including 
members of the immunoglobulin superfamily (CD28) and members of the tumor necrosis factor (TNF) 
superfamily (e.g. CD40L, CD134 [OX-40], and CD137 [4-1BB])[15]. 
 
Because signaling through the cytosolic domain of the scFv-TCRζ single chain construct does not fully 
replicate the multichain TCR signaling complex, chimeric antigen receptors bearing only the TCRζ signaling 
modules are not sufficient to drive proliferation or cytokine production in peripheral T cells. However, 4-
1BB, a T cell co-stimulatory receptor induced by TCR activation, is critical for long-term proliferation of 
CD8 cells whereas CD28 is essential for sustained CD4 cell proliferation [16, 17]. Consistent with this 
finding, we have found that “bipartite receptors” comprised of TCRζ and either CD28 or 4-1BB signaling 
modules substantially improve the function and proliferation of T cells in vivo [17]. Our team of PENN 
investigators has applied this strategy to the development of CAR T cells specific for CD19 (CART19) and 
demonstrated the long-lived persistence of CART19 cells in patients with treatment-refractory leukemia 
[9, 11]. In a proof-of-concept study, we have demonstrated that T cells expressing a CD19-specific CAR 
(CART19) can have potent anti-leukemic effects in patients with advanced, chemotherapy-resistant [9, 11, 
18-20]. Using a patient’s own T cells, we engineered autologous T cells to permanently express a CD19-
specific CAR using a lentiviral vector [21]. We found that CART19 cells upon adoptive transfer by 
intravenous administration can persist for more than 5 years in some patients with advanced, 
chemotherapy-resistant leukemia. Importantly, the CART19 cells eliminated leukemic CD19+ B cells as 
well as normal CD19+ B cells in responding patients with a resultant hypogammaglobulinemia that was 
 
 
 
 
 
 


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an expected adverse event.  In August 2017, the FDA approved CART19 cells (Kymriah) for the treatment 
of acute lymphoblastic leukemia.  
 
We have also applied a similar approach to develop a CAR specific for alpha folate receptor [17]. Here, we 
have used the same type of lentiviral transduction system and the same type of CAR construct as used in 
the CART19 cells, comprised of an alpha folate receptor specific scFv fused to the 4-1BB and CD3z signaling 
domains, to generate MOv19-BBz CAR T cells. The main difference between the anti-CD19 CAR and anti-
aFR CAR constructs rely on the origin of the scFv portion of the construct which is specific to the target 
protein.   
1.1.3 α Folate Receptor (αFR) 
The α-isoforms of the folate receptor (FR) is a glycosylphosphatidylinositol-anchored membrane proteins 
that bind folic acid with high affinity (Kd ~1 nM) and mediate the cellular uptake of this vitamin and drug 
conjugates thereof via receptor-mediated endocytosis. The significance of the α-isoform of folate 
receptor (aFR) as a tumor marker was discovered in 1991 when amino acid sequence analysis of a protein 
enriched on the surface of a human ovarian carcinoma cell line was shown to be the aFR [22]. Monoclonal 
antibodies (MOv18 and MOv19) that react with the aFR revealed that it was expressed on a majority of 
nonmucinous ovarian carcinomas; however, little to no reactivity was detected on nonepithelial tumors 
and normal tissues [22]. Subsequent analyses have shown elevated aFR expression in approximately 90% 
of ovarian carcinomas as well as numerous other cancers, including endometrial, kidney, lung, 
mesothelioma, breast, brain, and myeloid leukemia [23-33]. Of note, chemotherapy does not alter 
expression rates in the remaining vital tumor tissue, indicating that folate-targeted agents can have a 
place in the treatment for ovarian cancer, before as well as after chemotherapy [34]. 
 
By contrast, aFR low-level expression in normal human tissues is limited to the luminal surface of cells 
located in the bronchial epithelium, renal tubules and the choroid plexus, intestinal brush-border 
membranes, type 1 and type 2 pneumocytes of the lung, salivary glands, parathyroid and placental tissue 
[35-41]. It is notable that aFR is expressed on the luminal surface of epithelial cells and therefore generally 
not in contact with folate circulating in the blood. Because of this polarized luminal surface expression, 
the sites where FRα is expressed are not accessible by circulating antibodies or folate-chemotherapeutic 
agents, as revealed by PET imaging of radiolabeled antibodies and folates, which visualized only tumor 
sites (reviewed in [42]). Further, on-target toxicity has not been observed in animals or humans treated 
with aFR targeted agents [43], as detailed further below. Because of this polarized luminal surface 
expression, healthy tissue sites expressing low levels of aFR are also not expected to be attacked by T cells 
recognizing surface αFR protein via a CAR. 
1.1.4 Rationale for using lentivirus vector 
A self-inactivating lentiviral vector (LV) will be used to transfer the CAR constructs into autologous T 
lymphocytes by ex vivo transduction. Lymphocytes will be isolated from leukapheresis product by 
elutriation and transduced with the LV. Lentiviral vector-mediated transduction of T lymphocytes isolated 
from the peripheral blood has been previously tested in other clinical trials to date by our UPENN group 
and other investigators.  
 
For an increased safety of T cell products modified by LV transduction, FDA recommends that patients 
with chronic infections (HIV, HBV, and HCV) be excluded. The main rationale for this exclusion was that 
these viruses may get co-activated during the manufacturing process and contaminate the T cell product; 
additionally, chronic infections can serve as trigger for autoimmunity and thus, ex vivo activation and 
expansion of T cells from patients with chronic infections may enhance the frequency of autoimmune T 


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cells in the T cell product and potentially result in autoimmunity.  Developing autoimmunity may not be 
an important consideration in cancer patients; however, this would make efficacy data interpretation 
challenging (biased toward increased efficacy). Additionally, patients with chronic infections have 
compromised immune system and T cell biology, and we think this patient subpopulation would not 
accurately reflect the safety profile of genetically modified T cells.  Moreover, this patient subpopulation 
may introduce outliers from the manufacturing feasibility perspective. The variations that these patients 
may introduce in the data analysis can be studied in a follow-up study following the establishment of the 
safety profile for CAR modified T cells.  
 
In collaboration with VIRxSYS, UPENN investigators performed the first trials using autologous T 
lymphocytes transduced with LV in HIV subjects; these were carried out at the UPENN under the direction 
of Dr. Carl June. No serious adverse events related to the infusion of these modified cells were found 
during the studies [44, 45]. Moreover, no adverse events related to LV transduction were noted on long-
term follow-up of 65 subjects administered 263 infusions with some being followed for over 8 years [46]. 
Another trial for HIV subjects and a number of others in cancer patients have been opened at UPENN and 
no adverse events related to the use of LV in T cells have been noted to date. To our knowledge, no such 
events have been reported by other investigators either.  
1.1.5 Lymphodepletion  
Adoptive immunotherapy strategies may be able to capitalize on homeostatic T cell proliferation [47], a 
recent finding that naive T cells begin to proliferate and differentiate into memory-like T cells when total 
numbers of naive T cells are reduced below a certain threshold [48, 49]. Lymphodepletion eliminates 
regulatory T-cells and other competing elements of the immune system that act as “cytokine sinks”, 
enhancing the availability of cytokines such as IL-7 and IL-15 [50]. This hypothesis has been tested clinically 
in patients with metastatic melanoma refractory of conventional treatments [51]. The patients received 
a lymphodepleting conditioning regimen consisting of cyclophosphamide (60mg/kg x 2 days) and 
fludarabine (25 mg/m2 x 5 days) prior to adoptive transfer of T cells. Patients with myeloma, NHL, and CLL 
have been treated with infusions of ex-vivo co-stimulated and expanded autologous T cells after 
lymphodepleting chemotherapy, and observed improved engraftment [9, 11, 20, 52, 53].  
 
Although it is fairly well established that lymphodepleting chemotherapy aids in the engraftment of 
infused T cells, it is not clear that lymphodepletion is absolutely required for effective T cell therapies, 
particularly when the T cell product is optimally cultured and has adequate potency. Lymphodepletion 
has been established in trials of infusions of tumor-infiltrating T cells (TILs) that have been extensively 
cultured in vitro prior to infusion; TILs are likely much less potent T cells for several reasons: 1) their T cell 
receptors are generally of low-avidity, 2) they have had prolonged exposure to antigen both in the host 
prior to harvesting and in the laboratory, 3) the culture conditions in the laboratory have made them 
dependent on big concentrations of cytokines, and 4) they are exhausted and have minimal proliferative 
potential. In our studies of RNA electroporated biodegradable anti-mesothelin CAR in T cells (14 subjects), 
we have seen transient responses even in the absence of lymphodepleting chemotherapy, despite the 
lack of proliferative capacity of the active cell product.  
 
Lymphodepleting chemotherapy has been used on nearly all CAR T cell clinical trials. While initial studies 
allowed investigators to choose different chemotherapy regimens for different patients based on their 
prior treatment histories, more recent studies have been more prescriptive with the recognition that the 
lymphodepletion regimen affects clinical activity and toxicity. For example, Turtle et al. compared results 
obtained in sequential cohorts of non-Hodgkin lymphoma patients treated with a CD28-based second-
generation anti-CD19 CAR following cyclophosphamide with or without fludarabine (Cy vs Cy/Flu) [54]. 


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Subjects receiving Cy/Flu were more likely to have a complete response (50% vs 8%) and exhibited more 
robust in vivo proliferation and more durable in vivo persistence. Cy/Flu was also associated with higher 
frequency of severe CRS and neurotoxicity, though this toxicity differential was only apparent in the 
highest cell-dose cohort. These data suggest that fludarabine contributes to in vivo CAR T cell expansion 
and persistence, leading to increased efficacy but also perhaps increased toxicity. However, fludarabine 
is likely just one of many factors (e.g., cell dose, CAR design specifications, target antigen expression, 
disease burden, pre-manufacturing T cell phenotype) contributing to efficacy and toxicity profile of CAR T 
cell treatment regimens. The optimal lymphodepletion regimen likely varies by CAR T cell product and 
clinical setting and will need to be determined empirically through clinical investigation. 
 
Cyclophosphamide and fludarabine used in combination with adoptively transferred lymphocytes for the 
treatment of neoplasia induce modulation of several cytokines and homeostatic proliferation of the 
transferred lymphocytes, promotes homing of those lymphocytes to secondary lymphoid organs, and 
contributes to in vivo T cell persistence.  This provides a rationale for combining adoptive immunotherapy 
with chemotherapy [55, 56]. The main goal of using both cyclophosphamide and fludarabine is to achieve 
lymphodepletion that may enhance engraftment of adoptive T cells, while minimizing complications from 
neutropenia/myelosuppression.  Based on previous experience in our CAR T cell program, we plan to use 
the approved doses for both cyclophosphamide and fludarabine in this trial.    
1.1.6 Local versus systemic administration of CAR T cells  
The route of CART administration is an area of interest [57, 58] due to the finding that trafficking of CART 
cells to solid tumors is limited [59]. We previously showed that local intratumoral administration of anti-
aFR CAR T cells in mice bearing subcutaneous ovarian cancer is superior to systemic intravenous 
administration [17].  Similarly, a paper published by Memorial Sloan Kettering Cancer Center indicates 
that intrapleural (IP) delivery of anti-mesothelin redirected CAR T cells in mice is superior to systemic 
delivery [57]. This publication was followed by opening of a clinical trial testing the safety of anti-
mesothelin redirected CAR T cells (iCasp9M28z T cells) with or without cyclophosphamide preconditioning 
(1.5 g/m2) in patients with malignant pleural disease from mesothelioma, lung cancer, or breast cancer by 
intrapleural administration (NCT02414269). Other studies are also testing the merits of local/intratumoral 
route of administration (NCT02498912, NCT01818323) of CAR T cells in solid tumors. As indicated above, 
in a clinical trial conducted by Canevari and colleagues in the 1990s, activated T cells armed with an aFR-
specific bispecific antibody were safely delivered into the peritoneal cavity of patients with recurrent 
ovarian cancer with 27% of evaluable patients experiencing cancer regression [60].  In addition, in a 
preclinical ovarian cancer xenograft model, we have shown that local delivery of MOv19-BBz CAR T cells 
results in enhanced and more rapid antitumor activity (Figure 8, Section 1.3.1, below), compared to 
systemic administration [17]. Similarly, intraperitoneal injection of EpCAm specific CAR T cells was  
recently shown to be effective in mediating antigen-specific killing of human ovarian cancer cells in vivo 
in a preclinical xenograft model [61]. 
 
Thus, we propose to test the safety and efficacy of IP CAR T cell administration, test the CART escape and 
persistence into the blood, and directly compare to the same parameters in the presence or absence of 
lymphodepleting cyclophosphamide + fludarabine as a preconditioning regimen at the same T cell dose.  


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1.2 Pharmacology of modified T cells 
1.2.1 Mechanism of action  
Redirected T cells have been shown in experimental models to bind to cells that express the target 
antigen. Over the past decade, CARs directed against a wide variety of tumor antigens have been 
developed [62, 63]. In the case of MOv19-BBz CAR T cells, they specifically and efficiently lyse aFR-
expressing tumor cells (Figure 5 middle graph). Furthermore, MOv19-BBz CAR T cells engraft and 
eradicate aggressive aFR-expressing tumor cells in immunodeficient mice (Figure 7-8, below). There are 
however several potential limitations to the CAR T cells: 1) the tumor must express the target antigen on 
the cell surface; 2) large amounts of shed or soluble antigen may inhibit the CAR T cells; 3) the chimeric 
receptor may be immunogenic, resulting in the elimination of the redirected T cells by the host immune 
system, even though the CAR structure of completely human sequences minimizes its immunogenicity. 
Indeed, anti-aFR specific antibodies (MOv18) and CAR T cells using mouse derived scFvs have been shown 
to induce humoral immune responses that dampen their activity [60, 64].   
 
It is possible that lymphodepletion as administered to subjects in Cohorts 2 and 3 will aid in T cell 
engraftment. Our hypothesis is that T cell engraftment and persistence of MOv19-BBz CAR T cells will 
correlate with anti-tumor efficacy.  
1.2.2 Absorption, distribution and metabolism  
Lymphocytes have complex trafficking and survival kinetics, and after adoptive transfer several fates have 
been demonstrated: 1) margination; 2) exit from the peripheral blood with trafficking to lymphoid tissues; 
and 3) death by apoptosis. Following an intravenous dose, retrovirally modified and adoptively transferred 
T cells have been shown to persist in the circulation for at least 10 years in immunodeficient SCID patients 
due to the replicative competence of T cells [65]. Human CD8 CTLs have an elimination half-life from the 
peripheral blood of about 8 days, and this increases to about 16 days when low doses of IL-2 are given 
[66]. In patients with HIV infection, it has been found that the mean half-life of lentivirally modified CD4 
T cells in the circulation of 17 patients following a single infusion was 23.5 (± 7.7) days in patients [67]. 
Adoptively transferred human T cells have been shown to traffic to tumor and secondary lymphoid tissues 
[51, 66, 68, 69].  Only limited studies are available with CAR T cell infusions in humans with cancer, and 
the survival of intravenously infused cells has been disappointing with most of the cells disappearing in a 
few days in the reported studies [70], with the notable exception of the CART19 cells that we recently 
reported [9, 11, 18, 20]. Additionally, our current experience with a different CAR T cell product targeting 
EGFRvIII antigen in glioblastoma patients indicates that genetically redirected T cells are detectable in the 
brain of treated patients at more than 6 months post-infusion.  Alternatively, our recent clinical 
experience with a murine scFv based anti-mesothelin CAR product in patients with mesothelin-expressing 
tumors showed that the mesothelin CAR T cells were detectable up to, but not more than, one month 
after infusion. Some patients developed human anti-mouse antibody responses, suggesting that an 
immune response against the CAR T cells might account in part for the lack of longer CAR T cell persistence. 
These data indicate that CAR T cells have the potential to be long lasting in vivo without safety concerns.  
1.2.3 Drug interactions  
Autologous aFR specific CAR T cells are expected to retain many of the properties of natural polyclonal T 
cells. As such, they will be expected to be inhibited by immunosuppressive agents such as corticosteroids, 
immunophilins such as cyclosporine and tacrolimus, methotrexate, mycophenolate mofetil, 
alemtuzumab, daclizumab, ontak, and mTOR inhibitors such as rapamycin. Corticosteroids were able to 
eliminate human engineered T cells in two different trials [71, 72], and to block effector function in our 


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CART19 trial [11]. Lymphocytes are especially susceptible to cytotoxic and chemotherapeutic agents that 
are commonly administered for hematologic malignancies such as cyclophosphamide and fludarabine. 
1.2.4 Immune elimination 
It is likely that MOv19-BBz CAR T cells will be immunogenic because of epitopes derived from the mouse 
scFv and new epitopes that are created at the fusion joint of human signaling domains that are not 
normally juxtaposed.  Immunogenicity of the CAR could lead to the rejection of the adoptively transferred 
T cells. The basis for this supposition is that human retrovirally-modified CTLs expressing a fusion protein 
consisting of hygromycin:HSV thymidine kinase were eliminated by host CTLs in patients with advanced 
HIV infection[73]; importantly, this immune mediated elimination was not accompanied by adverse 
effects and required 6 to 8 weeks to occur. Multiple other studies report CAR T cells elimination possible 
by immune mechanisms, most of them testing CAR constructs based on mouse sequences [64, 71, 74]. 
Indeed, early first generation aFR CAR T cells that used the MO18 scFv was shown to be immunogenic and 
elicit CAR specific serum Ig responses [64]. 
 
At UPENN, we have treated more than 29 patients with CAR T cells targeting mesothelin. The construct 
used in these studies was based on a mouse derived scFv (SS1) and thus, CAR T cells were expected to be 
rejected by humoral and /or cellular immune mechanisms.  Our data to date indicate that CART-meso 
cells (ss1 construct) were able to persist transiently, but did not persist more than 28 days post-infusion 
(for lentivirus transduced T cells). Lymphodepleting chemotherapy as a preconditioning regimen may 
increase the persistence of the infused CAR T cells that contain mouse sequences.  
1.3 Main Investigational Agent 
The investigational agent in this protocol is MOv19-BBz CAR T cells, which are autologous T cells 
transduced with chimeric antigen receptor (CAR) composed of the MOv19 anti-alpha folate receptor 
specific scFv fused to 4-1BB and TCRzeta signaling domains (Figure 2).  MOv19-BBz CAR T cells will be 
manufactured using the lentiviral transduction platform, the same as multiple other investigational 
cellular products tested at UPENN. The same technology that is used to transduce CART19 cells will be 
used to transduce MOv19-BBz CAR T cells (lentiviral transduction). The MOv19 scFv with specificity for 
aFR is derived from the murine MOv19 antibody developed by our research collaborators, Drs. Silvana 
Canevari and Mariangela FIgini [75]. The scFv redirects specificity of the transduced T cells to aFR 
expressing cells [17]. The intracellular signaling domain of the CAR molecule is comprised of the TCRζ  and 
4-1BB signaling modules previously tested in clinical studies [18, 19, 76, 77], both entirely of the native 
human sequences. The CAR receptors are “universal” in that they bind antigen in an MHC-independent 
fashion, thus, one receptor construct can be used to treat a population of patients with aFR antigen-
positive tumors. 
 
The engineered T cells will be manufactured at the UPENN Clinical Cell and Vaccine Production Facility 
(CVPF). At the end of cell cultures, the cells are cryopreserved.  
1.3.1 Preclinical data  
This section provides information regarding the design and scientific rationale for testing the MOv19-BBz 
CAR T cells in humans. The anti-alpha folate receptor CAR construct was generated in the Powell lab [17]. 
The MOv19 antibody was isolated from mice immunized with human cancer by Silvana Canevari and 
Mariangela Figini and shown to bind specifically to aFR [75]. The MOv19 scFv was subsequently cloned by 
the same group [78].  
 


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An extensive literature supports the use of engineered T cells for tumor immunotherapy in rodent tumor 
models [79-83]. Others have used soluble bispecific antibody comprised of an anti-CD3 antibody fused to 
the MOv19 antibody, which is functionally similar to the MOv19 scFv construct contained in the aFR CAR, 
to treat cancer patients with aFR-positive tumors, and found the compound to have adequate safety and 
some clinical activity [84]. Similarly, naked anti-aFR specific monoclonal antibody (Farletuzumab; MORAb-
003) has been tested in Phase I, II and III studies with some clinical efficacy and a favorable toxicity profile 
[85, 86]. The incorporation of signaling modules such as CD28 and 4-1BB in T body constructs increases 
potency of the engineered T cells in pre-clinical studies [87-92]. Over the past decade improved T cell 
culture systems and T cell transduction conditions have been developed [93, 94]. The T-cell culture 
systems have been tested in phase I/II trials in patients with HIV infection and hematologic malignancies. 
The culture systems use anti-CD3 and CD28 costimulation and have proven to be efficient and feasible for 
large scale manufacturing, thereby overcoming a major barrier to adoptive immunotherapy. No significant 
safety concerns have emerged with well more than 1000 patients treated to date with CD4 and CD8 T 
cells, with and without genetic engineering with retroviral vectors [44, 52, 53, 95-100].  
 
 
 
 
 
 
 
 
 
 


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1.3.2 Clinical data to date 
 
CAR cells directed to alpha folate receptor 
Early on in the development and testing of CAR T cell therapy, FRα emerged as an attractive target utilizing 
the chimeric antibody receptor (CAR)-T lymphocyte approach. In one of the first phase I studies of CAR T 
cells for cancer, patients with heavily pretreated ovarian cancer received adoptive transfer therapy using 
autologous or allogeneic MOv18-z aFR CAR T cells in combination with high dose Interleukin-2 (IL-2) [64]. 
This trial consisted of two arms, the first which received three cycles of escalating doses of CAR T cells 
expanded with aCD3 Ab and IL-2 for doses of 3 x 109, 1 x 1010 and 3-5 x 1010 respectively, combined with 
systemic IL-2.  The second arm received 1-2 cycles (depending upon the number of cells available) of cells 
expanded with allogeneic PBMCs and IL-2, followed by allogeneic stimulation in vivo with live unirradiated 
PBMCs. Doses ranged from 4-169 x 109 cells, and two of six patients received 2 cycles. Cells were modified 
using a clinical retroviral vector provided by Cell Genesys containing the neomycin resistance gene, and 
were selected for using G418 after transduction.  Grade 3 and 4 adverse events were observed in Arm 1, 
but were attributed to IL-2 administration.  No serious adverse events were attributed to CAR T cell 
administration.  Persistence of modified cells was poor, rapidly declined and did not exceed 3 weeks.  No 
effect on tumor, as measured by imaging and CA-125 antigen was observed in all patients likely resulting 
from the poor CAR expression, poor in vivo persistence and poor function.  In hindsight, the poor clinical 
results appeared to be explained by technical limitations in the study, such as low expression of the CAR 
construct due to the use of suboptimal gene transfer systems, and the short persistence of the transferred 
CAR T cells due to the absence of costimulatory domains in the CAR construct. Our preclinical results 
(Section 1.4) show that these limitations can now be overcome with the use of recombinant viruses for 
efficient gene transfer and the incorporation of a 4-1BB costimulatory domain into the intracellular tail of 
the aFR CAR construct [17].   
 
Targeting aFR with antibodies, antibody-drug conjugates, and T cells 
Various strategies used in the clinic for targeting the aFR protein in ovarian cancer has been reviewed [43]. 
A summary of the published results is provided in this section.  
 
The safety of targeting αFR has been demonstrated by naked antibody therapy (farletuzumab) or radio-
immunotherapy clinical studies, where toxicity has been generally low-grade and medically manageable 
[103]. Farletuzumab was also well-tolerated as single agent, without additive toxicity when administered 
with chemotherapy [104]. Similarly, combination farletuzumab/carboplatin/pegylated liposomal 
doxorubicin therapy was generally well tolerated, with no farletuzumab-related grades 3-4 adverse events 
[105]. In a Phase III randomized trial of farletuzumab at two doses versus placebo in 1100 women with 
ovarian cancer, the overall safety profile was comparable across all treatment groups, with no new safety 
signals identified in this study population [106].  
 
In an antibody-guided radio-immunotherapy study, there was no on-target toxicity observed in 16 ovarian 
cancer patients treated with a single i.p. dose of 131I-MOv18 but complete response (CR) was observed in 
five patients, no change (NC) in six patients, and progressive disease (PD) in five patients [107]. 
Unfortunately, these agents exhibited only modest single-agent activity and neither demonstrated 


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meaningful efficacy over chemotherapy alone when evaluated as part of combination regimens in Phase 
III trials. 
 
The differential expression of aFR and its ability to internalize large molecules made the receptor well-
suited for antibody-drug conjugate based therapeutic strategies. Antibody or folate conjugates targeting 
aFR have shown a similar safety profile in clinical trials.  In phase I and phase I/Ib studies of folate immune 
(EC90 vaccine with GPI-0100 adjuvant followed by EC17, folate-fluorescein), folate immune was shown to 
be safe and well tolerated in patients with recurrent or metastatic RCC, but cancer responses were 
minimal [108, 109]. No dose-limiting toxicities were observed in the phase I/Ib study, and only 2 dose-
limiting toxicities (DLTs) were observed in the Phase I trial: one hypersensitivity reaction (owing to an 
impurity in the batch of vaccine) and one case of acute pancreatitis, which are unrelated to the aFR target 
[108, 109].  
 
More recently, dose-escalation in the first-in-human Phase I trial was completed [110].  This study 
included 44 individuals with aFR-positive solid tumors.  Dose-limiting toxicities included grade 3 
hypophosphatemia and grade 3 punctate keratitis.  The principal treatment-related adverse effects 
included fatigue and diarrhea, with the majority of cases being mild (grade 1 or 2) and readily managed 
without requiring discontinuation of treatment.  Grade 1 or 2 peripheral neuropathy was also seen, likely 
a consequence of the maytansinoid payload.  Dosing was changed to utilize adjusted ideal body weight, 
after which the visual and corneal abnormalities were generally grade ≤2 and felt to be off-target and 
potentially associated with the payload.  The strongest signals of clinical benefit were seen in patients 
with epithelial ovarian cancer, prompting an expansion cohort in this population.  The phase I expansion 
study of the FRα-targeting antibody-drug conjugate mirvetuximab soravtansine (IMGN5=853; a 
humanized anti-FRα antibody linked to the maytansinoid DM4) in 27 women with heavily pre-treated 
ovarian cancer showed a confirmed objective response rate (ORR) of 22%, including two complete 
responses and four partial responses [111]. Adverse events were generally mild (≤grade 2) with 
keratopathy (48%), fatigue (44%), diarrhea, and blurred vision (each 37%) being the most common 
treatment-related toxicities. These toxicities were associated with action of the DM4 toxin, and were 
unrelated to aFR expression in those sites. One patient experienced grade 3 hypokalemia. Low-grade 
pneumonitis was observed in a small number of patients; grade I (n= 3; 11.1%) and grade II (n= 1, 3.7%), 
as was headache; grade I (n= 4; 14.8%) and grade II (n= 1, 3.7%).  Of note, superior efficacy measures were 
observed in the subset of patients with the highest FRα levels in their tumor (ORR, 31%; progression-free 
survival, 5.4 months), which rationalizes the prescreening and selection of patients with tumors having 
baseline aFR expression prior to administration of aFR targeted therapies. 
 
Patient T cells that target aFR have been administered in clinical trials of adoptive T cell transfer for ovarian 
cancer with promising results reported. A bispecific antibody approach for FRα-directed autologous T cells 
targeting FRα and CD3 in combination with IL-2 provided promising data for adoptive T cell transfer 
approaches [60, 84]. Patient T cells were activated outside of the body, and then armed with F(ab')2 
fragments of the bispecific monoclonal antibody (MAb) OC/TR which is directed to the CD3 molecule on 
T lymphocytes and to the folate receptor on ovarian carcinoma cells. Intraperitoneal (IP) delivery resulted 
in significant clinical responses with a toxicity profile most related to IL-2 administration. Of the 19 
patients evaluated by surgery and histology, three showed complete response, one showed complete 
intraperitoneal response with progressive disease in retroperitoneal lymph nodes, three showed partial 
response, seven had stable disease, and five had progressive disease. The overall intraperitoneal response 
rate was 27% (95% confidence interval [CI] = 10%-44%).  
 


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1.4 Toxicities associated with CART cells 
1.4.1 Fatal SAEs with CARs  
Two studies have reported fatal SAEs following CAR infusion in patients with malignancy.  Brentjens et al 
designed a retrovirally-transduced CAR against the CD19 molecule for patients with B cell lymphoma 
[112]. The CD19 CAR was the second generation design containing CD28 and CD3ζ signaling domains. A 
total of 7 subjects have been treated on this protocol, 6 without SAE. However, subject four in this study 
was a 69 year old man with refractory CLL and who had a significant past medical history of myocardial 
infarction, coronary artery disease, hypertension, and chronic renal failure. This was the 4th patient in the 
study and the first one on the cohort undergoing lymphodepletion. This subject received pre-T cell 
conditioning with 1.5g/m2 of cyclophosphamide followed 2 days later by infusion with genetically 
modified CD19 CAR T cells at 1.2-3x107 cells/kg. Twenty hours following T cell infusion, the patient 
developed persistent fever (transient fever was observed in the first 3 subjects on the study too) and 
hypotension that was rapidly followed by respiratory distress despite negative chest x-ray, hypoxemic 
respiratory failure, and acute renal failure. The family decided to remove further life sustaining therapies 
and the patient expired 44h post-T cell infusion. The post-mortem pathology report failed to support a 
diagnosis of tumor lysis syndrome as the primary source of renal failure. Analysis of serum cytokines 
revealed elevated levels of IL-2, IL-7, IL-15, and IL-12 following cyclophosphamide therapy which may have 
been secondary to a prior subacute infection exacerbated by the immune suppression associated with 
cyclophosphamide-mediated lymphodepletion.  The authors concluded that concomitant sepsis was the 
most likely cause of death and attributed the etiology of the death as “possibly related” to CAR T cell 
infusion [112].  
 
The second case of a fatal SAE related to CAR T cells was reported by the NCI group [113]. This study 
attempted to treat cancer patients with overexpressing ERBB2 tumors with an anti-ERBB2 CAR of 3rd 
generation (containing CD28, 41BB and CD3ζ signaling domains). The first subject in the study was a 39-
year-old female with colon cancer metastatic to lungs and liver. The patient received lymphodepleting 
regimen (60mg/kg cyclophosphamide daily for 2 days followed by fludarabine 25mg/m2 for the next 5 
days) followed the next day by retrovirally-transduced 1010 ERBB2 CAR T cell (transduction efficiency 79%). 
At 15min post-infusion, the patient began to develop dyspnea and hypoxia with pulmonary infiltrates on 
chest x-ray. The patient progressed into hypoxemic respiratory failure requiring mechanical ventilatory 
support, vasopressor-dependent hypotension, and cardiopulmonary arrest. The patient was initially 
resuscitated and started on high dose steroids, but despite aggressive supportive care, the patient expired 
5 days after infusion. Serum cytokine measurements demonstrated a dramatic rise in pro-inflammatory 
cytokines (IFN-γ, TNF-α, IL-6, GM-CSF) within 4 hours of infusion consistent with a cytokine storm initiating 
multi-system organ failure. Dr. Morgan postulates that upon first pulmonary circulation passage [113], 
the CAR ERBB2 T cells bound to native low level expression pulmonary epithelial cell ERBB2 proteins [114], 
leading to CAR activation and pulmonary microvascular injury.  
 
Other fatal SAEs have been reported.  Two events occurred in April 2014 at the Memorial Sloan Kettering 
Cancer Center using CD19 specific CAR redirected T cells [115]. Fatal events have occurred at the 
University of Pennsylvania using CART-19 T-cells (a CD19-specific CAR using a lentiviral vector) in patients 
with acute lymphoblastic leukemia (ALL).  Three of the first six adult ALL subjects infused on UPCC21413 
died as a result of refractory Cytokine Release Syndrome (CRS) in the setting of intercurrent infections. 
Thereafter, the single dose administered in UPCC21413 was reduced to 1-5x107 CART19 cells. In the next 
six adult ALL subjects treated at the de-escalated dose, two died from an intracranial bleed and sepsis, 
respectively.  


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In July 2017, the FDA initiated the clinical hold of Juno’s Phase II clinical trial of their CD19 CAR product 
(JCAR015), known as ROCKET, in adult relapsed or refractory B cell acute lymphoblastic leukemia after 
two patient deaths from cerebral edema that appear to be treatment-related [116]. This followed an early 
death that was determined to be due to confounding factors. The fludarabine preconditioning regimen 
was proposed as the problem, since cerebral edema as a toxicity was not prevalent in JCAR015 with 
cyclophosphamide preconditioning only. 
 
In December 2017, another fatal event occurred in a mesothelioma patient treated with investigational 
CART cells targeting mesothelin. At 2 days after infusion, the patient developed respiratory distress 
progressing to hypoxemic respiratory failure not responding to standard of care treatment, and expired 
5 days after the infusion. The investigation on this event is ongoing.  
1.4.2 Non-fatal SAEs 
Our group at UPenn experienced one life-threatening SAE of anaphylaxis following intravenous (IV) 
infusions of autologous T cells expressing an anti-mesothelin CAR. In that case, the subject was 
administered repeated doses of the same product, and upon infusion of the 3rd dose following a rest 
period, he developed an allergic (anaphylaxis) response to the T cell product. The results of this 
investigation were published [117].  
 
As of December 2021, we have administered 1.4 x 107- 1.1x109 autologous CART-19 cells into over 500 
patients on multiple clinical studies conducted at Penn and the Children’s Hospital of Philadelphia under 
the University of Pennsylvania 
 and 
  
Subjects experienced manageable toxicities mostly related to tumor lysis syndrome, cytokine release 
syndrome (CRS), and macrophage activation syndrome (MAS), and the expected on target toxicity of B 
cell aplasia.   Tumor lysis syndrome is related to the type and burden of disease and is more frequently 
encountered in hematologic malignancies than solid tumors. MAS appears to be a reaction to immune 
activation that occurs from the CRS, and therefore should be considered a manifestation of CRS.  
 
A more detailed presentation of the CRS /MAS clinical manifestations and subject management is 
provided in Sections 1.6 and 5.3.1.4. 
1.5 Trial Rationale 
Immunotherapy is a novel and promising approach for the treatment of solid tumors; immunotherapy 
with CART cells in particular has the potential advantage of targeted therapies that can invoke a rapid 
tumor response, and the advantage of long-lived responses that are the hallmark of engagement of the 
adaptive immune system such as memory T cells.  
 
This Phase I study poses the hypothesis that targeting the aFR antigen that is widely and frequently 
expressed in multiple tumor types, particularly epithelial ovarian cancer, will be safe, feasible, and result 
in anti-tumor responses. Furthermore, this study addresses the questions of whether lymphodepletion is 
necessary for engraftment and persistence of MOv19-BBz CAR T cells in patients with solid tumors, and 
whether intraperitoneal administration is safe and feasible.  


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1.6 Potential risks and benefits  
1.6.1 Risks of MOv19-BBz CAR T cells 
This protocol is designed to determine the safety and feasibility of intraperitoneal administration of 
permanently modified CAR T cells that target alpha folate receptor.  MOv19-BBz CAR T cells will be given 
as a single agent alone or in combination with a lymphodepleting dose of cyclophosphamide + fludarabine. 
Given that the patient populations recruited for this protocol have limited therapeutic options, we believe 
that the below risks are acceptable.   
 
MOV19-BBz Expected Adverse Events 
Our current safety experience with MOv19-BBz CAR T cells is included in Table 1-1 below. 


