Duvelisib Exposure to Enhance Immune Profiles of T Cells in Patients With Diffuse Large B Cell Lymphoma (DEEP T CELLS)
Phase: EARLY_PHASE1
Conditions: Recurrent Diffuse Large B-Cell Lymphoma, Refractory Diffuse Large B-Cell Lymphoma
Sponsor: Emory University

Protocol Title: Duvelisib Exposure to Enhance Immune Profiles of T Cells in Patients with Diffuse 
Large B Cell Lymphoma (DEEP T CELLS)  
Page 1 of 56
Protocol Version: Version 22, 4/25/2023
PROTOCOL TITLE:  Duvelisib Exposure to Enhance Immune Profiles of T Cells in Patients with Diffuse 
Large B Cell Lymphoma (DEEP T CELLS)
WINSHIP PROTOCOL #:           Winship5085-20
COORDINATING CENTER: 
Winship Cancer Institute, Emory University
PRINCIPAL INVESTIGATOR:
Edmund K. Waller, MD/PhD
Professor, Department of Hematology/Medical Oncology
Winship Cancer Institute, Emory University
1365 Clifton Road, B5119
Atlanta, GA 30322
404-727-4995
ewaller@emory.edu
CO-INVESTIGATORS:
Sanjay Chandrasekaran, MD
Hematology/Medical Oncology Fellow
Winship Cancer Institute,
Emory University
1365 Clifton Road
Atlanta, GA 30322
253-670-1741
schandrasekaran@emory.edu 
Aseala Abousaud, PharmD
Winship Cancer Institute, 
Emory University 
1365 Clifton Road, 
Atlanta, GA 30322
Aseala.abousaud@emoryhealthcare.org
C. Ronnie Funk, MD
Internal Medicine Resident
Winship Cancer Institute, 
Emory University 
1365 Clifton Road 
Atlanta, GA 30322
Ronnie.Funk@emory.edu

Protocol Title: Duvelisib Exposure to Enhance Immune Profiles of T Cells in Patients with Diffuse 
Large B Cell Lymphoma (DEEP T CELLS)  
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Protocol Version: Version 22, 4/25/2023
STATISTICIAN:
Yuan Liu, PhD
Research Assistant Professor
Department of Biostatistics and Bioinformatics
Emory University
1518 Clifton Rd. Atlanta GA 30322
Yliu31@emory.edu
                                     
VERSION:  Version 22; 04/25/2023
FUNDING SOURCE:  Funding will be covered by Secura Bio and Novartis. 
INVESTIGATIONAL PRODUCT (IP): Duvelisb; Secura Bio
OTHER AGENT(S):  Chimeric Antigen Receptor T Cells; Novartis 
☒  Study Exempt from IND Requirements per 21 CFR 312.2(b).  

Protocol Title: Duvelisib Exposure to Enhance Immune Profiles of T Cells in Patients with Diffuse 
Large B Cell Lymphoma (DEEP T CELLS)  
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Protocol Version: Version 22, 4/25/2023
REVISION HISTORY (From v19 2/23/21 to v21 6/14/2022)
#
Section
Page(s)
Description of Changes
1
1.2
8
Schema Clarified Duvelisib D0 vs CAR-T Days 0-90 
2
1.3
9
Clarified CAR-T Day 0 as cD0
3
2.0
10
Clarified as “duvelisib consumed as documented by the patient”
4
3.0
11
Edit: cannot be downregulated on “normal” B cells.
5
4.2.1
18
Clarified language re: missed doses
6
5.3
19
Clarified stopping rules re: significant toxicities 
7
5.3
19
Clarified no allowance for dose interruptions 
8
5.6
20
Clarified COVID PCR testing rules and negative testing 
9
5.7
21
Defined severe non-compliance 
10
11.1
29
Re: Sterilization – added salpingectomy 
11
12
30
Clarified # to consent vs enroll at primary and sub-site
12
17.5.2
34
Clarified # doses to meet primary endpoint >/= to 75%
13
18.4
39
Added Secura email contact, changed Novartis to cell 
manufacturer
14
18.4
40
Duvelisib related SAE contact info for Secura for reporting
15
20.0
44
Clarified roles of sponsor vs supporter vs cell manufacturer
16
21.0
45
Edit: if so by whom (eg: sponsor, “supporter,” subject …
17
11.2
29
Updated exclusion criteria with word “known”
18
1.1, 3.1, 
3.2, 5.1, 
11.1, 13
7,8,12,15,
16, 29, 31
Include relapsed/refractory follicular lymphoma eligible to 
receive commercial tisagenlecleucel as part of the eligibility 
criteria
19
1.3
10
Change window for day 15 assessment to + 2 days
20
1.3
10
Change window for assessment post-CART to + 2 days
21
1.1,2, 
3.2, 5.1 
7, 8, 15, 
20
Change duration of duvelisib exposure from 2 weeks to 8-15 
days
Removed University of Chicago as a site

Protocol Title: Duvelisib Exposure to Enhance Immune Profiles of T Cells in Patients with Diffuse 
Large B Cell Lymphoma (DEEP T CELLS)  
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Protocol Version: Version 22, 4/25/2023
Table of Contents
1.
Study Summary..............................................................................................................................6
1.1
Synopsis......................................................................................................................................6
1.2
Schema .......................................................................................................................................8
1.3 Schedule of Assessments ................................................................................................................9
2.
Objectives (and Endpoints) ........................................................................................................10
3.
Background..................................................................................................................................11
3.1 Study Rationale .............................................................................................................................14
3.2 Clinical Experience ........................................................................................................................14
4.
Study Intervention/Investigational Agent..................................................................................15
4.1 Description....................................................................................................................................15
4.2 Drug/Device Handling ...................................................................................................................17
5.
Procedures Involved....................................................................................................................19
5.1 Study Design..................................................................................................................................19
5.2 Dosing and Administration............................................................................................................19
5.3 Interruption/Disruption of Treatment ..........................................................................................19
5.4 Dose Modification.........................................................................................................................19
5.5 Concomitant medication...............................................................................................................19
5.6 Study Procedures ..........................................................................................................................20
5.7 Description of Study Procedures...................................................................................................21
6.
Data and Specimen Banking.......................................................................................................23
7.
Tisagenlecleucel Apheresis Phase ............................................................................................23
7.1 Apheresis Collection......................................................................................................................23
7.2 Chemotherapy post-apheresis......................................................................................................23
7.3 Tisangenlecleucel Infusion ............................................................................................................23
7.4 Post-Tisangenlecleucel Monitoring...............................................................................................24
8.
Measurement of Effect ................................................................................................................24
8.1 RECIST Criteria v 1.1......................................................................................................................24
8.2 Evaluation of Disease:...................................................................................................................26
8.3 Evaluation of Best Overall Response:............................................................................................26
8.4. Assessment of Engraftment:........................................................................................................27
9.
Sharing of Results with Patients................................................................................................27
10. Study Timelines ...........................................................................................................................27
10.1 Duration of therapy.....................................................................................................................27
10.2 Duration of follow-up..................................................................................................................27
11. Inclusion and Exclusion Criteria ................................................................................................28
11.1 Inclusion Criteria .........................................................................................................................28

