A Phase 2, Open-Label, Multicenter, Basket Study Evaluating the Efficacy of Brexucabtagene Autoleucel in Adults With Rare B-cell Malignancies (ZUMA-25)
Phase: PHASE2
Conditions: Relapsed/Refractory Waldenstrom Macroglobulinemia, Relapsed/Refractory Richter Transformation, Relapsed/Refractory Burkitt Lymphoma, Relapsed/Refractory Hairy Cell Leukemia
Sponsor: Kite, A Gilead Company

CLINICAL STUDY SUBPROTOCOL
Protocol Title:
A Phase 2, Open-Label, Multicenter, Basket 
Study Evaluating the Efficacy of Brexucabtagene 
Autoleucel in Adults with Rare B-cell 
Malignancies (ZUMA-25) – Substudy B – 
Relapsed/Refractory Richter Transformation
Note:
This subprotocol should be used in conjunction 
with the KT-US-568-0138 master protocol
Protocol Number:
KT-US-568-0138-B (ZUMA-25B)
Indication:
Relapsed/refractory Richter transformation
Kite Investigational Product: 
Brexucabtagene autoleucel
Kite IND Number:
028542
EU CT Number:
2022-501260-18-00
Clinical Trials.gov Identifier:
NCT05537766
Sponsor:
Kite Pharma, Inc.
2400 Broadway
Santa Monica, CA 90404
United States of America
Contact Information:
The medical monitor name and contact information is 
provided on the Key Study Team Contact List 
Protocol Version/Date:
Original: 23 May 2022
Amendment 1.0: 20 July 2022
Amendment 1.1: 12 January 2023
Amendment 2.0: 01 March 2023
Amendment 3.0: 17 August 2023
This study will be conducted under United States (US) Food and Drug Administration (FDA) 
Investigational New Drug (IND) application regulations (21 Code of Federal Regulations 
Part 312); however, sites located in the European Economic Area, and Switzerland are not 
included under the IND application and are not considered to be IND application sites.

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This study will be conducted in compliance with this protocol and in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki, and that are consistent with 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) and applicable 
regulatory and local requirements.
CONFIDENTIALITY STATEMENT
This document contains confidential information of Kite Pharma, Inc., a wholly owned subsidiary of 
Gilead Sciences Inc. This document must not be disclosed to anyone other than the study site research 
staff, collaborators, and members of the Institutional Review Board/Independent Ethics Committee, a 
scientific review board, or an equivalent. The information in this document cannot be used for any 
purpose other than the conduct of the clinical investigation without the prior written consent of 
Kite Pharma, Inc. 

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TABLE OF CONTENTS
CLINICAL STUDY SUBPROTOCOL..........................................................................................................................1
TABLE OF CONTENTS................................................................................................................................................3
LIST OF IN-TEXT TABLES .........................................................................................................................................4
LIST OF IN-TEXT FIGURES........................................................................................................................................4
PROTOCOL SYNOPSIS................................................................................................................................................5
LIST OF ABBREVIATIONS.......................................................................................................................................10
1.
INTRODUCTION................................................................................................................................................11
1.1.
Disease Background ................................................................................................................................11
1.1.1.
Epidemiology ........................................................................................................................11
1.1.2.
Diagnosis ...............................................................................................................................11
1.1.3.
Current Treatment Approaches .............................................................................................12
2.
OBJECTIVES AND ENDPOINTS......................................................................................................................13
3.
STUDY DESIGN.................................................................................................................................................14
3.1.
Study Design ...........................................................................................................................................14
3.1.1.
Rationale for Study Design Elements....................................................................................15
4.
SUBJECT POPULATION...................................................................................................................................16
4.1.
Number of Subjects and Subject Selection .............................................................................................16
4.2.
Eligibility Criteria....................................................................................................................................16
4.2.1.
RT Substudy-specific Inclusion Criteria ...............................................................................16
4.2.2.
RT Substudy-specific Exclusion Criteria ..............................................................................16
5.
STUDY TREATMENT........................................................................................................................................17
5.1.
Description of Study Treatment ..............................................................................................................17
5.2.
Prior and Concomitant Medications and Permitted Treatments..............................................................17
6.
STUDY ASSESSMENTS UNIQUE TO RICHTER TRANSFORMATION .....................................................18
6.1.
Medical and Treatment History...............................................................................................................18
6.2.
Brain Magnetic Resonance Imaging .......................................................................................................18
6.3.
Lumbar Puncture .....................................................................................................................................19
6.4.
Disease Assessments for DLBCL-RT and Underlying CLL ..................................................................19
6.4.1.
Imaging Requirements...........................................................................................................20
6.4.2.
Bone Marrow Aspirate/Biopsy..............................................................................................21
6.4.3.
Hematology Assessment .......................................................................................................25
6.4.4.
CLL Measurable Residual Disease Assessment....................................................................25
6.5.
Clonality Assessment ..............................................................................................................................25
6.6.
Tumor Biopsy..........................................................................................................................................25
6.7.
Disease-specific Exploratory Assessments .............................................................................................26
7.
STUDY PROCEDURES UNIQUE TO RICHTER TRANSFORMATION.......................................................27
7.1.
Screening .................................................................................................................................................27
7.2.
Optional Bridging Therapy......................................................................................................................27
8.
ADVERSE EVENTS AND TOXICITY MANAGEMENT................................................................................29
8.1.
Safety Review Team and Data Safety Monitoring Board.......................................................................29
9.
STATISTICAL CONSIDERATIONS.................................................................................................................30

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9.1.
Hypothesis ...............................................................................................................................................30
9.2.
Definition of Substudy Endpoints ...........................................................................................................30
9.2.1.
Definition of Substudy Primary Endpoints ...........................................................................30
9.2.2.
Definition of Substudy Secondary Endpoints .......................................................................30
9.2.3.
Definition of Other Substudy Endpoints of Interest..............................................................31
9.3.
Determination of Sample Size.................................................................................................................31
9.4.
Planned Analyses.....................................................................................................................................32
9.4.1.
Interim Analysis and Early Stopping Guidelines ..................................................................32
9.4.2.
Primary Analysis ...................................................................................................................32
9.4.3.
Follow-Up Analysis...............................................................................................................32
9.4.4.
Final Analysis........................................................................................................................32
10.
RESPONSIBILITIES...........................................................................................................................................33
11.
REFERENCES.....................................................................................................................................................34
12.
APPENDICES......................................................................................................................................................37
12.1.
Sponsor and Investigator Signature Page................................................................................................38
12.2.
Schedule of Assessments.........................................................................................................................39
12.3.
Disease Response Criteria .......................................................................................................................49
12.3.1.
International Working Group Lugano Classification (Richter 
Transformation).....................................................................................................................49
12.3.2.
International Workshop on Chronic Lymphocytic Leukemia 2018 Criteria 
(Chronic Lymphocytic Leukemia)........................................................................................53
12.4.
Protocol Amendment History..................................................................................................................55
12.4.1.
Amendment 1.0 (dated 20 July 2022) ...................................................................................55
12.4.2.
Amendment 1.1 EU-specific Amendment (dated 12 January 2023).....................................56
12.4.3.
Amendment 2.0 (dated 01 March 2023)................................................................................57
12.4.4.
Amendment 3.0 (dated 17 August 2023) ..............................................................................58
LIST OF IN-TEXT TABLES
Table 1.
Substudy-specific Objectives and Endpoints ..........................................................................13
Table 2.
Bridging Therapy Regimens....................................................................................................28
Table 3.
Definitions of Substudy Secondary Endpoints........................................................................31
Table 4.
Definitions of Substudy Exploratory Endpoints......................................................................31
Table 5.
Schedule of Assessments: Screening, Pretreatment, Treatment, and Post-treatment 
Periods .....................................................................................................................................39
Table 6.
Schedule of Assessments: Post-treatment Follow-up Period ..................................................46
Table 7.
Deauville 5-point Scale for Positron Emission Tomography Scoring ....................................49
Table 8.
International Workshop on Chronic Lymphocytic Leukemia 2018 Response Criteria ..........53
Table 9.
Chronic Lymphocytic Leukemia Disease Response Assessment ...........................................54
LIST OF IN-TEXT FIGURES
Figure 1.
Bone Marrow Assessment Schema .........................................................................................24

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PROTOCOL SYNOPSIS
Kite Pharma, Inc.
2400 Broadway
Santa Monica, CA 90404
Protocol Title: A Phase 2, Open-Label, Multicenter, Basket Study Evaluating the Efficacy of 
Brexucabtagene Autoleucel in Adults with Rare B-cell Malignancies (ZUMA-25)
Substudy B – Relapsed/Refractory Richter Transformation
Indication: Adult subjects with relapsed/refractory (r/r) Richter transformation (RT)
Kite IND Number: 028542
EU CT Number: 2022-501260-18-00
Clinical Trials.gov Identifier: NCT05537766
Kite Investigational Product: Brexucabtagene autoleucel
Other Investigational Product/IND Number: Not applicable
IDE Number: Not applicable
Number of Study Sites Planned: Approximately 25
Objectives and Endpoints: Objectives and endpoints that are common to all indications are 
detailed in the KT-US-568-0138 master protocol.
Additional objectives and endpoints that are specific to this substudy are detailed below.
Primary Objective
Primary Endpoint
•
To evaluate the efficacy of brexucabtagene 
autoleucel on diffuse large B-cell lymphoma 
(DLBCL)-RT in subjects with RT, by 
determining the objective response rate (ORR) 
by central assessment
•
ORR, defined as the proportion of subjects who 
achieve a best response of either complete 
response (CR) or partial response (PR). 
Response will be determined by central 
assessment per the Lugano Classification 
{Cheson 2014}
Secondary Objectives
Secondary Endpoints
•
To evaluate the efficacy of brexucabtagene 
autoleucel on DLBCL-RT in subjects with RT, 
by determining the ORR by investigator 
assessment
•
ORR, defined as the proportion of subjects who 
achieve a best response of either CR or PR. 
Response will be determined by investigator 
assessment per the Lugano Classification 
{Cheson 2014}
•
To evaluate the efficacy of brexucabtagene 
autoleucel on DLBCL-RT based on clonal 
relationship to the underlying chronic 
lymphocytic leukemia (CLL) by central 
assessment
•
ORR, defined as the proportion of subjects who 
achieve a best response of either CR or PR by 
central assessment per the Lugano Classification 
{Cheson 2014}, in subgroups by clonal 
relationship to the underlying CLL. Clonality 
will be assessed by central assessment

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•
To evaluate the efficacy of brexucabtagene 
autoleucel on the underlying CLL by 
investigator assessment
•
ORR, defined as the proportion of subjects who 
achieve a best response of either CR, CR with 
incomplete marrow recovery (CRi), or PR per 
International Workshop on Chronic 
Lymphocytic Leukemia (IWCLL) 2018 criteria 
{Hallek 2018}
Exploratory Objectives
Exploratory Endpoints
•
To evaluate the CLL measurable residual disease 
(MRD) negative response rate in subjects who 
have achieved a CR
•
Rate of MRD negative response among subjects 
who have achieved a CR. MRD will be done by 
local assessment
•
To evaluate the efficacy of brexucabtagene 
autoleucel on DLBCL-RT based on receipt of 
bridging therapy
•
ORR, defined as the proportion of subjects who 
achieve a best response of either CR or PR, in 
subgroups by receipt of bridging therapy 
(yes/no)
Study Design: This substudy protocol contains details regarding all elements of the study that 
are unique to subjects with RT. In contrast, the KT-US-568-0138 master protocol contains 
additional information that is common for all indications in this basket study. Both the 
KT-US-568-0138 master protocol and this substudy protocol should be referenced in parallel.
This is a Phase 2, open-label, multicenter study evaluating the efficacy of brexucabtagene 
autoleucel in subjects with r/r RT.
Initially, 1 subject will be enrolled and infused. No additional subjects will be enrolled until 
the subject has been monitored for at least 28 days post-infusion. Subsequently, an additional 
2 subjects can be enrolled in parallel. After these initial 3 subjects have been evaluated for at 
least 28 days, the safety review team (SRT) will make recommendations on the further 
conduct of this substudy.
Following enrollment, eligible subjects will be treated with cyclophosphamide and fludarabine 
lymphodepleting chemotherapy, followed by an initial dose of 2 x 106 anti-CD19 chimeric 
antigen receptor (CAR) T cells/kg body weight. Following review by the SRT, the dose may 
be lowered to 1 x 106 anti-CD19 CAR T cells/kg body weight.
Disease response will be assessed at Day 28, Month 3, and then every 3 months up to 
Month 12, followed by every 6 months up to Month 24.
Additional study details are provided in the KT-US-568-0138 master protocol.
Subjects enrolled in this substudy may receive optional bridging therapy to stabilize disease as 
described in Section 7.2. If already receiving a Bruton’s tyrosine kinase (BTK) inhibitor, 
subjects may receive ibrutinib through screening and leukapheresis at the discretion of the 
investigator, as described in Section 5.2 and Section 7.1.
The study schema is detailed in Figure 1 of the KT-US-568-0138 master protocol.
Number of Subjects Anticipated to be Enrolled and Treated: Approximately 60 subjects 
with r/r RT will be enrolled and treated in this substudy. Three to 6 additional subjects may be 
enrolled if the SRT recommends proceeding at the lower dose level.

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Target Population: Male or female adults ≥ 18 years of age with CLL and r/r RT
Duration of Treatment and of Study Participation: The treatment period will be 1 week 
following infusion, and the duration of the study is 24 months.
Eligibility Criteria Unique to the RT Substudy:
In addition to the common eligibility criteria specified in the KT-US-568-0138 master 
protocol, all of the following additional substudy-specific eligibility criteria must also be met.
RT Substudy-specific Inclusion Criteria:
1) Confirmed diagnosis of CLL based on IWCLL 2018 criteria {Hallek 2018} 
(Section 12.3.2), with histologically confirmed RT to a DLBCL subtype
2) Relapsed or refractory disease after any first-line chemoimmunotherapy, defined as at least 
1 of the following:
a) Refractory disease, defined as progressive disease or stable disease as best response to 
first-line therapy
b) Relapsed disease, defined as complete remission to first-line therapy followed by 
biopsy-proven disease relapse. Subjects will be eligible regardless of the duration of 
remission prior to relapse.
3) At least 1 measurable lesion based on the Lugano Classification {Cheson 2014}. Lesions 
that have been previously irradiated will be considered measurable only if progression has 
been documented following completion of radiation therapy
RT Substudy-specific Exclusion Criteria:
1) Diagnosis of RT not of DLBCL subtype (including, but not limited to, Hodgkin lymphoma 
and prolymphocytic leukemia)
2) Prior allogeneic or autologous stem cell transplant < 3 months prior to screening and/or 
< 4 months prior to planned infusion of brexucabtagene autoleucel
3) Presence of active graft-versus-host disease following prior stem cell transplant
Study Procedures: Subjects will undergo procedures and assessments as detailed in the 
schedule of assessments (see Section 12.2).
Investigational Product and Study Treatments, Dose, and Mode of Administration:
Treatment consists of a lymphodepleting chemotherapy regimen, followed by a single infusion 
of brexucabtagene autoleucel. Additional details are provided in the KT-US-568-0138 master 
protocol.