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Off-tumor on-target toxicity  
We expect minimal toxicity based on the restricted polarized expression of aFR which distributes in the 
luminal surface of tubular epithelium of the kidney, bronchial airway epithelium, choroid plexus, and 
placenta.  This is further supported by previous clinical safety data specifically with aFR specific 
immunochemotherapy conjugates, antibody drug conjugates, radioimmunotherapy conjugates, with 
bispecific antibody redirecting T cells to alpha folate receptor and engineered T cells recognizing alpha 
folate receptor (reviewed in [43]).  In spite of this luminal expression, the primary off-tumor on-target 
toxicity that may be anticipated is that engineered T cells will cause damage to sites of aFR expression 
including the bronchial epithelium, renal tubules, the choroid plexus, intestinal brush-border membranes, 
salivary glands, parathyroid and type 1 and type 2 pneumocytes of the lung.   
 
The risk of pneumonitis resulting from involvement of the bronchial epithelium is anticipated to be lower 
than that of IV administration. 
 
Evidence of on-target adverse events and immunopathology has not been reported in trials of various aFR 
targeted agents conducted over more than two decades.  Section 1.3.2.2 describes a recent phase I 
expansion study of a FRα-targeting antibody-drug conjugate, wherein adverse events were generally mild 
and unrelated to aFR targeting, however, low-grade pneumonitis was observed in a small number of 
patients; grade I (n= 3; 11.1%) and grade II (n= 1, 3.7%), as was headache; grade I (n= 4; 14.8%) and grade 
II (n= 1, 3.7%) [118]. While the mode of action resulting in these adverse events is not known, these are 
sites of aFR expression. As our CAR T cell approach is different in mode of action from the antibody drug 
conjugate, off-tumor toxicity may be expected.  
 
There are two forms of “on-target” toxicity attributable to CAR T cells, one with rapid onset that results 
from synchronized activation of CAR T cells occurring during first pass through the vasculature, and 
another one that is dependent on biodistribution of CAR T cells trafficking to sites of antigen, a process 
that does not occur for at least 24 hours after infusion. The fatal case at the NCI was attributed to 
synchronous activation of 1010 CAR T cells encountering the specific ERBB2 antigen upon passing through 
the pulmonary capillary bed that resulted in rapid and profound systemic cytokine release following 
intravenous infusion [113]. We think that this scenario is not expected for MOV19-BBz CAR T cells, as aFR 
is expressed on the apical surface of vascular endothelial cells of the lungs and unavailable to aFR targeted 


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agents, and the biodistribution of CAR T cells administered into the peritoneal cavity will reduce lung 
accumulation and preferentially accumulation in tumor. The second type of toxicity reported with CAR T 
cells is consequent to cells trafficking following initial biodistribution and encountering cognate antigen 
on normal tissues. This kind of toxicity develops with delayed kinetics and in a non-synchronous fashion.  
 
This type of toxicity developed 4-7 days after infusion of anti-CAIX CAR T cells upon activation by antigen 
present on bile ducts, and was easily managed with a short course of adrenal corticosteroids (Lamers et 
al., 2006, Lamers et al., 2011). aFR is reported to be expressed in the bronchial epithelium, renal tubules, 
the choroid plexus, intestinal brush-border membranes, salivary glands, thyroid and type 1 and type 2 
pneumocytes of the lung, thus the encounter of the antigen requires MOV19-BBz CAR T cells to traffic to 
these sites. Given the known aFR distribution (i.e. not expressed within the vascular system) and safety of 
aFR targeted approaches to date, we do not anticipate immediate toxicity, but rather only the potential 
for delayed toxicity that may become evident several days post-infusion.  
 
Of note, in our UPENN studies testing autologous T cells re-directed to mesothelin with an anti- 
mesothelin CAR (SS1 scFv), we have not observed any significant serosal toxicity (pleuritis, peritonitis, 
pericarditis).   
 
Management. In the event of aFR  reaction on normal tissue and inflammatory process leading to fluid 
accumulation, these cavities can be quickly and readily accessed in a minimally invasive fashion to 
remove the fluid as anti-lymphocyte therapy is initiated. T cell ablating therapies including 
corticosteroids, chemotherapy such as cyclophosphamide, or immunotherapy such as alemtuzumab 
may also be considered at the investigators’ discretion. 
 
Robust (but not leukemogenic) T cell proliferation  
Participation in this study will expose the patient to genetically engineered autologous T cells. The 
signaling domains in the CARs could mediate uncontrolled T cell proliferation; however, we have not 
observed this toxicity in our pre-clinical models or other UPenn clinical trials. In the context of this 
protocol, it is possible that the T cells will proliferate in response to signals from the aFR expressing cancer 
and normal cells. This could be beneficial or harmful depending on the extent and the nature (local or 
generalized) of proliferation.  
 
Management. In this case, corticosteroids and chemotherapy would be given to eradicate the CAR 
cells; this has worked in previous cases [71]. T cell ablating therapies including corticosteroids, 
chemotherapy such as cyclophosphamide, or immunotherapy such as alemtuzumab may also be 
considered at the investigators’ discretion. Leukemogenic T cell proliferation which is uncontrolled, 
clonal, and potentially related to insertional mutagenesis from transduction is discussed under 
“Clonality and insertional oncogenesis” below. Robust T cell proliferation can be associated with 
cytokine release syndrome.  
 
Cytokine release syndrome (CRS)/Macrophage Activation Syndrome (MAS)    
An expected toxicity of cell therapies in general is CRS. Subjects treated with CART19 therapy at UPenn 
have often developed a CRS and MAS. The risk factors for development of these syndromes are still under 
investigation, but high baseline tumor burden was shown in ALL to be a risk factor [119]; it is not yet clear 
whether this toxicity will be manifested in subjects treated with CARs directed to other antigens such as 
aFR; it is unknown if the manifestations of the CRS in solid tumor subjects will be similar with that in 
CART19 treated subjects. This study will provide such new knowledge; due to the occurrence of severe 


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CRS in CART19 studies, it is therefore considered a possible risk in this protocol. The CRS characteristics, 
CRS grading, and management of CRS in CART19 studies is presented next and can be used to guide the 
PI if such toxicity is to occur in this protocol. 
 
CRS overview: CRS is a potential risk in this study and may result from on-target toxicity, as has been 
observed in other CAR T cell studies. The experience gained from the CART19 studies at UPenn CCI 
indicates that CRS development likely correlates with efficacy, CRS grading directly correlates with tumor 
burden, and kinetics of onset are gradual within days following CART cells infusion. The CRS signature is 
elevation of cytokines, most prominently IL-6, IFN-γ, IL-8, solCD25, solIL6R, solgp130, and, to a lesser 
extent, IL-2, IL-10, and TNF [119]. It is still unknown whether CRS/MAS is beneficial or harmful to the anti-
tumor response. Elevations in clinically available markers of inflammation including ferritin and CRP have 
also been observed to correlate with the clinical CRS syndrome. 
 
CRS clinical manifestations: CRS diagnosis is based on clinical symptoms and events. The CRS typically 
starts with several days of fevers. In all cases, evaluations for infections are done. Fevers tend to be spiking 
and can be associated other clinical manifestations such as fatigue, anorexia, nausea, vomiting, diarrhea, 
myalgias, arthralgias, headache, rash, hypotension (occasionally requiring pressor support), tachypnea, 
hypoxia (occasionally requiring ventilator support), altered mental status including delirium confusion (in 
several patients) and word finding difficulties, evidence of disseminated intravascular coagulation, as well 
as MAS. Additional symptoms of CRS may also include rigors, sweating, dyspnea, and seizures.  In some 
cases, CRS, TLS and hypotension have led to acute kidney injury and several patients have required at least 
transient dialysis. The CRS has been effectively abrogated with anti-cytokine directed therapy, including 
tocilizumab in most patients.  Five patients on CART19 trials at UPENN have died of complications related 
to refractory CRS, in some cases this being associated with concomitant infections.  In addition, it is unclear 
if treating the CRS with anti-cytokine directed therapy adversely impacts the anti-tumor response.  
 
Features consistent with MAS or HLH have been observed in patients treated with CART19, coincident 
with clinical manifestations of the CRS. MAS appears to be a reaction to immune activation that occurs 
from the CRS, and therefore should be considered a manifestation of CRS. MAS is similar to 
Hemophagocytic lymphohistiocytosis (HLH); it is a reaction to immune stimulation by infection, 
autoimmune diseases or other precipitants, but is distinguished from familial or genetically mediated HLH. 
There are no definitive diagnostic criteria for MAS, but it is typically diagnosed by meeting HLH criteria. 
Some but not all features of MAS are typically observed. The clinical syndrome of MAS is characterized by 
high grade non-remitting fever, cytopenias affecting at least two of three lineages, and 
hepatosplenomegaly. It is associated with biochemical abnormalities, such as high circulating levels of 
serum ferritin, soluble interleukin-2 receptor (sCD25), and triglycerides, together with a decrease of 
circulating NK activity. Other findings include variable levels of transaminases up to signs of acute liver 
failure and coagulopathy with findings consistent with DIC. A pathologic feature of MAS is the presence 
of hemophagocytic CD163+ macrophages (HPC) in bone marrow or lymph-node aspirates.  
 
MAS diagnosis is based on the fulfillment of criteria established in 2004 for HLH associated with autosomal 
recessive disorders (familial HLH, fHLH). A diagnosis of non-familial HLH/MAS is made by having 5/8 
criteria:  
• 
Fever 
• 
Splenomegaly 
• 
Cytopenias (affecting 2: 2 lineages in the peripheral blood; hemoglobin <9, plts <100k, ANC <1000) 
• 
Fasting triglycerides 2: 265 mg/dL, Fibrinogen: = 1.5 g/L 


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• 
Hemophagocytosis in bone marrow or spleen or lymph nodes 
• 
Low or absent NK-cell activity 
• 
Ferritin > 500 g/L 
• 
Soluble CD25R > 2400 U/L 
 
Supportive clinical criteria include neurologic symptoms and cerebrospinal fluid pleocytosis, conjugated 
hyperbilirubinemia, and transaminitis, hypoalbuminemia and hyponatremia. Typically high fevers, 
cytopenias, and when performed hemophagocytosis in the bone marrow is observed (though marrow 
specimens at the time of the reaction are not often taken). Soluble CD25R and NK cell activity are not 
standard tests, though samples are taken for retrospective CD25R analysis. Therefore, patients may not 
meet strict definition of HLH/MAS, but given the constellation of findings, and the consistent dramatic 
elevation in Ferritin, this is indeed the reaction associated with the CRS.  
 
In addition, some subjects have become confused and disoriented, have had seizures or have become 
unresponsive.  These side effects may be caused by the CRS and MAS as in most instances, they resolved 
when the CRS was treated. However, one subject experienced a cognitive impairment which took over a 
month to resolve. While this might be a result of the chemotherapy that the individual received, we 
cannot exclude a role of T cells.   
 
Grading of CRS: The Common Terminology Criteria for Adverse Events (CTCAE) grading system was 
originally developed to capture a cytokine syndrome occurring during infusional therapy; therefore, it is 
inadequate to capture the delayed CRS that occurs after CART cells infusions.  The University of 
Pennsylvania has modified the CTC grading specifically to capture toxicity for protocols using CAR T cells. 
MAS/HLH observed signs and symptoms are a manifestation of CRS and will therefore not be graded 
separately (See Table 9-1 in Section 9.2).   
 
Management of CRS is described in Section 5.3.1.4. 
 
Immunogenicity favoring rejection  
Immunogenicity of this CAR construct is not known and thus, immunogenicity will be monitored as a 
secondary exploratory correlative endpoint. MOv19-BBz CAR T cells may be immunogenic due to the 
incorporation of the murine MOv19 scFv into the CAR construct and possible novel epitopes potentially 
created at the juxtaposition of various fragments within the CAR construct. A Mov18 based CAR was 
shown to induce a serum Ig response against the CAR [64]. In case of immune responses directed against 
the CAR constructs, it is expected that MOv19-BBz CAR T cells will be rejected. This rejection has not had 
clinical consequences in previous trials [71, 120].  
 
Anaphylaxis. Anaphylaxis resulting from the infusion of a single dose of lentivirus transduced CAR T cells 
has not been reported to date. Our group at UPENN experienced one life-threatening and related serious 
adverse event of anaphylaxis following intravenous (IV) infusion of autologous T cells expressing the anti-
mesothelin CAR under a separate clinical protocol (UPCC# 17510). This was the 24th infusion of RNA CART-
meso out of a total of 101 infusions administered on three clinical protocols (UPCC#17510, 21211, 08212).  
We have not experienced any other serious adverse events of anaphylaxis. The cell product was prepared 
using RNA electroporation technology rather than vector transduction in order to acquire a transient CAR 
expression T cell phenotype. The SAE was triggered at several minutes after mesothelin-CAR T cell infusion 
and developed into a cytokine storm with high levels of serum IL-6. Of note is that the subject had been 
safely administered two other RNA CART-meso cells infusions 42 days before the one triggering the SAE. 


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The results of our investigations indicated that this was an anaphylaxis reaction mediated by anti-mouse 
antibodies developed following the first two infusions. Due to this incidence and to assure subjects safety, 
we modified our RNA CAR protocols infusion schedule to remove prolonged rest periods between 
infusions, reduce the therapy to one cycle of 2-3 weeks, and exclude subjects who had received products 
of murine origin. Consequently, no other reaction has been noted in a total of 101 infusions of RNA CART-
meso cells. This risk of anaphylaxis is reduced in this protocol due to the administration of one MOv19-
BBz CART cell infusion. If it occurs, anaphylaxis will be managed with epinephrine, volume resuscitation, 
corticosteroids, and other supportive care as needed (oxygen, ventilation, beta2 agonists for 
bronchoconstriction, etc.). 
 
Tumor lysis syndrome (TLS)  
The risk of TLS is dependent on the disease and burden of disease, but in most cases, this risk will be low. 
This generally does not occur in patients with solid tumors. TLS resulting in renal insufficiency, or rapidly 
rising uric acid, or evidence of organ dysfunction will be managed with fluids and rasburicase as clinically 
indicated and determined by the treating physicians; other supportive care as needed.  
 
Neurologic toxicity   
Neurologic toxicity has emerged as a risk of CAR T cell therapy. Neurotoxicity after CAR T cell therapy has 
been described as biphasic, with an initial period of susceptibility occurring amidst systemic CRS and a 
second period of susceptibility occurring days later, often after resolution of CRS [123]. Manifestations 
range from mild, subtle signs such as diminished attention and impaired handwriting to more severe 
abnormalities such as seizure, disorientation, and somnolence. In its most severe form, cerebral edema 
develops and is potentially fatal. Neurotoxicity in the form of encephalopathy along with various focal 
neurological deficits (including word finding) have been observed with CART19. The mechanism 
underlying the neurotoxicity of CAR T cells is uncertain, though the similarity in syndromes observed with 
CARs directed against different antigens argues against a target-specific effect. The link between 
biomarkers of endothelial activation and severe CRS/neurotoxicity suggest that neurotoxicity is mediated 
by cytokine-induced endothelial dysfunction. No mechanism for the neurotoxicity of CAR T cells has been 
definitively established, however, and it is uncertain whether the findings cited here from other CAR T cell 
products can be extrapolated to the CAR T cells employed in this study. 
 
Intraperitoneal access administration of CAR T cells  
Local administration of MOv19-BBz CAR T cells is thought to reduce the risk of CART cells binding to low 
aFR levels that might be present on bronchial epithelium, renal tubules, the choroid plexus, intestinal 
brush-border membranes, salivary glands, thyroid and type 1 and type 2 pneumocytes of the lung and 
thus, decreasing the risk of on-target toxicities.   
 
Because the infusion criteria (Section 6.6) are evaluated immediately prior to cell infusion, one additional 
risk of IP catheter placement is that a subject who is deemed inappropriate for CAR T cell administration 
undergoes catheter placement.   
 


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Intraperitoneal Access. Some subjects with ovarian cancer may already have a catheter in place; 
however, in the event a catheter must be placed for Intraperitoneal (IP) administration, placement of 
the catheter will be performed by Interventional Radiology (IR) on the day of planned MOv19-BBz CAR 
T cell infusion.  Percutaneous techniques will be utilized in this protocol.  Percutaneous insertion with 
radiologic guidance has the advantage of minimally invasive and correct catheter positioning in the 
lower abdomen.  Safely accessing the intra-abdominal space for an individual patient may or may not 
require administration of a small volume of saline or contrast.   
 
Risks associated with the procedure include, but are not limited to, pain or discomfort at the needle 
insertion site, bleeding at the site, internal bleeding, injury to a blood vessel, organ puncture, and 
infection which may result in an infection of the blood stream. The development of any infection may 
result in the need for intravenous antibiotics. X-ray contrast material may be used at the time of 
catheter insertion.  Risks associated with the X-ray contrast material include an allergic reaction. 
Moderate sedation Moderate sedation may be used during the catheter placement.  The medications 
used for the moderate sedation are associated with the risks of aspiration (inhaling food or liquid into 
your lungs) or respiratory depression. In addition to these potential risks associated with the 
procedure, the X-ray contrast material, and the moderate sedation medications, there may be other 
unpredictable risks including death. 
 
Subjects will be asked to sign a standard hospital consent form for this procedure.  The subject will be 
closely monitored during the procedure by the anesthesia team and/or the primary proceduralist’s 
team and subsequently by the research team as per protocol. 
 
Intraperitoneal Administration of CAR T cells. The risk of peritoneal inflammation with IP 
administration is anticipated to be higher than that of IV administration given the direct 
administration into the peritoneal cavity.    
 
Clonality and insertional oncogenesis  
There is a risk that people who receive gene transfer may develop new tumors derived from their 
genetically modified cells. This risk is primarily associated with viral gene transfer vectors that integrate 
into the cellular DNA where they may dysregulate genes controlling proliferation. Transformation has not 
been observed following adoptive T cell transfer in hundreds of cancer and HIV patients receiving gamma-
retroviral modified T cells treated on multiple protocols at many academic centers, and in the 21 HIV 
patients treated with lentiviral modified T cells treated at University of Pennsylvania [44, 45].  Additionally, 
no adverse events have been reported on 65 subjects infused with 263 T cell infusions of autologous T 
cells modified with LV, some of them being followed for over 8 years [46]. 
 
To date, we are not aware that clinically evident insertional mutagenesis of T cells has been reported 
following adoptive transfer of engineered T cells. Lentiviral vectors may have a lower risk than retroviral 
vectors based on several considerations. Monitoring for T cell clonal outgrowth will be performed by Q-
PCR analysis for CAR-expressing cells and/or flow cytometric analysis (if feasible), and by CBC count.  If 
during long-term follow-up ≥ 1% of the subject’s sample is positive for vector sequences by qPCR, then 
the subject will be asked to return for a confirmatory blood test prior to the next study visit.  If ≥ 1% of 
the subject’s sample is positive upon the receipt of the confirmatory qPCR result, then the genomic vector 
integration sites will be determined.  Identified vector integration sites will be evaluated using 
bioinformatics approaches to determine if the integration events are in regions with known relationships 
to human cancers (i.e. near oncogenes).   A summary of any integration site analyses will be presented in 
the annual report to the FDA.  If oligo- or monoclonality of vector integration site is observed, this data 


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will be reported as an informational amendment to the IND with best efforts to submit this amendment 
within 30 days of data confirmation.  
 
Replication-competent lentivirus (RCL)   
It is theoretically possible that RCL may be generated during the MOv19-BBz CAR manufacturing phase or 
subsequently after introduction of vector-transduced cells into the patient. However, our CAR T cell 
manufacturing platform utilizes a third-generation lentiviral vector system that has been designed to 
eliminate such risk, and all viral vectors used for clinical T manufacture are confirmed negative for RCR/L 
via sensitive detection assays as part of vector lot release testing.  As such, RCL has not been detected in 
any of the T cell products or subjects samples tested under IND#14802 to date. This aligns with our 
extensive experience manufacturing lentiviral-transduced T cell products using similar or identical 
lentiviral vector design. As reported by Marcucci et al., 2018, RCR/L has not been detected in any products 
manufactured by UPenn Clinical Cell and Vaccine Production Facility (CVPF) using 17 different clinical 
vector lots under 8 INDs, either by qPCR detection assay or by the biological RCR assay. A total of 375 T 
cell products were included in this analysis, including 351 that were manufactured using third generation 
lentiviral vectors similar to that utilized in the above referenced IND. Since the publication of Marcucci et 
al. 2018, more than 170+ additional lentiviral-transduced CAR T cell products manufactured by UPenn 
CVPF have been tested by qPCR and met the release specification of < 50 average copies VSV-G per μg 
DNA. Five of these were also subjected to biological RCL testing, which confirmed the absence of RCL.  
These findings are confirmed by another publication reporting that 460 transduced T cell Products across 
26 clinical trials were negative for RCR/L (Cornetta, Duffy, Turtle, et al. 2018).  
 
The Marcucci et al. publication also included data from long-term monitoring for vector sequences in 305 
infused subject samples from UPenn clinical trials. No evidence of RCR/L in any of the subject samples 
evaluated was found, with almost 195 years of cumulative post-infusion follow-up time (Marcucci et al. 
2018). Similarly, Dr. Kenneth Cornetta’s group was unable to detect RCL in 296 clinical trial subjects 
screened for RCL post-infusion (Cornetta, Duffy, Turtle, et al. 2018), along with other similar historical 
analyses (Scholler et al. 2012; Mohanlal et al. 2016). To date, there have been no reports of confirmed 
RCR/L-positive results reported in the literature for manufactured T cell products or post-treatment 
patient samples (Bear et al. 2012; Cornetta, Duffy, Feldman, et al. 2018; Cornetta, Duffy, Turtle, et al. 
2018; Marcucci et al. 2018). These data support the overall safety of retroviral and third-generation 
lentiviral vectors in gene therapy clinical trials. 
 
Based on the available clinical data, prospective testing on post-infusion patient samples will not be 
performed as of Protocol V3.  Subject blood samples will be collected and banked at baseline (pre-
infusion) and post-infusion at Months 3, 6, and 12. All archived samples will be stored in temperature 
monitored and alarmed freezers at -80°C. In the event RCL is suspected, these archived samples will be 
used to investigate and perform VSV-G DNA testing. 
 
(False)-Positive HIV test   
If a positive HIV DNA assay result is obtained, the PI will be informed and the subject rescheduled for a 
retest for the DNA test.  If the second DNA test is positive, the patient will undergo a blood draw for 
isolation of HIV from his/her cells.  The virus will be sequenced and compared to sequences of the transfer 
vector and packaging constructs, as well as to available HIV sequences to determine the origin of the virus. 
Determination of the origin of the virus can be easily performed by evaluation for HIV accessory genes 
such as vif, vpr and vpu which are not present in the packaging constructs.  If the sequence is derived from 
wt-HIV then the patient will be referred to an infectious diseases specialist for further evaluation.  If an 


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RCL is confirmed, or the virus cannot be isolated from the blood draw, the patient will be scheduled for 
apheresis and will undergo a full biological RCL testing for detection and/or characterization of the RCL.     
 
Immune response to vector sequences  
It is possible that the subjects may develop an immune response to vector sequences (e.g., VSV-G). This 
may result in rejection of the gene therapy product in the future or limit subjects’ participation in future 
gene therapy studies. 
 
Autoimmune disease   
The use of genetically modified ex vivo expanded T cells could potentially result in the development of 
autoimmune disease(s).   
 
Reproductive risks  
The risks of MOv19-BBz CAR T cells on pregnancy are unknown.  It is possible the cells could cause harm 
to a fetus or children who are breastfeeding.  As such, it is recommended that all subjects of reproductive 
potential use at least one medical acceptable form of contraception for at least 1 year after their CAR T 
cell infusion.   The Investigators are also advised to counsel subjects on the importance of pregnancy 
prevention and the implications of an unexpected pregnancy.   
 
Please refer to Section 4.3 for additional information regarding pregnancy testing and medically 
acceptable birth control methods. 
 
The cells could also affect the fertility of study participants. The Investigators should discuss options for 
fertility preservation, if not already discussed as part of the participants’ routine cancer care. 
1.6.2 Research Procedures 
 
aFR Immunohistochemistry Test Failure 
The risk of a failed aFR immunohistochemistry test (false-positive) resulting in MOv19-BBz infusion in a 
patient with no aFR expression on her tumor is the same as the risks listed above, with the exception of 
TLS and CRS which are not expected due to the lack of tumor antigen expression. 
 
Potential risks of the apheresis procedure include nausea, vomiting, fainting or dizziness, seizures, skin 
rash, hives, flushing, blood loss, and infection. Tingling of the lips, muscle cramping and, very rarely, 
changes in heart rhythm can occur. These can be prevented or made milder by giving calcium 
supplements, either by mouth or in the vein, also called intravenous (IV).  
 


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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, a drug called ACD (acid-citrate-dextrose) 
will be used. This drug 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.  
 
After the apheresis procedure the patient may experience temporary discomfort, including irritation, 
swelling or bruising at the place where the needle was inserted into the vein to collect the blood. 
Apheresis can also occasionally cause hives, numbness and tingling, or swelling of the feet and ankles. 
 
Blood Draws 
Risks associated with blood draws include bruising, swelling, black and blue marks, fainting and/or 
infection at the site.  Rarely, patients may experience anemia from having blood drawn frequently.  
 
Tumor Biopsy 
Risks may differ depending on the type of biopsy performed; however, common side effects may include: 
pain, discomfort, soreness, bleeding, and bruising.   
1.6.3 Risks of lymphodepleting chemotherapy 
 
Fludarabine  
When administered as part of routine care, fludarabine has been associated with myelosuppression (dose 
limiting toxicity), fever, nausea and/or vomiting, skin rashes, myalgia, fatigue, autoimmune hemolytic 
anemia (may be life-threatening), and pulmonary toxicity (both pneumonia and pulmonary 
hypersensitivity reactions have been reported; fatal pulmonary toxicity has been described, especially 
when fludarabine was used in combination with pentostatin). Severe or fatal CNS toxicity presenting with 
loss of vision and progressive deterioration of mental status has been described primarily after high doses 
of fludarabine monophosphate, or at usual doses (25-30 mg/m2) in elderly patients. Very rarely described 
complications include transfusion-associated graft versus host disease, thrombotic thrombocytopenic 
purpura, and liver failure. Tumor lysis syndrome has been observed, especially in patients with advanced 
bulky disease. Opportunistic infections (protozoan, viral, fungal, and bacterial) have been observed. 
Please refer to the package inserts for additional information. We expect similar side effects when 
administered as part of this study.   
 
Cyclophosphamide 
When administered as part of routine care, cyclophosphamide has been associated with 
myelosuppression, hemorrhagic cystitis, syndrome of inappropriate antidiuretic hormone (SIADH), 
fatigue, hyperuricemia, azoospermia, amenorrhea, cardiotoxicity (myocardial necrosis) with high doses.  
We expect similar side effects when administered as part of this study.   
 
Fludarabine and Cyclophosphamide in Combination 
• 
Common: Lowered neutrophils/granulocytes that may lead to infection. Lowered platelets may 
lead to an increase in bruising or bleeding, Lowered red blood cells. Lowered lymphocytes may 
lead to infection, Fatigue, Nausea, Vomiting, Time away from work, Hair loss, Herpes zoster 
infection of the skin.  
• 
Less Likely: Allergic reaction, Severe allergic reaction that causes fever, aches and pains in the 
joints, skin rash, and swollen lymph glands, Stuffy or runny nose, sneezing, Sore throat, Abnormal 
fast heartbeat, Excessive sweating, Flushing, Itching, Rash, Swelling of the lips, eyes, tongue, and 


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throat which can be severe, Hives, Diarrhea, High blood sugar, Low blood potassium, Dizziness, 
Convulsion or seizure, Abdominal pain, Pain such as back, joint, and/or muscle pain, Headache, 
Wheezing, Cough, Shortness of breath, Inflammation of the lung which may cause difficulty 
breathing and difficulty getting oxygen, Infertility or sterility, Irregular menstrual periods. Some 
women may not resume their periods, SIADH, Increased production of tears associated with the 
administration of cyclophosphamide, Metallic taste, Cystitis and hematuria.  
• 
Rare But Serious: hemolytic anemia. Changes in vision or changes in degree of alertness both of 
which can be severe or fatal, Rash which may become severe, Potentially life-threatening 
condition affecting less than 10% of the skin in which cell death causes the outer skin layer to 
separate from the middle layer, Life-threatening condition affecting greater than 30% of the skin 
in which cell death causes the outer layer of skin to separate from the middle layer, Severe lung 
dysfunction resulting in the ability to breathe which can be life-threatening, Allergic reactions to 
blood transfusions, Tumor lysis syndrome - a rapid decline in the number of tumor cells that can 
lead to kidney failure and/or chemical imbalances that may have a serious effect on other organs 
such as heart. If this were to occur, subjects will receive close monitoring and blood tests, as well 
as appropriate medical treatment. It is possible that secondary malignancies including 
myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) may also be experienced. 
1.6.4 Potential Benefits 
It is possible that the anti-aFR CAR T cells will exert an anti-tumor effect; in two published trials, objective 
response rates of 22% and 27% were reported  in response to an aFR-specific antibody drug conjugate 
and IP infusion of T cells armed with an aFR-specific bispecific antibody, respectively [60, 118]. 
Additionally, the safety and efficacy of CAR T cells redirected against CD19 has established [19]. The safety 
and efficacy of CAR T cells specific for BCMA are tested in patients with multiple myeloma at UPENN and 
the preliminary results indicate that this cellular therapy is tolerable and induce durable responses 
(unpublished data). 
1.7 Justification of route and dose regimen for Main Investigational Product 
Route of Administration (ROA). For all cohorts, autologous MOv19-BBz CAR T cells will be administered as 
a single dose via intraperitoneal infusion (IP). In ovarian cancer, the tumor is often accessible in the 
peritoneal cavity and directed administration of therapeutic agents, such as CAR T cells, is possible. This 
route of administration is the most likely to result in distribution of MOv19-BBz CAR T cells to most sites 
of tumor.  The method of localized instillation for targeted therapeutic delivery has been employed 
previously at the University of Pennsylvania in patients with malignant mesothelioma who had pleural 
administration of agent [124-126] and elsewhere in ovarian cancer patients [127]. In one patient with 
pancreatic adenocarcinoma with peritoneal carcinomatosis and no other treatment options available, 
anti-mesothelin CAR T cells were safely delivered by intraperitoneal administration on a compassionate 
use basis at UPenn with the expectation that delivery of T cells via an IP route of administration may 
provide significant clinical benefit (UPCC#21211; IRB#814373).  
 
Dose Rationale for MOv19-BBz CART Product.  We have chosen to use a single dose of MOv19-BBz CAR T 
cells for this protocol at a starting dose of 1-3x107/m2. If this dose level is determined safe (both with and 
without lymphodepleting chemotherapy), the dose level will be increased to 1-3x108/m2. If safety 
concerns are seen at this starting dose level, the dose will be reduced to 1-3x106/m2.   
 
Due to the unknown effects of targeting aFR with second generation MOv19-BBz CART cells, we chose a 
more conservative dosing regimen compared to that used in an ongoing Phase I dose-escalation study 


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evaluating PSMA-CAR T cells infused in mCRPC patients after lymphodepleting chemotherapy 
(NCT01140373). The dose regimen we have selected is also similar to that used by our group in a study 
evaluating the safety of anti-mesothelin CAR T cells in other solid tumors, such as mesothelioma, ovarian 
cancer and pancreatic cancer subjects with and without lymphodepleting chemotherapy (NCT02159716). 
This anti-mesothelin CAR T cell trial is still ongoing, thus only preliminary safety results are available.  This 
includes one subject death at the 1-3x108/m2 dose level due to respiratory failure in the setting of 
concurrent Grade 4 CRS. The proposed study will utilize intraperitoneal administration of the CAR T cells 
to reduce potential toxicity by reducing exposure to the bronchial tissue containing alpha-folate receptor.   
2 
STUDY OBJECTIVES 
2.1  Primary objectives 
Determine the safety and feasibility of intraperitoneal administration of lentivirally transduced MOv19-
BBz CAR T cells in the target population.  Intraperitoneal administration of MOv19-BBz CAR T cells is 
planned with and without cyclophosphamide + fludarabine as lymphodepleting chemotherapy. 
2.2 Secondary objectives 
Clinical objectives: 
• 
Assess the clinical anti-tumor effect by standard criteria (RECIST 1.1 and irRECIST) for each tumor 
type.  
• 
Assess overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). 
 
Correlative objectives: 
• 
Evaluate MOv19-BBz CAR T cells engraftment and persistence in peripheral blood and peritoneal 
fluid. 
• 
Determine the bioactivity of MOv19-BBz CAR T cells in peripheral blood and peritoneal fluid. 
• 
Evaluate the development of anti-CART immune responses favoring rejection of MOv19-BBz CAR 
T cells. 
• 
Evaluate the development of secondary anti-tumor immune responses as a consequence of 
epitope spreading. 
• 
Evaluate the potential to follow tumor biomarker levels as a surrogate biomarker of anti-tumor 
activity. 
• 
Where tumor material or body fluids can be obtained: 
a. Measure trafficking of MOv19-BBz CAR T cells 
b. Evaluate aFR expression on tumor cells to assess for antigen-escape 
c. Analyze tumor microenvironment and cell interactions (if feasible) 
3 
STUDY DESIGN  
3.1 General Design 
This protocol will test the safety of up to 3 dose levels of MOv19-BBz CAR T cells administered 
intraperitoneally alone or after lymphodepletion with a moderate dose of cyclophosphamide + 
fludarabine administered two-four days prior to MOv19-BBz CAR T cells. The dose escalation follows a 3+3 
design. MOv19-BBz CAR T cells have been permanently modified to be directed to aFR protein with an 
anti-aFR scFv fused to the signaling domains of 4-1BB and TCRζ. Also, the safety of intraperitoneal 


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administration of CAR T cells will be evaluated.  The study population includes women with aFR-expressing 
ovarian cancer.  
 
As part of the informed consent process, subjects will be asked for permission to test their tumor for aFR 
expression as one of the eligibility criteria. Evaluation of aFR expression will occur on archived tumor 
tissue, if the patient has not had an anti-aFR directed therapy since the collection of the archived sample. 
However, if archived tumor tissue is not available, a fresh biopsy may be performed.   Once aFR  expression 
has been confirmed, subjects may be presented the informed consent for the main study.  
 
Patients with confirmed tumor cells with aFR expression and who meet all other inclusion criteria will be 
eligible to participate. The minimum requirement of FRα positivity by immunohistochemistry (IHC) is ≥70% 
of tumor cells with ≥2+ aFR staining. 
 
Once subjects are determined to be eligible by a physician-investigator and the monitoring visit for 
eligibility is completed, subjects will undergo apheresis to provide cells for MOv19-BBz CAR T cell 
manufacturing. If patients have an apheresis product collected prior to physician-investigator 
confirmation of eligibility for this study, this apheresis product may be used for CART cells manufacturing.  
In this instance, the subject will not need to undergo another apheresis, and CART manufacturing may be 
initiated immediately after the monitoring visit for eligibility has been completed.   
 
All subjects will be assigned a cohort for the interventional portion of the protocol (see below) as per the 
3+3 design.  Subjects will be followed up for safety and research assessments as detailed in the Schedule 
of Events (Appendix 1).   
 
Adverse events will be collected and evaluated during the protocol specified adverse event reporting 
period outlined in Section 9.1. While on study, subjects will be continually reassessed for evidence of 
acute and cumulative toxicity. At any time that a subject has progressed and/or initiates another anti-
cancer therapy, the subject may be discontinued from Primary Follow-up and enter long-term follow-up 
under this same protocol.  Long-term follow-up will continue for up to 15 years from their MOv19-BBz 
CAR T cell infusion.  During long-term follow-up, subjects will be monitored for delayed adverse events 
that may be associated with the administration of the MOv19-BBz CAR T cells. 
3.2 Cohort Assignment/Advancement 
This is a Phase I study evaluating the safety and feasibility of intraperitoneal administered lentiviral 
transduced MOv19-BBz CAR T cells with or without cyclophosphamide + fludarabine in a 3+3 dose 
escalation design.   
 
