Safety and Feasibility Study of Chimeric Antigen Receptor (CAR) T Cell Therapy With YESCARTA in the Outpatient Setting
Phase: PHASE4
Conditions: Large B-cell Lymphoma, Diffuse Large B-cell Lymphoma
Sponsor: Vanderbilt-Ingram Cancer Center

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CLINICAL STUDY PROTOCOL 
 
 
Safety and Feasibility Study of Chimeric Antigen Receptor 
(CAR) T Cell Therapy with YESCARTA in the Outpatient 
Setting 
Concept Summary Safely transitioning YESCARTA® (axicabtagene ciloleucel) 
treatment to the outpatient setting 
Investigational Site Vanderbilt-Ingram Cancer Center 
Support Kite Pharma, Inc. 
Clinicaltrials.gov number NCT05108805 
Sponsor-Investigator Olalekan O. Oluwole, MD, MPH 
Original Protocol Date 17 June 2021 
Protocol v2.0 21 December 2021 
Protocol v2.1 03 February 2022 
Protocol v3.0 13 April 2022 
Protocol v4.0 16 August 2022 
Protocol v4.1 11 November 2022 
Protocol v4.2 06 January 2023 
Protocol v4.3 05 September 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL SYNOPSIS 
 
Title Safely transitioning YESCARTA® (axicabtagene ciloleucel) treatment to the 
outpatient setting. 
Indication Exploring the feasibility of outpatient treatment with YESCARTA. 
Stucdy Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This study is an open label non-randomized treatment with YESCARTA in 
the outpatient setting. The purpose is to demonstrate that YESCARTA can 
be safely administered in the outpatient setting if we closely monitor 
subjects with physical exams, wearable devices, and telemedicine visits 
and only admit those who meet specified criteria 
 
Enrollment and apheresis: Eligible subjects are enrolled and apheresed per 
YESCARTA protocol 
 
Day -5 to -3: Pre-lymphodepleting Period. Subjects and family are trained 
to do vital signs, use wearable devices, and operate equipment suitable 
for telemedicine. Patients who remain eligible for outpatient therapy will 
proceed to receive lymphodepleting chemotherapy day -5 to -3 
 
Day 0:  
Subjects report to the clinic in the morning of day 0 for physical exam and 
laboratory tests. The Immune Effector Cell-Associated Encephalopathy 
(ICE) score will be calculated. 
 
YESCARTA is infused in the outpatient clinic and subject monitored for 2 
hours post-infusion before they are discharged to the apartment. A 
telemedicine evaluation is done at 16:30 PM and 22:00 ± 1 hour which 
includes a review of systems, physical exam including neurological 
assessment (ICE score), and vital signs. Subject will awake in AM, family 
will obtain vital signs at 06:30 ± 1 hour, and place a call to the covering NP 
to report the vital signs prior to presenting to the outpatient clinic at 08:00 
AM. 
 
Day 1 – Day 14:  
1. 08:00 AM: Subject reports to the outpatient clinic at 8am daily 
including weekends. Vital signs log reviewed by NP and equipment 
checked. Laboratory tests are ordered per protocol. Physical exam 
by NP and attending physician both of whom review all available 
data including the ICE score. Subject discharged back to the 
apartment by 10:00 AM or shortly after if no criteria for 
hospitalization are met. 
2. 12:00: Subject and family take their blood pressure and pulse 
oximeter using the device provided. They will call NP line if they 

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become aware of abnormal vital signs or a change in patient’s 
status. 
3. 16:30 and 22:00 ± 1 hour: Telemedicine visit with night NP. 
 
Telemedicine details: Subject and NP will activate the telemedicine App in 
their electronic device. Family will obtain vital signs (BP, HR, RR, SPO2) and 
provide NP with the information. NP will also review the previous vital 
signs at 12:00 and/or 16:30. Review of system questions are asked, and 
the answers given by subject recorded. Neurological assessment done, 
and ICE score calculated.  
 
Criteria for admission to the hospital: 
1. Fever ≥102̊ F or higher, or fever 100.4 to < 102 with a change in 
status (e.g. hypotension, altered mental status or other sign of end 
organ dysfunction). Fever < 102 alone without other symptom can 
be closely monitored in the outpatient setting per written 
institution guidelines.  
2. Hemodynamic instability: (any of the following) Hypotension that 
requires IV fluids, MAP < 20% of baseline or SBP < 90 mmHg or HR 
> 130/min 
3. Sustained hypoxia with SPO2 < 90% 
4. Abnormal neurological function (grade 1 or higher ICANS) based on 
the ICE score 
5. Other criteria at the discretion of the covering physician. 
 
For study requirements, refer to Section 7 and the schedule of 
assessments (SOAs) in Section 8 for details.  
 
A study schema is provided in Figure 1 (Section 6.3.4.2).  
Study 
Objectives The primary objective is to explore the feasibility of treating subjects with 
YESCARTA in the outpatient setting and determine the number of subjects 
who remain outpatient through 72 hours, 7, 14, and 30 days.  
Secondary Objectives are to identify risk factors that preclude outpatient 
administration, obtain clinical data that will inform the development of 
guidelines by which YESCARTA treatment can be done in safely in the 
outpatient setting, and assess the impact of telemedicine and close 
monitoring on specific outcomes including CRS and ICANS in subjects 

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treated with YESCARTA in the outpatient setting. Data from wearable 
device are collected for research only. 
Study 
Hypothesis  
No formal statistical hypothesis will be tested. All analyses will be 
descriptive. 
Study Endpoints 
1. Number of subjects that remain an outpatient at 3, 7 and 30 days 
after YESCARTA infusion.  
2. Time to requirement for inpatient hospitalization after YESCARTA 
infusion. 
3. Incidence/grade of adverse events, CRS and ICANS 
4. Incidence of steroid and/or tocilizumab administration 
5. YESCARTA treatment response rate. 
Sample Size Twenty subjects will receive YESCARTA treatment  
Study Eligibility Refer to Section 5 for a complete and detailed list of inclusion and 
exclusion criteria.  
Treatment 
1. Conditioning chemotherapy regimen consisting of 
cyclophosphamide 500 mg/m2/day and fludarabine 30 mg/m2/day 
will be administered for 3 days prior to YESCARTA infusion. Refer 
to Section 6 for chemotherapy treatment details.  
2. YESCARTA treatment consists of a single infusion of chimeric 
antigen receptor (CAR) transduced autologous T cells administered 
intravenously at a target dose of 2 x 106 anti-CD19 CAR T cells/kg. 
Refer to Section 6 and Section 7 for treatment details.  
Adjunct to treatment: oral dexamethasone 10 mg once daily for 3 days, 
starting prior to YESCARTA infusion on Day 0 
 
Safety Review 
and Data 
Monitoring 
A safety review team (SRT) will be established that consists of PI, sub-I and 
study sponsor representative. The SRT will review safety data after 10 
subjects are treated and make recommendations regarding further study 
conduct based on the overall safety profile of YESCARTA.  
Statistical 
Considerations 
The statistical reporting of the safety and efficacy endpoints will be 
entirely descriptive; no formal statistical testing will be performed.  
The subject incidence rates of AEs and clinically significant changes in 
safety lab values will be summarized. See Appendix E for detailed 
statistical considerations. 
 
 
 
STUDY GLOSSARY 
 
AE 
ALL 
ALT   
ANC   
Adverse event 
Acute lymphoblastic leukemia 
Alanine aminotransferase 
Absolute neutrophil count 

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ASCT   
AST   
AUC   
BBB   
BP   
BUN   
CAR   
CBC   
CLL   
CMP   
CMV   
CNS   
CPF 
CR   
CRF   
CRP   
CRS   
CSF   
CTCAE   
DLBCL   
DLT   
DOR   
DSMB   
eACTTM   
EBV   
ECG   
ECHO   
ECOG   
EQ-5D   
FAS   
FL 
GCP   
GOT   
GPT 
HCT   
HGBCL   
HIV   
HR   
HLH  
HSCT  
IB  
ICE   
ICANS   
IC  
ICF  
ICH  
ICU  
ID  
Autologous stem cell transplant 
Aspartate aminotransferase 
Area under the curve 
Blood brain barrier 
Blood Pressure                                                                                            
Blood urea nitrogen 
Chimeric antigen receptor 
Complete blood count 
Chronic lymphocytic leukemia 
Complete Metabolic panel                                                                                             
Cytomegalovirus 
Central nervous system 
Cell processing facility 
Complete response 
Case report form 
C-reactive protein 
Cytokine release syndrome 
Cerebrospinal fluid 
Common Terminology Criteria for Adverse Events                                               
Diffuse large B-cell lymphoma 
Dose-limiting toxicity 
Duration of response 
Data Safety Monitoring Board 
Engineered autologous cell therapy 
Epstein-Barr virus 
Electrocardiogram 
Echocardiogram 
Eastern Cooperative Oncology Group 
European Quality of Life-5 Dimensions 
Full analysis set 
Follicular lymphoma 
Good Clinical Practice 
Glutamic-oxaloacetic transaminase                                                                          
Glutamic-pyruvic transaminase 
Hematopoietic stem cell transplant                                                            
High grade B-cell lymphoma 
Human immunodeficiency virus                                                                                       
Heart Rate                                                                                                                          
Hemophagocytic lymphohistiocytosis  
Hematopoietic stem cell transplantation  
Investigator’s Brochure  
Immune Effector Cell-Associated Encephalopathy                                                  
Immune effector cell-associated neurotoxicity syndrome           
Investigator’s choice  
Informed consent form  
International Conference on Harmonization  
Intensive care unit  
Identification  

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IDSA  
IEC  
IFN  
IHC  
IL  
ImiD  
IP  
IPM  
IRB  
IRT  
IUD  
IV  
LDH 
LTFU  
LVEF  
mAb  
MASCC 
MDS  
mITT  
MRI  
NCI  
NHL  
NK  
NPT  
ORR  
OS  
PBMC  
PCR  
PD  
PET-CT  
PFS  
PK 
PO  
PR  
qd  
qPCR  
RCR  
REMS  
SAE  
scFv  
SCT  
SD  
SmPC  
SOA  
SRT  
SSAP  
TEAE  
TLS  
Infectious Diseases Society of America  
Independent Ethics Committee  
Interferon  
Immunohistochemistry  
Interleukin  
Immunomodulatory drug  
Investigational product  
Investigational Product Manual  
Institutional Review Board  
Interactive response technology  
Intrauterine device  
Intravenous  
Long-term follow-up  
Left ventricular ejection fraction  
Lactate Dehydrogenase                                                                                                
Monoclonal antibody                                                                    
Multinational Association of Supportive Care of Cancer                                                    
Myelodysplastic syndrome  
Modified intent-to-treat  
Magnetic resonance imaging  
National Cancer Institute  
Non-Hodgkin lymphoma  
Natural killer  
Nasopharyngeal-throat  
Objective response rate  
Overall survival  
Peripheral blood mononuclear cell  
Polymerase chain reaction  
Progressive disease  
Positron emission tomography-computed tomography  
Progression-free survival  
Pharmacokinetics 
Taken orally  
Partial response  
Every day  
Quantitative polymerase chain reaction  
Replication-competent retrovirus  
Risk Evaluation and Mitigation Strategy  
Serious adverse event  
Single-chain variable fragment  
Stem cell transplant  
Stable disease  
Summary of product characteristics  
Schedule of assessment  
Safety review team  
Supplementary statistical analysis plan  
Treatment-emergent adverse event  
Tumor lysis syndrome  

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TNF  
UA  
ULN  
USPI  
UTI  
WBC 
Tumor necrosis factor  
Urinalysis  
Upper limit of normal  
United States Prescribing Information  
Urinary tract infection  
White blood cell 
 
 
 
 
 

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1. OBJECTIVES 
 
1.1. 
Primary Objectives 
 
• 
To explore the feasibility of treating subjects with YESCARTA in the 
outpatient setting and guide the development of a subsequent, larger study 
that will determine the tolerability and safety profile of YESCARTA in the 
outpatient setting.  
 
• 
To determine the time to specific interventions post infusion and the 
number of subjects who remain outpatient through 72 hours, 7, 14, and 30 
days.  
 
 
1.2. 
Secondary Objectives 
 
• 
Identify risk factors that preclude outpatient administration, and to obtain 
clinical data that will guide the development of guidelines by which 
YESCARTA treatment in the outpatient setting can be done safely. 
 
• 
Assess the impact of close monitoring with telemedicine and close 
monitoring on specific outcomes including CRS and ICANS in subjects 
treated with YESCARTA in the outpatient setting. 
 
 
• 
Cumulative steroid exposure within 28 days post YESCARTA infusion. 
 
 
• 
To calculate the estimated cost of YESCARTA administered in the outpatient 
setting. 
 
 
1.3. 
Exploratory Objectives 
 
• 
Time from YESCARTA infusion to the following: fever, fever with 
neutropenia, fever without neutropenia. 
 
• 
Time from fever to Tocilizumab, fever to ICU admission, fever to low BP, 
fever to IV Fluid, fever to vasopressor, fever to onset to arrhythmias and 
fever to hospitalization. 
 
 
• 
Calculate modified Neutropenic Fever Symptom Burden (NFSB) score for 
days 1-3 for each subject. Appendix D 
 
 
• 
Obtain subject reported outcomes measured by Subject-Reported 
Outcomes Measurement Information System (PROMIS; Appendix F) [16, 17] 

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• 
Feasibility of using wearable devices to monitor vital signs in the outpatient 
setting. Data collected are for research only. 
 