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Safety Review Team and Data Safety Monitoring Board: An SRT, comprising the study 
sponsor and at least 1 study investigator, will be specifically chartered to review the safety 
data and make recommendations on further study conduct, progression, and/or dose 
modification after 3 or 6 subjects in this substudy have been treated with the initial dose 
(2 x 106 anti-CD19 CAR T cells/kg of body weight) and followed for 28 days, as detailed in 
the KT-US-568-0138 master protocol.
An independent Data Safety Monitoring Board (DSMB) will be chartered to review safety and 
efficacy data to make study conduct recommendations based on an analysis of risk versus 
benefit. The DSMB will review serious adverse event (SAE) information (listings or 
narratives) and suspected unexpected serious adverse reactions (SUSARs) on a regular basis 
throughout subject treatment in the study and per the DSMB charter or DSMB discretion. The 
DSMB may request additional safety or efficacy data or recommend modifying the study 
conduct. The sponsor may request additional reviews by the DSMB. Data submitted to the 
DSMB may or may not be source data verified to facilitate timely DSMB review.
SUSARs and SAE listings or narratives may be submitted to the DSMB chair as described in 
the DSMB charter.
Additional details regarding the SRT, DSMB, and dose-limiting toxicities are provided in the 
KT-US-568-0138 master protocol.
Statistical Methods:
Hypothesis: An alternative hypothesis is proposed with a target 50% ORR per central 
assessment against a null hypothesis that the ORR is ≤ 28%. The hypothesis is that the ORR to 
brexucabtagene autoleucel per central assessment is greater than 28%.
Sample Size Calculation: This single-arm, open-label substudy will enroll and treat 
60 subjects with the SRT-recommended dose of brexucabtagene autoleucel. This sample size 
will achieve a statistical power of ≥ 90% if there is at least a 22% improvement in ORR 
(brexucabtagene autoleucel: 50% versus historical control: 28%) with a type 1 error rate of 
0.025 (1-sided).
Analyses: An interim analysis will be conducted after 20 subjects (33%) have had the 
opportunity to be evaluated for response 3 months after treatment with brexucabtagene 
autoleucel. In this interim analysis, the DSMB will review investigatorreported data for both 
safety and efficacy (futility only). The non-binding futility boundary is ORR of 30.4% based 
on the beta spending function of rho family (parameter = 0.6), with a crossing probability of 
59% under the null hypothesis (ORR ≤ 28%). A decision will be made by the sponsor based 
on DSMB recommendation, with the complete benefit/risk profile of brexucabtagene 
autoleucel being taken into account. If the decision is made to discontinue the substudy, then 
this analysis will be considered the primary analysis of this substudy. Study enrollment will be 
paused following treatment of the 20th subject with brexucabtagene autoleucel and until data 
from the interim analyses have been assessed. 

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If the decision based on the interim analysis is to continue the substudy, a primary analysis 
will be conducted after 60 subjects have been enrolled and treated with the SRT-recommended 
dose of brexucabtagene autoleucel and the last subject has had the opportunity to be assessed 
for response at least 6 months after the brexucabtagene autoleucel infusion. 
Hypothesis testing will be based on the number of objective responders observed among the 
60 subjects, as described above. The point estimate of the ORR will be calculated, together 
with its 95% confidence interval using the Clopper-Pearson method. The p-value will be 
calculated based on exact test. If more than 60 subjects are treated with the SRT-recommended 
dose in this substudy by the time of data cutoff, all treated subjects will be included in the 
primary analysis.
A follow-up analysis may be performed after all treated subjects have had the opportunity to 
be assessed for response at least 18 months after the brexucabtagene autoleucel infusion to 
further evaluate the risk-benefit profile of brexucabtagene autoleucel, including the durability 
of response. This analysis will be descriptive.
Additional descriptive analyses may occur after the primary and follow-up analyses described 
above have been completed.
The final analysis will be performed after all subjects have completed the study, outstanding 
data queries have been resolved or adjudicated as unresolvable, and the data have been cleaned 
and finalized.
This study will be conducted in compliance with this protocol; the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines of 
Good Clinical Practice, including archiving of essential documents; and all applicable regulatory 
and local requirements.
This study will be conducted under United States Code of Federal Regulations Title 21 Part 312 
or equivalent.

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LIST OF ABBREVIATIONS 
ASCO
American Society of Clinical Oncology
BTK
Bruton’s tyrosine kinase
CAR
chimeric antigen receptor 
CLL
chronic lymphocytic leukemia
CNS
central nervous system
CR
complete response
CRi
complete response with incomplete marrow recovery
CRS
cytokine release syndrome
CSF
cerebrospinal fluid
CT 
computed tomography
DLBCL
diffuse large B-cell lymphoma
DSMB
Data Safety Monitoring Board
eCRF
electronic case report form
FDG
fluorodeoxyglucose
HL
Hodgkin lymphoma
ICANS
immune effector cell-associated neurotoxicity syndrome
IGHV
immunoglobulin heavy chain
IV
intravenous
IWCLL
International Workshop on Chronic Lymphocytic Leukemia
MRD
measurable residual disease
MRI
magnetic resonance imaging
ORR
objective response rate
OS
overall survival
PET
positron emission tomography
PR
partial response
r/r
relapsed/refractory
RT
Richter transformation
SAE
serious adverse event
SAP
statistical analysis plan
SOA
schedule of assessments
SOC
standard of care
SRT
safety review team
SUSAR
suspected unexpected serious adverse reaction

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1.
INTRODUCTION
Refer to the KT-US-568-0138 master protocol for information related to brexucabtagene 
autoleucel (KT-US-568-0138 master protocol – Section 1.1), previous clinical studies 
(KT-US-568-0138 master protocol – Section 1.2.2), and the study rationale (KT-US-568-0138 
master protocol – Section 1.4).
1.1.
Disease Background
1.1.1.
Epidemiology
Richter transformation (RT) is the occurrence of an aggressive lymphoma in patients with a 
previous or concomitant diagnosis of chronic lymphocytic leukemia (CLL), most commonly 
diffuse large B-cell lymphoma (DLBCL), accounting for 90% of cases, or Hodgkin lymphoma 
(HL), accounting for approximately 10% or less of cases {Bockorny 2012}. DLBCL-RT is rare, 
difficult to treat, and distinct from de novo DLBCL in its pathogenesis {Rossi 2008}. RT is 
reported in approximately 2% to 10% of CLL patients {Molica 2010, Petrackova 2021}. In the 
United States, approximately 500 patients are diagnosed with RT each year.
Disease outcomes are distinct for patients for whom RT is clonally related to the underlying CLL 
(approximately 70%) and those for whom the disease is clonally unrelated (approximately 30%). 
Clonally-related RT has a more aggressive course and higher rates of treatment resistance and 
TP53 aberrations compared with clonally-unrelated disease {Petrackova 2021, Rossi 2016}. 
While median overall survival (OS) for patients with nonclonal RT is approximately 62 months, 
it is relatively poor for patients with clonal RT, with a reported median OS of approximately 
10 months {Parikh 2014, Rossi 2011}.
1.1.2.
Diagnosis
Clinically, patients with RT present with an aggressive disease course characterized by rapidly 
enlarging lymph nodes, constitutional symptoms including fevers, night sweats, and 
unintentional weight loss, hepatosplenomegaly, frequent extranodal tissue involvement, and 
sudden elevations in serum lactate dehydrogenase {Parikh 2014}. Specific risk factors for the 
development of RT in a patient with CLL have yet to be identified; however, TP53 disruption, 
c-MYC abnormalities, unmutated immunoglobulin heavy chain (IGHV) (sequence deviating 
≤ 2% relative to germline reference), non-del13q cytogenetics, CD38 gene polymorphisms, 
stereotypy, and VH4-39 gene usage may be predisposing factors. Studies also indicate that 
patients with CLL who harbor NOTCH1 mutations have a signiﬁcantly higher probability of 
developing RT compared with those without this defect {Rossi 2012, Rossi 2018}.

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1.1.3.
Current Treatment Approaches
Various chemotherapy and chemo-immunotherapy regimens have been tested for DLBCL-RT, 
including OFAR-1, OFAR-2, R-CHOP, O-CHOP, R-Hyper-CVAD, R-EPOCH, DHAP/ESHAP, 
Hyper-CVXD, and R-Hyper-CVXD. Most frequently used are R-CHOP or R-CHOP–like 
regimens (ie, R-EPOCH) because they provide a good balance between efficacy and toxicity 
compared with the other regimens. Using such regimens, objective response rates (ORRs) have 
increased beyond 50%, but with limited complete responses (CRs) and mean OS remaining 
below 1 year {Rossi 2018}. To further improve outcomes, both autologous and allogeneic stem 
cell transplant have been proposed as consolidation therapy in DLBCL-RT. However, most 
patients (85% to 90%) with DLBCL-RT are unfit or do not achieve adequate response to proceed 
to transplant {Rossi 2018}. Many patients will accordingly need second-line therapy following 
relapse or refractoriness to frontline chemotherapy. In the relapsed/refractory (r/r) setting, no 
consensus on treatment exists, and CR rates are reported to be between 0% and 33% using 
venetoclax, pembrolizumab, or chemotherapy {Abrisqueta 2020, Davids 2017, Ding 2017, 
Faderl 2003, Thompson M C 2021, Visentin A 2017}.
The poor prognosis for patients with r/r DLBCL-RT has resulted in the use of various novel 
approaches including chimeric antigen receptor (CAR) T-cell therapies. In a retrospective 
analysis of 9 patients treated with axicabtagene ciloleucel, including 5 cases that were confirmed 
to be clonally related with high-risk features, the 8 evaluable patients (1 patient died before being 
evaluated for response) achieved an objective response, including 5 patients with CR and 
3 patients with partial response (PR) {Kittai 2020}. In a similar study, 8 subjects, of whom 
6 subjects had confirmed DLBCL-RT, were treated with CAR T-cell therapy. All subjects had 
received treatment post-transformation (eg, with R-CHOP, ibrutinib, and venetoclax) and had 
progressive disease before receiving a locally produced anti-CD19 CAR T-cell product. Five of 
8 subjects achieved a CR after a median follow-up duration of 6 months (range: 4 to 10 months), 
and 2 subjects proceeded to allogeneic stem cell transplant {Benjamini 2020}.
Taken together, current therapies are limited for patients with r/r RT, and preliminary results 
indicate that CAR T-cell therapies may represent a viable therapeutic option for this difficult to 
treat patient population.

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2.
OBJECTIVES AND ENDPOINTS
Refer to Section 2 of the KT-US-568-0138 master protocol for a summary of common objectives 
and endpoints for this study.
Additional objectives and endpoints that are specific for this substudy are detailed in Table 1.
Table 1.
Substudy-specific Objectives and Endpoints
Primary Objective
Primary Endpoint
•
To evaluate the efficacy of brexucabtagene 
autoleucel on DLBCL-RT in subjects with RT, by 
determining the ORR by central assessment
•
ORR, defined as the proportion of subjects who 
achieve a best response of either CR or PR. 
Response will be determined by central 
assessment per the Lugano Classification {Cheson 
2014}
Secondary Objectives
Secondary Endpoints
•
To evaluate the efficacy of brexucabtagene 
autoleucel on DLBCL-RT in subjects with RT, by 
determining the ORR by investigator assessment
•
ORR, defined as the proportion of subjects who 
achieve a best response of either CR or PR. 
Response will be determined by investigator 
assessment per the Lugano Classification {Cheson 
2014}
•
To evaluate the efficacy of brexucabtagene 
autoleucel on DLBCL-RT based on clonal 
relationship to the underlying CLL by central 
assessment
•
ORR, defined as the proportion of subjects who 
achieve a best response of either CR or PR by 
central assessment per the Lugano Classification 
{Cheson 2014}, in subgroups by clonal 
relationship to the underlying CLL. Clonality will 
be assessed by central assessment 
•
To evaluate the efficacy of brexucabtagene 
autoleucel on the underlying CLL by investigator 
assessment
•
ORR, defined as the proportion of subjects who 
achieve a best response of either CR, CRi, or PR 
per IWCLL 2018 criteria {Hallek 2018}
Exploratory Objectives
Exploratory Endpoints
•
To evaluate the CLL MRD negative response rate 
in subjects who have achieved a CR 
•
Rate of MRD negative response among subjects 
who have achieved a CR. MRD will be done by 
local assessment
•
To evaluate the efficacy of brexucabtagene 
autoleucel on DLBCL-RT based on receipt of 
bridging therapy
•
ORR, defined as the proportion of subjects who 
achieve a best response of either CR or PR, in 
subgroups by receipt of bridging therapy (yes/no)
Abbreviations: CLL, chronic lymphocytic leukemia; CR, complete response; CRi, complete response with incomplete marrow 
recovery; DLBCL, diffuse large B-cell lymphoma; IWCLL, International Workshop on Chronic Lymphocytic Leukemia; 
MRD, measurable residual disease; ORR, objective response rate; PR, partial response; RT, Richter transformation.

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3.
STUDY DESIGN
3.1.
Study Design
This substudy protocol contains details regarding all elements of the study that are unique to 
subjects with RT. In contrast, the KT-US-568-0138 master protocol contains additional 
information that is common for all indications in this basket study. Both the KT-US-568-0138 
master protocol and this substudy protocol should be referenced in parallel.
This is a Phase 2, open-label, multicenter study evaluating the efficacy of brexucabtagene 
autoleucel in subjects with r/r RT.
Initially, 1 subject will be enrolled and infused. No additional subjects will be enrolled until the 
subject has been monitored for at least 28 days post-infusion. Subsequently, an additional 
2 subjects can be enrolled in parallel. After these initial 3 subjects have been evaluated for at 
least 28 days, the safety review team (SRT) will make recommendations on the further conduct 
of this substudy.
Following enrollment, eligible subjects will be treated with cyclophosphamide and fludarabine 
lymphodepleting chemotherapy, followed by an initial dose of 2 × 106 anti-CD19 CAR 
T cells/kg body weight. Following review by the SRT, the dose may be lowered to 1 × 106 CAR 
T cells/kg body weight.
Disease response will be assessed at Day 28, Month 3, and then every 3 months up to Month 12, 
followed by every 6 months up to Month 24.
Additional details of the study design are provided in Section 3 of the KT-US-568-0138 master 
protocol.
Subjects enrolled in this substudy may receive optional bridging therapy to stabilize disease as 
described in Section 7.2. If already receiving a Bruton’s tyrosine kinase (BTK) inhibitor, subjects 
may receive ibrutinib through screening and leukapheresis at the discretion of the investigator, as 
described in Section 5.2 and Section 7.1.
The study schema is detailed in Figure 1 of the KT-US-568-0138 master protocol.
An SRT, comprising the study sponsor and at least 1 study investigator, will be specifically 
chartered to review the safety data and make recommendations on further study conduct, 
progression, and/or dose modification. Additional details of the SRT are provided in Section 8.1.
An independent Data Safety Monitoring Board (DSMB) will be chartered to review safety and 
efficacy data to make study conduct recommendations based on an analysis of risk versus 
benefit. The DSMB will review investigator-reported safety and efficacy data against the futility 
rules after 20 subjects (33%) in this substudy have been treated with the SRT-recommended dose 
of brexucabtagene autoleucel and have had the opportunity to be followed for 3 months after the 
brexucabtagene autoleucel infusion. Study enrollment will be paused following treatment of the 
20th subject with brexucabtagene autoleucel and until results from the interim analysis have been 
assessed. Additional details of the DSMB are provided in Section 8.1.