The trial will begin in Cohort 1 and progression from one cohort to another will occur chronologically and 
is dependent on dose limiting toxicity (per Section 5.4).  The DLT observation period is 28 days post CAR 
T cell infusion.  Infusions will be staggered to allow assessment of DLTs for cohort progression, expansion, 
or dose de-escalation. For example, the 2nd and 3rd subjects in each cohort may be infused and followed 
in parallel but only after the 1st subject in that cohort completes the day 28 visit without DLT. The formal 
DLT assessment/determination will be performed by the PI and Sponsor Medical Director prior to cohort 
advancement.   
 


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The Maximum Tolerated Dose (MTD) is defined as the dose at which 0 or 1 DLT occurs in 6 evaluable 
subjects tested within the dose range of this study.  In order to gather additional data and establish the 
MTD dose level, the respective cohorts may be expanded to treat up to 6 evaluable subjects.   
 
• 
Cohort 1: (n= 3 to 6 subjects):  Single infusion of 1-3x107/m2 lentivirally transduced MOv19-BBz 
CAR T cells on day 0 without lymphodepleting chemotherapy.   
o If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level. 
o If 0 DLT/3 subjects or 1 DLT/6 subjects occurs, the study will advance to Cohort 2.  
o If 2 DLT/3 subjects or 2 DLT/6 subjects occurs, then enrollment in this Cohort will be 
stopped and the dose will be de-escalated by 10-fold to 1-3 x 106 cells/m2 (Cohort -1). 
o If the number of manufactured CAR T cells does not meet the protocol-specified minimum 
dose for Cohort 1 subjects of 1 x 107/m2 cells, but does meet the protocol minimum dose 
requirement of at least 1 x 106/m2 cells, then the subject may receive the cells, but will 
not be included in the DLT assessment for Cohort 1. Thus, the subject would be evaluable 
for safety, but would be replaced in this cohort for formal DLT assessment.  If, however, 
the number of manufactured CAR T cells does not meet the minimum acceptable dose 
for infusion, then the cells will not be administered, and the subject will be replaced in 
the study.   
 
• 
Cohort -1: (n= 3 to 6 subjects): Single Infusion of 1-3x106/m2 lentivirally transduced MOv19-BBz 
CAR T cells on day 0 without lymphodepleting chemotherapy. 
o Dose de-escalated dose level, which will only enroll subjects in the event of 2 DLT/3 
subjects or 2 DLT/6 subjects occurs in Cohort 1.  
o Up to 6 subjects will be infused in Cohort -1 with ≤ 1 DLT/6 subjects to establish the MTD.  
  
• 
Cohort 2: (n= 3 to 6 subjects): Single infusion of 1-3x107/m2 lentivirally transduced MOv19-BBz 
CAR T cells on day 0 beginning 3 days (+/- 1 day) after lymphodepleting chemotherapy with 
cyclophosphamide + fludarabine.   
o If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level. 
o If 0 DLT/3 subjects or 1 DLT/6 subjects occurs, the study will advance to Cohort 3.  
o If 2 DLT/3 subjects or 2 DLT/6 subjects occurs, further infusions within this cohort and 
subsequent dose escalation would be halted.  If less than 6 subjects were infused in 
Cohort 1, up to 6 total subjects will be infused in Cohort 1 to establish the MTD.  
o If the number of manufactured CAR T cells does not meet the protocol-specified minimum 
dose for Cohort 2 subjects of 1 x 107/m2 cells, but does meet the minimum dose 
requirement of at least 1 x 106/m2 cells, then the subject may receive the cells but will not 
be included in the DLT assessment for Cohort 2. Thus, the subject would be evaluable for 
safety, but would be replaced in this cohort for formal DLT assessment.  If, however, the 
number of manufactured CAR T cells does not meet the minimum acceptable dose for 
infusion, then the cells will not be administered, and the subject will be replaced in the 
study.   
 
• 
Cohort 3: (n=3 to 6 subjects): Single infusion of 1-3x108/m2 lentivirally transduced MOv19-BBz 
CAR T cells on day 0 beginning 3 days (+/- 1 day) after lymphodepleting chemotherapy with 
cyclophosphamide + fludarabine.   
o If 0 DLT/3 or 1 DLT/3 subjects occur, the study will enroll an additional 3 subjects to 
confirm tolerability and MTD.   


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o If 2 DLT/3 subjects or 2 DLT/6 subjects occurs, further infusions within this cohort will be 
halted. If less than 6 subjects were infused in Cohort 2, up to 6 total subjects will be 
infused in Cohort 2 to establish the MTD.    
o If the number of manufactured CAR T cells does not meet the protocol-specified minimum 
dose for Cohort 2 subjects of 1 x 108/m2 cells, but does meet the minimum dose 
requirement of at least 1 x 106/m2 cells, then the subject may receive the cells but will not 
be included in the DLT assessment for Cohort 3. Thus, the subject would be evaluable for 
safety, but would be replaced in this cohort for formal DLT assessment.  If, however, the 
number of manufactured CAR T cells does not meet the minimum acceptable dose for 
infusion, then the cells will not be administered, and the subject will be replaced in the 
study.   
 
Subjects will be enrolled serially. Infusions will be staggered to allow assessment of DLTs for cohort 
progression, expansion, or dose de-escalation. The infusions for the first 2 subjects in each cohort will be 
staggered by 28 days; the second subject will not be infused until 28 days after the infusion of the first 
subject.  However the 2nd and 3rd subjects in each cohort may be infused and followed in parallel but only 
after the 1st subject in that cohort completes the day 28 visit without DLT. DLT are defined as per Section 
5.4.  
 
Subjects will be followed up for safety assessments and research assessments post infusion as detailed in 
the Schedule of Events (Appendix 1).  
3.3 Collection of Research Samples 
Peripheral blood samples will be obtained at defined time points to monitor for measures of safety and 
efficacy. Additional blood and tissue samples (e.g. fluids, tissue biopsy) that are obtained for clinical 
indications may also be sent for research analysis.  At any time that tissue or body fluids are obtained (for 
example, drainage of peritoneal fluid or pleural/ascites fluid), fluid samples that would otherwise be 
discarded may be used instead for research purposes (see Section 7.2).  These studies include, but are not 
limited to, MOv19-BBz CAR T cell persistence by Q-PCR and inflammation marker assessment with a 
LuminexTM-based cytokine and chemokine panel. If clinically feasible/appropriate, subjects will be asked 
to undergo an image-guided minimally invasive biopsy pre-infusion and on day 14 (±7) for research 
purposes.   
 
In case of unexpected AEs or SAEs, additional samples may be collected for research analysis, focused at 
evaluating the potential causality with the infused MOv19-BBz CAR T cells. Additional blood work for 
research evaluation may also be requested at any time at the investigators’ discretion, and is especially 
encouraged whenever there is a clinical concern for a potential toxicity related to MOv19-BBz CAR T cells, 
but also for subjects with an unusual efficacy; additional studies may identify critical biomarkers of 
potency which may inform future trial designs. The additional samples collected for research will not 
exceed 3 tablespoons of blood twice in a week, and one procedure for collecting tissue/lymph node 
samples in a month. 
3.4 Primary Study Endpoints 
This phase I study is designed to test the safety and feasibility of intraperitoneal administration of MOv19-
BBz CAR T cells in patients with aRF expressing ovarian cancer.  Intraperitoneal administration of MOv19-
BBz CAR T cells is planned with or without cyclophosphamide + fludarabine as lymphodepleting 
chemotherapy. 


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Safety of treatment will be defined by: 
• 
The occurrence of study related adverse events, defined as NCI CTCAE v5.0 greater than or equal 
to (≥) grade 3 signs/symptoms, laboratory toxicities and clinical events that are possible, probably, 
or definitely related to study treatment.   
 
Feasibility of treatment 
• 
Clinical feasibility is defined as the proportion of subjects enrolled on this protocol who do not 
receive MOv19-BBz CAR T cells. Reasons for this occurrence include rapid clinical deterioration or 
death, and subject withdrawal.  
• 
Manufacturing feasibility is determined based on the “manufacturing failures” products. The 
number of manufactured products that do not meet release criteria for vector transduction 
efficiency, CART+ cell number, T cell purity, viability, and sterility will be determined and defined 
as “manufacturing failures”.   
3.5 Secondary Study Endpoints 
Secondary endpoints include clinical responses and research correlative studies. 
3.5.1 Clinical Responses 
Preliminary evidence of efficacy will be determined by monitoring tumor response rates in those subjects 
with measurable disease. Tumor response will be assessed using radiographic imaging (i.e. CT imaging) 
and serum biomarkers in accordance with the Schedule of Events in Appendix 1.  
a. Radiographic responses will be measured according to Response Evaluation Criteria in Solid 
Tumors (RECIST 1.1).  Immune related response evaluation criteria in solid tumors Criteria 
(irRECIST) will be assessed when feasible.  
b. Serum biomarker responses will be evaluated according to clinical standards.  Serum biomarkers 
will not be used as the sole measurement of tumor response.  
c. Data will be analyzed descriptively for overall response rates (ORR), progression-free survival 
(PFS), and overall survival (OS). ORR and PFS, up to 5 years post-infusion or until subjects initiate 
a cancer-related therapy, will be evaluated. OS up to 15 years post-infusion will be evaluated.   
3.5.2 Research Correlative Studies 
The following studies will measure the effect of CAR T cell infusion on systemic adaptive and innate 
immunity. Analyses will be performed on peripheral blood samples (peripheral blood mononuclear cells 
and serum) and body fluids (including peritoneal fluid) collected at time-points as detailed in the Schedule 
of Events (Appendix 1). Additional analysis may also be performed on additional sample collections (e.g. 
fluids, tissue biopsies).  More specifically, in case of unexpected AEs or SAEs, additional samples may be 
collected for research analysis focused at evaluating the potential causality with the infused MOv19-BBz 
CAR T cells. Additional blood work for research evaluation may be requested at any time at the 
investigators’ discretion, and is especially encouraged whenever there is a clinical concern for a potential 
toxicity related to MOv19-BBz CAR T cells, but also for subjects with an unusual efficacy; additional studies 
may identify critical biomarkers of potency which may inform future trial designs. The additional samples 
collected for research will not exceed 3 tablespoon of blood twice in a week and up to 1 procedure for 
collecting tissue/lymph nodes samples in a month.  In addition, tissue samples (e.g. fluids, tissue biopsy) 
that are obtained as part of standard of care procedures for clinical indications may also be used for 
research analysis. 


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a. Evaluate leakage and persistence of MOv19-BBz CAR T cells in peripheral blood. This will be 
measured by Q-PCR for vector sequences. CAR T cell vector sequences will also be performed at 
time points according to the Appendix 1. This testing will occur until any 2 sequential tests are 
negative documenting “rejection” or loss of CAR T cells.  Data will be displayed graphically.  Flow 
cytometry will be used if feasible. 
b. Determine the bioactivity of MOv19-BBz CAR T cells. This will be evaluated by measuring 
modulation of cytokines, chemokines and growth factors by Luminex technology. In addition, we 
may assess bioactivity of CAR T cells (product and post-infusion specimens) via stimulation with 
aFR expression target cells using flow cytometry-based functional assay. 
c. Evaluate the development of immune responses favoring rejection of MOv19-BBz CAR T cells 
(including HACA, HAMA, and cellular immune responses directed to the MOv19-BBz CAR). 
Correlate the occurrence of such responses with loss of MOv19-BBz CAR T cells engraftment. 
d. Evaluate the development of secondary anti-tumor immune responses as a consequence of 
epitope spreading. If tumor tissue is available at baseline and post-infusion, the analysis of breath 
and hierarchy of T cell receptor and immunoglobulin rearrangements via deep sequencing may 
be used to demonstrate antigen spreading.  
e. Evaluate the potential to follow decreases in soluble tumor biomarker levels as a surrogate 
biomarker of anti-tumor activity. CA125 and SaFRP for all subjects will be measured before and 
after the infusion. This data will be correlated with radiographic information evaluating tumor 
status obtained at the same time-points and with clinical status. 
f. Where tumor material or body fluids can be obtained, we may attempt to:  
• 
detect presence of MOv19-BBz CAR T cells 
• 
measure aFR expression  
• 
analyze tumor microenvironment using flow cytometric, IHC and transcriptomic analysis; 
the breadth and hierarchy of the T cell repertoire via deep sequencing and compare with 
baseline specimens. 
 
For details on these assessments please see Section 7 of the clinical protocol.  
4 
SUBJECT SELECTION AND WITHDRAWAL 
4.1 Inclusion Criteria 
1. Histologically confirmed persistent or recurrent stage II to IV high grade serous epithelial ovarian, 
fallopian tube or primary peritoneal carcinoma.  Disease can be platinum-sensitive or platinum-
resistant. 
2. Failure of at least two prior chemotherapy regimens for advanced stage disease.  Prior therapies 
against PD-1 or PDL-1 are permissible.   
3. Confirmation of tumor aFR expression (≥70% of tumor cells with ≥2+ aFR staining).  
4. Subjects must have measureable disease as defined by RECIST 1.1 criteria. 
5. Patients with asymptomatic CNS metastases that have been treated and are off steroids are 
allowed. They must meet the following at the time of eligibility confirmation by physician-
investigator:  
a. No concurrent treatment for the CNS disease  
b. No progression of CNS metastasis on brain MRI at screening 
c. No evidence of leptomeningeal disease or cord compression 
6. Patients ≥ 18 years of age. 


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7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
8. Satisfactory organ and bone marrow function as defined by the following: 
i. Absolute neutrophil count ≥ 1,000/μl 
ii. Platelets ≥75,000/μl 
iii. Hemoglobin ≥ 9 g/dL 
iv. Total bilirubin ≤ 2.0x the institutional normal upper limit unless secondary to bile duct 
obstruction by tumor 
v. Creatinine ≤ 1.5x the institutional normal upper limit 
vi. Albumin ≥2 
vii. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 5x the 
institutional normal upper limit 
viii. Cardiac ejection fraction of ≥40%  
9. Blood coagulation parameters: PT such that international normalized ratio (INR) is ≤ 1.5 and a PTT 
≤ 1.2 time the upper limit of normal unless the patient is therapeutically anti-coagulated for 
history of cancer-related thrombosis and has stable coagulation parameters. 
10. Provides written informed consent. 
11. Subjects of reproductive potential must agree to use acceptable birth control methods, as 
described in protocol Section 4.3.  
4.2 Exclusion Criteria 
1. High grade serous ovarian, fallopian, or primary peritoneal cancer that is platinum refractory, 
defined as disease that has clinical or radiographic progression on platinum-based 
chemotherapy, as per the discretion of the treating physician.  
2. Patients with symptomatic CNS metastases are excluded. 
3. Participation in a therapeutic investigational study within 4 weeks prior to eligibility confirmation 
by physician-investigator, or anticipated treatment with another investigational product while on 
study. This refers to non-commercially approved investigational drugs different than those used 
in this protocol.  
4. Active invasive cancer other than ovarian cancers. Patients with active non-invasive cancers (such 
as non-melanoma skin cancer, superficial cervical and bladder cancer) are not excluded. 
5. HIV infection 
6. Hepatitis B or hepatitis C infection 
7. Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to >/= 
10 mg of prednisone. Patients with autoimmune neurologic diseases (such as multiple sclerosis) 
will be excluded.   
8. Patients with active and uncontrolled infection. 
9. Planned concurrent treatment with systemic high dose corticosteroids.  Patients may be on a 
stable low dose of steroids (<10 mg daily equivalent of prednisone). Corticosteroids treatment as 
anti-emetic prophylaxis on the day of lymphodepleting chemotherapy administration is allowed 
per institutional guidance.  The use of topical and/or inhaled steroids are not exclusionary.  
10. Patients requiring supplemental oxygen therapy. 
11. Prior therapy with lentiviral gene modified cells.  
12. History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, 
and Dextran 40) 


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13. Any ascites requiring therapeutic drainage within 4 weeks prior to eligibility confirmation by 
physician-investigator.  
14. Pregnant or breastfeeding women.  
15. Presence of any other condition that may increase the risk associated with study participation or 
may interfere with the interpretation of study results, and, in the opinion of the physician-
investigator, would make the patient inappropriate for entry into the study. 
 
Please refer to the Concomitant Therapy Section 5.6 for windows related to apheresis and MOv19-BBz 
CAR T cell infusion. 
4.3 Subject Recruitment 
Subjects will be identified through the clinical practices of the clinical investigators in the Division of 
Gynecologic Oncology and Division of Hematology Oncology at the Hospital of the University of 
Pennsylvania and its affiliated hospitals and through referrals from outside hospitals and physicians. No 
direct-to-patient advertising will be performed. The trial will be publicized on the websites of 
Clinicaltrials.gov and the Abramson Cancer Center of the Hospital of the University of Pennsylvania.  
4.4 Reproductive Status 
 
Females and transgender men of reproductive potential (who have reached menarche or who have not 
been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the 
preceding 24 months, or have not undergone a sterilization procedure [hysterectomy or bilateral 
oophorectomy]) must have a negative urine pregnancy test performed at screening and a negative serum 
pregnancy test prior to study treatment as per the Schedule of Events in Appendix 1. 
 
Due to the unknown risk of the MOv19-BBz CAR T cells with respect to pregnancy, as well as risks 
associated with lymphodepleting chemotherapy, it is recommended that all subjects of reproductive 
potential use at least one medically acceptable form of contraception during the study and for at least 1 
year after their last infusion of MOv19-BBz CAR T cells.  Investigators shall counsel subjects on the 
importance of pregnancy prevention and the implications of an unexpected pregnancy. 
 
Medically acceptable birth control includes the following methods: 
• 
Abstinence 
• 
Condoms (male or female) with or without a spermicidal agent 
• 
Diaphragm or cervical cap with spermicide 
• 
Hormonal/Non-hormonal Intrauterine device (IUD) 
• 
Hormonal-based contraception 
 
Subjects who are not of reproductive potential (females/transgender men who have been post 
menopausal for at least 24 consecutive months or have undergone hysterectomy, salpingotomy, and/or 
bilateral oophorectomy) do not require use of contraception. Acceptable documentation of sterilization 
or menopause is required and may take the form of written or oral attestation by clinician or clinician’s 
staff of one of the following: 
• 
Physician report/letter 
• 
Operative report or other source documentation in the subject record 
• 
Discharge summary 


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• 
Follicle stimulating hormone measurement elevated into the menopausal range 
4.5 Subject Withdrawal/Discontinuation 
4.5.1 Reasons for Subject Discontinuation 
Subjects who enroll but do not receive MOv19-BBz CAR T cells will be prematurely discontinued from the 
study, will not be followed, and will be replaced in the study. Reasons for premature discontinuation prior 
to receipt of MOv19-BBz CAR T cells include, but are not limited to, the following: 
1. The subject is lost to follow-up.   
2. The principal investigator judges that the subject, prior to MOv19-BBz CAR T cell infusion, is too 
ill to continue. 
3. Pregnancy- documented prior to MOv19-BBz CAR T cell infusion.  If pregnancy occurs after the 
subject has received MOv19-BBz CAR T cells, they will be kept active in the study for safety 
follow-up and pregnancy outcome. 
4. Voluntary withdrawal: a subject may remove himself/herself from the study at any time.   
5. Significant and rapid progression of malignancy, requiring alternative medical, radiation or 
surgical intervention, prior to MOv19-BBz CAR T cell infusion. 
6. A serious adverse event that requires the subject to be withdrawn from the trial prior to 
MOv19-BBz CAR T cell infusion.   
7. Technical difficulties are encountered in the T cell genetic modification and expansion 
procedure that precludes the generation of clinical cell doses that meet all Quality Control 
release criteria. 
8. Termination of the study. 
 
Reasons for discontinuation of subjects from primary follow-up after receipt of MOv19-BBz CAR T cells 
may include, but are not limited to, the below.  Subjects may not be discontinued from primary follow-up 
prior to the Day 28 safety follow-up visit for reasons other than subject withdrawal of consent or death. 
1. The subject is lost to follow-up. 
2. Voluntary withdrawal: a subject may remove himself/herself from the study at any time.   
3. Disease progression of targeted malignancy 
4. Receipt of alternative treatment for their targeted disease 
5. Completion of protocol required follow-up 
6. Termination of the study. 
 
Subjects who are discontinued from primary follow-up, will go into the long-term follow-up phase. 
Reasons for discontinuation of subjects from long-term follow-up after receipt of MOv19-BBz CAR T cells 
may include, but are not limited to, the following: 
1. The subject is lost to follow-up. 
2. Voluntary withdrawal: a subject may remove himself/herself from the study at any time.   
3. Completion of protocol required long-term follow-up. 
4. Death 
5. Termination of the study. 
 
The reasons for discontinuation from both primary and long-term follow-up (for example, voluntary 
withdrawal, toxicity, death) must be recorded appropriately. 


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4.5.2 Data Collection and Follow-up  
Follow-up data collection after receipt of gene-modified cell therapy clinical trials is specified by FDA.  As 
long as subjects have detectable cells transduced with the lentiviral vector, they should be followed for 
toxicity, immune reactions, and any long-term adverse events.   
 
In the event that a subject cannot return to the study site for follow-up visits because of subject 
preference or geographical concerns, the subject’s primary care physician and/or local oncologist will be 
asked to provide information from the subject’s medical record to the study team at protocol defined 
time points (including the results of any routine care examinations and/or laboratory assessments), and 
assist in the collection of protocol required blood samples (if applicable), which will be sent to the 
University of Pennsylvania for protocol-required analysis.  The subject and local provider will also be 
contacted via telephone by a member of the study team to assess any potential toxicity. 
 
In numerous previous cell therapy trials at the University of Pennsylvania, loss of follow-up is estimated 
to occur in less than 5% of cases. Every effort will be made to contact subjects who appear to be lost to 
follow-up in order to at least obtain survival data. In the event a subject fails to complete the follow-up 
requirements, documentation of all attempts to contact the subject includes at least 3 telephone contacts 
(on different days and at different times of the day), and a certified letter. 
4.5.3 Replacement Subjects 
All subjects who do not receive MOv19-BBz CAR T cells will be replaced.  Subjects have the option to 
receive a lower than target dose per cohort assignment, if the MOv19-BBz CAR T cell product meets CVPF 
release criteria and minimum acceptable dose for infusion, and the subject cannot or is not willing to 
perform a second apheresis, or if the second manufacturing process fails.  If a subject receives a lower 
than target dose per cohort assignment, they will be considered evaluable for safety, but will not be 
evaluable for response and will not be included in DLT evaluations (i.e. deemed Cohort non-evaluable and 
will be replaced in that cohort), but will follow all of the study visits as described in the Schedule of Events 
in Appendix 1. The minimum acceptable dose for infusion is 1x106 MOv19-BBz CAR T cells/m2. 
5 
INVESTIGATIONAL PRODUCTS  
5.1 Description 
5.1.1 MOv19-BBz CAR T cells 
MOv19-BBz CAR T cells are autologous T cells that have been engineered to express an extracellular single 
chain variable fragment (scFv) with aFR specificity. The T cells express an intracellular signaling molecule 
comprised of the TCR ζ chain, and 4-1BB. The MOv19-BBz CAR T cells are cryopreserved in infusible 
cryomedia (Section 5.3.1). Each bag will contain a dose of CAR positive T cells corresponding to the 
subject’s assigned cohort/dose level.  The total cell dose is dependent on the transduction efficiency; the 
volume of cells is dependent on the total cell dose with a minimum of 10 mLs per bag. The minimum 
acceptable dose for infusion is 1x106 MOv19-BBz CAR T cells/m2. 
5.1.2 Cyclophosphamide and Fludarabine 
Cyclophosphamide and fludarabine are cytotoxic chemotherapy agents used for lymphodepletion prior 
to MOv19-BBz CAR T cell administration in Cohorts 2 and 3. The main goal of using cyclophosphamide and 
fludarabine is to achieve lymphodepletion that may enhance engraftment of adoptive T cells, while 


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minimizing complications from neutropenia. The proposed regimen has been used widely in other studies 
and has been tolerated well. Although both cyclophosphamide and fludarabine are FDA-approved agents 
and will be prepared and infused in accordance with their FDA-approved labels and standard institutional 
practice, their use in this trial will be considered investigational.  This is due to the use of these drugs in 
combination as well as their use in this patient population.  Also, to our knowledge, cyclophosphamide 
and fludarabine have not been used for lymphodepletion prior to IP CAR T-cells. 
 
Cyclophosphamide and fludarabine will be administered as a regimen of cyclophosphamide 300 mg/m2 + 
fludarabine 30 mg/m2 daily over three days. Fludarabine doses will be rounded down to the nearest 50 
mg vial size, if the rounded dose does not differ by > 10% of the original dose prescribed. This 
lymphodepleting chemotherapy regimen must be scheduled so that the last day of therapy falls 3 days 
(+/- 1 day) prior to CAR T cell infusion.   
5.2 Treatment Regimen 
A single dose of MOv19-BBz CAR T cells will be administered by rapid intraperitoneal (IP) infusion (all 
Cohorts) via intraperitoneal catheter as follows.  
• 
Cohort 1: (n= 3 to 6 subjects):  Single infusion of 1-3x107/m2 lentivirally transduced MOv19-BBz 
CAR T cells on day 0 without lymphodepleting chemotherapy.   
• 
Cohort -1: (n= 3 to 6 subjects): Single Infusion of 1-3x106/m2 lentivirally transduced MOv19-BBz 
CAR T cells on day 0 without lymphodepleting chemotherapy.  Dose de-escalated dose level, 
which will only enroll subjects in the event of 2 DLT/3 subjects or 2 DLT/6 subjects occurs in Cohort 
1.  
• 
Cohort 2: (n= 3 to 6 subjects): Single infusion of 1-3x107/m2 lentivirally transduced MOv19-BBz 
CAR T cells on day 0 beginning 3 days (+/- 1 day) after lymphodepleting chemotherapy with 
cyclophosphamide + fludarabine.   
• 
Cohort 3: (n=3 to 6 subjects): Single infusion of 1-3x108/m2 lentivirally transduced MOv19-BBz 
CAR T cells on day 0, beginning 3 days (+/- 1 day) after lymphodepleting chemotherapy with 
cyclophosphamide + fludarabine.   
 
MOv19-BBz CAR T cells will be routinely administered on an outpatient basis, however inpatient 
administration may occur at treating investigator’s discretion. Clinic visits, hematology, and other safety 
laboratory tests will be performed according to the Schedule of Events (Appendix 1). Additional sample 
collection and assessments may be performed as clinically necessary to evaluate specific adverse events 
per Investigator discretion.  
5.3 Preparation and Administration of Study Drug(s) 
5.3.1 MOv19-BBz CAR T cells 
 
Manufacturing of MOv19-BBz CAR T cells 
The manufacture and release testing of MOv19-BBz CAR T cells will be performed by the Clinical Cell and 
Vaccine Production (CVPF) at the University of Pennsylvania. The MOv19-BBz CAR T cell product will be 
manufactured from the patients’ apheresis product.  
 
MOv19-BBz CART products are not released from the CVPF until release criteria for the infused cells (e.g., 
cell purity, sterility, identity) are met. At the end of cell cultures, the cells are cryopreserved in infusible 


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cryomedia in bags. Weight used for dosing will be the weight obtained prior to the apheresis procedure. 
Dosing will not be changed for changes in subject weight.  
 
Bags containing autologous modified CAR T cell products will be stored in a controlled and monitored 
freezer at the CVPF at the Hospital of the University of Pennsylvania until the subject is ready for infusion. 
Each dose will be packed and cryopreserved in infusion bag(s) in a volume dependent on the total cell 
number which is a function of the transduction efficiency. Each bag will contain an aliquot (volume 
dependent upon total cell dose) of cryomedia containing the following infusible grade reagents (% v/v): 
•  
     
 
 
A qualified alternative cryopreservation media contains the following infusible grade reagents (% v/v): 
•     
 
 
  
 
  
  
 
•  
 
 
Release and Preparation of MOv19-BBz CAR T cells 
The CVPF will release MOv19-BBz CAR T cells to the bedside for administration per CVPF SOPs.  The 
MOv19-BBz CAR T cells will not be released from the CVPF until release criteria for the infused cells are 
met.    
 
Packaging and Labeling 
The investigational product will have affixed to it a label containing the following statements: “FOR 
AUTOLOGOUS USE ONLY” and “Caution:  New Drug – Limited by Federal Law to Investigational Use”.  In 
addition, the label will have at least two unique identifiers, among other information required by law.   
 
Cell Thawing/Receipt of MOv19-BBz CAR T cells  
The frozen MOv19-BBz CAR T cells will be transported to the subject’s bedside in dry ice on the day of 
infusion.  The cells will be thawed by trained personnel using a water bath maintained between 36°C to 
38°C.  The bag will be gently massaged until the cells have just thawed.  There should be no frozen clumps 
left in the container at the time of infusion.    
 
If the MOv19-BBz CART product appears to be damaged or leaking, or otherwise appears to be 
compromised, it should not be infused and should be returned to the CVPF as specified below. 
 
Return or Destruction of Study Drug 
MOv19-BBz CAR T cells may need to be returned to the CVPF for a variety of reasons, including but not 
limited to: 1) Mislabeled product; 2) Condition of patient prohibits infusion/injection, and 3) Subject 
refuses infusion. Any unused product will be returned to CVPF.  Final disposition of the investigational 
product is to be documented. 


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Administration of MOv19-BBz CAR T cells 
Intraperitoneal Catheter Placement 
The subject will have an intraperitoneal catheter placed by Interventional Radiology according to standard 
hospital procedure, on the day of planned MOv19-BBz CAR T cell infusion, at a location determined by 
Interventional Radiology.  At this time the peritoneal cavity may be maximally drained. 
 
Evaluation Prior to MOv19-BBz CAR T cell Administration 
Following catheter placement, the subject will be transported to the outpatient clinical facility for 
continued care and receipt of cells.  Prior to CAR T cell administration, the subject will be evaluated by the 
treating physician for criteria specified in Section 6.6.   
 
Premedication for MOv19-BBz CAR T cells 
Premedication for CAR T cell infusions is given due to the possibility of side effects including transient 
fever, chills, rigors, myalgias/arthralgias, headache, fatigue, and/or nausea. Subjects will be pre-
medicated with acetaminophen 650 mg by mouth and diphenhydramine hydrochloride by mouth or IV 
prior to MOv19-BBz CAR T cell infusion. If Benadryl is contraindicated, an H2-blocker, such as ranitidine, 
will be administered. These medications may be repeated every six hours or as needed. A course of non-
steroidal anti-inflammatory medication may be prescribed if the patient continues to have fever not 
relieved by acetaminophen. It is recommended that patients do not receive systemic corticosteroids such 
as hydrocortisone, prednisone, prednisolone (Solu-Medrol), or dexamethasone (Decadron). If 
corticosteroids are required for an acute infusional reaction, an initial dose of hydrocortisone 100 mg is 
recommended.  
 
MOv19-BBz CAR T cell Administration 
The MOv19-BBz CAR T cell infusion will take place on an outpatient basis at the Hospital of the University 
of Pennsylvania.  T-cell infusions will be performed by a licensed Registered Nurse at the Hospital of the 
University of Pennsylvania.  
 
Prior to the infusion, two trained study team members will independently verify the information on the 
label of the product bag in the presence of the subject and confirm that the information correctly matches 
the participant.   
 
The transduced T cells will be instilled through the indwelling peritoneal catheter into the affected 
peritoneal space.  
 
Vital signs (temperature, respiration rate, pulse, blood pressure, and oxygen saturation by pulse oximetry) 
will be measured within 10 minutes prior and within 15 minutes after the infusion.  Thereafter, vital signs 
will be measured at 30 (+/- 5) minutes, 45 (+/- 5) minutes, and 60 (+/- 5) minutes after the infusion, and 
then every hour (+/- 10 minutes) for the next two hours until these signs are satisfactory and stable. If 
vital signs are not satisfactory and stable 3 hours after the MOv19-BBz CAR T cell infusion, vital signs will 
continue to be monitored as clinically indicated until stable.  The subject will be discharged when 
medically stable and in accordance with hospital policy.  Subjects will be instructed to return to the 
University of Pennsylvania within 24 hours after the first infusion for blood tests and follow-up 
examination according to the Schedule of Events (Appendix 1). 
 
Following the infusion, the subject should lie in the lateral decubitus position on the opposite side of the 
catheter for 15 minutes, if applicable.  The IP catheter will be removed prior to the subject being 
discharged. 


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Additional Safety Monitoring 
Emergency medical equipment (i.e. a crash cart) must be available for an emergency situation during the 
infusion in the event that the subject has an allergic response, or severe hypotensive crisis, or any other 
reaction to the infusion.    
 
Toxicity Management Considerations 
Please refer to Section 1.6/Potential risks and benefits for additional information.  
 
Febrile reaction  
In the unlikely event that the subject develops sepsis or systemic bacteremia following MOv19-BBz CAR T 
cell infusion, appropriate cultures and medical management will be initiated. If a contaminated MOv19-
BBz CART product is suspected, the product can be retested for sterility using archived samples that are 
stored in the CVPF. 
 
Infusion Reactions 
Several reactions may develop during and immediately after T cell infusions. A summary description of 
these reactions and the medical management is provided below: 
 
Flu-like symptoms 
• 
Fever/arthralgia/myalgia: The onset of these symptoms usually occurs 2 to 4 hours after 
the cell product administration. Management: Administration of acetaminophen or non-
steroidal anti-inflammatory drugs (NSAIDs) is effective in controlling and preventing 
symptoms. 
• 
Rigors/chills: These symptoms may occur during and/or after cell infusion administration. 
Management: The agent of choice to improve severe chills or rigors is an opioid such as 
dilaudid. If subjects develop rigors consistently after cell product administration, 
prophylactic administration of NSAIDS (e.g. ibuprofen) may prevent these reactions. 
 
Hemodynamic Effects 
• 
Edema: Adequate hydration is necessary to ensure renal perfusion, but over-hydration should 
be avoided. Subjects should be encouraged to drink electrolyte-containing fluids such as sport 
drinks and soups. Management: If diuretics are to be used to manage edema, they should be 
used with caution to avoid decreasing intravascular volume. If participants develop 
hypotension, IV fluids should be administered and appropriate evaluation with observation in 
an acute hospital bed is advisable. 
• 
Hypotension: Organ dysfunction, oliguria, and increases in BUN and creatinine are usually 
reversible upon discontinuation of cell product and 24 to 48 hours of supportive treatment. 
Management: On rare occasions, low doses of dopamine and fluid support may be warranted. 
Educating the subject to slowly rise from a supine to a sitting position and then to a standing 
position can prevent orthostatic hypotension. Evaluation in the Emergency Department if 
symptoms occur is advisable. 
 
Dermatologic Reactions 
Skin reaction: Dry skin, pruritis, erythema, and sloughing may occur following cell infusions. No 
interruption of therapy is usually needed. Skin rashes have been observed in approximately 20 to 
25% of subjects treated with T cells to date. The rashes have generally been transient 
maculopapular rashes that appear about a week after T cell administration. The rashes may 


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resemble those described in autologous graft versus host disease (GVHD), but to date, the 
pathogenesis has not been clarified. Management: Anti-histamines and topical corticosteroids, 
water or oil-based lotions, and oatmeal baths may help control the symptoms.  
 
Other potential short-term and long-term toxicities and their management include: 
 
Cytokine release syndrome (CRS) Cytokine release syndrome is caused by a release of inflammatory 
cytokines such as IL-6, IL-2R, IFN-γ, and IL6 receptor [128]. This type of reaction is common in cancer 
immunotherapy where antibodies bind T cells that release large amounts of cytokines, or cause rapid 
destruction of tumor/target cells. This causes a systemic inflammatory response similar to sepsis and 
includes fever, nausea, chills, rash, flushing, rigors, hypotension, tachycardia, headache, throat tightness, 
and dyspnea. Capillary leak with fluid retention is worsened by hydration commonly given to treat 
hypotension. The syndrome can be associated with pulmonary infiltrates, pulmonary edema, arrhythmias, 
and cardiac arrest. The syndrome is also associated with an elevation in LFTs, D-dimers, LDH, CR, uric acid 
and phosphorus from immune-mediated cytolysis of targeted cells, with release of intracellular contents 
as well as possible bystander effect (on neighboring, non-targeted cells).  
 