 
2. DISEASE BACKGROUND AND RATIONALE 
 
2.1. 
Background 
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of large B-cell 
lymphoma with approximately 22,000 new diagnoses each year in the United States. 
Cytotoxic chemotherapy is curative in 40 to 60% of the subjects. However, subjects with 
relapsed or chemotherapy refractory DLBCL have a particularly dire prognosis.[1]  
2.2. 
Yescarta 
Axicabtagene ciloleucel (YESCARTA®) is approved by the US Food and Drug Administration 
(FDA) based on ZUMA-1 data with objective response rate was 82%, the complete response 
rate was 54% and the overall rate of survival at 18 months was 52%.[2] The current 
standard practice is to only administer YESCARTA as inpatient and monitor for at least 7 to 
10 days for side effects including cytokine release syndrome (CRS) and Immune effector 
cell-associated neurotoxicity syndrome (ICANS). 
To date, YESCARTA is the best product in its class with the highest objective response rate 
and longest duration of response of any CAR T therapy. However, the prolonged hospital 
stays, and high cost have limited its use[3]. Furthermore, outpatient therapies in general are 
viewed more favorably due to less resource utilization and it is conceivable that many 
centers may opt for a competing product like tisagenlecleucel or lisocabtagene maraleucel 
because of the perceived notion that they might be more amenable to being used in the 
outpatient setting.[4, 5] 
 
2.3. 
Rationale for Outpatient Therapy 
Whereas YESCARTA treatment in the inpatient setting is feasible and the ZUMA-1 trial 
reported grade 3 or higher CRS and ICANS in 13% and 28% of subjects respectively, the 
impact of such a therapy in the outpatient setting and the safety profile of outpatient 
therapy remains largely unexplored.[6, 7] 
Zuma-1 data and our institution data suggest that fever is the earliest sign of CRS in the 
recipients of YESCARTA. In our database search of 20 subjects treated with YESCARTA at 
Vanderbilt, nine (45%) did not develop fever until after 72 hours from the time of YESCARTA 
infusion suggesting that there is the possibility that subjects could have been managed at 
least in part in the outpatient setting which will lead to a reduction in the total number of 
days spent in the hospital. A similar system was used to determine who could undergo HCT 
in the outpatient setting. That study showed a reduction in hospital length of stay and 
significant cost savings.[8]  

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At Vanderbilt, 70% of all allogeneic HCT are done in the out-patient setting. Most matched 
related and unrelated transplants are done in the outpatient setting with brief period of 
hospitalization to administer thymoglobulin, while we electively admit haploidentical 
transplant subjects till completion of high dose Cytoxan. In our single institution quality 
review for 2018, we performed 18 matched related transplants in the outpatient setting. 
Eight of the 18 subjects ended up being admitted and incurred a total of 42 hospital days at 
an average of 2.3 days per subject for the whole cohort. In that same year, we performed 4 
haploidentical transplants in the inpatient setting and incurred a total of 24 days of 
hospitalization which is an average of 6 days per subject (unpublished data). While cost 
comparisons are not as easy to do, we can postulate that the reduction in hospital length of 
stay translates into fewer interruptions in subject’s life, reduced exposure to hospital 
acquired infections, improved quality of life and healthcare savings. Currently, no risk model 
has been developed with the ability to carefully identify those who can safely be treated in 
the outpatient setting with any CAR T product and the benefit of using specific clinical 
parameters to determine who will benefit from early escalation of care to the inpatient 
setting is also unknown. 
 
2.4. 
Rationale for Selecting Vanderbilt Transplant and Cellular Therapy Program 
In 2005, Vanderbilt invested in the design of our outpatient transplant unit (OTU) where our 
HCT program is nested and with which we transitioned all hematopoietic cell transplants 
(autologous and allogeneic) to the outpatient setting. These subjects are only admitted if a 
clinical need arises which cannot be managed in the outpatient setting. Our internal quality 
data suggests that this transition has been cost-effective through reduction in number of 
hospital days per subject without negatively impacting transplant outcomes. The outpatient 
transplant unit is complete with a series of dedicated infusion bay areas where subjects can 
receive immediate attention from nurses, mid-level providers and attending physicians. 
Subjects are seen daily and as needed. The unit is open 8:00 AM – 5:00 PM, seven days a 
week. We also have a dedicated telemedicine service for cellular therapy subjects which can 
be utilized for any urgent issues or routine clinical monitoring when subject is not in the 
clinic.  Our quality metrics, subject outcomes, and subject satisfaction compare favorably to 
the other transplant centers which primarily manage the complex subjects in the inpatient 
units during early peri-transplant period. We transplant between 300 and 400 subjects 
annually and many of the subjects remain in the outpatient setting throughout the 
transplant process. Subjects are housed within 30 miles from the hospital in specified 
lodging facilities, and we have a tested system of stat bed(s) with which we can initiate 
specific therapy within 30 – 60 minutes at any time day or night. For the proposed pilot 
study, subjects will be housed in select apartments that allow for them to reach the hospital 
within 15 minutes. Our telemedicine service line has outcomes comparable to face to face 
clinic visits and has been successfully integrated into our HCT workflow (unpublished data).  
 
3. STUDY DESIGN 
 
3.1. 
General Study Design 

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This is an open label non-randomized feasibility study primarily designed to evaluate the 
safety and effectiveness of close monitoring and telemedicine in the treatment of subjects 
with YESCARTA in the outpatient setting.  
Study candidates are adults with recurrent large B-cell lymphoma who are refractory to 
prior chemotherapy or have had ASCT. They must have at least 1 measurable lesion and 
meet multiple organ function criteria.  
 
3.2. 
Rationale for Close Monitoring in the Outpatient Setting 
Subjects who are hospitalized get to have vital signs up to six times each day and physical 
exams and/or close monitoring by physician and 1 or more nurses which allows ample 
opportunities to pick up on and act on changes to the subject’s status. This is in stark 
contrast to the outpatient with whom there may be long gaps when there is no contact with 
any health personnel. The desire to bridge this gap and ensure safety in the outpatient 
setting is the rationale behind asking that outpatients be seen and examined twice each 
day.  
 
3.3. 
Participating Site and Number of Subjects 
Vanderbilt University Medical Center.  
 
3.4. 
Number of Subjects 
Participants in this study will be referred to as “subjects.” It is anticipated that 20 will be 
enrolled into this study.  
 
3.5. 
Study Duration 
 
3.5.1. Study Duration for Individual Subjects 
The duration of the study for individual subjects will vary. For a subject who completes the 
entire protocol from the date of informed consent through the completion of the long-term 
follow-up (LTFU) period, the duration of the study is 12 months. However, an individual 
subject’s study duration will vary depending on the subject’s screening requirements, 
response to treatment, and survival.  
 
3.5.2. Completion of Study 
Completion of the study is defined as the time at which the last subject completes the LTFU 
period visit, is considered lost to follow-up, withdraws consent, or dies. 
 
4. ENROLLMENT PROCEDURES 
 
 

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All patients MUST be registered prior to the start of study procedures such as tissue 
acquisition. Registration can only be conducted during the business hours of 8AM – 5PM 
Central Time, Monday through Friday. 
 
 
1) If a subject ID number is required prior to patient enrollment (i.e. at screening due 
to sample collection requirement), the site must submit the following documents 
with their email notification to the Study Coordinator: 
 
• Copy of the patient’s signed and dated Informed Consent including 
documentation of the consent process. 
 
• HIPAA authorization form (if separate from the main consent form). 
 
• VICC Patient Enrollment Form. 
 
 
The Study Coordinator will then provide a subject ID number via email. 
 
2) Email the following documents to the VICC CTO Registrar Office for eligibility review 
and (viccctsrregistraroffice@vumc.org): 
 
• Copy of the patient’s signed and dated Informed Consent, including 
documentation of the consent process. 
 
• HIPAA authorization form (if separate from the main consent form). 
 
 
• VICC Patient Enrollment Form. 
 
 
• Eligibility supporting documents such as pathology reports, laboratory 
tests, etc. or EMR access.  Note: all source documents should be de-
identified and screening/subject ID number added prior to sending. 
 
 
• Signed and completed Eligibility Checklist.  To be eligible for registration 
to the study, the participant must meet each inclusion and exclusion 
criterion listed in the eligibility checklist. 
 
 
 

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Note:  The VICC CTO Registrar Office requires 3 business days to review all documents and 
confirm eligibility. Registrations will only be accepted with prior notice and discussion with 
the Lead Institution.  Please email the clinical tr
 
vumc.org. 
 
Upon satisfactory review of eligibility documents submitted, the Study Coordinator will 
approve enrollment and issue a subject ID number if one was not issued at screening.  Once 
registration/enrollment confirmation from the Study Coordinator is received, proceed with 
protocol procedures. 
 
Please contact the assigned Study Contact with any questions regarding this process.  You 
can also reach out to your assigned CRA once the study is activated. 
 
The Study Coordinator will assign Subject ID numbers to all patients whose eligibility has 
been confirmed.  Only patients deemed eligible will be registered to the study.  
Sequence/study ID numbers will not be re-used if a patient screen fails. Following 
registration, eligible participants should begin the study consistent with the protocol no 
later than 28 days after registration/enrollment by the VICC Coordinating Center.   
 
Subjects who are unable to complete or meet the eligibility criteria will be permitted to 
rescreen one time.  If rescreening occurs within 28 days of the signing of the original 
informed consent, only the procedure(s)/assessment(s) that did not originally meet the 
eligibility criteria needs to be repeated; all other initial screening procedures/assessments 
do not need to be repeated.  If rescreening occurs, or leukapheresis is delayed, more than 
28 days from the signing of the original informed consent, subjects must be reconsented 
and repeat all screening procedures/assessments. 
 
If a participant does not begin the study following registration within the allowed time 
period, the participant’s registration on the study will be canceled.  The Study Contact will 
be notified of cancellations as soon as possible.  Patients being re-screened will need to 
consent to repeated procedures.  As such, the Coordinating Center will require a new, 
signed Informed Consent document. 
 
Issues that would cause treatment delays should be discussed with the sponsor-
investigator. 
As is generally accepted, standard of care procedures performed prior to consent, but 
within the protocol defined screening window for each assessment, can be used for study 
purposes.  All research-only procedures must be performed after patient consent. 
 
 

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5. SUBJECT ELIGIBILITY 
 
5.1. 
Inclusion Criteria (before leukapheresis) 
 
1. 
Age 18 years and above. 
 
2. 
Histologically proven large B cell lymphoma or transformed follicular lymphoma 
to DLBCL in relapse/refractory after two lines of therapies which included an 
anthracycline and CD20-targeted therapy. 
 
 
Or 
 
3. 
Chemotherapy refractory disease evidenced by lack of adequate response to first 
line therapy. This consists of either progressive disease as best response to first 
line therapy or stable disease as best response after 4 cycles of appropriate 
chemotherapy  
 
Or  
 
4. Refractory after ASCT at any time point 
 
And 
 
5. ECOG performance status 0-2. 
 
6. Adequate hematologic, hepatic, renal and cardiac function evidenced by:  
 
 
a. ANC ≥1000/µL 
 
b. Platelet ≥ 75,000/ µL  
 
 
c. T-bilirubin ≤ 1.5 mg/dL 
 
 
d. Normal serum creatinine or creatinine clearance ≥ 60 mL/min/1.73 m2  
 
 
e. Cardiac ejection fraction ≥ 50%  
 
 
f. Serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) ≤ 
5 times upper limit of normal (ULN). 
 
 
7. At least 1 measurable lesion 
 

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8. Baseline oxygen saturation ≥92% on room air. 
 
 
9. Ability to stay at a distance which allows for subjects to come in and for 
specific interventions like antibiotics and tocilizumab to be started in 1 hour or 
less. This is approximately 30 miles of Vanderbilt.  
 
 
10. A caregiver who can be educated to operate equipment for vital signs 
monitoring. 
 
 
11. Caregiver Eligibility 
 
i. Willingness to serve as a caregiver 
ii. Ability to read, write and operate a phone 
iii. Willingness to be taught to operate electronic device 
iv. Willingness and ability to assist subject to wear electronic device such 
including patch, blood pressure machine, thermometer 
v. Pass caregiver assessment test 
 
 
12. Subject and caregiver willing to be taught to operate an iPad or other 
electronic media for telemedicine, use wearable devices, and pass the 
caregiver competence test. 
 
 
5.2. 
 Exclusion Criteria 
 
1. History of malignancy other than nonmelanoma skin cancer or carcinoma in 
situ (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for 
at least 3 years.  
 
2. Known CD19 negative tumor. 
 
 
3. History of Richter’s transformation of CLL. 
 
 
4. Autologous stem cell transplant with therapeutic intent within 6 weeks of 
planned YESCARTA infusion. 
 
 
5. History of allogeneic stem cell transplantation.  
 
 

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6. Prior CAR therapy or other genetically modified T-cell therapy. 
 
 
7. History of severe, immediate hypersensitivity reaction attributed to 
aminoglycosides. 
 
 
8. Presence or suspicion of fungal, bacterial, viral, or other infection that is 
uncontrolled or requiring IV antimicrobials for management. Simple urinary 
tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if 
responding to active treatment and after consultation with the sponsor’s 
medical monitor. 
 
 
9. History of human immunodeficiency virus (HIV) infection or acute or chronic 
hepatitis B or hepatitis C infection. Subjects with history of hepatitis infection 
must have cleared their infection as determined by standard serological and 
genetic testing per current Infectious Diseases Society of America (IDSA) 
guidelines or applicable country guidelines. 
 
 
10. Presence of any in-dwelling line or drain (e.g., percutaneous nephrostomy 
tube, in-dwelling Foley catheter, biliary drain, or pleural/peritoneal/pericardial 
catheter). Dedicated central venous access catheters, such as a Port-a-Cath or 
Hickman catheter, are permitted. 
 
 
11. Subjects with detectable cerebrospinal fluid malignant cells, or brain 
metastases, or with a history of CNS lymphoma or primary CNS lymphoma, 
cerebrospinal fluid malignant cells or brain metastases. Patients with treated 
secondary CNS involvement of lymphoma are allowed. 
 
 
12. History or presence of CNS disorder, such as seizure disorder, cerebrovascular 
ischemia/hemorrhage, dementia, cerebellar disease, progressive multifocal 
leukoencephalopathy, or any autoimmune disease with CNS involvement if it 
impairs ability to complete an effective and reliable neurological assessment. 
 