Protocol Title: Duvelisib Exposure to Enhance Immune Profiles of T Cells in Patients with Diffuse 
Large B Cell Lymphoma (DEEP T CELLS)  
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Protocol Version: Version 22, 4/25/2023
11.2 Exclusion criteria.........................................................................................................................29
12. Local Number of Participants.....................................................................................................30
13. Recruitment Methods ..................................................................................................................30
14. Withdrawal of Patients ................................................................................................................31
15. Risks to Participants ...................................................................................................................31
16. Potential Benefits to Participants...............................................................................................32
17. Data Management and Confidentiality.......................................................................................32
17.1 Source Documents:.....................................................................................................................32
17.2 Case Report Forms:.....................................................................................................................32
17.3 Data Retention:...........................................................................................................................32
17.4. Transmission of Data:.................................................................................................................32
17.5 Statistical Plan:............................................................................................................................33
17.6 Data/Specimens:.........................................................................................................................35
18 Provisions to Monitor the Data to Ensure the Safety of Participants........................................36
19. Provisions to Protect the Privacy Interests of Participants ......................................................41
20. Economic Burden to Participants ..............................................................................................42
21. Consent Process..........................................................................................................................42
22. Setting...........................................................................................................................................43
23. Resources Available....................................................................................................................43
24. References....................................................................................................................................44
APPENDIX A
PERFORMANCE STATUS CRITERIA ....................................................................47
APPENDIX B: POTENT INHIBITORS AND INDUCERS AND SENSITIVE CLINICAL SUBSTRATES 
OF CYP3A.............................................................................................................................................48
APPENDIX C 
Drug Diary................................................................................................................50
APPENDIX D: Procedure protocol for analysis of T cells and Correlate Studies Sample 
Collection Process ..............................................................................................................................51
APPENDIX E Abbreviations and definition of terms ........................................................................53

Protocol Title: Duvelisib Exposure to Enhance Immune Profiles of T Cells in Patients with Diffuse 
Large B Cell Lymphoma (DEEP T CELLS)  
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Protocol Version: Version 22, 4/25/2023
1. Study Summary
1.1Synopsis
This pilot study will evaluate a 8 to 15 day exposure to duvelisib in patients with relapsed/refractory 
Diffuse Large B Cell Lymphoma (DLBCL) or follicular lymphoma prior to undergoing apheresis of a 
mononuclear cell product for the purpose of CAR-T manufacturing.   The primary objective of the 
study is to determine whether the immune profile of T cells can be favorably changed by short-term 
exposure to duvelisib prior to collection of mononuclear cells for CAR-T 19 cell manufacturing.  
Secondary objectives include feasibility of adherence to duvelisib for 8 to 15 day, assessment of 
manufacturing time of patients, assessment of proportions of CD27/CD28 T cells and CD4/CD8 
double negative Gamma Delta T cells to historical controls, comparison of rates cytokine release 
syndrome (CRS)neurotoxicity or ICU transfer and overall response rate (ORR) at 90 days. The study 
will also determine if a 8 to 15 day exposure to duvelisib is safe and well tolerated in this setting. 
Title:
Duvelisib Exposure to Enhance Immune Profiles of T Cells in Patients with Diffuse 
Large B Cell Lymphoma (DEEP T CELLS)
Study 
Description:
This Pilot study will evaluate whether an 8 to 15 day  exposure to Duvelisib will 
favorably change the immune profile of T cells prior to CAR-T 19 cell manufacturing.  
We hypothesize that short term exposure to Duvelisib will:

increase frequencies of CD27/28 double positive naïve and memory T 
cells. 

increase frequencies of CD8+CD45RO-CD27+ T cells.

increase frequencies of CD4/CD8 double negative Gamma Delta T cells.
Objectives:
Primary Objective:  

To assess changes in T cell phenotype after 8 to 15 day exposure to 
duvelisib prior to collection of mononuclear cells for CAR-T cell 
manufacturing.
Secondary Objectives:  

To evaluate compliance with duvelisib

To evaluate the CAR-T 19 manufacturing time 

To describe frequencies of CD27/28 double positive T cells and CD4/8 
double negative T cells 

To evaluate expansion and persistence of CAR-T cells 

To evaluate overall response rates following CAR-T cell therapy

To evaluate survival rates following CAR-T cell therapy 

To describe the frequency of CRS and neurotoxicity requiring ICU transfer 
(for CRS or neurotoxicity) and/or treatment 

Describe the safety and tolerability profile of duvelisib 

Protocol Title: Duvelisib Exposure to Enhance Immune Profiles of T Cells in Patients with Diffuse 
Large B Cell Lymphoma (DEEP T CELLS)  
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Protocol Version: Version 22, 4/25/2023
Endpoints:
Primary Endpoint:  

The fold increase in the proportion of T cell phenotypes expressing CD 
27/28 (to overall T cell count) after 8 to 15 day exposure to duvelisib
Secondary Endpoints: 

The proportion of duvelisib consumed as evaluated by the patient pill 
diaries.

Manufacturing time of CAR-T 19 cells in weeks (includes manufacturing 
failure)

The proportion of CD27/28 double positive T cells and CD4/8 double 
negative T cells

CAR-T kinetics assessment by PCR 

Overall response at 90 days after CAR-T cell infusion defined by the Tumor 
Response Assessment that are complete responders (CR) and partial 
responders (PR).

Progression-free Survival (PFS) at 90 days per RECIST 1.1 and Overall 
Survival at 90 days 

ICU transfer due to CRS and/or neurotoxicity or due to the treatment with 
tocilizumab and/or corticosteroids 

Grade III-V toxicities (as defined by CTCAE version 5.0)
Study 
Population:
20 patients will be enrolled with relapsed/refractory DLBCL or relapsed/refractory 
follicular lymphoma
Phase:
Pilot
Description of 
Sites/Facilities 
Enrolling 
Participants:
This study will be at Winship Cancer Institute, Emory University. 
Description of 
Study 
Intervention:
Duvelisib is an oral PI3K inhibitor that is given at a dose of 25mg BID prior to 
manufacturing of CAR-T cells. 
Study Duration:
We estimate that the duration of the study will be approximately 18 months.