Most UPENN patients who have responded to CART19 cells experienced CRS. The CRS was initially defined 
to describe an infusion reaction or reaction to antibodies. It is manifested by high fevers, anorexia, nausea, 
headache, rash, and, in some patients, hypotension, shortness of breath, hypoxia, delirium and 
biochemical evidence of disseminated intravascular coagulation (DIC) and macrophage activation 
syndrome (MAS). The clinical syndrome of MAS is characterized by high grade non-remitting fever, 
cytopenias affecting at least two of three lineages, and hepatosplenomegaly. It is associated with 
biochemical abnormalities, such as high circulating levels of serum ferritin, soluble interleukin-2 receptor 
(sCD25), and triglycerides, together with a decrease of circulating NK activity. Other findings include 
variable levels of transaminases up to signs of acute liver failure and coagulopathy with findings consistent 
with DIC. A pathologic feature of MAS is the presence of hemophagocytic CD163+ macrophages (HPC) in 
bone marrow or lymph node aspirates. MAS appears to be a reaction to immune activation that occurs 
from the CRS, and therefore should be considered a manifestation of CRS. Macrophage activation 
syndrome (MAS) is similar to Hemophagocytic lymphohistiocytosis (HLH); it is reactive to immune 
stimulation, infection, autoimmune diseases or other precipitants but is distinguished from familial or 
genetically-mediated HLH. 
 
Management: Upon developing the prodrome of high-persistent fevers following CAR infusion, patients 
should then be followed closely. Infection and tumor lysis syndrome work up should be immediately 
undertaken. Additional blood will be collected as soon as possible and sent to TCSL for real time cytokine 
analysis.  CRS management decisions should be based upon clinical signs and symptoms and response to 
interventions, not on laboratory values per se. Ferritin, CRP and serum cytokine levels should NOT be used 
for clinical management decisions. Additional blood collection is warranted and will be performed as 
needed to manage the CRS toxicity. This includes but it is not limited to analysis of D-dimers, ferritin, LDH, 
triglycerides, CRP, and haptoglobin. 
 
Mild CRS such as fever alone in the absence of organ dysfunction or hypotension can be managed with 
acetaminophen.  For higher grades CRS, all standard of care will be offered to assure subject wellbeing 
including treatment with steroids to prevent further cytokine activation and release, anti-histamines, and 
supportive care (fluids, pressors, intubation if needed). Because steroids are thought to interfere with CAR 
function and efficacy, if used, they should be rapidly tapered. In addition, the investigator or treating 


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physicians may choose to administer anti-cytokine therapy such as tocilizumab, siltuximab or other (such 
as anakinra).  
 
In addition to supportive care, tocilizumab may be administered in cases of moderate to severe CRS, 
especially if the patient exhibits any of the following: 
• 
Hemodynamic instability despite intravenous fluid challenges and moderate stable vasopressor 
support  
• 
Worsening respiratory distress, including pulmonary infiltrates, increasing oxygen requirement 
including high-flow O2, and/or need for mechanical ventilation.  
• 
Any other signs or symptoms of rapid deterioration despite medical management  
 
Tocilizumab is a recombinant humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody of 
the immunoglobulin (Ig) IgG1k subclass. It binds both the membrane bound and soluble forms for the IL-
6 receptor, and thus blocks IL-6 mediated pro-inflammatory effects. Tocilizumab has been approved for 
the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an 
inadequate response to one or more tumor necrosis factor (TNF) inhibitor therapies (i.e., infliximab). In 
2011, it received approval for children with systemic juvenile idiopathic arthritis. Most recently in 2017, 
the FDA approved tocilizumab for the management of CAR T cell-induced cytokine release syndrome.   
 
The moderate to severe cases of CRS observed required intervention with tocilizumab, with or without 
high dose corticosteroids, between 2 and 9 days after T cell infusion. This resulted in rapid reversal of the 
high persistent fevers and hemodynamic instability associated with CRS in most but not all patients. 
Patients with a suboptimal response to the first dose of tocilizumab have received a second dose of 
tocilizumab with CRS resolution.   Given the dramatic clinical improvement of patients after treatment 
with anti-cytokine therapy, patients with moderate to severe cytokine toxicities should be managed with 
administration of tocilizumab. Steroids have not always been effective in this setting and may not be 
necessary given the rapid response to tocilizumab. Not all Grade 4 CRS reactions following CART-19 have 
been immediately treated with tocilizumab and decisions are, in part, based upon the rapidity of the 
syndrome onset and underlying patient reserve.  
 
Tocilizumab should be used as a single, weight-based dose of 8 mg/kg at the time of hemodynamic 
instability. This management approach is designed to avoid life-threatening toxicities, while attempting 
to allow the CAR cells to establish a proliferative phase that appears to correlate with anti-tumor efficacy. 
Thus, the timing of the tocilizumab should be individualized, in close consultation with the Principal 
Investigator and/or expert consultants.  
 
Other anti-cytokine therapies, such as repeat administration of tocilizumab or use of siltuximab or 
etanercept, may also be considered if the patient does not respond to the initial dose of tocilizumab.  If 
the patient experiences ongoing CRS despite administration of anti-cytokine directed therapies, anti T-cell 
therapies such as cytoxan, ATG, campath may be considered.   
 


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A detailed treatment algorithm has been established for with clear criteria for CRS management following 
CART-19 administration and guidance on when to administer tocilizumab (Figure 5.3.1.4). This approach 
was designed to avoid life-threatening toxicities, while attempting to allow the CART-19 transduced cells 
to establish a proliferative phase which appears to correlate with tumor response. The management of 
CRS is based solely upon clinical parameters. This algorithm may be used to guide CRS management 
related to MOv19-BBz CAR T cell treatment; however, changes specific to the MOv19-BBz CAR T cells 
should be considered and based on clinical judgment. Specific CRFs have been developed for the capture 
of CRS elements, severity, management and response to intervention.  
 
Figure 5.3.1.4 CRS Management Algorithm 
 
 
 
 


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Neurologic Toxicity. 
Guidelines for management of neurologic toxicity are described in Table 5-1. The mechanism underlying 
neurotoxicity after CAR T cell administration is poorly understood. Anecdotal evidence suggests that anti-
IL6 therapies, which are effective for CRS, do not reverse neurotoxicity. Neurotoxicity can be 
asynchronous with cytokine release syndrome, often reaching its maximum intensity later than CRS or 
even arising after resolution of CRS. This has led to the appearance in some cases that treatment of CRS 
with anti-IL6 agents worsens or precipitates neurotoxicity; a causative relationship between anti-IL6 
therapy and neurotoxicity has not been conclusively established, however, and severe neurotoxicity has 
been observed in the absence of CRS and in cases where no anti-IL6 therapy has been used. The following 
principles guide the recommended management of neurotoxicity: 
– Most instances of neurologic toxicity are self-limited, but life-threatening complications such 
as cerebral edema develop in some cases. Corticosteroid therapy aimed at dampening CAR T 
cell proliferation and activity is therefore recommended for moderate (grade 2-3) 
neurotoxicity with the objective of preventing development of life-threatening, grade 4 
manifestations. The efficacy of corticosteroids is unproven, however, and corticosteroids may 
adversely affect CAR T cell efficacy. The recommended dose of corticosteroids is therefore 
stratified based on perceived risk of developing life-threatening complications; low/moderate 
doses are recommended for grade 2, moderate doses for grade 3, and high-doses for grade 4. 
In addition, it is recommended that cytotoxic chemotherapy be considered in grade 4 cases 
based on a report that cerebral edema improved promptly after cyclophosphamide 
chemotherapy in one case [129]. 
– Consultation with a neurologist is helpful for properly documenting and tracking neurologic 
abnormalities, evaluating for other potential etiologies of neurologic abnormalities, and 
managing neurologic emergencies such as seizure or elevated intracranial pressure.  
– Coagulopathy and thrombocytopenia should be aggressively managed. Both coagulopathy and 
thrombocytopenia often develop with CRS. Intracranial hemorrhage has been observed in 
conjunction with severe neurotoxicity. Intracranial hemorrhage may provide a portal of entry 
for CAR T cells and systemic cytokines to affect the CNS or may simply confound interpretation 
of neurologic abnormalities. In addition, a recent report suggests that thrombocytopenia is an 
independent risk factor for CAR-related neurotoxicity, and platelets may serve as a source of 
mediators that stabilize the endothelium and counteract destabilizing effects of cytokines 
elaborated during CAR T cell proliferation[130]. 
– CRS should be managed concurrently with neurotoxicity according to guidelines enumerated 
above. It is difficult to distinguish delirium secondary to CRS from mild/early CAR-related 
neurotoxicity (and these phenomena may not be distinct pathophysiologically). In general, for 
subjects with grade ≥2 neurologic toxicity in conjunction with CRS requiring tocilizumab, it is 
recommended that corticosteroids be administered together with or before tocilizumab to 
dampen a potentially exacerbating effect of tocilizumab on neurotoxicity.  
 


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Table 5-1:  Neurotoxicity management  
Neurologic Event 
Grade  
Toxicity Management Guidelines 
- 
If subject experiencing concurrent CRS, follow CRS management 
guidelines in parallel.  
Grade 1 
 
• 
Consider non-sedating antiseizure medicines (eg levetiracetam) for seizure 
prophylaxis. 
Grade 2 
 
 
 
 
• 
Consider neurology consultation 
• 
Perform head imaging, preferably MRI; consider lumbar puncture and/or 
funduscopic exam. 
• 
Consider dexamethasone 8-40 mg/day in divided doses  
• 
Consider non-sedating antiseizure medicines (eg.levetiracetam) for seizure 
prophylaxis  
• 
Administer platelet transfusion if platelet count <30000/µl; monitor for 
coagulopathy- if fibrinogen < 150 mg/dl give cryoprecipitate  
Grade 3 
 
 
 
• 
Consider neurology consultation 
• 
Perform head imaging, preferably MRI; consider lumbar puncture and/or 
funduscopic exam. 
• 
Administer dexamethasone 10mg every 6 hours. Continue dexamethasone 
use until the event is Grade 1 or less, then taper over 3 days 
• 
Consider non-sedating antiseizure medicines (eg.levetiracetam) for seizure 
prophylaxis  
• 
Administer platelet transfusion if platelet count <30000/µl; monitor for 
coagulopathy- if fibrinogen < 150 mg/dl give cryoprecipitate  
Grade 4 
 
 
• 
Consider neurology consultation 
• 
Perform head imaging, preferably MRI; consider lumbar puncture and/or 
funduscopic exam. 
• 
Administer methylprednisone 1000 mg intravenous per day for a total of 3 
days then taper as indicated.  Consider a 50% decrease every 3 days.   
• 
Consider non-sedating antiseizure medicines (eg.levetiracetam) for seizure 
prophylaxis 
• 
Administer platelet transfusion if platelet count <30000/µl; monitor for 
coagulopathy- if fibrinogen < 150 mg/dl give cryoprecipitate  
• 
Consider cytotoxic chemotherapy (e.g., cyclophosphamide 1.5 g/m2) 
 
Anaphylaxis 
According to our experience treating 14 subjects with anti-mesothelin SS1 CAR mRNA T cells (7 
mesothelioma subjects under UPCC# 17510, 6 pancreatic cancer subjects under UPCC# 08212, and one 
pancreatic cancer subject under UPCC# 21211), anaphylaxis is a rare but possible toxicity created by 
repeated CAR T cells infusions with long periods of time between infusions (See Section 1.6). Management 
of anaphylaxis includes epinephrine, volume resuscitation, and corticosteroids, and other supportive care 
as needed (oxygen, ventilation, beta2 agonists for bronchoconstriction, etc.). Management is generally 
similar to that described for cytokine release syndrome (as above), but with the use of epinephrine as the 
principal therapeutic medication. The dose of epinephrine used depends on the degree of systemic 
involvement (low dose for hypotension, high dose -1 mg iv repeated every minute as necessary) for PEA 
arrest, according to ACLS guidelines.  
 


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Off-Tumor On-Target Toxicities  
In the event of aFR reaction on normal tissue and inflammatory process leading to fluid accumulation, 
these cavities can be quickly and readily accessed in a minimally invasive fashion to remove the fluid as 
anti-lymphocyte therapy is initiated. T cell ablating therapies including corticosteroids, chemotherapy 
such as cyclophosphamide, or immunotherapy such as alemtuzumab may also be considered at the 
investigators’ discretion.  These toxicities should also be further managed per treating investigator 
discretion and standard clinical practice. 
 
For additional potential risks of therapy, please refer to Section 1.6.  
5.3.2 Cyclophosphamide  
Receipt of Cyclophosphamide 
Cyclophosphamide will be ordered through the site-designated research pharmacy for research purposes. 
 
Storage 
Cyclophosphamide will be a stored according to the manufacturing instructions in the approved package 
insert.  
 
Premedication for Cyclophosphamide 
It is anticipated that patients receiving cyclophosphamide may experience nausea and vomiting as a side 
effect of the treatment. Anti-emetic prophylaxis premedication for nausea (including corticosteroids) can 
be administered prior to infusion of chemotherapy according to the institutional standards. Choice of 
specific agent will be left to the discretion of the investigator, and may include corticosteroids as 
appropriate. For more details, see Sections 5.6 and 6.5. 
 
Cyclophosphamide Administration 
Cyclophosphamide will be administered at a dose of 300 mg/m2/day x 3 days by IV infusion either in the 
Hematology-Oncology infusion suite at the Perelman Center for Advanced Medicine or elsewhere at the 
Hospital of the University of Pennsylvania. Infusions will be scheduled so that the last day of 
chemotherapy falls 3 days (±1 day) prior to CAR T cell infusion (Day 0) (Section 6.6). Appropriate 
institutional procedures for proper handling and disposal of antineoplastic drugs will be followed. 
5.3.3 Fludarabine 
Receipt of Fludarabine 
Fludarabine will be ordered through the site-designated research pharmacy for research purposes. 
 
Storage 
Fludarabine will be a stored according to the manufacturing instructions in the approved package insert.  
 
Premedication for Fludarabine 
It is anticipated that patients receiving fludarabine may experience nausea and vomiting as a side effect 
of the treatment. Anti-emetic prophylaxis premedication for nausea (including corticosteroids) can be 
administered prior to infusion of chemotherapy according to the institutional standards. Choice of specific 
agent will be left to the discretion of the investigator, and may include corticosteroids as appropriate. For 
more details, see Sections 5.6 and 6.5. 
 


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Fludarabine Administration 
Fludarabine will be administered at a dose of 30 mg/m2/day x 3 days by intravenous infusion either in the 
Hematology-Oncology infusion suite at the Perelman Center for Advanced Medicine or elsewhere at the 
Hospital of the University of Pennsylvania. Fludarabine doses will be rounded down to the nearest 50 mg 
vial size, if the rounded dose does not differ by > 10% of the original dose prescribed. Infusions will be 
scheduled so that the last day of chemotherapy falls 3 days (±1 day) prior to CAR T cell infusion (Day 0) 
(Section 6.6). Appropriate institutional procedures for proper handling and disposal of antineoplastic 
drugs will be followed. 
 
Possible Reactions after Cyclophosphamide Infusion 
Potential risks of cyclophosphamide administration and their management are described in Section 1.6 
and 6.5.   
5.4 Dose-Limiting Toxicity (DLT) and Cohort Progression 
A dose limiting toxicity is defined as grade ≥3 hematologic or non-hematologic toxicity [NCI Common 
Terminology Criteria for Adverse Events (CTCAE v5.0)] which develops following dosing and through the 
Day 28 safety follow-up visit, is new (not existent before infusion), at least possibly related to T cells, and 
does not improve to Grade ≤ 2 within 7 days of optimal medical management.  Component events that 
are captured as adverse events of particular interest (such as hypoxia and hypotension in the setting of 
CRS) may not be evaluated separately against the DLT definition. 
 
Events excluded from the above DLT definition are: 
• 
Alopecia 
• 
Grade 3 electrolyte abnormalities 
• 
Hyperglycemia  
• 
Diarrhea 
• 
Nausea and vomiting that can be managed with supportive care 
• 
Grade 4 neutropenia/leukopenia or thrombocytopenia that improves to ≤ Grade 2 by Day 28 
5.5 Subject Compliance Monitoring 
Adherence to scheduled follow-up visits is important in order to assess the primary safety endpoint 
associated with this study. During the process of informed consent, each patient will be clearly informed 
of the study schedule, associated procedures, and the requirement for follow-up. Patients that are not 
able to commit to the study schedule will not be enrolled in the study. 
5.6 Prior and Concomitant Therapy 
All prescription and nonprescription medication, vitamins, herbal and nutritional supplements, or devices 
taken/used by the subject as well as any prior surgeries beginning within 30 days prior to consent will be 
recorded.  At every visit following the MOv19-BBz CAR T cell infusion, concomitant medications will be 
recorded in the medical record and on the appropriate CRF.  Any additions, deletions, or changes of these 
medications will be documented. All prior oncology therapies for their targeted disease will also be 
collected in the appropriate eCRF. 
 
Concomitant medications and therapies deemed necessary for the supportive care and safety of the 
subject are allowed.  Subjects may also continue to receive standard therapies and/or undergo routine 
care procedures for the management of their disease prior to receipt of study treatment and while their 


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product is being manufactured.  However, the following concomitant therapy guidelines must be adhered 
to during the study: 
• 
The addition of any other concurrent cancer treatment (including cytotoxic, hormonal, 
homeopathic, or immunologic therapy) will confound the assessment of safety and efficacy of the 
investigational product.   Thus, cancer treatment is not allowed within the 2 weeks before 
apheresis and 2 weeks before T cell infusion.  Medication intended solely for supportive care (e.g. 
analgesics, antiemetics, antidiarrheals, antidepressants or bisphosphonates, etc.) may be used at 
the investigator’s discretion. Palliative radiation therapy for symptom management is allowed. 
• 
PD-1 or PD-L1 targeted therapies are not allowed while the subject is in primary follow-up.  
• 
Prior aFR targeted therapies are permissible if received > 4 weeks from study treatment. 
• 
Prophylactic use of granulocyte colony-stimulating factor (G-CSF, filgrastim) may be used if 
medically indicated, particularly in a patient who is experiencing recurrent difficulties with 
neutropenia, however the effects of G-CSF on product manufacturing are unknown.  
• 
GM-CSF should be avoided due to potential to worsen CRS symptoms. Therapeutic use in patients 
with serious neutropenic complications such as tissue infection, sepsis syndrome, fungal infection, 
etc. may be considered at the investigator’s discretion, consistent with American Society of 
Clinical Oncology guidelines. The use of erythropoietin is also permitted at the discretion of the 
treating physician. 
• 
Use of systemic high dose (e.g. > 100 mg of prednisone daily or >40 mg dexamethasone daily or 
equivalent) corticosteroids or other immunosuppressant drugs should NOT be used as pre-
medication for MOv19-BBz CAR T cell infusion or following the infusion, unless under life 
threatening circumstances or to manage toxicity. Patients may be on a stable low dose of steroids 
(≤10mg daily equivalent of prednisone) if determined clinically appropriate, except if used for the 
treatment of CNS disease.  Corticosteroids treatment as anti-emetic prophylaxis on the day of 
lymphodepleting chemotherapy administration is allowed per institutional guidance.  Topical and 
inhaled steroids are permitted at any time as per clinical discretion.  
• 
The use of systemic cyclosporine or other immunosuppressive drugs while on study is not 
permitted unless deemed medically necessary by the investigator for treatment of adverse 
events.  
• 
Paracentesis: Therapeutic paracentesis may be performed at the time of CAR T cell infusion per 
clinical discretion.  Paracentesis should be avoided within 1 week after CAR T cell infusion.  
• 
Therapeutic anticoagulation is allowed while on study and may be held around the time of 
catheter placement as per standard clinical procedure. 
• 
Prophylaxis will be initiated post lymphodepleting chemotherapy.  To align with standard hospital 
practice in CAR T cell therapies using fludarabine and cyclophosphamide for lymphodepletion, the 
following prophylaxis is recommended. Alterations to these recommendations may be 
implemented as per physician-investigator clinical discretion. 
o 
Levofloxacin and fluconazole until count recovery (ANC ≥ 500), AND 
o 
Acyclovir and Bactrim for 100 days or until absolute CD4 ≥ 200 
6 
STUDY PROCEDURES 
Overview 
The study consists of 1) pre-screening 2) a screening/enrollment phase, 3) apheresis and T cell 
manufacturing, 4) pre-infusion safety check, 5) an intervention phase consisting of MOv19-BBz CAR T cell 
administration alone or following study-mandated chemotherapy, 6) primary follow-up visits, and 7) long-
term follow-up. The Schedule of Events is included in Appendix 1.  


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6.1 Screening  
Pre-Screening 
Patients will first be pre-screened for alpha folate receptor expression. The test for alpha folate receptor 
expression is a laboratory developed test, developed and conducted by the Hospital of the University of 
Pennsylvania Pathology and Laboratory Medicine lab to determine subject eligibility.  This test is not an 
approved FDA device and its use is investigational.   
 
Subjects will be asked to sign a separate pre-screening informed consent requesting permission to test 
their tumor for aFR expression.   Evaluation of aFR expression will occur on archived tumor tissue, if the 
patient has not had an anti-aFR directed therapy since the collection of the archived sample. However, if 
archived tumor tissue is not available, a fresh biopsy may be performed.  Once aFR expression has been 
confirmed, subjects may be presented the informed consent for the main study.  If the aFR expression of 
their tumor is known prior to signing the tissue testing consent for this study, the results of this testing 
will need to be confirmed as part of the subjects’ participation on this protocol.  Once aFR expression has 
been confirmed, subjects may proceed to the next step and be presented the informed consent for the 
main study.  
 
Screening 
Informed consent must be obtained before the subject can undergo any research-related procedures.  
Results obtained in routine clinical care prior to informed consent may also be used for screening purposes 
as long as they are obtained within the protocol required windows.  
 
Screening procedures include: 
• ECOG performance status  
• Complete medical history 
• Physical examination including vital sign assessments, height and weight 
• Review of concomitant medications 
• Leukapheresis screening- Subjects can be given the opportunity to undergo temporary central 
venous access for apheresis if peripheral access cannot be obtained.  
• Complete blood count and differential 
• Chemistry panel- including sodium, potassium, chloride, CO2, blood urea nitrogen, creatinine, 
glucose, magnesium, phosphate, total protein, albumin, calcium, alkaline phosphatase, total 
bilirubin, ALT, AST, uric acid, LDH 
• Coagulation Factors- PT, PTT, fibrinogen, INR 
• Viral serologies: HIV, Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody, Hepatitis B 
core antibody, and Hepatitis C antibody. If the HCV antibody is positive, a screening HCV RNA by 
any RT-PCR or bDNA assay must be performed. Eligibility will be determined based on the 
screening value. The test is not required if documentation of a negative result of a HCV RNA test 
performed within 60 days prior to screening is provided. 
• Autoantibody panel: ANA  
• Urinalysis 
• 12 lead Electrocardiogram (EKG) 
• Resting echocardiogram (ECHO) or MUGA- must be performed within 8 weeks prior to the CAR T 
cell infusion. 
• Urine β HCG pregnancy (women of childbearing potential) 
• CT chest/abdomen/pelvis-with or without contrast within 8 weeks of physician-investigator 
confirmation of eligibility.  CT scans are the preferred modality; however, other methodologies 


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may be utilized at the physician-investigator’s discretion, if performed in accordance with RECIST 
1.1 criteria.    
• MRI brain- required only if the subject has known CNS metastases  
 
In the event that the time between the above screening tests and the infusion of MOv19-BBz CAR T cells 
exceeds the 8-week Screening/Enrollment Window the following will be repeated: Physical Examination, 
Performance Status Assessment, Complete Blood Count with differential and Platelet Count, Chemistry 
Panel, 
Pregnancy 
test, 
HIV 
and 
Hepatitis 
B/C 
tests, 
echocardiogram/MUGA, 
and 
CT 
chest/abdomen/pelvis.   
6.2 Monitoring Visit for Eligibility 
Assignment of subject numbers will occur at the time of pre-screening consent, will be in ascending order, 
and no numbers will be omitted.  Subject numbers will be used on all study documentation.  Once 
assigned, the subject number must not be reused for any other subject and it must not be changed, even 
if the subject is rescreened. 
 
A Consent Notification Form should be completed at the time of Pre-Screening Consent and Main 
Informed Consent. Once required screening tests have been completed and the subject has been 
determined eligible by the Physician-Investigator, provide the documents listed below to: 
 
Sponsor Protocol Monitor and Sponsor Project Manager 
Center for Cellular Immunotherapies (CCI) 
 
Documents required: 
• 
Completed Eligibility Form  
• 
Redacted copy of signed subject informed consent and HIPAA Authorization 
• 
Redacted source documentation to confirm enrollment/eligibility (including patient past medical 
history, laboratory, radiological reports, physical exam, concomitant medications and any other 
source documentation to support that the patient meets eligibility criteria and has completed all 
required screening assessments). 
 
Upon receipt of screening and eligibility documentation, the Sponsor Protocol Monitor will review and 
provide documentation that the monitoring visit for eligibility has been completed.  This documentation 
must be received prior to apheresis and/or cell product manufacturing. 
6.3 Leukapheresis 
A large volume apheresis procedure will be carried out at the University of Pennsylvania Apheresis Center 
according to standard clinical procedures (~4-6 weeks prior to infusion of the MOv19-BBz CAR T cells). 
PBMC are obtained for CAR T cells during this procedure. From a single leukapheresis, the intention is to 
harvest at least 5 x 109 white blood cells to manufacture MOv19-BBz CAR T cells. The MOv19-BBz CAR T 
cell product is expected to be ready for release approximately 4 weeks later.  If the harvest of cells or the 
T cells manufacture is unsuccessful, subjects will have the option to undergo a second leukapheresis for a 
second manufacturing process. Subjects have the option to receive a lower than target dose if the MOv19-
BBz CART product meets CVPF release criteria, and the subject cannot or is not willing to perform a second 
apheresis, or if the second manufacturing process fails.  If a subject has previously had an adequate 
apheresis collection banked according to current Good Manufacturing Practices at the Clinical Cell and 


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Vaccine Production Facility, these cells may be used as the source of cells for MOv19-BBz CAR T cells 
manufacturing.  
 
Recommended criteria for apheresis product acceptance to initiate processing for clinical 
manufacturing to meet the dosing requirements includes the following specifications:  It is 
recommended that the patient have an absolute lymphocyte count (ALC) ≥500/µl, prior to undergoing 
apheresis.  If the patient’s ALC is <500/µl, it is recommended that a lymphocyte subset analysis (CD3, CD4, 
CD8 counts) be performed to confirm that the patient has an absolute CD3 count of ≥150/µl.  If the 
absolute CD3 count is <150/µl, it is recommended that the leukapheresis procedure be delayed until their 
ALC is ≥500/µl or absolute CD3 count is ≥150/µl.   
 
The apheresis product is transported to the CVPF for processing. A portion of the peripheral blood 
leukocytes will be saved for the TCSL laboratory at the University of Pennsylvania and used for baseline 
immunoassessment research assays, a portion will be sent to PDCS for biobanking, and the other portion 
used for The MOv19-BBz CAR T cell manufacturing in CVPF. Baseline blood leukocytes for FDA look-back 
requirements will also be obtained and cryopreserved.  
 
Historical Apheresis Sample 
Cryopreserved historical apheresis products collected from the patient as part of routine care or under a 
separate research protocol may be usable for the MOv19-BBz CAR T manufacturing if the sample was 
collected at an appropriately certified apheresis center and if the product meets adequate mononuclear 
cell yields.  
6.4 Pre-infusion safety visit (Week -2 to -1) 
1-2 weeks prior to the scheduled T cell infusion, subjects will be tested for baseline evaluations according 
to the Schedule of Events in Appendix 1. 
 
If the subject has an accessible tumor and it is determined clinically feasible, a baseline tumor biopsy will 
be performed prior to MOv19-BBz CAR T cell infusion.  This may include a CT-guided needle biopsy or 
needle aspiration of malignant effusion.  The baseline biopsy may occur any time prior to infusion between 
Day -14 and initiation of study treatment (i.e. lymphodepleting chemotherapy in applicable cohorts or 
MOv19-BBz CAR T cells).  This baseline biopsy sample will be used to evaluate the level of aFR expression 
and if feasible, other immune markers at baseline. If the subject had a fresh biopsy at pre-screening in 
order to evaluate aFR expression, a repeat biopsy at the pre-infusion timepoint is not required. 
6.5 Lymphodepleting chemotherapy administration (Cohorts 2 and 3 only)   
Subjects in Cohorts 2 and 3 will receive lymphodepleting chemotherapy as a regimen of 
cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2 daily over three days. Note: Fludarabine doses will 
be rounded down to the nearest 50 mg vial size, if the rounded dose does not differ by > 10% of the 
original dose prescribed. This lymphodepleting chemotherapy regimen must be scheduled so that the last 
day of therapy falls 3 days (+/- 1 day) prior to CAR T cell infusion.  Although both cyclophosphamide and 
fludarabine are FDA-approved agents and will be prepared and infused in accordance with their FDA-
approved labels and standard institutional practice, their use in this trial will be considered investigational.   
 
Lymphodepleting chemotherapy is NOT required if the subjects WBC ≤ 1,000 /μL or if the subject received 
bridging chemotherapy with cyclophosphamide or fludarabine as per routine care within 28 days of the 
1st day of the planned lymphodepleting chemotherapy regimen.  Subjects who receive lymphodepleting 


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chemotherapy but in whom their CAR T cell infusion is subsequently delayed >2 weeks after the first day 
of lymphodepleting chemotherapy may receive a second cycle of lymphodepleting chemotherapy prior 
to CAR T cell infusion at the discretion of the physician-investigator. 
 
Subjects will undergo assessments per the Schedule of Events in Appendix 1 prior to their first day of 
lymphodepleting chemotherapy. If >48 hours have passed since subject’s last blood work, a complete 
blood count with differential, and full chemistry panel will be repeated prior to initiating chemotherapy. 
 
The following criteria must be met in order to proceed with lymphodepleting chemotherapy 
administration:  
1) Patients should not have received systemic chemotherapy within 2 weeks prior to the scheduled 
MOv19-BBz CAR T cell infusion.  If chemotherapy was administered, then this procedure will be 
re-scheduled. 
2) Patients must have recovered from toxicities, including myelosuppression, resulting from routine 
care chemotherapy or other immunotherapies administered after physician-investigator 
confirmation of eligibility as per the discretion of the treating physician.  
3) Patients should not experience a significant change in performance status compared to initial 
eligibility criteria that would, in the opinion of the treating physician-investigator or PI, increase 
the risk of experimental cell infusion.  
4) Patients must not have laboratory abnormalities after physician-investigator confirmation of 
eligibility that, in the opinion of the treating physician-investigator or PI, may impact subject 
safety or the subjects’ ability to receive lymphodepleting chemotherapy or the MOv19-BBz CAR T 
cells. If this occurs, patients may have their treatment delayed until both the treating investigator 
and PI determine it is clinically appropriate to proceed.  
5) All subjects must undergo a Respiratory Virus Panel (RVP) within 10 days prior to MOv19-BBz CAR 
T cell infusion. If the patient is positive for influenza, Tamiflu® or equivalent should be 
administered per package insert. The patient must complete treatment prior to receiving 
lymphodepleting chemotherapy and MOv19-BBz cells. The test does not need to be repeated 
prior to the MOv19-BBz cell infusion; however if influenza signs and symptoms are present, the 
infusion should be delayed until the patient is asymptomatic. If the patient is positive for another 
virus on the RVP, the MOv19-BBz cell infusion will be delayed for at least 7 days to be sure clinical 
symptoms of a viral infection do not develop. If clinical symptoms develop, the lymphodepleting 
chemotherapy and CAR T cell infusion will be delayed until resolution of these symptoms. 
6) Patients should not experience any of the following specific toxicities:  
a. Pulmonary: New requirement for supplemental oxygen or presence of progressive 
radiographic abnormalities on chest x-ray (chest x-ray is not required at this juncture but 
should be evaluated if performed for clinical purposes) 
b. Cardiac: New cardiac arrhythmia not controlled with medical management.  
c. Hypotension requiring pressor support.  
d. Active Infection: Positive blood cultures for bacteria, fungus, or virus within 48-hours of 
T cell infusion. 
 
Anti-emetic prophylaxis: 
It is anticipated that patients receiving cyclophosphamide may experience nausea and vomiting as a side 
effect of the treatment. Premedication for nausea can be administered prior to infusion of chemotherapy. 
Choice of specific agent will be left to the discretion of the investigator. Corticosteroids treatment as anti-
emetic prophylaxis on the day of cyclophosphamide administration is allowed per institutional guidance 
per Section 5.6.   


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Prophylactic antibiotics will be administered post lymphodepleting chemotherapy per institutional 
standards and practices for cellular therapies as described in Section 5.6.   
 
Potential Side Effects 
See Section 1.6/ Risks of fludarabine and cyclophosphamide for more information. 
6.6 MOv19-BBz CART Product Administration (Day 0) 
CAR T cell infusion will begin 3 days (±1 day) after completion of chemotherapy (Cohorts 2 and 3). 
 
Prior to the administration of MOv19-BBz CAR T cells, all subjects will undergo tests/procedures in 
accordance with the Schedule of Events in Appendix 1.   Subjects will also have an intraperitoneal catheter 
placed by Interventional Radiology according to standard hospital procedure.   
 
The following criteria must be met in order to proceed with the MOv19-BBz CAR T cell infusion:  
a. Subjects in Cohorts 2 and 3 should not have received systemic chemotherapy other than 
lymphodepleting chemotherapy per protocol within 2 weeks prior to the MOv19-BBz CAR T cell 
infusion.  If chemotherapy was administered, then this infusion will need to be re-scheduled. 
b. Subjects should not experience a significant change in performance status compared to initial 
eligibility criteria that would, in the opinion of the treating physician-investigator or PI, increase 
the risk of experimental cell infusion.  
c. Subjects must not have laboratory abnormalities after physician-investigator confirmation of 
eligibility that, in the opinion of the treating physician-investigator or PI, may impact subject 
safety or the subjects’ ability to receive MOv19-BBz CAR T cells. If this occurs, subjects may have 
their treatment delayed until both the treating investigator and PI determine it is clinically 
appropriate to proceed.  
d. All subjects must undergo a Respiratory Virus Panel (RVP) within 10 days prior to MOv19-BBz CAR 
T cell infusion. If the subject is positive for influenza, Tamiflu® or equivalent should be 
administered per package insert. The subject must complete treatment prior to receiving 
lymphodepleting chemotherapy and MOv19-BBz cells. The test does not need to be repeated 
prior to the MOv19-BBz cell infusion; however if influenza signs and symptoms are present, the 
infusion should be delayed until the subject is asymptomatic. If the subject is positive for another 
virus on the RVP, the MOv19-BBz cell infusion will be delayed for at least 7 days to be sure clinical 
symptoms of a viral infection do not develop. If clinical symptoms develop, the lymphodepleting 
chemotherapy and CAR T cell infusion will be delayed until resolution of these symptoms. 
e. Subjects should not experience any of the following specific toxicities:  
a. Pulmonary: New requirement for supplemental oxygen or presence of progressive 
radiographic abnormalities on chest x-ray (chest x-ray is not required at this juncture but 
should be evaluated if performed for clinical purposes) 
b. Cardiac: New cardiac arrhythmia not controlled with medical management.  
c. Hypotension requiring pressor support.  
d. Active Infection: Positive blood cultures for bacteria, fungus, or virus within 48-hours of T 
cell infusion. 
 
