Radiation Therapy To Enhance CAR T Efficacy Early in Post-CAR T Cell Therapy Refractory Lymphoma: A Pilot Study
Phase: NA
Conditions: Hematologic Malignancy, Refractory Lymphoma
Sponsor: Massachusetts General Hospital

Page 1
NCI Protocol #:
N/A
DF/HCC Protocol #: 19-861 
TITLE:  Radiation Therapy To Enhance CAR T Efficacy Early in Post-CAR T Cell Therapy 
Refractory Lymphoma: A Pilot Study
Coordinating Center:
Massachusetts General Hospital (MGH) 
*Principal Investigator (PI)
Chirayu G. Patel, MD, MPH  
MGH Radiation Oncology
55 Fruit St
Cox 3
Boston, MA 02114
617-724-2340 (p)
617-726-3603 (f)
cpatel@mgh.harvard.edu
Co-PI:
Matthew J. Frigault, MD
MGH Cancer Center
MFRIGAULT@PARTNERS.ORG
Other Investigators:
Marcela Maus, MD, PhD – MGH Director of Cellular Immunotherapy Program
MVMAUS@mgh.harvard.edu
Kathleen Gallagher, PhD – Director of Immune Monitoring Lab
KGALLAGHER19@mgh.harvard.edu
IND #:  N/A
IND Sponsor:  N/A
 NCT04473937

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Other Agent(s):  MGH is the sponsor of this study. 
Version Date: JUL 16 2021

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CLINICAL STUDY PROTOCOL SYNOPSIS
Name of Sponsor/Company:
Department of Radiation Oncology, Massachusetts General Hospital (MGH) 
Name of Investigational Product:
N/A
Title of Study (Protocol Title): 
Radiation Therapy To Enhance CAR T Efficacy Early in Post-CAR T Cell Therapy Refractory 
Lymphoma: A Pilot Study
Protocol Number 19-861
Study center(s): MGH Cancer Center  / MGH Radiation Oncology
Principal Investigator: Chirayu G. Patel, MD, MPH
Investigator: Matthew J. Frigault, MD
Studied period (years): 1
Estimated date first patient enrolled: quarter 3, 2020
Estimated date last patient completed: quarter 1, 2022
Phase of development: Pilot
Objectives:
Primary Objective
To ascertain the safety and toxicity of radiotherapy in patients with hematologic malignancies who 
will undergo any CD19-targeted CAR T cell therapy 
Secondary Objective:
To evaluate the efficacy of radiotherapy in the above patients
To assess patient reported outcomes with regard to symptoms and side effects in RT following 
CAR T cell therapy
Exploratory Objective:
To assess immune infiltrates into lymphoma following radiotherapy
To evaluate mechanisms of interplay between radiotherapy and CAR T cell therapy, by 
examining serum cytokine levels and expression changes of key pathway mediators in 
lymphoma biopsy samples before and after radiotherapy 
Route and Regimen:
No investigational products are used in this trial. 
Procedures:
At specific time points as outlined in the schedule of assessments, subjects will undergo the following 
assessments/procedures: collection of informed consent, general medical history including previous 
treatments for lymphoma, physical exam including vital signs and performance status, blood draws for 
complete blood count (CBC), chemistry panels, cytokines, C-reactive protein, lymphocyte subsets, anti-
axicabtagene ciloleucel antibodies, and anti-CD19 CAR T cell analysis. Women of childbearing 
potential will undergo a urine or serum pregnancy test prior to radiotherapy as per standard protocol. 

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Subjects will also undergo a biopsy (core needle biopsy, or if not possible, FNA) shortly following RT.
Subjects will also undergo a PET/CT as standard of care to assess response to RT about 6 months after 
CAR T infusion. If there is evidence for complete response on the 6 month PET/CT scan, patients will 
have an additional PET/CT scan at 12 months after CAR T infusion to assess for continued complete 
response. Otherwise, patients will need further work-up regarding 6 month PET/CT scan. 
Routinely throughout the conduct of the study, subjects will be asked to report concomitant medications 
and adverse events and will have their disease assessed.
Methodology/Study Design: 
This is a pilot study evaluating the feasibility, safety, efficacy, and toxicity of radiotherapy
in patients with hematologic malignancies who will undergo any CD19-targeted CAR T cell therapy 
Pilot Study
The pilot study will enroll approximately 20 subjects with refractory hematologic malignancies 
following CAR T cell therapy. 
Each subject will proceed through the following study periods:
Screening
Enrollment
RT simulation, planning, and treatment
Biopsy following RT (on protocol)
Post treatment assessment period with a PET/CT following RT (as standard of care)
Long term follow-up period
For study requirements assigned to each study period, refer to Section 7 for details.
Long-term Follow-up
All subjects who complete the study, and those who withdraw from the study after receiving RT for 
reasons other than death, will be asked to participate in a long-term follow-up study for up to 6 months 
after their RT, with a focus on long-term efficacy and safety. These patients will also have long-term 
follow-up as part of CAR T cell therapy registry. After Month 24 patients will be followed via the 
CIBMTR immune effector cell therapy registry. 
Diagnosis and selection criteria: refractory hematologic malignancy following CAR T cell 
therapy
Inclusion Criteria 
1.
Patients must be able to undergo biopsy. Biopsy will be obtained for patients to 
exclude possibility of false negative residual FDG avidity on PET/CT that is not 
substantially increased relative to pre-CAR-T PET/CT. Exceptions are allowed for 
patients who have clearly progressive disease for whom delaying radiation therapy 
to obtain a biopsy may worsen outcome (such as cases of cord compression), and 
for patients for whom the risks of biopsy are high (such as patients with evidence 
for CNS involvement). 

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2.
Biopsy-confirmed refractory disease within 30-90 days following any CD19-targeted 
CAR T cell therapy for a  hematologic malignancy (these include relapsed or 
refractory large B-cell lymphoma after two or more lines of systemic therapy, 
including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, 
primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, DLBCL 
arising from follicular lymphoma, and mantle cell lymphoma). Of note, ‘refractory’ 
refers to patients who had early refractory disease after CAR-T cell therapy and not 
to patients who have received CAR-T for refractory disease, but had complete 
response to CAR-T cell therapy. 
3.
At least 1 measurable lesion according to the Lugano criteria1.  Lesions that have 
been previously irradiated will be considered measurable only if progression has 
been documented following completion of radiation therapy
4.
The following criteria pertain to pattern of progression:
o
Patients may have one refractory lesion without other residual or progressive 
disease as per PET/CT
o
Patients may have more than one refractory lesion, but with evidence for at 
least partial response of at least one other lesion as per PET/CT
o
Patients with more than one site of refractory disease without evidence for at 
least partial response of at least one other lesion are eligible if they are:
A. Symptomatic from a refractory lesion (such as cord compression or 
focal pain)  or
B. Have disease that can locally affect the spinal canal or brain if left 
untreated.
5.
Toxicities due to prior therapy must be stable and recovered to Grade 1 (except for 
clinically non-significant toxicities such as alopecia and prolonged cytopenias that 
are not expected to worsen during RT) if there is concern for overlap of anticipated 
radiation-related toxicity and toxicity from prior therapy due to where the RT field 
is located. 
6.
Age 18 or older
7.
Eastern Cooperative Oncology Group (ECOG) performance status of less than or 
equal to 2.
8.
Ability to understand and the willingness to sign a written informed consent 
document.
Exclusion Criteria
1.
Any medical condition likely to interfere with assessment of safety or efficacy of 
RT
2.
Patients with more than one site of disease without any evidence for response to 
CAR T cell therapy who are not focally symptomatic due to progressive disease or 
do not have disease that can locally affect the spinal canal or brain if left untreated 
3.
Women of child-bearing potential who are pregnant because of the potentially 
dangerous effects of the preparative chemotherapy on the fetus or infant. Females 
who have undergone surgical sterilization or who have been postmenopausal for at 
least 2 years are not considered to be of childbearing potential

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4.
In the investigators judgment, the subject is unlikely to complete all protocol-
required study visits or procedures, including follow-up visits, or comply with the 
study requirements for participation
1.1
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.
DSMC & SRT
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. Refer to Section 13.2 and Section 8.4.4.
Statistical methods:
The primary objective of this study is to assess the safety and toxicity of RT following CAR T cell 
therapy. The secondary objective includes assessment of efficacy and quality of life. In terms of 
number of patients we anticipate to enroll, 53 patients underwent axicabtagene ciloleucel or 
tisagenlecleucel therapy at MGH within the past year. With a modest 30% refractory disease rate, 16 
patients would have refractory disease and may be eligible for radiation therapy to achieve disease 
control. For the next one year, given the increasing rate of patients being referred for CAR T cell 
therapy, we expect that 80 patients are expected to undergo CD19-targeted CAR T cell therapy – as 
such, over 20 patients may be referred for RT. Univariate descriptive statistics with t-tests will be 
used to analyze pre- and post-RT QOL and toxicity data.
 

