Pilot Study of Tisagenlecleucel, CD19-targeted Chimeric Antigen Receptor (CAR) T Cells, in Patients With Primary Central Nervous System Lymphoma
Phase: PHASE1
Conditions: Primary CNS Lymphoma, Refractory Primary CNS Lymphoma, Relapsed Primary CNS Lymphoma
Sponsor: Matthew J. Frigault, M.D.

DF/HCC BIOMEDICAL PROTOCOL
Version Date: August 8, 2023
NCI Protocol #: N/A
DF/HCC Protocol #: 19-319
TITLE: Pilot study of tisagenlecleucel, CD19-targeted chimeric antigen receptor (CAR) T cells, 
in patients with primary central nervous system lymphoma.
Coordinating Center:
Massachusetts General Hospital (MGH) 
Principal Investigator (PI):
 Matthew J. Frigault, MD
MGH Cancer Center
Other Investigators:
Marcela Maus, MD, PhD
Jorg Dietrich, MD, PhD 
Yi-Bin Chen, MD 
MGH Cancer Center
IND Sponsor:
Matthew J Frigault, MD 
MGH Cancer Center
IND #: 19195
Protocol Type / Version # / Version Date: Version 4/August 8, 2023
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NCI Protocol #: 
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Name of Sponsor/Company:
DF/HCC Investigator Sponsored – Matthew Frigault, MD
Name of Investigational Product:
Tisagenlecleucel (Kymriah)
Name of Active Ingredient:
Tisagenlecleucel (Kymriah)
Title of Study (Protocol Title):
Pilot study of tisagenlecleucel, CD19-targeted chimeric antigen receptor (CAR) T cells, in 
patients with primary central nervous system lymphoma.
Protocol Number 19-319
Study center(s): MGH Cancer Center
Principal Investigator: Matthew J. Frigault, MD
Investigator: Yi-Bin Chen, MD
Studied period (years): 15
Estimated date first patient enrolled: quarter III, 2019 
Estimated date last patient completed: quarter III, 2020
Phase of development: Pilot
Objectives:
Primary:

To assess the safety of tisagenlecleucel in patients with primary CNS diffuse large B-cell 
lymphoma (PCNSL).
Secondary:

To assess the activity of tisagenlecleucel in patients with primary CNS diffuse large B- 
cell lymphoma (PCNSL).
Exploratory:

To assess long-term efficacy of tisagenlecleucel in patients with PCNSL.

Evaluate the expansion, persistence, and phenotype, of tisagenlecleucel T cells following 
infusion.

Evaluate cytokine profiles in the peripheral blood and CSF of subjects after infusion of 
tisagenlecleucel.

To assess impacts of tisagenlecleucel on quality of life and neurocognitive function post 
infusion.

To assess for correlative markers of tumor response/progression.

NCI Protocol #: 
DF/HCC Protocol #: 19-319
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Route and Regimen:
Tisagenlecleucel will be administered intravenously as a one-time rapid infusion following 
lymphodepleting chemotherapy.
Methodology/Study Design: This is a pilot study. A total of 6 subjects with PCNSL will be 
enrolled to this trial.
Bridging Therapy
At time of diagnosis/disease progression patients will be consented and screened for study 
eligibility. Bridging therapy will be allowed at the discretion of the study PI as is clinically 
indicated during CAR-T manufacturing.
Lymphodepletion
Subjects will receive 3 days of lymphodepleting chemotherapy starting Day -5, before the 
infusion of tisagenlecleucel on Day 0. Lymphodepletion can be performed either as an 
outpatient or inpatient per the investigator’s medical judgement.
Lymphodepletion treatment plan
Drug
Dose
Days
Cyclophosphamide    250 mg/m2 IV infusion over 30 min
-5, -4, -3
Fludarabine
25 mg/m2 IV infusion over 30 minutes 
administered immediately after the 
cyclophosphamide (fludarabine dose should be 
reduced based on renal function) a
-5, -4, -3
a Subjects with creatinine clearance 50 to 60 mL/min should have a 20% dose reduction 
of each daily fludarabine dose. Subjects with creatinine clearance of 30 to 49 mL/min 
should have a 40% dose reduction of each daily fludarabine dose.
Target Dose
A single dose level of 0.6 to 6.0 x108 CAR-positive T cells will be utilized based on the FDA 
approved product label.
Cytokine Release Syndrome (CRS), Neurotoxicity and Monitoring
The primary acute toxicity observed to date with CAR T cells have been CRS and neurotoxicity 
and this protocol will follow the recommendations and management for CRS using established 
consensus guidelines.

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For this protocol, CRS is defined as a constellation of symptoms which may include (but are 
not limited to) fever, chills, hypotension, dyspnea, hypoxia, confusion, mental status changes, 
seizures, myalgias, nausea and vomiting, and laboratory abnormalities including elevated AST, 
ALT, bilirubin, CRP, D-dimers, PT/INR, ferritin, urea and/or creatinine. Monitoring for CRS 
should include a physical exam, vital signs, and lab testing per the clinical trial schedule of 
events (SOE), unless otherwise clinically indicated, in which case additional clinical 
assessments or interventions should be performed at the discretion of the investigator or 
treating physician.
Any subject with a fever ≥100.0°F within 28 days of tisagenlecleucel infusion should have a 
work up for CRS. The diagnostic work-up of a CRS includes an evaluation for an infectious 
etiology (e.g., blood cultures, urine culture, chest X-ray, as required). Clinical laboratory tests 
include measurements of serum ferritin, C-reactive protein (CRP), comprehensive chemistries, 
coagulation, and blood counts. In addition, research blood tests for CAR+ T cells and cytokine 
assessments should be performed.
Within the first 28 days following infusion, subjects experiencing a fever ≥ 100.0°F, rapidly 
rising CRP, altered mental status, unstable vital signs, abnormal laboratory findings, or any 
other concerning medical conditions should be admitted for monitoring and further workup, at 
the discretion of the investigator or treating physician.
Treatment of CRS will follow institutional guidelines and may be modified in the future as 
newer standards become available. If admitted, subjects should be afebrile for 24 hours with 
declining inflammatory markers and resolution of any signs or symptoms suggesting of CRS 
and neurologic toxicity prior to discharge.
Neurologic Toxicity
Neurologic toxicity has been reported in anti-CD19 and anti-BCMA CAR T cell clinical trials, 
including confusion, agitation, obtundation, aphasia, seizures and myoclonus. To date, the 
neurologic toxicity has been reversible in a majority of cases however isolated events of fatal 
neurologic toxicity have been seen in CARs containing a CD28 costimulatory domain 2-4. 
Compared to CD28 containing CARs, tisagenlecleucel contains a 4-1BB costimulatory 
domain, which in comparison, has substantially lower neurotoxicity 5. Additionally, no deaths 
from severe neurotoxicity have been reported with any 4-1BB containing CAR supporting its 
use in PCNSL. Initially there was been concern that the presence of CNS disease may 
predispose patients to increased rates, and more severe neurotoxicity, however emerging data 
now suggests that CRS and neurotoxicity may be a product of a larger systemic inflammatory 
response as opposed to isolated CNS disease 6,7.
In the event of neurologic toxicity, it is recommended that investigators thoroughly assess and 
manage subjects for possible etiologies according to institutional guidelines, which may be 
modified in the future as more published guidelines become available. Treatment intervention

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with corticosteroids and/or cyclophosphamide has demonstrated success in other studies.
During the post-infusion period, subjects treated on this protocol will be monitored with routine 
neurocognitive assessments as per the SOE unless otherwise clinically indicated. In the event 
of suspected neurotoxicity, patients will undergo additional workup which may include a 
lumbar puncture, EEG, and/or CT/MRI imaging as clinically indicated and in coordination 
with neuro-oncology as per standard institutional practice. Neurotoxicity will be managed with 
dexamethasone, anakinra, and/or other agents as per the judgement of the clinical investigator. 
All patients will be started on prophylactic levetiracetam prior to CAR-T infusion.
Long-term Follow-up
Subjects will be transitioned to long-term follow-up (LTFU)  following disease progression and/or 
completion of the 24 month active treatment phase to maintain compliance with the requirements for 
subjects receiving genetically modified cells containing lentiviral vectors under IND. Subjects will be 
followed for up to 15 years. Subjects will be asked to participate in a separate 15-year registry study, 
such as CIBMTR. For subjects who consent to the registry study, data for LTFU will be collected 
with the registry study. 
In the event that patients are required to be enrolled to a separate LTFU protocol, as requested by 
FDA/Novartis, patients will be allowed to transition to this separate master protocol in compliance with 
regulatory authorities. 
Safety evaluations, including documentation of AEs and blood assessments, will be evaluated in all 
subjects until they have undetectable vector copy number (VCN) (where the definition of undetectable 
VCN is <0.0003 vector copies per diploid genome) in peripheral blood cells for 2 consecutive 
measurements at least 1 month apart, at least 6 months after drug product infusion. For subjects with 
no disease progression and undetectable VCN, these evaluations will be performed for up to 5 years 
post-CAR T cells infusion, or until disease progression.
Efficacy evaluations, including disease specific response assessments, will only be evaluated in subjects 
without disease progression, or until the time of disease progression/relapse in LTFU phase. Among 
these subjects, efficacy will be evaluated for at least 5 years post-CAR T cells infusion if VCN is 
undetectable, and up to 15 years post-tisagenlecleucel infusion if VCN remains detectable.
Diagnosis and selection criteria: Primary CNS Lymphoma
Inclusion criteria for enrollment/apheresis:
1. Primary CNS Lymphoma in high risk elderly patients
1. New diagnosis of primary CNS lymphoma.
2. Voluntarily sign informed consent form(s)
3. ≥60 years of age at the time of signing informed consent
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2
5. Have failed or are unable to tolerate definitive first-line methotrexate-based 
therapy as defined by:
i. Grade 3+ AKI and/or transaminitis preventing repeat treatment 
exposure and/or,
ii. Failure to achieve a complete response (per IPCG) following two 

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cycles of first line therapy,

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1. Definitive first-line therapies must include high dose 
methotrexate-based therapy but may also include 
temozolomide, high dose cytarabine, pemetrexed, 
lenalidomide, ibrutinib and rituximab.
iii. Whole-brain irradiation, lenalidomide monotherapy and ibrutinib 
monotherapy are considered first line therapy if patient was not 
eligible for methotrexate-based chemotherapy at time of initial 
treatment but now meets study eligibility criteria.
6. Adequate absolute lymphocyte count (ALC > 500 cells/ul) within one week of 
apheresis.
7. Adequate bone marrow function defined by absolute neutrophil count (ANC)
>1000 cells/mm3without growth factor support, and untransfused platelet 
count >50,000 mm3 within 7 days.
8.
Left ventricular ejection fraction >40%
9.
Adequate hepatic function defined by aspartate aminotransferase (AST) and/or 
alanine aminotransferase (ALT) <2.5 × upper limit of normal (ULN) and direct 
bilirubin <1.5 × ULN
10. Adequate renal function defined by creatinine clearance >30 ml/min using the 
Cockcroft-Gault formula
11. International ratio (INR) or partial thromboplastin time (PTT) <1.5 × ULN, unless on 
a stable dose of anticoagulant for a thromboembolic event.
12. The effects of tisagenlecleucel T cells on the developing human fetus are unknown. 
For this reason, women of child-bearing potential and men with partners of 
childbearing potential must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to leukapheresis for at least 1-year post 
tisagenlecleucel infusion and until CAR T cells are no longer present by qPCR on 
two consecutive tests. Should a woman become pregnant or suspect she is pregnant 
while she or her partner is participating in this study, she should inform her treating 
physician immediately. Men with partners of childbearing potential treated or 
enrolled on this protocol must also agree to use adequate contraception prior to 
leukapheresis and until 4 months after tisagenlecleucel T cells administration. 
Additional follow-up requirements are described in 7.4.6.
13. Ability and willingness to adhere to the study visit schedule and all protocol 
requirements
2. Relapsed/Refractory Primary CNS Lymphoma
1. Diagnosis of relapsed/refractory PCNSL having received at least one prior 
line of CNS directed therapy.
2. Voluntarily sign informed consent form(s)
3. ≥18 years of age at the time of signing informed consent
4. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
5. Adequate absolute lymphocyte count (ALC > 500 cells/ul) within one week of 
apheresis.

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6. Adequate bone marrow function defined by absolute neutrophil count (ANC)
>1000 cells/mm3without growth factor support, and untransfused platelet 
count >50,000 mm3.
7. Left ventricular ejection fraction >40%
8. Adequate hepatic function defined by aspartate aminotransferase (AST) 
and/or alanine aminotransferase (ALT) <2.5 × upper limit of normal (ULN) 
and direct bilirubin <1.5 × ULN
9. Adequate renal function defined by creatinine clearance >30 ml/min using the 
Cockcroft-Gault formula
10. International ratio (INR) or partial thromboplastin time (PTT) <1.5 × ULN, unless on 
a stable dose of anticoagulant for a thromboembolic event.
11. The effects of tisagenlecleucel T cells on the developing human fetus are unknown. 
For this reason, women of child-bearing potential and men with partners of 
childbearing potential must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to leukapheresis for at least 1-year post 
tisagenlecleucel infusion and until CAR T cells are no longer present by qPCR on 
two consecutive tests. Should a woman become pregnant or suspect she is pregnant 
while she or her partner is participating in this study, she should inform her treating 
physician immediately. Men with partners of childbearing potential treated or 
enrolled on this protocol must also agree to use adequate contraception prior to 
leukapheresis and until 4 months after tisagenlecleucel T cells administration. 
Additional follow-up requirements are described in 7.4.6.
12. Ability and willingness to adhere to the study visit schedule and all protocol 
requirements
Inclusion Criteria for Lymphodepletion/Cell Infusion:
3. No Active, uncontrolled, systemic bacterial, viral, or fungal infection.
4. Adequate renal function defined by creatinine clearance >30 ml/min using the 
Cockcroft-Gault formula
Exclusion criteria:
1. Prior treatment with an any investigational cellular therapy.
2.
Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine). Systemic steroids 
are allowed up to a dose of dexamethasone 4mg daily or equivalent.
3.
Ongoing systemic immunosuppression for acute and/or chronic GVH as a result of previous 
allogeneic bone marrow transplant.
4.
Significant co-morbid condition or disease which in the judgment of the Principal 
Investigator would place the subject at undue risk or interfere with the study; examples 
include, but are not limited to, cirrhotic liver disease, sepsis, and/or recent significant 
traumatic injury.
5.
Active, uncontrolled, systemic bacterial, viral, or fungal infection.
6.
Active hepatitis B or hepatitis C infection.
7.
HIV infection.

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8.
Subjects with a history of class III or IV congestive heart failure or non- ischemic 
cardiomyopathy.
9.
Subjects with second malignancies if the second malignancy has required therapy in the last 3 
years or is not in complete remission; exceptions to this criterion include successfully treated 
non-metastatic basal cell or squamous cell skin carcinoma, or prostate cancer that does not 
require therapy other than hormonal therapy.
10. Pregnant or lactating women
11. Live virus vaccines within 2 weeks prior to planned start of lymphodepleting 
chemotherapy.
Inclusion criteria for lymphodepletion/cell infusion:
1.
No active, uncontrolled, systemic bacterial, viral, or fungal infection. If febrile, the patient 
must be afebrile for 24 hours or blood cultures negative for 48 hours on appropriate antibiotic 
therapy
2. Oxygen saturation >92% on room air while awake
3. Infusion may be delayed by up to 7 days after completion of LD chemo in the event 
that these issues resolve in that time frame.
Endpoints:
Primary:
Incidence and maximal grade of adverse events (AEs) related to tisagenlecleucel including 
cytokine release syndrome and neurotoxicity per ASBMT 2018 consensus criteria8.
Secondary:
Overall response rate (ORR) at 1, 3, 6 and 12 months after tisagenlecleucel treatment per 
IPCG response criteria.
Exploratory endpoints:

Overall survival and progression-free survival

Detection and quantification of tisagenlecleucel in the peripheral blood and CSF.

Assessment of cytokine/chemokines profiling in peripheral blood and CSF, including IL- 
2, IL-6, IL-10, IFNγ, TNFα etc.

Detection of tumor specific RNA/DNA in initial biopsies, peripheral blood and CSF.

Longitudinal neurocognitive evaluation as per IPCG guidelines.

When available, pre/post tumor samples for gene and immune-profiling.
Duration of Subject Participation:
Subjects will be followed for AEs, clinical status, and laboratory parameters for up to 24 months after 
the infusion of tisagenlecleucel, unless they terminate early due to disease progression, or withdraw 
for a different reason. All patients who receive tisagenlecleucel will be transitioned to the long-term 
follow-up (LTFU) phase of this protocol following disease progression and/or completion of the 24-

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month active treatment phase to maintain compliance with the requirements for subjects receiving 
genetically modified cells containing lentiviral vectors under IND. Subjects will be followed for up to 
15 years. Subjects will be asked to participate in a separate 15-year registry study, such as CIBMTR. 
For subjects who consent to the registry study, data for LTFU will be collected with the registry study. 
Statistical methods:
Analyses will be primarily descriptive due to the preliminary nature of this study.