Please refer to Section 5.3 (Preparation and Administration of Study Drug) for complete details. Potential 
reactions after infusion are presented in Section 5.3.1.4. 


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6.7 Post-infusion visits and tumor biopsy 
Subjects will return to the center (outpatient clinic of the study investigators or treating physician) at days 
+1, +2(+1), +7 (±1), +10 (±1), +14 (±1), and +21 (±1) for safety follow-up and to have blood drawn for 
evaluation of the safety endpoints and secondary (research) endpoints per the Schedule of Events in 
Appendix 1.  
 
If the subject’s tumor is measurable by CT and accessible by image-guided biopsy, subjects will undergo a 
tumor biopsy under image guidance at day 14(±7) to evaluate the impact of therapy on the tumor 
microenvironment and to assess for the presence of CAR T cells and aFR expression. These will be 
compared to baseline values from fresh biopsies if available, or stored surgical tumor specimens as 
applicable.  Thus, the same tumor site biopsied at baseline should be preferentially biopsied at this 
timepoint.   
 
In case of unexpected AEs or SAEs, additional samples may be collected for research analysis, focused on 
evaluating the potential causality with the infused MOv19-BBz CAR T cells see Section 3.3/Collection of 
Research Samples. 
6.8 Day 28 (+/- 5 days): Safety and Tumor staging 
At this study visit, subjects will undergo tests and procedures in accordance with the Schedule of Events 
in Appendix 1.  Tumor response will be assessed as described in Section 7.1.  A mini-apheresis procedure 
(~5 L) will also be performed at this visit for research purposes.  A 60 ml blood draw may be substituted 
for the mini-apheresis procedure at the discretion of the treating investigator.  
6.9 Month 2 (+/- 5 days): Safety  
Subjects will return to the center at Month 2 following MOv19-BBz CAR T cell infusion. At this study visit, 
subjects will undergo tests and procedures in accordance with the Schedule of Events in Appendix 1.   
6.10 Month 3 (+/- 5 days): Safety and Tumor staging 
Subjects will return to the center at Month 3 following MOv19-BBz CAR T cell infusion. At this study visit, 
subjects will undergo tests and procedures in accordance with the Schedule of Events in Appendix 1.  In 
addition, tumor staging (CT chest/abdomen/pelvis) will be performed. A CT scan within 4 weeks of this 
visit is acceptable. Tumor response will be assessed as described in Section 7.1. 
6.11 Month 6 (+/- 5 days): Safety and Tumor staging 
Subjects will return to the center at Month 6 following MOv19-BBz CAR T cell infusion.  At this study visit, 
subjects will undergo tests and procedures in accordance with the Schedule of Events in Appendix 1.  In 
addition, tumor staging (CT chest/abdomen/pelvis) will be performed.  A CT scan within 4 weeks of this 
visit is acceptable.  Tumor response will be assessed as described in Section 7.1. 
6.12 Quarterly evaluations for up to 2 years post-infusion 
After month 6, subjects will be evaluated on a quarterly basis for up to 2 years post infusion or until the 
subjects’ disease progresses and/or they initiate another cancer-related therapy. At these study visits, 
subjects will undergo tests and procedures in accordance with the Schedule of Events in Appendix 1.   


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6.13 Long-term Follow-up Phase 
Subjects who complete or prematurely discontinue from primary study follow-up will enter into the long-
term follow-up phase of this study and will be followed for up to 15 years after the MOv19-BBz CAR T cell 
infusion.  The visit schedule during long-term follow-up is calculated from the time of the subject’s 
MOv19-BBz CAR T cell infusion (Day 0) and the time of discontinuation from primary follow-up.  Table 6-1 
indicates the 1st LTFU study visit that would need to be completed based on Day 0.  
 
Table 6-1:  1st LTFU study visit to be completed  
Last study visit in primary follow-up 
1st LTFU study visit 
<3 months 
3 mo 
≥3 months and <6 months 
6 mo 
≥6 months and <9 months 
9 mo 
≥9 months and <1 year 
1 yr 
>1 year and <1.5 years 
1.5 yr 
>1.5 years and <2 years 
2 yr 
= 2 year 
2.5 yr 
 
During long-term follow-up, subjects will undergo tests and assessments in accordance with the Schedule 
of Events in Appendix 1. Subjects who enter long-term follow-up prior to disease progression will be 
followed for response per routine clinical care, until the subject’s disease progresses post MOv19-BBz CAR 
T cell infusion or they begin a new cancer therapy. 
 
In the event that a subject cannot return to the University of Pennsylvania for follow-up visits, the 
subject’s local provider will also be asked to provide information from the patient’s medical record to the 
study team at protocol-defined time points (i.e. the results of routine care physical examinations and/or 
laboratory assessments), and assist in the collection of protocol-required blood samples for persistence 
testing, which will be sent to the University of Pennsylvania Translational and Correlative Studies 
Laboratory (TCSL). The patient’s local provider will also be asked to assist in the monitoring and reporting 
of protocol defined adverse events, and provide copies of documentation pertaining to the absence or 
presence of delayed adverse events, along with the relevant reports of tests and procedures.  After the 
Month 60 (5 year) follow-up visit, subjects will only be asked to return for study visits if there is evidence 
of ongoing persistence of CAR T-cells in the previous year. If there is no evidence of CAR T-cell persistence 
in the previous year, follow-up will be conducted via phone/email/mail.  The Follow-up Survey in 
Appendix 2 may be used to facilitate contact with the subject as required. The template Physician Letter 
in Appendix 3 may be used to contact the patient’s local provider and facilitate their assistance in 
identifying any protocol defined adverse events. 
 
Additional research blood may also be collected during the primary or long-term follow-up phases of the 
study.  The total amount of extra blood that may be collected will not exceed 3 tablespoons of blood 
twice in one week.  In addition, tumor tissue from tumor biopsies that are performed during long-term 
follow-up as part of routine care may be provided to TCSL for correlative studies.  


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7 
ASSESSMENTS 
7.1 Tumor assessments 
All subjects who receive the target dose of MOv19-BBz CAR T cell infusion will be considered evaluable 
for response. Baseline scans should be obtained within 28 days prior to infusion of MOv19-BBz CAR T cells 
and after any cancer therapy administered between collection and MOv19-BBz CAR T cell infusion.  In 
Cohorts 2 and 3, baseline scans should be obtained prior to lymphodepleting chemotherapy 
administration and MOv19-BBz CAR T cell infusion. 
 
Radiographic imaging (CT) assessment 
Radiographic responses will be measured using two imaging assessment approaches: 1) Response 
Evaluation Criteria in Solid Tumors (RECIST 1.1) and 2) immune related response evaluation criteria in solid 
tumors (irRECIST) when feasible. For RECIST 1.1 evaluation, the determination of antitumor efficacy will 
be based on objective tumor assessments made according to the system of unidimensional evaluation.  
The same method and technique should be used to characterize each identified and reported lesion at 
baseline, during the study treatment period, and during follow-up. Imaging-based evaluation rather than 
clinical examination is the required technique when either could be used to assess the antitumor effect 
of the treatment. Computed Tomography (CT) scan is the preferred method for the tumor assessment. 
While CT scans are the preferred modality, other methodologies (MRI, etc.) may be utilized at the 
physician-investigator’s discretion, if performed in accordance with RECIST 1.1 criteria.  Scans may be 
administered with or without contrast at the investigator’s discretion.  
 
Because immune therapy can cause an initial tumor volume increase due to inflammation prior to 
subsequent tumor shrinkage, an exploratory analysis of response status will also be conducted using the 
recently developed immune related response evaluation criteria in solid tumors (irRECIST) [131-133].  
Novel to the irRECIST is the measurement of overall tumor burden as a metric of disease progression, 
compared to the limitation of using only baseline lesion measurements according to RECIST 1.1. According 
the irRECIST, new lesions do not constitute disease progression if net tumor burden including new lesions 
is stable or decreases. The irRECIST also permit disease progression at a subsequent time point after first 
detection. This accounts for the period required for activated T-cells to infiltrate the tumor, which may 
cause initial tumor volume increase due to inflammation but can subsequently translate into tumor 
shrinkage. The irRECIST also classifies durable stable disease as clinical activity. Thus, this protocol will 
explore two distinct imaging criteria for determination of disease outcome in response to treatment with 
MOv19-BBz CAR T cells.   
 
For details, please see the Schedule of Events (Appendix 1), which summarizes information on the timing 
of study assessments.   
 
Tumor biomarkers 
Tumor biomarkers as appropriate for ovarian cancer patients, such as CA125, will be measured according 
to the Schedule of Events (Appendix 1).  
7.2 Research Correlative Studies Assessment 
The planned correlative studies are as follows: 
1. Determine the persistence of MOv19-BBz CAR T cells in peripheral blood.  
Peripheral blood mononuclear cells’ DNA will be evaluated by Q-PCR using a validated assay that 
detects a fragment unique to the CAR sequence. PBMC may also be used for a flow cytometry 


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based assay for determination of MOv19-BBz CAR T cells. These analyses will be performed in bulk 
on each patient on peripheral blood, tumor derived material where available, or other 
tissues/fluids (ascites, peritoneal fluid, etc.). The primary engraftment endpoint is the # DNA CAR 
vector copies at Day 28 after infusion.  CAR T cell vector sequences will be performed at pre- and 
all post-infusion study visits as outlined in the Schedule of Events (Appendix 1).  Additional testing 
may also be performed at unscheduled timepoints at the discretion of the Sponsor.  This analysis 
will continue until any 2 sequential tests are negative documenting loss of CAR T cells.  
Additionally, flow cytometry may be used to detect cells expressing the MOv19-BBz CAR 
construct, if feasible.  
 
2. Determine the bioactivity of MOv19-BBz CAR T cells in peripheral blood.  
Serum or fluid (e.g. ascites) will be analyzed using Luminex to determine the presence of a panel 
of cytokines/chemokines/immune factors. Measurements will be performed in batches to 
maximize utilization of immune assay kits. In addition, bioactivity of the manufactured and 
infused MOv19-BBz CAR T cells may be assessed by functional flow cytometry via detection of 
cytokine production and cytotoxic activity of the cells stimulated with an aFR-expressing cell line. 
 
3. Evaluate the development of immune responses favoring rejection of MOv19-BBz CAR T cells. 
Development of HAMA and HACA antibody responses are expected to result in elimination of 
MOv19-BBz CAR T cells. Cellular immune responses directed to the modified T cells may also 
develop and be measured. Correlate the occurrence of such responses with loss of engraftment 
of CAR T cells. 
 
4. Evaluate the development of secondary anti-tumor responses as a consequence of MOv19-BBz 
CAR T cells. Tumor cell death mediated by MOv19-BBz CAR T cells may expose the immune system 
to new antigens, leading to new immune responses directed to the tumor. The development of 
new immune responses that develop to established tumor cell lines may be assessed and 
displayed as appropriate to each assay. This may be determined using next-generation sequencing 
of T cell receptor and immunoglobulin rearrangements in the tumor at baseline and post-infusion. 
 
5. Evaluate the potential to follow tumor biomarker levels as a surrogate of anti-tumor activity. 
These data will be correlated with changes in imaging and clinical progression. MOv19-BBz CAR T 
cells may lower serum aFR levels in ovarian cancer patients. This could occur directly by MOv19-
BBz CAR T cells eliminating aFR-expressing cells or through binding to soluble aFR protein. 
 
6. Where tumor material or body fluids can be obtained: 
a. Measure trafficking of MOv19-BBz CAR T cells.  
b. Evaluate aFR expression on tumor cells to assess for antigen-escape.  
c. Analyze tumor microenvironment and cell interactions (if feasible)- Immune correlates 
such as local immune activation (using qRT-PCR); the breath and hierarchy of the B and T 
cell repertoire via deep sequencing and compare with baseline specimens. 
8 
STATISTICAL PLAN 
8.1 General Design Issues 
This is a single-center pilot study in cancer patients to evaluate the safety and feasibility of autologous T 
cells engineered to express a CAR that targets aFR. The standard 3+3 dose escalation scheme will be 


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implemented to explore 3 dose cohorts (Cohort 1: 1-3x107 cells/m2 without lymphodepleting 
chemotherapy; Cohort 2: 1-3x107 cells/m2 after lymphodepleting chemotherapy with cyclophosphamide 
+ fludarabine; Cohort 3: 1-3x108 cells/m2  after lymphodepleting chemotherapy with cyclophosphamide + 
fludarabine). Dose may be de-escalated to dose cohort -1 (1-3x106 cells/m2 without lymphodepleting 
chemotherapy) if 2 DLT/3 subjects or 2 DLT/6 subjects occurs in Cohort 1.  The Maximum Tolerated Dose 
(MTD) is defined as the dose at which ≤1 DLT occurs in 6 evaluable subjects tested within the dose range 
of this study.  In order to gather additional data and establish the MTD dose level, the respective cohorts 
may be expanded to treat up to 6 total evaluable subjects. 
8.2 Sample Size Determination 
This study will enroll approximately 9 to 18 subjects depending on the occurrence of DLT and the number 
of dose cohorts examined. With 9 or 18 evaluable subjects, the half-width of the exact 90% confidence 
interval (CI) will be no more than 27% or 21%, respectively.   
8.3 Endpoints for Primary Objectives 
The primary objective is to evaluate safety and feasibility. Safety will be evaluated by determining the 
frequency of adverse events. Clinical feasibility is defined as the frequency of subjects enrolled on this 
protocol who do not receive MOv19-BBz CAR T cells. Reasons for this occurrence include rapid clinical 
deterioration or death, and subject withdrawal. Manufacturing feasibility is determined based on the 
“manufacturing failures” products. The number of manufactured products that do not meet release 
criteria for vector transduction efficiency, CAR T cell number, T cell purity, viability, and sterility will be 
determined and defined as “manufacturing failures”.   
8.4 Endpoints for Secondary Objectives 
The secondary objective is to evaluate clinical endpoints of tumor response (e.g., overall response rate, 
ORR), progression-free survival (PFS) and overall survival (OS). Disease response will be evaluated using 
RECIST 1.1 criteria.  Immune related response evaluation criteria in solid tumors (irRECIST) will also be 
evaluated when feasible. The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have been used to assess 
the anti-tumor effect of a treatment. Additional correlative endpoints include MOv19-BBz CAR T cells 
engraftment and persistence in peripheral blood and body fluids (including peritoneal fluid), bioactivity of 
MOv19-BBz CAR T cells in peripheral blood and body fluids (including peritoneal fluid) and other secondary 
anti-tumor responses as a consequence of epitope spreading.  
8.5 Subject Population(s) for Analysis 
• 
The Screen Set comprises all patients who are screened for the study. 
• 
The Enrolled Set comprises all patients who sign an informed consent form and are 
determined eligible to participate in the study (excluding screen failures). 
• 
Screening Failure Set comprised all patients of who fail to meet the inclusion/exclusion criteria 
specified by the protocol. This set will be used to evaluate clinical and manufacturing feasibility 
endpoints.  
• 
The Safety Evaluable Set comprises all subjects who received minimum acceptable dose of the 
MOv19-BBz CAR T cells and will be used for the primary safety endpoints. 
• 
The Efficacy Evaluable Set comprises all patients who receive the MOv19-BBz CAR T cells at 
the intended dose range. Efficacy evaluable patients also include those with disease 


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progression or death prior to completion of study safety visits. The Efficacy Evaluable Set will 
be used for the secondary efficacy endpoints.  
• 
The Efficacy Non-Evaluable Set comprises patients who receive MOv19-BBz CAR T cells at 
lower than intended dose.  These subjects will be evaluable for safety, but will not be evaluable 
for response.  These subjects will also not be included in DLT evaluations, thus will be replaced 
in that cohort. 
• 
The Full Analysis Set (FAS) comprises all patients who received the MOv19-BBz CAR T cells. 
This set includes both safety and efficacy evaluable sets and will be used for feasibility, and 
secondary correlative endpoints or other exploratory analyses. 
8.6 Statistical Analysis of Primary and Secondary Endpoints 
This is a phase I to study safety and feasibility of MOv19-BBz CAR T cells. The statistical analysis will be 
primarily descriptive. Summary tables of patient depositions, baseline demographic and clinical 
characteristics of the patients will be presented. For the primary objective of safety, adverse events will 
be collected and evaluated for all patients during the protocol specified adverse event reporting period 
outlined in Section 9.1. AEs will be graded for severity using the National Cancer Institute (NCI) – Common 
Terminology Criteria (v5.0). Frequency and severity of all adverse events will be listed and tabulated by 
organ system for both overall and within major categories and by grade. Descriptive and exact 90% 
confidence intervals will be produced for adverse event rates. Feasibility endpoints will be analyzed using 
proportions and exact 90% confidence intervals. For the secondary clinical endpoints, rates of clinical 
responses (e.g., overall response rate) will be summarized using proportions and with exact 90% 
confidence intervals. Distributions of progression-free (PFS) and overall survival (OS) will be presented 
graphically using Kaplan-Meier curves. Overall survival is defined as the time from the date of the infusion 
to the date of death due to any reason. In case a subject is alive at the date of last contact on or before the 
date of data cutoff, OS is censored at the date of last contact. Cause of death will be described when 
applicable. Progression-free survival is defined as the time from the date of the infusion to the date of first 
documented disease progression or death whenever comes first. Patients will be censored at the date of 
last documented disease evaluation. Median survival times, PFS and OS probabilities at specific time point 
(e.g., 6 month, 12 month) will also be presented. Descriptive statistics will be applied to correlative 
endpoints such numbers of modified CAR T cells in peripheral blood, HACA, measures of host immunity 
to aFR and measures of adaptive immune function. Relative persistence and trafficking to blood (and 
optionally tumor) of the MOv19-BBz CAR T cells will be examined by plotting the number of CAR T cells in 
blood, and the tracking of soluble biomarker levels over time. Correlations between two continuous 
measures will be determined with non-parametric Spearman rank correlations. We will compute exact 
90% confidence intervals for proportions and means when appropriate. Statistical tests if performed will 
be limited. Efficacy or correlative analyses will be mainly exploratory and used to generate hypothesis for 
future studies. No adjustment of multiple testing will be made. Possible statistical evaluations may include 
examining the within-subject change in biomarker values between specific time points via a Wilcoxon 
signed-rank test (or its parametric test analog if the normally assumption is satisfied) and to compare a 
continuous (e.g., biomarker) variables between two independent groups of subjects (e.g., responder vs. 
non-responder) via a Wilcoxon rank sum or two sample t-test. 


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9 
SAFETY AND ADVERSE EVENTS 
9.1 Definitions 
9.1.1 Adverse Event 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  Intercurrent illnesses or injuries should be regarded as adverse 
events.  
9.1.2 Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event (SAE) is any AE or 
protocol-defined AE that is:  
• 
fatal 
• 
life-threatening 
• 
requires or prolongs hospital stay 
• 
leads to a persistent or significant disability or incapacity or substantial disruption of the ability 
to conduct normal life functions 
• 
a congenital anomaly or birth defect 
• 
an important medical event 
 
Hospitalizations that meet the following criteria should not be reported as serious adverse events: 
• 
Routine treatment or monitoring of the studied indication, not associated with any deterioration 
in condition, such as preplanned study visits and preplanned hospitalizations for study procedures 
or treatment administration 
• 
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication 
under study and has not worsened since signing the informed consent 
• 
Social reasons and respite care in the absence of any deterioration in the subject’s general 
condition 
 
Note: Treatment on an emergency outpatient basis that does not result in hospital admission and involves 
an event not fulfilling any of the definitions of a SAE given above is not a serious adverse event.   
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance. They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above. For example, drug overdose or abuse, a seizure that did not result 
in in-subject hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
9.1.3 Unexpected adverse events 
An adverse event is considered unexpected if the event and/or severity (grade) of the event, is not 
consistent with the risk information described in the investigator brochure or protocol.  An investigator 
brochure is not currently available for this investigational product.  Please refer to the Expected Adverse 
Event Table (Table 1-1) for determinations of expectedness.  The package insert may be referenced for 
expected toxicities of fludarabine and cyclophosphamide. 


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9.1.4 Related adverse events 
An adverse event is considered related to participation in the research if there is a reasonable possibility 
that an event was caused by an investigational product, intervention, or research-required procedures.  
For the purposes of this study, "reasonable possibility" means there is evidence to suggest a causal 
relationship.  Related adverse events will be classified as possibly related, probably related, and definitely 
related. 
• 
Possibly Related: There is some evidence to suggest a causal relationship, however other factors 
may have contributed to the event. 
• 
Probably Related: There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely.  
• 
Definitely Related: There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out.  
9.1.5 Unanticipated Adverse Device Effect (UADE) 
 (Note: Device refers to the aFR Immunohistochemistry Test) Is any serious adverse effect on health or 
safety, or any life threatening problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application, or any other unanticipated serious problem associated with a device 
that relates to the rights, safety, or welfare of subjects.  
9.1.6 Protocol-defined Adverse Events (PDAEs) 
During long-term follow-up, only protocol‐defined adverse events (PDAEs) will be collected and reported. 
Protocol-defined adverse events that are also determined to be serious as defined above will be 
considered protocol-defined serious adverse events (PDSAEs) and require expedited reporting to the 
sponsor per Section 9.3. 
 
The PDAEs are as follows: 
1. New incidence or exacerbation of a pre‐existing neurologic disorder 
2. New incidence or exacerbation of a prior rheumatologic or other autoimmune disorder 
3. New incidence of hematologic disorder 
4. New malignancy (T cell & non T cell)  
5. Any serious adverse event or condition the investigator believes may have a reasonable 
relationship to CAR T cell therapy (including unexpected illnesses or hospitalizations in this 
patient population) 
 
The following correlative laboratory results will also constitute a protocol-defined adverse event, however 
these events will be identified by the Sponsor and subsequently reported to the PI/site and FDA: 
1. Positive RCL test result 
2. Vector insertion site sequencing result with a mono- or oligoclonal vector integration 
pattern or in a location near a known human oncogene 
9.1.7 Adverse Event Reporting Period 
For this study, collection of adverse events will begin at the time of apheresis and will continue until the 
subject is off-study. For subjects who do not undergo apheresis on this study (i.e. historical apheresis 
product available), adverse event reporting period will begin at the time of CAR T cell infusion (Cohorts 1 
and -1) or at the start of lymphodepleting chemotherapy (Cohorts 2 and 3).  Collection of adverse events 
will continue until the subject is off-study. 


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All adverse events will be collected during Primary Follow-up. After transitioning to long-term follow-up 
(LTFU), subjects will only be followed for PDAEs. Subjects may not be transitioned to LTFU prior to the Day 
28 safety follow-up visit.  
9.1.8 Preexisting Condition/General Physical Examination Findings 
A preexisting condition is one that is present prior to the start of the Adverse Event Reporting Period.  All 
clinically significant abnormalities should be recorded as a preexisting condition on the medical history 
eCRF. During the course of the study, a preexisting condition should be recorded as an adverse event if 
the frequency, intensity, or the character of the condition worsens.  Preexisting conditions that improve 
should also be recorded appropriately. 
9.1.9 Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if determined to be clinically 
significant by the physician-investigator.  Repeat testing to confirm the abnormality may be performed as 
per clinical discretion. 
 
Laboratory abnormalities that meet the criteria for Adverse Events should be followed until they have 
returned to normal or an adequate explanation of the abnormality is found. When an abnormal laboratory 
or test result corresponds to a sign/symptom of an already reported adverse event, it is not necessary to 
separately record the lab/test result as an additional event. Laboratory abnormalities that do not meet 
the definition of an adverse event, should not be reported as adverse events.  A Grade 3 or 4 event 
(severe) as per CTCAE does not automatically indicate a SAE unless it meets the definition of serious 
defined above and/or as per investigator’s discretion.  Whenever possible, a diagnosis, rather than a 
symptom should be provided (i.e. anemia instead of low hemoglobin).   
9.2 Recording of Adverse Events 
Safety will be assessed by monitoring and recording potential adverse effects of the treatment using the 
Common Terminology Criteria for Adverse Events version 5.0.  If CTCAE grading does not exist for an 
adverse event, the severity of mild, moderate, severe, life-threatening, and death, corresponding to Grades 
1-5, will be used whenever possible.  Specialized grading systems have also been developed to more 
appropriately capture events of Cytokine Release Syndrome and CAR Neurotoxicity as described in Section 
9.2.1 and Section 9.2.2 below. 
 
Subjects will be monitored through interval medical history evaluations, physical examinations, and clinical 
laboratory assessments as per the Schedule of Events in Appendix 1.  Adverse events will be collected on 
an ongoing basis throughout the subject’s participation; using testing/examinations, non-directive 
questioning (e.g. review of systems), subject self-reporting, etc.  Information on all adverse events should 
be recorded in the source documentation.  All clearly related signs, symptoms, and abnormal diagnostic 
procedures results should be recorded in the source document, though should be grouped under one 
diagnosis. To the extent possible, adverse events should be recorded as a diagnosis and symptoms used to 
make the diagnosis recorded within the diagnosis event.  Do not list symptoms separately if a diagnosis can 
be assigned. The safety team may require events be reported separately if they occur as SAEs (or in the 
context of a SAE) even if they can also be considered a constituent of another AE such as CRS. 
 
All adverse events occurring during the adverse event reporting period (defined in Section 9.1 above) 
must be recorded.  If there are no adverse events identified during a study visit occurring after the AE 


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reporting period commences, physician-investigator confirmation of the absence of adverse should be 
documented. 
 
Adverse events that begin in Primary Follow-up and are ongoing at the time the subject enters the LTFU 
phase of the study will continue to be followed in LTFU until: a) the adverse event resolves; b) the subject 
discontinues participation (i.e. End of Study); or c) there is a change in the adverse event that would 
normally require the event be captured as a new event (i.e. change in attribution).   Please refer to the 
CRF Completion Guidelines (CCG) for specific instructions on data entry. 
 
As much as possible, each adverse event should be evaluated to determine the following information: 
1. The severity grade (CTCAE Grade 1-5) 
2. Duration 
3. Its relationship to the study treatment (as defined in Section 9.1)  
4. Expectedness to study treatment (as defined in Section 9.1) 
5. Action taken with respect to study or investigational treatment 
6. Whether medication or therapy was administered 
7. Whether it is serious (as defined as in Section 9.1) 
 
Physician-investigator assessment of whether an adverse event is serious (as defined by Section 9.1.2) 
must occur within 24 hours from the date the adverse event is first identified, in order to meet SAE 
reporting requirements described in Section 9.3.  Additional assessment of non-serious adverse events, 
including grade and relationship to study treatment, should occur within 7 days from the date of 
knowledge of the adverse event or from the date of the study visit where the absence of adverse events 
was confirmed.  Accelerated timelines for adverse event assessments and reporting may be requested in 
the event of emergent safety concerns and/or to address time-sensitive requests from the DSMB/FDA 
 
All adverse events should be treated appropriately. If a concomitant medication or non-drug therapy is 
given, this action should be recorded.  Once an adverse event is detected, it should be followed until its 
resolution or until it is judged to be permanent, and evaluated for any changes in severity, the suspected 
relationship to the study treatment, the interventions required to treat it, and the outcome.   
 
Progression of malignancy, documented appropriately in the medical records, should not be reported as 
a serious adverse event.  Adverse events that occur concurrently with the progression of malignancy but 
that are not related to disease progression (i.e. deep vein thrombosis or hemoptysis) will be reported as 
an adverse event as described above.  Progression of malignancy resulting in death that occurs during 
Primary Follow-up should be reported as a serious adverse event. During long-term follow-up, any death 
determined to be related to disease progression would not qualify as a protocol-defined adverse event. 
 
Serious adverse events that are still ongoing at the end of the adverse event reporting period must be 
followed to determine the final outcome.  Any serious adverse event that occurs after the adverse event 
reporting period and is considered to be possibly related to the study treatment or study participation 
should be recorded and reported. 
9.2.1 Cytokine Release Syndrome Grading System  
A protocol specific grading system (Table 9-1) has been developed to capture cytokine release syndrome 
(CRS) in CAR T-cell protocols.  Please refer to Section 1.6 for additional detail on CRS in CAR T-cell therapy.   
 


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The start date of CRS is a retrospective assessment of the date of onset of persistent fevers and/or myalgia 
consistent with CRS and not explained by other events (i.e. sepsis). The stop date of CRS is defined as the 
date when the patient has been afebrile for 24 hours and off vasopressors for 24 hours. For the purposes 
of defining the CRS start date, a fever is defined as a temperature of 100.4°F/38°C. 
 
CRS will be considered ongoing until all signs and symptoms leading to the diagnosis of CRS have resolved, 
or there are alternative causes for these events (i.e., sepsis, etc).  Therefore, the CRS stop date is defined 
as the date when the subject meets all of the following criteria.  The stop date would be considered the 
date the last criteria was successfully met.  
• 
The subject is afebrile for 24 hours; or an alternative cause of fever has been identified. 
• 
The subject is durably off vasopressors (defined as the time pressors are off, but must be off for 
a minimum of 24 hours); or the use of vasopressors is attributable to another cause. 
• 
The subject is no longer requiring oxygen (defined as the time oxygen and mechanical ventilation 
have been discontinued, but must be off for a minimum of 24 hours); or the use of oxygen and/or 
mechanical ventilation is attributable to another cause. 
 
Table 9-1: CRS grading criteria 
CRS Toxicity Grade (Modified) 
1 
2 
3 
4 
5 
Mild reaction: 
Treated with 
supportive care 
such as anti-
pyretics, anti-
emetics 
Moderate reaction 
requiring IV fluids or 
parenteral nutrition; 
some signs of organ 
dysfunction (i.e. 
grade 2 creatinine 
or grade 3 liver 
function tests [LFTs] 
related to CRS and 
not attributable to 
any other 
condition).  
Hospitalization for 
management of CRS 
related symptoms 
including fevers 
with associated 
neutropenia.  
More severe reaction: 
Hospitalization required for 
management of symptoms 
related to organ dysfunction 
including grade 4 LFTs or grade 
3 creatinine related to CRS and 
not attributable to any other 
conditions.  This excludes 
management of fever or 
myalgias.  Includes hypotension 
treated with IVFs* or low-dose 
pressors, coagulopathy 
requiring fresh frozen plasma 
(FFP) or cryoprecipitate, and 
hypoxia requiring supplemental 
oxygen (nasal cannula oxygen, 
high flow oxygen, Continuous 
Positive Airway Pressure [CPAP] 
or Bilateral Positive Airway 
Pressure [BiPAP].  Patients 
admitted for management of 
suspected infection due to 
fevers and/or neutropenia may 
have grade 2 CRS. 
Life-threatening 
complications 
such as 
hypotension 
requiring high 
dose pressors 
(see Table 9-2), 
or hypoxia 
requiring 
mechanical 
ventilation 
Death 


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* CRS Grade 3 language clarification: “hypotension treated with intravenous fluids” is further defined as 
hypotension requiring multiple fluid boluses for blood pressure support. 
 
Table 9-2: High Dose Vasopressor Use 
Definition of “High-Dose” Vasopressors 
Vasopressor 
Dose for ≥ 3 hours 
Norepinephrine monotherapy 
≥ 0.2 mcg/kg/min 
or ≥ 20 mcg/min (if institutional practice is to use flat dosing) 
Dopamine monotherapy 
≥ 10 mcg/kg/min 
or ≥ 1000 mcg/min (if institutional practice is to use flat dosing) 
Phenylephrine monotherapy 
≥ 2 mcg/kg/min 
or ≥ 200 mcg/min (if institutional practice is to use flat dosing) 
Epinephrine monotherapy 
≥ 0.1 mcg/kg/min 
or ≥ 10 mcg/min (if institutional practice is to use flat dosing) 
If on vasopressin 
High-dose if vaso +  Norepinephrine Equivalent (NE) of >0.1 
mcg/kg/min (or 10mcg/min) (using Vasopressin and Septic Shock 
Trial (VASST) formula) 
If on combination vasopressors 
(not vasopressin) 
Norepinephrine equivalent of ≥ 0.2 mcg/kg/min  
(or ≥ 20 mcg/min) (using VASST formula) 
Vasopressin and Septic Shock Trial (VASST) Equivalent Equation: 
Norepinephrine equivalent dose = [norepinephrine (mcg/min)] + [dopamine (mcg/kg/min) ÷ 2] + 
[epinephrine (mcg/min)] + [phenylephrine (mcg/min) ÷10]  
Criteria previously published [134]. 
 
9.2.2 Grading System for CAR Neurotoxicity 
As described above (Section 1.6), neurotoxicity has been observed with CAR T cell products. Since the 
myriad manifestations of CAR-related neurotoxicity may not fall cleanly under a single CTCAE category, 
this study will utilize the grading system in Table 9-3 to categorize adverse events that are: a) judged by 
the investigator to constitute neurotoxicity related to CAR T cells; and b) which can be evaluated using 
the event descriptions included in Table 9-3 below. To align with CTCAE V5.0 reporting criteria, for 
qualifying events, the CTCAE Term “Nervous System Disorders – Other, Specify” will be utilized in 
accordance with the corresponding grades below, with additional toxicity detail reported as “CAR 
Neurotoxicity”.   
 
Constituent adverse events of neurotoxicity will contribute to an evaluation of the overall neurotoxicity 
grade as described in Table 9-3. All other events, including specific component neurotoxicity adverse 
events, will also be reported separately and will be graded in accordance with CTCAE 5.0 (e.g. seizures, 
cerebral edema, headache, tremors, etc).   
 
If a non-qualifying event becomes a qualifying event, it would be followed by both the original CTCAE 
term, as well as the new CAR Neurotoxicity event term, as these events are evaluated differently and may 
have different start/stop dates.   
 


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Table 9-3: Neurotoxicity grading system 
Neurologic Event 
Grade  
Event Descriptions  
Grade 1 
 
 
• 
Mild impairment or confusion 
• 
No objective evidence of increased intracranial pressure 
Grade 2 
 
 
 
 
• 
Moderate impairment or confusion 
• 
No objective evidence of increased intracranial pressure (or not assessed) 
• 
Symptoms limiting instrumental ADLs 
• 
Aphasia- receptive or expressive characteristics; ability to read, write or 
communicate intelligibly is not impaired or only mildly impaired 
Grade 3 
 
 
 
• 
Severe Impairment 
o Grade 3 confusion (severe disorientation) 
o Grade 3 somnolence (obtundation or stupor) 
o Grade 3 encephalopathy (severe symptoms) 
• 
Stage 1-2# Papilledema (if assessed); CSF opening pressure <20 mmHg (if 
assessed) 
• 
Seizure 
• 
Symptoms limiting self-care ADLs 
• 
Aphasia- Severe receptive or expressive characteristics, impairing ability to read, 
write or communicate intelligibly  
Grade 4 
 
 
• 
Life-threatening consequences 
o Grade 4 confusion (life-threatening consequences; urgent intervention 
indicated) 
o Grade 4 somnolence (obtundation or stupor) 
o Grade 4 encephalopathy (life-threatening consequences) 
• 
Stage 3-5 papilledema# (if assessed); CSF opening pressure ≥20 mmHg (if 
assessed); evidence of cerebral edema on brain imaging. 
• 
Status epilepticus 
• 
New, focal and sustained motor weakness 
• 
Requirement for mechanical ventilation due to neurologic symptoms 
#Papilledema is staged according to the modified Frisen scale.  
9.3 Reporting of Serious Adverse Events  
Every SAE, UADE and PDSAE (during LTFU), regardless of suspected causality, occurring during the 
adverse event reporting period defined in Section 9.1 must be reported to the sponsor within 24 hours of 
learning of its occurrence. The original SAE notification may take place by email to meet the 24-hour 
reporting window.   
 
Within 3 business days of initial knowledge of the event, the investigator must submit a complete SAE 
form to the Sponsor along with any other diagnostic information that will assist the understanding of the 
event.  The Investigator will keep a copy of this SAE Form on file at the study site.   
 