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Study Glossary
Abbreviation or Term
Definition/Explanation
AE
Adverse event
ALL
Acute lymphoblastic leukemia
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
ASCT
Autologous stem cell transplant
AST
Aspartate aminotransferase
CAR
Chimeric antigen receptor 
CAR
Chimeric antigen receptor positive
CBC
Complete blood count
CLL
Chronic lymphocytic leukemia
CMV
Cytomegalovirus
CNS
Central nervous system
CPF
Cell processing facility
CR
Complete response
CRF
Case report form
CRS
Cytokine release syndrome
CSF
Cerebrospinal fluid
CTCAE
Common Terminology Criteria for Adverse Events
DLBCL
Diffuse large B cell lymphoma
DLT
Dose-limiting toxicity
DOR
Duration of response
DSMB
Data Safety Monitoring Board
DVT
Deep vein thrombosis
eACT™
Engineered autologous cell therapy 
EBV
Epstein-Barr virus
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EEG
Electroencephalogram
End of Study for 
individual subject
Defined as when the last day that protocol specified assessments are conducted for 
an individual subject
End of Study (primary 
completion)
Defined as when the last subject is assessed or received an intervention for the 
purposes of final collection of data for the primary endpoint at Month 6
End of Study (end of trial)
Defined as when the last subject is assessed or received an intervention for 
evaluation in the study, including survival assessments 

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Abbreviation or Term
Definition/Explanation
FAS
Full analysis set
FL
Follicular lymphoma 
Healthcare Facility
Clinical trial site
HGBCL
High grade B-cell lymphoma 
HLH
Hemophagocytic lymphohistiocytosis
IB
Investigator’s Brochure
ICF
Informed consent form
ICU
Intensive care unit
IP
Investigational product
IRB/IEC
Institutional Review Board/Independent Ethics Committee
IRRC
Independent Radiological Review Committee
IWG
International Working Group 
KTE-C19/axicabtagene 
ciloleucel
Autologous T cells transduced with retroviral vector containing anti-CD19 
CD28/CD3 zeta chimeric antigen receptor
LTFU
Long-term follow-up
LVEF
Left ventricular ejection fraction
mITT
Modified intent-to-treat
MMSE
Mini-Mental Status Exam
MRI
Magnetic resonance imaging
MSGV1
Murine stem cell virus-based vector
NaCl
Sodium chloride
NCI
National Cancer Institute
NHL
Non-Hodgkin lymphoma
ORR
Objective response rate
OS
Overall survival
PET-CT
Positron emission tomography–computed tomography
PBMC
Peripheral blood mononuclear cell
PMBCL
Primary mediastinal B-cell lymphoma 
PD
Progressive disease
PR
Partial response
PRO
RCR 
Patient Reported Outcome - Common Terminology Criteria for Adverse Events
Replication-competent retrovirus
SAE
Serious adverse event
scFv
Single chain variable fragment

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Abbreviation or Term
Definition/Explanation
SD
Stable disease
SMS
Safety management study
SOA
Schedule of assessment
SUSAR
Suspected unexpected serious adverse reaction
Study Day 0
Defined as the first day that axicabtagene ciloleucel is administered to the subject
TEAEs
Treatment-emergent adverse event
TFL
Transformed follicular lymphoma
ULN
Upper limit of normal
VAS
Visual analogue scale

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Study Schema

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TABLE OF CONTENTS
CLINICAL STUDY PROTOCOL SYNOPSIS ..............................................................................3
Inclusion Criteria .................................................................................................................4
Exclusion Criteria ................................................................................................................5
1.1
Inclusion of Women and Minorities ........................................................................6
2.
OBJECTIVES....................................................................................................................15
2.1
Study Design..........................................................................................................15
2.2
Protocol Objectives................................................................................................16
3.
BACKGROUND ...............................................................................................................16
3.1
Disease Background and Rationale .......................................................................16
3.2
Radiation Therapy for Refractory Lymphoma/Leukemia Following CAR 
T Cell Therapy.......................................................................................................18
3.3
Correlative Studies Background ............................................................................19
4.
PARTICIPANT SELECTION...........................................................................................20
4.1
Diagnosis and selection criteria: refractory hematologic malignancy 
following any CD19-targeted CAR T cell therapy................................................20
Inclusion Criteria ...............................................................................................................20
Exclusion Criteria ..............................................................................................................21
4.2
Inclusion of Women and Minorities ......................................................................21
5.
REGISTRATION PROCEDURES ...................................................................................21
5.1
General Guidelines for DF/HCC Institutions ........................................................21
5.2
Registration Process for DF/HCC Institutions.......................................................22
6.
TREATMENT PLAN........................................................................................................22
6.1
Study treatment......................................................................................................22
6.2
Rationale for Study Treatment Dosing ..................................................................22
6.3
Excluded Medications............................................................................................22
6.4
Subsequent Therapy...............................................................................................23
6.5
Duration of Follow Up...........................................................................................23
6.6
Criteria for Taking a Participant Off Study ...........................................................23
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................24
7.1
Expected Toxicities................................................................................................24
7.2
Adverse Events ......................................................................................................24
7.3
Adverse Event Characteristics...............................................................................25
7.4
Procedures for AE and SAE Collection and Reporting.........................................26
7.5
Reporting to the Food and Drug Administration (FDA) .......................................29
7.6
Reporting to the NIH Office of Biotechnology Activities (OBA).........................29
7.7
Reporting to the Institutional Biosafety Committee (IBC)....................................29
7.8
Reporting to Hospital Risk Management...............................................................29

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7.9
Routine Adverse Event Reporting .........................................................................29
8.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................29
8.1
Biomarker Studies..................................................................................................29
8.2
Laboratory Correlative Studies..............................................................................30
9.
STUDY CALENDAR .......................................................................................................30
9.1
Informed Consent...................................................................................................30
9.2
Demographic Data .................................................................................................31
9.3
Medical and Treatment History .............................................................................31
9.4
Physical Exam, Vital Signs, Performance Status...................................................31
9.5
Laboratory..............................................................................................................31
9.6
Biomarkers.............................................................................................................32
9.7
Description of Study Periods .................................................................................32
10.
MEASUREMENT OF EFFECT .......................................................................................39
10.1
Disease Response Assessment...............................................................................39
11.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................39
11.1
Data Reporting.......................................................................................................39
11.2
Data Safety Monitoring..........................................................................................39
12.
STATISTICAL CONSIDERATIONS...............................................................................40
12.1
Study Endpoints.....................................................................................................40
12.2
Sample Size, Accrual Rate and Study Duration ....................................................41
12.3
Interim Monitoring Plan ........................................................................................42
12.4
Analysis of Primary and Secondary Endpoints .....................................................42
12.5
Reporting and Exclusions ......................................................................................43
13.
Ethical and Regulatory requirements.................................................................................44
13.1
Independent Review Board/Independent Ethics Committee.................................44
13.2
Subject Confidentiality ..........................................................................................44
13.3
Investigator Signatory Obligations ........................................................................44
13.4
Protocol Amendments and Termination................................................................44
13.5
Study Documentation and Archive........................................................................45
13.6
Study Monitoring and Data Collection..................................................................45
14.
PUBLICATION PLAN .....................................................................................................46
REFERENCES ..............................................................................................................................47
APPENDIX A................................................................................................................................49
Score 10: No impairment ...........................................................................................................52

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2.
OBJECTIVES
The primary objectives of this study are to evaluate the safety and toxicity of radiotherapy in 
patients with hematologic malignancies who will undergo any CD19-targeted CAR T cell therapy.
Key secondary objectives includes determination of efficacy of RT following CAR-T therapy., 
and assessment of patient reported outcomes with regard to symptoms and side effects in RT 
following CAR T cell therapy
Exploratory objectives include determination of immune infiltrates into pre- vs. post-RT biopsy 
samples and changes in anti-CD19 CAR T cells and cytokine profiles pre- vs. post-RT blood 
samples. 
2.1
Study Design
Study 19-861 is a single center, pilot study evaluating the feasibility safety and efficacy of 
radiotherapy in patients with hematologic malignancies who will undergo any CD19-targeted CAR T cell 
therapy.
Approximately 20 subjects with hematologic malignancies with refractory disease following 
CAR-T cell therapy, including DLBCL, PMBCL, high grade lymphoma, TFL, or mantle cell 
lymphoma will be enrolled to evaluate the addition of radiotherapy in terms of achieving partial 
or complete response, and disease-free survival, as applicable. Specimens will be collected for 
translational analysis to study the interaction of RT and the immune microenvironment. 
If addition of radiotherapy is safe and effective in these patients, RT may be a useful adjunct in 
patients with early refractory disease following CAR T cell therapy. A larger study would be done 
to investigate important determinants of eliciting RT response following CAR T cell therapy. 
For study requirements assigned to each study period, please refer to the schedule of assessments 
(SOA) and Section 11 for details.
Each subject will proceed through the following study periods:
Screening
Enrollment
RT Treatment Period
Post treatment assessment period with a biopsy (research) and PET/CT following RT (as standard 
of care)
Long term follow-up period
A study schema is drawn out and described at the end of the protocol synopsis section.

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2.2
Protocol Objectives
Primary Objective
To ascertain the safety and toxicity of radiotherapy in patients with hematologic malignancies who will 
undergo any CD19-targeted CAR T cell therapy 
Secondary Objective:
To evaluate the efficacy of radiotherapy in the above patients
Exploratory Objective:
To assess immune infiltrates into lymphoma following radiotherapy
To evaluate mechanisms of interplay between radiotherapy and CAR T cell therapy, by examining 
serum cytokine levels and expression changes of key pathway mediators in lymphoma biopsy 
samples before and after radiotherapy
3. BACKGROUND
3.1
Disease Background and Rationale
Non-Hodgkin lymphoma (NHL) is a heterogeneous group of cancers originating in B 
lymphocytes, T lymphocytes or natural killer cells.  In the United States, B cell lymphomas 
represent 80-85% of cases reported.  In 2013, approximately 69,740 new cases of NHL and over 
19,000 deaths related to the disease were estimated to occur.  Non-Hodgkin lymphoma is the most 
prevalent hematological malignancy and is the seventh leading site of new cancers among men 
and women and account for 4% of all new cancer cases and 3% of deaths related to cancer 2.  Large 
B-cell lymphomas represent the most common sub-group of NHL 3.
3.1.1
Diffuse Large B-cell Lymphoma
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of large B-cell lymphoma, 
accounting for approximately 30% of NHL cases.  There are approximately 22,000 new diagnoses 
of DLBCL in the United States each year.  In the past two decades, progress has been made in 
understanding the biological heterogeneity of DLBCL and in improving survival with 
combinations of CHOP and immunotherapy.  The addition of rituximab into combination therapies 
for DLBCL have greatly improved patient outcomes.  However, patients with chemotherapy-
refractory DLBCL following treatment under the current standards of care still have a particularly 
dire prognosis, with no curative treatment options 4.
The population with the highest unmet need continues to consist of patients who do not respond 
to first line combination chemotherapy (typically R-CHOP) or who do not respond to their last 
course of combination chemotherapy, as the disease is mostly insensitive to subsequent 
combination chemotherapy (typically R-ICE, R-ESHAP) (Table 1).  In a review of 64 patients 
with DLBCL with disease progression during first line chemotherapy or only transient response 
 days) after end of induction treatment, the response rate to second line therapy was 15% and 
the median overall survival (OS) was 6 months, and no patient survived more than 26 months after 
first diagnosis 5.  An analysis of outcome in 1126 patients with DLBCL after first line R-CHOP 
included 33 patients with primary refractory DLBCL who received second line therapy with 