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SCHEMATIC OF CLINICAL STUDY
TABLE OF CONTENTS
SCHEMATIC OF CLINICAL STUDY ........................................................................................10
1.
OBJECTIVES ....................................................................................................................13
1.1
Study Design..........................................................................................................13
1.2
Primary Objectives and Endpoints.........................................................................13
1.3
Secondary Objectives and Endpoints.....................................................................13
1.4
Exploratory Objectives and Endpoints...................................................................13
2.
BACKGROUND................................................................................................................13
2.1
Primary CNS Lymphoma (PCNSL).......................................................................13
2.2
CD19 and tisagenlecleucel .....................................................................................14
2.3
Rationale for Study ................................................................................................15
2.4
Exploratory Studies Background............................................................................17
3.
PARTICIPANT SELECTION ...........................................................................................17
3.1
Inclusion Criteria....................................................................................................17
3.2
Exclusion Criteria...................................................................................................20
3.3
Inclusion of Women and Minorities.......................................................................20
4.
REGISTRATION PROCEDURES....................................................................................20
4.1
General Guidelines for DF/HCC Institutions.........................................................20
4.1
Registration Process for DF/HCC Institutions .......................................................21
4.2
General Guidelines for Other Investigative Sites...................................................21
4.3
Registration Process for Other Investigative Sites.................................................21

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5.
TREATMENT PLAN ........................................................................................................21
5.1
Study treatment.......................................................................................................21
5.2
Leukapheresis.........................................................................................................22
5.3
Dosing Regimen.....................................................................................................22
5.4
Lymphodepleting chemotherapy............................................................................22
5.5
Tisagenlecleucel infusion.......................................................................................23
5.6
General Concomitant Medication and Supportive Care Guidelines ......................25
5.7
Duration of Active Treatment Phase and Pausing Criteria ....................................26
5.8
Duration of Follow Up and Long-Term Follow-up Phase.....................................27
5.9
Criteria for Taking a Participant Off Study............................................................28
6.
DOSING DELAYS/DOSE MODIFICATIONS ................................................................29
7.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS.............................29
7.1
Expected Toxicities ................................................................................................29
7.2
Adverse Events.......................................................................................................34
7.3
Adverse Event Characteristics................................................................................35
7.4
Procedures for AE and SAE Collection and Reporting..........................................35
7.5
Reporting to the Food and Drug Administration (FDA)........................................39
7.6
Reporting to the NIH Office of Biotechnology Activities (OBA).........................39
7.7
Reporting to the Institutional Biosafety Committee (IBC) ....................................39
7.8
Reporting to Hospital Risk Management ...............................................................40
7.9
Routine Adverse Event Reporting..........................................................................40
8.
PHARMACEUTICAL INFORMATION ..........................................................................40
8.1
Study drug preparation and dispensation ...............................................................40
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES.........................................43
9.1
Biomarker Studies..................................................................................................43
9.2
Laboratory Correlative Studies ..............................................................................43
10.
STUDY CALENDAR........................................................................................................44
10.1 Schedule of Events.....................................................................................................44
~ Wk (-) 6 to 415.......................................................................................................................................................................46
~ Wk (-) 415 .................................................................................................................................................................................46
Serology: IDM Panel (5ml) ..............................................................................................47
10.2
Study Assessments .................................................................................................52
11.
MEASUREMENT OF EFFECT........................................................................................55
12.
DATA REPORTING / REGULATORY REQUIREMENTS............................................55
12.1
Data Reporting .......................................................................................................55
12.2
Data Safety Monitoring..........................................................................................55

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12.3
Collaborative Agreements Language .....................................................................56
13.
STATISTICAL CONSIDERATIONS. ..............................................................................56
13.1
Study Design/Endpoints .........................................................................................56
13.2
Sample Size, Accrual Rate and Study Duration.....................................................57
13.3
Statistical Analysis .................................................................................................57
13.4
Stratification Factors ..............................................................................................58
13.5
Interim Monitoring Plan.........................................................................................58
13.6
Analysis of Primary Endpoints...............................................................................58
13.7
Analysis of Secondary and Exploratory Endpoints................................................58
13.8
Reporting and Exclusions.......................................................................................58
13.9
Good Clinical Practice............................................................................................59
13.10 Ethical Considerations............................................................................................59
13.11 Biosafety Considerations........................................................................................59
13.12 Subject Information and Informed Consent...........................................................60
13.13 Subject Confidentiality...........................................................................................60
13.14 Protocol Compliance..............................................................................................60
13.15 Direct Access to Source Data.................................................................................60
13.16 Case Report Form Completion...............................................................................61
13.17 Record Retention....................................................................................................61
13.18 Liability and Insurance...........................................................................................61
14.
PUBLICATION PLAN AND PRESENTATION OF THE STUDY FINDINGS.............62
APPENDIX A: PERFORMANCE STATUS CRITERIA ............................................................62
Score 10: No impairment ...............................................................................................................67
APPENDIX C: IPCG RESPONSE CLASSIFICATION .................................................................68
References: .....................................................................................................................................69

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1. OBJECTIVES
1.1
Study Design
This is a pilot study. A total of 12 subjects with primary CNS lymphoma be enrolled to this trial. 
This study will enroll two patient populations to include primary CNS lymphoma in high risk 
elderly patients, and relapsed/refractory primary CNS lymphoma following standard therapy. 
Primary CNS lymphoma is differentiated from secondary CNS lymphoma which occurs in the 
setting of systemic disease.
1.2
Primary Objectives and Endpoints
The primary objective of this study is to assess the safety of tisagenlecleucel in patients with 
primary CNS diffuse large B-cell lymphoma (PCNSL). The primary endpoint of this study is the 
incidence of adverse events (AEs) related to tisagenlecleucel including cytokine release syndrome 
and neurotoxicity.
1.3
Secondary Objectives and Endpoints
The secondary objective for this study is to assess the activity of tisagenlecleucel in patients with 
primary CNS diffuse large B-cell lymphoma (PCNSL). The main secondary endpoint for this study 
will be overall response rate (ORR) at 1, 3, 6 and 12 months after tisagenlecleucel treatment per 
IPCG response criteria.
1.4
Exploratory Objectives and Endpoints
The main exploratory objectives are to evaluate overall, and progression-free survival of patients 
treated with tisagenlecleucel with PCNSL. Additional objectives include detection and 
quantification of tisagenlecleucel and tumor specific mutations in biopsies, the peripheral blood 
and CSF, assessment of cytokine/chemokine profiling in peripheral blood and CSF, longitudinal 
neurocognitive evaluation as per IPCG guidelines, and when available, assess pre/post tumor 
samples for gene and immune-profiling.
2. BACKGROUND
2.1
Primary CNS Lymphoma (PCNSL)
Primary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin lymphoma 
(NHL) confined to the brain, leptomeninges, eyes and/or spinal cord 9. The prognosis of PCNSL 
is inferior to that of other NHL subtypes including other organ-specific subtypes of extranodal 
NHL. The 5- and 10-year survival proportions for PCNSL are 29.3% and 21.6%, respectively. 
An estimated 1,425 cases of PCNSL were diagnosed each year in the United States from 2007 to 
2011 and the number of cases is expected to increase further with the aging of the U.S. population

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10. Between 1970 and 2000, the incidence of PCNSL increased, largely due to the human 
immunodeficiency virus (HIV) pandemic. Since 2000, there has been a further increase in the 
incidence of PCNSL, especially in the elderly, with nearly half of all cases of PCNSL occurring 
in patients older than 60 11. Age itself is negatively prognostic as the overall median survival for 
patients over the age of 65 with newly diagnosed PCNSL is only 7 months with standard first line 
therapy only demonstrating a 2-year PFS of 37.3% 12,13. Given these low long-term response rates, 
high-dose chemotherapy followed by autologous stem cell transplantation (HDC-ASCT) has been 
investigated as consolidation following CR1. HDC-ASCT is a promising approach, however 
treatment related toxicity is often significant and limiting in patients over the age of 60 
demonstrating the need for newer, less toxic therapies in this patient population 14.
In the setting of relapsed or refractory PCNSL, optimal therapy has yet to be determined and has 
only been studied in relatively small studies using heterogeneous therapies. Despite high initial 
response rates with methotrexate-based induction therapy, most patients with PCNSL relapse. In 
general, prognosis for patients with relapsed or progressive PCNSL is poor with a median survival 
of approximately 4 months 15. In a study of 256 PCNSL patients with relapsed or refractory PCNSL 
survival was worse in those patients who had refractory PCNSL and in those who relapsed within 
one year versus those who relapsed after one year 16. Although relapses in PCNSL are 
predominantly within the CNS, relapses in extraneural organs are reported in up to 17% of patients. 
Late relapses also appear to occur more commonly in primary CNS DLBCL versus systemic 
DLBCL. In a long-term follow-up study 26% of all relapses were after 5 years and 1.7% were 
after 10 years 17. Treatment for relapsed or refractory PCNSL has not been standardized and 
prognosis is poor for most of this patient population. Response rates to salvage chemotherapy in 
patients with relapsed or refractory PCNSL have not been systematically reported for cytotoxic or 
biological agents. Given the lack of a standard of care and the poor prognosis, older patients with 
poor functional status and patients with relapsed or refractory PCNSL represent an unmet medical 
need.
2.2
CD19 and tisagenlecleucel
CD19 is a 95-kDa glycoprotein present on B Cells from early development until differentiation 
into plasma cells. It is a member of the immunoglobulin superfamily and a component of a B-cell 
surface signal transduction complex that positively regulates signal transduction through the B- 
cell receptor. CD19 is an attractive therapeutic target because it is expressed by most B-cell 
malignancies, including B-cell non-Hodgkin lymphoma. Importantly, the CD19 antigen is not 
expressed on hematopoietic stem cells or any normal tissue apart from those of the B-cell lineage. 
CD19-specific chimeric antigen receptors (CARs) are single chain variable fragments (scFv) fused 
to a transmembrane domain and cytoplasmic signaling domains. Expression of the CD19-directed 
CAR in autologous T cells is achieved by ex vivo transduction using a recombinant retroviral or 
lentiviral vector. The CAR is expressed on the T cell surface and redirects the transfected T cells 
to CD19-expressing lymphoma cells, leading to CD19-specific tumor cell recognition, lysis, 
cytokine secretion and T cell proliferation. In clinical studies, CD19-targeted CARs have 
demonstrated encouraging activity in adult and pediatric subjects with refractory/relapsed B-cell 
acute lymphoblastic leukemia (ALL) and B-cell NHL. Based on these successful data

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tisagenlecleucel was approved for the treatment of patients up to 25 years of age with 
relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL) and adults with relapsed 
refractory diffuse large B-cell lymphoma (DLBCL). In the setting of DLBCL, it is provided in a 
single-dose unit containing 0.6 to 6.0 x 108 chimeric antigen receptor (CAR)-positive T cells and 
infused following a lymphodepleting chemotherapy regimen consisting of cyclophosphamide and 
fludarabine or bendamustine. Tisagenlecleucel was recently FDA approved for relapsed/refractory 
DLBCL based on Phase II data from the JULIET study (NCT02445248) demonstrating an overall 
response rate of (ORR) 50% with median duration of response having not been met 5
2.3
Rationale for Study
2.3.1
Rationale for CAR-T in PCNSL
CAR T cells have shown significant activity in the treatment of certain relapsed/refractory CD19+ 
B-cell malignancies. Of the available US based clinical trials currently open involving CAR T 
cells for lymphoma/leukemia, none specifically address primary CNS lymphoma which has a 5- 
and 10- year survival of 29.3 and 21.6% respectively. Anecdotal experience in secondary CNS 
lymphoma suggest both activity and safety of CAR-T cells for DLBCL 18,19. Despite case reports 
of CD19 directed CAR-T cell activity in the CNS, patients with PCNSL are excluded from the 
recently approved large cell lymphoma labels and ongoing clinical trial efforts. More recent data 
has suggested the viability of CAR-T cells for secondary CNS lymphoma. A 68-year-old female 
with DLBCL and cerebral involvement refractory to several chemotherapy regimens including 
allogeneic stem cell transplant was treated on NCT02631004 with CD19-directed CAR-T cells 
and achieved a CR at 1-month follow-up 18. Similar activity was also seen in children and adults 
with refractory or relapsed ALL with CNS involvement suggesting that tisagenlecleucel may be a 
viable treatment option for patients with CNS based B-cell malignancies such as PCNSL1,19. 
Interestingly in both pediatric and adult patients with ALL, and adults with CLL, prior studies with 
tisagenlecleucel
demonstrated higher levels 
of CAR transgene in the 
CSF than compared to 
peripheral blood at day 28 
and months 3 and 6 when 
expressed per microgram 
of genomic DNA (Figure 
1A). As CSF penetration 
will  be  critical  for  the
treatment of PCNSL, it is important to also note that no central nervous system relapses have been 
observed in patients with pediatric B-ALL1 implying these levels are biologically active and 
sufficient for disease clearance. Despite CNS penetration, quantification of CAR-T cells in the 
CSF did not correlate with neurologic toxicity suggesting the mere presence of T cells within the 
CNS space does not mediate high grade or fatal neurotoxicity (Figure 1B).
Figure 1 – Mueller et al1.

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2.3.2
Rationale for Starting Dose
The starting dose for this trial was determined based on the current FDA approved dose of 0.6 to
6.0 x 108. To date no relationship between tisagenlecleucel dose, maximal in vivo expansion, 
clinical responses has treatment related toxicities20.
2.3.3
Rationale for Lymphodepletion
Clinical data from previous studies suggest that the expansion and activity of adoptively 
transferred T cells can be enhanced by using lymphodepleting agents.
Lymphodepletion acts via several mechanisms to augment T cell activity post transfer, including 
to increase the efficacy of the transferred T cells both by several potential mechanisms: 1) reducing 
tumor burden, 2) making ‘space’ for engraftment of the transferred T cells, 3) triggering increase 
in homeostatic cytokines production and 4) by reducing the number of immunosuppressive 
regulatory T cells. The removal of endogenous T cells and natural killer cells leads to the 
stimulation of IL-15 and IL-7, which increases T cell function and anti-tumor activity 21.
Fludarabine and cyclophosphamide are effective lymphodepleting agents and have been used as a 
lymphodepletive regimen in other CAR T cell therapy trials that have demonstrated persistence 
and activity of transferred cells 22. The effectiveness of the combined use of both fludarabine and 
cyclophosphamide is evidenced in its effect on indoleamine 2,3-dioxygenase (IDO), and inhibitor 
of immune cells and CAR T activity: fludarabine and mafosfamide (a cyclophosphamide analog) 
downregulates IDO expression, and in combination with CD19+ CAR T cells, produced a better 
response than fludarabine or CAR+ T cells alone 23.
A dose of 250 mg/m2 of cyclophosphamide and 25 mg/m2 of fludarabine administered daily for 3 
days has been selected as the regimen for this trial. This regimen has been tolerated by adult large 
cell lymphoma patients in both the JULIET study and commercially following FDA approval24,25.
2.3.4
Rationale for Long-Term Follow-up Phase
The FDA recommends long-term follow-up for subjects treated with gene therapy drug products 
to monitor for delayed adverse events (AEs) due to the hypothetical safety concern that any ex 
vivo-gene modified autologous cell could include insertional mutagenesis. However, the potential 
for insertional mutagenesis and/or tumorigenicity is considered negligible for CAR T cells 26,27, 
based upon their terminal differentiation and the extensive clinical experience to date with long- 
term follow-up of patients receiving other CAR T cell products 28. Ex vivo cultured primary human 
T cells were the first targets for human gene transfer experiments, using gamma-retroviral vectors 
performed at the National Cancer Institute (NCI) beginning in 1989 29. Thus, there exist 25 years 
of data concerning the biological implications of retroviral vector transduction of mature human 
T cells. To date, there is no report of a transformational event associated with a vector insertion in 
mature primary human T cells using either gamma-retroviral or lentiviral vectors. In addition to 
ongoing AE monitoring, patients will also be followed for durability of clinical response.
Therefore, after monitoring of subjects in the parent study has been completed (24 months after 
tisagenlecleucel T cells infusion, or <24 months after tisagenlecleucel T cells due to disease