Protocol Title: Duvelisib Exposure to Enhance Immune Profiles of T Cells in Patients with Diffuse 
Large B Cell Lymphoma (DEEP T CELLS)  
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Protocol Version: Version 22, 4/25/2023
1.2  Schema
Screening
Days -14 to 0
• Total n= 20
• Obtain informed consent
• Screen potential participants by inclusion and exclusion criteria
• Obtain history, document
 Refer to Section 1.3, Schedule of Activities
Day 1
• Administer initial dose of Duvelisib 
Follow-up assessments of study endpoints and safety 
Baseline assessments/ Study Intervention
Day 8
• Refer to Section 1.3, Schedule of Activities
Day 15
•  Refer to Section 1.3, Schedule of Activities 
Post CAR-T 19 Infusion Assessments
CART-T Day 0-90
• Refer to Section 1.3, Schedule of Activities 

Protocol Title: Duvelisib Exposure to Enhance Immune Profiles of T Cells in Patients with Diffuse 
Large B Cell Lymphoma (DEEP T CELLS)  
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Protocol Version: Version 22, 4/25/2023
1.3 Schedule of Assessments
Table 1: Pre and During Study Assessments on duvelisib (Day 1= First day of duvelisib)
Procedures and Tests
Days -14 to 0
Day 8 +/-1
Day 15 +/-2
Medical History
X
Physical Exam
X
X
X
Performance Status
X
X
X
Vital Signs
X
X
X
Labs:*
X
X
X
          CBC
X
X
X
          CMP
X
X
X
          TSH
X
           Magnesium
X
Phosphorous
X
X
X
           HIV Ag/Ab
X
           Hepatitis Serologies
X
Covid-19 PCR (-7 
to 0)
X
EKG
X
Immunophenotyping of T-
Cells
X
X
PET/CT*
X
Serum or Urine Pregnancy 
Test**
X
Adverse Events
X
X
* Standard-of-care
** Standard-of-care. Also see section 11.1 regarding risk to fetus and requirement for contraception 
while on study
Table 2: Post CAR-T 19 Cell Infusion Assessments (post-hospital discharge, will be captured 
with chart review) (CAR-T Day 0 (cD0)= Date of CAR-T infusion)
Procedures and 
Tests
Day 7 +/-1
(post CAR-T)
Day 14 +/-2 
(post CAR-T)
Day 28 +/-2 
(post CAR-T)
Day 42 +/-3 
(post CAR-T)
Day 90 +/-3 
(post CAR-T)
CAR-T 19 PCR*
X
X
X
X
X
Immunophenotype of 
CAR-T*
X
X
X
X
X
PET/CT or CT*
X
* Standard-of-care

Protocol Title: Duvelisib Exposure to Enhance Immune Profiles of T Cells in Patients with Diffuse 
Large B Cell Lymphoma (DEEP T CELLS)  
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Protocol Version: Version 22, 4/25/2023
2. Objectives (and Endpoints)
OBJECTIVES
ENDPOINTS
Primary
1.
To assess the increase in CD27+/CD28+ 
T cells, after 8 to 15 day exposure 
duvelisib prior to collection of mononuclear 
cells for CAR-T cell manufacturing.
1.
The fold change increase in proportion of 
T cell phenotypes co-expressing CD27/28 
using multiparametric flow cytometry.
Secondary
1.
To evaluate patient compliance with   
duvelisib.
2.
To 
evaluate 
the 
time 
required 
for 
manufacturing CAR-T using mononuclear 
cells from duvelisib-treated patients.
3.
To describe the frequencies of CD27/28 
double positive T cells and CD4/8 double 
negative T cells
4.
To evaluate expansion and persistence of 
CAR-T cells 
5.
To evaluate overall response rates 
following CAR-T cell therapy
6.
To evaluate survival rates following CAR-
T cell therapy 
7.
To describe the frequency of CRS and 
neurotoxicity requiring ICU transfer (for 
CRS or neurotoxicity) and/or treatment
 
8.
Describe the safety and tolerability profile 
of duvelisib
1.
The proportion of duvelisib consumed as 
documented by  the patient on the pill 
diaries.
2.
Manufacturing time of CAR-T 19 cells in 
weeks (includes manufacturing failure)
3.
The proportion of CD27/28 double positive 
T cells and CD4/8 double negative T cells
4.
CAR-T kinetics assessment by PCR 
5.
Overall response (per iRECIST) at 90 days 
after CAR-T cell infusion defined by the 
Tumor Response Assessment that are 
complete responders (CR) and partial 
responders (PR).
6.
Progression-free Survival (PFS) at 90 
days per RECIST 1.1 and Overall Survival 
at 90 days
7.
ICU 
transfer 
due 
to 
CRS 
and/or 
neurotoxicity or due to the treatment with 
tocilizumab and/or corticosteroids 
8.
Grade III-V toxicities (as defined by 
CTCAE version