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curative intent.  Only 3 (9%) patients were able to receive autologous stem cell transplantation 
(ASCT), and only 1 (3%) patient achieved long term survival 6.  Seshadri et al analyzed 120 
patients who did not respond to second line platinum-based chemotherapy regimens (e.g., R-ICE) 
and showed that only 14% responded to their third line therapy 7.  Ardeshna et al followed 19 
patients with large B-cell lymphoma, and 9 patients with TFL who did not respond to second line 
chemotherapy.  Only 5 of the 28 total patients (18%) responded to third line chemotherapy 8. 
Table 1.
Historical Responses in Refractory NHL (SD or PD to Last Line of Therapy)
Setting
Outcome to Subsequent Therapy
Refractory to 1st line
     9 (n=28)
ORR 21%
     5 (n=64)
ORR 15%, median OS 6 mos
     8 (n=5)
ORR 0%
     6 (n=33)
Proceeded to ASCT 9%, 3% survived > 1 year
     10 (n = 111)
ORR 23%, median OS 10 mos
     11 (n=10)
ORR 10%
     
Refractory to 2nd line
     12 (n=55)
Median OS 5 mos
     8 (n=28)
ORR 18%, median OS (large B-cell lympohoma) <6 mos
     7 (n=73)
ORR 14%
Relapsed post ASCT
     13 (N=45)
Median OS 8 mos
These consistently discouraging results demonstrate that new treatment options are urgently 
needed for patients whose tumors have demonstrated a lack of response to chemotherapy.  
3.1.2
Primary Mediastinal B-cell Lymphoma and Transformed Follicular Lymphoma
Primary mediastinal B-cell lymphoma (PMBCL) has distinct clinical, pathological, and molecular 
characteristics compared to DLBCL.  PMBCL is thought to arise from thymic (medullary) B cells 
and represents approximately 3% of patients diagnosed with large B-cell lymphoma.  PMBCL 
is typically identified in the younger adult population in the fourth decade of life with a slight 
female predominance 14,15.  Gene expression profiling suggests deregulated pathways in PMBCL 
overlap with Hodgkin lymphoma.  Initial therapy of PMBCL generally includes anthracycline-
containing regimens with rituximab with or without involved field radiotherapy.  A recent Phase 
2, prospective study of infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide 
with vincristine, prednisone, and rituximab (DA-EPOCH-R) demonstrated radiotherapy may not 
be required 16.
Follicular lymphoma (FL), a B cell lymphoma, is the most common indolent (slow-growing) form 
of NHL, accounting for approximately 20% to 30% of all NHLs.  Some patients with FL will 
transform (TFL) histologically to DLBCL which is more aggressive and associated with a poor 
outcome.  Histological transformation to DLBCL occurs at an annual rate of approximately 3% 
for 15 years with the risk of transformation continuing to drop in subsequent years.  The biologic 
mechanism of histologic transformation is unknown.  Initial treatment of TFL is influenced by 
prior therapies for follicular lymphoma but generally includes anthracycline-containing regimens 
with rituximab to eliminate the aggressive component of the disease 17.  

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Treatment options for relapsed/refractory PMBCL and TFL are similar to those in DLBCL.  Given 
the low prevalence of these diseases, no large prospective randomized studies in these patient 
populations have been conducted.  Patients with chemotherapy refractory disease have a similar 
or worse prognosis 18 to those with refractory DLBCL.  
In addition, the international, multicohort retrospective non-Hodgkin lymphoma research 
(SCHOLAR-1) study retrospectively evaluated outcomes in patients with chemorefractory 
DLBCL, PMBCL, and TFL.  SCHOLAR-1 integrated data from two Phase 3 studies (LYSARC-
CORAL and Canadian Cancer Trials Group LY.12) and 2 observational cohorts (MD Anderson 
Cancer Center and Mayo Clinic/University of Iowa Specialized Program of Research Excellence).  
Among 861 patients, 635 were included based on chemorefractory search criteria.  Outcomes were 
consistently poor, regardless of refractory subgroup and across cohorts.  The results of SCHOLAR-
1 indicated that patients with chemorefractory, aggressive DLBCL represent a homogenous patient 
population with a response rate of 26% (complete response [CR] rate of 7%) and median overall 
survival of 6.3 months 19.
3.1.3
High Grade B-cell Lymphoma
In 2016, the World Health Organization introduced a new category of large B-cell lymphomas 
called high grade B-cell lymphoma (HGBCL) 20.  This designation includes large B-cell 
lymphomas with MYC and BCL2 and/or BCL6 rearrangements that are phenotypically 
intermediate to DLBCL or B-cell lymphoma, unclassifiable (this latter category has since been 
eliminated).  MYC rearrangements in large B-cell lymphomas are associated with a poor prognosis 
that is worsened in cases of concomitant BCL2 and/or BCL6 alterations, ie, double- or triple-hit 
lymphomas.  As such, patients with HGBCL are likely to face poor survival outcomes.
3.2
Radiation Therapy for Refractory Lymphoma/Leukemia Following 
CAR T Cell Therapy
3.2.1
Background and Significance
MGH is on the forefront of academic institutions employing chimeric antigen receptor (CAR) T 
cell therapy, with 200+ patients already treated at MGH since the first FDA approval of axicel  
(axicabtagene ciloleucel; Yescarta)1 and tisacel (tisagenlecleucel; Kimrayah)2 in 2017. Eligible 
patients for these commercial CAR T cell products have ALL (acute lymphoblastic leukemia) or 
relapsed or refractory large B cell lymphoma after at least 2 lines of systemic therapy1. In addition, 
30 new protocols of investigational CAR T cell therapy are underway at MGH, making it amongst 
the most active cellular therapy research programs across the world.
CAR T cell therapy is an exciting example of genetically modifying a patient’s T cells to target 
tumor cells for death for patients with the above relapsed/refractory hematologic malignancies 
who otherwise have very limited, if any, remaining options to achieve cure. A patient first 
undergoes leukapheresis to collect peripheral blood mononuclear cells (PBMCs)1. The T cells are 
isolated in a manufacturing laboratory and are genetically engineered most commonly via a viral 
vector to target an antigen displayed by the patient’s tumor cells, which thus far has been CD19. 
These cells are then expanded and cryopreserved, for shipment back to the hospital. The patient is 

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admitted for infusion of the CAR T cells, basically a re-introduction of modified T cells into the 
patient’s body. The time from eligibility determination for CAR T cells to the infusion of the CAR 
T cells can take as long as 2-3 months1.  
While response rates range from 50 - 80%, durable responses are only seen in 30-40% of patients 
at long term time points, demonstrating that 60% of patients will eventually relapse following CAR 
T cell therapy2–4. Although, the best predictor of durable response is the ability for a patient to 
achieve a complete response (CR), only 40-52% of patients will achieve CR at early day 30 re-
staging. Of the remaining patients with partial response, stable disease, or progressive disease, 
only 10-15% will subsequently convert to a CR at later timepoints without any clear predictor of 
later response emphasizing the need for better consolidative strategies. 
The post-CAR T day 30 timepoint represents a unique opportunity to stimulate the immune system 
and to enhance CAR T-dependent cellular toxicity in a setting in which patients have no reliably 
effective therapeutic options other than local radiotherapy. These patients may have localized 
masses in a limited number of sites which are symptomatic or may become symptomatic. 
Importantly, given the sheer bulk of some of these masses, relapse after CAR T cell therapy 
remains a concern. Based on a recently presented multicenter retrospective study of 
chemorefractory high grade B cell lymphoma who underwent axicel, patients with tumor diameter 
< 5 cm tended to have improved outcomes 5. In bone marrow transplant patients, for example, 
radiotherapy is administered for localized refractory/relapsed sites, including bulky masses, in the 
peritransplant setting6 . No clinical trials on RT and CAR T cell therapy have yet been published, 
but Memorial Sloan Kettering7  and University of Pennsylvania8 are currently studying RT in the 
pre-CAR T cell therapy bridging setting.
In addition to potential local control benefit, even more exciting is that radiotherapy has the 
potential to improve immunologic response against cancer cells, to act in synergy with CAR T cell 
therapy, to produce long term cures. Potential mechanistic reasons for failure following CAR T 
cell therapy include downregulation of the tumor-associated antigen, mutation of tumor cells to a 
more rapidly dividing phenotype, and inability of CAR T cells to adapt to a changing tumor-
associated antigen repertoire1,9. Low dose radiotherapy may enhance immune-directed tumor death 
by providing an antigen-independent mechanism of tumor cells resistant to CAR T cell due to 
downregulation of the receptor against which the CAR T cell are targeted to based on a murine 
model of pancreatic ductal adenocarcinoma7. Based on trials of immune checkpoint inhibitor 
therapy, RT contributes to immunomodulation by upregulating chemokines, which appears to help 
T cells locate and infiltrate the tumor, resulting in radiosensitization 10. As such, it is conceivable 
that radiotherapy may help CAR T cells infiltrate into early refractory disease as at a timepoint 
that the CAR T cells are still very active. 
3.3
Correlative Studies Background
Correlative studies will be performed on peripheral blood and tumor biopsies, before and after 
radiation therapy to investigate mechanisms involving potential synergy between RT and CAR T 
cell therapy. The effectiveness of CAR 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 when possible PCR analysis using peripheral blood samples as per standard SOPs. 
Samples will be collected per the protocol Schedule of Events (see 11.1 Schedule of Events). 
Periodic monitoring of anti-inflammatory cytokines secretion will be performed to determine 
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will be evaluated at the eligibility and in subjects failing following RT. 
Additional testing may be done depending on the clinical condition; for instance, patients with an 
atypical skin rash following RT 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 will be analyzed for the presence of 
CAR-T cells by flow cytometry and/or IHC. 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. Additional clinical samples testing 
may be performed based on the Exploratory Endpoints as listed in Section 2.4.
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, and pathology 
samples will be delivered to MGH Pathology Department. Documentation 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 assays.
4. PARTICIPANT SELECTION
All subjects must sign and date the IRB/IEC approved consent form before initiating any study 
specific procedures or activities that are not part of a subject’s routine care.  Refer to Section 10 
for details.
Each subject who enters the screening period will receive a unique subject identification (ID) 
number before any study specific procedures or activities are initiated.  This number will be used 
to identify the subject throughout the study and must be used on all study documentation related 
to the subject.  Furthermore, the subject identification number must remain constant throughout 
the entire clinical study, it must not be changed after enrollment or if the subject is rescreened or 
retreated.
4.1
Diagnosis and selection criteria: refractory hematologic malignancy following 
any CD19-targeted CAR T cell therapy
Inclusion Criteria 
1. Biopsy-confirmed refractory disease within 30 to 90 days following any CD19-targeted 
CAR T cell therapy for a  hematologic malignancy (these include relapsed or refractory 
large B-cell lymphoma after two or more lines of systemic therapy, including diffuse 
large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-
cell lymphoma, high grade B-cell lymphoma, DLBCL arising from follicular lymphoma, 
and mantle cell lymphoma)