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The end-of-study is defined in the Master protocol (refer to Section 3.4 of the Master protocol).
3.1.1.
Rationale for Study Design Elements
3.1.1.1.
Rationale for Bridging Therapy
Due to the aggressive nature of RT, bridging therapy may be administered at the discretion of the 
investigator, if deemed necessary for disease control between leukapheresis and availability of 
brexucabtagene autoleucel. Bridging therapy regimens and timing requirements are described in 
Section 7.2.
3.1.1.1.1.
Rationale for Allowance of Ibrutinib Through Screening and Leukapheresis
If deemed necessary for disease control, and per investigator discretion, ibrutinib treatment will 
be a non-mandatory treatment option through screening and leukapheresis as described in 
Section 5.2 and Section 7.1. Previous data have shown that ibrutinib is not harmful for the 
leukapheresis product; however, these data are strongest for ibrutinib (and not acalabrutinib or 
zanubrutinib) possibly due to differences in the impact on T-cell function between these drugs 
{Davis J. E 2021}. Thus, ibrutinib only will be allowed through screening and leukapheresis.

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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 60 subjects with r/r RT who have received 1 line of prior therapy will be enrolled 
and treated. Three to 6 additional subjects may be enrolled if the SRT recommends proceeding at 
the lower dose level (refer to Section 8.10.1 of the KT-US-568-0138 master protocol for 
additional details).
4.2.
Eligibility Criteria
To be enrolled in the study, subjects must meet the common eligibility criteria detailed in 
Section 4.2 of the KT-US-568-0138 master protocol. In addition, subjects must also meet all of 
the additional substudy-specific eligibility criteria detailed in Section 4.2.1 and Section 4.2.2.
4.2.1.
RT Substudy-specific Inclusion Criteria
1) Confirmed diagnosis of CLL based on International Workshop on Chronic Lymphocytic 
Leukemia (IWCLL) 2018 criteria {Hallek 2018} (Section 12.3.2), with histologically 
confirmed RT to a DLBCL subtype
2) Relapsed or refractory disease after any first-line chemoimmunotherapy, defined as at least 1 
of the following:
a) Refractory disease, defined as progressive disease or stable disease as best response to 
first-line therapy
b) Relapsed disease, defined as complete remission to first-line therapy followed by 
biopsy-proven disease relapse. Subjects will be eligible regardless of the duration of 
remission prior to relapse.
3) At least 1 measurable lesion based on the Lugano Classification {Cheson 2014}. Lesions that 
have been previously irradiated will be considered measurable only if progression has been 
documented following completion of radiation therapy
4.2.2.
RT Substudy-specific Exclusion Criteria
1) Diagnosis of RT not of DLBCL subtype (including, but not limited to, HL and 
prolymphocytic leukemia)
2) Prior allogeneic or autologous stem cell transplant < 3 months prior to screening and/or 
< 4 months prior to planned infusion of brexucabtagene autoleucel
3) Presence of active graft-versus-host disease following prior stem cell transplant

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5.
STUDY TREATMENT
5.1.
Description of Study Treatment
Study treatment consists of lymphodepleting chemotherapy and a single infusion of 
brexucabtagene autoleucel, as described in Section 3.2 of the KT-US-568-0138 master protocol.
Subjects enrolled in this substudy may receive optional bridging therapy as described in 
Section 7.2. Permitted bridging therapy regimens are detailed in Table 2.
Prior and concomitant medications that are either unique to RT or that are managed differently 
for subjects with RT are described below. Refer to Section 5 of the KT-US-568-0138 master 
protocol for additional details regarding brexucabtagene autoleucel treatment, prior and 
concomitant medications, and excluded medications.
5.2.
Prior and Concomitant Medications and Permitted Treatments
Subjects who were receiving ibrutinib prior to study entry, and for whom investigators deem it to 
be required, are permitted to continue this therapy through leukapheresis and up to 5 half-lives 
(30 hours) prior to the start of lymphodepletion, at the investigator’s discretion. Subjects 
receiving another BTK inhibitor and who require continued BTK inhibitor treatment should 
switch to ibrutinib at the discretion of the investigator at the start of screening.
If subjects continue ibrutinib through the screening period and leukapheresis, a new baseline 
disease assessment must be performed at least 5 half-lives (30 hours) after cessation of ibrutinib 
treatment and before initiating lymphodepleting chemotherapy.

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6.
STUDY ASSESSMENTS UNIQUE TO RICHTER 
TRANSFORMATION
The study assessments that are either unique to RT or that are managed differently for subjects 
with RT are described here. Please refer to Section 6 of the KT-US-568-0138 master protocol for 
details of all other study assessments. Study assessments described in the KT-US-568-0138 
master protocol and herein are to be performed according to the schedule of assessments (SOA) 
presented in Section 12.2 (Table 5 and Table 6) of this substudy protocol.
6.1.
Medical and Treatment History
For subjects with RT, the medical and treatment history should also document the prior 
diagnosis, treatment, and response to treatment of the underlying CLL.
6.2.
Brain Magnetic Resonance Imaging
If required, brain magnetic resonance imaging (MRI) will be performed with contrast whenever 
possible or without contrast in case of contraindication.
Screening:
•
At screening, subjects with current symptoms or clinical signs of central nervous system 
(CNS) malignancy, such as severe headaches, neck stiffness, seizures, encephalopathy, 
cranial nerve deficits, or any focal neurological findings on physical examination, must 
undergo brain MRI to rule out current CNS metastasis, in which case such subjects are not 
eligible for the study.
•
If required, the MRI should be performed as close to enrollment/leukapheresis as possible 
and within 28 days before leukapheresis for eligibility. An MRI collected as standard of care 
(SOC) within this timeframe is acceptable.
•
After the initial screening and eligibility confirmation, if the subject presents with new-onset 
symptoms or clinical signs of CNS malignancy/disease, a repeat MRI is required to reassess 
eligibility prior to the start of lymphodepleting chemotherapy.
•
CNS involvement will be assessed by local review, and images will not be sent for central 
review.
Post-infusion:
•
Subjects with new-onset symptoms of CNS malignancy/disease, as described above, are 
recommended to have a brain MRI. 
•
In addition, in the case of cytokine release syndrome (CRS) and immune effector 
cell-associated neurotoxicity syndrome (ICANS), refer to the American Society of Clinical 
Oncology (ASCO) management guidelines for guidance of requirements for brain imaging 

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{Santomasso 2021}. In summary: i) brain MRI can be considered for all grades of CRS; 
ii) brain MRI or other neuroimaging can be considered for ICANS Grade 2 or higher, as 
supported by the ASCO management guidelines.
•
A brain MRI only needs to be submitted to the independent central reviewer when there is 
evidence of disease progression.
6.3.
Lumbar Puncture
Opening pressures should be measured with each lumbar puncture when possible and recorded in 
the subject’s site chart.
Screening:
•
Subjects with symptoms or clinical signs of CNS malignancy (eg, new-onset severe 
headaches, neck stiffness, or focal neurologic findings) or leptomeningeal carcinomatosis 
will have a lumbar puncture performed at screening for examination of cerebrospinal fluid 
(CSF) to determine the presence of CNS malignancy. There must be no evidence of CNS 
involvement to be eligible for this study.
•
After the initial screening and eligibility confirmation, if the subject presents with new-onset 
symptoms or clinical signs of CNS malignancy/disease, a repeat lumbar puncture is required 
to reassess eligibility prior to the start of lymphodepleting chemotherapy.
Post-infusion:
•
Subjects with symptoms or clinical signs of CNS malignancy, such as new-onset severe 
headaches, neck stiffness, seizures, encephalopathy, cranial nerve deficits, or any focal 
neurologic findings on physical examination, will have a lumbar puncture for examination of 
CSF (and brain MRI as described in Section 6.2).
•
In the case of CRS and ICANS, refer to the ASCO management guidelines for guidance for 
requirements for lumbar puncture examination {Santomasso 2021}. In summary: i) lumbar 
puncture is recommended for consideration in cases of CRS; ii) for ICANS, a lumbar 
puncture is recommended for Grade 3 or higher neurotoxicity and may be considered for 
Grade 2.
CSF samples will be analyzed at the local laboratory. An aliquot will be sent to the central 
laboratory for assessment of analytes (including cytokines) and immune cell subsets.
6.4.
Disease Assessments for DLBCL-RT and Underlying CLL
Disease response for DLBCL-RT will be assessed according to the Lugano Classification 
{Cheson 2014} (Section 12.3.1).

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Assessment of the underlying CLL will be based on IWCLL 2018 criteria {Hallek 2018} 
(Section 12.3.2).
Disease assessments will be performed according to the schedule presented in the SOA (Table 5 
and Table 6) and as described below. In addition, subjects with symptoms suggestive of disease 
progression should be evaluated for progression at the time symptoms occur, even if this requires 
an unscheduled visit.
6.4.1.
Imaging Requirements
Positron emission tomography (PET)-diagnostic computed tomography (CT) scans are required 
in all subjects at screening, after bridging therapy (if applicable), and at the disease response 
assessment time points specified in the SOA (Table 5 and Table 6).
For all PET-CT scans, the following requirements should be met:
•
The CT must be of diagnostic quality with intravenous (IV)-iodinated contrast, performed by 
either of the following modalities, depending on the site’s capability:
as part of a combined PET-diagnostic CT; or
as a separate diagnostic-quality CT (with IV-iodinated contrast)
•
The PET-diagnostic CT scan must include the neck, chest, abdomen, and pelvis, along with 
appropriate imaging of all other sites of disease.
•
If IV-iodinated contrast is contraindicated per the investigator, then the diagnostic CT scan 
can use non-iodinated contrast. If non-iodinated contrast is not available or not recommended 
by the investigator, then the diagnostic CT can be nonenhanced.
•
In cases where CT with contrast is contraindicated, MRI of the abdomen and pelvis and CT 
of the chest without contrast is an acceptable alternative.
•
All screening/baseline and disease assessment PET-diagnostic CT scans will be submitted to 
and reviewed by an independent central reviewer.
•
Technical and shipping requirements for the PET-diagnostic CT scans will be outlined in the 
study imaging manual.
•
On-study images will be performed with the same imaging modality and anatomical location 
as imaged at baseline.
•
The PET portion of the PET-diagnostic CT scan will be scored per the Deauville 5-point 
scale. Both the PET and CT portions of the scan will be interpreted according to the Lugano 
Classification {Cheson 2014}. Refer to Section 12.3.1 for additional details.

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Screening/Baseline:
•
To confirm eligibility and/or to establish baseline (if bridging therapy is administered), 
PET-diagnostic CT scans are required at screening.
•
PET-diagnostic CT scans should be performed as close to enrollment/leukapheresis as 
possible and within 28 days before leukapheresis for eligibility (unless imaging is available 
from SOC assessment within 28 days before enrollment), with the following clarifications:
A PET-diagnostic CT scan performed at the study site after the subject’s last line of 
therapy and before signing of the informed consent form may be used for confirmation of 
eligibility, if relevant requirements described above are fulfilled and if it was performed 
within 28 days before enrollment/leukapheresis and no other anticancer treatment has 
been administered. (For subjects who are referred, a screening image is required.)
If a PET-diagnostic CT scan is performed > 28 days before the initiation of 
lymphodepleting chemotherapy or if the subject receives any anticancer therapy (bridging 
therapy) between the last PET-diagnostic CT scan and initiation of lymphodepleting 
chemotherapy, the PET-diagnostic CT scan must be repeated before lymphodepleting 
chemotherapy to establish a new baseline.
Disease Assessment:
•
The PET-diagnostic CT scans will be performed at the time points outlined in the SOA 
(Table 5 and Table 6) through Month 24 or until disease progression, whichever comes first.
•
A PET-diagnostic CT scan can be performed at any time disease progression is suspected.
•
To limit radiation exposure, investigators are encouraged to leave at least 4 weeks between 
consecutive scans.
6.4.2.
Bone Marrow Aspirate/Biopsy
Bone marrow aspirate and biopsy samples are required in all subjects and will be analyzed by the 
investigator at the local laboratory.
For the DLBCL-RT, the assessment of bone marrow will be in accordance with the Lugano 
Classification and will only be evaluated if the DLBCL-RT is not fluorodeoxyglucose 
(FDG)-avid (Figure 1).
For the underlying CLL, the bone marrow assessment will be performed in accordance with the 
IWCLL 2018 disease response criteria (Section 12.3.2).

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The following requirements for the bone marrow assessment must be met:
•
Local SOC assessment methods should be performed (immunohistochemistry, flow 
cytometry, or other). These will be reported in the electronic case report form (eCRF).
•
For the underlying CLL, attempts should be made to characterize the presence of and 
percentage of CLL lymphocytes or presence of clonal B-lymphoid nodules per the IWCLL 
2018 criteria (Section 12.3.2).
•
For CLL, the data to be reported in the eCRF are based upon the IWCLL 2018 criteria and 
morphological status of the bone marrow (ie, normocellular for age, no or increase in CLL 
lymphocytes, no or presence of clonal B-lymphoid nodules, increase in CLL cells by ≥ 50% 
on successive biopsies).
•
For DLBCL-RT, the data to be reported in the eCRF will be per the Lugano Classification 
(ie, bone marrow involvement assessed via PET-CT or via bone marrow aspirate and biopsy 
in the absence of PET-CT imaging).
•
For bone marrows assessed per the Lugano Classification, if applicable, data extracted from 
the eCRF will be provided to the vendor performing the independent central assessment of 
the primary endpoint.
Screening/Baseline (for both CLL and DLBCL-RT disease status assessments):
•
Bone marrow aspirate and biopsy samples are required in all subjects at screening and after 
bridging therapy (if applicable), in order to assess the underlying CLL and to assess 
DLBCL-RT in case of a negative screening PET-CT (non-FDG-avid tumor) (Figure 1).
•
At screening, bone marrow samples are also required to be sent to the central laboratory for 
retrospective central confirmation of disease diagnosis (refer to the central laboratory manual 
for details).
Disease/Response Assessment:
For the CLL disease response assessment:
•
A bone marrow aspirate and biopsy are required at Day 28 and Month 3 for the underlying 
CLL response assessment. Beyond Month 3 and through Month 24, further bone marrow 
assessment is only required at Month 12 and Month 24, only in those subjects who responded 
(CR, CR with incomplete marrow recovery [CRi], or PR) at Month 3, in order to confirm CR 
per IWCLL 2018 criteria (Figure 1).
•
To confirm a CR, the bone marrow aspirate and biopsy must show no evidence of disease by 
morphology or, if indeterminate by morphology, must be negative by immunohistochemistry.

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•
In subjects who experience disease progression or who achieve a CR of CLL but 
subsequently relapse, if a bone marrow aspirate (that is clinically indicated in the 
management of a study treated subject) is acquired, a portion of the aspirate should be sent to 
the central laboratory if feasible for additional exploratory analyses (refer to the central 
laboratory manual for details).
For the DLBCL-RT disease response assessment:
•
For DLBCL-RT, the assessment of bone marrow involvement will be in accordance with the 
Lugano Classification, and a bone marrow aspirate and biopsy are only indicated if the 
DLBCL-RT is not FDG-avid. If the required screening bone marrow assessment in this case 
is positive, further bone marrow assessments are required to confirm a CR at the disease 
response assessment time points outlined in the SOA (Figure 1).
•
To confirm a CR, the bone marrow aspirate and biopsy must show no evidence of disease by 
morphology or, if indeterminate by morphology, must be negative by immunohistochemistry.