Protocol Title: Duvelisib Exposure to Enhance Immune Profiles of T Cells in Patients with Diffuse 
Large B Cell Lymphoma (DEEP T CELLS)  
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Protocol Version: Version 22, 4/25/2023
3. Background
Diffuse Large B Cell Lymphoma (DLBCL) and relapsed/refractory follicular lymphoma: 
Lymphoma is a group of blood cell tumors that arise from the lymphatic systems and can be 
separated into two categories: Non-Hodgkin Lymphoma (NHL) and Hodgkin Lymphoma (HL).  NHL 
accounts for about 4% of all cancers with an estimated 74,000 new cases diagnosed in 2018.1 There 
will be an estimated 20,000 deaths from NHL, which accounts for 3% of all cancer deaths.   Diffuse 
large B cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most common NHL, accounting 
for nearly 65% of cases.2  Standard treatment for DLBCL is a rituximab based regimen in 
combination with cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone (R-CHOP 
or R-EPOCH).3  The five year overall survival (OS) for DLBCL is 62% in the United States and for 
localized DLBCL, the OS is even more impressive at over 80%.4,5 Despite the favorable outcomes 
with DLBCL, one third of patients will have relapsed or refractory disease.2 These patients are 
treated with salvage chemotherapy and consolidation treatment with autologous stem cell transplant 
(ASCT).  Unfortunately, about 50% of those patients that receive ASCT will ultimately relapse, and 
further treatment options become severely limited with a median OS of 6.2 months.4 
Recently, a novel immunotherapy that manufactures T cells to express the chimeric antigen receptor 
(CAR-T cells) against CD19, that is pan-expressed on B cells, has been shown to have high 
response rates in relapsed/refractory B cell cancers including those that have previously received 
an ASCT.6  CAR-T cells provide a promising new treatment for heavily pre-treated patients with B 
cell malignancies, however, there are a sub-group of patients who are unable to manufacture a 
sufficient amount of CAR-T cells, have poor expansion of CAR-T cells in vivo, or lose persistence of 
their CAR-T cells post infusion. Thus, better manufacturing of T cells to make them more potent with 
longer duration are critical to enhancing the success of CAR-T cells.
Chimeric Antigen Receptor T (CAR-T) Cells:
Chimeric antigen receptor (CAR) T cells are genetically engineered T cells that recognize specific 
tumor antigens.7 The genes encoding for the CAR are inserted into the T cells using a viral vector 
with RNA genetic material that is then reverse transcribed into the T cells DNA.8 The CAR is then 
transcribed and translated and then expressed on the cell surface where it is able to recognize tumor 
antigens. There are two components of the CAR including the antigen-recognition domain and the 
T cell signaling domain.  In earlier generations of CARs, the T cell signaling domain only contained 
an intracellular activation domain.  Newer generations have added a single co-stimulatory domain 
(CD28 or 4-1BB) or two co-stimulatory domains (See Figure 1).  For B cell malignancies, including 
acute lymphoblastic leukemia (ALL) and DLBCL, the most common antigen used for CAR-T cells 
manufacturing is CD19. CD19 is pan-expressed on B cells and cannot be downregulated on normal 
B cells. Numerous single center and multi-center studies have been published about CD19 CAR-T 
cells against NHL and has shown an overall response rate (ORR) ranging from 71%-100%.7
Remissions of hematologic malignancy with CAR T cell therapy are associated with one of two 
profiles of CAR T cell expansion kinetics. Some trials positively associate the ratio of peak CAR T to 
tumor cells with remission, whereas the bulk of trials associate long-term persistence of CAR T with 
continued remission. In support of the latter mechanism, expansion and persistence of a single clone 
(defined by CAR insertion site) comprising 94% of the total CAR T cells was sufficient to induce 
remission. In study of 41 patients who received CAR T cell therapy to treat CLL, Fraietta et al 
associated the frequency of CD8+CD27+CD45RO- T cells prior to CAR T manufacture with 

Protocol Title: Duvelisib Exposure to Enhance Immune Profiles of T Cells in Patients with Diffuse 
Large B Cell Lymphoma (DEEP T CELLS)  
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Protocol Version: Version 22, 4/25/2023
remission.9 These clinical observations suggest CAR T cell phenotype, such as expression of CD27 
and CD28, influences response to therapy.  
Figure 1: Structure of CAR-T cells (Brudno & Kochenderfer)
Phosphoinositide 3-Kinase (PI3K)
PI3K proteins are divided into three classes of which only Class IA PI3K molecules have been 
implicated in human cancers, prompting development of isoform-selective inhibitors to Class IA 
PI3K.10 Analysis of evolutionary conservation across known class I PI3K signaling cascades reveals 
the greatest conservation in signaling along the insulin/IGF-1/AKT pathway, suggesting PI3K 
primarily evolved to regulate cellular proliferation and metabolic changes in response to glucose.11   
PI3Ks are involved in the generation of lipid second messengers and contain eight catalytic subunits 
of PI3K, with the P110 gamma and the P110 delta subunits being expressed at much higher levels 
in immune cells.12,13 The PI3K p110 subunits work by phosphorylating phosphatidylinositol 4,5 
bisphosphate (PIP2) into phosphatidylinositol 3, 4,5 triphosphate (PIP3), which enables anchorage 
and association of cytosolic proteins near the lipid bilayer, enabling complex signal transduction 
cascades to occur.10   In the case of T cells, metabolism of glucose is closely linked to the replicative 
capacity of the cells, with T cells capable of oxidative phosphorylation exhibiting enhanced replicative 
capacity whereas T cells that rely upon glycolysis exhibit reduced replicative potential, as reviewed 
by Van der Windt et al 2013.14
PIP3 then goes on to function as a second messenger that initiates multiple signaling cascades, 
including the phosphorylation of AKT, a serine/threonine protein kinase, leading to downstream 

Protocol Title: Duvelisib Exposure to Enhance Immune Profiles of T Cells in Patients with Diffuse 
Large B Cell Lymphoma (DEEP T CELLS)  
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Protocol Version: Version 22, 4/25/2023
survival and differentiation signals such as mechanistic target of rapamycin 1 (mTOR).15,16 mTOR, 
also a serine/threonine kinase, is regulated by amino acids and glucose levels. Upon T cell 
activation, there is an increase in uptake of amino acids and glucose leading to activation of mTOR1 
and this activation is required to maintain the T cell effector functions. 17-20 Activation of mTOR1 also 
promotes induction of aerobic glycolysis, as well as assistance in maintaining it, which leads to 
increased differentiation and effector functions, which are shown to be less efficacious in terms of 
adoptive T cell therapies.20 By inhibiting mTOR through inhibition of PI3K. PI3K inhibitors promotes 
memory T cell phenotype by inhibiting aerobic glycolysis and preventing terminal differentiation.20 
One PI3K inhibitor, Idelalisib, inhibits only the delta catalytic subunit, which blocks lymphocyte 
function.11  Duvelisib, another PI3K inhibitor, demonstrates inhibition of both PI3K-delta and gamma, 
but is much more selective for the delta than the gamma isoform of PI3K.15 15 Indeed, using whole 
blood assays, duvelisib achieves inhibition of PI3K delta and gamma at clinically feasible doses 
(Pachter and Weaver, SITC 2008), which may be important for modulating ratios of CD8:CD4 T cells 
(Funk et al., SITC 2019; unpublished data, Waller Lab). By targeting either PI3K delta alone or both 
PI3K delta and gamma catalytic subunits, that are predominantly expressed on immune cells, PI3K 
inhibitors lead to partial blockade of terminal differentiation of T cells. 
T cells and Cancer Immunotherapy
T cells can be categorized based upon whether their T cell receptor (TCR) recognizes antigen by 
major histocompatibility complex (MHC) in an independent or dependent manner. Alpha Beta T cells 
contain a TCR that recognize peptide presented by class I or II MHC, whereas Gamma Delta T cells 
recognize antigens independent of MHC.  Gamma Delta T cells are a small and unique population 
of T cells that compromise less than 5% of the total T cell population.21   They generally do not 
express CD4 or CD8 and have the unique role of serving as both effector T cells and initiating and 
maintaining adaptive immune responses.22  Gamma-Delta T cells are able to secrete cytokines, 
including IL-4 and TNFa, that can directly attack and kill tumor cells.  They can also act as antigen 
presenting cells (APCs) and have the capacity to induce CD4+ and CD8+ antigen specific T cells.23  
Pre-clinical studies have shown that gamma delta CAR-T cells have a more naïve T cell phenotype 
and that their cytotoxicity was equivalent to alpha beta CAR-T cells.24
Alpha Beta(+) TCR T cells are the predominant T cells compromising >95% of T cells and can be 
further  sub-categorized into helper, cytotoxic, memory or regulatory T cells.23 Naïve T cells are 
antigen inexperienced and are characterized by the expression of  CD45RA, CD62L and the co-
stimulatory molecules CD27 and CD28.  Central memory T cells, which have previously encountered 
an antigen, express CD45RO, CD27 and CD62L and thus, retain their proliferative capacity. Effector 
memory T cells lack CD27 and CD62L which reduces their proliferative capacity.25
One unintended consequence of cytotoxic chemotherapy, is depletion of healthy T cells, including 
naïve and central memory T cell subsets, that have the most potent ability to respond to malignant 
antigens, have greater expansion potential and greater anti-cancer activity.26-27   Numerous studies 
have shown superior persistence and anti-tumor activity with minimally differentiated T cells, 
including naïve, stem cell and central memory T cells.28-30  
These observations also apply to CAR T cells, as study of determinant of outcomes revealed that 
frequencies of memory and naïve cells prior to CAR T manufacture appear to be associated with 
remissions.31  
Heavily pre-treated patients with DLBCL exhibit a deficiency in naïve and minimally differentiated T 
cells, which renders their total T cell product collected by apheresis less able to expand during ex 
vivo culture as necessary during CAR-T cell manufacturing. T cells that are both CD27 negative and 
CD28 negative are considered senescent. Accordingly, culture of CD27negative/CD28negative cells 