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2. At least 1 measurable lesion according to the Lugano criteria1.  Lesions that have been 
previously irradiated will be considered measurable only if progression has been 
documented following completion of radiation therapy
3. Toxicities due to prior therapy must be stable and recovered to  Grade 1 (except for 
clinically non-significant toxicities such as alopecia) if there is concern for overlap of 
anticipated radiation-related toxicity and toxicity from prior therapy due to where the 
radiation therapy field is located. 
4. Age 18 or older
5. Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 
2. 
6. Females of childbearing potential must have a negative serum or urine pregnancy test 
(females who have undergone surgical sterilization or who have been postmenopausal for 
at least 2 years are not considered to be of childbearing potential)
7. Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria
1. Any medical condition likely to interfere with assessment of safety or efficacy of RT
2. Women of child-bearing potential who are pregnant because of the potentially dangerous 
effects of the preparative chemotherapy on the fetus or infant. Females who have 
undergone surgical sterilization or who have been postmenopausal for at least 2 years are 
not considered to be of childbearing potential
3. In the investigators’ judgment, the subject is unlikely to complete all protocol-required 
study visits or procedures, including follow-up visits, or comply with the study 
requirements for participation
4.2
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.
5. REGISTRATION PROCEDURES 
5.1
General Guidelines for DF/HCC Institutions
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.  
5.2
Registration Process for DF/HCC Institutions
Applicable DF/HCC policy (REGIST-101) must be followed.  
6. TREATMENT PLAN
6.1
Study treatment 
No investigational treatment is included in this study. Radiation therapy is only offered as a 
standard-of-care treatment. 
6.2
Rationale for Study Treatment Dosing 
The dose/fractionation of radiotherapy is not being experimentally studied – the radiation 
oncologist will follow best judgement and International Lymphoma Radiation Oncology Group 
(ILROG) guidelines for refractory DLBCL (if applicable) to decide on an appropriate, standard 
of care dose for radiation, regardless of whether or not patient decides to be on the pilot study.
The lesion receiving radiation will be a refractory site of disease following CAR T cell therapy 
that in most cases, has undergone biopsy, unless an exception is met as per inclusion criteria. For 
patients with more than one refractory lesion, radiation therapy may be provided to one site only 
or to a limited number of sites (with only one site getting biopsy). While there is no explicit limit 
on the number of sites to receive radiation therapy due to patient variety, this decision will be 
guided based on symptoms due to mass effect, spinal canal or brain involvement, and anticipated 
toxicity of providing radiation therapy to more than one site. In the vast majority of cases, 
radiation therapy will be limited to one or two sites. 
6.3
Excluded Medications
Corticosteroids and other immunosuppressive drugs should also be avoided for 3 months after 
CAR T cell administration, unless used to manage CAR T cell-related toxicities. Other medications 
that might interfere with the evaluation of the investigational product, such as non-steroidal 
anti-inflammatory agents should also be avoided for the same time period unless medically 
necessary.  Physiologic steroids (less than or equal to 5mg/day) will be allowed on study. 
Treatment for lymphoma such as chemotherapy, immunotherapy, targeted agents, radiation, and 
high dose corticosteroid, other than defined/allowed in this protocol, and other investigational 
agents are prohibited, except as needed for treatment of disease progression after the CAR T cell 
infusion and radiation therapy. Patients will be allowed to remain on maintenance therapy 
(ibrutinib, revlimid, etc) if these medications were initiated prior to and continued during CAR-T 
infusion.

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6.4
Subsequent Therapy 
Subsequent therapy administered after the CD19-targeted CAR T cell therapy infusion for a subject’s 
disease, such as non-study specified chemotherapy, immunotherapy, targeted agents, as well as 
stem cell transplant and radiation therapy, will be recorded until the subject completes the long-
term follow-up period, is considered lost to follow-up, withdraws consent, or dies.  
6.5
Duration of Follow Up
Long-term Follow-up Period
All subjects who complete the study, and those who withdraw from the study after receiving RT 
for reasons other than death, will be asked to participate in a long-term follow-up study for up to 
6 months after their RT, with a focus on long-term efficacy and safety. These patients will also 
have long-term follow-up as part of CAR T cell therapy registry. After Month 24 patients will be 
followed via the CIBMTR immune effector cell therapy registry. 
6.6
Criteria for Taking a Participant Off Study
6.6.1
Subject Withdrawal
Subjects have the right to withdraw from the study at any time and for any reason without prejudice 
to their future medical care by the physician or at the institution.
Subjects can decline to continue to receive study required treatment and/or other protocol required 
procedures at any time during the study but continue to participate in the study.  This is referred to 
as partial withdrawal of consent.
If partial withdrawal of consent occurs, the investigator must discuss with the subject the 
appropriate process for discontinuation from protocol required therapies and must discuss options 
for continued participation, completion of procedures and the associated data collection as outlined 
in the SOA. The level of follow-up and method of communication should also be discussed 
between the research staff and the subject and documented in the source documents.
Withdrawal of full consent from a study means that the subject does not wish to receive further 
protocol required therapy or undergo procedures and the subject does not wish to continue further 
study follow-up.  Subject data collected up to withdrawal of consent will be retained and included 
in the analysis of the study, and where permitted by local regulations, publicly available data (death 
records) can be included after withdrawal of consent.  The investigator is to discuss with the subject 
appropriate procedures for withdrawal from the study. 
As part of the study sites may be asked to conduct searches of public records, such as those 
establishing survival status, if available, to obtain survival data for any subject for whom the 
survival status is not known. Sites may be also asked to also retrieve autopsy reports to confirm 
status of disease at the time of death. 
The investigator and/or sponsor can also decide to withdraw a subject from the investigational 
product and/or other protocol-required therapies, protocol procedures, or the study as a whole or 
at any time prior to study completion.

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6.6.2
Reasons for Removal from Study
Reasons for removal of a subject from the study are as follows:
Subject withdrawal of consent from further follow-up
Investigator decision
Lost to follow-up 
Death
The reason for taking a participant off study, and the date the participant was removed, 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 
REGIST-101.
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
7.1
Expected Toxicities
To date, the following important risks have been identified with axicel and tisacel:  CRS, 
neurologic toxicities, infections, and cytopenias.  Grading and management of these toxicities will 
be performed utilizing the recently released ASTCT CRS/ICANS grading system21. Please refer 
to the current product label for axicel,tisacel, lisocabtagene maraleucel, and brexucabtagene 
autoleucel for discussion of CRS and neurotoxicity (ICANS). Treatment with RT will occur after 
30 day post-infusion period during which centers are FDA mandated to observe for peak toxicities. 
Additional information and management recommendations can also be found in appendix A.  The 
following are important risks identified with radiation therapy but depend upon the target site for 
radiation therapy: dermatitis, pneumonitis, esophagitis, fatigue. 
7.2
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial subject.  The 
event does not necessarily have a relationship to treatments provided leading to study eligibility.  
The investigator is responsible for ensuring that any adverse events observed by the investigator 
or reported by the subject are recorded in the subject’s medical record. 
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition has increased in severity, frequency, 
and/or duration or has an association with a worse outcome.  A pre-existing condition that has not 
worsened during the study or involves an intervention such as elective cosmetic surgery or a 
medical procedure while on study, is not considered an adverse event.
Interventions for pretreatment conditions (such as elective cosmetic surgery) or medical 
procedures that were planned before study participation are not considered adverse events.  
Hospitalization for study treatment infusions or precautionary measures per institutional policy are 
not considered adverse events.

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The term “disease progression” as assessed by measurement of malignant lesions on radiographs 
or other methods should not be reported as adverse events.  Death due to disease progression in 
the absence of signs and symptoms should be reported as the primary tumor type (e.g., B-Cell 
Lymphoma). 
For situations when an adverse event or serious adverse event is due to the disease under 
investigation report the signs and symptoms.  Worsening of signs and symptoms of the malignancy 
under study should also be reported as adverse events in the appropriate section of the CRF. 
The investigators clinical judgment is used to determine whether a subject is to be removed from 
treatment due to an adverse event.  In the event a subject request to withdraw from protocol 
required therapies or the study due to an adverse event, the subject should undergo the procedures 
outlined in the Month 3 visit of the SOA. 
7.2.1
Definition of Serious Adverse Events
A serious adverse event is defined as an adverse event that meets at least 1 of the following serious 
criteria:
Fatal
Life threatening (places the subject at immediate risk of death)
Requires in patient hospitalization or prolongation of existing hospitalization
Results in persistent or significant disability/incapacity
Congenital anomaly/birth defect
Other medically important serious event
An adverse event would meet the criterion of “requires hospitalization” if the event necessitated 
an admission to a healthcare facility (eg, overnight stay). 
Events that require an escalation of care when the subject is already hospitalized should be 
recorded as a serious adverse event. Examples of such events include movement from routine care 
in the hospital to the ICU or if that event resulted in a prolongation of the existing planned 
hospitalization. 
If an investigator considers an event to be clinically important, but it does not meet any of the 
serious criteria, the event could be classified as a serious adverse event with the criterion of “other 
medically important serious event.” 
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 CAR T cells treatment. Additionally, patients will also self-report adverse event 
outcomes pertaining to the region of interest as per their RT treatment field. 
CTCAE term (AE description) and grade: All non-CRS/ICANS toxicities will be graded 