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Figure 1.
Bone Marrow Assessment Schema
Abbreviations: CLL, chronic lymphocytic leukemia; CR, complete response; CRi, complete response with incomplete marrow recovery; DLBCL, diffuse large B-cell lymphoma; 
FDG, fluorodeoxyglucose; PET-CT, positron emission tomography-computed tomography; PD, progressive disease; PR, partial response; RT, Richter transformation; SD, stable 
disease.
Notes: All bone marrow assessments will be performed at the local laboratory. Bone marrow samples collected at screening and at progression or relapse (in subjects who achieve 
a
CR of CLL; if collected per standard of care) should also be sent to the central laboratory (see Section 6.4.2 and the central laboratory manual).
Post-bridging (if applicable)
CLL Bone Marrow Assessment Requirements
Screening PET-CT
Screening PET-CT is 
positive (tumor is 
FDG-avid)
Screening PET-CT is 
negative (tumor is not 
FDG-avid)
No bone marrow 
assessment required at 
screening or 
post-bridging (if 
applicable) or at later 
disease assessments
Bone marrow assessment 
required at screening
Bone marrow assessment 
negative at screening
No further bone marrow 
assessments required 
post-bridging (if 
applicable) or at later 
disease assessments
Bone marrow assessment 
positive at screening
Bone marrow 
assessments required 
post-bridging (if 
applicable) and to 
confirm CR
DLBCL-RT Bone Marrow Assessment Requirements 
(if not already collected as part of the CLL component)
Screening bone marrow 
assessment to confirm CLL
Day 28
If CR, CRi, or PR of 
CLL at Month 3
Bone marrow 
assessments required at 
Month 12 and Month 24 
if all other CLL response 
criteria indicate a CR
If SD or PD of CLL at 
Month 3
No further bone marrow 
assessments required
Month 3
I 
I 
I 
i 
i 
i 
i 
I 
i 
i 
i 
i 

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6.4.3.
Hematology Assessment
Local laboratory measurement of blood lymphocytes, platelet count, and hemoglobin are 
required at screening, after bridging therapy (if applicable), and at all time points indicated in the 
SOA for CLL disease response assessments, per the IWCLL 2018 criteria.
6.4.4.
CLL Measurable Residual Disease Assessment
Measurable residual disease (MRD) assessments by evaluation of bone marrow aspirate or 
peripheral blood will be performed by the investigator at their local laboratory at Day 28 and 
Month 3, as specified in the SOA (see Section 12.2).
Beyond Month 3 and through Month 24, MRD should also be assessed when the subject’s 
hematological and radiological response is consistent with CR/CRi, in order to 
establish/re-confirm a CR/CRi with MRD negative response per IWCLL 2018 criteria.
Details of the sample used for the assessment and the methodology used (eg, 6-color flow 
cytometry, allele-specific oligonucleotide polymerase chain reaction [PCR], or high-throughput 
sequencing) will be reported in the eCRF.
6.5.
Clonality Assessment
To retrospectively assess the clonal relationship of the DLBCL to the underlying CLL, the IGHV 
gene will be sequenced and compared between the CLL tumor cells (from screening bone 
marrow aspirate) and the DLBCL cells (from the tumor biopsy). The analysis can be done by 
bulk sequencing and without prior CLL cell isolation if the immunophenotype of bone marrow 
cells is able to exclude the presence of DLBCL cells; otherwise, isolation of CLL based on cell 
surface markers (eg, CD43) should be done before bulk sequencing. Sample collection is 
described in Section 6.6.
6.6.
Tumor Biopsy
Screening:
To retrospectively confirm eligibility, archival tumor biopsy collected after the original diagnosis 
of RT must be submitted to the central laboratory for confirmation of diagnosis. This will consist 
of either 1 formalin-fixed paraffin-embedded tumor block or at least 20 unstained slides. Should 
an archived tumor sample be unavailable or insufficient, a fresh tumor sample is required to be 
obtained before initiation of lymphodepleting chemotherapy. However, a new biopsy is only to 
be acquired if the location is easily accessible, and if appropriate taking into account subject 
safety.
In addition, to investigate clonal relationship to the underlying CLL, archived and cryopreserved 
or freshly collected and snap-frozen tumor biopsy must be submitted to the central laboratory.

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Disease Progression:
If a tumor biopsy that is clinically indicated in the management of a study treated subject is 
acquired, a portion of the biopsy should be sent to the central laboratory for additional 
exploratory analyses.
Refer to Section 6.7 for details on tumor biopsies for exploratory analyses.
6.7.
Disease-specific Exploratory Assessments
Peripheral blood from screening and either archived (at time of RT diagnosis) or fresh tumor 
biopsy samples will be collected in order to perform genetic testing for evaluation of mutations 
in CDKN2A, NOTCH1, MYC, and TP53 to confirm the RT diagnosis and for use as prognostic 
markers in exploratory analyses.
In addition, exploratory analysis of peripheral blood and, where applicable, bone marrow 
aspirates might include evaluation of Vysis fluorescence in situ hybridization (FISH) testing (p53 
del17p; ATM del11q; Del 13q; Trisomy 12) and cytogenetics (chromosome/karyotype analysis) 
of the underlying CLL disease. Single-cell transcriptomics and proteomics of immune cell 
subsets in pre- and post-infusion peripheral blood mononuclear cells might be performed to 
uncover mechanisms of treatment resistance.

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STUDY PROCEDURES UNIQUE TO RICHTER 
TRANSFORMATION 
Final 
Amendment 3.0 
Refer to Section 7 of the KT-US-568-0138 master protocol for the list of procedures for this 
study. Additional procedures for this RT subprotocol are listed below. 
For sho1i-te1m disease control, optional bridging therapy is allowed per investigator discretion. 
To exclude any impact of bridging therapy, a new baseline for subjects receiving bridging 
therapy is required as outlined in the SOA. 
7.1. 
Screening 
Subjects cunently on a BTK inhibitor when entering the screening period may continue (if on 
ibrntinib) or should be switched to ibrntinib (if on other BTK inhibitor treatment), which may be 
used through leukapheresis and up to 5 half-lives (30 hours) prior to the staii of lymphodepletion 
(refer to Section 5.2). 
7.2. 
Optional Bridging Therapy 
Bridging therapy will be pe1mitted at the discretion of the investigator, if deemed required to 
control disease after leukapheresis. Bridging therapy is recommended for subjects with high 
disease burden. Bridging therapy may be administered after leukapheresis, and the last dose of 
any bridging therapy regimen must be completed at least 7 days or 5 half-lives, whichever is 
sho1ier, before initiating lymphodepleting chemotherapy. 
If a subject receives any bridging therapy between leukapheresis and lymphodepleting 
chemotherapy, then the baseline imaging and any additional assessments to confnm measurable 
disease must be repeated after the bridging therapy and before lymphodepleting chemotherapy 
commences to establish a new baseline. For subjects who receive iirndiation as bridging therapy, 
inadiated lesions can no longer serve as target lesions, and other target lesions must be present to 
allow for response assessment. 
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Bridging therapy will be supplied by the study site. Sites should refer to the cunent product label 
for guidance on packaging, storage, preparation, administration, and toxicity management of 
bridging therapy. 
Regardless of the choice of bridging regimen, all organ and man ow functional parameters listed 
in the KT-US-568-0138 master protocol common inclusion criteria must be met before initiation 
of lymphodepleting chemotherapy, and all toxicities related to bridging therapy must return to 
Grade 1 or lower or baseline levels before initiation of lymphodepleting chemotherapy. 
The procedures to be perfo1med during the period in which bridging therapy is administered are 
detailed in the SOA (Section 12.2). 
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8.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
Refer to Section 8 of the KT-US-568-0138 master protocol for adverse events and toxicity 
management. The SRT and independent DSMB for this subprotocol are described below.
8.1.
Safety Review Team and Data Safety Monitoring Board
An SRT, comprising the study sponsor and at least 1 study investigator, will be specifically 
chartered to review the safety data and make recommendations on further study conduct, 
progression, and/or dose modification after 3 to 6 subjects in this substudy have been treated 
with the initial dose (2 x 106 anti-CD19 CAR T cells/kg of body weight) and followed for 
28 days, as detailed in the KT-US-568-0138 master protocol.
An independent DSMB will be chartered to review safety and efficacy data to make study 
conduct recommendations based on an analysis of risk versus benefit. The DSMB will review 
investigator-reported safety and efficacy data against the futility rules after 20 subjects (33%) in 
this substudy have been treated with the SRT-recommended dose of brexucabtagene autoleucel 
and have had the opportunity to be followed for 3 months after the brexucabtagene autoleucel 
infusion. Study enrollment will be paused following treatment of the 20th subject with 
brexucabtagene autoleucel and until results from this interim analysis have been assessed. The 
DSMB will also review serious adverse event (SAE) information (listings or narratives) and 
suspected unexpected serious adverse reactions (SUSARs) on a regular basis throughout subject 
treatment in the study and per the DSMB charter or DSMB discretion. The DSMB may request 
additional safety or efficacy data or recommend modifying the study conduct. The sponsor may 
request additional reviews by the DSMB. Data submitted to the DSMB may or may not be 
source data verified to facilitate timely DSMB review.
SUSARs and SAE listings or narratives may be submitted to the DSMB chair as described in the 
DSMB charter.
Additional details regarding the SRT, DSMB, and dose-limiting toxicities are provided in 
Section 8.10.1, Section 8.10.2, and Section 8.1.2 of the KT-US-568-0138 master protocol, 
respectively.

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9.
STATISTICAL CONSIDERATIONS
An overview of the statistical considerations that are specific to this subprotocol are provided 
below. Refer to Section 9 of the KT-US-568-0138 master protocol for an overview of the 
statistical considerations that are common across indications.
Details of the statistical analysis plan (SAP) will be provided in the SAP document.
9.1.
Hypothesis
An alternative hypothesis is proposed with a target 50% ORR per central assessment against a 
null hypothesis that the ORR is ≤ 28%. The reference rate of 28% was based on a systematic 
literature review and meta-analysis {Abrisqueta 2020, Davids 2017, Ding 2017, Faderl 2003, 
Thompson M C 2021, Visentin A 2017}. The hypothesis is that the ORR to brexucabtagene 
autoleucel per central assessment is greater than 28%.
The hypothesis testing will be conducted at a significance level of 0.025 (1-sided). The responses 
from subjects in the study population are assumed to be independent and follow a binomial 
distribution.
9.2.
Definition of Substudy Endpoints
In addition to the secondary and exploratory endpoints detailed in the KT-US-568-0138 master 
protocol, the endpoints outlined below also apply to this substudy.
9.2.1.
Definition of Substudy Primary Endpoints
The primary endpoint for this substudy is the ORR, defined as the proportion of subjects who 
achieve a best response of either CR or PR, by central assessment per the Lugano Classification 
{Cheson 2014}.
9.2.2.
Definition of Substudy Secondary Endpoints
Secondary endpoints for this substudy are defined in Table 3.

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Table 3.
Definitions of Substudy Secondary Endpoints
Secondary Endpoint
Definition
ORR in DLBCL-RT by investigator assessment
Proportion of subjects who achieve a best response of either 
CR or PR by investigator assessment per the Lugano 
Classification {Cheson 2014}
ORR in DLBCL-RT based on clonal relationship 
to the underlying CLL by central assessment
Proportion of subjects who achieve a best response of either 
CR or PR by central assessment per the Lugano 
Classification {Cheson 2014}, in subgroups by clonal 
relationship to the underlying CLL. Clonality will be 
assessed by central assessment. 
ORR in CLL by investigator assessment
Proportion of subjects who achieve a best response of either 
CR, CRi, or PR by investigator assessment per IWCLL 
2018 criteria {Hallek 2018}
Abbreviations: CLL, chronic lymphocytic leukemia; CR, complete response; CRi, complete response with incomplete marrow 
recovery; DLBCL, diffuse large B-cell lymphoma; IWCLL, International Workshop on Chronic Lymphocytic Leukemia; ORR, 
objective response rate; PR, partial response; RT, Richter transformation.
9.2.3.
Definition of Other Substudy Endpoints of Interest
Exploratory endpoints for this substudy are defined in Table 4.
Table 4.
Definitions of Substudy Exploratory Endpoints
Exploratory Endpoint
Definition
Rate of MRD negative response of CLL among 
subjects who have achieved a CR
Incidence of an MRD negative response among subjects 
who achieve a CR, where MRD negative is defined as 
MRD < 10−4 per the standard assessment as done by the 
local laboratory
ORR in DLBCL-RT based on receipt of bridging 
therapy
Proportion of subjects who achieve a best response of either 
CR or PR, in subgroups by receipt of bridging therapy 
(yes/no)
Abbreviations: CLL, chronic lymphocytic leukemia; CR, complete response; DLBCL, diffuse large B-cell lymphoma; 
MRD, measurable residual disease; ORR, objective response rate; PR, partial response; RT, Richter transformation.
9.3.
Determination of Sample Size
This single-arm, open-label substudy will enroll and treat 60 subjects with the 
SRT-recommended dose of brexucabtagene autoleucel. This sample size will achieve a statistical 
power of ≥ 90% if there is at least a 22% improvement in ORR (brexucabtagene autoleucel: 50% 
versus historical control: 28%) with a type 1 error rate of 0.025 (1-sided) under the 2-look design 
based on normal approximation, with variance of standardized test statistic under null hypothesis 
(H0) using EAST (Version 6.5). The empirical power is 91% per simulation based on binomial 
distribution without normal approximation. Statistically significant treatment effect can be 
claimed in this substudy if ≥ 24 responders (≥ 40.0%) are observed among the 60 subjects at the 
primary analysis.

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9.4.
Planned Analyses
9.4.1.
Interim Analysis and Early Stopping Guidelines
An interim analysis will be conducted after 20 subjects (33%) have had the opportunity to be 
evaluated for response 3 months after treatment with brexucabtagene autoleucel. Study 
enrollment will be paused following treatment of the 20th subject with brexucabtagene autoleucel 
and until results from this interim analysis have been assessed. In this interim analysis, the 
DSMB will review investigator-reported data for both safety and efficacy (futility only). The 
non-binding futility boundary is ORR of 30.4% based on the beta spending function of rho 
family (parameter = 0.6), with a crossing probability of 59% under the null hypothesis 
(ORR ≤ 28%). The futility boundary is crossed if ≤ 6 responders are observed among the 
20 subjects. A decision will be made by the sponsor based on DSMB recommendation, with the 
complete benefit/risk profile of brexucabtagene autoleucel being taken into account. If the 
decision is made to discontinue the substudy, then this analysis will be considered the primary 
analysis of this substudy.
9.4.2.
Primary Analysis
If the decision based on the interim analysis is to continue the substudy, a primary analysis will 
be conducted after 60 subjects have been enrolled and treated with the SRT-recommended dose 
of brexucabtagene autoleucel (modified intent-to-treat [mITT] analysis set) and the last subject 
has had the opportunity to be assessed for response at least 6 months after the brexucabtagene 
autoleucel infusion.
Hypothesis testing will be based on the number of objective responders observed among the 
60 subjects, as described above. The point estimate of the ORR will be calculated, together with 
its 95% confidence interval using the Clopper-Pearson method. The p-value will be calculated 
based on exact test. If more than 60 subjects are treated with the SRT-recommended dose in this 
substudy by the time of data cutoff, all treated subjects will be included in the primary analysis.
9.4.3.
Follow-Up Analysis
A follow-up analysis may be performed after all treated subjects have had the opportunity to be 
assessed for response at least 18 months after the brexucabtagene autoleucel infusion to further 
evaluate the risk-benefit profile of brexucabtagene autoleucel, including the durability of 
response. This analysis will be descriptive.
Additional descriptive analyses may occur after the primary analysis and follow-up analysis 
described above have been completed.
9.4.4.
Final Analysis
The duration of the study is 24 months. The final analysis will be performed after all subjects 
have completed the study, outstanding data queries have been resolved or adjudicated as 
unresolvable, and the data have been cleaned and finalized.