 
13. Subjects with cardiac atrial or cardiac ventricular lymphoma involvement. 
 
 
14. History of myocardial infarction, cardiac angioplasty or stenting, unstable 
angina, or other clinically significant cardiac disease within 12 months of 
enrolment. 
 

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15. Requirement for urgent therapy due to tumor mass effects (e.g., blood vessel 
compression, bowel obstruction, or transmural gastric involvement). 
 
 
16. Primary immunodeficiency.  
 
 
 
17. Any medical condition likely to interfere with assessment of safety or efficacy 
of study treatment. 
 
18. Live vaccine ≤ 6 weeks prior to planned start of conditioning regimen.  
 
 
19. History of severe immediate hypersensitivity reaction to any of the agents 
used in this study.  
 
 
20. Women of child-bearing potential who are pregnant or breastfeeding because 
of the potentially dangerous effects of the preparative chemotherapy on the 
fetus or infant. Females who have undergone surgical sterilization or who 
have been postmenopausal for at least 2 years are not considered to be of 
childbearing potential.  
 
 
21. Subjects of both genders who are not willing to practice birth control from the 
time of consent through 6 months after the completion of conditioning 
chemotherapy.  
 
 
22. In the investigator’s judgment, the subject is unlikely to complete all protocol-
required study visits or procedures, including follow-up visits, or comply with 
the study requirements for participation.  
 
 
23. History of autoimmune disease (e.g. Crohn’s, rheumatoid arthritis, systemic 
lupus) resulting in end organ injury or requiring systemic 
immunosuppression/systemic disease modifying agents within the last 2 
years. 
 
 
24. Must not have received immunomodulating agents including checkpoint 
inhibitors, BTK inhibitors, and Revlimid within 2 months or 5 half-lives 
whichever is shorter.  
 
 
 

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6. PROTOCOL TREATMENT 
 
6.1. 
Treatment Terminology 
Bridging therapy refers to treatment used to control a subject’s disease prior to 
lymphodepleting chemotherapy. 
 
Telemedicine refers to the use of specified video and audio software with the purpose to 
evaluate the status of the subject. 
 
6.2. 
Study Treatment 
 
6.2.1. Pre-lymphodepleting period  
 
6.2.1.1. 
Leukapheresis  
Leukapheresis refers to the procedure for collecting peripheral blood 
mononuclear cells (PBMCs) that are used to manufacture the subject-specific 
YESCARTA treatment. Subjects will undergo leukapheresis to obtain T cells for 
the manufacturing of YESCARTA. Leukapheresed cells obtained will be shipped to 
the supporter’s manufacturing facility as described in the Investigational Product 
Manual (IPM).  
 
6.2.1.2. 
Bridging Therapy 
Bridging therapy will be obtained by the investigative site unless otherwise 
noted.  
 
Table 1. Bridging Therapy 
Type 
Therapy Regimen 
Timing and washout 
Corticosteroid 
Dexamethasone at a dose of 20 mg to 
40 mg or equivalent, either PO or IV 
daily for 1 to 4 days. 
May be administered after 
apheresis/enrollment and must be 
completed at least 5 days prior to the start 
of lymphodepleting chemotherapy. 
HDMP + Rituximab 
 
1 gram/m2 of high dose 
methylprednisolone (HDMP) for 3 days 
in combination with rituximab at 375 
mg/m2 weekly for 3 weeks. 
May be administered after enrollment and 
completed at least 7 days prior to the start 
of lymphodepleting chemotherapy. 
 
6.2.1.3. 
Subject and caregiver training 
Subject and caregiver education procedure included a series of training sessions 
designed to equip them with necessary skills to take reliable and reproducible 
vital signs. It also includes training to operate a tablet, laptop or smartphone 
application that will be used for the telemedicine encounter. This process ends 
with a caregiver certification process during which the nurse formally tests and 
verifies that family can measure vital signs reliably. A dry run of the telemedicine 

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on a set date will also be done and be repeated as needed till all aspects are 
completed without error. Upon successful completion of caregiver education 
and dry run, the subject will proceed to get lymphodepletion chemotherapy as 
from Day -5. 
 
6.2.1.4. 
Verification of Eligibility to proceed to Lymphodepletion Therapy 
Preparation for lymphodepleting chemotherapy is done between  
Day -9 and Day -6 to ensure that only those who remain eligible per criteria 
below will continue the treatment pathway for outpatient YESCARTA. Ineligible 
patients will receive YESCARTA per standard of care. This second screening does 
not require another consent.  
1. ANC ≥1k/µL, 
 
2. Platelet ≥ 75k/ µL, 
 
 
3. T-bili ≤ 1.5 mg/dL,  
 
 
4. Creatinine clearance ≥ 60 mL/min/1.73 m2, and  
 
 
5. Oxygen saturation ≥92% on room air. 
 
 
6.2.2. Lymphodepletion Chemotherapy 
Lymphodepleting chemotherapy refers to fludarabine and cyclophosphamide used for 
lymphodepletion before administration of YESCARTA. Lymphodepleting chemotherapy will 
be supplied by the investigative site unless otherwise noted. Refer to the current product 
label for guidance on packaging, storage, preparation, administration, and toxicity 
management associated with the administration of chemotherapy agents. 
 
6.2.2.1. 
Fludarabine  
Fludarabine phosphate is a synthetic purine nucleoside that differs from 
physiologic nucleosides in that the sugar moiety is arabinose instead of ribose or 
deoxyribose. Fludarabine is a purine antagonist antimetabolite. Refer to the 
most recent version of the package insert for specific details surrounding the 
administration of fludarabine.  
 
6.2.2.2. 
Cyclophosphamide  
Cyclophosphamide is a nitrogen mustard-derivative that acts as an alkylating 
agent following conversion to active metabolites in the liver and has potent 
immunosuppressive activity. The serum half-life after IV administration ranges 
from 3 to 12 hours; the drug and/or its metabolites can be detected in the serum 
for up to 72 hours after administration. Refer to the current version of the 

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package insert for specific details associated with the administration of 
cyclophosphamide.  
 
6.2.2.3. 
Mesna  
Mesna is a detoxifying agent used to inhibit the hemorrhagic cystitis induced by 
chemotherapy. The active ingredient in mesna is a synthetic sulfhydryl 
compound designated as sodium-2- mercaptoethane sulfonate with a molecular 
formula of C2H5NaO3S2. Mesna should be administered per institutional 
guidelines. Refer to the current version of the package insert for specific details 
surrounding the administration of mesna.  
 
6.2.3. YESCARTA 
YESCARTA is supplied cryopreserved in cryostorage bags. The product in the bag is slightly 
cloudy and cream to yellow color. The cryostorage bag containing YESCARTA arrives frozen 
in a liquid nitrogen dry shipper. The bag must be stored in a vapor phase of liquid nitrogen 
and remain frozen until the subject is ready for treatment to assure that viable live 
autologous cells are administered to the subject. Several inactive ingredients are added to 
the product to assure viability and stability of the live cells through the freezing, thawing, 
and infusion process.  
YESCARTA is a subject-specific product. The product is labelled per sponsor protocol. Upon 
receipt, verification that the product and subject-specific labels match the subject’s 
information is essential. Do not infuse the product if the information on the subject specific 
label does not match the intended subject. The volume of YESCARTA infused, the thaw 
start/stop time, and YESCARTA administration start/stop time will all be noted in the subject 
medical record. The product must not be thawed until the subject is ready for the infusion. 
Refer to the IPM for details and instructions on storage, thawing, and administration of 
YESCARTA. There have been no instances of accidental overdose of subjects in this program 
to date. In case of accidental overdose, treatment should be supportive. Corticosteroid 
therapy may be considered if any dose is associated with severe toxicity. Toxicity 
management guidelines are found in the current product IB version 10.0 (e.g. Section 6.5) 
and should be consulted. If any problems related to the use of YESCARTA or any products 
that support the management of YESCARTA (e.g., cryostorage bags, subject ID labels) are 
identified, research staff should report the problem per the instructions in the IPM.  
 
6.2.4. Concomitant Therapy  
Concomitant therapy refers to treatment that subjects receive during the conduct of the 
study. During the course of the study, investigators may prescribe any concomitant 
therapies deemed necessary to provide adequate supportive care except those medications 
listed in Section 6.2.5. All concomitant therapies, including medications, intubation, dialysis, 
oxygen, and blood products, will be recorded.  
All concurrent therapies, including medications, intubation, dialysis, oxygen, and blood 
products, will be recorded from the date of the informed consent through day 30 after 
completing treatment with YESCARTA or until disease progression, whichever occurs first.  

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For subjects who are enrolled but not dosed with YESCARTA, concurrent therapies will only 
be recorded from the date of the informed consent through 30 days after the last study 
specific procedure (e.g., leukapheresis, lymphodepleting chemotherapy). For subjects who 
are not enrolled (e.g., screen failure or not leukapheresed), only concurrent therapies 
related to any serious adverse event(s) will be recorded.  
 
6.2.5. Excluded Medications  
Corticosteroid therapy at a pharmacologic dose (≥ 5 mg/day of prednisone or equivalent 
doses of other corticosteroids) and other immunosuppressive drugs must be avoided for 7 
days prior to leukapheresis, and 5 days prior to YESCARTA administration. Corticosteroids 
and other immunosuppressive drugs should also be avoided for 3 months after YESCARTA 
administration, unless used to manage YESCARTA related toxicities (refer to the investigator 
brochure version 10.0 and YESCARTA package insert). Other medications that might 
interfere with the evaluation of the investigational product, such as non-steroidal anti-
inflammatory agents should also be avoided for the same time period unless medically 
necessary.  
Treatment for lymphoma such as chemotherapy, immunotherapy, targeted agents, 
radiation, and high dose corticosteroid, other than defined/allowed in this protocol, and 
other investigational agents are prohibited, except as needed for treatment of disease 
progression after the YESCARTA infusion.  
 
6.3. 
Study Treatment Schedule  
 
6.3.1. Leukapheresis (Within Approximately 5 Days of Eligibility Confirmation)  
Subjects will undergo leukapheresis (12-15 liter apheresis with a goal to target 
approximately 5-10 x 10^9 mononuclear cells) for the manufacturing of YESCARTA. 
Leukapheresed cells are shipped to the cell processing facility (CPF) overnight as described 
in the Investigational Product Manual. Once a subject commences leukapheresis, the 
subject is considered enrolled in the study.  
 
6.3.2. Chemotherapy General Instructions  
Subjects will initiate lymphodepleting chemotherapy with cyclophosphamide and 
fludarabine beginning on Day -5.  
 
6.3.3. YESCARTA General Instructions 
The following medications should be administered approximately 1 hour prior to YESCARTA 
infusion.  
• Acetaminophen 500 to 1000 mg PO  
• Diphenhydramine (12.5 to 25 mg IV or 25 mg PO)  
• Dexamethasone 10mg PO, 1 hour before Yescarta infusion and on days 1 and 2 
Central venous access, such as a port or a peripherally inserted central catheter, is required 
for the administration of YESCARTA. Catheter care, per institutional guidelines, should be 

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followed. Materials and instructions for the thawing, timing, and administering of YESCARTA 
are outlined in the Investigational Product Manual which must be reviewed prior to 
administration of YESCARTA.  
 

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 .02222 
6.3.4. Post Infusion Monitoring 
Figure 1: Subject’s daily monitoring workflow during first 14 days after YESCARTA infusion. 
 
6.3.4.1. 
Day Zero 
Subject will report to the clinic in the morning for evaluation including physical 
exam and laboratory tests. Baseline BP, HR, RR, SPO2, laboratory tests (CBC, 
CMP, LDH, CRP, ferritin, magnesium, uric acid, phosphorus, and fibrinogen) will 
be obtained. Baseline neurological exam details are verified. The Immune 
Effector Cell-Associated Encephalopathy (ICE) score will be calculated. [9] 
YESCARTA will be infused in the outpatient clinic and subject monitored for 2 
hours post-infusion before they are discharged to the apartment. Telemedicine 
visit by NP is done at 16:30 PM and 22:00 ± 1 hour. This includes a review of 
systems, physical exam including neurological assessment (ICE score), and vital 
signs Subject will awake in am, obtain vital signs at 06:30 ± 1 hourand call in with 
the vital signs prior to presenting to the outpatient clinic at 8am.  
 
6.3.4.2. 
Day 1 – Day 14: (Figure 1)  
 
  
1. 
6:00 AM:  
Subject and family take their vital signs (BP, HR, RR, SPO2) and record in the 
logbook. Call NP line if pre-specified criteria for hospital admission are met. 
2. 
8:00 AM:  
Subject will report to the outpatient clinic at 8am daily including weekends. Vital 
signs log reviewed by nurse practitioner (NP) and equipment checked for 
functionality. Laboratory tests including correlatives are ordered per protocol. 
Physical exam by NP and attending physician both of whom will review all 
available data including the ICE score. Subject discharged back to the apartment 
by 10:00 AM or shortly after if no criteria for hospitalization are met. 
 
3. 
12:00 noon:  
Subject and family take their vital signs (BP, HR, RR, SPO2) and record in the 
logbook. Call NP line if pre-specified criteria for hospital admission are met. 
 
 
4. 
16:30 and 22:00 ± 1 hour:  
Telemedicine visit. Vitals log reviewed. Vitals checked (BP, HR, RR, SPO2), and ICE 
score calculated. Subject will remain in apartment if no criteria for admission are 
met.  
 
 
5. 
 
 

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Wearable device details:  Subjects are trained to apply the devices which comprises of a 
patch that is applied on the left anterior chest, a blood pressure cuff that they will apply 
intermittently on the forearm, and a pulse oximeter that they will apply intermittently to 
the digits. They will wear the patch continuously but only apply the BP cuff and pulse 
oximeter at specific times as stated in the chart above. If patient fails to apply the BP cuff 
and pulse oximeter at the time stipulated, a vendor systems generated reminder will go to 
them. Any alerts issued by vendor can be viewed by the PI and all authorized users of the 
program. Data are recorded in the device database and are for research only but are 
accessible by specific clinical trial staff. Please see appendix G for more details 
Telemedicine details: Subject and NP will activate the telemedicine App in their electronic 
device. Family will obtain vital signs (BP, HR, RR, SPO2) and provide NP with the figures. NP 
will also review the previous vital signs. Review of system questions are asked, and the 
answers given by subject recorded. Neurological assessment will be done, and ICE score 
calculated.  
 