Protocol Title: Duvelisib Exposure to Enhance Immune Profiles of T Cells in Patients with Diffuse 
Large B Cell Lymphoma (DEEP T CELLS)  
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Protocol Version: Version 22, 4/25/2023
sorted from patients with DLBCL by FACS (fluorescent activated cell sorting) revealed no expansion, 
further validating these cells are senescent. Heavily pre-treated DLBCL patients have a significantly 
higher proportion of CD27/CD28 double negative T cells compared to healthy controls and newly 
diagnosed DLBCL patients.16   DLBCL patients also have a much higher ratio of memory T cells to 
naïve T cells compared to healthy controls.27  We reported decreases in CD27/CD28 co-expression 
upon T cells of one patient with DLBCL treated with CTL019 prior to subsequent CAR T decay.32 In 
this patient, 60% of her total CD8 cells and 20% of CD4 cells exhibited loss of both CD27 and CD28 
expression, a phenotypic change heralding T cell senescence and a decay of CAR T numbers.  
Collectively, this body of literature suggests that expression of co-stimulatory molecules such as 
CD27 and CD28 represent a phenotypic marker denoting T cells with an underlying phenotype that 
is more capable of inducing CAR T- mediated remissions. Thus, strategies to enhance frequencies 
of naïve and memory cells prior to ex vivo expansion, resulting in fewer terminally differentiated cells 
during expansion, can help improve the quality of T cells needed for manufacturing.27 
3.1 Study Rationale
Relapsed/Refractory Diffuse Large B Cell Lymphoma (DLBCL) has a dismal prognosis, especially 
with relapse/refractory disease after autologous stem cell transplantation. Recently, a new adoptive 
cell transfer therapy, CAR-T cells, that manufactures a patient’s T cells to express artificial receptors 
on their cell surface has shown promising results in patients that relapse or have refractory disease. 
However, there are subset of patients that fail to manufacture a sufficient amount of CAR-T cells ex 
vivo, have poor expansion in vivo or lose persistence of their CAR-T cells after infusion.  This has 
been attributed to relapsed/refractory DLBCL patients having a predominance of more differentiated 
T cells that are senescent and have poor expansion potential for CAR-T cell manufacturing. 
This pilot study will examine if a 2-week exposure to Duvelisib, will favorably change a patient’s T 
cell phenotype for manufacturing of more potent CAR-T cells for relapsed/refractory DLBCL and 
relapsed/refractory follicularlymphoma patient receiving commercial tisagenlecleucel.
3.2 Clinical Experience
3.2.1 Pre-Clinical Studies
Based upon this rationale, a series of preclinical studies involving ex vivo culture of mononuclear 
cells from healthy volunteers and patients with DLBCL, we showed that the addition of duvelisib, an 
FDA-approved PI3K delta and gamma inhibitor, significantly augmented overall expansion of T-cells 
from healthy donors and DLBCL patients.16  Phenotypic analysis of these cells revealed increased 
frequencies of non-senescent, naïve and memory T-cells that express both CD27 and CD28.16 
Duvelisib enhanced expansion of T cells from patients with DLBCL, while increasing expression of 
co-stimulatory molecules.  More recently, we have shown that incubation with pharmacologically 
achievable and clinically relevant doses of duvelisib recapitulated the effect of duvelisib on T-cell 
expansion in healthy donors and patients with CLL (Funk et al., SITC 2019; unpublished data).
To assess the influence of PI3K delta and gamma inhibitor during ex vivo T cell culture, dose-
response experiments of duvelisib or idelalisib (PI3K delta inhibitor) assessing the influence of these 
drugs upon T cell number and quality across logarithmic scales revealed a dose-dependent increase 
in the frequency of both CD8 positive T-cells and CD3 positive but CD4 negative CD8 negative cells, 
with corresponding decreases in CD4 cells (Funk et al., SITC 2019;unpublished data). These 
differences in the ratios of these T cells are particularly observed at doses of PI3K inhibitor sufficient 
to inhibit both PI3K delta and gamma. In a survey of the literature, Stock et al. (2019) reported a 
similar observations in that the ratio of CD8:CD4 T cells from patients with CLL increased when 
cultured with 1M idelalisib, such that ratios of CD8:CD4 T cells became more similar to those 
observed T cells cultured from healthy volunteers.33 Of note, 1M idelalisib is sufficient to inhibit both 