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progression) subjects will be transitioned to the long-term follow-up phase and followed for up 
to 15 years on protocol or in separate 15-year registry, such as CIBMTR.
2.4
Exploratory Studies Background
Correlative studies will be performed on peripheral blood, bone marrow/tumor biopsies and, if 
available, CSF samples to evaluate PK/PD markers related to safety and/or efficacy. The 
effectiveness of tisagenlecleucel T cells may depend on the expansion and persistence of CAR T 
cells in subjects. Therefore, the expansion and persistence will be monitored by flow cytometry 
and PCR analysis using peripheral blood samples as per standard SOPs. Samples will be collected 
per the protocol Schedule of Events (see 10.1 Schedule of Events). Periodic monitoring of anti- 
inflammatory cytokines secretion will be performed to determine correlation between 
tisagenlecleucel effectiveness and/or toxicity.
Additional testing may be done depending on the clinical condition; for instance, patients with 
symptoms suggestive of cytokine release syndrome or with skin rash or other findings that may 
concern the investigators may have more frequent monitoring to enhance the safety of this trial.
If tumor tissues or bone marrow aspirates become available as part of routine clinical care, a 
sample will be collected for research analysis. Tissue samples (including CSF) will be analyzed 
for the presence of tisagenlecleucel T cells by PCR and/or flow cytometry as well as tumor specific 
RNA/DNA. Additionally, different T cell subsets may have demonstrated different effector 
function and persistence and, therefore, T cell immunophenotyping will be performed by flow 
cytometry. Peripheral blood samples may also be analyzed for cytokine/chemokine levels by 
Luminex 
technology. 
Tumor 
tissue 
will 
be 
analyzed 
for 
CD19 
expression 
by 
immunohistochemistry and/or flow cytometry. In addition, baseline leukapheresis and 
tisagenlecleucel final product will be banked and may be analyzed by immunophenotyping, PCR 
and gene expression profiling.
Neuro-cognitive assessments will be performed per published schedules and in collaboration with 
neuro-oncology as per the SOE (see 10.1 Schedule of Events).
2.5
3. PARTICIPANT SELECTION
3.1
Inclusion Criteria

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Primary CNS Lymphoma in high risk elderly patients
1. New diagnosis of primary CNS lymphoma.
2. Voluntarily sign informed consent form(s)
3. ≥60 years of age at the time of signing informed consent
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2
5. Have failed or are unable to tolerate definitive first-line methotrexate-based 
therapy as defined by:
i. Grade 3+ AKI and/or transaminitis preventing repeat treatment exposure 
and/or,
ii. Failure to achieve a complete response (per IPCG) following two cycles of 
first line therapy,
1. Definitive first-line therapies must include high dose methotrexate- 
based therapy but may also include temozolomide, high dose 
cytarabine, pemetrexed, lenalidomide, ibrutinib and rituximab.
iii. Whole-brain irradiation, lenalidomide monotherapy and ibrutinib 
monotherapy are considered first line therapy if patient was not eligible 
for methotrexate-based chemotherapy at time of initial treatment but now 
meets study eligibility criteria.
6. Adequate absolute lymphocyte count (ALC > 500 cells/ul) within one week of 
apheresis.
7. Adequate bone marrow function defined by absolute neutrophil count (ANC)
>1000 cells/mm3without growth factor support, and untransfused platelet count
>50,000 mm3 within 7 days.
8. Left ventricular ejection fraction >40%
9. Adequate hepatic function defined by aspartate aminotransferase (AST) and/or 
alanine aminotransferase (ALT) <2.5 × upper limit of normal (ULN) and direct 
bilirubin <1.5 × ULN
10. Adequate renal function defined by creatinine clearance >30 ml/min using the 
Cockcroft-Gault formula
11. International ratio (INR) or partial thromboplastin time (PTT) <1.5 × ULN, unless 
on a stable dose of anticoagulant for a thromboembolic event.
12. The effects of tisagenlecleucel T cells on the developing human fetus are 
unknown. For this reason, women of child-bearing potential and men with 
partners of childbearing potential must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to leukapheresis for 
at least 1-year post tisagenlecleucel infusion and until CAR T cells are no longer 
present by qPCR on two consecutive tests. Should a woman become pregnant or 
suspect she is pregnant while she or her partner is participating in this study, she 
should inform her treating physician immediately. Men with partners of 
childbearing potential treated or enrolled on this protocol must also agree to use 

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adequate contraception prior to leukapheresis and until 4 months after 
tisagenlecleucel T cells administration. Additional follow-up requirements are 
described in 7.4.6.

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13. Ability and willingness to adhere to the study visit schedule and all protocol 
requirements
Relapsed/Refractory Primary CNS Lymphoma
1. Diagnosis of relapsed/refractory PCNSL having received at least one prior line of 
CNS directed therapy.
2. Voluntarily sign informed consent form(s)
3. ≥18 years of age at the time of signing informed consent
4. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
5. Adequate absolute lymphocyte count (ALC > 500 cells/ul) within one week of 
apheresis.
6. Adequate bone marrow function defined by absolute neutrophil count (ANC)
>1000 cells/mm3without  growth  factor  support,  untransfused  platelet  count
>50,000 mm3, and untransfused hemoglobin >9 g/dL.
7. Left ventricular ejection fraction >40%
8. Adequate hepatic function defined by aspartate aminotransferase (AST) and/or 
alanine aminotransferase (ALT) <2.5 × upper limit of normal (ULN) and direct 
bilirubin <1.5 × ULN
9. Adequate renal function defined by creatinine clearance >30 ml/min using the 
Cockcroft-Gault formula
10. International ratio (INR) or partial thromboplastin time (PTT) <1.5 × ULN, unless on a 
stable dose of anticoagulant for a thromboembolic event.
11. The effects of tisagenlecleucel T cells on the developing human fetus are unknown. For 
this reason, women of child-bearing potential and men with partners of childbearing 
potential must agree to use adequate contraception (hormonal or barrier method of birth 
control; abstinence) prior to leukapheresis for at least 1-year post tisagenlecleucel infusion 
and until CAR T cells are no longer present by qPCR on two consecutive tests. Should a 
woman become pregnant or suspect she is pregnant while she or her partner is participating 
in this study, she should inform her treating physician immediately. Men with partners of 
childbearing potential treated or enrolled on this protocol must also agree to use adequate 
contraception prior to leukapheresis and until 4 months after tisagenlecleucel T cells 
administration. Additional follow-up requirements are described in 7.4.6.
12. Ability and willingness to adhere to the study visit schedule and all protocol 
requirements
Inclusion Criteria for Lymphodepletion/Cell Infusion:
1. No Active, uncontrolled, systemic bacterial, viral, or fungal infection.
2. Adequate renal function defined by creatinine clearance >30 ml/min using the 
Cockcroft-Gault formula

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3.2
Exclusion Criteria
1. Prior treatment with an any investigational cellular therapy.
2. Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine). Systemic 
steroids are allowed up to a dose of dexamethasone 4mg daily or equivalent.
3. Ongoing systemic immunosuppression for acute and/or chronic GVH as a result of 
previous allogeneic bone marrow transplant.
4. Significant co-morbid condition or disease which in the judgment of the Principal 
Investigator would place the subject at undue risk or interfere with the study; examples 
include, but are not limited to, cirrhotic liver disease, sepsis, and/or recent significant 
traumatic injury.
5. Active, uncontrolled, systemic bacterial, viral, or fungal infection.
6. Active hepatitis B or hepatitis C infection.
7. HIV infection.
8. Subjects with a history of class III or IV congestive heart failure or non- ischemic 
cardiomyopathy.
9. Subjects with second malignancies if the second malignancy has required therapy in 
the last 3 years or is not in complete remission; exceptions to this criterion include 
successfully treated non-metastatic basal cell or squamous cell skin carcinoma, or 
prostate cancer that does not require therapy other than hormonal therapy.
10. Pregnant or lactating women
11. Live virus vaccines within 2 weeks prior to planned start of lymphodepleting 
chemotherapy.
3.3
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.
4. REGISTRATION PROCEDURES
4.1
General Guidelines for DF/HCC Institutions
MGH and DF/HCC Institutions will register eligible participants in the Clinical Trials 
Management System (CTMS) OnCore. Registrations must occur prior to the initiation of any 
protocol-specific therapy or intervention. Any participant not registered to the protocol before 
protocol-specific therapy or intervention begins will be considered ineligible and registration will 
be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
Following registration, participants may begin protocol-specific therapy and/or intervention. 
Issues that would cause treatment delays should be discussed with the Overall Principal

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Investigator (PI). If the subject does not receive protocol therapy following registration, the subject 
must be taken off-study in the CTMS (OnCore) with an appropriate date and reason entered and 
another patient may be screened for enrollment.
4.1
Registration Process for DF/HCC Institutions
DF/HCC policy (REGIST-101) must be followed.
4.2
General Guidelines for Other Investigative Sites
N/A
4.3
Registration Process for Other Investigative Sites
N/A
5. TREATMENT PLAN
5.1
Study treatment
The overall treatment plan for this study (Protocol #), including screening, leukapheresis, cell 
infusion, and follow-up visits described in the Schematic of the Clinical Study.
Tisagenlecleucel is an autologous cellular immunotherapy product that is comprised of CD3+ T 
cells that have undergone ex vivo T cell activation, gene modification, expansion and formulation 
in infusible cryo media. The transgene to be expressed via lentiviral vector transduction is a CAR 
targeted against the CD19 antigen. The CAR contains a murine scFv that targets CD19 linked to a 
trans membrane region derived from the CD8 receptor, which is linked to an intracellular bipartite 
signaling chain of TCR-ζ (or CD3-ζ) and 4-1BB intracellular signaling do mains. The extracellular 
scFv with specificity for CD19 is derived from a mouse monoclonal antibody. T cells which are 
enriched from a patient leukapheresis unit are expanded ex vivo using commercially available 
magnetic beads that are coated with anti-C D3 and anti-CD28 monoclonal antibodies. The cells 
are transduced with the CD19 CAR lentiviral vector which ensures that only peripheral white 
blood cells enriched for lymphocytes are exposed to the vector. The residual non-integrated vector 
is washed away during the process. Tisagenlecleucel cells will be expanded ex vivo for up to 10 
days. At the end of the culture, the tisagenlecleucel cells are depleted of magnetic beads, washed, 
concentrated, and cryopreserved. Results from a release testing procedure are required prior to 
release of the product for infusion.

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5.2
Leukapheresis
Prior Anti-Cancer Treatment
Subjects should not receive any prior systemic therapy or anti-tumor directed therapy within 2 
weeks prior to lymphodepletion. No lymphodepleting agents (e.g., cyclophosphamide, 
bendamustine) should be administered within 2 weeks of leukapheresis, and other therapies (e.g., 
immunomodulatory agents or antibodies) should be discussed with the medical monitor. BTKi and 
IMiDs are allowed prior, during, and following leukapheresis.
Avoidance of Corticosteroids
Therapeutic doses of steroids should ideally be stopped >72 hours prior to leukapheresis and/or 
tisagenlecleucel infusion, however may be continued if deemed medically necessary. If continued, 
they should not exceed 4mg dexamethasone daily or equivalent may be higher at the discretion of 
the Principle Investigator.
Use of Previously Frozen Leukapheresis Product
If patients have previously frozen leukapheresis product that meets incoming product specification 
for subsequent manufacturing, such product may be used following discussion with Novartis.
5.3
Dosing Regimen
A single dose level of 0.6 to 6.0 x108 CAR-positive T cells will be utilized based on the FDA 
approved product label.
5.4
Lymphodepleting chemotherapy
It is anticipated that many patients will have been receiving chemotherapy for relapsed or resistant 
disease. Prior to tisagenlecleucel cell infusion, an additional lymphodepleting chemotherapy cycle 
is planned.
When given, lymphodepleting chemotherapy should be started no more than 2 weeks before 
tisagenlecleucel infusion so that the tisagenlecleucel cells will be given within 14 days following 
completion of the lymphodepleting chemotherapy. Ideally patients will receive tisagenlecleucel 
48-72 hours following completion of lymphodepleting chemotherapy. The purpose of this 
chemotherapy is to induce lymphopenia in order to facilitate engraftment and homeostatic 
expansion of tisagenlecleucel cells.
Lymphodepletion treatment plan
Drug
Dose
Days
Cyclophosphamide
250 mg/m2 IV infusion over 30 min
-5, -4, -3

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Fludarabine
25 mg/m2 IV infusion over 30 minutes administered 
immediately 
after 
the 
cyclophosphamide 
(fludarabine dose should be reduced based on renal 
function) a
-5, -4, -3
a Subjects with creatinine clearance 50 to 60 mL/min should have a 20% dose reduction of each
daily fludarabine dose. Subjects with creatinine clearance of 30 to 49 mL/min should have a 
40% dose reduction of each daily fludarabine dose.
Chemotherapy should be administered per institutional guidelines. On Days -5, -4, and -3, subjects 
should receive pre-hydration with 1000 mL 0.9% sodium chloride IV over 1 to 3 hours.
Anti-emetics will be administered and include the use of ondansetron, oral or IV, or similar 
serotonin inhibitor, on days -5, -4 and -3 prior to chemotherapy but dexamethasone or other 
steroids are not to be administered for nausea. Subjects may receive education and prescriptions 
for anti-emetics such as ondansetron, lorazepam, or prochlorperazine for use when not in clinic.
After the administration of fludarabine on Days -5, -4 and -3, subjects should receive 1000 mL 
0.9% sodium chloride IV over 1 to 2 hours. Diuretics may be used as needed based on clinical 
assessment.
On Days -2 and -1, there are no required clinical interventions except those for supportive care 
including continued anti-emetics for nausea. Subjects should be encouraged to increase fluid intake 
to minimize bladder toxicity or be supplemented with IV hydration at clinical discretion.
Anti-epileptic drugs (e.g. Keppra) should be given to all patients started on D-5 of 
lymphodepletion if not on already. In the event that a patient does not tolerate Keppra, an 
alternative agent will be determined in collaboration with neuro-oncology.
5.5
Tisagenlecleucel infusion
The tisagenlecleucel cell product will be prepared and released by the manufacturing facility to 
the study site approximately 3 to 4 weeks after manufacturing has commenced, provided all 
required safety and quality release criteria have been met. Upon receipt of the cryopreserved 
tisagenlecleucel cell product, an inventory must be performed, and a drug receipt log filled out and 
signed by the person accepting the shipment. The cryopreserved tisagenlecleucel cell product 
should be kept in the vapor phase of liquid nitrogen until tisagenlecleucel infusion. For details on 
the cryopreserved components, and the specific storage and handling requirements of 
tisagenlecleucel, see the commercial product handling manual.
All patients will be staggered by 28 days between infusions to allow for full safety evaluation 
following infusion.
All patients will be required to be on anti-epileptic drugs (eg. Keppra 500mg BID), prior to T cell 
infusion. In the event that a patient does not tolerate Keppra, an alternative agent will be 
determined in collaboration with neuro-oncology.

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Prior to tisagenlecleucel infusion the following criteria must be met:
1. No active, uncontrolled, systemic bacterial, viral, or fungal infection. If febrile, the patient 
must be afebrile for 24 hours or blood cultures negative for 48 hours on appropriate 
antibiotic therapy
2. Oxygen saturation >92% on room air while awake
If patients are taking any of the following medications, their infusion must be delayed until the 
medications have been stopped according to the below:
1. Steroids: Therapeutic doses of steroids should ideally be stopped >72 hours prior to 
tisagenlecleucel infusion, however may be continued if deemed medically necessary. If 
continued, they should not exceed 4mg dexamethasone daily or equivalent.
2. Antiproliferative Therapy:

All antiproliferative therapies must have been stopped ≥ 2 weeks prior to 
tisagenlecleucel infusion (excluding BTKi or IMiDs).

Immunosuppressive therapies: Any drug used for immunosuppression must be 
stopped>4 weeks prior to tisagenlecleucel infusion (e.g. calcineurin inhibitors, 
methotrexate or other chemotherapy drugs, mycophenolate, steroids [see above], 
rapamycin, or immunosuppressive antibodies such as rituximab, anti-TNF, anti-IL6 
or anti-IL6R).

Immune checkpoint blockade (eg. Pembrolizumab, ipilumimab, nivolumab, etc) 
must be held ≥ 4 weeks prior to tisagenlecleucel infusion.
3. CNS disease prophylaxis:

CNS prophylaxis treatment must be stopped >2 week prior to tisagenlecleucel 
infusion (e.g. intrathecal methotrexate).
4. Myeloid growth factors, particularly granulocyte macrophage- colony stimulating factor 
(GM-CSF), are not recommended during the first 3 weeks after tisagenlecleucel infusion 
or until CRS has resolved. Short acting granulocyte colony stimulating factor (G-CSF) 
should be stopped 72 hours prior to tisagenlecleucel infusion and long acting G-CSF should 
be stopped 10 days prior to tisagenlecleucel infusion.
5. Radiotherapy:

Non-CNS site of radiation must be completed > 2 weeks prior to tisagenlecleucel 
infusion

CNS directed radiation must be completed > 2 weeks prior to tisagenlecleucel 
infusion
6. Anti T-cell Antibodies: It is strongly recommended that administration of any T cell lytic 
or toxic antibody (e.g., alemtuzumab) within 8 weeks prior to tisagenlecleucel be 
discontinued since residual lytic levels may destroy the infused tisagenlecleucel cells 
and/or prevent their in vivo expansion.
Infusion may be delayed by up to 7 days after completion of LD chemo in the event that these 
issues resolve in that time frame.