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per CTCAE by the Investigator. The descriptions and grading scales found in the revised 
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
PRO-CTCAE – Patients will also have the opportunity to self-report adverse event 
outcomes. The descriptions and grading scales found in the NCI Patient Reported 
Outcomes. Common Terminology Criteria for Adverse Events (PRO-CTCAE) version 1.0 
will be utilized. A copy of the possible items for PRO-CTCAE will can be downloaded 
from the NCI website. Patient will be asked to fill out the applicable section of the survey 
depending on their radiation treatment site, including items for pain and mood for all 
patients: 
https://healthcaredelivery.cancer.gov/pro-ctcae/instrument.html
ASTCT CRS/ICANS: Any delayed CAR-T related CRS and/or neurotoxicity (ICANS) 
will be graded using the ASTCT 2019 CRS/ICANS grading system (appendix A).
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  
7.4.1
Reporting of Adverse Events
The investigator is responsible for ensuring that all adverse events observed by the investigator or 
reported by the subject that occur from enrollment (ie, radiation therapy consultation) through 
3 months after RT are monitored and reported.  After 3 months, targeted adverse events including 
(eg, neurological, hematological, infections, autoimmune disorders, and secondary malignancies) 
will be monitored and reported for 6 months after treatment with axicel or tisacel or until disease 
progression, whichever occurs first.
The investigator must address the below for adverse events: 

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Adverse event diagnosis or syndrome (if not known, signs or symptoms)
Dates of onset and resolution
Severity
Assessment of relatedness to investigational product, lymphodepleting chemotherapy or 
study procedures
Action taken
In reviewing adverse events, investigators must assess whether the adverse event is possibly 
related to 1) CAR T cell therapy product 2) RT, or 3) any protocol-required study procedure.  The 
relationship is indicated by a yes or no response and entered into the CRF.  A yes response should 
indicate that there is evidence to suggest a causal relationship between the study treatment or 
procedure and the adverse event.  Additional relevant data with respect to describing the adverse 
event will be collected in the CRFs.
The investigator is responsible for reviewing laboratory test results and determining whether an 
abnormal value in an individual study subject represents a clinically significant change from the 
subject’s baseline values. In general, abnormal laboratory findings without clinical significance 
(based on the Investigator's judgment) are not to be recorded as adverse events.  However, 
abnormal laboratory findings that result in new or worsening clinical sequelae, require therapy or 
adjustment in current therapy are considered adverse events.  Where applicable, clinical sequelae 
(not the laboratory abnormality) are to be recorded as the adverse event.  
The investigator is expected to follow reported adverse events until stabilization or resolution.  If 
a subject begins a new anticancer therapy, the adverse event reporting period for non-serious 
adverse events ends at the time the new treatment is started.
7.4.2
Reporting of Serious Adverse Events and Non-serious CRS events Grade  3
The investigator is responsible for reporting all serious adverse events observed by the investigator 
or reported by the subject that occur after signing of the consent through 3 months after the 
RT.  After 3 months, only serious targeted adverse events (e.g., neurological, hematological, 
infections, autoimmune disorders, and secondary malignancies) observed by the investigator or 
reported by the subject will be reported for 6 months after RT or until disease progression, 
whichever occurs first.   For subjects who screen fail or are enrolled but do not receive RT, the 
reporting period for serious adverse events ends 30 days after the last procedure (e.g., biopsy).  
Serious events that the investigator assesses as related to RT should be reported regardless 
of the study period.
All serious adverse events and non-serious CRS events  Grade 3 22 must be submitted within 24 
hours following the investigators knowledge of the event using a SAE Report Form. Refer to 
the SAE Report Form for instructions on how to submit the SAE report.  Subsequently, all 
serious adverse events will be reported to the health authorities per local reporting guidelines.
Progression of the malignancy during the study should not be reported as a serious adverse event. 
Adverse events associated with disease progression may be reported as serious adverse event.  If 
the malignancy has a fatal outcome within 3 months of the last day of the lymphodepleting therapy, 

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CAR T infusion, or RT, then the event leading to death must be recorded as a serious adverse event 
with CTCAE Grade 5.
Death must be reported if it occurs during the serious adverse event reporting period, irrespective 
of any intervening treatment.
Any death occurring after the first dose of chemotherapy, for the purpose of pre-lymphodepletion, 
and within 3 months of the CAR T infusion or RT, regardless of attribution to treatment, requires 
expedited reporting within 24 hours.  Any death occurring greater than 3 months after the CAR T 
infusion or RT requires expedited reporting within 24 hours only if it is considered related to 
treatment.
7.4.3
Pregnancy and Lactation
There is no relevant clinical experience with CAR T cell therapy in pregnant or lactating women, 
and animal reproductive studies have not been performed.  Women of childbearing potential must 
have a negative pregnancy test prior to enrollment because of the potentially dangerous effects of 
the RT on the fetus. RT should not be administered to pregnant women.
If a pregnancy occurs in a female subject enrolled into the study, or a female partner of a male 
subject, within 6 months of completing RT, the pregnancy must be reported to the PI.  Information 
regarding the pregnancy and/or the outcome may be requested by the PI. 
In addition to reporting any pregnancies occurring during the study, investigators should monitor 
for pregnancies that occur after the last dose of axicel or tisacel through 6 months for female 
subjects and for 6 months for the female partner of the male subjects.
The pregnancy should be reported to the PI contact within 24 hours of the investigator knowledge 
of the pregnancy event. 
7.4.4
Criteria to Pause Enrollment
Enrollment will be paused if any of the following criteria is met:
1) Any subject with grade 4+ RT-related adverse events 
or
2) Subject incidence of the following Grade 4+ CAR-T-related adverse events lasting more than 
7 days is > 33%:
Neurologic toxicities
CRS (per ASTCT 2019) 
Other non-hematological serious adverse event
Infection (treatment-related)
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. 

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7.5
Reporting to the Food and Drug Administration (FDA)
Not applicable.
7.6
Reporting to the NIH Office of Biotechnology Activities (OBA)
Not applicable.
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. 
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.
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 8.1) and the characteristics of an 
observed AE (Section 8.2) will determine whether the event requires expedited reporting in 
addition to routine reporting.
8. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
8.1
Biomarker Studies
N/A, no biomarker studies.

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8.2
Laboratory Correlative Studies
Biomarker analysis will be performed on blood and tumor samples to evaluate predictive and 
pharmacodynamic markers for CD19-targeted CAR T cell therapy.  Prognostic markers specific 
for large B-cell lymphoma and related to the tumor immune environment may also be evaluated 
in archived and fresh tumor biopsies. 
The presence, expansion, persistence, and immunophenotype of transduced anti-CD19 CAR T 
cells will be monitored in the blood primarily by PCR analysis, complemented by flow 
cytometry.  Expansion and persistence in peripheral blood will also be monitored by a CD19 CAR 
specific quantitative polymerase chain reaction assay (qPCR).  
Levels of serum cytokines will be evaluated in serum to characterize the pharmacodynamic and 
safety profile of CAR T cell therapy before and after radiotherapy.  The following pro-
inflammatory, homeostatic and immune modulating cytokines may be included in the panel:  IL-
6, IL-15, IL-17a, TNF- , GM-CSF, IFN- , IL-12p40/p70 and IL-13; immune effector molecules: 
Granzyme A, B and Perforin; correlates of acute phase response: CRP and SAA; Chemokines 
MIP-1 , 
 MCP-1, IP-10, and IL-8.  In addition, IL1Ra, 
 and ferritin, will also be 
measured.   
Additional translational samples of PBMC, serum cytokines, tissue, and bone marrow may be 
taken for additional genomics sequencing, RNA expression profiling, cytokine/biomarker analysis 
and flow cytometry, and tumor profiling. This may also include tumor samples for genomic, 
transcriptional and protein expression analysis. Samples will be analyzed within a local immune 
monitoring facility. 
9. STUDY CALENDAR
Assessments must be performed prior to administration of any study agent. Study assessments and 
agents should be administered within + 28 days of the protocol-specified date, unless otherwise 
noted.
Research staff should refer to the SOAs for an outline of the procedures required.  The visit 
schedule is calculated from RT start date. An overview of study assessments/procedures is 
outlined below.  
9.1
Informed Consent
Before a subject’s participation in the clinical study, the investigator is responsible for obtaining 
written informed consent from the subject after adequate explanation of the study design, 
anticipated benefits and the potential risks.  Subjects should sign the most current IRB/IEC 
approved ICF prior to any study specific activity or procedure is performed.
The consent process and the subject’s agreement or refusal to participate in the study is to be 

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documented in the subject’s medical records.  If the subject agrees to participate, the ICF is to be 
signed and personally dated by the subject and by the person who conducted the informed consent 
discussion.  The original signed ICF will be retained in accordance with institution policy and 
IRB/IEC requirements with a copy of the ICF provided to the subject.
All subjects who are enrolled into the study should be re-consented with any updated version of 
the IRB/IEC approved ICF if relevant to their participation in the study.
9.2
Demographic Data
Demographic data will be collected to include sex, age, race, ethnicity, and country of enrollment 
to study their possible association with subject safety and treatment effectiveness.
9.3
Medical and Treatment History
Relevant medical history prior to the start of adverse event reporting will be collected.  Relevant 
medical history is defined as data on the subject’s concurrent medical condition that would be 
typically shared in a referral letter.  All findings will be recorded in the CRFs.
In addition to the medical history, all history related to the subject’s disease, treatment and 
response to treatment will be collected and must date back to the original diagnosis.
For subjects who are being referred from another clinic or institution to the participating research 
center, copies from the subject’s chart should be obtained.
9.4
Physical Exam, Vital Signs, Performance Status
Physical exams will be performed during screening and at times noted in the SOA.  Changes noted 
in subsequent exams when compared to the baseline exam will be reported as an adverse event. 
Performance status as measured by the ECOG scale will be performed to quantify the subject’s 
general well-being and ability to perform activities of daily life.
9.5
Laboratory
The below samples will be collected at the time points indicated in the SOA.  Additional samples 
(eg, blood, tissue, etc) may be collected as needed for further safety testing.
Local lab analysis:  
Sodium (Na), potassium (K), chloride (Cl), total CO2 (bicarbonate), creatinine, glucose, 
blood urea nitrogen (BUN) or urea (if BUN test cannot be analyzed by the local lab), 
albumin, calcium total, magnesium total (Mg), inorganic phosphorus, alkaline 
phosphatase, ALT/GPT, AST/GOT, total bilirubin, direct bilirubin, LDH, uric acid
C-reactive protein (CRP) 
Complete Blood Count (CBC) with Differential 
A urine or serum sample will be collected and assessed locally for females of childbearing 
potential.  If the screening pregnancy test is positive, the subjects should not be enrolled.  