6.3.5. Criteria for Hospital Admission 
 
1. 
Fever ≥102̊ F or higher, or fever 100.4 to < 102 with a change in status (e.g. 
hypotension, altered mental status or other end organ dysfunction). Fever < 102 
alone without other symptom can be closely monitored in the outpatient setting 
per written institution guidelines. [10, 11] 
 
2. 
Hemodynamic instability: (any of the following) Hypotension that requires IV 
fluids, MAP < 20% baseline or SBP < 90 mmHg or HR > 130/min 
 
 
3. 
Hypoxia with SPO2 < 90% 
 
 
4. 
Abnormal neurological function (grade 1 or higher ICANS) based on the ICE score 
as stated on Table 3 
 
 
5. 
Other criteria at the discretion of the covering physician (discussed with PI). 
  
Subjects that meet the criteria specified above will be admitted either as observation or 
inpatient depending on the severity of symptoms. 
 
The following will trigger admission to observation status: Grade 2 CRS responding to fluids 
and hypoxia responding to supplemental oxygen by nasal cannula. Such subjects will be 
reviewed by treating physician who may recommend that they may be discharged to 
continue outpatient monitoring if there is resolution of symptoms. If the same symptom 

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corticosteroids, fever is no longer required to grade subsequent CRS severity. In this case, 
CRS grading is driven by hypotension and/or hypoxia. 
 
b. CRS grade is determined by the more severe event: hypotension or hypoxia not attributable 
to any other cause. For example, a patient with temperature of 39.5° C, hypotension 
requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as Grade 
3 CRS. 
  
c. Low-flow nasal cannula is defined as oxygen delivered at ≤ 6 L/minute. Low flow also 
includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is 
defined as oxygen delivered at > 6 L/minute. 
 
 
 

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3. Vital signs, including blood pressure, heart rate, and temperature. 
 
 
4. ECOG performance status. 
 
 
5. Baseline PET-CT of the neck, chest, abdomen, and pelvis: 
  
a. PET-CT performed after the subject’s last line of therapy and prior to signing the 
informed consent may be used. 
 
b. If a subject receives bridging therapy, a repeat PET-CT is recommended to 
establish a new baseline. 
 
 
6. Bone marrow aspirate/biopsy as needed (if not done within 12 months of screening). 
 
7. Laboratory tests (may be drawn anytime between signing of informed consent and prior 
to the start of lymphodepleting chemotherapy): 
 
a. Chemistry panel 
b. Complete blood count (CBC) with differential 
c. β-HCG pregnancy test (serum or urine) on all women of childbearing potential 
d. C-reactive protein (CRP) 
e. Blood draws for cytokines and PBMC. 
 
8. AE and SAE reporting (see below Section 10). 
 
9. Concomitant medications documentation and previous cancer treatment history. 
 
 
7.4. 
Physical Exam, Vital Signs, Performance Status, and ICANS Score 
A full neurological assessment including ICE score will be completed during screening to 
establish a baseline. Subsequent post-baseline assessments will be performed before as 
specified in the SOA. 
 
7.5. 
Cardiac Function 
Cardiac function, as measured by left ventricular ejection fraction (LVEF), and 
electrocardiogram (ECG) will be assessed during the screening period to confirm study 
eligibility. 
 
7.6. 
Bone Marrow Biopsy if not previously done 
A bone marrow aspirate/biopsy will be performed at screening, if not previously performed 
within 12 months of signing consent, to assess bone marrow involvement. 
 

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7.7. 
Lumbar Puncture 
Subjects with symptoms of central nervous system malignancy, such as new onset severe 
headaches, neck stiffness, or any focal neurologic findings on physical exam, will have 
lumbar puncture performed at the screening visit for examination of CSF. 
 
7.8. 
Disease response Assessment 
PET with non-contrast CT scan will be done as SOC as from day + 30. Response assessment 
per Cheson 2014.[12] 
 
 

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7.9. 
Laboratory 
The below samples will be collected at the time points indicated in the SOA. Additional 
samples (e.g., blood, urine, CSF, tissue, etc.) may be collected as needed for further safety 
testing: 
 
1. Sodium (Na), potassium (K), chloride (Cl), total CO2 (bicarbonate), creatinine, 
glucose, blood urea nitrogen (BUN) or urea (if BUN test cannot be analyzed by the 
local lab), albumin, calcium total, magnesium total (Mg), inorganic phosphorus, 
alkaline phosphatase, ALT/glutamic-pyruvic transaminase (GPT), AST/glutamic-
oxaloacetic transaminase (GOT), total bilirubin, direct bilirubin, lactate 
dehydrogenase (LDH), phosphorus and uric acid.  
 
2. C-reactive protein (CRP) ferritin. 
  
3. Complete blood count (CBC) with differential and platelet count. 
  
4. A urine or serum sample will be collected and assessed locally for females of 
childbearing potential. If the screening pregnancy test is positive, the subjects 
should not be enrolled. 
 
 
7.10. Correlative sample storage for potential future biomarker analysis 
Biomarker analysis will be performed on blood and tumor samples to evaluate 
pharmacodynamic markers for Yescarta. 
 
Correlative laboratory tests include: 
1. Cytokine panel (including IL-1, IL-2, IL-6, IL-10, IL-15, granzyme B, TNF, IFN gamma, 
MCP1, GMCSF), CAR T cell quantification at day -5, 0, 1, 2, 3, 4, 7, 14, 30 (day 30 +/- 3 
days) 
2. CBC with differentials, ALC, monocyte count, LDH, chemistry (CMP including calcium, 
LDH, uric acid, phosphorus, magnesium), fibrinogen, CRP, ferritin 
3. Product attributes, transduction rate, viability, IFN gamma in culture, pre-infusion 
doubling time 
4. Optional paired CSF samples at day -5 and day +1. Optional paired tissue biopsy at 
day -5 and 2. We will make every effort to collect relapse biopsy specimen to better 
understand the mechanisms of tumor escape. 
5. T cell elispot analysis for CART cell immunogenicity by peripheral blood at apheresis, 
day 30 (+/- 3 days), month 3, 6 and 12 
6. Lymphocyte subsets to interrogate the pattern of recovery of B and T cells including 
the pattern of CD4 lymphopenia. Collect at apheresis, day zero, day 30 (+/- 3 days), 
months 3, 6 and 12 
7. Collect CSF specimens in subjects with grade ≥2 ICANS when feasible. Correlative 
testing will be done at the end of the study based on a mutually agreed upon plan 
between Vanderbilt and Kite translational research  

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PBMC, serum and plasma are collected at specific time points as stated above. PBMCs are 
cryopreserved per lab manual and will be sent to Kite in batches. Samples will be analyzed 
at the end of the study for clues as to what series of parameters may be predictive of need 
for more care including hospitalization. 
 
The samples will be collected per SOA and batch run at the end of the study. We will 
retrospectively check to see if any specific lab parameter may be predictive of need for 
more care including hospitalization. 
 
7.11. Description of Study Periods 
Investigative sites will maintain a log of all screened subjects who were reviewed and 
evaluated for study participation. Information collected on the screening log should include 
limited information such as the date of screening, date the subject was enrolled or the 
reason for why the subject failed screening. 
 
7.11.1.  Screening 
The screening period begins on the date the subject signs the IRB/IEC approved ICF and 
continues through confirmation of enrollment. Informed consent must be obtained before 
completion of any non-standard of care study specific procedures. After written informed 
consent has been obtained, subjects will be screened to confirm study eligibility and 
participation. Only subjects who meet the eligibility criteria listed above in protocol Section 
5 and who commence leukapheresis will be enrolled in the study.  
 
The following assessments/procedures are to be completed during the screening period at 
the time points outlined in the SOA: 
 
1. Medical history and disease assessment. 
 
2. Physical examination including height and weight. 
 
3. Subjects with symptoms of central nervous system malignancy such as new onset 
severe headaches, neck stiffness, or any focal neurologic findings on physical exam 
will have lumbar puncture for examination of cerebral spinal fluid. 
 
4. Vital signs, including blood pressure, heart rate, oxygen saturation, and 
temperature. 
 
5. ECOG performance status. 
 
6. ECG. 
 
 
7. ECHO for confirmation of normal cardiac function (e.g., LVEF) and pericardial 
effusion assessment 
 
 

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8. Imaging Studies with PET with non-contrast CT scan to confirm measurable disease. 
CT chest, abdomen and pelvis is acceptable as clinically indicated. 
 
 
9. Brain MRI. 
 
 
 

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10. Baseline PET with non-contrast CT scan of the neck, chest, abdomen and pelvis: 
 
a. PET with non-contrast CT scan performed following the subjects last line of 
therapy and prior to signing the consent may be used for confirmation of 
measurable disease. CT chest, abdomen and pelvis is acceptable as clinically 
indicated 
 
b. If PET with non-contrast CT scan is performed > 28 days prior to the initiation 
of lymphodepleting chemotherapy and if subject receives any anti-cancer 
therapy between screening and lymphodepleting chemotherapy, the scans 
must be repeated to establish a new baseline. CT chest, abdomen and pelvis 
is acceptable as clinically indicated 
 
 
11. Bone marrow aspirate/biopsy as needed (if not done at initial diagnosis or between 
diagnosis and screening). 
 
12. Laboratory tests: 
 
 
a. Chemistry panel 
 
b. CBC with differential. 
 
 
13. β-HCG pregnancy test (serum or urine) on all women of child-bearing potential 
 
7.11.2. Enrollment/Leukapheresis 
Before leukapheresis commences, the following criteria must be met. If leukapheresis is 
delayed beyond 5 days, baseline CBC with differential and chemistry panel must be 
repeated to verify eligibility. 
 
1. No evidence or suspicion of an infection. 
 
2. Corticosteroid therapy at a pharmacologic dose (≥5 mg/day of prednisone or 
equivalent doses of other corticosteroids) and other immunosuppressive drugs must 
be avoided for 7 days prior to leukapheresis. 
 
 
3. Once a subject commences leukapheresis, the subject will be considered enrolled 
into the study. 
 
 
The following procedures/requirements will occur on the leukapheresis collection day and 
as outlined in the SOA: 
 
1. Vital signs, including blood pressure, heart rate, oxygen saturation, and 
temperature. 
 
2. Weight. 

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3. Laboratory tests (to be drawn prior to leukapheresis, on the day of or day before 
leukapheresis): 
 
 
a. Chemistry panel 
 
b. CBC with differential, CRP, ferritin, LDH 
 
 
c. Anti-CD19 CAR T cells 
 
 
d. Lymphocyte subsets 
 
 
e. Cytokine levels 
 
 
f. Anti-YESCARTA antibodies. 
 
 
4. Adverse/Serious Adverse Event reporting. 
 
5. Concomitant medications documentation. 
 
 
7.12.3. Requirements for Initiating Lymphodepleting Chemotherapy 
Lymphodepleting chemotherapy and YESCARTA infusion should only be initiated after it is 
reasonably assured that cell infusion can safely proceed. Subject will have a mini screen to 
ensure that they are able to be treated outpatient before proceeding. 
 
If temperature rises above 38°Celsius or CRP above 100 mg/L within 72 hours of 
lymphodepleting chemotherapy, additional testing must be performed with satisfactory 
results before proceeding.  
 
The subject must not have received systemic antimicrobials for the treatment of known or 
suspected infection within 48 hours before lymphodepleting chemotherapy (prophylactic 
use of antimicrobials is allowed). 
 
Treatment course of any antimicrobials given for known or suspected antecedent infection 
should be completed as appropriate before stopping or switching to prophylactic 
antimicrobials. 
 
If the subject is confirmed to have an infectious process for which antimicrobials are not 
available (e.g., viral pneumonia), the infection must be clinically resolved as determined by 
the investigator and in consultation with infectious disease service (if applicable). 

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The most recently collected blood, urine, or other body fluid cultures must show no growth 
for at least 48 hours, and any other infectious workup performed (e.g., bacterial, viral 
serologies, PCR, stood studies, imaging studies) must be negative. If clinical suspicion is for 
an infection for which cultures are unlikely to be positive within 48 hours (e.g., fungal 
infection), adequate time must be allowed for cultures to become positive. 
 
Once the above criteria are met, then the subject can proceed with lymphodepleting 
chemotherapy. 
 
7.12.4. Lymphodepleting Chemotherapy Administration 
The following procedures will be completed during Day –5 to Day –3 as listed in the SOA: 
 
• Vital signs, including blood pressure, heart rate, oxygen saturation, and temperature 
• Laboratory tests (to be drawn prior to chemotherapy) 
• Chemistry Panel 
• CBC with differential 
• Fludarabine and cyclophosphamide administration 
• Adverse/Serious Adverse Event reporting 
• Concomitant medications documentation. 
 
7.12.5. Requirements for Initiating YESCARTA Infusion 
These are the same as for lymphodepleting chemotherapy (i.e. above Section 7.12.3). 
 
If the YESCARTA infusion is delayed > 2 weeks (14 days) from the planned infusion date, 
established institutional standards should be followed regarding the need for repeat 
lymphodepleting chemotherapy. 
 
7.12.6. Monitoring After YESCARTA Infusion 
All subjects will receive YESCARTA infusion at a healthcare facility followed by close 
monitoring for signs and symptoms of CRS and neurologic toxicities. Subjects may be 
hospitalized at any time post infusion and be observed for CRS and neurologic toxicities in 
the hospital setting, if deemed appropriate by the investigator. 
 
If subjects are hospitalized, subjects should not be discharged from the hospital until all 
YESCARTA related non-hematological toxicities return to ≤ Grade 1 or return to Baseline as 
determined by the treatment team. Subjects may be discharged with non-critical and 
clinically stable or improving toxicities (e.g., renal insufficiency) even if > Grade 1, if deemed 
appropriate by the investigator. 
 