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5.6
General Concomitant Medication and Supportive Care Guidelines
Prior Medication
All medications taken within 30 days prior to the start of screening assessments are to be recorded 
in the Prior and Concomitant Medication CRF.
Concomitant Medications and Therapies
All concomitant medications and therapies (i.e., those that are taken by the subject after signing 
the informed consent form) will be recorded in the Concomitant Medication CRF.
Infection Surveillance and Antibiotic prophylaxis

Subjects with serum IgG level less than 400 mg/dL will receive intravenous immunoglobulin 
replacement as needed to maintain an IgG level above 400 mg/dL if the subject has had one or 
more bacterial infections and is not neutropenic while enrolled on the protocol. An example 
of an intravenous immunoglobulin infusion to be used for this purpose would be Gammunex 
500 mg/kg given as a single dose. Intravenous immunoglobulin infusions should be preceded 
by premedication with diphenhydramine and acetaminophen, and rate of infusion should be 
started at low rates and escalated in a step-wise manner.

Subjects with a history of herpes simplex virus infection should receive herpes simplex virus 
prophylaxis at the discretion of the investigator.

Subjects with a CD4 T cell count of <200 will be maintained on pneumocystis prophylaxis 
with trimethoprim-sulfamethoxazole 1 double-strength tablet every Monday-Wednesday- 
Friday. If subjects cannot tolerate trimethoprim sulfamethoxazole, an alternative pneumocystis 
prophylaxis will be used.

Patients should be started on viral prophylaxis with initiation of lymphodepleting 
chemotherapy if not on already. Patients with prolonged neutropenia (>10 days) or who are 
started on steroids for management of Patients with neutropenia should be started on 
antimicrobial prophylaxis CRS/Neurotox should be started on antifungal prophylaxis.
o
Antimicrobial prophylaxis

Ciprofloxacin 500mg BID or levofloxacin 500mg BID

Acyclovir 400mg BID or famvir 500mg BID

Fluconazole 400mg daily.
Blood product support
Transfusion support of platelets and packed RBCs may be used at the discretion of the treating 
investigator. Leukocyte filters are encouraged for all platelet and packed RBC transfusions.

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Anti-emetics, Anti-diarrheal and Growth Factors
Anti-emetics, anti-diarrheas and growth factor support may be administered at the discretion of 
the investigator and it is suggested utilization follow the American Society of Clinical Oncology 
guidelines. Steroids should NOT be used as an anti-emetic regimen. Myeloid growth factors, 
particularly G-CSF and GM-CSF, are not recommended during the first 3 weeks after 
tisagenlecleucel infusion or until CRS has resolved.
Guidelines for the management of Acute Toxicities occurring following the administration 
of tisagenlecleucel T cells
The management of CRS is discussed in Section 7 and Appendix B. These guidelines are published 
recommendations based on the observation and management of CRS in other active CAR T 
programs.
Anti-Cancer Therapy
After receiving tisagenlecleucel T cells, subjects should not receive any other therapy that is or 
may be active against the identified malignancy including other chemotherapies, biologics, 
radiation therapy or any other investigational agents other than tisagenlecleucel T cells. BTKi and 
IMIDs will be allowed as maintenance therapy before, during and after CAR-T infusion. Localized 
radiation for symptomatic relief may be allowed after discussion with the medical monitor. The 
use of bisphosphonates is acceptable at the discretion of the investigator.
5.7
Duration of Active Treatment Phase and Pausing Criteria 
Subjects will be followed for AEs, clinical status, and laboratory parameters for up to 24 months 
after the infusion of tisagenlecleucel T cells, unless they terminate early due to disease 
progression, or withdraw for a different reason. All subjects who receive tisagenlecleucel T cells 
will be transitioned to the long-term follow-up (LTFU) phase following disease progression 
and/or completion of the 24-month active treatment period to maintain compliance with the 
requirements for subjects receiving genetically modified cells containing lentiviral vectors under 
IND.
Study enrollment will start at time of apheresis however only patients who are infused will be 
analyzed in subsequent data analysis.
Enrollment and treatment with drug product may be temporarily suspended for any of the 
following reasons pending review and recommendations from the DSMC or the Sponsor:

Death that is not related to disease progression within 30 days of the tisagenlecleucel T 
cells infusion*

Determination of unexpected, clinically significant, or unacceptable risk to subjects

2 or more instances of grade 4 CRS (ASTCT 2019), or CTCAE-defined grade 4 organ- 
specific toxicity affecting the kidney, liver, lungs, or heart, and for a single instance of 
grade 4 ICANS, cerebral edema, or other grade 4 CNS events such as hemorrhage.

Any subject develops detectable replication competent lentivirus (RCL) during the study

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
The study may be paused pending notification of the health authorities and the DSMC for 
investigation and possible protocol amendment if any subject experiences any of the 
following events within three weeks of the tisagenlecleucel infusion:
o
Life-threatening (grade 4) toxicity attributable to protocol therapy that is 
unmanageable, unexpected and unrelated to chemotherapy and attributable to 
protocol therapy. High fevers, hypotension, hypoxia, disseminated intravascular 
coagulation, encephalopathy (e.g. lethargy, confusion, aphasia, seizure), ICU 
admission, dialysis and mechanical ventilation are expected. The expected side 
effects can also result in grade 4 liver toxicity, nephrotoxicity and cardiac 
dysfunction.
*All events causing a study pause or stop will be reported to the FDA in an expedited manner.
*Any death that is not due to disease progression within 30 days after receiving tisagenlecleucel T 
cells will result in a hold of further enrollment and treatment with drug product until an 
investigation into the cause of death is performed. If it is determined that the death was not related 
to the drug product, then enrollment/treatment with drug product may restart. If the relationship 
between the drug product and the death is not clear, or it appears that the death may be related to 
study drug, enrollment and treatment with drug product will be held until after discussion with 
the sponsor.
5.8
Duration of Follow Up and Long-Term Follow-up Phase
All subjects who complete the 24 month active treatment period and/or progress, will be transitioned 
to the long-term follow-up (LTFU) phase of this protocol following disease progression and/or 
completion of the 24-month active treatment period to maintain compliance with the requirements 
for subjects receiving genetically modified cells containing lentiviral vectors under IND. Subjects 
will be followed for up to 15 years and will be asked to participate in a separate 15-year registry 
study, such as CIBMTR. For subjects who consent to the registry study, data for LTFU will be 
collected with the registry study. 

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Participants removed from protocol therapy for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event.
5.9
Criteria for Taking a Participant Off Study
Subjects have the right to withdraw from the study at any time for any reason, without prejudice 
to further medical follow up. Should a subject decide to withdraw, all efforts will be made to 
complete and report the observations as thoroughly as possible. The Investigator and Sponsor also 
have the right to withdraw subjects from the study at any time due to protocol noncompliance, 
poor tolerance, or potential safety risks.
It is expected that the most common reason for withdrawal from the study will be disease 
progression. Subjects, however, may withdraw from this study at any time, for any reason. Other 
than progressive disease or death, other possible reasons for study withdrawal include:

Toxicity

Subject preference, including decision to undergo alternative treatment

Physician preference

Adequate cells are not collected during harvests, or failure of transduced cells to be 
dispositioned for clinical use

Any medical condition which, in the opinion of the Investigators, would put the 
subject at risk for treatment or follow-up studies, or

Closure of the study
If a subject is found to have disease progression based on defined response criteria, it is 
anticipated that they will be transitioned to this study’s LTFU phase or followed on a 
registry/study that meets the requirements for subjects receiving genetically modified cells 
containing lentiviral vectors under IND. If a subject is found to have disease progression without 
meeting specific response criteria, the subject may be withdrawn at their own or the 
Investigator’s discretion based on the subject’s best interest, and then be transitioned to this 
study’s LTFU phase or a registry/study that meets the requirements for subjects receiving 
genetically modified cells containing lentiviral vectors under IND.
Subjects withdrawn from active treatment at any time after receiving tisagenlecleucel T cells, 
regardless of the reason will be transitioned to the study’s LTFU phase or appropriate 
registry/study and followed for up to 15 years .
The reason for transitioning to LTFU, and the date the participant was transitioned, must be 
documented in the case report form (CRF). In addition, the study team will ensure Off 
Treatment/Off Study information is updated in OnCore in accordance with DF/HCC policy 
RESIST-101.

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6. DOSING DELAYS/DOSE MODIFICATIONS
In the case of medical or natural emergencies (i.e., holidays, snowstorms, acute infection) 
occurring after initiation of chemotherapy, the infusion of tisagenlecleucel may be delayed up to 
one week at the investigator’s discretion. Subjects who do not initiate chemotherapy within 8 
weeks of enrollment will be withdrawn; however, their tisagenlecleucel product will be stored 
for up to 1 year if they re-enroll at a later date.
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS
7.1
Expected Toxicities
7.1.1 Cytokine Release Syndrome (CRS) and Monitoring
The primary acute toxicity observed to date with CAR T cells has been CRS, and this protocol will 
follow the recommendations and management for CRS using established consensus guidelines. 
CRS and neurotoxicity grading will be performed utilizing the 2018 ASMBT consensus criteria.
For this protocol, CRS is defined as a constellation of symptoms which may include (but are not 
limited to) fever, chills, hypotension, dyspnea, hypoxia, confusion, mental status changes, seizures, 
myalgias, nausea and vomiting, and laboratory abnormalities including elevated AST, ALT, 
bilirubin, CRP, D-dimers, PT/INR, ferritin, urea and/or creatinine (see Table 1).
Monitoring for CRS should include a physical exam, vital signs, and lab testing per the clinical 
trial schedule of events (SOE), unless otherwise clinically indicated, in which case additional 
clinical assessments or interventions should be performed at the discretion of the investigator or 
treating physician.
Any subject with a fever ≥100.0°F within 28 days of tisagenlecleucel T cell infusion should have 
a work up for CRS. The diagnostic work-up of a CRS includes an evaluation for an infectious 
etiology (e.g., blood cultures, urine culture, chest X-ray, as required). Clinical laboratory tests 
include measurements of serum ferritin, C-reactive protein (CRP), comprehensive chemistries, 
coagulation, and blood counts. In addition, research blood tests for CAR+ T cells and cytokine 
assessments should be performed at least every other day in addition to the schedule of events.
Within the first 28 days following infusion, subjects experiencing a fever ≥ 100.0°F, rapidly rising

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CRP, altered mental status, unstable vital signs, abnormal laboratory findings, or any other 
concerning medical conditions should be admitted for monitoring and further workup, at the 
discretion of the investigator or treating physician.
Treatment of CRS will follow protocol guidelines and may be modified in the future as newer 
standards become available.
If admitted, subjects should be afebrile for 24 hours with declining inflammatory markers and 
resolution of any signs or symptoms suggesting of CRS and neurologic toxicity prior to discharge.
Table 1:    Clinical Signs and Symptoms Associated with CRS
Organ System
Symptoms
Constitutional
Fever +/- rigors, malaise fatigue, anorexia, myalgias, arthralgias, nausea, vomiting, 
headache
Skin
Rash
Gastrointestinal
Nausea, vomiting, diarrhea
Respiratory
Tachypnea, hypoxemia
Cardiovascular
Tachycardia, widened pulse pressure, hypotension, increased cardiac output 
(early), potentially diminished cardiac output (late)
Coagulation
Elevated D-Dimer, hypofibrinogenemia +/- bleeding
Renal
Azotemia
Hepatic
Transaminitis, hyperbilirubinemia
Neurologic
Headache, mental status changes, confusion, delirium, word finding difficulty or 
frank aphasia, hallucinations, tremor, dysmetria, altered gait, seizures
Guidelines for the management of toxicities related to tisagenlecleucel T cells infusion have been 
provided in Appendix B. These guidelines are based on available literature for the management of 
CRS and may need to be adjusted based on the individual clinical circumstances of each subject. 
The guidelines are not protocol required therapy as they may need to be adjusted but serve to 
provide a single consistent framework for the evaluation and management of CRS and 
tisagenlecleucel T cells related toxicity to mitigate risk to subject.
7.1.1.1
Temperature Self-Monitoring
Treated subjects must take their temperature every 6 to 8 hours from Day 0 through Day 10 post 
tisagenlecleucel T cells infusion and contact their treating investigator for any fever ≥100.0°F 
through Day 28 post tisagenlecleucel T cells infusion. Subjects should not take any nonsteroidal 
anti-inflammatory drugs (NSAIDs) such as ibuprofen (Motrin, Advil), Naproxen Sodium (Aleve), 
aspirin or acetaminophen (Tylenol) because these can mask fevers. Fevers are a critically 
important sign that requires subjects to report to the treating institution as soon as possible. Fevers 
might possibly be the only warning of life-threatening toxicity that can quickly arise in subjects 
receiving CAR T cells. If subjects are in clinic for a visit when a self-monitoring temperature is to 
be done the temperature may be taken in the clinic by clinic staff. At the discretion of individual 
investigators, subjects may be hospitalized for AE monitoring if preferred.

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Subjects are required to stay within a 30-mile radius of the treating institution; subjects should be 
evaluated and/or admitted to the treating institution due to the institution’s familiarity with the 
treatment protocol and appropriate management of CRS.
7.1.2
Neurologic Toxicity
Neurologic toxicity has been reported in anti-CD19 and anti-BCMA CAR T cell clinical trials, 
including confusion, agitation, obtundation, aphasia, seizures and myoclonus. To date, the 
neurologic toxicity has been reversible in a majority of cases however isolated events of fatal 
neurologic toxicity have been seen in CARs containing a CD28 costimulatory domain 2-4,30.
Because these syndromes are only now being characterized in the setting of CAR T cell therapy, 
in the event of neurologic toxicity it is recommended that investigators thoroughly assess and 
manage subjects for possible etiologies according to institutional guidelines (See Appendix B), 
which may be modified in the future as more published guidelines become available. Treatment 
intervention with corticosteroids and/or cyclophosphamide has demonstrated success in other 
studies 31. Grading and management of neurotoxicity will be performed as per 2018 Lee criteria8.
During the post-infusion period, subjects treated on this protocol will be monitored with routine 
neurocognitive assessments as per the SOE unless otherwise clinically indicated. In the event of 
suspected neurotoxicity, patients will undergo additional workup which may include a lumbar 
puncture, EEG, and/or CT/MRI imaging as clinically indicated and in coordination with neuro- 
oncology as per standard institutional practice. Neurotoxicity will be managed with 
dexamethasone, anakinra, and/or other agents as per the judgement of the clinical investigator.
7.1.3 B cell aplasia and hypo/agammaglobulinemia
Transient or permanent B-cell aplasia with associated hypogammaglobulinemia or 
agammaglobulinemia is an expected-on target effect of tisagenlecleucel therapy in patients with 
sustained tumor response. This occurs since non-malignant B cells express CD19 and is expected 
to resolve if and when the tisagenlecleucel cells are cleared.
Monitor immunoglobulin levels after treatment with tisagenlecleucel. Hypo/agammaglobulinemia 
is typically managed with immunoglobulin replacement therapy dependent upon age specific, 
disease-specific and local institutional guidelines. Use infection precautions including antibiotic 
prophylaxis as appropriate and per local standard of care. In general B cell aplasia and 
hypogammaglobulinemia, of various causes, can be associated with increased rates of infection. 
Such infections are typically sinopulmonary but other sites and types of infections have also been 
reported.
Other 
potential 
complications 
of 
B 
cell 
aplasia 
include 
progressive 
multifocal 
leukoencephalopathy (PML) and reactivation of hepatitis B virus. Neither PML nor reactivation 
of hepatitis B virus have been observed to date with tisagenlecleucel. However, in other therapies 
associated with B cell aplasia these complications have been observed.