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Additional blood draws for PBMC and serum, as well as tissue may be collected and 
stored locally for subsequent translational research studies to include, but not limited 
to, cytokine analysis, FLOW and expression phenotyping, DNA/RNA sequencing, 
IHC/RNA ISH, and/or correlative studies. 
Blood draws for PBMC (lymphocyte subsets, and anti-CD19 CAR T cell levels) and 
cytokine analysis will be performed at intervals outlined in the SOA.  
Archived tumor tissue
o
Fresh tumor samples will be collected for central pathology review and evaluation 
of prognostic markers specific for large B-cell lymphoma and pertaining to the 
tumor immune environment.  Additional analysis may include CD19 expression, 
gene 
expression 
profiling, 
and 
analysis 
of 
tumor-specific 
DNA 
alterations.  Remaining tumor samples may be stored for future exploratory 
analysis of DNA (somatic mutations), RNA, or protein markers.
9.6
Biomarkers
Biomarker analysis will be performed on blood and tumor samples to evaluate predictive and 
pharmacodynamic markers for CAR T cell therapy and described in Section 10.1. 
9.7
Description of Study Periods
9.7.1
Screening
The screening period begins on the date the subject signs the IRB/IEC approved ICF and continues 
through confirmation of enrollment.  Informed consent must be obtained before completion of any 
non-standard of care study specific procedures.  Procedures that are part of standard of care are 
not considered study specific procedures and may be performed prior to obtaining consent and 
used to confirm eligibility.  Confirmation of this data must occur within the time allowance as 
outlined below and in the SOA.
After written informed consent has been obtained, subjects will be screened to confirm study 
eligibility and participation.  Only subjects who meet the eligibility criteria listed in Section 4 will 
be enrolled in the study.  If at any time prior to enrollment the subject fails to meet the eligibility 
criteria, the subject should be designated as a screen failure on the subject screening log with the 
reasons for failing screening.
The following assessments/procedures are to be completed during the screening period at the time 
points outlined in the SOA:
Medical history and disease assessment
Physical examination
o
Subjects with symptoms of central nervous system malignancy such as new onset 
severe headaches, neck stiffness, or any focal neurologic findings on physical exam 
will have lumbar puncture for examination of cerebral spinal fluid.
Vital signs, including blood pressure, heart rate, oxygen saturation, and temperature
ECOG performance status 

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Imaging Studies
o
PET CT post-CAR T cell therapy
PET-CT performed following the subject’s therapy and prior to signing the 
consent may be used for confirmation of eligibility. 
PET CT should be performed as close to enrollment as possible.  
Labs 
o
Chemistry panel
o
CBC with differential
Serious Adverse Event reporting (refer to Section 8 for safety reporting guidelines)
Concomitant medications documentation and previous cancer treatment history
Once eligibility confirmed, collection of archived tumor sample, as well as fresh tumor 
sample(s) after RT. 
9.7.2
Enrollment Period & RT simulation/planning
No specific restrictions are made for the use of RT after biopsy-confirmed relapse following 
CAR T cell therapy. Prior RT is not an exclusion criterion given the technologies available to 
safely deliver re-irradiation in many scenarios with modern technology. The RT simulation 
consists of imaging patients in the treatment position with using custom immobilization. After a 
planning period of 7-14 days, depending on complexity of treatment plan, patients begin 
radiation therapy. PET-CT imaging will be repeated if >28 days from prior imaging and 
enrollment.
9.7.3
RT Treatment
Patients are seen weekly during RT as per standard of care to monitor toxicities of RT. Subject 
will allow study personnel to continue to access medical records so that information related to 
subjects health condition and initial treatment response may be obtained.  The following 
procedures will be completed for subjects as outlined in the SOA:
Physical exam 
Vital signs, including blood pressure, heart rate, oxygen saturation, and temperature
Labs
o
Chemistry Panel 
o
CBC with differential
o
Cytokine levels
o
Lymphocyte subsets 
o
Translational lab collection.  
Adverse/Serious Adverse Event reporting (refer to Section 8 for safety reporting 
guidelines)
Concomitant medications documentation 

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If a subject is admitted to the hospital with any RT, CAR T- related adverse event(s), the following 
labs will be collected on the day of hospital re-admission and then weekly through and 
including on the day of discharge:
Translational labs (two 10cc purple top tubes)
Cytokines (one 10cc red top tube)
9.7.4
Post RT Period
Patients are seen weekly for one month following RT. Subject will allow study personnel to 
continue to access medical records so that information related to subjects health condition and 
initial treatment response may be obtained.  The following procedures will be completed for 
subjects as outlined in the SOA:
Seven to fourteen days after beginning RT, patients will undergo a core-needle biopsy (FNA 
acceptable if core-needle unable to be done for any reason). This biopsy will allow a direct 
comparison of inflammatory cytokine and T cell infiltration into the tumor in comparison to pre-
RT biopsy that confirmed refractory disease. If it is deemed unsafe to proceed biopsy may be 
deferred as other immune correlates will be collected from peripheral blood and serum. 
Physical exam 
Vital signs, including blood pressure, heart rate, oxygen saturation, and temperature
Labs
o
Chemistry Panel 
o
CBC with differential
o
Cytokine levels
o
Lymphocyte subsets 
o
Translational lab collection.  
Adverse/Serious Adverse Event reporting (refer to Section 8 for safety reporting 
guidelines)
Concomitant medications documentation 
If a subject is admitted to the hospital with any RT, CAR T- related adverse event(s), the following 
labs will be collected on the day of hospital re-admission and then weekly through and 
including on the day of discharge:
Translational labs (two 10cc purple top tubes)
Cytokines (one 10cc red top tube)
At any time during the post treatment assessment period, if a subject progresses and is either not 
eligible for re-treatment or chooses not to pursue re-treatment, the subject will proceed directly to 
the Month 3 visit and be followed for survival, subsequent therapy and disease outcomes in the 
long term follow-up period.  A translational lab set and serum sample (for cytokine evaluation) 
should be collected at the time of progression, prior to starting any subsequent anti-cancer therapy.

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9.7.5
Long-term Follow-up Period
All subjects who complete the study, and those who withdraw from the study after receiving RT 
for reasons other than death, will be asked to participate in the long-term follow-up portion of this 
study up to 12 months from CAR-T infusion, with a focus on long-term efficacy and safety. These 
patients will also have long-term follow-up as part of the FDA mandated CIBMTR CAR T cell 
therapy registry. 
The following procedures will be completed for subjects who are enrolled at the time points of 6, 
9, and 12 months following CAR-T infusion, as outlined in the SOA (Long-term Follow-up 
Period) Table 3:
Physical exam
CTCAE/PRO-CTCAE Surveys
PET-CT/ Disease assessment at 6 and 12 months per standard of care  
Survival status
Labs 
o
CBC with differential 
o
Cytokine levels
o
Lymphocyte subsets 
o
Translational lab collection.  
Subsequent therapy for the treatment of NHL 
Refer to Sections 8.4 for targeted adverse/serious adverse event reporting
o
Including neurological, hematological, infections, autoimmune disorders, and 
secondary malignancies 
Targeted concomitant medication documentation (for 12 months or until disease 
progression, whichever occurs first)
o
Including 
gammaglobulins, 
immunosuppressive 
drugs, 
anti-infectives, 
and 
vaccinations
Subjects may be contacted by telephone to confirm survival status and report targeted concomitant 
medication use.
If a subject progress in the LTFU phase, the subject will continue to be followed for survival status 
and subsequent therapy for the treatment of NHL.  A translational lab sample and serum (for 
cytokine evaluation) should be collected at the time of progression as part of CAR T cell therapy 
protocol, prior to starting any subsequent anti-cancer therapy. 
Should the subject fail to return to the clinic for a scheduled protocol specific visit, sites will need 
to make 2 attempts by a combination of telephone and mail to contact the subject. Sites must 
document both attempts to contact the subject.  If a subject does not respond within 1 month after 
the second contact the subject will be considered lost to follow-up and no additional contact will 
be required. 
As patients will be receiving commercial product, patients will also have long-term follow-up as 
part of FDA mandated CAR T cell therapy registry. 

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Table 2.
Schedule of Assessments
Procedures
Screening
Enrollment & 
RT Planning
Radiotherapy
Post Radiotherapy Period
Day
No longer than 14  days from 
biopsy and within 28 days of 
enrollment
Within 14 days 
of Initiation of 
Radiotherapy 
Day 0
Weekly through 
completion (± 7 
days)
Week 1 Post-
Treatment
(± 7 days)
Week 2 Post- 
Treatment
(± 7 days)
Week 3 Post-
Treatment
(± 7 days)
Week 4 Post- 
Treatment
(± 7 days)
Informed consent
X
Medical history 
X
ECOG Performance Status
X
X
X
X
CRS/ICANS Consensus 
Grading
X
X
X
CTCAE/PRO-CTCAE 
Surveys
X
X
Tumor Biopsy
X1,2 
(w/in 90 days of CAR T infusion)
X2
PET-CT/ disease assessment
X3
RT Planning
X
Physical exam
X
X
Vital signs 
(BP, HR, O2 sat, temp)
X
X
Weight 
(plus Height at screening)
X
Blood draw for Chemistry 
panel
X
X
X
X
X
X
X
Blood draw for CBC 
w/differential
X
X
X
X
X
X
X
Blood draw for C-reactive 
protein (CRP)
X
X
X
X
X
X
X
Blood draw for Lymphocyte 
subsets3
X
X
X
X
X
X
Blood draw for Cytokines4,5
X
X
X
X
X
X
Blood draw for translational 
lab collection 4, 6
X
X
X
X
X
X
Radiotherapy7
X
Adverse events/ 
Concomitant medication
X
X
X
X
X
X
X
X
1 Tumor biopsy: Either FFPE tumor block or up to 20 unstained slides. Fresh tumor biopsies are preferred however archival tissue is acceptable if obtained prior to screening period but following CAR-T 
infusion without intervening therapy. 
2 Tumor biopsy may be deferred if not deemed clinically appropriate and safe. 
3 PET-CT (Neck-Chest-Abdomen-Pelvis)/disease assessment: If recent PET-CT performed > 45 days from enrollment, baseline scans must be repeated. 