New or follow-up information on SAEs/PDSAEs/UADEs should be promptly reported as updates become 
available.  
 


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At a minimum follow-up SAE Forms should be submitted: 
• 
Within 1 week of ICU admission or any life-threatening event  
• 
Within 2 weeks of hospital discharge 
 
Follow-up information should be submitted as an amendment to the initial SAE form, and should include 
both the follow-up number and report date.  The follow-up information should describe whether the 
event has resolved or continues, if there are any changes in assessment, if and how it was treated, and 
whether the patient continued or withdrew from study participation.    
 
Report serious adverse events by email to: 
 
 Attention:  Clinical Safety Manager or designee 
Center for Cellular Immunotherapies (CCI) 
University of Pennsylvania 
     
At the time of the initial report, the following information should be provided: 
• 
Study identifier 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current Subject status 
• Whether study treatment was discontinued 
• The reason the event is classified as serious 
• Investigator assessment of the association 
between the event and study treatment 
• Expectedness relative to investigational 
product(s) 
9.3.1  Investigator Reporting:  Local Regulatory Review Committees 
Report events to local regulatory review committees per institutional requirements. 
9.3.2 Pregnancies 
The majority, if not all subjects enrolled on this trial are likely to have undergone surgical removal of the 
ovaries and thus, not be of childbearing potential.  However, to ensure subject safety, each pregnancy 
occurring while the subject is on study treatment must be reported to protocol sponsor within 24 hours 
of learning of its occurrence. The pregnancy should be followed up to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any birth 
defects, congenital abnormalities, or maternal and/or newborn complications.  If a pregnancy occurs on 
study, this will be reported as an SAE using the SAE Report Form. 
9.4 Toxicity Management, Stopping Rules and Study Termination 
It is expected that AEs may occur frequently in this population based on the underlying advanced cancer 
and that these can be SAEs. Therefore, there is no specific occurrence of SAEs that define a stopping rule, 
but the review of SAEs will form the basis for potential early stopping of the study. Only unexpected SAEs 
that are related to the MOv19-BBz CAR T cells would define a stopping rule. The review of these adverse 
events, and any decision to prematurely stop subject enrollment, will be determined by the Sponsor. 
 
In addition to the above, premature termination of the clinical trial may also occur because of a regulatory 
authority decision, determination that there are problems in the cell product generation, or as a result of 
safety concern.  Additionally, recruitment may be stopped for reasons of particularly low recruitment, 
protocol violations, or inadequate data recording.  


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9.4.1 Criteria for stopping or pausing the study 
The study will be reviewed for potential termination if: 
• 
Any subject develops uncontrolled T cell proliferation that does not respond to management. 
• 
The study meets the DLT safety signal for grade 3 AEs described in Section 5.4. If 2 DLTs occur in 
Cohort 1, we will dose de-escalate by 10-fold to Cohort -1. If 2 DLTs occur in the de-escalated 
cohort, Cohort -1, the study will be stopped.  
• 
Premature study termination may occur if the Investigator, Sponsor, Study Funder, DSMC, 
Medical Director, DSMB, or any independent review board or regulatory body decides for any 
reason that subject safety may be compromised by continuing the study. 
• 
Premature study termination may occur if the Sponsor decides to discontinue the development 
of the intervention to be used in this study. 
 
Subject accrual will be paused if death occurs within 30 days of study treatment. Accrual will be held until 
an investigation is performed and the safety data is evaluated by the DSMB and applicable changes are 
implemented (as appropriate). The outcome of the DSMB review will be shared with the Sponsor.  This 
information will then be provided to the FDA and site (for local regulatory submission) in the form of an 
outcome letter.  If all parties are in agreement as to the event resolution, then the pause will be lifted.   
 
The protocol will be paused and subject accrual suspended to review the manufacturing process should 
there be ≥33% failed manufacturing products (i.e. failure to release the product and/or failure to reach 
the target dose).   
9.4.2 General toxicity considerations 
Infusion related toxicities and their management are described in Section 5.3.1.4.  
Other potential toxicities and their management are described in Section 1.6.  
9.5 Protocol Exceptions and Deviations 
Exception 
A one-time, intentional action or process that departs from the approved study protocol, intended for 
one occurrence. If the action disrupts the study progress, such that the study design or outcome 
(endpoints) may be compromised, or the action compromises the safety and welfare of study subjects, 
advance documented approval from the Regulatory Sponsor and local regulatory review committees per 
institutional guidelines is required. Approval from the Regulatory Sponsor must be received prior to 
submission to local regulatory review committees for approval.   
 
Deviation 
A one-time, unintentional action or process that departs from the approved study protocol, involving one 
incident and identified retrospectively, after the event occurred. If the event has any potential impact on 
the study design, may affect the outcome (endpoints) or compromises the safety and welfare of the 
subjects, the deviation must be reported to the Regulatory Sponsor within 10 business days of PI 
knowledge, and to local regulatory review committees per institutional guidelines.  Acknowledgement 
from the Regulatory Sponsor must be received prior to submission to local regulatory review committees.  
 
Other deviations should be appropriately documented (such as a subject missing a visit is not an issue 
unless a critical/important treatment or procedure was missed and must have been done at that specific 
time) per site policies/procedures.  
 


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Include the following information on the Sponsor supplied exception/deviation form:  protocol number, 
subject study number, comprehensive description of the exception/deviation from the protocol, rationale 
and corrective and preventative action plan (deviations only).  Ensure all completed exception/deviation 
forms are signed by the Principal Investigator (or Physician Sub-investigator) and submitted to the Sponsor 
Project Manager for review.    
 
Attention: Sponsor Project Manager  
Center for Cellular Immunotherapies (CCI) 
University of Pennsylvania 
 
Once approval of the exception request or acknowledgement of the deviation has been granted by the 
Regulatory Sponsor, the exception or deviation will be submitted to all applicable committees for review 
and approval/acknowledgement as per institutional guidelines. 
9.6 Data and Safety Monitoring Board  
An Independent Data and Safety Monitoring Board (DSMB) comprised of at least four individuals including 
physicians with experience in oncology and/or gene transfer therapy will be assembled, and will work 
under a charter specifically developed for safety oversight of this study. The DSMB will provide 
guidance/advice to the Sponsor. The DSMB will evaluate patient-subject safety as specified in the DSMB 
Charter. 
 
The DSMB will review safety data at the following timepoints: 
• Approximately every 6 months.  
• If necessary, additional meetings of the DSMB may be held if safety issues arise in between 
scheduled meetings. 
 
It is envisioned that the DSMB may make four types of recommendations, namely: 
• No safety or efficacy issues, ethical to continue the study as planned 
• Serious safety concerns precluding further study treatment, regardless of efficacy 
• Overwhelming evidence for futility, recommend stopping the study. 
• Recommendation to continue the study but proposing an amendment to the protocol (e.g., 
incorporate an additional safety assessments) 
 
A sponsor representative will share the outcome of the DSMB meeting with the PI via email, for 
submission to local regulatory review committees as required per institutional policy.   
10 
DATA HANDLING AND RECORDKEEPING 
10.1 Confidentiality 
Information about study subjects obtained as part of this study will be kept confidential and managed 
according to the requirements of the Health Insurance Portability and Accountability Act (HIPAA) of 1996.  
Those regulations require a signed subject authorization informing the subject of the following:  
• 
What protected health information (PHI) will be collected from subjects in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 


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• 
The rights of a research subject to revoke their authorization for use of their PHI  
 
In the event that the subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
10.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in 
source documents   Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. 
 
The investigator must maintain source documents for each subject in the study, consisting of case and 
visit notes (hospital or clinical medical records) containing demographic and medical information, 
laboratory data, and the results of any other tests or assessments. All information recorded on the eCRFs 
must be traceable to source documents in the subject’s file. The investigator must also keep the original 
signed informed consent form, and a signed copy must be given to the subject. 
 
Paper based records will be kept in a secure location and only be accessible to personnel involved in the 
study. Computer-based records or files will only be made available to personnel involved in the study 
through the use of access privileges and passwords. Whenever feasible, subject identifiers will be redacted 
from study related records and replaced with study assigned identification numbers. 
10.3 Data Management 
Data management responsibilities will be governed by CCI Clinical Operations policies/procedures 
including current Clinical Operations Standard Operating Procedures (SOPs), Guide to Daily Operations 
(GDOs) and Work Instructions (WI).   
 
A part 11 compliant electronic data capture (EDC) system will be used as the primary data collection tool 
for the purposes of this study.  All data requested on the study-specific eCRF must be recorded. Data entry 
will be performed by clinical site team members who have been delegated this responsibility by the 
Principal Investigator and who have completed all required protocol and database training.  The Principal 
Investigator is responsible for assuring that the data entered into eCRF is complete, accurate, and that 
entry and updates are performed in a timely manner. 


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10.4 Sharing of Study Data  
Participants will have access to research related information within their medical record through Penn 
Medicine’s patient portal – called MyPennMedicine (MPM). This includes information from all clinical 
tests/procedures required as part of their study participation.  Results of research testing conducted in 
non-CLIA certified laboratories will not be included in the participant’s medical record or made available 
to the patient.  
10.5 Future Use of Research Data/Specimens 
Blood or other samples obtained from the participant will be stored indefinitely and used for future 
research. Study data and samples may also be shared with other researchers within Penn, or other 
research institutions, as well as with for-profit pharmaceutical or biotechnology companies.  This future 
research may include genetic testing and/or whole genome sequencing. Data/specimens used for future 
research will be coded using the unique subject identifier. There are no plans to tell participants about 
future testing on their specimens, or share the results of this analysis.   
10.6 Records Retention 
 Essential study essential documents must be retained for a minimum of 2 years after the last approval of 
a marketing application in an International Conference on Harmonization (ICH) region and until there are 
no pending or contemplated marketing applications in an ICH region, or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period if required by local regulations or per sponsor agreement.  In such 
an instance, it is the responsibility of the sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained. No records will be destroyed without the written consent of 
the sponsor.  
11 
STUDY MONITORING, AUDITING, AND INSPECTING 
11.1 Study Monitoring Plan 
 This study will be monitored according to the Sponsor Data and Safety Monitoring Plan.   
 
Interim Monitoring Visits will be conducted during the course of the study. The Monitors will assure that 
submitted data are accurate and in agreement with source documentation; verify that investigational 
products are properly stored and accounted for, verify that subjects’ consent for study participation has 
been properly obtained and documented, confirm that research subjects entered into the study meet 
inclusion and exclusion criteria, and assure that all essential documentation required by Good Clinical 
Practices (GCP) guidelines are appropriately filed. 
 
At the end of the study, Monitors will conduct a close-out visit and will advise on storage of study records 
and disposition of unused investigational products. 
 
The investigator will allocate adequate time for such monitoring activities. The Investigator will also 
ensure that the monitor or other compliance reviewer is given access to all the above noted study-related 
documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has adequate 
space to conduct the monitoring visit. 


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11.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the sponsor, 
government regulatory bodies, and University compliance groups.  The investigator will ensure the 
capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.).  
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance offices. 
 
The Principal Investigator must notify the Sponsor in real-time if an audit/inspection notification is 
received. 
12 
ETHICAL CONSIDERATIONS 
This study is to be conducted according to US and international standards of Good Clinical Practice (FDA 
Title 21 part 312 and International Conference on Harmonization guidelines), applicable government 
regulations, the revised Common Rule, and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the study conduct.  
The decision of the IRB concerning the conduct of the study will be made in writing to the investigator and 
a copy of this decision will be provided to the sponsor before commencement of this study.   
 
All subjects for this study will be provided a consent form describing this study and providing sufficient information 
for subjects to make an informed decision about their participation in this study. All consent forms will be submitted 
with the protocol for review and approval by the University of Pennsylvania IRB. The Investigator (according to 
applicable regulatory requirements), or a person designated by the Investigator, will facilitate the informed consent 
discussion with the participant, in language and terms they are able to understand.  All subjects must have the cognitive 
ability to provide consent as determined by the treating physician-investigator.  Written informed consent will be 
signed/dated by the participant and the person conducting the informed consent discussion.  A copy of the signed/dated 
informed consent will be provided to the participant, and the original consent should be retained for the investigator’s 
research records.  Participant consent, using the IRB-approved consent form, must be obtained before that subject 
undergoes any study-specific procedures.   
 
The protocol is listed under clinicaltrials.gov. 
13 
STUDY FINANCES 
13.1 Funding Source 
This study will be funded through awards from Ovacure, the Alliance for Cancer Gene Therapy, Ovarian 
Cancer Alliance of Greater Cincinnati, the NIH, and Penn Internal Funds. 
13.2 Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on Conflicts 
of Interest Related to Research.  This requires that any individuals who have a role in the design, conduct, 
or analysis of this clinical trial disclose all potential conflict of interest as part of their participation in this 
clinical trial, including changes in their conflict of interest as they occur.  Persons who have a perceived 


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CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
conflict of interest will be required to have such conflicts managed in a way that is appropriate to their 
participation in the design and conduct of this trial. 
13.3 Subject Stipends or Payments 
There is no subject stipend/payment for participation in this protocol. 
14 
PUBLICATION PLAN 
Publication of the results of this trial will be governed by University of Pennsylvania policies, the Center 
for Cellular Immunotherapies (CCI) Authorship Guidance, and any applicable contractual agreements.  
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of 
the information provided by the sponsor for the purposes of performing the study, will be published or 
passed on to any third party without the consent of the study sponsor.  Any investigator involved with 
this study is obligated to provide the sponsor with complete test results and all data derived from the 
study. 


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15 
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anti-tumor activity of CIR engineered T cells is enhanced by costimulatory signaling through CD137 
(4-1BB). Cancer Research, 2011. 
103. Konner, J.A., et al., Farletuzumab, a humanized monoclonal antibody against folate receptor alpha, 
in epithelial ovarian cancer: a phase I study. Clin Cancer Res, 2010. 16(21): p. 5288-95. 
104. Armstrong, D.K., et al., Farletuzumab (a monoclonal antibody against folate receptor alpha) in 
relapsed platinum-sensitive ovarian cancer. Gynecol Oncol, 2013. 129(3): p. 452-8. 
105. Kim, K.H., et al., Phase 1b safety study of farletuzumab, carboplatin and pegylated liposomal 
doxorubicin in patients with platinum-sensitive epithelial ovarian cancer. Gynecol Oncol, 2016. 
140(2): p. 210-4. 
106. Vergote, I., et al., A Randomized, Double-Blind, Placebo-Controlled, Phase III Study to Assess Efficacy 
and Safety of Weekly Farletuzumab in Combination With Carboplatin and Taxane in Patients With 
Ovarian Cancer in First Platinum-Sensitive Relapse. J Clin Oncol, 2016. 34(19): p. 2271-8. 
107. Sudimack, J. and R.J. Lee, Targeted drug delivery via the folate receptor. Adv Drug Deliv Rev, 2000. 
41(2): p. 147-62. 
108. Amato, R.J., et al., A phase I study of folate immune therapy (EC90 vaccine administered with GPI-
0100 adjuvant followed by EC17) in patients with renal cell carcinoma. J Immunother, 2013. 36(4): 
p. 268-75. 
109. Amato, R.J., et al., A Phase I/Ib study of folate immune (EC90 vaccine administered with GPI-0100 
adjuvant followed by EC17) with interferon-alpha and interleukin-2 in patients with renal cell 
carcinoma. J Immunother, 2014. 37(4): p. 237-44. 
110. Moore, K.N., et al., Phase 1 dose-escalation study of mirvetuximab soravtansine (IMGN853), a folate 
receptor alpha-targeting antibody-drug conjugate, in patients with solid tumors. Cancer, 2017. 
123(16): p. 3080-3087. 
111. Moore, K.N., et al., Safety and Activity of Mirvetuximab Soravtansine (IMGN853), a Folate Receptor 
Alpha-Targeting Antibody-Drug Conjugate, in Platinum-Resistant Ovarian, Fallopian Tube, or 
Primary Peritoneal Cancer: A Phase I Expansion Study. J Clin Oncol, 2017. 35(10): p. 1112-1118. 
112. Brentjens, R., et al., Treatment of chronic lymphocytic leukemia with genetically targeted 
autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. Mol Ther, 
2010. 18(4): p. 666-8. 
113. Morgan, R., et al., Case Report of a Serious Adverse Event Following the Administration of T Cells 
Transduced With a Chimeric Antigen Receptor Recognizing ERBB2. Molecular Therapy, 2010. 18(4): 
p. 843-51. 
114. Press, M.F., C. Cordon-Cardo, and D.J. Slamon, Expression of the HER-2/neu proto-oncogene in 
normal human adult and fetal tissues. Oncogene, 1990. 5(7): p. 953-62. 
115. Carroll, J. UPDATED: two deaths force MSK to hit the breaks on engineered T cell cancer study. 
FierceBiotech, 2014. 
116. Lerman, R. Juno Therapeutics shuts down clinical trial of cancer drug after patient deaths. The 
Seattle Times, Technology, 2017. 
117. Maus, M.V., et al., T Cells Expressing Chimeric Antigen Receptors Can Cause Anaphylaxis in Humans. 
CANCER IMMUNOLOGY RESEARCH., 2013. 1(1). 
118. Martin, L.P., et al., Characterization of folate receptor alpha (FRalpha) expression in archival tumor 
and biopsy samples from relapsed epithelial ovarian cancer patients: A phase I expansion study of 
the FRalpha-targeting antibody-drug conjugate mirvetuximab soravtansine. Gynecol Oncol, 2017. 
147(2): p. 402-407. 
119. Teachey, D.T., et al., Identification of Predictive Biomarkers for Cytokine Release Syndrome after 
Chimeric Antigen Receptor T-cell Therapy for Acute Lymphoblastic Leukemia. Cancer Discov, 2016. 


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120. Jensen, M.C., et al., Antitransgene rejection responses contribute to attenuated persistence of 
adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. 
Biol Blood Marrow Transplant, 2010. 16(9): p. 1245-56. 
121. Cornetta, K., et al., Absence of Replication-Competent Lentivirus in the Clinic: Analysis of Infused T 
Cell Products. Mol Ther, 2018. 26(1): p. 280-288. 
122. Lyon, D., N. Lapteva, and A.P. Gee, Absence of Replication-Competent Retrovirus in Vectors, T Cell 
Products, and Patient Follow-Up Samples. Mol Ther, 2018. 26(1): p. 6-7. 
123. Neelapu, S.S., et al., Chimeric antigen receptor T-cell therapy - assessment and management of 
toxicities. Nat Rev Clin Oncol, 2018. 15(1): p. 47-62. 
124. Sterman, D.H., et al., Adenovirus-mediated herpes simplex virus thymidine kinase/ganciclovir gene 
therapy in patients with localized malignancy: results of a phase I clinical trial in malignant 
mesothelioma. Hum Gene Ther, 1998. 9(7): p. 1083-92. 
125. Sterman, D.H., et al., Long-term follow-up of patients with malignant pleural mesothelioma 
receiving high-dose adenovirus herpes simplex thymidine kinase/ganciclovir suicide gene therapy. 
Clin Cancer Res, 2005. 11(20): p. 7444-53. 
126. Sterman, D.H., et al., Pilot and Feasibility Trial of Immuno-Gene Therapy of Malignant Mesothelioma 
Using Intrapleural Delivery of Adenovirus- Interferon-Alpha Combined with Chemotherapy. Clin 
Cancer Res, 2016. 
127. Hasenburg, A., et al., Adenovirus-mediated thymidine kinase gene therapy in combination with 
topotecan for patients with recurrent ovarian cancer: 2.5-year follow-up. Gynecol Oncol, 2001. 
83(3): p. 549-54. 
128. Teachey, D.T., et al., Identification of Predictive Biomarkers for Cytokine Release Syndrome after 
Chimeric Antigen Receptor T-cell Therapy for Acute Lymphoblastic Leukemia. Cancer Discov, 2016. 
6(6): p. 664-79. 
129. Garfall, A., et al. Posterior Reversible Encephalopathy Syndrome (PRES) after Infusion of Anti-Bcma 
CAR T Cells (CART-BCMA) for Multiple Myeloma: Successful Treatment with Cyclophosphamide. in 
58th ASH Annual Meeting and Exposition. 2016. Blood. 
130. Gust, J., et al., Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after 
Adoptive Immunotherapy with CD19 CAR-T Cells. Cancer Discov, 2017. 7(12): p. 1404-1419. 
131. Nishino, M., et al., Developing a common language for tumor response to immunotherapy: immune-
related response criteria using unidimensional measurements. Clin Cancer Res, 2013. 19(14): p. 
3936-43. 
132. Wolchok, J.D., et al., Guidelines for the evaluation of immune therapy activity in solid tumors: 
immune-related response criteria. Clin Cancer Res, 2009. 15(23): p. 7412-20. 
133. Bohnsack O, H.A., Ludajic K. , Adaptation of the immune related response criteria: irRECIST Annals 
of Oncology, 2014. 25(suppl_4, 1 ): p. iv369. 
134. Russell, J.A., et al., Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl 
J Med, 2008. 358(9): p. 877-87. 
  
 


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16 
APPENDIX 1 - SCHEDULE OF EVENTS  
 
Trial Period 
~Week -8  
~Week -6 
to -4  
~Week  
-2 to -1 
Between 
Pre-Infusion 
Visit and 
Day 0  
Day 
024 
Day 
1 
Day 2 
(+1), 7, 
10, 14, 
21 (±1 
day) 
Day 
28(±5) 
Month 
2, 3, 6 
(±5 
days) 
Month 
9, 12, 
15, 18, 
21, 24 
(±2 
weeks) 
Long-term Follow-up22 
Visits 
Screening 
Apheresis 
Pre-
Infusion 
Safety 
LD Chemo- 
Therapy31 
Infusion 
Follow 
-up 
Follow 
-up 
Follow 
-up 
Follow 
-up 
Follow 
-up 
M3, 
M6, M9 
(+/- 1 
month) 
M12, M18, 
and q6 
months up 
to M60 
(+/- 2 
months) 
Annual 
Visits Years 
6 to 15 (if 
evidence of 
vector-
modified 
cells)32 
Annual 
Visits Years 
6 to 15 
(if no 
evidence of 
vector-
modified 
cells)32 
CLINICAL  ASSESSMENTS 
 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recent Med History 
and Physical Exam 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital Sign 
Assessments1 
X 
 
X 
X 
X14 
X 
X 
X 
X 
X 
 
 
 
 
Concomitant Meds 
X 
 
X--------------------------------------------------------------------------------------------------X 
X25------------------------------------------------X25 
ECOG Performance 
Status 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Adverse Events15 
 
X----------------------------------------------------------------------------------------------------------------X 
X23------------------------------------------------X23 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram/ 
MUGA 
X30 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leukapheresis 
screening2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Survival Follow-up 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X33 
CLINICAL  LABORATORY TESTS 
 
CBC with differential 
(4 ml-lavender top) 
X 
 
X 
X 
X24 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Trial Period 
~Week -8  
~Week -6 
to -4  
~Week  
-2 to -1 
Between 
Pre-Infusion 
Visit and 
Day 0  
Day 
024 
Day 
1 
Day 2 
(+1), 7, 
10, 14, 
21 (±1 
day) 
Day 
28(±5) 
Month 
2, 3, 6 
(±5 
days) 
Month 
9, 12, 
15, 18, 
21, 24 
(±2 
weeks) 
Long-term Follow-up22 
Visits 
Screening 
Apheresis 
Pre-
Infusion 
Safety 
LD Chemo- 
Therapy31 
Infusion 
Follow 
-up 
Follow 
-up 
Follow 
-up 
Follow 
-up 
Follow 
-up 
M3, 
M6, M9 
(+/- 1 
month) 
M12, M18, 
and q6 
months up 
to M60 
(+/- 2 
months) 
Annual 
Visits Years 
6 to 15 (if 
evidence of 
vector-
modified 
cells)32 
Annual 
Visits Years 
6 to 15 
(if no 
evidence of 
vector-
modified 
cells)32 
Comprehensive 
Metabolic Panel  
(5 ml-gold top)16 
X 
 
X 
X 
X24 
X 
X 
X 
X 
X 
X 
X 
X 
 
PT, aPTT, fibrinogen  
(7.5 ml-blue top) 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Autoantibodies, ANA  
(1 ml-gold top) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral screens: HIV, 
HCV, HBV,  
(20ml – gold top)17 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
X 
X 
X24 
 
 
 
X 
 
 
 
 
 
Urine pregnancy 
test9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy 
test9 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Ferritin, haptoglobin, 
CRP (4ml-gold top)19 
 
 
X 
 
X24 
 
 
 
 
 
 
 
 
 
Triglycerides (1 ml- 
gold top) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Tumor Biomarker 
CA125 (5ml- gold 
top) 
 
 
X 
 
X 
 
X35 
X 
X 
X 
 
 
 
 


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Trial Period 
~Week -8  
~Week -6 
to -4  
~Week  
-2 to -1 
Between 
Pre-Infusion 
Visit and 
Day 0  
Day 
024 
Day 
1 
Day 2 
(+1), 7, 
10, 14, 
21 (±1 
day) 
Day 
28(±5) 
Month 
2, 3, 6 
(±5 
days) 
Month 
9, 12, 
15, 18, 
21, 24 
(±2 
weeks) 
Long-term Follow-up22 
Visits 
Screening 
Apheresis 
Pre-
Infusion 
Safety 
LD Chemo- 
Therapy31 
Infusion 
Follow 
-up 
Follow 
-up 
Follow 
-up 
Follow 
-up 
Follow 
-up 
M3, 
M6, M9 
(+/- 1 
month) 
M12, M18, 
and q6 
months up 
to M60 
(+/- 2 
months) 
Annual 
Visits Years 
6 to 15 (if 
evidence of 
vector-
modified 
cells)32 
Annual 
Visits Years 
6 to 15 
(if no 
evidence of 
vector-
modified 
cells)32 
aFR Expression 
Testing34 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Respiratory Virus 
Panel (RVP) 
 
 
X20 
 
 
 
 
 
 
 
 
 
 
 
Radiographic  imaging 
 
Tumor imaging3 
X26 
 
X26 
 
 
 
 
X 
X10 
  
 
 
 
 
Brain MRI 
X27 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interventions 
 
Apheresis 
 
X2,5 
 
 
 
 
 
X21 
  
  
 
 
 
 
Lymphodepleting 
Chemotherapy 
(Cohorts 2 + 3 only) 
 
 
 
X6 
 
 
 
  
  
  
 
 
 
 
T cell infusion 
 
 
 
 
X28 
 
 
  
  
  
 
 
 
 
Tumor biopsy  
X18 
 
X13 
 
 
 
X8 
 
  
  
 
 
 
 
Research  specimens4 
 
Serum (~6ml- red 
top tube)11 
 
 
X 
 
X7 
X 
X 
X 
X 
X 
 
 
 
 
PBMC (~25ml- 
Purple Top EDTA)12 
 
 
X 
 
X 7 
X 
X 
X 
X 
X 
X 
X 
X 
 
DNA (qPCR 
persistence)29 
 
 
 
 
X7 
X 
X 
X 
X 
X 
X 
X 
X 
 


MOv19-BBz CAR T cells in aFR expressing Ovarian Cancers 
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Trial Period 
~Week -8  
~Week -6 
to -4  
~Week  
-2 to -1 
Between 
Pre-Infusion 
Visit and 
Day 0  
Day 
024 
Day 
1 
Day 2 
(+1), 7, 
10, 14, 
21 (±1 
day) 
Day 
28(±5) 
Month 
2, 3, 6 
(±5 
days) 
Month 
9, 12, 
15, 18, 
21, 24 
(±2 
weeks) 
Long-term Follow-up22 
Visits 
Screening 
Apheresis 
Pre-
Infusion 
Safety 
LD Chemo- 
Therapy31 
Infusion 
Follow 
-up 
Follow 
-up 
Follow 
-up 
Follow 
-up 
Follow 
-up 
M3, 
M6, M9 
(+/- 1 
month) 
M12, M18, 
and q6 
months up 
to M60 
(+/- 2 
months) 
Annual 
Visits Years 
6 to 15 (if 
evidence of 
vector-
modified 
cells)32 
Annual 
Visits Years 
6 to 15 
(if no 
evidence of 
vector-
modified 
cells)32 
TOTAL  BLOOD  DRAWS 
 
Total clinical blood 
draw (~mL) 
9 
0 
22.5 
9 
14 
9 
Up to 
14 
14 
14 
14 
9 
9 
9 
 
Total research blood 
draw (~mL) 
28.5 
0 
36 
0 
62 
31 
31 
31-91 
31 
31 
25 
25 
25 
 
Total blood draw 
(~mL) 
37.5 
0 
58.5 
9 
76 
40 
Up to 
45 
45-91 
45 
45 
34 
34 
34 
 
Total blood draw 
(Tbsp., 
approximate) 
2.5 
0 
4 
0.6 
5.1 
2.7 
Up to 3 
3-6 
3 
3 
2.3 
2.3 
2.3 
 
1. Includes weight/height at screening/enrollment only. Vital signs include blood pressure, body temperature, heart rate and oxygen saturation via pulse 
oximetry.   
2. If a subject’s veins are not adequate for apheresis procedure, the subject may have a central venous apheresis catheter line placed by interventional 
radiology.  It is recommended that the patient have an absolute lymphocyte count (ALC) ≥500/µl, prior to undergoing apheresis.  If the patient’s ALC is 
<500/µl, it is recommended that a lymphocyte subset analysis (CD3, CD4, CD8 counts) be performed to confirm that the patient has an absolute CD3 
count of ≥150/µl.  If the absolute CD3 count is <150/µl, it is recommended that the leukapheresis procedure be delayed until their ALC is ≥500/µl or 
absolute CD3 count is ≥150/µl.  Up to a 4 week delay may occur; following this, further discussion is needed with the study PI and the CVPF prior to 
proceeding.   
3. CT is the preferred method for tumor assessment, however other methodologies (MRI, etc.) may be utilized at the physician-investigator’s discretion, 
if performed in accordance with RECIST 1.1 criteria.  Scans may be administered with or without contrast at the investigator’s discretion.   Please refer 
to Section 7.1 for additional details. 


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4. Additional blood draws may be performed at the discretion of the investigator (for example, to evaluate clinical events). Moreover, additional tissue 
and fluid collections from the standard of care procedures may be used for research studies.  
5. Subjects have the option for a second apheresis in case the T cell product is not successfully manufactured from the first apheresis.  Please refer to 
Section 6.3 for additional information.  
6. Cyclophosphamide + fludarabine for subjects participating in Cohorts 2 + 3 only. Please refer to Section 6.5 for additional information 
7. Blood draw before infusion and ~1 hour after T cell infusion. 
8. If the subject’s tumor is measurable by CT and accessible by image-guided biopsy, subjects will undergo a tumor biopsy under image guidance at day 
14(±7) to evaluate the impact of therapy on the tumor microenvironment and to assess for the presence of CAR T cells and aFR expression. These will 
be compared to baseline values from fresh biopsies or stored surgical tumor specimens, if available.  
9. Participants of childbearing potential only. The serum pregnancy test performed at the Pre-Infusion Visit must occur prior to the first day of 
lymphodepleting chemotherapy. 
10. Months 3 and 6 only; thereafter to be performed per clinical discretion. Imaging performed within 4 weeks of the M3 and M6 visits will be accepted.  
11. Correlative testing/analysis includes multiplex cytokine analysis, immunogenicity (HAMA/HACA), and serum aFR protein expression (SaFRP) and will be 
performed as indicated.  All serum samples to be delivered to the TCSL for processing, storage and analysis (as applicable).  
12. A portion of these samples will be archived at the TCSL.  In the event RCL is suspected, these archived samples will be used to further investigate and 
perform VSV-G DNA testing.  
13. If the subject has an accessible tumor and it is determined clinically feasible, a baseline tumor biopsy will be performed prior to MOv19-BBz CAR T cell 
infusion.  The baseline biopsy may occur any time prior to infusion between Day -14 and initiation of study treatment (i.e. lymphodepleting 
chemotherapy in applicable cohorts or MOv19-BBz CAR T cells).  This baseline biopsy sample will be used to evaluate the level of aFR expression and if 
feasible, other immune markers at baseline. If the subject had a fresh biopsy at pre-screening in order to evaluate aFR expression, a repeat biopsy at 
the pre-infusion timepoint is not required. 
14. On Day 0, vital signs (temperature, respiration rate, pulse, blood pressure, and oxygen saturation by pulse oximetry) will be measured within 10 minutes 
prior and within 15 minutes after the infusion. Thereafter, vital signs will be measured at 30 (+/- 5) minutes, 45 (+/- 5) minutes, and 60 (+/- 5) minutes 
after the infusion, and then every hour (+/- 10 minutes) for the next two hours until these signs are satisfactory and stable. If vital signs are not 
satisfactory and stable 3 hours after the infusion, vital signs will continue to be monitored as clinically indicated until stable.   
15. Collection of adverse events will begin at time of apheresis and will continue until the subject is off-study.  Please see Section 9.1 for additional 
information.   
16. Chemistry panel including sodium, potassium, chloride, CO2, blood urea nitrogen, creatinine, glucose, magnesium, phosphate, total protein, albumin, 
calcium, alkaline phosphatase, total bilirubin, ALT, AST, uric acid, LDH 
17. HIV, Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody, Hepatitis B core antibody, and Hepatitis C antibody. If the HCV antibody is 
positive, a screening HCV RNA by any RT-PCR or bDNA assay must be performed. Eligibility will be determined based on the screening value. The test is 
not required if documentation of a negative result of a HCV RNA test performed within 60 days prior to screening is provided. 


MOv19-BBz CAR T cells in aFR expressing Ovarian Cancers 
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18. Evaluation of aFR expression will occur on archived tumor tissue, if the subject has not had an anti-aFR directed therapy since the collection of the 
archived sample. However, if archived tumor tissue is not available, a fresh biopsy may be performed.  Once aFR expression has been confirmed, 
subjects may be presented the informed consent for the main study.  If the aFR expression of their tumor is known prior to signing the tissue testing 
consent for this study, the results of this testing will need to be confirmed as part of the subjects’ participation on this protocol.  Once aFR expression 
has been confirmed, subjects may proceed to the next step and be presented the informed consent for the main study.  
19. Repeated as clinically indicated or if HLH/MAS or CRS is suspected. 
20. All subjects must undergo a Respiratory Virus Panel (RVP) within 10 days prior to MOv19-BBz CAR T cell infusion. If the patient is positive for influenza, 
Tamiflu® or equivalent should be administered per package insert. The subject must complete treatment prior to receiving lymphodepleting 
chemotherapy and MOv19-BBz cells. The test does not need to be repeated prior to the MOv19-BBz cell infusion; however if influenza signs and 
symptoms are present, the infusion should be delayed until the subject is asymptomatic. If the subject is positive for another virus on the RVP, the 
MOv19-BBz cell infusion will be delayed for at least 7 days to be sure clinical symptoms of a viral infection do not develop. If clinical symptoms develop, 
the lymphodepleting chemotherapy and CAR T cell infusion will be delayed until resolution of these symptoms. 
21. A mini-apheresis procedure (~5 L) will be performed at this visit for research purposes.  A 60 ml blood draw may be substituted for the mini-apheresis 
procedure at the discretion of the treating investigator. 
22. Please refer to Section 6.13 for long-term follow-up requirements. 
23. Please refer to Section 9.1 for protocol-defined adverse event (PDAE) reporting requirements in long-term follow-up. 
24. All tests/procedures will be performed pre-infusion on Day 0 unless otherwise specified. The results of the CBC with differential and comprehensive 
metabolic panel must be reviewed by a physician-investigator prior to the infusion.   
25. During long-term follow-up, only medications used to treat the subject’s cancer will be collected. 
26. Imaging performed within 8 weeks of subject signing main consent will be accepted.  Baseline imaging should be obtained within 28 days prior to 
infusion of MOv19-BBz CAR T cells and after any cancer therapy administered between collection and MOv19-BBz CAR T cell infusion.  In cohorts 2 and 
3, baseline scans should be obtained prior to lymphodepleting chemotherapy administration and MOv19-BBz CAR T cell infusion. 
27. Required at screening for subjects with known CNS metastases. 
28. Please refer to Section 5.3.1.3, 5.6, and 6.6 for additional information.  
29. Testing for persistence by Q-PCR will continue until any 2 sequential tests are negative documenting loss of CAR T cells.  Thereafter samples will continue 
to be collected and archived.  
30. ECHO/MUGA must be performed within 8 weeks prior to the CAR T cell infusion. 
31. Lymphodepleting chemotherapy will be scheduled so that the last day of chemotherapy falls 3 days +/- 1 day prior to CAR T cell infusion.  Please refer 
to Section 6.5 for additional information on protocol required lymphodepleting chemotherapy.  
32. Visit window ±60 days 
33. Survival follow-up may be conducted via the Penn Patient Portal, phone or email/mail. The Follow-up Survey in Appendix 2 may be used to facilitate 
contact with the subject as required. 