Subjects should be instructed to remain within proximity of the clinical study site for at least 
4 weeks following YESCARTA infusion. Subjects and their family members/caregivers should 
be educated on potential CRS and neurologic symptoms, such as fever, dyspnea, confusion, 
aphasia, dysphagia, somnolence, encephalopathy, ataxia, or tremor. 

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Subjects or their family members/caregivers should be instructed to immediately contact 
the treating investigator or seek immediate medical attention if any of these symptoms 
develop. 
 
During this period, the following procedures will be completed at the time points outlined in 
the SOA. 
 
7.12.7. Post-treatment Assessment Period 
After completing YESCARTA infusion, all subjects will be followed in the post-treatment 
assessment period. Counting from Day 0 (YESCARTA infusion), subjects will return to the 
clinic at the Intervals stated in the SOA. 
 
7.12.8. Long-term Follow-up Period 
All enrolled subjects will be followed in the long-term follow-up period for survival and 
disease status. Subjects will begin long-term follow-up after completion of the Day 30 visit.  

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2.  Targeted review of non-serious and serious Adverse Events of Special Interest (AESI, as defined in protocol Section 10.6) and concomitant medications 
used to prevent or treat such events will be conducted as indicated and until at least 30 days after initiation of YESCARTA infusion. 
3. 
Hematopathology review of archival tissue slides to confirm diagnosis. 
4.  Lumbar puncture (LP) at screening if clinically indicated. LP also to be done for new onset neurological symptom(s). 
5.  Optional paired samples of tumor on Day -5 (before lymphodepleting chemo) and Day 2 (48 hours post CAR T infusion). 
6.  PET scan can be replaced with a CT scan in cases where a PET scan is out of window and a second PET scan cannot be obtained or as clinically 
indicated. Preparation for lymphodepleting chemotherapy requires new PET with non-contrast CT scan if debulking therapy given and if the first screening 
images are > 28 days. CT chest, abdomen and pelvis can be substituted for PET as clinically indicated 
7.  Blood for cytokine levels, PBMC and quantification of CAR T cells at screening, Days – 5, 0, 1, 2, 3, 4, 7, 14, 30 (±3 days). 
8.  Bridging therapy is optional as determined by the treating physician and will be given after apheresis. See Section 6. 
9.  Tocilizumab may be given between Day 0-14 in the event of cytokine release syndrome (CRS). 
10.  Keppra may be given from Day 0-28 and then taper to off.  
11.  Plasma sample for MRD assessment by clonoseq and capseq. 
12.  12-Month post-treatment visit is for additional blood collection tests only as noted in the schedule of assessments. 
13.  QoL survey (Subject-Reported Outcomes Measurement Information System (PROMIS)) 14 days prior to lymphodepletion +/- 5 days 
14.  QoL survey 3, 6. 9 and 12 months post-treatment follow up +/- 14 days 
15.  Dexamethasone 10mg should be given PO before axicabtagene ciloleucel infusion on Day 0. Dexamethasone can be given at any time on Days 1 and 2. 
16. Brain imaging by MRI or CT if clinically indicated. CT acceptable if MRI is not able to be obtained 
 
  

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9. 
SUBJECT WITHDRAWAL 
 
Subjects have the right to withdraw from the study at any time and for any reason without 
prejudice to their future medical care by the physician or at the institution. 
 
Subjects can decline to continue to receive study required treatment and/or other protocol 
required procedures at any time during the study but continue to participate in the study. 
This is referred to as partial withdrawal of consent. 
 
If partial withdrawal of consent occurs, the investigator must discuss with the subject the 
appropriate process for discontinuation from investigational product, study treatment or other 
protocol required therapies and must discuss options for continued participation, completion 
of procedures and the associated data collection as outlined in the SOA. The level of follow up 
and method of communication should also be discussed between the research staff and the 
subject and documented in the source documents. 
 
Withdrawal of full consent from a study means that the subject does not wish to receive 
further protocol required therapy or undergo procedures and the subject does not wish to 
continue further study follow-up. Subject data collected up to withdrawal of consent will be 
retained and included in the analysis of the study, and where permitted by local regulations, 
publicly available data (death records) can be included after withdrawal of consent. The 
investigator is to discuss with the subject appropriate procedures for withdrawal from the 
study. 
 
Public records, such as those establishing survival status, if available, may be searched to obtain 
survival data for any subject for whom the survival status is not known. Autopsy reports may 
also be retrieved to confirm status of disease at the time of death. 
 
The investigator and/or sponsor can also decide to withdraw a subject from the 
investigational product and/or other protocol-required therapies, protocol procedures, or the 
study as a whole or at any time prior to study completion. 
 
9.1. 
 Reasons for Removal from Treatment 
Reasons for removal from protocol required investigational products or procedures include 
any of the following: 
1. Adverse Event 
2. Subject request 
3. Product not available 
4. Lost to Follow-up 
5. Death 
6. Decision by sponsor. 
 
 

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9.2. 
Reasons for Removal from Study 
1. Reasons for removal of a subject from the study are as follows: 
2. Subject withdrawal of consent from further follow-up 
3. Investigator decision 
4. Lost to follow-up 
5. Death. 
 
10.1 
General Considerations 
Information on adverse events, whether serious or not, whether reported by the participant, 
directly observed, or detected by physical examination, laboratory test or other means, will be 
collected, recorded, followed and reported as described in the following sections. 
 
The therapy administered in this trial – YESCARTA (axicabtagene ciloleucel) – is an approved 
treatment for the patient population eligible to participate in this study.  Therefore, collection 
of data regarding adverse events and serious adverse events will be limited in this study: 
 
• After informed consent but prior to initiation of YESCARTA infusion, serious and non-
serious adverse events should be reported only if possibly, probably or definitely 
attributed by the patient’s study physician to a protocol-mandated research procedure 
or intervention. 
 
• Any serious adverse event that occurs ≤ 30 days after initiation of YESCARTA, regardless 
of causality to participation in the study, must be reported to the Study Coordinator 
fashion as directed below (Reporting Procedures). 
 
 
• For purposes of this study, cytokine release syndrome, neurological events, 
hematological severe infections greater than or equal to Grade 3, autoimmune events, 
and secondary malignancy events are considered Adverse Events of Special Interest 
(AESI).   
  
• From the time of initiating YESCARTA infusion and until at least 30 days after initiation 
of the YESCARTA infusion, all adverse events of special interest (AESI) experienced by a 
participant must be collected in the study data, regardless of attribution to participation 
in the study. 
  
Additionally (as addressed below in Section 10.6), if an event of special interest (AESI) is 
also a non-serious adverse event (AE) greater than or equal to Grade 3, or a serious 
adverse event (SAE) of any grade, the AESI must also be reported in an expedited 
manner by the site to the Study Coordinator, within 24 hours of the investigator 
becoming aware of the event (i.e. a ‘substantial’ AESI must not only be conventionally 
recorded in the general study data/electronic case report form, but also reported via 
expedited alert). 
 

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• During the 30-day follow-up period (i.e. the 30 days following initiation of the YESCARTA 
infusion), non-serious adverse events which are not adverse events of special interest 
(AESI) are required to be recorded in the study data only if, in the opinion of the 
investigator, there is a reasonable possibility the event is attributable to a protocol-
mandated research procedure or intervention.  For example, provided they are not 
adverse events of special interest (AESI), non-serious adverse events related to disease, 
standard-of-care YESCARTA or the next phase of the patient’s disease treatment or 
management are not required to be recorded in the study data.  All serious adverse 
events (SAEs) and adverse events of special interest (AESI) occurring within the 30-day 
follow-up period must be reported, regardless of suspected causality. 
 
• Participants who experience an ongoing serious adverse event (SAE) or an adverse event 
of special interest (AESI) > 30 days after initiation of YESCARTA deemed possibly, 
probably or definitely related to YESCARTA, will continue to be contacted by a member 
of the study team until the event is resolved, stabilized, or determined to be irreversible 
or not clinically significant by the participating investigator. 
 
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study.  The investigator should notify the IRB and 
the Study Coordinator of any unanticipated death or adverse event occurring after a participant 
has discontinued or terminated study participation that may reasonably be related to the study. 
 
10.3 
Grading of Adverse Events 
Adverse events will be graded according to the NCI’s Common Terminology Criteria for Adverse 
Events (NCI CTCAE), Version 5.0, dated November 27, 2017, currently locatable via the 
following URL: 
<https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick
_Reference_8.5x11.pdf>. 
 
If events are not listed in the CTCAE, severity may be designated as mild, moderate, severe, life-
threatening, or fatal which respectively correspond to Grades 1, 2, 3, 4, and 5 on the NCI 
CTCAE, with the following definitions: 
 
• Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated; 
 
• Moderate: Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL) such as preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc; 
  
• Severe: Medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL such as 
bathing, dressing and undressing, feeding self, using the toilet, taking medications; 
 

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• Life-threatening: Urgent intervention indicated to prevent risk of death present at 
the time of the event; 
  
• Fatal: An event that results in the death of the patient. 
10.4.1. 
Adverse Event (AE) 
An adverse event is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of study 
treatment or any procedure specified in the protocol, even if the event is not 
considered to be related to the study. 
 
Abnormal laboratory values or diagnostic test results constitute adverse events only 
if they induce clinical signs or symptoms or require treatment or further diagnostic 
tests. 
10.4.2. 
Serious Adverse Event (SAE) 
A serious adverse event is an undesirable sign, symptom or medical condition which: 
 
• Is fatal or life-threatening; 
 
• Requires or prolongs inpatient hospitalization; 
 
 
• Results in persistent or significant disability/incapacity; 
 
 
• Constitutes a congenital anomaly or birth defect; or 
 
 
• Jeopardizes the participant and requires medical or surgical intervention to 
prevent one of the outcomes listed above. 
 
 
Events not considered to be serious adverse events are hospitalizations for: 
 
• Routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures. 
• Admission for closer monitoring for known side effects of therapy such as 
cytokine release syndrome and neurological events do not qualify as an SAE.   
 
• Elective or pre-planned treatment for a pre-existing condition that did not 
worsen. 
 
 
• Emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission. 
 
 

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• Respite care. 
 
 
10.4.3. 
Expectedness 
Expected:  Expected adverse events are those that have been previously identified as 
resulting from administration of the agent.  For the purposes of this study, an adverse 
event is considered expected when it appears in the current adverse event list, the 
Investigator’s Brochure, the package insert or is included in the informed consent 
document as a potential risk. 
 
Unexpected:  An adverse event is considered unexpected when it varies in nature, 
intensity or frequency from information provided in the current adverse event list, 
the Investigator’s Brochure, the package insert or when it is not included in the 
informed consent document as a potential risk. 
 
10.4.4. 
Attribution 
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment.  Attribution will be assigned as follows: 
 
• Definite – The AE is clearly related to the study treatment. 
 
• Probable – The AE is likely related to the study treatment. 
 
 
• Possible – The AE may be related to the study treatment. 
 
 
• Unlikely – The AE is doubtfully related to the study treatment. 
 
 
• Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
10.5. 
Reporting Procedures 
 
10.5.1. General Considerations 
Investigators should use correct medical terminology/concepts when reporting Aes 
or SAEs, and avoid colloquialisms and abbreviations.  If known at the time of 
reporting, a diagnosis should be reported rather than individual signs and symptoms 
(e.g. record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases).  However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, it 
is acceptable to report the information that is currently available.  If a diagnosis is 
subsequently established, it should be reported as follow-up information. 
 

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All deaths that occur during the protocol-specified AE reporting period, regardless of 
attribution, will be reported to relevant bodies including Kite Pharmacovigilance, 
Vanderbilt,  and CIBMTR.  When recording a death, the event or condition that 
caused or contributed to the fatal outcome should be reported as the single medical 
concept.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, report “Unexplained Death.”  Deaths that occur during the protocol 
specified adverse event reporting period that are attributed by the investigator solely 
to progression of disease should be recorded only in the study eCRF and not reported 
as an SAE. 
 
A pre-existing medical condition is one that is present prior to initiation of protocol 
specified treatment.  Such conditions should be reported as medical and surgical 
history.  A pre-existing medical condition should be re-assessed throughout the trial 
and reported as an AE or SAE only if the frequency, severity, or character of the 
condition worsens during the study.  When reporting such events, it is important to 
convey the concept that the pre-existing condition has changed by including 
applicable descriptors (e.g., “more frequent headaches”). 
Any AE that results in transfer to the Intensive Care Unit (ICU) should be documented 
and reported as an SAE.  If a patient is hospitalized to undergo a medical or surgical 
procedure as a result of an AE, the event responsible for the procedure, not the 
procedure itself, should be reported as the SAE.  For example, if a patient is 
hospitalized to undergo coronary bypass surgery, record the heart condition that 
necessitated the bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for pre-existing conditions; or 
 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study; or 
 
 
• Hospitalization or prolonged hospitalization for scheduled therapy of the 
target disease of the study. 
 
 
10.5.2. Serious Adverse Events 
All serious adverse events, regardless of causality to study drug, will be reported to 
the Principal Investigator and the Study Coordinator at the institution. 
 
All serious adverse events must be reported to the Study Coordinator within 24 hours 
of the investigator becoming aware of the event.  Events should be reported using 
the Vanderbilt SAE form, located in the packet of supplemental forms.  This form 
must be fully completed and emailed (preferred), faxed, or scanned to the Study 
Coordinator. 

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The Study Coordinator will disseminate information regarding serious adverse events 
to the participating site as described in FDA guidance only in the case that the 
event(s) is/are unexpected, and is/are believed to be related (i.e., possibly, probably 
or definitely) to the study device/medication.  The Study Coordinator will be 
responsible for reporting of events to supporters, as appropriate (outlined below). 
 
10.5.3. Institutional Review Board 
All adverse events and serious adverse events will be reported to the IRB per current 
institutional standards.  If an adverse event requires modification of the informed 
consent, these modifications will be provided to the IRB with the report of the 
adverse event.  If an adverse event requires modification of the study protocol, these 
modifications will be provided to the IRB as soon as is possible. 
 