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10.
RESPONSIBILITIES
Please refer to Section 10 of the KT-US-568-0138 master protocol for details regarding 
investigator and sponsor responsibilities.

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11.
REFERENCES
Abrisqueta P, Delgado J, Alcoceba M, Oliveira AC, Loscertales J, Hernandez-Rivas JA, et al. 
Clinical outcome and prognostic factors of patients with Richter syndrome: real-
world study of the Spanish Chronic Lymphocytic Leukemia Study Group 
(GELLC). Br J Haematol 2020;190 (6):854-63.
Benjamini O, Shimoni A, Besser M, Shem-Tov N, Danylesko I, Yerushalmi R, et al. Safety and 
Efficacy of CD19-CAR T Cells in Richter's Transformation after Targeted 
Therapy for Chronic Lymphocytic Leukemia. Blood  2020;136 (Supplement 
1):40.
Bockorny B, Codreanu I, Dasanu CA. Hodgkin lymphoma as Richter transformation in chronic 
lymphocytic leukaemia: a retrospective analysis of world literature. Br J 
Haematol 2012;156 (1):50-66.
Cazelles C, Belhadj K, Vellemans H, Camus V, Poullot E, Gaulard P, et al. Rituximab plus 
gemcitabine and oxaliplatin (R-GemOx) in refractory/relapsed diffuse large B-cell 
lymphoma: a real-life study in patients ineligible for autologous stem-cell 
transplantation. Leuk Lymphoma 2021;62 (9):2161-8.
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations for initial evaluation, staging, and response assessment of 
Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 
2014;32 (27):3059-68.
Cunningham D, Hawkes EA, Jack A, Qian W, Smith P, Mouncey P, et al. Rituximab plus 
cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with 
newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 
comparison of dose intensification with 14-day versus 21-day cycles. Lancet 
2013;381 (9880):1817-26.
Davids MS, Roberts AW, Seymour JF, Pagel JM, Kahl BS, Wierda WG, et al. Phase I First-in-
Human Study of Venetoclax in Patients With Relapsed or Refractory Non-
Hodgkin Lymphoma. J Clin Oncol 2017;35 (8):826-33.
Davis J. E, Sharpe C, Mason K, Tam C. S, Koldej R. M, Ritchie D. S. Ibrutinib protects T cells 
in patients with CLL from proliferation‑induced senescence. Journal of 
Translational Medicine 2021;473 (19):1-13.
Ding W, LaPlant BR, Call TG, Parikh SA, Leis JF, He R, et al. Pembrolizumab in patients with 
CLL and Richter transformation or with relapsed CLL. Blood 2017;129 
(26):3419-27.

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Protocol KT-US-568-0138-B (ZUMA-25B) – Richter Transformation
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Dunleavy K, Fanale MA, Abramson JS, Noy A, Caimi PF, Pittaluga S, et al. Dose-adjusted 
EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, 
and rituximab) in untreated aggressive diffuse large B-cell lymphoma with MYC 
rearrangement: a prospective, multicentre, single-arm phase 2 study. Lancet 
Haematol 2018;5 (12):e609-e17.
Faderl S, Thomas DA, O'Brien S, Garcia-Manero G, Kantarjian HM, Giles FJ, et al. Experience 
with alemtuzumab plus rituximab in patients with relapsed and refractory 
lymphoid malignancies. Blood 2003;101 (9):3413-5.
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, et al. Guidelines 
for diagnosis, indications for treatment, response assessment and supportive 
management of chronic lymphocytic leukemia. Blood 2018.
Kittai AS, Bond DA, William B, Saad A, Penza S, Efebera Y, et al. Clinical activity of 
axicabtagene ciloleucel in adult patients with Richter syndrome. Blood Adv 
2020;4 (19):4648-52.
Molica S. A systematic review on Richter syndrome: what is the published evidence? Leuk 
Lymphoma 2010;51 (3):415-21.
Parikh SA, Kay NE, Shanafelt TD. How we treat Richter syndrome. Blood 2014;123 (11):1647-
57.
Petrackova A, Turcsanyi P, Papajik T, Kriegova E. Revisiting Richter transformation in the era 
of novel CLL agents. Blood Rev 2021;49:100824.
Rossi D, Bruscaggin A, Spina V, Rasi S, Khiabanian H, Messina M, et al. Mutations of the 
SF3B1 splicing factor in chronic lymphocytic leukemia: association with 
progression and fludarabine-refractoriness. Blood 2011;118 (26):6904-8.
Rossi D, Cerri M, Capello D, Deambrogi C, Rossi FM, Zucchetto A, et al. Biological and 
clinical risk factors of chronic lymphocytic leukaemia transformation to Richter 
syndrome. Br J Haematol 2008;142 (2):202-15.
Rossi D, Rasi S, Fabbri G, Spina V, Fangazio M, Forconi F, et al. Mutations of NOTCH1 are an 
independent predictor of survival in chronic lymphocytic leukemia. Blood 
2012;119 (2):521-9.
Rossi D, Spina V, Gaidano G. Biology and treatment of Richter syndrome. Blood 2018;131 
(25):2761-72.
Rossi JM, Sherman M, Xue A, wei-Shen Y, Navale L, Rosenberg SA, et al. Levels of IL-15 and 
GM-CSF Are Elevated One Day After Anti-CD19 CAR T Cell Infusion in 
Patients Who Had an Objective Response or Experienced a Grade ≥3 Neurologic 
AE [Presentation]. EMA Workshop; 2016 15-16 November; London, England. 

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Santomasso BD, Nastoupil LJ, Adkins S, Lacchetti C, Schneider BJ, Anadkat M, et al. 
Management of Immune-Related Adverse Events in Patients Treated With 
Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline. J Clin Oncol 
2021;39 (35):3978-92.
Tanaka N, Imai Y, Yoshinaga K, Shiseki M, Tanaka J. Fractionated ifosfamide, carboplatin, and 
etoposide with rituximab as a safe and effective treatment for relapsed/refractory 
diffuse large B cell lymphoma with severe comorbidities. Annals of hematology 
2020;99 (11):2577-86.
Thompson M C, Coombs C. C, Roeker L. E, Pagel J. M, Jensen J. L, Battiato K. E, et al. 
Outcomes of Chronic Lymphocytic Leukemia and Richter Transformation 
Following Discontinuation of Non-Covalent Bruton's Tyrosine Kinase Inhibitors. 
Blood 2021;138 (1).
Visentin A, Imbergamo S, Scomazzon E, Frezzato F, Gurrieri C, Piazza F, et al. B-Cell Receptor 
Inhibitors are Active and Effective Drugs in Relapsed/Refractory Richter 
Syndrome. Rome, Italy: Ferrata Storti Foundation; 2017. (European Hematology 
Association, ed. S3; vol 102).

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12.
APPENDICES
Section 12.1
Sponsor and Investigator Signature Page
Section 12.2 
Schedule of Assessments
Section 12.3 
Disease Response Criteria
Section 12.4
Protocol Amendment History

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12.1.
Sponsor and Investigator Signature Page
KITE PHARMA, INC.
2400 BROADWAY
SANTA MONICA, CA 90404
STUDY ACKNOWLEDGMENT
A Phase 2, Open-Label, Multicenter, Basket Study Evaluating the Efficacy of Brexucabtagene Autoleucel 
in Adults with Rare B-cell Malignancies (ZUMA-25) – Substudy B – Relapsed/Refractory Richter 
Transformation
Amendment 3.0, 17 AUGUST 2023
This protocol has been approved by Kite Pharma, Inc. The following signature documents this approval.
See appended signature page
See appended signature page
Kite Medical Monitor Name (Printed) 
Signature
See appended signature page
Date
INVESTIGATOR STATEMENT
I have read the protocol, including all appendices, and I agree that it contains all necessary details for me 
and my staff to conduct this study as described. I will conduct this study as outlined herein and will make 
a reasonable effort to complete the study within the time designated.
I agree to comply with the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Harmonised Tripartite Guideline on Good Clinical Practice and 
applicable national or regional regulations and guidelines. I will provide all study personnel under my 
supervision copies of the protocol and access to all information provided by Kite Pharma, Inc. I will 
discuss this material with them to ensure that they are fully informed about the investigational product 
and study.
I agree and will ensure that financial disclosure statements will be completed by:
•
Me (including, if applicable, my spouse, legal partner, and dependent children)
•
Subinvestigators (including, if applicable, their spouse, legal partner, and dependent children) at the 
start of the study and for up to 1 year after the study is completed.
I agree to ensure that the confidential information contained in this document will not be used for any 
purpose other than the conduct of the clinical investigation without prior written consent from 
Kite Pharma, Inc.
Principal Investigator Name (Printed)
Signature
Date
Study Site Number

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12.2.
Schedule of Assessments
Table 5.
Schedule of Assessments: Screening, Pretreatment, Treatment, and Post-treatment Periods
Timeframe:
Screening
Pretreatment Period
Treatment Period
Post-treatment Follow-up Period
Enrollment/ 
Leukapheresis
Optional Bridging Therapy
Note: bridging therapy is 
optional, and these 
procedures only apply if 
bridging therapy has been 
administered
Lymphodepleting 
Chemotherapy
Infusion of 
Brexucabtagene 
Autoleucel and 
Monitoring
(Each visit calculated from D0)
Procedure
Within 
28 days 
before 
enrollment
Within approx. 
5 days after 
eligibility 
confirmation
Dosing of 
bridging 
therapy and 
monitoring
Post-
bridging 
therapy 
disease 
assessment
D−5
D−4
D−3
D0
D1 to D7a
D14
(±2 d)
D28
(±3 d)
W8
(±1 
w)
M3
(±2 w)
Suspected Disease Progressionb
Informed consent
X
Demographic data
X
Medical history
X
Previous cancer 
treatment history
X
Physical 
examinationc
X
X
X
X
X
X
X
Daily
X
X
X
X
X
Weight (height at 
screening only)
X
X
Vital signsd
X
X
X
X
X
X
X
X
Daily
X
X
X
X
X
Neurologic 
examinatione
X
X
QOD
X
X
X
X
ECOG performance 
status
X
X
LVEF (ECHO or 
MUGA)
X
ECG
X
Brain MRI (if 
applicablef)
Xf
Lumbar puncture (if 
applicableg)
Xg

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Timeframe:
Screening
Pretreatment Period
Treatment Period
Post-treatment Follow-up Period
Enrollment/ 
Leukapheresis
Optional Bridging Therapy
Note: bridging therapy is 
optional, and these 
procedures only apply if 
bridging therapy has been 
administered
Lymphodepleting 
Chemotherapy
Infusion of 
Brexucabtagene 
Autoleucel and 
Monitoring
(Each visit calculated from D0)
Procedure
Within 
28 days 
before 
enrollment
Within approx. 
5 days after 
eligibility 
confirmation
Dosing of 
bridging 
therapy and 
monitoring
Post-
bridging 
therapy 
disease 
assessment
D−5
D−4
D−3
D0
D1 to D7a
D14
(±2 d)
D28
(±3 d)
W8
(±1 
w)
M3
(±2 w)
Suspected Disease Progressionb
PROs: 
EORTC-QLQ-C30 
and EQ-5D-5Lh
X
X
X
X
X
Disease response assessments (CLL hematology components are captured within CBC under local laboratory assessments; please also refer to the imaging manual and central 
laboratory manual for guidance)
PET-diagnostic CTi
X
X
X
X
X
Bone marrow 
aspirate and biopsyj
X
X
X
X
X
Bone marrow or 
peripheral blood 
assessment of MRD 
for CLLk
X
X
Archived/fresh tumor 
samplel
X
X
Overall response 
assessment for RT 
and CLL
X
X
X
Local laboratory assessments
Chemistry panel 
(CrCl at screening) 
(serum)
X
X
X
X
X
X
Xm
Daily
X
X
X
X
X
CBC with differential 
(blood)
X
X
X
X
X
X
X
Xm
Daily
X
X
X
X
X
LDHn, CRP, ferritin 
(serum)
X
X
Xm
Daily
X
X
X

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Timeframe:
Screening
Pretreatment Period
Treatment Period
Post-treatment Follow-up Period
Enrollment/ 
Leukapheresis
Optional Bridging Therapy
Note: bridging therapy is 
optional, and these 
procedures only apply if 
bridging therapy has been 
administered
Lymphodepleting 
Chemotherapy
Infusion of 
Brexucabtagene 
Autoleucel and 
Monitoring
(Each visit calculated from D0)
Procedure
Within 
28 days 
before 
enrollment
Within approx. 
5 days after 
eligibility 
confirmation
Dosing of 
bridging 
therapy and 
monitoring
Post-
bridging 
therapy 
disease 
assessment
D−5
D−4
D−3
D0
D1 to D7a
D14
(±2 d)
D28
(±3 d)
W8
(±1 
w)
M3
(±2 w)
Suspected Disease Progressionb
β-hCG pregnancy 
test ([WOCBP] 
serum or urine)
X
Xo
Xo
X
X
X
Serology for EU/CH 
sites (serum)p
Xp
Xp
HIV positive subjects 
only: HIV viral load 
and CD4 count
Xq
X
X
X
Central laboratory assessments (please refer to the central laboratory manual for guidance)
CBC with differential 
(blood)r
X
Xs
Xm
D3, D7
X
X
X
X
X
Anti-brexucabtagene 
autoleucel antibodies 
(serum)
X
X
X
X
Analytes, including 
cytokines 
(serum/plasma)t
Xs
Xs
Xm
D1, D2, 
D3, D5, 
D7
X
X
X
X
X
Brexucabtagene 
autoleucel CAR 
T-cell levels and 
exploratory analyses 
(PBMCs)t
Xs
Xs
Xm
D3t, D7
X
X
X
X
X
RCR (PBMCs)u
Xm
X
Leukapheresis
X
Bridging therapy 
(optional)v
X