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34. aFR expression testing will be performed on archived/fresh tumor tissue specimens collected at protocol defined timepoints- Screening, Pre-Infusion 
Safety and Day 14 (+/- 7 days).  Please refer to the Tissue Handling Manual for additional instructions. 
35. Day 14 only


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17 
APPENDIX 2 - LONG-TERM FOLLOW-UP SURVEY  
 
This follow-up survey is for: 
• 
Subjects who cannot return for an onsite visit at any time point. 
• 
Subjects to be contacted annually because they had no sign of gene therapy product at the 
5-year follow-up visit or later and are, therefore, not required to return for any remaining 
future onsite visits.   
 
Follow-Up  Survey 
  
Name of Participant: ______________________________________       
 
Method of Contact. Document method of contact 
  
Mail: 
______________________________________________________________ 
  
  
 
Email: 
Phone: 
______________________________________________________________ 
______________________________________________________________ 
Above information to be filled out by Coordinator 
1) Today’s Date:_______/_______/____________    
                                  MM            DD                 YYYY 
 
2) Update contact information. Document any changes below since your last study visit or last contact 
with the study team. 
  
Phone: 
______________________________________________________________ 
  
Email: 
______________________________________________________________ 
  
Address: 
______________________________________________________________ 
 
Preferred method of contact: ______________________________________________ 
 
3) Have you been diagnosed with any type of cancer since your last study visit or last contact with the 
study team?  
  No, I have not been diagnosed with Cancer.  
  Yes, I have been diagnosed with Cancer. [Please complete the fields below.] 
• 
Cancer Diagnosis: ________________________________________________ 
• 
Type of Cancer: __________________________________________________ 


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Follow-Up  Survey 
• 
Date of Diagnosis: ________________________________________________ 
4) Have you developed any of the following symptoms since your last study visit or last contact with the 
study team?  
  
Experienced a worsening or new loss of feeling in any part of your body, especially hands and feet 
  
Experienced a worsening or new loss of control of any body part (arms, legs…) 
 
Experienced a worsening or had a seizure 
 
Experienced a worsening or new experience memory loss 
Please explain if necessary: 
5) Have you developed a worsening or arthritis or been recently diagnosed with arthritis by a doctor since 
your last study visit or last contact with the study team? 
  Yes 
  No 
Arthritis: Most kinds of arthritis cause pain and swelling in your joints.  
6) Have you developed a worsening of your autoimmune disease or been recently diagnosed with an 
autoimmune disease by a doctor since your last study visit or last contact with the study team?  
  Yes 
  No 
Autoimmune Disease:   The body’s immune system protects you from disease and infection. 
Autoimmune diseases are when your immune system attacks healthy cells in your body by mistake.  
Autoimmune diseases can affect many parts of the body.  
7) Have you had any new or unexpected illnesses or been hospitalized unexpectedly?  
 
 Yes 
 No 
 
If yes, please explain:   
 
Completed By: 
 
_____________________________________________________________________________________ 
Name  
 
 
Signature  
 
 
Date 
 
 
 
 
 


MOv19-BBz CAR T cells in aFR expressing Ovarian Cancers 
Page 106 of 106 
Version 7.02-09-2023 
 
 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
18 
APPENDIX 3 - EXAMPLE PHYSICIAN LETTER 
EXAMPLE LETTER TO PHYSICIANS 
[date] 
[name and address] 
Dear [physician name], 
 
Your patient [patient name] is participating in a clinical research study that requires 15 year monitoring 
for adverse events.  To aid in reporting of adverse events that are possibly related to the clinical research 
study, we are asking the patients on our research study to designate a primary care physician or local 
oncologist that may help in the monitoring and reporting of adverse events.  Your patient has designated 
you.  If upon any of your visits with your patient, any of the following events are reported or discovered, 
please contact the study coordinator as soon as possible:  
 
1. New malignancies 
2. New incidence or exacerbation of a pre-existing neurologic disorder 
3. New incidence or exacerbation of a prior rheumatologic or other autoimmune disorder 
4. New incidence of a hematologic disorder. 
5. Events that may be unexpected in this patient population and thus potentially related to the 
investigational product they received.  
 
If your patient experiences any of these events, please contact the study coordinator below as soon as 
you can so that we can record the event and then monitor your patient’s health if necessary.  When you 
call, remember to mention the protocol number of the study which is UPCC 03818, Subject ID (XXX) and 
the brief study title which is “MOv19-BBz CAR T cells in aFR expressing recurrent high grade serous 
ovarian, fallopian tube, or primary peritoneal cancer”. 
 
Study Coordinator 
Name 
Address 
Phone 
Email 
 
In addition, if your patient cannot return to the University of Pennsylvania for some of their follow-up 
visits, we will contact you to provide information from their medical record, including the results of any 
routine care physical examinations and/or laboratory assessments performed. We may also ask for your 
assistance in the collection of protocol required blood samples, which will need to be sent to the 
University of Pennsylvania for required analysis.  
 
If you have any questions about this letter or the study itself, please do not hesitate to contact the above 
study nurse or physician. 
 
Thank you for your support in helping us to monitor for delayed adverse events.   
 
Best regards, 
[Principal Investigator] 

ICF_000.pdf: 
 
Informed Consent Form 
Title 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha 
Redirected T Cells for Recurrent High Grade Serous Ovarian, Fallopian Tube, or 
Primary Peritoneal Cancer 
NCT 
NCT03585764 
Date 
09-Feb-2023 
 
 
 
 
 
 
 
 
 




Informed Consent Form and HIPAA Authorization - UPCC 03818 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
UPCC 03818 Main ICF V11.02-09-2023 
2 of 40 
Please note that there are other factors to consider before agreeing to participate such as 
additional medical procedures, use of your personal information, costs, and other possible risks 
not discussed here.  If you are interested in participating, a member of the study team will 
review the full information with you.  You are free to decline or stop your participation at any 
time during or after the initial consenting process.  
 
Why am I being asked to volunteer? 
You are being invited to participate in a research study because you have ovarian, fallopian 
tube, or primary peritoneal cancer that continues to grow and spread (metastatic) after 
standard treatment with at least two prior chemotherapies.  Your cancer is also positive for a 
protein called aFR (alpha folate receptor).  Your participation is voluntary which means you can 
choose whether or not you want to participate.  
 
Before agreeing to participate in this research study, it is important that you read the following 
explanation of the proposed procedures and how long you will be in the study. This document 
describes the purpose, procedures, benefits, risks, discomforts and precautions of the study. It 
also describes the alternative procedures that are available to you and your right to withdraw 
from the study at any time.   
 
We are asking that you participate in a research study.  When you take part in a research study, 
you and the study doctor must follow a set plan called the “study protocol.” This is different 
from receiving care outside of the research study.  When you receive medical care from your 
own doctor, he or she develops a plan of care just for you and your individual needs. When 
participating in the research study, the study doctor usually cannot adjust the plan for you as he 
or she needs to follow the study protocol.  However, this research plan includes steps to follow 
if you are not doing well.  It's important to understand that a clinical trial is an experiment. By 
its nature, that means the answer to the research question is still unknown. 
 
Please take time to read the following information carefully. You may wish to discuss it with 
your family, friends, and your personal doctor (i.e., your family doctor or primary care doctor). 
If you have any questions, you may ask your study doctor and/or the research team for more 
information. Take time to decide whether or not you wish to take part. If you decide to 
participate, you will be asked to sign this form.  If you decide to participate, you can change 
your mind at any time and withdraw from the study without giving a reason.  
 
What is the purpose of this research study? 
This research study will take some of your own white blood cells, called T cells, and modify 
them by introducing a receptor (chimeric antigen receptor, CAR) that recognizes aFR protein, so 
that they can identify and possibly kill cancerous cells expressing aFR protein.  The T cells also 
will include a receptor that may help them kill cancer cells better. The modification is a genetic 
change, or gene transfer, to your normal T cells. These modified cells are called MOv19-BBz CAR 
T cells.   
 


Informed Consent Form and HIPAA Authorization - UPCC 03818 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
UPCC 03818 Main ICF V11.02-09-2023 
3 of 40 
The use of MOv19-BBz CAR T cells is experimental and has not been approved by the Food and 
Drug Administration (FDA).  This is the first time MOv19-BBz CAR T cells are being tested in 
humans. The MOv19-BBz CAR T cells will be administered directly into your abdominal cavity 
via intraperitoneal infusion. This type of administration is also considered experimental.  
 
At this time, we do not know the best and safest dose of MOv19-BBz CAR T cells.  The goal of 
this research study is to identify a safe dose of the MOv19-BBz CAR T cells in people with 
ovarian cancer.  This will be done by using three different planned doses of the MOv19-BBz CAR 
T cells in small groups of participants in this research study.  These small groups of participants 
are called cohorts.  Some cohorts of participants will receive chemotherapy also, and other 
cohorts will not.  Therefore, this study will involve up to 4 cohorts and 3 different dose levels of 
MOv19-BBz CART cells.  If the lowest dose of MOv19-BBz CAR T cells are determined to be safe, 
higher dose levels will be evaluated.  
 
When your own blood cells are taken, there may not be enough cells to make the planned 
study dose of the modified cells.  If this occurs, and if the study physicians feel it is safe and 
poses no additional risk to you, they may recommend giving you a lower T-cell dose. If you 
decide not to receive this lower T-cell dose, you will no longer be able to participate in this 
research study. If you do receive a T-cell dose that is lower than the planned study dose, you 
will undergo the same schedule of visits and procedures as participants who receive the 
planned study dose. 
 
In addition, subjects in certain cohorts will also receive chemotherapy a few days prior to their 
MOv19-BBz CAR T cell infusion. The chemotherapy drugs being used as part of this study are 
cyclophosphamide and fludarabine, which are approved by the FDA for treatment of certain 
types of cancers, but have not been approved for use in ovarian cancer. You will receive 
cyclophosphamide and fludarabine through an IV (intravenously through a vein) over 3 days. 
The purpose of this chemotherapy is to help the CAR T cells grow and survive in your body.  
Therefore, the use of chemotherapy as part of this study is considered investigational.   
 
Subjects will be assigned to cohorts based on when they enroll on the study and available 
safety experience.  Cohort 3 evaluated the highest dose of MOv19-BBz CAR T cells following 
chemotherapy, and was prematurely closed in January 2023 due to severe toxicity, including 
side effects that possibly contributed to the death of a study participant. You are being asked to 
participate in Cohort 2, which uses a lower dose of MOv19-BBz CAR T cells following 
chemotherapy.    
 
How long will I be in the study?  
If you choose to participate, the main portion of the study will take up to 2 years from the 
infusion of the MOv19-BBz CAR T cells to complete. You will be asked to come to the Hospital of 
the University of Pennsylvania 2-3 times during the screening process in order to make sure you 
are eligible to receive the MOv19-BBz CAR T cells, and to prepare you for the experimental 
treatment. Treatment itself may involve chemotherapy given over the course of three days, and 


Informed Consent Form and HIPAA Authorization - UPCC 03818 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
UPCC 03818 Main ICF V11.02-09-2023 
4 of 40 
a one-time infusion of the cells.  Once you receive the MOv19-BBz CAR T cells, you will be 
monitored very closely by your doctors and study team as either an outpatient or inpatient 
depending on your clinical condition.  Each of these visits should take about 1 to 4 hours. 
 
After you complete the main portion of the study, you will continue to be followed in long-term 
follow-up.  During the long-term follow-up portion of the study, you will be followed for up to 
15 years after you receive your MOv19-BBz CAR T cells, or until you withdraw from the study 
for any reason.    
 
How many other people will be in the study? 
It is expected that up to 18 adults will receive MOv19-BBz CAR T cells as part of this research 
study at the Hospital of the University of Pennsylvania.     
 
What am I being asked to do? 
Please note that a list of terms that are used throughout this consent form is provided at the 
end of this consent with explanations. 
 
Procedures 
Prior to taking part in this study, you and your doctor should discuss the current standard 
treatments for your cancer. The study doctor will ask you to read and sign this Informed 
Consent Form after all of your questions have been satisfactorily answered.  
 
Once you decide to participate, you will have to undergo a screening process to determine if 
you are able to join the study.  In order to determine if you are eligible to participate in this 
study, you will be required to undergo the following tests and evaluations: 
 


Informed Consent Form and HIPAA Authorization - UPCC 03818 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
UPCC 03818 Main ICF V11.02-09-2023 
5 of 40 
Day 
Part of 
Your 
Standard 
Medical 
Care? 
Procedures 
Screening 
Phase:  
Approximately 
2 months prior 
to receiving  
MOv19-BBz 
CAR T cells  
No 
These procedures will check to see if you are eligible to 
participate in the study and will take approximately 1-2 hours. 
• Review of list of medications 
• Blood is drawn for clinical laboratory tests (which includes the 
HIV, hepatitis B and hepatitis C tests, to see how well your 
blood clots, blood tests to assess additional chemistry levels, 
and if you have any active infections).  This requires a blood 
draw of about 2 tablespoons.  
• Electrocardiogram (EKG)  
• ECHO/MUGA 
• Leukapheresis screening to see if the veins in your arms are 
adequate for the apheresis procedure 
Yes 
• Review of your relevant medical history and current medical 
conditions 
• Physical Exam including vital signs (temperature, blood 
pressure, heart rate (pulse), and blood oxygen levels), height 
and weight 
• Routine blood tests to assess your blood cell counts (to assess 
the number of each type of blood cell), blood chemistry levels 
(to test your organ function and the minerals in your blood).  
This requires a blood draw of about ½ tablespoon.  
• A urine sample will be obtained for routine analysis  
• Urine pregnancy test if you are a female/transgender male of 
childbearing potential 
• Disease assessments- CT scan of your chest/abdomen/pelvis.  
If you have already had these scans recently as part of your 
routine care, they may not need to be repeated. 
• Brain MRI only if you have a history of cancer that has spread 
to your brain  
 
Reporting of a positive HIV, hepatitis B and hepatitis C test:  You will be tested for HIV, hepatitis 
B and hepatitis C as one of the screening requirements prior to participating in this study.  If 
you test positive for HIV, hepatitis B or hepatitis C, by law we have to report the positive test 
results to the City of Philadelphia Health Department and/or PA Department of Health.  
Personal identifiers such as name, sex, date of birth, address, and phone number will be 
reported. For more information about the requirements reporting infectious diseases to the 
City of Philadelphia Health Department, please visit https://hip.phila.gov/ReportDisease. For 




Informed Consent Form and HIPAA Authorization - UPCC 03818 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
UPCC 03818 Main ICF V11.02-09-2023 
7 of 40 
 
Day 
 
 
Part of 
Your 
Standard 
Medical 
Care? 
 
Procedures 
You may not have to undergo this apheresis procedure if you 
have had T cells collected on another research study or at 
another facility.  We may be able to use your T cells collected 
from the other study if they are acceptable to make your 
MOv19-BBz CAR T cells for this study.  
  
Pre-Infusion 
Safety Visit 
Approximately 1 
to 2 weeks 
before you 
receive MOv19-
BBz CAR T cells  
No 
• Review of current medical conditions, list of medications, 
and symptoms/side effects 
• Respiratory virus panel (RVP) for the flu and other viral 
infections will be performed   within 10 days prior to 
infusion of your T cells – this test involves swabbing of your 
throat and nostrils using a cotton swab. 
o If your RVP test is positive but you do not have any flu 
symptoms you will receive an antiviral medication 
called Tamiflu as standard medical care and your T cell 
infusion will be delayed until you complete this 
medication.  
o If your RVP test is positive and you have flu symptoms 
you will receive Tamiflu.  Your infusion will be delayed 
for at least 7 days and all clinical symptoms must be 
resolved before you can receive your T cells. 
o If your RVP test finds another virus, including the 
virus that causes COVID-19, your treatment will be 
delayed for at least 7 days, and until symptoms have 
resolved. 
 
• Blood for clinical lab tests, to assess additional chemistry 
levels, and for research analysis.  This requires a blood 
draw of up to 2 ½ tablespoons. 
• A urine sample will be obtained for routine analysis.  
• Blood pregnancy test if you are a female/transgender male 
of childbearing potential (about ½ teaspoon) 
• Tumor biopsy if determined clinically appropriate by your 
study doctor. The doctor may use ultrasound or CT scan or 
both, to precisely locate the tumor for biopsy.  This tissue 
will be used for research purposes.  If you already 


Informed Consent Form and HIPAA Authorization - UPCC 03818 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
UPCC 03818 Main ICF V11.02-09-2023 
8 of 40 
 
Day 
 
 
Part of 
Your 
Standard 
Medical 
Care? 
 
Procedures 
underwent a biopsy at screening in order to evaluate your 
eligibility to participate in this study, a repeat biopsy pre-
infusion is not required.  
• Disease assessments- CT scan of your 
chest/abdomen/pelvis if you have not had one within 8 
weeks of your CAR T cell infusion.   
Yes 
• Physical Exam including an assessment of your vital signs 
• Routine blood tests to assess your blood cell counts, blood 
chemistry levels, how fast your blood clots, and to measure 
biomarkers for your disease.  This requires a blood draw of 
about 1 ½ tablespoons.  
Chemotherapy 
(Cohorts 2 and 
3 only)   
Last day of 
chemotherapy 
will end 
approximately 
3 days before 
your MOv19-
BBz CAR T cell 
infusion 
No 
If you are participating in cohort 2 or 3, you will receive 
chemotherapy with cyclophosphamide in combination with 
another chemotherapy called fludarabine.  The purpose of the 
chemotherapy is to “make room” to help the CAR T cells 
expand and grow in your body. Chemotherapy is given 
intravenously (through a vein), and you will also receive 
nausea medications and intravenous fluids before and after 
the chemotherapy.  Chemotherapy will be given over 3 days.  
Each visit will last about 4 hours.   
 
The following procedures will be done before the first dose of 
chemotherapy: 
• Review of your current medical conditions, list of 
medications, and symptoms/side effects 
• Blood test for routine lab tests (requires a blood draw of 
about ½ tablespoon) 
• A urine sample will be obtained for routine analysis. 
Yes 
The following procedures will be done before the first dose of 
chemotherapy: 
• Physical examination including an assessment of your vital 
signs 
• Routine blood tests to assess your blood cell counts (to 
assess the number of each type of blood cell), blood 
chemistry levels (to test your organ function and the 




Informed Consent Form and HIPAA Authorization - UPCC 03818 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
UPCC 03818 Main ICF V11.02-09-2023 
10 of 40 
 
Day 
 
 
Part of 
Your 
Standard 
Medical 
Care? 
 
Procedures 
next 2 hours or until satisfactory and stable 
• Blood tests to assess additional chemistry levels, disease 
status, and for research analysis collected prior to 
receiving the MOv19-BBz CAR T cells and ~1 hour after 
(requires about 4 ¾ tablespoons of blood)  
• A urine sample will be obtained for routine analysis. 
 
You will be allowed to go home 3 hours after your infusion if 
you feel well and have not experienced unexpected reactions 
to the infusion. 
Yes 
 
 
• Physical Exam including an assessment of your vital signs 
• Routine blood tests to assess your blood cell counts and 
blood chemistry levels. This requires a blood draw of about 
½ tablespoon. 
Safety Follow-up 
Visit 
1 day after 
receiving MOv19-
BBz CAR T cells 
No 
• Review of your current medical conditions, list of 
medications, and symptoms/side effects 
• Blood tests to assess additional chemistry levels and for 
research analysis (including tests for detection of MOv19-
BBz CAR T cells) requires a blood draw of about 
2 tablespoons. 
Yes 
• Physical exam including an assessment of your vital signs  
• Routine blood tests to assess your blood cell counts and 
blood chemistry levels. This requires a blood draw of about 
½ tablespoon. 
Safety Follow-up 
Visits 
Days 2, 7, 10, 14, 
and 21 after 
receiving MOv19-
BBz CAR T cells  
No 
• Review of your current medical conditions, list of 
medications, and symptoms/side effects 
• Blood tests to assess additional chemistry levels, disease 
status, and for research analysis (including tests for 
detection of MOv19-BBz CAR T cells).  Requires a blood 
draw of about 2 ¾ tablespoons. 
• Day 14 Visit: Tumor biopsy if determined clinically 
appropriate by your study doctor. The doctor may use 
ultrasound or CT scan or both, to precisely locate the tumor 
for biopsy.  This tissue will be used for research purposes. 


Informed Consent Form and HIPAA Authorization - UPCC 03818 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
UPCC 03818 Main ICF V11.02-09-2023 
11 of 40 
 
Day 
 
 
Part of 
Your 
Standard 
Medical 
Care? 
 
Procedures 
Yes 
• Physical exam including an assessment of your vital signs  
• Routine blood tests to assess your blood cell counts and 
blood chemistry levels. This requires a blood draw of about 
½ tablespoon. 
Safety Follow-up 
Visit 
Day 28  
No 
 
• Review of your current medical conditions, list of 
medications, and symptoms/side effects  
• Blood tests to assess additional chemistry levels and for 
research analysis (including tests for detection of MOv19-
BBz CAR T cells) 2 tablespoons. 
• Apheresis (about 4 tablespoons of blood) 
Yes 
• Physical exam including an assessment of your vital signs  
• Routine blood tests to assess your blood cell counts, blood 
chemistry levels, and to measure biomarkers for your 
disease. This requires a blood draw of about 1 tablespoon.  
• Disease assessments- CT scan of your 
chest/abdomen/pelvis.  Additional scans may be performed 
as determined necessary by your study doctor.  
Follow-up Visits 
Months 2, 3, and 
6  
No 
 
 
• Review of your current medical conditions, list of 
medications, and symptoms/side effects. 
• Blood tests to assess additional chemistry levels and for 
research analysis (including tests for detection of MOv19-
BBz CAR T cells). This requires a blood draw of about 
2 tablespoons. 
Yes 
 
• Physical exam including an assessment of your vital signs  
• Routine blood tests to assess your blood cell counts, and 
blood chemistry levels. This requires a blood draw of about 
2 teaspoons.  
• A urine sample will be obtained for routine analysis. 
• Blood test to measure biomarkers for your disease. This 
requires a blood draw of about 1 teaspoon. 
• Months 3 + 6 Only – disease assessments 
o CT scan of your chest/abdomen/pelvis  
o Additional scans may be performed as determined 
necessary by your study doctor.  








Informed Consent Form and HIPAA Authorization - UPCC 03818 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
UPCC 03818 Main ICF V11.02-09-2023 
15 of 40 
collected from you will be 3 tablespoons of blood twice in one week, in addition to the 
protocol-defined time points listed above.   
 
In addition, if you undergo a biopsy as part of your routine treatment while you are on study, a 
sample of this tumor tissue will be collected for research purposes.  
 
The study team may “bank” (store) some of your blood samples collected throughout your 
participation in this study.  These samples will be kept frozen and will not identify you by name.  
The blood samples will only be used by the study team to go back and do testing on your blood 
if an unexpected event occurs. 
 
Request for Autopsy: 
In order for the study doctors to learn more about your disease and the safety and function of 
the MOv19-BBz CAR T cells, they may request to perform an autopsy in the event of your death.  
Your family will make the final decision as to whether or not an autopsy can be performed and 
will be required to sign forms that will authorize the autopsy.  Therefore, please inform your 
family of your wishes.  If an autopsy is performed, samples obtained during this procedure will 
be used for research purposes.   
 
What are the possible risks or discomforts? 
As of December 2022, MOv19-BBz CAR T cells have been given to 9 subjects at the University of 
Pennsylvania.  In addition, over 500 adults and children with leukemia, lymphoma, and multiple 
myeloma have also received different types of CAR T cells as part of University of Pennsylvania 
sponsored research studies.   
 
This section describes the most common side effects seen in subjects receiving other CAR T 
cell therapies at the University of Pennsylvania, as well as the side effects seen in subjects 
receiving Mov19-BBz cells to date.  These side effects can range from mild to severe, and have 
resulted in death in rare cases.  These side effects may occur together as part of a syndrome 
(a group of symptoms that indicate a specific condition or disorder) or as independent events.   
 
This research may also involve risks that are currently unknown or unexpected.  Therefore, it 
is important that you tell your doctor if you are experiencing any problems.  If you see a 
doctor other than your study doctor, please let them know that you are involved in a 
research study.   It is very important that you contact your study doctor immediately if you 
develop signs of fever or other new abnormal symptoms.  This may require you to go into the 
hospital so the study team can monitor or help treat these side effects.  It is possible that you 
will have side effects from these study drugs that are difficult or not possible to fully reverse. 
 
In an effort to detect any potential side effects early and avoid any delays in management of 
these toxicities, participants treated with MOv19-BBz CAR T cells will be asked to stay 
within a one-hour drive to the Hospital of the University of Pennsylvania following infusion. 
 


Informed Consent Form and HIPAA Authorization - UPCC 03818 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
UPCC 03818 Main ICF V11.02-09-2023 
16 of 40 
 
Cytokine Release Syndrome (CRS)/Macrophage Activation Syndrome (MAS) 
Rapidly growing activated CAR T cells release proteins and chemicals called cytokines.  Release 
of large amounts of certain cytokines can cause a “cytokine release syndrome”, which is a 
severe flu-like syndrome.  Macrophage activation syndrome is an activation of your immune 
system associated with the cytokine release syndrome.    Symptoms of these severe flu-like 
syndromes include high fevers, chills and shaking, muscle aches, joint aches, sweating, nausea, 
vomiting, loss of appetite, fatigue, headache, fast heart rate, liver problems, and kidney 
problems that may require dialysis; it can sometimes also increase risk of bleeding.  People can 
also have trouble breathing and dangerously low blood pressure.  Some people need to be 
treated with a ventilator (a breathing machine).    Some people need support with special blood 
products.  Many people with cytokine release syndrome have had to be cared for in an 
intensive care unit at the hospital.  Cytokine release syndrome can be mild or severe and has 
resulted in death.  
 
These side effects may or may not be reversible. Medications are available to potentially 
reverse or lessen the severity of the CRS and MAS (such as tocilizumab). It is unknown whether 
these medicines may make your CAR T cells less effective.  The best time to administer 
medications to treat the cytokine release syndrome and macrophage activation syndrome is 
not currently known.    These medications may also have their own side effects, may weaken 
the immune system and increase the chance of serious infections.   
 
In addition, some participants with cytokine release syndrome have become very confused and 
disoriented (unaware of who they are and or where they are, not recognizing family and 
friends, unaware of the date and unaware of their health problems).  Some participants have 
had seizures or have even become unresponsive.  We believe these side effects are caused by 
the cytokine release syndrome and macrophage activation syndrome.  In most cases, these 
problems resolved over time.   
 
Neurological Toxicity 
The following events have been seen in patients receiving CAR T cells.  Some events are 
common, and most are rare.   
• Headache 
• Difficulty speaking (aphasia) 
• Delirium, confusion, or decreased alertness - which may be mild to severe  
• Hallucinations  
• Seizures (uncontrollable shaking/convulsions) 
• Tremors 
• Dizziness 
• Anxiety 
• Difficulty sleeping or sleep disorders 
• Tingling and/or weakness in hands and feet (peripheral neuropathy) 


Informed Consent Form and HIPAA Authorization - UPCC 03818 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
UPCC 03818 Main ICF V11.02-09-2023 
17 of 40 
• Meningitis (Inflammation of the lining around the spinal cord and brain). May result in 
headaches, nausea, vomiting, vision problems, and increased pressure in your brain.   It 
may also lead to seizures and death. 
• Loss of ability to move 
• Severe weakness 
• Swelling in the brain 
 
Many of these side effects have occurred with or just after cytokine release syndrome/ 
macrophage activation syndrome (CRS/MAS) as described above.  Some patients have also 
experienced neurological side effects without CRS/MAS.  While neurological side effects have 
improved in most participants, there is a possibility that you could experience side effects that 
will not improve and may result in death. 
 
Infusion/Allergic Reactions 
Infusion-related reactions may occur, as with other cellular products or transfusions.  While 
rare, symptoms of infusion-related reactions can include: 
• Fever 
• Chills  
• Nausea 
• Hives or other rashes 
• Changes in blood pressure 
 
More commonly, subjects have experienced an unusual taste in their mouth immediately after 
the infusion.  This is caused by one of the ingredients in the product.   This may also cause a 
temporary odor to your breath.  
 
More Common Side Effects (occurring in > 10% of patients): 
• Significant decreases in B-cell counts: CAR T cells can kill cancerous B-cells but can also 
kill normal B-cells.  This happens because CAR T cells cannot tell the difference between 
cancerous B-cells and normal B-cells.  Normal B-cells fight viral and bacterial infections 
by producing antibodies known as immunoglobulins.  Decreasing the number of normal 
B-cells puts you at risk of potentially life-threatening viral and bacterial infections 
(including but not limited to pneumonia).  If your immunoglobulins are too low, your 
doctor may give you intravenous immunoglobulin (IVIG).  It is possible that your B-cells 
may never return, in which case you may have a life-long risk for viral and bacterial 
infections and need repeated doses of IVIG.   
• Hypogammaglobulinemia: low immunoglobulin levels which may impair your immune 
system and may increase your risk of infection.  


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• Significant decreases in blood counts, including neutropenia (low white blood cell 
count), anemia (low red blood cell count), and thrombocytopenia (low platelet counts) 
are common. This will be related to the chemotherapy you receive prior to the MOv19-
BBz CAR T cell infusion (if given), and may also be related to the MOv19-BBz CAR T cell 
infusion. These decreases can last weeks or, much more rarely, months. These 
decreases may result in the need for transfusions (i.e. anemia and thrombocytopenia) 
and increase the risk of severe infections. 
• Fever  
• Infections 
• Sepsis- a serious infection which may be fatal  
• Decreases and increases in your blood pressure 
• Shortness of breath or abnormal rapid breathing 
• Liver function test abnormalities 
• Electrolyte abnormalities (changes in the levels of certain salts in your body, like 
sodium) 
• Acute kidney injury - kidney failure or damage that can happen very quickly. 
• Hypoxia - low levels of oxygen in parts of the body 
• Pulmonary edema- excess fluid in the lungs that may make it difficult to breathe 
• Bleeding 
• Increased/abnormal heart rate 
• Nausea 
• Vomiting 
• Diarrhea 
• Constipation 
• Abdominal pain 
• Pain in your extremities (arms and legs) 
• Fatigue 
• Decreased appetite 
• Weight loss 
• Muscle and joint aches 
• Swelling  
• Cough 
• Hives or other rashes, which may cause itching 
 


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Less Common Side Effects (occurring in ≥ 1% and ≤ 10% of patients): 
• Chills 
• Back Pain 
• Accumulation of fluid in your body (edema) which may cause pain or swelling 
• Sinus congestion  
• Coagulation (blood clotting) problems- either a decrease in the capacity to produce clots 
leading to increased risk of bleeding or increase in the clot production leading to a blood 
clot (thrombosis) 
• Tumor Lysis Syndrome:  this happens when cells are killed too quickly for the body to get 
rid of the dead cells.  Tumor lysis syndrome can cause kidney damage and increases in 
blood potassium, uric acid, calcium and phosphorus.  Treatment may require 
hospitalization, including intensive care.   
• Heart attack and heart failure 
• Multiple critical organ failure or dysfunction (when an organ does not perform as 
expected) 
• Visual impairment or blurry vision 
 
Rare, Unexpected or Potential Side Effects (have not yet occurred or occurring in less than 1% 
of patients) 
• Excessive T cell growth:  though it is expected that the CAR T cells will grow in your 
body, it is possible the T cell growth could be excessive and cause medical problems. In 
this case, your doctor may recommend treatment to kill them.  This can be done by 
giving drugs called corticosteroids. If the MOv19-BBz CAR T cell growth is not controlled 
by the corticosteroid treatment, your doctor may recommend a type of chemotherapy. 
• Inability to respond to future gene therapies: you may be less likely to respond to similar 
gene transfer trials in the future because you may develop an immune response to the 
biological delivery vehicle, called a vector, which is used for the gene transfer in your 
T cells. 
• Autoimmune disease:  the use of MOv19-BBz CAR T cells could lead to an autoimmune 
disease.  An autoimmune disease is when your immune system mistakenly attacks your 
own body.  Autoimmune disease can affect many parts of  your body, like  your nerves, 
muscles,  the  endocrine  system  (system  that  directs  your  body’s  hormones  and  
other chemicals), skin, liver, and digestive system. 


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• New occurrence of cancer:  there is a chance that the genetic modification made to your 
T cells could cause other cancers.  This could be caused by the virus (called a vector) 
used to genetically modify your T cells. In a prior gene therapy study for a childhood 
disease called Severe Combined Immunodeficiency (SCID), a viral vector caused 
leukemia in a small portion of patients. Some patients who developed the leukemia 
were successfully treated while others were not. The vector used in the SCID study is 
different than the vector used in this research study. Other cancers have been observed 
in patients who have received CAR Therapy.  The relationship of these cancers to the 
CAR therapy is not known at this time. Based on the way the vector used in this study 
works, we think the risk of the vector causing other cancers is low.  While this risk is low, 
you will be monitored for development of any new cancers throughout the scheduled 
protocol visits. If a new cancer develops while you are on study, you will be treated by 
standard of care clinical procedures, and the cancer will be investigated to determine if 
the lentiviral vector contributed to its development.  
• Potential risks associated with a Replication Competent Lentivirus or “RCL”:  the 
lentiviral vector that is used to transfer the MOv19-BBz CAR T genetic material into your 
T cells has been designed so that it does not grow once inside your T cells and remains 
inactive. However, there is a risk that portions of the vector could mutate (change) in 
your T cells and allow it become active (i.e. grow and spread to other cells).  This would 
be called a replication competent lentivirus, or “RCL”.  The specific risks associated with 
RCL are unknown. In the worst possible case it may make you sicker than you are now. 
To date, no patient treated at UPenn with other gene modified T cells using lentiviral 
vector has developed an RCL. 
• Positive HIV Test:  the lentiviral vector that is used to transfer the MOv19-BBz genetic 
material to your T cells is made up of parts of the human immunodeficiency virus or HIV.  
The lentiviral vector does not behave like HIV and it cannot cause the HIV disease. Most 
of the lentiviral vector is washed away during the manufacturing process of your T cells; 
however, there is a possibility it may cause a positive test result for HIV.  If you test 
positive for HIV, you can have a more sensitive test done to determine whether or not 
you are truly HIV positive. 
• Antibody formation:  Your white blood cells isolated by the apheresis procedure will 
have further processing that will isolate the T cells (type of white blood cell) needed for 
your treatment. The separation is accomplished by using a system in which mouse 
antibodies are used.  Residual mouse antibodies, which are proteins that are foreign to 
your body, can elicit an antibody response in your body. Furthermore, it is also possible 
that you may develop antibodies to other residual proteins used during the preparation 
of MOv19-BBz CAR T cells (e.g. VSV-G or HIV proteins that are present on the vector) 
that may not have been completely removed during the manufacturing process. The 
result of this is that your body could develop antibodies to the "foreign" proteins, which 
could lead to an allergic reaction, such as skin rash, itching and fever.  More serious 
allergic reactions that require medical treatment could also occur, such as shortness of 
breath and drop in your blood pressure.  It is possible that you will develop an immune 
response against the MOv19-BBz CAR T cells, and that this may result in the loss of 


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MOv19-BBz CAR T cells from your body.  Development of anti-mouse antibodies could 
prevent you from getting other therapies that use mouse derived antibodies in the 
future. 
• Inflammation: Your T cells will be modified to attack a certain protein called aFR which is 
located on the surface of your cancer cells.  aFR is also found at low levels on the normal 
cells of your body including your kidney and small intestine. It is possible that treatment 
with these modified T cells may cause inflammation of these linings. The symptoms of 
this inflammation may include pain, bloating, distended abdomen, shortness of breath, 
pressure in the chest, fast or irregular heartbeats. Should significant inflammation occur, 
your doctors will treat you with steroids to decrease the inflammation.   The T cells may 
also affect the salivary glands in your neck, which may cause dry mouth. 
• On Target, Off Tumor Effects: As the target of the T cells is also on some of your kidney 
cells and some of the cells your brain, it is possible that you may experience 
inflammation in these areas as well.  
• Anaphylactic reaction or anaphylactic shock: In a previous study testing patient T cells 
expressing a CAR that recognized a protein other than aFR, one patient experienced an 
anaphylactic reaction (or allergic reaction) after receiving multiple doses of the CAR T 
cells. Parts of this CAR were made using genes and proteins from mice. This anaphylactic 
reaction was most likely due to repeated exposure to the mouse components of the 
CAR. In the current study, we are testing a CAR construct that also contains mouse 
genes, in addition to human genes. Thus there is risk of developing an allergic reaction. 
However, in this study, you will only receive one dose of CAR T cells, thus the risk for an 
allergic reaction is lower. If a patient develops an allergic reaction that we could have 
not predicted, we will provide all necessary care for their allergic reaction which may 
include giving additional medications, providing life support and CPR and admission to 
the hospital for further care. 
 