10.5.4. Reporting to Supporters 
Vanderbilt University Medical Center will notify the funder of any serious adverse 
event (SAE) that occurs during the reporting period as defined above in Section 10.2.  
Within 2 working days after the Study Coordinator initially receives the safety 
information from the site, the Study Coordinator will report the SAE (on the 
MedWatch, funder, or Vanderbilt SAE form approved by the study team and funder) 
to a point of contact specified by the funder – for example to Kite/Gilead via email at 
.  Follow-up SAE reports received by the Study Coordinator 
should be sent within 2 working days to the funder using the same procedure used 
for transmitting the initial report. 
 
10.6. Adverse Events of Special Interest (AESI) 
Selected non-serious and serious adverse events are also known as Adverse Events of Special 
Interest (AESI).  In this trial, adverse events of special interest include: 
 
• 
Neurological events ≥ Grade 3. 
 
• 
Hematological severe infections ≥ Grade 3, 
 
 
• 
Autoimmune events, and 
 
 
• 
Secondary malignancy events, 
 
 
• 
Cytokine release syndrome ≥ Grade 3.  
 
 
Within the reporting period outlined above in Section 10.2 and according to SAE reporting 
procedures outlined in Section 10.5, all adverse events of special interest (AESI) meeting the 
following criteria must be reported in an EXPEDITED manner by the site to the Study 

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Coordinator within 24 hours of the investigator becoming aware of the event – regardless of 
attribution to participation in the study: 
 
• 
AESI that is a non-serious adverse event (AE) ≥ Grade 3, or 
 
• 
AESI that is a serious adverse event (SAE) of any grade. 
 
11. STATISTICAL CONSIDERATIONS 
 
11.1. General Analysis Plan  
No formal hypothesis will be tested in this study. Data analysis will be descriptive. No group 
comparisons will be made.  Continuous variable will be summarized using the minimum value, 
maximum value, 25th, 50th (median), and 75th percentiles as well as the mean and standard 
deviation.  Categorical variables will be summarized in frequency tables. [13-15] See appendix E 
for detailed statistical considerations. 
 
 
 

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11.2. Study Endpoints 
 
 
11.2.1. Primary Endpoints 
 
1. Number of subjects that remain an outpatient at 3, 7 and 30 days after 
YESCARTA infusion.  
 
2. Time to requirement for inpatient hospitalization after YESCARTA infusion. 
 
 
11.2.2. Secondary Endpoints 
 
1. Incidence of Aes and clinically significant changes in safety lab values. 
2. Incidence/grade of adverse events. 
 
3. Incidence/grade of CRS and ICANS. 
  
4. Incidence of steroid and/or tocilizumab administration. 
  
5. YESCARTA treatment response rate. 
  
6. Time to intervention defined as the time interval between when the call was 
made to admit the subject for an adverse event of interest and the time that 
specific intervention was given. 
  
7. Rate of use of tocilizumab, corticosteroids, vasopressors.  
 
 
11.2.3. Exploratory Endpoints 
 
1. Levels of inflammatory cytokines in subject’s serum before and after YESCARTA 
infusion. 
 
2. Investigation for potential predictive markers for grade 3 or higher toxicity or 
need for hospitalization.  
 
 
3. Modified NF symptom burden score for days 1-3 for each subject (appendix D) 
  
4. Subject reported outcomes measured by Subject-Reported Outcomes 
Measurement Information System (PROMIS) [16, 17]. 
 
 

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11.3. Sample Size 
Twenty subjects will receive YESCARTA treatment at a maximum of two sites. Subjects 
who are unable to proceed with CART infusion and monitoring for 14 days on study will 
be replaced. 
 
12. DATA SAFETY AND MONITORING 
 
12.1. Data Management and Reporting 
Participating institutions will collaborate with Vanderbilt for patient accrual.  The Vanderbilt 
University Office of Research will be used as a central location for data processing and 
management.  Vanderbilt University, with collaboration from a consortium of institutional 
partners, has developed a software toolset and workflow methodology for electronic collection 
and management of research and clinical trial data.  REDCap (Research Electronic Data Capture) 
is a secure, web-based application that is flexible enough to be used for a variety of types of 
research.  REDCap provides an intuitive user interface that streamlines project development 
and improves data entry through real-time validation rules (with automated data type and 
range checks).  REDCap also provides easy data manipulation (with audit trails for reporting, 
monitoring and querying patient records) and an automated export mechanism to common 
statistical packages (SPSS, SAS, Stata, R/S-Plus).  In addition to traditional data capture 
functionality, REDCap’s survey capabilities are a powerful tool for building and managing online 
surveys.  The research team can create and design surveys in a web browser and engage 
potential respondents using a variety of notification methods.  All data collection projects rely 
on a thorough, study-specific data dictionary, defined by all members of the research team in 
an iterative, self-documenting process.  This iterative development and testing process results 
in a well-planned and individualized data collection strategy. 
 
REDCap servers are housed in a local data center at Vanderbilt, and all web-based information 
transmission is encrypted.  REDCap was developed specifically around HIPAA-Security 
guidelines and is recommended to Vanderbilt researchers by both our Privacy Office and 
Institutional Review Board.  REDCap has been disseminated for local use at more than 940 
other academic/non-profit consortium partners in 75 countries.  Vanderbilt leads the REDCap 
Consortium, which currently supports more than 99,000 projects and 128,000 users.  More 
information about the consortium and system security can be found at 
http://www.projectredcap.org/.  
 
12.2. Auditing and Monitoring 
The Vanderbilt-Ingram Cancer Center (VICC) oversees patient safety and data monitoring for its 
investigator-initiated and NIH-NCI funded clinical trials through its Data and Safety Monitoring 
Committee (DSMC).  The purpose of the DSMC is to ensure the efficient implementation and 
management of the VICC Data and Safety Monitoring Plan (DSMP).  The Committee maintains 
authority to intervene in the conduct of studies as necessary to ensure clinical research 
performed at VICC achieves the highest quality standards. 
 

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The VICC DSMC meets on a quarterly basis and ad hoc to discuss data and safety monitoring of 
clinical trials and to oversee the VICC DSMP.  Internal audits for compliance with adverse event 
reporting, regulatory and study requirements, and data accuracy and completion are conducted 
according to the VICC DSMP according to study phase and risk.  The committee reviews all 
serious adverse events (SAE) on Vanderbilt sponsored investigator-initiated studies on a 
quarterly basis and provides DSMC SAE review reports to the Vanderbilt IRB. 
 
The trial additionally will be monitored by the VICC Multi-Institutional Coordinating Center.  The 
actual frequency of monitoring will depend on the enrollment rate and performance of the site. 
Monitoring will be conducted through onsite and/or remote monitoring, teleconferences with 
the Investigator and site staff, and appropriate communications by mail, fax, email, or 
telephone.  The purpose of monitoring is to ensure that the study is conducted in compliance 
with the protocol, standard operating procedures (SOPs), and other written instructions, and to 
ensure the quality and integrity of the data. 
 
During scheduled monitoring visits, investigators and the investigational site staff must be 
available to discuss the progress of the trial, make necessary corrections to case report form 
entries, respond to data clarification requests, provide required regulatory documents, and 
respond to any other trial-related inquiries of the monitor. 
 
12.3. Data Handling and Record Keeping 
An electronic case report form (eCRF) is required and must be completed for each included 
participant.  The completed dataset should not be made available in any form to third parties, 
except for authorized representatives of appropriate Health/Regulatory Authorities, without 
written permission from Vanderbilt. 
 
To enable evaluations and/or audits from health authorities and Vanderbilt, the site 
investigator agrees to keep records including: The identity of all participants (sufficient 
information to link records; e.g., hospital records), all original signed informed consent forms, 
copies of all source documents, and detailed records of drug disposition.  To comply with 
international regulations, the records should be retained by the investigator in compliance with 
regulations. 
 
Queries resulting from review of the eCRFs will be generated for the site and corrections will be 
made by the study site personnel.  This will be done on an ongoing basis. 
 
13. REGULATORY CONSIDERATIONS 
 
13.1. Protocol Review and Amendments 
Information regarding study conduct and progress will be reported to the Institutional Review 
Board (IRB) per current institutional standards. 
 
The trial will not be initiated until there is approval by the local IRB of the protocol, informed 
consent document and any other material used to inform the patient about the nature of the 

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trial.  The IRB should be duly constituted according to local regulatory requirements.  The 
investigator will inform the IRB of the progress of the trial at least yearly. 
 
Any changes to the protocol will be made in the form of a written amendment and must be 
approved by the sponsor-investigator and the local IRB prior to local implementation.  All 
amendments will also be submitted as necessary to the FDA by the sponsor-investigator (or 
designee). 
 
Protocol changes to eliminate an immediate hazard to a trial patient may be implemented by 
the investigator immediately.  The investigator must then immediately inform the local IRB; and 
the sponsor-investigator (or designee), who will communicate as appropriate with the FDA. 
 
The sponsor-investigator (or designee) is responsible for the coordination and development of 
all protocol amendments and will disseminate this information to the participating centers. 
 
13.2. Informed Consent 
The investigator (or designee) will explain to each participant the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved and any discomfort it may entail.  Each participant will be informed that participation 
in the study is voluntary, that s/he may withdraw from the study at any time, and that 
withdrawal of consent will not affect subsequent medical treatment or relationship with the 
treating physician(s) or institution.  The informed consent will be given by means of a standard 
written statement, written in non-technical language, which will be IRB approved.  The 
participant should read and consider the statement before signing and dating it and will be 
given a copy of the document.  No patient will enter the study or have study-specific 
procedures done before his/her informed consent has been obtained. 
 
In accordance with the Health Information Portability and Accountability Act (HIPAA), the 
written informed consent document (or a separate document to be given in conjunction with 
the consent document) will include a subject authorization to release medical information to 
the study sponsor and supporting agencies and/or allow these bodies, a regulatory authority, or 
Institutional Review Board access to subjects’ medical information that includes all hospital 
records relevant to the study, including subjects’ medical history. 
 
13.3. Confidentiality 
It is the responsibility of the investigator to ensure that the confidentiality of all patients 
participating in the trial and all of their medical information is maintained.  Case report forms 
(CRFs) and other documents submitted to regulatory authorities must not contain the name of 
a trial patient.  All patients in the trial will be identified by a unique identifier which will be used 
on all CRFs and any other material submitted to regulatory authorities.  All case report forms 
and any identifying information must be kept in a secure location with access limited to the 
study staff directly assisting with the trial. 
 
13.4. Study Termination 

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The sponsor-investigator reserves the right to terminate the study at any site and at any time.  
Reasons for study termination may include, but are not limited to, the following: 
• Investigator non-compliance with the protocol, GCP or regulatory requirements. 
• Insufficient enrollment. 
• Safety concerns. 
• Decision by suppliers to modify or discontinue the availability, development or 
manufacture of protocol-indicated treatment. 
• A request to discontinue the study by the IRB or recognized regulatory authority. 
 
14. STUDY COORDINATION 
 
14.1. Trial Compliance 
This is an investigator-initiated study.  The Principal Investigator, Olalekan O. Oluwole, MD, 
MPH (who may also be referred to as the Sponsor-Investigator), is conducting the study and 
acting as the sponsor.  Therefore, the legal and ethical obligations of the Principal Investigator 
include both those of a sponsor and those of a principal investigator. 
 
Vanderbilt is the Coordinating Center for this study.  All aspects of the study will be carefully 
monitored by the Coordinating Center for compliance with applicable government regulations 
with respect to current GCP and standard operating procedures. 
 
14.2. Changes to Protocol and Informed Consent Document 
Any change to the protocol or informed consent document must be reviewed and approved by 
the investigator before being submitted to the Institutional Review Board/Independent Ethics 
Committee at participating institutions.  Amendments should not be implemented until all 
necessary approvals have been obtained, except when necessary to eliminate an immediate 
hazard to study subjects. 
 
14.3. Protocol Deviations 
The Coordinating Center is responsible for implementing and maintaining quality assurance and 
quality control to ensure that studies are conducted according to the protocol, GCP, and all 
applicable regulatory requirements.  A protocol deviation is any noncompliance with the 
protocol.  Noncompliance can be on the part of the study participant, the investigator, or the 
study site staff.  Deviations to the protocol are not permitted except when necessary to 
eliminate an immediate hazard to study subjects. 
 
14.4. Monitoring and Quality Assurance 
As the Coordinating Center, Vanderbilt has responsibilities to health authorities to take all 
reasonable steps to ensure the proper conduct of the study with regard to ethics, protocol 
adherence, integrity, validity of the data recorded on the CRFs, and adherence to regulations 
regarding Good Clinical Practice (GCP) and the protection of human subjects. 
 
In accordance with applicable regulations, GCP, and Coordinating Center procedures, sites will 
be contacted prior to the start of the study to review with site staff the protocol, study 

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requirements, and their responsibilities to satisfy regulatory, ethical, and Coordinating Center 
requirements. 
 
During the course of the study, the Coordinating Center will routinely monitor sites for protocol 
compliance, compare CRFs with original source documents from individual subjects, assess drug 
accountability, and ensure that the study is being conducted according to the pertinent 
regulatory requirements.  The review of subject medical records will be performed in a manner 
to ensure that subject confidentiality is maintained.  Monitoring visits will primarily be 
conducted remotely, and sites are required to provide the appropriate source documentation 
in order to allow for proper oversight per GCP.  Investigators must agree to cooperate with the 
Coordinating Center to ensure that any problems detected are resolved. 
 
 

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14.5. Data Verification 
Data will be collected via eCRFs and entered into the database per Coordinating Center 
guidelines. The Coordinating Center will check data accuracy by performing source data 
verification.  Source data verification is a direct comparison of the entries made on the CRFs 
against the appropriate source documentation.  This will be conducted remotely, with the 
possibility of on-site verification periodically.  Discrepancies in the data will be brought to the 
attention of the investigator and/or the investigator’s staff.  Any necessary corrections will be 
made directly to the eCRFs or via queries by the investigator and/or the investigator’s staff. 
 