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4 Prior to radiotherapy on Day 0, then weekly through 4 weeks post radiotherapy. 
5 Cytokines: 5cc red top tubes
6 Translational Labs: Two 10cc purple top tubes
7 Radiotherapy: Individual patient course may vary depending on optimal treatment strategy.  
8 Tumor biopsy: Either FFPE tumor block or up to 20 unstained slides. If possible, repeat tumor biopsy to be obtained in the event of disease progression. 
Table 3.
Schedule of Assessments (Long-term Follow-up Period)
Procedure
Long Term Follow-up Period 
(Each visit calculated from CAR-T infusion)
Visit Frequency
Month 6
Month 9
Month 12
Physical exam
X
X
X
CTCAE/PRO-CTCAE Surveys
X
X
X
PET-CT/disease assessment1
X
X
Survival Status
X
X
X
Blood draw for CBC w/differential 3
X
X
X
Blood draw for Lymphocyte subsets 3
X
X
X
Blood draw for Cytokines4,5
X
X
X
Blood draw for translational lab 
collection 4, 6
X
X
X
Targeted AE/SAEs 7
X
X
X
Targeted concomitant medication 8
X
X
X
Subsequent therapy for NHL9
X
X
X
1 PET-CTs/disease assessments will continue through Month 12 or until disease progression, whichever comes first, as is performed per standard of care. 
3 Subjects will continue to provide samples for CBC w/diffs, lymphocyte subsets and anti-CD19 CAR T cells through Month 12 as per standard of care
4 Monthly starting 6 months from CAR-T infusion 
5 Cytokines: 5cc red top tubes
6 Translational Labs: Two 10cc purple top tubes
7 Targeted AEs/SAEs will be collected for 24 months or until disease progression (whichever occurs first)
8  Targeted concomitant medications will be collected for 24 months or until disease progression (whichever occurs first)
9 Subsequent therapy administered after CAR-T infusion for a subjects’ disease such as non-study specified chemotherapy, immunotherapy, targeted agents, as well as stem cell transplant must be 
collected until subject completes the long term follow up period, is considered lost to follow up, withdraws consent, or dies.  Subjects may be contacted by telephone to collect information about 
subsequent therapy for NHL and to assess survival status.

Page 39
10. MEASUREMENT OF EFFECT
10.1
Disease Response Assessment
Subjects will be evaluated for disease response by the site investigator at times indicated in the 
SOA.  Disease assessments will be evaluated per the Lugano Criteria1 for Malignant Lymphoma 
23as applicable (appendix B).  Flow cytometric, molecular or cytogenetic studies will not be used 
to determine response.
Pre-RT PET-CT scans of the neck, chest, abdomen and pelvis is required.  Subjects will undergo 
additional PET-CT tumor assessment as part of standard of care.  
After RT, disease assessments will be used to determine the time when progressive disease occurs.  
Subjects with symptoms suggestive of disease progression should be evaluated for progression at 
the time symptoms occur even if it is off schedule as per the SOA. 
11. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 8.0 
(Adverse Events: List and Reporting Requirements).
11.1
Data Reporting
11.1.1 Method
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the 
data for this study.
11.1.2 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.
11.2
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. In additional to the DF/HCC DSMC, a safety review team (SRT) comprised of 
the study sponsor and Kite/Gilead, will review the safety data and make recommendations on 
further study conduct as described below.  
The DSMC will review each protocol up to four times a year with the frequency determined by 

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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 for Phase I or II protocols; for gene therapy protocols, 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. STATISTICAL CONSIDERATIONS
The primary objective is to ascertain the safety and toxicity of radiotherapy in patients with 
hematologic malignancies who will undergo CD19-targeted CAR T cell therapy.  The secondary 
objectives are to evaluate the efficacy of radiotherapy in these patients. Exploratory objectives 
include assessing T cell infiltration, including CAR T cells, into lymphoma following radiotherapy 
and evaluating mechanisms of interplay between radiotherapy and CAR T cell therapy, by 
examining serum cytokine levels and expression changes of key pathway mediators in lymphoma 
biopsy samples before and after radiotherapy
This protocol is designed to assess the impact of radiation therapy. 
12.1
Study Endpoints
Primary Endpoint:
Rate and severity of RT-related toxicity as per CTCAE v5.0 criteria during RT or within 
the first 30 days of completing RT. 
Secondary Endpoints:
Duration of response (DOR): Among subjects who experience an objective response, 
DOR is defined as the date of their first objective response (which is subsequently 
confirmed) to disease progression per Lugano criteria1 or death regardless of cause. 
Subjects not meeting the criteria for progression or death by the analysis data cutoff date 
will be censored at their last evaluable disease assessment date and their response will be 
noted as ongoing.
Objective response rate (ORR) per IRRC: ORR per IRRC is defined as the incidence of 
either a complete response or a partial response by Lugano criteria1 as determined by the 
IRRC.  All subjects that do not meet the criteria for an objective response by the analysis 
data cutoff date will be considered non-responders.  
Progression-free Survival (PFS): PFS is defined as the time from RT completion date to 
the date of disease progression per Lugano criteria1 or death from any cause.  Subjects not 
meeting the criteria for progression by the analysis data cutoff date will be censored at their 
last evaluable disease assessment date.  

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Overall survival (OS):  OS is defined as the time from RT completion to the date of death.  
Subjects who have not died by the analysis data cutoff date will be censored at their last 
contact date.
Exploratory Endpoints:
Levels of anti-CD19 CAR T cells in blood
Levels of cytokines in serum 
Incidence of anti-axicabtagene ciloleucel antibodies
Investigation of potential biomarker development based on assessment of blood cells, 
tumor cells and the proposed actions of the investigational product.
External collaboration with BostonGene, a biotechnology company: anonymized tumor 
samples from core-needle biopsy and blood (paired pre-RT and post-RT samples for each 
patient) will be made available for Next-Generation Sequencing (NGS) and analysis 
following sample collection from all enrolled patients. BostonGene will perform NGS and 
analysis. In order to assist with clinical correlation of NGS data, BostonGene will be 
provided with anonymized data for each sample with regard to clinical characteristics (age, 
diagnosis, prior therapies, response on imaging, pathology results, blood counts, and 
cytokine profiles). Anonymized patient samples will be delivered by secure courier. All 
data will be anonymized (free from any patient identifiers) and securely transmitted with 
approved methods as per MGH IS. 
The primary objective of this study is to assess safety and toxicity of RT following CAR T cell 
therapy.  The assessment of ORR is a secondary objective, and the analysis will be descriptive. 
12.2
Sample Size, Accrual Rate and Study Duration
In terms of number of patients we anticipate to enroll, 53 patients underwent axicel or tisacel 
therapy at MGH within the past year. With a modest 30% refractory disease rate, 16 patients 
would have refractory disease and may be eligible for radiation therapy to achieve disease 
control. For the next one year, given the increasing rate of patients being referred for CAR T cell 
therapy, we expect that 80 patients are expected to undergo axicel or tisacel therapy – as such, 
we modestly anticipate enrolling 20 patients who are candidates for RT on this study. In 
terms of sample size calculation, with a 95% confidence level and a confidence interval of 10, 
with 0.3 (refractory disease rate) * 80 patients = 24 eligible in the population, the required 
sample size is 19 patients. It is noted that this is a pilot study, where the primary objective is 
assessing safety and toxicity, within the limits of what a pilot study can establish. Typically 
recommended ranges for pilot study sample sizes tend to range from 10 – 30. The number 20 is 
based primarily on how many patients can be accrued within a year and how many patients there 
is funding for. We are most concerned about Grade 4 or higher toxicity within RT field. Patients 
will have many different anatomic sites in terms of radiation treatment. Inherently, while a 
sample size calculation can be done as an exercise, the validity of it is highly questionable given 
the multiple anatomic sites to which patients may receive RT and no published data of patients 
who undergo RT following CAR T cell therapy. Results from this pilot study will be used to 
design a larger study, and for that, sample size can be computed based on what safety and 

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toxicity-related events are seen in the pilot study.  Univariate descriptive statistics with t-tests 
will be used to analyze pre- and post-RT QOL and toxicity data.
All subjects will be followed for survival for up to approximately 15 years after the last subject 
receives CAR T cell therapy, with data collected through the CIBMTR data registry starting at 
Month 24. 
12.3
Interim Monitoring Plan
Interim Analysis and Early Stopping Rules
The SRT will review safety data when 3 and 10 subjects treated have had the opportunity to be 
followed for 30 days, respectively.  The study will be stopped if any patients develop grade 4 or 
higher toxicity attributed to RT rather than to lymphoma progression or other cause as per SRT.
Safety Interim Analysis
The SRT will review AE and SAE information on a regular basis throughout subject treatment in 
Phase 2 of the study.  The SRT may request additional safety data or modifying the study conduct.  
The sponsor may request additional reviews by the SRT if safety concerns are identified. Data 
submitted to the SRT may be monitored or unmonitored to facilitate timely review.  
Efficacy Interim Analysis
There is no planned efficacy interim analysis for this portion of the study. 
12.4
Analysis of Primary and Secondary Endpoints
Planned Method of Analysis
The primary analysis of all treated subjects will take place once they have had the opportunity to 
be followed for 6 months.  
Descriptive analyses may occur at any time.
Objective Response Rate
The incidence of objective response and exact 2-sided 95% confidence intervals will be generated.  
Duration of Response
The competing-risk analysis method 24,25 will be used to estimate the cumulative incidence of 
relapse.  The cumulative incidence of relapse in the presence of non-disease related mortality (the 
competing risk) will be estimated along with 2-sided 95% confidence intervals at 3-month 
intervals.  
Progression-free Survival
Kaplan-Meier estimates and 2-sided 95% confidence intervals will be generated for progression-
free survival time.  Estimates of the proportion of subjects alive and progression-free at 3-month 
intervals will be provided.