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PI3K delta and gamma, but idelalisib cannot be administered at doses that achieve drug levels 
sufficient to inhibit PI3K gamma.  Further analysis of the CD3 positive CD4 negative CD8 negative 
subset revealed that duvelisib (and idelalisib) significantly increase absolute numbers of Gamma 
Delta T-cells following 10 to 15-day ex vivo culture, particularly at doses sufficient to inhibit both PI3K 
delta and gamma (unpublished data).   The T-cells expanded with a PI3K delta inhibitor (idelalisib) 
have improved survival following transfer to NSG mice as well as enhanced cytotoxicity against 
lymphoma targets using human and murine preclinical model systems.16 
In summary, a body of preclinical literature and data suggest that modulation of the PI3K pathway, 
utilizing duvelisib, an isoform-selective inhibitor of PI3K delta and gamma, represents a strategy with 
potential to enhance the phenotype and expansion of T cells from patients with DLBCL and 
relapsed/refractory follicular lymphoma, which may enhance CAR T cell mediated outcomes.  In an 
effort to translate these preclinical observations to the clinic, we hypothesize that 8 to 15 days of 
duvelisib exposure in patients with DLBCL or relapsed/refractory follicular lymphoma will enhance 
frequencies of T cells with replicative potential, so that mononuclear apheresis product collected for 
CAR-T manufacture following duvelisib exposure will result in faster manufacturing time than 
historical controls. We predict that one benefit of a reduced manufacture duration will be enhanced 
viability of the final CAR T cell product. Further, we hypothesize the enhanced yield of metabolically 
fit T cells will lead to generation of CAR T cells that will exhibit enhanced in vivo persistence and 
proliferation, significant since these factors are associated with longer remissions. Further, we 
predict infusion of CAR-T-cell product generated from patients pre-treated with duvelisib will not 
result in significantly different levels of CRS or neurotoxicity compared to patients treated with CAR-
T-cells manufactured from a mononuclear cell apheresis product collected without prior exposure to 
PI3K inhibitors.   
3.2.2 Pre-Clinical Pharmacology of Duvelisib and T Cell Expansion
Duvelisib is a highly potent dual PI3K delta and gamma inhibitor with a whole blood IC50 of 0.4M 
for inhibition of the delta subunit and whole blood IC50 of 1.6M for inhibition of the gamma subunit 
(Pachter & Weaver, SITC 2018).   We have seen optimal T cell expansion at duvelisib concentrations 
of 40nM to 0.4 M at 14 days.
3.2.3 PI3K Inhibitors in Clinical Settings
PI3 kinase (PI3K) inhibitors are FDA-approved for treatment of relapsed follicular lymphoma (FL) 
and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Orally bioavailable drugs 
are typically dosed once or twice a day with the goal of inhibiting signaling through the PI3K-AKT 
pathway causing reduction in the growth of malignant lymphoma cells and induction of apoptosis. 
PI3K inhibitors are generally well tolerated and can be given for weeks to months as continuous 
therapy without significant hematological toxicity. One common feature of treatment with PI3K 
inhibitors is the development of late autoimmune disease, including colitis, pneumonitis and rash, by 
blockade of differentiation into regulatory T cells which are necessary for self-tolerance and down-
regulation.34 
4. Study Intervention/Investigational Agent
4.1 Description
4.1.1 Duvelisib 

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Duvelisib is an oral PI3K inhibitor.  FDA approved duvelisib (Copiktra, IPI-145) on September 24, 
2018. Duvelisib is approved for the treatment of adult patients with relapsed or refractory chronic 
lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior systemic 
therapies, and relapsed or refractory follicular lymphoma (FL) after at least two prior systemic 
therapies. Refer to the approved labeling for more details on specific indications and for detailed 
information on duvelisib.
4.1.2. Tisagenlecleucel Product
Tisagenlecleucel is an autologous cellular immunotherapy product that is comprised of CD3+ T cells 
that have undergone ex vivo T cell activation, gene modification, expansion md formulation in 
infusible cryomedia. The transgene to be expressed via lentiviral vector transduction is a CAR 
targeted against the CD19 antigen. The CAR contains a murine scFv that targets CD19 linked to a 
transmembrane region derived from the CD8 receptor, which is linked to an intracellular bipartite 
signaling chin of TCR-§ (or CD3-{) and 4-1BB intracellular signaling domains. The extracellular 
scFv with specificity for CD19 is derived from a mouse monoclonal antibody. T cells which we 
enriched from a patient leukapheresis unit are expanded ex vivo using commercially available 
magnetic beads that are coated with anti-CD3 and anti-CD28 monoclonal antibodies. The cells are 
transduced with the CD19 CAR lentiviral vector which ensures that only peripheral white blood cells 
enriched for lymphocytes are exposed to the vector. The residual non-integrated vector is washed 
away during the process. CTL019 cells will be expanded ex vivo for rip to 10 days. At the end of the 
culture, the CTL019 cells are depleted of magnetic beads, washed, concentrated, and 
cryopreserved. Results from a release testing procedure are required prior to release of the product 
for infusion.
4.1.3. Tisagenlecleucel Dose: 
A dose of Tisagenlecleucel transduced cells for patients will consist of a single infusion of 1 to 5 x108 
Tisangenlecleucel transduced cells.
4.1.4 Tisagenlecleucel Infusion: 
The Tisagenlecleucel cell product will be prepared and released by the manufacturing facility to the 
study site approximately 3 to 4 weeks after manufacturing has commenced, provided all required 
safety and quality release criteria have been met. Upon receipt of the cryopreserved CTL019 cell 
product, an inventory must be performed, and a drug receipt log filled out and signed by the person 
accepting the shipment. The cryopreserved tisagenlecleucel should be kept in the vapor phase of 
liquid nitrogen until infusion. 
Prior to CTL019 infusion the following criteria must be met:
1. All patients must undergo a rapid influenza diagnostic test within 10 days prior to the pined 
CLT0l9 infusion. If the patient is positive for influenza, oseltamivir phosphate or zanamivir should 
administered for 10 days as preventative treatment. The patient must complete their 10 -day 
preventative treatment course prior to receiving tisagenlecleucel. The test does not need to be 
repeated prior to infusion however, if flu-like or respiratory signs and symptoms are present, 
CTL019 infusion should be delayed until the patient is asymptomatic.
2. COVID-19 screening will occur prior to duvelisib initiation [see section 5.6]. Based on medical 
assessment, CTL019 infusion will be delayed in symptomatic patients (symptoms including but 
not limited to fever, cough, sore throat, loss of taste/smell, headaches, myalgias) suspected to 
have active COVID-19 disease until the patient is asymptomatic.  
3. Patient should not experience a significant change in clinical status compared to initial eligibility 
criteria that would, in the opinion of the treating physician, increase the risk of adverse events 
associated with experimental cell infusion.