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The safety of immunization with live viral vaccines during or following tisagenlecleucel treatment 
has not been studied. Vaccination with live virus vaccines is not recommended for at least 2 weeks 
prior to the start of lymphodepleting chemotherapy, during tisagenlecleucel treatment, and until 
immune recovery following treatment with tisagenlecleucel.
Pregnant women who have received tisagenlecleucel may have hypo/agammaglobulinemia. 
Immunoglobulin levels should be assessed in newborns of mothers treated with tisagenlecleucel.
7.1.4 Hypersensitivity Reactions
Hypersensitivity reactions may occur with an infusion of tisagenlecleucel. Serious hypersensitivity 
reactions, including anaphylaxis, may be due to the dimethyl sulfoxide (DMSO) or dextran 40 in 
tisagenlecleucel. Hypersensitivity prophylaxis should follow institutional standards, however 
steroids should not be given.
7.1.5 Serious Infections
Serious infections, including life-threatening or fatal infections, occurred in patients after 
tisagenlecleucel infusion. In the JULIET study, infections (all Grades) after tisagenlecleucel 
infusion occurred in 59% of the patients, including 35% with Grade 3-4 infections and 2 patients 
(3%) with fatal infections. In the JULIET study, infections (all Grades) after tisagenlecleucel 
infusion occurred in 34% of patients including 20% with grade 3-4 infections and 1 patient (1%) 
with a fatal infection. Prior to tisagenlecleucel infusion, infection prophylaxis should follow local 
guidelines, and after treatment the patient should be monitored for signs and symptoms of infection 
and treated appropriately.
Febrile neutropenia (Grade 3 or 4) was also observed in 37% of patients in JULIET and 17% of 
patients in JULIET. Febrile neutropenia may be concurrent with CRS. In the event of febrile 
neutropenia, the patient should be evaluated for infection and managed with broad-spectrum 
antimicrobials, fluids and other supportive care as medically indicated.
7.1.6 Cytopenias Note Resolved by Day 28
Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and 
tisagenlecleucel infusion. In JULIET, Grade 3 and 4 cytopenias not resolved by day 28 following 
tisagenlecleucel treatment included neutropenia (40%), and thrombocytopenia (27%) among 
responding patients. At 56 days following tisagenlecleucel, 17% and 12% of responding patients 
had Grade 3 and 4 neutropenia or thrombocytopenia, respectively.
In JULIET, Grade 3 and 4 cytopenias not resolved by day 28 following tisagenlecleucel treatment 
included neutropenia (24%), and thrombocytopenia (40%) among responding patients. At data 
cutoff 5% and 16% of responding patients had Grade 3 and 4 neutropenia or thrombocytopenia, 
respectively.

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Prolonged neutropenia has been associated with increased risk of infection. Myeloid growth 
factors, particularly GM-CSF, are not recommended during the first 3 weeks after tisagenlecleucel 
infusion or until CRS has resolved.
7.1.7 Progressive Multifocal Leukoencephalopathy (PML)
PML is rare but well described with antibody therapies causing B cell aplasia32. It is a 
demyelinating disease of the central nervous system, resulting from infection of oligodendrocytes 
and astrocytes, mostly with JC virus. PML classically has a subacute clinical presentation with 
focal neurologic deficits, such as weakness, speech difficulties, unsteady gait and hemiparesis. 
Ophthalmic symptoms are relatively common, occurring as homonymous hemianopia which 
progresses to cortical blindness. Seizure and headache are uncommon. Dementia, manifesting as 
deficits in cognition, personality changes, and memory impairment are also common, but rarely 
occurs in the absence of the focal neurologic deficits of PML. Lesions identified by radiographic 
assessment are generally confined to the white matter with occipitoparietal lobe lesions without 
mass effect being most common.
In general, patients with known B cell aplasia are at increased risk for PML. Patients should be 
monitored at regular intervals for any new or worsening neurological symptoms or signs that may 
be suggestive of PML. The clinician should evaluate the patient to determine if the symptoms are 
indicative of neurological dysfunction, and if so, whether these symptoms are possibly suggestive 
of PML. Consultation with a neurologist should be considered as clinically indicated.
7.1.8 Uncontrolled T Cell Proliferation
Tisagenlecleucel transduced cells could theoretically proliferate without t h e control of normal 
homeostatic mechanisms. In pre-clinical studies and clinical experience to date tisagenlecleucel 
transduced cells have only proliferated in response to physiologic signals or upon exposure to 
CD19 antigen33-35. In the context of tisagenlecleucel therapy, it is expected that the T cells will 
proliferate in response to signals from the CD19 expressing malignant tumor and normal B cells. 
This could be beneficial or harmful depending on the extent of proliferation.
If uncontrolled T cell proliferation occurs (e.g., expansion of T cells in the absence of CD19 
antigen), patients may be treated with corticosteroids such as methylprednisolone (2 mg/kg/d 
i.v.) or chemotherapy, such as high dose cyclophosphamide. Investigators should further discuss 
this with Novartis. Toxicity associated with allogeneic or autologous T cell infusions has been 
managed with a course of pharmacologic immunosuppression. T cell-associated toxicity has 
been reported to respond to systemic corticosteroids36. This theoretical toxicity is distinct from 
the toxicity associated with a CRS that develops during T cell proliferation upon exposure to 
CD19 expressing cells. CRS associated with T cell expansion is managed with anti-cytokine 
therapy, not immunosuppressants.

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7.2
Adverse Events
Monitoring of AEs will be conducted from informed consent through the duration of the study. 
AEs for all subjects, will be recorded in the CRFs from the time informed consent is signed through 
discontinuation or completion of study.
For tisagenlecleucel T cells infused subjects who discontinue from the study for reasons other than 
withdrawal of consent and who do not enroll in the long-term follow up study, all ongoing AEs 
will be monitored until they are completely resolved or determined to be a stable or chronic 
condition, and no new AEs will be recorded unless they are related to study procedure or drug 
product, as determined by the Investigator.
For subjects who discontinue from the study after leukapheresis but before CAR T cells infusion, 
ongoing AEs will be followed up for 30 days post-discontinuation, and no new AEs will be 
recorded unless they are related to study procedure, as determined by the Investigator.
An AE is any untoward medical occurrence associated with the use of a drug in subjects, whether 
or not considered drug related. An AE may include a change in physical signs, symptoms, and/or 
clinically significant laboratory change occurring in any phase of a clinical study. This definition 
includes intercurrent illnesses or injuries, and exacerbation of pre-existing conditions. A pre- 
existing condition is a clinical condition (including a condition being treated) that is diagnosed 
before the subject signs the informed consent form and is documented as part of the subject’s 
medical history.
Serious Adverse Events
An SAE is any AE occurring at any dose and regardless of causality that:

Results in death.

Is immediately life-threatening; i.e. the subject was at immediate risk of death at the time 
of the event. It does not include an adverse event that, had it occurred in a more severe 
form, might have caused death.

Requires in in-patient hospitalization or prolongation of existing in-patient hospitalization. 
Hospitalization admissions occurring during the study period that are for procedures 
planned prior to study entry do not meet these criteria, unless there is a complication 
resulting from procedure that prolongs hospitalization.

Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a subject’s ability to conduct normal life functions.

Is a congenital anomaly/birth defect.

Is an important medical event. An important medical event is an event that may not result 
in death, be life-threatening, or require hospitalization, but may be considered serious 
when, based upon appropriate medical judgment, it may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 of the outcomes listed above

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Medical Events of Special Interest (ESIs)
Grade 3 or greater CRS events and Grade 3 or greater events of neurologic toxicity are medical 
ESIs, and therefore immediately reportable to the Sponsor, even if the events do not meet SAE 
criteria.
All ESIs will be reported to the Sponsor within 24 hours of the Investigator’s first knowledge of 
the event, even if the experience does not appear to be related to tisagenlecleucel T cells infusion. 
All ESIs should be reported to the Sponsor as specified in the SOM.
7.3
Adverse Event Characteristics
Adverse Event Assessment
For all AEs, the Investigator must determine both the severity of the AE and the relationship of 
the AE to tisagenlecleucel T cells treatment.

CTCAE term (AE description) and grade: The descriptions and grading scales found in 
the revise NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
will be utilized for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded 
from the CTEP web site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm

For expedited reporting purposes only:
o
AEs for agents utilized in this study should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information 
which is provided.
o
Other AEs for the protocol that do not require reporting are outlined in the next 
section (Expedited Adverse Event Reporting) and under the sub-heading of 
Protocol-Specific Expedited Adverse Event Exclusions.

Attribution of the AE:
o
Definite – The AE is clearly related to the study treatment.
o
Probable – The AE is likely related to the study treatment.
o
Possible – The AE may be related to the study treatment.
o
Unlikely – The AE is doubtfully related to the study treatment.
o
Unrelated – The AE is clearly NOT related to the study treatment.
7.4
Procedures for AE and SAE Collection and Reporting

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7.4.1
Each subject must be carefully monitored for the development of any AEs. This 
information should be obtained in the form of non-leading questions (e.g., “How are you 
feeling?”) and from signs and symptoms detected during each examination, laboratory 
assessments, observations of study personnel, and spontaneous reports from subjects. AEs 
for all subjects will be recorded in the AE CRF. Any clinically significant laboratory 
abnormality or other clinically significant findings is considered an AE and must be 
recorded on the appropriate pages of the CRF. Refer to the CRF Completion Guidelines 
for additional instructions on documenting AEs.
7.4.2
In the event of an unanticipated problem or life-threatening complications treating 
investigators must immediately notify the Overall PI.
7.4.3
Investigators must report to the Overall PI any adverse event (AE) that occurs after the 
initial dose of study treatment, during treatment, or within 30 days of the last dose of 
treatment on the local institutional SAE form.
7.4.4
Instructions for rapid notification of serious adverse events and Reporting 
responsibility
Each serious adverse event (but not pregnancies) must be reported by the investigator to 
Novartis within 24 hours of learning of its occurrence, even if it is not felt to be treatment- 
related. Follow-up information about a previously reported serious adverse event must also 
be reported to Novartis within 24 hours of receiving it. If the serious adverse event has not 
been previously documented (new occurrence) and it is thought to be related to study drug 
(or therapy), the Medical Safety Expert of the Drug Safety & Epidemiology (DS&E) 
Department may contact the investigator to obtain further information. If warranted, an 
investigator alert may be issued, to inform all investigators involved in any study with the 
same drug (or therapy) that this serious adverse event has been reported.
7.4.5 Reporting Procedures
The investigator must complete the FDA MedWatch 3500a form and Novartis SAE 
coversheet in English, assess the relationship to study treatment and send the initial 
completed MedWatch form and Novartis SAE coversheet by fax 1.877.778.9739 or by 
email:clinicalsafetyop.phuseh@novartis.com, within 24 hours to the local Novartis Drug 
Safety & Epidemiology (DS&E) Department. The investigator must then ensure that the 
form and coversheet are accurately and fully completed with follow-up information and 
fax those to Novartis DS&E Department within 2 to 3 calendar days for deaths or life- 
threatening events and 5 calendar days for other serious adverse events. The original and 
the duplicate copies of the FDA MedWatch form, Novartis SAE coversheet, and the fax 
confirmation sheet must be kept with the case report forms at the study site.
Follow-up information should describe whether the event has resolved or continues, if and 
how it was treated, whether the blind was broken or not, and whether the patient continued 
or discontinued study participation. The MedWatch form, Novartis SAE coversheet, and 
fax confirmation sheet must be retained. Pregnancy follow-up should describe the outcome 
of the pregnancy, including any voluntary or spontaneous termination, details of the birth,

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and the presence or absence of any congenital abnormalities or birth defects. Additionally, 
specific events will trigger direct reporting to Novartis as below:
Interventional Clinical Trial WITH a Novartis IMP
Collection by Sponsor
Transfer to Novartis

All SAEs

All reports of drug exposure 
during pregnancy and 
pregnancy outcome. Pregnancy 
reports and outcomes should 
be collected for the female 
partners of any males who took 
tisagenlecleucel in this study, 
provided consent has been 
obtained from the female 
partner

All non-serious AEs

All reports of misuse and abuse 
of tisagenlecleucel, other 
medication errors and uses 
outside of what is foreseen in 
the protocol (irrespective if a 
clinical event has occurred)
Within 24 hours of awareness:

All neurotoxicity AEs with severity
≥Grade 4

Death (including fatal SAEs or fatal 
disease progression) irrespective of 
causality, if it occurs within 30 days 
post tisagenlecleucel infusion. After 
30 days, Death (including fatal SAEs 
or fatal disease progression) should 
be reported as SAE only, if there is 
at least a possible causal 
relationship to tisagenlecleucel
Within 15 days of awareness:

All collected SAEs in subjects 
exposed to tisagenlecleucel

All collected pregnancy reports and 
outcomes in subjects exposed to 
tisagenlecleucel. Pregnancy reports 
and outcomes should be collected 
for the female partners of any males 
who took tisagenlecleucel in this 
study, provided consent has been 
obtained from the female partner

All collected reports of abuse and 
misuse of tisagenlecleucel, other 
medication errors and uses outside 
of what is foreseen in the protocol 
(irrespective if a clinical event has 
occurred)
In periodic 1-monthly batches

All non-serious AEs
7.4.6 Pregnancies
Any pregnancy that occurs during study participation should be reported. To ensure patient 
safety each pregnancy must also be reported to Novartis within 24 hours of learning of its 
occurrence. The pregnancy should be followed up to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or absence of any 
birth defects, congenital abnormalities or maternal and newborn complications.

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Women of child bearing potential (WOCBP) and sexually active males must be informed 
that receiving the study treatment may pose unknown risks to the fetus if pregnancy were 
to occur during the study, and agree that in order to participate in the study they must 
adhere to the contraception requirements outlined in the exclusion criteria. If there is any 
question that the subject will not reliably comply, they should not be entered or continue 
in the study. WOCBP and sexually active males who receive tisagenlecleucel must 
adhere to contraception requirements for at least 12 months following tisagenlecleucel 
infusion and until CAR T cells are no longer present by qPCR on two consecutive tests.
Women of child-bearing potential must have a negative urine pregnancy test performed 
within 24 hours before leukapheresis, lymphodepletion and prior to tisagenlecleucel 
infusion. Additional pregnancy testing might be performed if requested by local 
requirements.

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7.4.5
DF/HCC Adverse Event Reporting Guidelines
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy.
7.5
Reporting to the Food and Drug Administration (FDA)
The Sponsor of this study will be responsible for all communications with the FDA. The Sponsor 
will report to the FDA, any serious adverse event that meets the FDA’s criteria for expedited 
reporting following the reporting requirements and timelines set by the FDA.
7.6
Reporting to the NIH Office of Biotechnology Activities (OBA)
The Study sponsor will be responsible for all communications with the OBA. The Sponsor will 
report to the OBA, any serious adverse event that meets the OBA’s criteria for expedited reporting 
following the reporting requirements and timelines set by the OBA.
If the dosing site is a recipient of funding from the National Institutes of Health (NIH) for 
recombinant research, the dosing site will ensure that an Institutional Biosafety Committee (IBC) 
is in place that is composed of at least 5 appropriately-qualified members. The IBC will ensure 
that the site conforms to the requirements set forth in the Section IV-B-2 of the NIH Guidelines 
for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, promulgated by the 
NIH/Office of Biotechnology Activities (NIH/OBA). The Investigator will be responsible for 
petitioning the IBC and obtaining approval prior to enrolling any subject in the study. The 
Investigator will also be required to obtain and follow all biohazard safety guidelines promulgated 
by the IBC, and to report all findings as required to the IBC and to NIH/OBA.
This protocol and any accompanying material provided to the subject (such as subject information 
sheets, Informed Consent Form, or descriptions of the study used to obtain informed consent) will 
be submitted by the Sponsor and/or the site to the legally constituted and chartered Institutional 
Biosafety Committee (IBC). The clinical site will be approved by the IBC in accordance with local 
procedures and country specific regulatory requirements. Documentation of IBC approval must be 
in place prior to product shipment to the site. At the discretion of the specific IBC and within 
federal requirements, IBC oversight of individual sites is suggested to be terminated provided (1) 
all subjects at that site have completed dosing by at least 90 days, and (2) all investigational 
materials have been fully accounted for and either returned to the Sponsor, destroyed on site, or 
shipped to a duly licensed destruction facility.
7.7
Reporting to the Institutional Biosafety Committee (IBC)
Participating investigators will register and report on research protocols involving biohazards (i.e., 
recombinant DNA or infectious agents) according to the reporting requirements set by their 
respective IBC.