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Overall Survival
Kaplan-Meier estimates and 2-sided 95% confidence intervals will be generated for OS.  Estimates 
of the proportion of subjects alive at 3-month intervals will be provided.
Safety
Subject incidence rates of adverse events including all, serious, fatal, CTCAE version 5.0 Grade 3 
or higher and treatment related AEs reported throughout the conduct of the study will be tabulated 
by preferred term and system organ class.  Changes in laboratory values and vital signs will be 
summarized with descriptive statistics.  The incidence of concomitant medications will be 
summarized.
Tables and/or narratives of deaths though the long-term follow-up and treatment related SAEs will 
be provided.
12.5
Reporting and Exclusions
The statistical reporting of the safety and efficacy endpoints will be compared to historical controls 
of patients with refractory disease following CAR T cell therapy who did not undergo RT. Subject 
incidence rates of axicel or tisacel-related adverse events, and ORRs will be summarized. DOR, 
PFS, and OS will also be summarized. 
Analysis Subsets  
Access to Individual Subject Treatment Assignments
This is a single arm, open-label study and subjects and investigators will be aware of treatment 
received.  Data handling procedures for the the study will be devised to reduce potential sources 
of bias and maintain the validity and credibility of the study.  These procedures will be outlined in 
the study statistical analysis plan and Trial Integrity Document.

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13. ETHICAL AND REGULATORY REQUIREMENTS
13.1
Independent Review Board/Independent Ethics Committee
A copy of the protocol, ICF and any additional subject or trial information such as subject 
recruitment materials must be submitted to each sites respective IRB/IEC for approval. Once 
approval is obtained from the IRB/IEC, all documents must be provided to the key sponsor contact 
before subject recruitment can begin.
The investigator must also receive IRB/IEC approval for all protocol and ICF changes or 
amendments. Investigators must ensure that ongoing/continuous IRB/IEC approval (ie, annual 
approval) is provided throughout the conduct of the study.  Copies of IRB/IEC approval are to be 
forwarded to the key sponsor contact for archiving.
During the course of the study, investigators are to submit site specific and study serious adverse 
events (provided to the site by the key sponsor contact) along with any protocol deviations to their 
IRB/IEC in accordance with their respective IRB/IEC policies. 
13.2
Subject Confidentiality
Subject confidentiality must be contained at all material submitted to the key sponsor contact. The 
following rules are to be applied.
Subjects will be identified by a unique identification number
Date of birth or year of birth/age at time of enrollment will be reported according with local 
laws and regulations
For reporting of serious adverse events, subjects will be identified by their respective subject 
identification number, initials and data of birth or year of birth (as per their local reporting 
requirements for both initials and date of birth)
Per federal regulations and ICH/GCP guidelines, investigators and institutions are required to 
permit authorization to the sponsor, CRO, IRB/IEC and regulatory agencies to subject’s original 
source documents for verification of study data.  The investigator is responsible for informing 
potential subjects that such individuals will have access to their medical records which includes 
personal information.
13.3
Investigator Signatory Obligations
Each clinical study report will be signed by the coordinating investigator.  The coordinating 
investigator will be identified by the Sponsor under the following criteria:
A recognized expert in the disease setting
Provided significant contributions to the design or analysis of study data
Participate in the study and enrolled a high number of eligible subjects
13.4
 Protocol Amendments and Termination
If the protocol is amended, the investigators agreement with the amendment and the IRB/IEC 
approval of the amendment must be obtained.  Documentation acknowledging approval from both 
parties are to be submitted to the key sponsor contact.

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Both Sponsor and the investigator reserve the right to terminate the investigators participation in 
the study as per the terms of the agreement in the study contract.  The investigator is to provide 
written communication to the IRB/IEC of the trial completion or early termination and provide the 
CRO with a copy of the correspondence.
13.5
Study Documentation and Archive
The investigator will maintain a list of qualified staff to whom study responsibilities have been 
delegated.  These individuals authorized to fulfil these responsibilities should be outlined and 
included in the Delegation of Authority Form.
Source documents are original documents, data and records for which the study data are collected 
and verified.  Example of such source documents may include, but are not limited to, hospital 
records and patient charts, laboratory, pharmacy, radiology and records, subject diaries, 
microfiches, correspondence and death registries.  Case report form entries may be considered as 
source data if the site of the original data collection is not available.  However, use of the CRFs as 
source documentation as a routine practice is not recommended.
The investigator and study staff are responsible for maintaining a comprehensive and centralize 
filing system of all subject records that are readily retrieved to be monitored and or audited at any 
time by the key sponsor contact, regulatory authorities and IRB/IECs. The filing system will 
include at minimum:
Subject content including ICFs and subject identification lists
Protocols and protocol amendments, investigator brochure, copies of pre-study 
documentation, and all IRB/IEC and sponsor communication
Proof of receipt, experimental treatment flow records and experimental product related 
correspondence.
Original source documents supporting entries into CRFs must be maintained at the site and readily 
available upon request. No study documents should be discarded without prior written agreement 
between Sponsor and the investigator. Should storage no longer be available to archive source 
documents or must be moved to an alternative location, the research staff should notify the key 
sponsor contact prior to the shipping the documents.
13.6
Study Monitoring and Data Collection
The key sponsor contact, monitors, auditors or regulatory inspectors are responsible for contacting 
and visiting the investigator for the purpose of inspecting the facilities and verifying source 
documents and records assuring that subject confidentially is respected.
The monitor is responsible for source document verification of CRF data at regular intervals during 
the study. Protocol adherence, accuracy and consistency of study conduct and data collection with 
respect to local regulations will be confirmed. Monitors will have access to subject records as 
identified in Section 14.5.
By signing the investigator agreement, the investigator agrees to cooperate with the monitor to 
address and resolve issues identified during monitoring visits.

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In accordance with ICH GCP and the audit plan, a site may be chosen for a site audit. A site audit 
would include, but is not limited to, an inspection of the facility (ies), review of subject and study 
related records, and compliance with protocol requirements as well as ICH GCP and applicable 
regulatory policies.
All data will be collected in an electronic CRF system. All entries must be completed in English 
and concomitant medications should be identified by tradenames. For further details surrounding 
the completion of CRFs, please refer to the CRF com
14. PUBLICATION PLAN
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome data 
are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate and 
Study Duration. If a report is planned to be published in a peer-reviewed journal, then that initial 
release may be an abstract that meets the requirements of the International Committee of Medical 
Journal Editors. A full report of the outcomes should be made public no later than three (3) years 
after the end of the study. 
Any publication, in any form, that is derived from this study must be submitted to Kite Pharma for review 
and approval. The study contract between the institution, principal investigation and Kite Pharma or its 
delegate will outline the requirements for publication review.
Authorship of publications from data generated in the study will be determined based on the 
uniform requirements for manuscripts submitted to biomedical journals (as outlined in the 
International Committee of Medical Journal Editors) which states: 
Authorship should be based on:
o
Substantial contributions to the conception or design of the work, acquisition of data, 
analysis, or interpretation of data for the work; AND
o
Drafting the article or revising it critically for important intellectual content; AND
o
Final approval of the version to be published; AND
o
Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work re appropriately 
investigated or resolved
Funding, collection of data or general supervision of the research alone or in combination does not 
qualify an individual for authorship.
Any publication, in any form, that is derived from this study must be submitted to the Sponsor for 
review and approval. The study contract between the institution, principal investigation and 
Sponsor or its delegate will outline the requirements for publication review.

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doi:10.1093/annonc/mdj030 (2006).
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Lee, D. W. et al. ASTCT Consensus Grading for Cytokine Release Syndrome and 
Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow 
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competing risk. Journal of the American Statistical Association 94, 496-509 (1999).

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APPENDIX A
CYTOKINE RELEASE SYNDROME (CRS) AND NEUROTOXICITY 
MANAGEMENT
Table 1. CRS Grading System – ASTCT 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 
vasopressors
Requiring one 
vasopressor with 
or without 
vasopressin
Requiring multiple 
vasopressors 
(excluding 
vasopressin)
And/or‡
Hypoxia 
None
Requiring low-flow 
nasal cannula^ or 
blow-by
Requiring high-
flow nasal 
cannula^, 
facemask, non-
rebreather mask, 
or Venturi mask
Requiring positive 
pressure (eg: 
CPAP, BiPAP, 
intubation and 
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 2. 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 
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 
Table 3. Anti-IL6 Therapy and Dosing Recommendations

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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 4 doses 
total)
Maximum 
800 mg per 
dose
IL-6 receptor 
antagonist
First line 
agent Doses 
can be given 
8 hours apart
Table 4. Grading of Neurotoxicity (Lee et al., 2018)
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 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 

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global aphasia. But a patient with an ICE score of 0 may be classified as having Grade 4 ICANS if the 
patient is unarousable.
 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 5. Encephalopathy assessment tools for grading of Immune effector Cell-
Associated Neurotoxicity Syndrome (ICANS).
Immune effector Cell-associated Encephalopathy (ICE)
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
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 6. 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 
 neurotoxicity. 
Grade 4
ICU care, consider mechanical ventilation for airway protection. 
High-dose corticosteroids, methylprednisolone 1000 mg/day IV x3 days
Consider repeat neuroimaging (CT or MRI) every 2–3 days if patient has 
persistent grade 
 neurotoxicity.
Treat convulsive status epilepticus per institutional guidelines. 

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APPENDIX B
Lugano criteria for response assessment in lymphoma (Cheson 2014)
Continued on next page

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