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4.
Rapidly progressing patients, or patients experiencing laboratory abnormalities after enrollment, 
that in the opinion of the treating investigator or PI may impact patient safety or the patients’ ability 
to receive the  infusion, may have their infusion delayed until both the treating investigator and PI 
determine it is clinically appropriate to proceed with the infusion.
5.
Patients experiencing toxicities from their preceding lymphodepleting chemotherapy will have their 
infusion schedule delayed until these toxicities have resolved. The specific toxicities wanting 
delay of infusion include:
a.
Pulmonary: Requirement for supplements oxygen to keep saturation greater than 91% or 
presence of progressive radiographic abnormalities on chest x-ray
b. Cardiac: New cardiac arrhythmia not controlled with medical management
c.
Hypotension requiring vasopressor support
d.
Uncontrolled active infection, as evidenced by positive blood cultures for bacteria, fungus, or 
PCR positivity for viral DNA in blood within 72 hours of infusion, or clinical or radiographic 
evidence of active infection.
Following lymphodepleting chemotherapy patients must not have progressive disease in order to 
receive infusion, as this will potentially put them at an unacceptable risk for severe CRS. Patients 
should not receive infusion if they exhibit significant progression of disease following lymphodepleting 
chemotherapy as evidenced by:
a.
Significant increase in nodal disease
b.
Significant increase in extra-nodal disease
c.
Occurrence of new lymphoma manifestations
d.
Clinical evidence of CNS disease
6.
If patients are taking any of the following medications, their infusion must be delayed until the 
medications have been stopped according to the below:
a. Steroids: Therapeutic doses of steroids must be stopped >72 hours prior to tisagenlecleucel 
infusion. However, the following physiological replacement doses of steroids we allowed: 6-
12 mg/m2/day hydrocortisone or equivalent
b.
Antiproliferative Therapy:
c.
All anti-proliferative therapies must have been stopped > 2 weeks prior to tisagenlecleucel 
infusion
d.
Immunosuppressive therapies: Any drug used for immunosuppression must be stopped > 4 
weeks prior to tisagenlecleucel infusion (e.g. calcineurin inhibitors, methotrexate or other 
chemotherapy drugs, mycophenolate, steroids [see above], rapamycin, thalidomide or 
immunosuppressive antibodies such as rituximab, anti-TNF, anti-IL6 or anti-IL6R)
e.
CNS disease prophylaxis must be stopped 1 week prior to tisagenlecleucel infusion (e.g. 
intrathecal methotrexate).
Patients experiencing toxicities from their preceding chemotherapy will have their tisagenlecleucel 
infusion delayed until the above toxicities have been resolved. If any of the above criteria are not met 
and a period of delay is 4 or more weeks from completing lymphodepleting chemotherapy and the 
WBC is >1000/microL, the patient will need to be re-treated with lymphodepleting chemotherapy, and 
these criteria will need to be re-established prior to tisagenlecleucel infusion.
4.2 Drug/Device Handling
4.2.1 Acquisition and Accountability 
Duvelisib will be provided by Secura Bio and will be packaged and labeled by Secura Bio.

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The sponsor will acknowledge receiving the medication by completing and documenting forms 
indicating shipment content and condition. Records of duvelisib received at, dispensed from 
and returned by the study site will be documented in the drug inventory log (DIL). Duvelisib will 
be dispensed by clinical research staff per the protocol of the Winship Cancer Institute and 
dispensation of the study drug must be documented. Duvelisib should be taken at 
approximately the same times on each day and should be taken with 8 oz of water.  Patients 
will be required to maintain a medication diary of each dose of medication.  The medication 
diary (Appendix E) will be returned to clinic staff at the end of completion treatment or at the 
time of withdrawal from the study.
If a dose of duvelisib is missed by fewer than 6 hours, the missed dose can be taken right away 
and the next dose taken on schedule.  If a dose is missed by more than 6 hours, the dose is 
skipped the next dose taken at the usual time. Patients will not be allowed to make up missed 
doses and a missed dose should also be recorded in the patient’s diary. Incorrect dosing should 
also be reported in the patient’s diary and documented in the case report form. Damaged 
medication will be replaced. 
Patients will be asked to return all unused duvelisib and packaging at the end of the study or at 
the time of study treatment discontinuation. Duvelisib supply will be disposed of per Winship’s 
Investigational Drug Service (IDS) SOP. Compliance will be assessed by the investigator and/or 
study personnel at each patient visit and information provided by the patient and/or caregiver 
(collection of drug diary) will be captured in the Drug Accountability Form. This information must 
be captured in the source document at each patient visit.  Dose changes and interruptions of 
study drug must be specifically documented in the patient source documents and eCRF.
4.2.2. Formulation, Appearance, Packaging and Labeling
Duvelisib comes in two strengths: 15mg and 25mg.  Patients will be provided twenty-eight (28) 
25mg tablets. The contents of the label will be in accordance with regulatory requirements.  
4.2.3 Product Storage and Stability
Duvelisib will be stored at the Emory Investigational Pharmacy. Duvelisib will be stored at room 
temperature between 20-25 degrees Celsius.
4.2.4. Safety of Duvelisib 
Immune related toxicities are the most common non-hematological adverse event (AE) with 
duvelisib. Infection, elevated AST/ALT and diarrhea are the most common non-hematological 
AEs. The rates of diarrhea ranged from 42-51% in clinical trials with a median onset of 2.2-4 
months.35,36 The median time of onset for AST/ALT elevation was 1.2 months and occurred in 
39% of patients in one phase I clinical trial.35 Other non-hematological AE’s that have been 
reported include maculopapular rash, pyrexia and colitis.  Neutropenia was the most common 
hematological AE, occurring in 29%-39% of patients in clinical trials.  Infections has also been 
reported in 61-69% of patients with upper respiratory tract infections and pneumonia being the 
most common infections.36,37 There have also been reports of Pneumocystis jirovecci with the 
use of duvelisib.