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The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki. The IRB/IEC and other appropriate institutional regulatory bodies will review all 
appropriate study documentation in order to safeguard the rights, safety, and well-being of the 
subjects. The study will only be conducted at sites where IRB/IEC and other appropriate 
institutional regulatory body approvals have been obtained. The protocols, informed consents, 
written information given to the subjects, safety updates, annual progress reports, and any revisions 
to these documents will be provided to the IRB/IEC and other appropriate institutional regulatory 
bodies by the Investigator.
7.8
Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant safety 
reports, sentinel events or unanticipated problems that require reporting per institutional policy.
7.9
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms. AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions.
8. PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1.
8.1
Study drug preparation and dispensation
Upon release from the manufacturing facility, the cryopreserved tisagenlecleucel cell product is 
shipped to the investigator. Upon receipt of the cryopreserved tisagenlecleucel cell product, and 
inventory must be performed, and a drug receipt log filled out and signed by the person accepting 
the shipment. It is important that the designated study staff counts and verifies that the shipment 
contains all the items noted in the shipment inventory. Any damaged or unusable tisagenlecleucel 
cell product in a given shipment will be documented in the study files. The investigator must notify 
the sponsor of any damaged or unusable tisagenlecleucel cell product that was supplied to the 
investigator’s site.
After logging the tisagenlecleucel cells, they will be stored safely and properly (Section 8.1.2). 
Please note the time between product thawing and completion of the infusion should not exceed 
30 minutes to maintain maximum product viability. Therefore, to ensure this timeframe, the 
product should be thawed in close proximity to the patient’s bedside. Additionally, after cell 
thawing the tisagenlecleucel cell product should NOT be washed prior to infusion, all contents will 
be infused. If the tisagenlecleucel cell product appears to have a damaged or leaking bag, or 
otherwise appears to be compromised, it should not be infused, and should be returned to the

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manufacturing facility. This issue should be documented properly, and the manufacturing facility 
should be notified on handling of the product.
In rare instances a patient’s incoming apheresis or outgoaing product may not meet commercial 
release testing criteria. These cases will be discussed with Novartis on a case by case basis prior 
to proceeding forward with patient re-collection or infusion on commercially non-conforming 
product.
8.1.1
Study drug packaging and labeling
As tisagenlecleucel is an FDA approved product, packaging and labeling will follow commercial 
formatting and documentation.
8.1.2
Drug supply and storage
Tisagenlecleucel cell product must be received, handled and stored safely and properly by 
designated personnel at the site. Upon receipt, the tisagenlecleucel cell product should be stored 
according to the instructions specified on the product labels. Personnel receiving, handling and 
storing tisagenlecleucel cell product must complete REMS or RMP training accordingly.
8.1.3
Study drug disposal and destruction
Tisagenlecleucel cell product may require disposal for a variety of reasons, including but not 
limited to: 1) Mislabeled product; 2) Condition of patient prohibits infusion, and/or 3) Patient 
refuses infusion. Any unused product and all used infusion supplies, including the infusion bag 
and tubing, must be disposed of according to local institutional standard operating procedures.
In the event that tisagenlecleucel study cell product manufactured by Novartis was not shipped to 
the site for infusion, it will be managed per manufacturing facility process. The tisagenlecleucel 
product will either be utilized for research purposes or it will be destroyed.
8.1.4
Administration
The treating physician should evaluate the patient just prior to infusion to ensure that 
tisagenlecleucel infusion is clinically appropriate. Prior to tisagenlecleucel preparation, the patient 
identity must be matched with the patient identifiers on the tisagenlecleucel infusion bag. 
Tisagenlecleucel is for autologous use only. Employ universal precautions to avoid potential 
transmission of infectious diseases when handling the product.
The infusion bag must be inspected for any breaks or cracks prior to thawing. If the bag is 
compromised, the contents should not be infused and Novartis should be called at 1-844- 
4KYMRIAH.

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The timing of tisagenlecleucel thaw and infusion should be coordinated. If more than one bag is 
being infused for the treatment dose, wait to thaw/infuse the bag until it is determined that the 
previous bag is safely administered. The infusion time should be confirmed in advance, and the 
start time for thaw adjusted so that tisagenlecleucel is available for infusion when the recipient is 
ready.
The infusion bag must be placed inside a second, sterile bag in case of a leak and to protect ports 
from contamination. Tisagenlecleucel should be thawed at 37°C using either a water bath or dry 
thaw method until there is no visible ice in the infusion bag. The bag will be removed from thawing 
device immediately; and the product bag should not be stored at 37°C. Once thawed and at room 
temperature (20°C to 25°C), it should be infused within 30 minutes.
Tisagenlecleucel should not be washed, spun down, and/or re-suspended in new media prior to 
infusion. The contents of the thawed infusion bag should be inspected for any visible cell clumps. 
If visible cell clumps remain, the contents of the bag can be gently mixed. Small clumps of cellular 
material should disperse with gentle manual mixing. Tisagenlecleucel should NOT be infused if 
clumps are not dispersed, the infusion bag is damaged or leaking, or otherwise appears to be 
compromised. Call Novartis at 1-844-4KYMRIAH.
Tisagenlecleucel infusion should be performed using precautions for immunosuppressed patients. 
Protective isolation should follow institutional standards and policies. Emergency medical 
equipment should be available during the infusion in case the patient has a significant reaction to 
the infusion such as anaphylaxis or severe hypotension.
The site must confirm that two doses of tocilizumab are on site and available for administration 
prior to tisagenlecleucel infusion.
The tisagenlecleucel dose will be administered via intravenous (IV) infusion through a latex free
i.v. tubing WITHOUT a leukocyte filter (approximately 10 – 20 mL per minute adjusted as 
appropriate for smaller children and smaller volumes). The volume in the infusion bag ranges from 
10-50mL. All contents of the infusion bag should be infused. If more than one bag is being infused 
for the treatment dose, wait to thaw/infuse the bag until it is determined that the previous bag is 
safely administered. It is recommended that the infusion should be completed within 30 minutes 
of thawing the cryopreserved product. The tubing should be primed with saline and the setup 
should also contain a Y-arm with an attached supplemental saline bag to be used after the initial 
infusion is completed. This will allow any remaining product left behind within the bag and tubing 
to be recovered and infused while maintaining a closed tubing system. Cells from all bag(s) should 
be infused to complete a single dose.
Vital signs (temperature, respiration rate, pulse, pulse oximetry, and blood pressure) will be taken 
prior to, during and immediately after the infusion and then approximately every 15 minutes for 
one hour and repeated at 2 hours. If vital signs are unsatisfactory and unstable, continue to monitor 
the patient until vital sign stabilization.

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Tisagenlecleucel contains human cells genetically modified with a lentivirus, all used infusion 
supplies, including the infusion bag and tubing, must be handled and disposed of according to local 
institutional biosafety standard operating procedures.
Following tisagenlecleucel infusion: Should emergency treatment be required in the event of life- 
threatening hypersensitivity or other acute infusion-related reaction, supportive therapy such as 
oxygen, bronchodilators, epinephrine, antihistamines, and corticosteroids should be given 
according to local institutional guidelines. Patients should be evaluated and carefully monitored 
until complete resolution of signs and symptoms. Patient or patient’s caregiver should monitor the 
patient’s temperature four times daily for the first 14 days post tisagenlecleucel infusion. The 
patient or patient’s caregiver should be instructed to call the treating physician promptly with any 
signs and symptoms of CRS or neurologic toxicities for possible hospitalization.
Patients and their caregivers should plan to stay within 30 miles of the treatment site for at least 4 
weeks after tisagenlecleucel infusion, unless otherwise indicated by the treating physician.
While patients are admitted, and at each study visit, ICE/ICANS assessments will be performed.
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
9.1
Biomarker Studies
N/A
9.2
Laboratory Correlative Studies
The persistence, biodistribution and immunologic effects of tisagenlecleucel T cells will be 
evaluated using peripheral blood samples. For molecular studies (Q-PCR), immune phenotyping 
and functional assays, peripheral blood will be collected in Lavender top (K2EDTA) tubes. For 
cytokine analyses peripheral blood samples will be collected in red top (no additive) tubes. CSF 
will be stored and clear vials and processed as soon as possible.
Samples will be collected per the protocol Schedule of Events (see Section 10.1 Schedule of 
Events).
If tumor tissues, bone marrow aspirates, and/or CSF become available as part of routine clinical 
care, a sample will be collected for research analysis. Tissue samples will be analyzed for the 
presence of tisagenlecleucel T cells by PCR and/or flow cytometry. Peripheral blood samples may 
also be analyzed for cytokine levels by Luminex technology. Tumor tissue will be analyzed for 
CD19 expression by immunohistochemistry and/or flow cytometry.
All research samples will be delivered, processed, and frozen as per SOP to the Maus/Immune 
monitoring Laboratory at the MGH Cancer Center for storage and bulk analyses. Documentation

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of sample receipt, processing, and storage and primary data from the research analyses will be 
collected and stored in the processing lab personnel. All research analyses will be performed based 
on assay-specific SOP using qualified and, if possible, validated assays.
10. STUDY CALENDAR
10.1 Schedule of Events
Evaluations and procedures identified in the Schedule of Events may be performed at unscheduled 
visits, as clinically indicated, at the Investigator’s discretion in consultation with the Sponsor.
Study Procedures
The study consists of 1) a screening phase, 2) followed by an intervention/treatment phase 
consisting of infusion of tisagenlecleucel T cells and 3) follow up. Schedule of evaluations and 
infusion is included in Section 10.1.
Subject Screening and Registration
Subjects willing to participate in the study will provide written informed consent according to 
Good Clinical Practice (GCP). Written informed consent must be obtained before the conduct of 
any Screening tests.
Upon signing the informed consent and a manufacturing slot is confirmed, the subject will be 
registered and assigned a unique subject number. Once a subject number has been assigned, it 
cannot be reused, and the number stays with the subject even if the subject is subsequently 
determined to be ineligible for the study.
Leukapheresis must occur ≤28 days after the start of assessments in Screening. Thus, if 
re-screening is necessary:
Informed Consent and Demographics need not be repeated
Only new Medical History and Disease History since previous screening will be collected 
All other assessments in Table 2 for enrollment must be repeated.
The subject will maintain their originally assigned unique subject number.
Re-screening of assessments during Baseline may be performed at the discretion of the Investigator 
and Sponsor.
Pre-leukapheresis evaluation
The following tests must be performed within four weeks (except where noted) prior to 
leukapheresis:

Medical history including prior treatment, current medications, and drug allergies.

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
Physical exam including vital signs, pulse oximetry, height, weight, and ECOG 
performance status

Laboratory studies including CBC with differential, coagulation factors (INR/aPTT, d- 
dimer and fibrinogen), comprehensive metabolic panel (includes sodium, potassium, 
bicarbonate, BUN, creatinine, glucose, total bilirubin, alkaline phosphatase, AST, ALT, 
albumin, calcium, magnesium, phosphorus, LDH, uric acid) and inflammatory markers 
(CRP and ferritin)

Serum pregnancy test (females of childbearing potential)

Baseline IDM Panel – (HIV/HCV/HBV serology, and EBV/CMV serology)

12 lead electrocardiogram (EKG)

Baseline echocardiogram or MUGA scan (to be completed within 4 weeks of 
leukapheresis).
Additional information regarding subject eligibility for this trial is listed in Section 3.
Screen Failures
Subjects are screen failures if:
they cannot finish assessments for Screening or are ineligible based on those assessments, 
they meet eligibility criteria during Screening but do not undergo leukapheresis
Data collected on Screen Failure subjects will only include: 
Demography
Eligibility
Note: Subjects who discontinue from the study after leukapheresis but prior to infusion with 
tisagenlecleucel T cells will be considered withdrawals. All study data collected through the point 
of withdrawal will be captured for subjects who discontinue early.
Long-Term Follow-up Phase
Patients will be transitioned to the long-term follow-up (LTFU) phase of this protocol following 
disease progression and/or completion of the 24-month active treatment phase to maintain 
compliance with the requirements for subjects receiving genetically modified cells containing 
lentiviral vectors under IND. Subjects will be followed for up to 15 years and will be asked to 
participate in a separate 15-year registry study, such as CIBMTR. For subjects who consent to the 
registry study, data for LTFU will be collected with the registry study. 

Endpoint/LP
Table 2:
Schedule of Study Procedures and Assessments – Active Treatment Phase
~ Wk (-) 6 to 415
~ Wk (-) 415
~Week (-) 2-121
~ Day (-) 5-317
~ Day (-) 1*
D 0*
D+1*
D+2$ 
(+1d)
D+4$ 
(+ 2d)
D+7 
(+/- 2d)
D+10 
(+/-2d)
D+14 
(+/-3d)
D+21 
(+/- 3d)
D+28 
(+/-3d)
Monthly to 6 mo. 
(+/-2 wk)
Quarterly to Year 
25
(+/- 1 mo)
Assessment
Screening
Apheresis
Re-Staging
LD Chemo- 
therapy
Pre –Infusion
Infusion
Post Infusion
Follow-up
Follow-up
Follow-up
Follow-up
Follow-up
Follow-up
Follow up
Response
at 1, 3, 6 and
12 months 
and Follow - 
up
Clinical Assessments
Inform Consent
X
Vital signs
X
X
X
X
X1
X
X
X
X
X
X
X
X
X
X
Recent Med. History, Physical 
Examination
X
X
X
X11
X
X
X
X
X
X
X
X
X
X
ECOG
X
X
X
Concomitant Medications
X
X
X
X11
X
X
X
X
X
X
X
X
X
X
Venous Access Assessment
X
Clinical Disease Staging/ Disease 
monitoring (PET/CT/MRI)/Tumor 
response assessments4
X
X
X
X
X
Lumbar Puncture3 (cytology/flow)
X
X
X
X
X
X
ECHO/MUGA
X13
EKG
X
Patient monitoring16
X
X
X
X
X
X
X
X
X
X
X
AEs/SAEs
X11
X
X
X
X
X
X
X
X
X
X
ICE/ICANS assessment
X
X
X
X
X
X
X
X
X
X
X
Neurocognitive Assessments18
X
X18
X
X18
Clinical Labs Testing
Blood for Serum pregnancy test2 
(1 ml SST)
X
Urine pregnancy test2
X
X
X
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Page 46

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Endpoint/LP
~ Wk (-) 6 to 415
~ Wk (-) 415
~Week (-) 2-121
~ Day (-) 5-317
~ Day (-) 1*
D 0*
D+1*
D+2$ 
(+1d)
D+4$ 
(+ 2d)
D+7 
(+/- 2d)
D+10 
(+/-2d)
D+14 
(+/-3d)
D+21 
(+/- 3d)
D+28 
(+/-3d)
Monthly to 6 mo. 
(+/-2 wk)
Quarterly to Year 
25
(+/- 1 mo)
Assessment
Screening
Apheresis
Re-Staging
LD Chemo- 
therapy
Pre –Infusion
Infusion
Post Infusion
Follow-up
Follow-up
Follow-up
Follow-up
Follow-up
Follow-up
Follow up
Response
at 1, 3, 6 and
12 months 
and Follow - 
up
Blood CBC, differential 
(5 ml EDTA)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood Chemistry/Metabolic Panel12 
(3 ml SST)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood for CD3/CD4/CD8/CD19 FLOW 
(4ml lav)
X
X
X
X
X
X6
X6
Serology: IDM Panel (5ml)
X
Coagulation Factors (PT, PTT, INR, 
fibrinogen, D-dimer)
X
X
X
X
X
X
X
X
X
X
X
X
X
Inflammatory markers 
(CRP, Ferritin)
X
X
X
X
X
X
X
X
X
X
X
X
X
Intervention
Leukapheresis
X8
Lymphodepletion
X
Tisagenlecleucel infusion
X
Translational lab testing peripheral blood mononuclear cells 25 cc (Lavender)10, 14
DNA/VCN (qPCR)9
X
X
X
X
X
X
X
X
X
X
X
X
RCL testing9
X
X
X20
X20
PBMC (functional assays, 
Tisagenlecleucel T cells 
immunophenotyping, etc)
X22
X
X14
X
X
X
X
X
X
X
X
X
X
Translational lab testing peripheral blood serum 5 cc (Red)7, 10
Multiplex cytokines
X22
X
X7
X
X
X
X
X
X
X
X
X
X
Translational lab testing CSF 4 cc black top10