Reproductive Risks 
The reproductive risks of MOv19-BBz are not known at this time.  It is possible the cells could 
cause harm to an unborn child or children who are breastfeeding.  The cells could also affect 
male/female fertility.  If you have not already spoken to your treating physician about options 
for fertility preservation (which can include collection of eggs or sperm) you and your study 
doctor may discuss this in more detail.   
 
If you are capable of becoming pregnant, you will undergo a urine pregnancy test prior to entry 
into the research study and a serum pregnancy test prior to the MOv19-BBz CAR T cell infusion. 
If you are found to be pregnant or breastfeeding at that time you will not be allowed to 
participate in the research study. 
 
All study participants who are capable of becoming pregnant or fathering a child, MUST use at 
least one method of birth control for at least one year after your CAR T cell infusion. 
 


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Examples of medically acceptable birth control methods include any of the following:  
 
• Total abstinence (no sexual relations) 
• Female sterilization- surgical removal of both ovaries (female reproductive system that 
stores and releases eggs for fertilization and produces female sex hormones), or tubal 
ligation (having your “tubes tied”) at least six weeks prior to signing this consent.  
• Male sterilization 
• Condoms with or without a spermicidal agent 
• Diaphragm or cervical cap with spermicide 
• A hormonal or non-hormonal intrauterine device (IUD) 
• Hormonal based contraception (including the birth control pill, vaginal rings, etc.) 
 
If you do become pregnant or suspect you may be pregnant, you must tell the investigator 
immediately and consult an obstetrician or maternal-fetal specialist. If you become pregnant 
while you are on this research study, you will continue to be followed in long-term follow-up.  
Your study doctor will also follow your pregnancy until outcome to monitor your safety.   
 
If your partner becomes pregnant, you must tell the study doctor as soon as possible.  
 
Pregnancy outcomes will be collected for any children fathered by study participants. Consent 
to report information regarding these pregnancy outcomes will be requested. 
 
Risks Associated with Cyclophosphamide (Cohorts 2 and 3 only): 
Common (over 10%): 
• Decrease of white blood counts (which may result in infections) 
• Decrease in platelets (cells that help your blood to clot) 
• Decrease in red blood cell counts (which can cause anemia) 
• Nausea and vomiting 
• Temporary hair thinning or hair loss (beginning 3-6 weeks after administration) 
• Sterility (inability to have children) 
• Acute hemorrhagic cystitis (inflammation of the bladder causing blood in the urine) 
 
Less common (1-10%): 
• Facial flushing 
• Headache 
• Skin rash 
• Nasal congestion, runny eyes, runny nose, sinus congestion, and sneezing during or 
immediately after the infusion 
 


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Risks Associated with Fludarabine (Cohorts 2 and 3 only) 
Common:  
• Decrease of white blood counts (which may result in infections)  
• Decrease in platelets (cells that help your blood to clot)  
• Decrease in red blood cell counts (which can cause anemia)  
• Fever 
• Nausea and vomiting 
• Skin rashes 
• Muscle pain 
• Fatigue (tiredness) 
• Pneumonia 
• Nervous system toxicity such as changes in vision or changes in degree of alertness both 
of which can be severe or fatal, deterioration of mental status 
• Allergic reaction causing breathing difficulty 
 
Rare: 
• Thrombotic thrombocytopenic purpura (TTP) - a rare blood disorder where blood clots 
form in small blood vessels throughout the body. 
• Liver failure 
• Tumor lysis syndrome - when tumor cells are killed too quickly for the body to get rid of 
the dead cells.  Tumor lysis syndrome can cause kidney damage and increases in blood 
potassium, uric acid, calcium and phosphorus.  Treatment may require hospitalization, 
including intensive care. 
• Opportunistic infections (protozoan, viral, fungal, and bacterial) 
• Autoimmune disorders 
 
Risks of fludarabine combined with cyclophosphamide (Cohorts 2 and 3 only) 
Common:  
• Decrease of white blood counts (which may result in infections)  
• Decrease in platelets (cells that help your blood to clot) leading to bleeding or easy 
bruising 
• Decrease in red blood cell counts (which can cause anemia)  
• Fatigue 
• Nausea and vomiting  
• Temporary hair thinning or hair loss  
• Skin infection 


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Less Likely:  
• Allergic reaction 
• Severe allergic reaction that causes fever, aches and pains in the joints, skin rash, and 
swollen lymph glands, stuffy or runny nose, sneezing, sore throat, abnormal fast 
heartbeat, excessive sweating, flushing, itching, rash, swelling of the lips, eyes, tongue, 
and throat which can be severe, hives, diarrhea, high blood sugar, low blood potassium, 
dizziness, convulsions or seizures 
• Abdominal pain,  
• Back, joint, and/or muscle pain 
• Headache 
• Wheezing 
• Cough 
• Shortness of breath 
• Inflammation (swelling) of the lung which may cause difficulty breathing and difficulty 
getting oxygen, 
• Sterility (inability to have children), irregular menstrual periods 
• Increased production of tears,  
• Metallic taste, and 
• Acute hemorrhagic cystitis (inflammation of the bladder causing blood in the urine)  
 
Rare but Serious:  
• Hemolytic anemia 
• Changes in vision or changes in degree of alertness both of which can be severe or fatal 
• Rash which may become severe 
• Separation of your outer and middle skin layers which may be life-threatening  
• Difficulty breathing 
• Allergic reactions to blood transfusions 
• Tumor lysis syndrome that can lead to kidney and heart failure 
• Secondary cancers- including myelodysplastic syndrome (MDS) and acute myeloid 
leukemia (AML) 
 
Apheresis 
Side effects that can occur during T-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 in the vein, also called intravenous (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, a drug called ACD (acid-citrate-
dextrose) will be used. This drug 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. After 


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Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
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the apheresis procedure you may experience temporary discomfort, including irritation, 
swelling or bruising at the place where the needle was inserted into your vein to collect the 
blood. Apheresis can also occasionally cause hives, numbness and tingling, or swelling of your 
feet and ankles. 
 
Tumor Biopsy 
A biopsy is an invasive test in which your cells and/or tissue are collected for examination. It 
involves the surgical removal of a small bit of tissue for examination. Your study doctor will 
explain this procedure to you in more detail, and you will be given a standard hospital consent 
form to sign detailing your specific type of biopsy prior to the procedure.  
Likely risks: 
• Pain 
• Discomfort 
• Soreness 
• Minor bleeding 
• Bruising 
 
Less likely risks: 
• Redness 
• Swelling 
• Bleeding 
 
Rare risks: 
• Bleeding that is life-threatening  
• Possible damage to adjacent organs 
• Drainage from the biopsy site 
• Abnormal wound healing 
• Fever 
• Infection 
• Allergic reaction to the medication used to numb the skin over the biopsy site 
 
Intravenous Catheter Placement (IV) 
Placement of an IV catheter involves putting a small, short plastic tube in your vein.  
Occasionally the procedure can cause local infections, pain or bleeding from the needle stick, 
bruising of the skin, inflammation or irritation of the vein (also known as phlebitis). 
 
Radiation Exposure 
This research study may involve exposure to radiation from a CT scan if used to direct the 
biopsy procedure or a MUGA scan used to assess your eligibility to participate in this study.  
Therefore, you may receive a radiation dose.  At doses much higher than you will receive, 


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radiation is known to increase the risk of developing cancer after many years.  At the dose you 
will receive, it is very likely that you will see no effects at all. 
 
aFR Testing 
The test for aFR expression used in the screening procedures for this study has been developed 
in a laboratory and is not approved by the Food and Drug Administration (FDA). It is possible 
that the results of the aFR test are incorrect, and that your tumor does not express aFR. The 
risks associated with a failed aFR test (i.e. “false-positive”) would be due to your T cells 
attacking aFR on normal cells of your body. Therefore, the risk of a failed aFR test are the same 
as the risks described in the “Inflammation” section above.  
 
Blood Draws 
Occasionally there are risks associated with blood draws such as bruising, swelling, black and 
blue marks, fainting and/or infection at the site.   You may also experience a decrease in 
hemoglobin and hematocrit (red blood cell number, called anemia) from having blood drawn 
frequently. Approximately 49 tablespoons (about 3 cups) of blood will be drawn for research 
purposes during this research study over the period of two years, and approximately 39 
tablespoons of blood (about 2 ½ cups) during long-term follow-up for up to 15 years.  
 
Intraperitoneal Administration of CAR T Cells  
The risk of peritoneal inflammation with IP administration is anticipated to be higher than that 
of IV administration given the direct administration into the peritoneal cavity.    
 
Intraperitoneal Catheter Placement 
Risks associated with the procedure include, but are not limited to, pain or discomfort at the 
needle insertion site, bleeding at the site, internal bleeding, injury to a blood vessel, organ 
puncture, and infection which may result in an infection of the blood stream. The development 
of any infection may result in the need for intravenous antibiotics. X-ray contrast material may 
be used at the time of catheter insertion. Risks associated with the X-ray contrast material 
include an allergic reaction. Moderate sedation is used during the catheter placement. The 
medications used for the moderate sedation are associated with the risks of aspiration (inhaling 
food or liquid into your lungs) or respiratory depression. In addition to these potential risks 
associated with the procedure, the X-ray contrast material, and the moderate sedation 
medications, there may be other unpredictable risks including death.  
 
You will be asked to sign a standard hospital consent form for this procedure.  You will be 
closely monitored during the procedure by the anesthesia team and/or the primary 
proceduralist’s team and subsequently by the research team. 
 
Another risk of intraperitoneal catheter placement is that the study doctor may decide that 
administration of the CAR T-cell infusion might not be clinically appropriate for you after you’ve 
had the IP catheter placed. 


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Genetic Testing 
Additional research performed using your blood and tissue samples may include genetic 
testing. Even without your name or other identifiers, your genetic information is unique to you. 
The researchers believe the chance that someone will identify you is very small, but the risk 
may change in the future as people come up with new ways of tracing information. 
 
There can be a risk in knowing genetic information. New health information about inherited 
traits that might affect you or your blood relatives could be found during a research study. Even 
though your genes are unique, you share some of the same genes with your blood relatives. 
Although we are not able to know all of the risks from taking part in research on inherited 
traits, we believe that the risks to you and your family are very low, because your samples will 
be coded. Research results will not be returned to you or your doctor.  
 
Very rarely health or genetic information could be misused by employers, insurance companies, 
and others. For example, it could make it harder for you to get or keep a job or insurance, or life 
insurance companies may charge a higher rate based on this information. We believe the 
chance these things will happen is very small, but we cannot make guarantees. 
 
A federal law (Genetic Information Non-Discrimination Act, GINA) helps reduce the risk from 
health insurance or employment discrimination. The law does not include other types of misuse 
by life insurance or long term care insurance. If you want to learn more about GINA, you can 
find information about it on the internet or ask the study staff. 
What if new information becomes available about the study? 
During the course of this research study, we may find more information that could be 
important to you. This includes information that, once learned, might cause you to change your 
mind about being in the research study.  We will notify you as soon as possible if such 
information becomes available. In order to provide this information to you, you must provide 
your current address and telephone number to the study doctor and must update this 
information so that the research staff will be able to contact you to give you any new 
information learned from this research study in the future. 
 
What are the possible benefits of the study? 
You may not get any benefit from being in this research study.  However, while you may not 
benefit personally, the knowledge learned from your participation in this research study may 
benefit other patients in the future. It is possible that your disease and/or health may worsen 
as a result of participating in this study. 
 
What other choices do I have if I do not participate? 
Your other choices may include: 
• 
Getting treatment or care for your cancer without being in a research study 


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• 
Taking part in another research study 
• 
Getting no treatment 
 
Will I be paid for being in this research study? 
You will not be paid for participating in this research study. 
 
Will I have to pay for anything? 
The research study will cover the cost of research related tests, procedures and clinic visits. 
There is no cost for the investigational T-cell product that you will receive during your 
participation.  For subjects participating in cohorts 2 and 3, there will also be no cost to you for 
the cyclophosphamide and fludarabine or their administration. 
 
This research study also requires that you receive certain standard medical tests and 
examinations during the course of the research study. These exams, tests or procedures are 
part of routine cancer care and may be done even if you were not in this research study. The 
costs of these standard tests and examinations will be the responsibility of you and/or your 
health insurance provider. Some health plans will not pay these costs for people taking part in 
studies. Check with your health plan or insurance company to find out what they will pay for. 
Taking part in this research study may or may not cost your insurance company more than the 
costs of getting regular cancer treatment. You are expected to pay for any costs not paid by 
your insurance provider (including co-pays and deductibles). 
 
What happens if I am injured or hurt during the research study? 
If you have a medical emergency during your participation on this study, you should go to the 
nearest emergency room.  You should contact the Principal Investigator or Emergency contact 
listed on page one of this form. You may also contact your own doctor, or seek treatment 
outside of the University of Pennsylvania.  Be sure to tell the doctor or their staff that you are in 
a research study being conducted at the University of Pennsylvania. Ask them to call the 
telephone numbers on the first page of this consent form for further instructions or 
information about your care. 
 
We will offer you the care needed to treat injuries directly resulting from taking part in this 
research.  We may bill your insurance company or other third parties, if appropriate, for the 
costs of the care you get for the injury, but you may also be responsible for some of them.  
There are no plans for the University of Pennsylvania to pay you or give you other 
compensation for the injury.   
 
Financial compensation for such things as traveling, parking, lost wages, disability or discomfort 
due to injury is not available.   
 
You will not lose any of your legal rights when you sign this form. 
 


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When is the research Study over? Can I leave the Research Study 
before it ends? 
This research study is expected to end after all participants have completed all visits, and all 
information has been collected.  Your participation in this research study may also be stopped 
at any time by your study doctor, study Sponsor, or the Food and Drug Administration (FDA) 
without your consent because: 
• The Principal Investigator feels it is necessary for your health or safety.  Such an action 
would not require your consent, but you will be informed if such a decision is made and 
the reason for this decision.  
• You have not followed study instructions. 
• The Sponsor, the study Principal Investigator, or the Food and Drug Administration 
(FDA) has decided to stop the study. 
 
If you decide not to participate, you are free to leave the research study at any time.  You may 
do this by contacting the investigator noted on page one of this consent. Withdrawal will not 
interfere with your future care. 
 
Who can see or use my information? How will my personal 
information be protected? 
 We will do our best to make sure that the personal information obtained during the course of 
this research study will be kept private.  However, we cannot guarantee total privacy.  Your 
personal information may be given out if required by law.  Only the minimum necessary data 
will be provided to the people/entities named below and when possible participants will be 
identified with a unique study identification number. If information from this study is published 
or presented at scientific meetings, your name and other personal information will not be used. 
This study is being overseen by the Food and Drug Administration (FDA), who may also review 
your research records. 
 
Electronic Medical Records and Release of Study Related Information 
An Electronic Medical Record (EMR) is an electronic version of your medical chart within a 
health system. An EMR is simply a computerized version of a paper medical record. 
 
What may be placed in the EMR? 
Information related to your participation in the research (e.g., laboratory tests, notes from your 
physician, imaging studies, and clinical procedures, etc.) may be placed in your EMR maintained 
by Penn Medicine. 
 
Once placed in your EMR, your information may be accessible to appropriate Penn Medicine 
workforce members that are not part of the research team.  Information within your EMR may 
also be shared with others who are determined by Penn Medicine to be appropriate to have 
access to your EMR (e.g., health insurance company, disability provider, etc.). 


Informed Consent Form and HIPAA Authorization - UPCC 03818 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
UPCC 03818 Main ICF V11.02-09-2023 
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Penn Medicine also participates in automated information sharing through Health Information 
Exchanges (HIEs). HIEs securely share parts of your electronic health record, including research 
information, with other healthcare organizations involved in your care. This information is 
shared to improve the quality, safety and efficiency of your healthcare. To request that your 
health information not be shared through HIEs, please call 
. 
 
Will I, as a participant, have access to research related information within the EMR? 
The 21st Century Cures Act requires healthcare institutions to allow patients increased access 
to their electronic medical record. As part of your participation in this research, you will have 
access to research related information within your EMR through Penn Medicine’s patient portal 
– called MyPennMedicine (MPM). 
 
Information that may be placed in the medical record 
Your medical record may include information physical examinations, clinical assessments, and 
medication orders/administration records required as part of your participation in this study.  
Your medical record will also include results from laboratory tests, imaging studies, and clinical 
procedures, etc. (or any results that would have been placed in the medical record, regardless 
of research participation).  
 
Information placed in the medical record is part of the designated record set and you have a 
right to review this information per HIPAA regulations. 
 
Information that may not be placed in the medical record 
Information from the collection and handling of clinical samples for research purposes will not 
be included in your medical record.  This includes the results from biospecimen testing 
conducted in a laboratory that is not part of the HIPAA covered entity OR results from testing 
conducted in a non-CLIA certified laboratory (i.e., the results would not have been placed in the 
medical record as part of clinical care). 
 
Will I receive the results of research testing? 
Most tests done in research studies are only for research and have no clear meaning for your 
routine medical care. Research results will not be returned to you because they would not be 
relevant to your routine medical care. 
 
Will information about this study be available to the public? 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov and included 
on University of Pennsylvania websites. These postings will not include information that can 
identify you. At most, the website will include a summary of the results.  You can search this 
website at any time.  
 


Informed Consent Form and HIPAA Authorization - UPCC 03818 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
UPCC 03818 Main ICF V11.02-09-2023 
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What information about me may be collected, used or shared with 
others? 
 
The following personal health information will be collected, used for research, and may be 
disclosed during your involvement with this research study: 
 
• Name, address, telephone number, 
e-mail address, date of birth 
• Personal and family medical history, 
allergies; prior hospital 
admission/discharge information 
• Current and past medications or 
therapies 
• Medical record number 
• Sex assigned at birth, gender 
• Information from a physical 
examination that generally also 
includes blood pressure reading, 
heart rate, and temperature 
• Results of tests and procedures you 
will undergo during this research 
study as described in this informed 
consent form 
 
Why is my information being used? 
Your information is used by the research team to contact you during the research study. Your 
information and results of tests and procedures are used to: 
• do the research 
• oversee the research 
• to see if the research was done right 
• evaluate and manage research functions. 
 
Where may my information be stored? 
Information related to your participation in clinical research will be contained in a clinical trial 
management system (CTMS). A clinical trial management system (CTMS) is used to register your 
information as a participant in a study. This allows for your research data to be entered and 
stored for the purposes of study operational and financial applications and other activities 
required as part of the conduct of the research. Once placed in the CTMS your information may 
be accessible to other authorized personnel at Penn Medicine that support research 
operations. Your information may also be held in other research databases. 
 
Who may use and share information about me? 
The following individuals may use or share your information for this research study: 
• The Principal Investigator and the study team 
• Other authorized personnel at Penn Medicine and the University of Pennsylvania, 
including offices that support research operations. 
• Other research personnel with access to the databases for research and/or study 
coordination and as otherwise approved by the IRB. 
 


Informed Consent Form and HIPAA Authorization - UPCC 03818 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
UPCC 03818 Main ICF V11.02-09-2023 
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As part of your participation in this study, we may need to contact you via the Penn patient 
portal called MyPennMedicine (MPM), phone and/or email/mail to facilitate scheduling, send 
you appointment notes or send you information about your participation in the study.  Email 
communications are often not secure and may be seen by others as a result.  By agreeing to 
participate in this study, you accept this potential risk.  If you wish for us to use a different 
means to communicate with you during the course of the trial, please discuss this with the 
research team and alternative methods can be arranged.  
 
Who, outside of Penn Medicine, might receive my information? 
The following Study Funders: 
• OvaCure and their authorized agents 
• Alliance for Cancer Gene Therapy and their authorized agents 
• Ovarian Cancer Alliance of Greater Cincinnati and their authorized agents 
• National Institutes of Health (NIH) and their authorized agents 
 
Regulatory and safety oversight organizations 
• The Food and Drug Administration 
• The Office of Human Research Protections 
• The NIH Office of Biotechnology Activities and their committees overseeing gene 
therapy research 
• The Study Data and Safety Monitoring Board  
• Public Health agencies and other governmental agencies (including non-U.S.) as 
authorized or required by law 
 
Once your personal health information is disclosed to others outside of Penn Medicine, it may 
no longer be covered by federal privacy protection regulations. 
 
The Principal Investigator or study staff will inform you if there are any additions to the list 
above during your active participation in the trial. Any additions will be subject to Penn 
Medicine procedures developed to protect your privacy. 
 
How long may Penn Medicine use or disclose my personal health 
information? 
Your authorization for use of your personal health information for this specific research study 
does not expire.  Your information may be held in a research database.  However, Penn 
Medicine may not re-use or re-disclose information collected in this research study for a 
purpose other than this research study unless: 
• You have given written authorization 
• The University of Pennsylvania’s Institutional Review Board grants permission 
• As permitted by law 
 


Informed Consent Form and HIPAA Authorization - UPCC 03818 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
UPCC 03818 Main ICF V11.02-09-2023 
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Can I change my mind about giving permission for use of my 
information? 
Yes. You may withdraw or take away your permission to use and disclose your health 
information at any time. You do this by sending written notice to the investigator for the 
research study. If you withdraw your permission, you will not be able to stay in this research 
study. 
 
What if I decide not to give permission to use and give out my health 
information? 
Then you will not be able to be in this research study. 
 
What may happen to my information and samples collected on this 
study? 
As outlined above, you will have research samples (or specimens) collected as part of your 
participation in this study.    Depending on the type of specimen, these samples may be labeled 
with identifiable information. It is possible that your specimens may be used to establish 
products that could be patented, licensed, or sold, which could make money for others.  If this 
happens, there are no plans to tell you or provide financial compensation to you or your family.   
 
Whole genome sequencing will not be conducted on your samples as part of the planned study 
analysis. However, this may be performed as part of future use of your specimens (described in 
more detail below). Whole genome sequencing involves analyzing your entire personal genetic 
code.  Please refer to the risks section of the consent for the risks of genetic testing. 
 
Future Use of Data and Specimens 
Blood, remaining unmanufactured cells (from your apheresis collections), unused 
manufactured CAR T cells or other samples obtained from you while you are participating in 
this study will be stored indefinitely and used for future research. Your study data and samples 
may be shared with other researchers within Penn, or other research institutions as well as with 
for-profit pharmaceutical or biotechnology companies.  There are no plans to tell you about any 
of the specific testing that will be done.  This future research may include genetic testing and/or 
whole genome sequencing. Whole genome sequencing involves analyzing your entire personal 
genetic code. It is possible that you may have chosen not to participate in these future research 
studies, if you had been approached for participation. Please refer to the risks section of the 
consent for the risks of genetic testing.   
 
You will not be given the results of any future testing performed on your samples.   
 
You will also not directly benefit from any future research with your specimens. However, it is 
possible this research may help others by improving our understanding of your disease and 
possible treatments. 


Informed Consent Form and HIPAA Authorization - UPCC 03818 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
UPCC 03818 Main ICF V11.02-09-2023 
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There is also a risk of breach of confidentiality (unintentional release of your information). We 
will do our best to make sure that this does not happen. However, we cannot guarantee total 
privacy. We will protect your confidentiality during storage and sharing by using coded 
specimens.  Coded means that all direct identifiers (name, initials, medical record numbers) 
have been removed.  However, your samples will still include your unique subject identification 
number and may be linked back to information/data that was collected from you as part of this 
study (i.e., disease response, safety, diagnosis, etc).  However, the information shared with 
other researchers will also be coded.  It will not be possible for future researchers to identify 
you.  The future use of your samples only applies to the samples collected on this study. 
 
As part of your consent to participate in this study, you are agreeing to the use of your samples 
as outlined above.  If you have any questions about the storage of your samples, or would like 
to withdraw your permission to use and store these samples at any time, please contact the 
study doctor, Dr. Shah at 
.  However, any samples that have already been used 
for research purposes will be retained.  After all research analysis on these samples is complete, 
these samples may be destroyed at any time without notice.  
 
Genomic Data Sharing  
Genomic studies examine genetic differences in the entire human genome (the complete set of 
human genes called whole genome sequencing or WGS) to determine changes and mutations 
in DNA, and the association between these genetic differences and health conditions.  The 
significance of these results may not be well-defined.  Not all genetic variations affect one’s 
health.  As this is an NIH-funded study, we are required to send this data to a NIH designated 
data repository that includes all kinds of genomic data from studies funded by the NIH.  
 
The aim of collecting this information is to look for genetic connections that may: 
• Increase the likelihood of getting a certain disease (such as asthma, cancer, diabetes, 
heart disease or mental illness) or a condition (such as high blood pressure or obesity) 
• Affect the progress of a certain disease or condition 
• Affect treatments (medicines, etc.) that work for certain diseases in some people, but 
not others 
 
The data that is shared will not include any direct identifiers (such as your name) and will be 
coded.  The key to this code, which links your data back to your identifiers, will not be shared.  
The repository is a controlled-access repository.  Controlled-access data is only available to 
researchers and companies who apply to the NIH. The NIH will review data requests for 
scientific merit and for methods to protect data and methods to ensure data will be used for 
the approved purpose.  We will not know what types of health-related research will be done 
with the data that are sent to the repository.  
 
There may be risks to your privacy and the privacy of your relatives from storing your 
information in the repository.  Although the NIH takes measures to protect privacy, we do not 


Informed Consent Form and HIPAA Authorization - UPCC 03818 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
UPCC 03818 Main ICF V11.02-09-2023 
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know how likely it is that your identity could be re-connected with your genetic and health 
information. If your genetic information were re-identified, personal information about you, 
your health and your disease could become known to others.  This could present unknown 
risks.  Current federal law will help protect you from genetic discrimination in health insurance 
and employment. Please also refer to the risks of the consent for the risks of genetic testing for 
additional information.  
 
There is no direct benefit to you from placing your genetic information in this database.  
However, allowing researchers to study your genetic information may lead to a better 
understanding of how genes affect health, therefore may help other people in the future.   
  
Who can I call with questions, complaints or if I’m concerned about 
my rights as a research participant? 
If you have questions, concerns or complaints regarding your participation in this research 
study or if you have any questions about your rights as a research participant, you should speak 
with the Principal Investigator listed on page one of this form.   If a member of the research 
team cannot be reached, or you want to talk to someone other than those working on the 
research study, you may contact the Office of Regulatory Affairs with any concerns or 
complaints at the University of Pennsylvania by calling (215) 898-2614. 
 
Financial Conflict of Interest 
The University of Pennsylvania (the Sponsor of this study) and Dr. Daniel Powell (a scientific 
advisor for this study) have significant financial interest in the study drug being evaluated in 
this research protocol.  It is possible this technology will be licensed to an outside company in 
the future.  If this occurs and the study drug proves to be effective, it is possible that both the 
University and Dr. Powell will receive significant financial benefit. 
 
When you sign this form, you are agreeing to take part in this research study. This means that 
you have read the consent form and your questions have been answered.  Your signature also 
means that you are permitting Penn Medicine and the University of Pennsylvania to use your 
protected personal health information collected about you for research purposes within our 
institution. You are also allowing Penn Medicine and the University of Pennsylvania to disclose 
that protected personal health information to outside organizations or people involved with the 
operations of this research study. 


Informed Consent Form and HIPAA Authorization - UPCC 03818 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
UPCC 03818 Main ICF V11.02-09-2023 
36 of 40 
A copy of this consent form and Research Participant HIPAA Authorization describing your 
confidentiality and privacy rights for this research study will be given to you. By signing this 
document you are permitting the Penn Medicine and the University of Pennsylvania to use and 
disclose personal health information collected about you for research purposes as described 
above. 
 
 
Name of  Participant  
                  Signature of Participant*  
 
             Date 
 
 
 
Name of Person Obtaining Consent             Signature of Person Obtaining Consent                           
Date 
* 
 N/A- Non-English Speaker 


Informed Consent Form and HIPAA Authorization - UPCC 03818 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
UPCC 03818 Main ICF V11.02-09-2023 
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The below section should only be used when consenting a non-English speaker. In this 
instance, only the participant’s name will be printed above and the Interpreter/Witness will 
sign this consent below attesting to the following information. 
 
Interpreter/Witness: 
By signing this form, you are indicating that:  
•    The information in the Informed Consent Form/HIPAA Authorization, as well as any 
additional information conveyed by the person obtaining consent, was presented to the 
participant in a language preferred by and understandable to the participant; and 
•    The participant’s questions were interpreted and the responses of the person obtaining 
consent were presented in a language preferred by and understandable to the 
participant. 
•    At the conclusion of the consent conference, the  participant was asked in a language 
preferred by and understandable to the participant if s/he understood the information 
in the Informed Consent Form/HIPAA Authorization as well as any additional 
information conveyed by the person obtaining consent (including responses to the  
participant's questions) and responded affirmatively. 
 
 
 
Name of Interpreter 
Signature of Interpreter 
Date 
 
 
 
Name of Witness*       
Signature of Witness 
Date 
*If different than Interpreter; otherwise this may be left blank.  
 


Informed Consent Form and HIPAA Authorization - UPCC 03818 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
UPCC 03818 Main ICF V11.02-09-2023 
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List of Terms Used in the Consent: 
 
Autoimmune disease - When the body's immune system attacks and damages its own normal 
organs or tissues. 
 
Biopsy - A tumor biopsy is a common and routine procedure, however the tumor biopsies 
performed as part of this study will be done for research purposes only. The type of biopsy you 
undergo depends on your disease.  These biopsies will be done by a qualified physician. The 
doctor will numb the biopsy area with a medicine used to minimize unnecessary pain or 
discomfort (such as lidocaine), which is similar to that which you may get when you go to the 
dentist. The doctor may use ultrasound or CT scan or both, to precisely locate the tumor for 
biopsy. One or two needles, about the size of IV needles, will be inserted through the skin into 
the site where your cancer is present, and the appropriate samples will be removed. In some 
case, tumor cells may be obtained simply from a blood sample or some other body fluid which 
may have tumor cells in it.  Your study doctor will explain this procedure to you in more detail.  
You will be asked to sign a separate hospital consent form further describing the biopsy 
procedure. 
 
Blood draw – When blood is taken from a vein using a needle, in order to monitor your health 
and for research. 
 
CT-Scan – The CAT (Computerized Axial Tomography) scan, also known as the CT (computed 
tomography) scan, is an x-ray technique that produces a film representing a detailed cross 
section of body tissues and structures. The standard CT scan procedure is painless, noninvasive, 
and requires no special preparation. 
 
In this test, a computerized axial tomography (CAT or CT) scanner is used to produce a series of 
cross-sectional x-ray pictures of a selected part of the body. A computer operates the scanner, 
and the resulting picture represents a slice of the body. Areas above and below the chosen slice 
do not appear on the image.  Information from several slices can be combined to create a view 
across the body from any angle, and it produces pictures with 10 to 20 times the detail of 
regular x-rays. 
 
ECHO/MUGA – Both an echo (or echocardiogram) and a MUGA are test that are used to find 
out if the heart is functioning normally.   An echo uses sound waves produce pictures of the 
heart. A MUGA uses a special camera that follows the radioactive substance that is given in 
your vein to produce images of your heart. 
 


Informed Consent Form and HIPAA Authorization - UPCC 03818 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
UPCC 03818 Main ICF V11.02-09-2023 
39 of 40 
Electrocardiogram - An electrocardiogram (EKG or ECG) is a test that checks for problems with 
the electrical activity of your heart. An EKG translates the heart's electrical activity into line 
tracings on paper. The spikes and dips in the line tracings are called waves.  During an EKG, 
several electrodes are attached to the skin on each arm and leg and on your chest. These are 
hooked to a machine that traces your heart activity onto a paper. If an older machine is used, 
the electrodes may be moved at different times during the test to measure your heart's 
electrical activity from different locations on your chest. 
 
Immune System - The body's defense system against infections and diseases like cancer. 
 
Immunity - protection against a foreign invader (like cancer or a germ). 
 
Infectious disease testing - Blood tests to check for any sign of previous viral infection such as 
HIV (which causes AIDS), hepatitis B and C.  
 
Intraperitoneal – means within or administered through the peritoneum. The peritoneum is a 
thin, transparent membrane that lines the walls of the abdominal (peritoneal) cavity and 
contains/encloses the abdominal organs such as the stomach and intestines. 
 
Lentivirus – a virus-like particle that is made from the human immunodeficiency virus (HIV) 
virus but cannot cause HIV infection or disease.  It is used to deliver or transfer the new genetic 
material into the T cells. 
 
Medical History – the doctor or study nurse will ask you about all previous medical conditions, 
past and current medications you may have taken, and participation in any prior clinical trials. 
 
Physical Examination – A doctor or nurse will examine you and ask you how you are feeling and 
may include obtaining your height and weight and vital signs (temperature, blood pressure, 
heart rate, or blood oxygen levels). 
 
Previous viral infections tests - Blood tests to check for any sign of previous viral infection such 
as HIV (which causes AIDS), hepatitis B, hepatitis C and Cytomegalovirus (CMV). 
 
Redirected or “gene-modified” T cells – T cells that contain a new gene or new genetic material 
that may result in the ability of the T cells to recognize and attack cancer cells that they could 
not identify before. 
 
Retrovirus ‐ A type of virus that is made up of RNA.  After the virus enters the cell, it uses an 
enzyme (called reverse transcriptase) which transforms the RNA into DNA.   The virus DNA is 
then inserted into the infected cell's DNA.  A lentivirus is a type of retrovirus that can insert 
itself in both dividing and non‐dividing cells while a retrovirus can only insert itself in dividing 
cells.     
 


Informed Consent Form and HIPAA Authorization - UPCC 03818 
Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor–alpha Redirected T Cells for  
Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
UPCC 03818 Main ICF V11.02-09-2023 
40 of 40 
T cells – Type of white blood cell that helps fight against infection and cancer; also known as 
T-lymphocytes. 
 
Transfusion - A procedure for giving a blood cell product to a patient through the vein or 
through a catheter ("tube") which is inserted into a vein.