14.6. Study Documentation 
Each participating site is responsible for submitting copies of all relevant regulatory 
documentation to the Coordinating Center.  The required documents include but are not 
limited to the following: local IRB approvals (i.e., protocol, consent form, amendments, patient 
brochures, recruitment material, etc.), IRB membership rosters, summary of unanticipated 
problems or protocol deviations, and documentation of expertise of the investigators.  The 
Coordinating Center will provide each participating site with a comprehensive list of the 
necessary documents.  It is the responsibility of the participating sites to maintain copies of all 
documentation submitted to the Coordinating Center. 
 
The requirements for data management, submissions, and monitoring are outlined below.  The 
participating sites will submit all the research related information inclusive of: 
 
• Source documents (patient registration list, CRF info, toxicity assessments, tumor 
measurements / responses, etc.) are required to be provided within 30 days of visit or 
10 days in advance of a monitoring visit or audit, 
 
• Essential Documents (IRB approval documents, financial disclosure forms, 1572, 
delegation of authority log, protocol training, etc.) are required to be provided within 
one week of receiving the updated documents. 
 
Personnel from the VICC Clinical Trials Office will monitor the trial and may periodically visit the 
investigative site to assure proper conduct of the trial and proper collection of the data.  The 
investigators at other sites will allow the monitor to review all source documents used in the 
preparation of the case reports. 
 
14.7. Closure of the Study 
The Coordinating Center reserves the right to discontinue a site at any time during the study for 
medical or administrative reasons such as: 
• Unsatisfactory enrollment; 
• GCP noncompliance; 
• Inaccurate or incomplete data collection; 
• Falsification of records; 
• Failure to adhere to the study protocol. 
 

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14.8. Records Retention 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining to the 
conduct of this study, including CRFs, consent forms, laboratory test results, and medication 
inventory records, must be retained by each Principal Investigator for 2 years after marketing 
application approval.  If no application is filed, these records must be kept 2 years after the 
study is discontinued and the applicable national and local health authorities are notified. 
 
Following closure of the study, each participating center will maintain a copy of all site study 
records in a safe and secure location.  The Coordinating Center will inform the investigator at 
such time that the records may be destroyed. 
 
14.9. Publication 
It is understood that any manuscript or releases resulting from the collaborative research must 
be approved by the sponsor-investigator and will be circulated to applicable participating 
sites/investigators prior to submission for publication or presentation. 
 
 
17. REFERENCES 
1. 
Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, Link BK, Hay A, Cerhan JR, Zhu L et 
al: Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 
study. Blood 2017, 130(16):1800-1808. 
2. 
Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, Lin Y, Braunschweig I, Hill BT, 
Timmerman JM et al: Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell 
lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. The Lancet Oncology 2019, 20(1):31-42. 

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3. 
Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S 
et al: ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with 
Immune Effector Cells. Biology of blood and marrow transplantation : journal of the American Society for 
Blood and Marrow Transplantation 2019, 25(4):625-638. 
4. 
Borchman P, Tam, Constantine S., Jager, Ulrich, McGuirk, Joseph P., Holte, Harald, Waller, Edmund K., 
Jaglowski, Samantha M., Bishop, Michael R., Andreadis, Charalambos, Foley, Stephen Ronan, Westin, 
Jason R., Fleury, Isabelle, Ho, P. Joy, Mielke, Stephan, Salles, Gilles, Maziarz, Richard T., Anak, Ozlem, 
Pacaud, Lida Bututeishvili, del Corral, Chistopher, Awasthi, Rakesh, Agoulnik, Sergei, Tai, Feng, Schuster, 
Stephen J.: An Updated Analysis of JULIET, a Global Pivotal Phase 2 Trial of Tisagenlecleucelin Adult 
Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma. In: 23rd Congress of EHA: 2018; 
Stockholm, Sweden: prIME Oncology; 2018. 
5. 
Abramson JS, Palomba ML, Gordon LL, Lunning MA, Wang ML, Arnason JE, Mehta A, Enkhtsetseg P, 
Maloney DG, Andreadis C et al: Pivotal Safety and Efficacy Results from Transcend NHL 001, a 
Multicenter Phase 1 Study of Lisocabtagene Maraleucel (liso-cel) in Relapsed/Refractory (R/R) Large B 
Cell Lymphomas. Blood 2019, 134(1):1. 
6. 
Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, Braunschweig I, Oluwole OO, Siddiqi 
T, Lin Y et al: Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. The New 
England journal of medicine 2017, 377(26):2531-2544. 
7. 
Rossi J, Paczkowski P, Shen YW, Morse K, Flynn B, Kaiser A, Ng C, Gallatin K, Cain T, Fan R et al: Preinfusion 
polyfunctional anti-CD19 chimeric antigen receptor T cells are associated with clinical outcomes in NHL. 
Blood 2018, 132(8):804-814. 
8. 
Reid RM, Baran A, Friedberg JW, Phillips GL, 2nd, Liesveld JL, Becker MW, Wedow L, Barr PM, Milner LA: 
Outpatient administration of BEAM conditioning prior to autologous stem cell transplantation for 
lymphoma is safe, feasible, and cost-effective. Cancer medicine 2016, 5(11):3059-3067. 
9. 
Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S 
et al: ASBMT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated 
with Immune Effector Cells. Biology of blood and marrow transplantation : journal of the American 
Society for Blood and Marrow Transplantation 2018. 
10. 
Ahn S, Rice TW, Yeung SJ, Cooksley T: Comparison of the MASCC and CISNE scores for identifying low-
risk neutropenic fever patients: analysis of data from three emergency departments of cancer centers in 
three continents. Supportive care in cancer : official journal of the Multinational Association of Supportive 
Care in Cancer 2018, 26(5):1465-1470. 
11. 
Taplitz RA, Kennedy EB, Bow EJ, Crews J, Gleason C, Hawley DK, Langston AA, Nastoupil LJ, Rajotte M, 
Rolston K et al: Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: 
American Society of Clinical Oncology and Infectious Diseases Society of America Clinical Practice 
Guideline Update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
2018, 36(14):1443-1453. 
12. 
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA: Recommendations for 
initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the 
Lugano classification. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 2014, 32(27):3059-3068. 
13. 
Thall PF, Simon RM, Estey EH: Bayesian sequential monitoring designs for single-arm clinical trials with 
multiple outcomes. Statistics in medicine 1995, 14(4):357-379. 
14. 
Thall PF, Simon RM, Estey EH: New statistical strategy for monitoring safety and efficacy in single-arm 
clinical trials. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
1996, 14(1):296-303. 
15. 
Thall PF, Sung HG: Some extensions and applications of a Bayesian strategy for monitoring multiple 
outcomes in clinical trials. Statistics in medicine 1998, 17(14):1563-1580. 
16. 
Chakraborty R, Sidana S, Shah GL, Scordo M, Hamilton BK, Majhail NS: Patient-Reported Outcomes with 
Chimeric Antigen Receptor T Cell Therapy: Challenges and Opportunities. Biology of blood and marrow 
transplantation : journal of the American Society for Blood and Marrow Transplantation 2019, 25(5):e155-
e162. 

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17. 
Shaw BE, Syrjala KL, Onstad LE, Chow EJ, Flowers ME, Jim H, Baker KS, Buckley S, Fairclough DL, Horowitz 
MM et al: PROMIS measures can be used to assess symptoms and function in long-term hematopoietic 
cell transplantation survivors. Cancer 2018, 124(4):841-849. 
 
 
 

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APPENDICES 
 
Appendix A: YESCARTA Patient and Caregiver Education   
 
Appendix B:  YESCARTA Caregiver Pre-Test 
 
Appendix C:  YESCARTA Caregiver Post-Test 
 
Appendix D:  Clinical Practice Guideline for Outpatient Management of Febrile Neutropenia in  
Patients Receiving Commercial CAR T-Cell Therapy 
 
Appendix E:  Detailed Statistical Considerations 
 
Appendix F:  PROMIS-29 Profile v2.1 
 
Appendix G: Biofourmis Wearable Device 
 
 
 
 
 
 
 
 
 
 

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Appendix A 
Vanderbilt University Medical Center 
YESCARTA Patient and Caregiver Education: Self-monitoring for CAR T toxicities 
 
Date: 
 
General consideration:  
You are part of patient’s care team and we need your help to monitor the patient’s wellbeing while not 
in the clinic or hospital. It is very important that you pay attention to any new symptoms or signs and 
report to us immediately. Below is the summary common symptoms/signs of CAR T therapy associated 
toxicities. This is NOT a complete list and you should not hesitate to call us with any new issue which 
may arise while at home.  
 
I.Vital Signs: equipment, testing, results  
• 
What equipment will you use?   
o 
Blood Pressure Cuff – used to take patient’s blood pressure and heart rate 
o 
Pulse Oximeter – used to measure patient’s oxygen and heart rate  
o 
Thermometer – used to take patient’s temperature  
• 
How often will take vitals for patient  
o 
Patient will have vital signs done during clinic visits at 8am  
o 
The caregiver will be responsible for vital signs at 6am, 12pm, 4:30, 10pm,   
• 
How will you report vital signs?   
o 
Patient will have a video conference call with night NP at 4:30pm and 10:00 PM ± 1 hour 
for at least first 14 days after Car-T infusion  
o 
Patient will call night NP at 6am to report 6am vital signs.  
 
Things to monitor at Home: 
II.Signs of Infection  
• 
Fever:  You will take your temperature 6am, 12pm, ≤10pm, 
o 
A temperature higher than 100.3 F is a reason to call at any time 
• 
Redness and/or tenderness around patient’s venous catheter site  
• 
Dizziness, shortness of breath, cough, altered mental status 
 
III.Cytokine Release Syndrome (CRS)  
• 
What is CRS?  
o 
This is an inflammatory process that impacts many organs. CRS typically occurs within 
first week after CAR-T infusion.   
• 
What are CRS symptoms?  
o 
Fever   
o 
Chills  
o 
Dizziness/lightheadedness 
o 
Shortness of breath 
o 
Altered mental status 
o 
Low blood pressure (Please call if systolic blood pressure drops below ____ mm Hg) 

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o 
Fast heart rate (Please call if hear rate is above 120 beats/min) 
o 
Low blood oxygen levels (Please call if pulse oxygen level fall below 90 %). 
• 
How do we treat CRS?   
o 
Intravenous fluids  
o 
Supplemental Oxygen  
o 
Tocilizumab (medication to reverse CRS)  
o 
Steroids.  
 
IV.Neurotoxicity  
• 
What is Neurotoxicity?  
o 
This is a collection of symptoms that impact patient’s mental status related to CAR T 
therapy administration.  
• 
What are Neurotoxicity symptoms?  
o 
Confusion  
o 
Headache 
o 
Delirium (confused thinking and reduced awareness of environment, for example to 
time and place; usually with rapid onset)  
o 
Difficulty finding words/speaking  
o 
Difficulty following commands  
o 
Memory lapses 
o 
Hallucinations (seeing or hearing things which does not exist) 
o 
Dizziness   
o 
Tremors  
o 
Seizures/ convulsions 
o 
Lethargy (lack of energy and enthusiasm).   
• 
How do we treat Neurotoxicity?   
o 
Steroids.   
 
V.  Monitoring  
• 
How will the patient be monitored?   
o 
You will be seen every day in our Outpatient Transplant Unit (OTU) at 8:00am and a nurse 
will visit the apartment at 4:30pm ± 1 hour daily for 14 days after your CAR-T infusion (Day 
0)  
o 
You will have your labs and vitals taken daily in clinic.   
o 
You will have a video conference telehealth visit with the night NP at 10pm. At that 
time, you will take your vital signs and answer questions.  
o 
You will take your vitals at 6am and then have a morning phone call with night NP to 
report overnight vital signs.   
o 
Once you are discharged from the OTU, you will transition to the CAR-T long term care 
clinic. This typically occurs between 14 and 30 days after CAR-T infusion.   
 
Official Use only  
 
 
 
 
 
 
Version date: 
Approved by: 

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Appendix B 
 
 
 
 
Vanderbilt University Medical Center 
YESCARTA Caregiver Pre-Test 
 
Date:  
 
Subject ID: 
1. What temperature is considered serious and warrants a call to Vanderbilt?  
a. 100.0°F 
b. 99.5°F 
c. 100.4°F 
d. 97.6°F 
2. Which symptom may mean the patient is experiencing neurotoxicity?  
a. Tremors 
b. Confusion 
c. Being extra sleepy 
d. All of the above 
3. What times do we need the patient to connect to the telehealth monitoring system?  
a. 10:00 PM 
b. 2:00 AM 
c. 6:00 AM 
d. None of the above  
4. Please perform 3 blood pressures on patient and write down values:  
a.     
b.     
c.     
5. Please take the patient’s temperature 3 times and write down values:  
a.   
b.     
c.     
6. Please take patient’s pulse oxygen levels and write down values: 
a.    
b.    
c.    
7. Please check patient’s heart rate and write down values:  
a.    
b.    
c.    
8. What symptom may mean the patient is experiencing cytokine release syndrome (CRS)?  
a. Chills 
b. Low blood pressure 
c. Fever 
d. All of the above 
Official Use only 
 
 
 
 
 
Appendix                 Version 
Date: 
Score: 
Pass/Fail 
Comment: 
Reviewer’s 
initials: 

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Appendix C 
Vanderbilt University Medical Center 
YESCARTA Caregiver Post-Test 
 
Date:  
 
Subject ID: 
1. What temperature is considered serious and warrants a call to Vanderbilt?  
a. 100.0°F 
b. 99.5°F 
c. 100.4°F 
d. 97.6°F 
2. Which symptom may mean the patient is experiencing neurotoxicity?  
a. Tremors 
b. Confusion 
c. Being extra sleepy 
d. All of the above 
3. What times do we need the patient to connect to the telehealth monitoring system?  
a. 10:00 PM 
b. 2:00 AM 
c. 6:00 AM 
d. None of the above  
4. Please perform 3 blood pressures on patient and write down values:  
a.     
b.     
c.     
5. Please take the patient’s temperature 3 times and write down values:  
a.   
b.     
c.     
6. Please take patient’s pulse oxygen levels and write down values: 
a.    
b.    
c.    
7. Please check patient’s heart rate and write down values:  
a.    
b.    
c.    
8. What symptom may mean the patient is experiencing cytokine release syndrome (CRS)?  
a. Chills 
b. Low blood pressure 
c. Fever 
d. All of the above  
Official Use only  
 
 
 
 
Score 
Pass/Fail 
Comment: 
Reviewer’s initials: 
 

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Appendix D 
Suggested Guideline for Outpatient Management of Febrile Neutropenia in  
Patients Receiving Immune Effector-Cell Therapy 
Modified Neutropenic Fever Symptom Burden (NFSB) score: Modified from MASCC 
Introduction: 
Prevention and appropriate management of febrile neutropenia (FN) is important because the rate 
of major complications (e.g., hypotension, acute renal, respiratory, and heart failure) in the 
context of FN is approximately 25% to 30%, and the mortality rate ranges up to 11%. Fever is a 
common toxicity associated with immune effector cell (IEC) therapy and may be indicative of an 
infectious process, cytokine release syndrome, or both. Patients receiving this therapy who 
present with fever (Tmax ≥100.4° F) and concomitant neutropenia (absolute neutrophil count 
≤500 cells/mm3) must be treated according to standard FN guidelines. However, fever in this 
population can at times be stable and otherwise asymptomatic and therefore, may warrant 
consideration of outpatient FN management. Several tools exist and have been validated to help 
determine whether oncology patients are at a low or high risk for medical complications as a 
result of an FN episode and are recommended for use in determining which patients are 
candidates for inpatient or outpatient FN treatment.  
 