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Timeframe:
Screening
Pretreatment Period
Treatment Period
Post-treatment Follow-up Period
Enrollment/ 
Leukapheresis
Optional Bridging Therapy
Note: bridging therapy is 
optional, and these 
procedures only apply if 
bridging therapy has been 
administered
Lymphodepleting 
Chemotherapy
Infusion of 
Brexucabtagene 
Autoleucel and 
Monitoring
(Each visit calculated from D0)
Procedure
Within 
28 days 
before 
enrollment
Within approx. 
5 days after 
eligibility 
confirmation
Dosing of 
bridging 
therapy and 
monitoring
Post-
bridging 
therapy 
disease 
assessment
D−5
D−4
D−3
D0
D1 to D7a
D14
(±2 d)
D28
(±3 d)
W8
(±1 
w)
M3
(±2 w)
Suspected Disease Progressionb
Fludarabine/ 
cyclophosphamidew
X
X
X
Brexucabtagene 
autoleucel infusion 
(IV) and 
premedications
X
Concomitant 
medications
X
X
X
X
X
X
X
X
Daily
X
X
X
X
X
Adverse events and 
serious adverse 
eventsx
X
X
X
X
X
X
X
X
Daily
X
X
X
X
X
Abbreviations: approx., approximately; ASCO, American Society of Clinical Oncology; CAR, chimeric antigen receptor; CBC, complete blood count; CLL, chronic lymphocytic 
leukemia; CNS, central nervous system; CR, complete response; CrCl, creatinine clearance; CRi, complete response with incomplete marrow recovery; CRP, C-reactive protein; 
CRS, cytokine release syndrome; CSF, cerebrospinal fluid; CT, computed tomography; D/d, day; DLBCL, diffuse large B-cell lymphoma; ECG, electrocardiogram; ECHO, 
echocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC-QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; 
EQ-5D-5L, European Quality of Life 5-Dimension 5-Level scale; EU, European Union; FDG, fluorodeoxyglucose; hCG, human chorionic gonadotropin; ICANS, immune effector 
cell-associated neurotoxicity syndrome; ICE, immune effector cell-associated encephalopathy; ICF, informed consent form; IV, intravenous; IWCLL, International Workshop on 
Chronic Lymphocytic Leukemia; LDH, lactate dehydrogenase; LVEF, left ventricular ejection fraction; M, month; MRD, measurable residual disease; MRI, magnetic resonance 
imaging; MUGA, multigated acquisition scan; PBMC, peripheral blood mononuclear cell; PET, positron emission tomography; PR, partial response; PRO, patient-reported 
outcome; QOD, every other day; RCR, replication-competent retrovirus; RT, Richter transformation; SOA, schedule of assessments; SOC, standard of care; W/w, week; WOCBP, 
women of childbearing potential.
Note: Please refer to the footnotes listed below in parallel with Section 6 of this protocol and the KT-US-568-0138 master protocol.
a
For EU and CH, post-infusion monitoring extended by monitoring on Days 8, 9, and 10 (vital signs, blood draw for chemistry panel with CRP and CBC and neurological 
examination). For EU, the subject may remain hospitalized or return to the clinic daily for this extended monitoring, at the discretion of the investigator. For CH, patients must 
remain hospitalized.
b
Subjects with symptoms suggestive of disease progression should be evaluated for progression at the time symptoms occur, even if this requires an unscheduled visit.
c
Physical examination will include assessment of splenomegaly and lymphadenopathy. Subjects with symptoms or clinical signs related to CRS should undergo physical 
examination at least daily until symptoms resolve to baseline.

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d
Vital signs will include blood pressure, heart rate, respiration rate, oxygen saturation, and temperature. It is recommended that vital signs are monitored during and after study 
treatment and then routinely per institutional guidelines. Vital signs may be monitored more frequently as clinically indicated.
e
Neurologic examination: A neurologic examination, including an ICE cognition assessment, should be performed on Day 0 before the brexucabtagene autoleucel infusion and 
should be performed every other day during the hospitalization period. If a subject hospitalization is extended beyond Day 7, a neurologic examination including a cognition 
assessment will continue to be performed as clinically indicated.
f
Brain MRI:
•
Screening through start of lymphodepletion: At screening, subjects with current symptoms or clinical signs of CNS malignancy, such as severe headaches, neck stiffness, 
seizures, encephalopathy, cranial nerve deficits, or any focal neurological findings on physical examination, must undergo brain MRI to rule out current CNS metastasis, 
in which case such subjects are not eligible for the study. After the initial screening and eligibility confirmation, if the subject presents with new-onset symptoms or 
clinical signs of CNS malignancy/disease, a repeat MRI is required to reassess eligibility prior to the start of lymphodepleting chemotherapy (see Section 6.2).
•
Post-infusion: Subjects with new-onset symptoms of CNS malignancy/disease, as described above, are recommended to have a brain MRI. In addition, in the case of 
CRS and ICANS, refer to the ASCO management guidelines for guidance of requirements for brain imaging {Santomasso 2021}. In summary: i) brain MRI can be 
considered for all grades of CRS; ii) brain MRI or other neuroimaging can be considered for ICANS Grade 2 or higher, as supported by the ASCO management 
guidelines.
g
Lumbar puncture: Opening pressures should be measured with each lumbar puncture when possible and recorded in the subject’s site chart.
•
Screening: Subjects with symptoms or clinical signs of CNS malignancy (eg, new-onset severe headaches, neck stiffness, or focal neurologic findings) or leptomeningeal 
carcinomatosis will have a lumbar puncture performed at screening for examination of CSF to determine the presence of CNS malignancy. There must be no evidence of 
CNS involvement to be eligible for this study. After the initial screening and eligibility confirmation, if the subject presents with new-onset symptoms or clinical signs of 
CNS malignancy/disease, a repeat lumbar puncture is required to reassess eligibility prior to the start of lymphodepleting chemotherapy.
•
Post-infusion: Subjects with symptoms or clinical signs of CNS malignancy, such as new-onset severe headaches, neck stiffness, seizures, encephalopathy, cranial nerve 
deficits, or any focal neurologic findings on physical examination, will have a lumbar puncture for examination of CSF, including sending a sample to the central 
laboratory. In the case of CRS and ICANS, refer to the ASCO management guidelines for guidance for requirements for lumbar puncture examination {Santomasso 
2021}. In summary: i) lumbar puncture is recommended for consideration in cases of CRS; ii) for ICANS, a lumbar puncture is recommended for Grade 3 or higher 
neurotoxicity and may be considered for Grade 2 (see Section 6.3).
h
PROs are to be completed by the subject before any study-specific assessments or procedures are performed (excluding blood draws) and before the subject receives any 
disease status information or the brexucabtagene autoleucel infusion on Day 0.
i
PET-diagnostic CT:
•
Screening/baseline: PET-CT scan should be performed as close to enrollment/leukapheresis as possible and within 28 days before leukapheresis for eligibility (unless 
imaging is available from SOC assessment within 28 days before enrollment). If a PET-CT scan is performed > 28 days before the initiation of lymphodepleting 
chemotherapy or if the subject receives any anticancer therapy (bridging therapy) between the last PET-CT scan and initiation of lymphodepleting chemotherapy, a new 
baseline PET-CT scan must be performed before lymphodepleting chemotherapy.
•
Disease assessment: PET-CT is required for each disease response assessment per the SOA and at any time disease progression is suspected.
•
To limit radiation exposure, investigators are encouraged to leave at least 4 weeks between consecutive scans.
j
Bone marrow aspirate and biopsy:
Screening/baseline:
•
Bone marrow aspirate and biopsy samples are required in all subjects at screening and after bridging therapy (if applicable), in order to assess the underlying CLL and to 
assess DLBCL-RT in case of a negative screening PET-CT (non-FDG-avid tumor).
•
At screening, bone marrow samples are also required to be sent to the central laboratory for retrospective central confirmation of disease diagnosis (refer to the central 
laboratory manual for details).

Brexucabtagene Autoleucel
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CONFIDENTIAL
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Disease/response assessment:
•
For CLL: A bone marrow aspirate and biopsy are required at Day 28 and Month 3 for the underlying CLL response assessment. Beyond Month 3 and through Month 24, 
further bone marrow assessment is only required at Month 12 and Month 24, only in those subjects who responded (CR, CRi, or PR) at Month 3, in order to confirm CR 
per IWCLL 2018 criteria {Hallek 2018} (see Section 6.4.2). To confirm a CR, the bone marrow aspirate and biopsy must show no evidence of disease by morphology or, 
if indeterminate by morphology, must be negative by immunohistochemistry. In subjects who experience disease progression or who achieve a CR of CLL but 
subsequently relapse, if a bone marrow aspirate (that is clinically indicated in the management of a study treated subject) is acquired, a portion of the aspirate should be 
sent to the central laboratory if feasible for additional exploratory analyses (refer to the central laboratory manual for details).
•
For DLBCL-RT: The assessment of bone marrow involvement will be in accordance with the Lugano Classification {Cheson 2014}, and a bone marrow aspirate and 
biopsy are only indicated if the DLBCL-RT is not FDG-avid. If the required screening bone marrow assessment in this case is positive, further bone marrow assessments 
are required to confirm a CR. To confirm a CR, the bone marrow aspirate and biopsy must show no evidence of disease by morphology or, if indeterminate by 
morphology, must be negative by immunohistochemistry.
k
Bone marrow or peripheral blood assessment of MRD for CLL: To be performed at Day 28 and Month 3. Beyond Month 3 and through Month 24, MRD should also be 
assessed when the subject’s hematological and radiological response is consistent with CR/CRi, in order to establish/re-confirm a CR/CRi with MRD negative response per 
IWCLL 2018 criteria.
l
Archived/fresh tumor sample(s):
•
Screening: Archival tumor biopsy collected after the original diagnosis of RT must be submitted to the central laboratory. Archived tumor biopsy samples will consist of 
either 1 formalin-fixed paraffin-embedded tumor block or at least 20 unstained slides. Should an archived tumor sample be unavailable or insufficient, a fresh tumor 
sample is required to be obtained before initiation of lymphodepleting chemotherapy. In addition, to investigate clonal relationship to the underlying CLL, archived and 
cryopreserved or freshly collected and snap-frozen tumor biopsy must be submitted to the central laboratory.
•
Disease progression: If a tumor biopsy that is clinically indicated in the management of a study-treated subject is acquired, a portion of the biopsy should be sent to the 
central laboratory for additional exploratory analyses.
m
Assessments may be performed on the day before administration of brexucabtagene autoleucel (ie, on Day −1). For tests performed at the central laboratory, this decision will 
be driven by the availability of the central laboratory to process samples on the day they are collected from the subject (refer to the laboratory manual for holidays). For 
samples collected on Day 0, collection will occur before the start of the brexucabtagene autoleucel infusion.
n
LDH should continue to be monitored after the baseline assessment as clinically indicated.
o
Pregnancy test (serum or urine): For EU/CH study sites, the test will be completed within 7 days before both leukapheresis and lymphodepleting chemotherapy for females of 
childbearing potential.
p
Serology tests for EU/CH study sites (serum): Serology tests (ie, HIV, hepatitis B virus, hepatitis C virus, and syphilis) will be done per institutional guidelines and EU/CH 
regulations. Testing may be done within the 30 days before leukapheresis/enrollment and/or on the day of leukapheresis/enrollment.
q
Hepatitis B and C testing is also required at screening.
r
CBC with differential (blood): At the time points at which PBMC samples are collected for analysis of brexucabtagene autoleucel CAR T-cell levels, blood samples will also 
be collected and sent to the central laboratory for assessment of CBC with differential (these samples are in addition to samples collected at the specified time points and that 
are sent to the local laboratory for assessment of CBC with differential for clinical/safety evaluation).
s
Baseline for assessments of brexucabtagene autoleucel CAR T cells and analytes: A sample will be collected at enrollment/before the leukapheresis procedure. Subjects who 
receive bridging therapy will also have a blood sample collected before receiving the first dose of lymphodepleting chemotherapy. 
t
Analytes (including cytokines) (serum/plasma) and brexucabtagene autoleucel CAR T cells (PBMCs):
•
Samples on Day 3 may be collected ± 1 day
•
If a subject is re-admitted to the hospital after the initial hospitalization observation period with any brexucabtagene autoleucel-related adverse events, blood samples for 
assessment of brexucabtagene autoleucel CAR T cells and serum analytes will be collected on the day of hospital re-admission and then weekly through, and including, 
the day of discharge, if the samples were not already collected on the same days as per the SOA (ie, 2 identical collections on the same day are not needed).

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CONFIDENTIAL
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•
If the subject experiences a Grade 3 or higher brexucabtagene autoleucel-related toxicity, such as Grade 3 CRS or neurologic event, 1 additional blood draw for 
brexucabtagene autoleucel CAR T cells (PBMCs) and serum analytes will be collected at the time of the Grade 3 or higher brexucabtagene autoleucel-related toxicity 
and upon resolution of the event, if the samples were not already collected on the same days as per the SOA (ie, 2 identical collections on the same day are not needed).
•
Blood samples for assessment of brexucabtagene autoleucel CAR T cells and serum analytes should be collected at the time of disease progression prior to starting 
subsequent anticancer therapy.
•
Exploratory T-cell immunogenicity will be performed with PBMCs at leukapheresis and Month 3. Extra blood collection is required for such testing.
•
Exploratory analyses will include lymphocyte subsets.
u
RCR (PBMCs):
•
Samples will be collected at baseline (before CAR T-cell infusion) and at Month 3.
•
If a subject develops a secondary malignancy during the study, every effort should be made to obtain a blood sample to assay for RCR and vector elements. In the case of 
a secondary malignancy, every effort will be made to obtain a blood sample (PBMC) and biopsy sample of the neoplastic tissue or the pertinent autopsy tissue to start a 
testing workflow, including tests such as transgene elements, RCR, presence of common cancer-drivers/mutations and insertional mutagenesis (see Section 6.3.15.3 of 
the KT-US-568-0138 master protocol).
v
Bridging therapy may be administered per investigator discretion if deemed required for disease control. Refer to Section 7.2 for details.
w
Mesna will be administered around the time of the cyclophosphamide dose according to institutional standards (refer to Section 5.1.2.3 and Section 7.5.3 of the KT-US-568-0138 
master protocol).
x
Collection of serious adverse events starts from signing of the screening ICF, and collection of adverse events starts from commencement of the leukapheresis procedure.