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Endpoint/LP
~ Wk (-) 6 to 415
~ Wk (-) 415
~Week (-) 2-121
~ Day (-) 5-317
~ Day (-) 1*
D 0*
D+1*
D+2$ 
(+1d)
D+4$ 
(+ 2d)
D+7 
(+/- 2d)
D+10 
(+/-2d)
D+14 
(+/-3d)
D+21 
(+/- 3d)
D+28 
(+/-3d)
Monthly to 6 mo. 
(+/-2 wk)
Quarterly to Year 
25
(+/- 1 mo)
Assessment
Screening
Apheresis
Re-Staging
LD Chemo- 
therapy
Pre –Infusion
Infusion
Post Infusion
Follow-up
Follow-up
Follow-up
Follow-up
Follow-up
Follow-up
Follow up
Response
at 1, 3, 6 and
12 months 
and Follow - 
up
Multiplex cytokines
X
X
X
X
X
Immune cell subset immunophenotyping3, 19
X
X
X
X
X
* The Clinical Investigator will review all re-and post-infusion lab results to determine that it is appropriate to proceed with the infusion. Any abnormal results and that is a change from the previous 
value will be reviewed by the PI prior to the infusion. Any changes in lab results from the prior value will be reviewed by investigators.
$ Translational lab testing that falls on weekends, and out of study window, will not be collected or considered a deviation.
1.
Vital signs should be taken prior to CAR T cells infusion, once during the infusion, once at the end of infusion, and then approximately every 15 minutes for one hour and repeated at 2 hours.
2.
Pregnancy testing – for females of childbearing potential only (not required if documentation of menopause/hysterectomy ie. surgical, chemo induced, physiologic, or etc.)
3.
May deferred if not clinically safe.
4.
Baseline imaging for tumor response assessments will be done within 4 weeks of infusion. Imaging for tumor response assessments post Tisagenlecleucel T cell infusion will be done after 
months 1, 3, 6 and 12. Tumor response assessment criteria is described in Section 11. MRI studies should be performed with perfusion imaging if possible.
5.
After completion of the main study protocol (up to 2 years), subjects will be enrolled into a designated long term follow up protocol for up to 15 years post Tisagenlecleucel T cell infusion. 
Subjects will be monitored for delayed adverse events associated with CAR T lentiviral gene therapy.
6.
Blood for CD3/CD4/CD8/CD19 will be taken at 3, 6, 12, 18 at 24 months.
7.
Blood for research testing (5 cc red top) will be taken prior infusion and between 20-120 minutes post-infusion.
8.
12-15 liter apheresis product will be delivered to Novartis.
9.
These samples will be banked for later analysis.
10.
Samples should be delivered to the testing labs as soon as possible. If required to keep samples after hours, please keep red top tubes upright, lavender top tubes should be kept at room 
temperature on rotating platforms. CSF should be kept at room temp and processed as soon as possible. In the event of unexpected events, research samples collection may be done as 
necessary. This should be done at the PI’s discretion.
11.
Medical history, physical exams and concomitant medications information need to be collected prior to T cells infusion on Day 0. Any adverse events will be collected from the starting the 
day of infusion of the Tisagenlecleucel T cell.
12.
Laboratory studies using comprehensive metabolic panel (includes sodium, potassium, bicarbonate, BUN, creatinine, glucose, total bilirubin, direct bilirubin, alkaline phosphatase, AST, 
ALT, albumin, calcium, magnesium, phosphorus, LDH, uric acid, CPK). (See Section 10.2 for details)
13.
Baseline echocardiogram or MUGA scan (to be completed within 6 weeks of planned CAR T cell infusion).
14.
PBMC samples are only required before CAR-T infusion, multiplex cytokines should be drawn before CAR-T infusion and 20-120 min after infusion.
15.
The intent of these windows is to ensure subjects are infused within 6 weeks of enrollment. If the subject completes these visits within a shorter timeframe than 6 weeks, this will not be 
considered a protocol violation/deviation.
16.
Patient monitoring will occur from Day 0 through Day 7 post tisagenlecleucel infusion excluding weekends and holidays, and should include a physical exam and vital signs every 8 hours

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while admitted unless otherwise clinically indicated. After discharge subjects must take temperature through D +28, and contact their treating investigator for any fever ≥100.0° F which will 
require hospitalization until the subject has been afebrile for 18 hours; Subjects must remain within 30 miles of site.
17.
Only vital signs are required on D-4, and D-3 of lymphodepletion. Medical history, physical exam, ECOG, and concomitant medications are required D-5 only.
18.
Neurocognitive assessments will follow IPCG guidelines and will be obtained D0, day 28 and month 6.
19.
FLOW phenotyping and RNA profiling will be performed when samples allow.
20.
RCL testing to be performed at baseline, 1 month, 3, 6, 9, 12 months, bi-annually thereafter up until year 2 and transition to LTFU phase.
21.
Re-staging assessments may extend beyond the defined 1-2 week window, including up to the LDC window as clinically indicated.
22.
PBMC and multiplex cytokines only need to be drawn on D-5 prior to initiation of lymphodepleting chemotherapy.

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10.2
Study Assessments
Tumor cells CD19 Expression and Tumor Burden 
Demographics and Medical History
Demographic data includes gender, age, race, and ethnicity.
A complete medical history should include all relevant prior and current medical history, and 
should also include anti-cancer therapies, including start and end dates of prior therapies, best 
response, date of progression or relapse, and reason for progression.
Physical Examination and Vital Signs
A physical examination includes general appearance; head eyes, ears, nose, and throat; 
cardiovascular; dermatologic, abdominal; genitourinary; lymph nodes; hepatic; musculoskeletal; 
respiratory; and neurological, and weight. Height is also to be measured at Screening.
Vital signs include systolic/diastolic blood pressure, pulse, respiration rate, and temperature. On 
the day of infusion, vital signs should be taken prior to Tisagenlecleucel T cells infusion, once 
during the infusion, once at the end of infusion, and then hourly for 4 hours.
Echocardiogram will also be performed.
Performance Status
Eastern Cooperative Oncology Group (ECOG) performance status assessment is to be assessed 
according to the Schedule of Events.
Response assessments will be made according to IPCG Consensus guidelines.
Laboratory Tests 
Clinical Laboratory Tests
Clinical laboratory tests (Table 3) are to be performed by the local laboratory and reviewed by the 
Investigator or qualified designee (e.g., physician’s assistant, nurse practitioner).
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Table 3:
Clinical Laboratory Tests
Hematology
Serum Chemistry
Coagulation
Enzymes
&
Liver 
Studies
CBC with differential 
ferritin
fibrinogen
sodium
potassium, chloride 
bicarbonate 
creatinine
glucose
blood urea nitrogen 
calcium
uric acid 
phosphate 
magnesium
C-reactive protein
Creatinine phosphokinase
prothrombin time (PT)/ 
partial 
thromboplastin 
time (PTT), international 
normalized ratio (INR), 
fibrinogen, d-dimer
AST 
ALT
alkaline phosphatase 
total and direct bilirubin 
albumin
LDH
Abbrev.: CBC, complete blood count; AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, 
lactate dehydrogenase
CBC includes hematocrit, hemoglobin, red blood cell (RBC) count, white blood cell (WBC) count with differential, 
and platelet count.
Blood will also be collected for analysis of T cell subsets, including CD4+ and CD8+ cells. 
Additional clinical laboratory tests may be performed at the Investigator’s discretion.
Additional Eligibility-Determining Laboratory Tests
During Screening, blood samples will be collected for additional eligibility-determining laboratory 
tests, as follows:
Serology
Screening serology will be evaluated using standard methods. The serology panel should 
include the following:
o
HIV-1 and HIV-2
o
hepatitis B virus core antibody (HBcAb)
o
hepatitis B virus surface antibody (HBsAb)
o
hepatitis B virus surface antigen (HBsAg)
o
hepatitis C virus (HCV) antibody
o
HCV RNA
o
Cytomegalovirus (CMV) antibody
o
Epstein-Barr Virus (EBV) antibody
Blood may also be drawn for additional serology testing if subject has risk factors or 
clinical evidence of infection with other communicable disease agents or disease.
Serology should be performed within 28 days prior to leukapheresis. Additional serology 
may be performed if required according to country-specific and institutional guidelines.

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Serum β-human chorionic gonadotropin pregnancy test
Required for women of child-bearing potential.
Blood, Bone Marrow, Tissue and CSF Analysis for CAR and CD19
CAR+ T cells and CD19+ cells will be quantified in peripheral blood, bone marrow, tumor biopsies 
and CSF when possible.
Soluble factors/Multiplex Cytokines
Serum will be analyzed for GM-CSF, IL-1β, IL-2, IL-6, IL-8, IFN-γ, IL-10, IL-12p70, MCP-1, 
and TNFα, in addition to other cytokines as identified. Quantification of markers of endothelial 
activation, including d-dimer, PTT, INR, ANG1, ANG2, gal-3, VWF multimers, may also be 
examined as exploratory studies.
Blood Collection for Research
Blood will be collected and stored for potential analyses of B cell subtypes, T cell subtypes, and/or 
markers of T cell exhaustion.
CAR T Cell Phenotyping
Blood will be collected and analyzed for CAR T cell phenotyping, which includes the analysis of 
CAR T cell subsets and markers of memory, activation, and trafficking.
Gene Expression
Whole blood, bone marrow aspirate or tissue biopsies will be collected and may be analyzed for 
gene expression per standard SOPs and according to the NIH standards to avoid uncover single 
nucleotide polymorphisms (SNPs) that are unique to individuals.
Tissue Collection
Blood, Bone Marrow, CSF and Tumor for Future Research
Aside from protocol-specified bone marrow aspirate and biopsies, additional bone marrow and 
tissue samples may be collected outside the Schedule of Events and is encouraged in the event of 
unexpected clinical findings such as toxicity or delayed response. These samples, as well as 
leftover samples from protocol-specified procedures, may be used for biomarker analyses of 
proteins, DNA, RNA, and other molecules to study PCNSL, and/or gene therapy. Such samples 
may be stored until the samples are exhausted or until the repository is discontinued. The Sponsor 
will be the custodian of the samples in the repository and any unused samples will be destroyed at 
the Sponsor’s discretion.
Collection and storage of the samples described above will be subject to discretionary approval 
from each center’s Institutional Review Board (IRB) / Independent Ethics Committee (IEC) and 
the subject’s specific written consent. Samples will be labeled with a unique identification number 
that includes no subject identifying information.

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Note that leukapheresis product collected as part of the manufacture of the drug product may be 
used to study the manufacturing process. In particular extra leukapheresis product may be used to 
understand how the process may be improved or made more robust. These potential studies are 
not optional.
11. MEASUREMENT OF EFFECT
Although response is not the primary endpoint of this trial, participants with measurable disease 
will be assessed by standard criteria for their disease as would any large cell lymphoma patient 
treated with CAR-T. For the purposes of this study, participants should be assessed for response 
at day 28, 3 months, 6 months, 12 months and 24 months after tisagenlecleucel T cell infusion as 
is standard for commercial tisagenlecleucel. Staging imaging will be performed via MRI imaging 
of the brain with perfusion imaging. Additionally, lumbar punctures will be performed at these 
same time points as this is required for complete response assessment per IPCG consensus 
guidelines (Appendix C). MRI imaging will be performed with perfusion imaging.
12. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements).
12.1
Data Reporting
12.1.1 Method
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the 
data for this study.
12.1.2 Responsibility for Data Submission
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the Office of Data Quality (ODQ) in accordance with DF/HCC policies.
12.2
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of medical oncologists, research 
nurses, pharmacists and biostatisticians with direct experience in cancer clinical research. 
Information that raises any questions about participant safety will be addressed with the Overall 
PI and study team.

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The DSMC will review each protocol up to four times a year with the frequency determined by 
the outcome of previous reviews. Information to be provided to the committee may include: up- 
to-date participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring within 30 
days of intervention and summary of all deaths while being treated and during active follow-up; 
any response information; audit results, and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request.
12.3
Collaborative Agreements Language
“N/A”
13. STATISTICAL CONSIDERATIONS
13.1
Study Design/Endpoints
General Design Issues
This is a pilot study to evaluate the safety and tolerability, and persistence and engraftment of 
tisagenlecleucel T cells in primary CNS lymphoma. Failure to complete the study due to the 
stopping rules (described in Section 5.7) being invoked will be the main basis for determining 
safety of this study. This study is primarily intended to provide data to be used to plan a preliminary 
study to assess safety and feasibility.
Upon enrollment, patients will undergo baseline tumor assessment, and research blood samples 
will be collected. At dosing, patients will receive redirected autologous T cells against CD19 
(Tisagenlecleucel T cells).
Patients will be monitored according to the Schedule of Events (Section 10.1). Observation and 
monitoring of patients will continue through week 24 post dosing, and every three months until 
two years.
This study aims to evaluate 12 patients from either treatment group. All subjects who are infused 
with Tisagenlecleucel T cells will be evaluated for safety.
Primary Endpoints
The primary endpoint of this study is rate and grade of adverse events including (but not limited 
to) cytokine release syndrome and neurotoxicity per 2018 ASBMT consensus criteria8. The 
primary objective is to assess the safety of tisagenlecleucel in patients with PCNSL. Safety will be 
evaluated based on monitoring of the occurrence of study related adverse events that are 
“possibly”, “likely”, or “definitely” related to study treatment any time from the first day of study 
treatment until Month 12 while the subject is enrolled on this study.

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Secondary Endpoints
The secondary endpoint of this study is the proportion of patients with PCNSL with objective 
disease response to tisagenlecleucel per IPCG response criteria.
This will be assessed by evaluation of disease specific response at months 1, 3, 6, and 12.
Patients who are lost to follow up without a known date of progression or death due to any cause 
will be censored at the date of their last available tumor assessment.
Exploratory Endpoints
The exploratory objectives are to assess long-term efficacy of tisagenlecleucel in patients with 
PCNSL, to evaluate the expansion, persistence, and phenotype, of tisagenlecleucel T cells 
following infusion, evaluate cytokine profiles in the peripheral blood and CSF of subjects after 
infusion of tisagenlecleucel, to assess impacts of tisagenlecleucel on quality of life and 
neurocognitive function post infusion, to assess for correlative markers of tumor 
response/progression. Endpoints to include: a) to evaluate the overall and progression free survival 
of patients post tisagenlecleucel, 2) detection and quantification of tisagenlecleucel and tumor 
specific RNA/DNA in biopsies, the peripheral blood and CSF 3) Assessment of 
cytokine/chemokine profiles in peripheral blood and CSF, including IL-2, IL-6, IL-10, IFNγ, 
TNFα etc. 4) longitudinal neurocognitive evaluation as per IPCG guideline per published schedule,
5) when available, analyze pre/post tumor samples for gene and immune-profile.
13.2
Sample Size, Accrual Rate and Study Duration
This is a pilot study to assess tisagenlecleucel in PCNSL. A larger follow-up study may be 
designed pending results from this initial cohort.
Subjects will be followed for AEs, clinical status, and laboratory parameters for up to 24 months 
after the infusion of Tisagenlecleucel T cells, unless they terminate early due to disease 
progression, or withdraw for a different reason. All subjects who receive Tisagenlecleucel T cells 
will be will be transitioned to the long-term follow-up (LTFU) phase of this protocol following 
disease progression and/or completion of the 24-month active treatment period to maintain 
compliance with the requirements for subjects receiving genetically modified cells containing 
lentiviral vectors under IND. Subjects will be followed for up to 15 years and will be asked to 
participate in a separate 15-year registry study, such as CIBMTR. For subjects who consent to 
the registry study, data for LTFU will be collected with the registry study. We anticipate 
accruing the study population within 12 months.
13.3
Statistical Analysis
The statistical analysis will be primarily descriptive in keeping with the exploratory nature of the
study. Incidence of CRS and/or NT will be tabulated, by grade and treatment attribution. Time to 
these AEs will also be analyzed. Summary statistics will be calculated (median, mean, range for 
continuous variables; frequency and percentage for discrete variables). Time to event outcomes 

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will be estimated using Kaplan Meier method or cumulative incidence curves. Only patients who 
are infused will be analyzed in subsequent data analysis.

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13.4
Stratification Factors
N/A
13.5
Interim Monitoring Plan
No interim analysis is planned due to the small sample size.
13.6
Analysis of Primary Endpoints
The frequency, grade, and duration of all adverse events that are at least “possibly” related to the 
study drug will be listed and summarized.
13.7
Analysis of Secondary and Exploratory Endpoints
The number and proportion of patients with objective disease response at month 1, 3, 6 and 12 
will be reported. Overall survival and progression-free survival will be plotted and summarized 
using the Kaplan-Meier method. Additional exploratory analyses will be primarily descriptive, 
with results presented graphically and/or as summary statistics.
13.8
Reporting and Exclusions
13.8.1 Evaluation of Toxicity
All participants will be evaluable for any drug related toxicity from the time of their first 
treatment. Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). All subjects who initiate any study procedures will be included in 
the assessment of safety. Subject incidence rates of AEs, including SAEs, fatal and 
treatment related AEs will be reported through the conduct of the study. Changes in clinical 
laboratory test results, vital signs and physical examination findings will be summarized 
with descriptive statistics as appropriate. Laboratory parameters will be summarized for 
changes across study by using descriptive statistics including shifts relative to CTCAE 
criteria for laboratory abnormalities. Laboratory measures will also be compared with their 
corresponding normal ranges and the incidence of abnormally high and abnormally low 
laboratory values will be calculated for each relevant protocol-specified laboratory test. 
Laboratory values that are of Grade 3 severity or greater will be tabulated by dose and 
listed on an individual subject basis.
All treated subjects will be followed for overall survival for up approximately 15 years 
after T cell infusion.