Conditions/situations that are considered a contraindication to the outpatient management of FN 
and are therefore not eligible to be treated according to this guideline include: 
• Poor pulmonary function (FEV1/DLCO <50%, need for O2, COPD) 
• Mucositis 
• Known specific, active infection such as pneumonia or central line-associated 
bloodstream infection 
• Concern for infection with a resistant organism (ESBL, MRSA, VRE) 
 
Of note, IEC patients who are non-neutropenic and experience fever may also be treated 
according to this guideline per clinician discretion. 
 
Risk Assessment: 
The risk index table1 below has been established by the Vanderbilt Ingram Cancer Center 
Immune Effector-Cell Committee to identify patients who are candidates for outpatient 
management of FN based on their potential risk for medical complications.  
 
Modified Neutropenic Fever Symptom Burden (NFSB) score 
Characteristic 
Score 
Fever < 102°F 
2 
Fever ≥ 102°F 
5 
New or progressive symptoms based on ROS 
5 
Hypotension (systolic blood pressure ≤ 90mmHg or mean arterial pressure ≤ 65 
mmHG AND blood pressure/MAP within 80% of baseline value) 
5 
Hypoxia (02 < 90%) 
5 
Age > 65 years 
2 
Dehydration (IVF in last 24 hours) 
3 
Recent infection or antifungal prescription 
4 

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NOTE: Maximum score is 29; Scoring is cumulative 
 
 
 
Decision Tree: 
<5 points = Outpatient Management 
5-7 points = Admit to observation 
≥8 = Admit to inpatient 
 
1. Risk index table will be reviewed for purposes of validation after 5 patients have been assessed utilizing this scoring tool. 
 
Treatment:  
If the patient is deemed a potential candidate for outpatient treatment of FN, the following steps 
should be followed: 
1. The patient should present to VUMC for evaluation (clinic or emergency 
department, if after hours) within 1 hour of identification of fever.  
 Draw appropriate cultures (blood/urine)  
 Administer the first dose of IV broad-spectrum β-lactam antibiotic 
(cefepime or piperacillin-tazobactam as outlined in VUMC Empiric Anti-
Infective Algorithm for Febrile Neutropenia) 
 Obtain standard radiographic imaging (chest X-Ray) as outlined in VUMC 
Empiric Anti-Infective Algorithm for Febrile Neutropenia 
2. . 
 The clinic APP or inpatient nocturnist will then determine, with 
consultation from the SCT and/or IEC attending, if needed, if the patient is 
eligible for outpatient management (score ≥21 and no other 
contraindications) 
3. If eligible, the patient should begin usual FN treatment (cefepime, piperacillin-
tazobactam) via home infusion  
a) If home infusion or next clinic administration time will be delayed past 
when the next dose of IV antibiotics is due, the patient may begin an 
ORAL empiric antibiotic regimen with amoxicillin/clavulanate 1 g PO 
q12h (or clindamycin 600 mg PO q8h in case of penicillin allergy) and 
continue prophylactic levofloxacin until IV therapy is secured 
i. 
All patients will be given a 48-hour supply of 
amoxicillin/clavulanate or clindamycin along with all other IEC 
medications on the first day of lymphodepleting chemotherapy to 
use for this purpose 
4. The patient must be seen daily by a health care provider and have daily CBC with 
differential monitoring while receiving outpatient FN treatment 
5. For 72 hours following the onset of the febrile episode and initiation of outpatient 
FN management, the patient will be physically seen by a provider at the daily 
1630 visit/lab check 
6. Patients initially managed as outpatients for FN should be evaluated for admission 
if any of the following occur: 
a) Failure to defervesce after 24-48 hours of empiric antibiotic treatment 

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b) New or progressive signs/symptoms of infection (not attributable to other 
causes), including concomitant CRS and/or ICANS 
  
References: 
1. Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient Management of Fever and 
Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology 
and Infectious Diseases Society of America Clinical Practice Guideline Update. J Clin 
Oncol. 2018;36(14):1443-1453. 
2. Klastersky J, Paesmans M, Rubenstein EB, et al. The Multinational Association for 
Supportive Care in Cancer Risk Index: A Multinational Scoring System for Identifying 
Low-Risk Febrile Neutropenic Cancer Patients. J Clin Oncol. 2000;18(16):3038-3051. 
3. VUMC Empiric Anti-Infective Algorithm for Febrile Neutropenia. https://prd-medweb-
cdn.s3.amazonaws.com/documents/vasp/files/FN%20Algorithm%208_18.pdf

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Appendix E 
Detailed Statistical Considerations 
 
This is an open label, pilot clinical trial to evaluate the feasibility of safely delivering Axi-cel 
therapy in the outpatient setting.  The primary objective of this study is to collect data on a 
sample of 20 patients to provide data with which to plan a larger, more definitive trial.  
Sample size was chosen to complete accrual in 24 months. 
 
With 20 observations, categorical variables will be measured with a precision (1/2 of a 95% 
confidence interval) no larger than 20%. Similarly, the precision of measurement for 
continuous variables will be proportional to 0.447 standard deviations. 
 
Endpoints 
Many endpoints will be measures including patient characteristics, response to therapy by 
RECIST 1.0 criteria, progression-free (PFS) and overall (OS) survival. PFS is defined as the 
time from start of therapy to disease progression or death for any reason. OS is defined as the 
time from start of therapy to death for any reason.  Patients progression-free and alive (PFS) 
or alive (OS) at last follow-up will be censored. The distributions of PFS and OS will be 
estimated using the Kaplan-Meier (product limit) method. Adverse events according to 
ASTCT guidelines and CTCAE 5.0 criteria.1  Feasibility metrics include the proportion of 
planned doses delivered, 14-day incidence of hospitalization by type and overall, and the 
proportion of patients that were managed successfully via telemedicine (see above for more 
details) for more than 3 days post infusion.  95% confidence intervals will be estimated for 
all endpoints. 
 
General Analysis Plan 
Data analysis will be descriptive. No group comparisons will be made.  Continuous variable 
will be summarized using the minimum value, maximum value, 25th, 50th (median), and 75th 
percentiles as well as the mean and standard deviation.  Categorical variables will be 
summarized in frequency tables.   
 
Continuous Monitoring of Two Important Toxicities 
We will carefully monitor two toxicities, CRS and neurotoxicity.  Toxicity rates from 
published data for these events are 15% and 30% respectively.  Toxicity will be monitored 
simultaneously and independently in 20 patients using the Bayesian approach of Thall, 
Simon, Estey (1995, 1996) as extended by Thall and Sung (1998). 2-4 The probabilities of  
toxicity for the historical data for these two events are modeled by beta distributions 
(Beta(0.3, 1.7) and Beta(0.6, 1.4), respectively), representing 15% and 30% toxicity for an 
effective sample size of 2 patients.  The prior probabilities of toxicity for the experimental 
regimen are also modeled by beta distributions the same means as the corresponding beta 
distributions for the historical data, also with an effective sample size of  2 patients   

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Neurotoxicty.  Denoting the historical probabilities of toxicity for each endpoint by 
{p(OR,H) , p(TOX,H)}, the following decision criteria will be applied.  Stop if 
Prob{p(Neurotoxicity,H)  < p(Neurotoxicity,E)| data} > 0.75 provides the following 
monitoring rule, 
 
                                | Stop the trial if there are 
                                | this many toxicities total: 
                                |------------------------------------------------------------ 
# Patients              | # Toxicities 
| --------------------------------|------------------------------------------------------------ 
1-5                          | Never stop with this many patients 
6-7                          | 4-7 
8-9                          | 5-9 
10-11                     | 6-11 
12-13                     | 7-13 
14-15                     | 8-15 
16-17                     | 9-17 
18-19                     | 10-19 
20                           | Always stop with this many patients 
 
The monitoring rule becomes effective when 6 patients have been treated.  If the true 
neurotoxicity rate is 30%, this rule stops early 17% of the time.  For a 50% event rate, this rule 
stops 70% of the time.   
 
CRS. Denoting the historical probabilities of toxicity for each endpoint by {p(OR,H) , 
p(TOX,H)}, the following decision criteria will be applied.  Stop if Prob{p(CRS,H)  < p(CRS,E)| 
data} > 0.79 provides the following monitoring rule, 
 
                                | Stop the trial if there are 
                                | this many toxicities total: 
                                |------------------------------------------------------------ 
# Patients              | # Toxicities 
| --------------------------------|------------------------------------------------------------ 
1-5                          | Never stop with this many patients 
6-9                          | 3-9 
10-13                     | 4-13 
14-17                     | 5-17 
18-19                     | 6-19 
20                           | Always stop with this many patients 
  
  
This is for the event where 15% toxicity it expected and acceptable.  If the true toxicity is 15%, 
this rule stops the trial early 18% of the time.  If the true toxicity is 30%, this rule stops the study 
early (i.e., by an accrual of 19 patients) 69% of the time.  

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References  
 
1. 
Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN et al. ASTCT Consensus 
Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune 
Effector Cells. Biology of blood and marrow transplantation : journal of the American Society for 
Blood and Marrow Transplantation 2019; 25(4): 625-638. e-pub ahead of print 2018/12/29; doi: 
10.1016/j.bbmt.2018.12.758 
 
2. 
Thall PF, Simon RM, Estey EH. Bayesian sequential monitoring designs for single-arm clinical 
trials with multiple outcomes. Statistics in medicine 1995; 14(4): 357-379. e-pub ahead of print 
1995/02/28;  
 
3. 
Thall PF, Simon RM, Estey EH. New statistical strategy for monitoring safety and efficacy in 
single-arm clinical trials. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology 1996; 14(1): 296-303. e-pub ahead of print 1996/01/01; doi: 
10.1200/jco.1996.14.1.296 
 
4. 
Thall PF, Sung HG. Some extensions and applications of a Bayesian strategy for monitoring 
multiple outcomes in clinical trials. Statistics in medicine 1998; 17(14): 1563-1580. e-pub 
ahead of print 1998/08/12;  
 
 
 
 
 

 
 
Appendix G: Biofourmis Wearable Device 
 
Introduction 
Subjects undergoing CART therapy are admitted to the hospital for 7 days or longer for close 
monitoring. During that time, the close monitoring consists of physical exam up to four times 
(One by physician, one by NP, twice by nurses) and vitals are measured at least six times (every 
4 hours x 24 hours).  
Biofourmis has FDA/IDE certified wearable devices that are already in use in the clinical setting 
This project explores how wearable devices might be of use in the research setting to enhance the 
close monitoring of patients and bridge the gap between the impatient and outpatient setting Data 
are collected for research purposes only. 
 
Data captured 
Body surface temperature, Respiratory rate, Heart rate, Blood Pressure, Oxygen saturation 
 
Devices 
1. Seven-day patch to be worn on the left anterior chest 
2. Blood Pressure cuff to be worn on the arm intermittently 
3. Pulse oximeter device to be worn on the digits intermittently 
Device Clearances: BP cuff and pulse oximeter are FDA approved while the patch is IDE 
approved 
 
Methods 
Subjects are trained to apply the devices which comprises of a patch that is applied on the left 
anterior chest and worn continuously, a blood pressure cuff that is applied intermittently on the 
arm, and a pulse oximeter applied intermittently to the digits. The BP cuff and pulse oximeter are 
applied at specific times (6am, 12 noon, 16:30 +/- 1 hour and 22:00) while the patch captures 
heart rate, temperature, and respiratory rate continuously. If patient fails to apply the BP cuff and 
pulse oximeter at the time stipulated, a vendor system generated reminder will go to them. Any 
alerts issued by vendor can be viewed by the PI and all authorized users of the program. Data are 
recorded in the device database and are for research only but are accessible by specific clinical 
trial staff.  
Between day -5 and day zero: Subjects are taught to apply and use devices 
Day zero: Subjects are given the devices and begin to wear them 
Day zero through day +14: Subjects use the devices as directed 
Day 14 – 21: Devices are returned to the vendor 
 
Data management 
This is an exploratory objective. We will track the frequency of abnormal vital signs, any alarms 
generated by system and time to resolution of the alarms. Data collected will be analyzed post 
hoc using machine learning to evaluate for any predictive pattern for hospitalization and other 
outcomes.