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Table 6.
Schedule of Assessments: Post-treatment Follow-up Period
Timeframe:
Long-term Follow-up Period (Each visit calculated from Day 0)
Procedure
M6
(± 2 w)
M9
(± 2 w)
M12
(± 2 w)
M18
(± 1 M)
M24
(± 1 M)
Suspected 
Disease 
Progressiona
Physical examinationb
X
X
X
X
X
X
Vital signs
X
PROs: EORTC-QLQ-C30 and EQ-5D-5Lc
X
X
X
X
X
Disease response assessments (CLL hematology components are captured within CBC under local laboratory assessments; please also refer to the imaging 
manual and central laboratory manual for guidance)
PET-diagnostic CTd 
X
X
X
X
X
X
Bone marrow aspirate and biopsye
Xe
Xe
X
Bone marrow or peripheral blood assessment of 
MRD for CLLf
Xf
Overall response assessment for RT and CLL
X
X
X
X
X
X
Local laboratory assessments
CBC with differential (blood)g
X
X
X
X
X
X
Chemistry panel (serum)
X
LDHh
X
X
β-hCG pregnancy test ([WOCBP] serum or urine)
X
HIV positive subjects only: HIV viral load and CD4 
count
X
X
X
X
X
Central laboratory assessments (please refer to the central laboratory manual for guidance)
CBC with differential (blood)g
X
X
X
X
X
X
Analytes, including cytokines (serum/plasma)i
X
Anti-brexucabtagene autoleucel antibodies (serum)
X
X
X
X
Brexucabtagene autoleucel CAR T-cell levels and 
exploratory analyses (PBMCs)i
X
X
X
X
X
X

Brexucabtagene Autoleucel
Protocol KT-US-568-0138-B (ZUMA-25B) – Richter Transformation
Final
Kite Pharma, Inc.
Amendment 3.0
CONFIDENTIAL
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17 August 2023
Timeframe:
Long-term Follow-up Period (Each visit calculated from Day 0)
Procedure
M6
(± 2 w)
M9
(± 2 w)
M12
(± 2 w)
M18
(± 1 M)
M24
(± 1 M)
Suspected 
Disease 
Progressiona
RCR (PBMCs)j
X
X
Tumor biopsyk
X
All brexucabtagene autoleucel-related SAEs and any 
deaths regardless of causality
X
X
X
X
X
X
Targeted AE/SAEsl
X
X
X
X
Xl
X
Targeted concomitant medicationsm
X
X
X
X
X
X
Subsequent therapy for RTn
X
X
X
X
X
X
Survival statuso
X
X
X
X
X
X
Abbreviations: AE, adverse event; CAR, chimeric antigen receptor; CBC, complete blood count; CLL, chronic lymphocytic leukemia; CR, complete response; CRi, complete 
response with incomplete marrow recovery; CRS, cytokine release syndrome; CT, computed tomography; DLBCL, diffuse large B-cell lymphoma; EORTC-QLQ-C30, European 
Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; EQ-5D-5L, European Quality of Life 5-Dimension 5-Level scale; FDG, fluorodeoxyglucose; 
GP, general practitioner; hCG, human chorionic gonadotropin; HCP, healthcare provider; IWCLL, International Workshop on Chronic Lymphocytic Leukemia; LDH, lactate 
dehydrogenase; LTFU, long-term follow-up; M, month; MRD, measurable residual disease; PBMC, peripheral blood mononuclear cell; PET, positron emission tomography; 
PR, partial response; PRO, patient-reported outcome; RCR, replication-competent retrovirus; RT, Richter transformation; SAE, serious adverse event; SOA, schedule of 
assessments; w, week; WOCBP, women of childbearing potential.
Note: Please refer to the footnotes listed below in parallel with Section 6 of this protocol and the KT-US-568-0138 master protocol.
a
Subjects with symptoms suggestive of disease progression should be evaluated for progression at the time symptoms occur, even if this requires an unscheduled visit.
b
Physical examination will include assessment of splenomegaly and lymphadenopathy.
c
PROs are to be completed before any assessments or procedures are performed (excluding blood draws) and before the subject receives any disease status information.
d
PET-diagnostic CT: PET-CT is required for each disease response assessment per the SOAs and at any time disease progression is suspected. To limit radiation exposure, 
investigators are encouraged to leave at least 4 weeks between consecutive scans.e
Bone marrow aspirate and biopsy:
•
For CLL: Beyond Month 3 and through Month 24, further bone marrow assessment is only required at Month 12 and Month 24, only in those subjects who responded 
(CR, CRi, or PR) at Month 3, in order to confirm CR per IWCLL 2018 criteria (see Section 6.4.2). To confirm a CR, the bone marrow aspirate and biopsy must show no 
evidence of disease by morphology or, if indeterminate by morphology, must be negative by immunohistochemistry. In subjects who experience disease progression or 
who achieve a CR of CLL but subsequently relapse, if a bone marrow aspirate (that is clinically indicated in the management of a study-treated subject) is acquired, a 
portion of the aspirate should be sent to the central laboratory if feasible for additional exploratory analyses (refer to the central laboratory manual for details).
•
For DLBCL-RT: The assessment of bone marrow involvement will be in accordance with the Lugano Classification, and a bone marrow aspirate and biopsy are only 
indicated if the DLBCL-RT is not FDG-avid. If the required screening bone marrow assessment in this case is positive, further bone marrow assessments are required to 
confirm a CR. To confirm a CR, the bone marrow aspirate and biopsy must show no evidence of disease by morphology or, if indeterminate by morphology, must be 
negative by immunohistochemistry.
f
Bone marrow or peripheral blood assessment of MRD for CLL: Beyond Month 3 and through Month 24, MRD should also be assessed when the subject’s hematological and 
radiological response is consistent with CR/CRi, in order to establish/re-confirm a CR/CRi with MRD negative response per IWCLL 2018 criteria.

Brexucabtagene Autoleucel
Protocol KT-US-568-0138-B (ZUMA-25B) – Richter Transformation
Final
Kite Pharma, Inc.
Amendment 3.0
CONFIDENTIAL
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17 August 2023
g
CBC with differential (blood):
•
Local laboratory assessments: Blood will be collected at the time points specified through Month 24 or until disease progression, whichever occurs first, and sent to the 
local laboratory for clinical/safety evaluation.
•
Central laboratory assessments: Blood will be collected at the time points specified through Month 24 and sent to the central laboratory for assessment of CBC with 
differential (these samples are in addition to samples collected at the specified time points that are sent to the local laboratory for assessment of CBC with differential for 
clinical/safety evaluation).
h
LDH should continue to be monitored after the baseline assessment as clinically indicated.
i 
Analytes (including cytokines) (serum/plasma) and brexucabtagene autoleucel CAR T cells (PBMCs):
•
If a subject is re-admitted to the hospital after the initial hospitalization observation period with any brexucabtagene autoleucel-related AEs, blood samples for 
assessment of brexucabtagene autoleucel CAR T cells and serum analytes will be collected on the day of hospital re-admission and then weekly through, and including, 
the day of discharge, if the samples were not already collected on the same days as per the SOA (ie, 2 identical collections on the same day are not needed).
•
If the subject experiences a Grade 3 or higher brexucabtagene autoleucel-related toxicity, such as Grade 3 CRS or neurologic event, 1 additional blood draw for 
brexucabtagene autoleucel CAR T cells (PBMCs) and serum analytes will be collected at the time of the Grade 3 or higher brexucabtagene autoleucel-related toxicity 
and upon resolution of the event, if the samples were not already collected on the same days as per the SOA (ie, 2 identical collections on the same day are not needed).
•
Blood samples for assessment of brexucabtagene autoleucel CAR T cells and serum analytes should be collected at the time of disease progression prior to starting 
subsequent anticancer therapy.
•
Exploratory analyses will include lymphocyte subsets.
j
RCR (PBMCs):
•
Samples will be collected at Month 6 and Month 12 and analyzed. Additional samples will be collected and analyzed only if an RCR event is clinically suspected and/or 
a subject’s PBMC sample tests positive for RCR at any time point within the first 12 months following brexucabtagene autoleucel infusion.
•
If a subject develops a secondary malignancy during the study or follow-up and RCR is suspected, every effort should be made to obtain a blood sample to assay for 
RCR and vector elements. In the case of a secondary malignancy, every effort will be made to obtain a blood sample (PBMC) and biopsy sample of the neoplastic tissue 
or the pertinent autopsy tissue to start a testing workflow, including tests such as transgene elements, RCR, presence of common cancer-drivers/mutations and insertional 
mutagenesis (see Section 6.3.15.3 of the KT-US-568-0138 master protocol).
k
If a tumor biopsy that is clinically indicated in the management of a study-treated subject is acquired, a portion of the biopsy should be sent to the central laboratory for 
additional exploratory analyses.
l
Targeted AEs/SAEs include neurologic events, hematologic events, serious infections, autoimmune disorders, and secondary malignancies. From 3 months after the 
brexucabtagene autoleucel infusion, targeted AEs/SAEs will be reported through Month 24 after the initial brexucabtagene autoleucel infusion or until disease progression 
and/or the start of subsequent anticancer therapy, whichever occurs first. After Month 24, the subject will transition to the LTFU study where targeted AEs/SAEs will be 
reported through 15 years. All new malignancies (defined as the development of any new malignancies occurring after the administration of brexucabtagene autoleucel) are to 
be reported; however, only secondary malignancies (defined as the development of any new malignancy suspected to be possibly related to brexucabtagene autoleucel) are 
considered to be targeted AEs/SAEs.
m
Targeted concomitant medications will be collected up to 24 months after the brexucabtagene autoleucel infusion or until disease progression or the start of subsequent 
anticancer therapy, whichever occurs first. (Reporting will continue through 60 months as part of the LTFU study.)
n
Subsequent anticancer therapy administered after brexucabtagene autoleucel infusion for a subject’s disease will be collected until 1 of the following occurs: subject 
completes the post-treatment follow-up period, is considered lost to follow-up, withdraws consent, or dies. The subject and/or the referring HCP and/or GP may be contacted 
directly by telephone or email to collect information about subsequent therapy.
o
Subject and/or referring HCP and/or GP may be contacted directly by telephone or email to assess survival status.

Brexucabtagene Autoleucel
Protocol KT-US-568-0138-B (ZUMA-25B) – Richter Transformation
Final
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Amendment 3.0
CONFIDENTIAL
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12.3.
Disease Response Criteria
12.3.1.
International Working Group Lugano Classification (Richter 
Transformation)
Disease assessments are to be performed according to the International Working Group Lugano 
Response Criteria for Malignant Lymphoma {Cheson 2014}; refer also to instructions provided 
in the study imaging manual.
The Deauville 5-point scale (5PS) is used for positron emission tomography (PET) scoring; the 
scores and their descriptions are presented in Table 7.
Table 7.
Deauville 5-point Scale for Positron Emission Tomography Scoring
Score
Description
1
No uptake above background
2
Uptake ≤ mediastinum
3
Uptake > mediastinum but ≤ liver
4
Uptake moderately higher than liver
5
Uptake markedly higher than liver and/or new lesions
X
New areas of uptake unlikely to be related to lymphoma
Source: {Cheson 2014}.
12.3.1.1.
Complete Remission
12.3.1.1.1.
Complete Metabolic Response for PET−Computed Tomography-based Response
The designation of complete metabolic response requires all of the following:
•
A 5PS score of 1, 2, or 3, with or without a residual mass:
In Waldeyer’s ring or extranodal sites with high physiologic uptake or activation within 
the spleen or marrow, uptake may be greater than normal in the mediastinum and/or liver. 
In this circumstance, complete metabolic response may be inferred if uptake at sites of 
initial involvement is no greater than surrounding normal tissue even if the tissue has 
high physiologic uptake.
•
No new sites of disease should be observed
•
No evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow

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12.3.1.1.2.
Complete Radiologic Response for Computed Tomography-based Response
The designation of complete radiologic response requires all of the following:
•
Target nodes/nodal masses must regress to ≤ 1.5 cm in longest transverse diameter (LDi) of a 
lesion
•
No extra lymphatic sites of disease
•
Absent nonmeasured lesion
•
Organ enlargement regress to normal
•
No new sites of disease should be observed
•
Bone marrow normal by morphology; if indeterminate, immunohistochemistry negative
12.3.1.2.
Partial Remission
12.3.1.2.1.
Partial Metabolic Response for PET–Computed Tomography-based Response
The designation of partial metabolic response requires all of the following:
•
A 5PS score of 4 or 5, with reduced uptake compared to baseline (screening), and residual 
mass(es) of any size.
Note:
At the interim, these findings suggest responding disease
At the end of treatment, these findings suggest residual disease
•
No new sites of disease should be observed
•
Residual uptake is higher than uptake in normal bone marrow but reduced compared with 
baseline (diffuse uptake is compatible with reactive changes from chemotherapy allowed)
If there are persistent focal changes in the marrow in the context of a nodal response, 
consideration should be given to further evaluation with magnetic resonance imaging or biopsy 
or an interval scan.
12.3.1.2.2.
Partial Radiologic Response for Computed Tomography-based Response
The designation of partial radiologic response requires all of the following:
•
≥ 50% decrease in the sum of the product of the perpendicular diameters of up to 6 target 
measurable nodes and extranodal sites.
When a lesion is too small to measure on a computed tomography (CT) scan, assign 
5 mm × 5 mm as the default value

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When the lesion is no longer visible, assign 0 x 0 mm
For a node > 5 mm × 5 mm, but smaller than normal, use the actual measurement for 
calculation
•
Absent/normal, regressed, but no increase of nonmeasured lesions
•
Spleen must have regressed by > 50% in length beyond normal
•
No new sites of disease should be observed
12.3.1.3.
Stable Disease
12.3.1.3.1.
No Metabolic Response for PET–CT-based Response
The designation of no metabolic response requires all of the following:
•
A 5PS score of 4 or 5, with no significant change in FDG uptake compared with baseline 
(screening) at an interim time point or the end of treatment
•
No new sites of disease should be observed
•
No change from baseline in bone marrow
12.3.1.3.2.
Stable Radiologic Disease for CT-based Response
The designation of stable radiologic disease requires all of the following:
•
< 50% decrease from baseline in the sum of the product of the perpendicular diameters of up 
to 6 dominant, measurable nodes and extranodal sites; no criteria for progressive disease 
(PD) are met
•
No increase consistent with progression in nonmeasured lesion and organ enlargement
•
No new sites of disease should be observed
12.3.1.4.
Progressive Disease
12.3.1.4.1.
Progressive Metabolic Disease for PET–CT-based Response
The designation of progressive metabolic disease requires at least 1 of the following:
•
A 5PS score 4 or 5 with an increase in intensity of uptake from baseline nadir and/or
•
New FDG-avid foci consistent with lymphoma at an interim time point or the end of 
treatment assessment

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•
New FDG-avid foci consistent with lymphoma rather than another etiology (eg, infection or 
inflammation). If uncertain regarding the etiology of new lesions, a biopsy or interval scan 
may be considered
•
New or recurrent FDG-avid foci in bone marrow
12.3.1.4.2.
Progressive Radiologic Disease for CT-based Response
The designation of progressive radiologic disease requires at least 1 of the following:
•
An individual node/lesion must be abnormal with:
LDi > 1.5 cm, and
An increase by ≥ 50% from the cross product of LDi and perpendicular diameter nadir, 
and
An increase in LDi or shortest transverse diameter, shortest axis perpendicular to the LDi, 
(shortest transverse diameter) from nadir
■
0.5 cm for lesions ≤ 2 cm
■
1.0 cm for lesions > 2 cm
In the setting of splenomegaly, the splenic length must increase by > 50% of the extent of 
its prior increase beyond baseline (eg, a 15-cm spleen must increase to > 16 cm). If there 
is no prior splenomegaly, the spleen must increase by ≥ 2 cm from baseline
New or recurrent splenomegaly
•
New or clear progression of preexisting nonmeasured lesions
•
New lesion:
Regrowth of previously resolved lesions
A new node > 1.5 cm in any axis
A new extranodal site > 1.0 cm in any axis; if < 1.0 cm in any axis, its presence must be 
unequivocal and attributable to lymphoma
Assessable disease of any size unequivocally attributable to lymphoma
•
New or recurrent bone marrow involvement

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12.3.2.
International Workshop on Chronic Lymphocytic Leukemia 2018 Criteria 
(Chronic Lymphocytic Leukemia)
The determination of chronic lymphocytic leukemia (CLL) response and progression will be 
based on standardized International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 
2018 criteria {Hallek 2018}, as presented in Table 8 and Table 9.
Table 8.
International Workshop on Chronic Lymphocytic Leukemia 2018 
Response Criteria
Parameter
CR
PR
PD
SD
Group A (indicating tumor load)
Lymphadenopathya
None ≥ 1.5 cm
Decrease ≥ 50%
Increase by ≥ 50% 
or new lymph 
nodes ≥ 1.5 cm
Change of −49% 
to +49%
Hepatomegaly
Liver size normal
Decrease ≥ 50%
Increase by ≥ 50%
Change of −49% 
to +49%
Splenomegaly
Spleen size < 13 cm
Decrease ≥ 50%
Increase by ≥ 50%
Change of −49% 
to +49%
Circulating 
lymphocyte count
< 4,000/µL
Decrease of ≥ 50% 
from baseline
Increase by ≥ 50% 
over baselineb to 
≥ 5,000/µL
Change of −49% 
to +49%
Group B (indicating function of the hematopoietic system)
Platelet count
≥ 100,000/µL
≥ 100,000/µL or 
increase by 
≥ 50% from baseline
Decrease by ≥ 
50% from baseline 
due to CLL
Change of −49% 
to +49%
Hemoglobin
≥ 11 g/dL without 
red blood cell 
transfusions or 
erythropoietin 
support for at least 
4 weeks
≥ 11 g/dL or increase 
by 
≥ 50% from baseline 
without red blood cell 
transfusions or 
erythropoietin support 
for at least 4 weeks
Decrease by ≥ 2 
g/dL
Increase 
< 11.0 g/dL or 
< 50% over 
baseline, or 
decrease < 2 g/dL
Bone marrow
Normocellular for 
age, 
no increase in CLL 
lymphocytes, 
no clonal B-
lymphoid nodulesc
CLL cells or clonal 
B-lymphoid nodules 
present
Increase in CLL 
cells by ≥ 50% on 
successive 
biopsies
No change in 
marrow infiltrate
Abbreviations: CLL, chronic lymphocytic leukemia; CR, complete response; CRi, complete response with incomplete marrow 
recovery; PD, progressive disease; PR, partial response; SD, stable disease.
a
Assessed as sum of the products of up to 6 lymph nodes.
b
Subjects with treatment-related lymphocytosis should not be rated PD and remain on study treatment if other criteria for PD 
are absent.
c
In case of B-lymphoid nodules, assessment is recommended to clarify if the population is clonal. If not, subjects can be 
assessed as CR/CRi if all other criteria are fulfilled.
Source: {Hallek 2018}.