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13.8.2 Evaluation of the Primary Efficacy Endpoint
The primary endpoint for this trial will be related to safety, including the incidence of and 
maximal grade of CRS and neurotoxicity.
ADMINISTRATIVE REQUIREMENTS
13.9
Good Clinical Practice
The study will be conducted in accordance with the International Conference on Harmonization 
(ICH) Guideline for GCP and the appropriate regulatory requirement(s). The Investigator will be 
thoroughly familiar with the appropriate use of Tisagenlecleucel as described in the protocol. 
Essential clinical documents will be maintained to demonstrate the validity of the study and the 
integrity of the data collected. Master files will be established at the beginning of the study, 
maintained for the duration of the study and retained per the appropriate regulations.
13.10 Ethical Considerations
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki. The IRB/IEC and other appropriate institutional regulatory bodies will review all 
appropriate study documentation to safeguard the rights, safety, and well-being of the subjects. 
The study will only be conducted at sites where IRB/IEC and other appropriate institutional 
regulatory body approvals have been obtained. The protocols, informed consents, advertisements 
(if applicable), written information given to the subjects, safety updates, annual progress reports, 
and any revisions to these documents will be provided to the IRB/IEC and other appropriate 
institutional regulatory bodies by the Investigator.
13.11 Biosafety Considerations
If the dosing site is a recipient of funding from the National Institutes of Health (NIH) for 
recombinant research, the dosing site will ensure that an Institutional Biosafety Committee (IBC) 
is in place that is composed of at least 5 appropriately-qualified members. The IBC will ensure 
that the site conforms to the requirements set forth in the Section IV-B-2 of the NIH Guidelines 
for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, promulgated by the 
NIH/Office of Biotechnology Activities (NIH/OBA). The Investigator will be responsible for 
petitioning the IBC and obtaining approval prior to enrolling any subject in the study. The 
Investigator will also be required to obtain and follow all biohazard safety guidelines promulgated 
by the IBC, and to report all findings as required to the IBC and to NIH/OBA.
This protocol and any accompanying material provided to the subject (such as subject information 
sheets, Informed Consent Form, or descriptions of the study used to obtain informed consent) will 
be submitted by the Sponsor and/or the site to the legally constituted and chartered Institutional 
Biosafety Committee (IBC). Additional materials may be submitted to the IBC according to the 
specific Committee and federal (United States’ National Institutes of Health or foreign equivalent) 
requirements. Documentation of IBC approval must be in place prior to product shipment to the

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site. At the discretion of the specific IBC and within federal requirements, IBC oversight of 
individual sites is suggested to be terminated provided (1) all subjects at that site have completed 
dosing by at least 90 days, and (2) all investigational materials have been fully accounted for and 
either returned to the Sponsor, destroyed on site, or shipped to a duly licensed destruction facility.
13.12 Subject Information and Informed Consent
After the study has been fully explained, written informed consent will be obtained from the 
subject or his/her legal representative prior to study participation. The method of obtaining and 
documenting the informed consent and the contents of the consent will comply with ICH-GCP and 
all applicable regulatory requirement(s).
13.13 Subject Confidentiality
In order to maintain subject privacy, all CRFs, accountability records, study reports, and 
communications will identify the subject by initials and the assigned subject number. The 
Investigator will grant monitor(s) and auditor(s) from the Sponsor or its designee and regulatory 
authority(ies) access to the subject’s original medical records for verification of data gathered on 
the CRFs and to audit the data collection process. The subject’s confidentiality will be maintained 
and will not be made publicly available to the extent permitted by the applicable laws and 
regulations.
13.14 Protocol Compliance
The Investigator will conduct the study in compliance with the protocol provided by the Sponsor, 
and given approval/favorable opinion by the IRB/IEC and other appropriate institutional 
regulatory bodies. Modifications to the protocol should not be made without agreement of both 
the Investigator and the Sponsor. Changes to the protocol will require written IRB/IEC and other 
appropriate institutional regulatory body approval/favorable opinion prior to implementation, 
except when the modification is needed to eliminate an immediate hazard(s) to subjects. The 
IRB/IEC may provide, if applicable regulatory authority(ies) permit, expedited review and 
approval/favorable opinion for minor change(s) in ongoing studies that have the approval
/favorable opinion of the IRB/IEC and other appropriate institutional regulatory bodies. The 
Sponsor will submit all protocol modifications to the regulatory authority(ies) in accordance with 
the governing regulations.
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the Investigator will contact the Sponsor, if circumstances permit, to discuss the planned 
course of action. Any departures from the protocol must be fully documented in the CRF and 
source documentation.
13.15 Direct Access to Source Data
Monitoring and auditing procedures developed by the Sponsor will be followed, in order to comply 
with GCP guidelines.
The study will be monitored by the Sponsor or its designee. Monitoring will be done by personal 
visits from a representative of the Sponsor (site monitor) and will include on-site review of the 
CRFs for completeness and clarity, cross-checking with source documents, and clarification of

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administrative matters will be performed. The review of medical records will be performed in a 
manner to ensure that subject confidentiality is maintained.
The site monitor will ensure that the investigation is conducted according to protocol design and 
regulatory requirements by frequent communications (letter, e-mail, telephone, and fax).
Regulatory authorities, the IRB/IEC and other appropriate institutional regulatory bodies, and/or 
the Sponsor may request access to all source documents, CRFs, and other study documentation for 
on-site audit or inspection. Direct access to these documents must be guaranteed by the 
Investigator, who must provide support at all times for these activities.
13.16 Case Report Form Completion
CRFs will be completed for each study subject. It is the Principal Investigator’s responsibility to 
ensure the accuracy, completeness, and timeliness of the data reported in the subject’s CRF. Source 
documentation supporting the CRF data should indicate the subject’s participation in the study and 
should document the dates and details of study procedures, AEs, and subject status.
The Principal Investigator or designated representative should complete the CRF screens as soon 
as possible after information is collected, preferably on the same day that a study subject is seen 
for an examination, treatment, or any other study procedure. Any outstanding entries must be 
completed immediately after the final examination. An explanation should be given for all missing 
data.
The Principal Investigator must sign and date the Investigator’s Statement at the end of the CRF 
to endorse the recorded data.
For data to be collected on screen fails and early withdrawal, see Section 10.1.
13.17 Record Retention
The Investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s). Records will be retained for at least 2 years following marketing application 
approval or 2 years after formal discontinuation of the clinical development of the investigational 
product or per applicable regulatory requirement(s). If the Investigator withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person willing to 
accept the responsibility. The Sponsor must be notified in writing if a custodial change occurs.
The Sponsor has full rights over any invention, discovery, or innovation, patentable or not, that 
may occur when performing the study.
13.18 Liability and Insurance
The Sponsor has subscribed to an insurance policy covering, in its terms and provisions, its legal 
liability for injuries caused to participating persons and arising out of this research performed 
strictly in accordance with the scientific protocol as well as with applicable law and professional 
standards.

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14. PUBLICATION PLAN AND PRESENTATION OF THE STUDY 
FINDINGS
It is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer reviewed scientific or medical journal.
APPENDIX A: PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Grade
Descriptions
0
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
2
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours.
3
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
4
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair.
5
Dead.

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APPENDIX B: CYTOKINE RELEASE SYNDROME (CRS) AND NEUROTOXICITY 
MANAGEMENT
Monitoring and Management of late reactions following immune effector cell infusion
Monitoring: Patients will be assessed at a minimum of every 8 hours for signs and symptoms of 
CRS and graded per modified Lee criteria described in table 6. The following labs will be 
performed at least daily: CBC w/diff, CMP, Phos, LDH, PT/INR, PTT, fibrinogen, d-dimer, CRP, 
ferritin, and with increased frequency as clinically indicated. Grading of ICANS will be assessed 
per Lee 2019 described in tables 9 & 10.
Management: In the event that toxicity is suspected, patients will be placed on continuous 
telemetry including continuous O2 monitoring. Vital checks will be assessed at an increased 
frequency as clinically indicated and supportive measures including fluid management, respiratory 
support, and vasopressors/inotropic support will be provided. Patients with rapid clinical decline, 
extensive comorbidities, or older age, will be evaluated by ICU triage. Patients with fevers/febrile 
neutropenia will be treated as septic/febrile neutropenia with broad spectrum antibiotics. Specific 
infectious prophylaxis will also be started at time of lymphodepletion per clinical discretion until 
resolution of symptoms. Patients with neurologic toxicity will be managed in collaboration with 
neuro-oncology.
Pharmacologic therapy may include:
1. Anti-IL6 therapy can be administered as clinically indicated per table 7 & 8.
2. Corticosteroids can be administered as clinically indicated per table 7 & 10.
3. Low and high dose vasopressor support as clinically indicated.
4. Antiepileptic drugs to include keppra at first sign of CRS/neurotoxicity, starting dose 
500mg BID, additional recommendations per neuro-oncology immune effector toxicity 
management.

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Table 4. CRS Grading System – ASBMT CRS Consensus Grading
CRS Parameter
Grade 1
Grade 2
Grade 3
Grade 4
Fever†
Temperature
38°C
Temperature
38°C
Temperature
38°C
Temperature
38°C
With either:
Hypotension
None
Not requiring
Requiring one
Requiring
vasopressors
vasopressor with
multiple
or without
vasopressors
vasopressin
(excluding
vasopressin)
And/or‡
Hypoxia
None
Requiring low-
Requiring high-
Requiring
flow nasal
flow nasal
positive pressure
cannula^ or
cannula^,
(eg: CPAP,
blow-by
facemask, non-
BiPAP,
rebreather mask,
intubation and
or Venturi mask
mechanical
ventilation)
CPAP: Continuous positive airway pressure; BiPAP: Bilevel positive airway pressure
† Fever is defined as temperature 38°C not attributable to any other cause. In patients who have 
CRS then receive antipyretics or anti-cytokine therapy such as tocilizumab or steroids, fever is no 
longer required to grade subsequent CRS severity. In this case, CRS grading is driven by 
hypotension and/or hypoxia.
‡ 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 one 
vasopressor and hypoxia requiring low-flow nasal cannula is classified as having Grade 3 CRS.
Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not 
influence CRS grading.
^ Low-flow nasal cannula is defined as oxygen delivered at  6 liters/minute. Low flow also 
includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is 
defined as oxygen delivered at > 6 liters/minute.

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Table 5. Management of CRS by Grade
CRS
Grade
Anti-IL-6 Therapy
Corticosteroids
Additional Supportive Care
Grade 1
For prolonged CRS (>3 days) 
in patients with significant 
symptoms and/or 
comorbidities, consider 
tocilizumab as per Grade 2
N/A

Empiric broad-spectrum antibiotics, 
consider granulocyte colony- 
stimulating factor (G-CSF) if 
neutropenic and concern for 
infectious etiology

Maintenance IV fluids for hydration

Symptomatic management of organ 
toxicities
Grade 2
Tocilizumab 8 mg/kg IV over 
1 hour (not to exceed 800 
mg/dose). Repeat in 8 hours if 
no improvement; no more than 
3 doses in 24 hours, with a 
maximum of 4 doses total
For persistent refractory 
hypotension after 1–2 
doses of anti-IL-6 
therapy: Dexamethasone 
10 mg IV every 6 hours 
(or equivalent)

IV fluid bolus as needed

For persistent refractory hypotension 
after two fluid boluses and anti-IL-6 
therapy: Start vasopressors, consider 
transfer to intensive care unit (ICU), 
consider echocardiogram, and initiate 
other methods of hemodynamic 
monitoring

Manage per Grade 3 if no 
improvement within 24 hours after 
starting anti-IL-6 therapy

Symptomatic management of organ 
toxicities
Grade 3
Anti-IL-6 therapy as per Grade 
2 if maximum dose not 
reached within 24-hour period
Dexamethasone 10 mg IV 
every 6 hours (or 
equivalent). If refractory, 
manage as grade 4

Transfer to ICU, obtain 
echocardiogram, and perform 
hemodynamic monitoring

Supplemental oxygen including high- 
flow oxygen delivery and 
noninvasive positive pressure 
ventilation

IV fluid bolus and vasopressors as 
needed.

Symptomatic management of organ 
toxicities
Grade 4
Anti-IL-6 therapy as per Grade 
2 if maximum dose not 
reached within 24-hour period
Dexamethasone 10 mg IV 
every 6 hours (or 
equivalent). If refractory, 
consider 
methylprednisolone 1000 
mg/day IV

ICU care and hemodynamic 
monitoring

Mechanical ventilation as needed

IV fluid bolus and vasopressors as 
needed

Symptomatic management of organ 
toxicities

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Table 6. Anti-IL6 Therapy and Dosing Recommendations
DRUG
RECOMMENDED 
DOSE FOR CRS 
AND/OR 
NEUROTOXICITY
MAXIMUM 
DOSE
MECHANISM 
OF ACTION
COMMENTS
TOCILIZUMAB
8 mg/kg IV for up to 
three doses in a 24- 
hour period
Maximum 
800 mg per 
dose
IL-6 receptor 
antagonist
First line agent 
Doses can be 
given 8 hours 
apart
(Maximum 4 doses
total)
Table 7. Grading of Neurotoxicity (Lee et al. 20188)
Neurotoxicity 
Domain
Grade 1
Grade 2
Grade 3
Grade 4
ICE Score^
7-9
3-6
0-2
0 (patient is unarousable 
and unable to perform 
ICE)
Depressed level of 
consciousness
Awakens 
spontaneously
Awakens to 
voice
Awakens only to tactile 
stimulus
Patient is unarousable or 
requires vigorous or 
repetitive tactile stimuli to 
arouse. Stupor or coma
Seizure
N/A
N/A
Any clinical seizure 
focal or generalized that 
resolves rapidly; or Non- 
convulsive seizures on 
EEG that resolve with 
intervention
Life-threatening 
prolonged seizure (>5 
min); or
Repetitive clinical or 
electrical seizures without 
return to baseline in 
between.
Motor findings§
N/A
N/A
N/A
Deep focal motor 
weakness such as 
hemiparesis or paraparesis
Raised ICP / 
Cerebral edema
N/A
N/A
Focal/local edema on 
neuroimaging#
Diffuse cerebral edema on 
neuroimaging; 
Decerebrate or decorticate 
posturing; or Cranial 
nerve VI palsy; or

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
Orientation: Orientation to year, month, city, hospital: 4 points

Naming: Name 3 objects (e.g., point to clock, pen, button): 3 points

Following commands: (e.g., Show me 2 fingers or Close your eyes and stick out your tongue): 1 point

Writing: Ability to write a standard sentence (e.g., Our national bird is the bald eagle): 1 point

Attention: Count backwards from 100 by ten: 1 point
Immune effector Cell-associated Encephalopathy (ICE)
Papilledema; or Cushing's 
triad
‡ ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, 
raised ICP/cerebral edema) not attributable to any other cause. For example, a patient with an ICE score of 3 who has 
a generalized seizure is classified as having Grade 3 ICANS.
^A patient with an ICE score of 0 may be classified as having Grade 3 ICANS if the patient is awake with global 
aphasia. But a patient with an ICE score of 0 may be classified as having Grade 4 ICANS if the patient is unarousable.
Depressed level of consciousness should be attributable to no other cause (e.g. no sedating medication)
§ Tremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE v5.0 
but they do not influence ICANS grading.
# Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded 
from ICANS grading. It may be graded according to CTCAE v5.0.
ICE: Immune effector Cell-associated Encephalopathy; ICP: Intracranial pressure; EEG: electroencephalogram.
Table 8. Encephalopathy assessment tools for grading of Immune effector Cell-Associated 
Neurotoxicity Syndrome (ICANS).
Score 10: No impairment 
Score 7-9: Grade 1 ICANS
Score 3-6: Grade 2 ICANS
Score 0-2: Grade 3 ICANS
Score 0 due to patient unarousable and unable to perform ICE assessment: Grade 4 ICANS
Table 9. Management of ICANS
Treatment by 
Grade
Grade 1

Supportive care
Grade 2

Supportive care

Dexamethasone 10 mg IV x 1. Can repeat every 6 hours or methylprednisolone 1 
mg/kg IV every 12 h if symptoms worsen.
Grade 3

ICU care is recommended.

Dexamethasone, 10 mg IV every 6 h

Consider repeat neuroimaging (CT or MRI) every 2–3 days if patient has persistent 
grade ≥3 neurotoxicity.
Grade 4

ICU care, consider mechanical ventilation for airway protection.

High-dose corticosteroids, methylprednisolone 1000 mg/day IV x3 days

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
Consider repeat neuroimaging (CT or MRI) every 2–3 days if patient has persistent 
grade ≥3 neurotoxicity.

Treat convulsive status epilepticus per institutional guidelines.
APPENDIX C: IPCG RESPONSE CLASSIFICATION
Response
Response Criteria for Primary Central Nervous System Lymphoma 
Corticosteroid
Brain Imaging
Dose
Eye Examination
CSF Cytology
CR
No contrast enhancement
None
Normal
Negative
CRu
No contrast enhancement
Any
Normal
Negative
Minimal abnormality
Any
Minor RPE abnormality
Negative
PR
50% decrease in enhancing tumor
Irrelevant
Minor RPE abnormality or normal
Negative
No contrast enhancement
Irrelevant
Decrease in vitreous cells or retinal infiltrate
Persistent or suspicious
PD
25% increase in lesion
Irrelevant
Recurrent or new ocular disease
Recurrent or positive
Any new site of disease: CNS or systemic
Abbreviations: CR, complete response; CRu, unconfirmed complete response; RPE, retinal pigment epithelium; PR, partial response; PD, progressive disease.

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