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Table 9.
Chronic Lymphocytic Leukemia Disease Response Assessment
Overall Disease Response
Criteria in Table 8
Additional Criteria
CR
All criteria in Group A and B
No disease related symptoms should 
be present, neutrophil count 
≥ 1,500/µL
CRi
All criteria for CR are met except with 
platelet count < 100,000/µL, hemoglobin 
< 11 g/dL, or neutrophil count < 1,500/µL
PRa
At least 1 criterion from Group A and 
1 from Group B must be fulfilled
If only 1 criterion is abnormal at 
baseline from Group A or B, only that 
criterion must improve
SD
Subjects who have not achieved a CR or a 
PR, and who have not exhibited PD, will 
be considered to have SD (which is 
equivalent to a nonresponse)
PD
Presence of at least 1 of the criteria from 
Group A or Group B
Constitutional symptoms alone do not 
define PD. A bone marrow biopsy 
should be performed to confirm 
progression if blood count changes are 
the only evidence of progression.
Abbreviations: CR, complete response; CRi, complete response with incomplete marrow recovery; PD, progressive disease; PR, 
partial response; SD, stable disease.
a
Nodular PR is defined as a CR/CRi with the presence of nodules of clonal lymphocytes in the bone marrow and will be 
considered a PR for the purposes of this study.
Source: {Hallek 2018}.
12.3.2.1.
Measurable Residual Disease Response Rate
The measurable residual disease (MRD) response is assessed by evaluation of bone marrow 
aspirate or peripheral blood with 6-color flow cytometry, allele-specific oligonucleotide 
polymerase chain reaction (PCR), or high-throughput sequencing. MRD negativity is defined as 
fewer than 1 CLL cell per 10,000 leukocytes (0.01%) (ie, < 10−4). Subjects are defined as MRD 
negative if their disease burden is below this threshold.

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12.4.
Protocol Amendment History
A high-level summary of amendment changes are provided in tabular form in the subsection 
below. Minor changes such as the correction of typographic errors, grammar, or formatting are 
not detailed.
12.4.1.
Amendment 1.0 (dated 20 July 2022)
Changes from the original protocol (dated 23 May 2022) to Amendment 1.0 (dated 20 July 2022) 
are detailed below.
Section Number and Name
High-level Description of Change
Brief Rationale
Synopsis Number of study sites 
planned
Number of study sites increased from 
approximately 40 to 50
To optimize enrolment 
Section 6.4.2 Bone marrow 
aspirate/biopsy
Disease/Response Assessment:
For the CLL disease response assessment:
•
In subjects who experience disease 
progression or who achieve a CR of CLL 
but subsequently relapse, if a bone 
marrow aspirate (that is clinically 
indicated in the management of a study 
treated subject) is acquired, a portion of 
the aspirate should be sent to the central 
laboratory if feasible for additional 
exploratory analyses (refer to the central 
laboratory manual for details).
Addition to clarify samples 
are applicable only for study 
treated subjects.
Section 6.6 Tumor Biopsy
If a tumor biopsy that is clinically indicated in 
the management of a study treated subject is 
acquired, a portion of the biopsy should be 
sent to the central laboratory for additional 
exploratory analyses.
Addition to clarify samples 
are applicable only for study 
treated subjects.
Section 7.2 Optional bridging 
therapy
Table 2 ‘Bridging Therapy Regimens’ updated 
to include  details for R-ICE,and R-GEMOX
Added R-ICE and R-
GEMOX as optional 
bridging therapy regimens, 
in view of subjects that may 
already have received R-
CHOP and DA-EPOCH-R
Section 12.2 Schedule of 
assessments, Table 5 Schedule of 
Assessments: Screening, 
Pretreatment, Treatment, and 
Post-treatment Periods
Footnotes j and l updated to indicate samples 
are only applicable for study treated subjects, 
aligning with language in Sections 6.4.2 and 
6.6 described above
Addition to clarify samples 
are applicable only for study 
treated subjects
Section 12.2 Schedule of 
assessments, Table 5 Schedule of 
Assessments: Screening, 
Pretreatment, Treatment, and 
Post-treatment Periods
Removed schedule of a lumbar puncture (if 
applicable) at suspected Disease Progression
Correction. A lumbar 
puncture at suspected 
Disease Progression is not 
required

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Section Number and Name
High-level Description of Change
Brief Rationale
Section 12.2 Schedule of 
assessments, Table 5 Schedule of 
Assessments: Screening, 
Pretreatment, Treatment, and 
Post-treatment Periods
Added schedule of PROs: EORTC-QLQ-C30 
and EQ-5D-5L at Post-bridging therapy 
assessment (if applicable)
Correction. Added an 
applicable PROs assessment 
timepoint.
Section 12.2 Schedule of 
assessments, Table 6 Post-
treatment Follow-up Period
Footnotes e and k updated to indicate samples 
are only applicable for study treated subjects, 
aligning with language in Sections 6.4.2 and 
6.6 described above
Addition to clarify samples 
are applicable only for study 
treated subjects
12.4.2.
Amendment 1.1 EU-specific Amendment (dated 12 January 2023)
A high-level summary of this amendment is provided in tabular form in the subsection below. 
Minor changes such as the correction of typographic errors, grammar, or formatting are not 
detailed.
For changes from Amendment 1 to Amendment 2, please refer to Section 12.4.2 and 
Section 12.4.3. Amendment 2 incorporates all changes in Amendment 1.1 together with the 
changes outlined in Section 12.4.3.
Protocol changes that are common across all substudies are detailed in the Master protocol 
(Appendix 12.10).
Section Number and Name
High-level Description of Change
Brief Rationale
Title page and Synopsis
EU CT and NCT numbers added
EU CT and NCT numbers 
previously not available
Synopsis Statistical Methods 
and Sections 9.1 Hypothesis 
and 9.4.2 Primary Analysis
•
“significantly” removed from statement 
that “The hypothesis is that the ORR to 
brexucabtagene autoleucel per central 
assessment is significantly greater than 
28%.”
•
Text edited to now state that the p-value 
‘will be’ calculated based on an exact test, 
rather than ‘may be’ tested.
For clarity
Section 3.1 Study Design
Text added to detail that the end of study is 
defined in the Master protocol (Section 3.4). 
(Defined as the LPLV within each specific 
substudy)
For clarity
Synopsis (Eligibility Criteria 
Unique to the RT Substudy) 
and Section 4.2.1 RT 
Substudy-specific Inclusion 
Criteria
Inclusion criterion 2 updated to (i) allow any 
first line chemoimmunotherapy, and (ii) 
Subjects will be eligible regardless of the 
duration of remission prior to relapse
For clarity 

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Section Number and Name
High-level Description of Change
Brief Rationale
Section 6.6 Tumor Biopsy
Text updated to state that “a new biopsy is only 
to be acquired if the location is easily 
accessible, and if appropriate taking into 
account subject safety”
Self-explanatory
Section 12.2 Schedule of 
Assessments Table 5
Pregnancy test added at Day 28
Alignment with CTFG 
guidelines for pregnancy 
testing following 
administration of fludarabine 
and cyclophosphamide
12.4.3.
Amendment 2.0 (dated 01 March 2023)
Changes from Amendment 1.1 (dated 12 January 2023) to Amendment 2 (dated 01 March 2023) 
are detailed below
Section Number and Name
High-level Description of Change
Brief Rationale
Title Page
Study title updated to read “A Phase 2, Open-
Label, Multicenter, Basket Study Evaluating 
the Efficacy of Brexucabtagene Autoleucel in 
Adults with Rare B-cell Malignancies 
(ZUMA-25) – Substudy B – 
Relapsed/Refractory Richter Transformation”. 
The evaluation of safety removed from the 
study title.
Request during Part 1 EU-
CTR application to update the 
trial title to focus on the 
primary endpoint only.
Title Page
Amendment history added
Self-explanatory
Section 6.2 Brain Magnetic 
Resonance Imaging
At screening, CNS involvement will be 
assessed by local review, and images will not 
be sent for central review
At screening, a brain MRI only needs to be 
submitted to the independent central reviewer 
when there is evidence of disease progression
For clarification
 Section 12.2 Schedule of 
Assessments, Table 5 
Schedule of Assessments: 
Screening, Pretreatment, 
Treatment, and Post-
Treatment Periods
Removed requirement for PRO assessment at 
post-bridging therapy assessment 
Correction of typo. The PRO 
assessment will be at day -5 in 
all subjects, regardless of 
bridging therapy
Section 12.2 Schedule of 
Assessments, Table 5 
Schedule of Assessments: 
Screening, Pretreatment, 
Treatment, and Post-
Treatment Periods
Footnote a: For EU and UK, the subject may 
remain hospitalized or return to the clinic daily 
for this extended monitoring, at the discretion 
of the investigator. For CH, patients must 
remain hospitalized for 10 days post 
brexucabtagene autoleucel infusion
Requirement by the Swiss 
Regulatory Authority

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Section Number and Name
High-level Description of Change
Brief Rationale
Section 12.2 Schedule of 
Assessments, Table 5 
Schedule of Assessments: 
Screening, Pretreatment, 
Treatment, and Post-treatment 
Periods
Footnotes ‘o’ pregnancy testing and ‘p’ 
serology testing updated to include Switzerland
Request by Swiss Regulatory 
Authority and alignment with 
Master protocol Section 6
Section 12.2 Schedule of 
Assessments, Table 5 
Schedule of Assessments: 
Screening, Pretreatment, 
Treatment, and Post-
Treatment Periods
Footnote t: Samples on Day 3 may be collected 
± 1 day
Provides flexibility regarding 
central laboratory sample 
collection when the Day 3 
visit falls over a weekend
Section 12.2 Schedule of 
Assessments, Table 6 
Schedule of Assessments: 
Post-Treatment Follow-up 
Period
Window for M18 changed from ±2 weeks to 
±1 month
Provides added flexibility
12.4.4.
Amendment 3.0 (dated 17 August 2023)
Changes from Amendment 2.0 (dated 01 March 2023) to Amendment 3.0 (dated 17 August 
2023) are tabulated below.
Section Number and Name
High-level Description of Change
Brief Rationale
General
Correction of typographical errors 
Removed references to study sites in the UK as 
UK is no longer participating.
Self-explanatory
Synopsis – Study Design
The evaluation of safety removed from the 
study
title.
Request from EMA reviewer 
during Part 1 EU-CTR 
application to update the trial 
title to focus on the primary 
endpoint only
Synopsis - – Number of Study 
Sites Planned
Number of participating sites amended to 
approximately 25
 Number of sites reduced due 
to early termination of 
substudies A and D
Synopsis – Statistical Methods
Added language to indicate that study 
enrollment will be paused following treatment 
of the 20th subject with brexucabtagene 
autoleucel and until data from the interim 
analyses have been assessed
To allow the Sponsor to 
review for futility prior to 
exposing additional subjects 
to study treatment 
Section 3.1 Study Design
Added language to indicate that study 
enrollment will be paused following treatment 
of the 20th subject with brexucabtagene 
autoleucel and until data from the interim 
analyses have been assessed
To allow the Sponsor to 
review for futility prior to 
exposing additional subjects 
to study treatment 

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Section Number and Name
High-level Description of Change
Brief Rationale
Section 6.4.1 Imaging 
Added language to specify that to limit 
radiation exposure, investigators are 
encouraged to leave at least 4 weeks between 
consecutive scans
Language added to encourage 
investigators to limit radiation 
exposure of subjects
Section 8.1 SRT and DSMB
Added language to indicate  that study 
enrollment will be paused following treatment 
of the 20th subject with brexucabtagene 
autoleucel and until data from the interim 
analyses have been assessed
To allow the Sponsor to 
review for futility prior to 
exposing additional subjects 
to study treatment
Section 9.4.1 Interim Analysis 
and Early stopping Guidelines
Added language to indicate that study 
enrollment will be paused following treatment 
of the 20th subject with brexucabtagene 
autoleucel and until data from the interim 
analyses have been assessed
To allow the Sponsor to 
review for futility prior to 
exposing additional subjects 
to study treatment
Section 12.2 Schedule of 
Assessments, Table 5 
Schedule of Assessments: 
Screening, Pretreatment, 
Treatment, and Post-
Treatment Periods
Footnote e- added clarifying text that 
neurological should be performed every other 
day during the hospitalization period
To clarify requirements for 
neurological assessments
Section 12.2 Schedule of 
Assessments, Table 5 
Schedule of Assessments: 
Screening, Pretreatment, 
Treatment, and Post-
Treatment Periods
Footnote i: added that “To limit radiation 
exposure, investigators are encouraged to leave 
at least 4 weeks between consecutive scans”
To limit radiation exposure of 
subjects
Section 12.2 Schedule of 
Assessments, Table 6 
Schedule of Assessments: 
Post-Treatment Follow-up 
Period
Footnote d: added that “To limit radiation 
exposure, investigators are encouraged to leave 
at least 4 weeks between consecutive scans”
To limit radiation exposure of 
subjects

ZUMA-25_RT Amendment 3
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Development
eSigned
21-Aug-2023
12:54:17
PPD