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5. Procedures Involved
5.1 Study Design
This is an open-label pilot clinical trial prospective study of treating patients with relapsed/refractory 
DLBCL or relapsed/refractory follicular lymphoma with duvelisib at a dose of 25 mg p.o. b.i.d. for 8 
to 15 days prior to collection of mononuclear cells by apheresis for the purpose of CAR-T 
manufacturing.  The intended duration of duvelisib exposure is 2 weeks. The duration of duvelsib 
may be adjusted to a period between 8 and 15 days depending upon the schedule of apheresis, with 
the last dose of duvelisib on the day of apheresis.
5.2 Dosing and Administration
In the phase I study with duvelisib in hematological malignancies, the maximum tolerated dose 
(MTD) was 75mg BID.  However, peak inhibition of the p-AKT pathway was not dose              
dependent and was maximally inhibited at 25mg BID, and this is the FDA approved dose.35
5.3 Interruption/Disruption of Treatment 
Duvelisib is a BID medication.  Doses that are missed or not absorbed (i.e., vomiting) will not be 
made up with additional dosing after the 8 to 15 day study period.
Duvelisib can be stopped for any clinically significant toxicity, including if any of the following are 
observed:

Grade 3 or 4 hematologic toxicity (19) as defined by the CTCAE version 5.0)

Grade 3 or 4 non-hematological toxicity
For grades 1-2 as defined by the CTCAE, will not have any dose modifications and will be treated 
with supportive care. If study drug is stopped due to an AE, it will not be resumed, and the patient 
may proceed to leukapheresis on schedule. No allowance will be made for dose interruptions
5.4 Dose Modification
No dose modifications will be allowed on this study. 
5.5 Concomitant medication
5.5.1 Acceptable Concomitant Medications
Duvelisib is a moderate inhibitor of CYP3A4 and monitoring of patients on sensitive medications 
that are CYP3A4 substrates will be required.  Please Appendix B for known substrates of CYP3A. 
Concomitant medication (including prescribed, over the counter, herbal or vitamin supplements) 
used by the patient prior to 14 days to enrollment are permitted.  All medications should be 
reported to the investigators and recorded in the concomitant medications page.
5.5.2 Prohibited Medications and Food
Patients on strong inducers or inhibitors of CYP3A within 14 days of starting duvelisib are 
excluded from the study. Concomitant use of medications known to be strong inducers or 

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inhibitors of CYP3A should be avoided unless deemed to be necessary by the PI.  In this 
instance, patients should be carefully monitored for reduced drug efficacy or SAE from drug-drug 
interaction.  Please see Appendix B for known potent inhibitors and inducers of CYP3A.  Other 
anti-neoplastic drugs, radiotherapy and other investigational drugs are prohibited during the 
study period.
5.5.3 Supportive Medications 
Because of increased incidences of PJP pneumonia, patients on study will be provided with PJP 
prophylaxis while on treatment with duvelisib. Following completion of duvelisib, PJP prophylaxis 
will be stopped if CD4+ T cell count is greater than 200 cells/microL. 
5.6 Study Procedures
Screening Phase: 
All screening evaluations must be conducted and reviewed by the primary investigator to confirm 
that patients meet the eligibility criteria.  The following procedures will be performed during the 
screening visit:

Informed Consent

Medical History, Physical Exam, Assessment of Performance Status

Electrocardiogram (EKG)

Labs: Complete Blood Count (includes hemoglobin, platelets, and white blood cell count with 
differential), Comprehensive metabolic panel (includes sodium, potassium, chloride, creatinine, 
AST, ALT total bilirubin and alkaline phosphatase), Coagulation Testing (PT/INR, PTT), Thyroid 
Stimulating Hormone (TSH)

T cell count phenotyping via flow cytometry 

Pregnancy Test (for women of childbearing potential)

Infectious Work Up: HIV antigen/antibody, Hepatitis C antibody and Hepatitis B antibodies with 
viral loads (if known history of treated Hepatitis B or C).

COVID-19 screening by PCR: During the screening period within 7 days of initiation of duvelisib. 
o
If asymptomatic and PCR negative: Ok to proceed 
o
If PCR+ and:

Asymptomatic: Wait 14 days and initiate duvelisib

Symptomatic: Wait 14 days after resolution of symptoms and initiate 
duvelisib

A negative PCR is not required after a 14 day wait period  
Please see section 1.2 (Table 1) for schedule for screening and pre-screening assessments. Pre-
screening assessments will be completed within two weeks of initiation of duvelisib treatment.
Treatment Phase:
Procedures to be conducted during the treatment phase of the study are presented in the Schedule of 
Assessments (Section 1.3, Table 1).

Brief medical history

Symptom-directed physical exam 

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
ECOG Performance Status

Vitals signs, weight 

Review of prior/concomitant medications 

Labs: Complete Blood Count (includes hemoglobin, platelets, and white blood cell count with 
differential), Comprehensive metabolic panel (includes sodium, potassium, chloride, creatinine, 
AST, ALT total bilirubin and alkaline phosphatase), Thyroid Stimulating Hormone (TSH)

T cell count and phenotyping (days 1 and 15 only)

AE monitoring (days 8 and 15)
Post CAR-T 19 Cell Infusion Assessments
Procedures to be conducted during the post CAR-T 10 cell infusion phase of the study are presented 
in the Schedule of Assessments (Section 1.3 Table 2). 

CAR T 19 PCR

CAR T phenotyping

PET/CT or CT (day 90 only post CAR T)
5.7 Description of Study Procedures
Definition of Study Assessments
All patients will be closely monitored for safety and tolerability throughout the study.  Patients will 
continue dosing until they experience intolerable AE’s, patient withdrawal or termination of the study.  
Patients may be discontinued from study treatment in the following situations: 1) patients has 
decided to withdrawal from the study, 2) Intolerable adverse events, 3) confirmed disease 
progression or lack of benefit, 4) pregnancy, or 5) severe noncompliance (including but not limited 
to receiving less than 75% of duvelisib doses (23/28 doses). The schedule of activities is listed in 
section 1.3.
Medical History
Medical history and demographics will be collected at screening.  Medical history will include other 
significant co-morbidities, previous surgeries, cancer history, previous chemotherapy and outcomes, 
use of tobacco, alcohol and recreational drugs and any known toxin exposure. Demographics data 
will include age, sex and self-identified race/ethnicity. 
Performance Status
The ECOG performance status (see appendix A) will be assessed at screening and throughout the 
study (days 1, 8 and 15 during treatment with duvelisib; days 7,14,28,42 and 90 post CAR-T 
infusion).
      Physical Exam
Physical exam will include examination of all body systems, including assessment of general 
appearance, weight, height, head, neck, lymph nodes, heart, lungs, abdomen, extremities, skin and 
nervous system.  A physical exam will be performed on screening and on days 1,8 and 15.

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Laboratory Data
Blood samples for chemistry, hematology, viral serologies, leukocyte immunophenotyping and 
pregnancy (for pre-menopausal patients) will be analyzed at Winship Cancer Institute laboratory.  
The chemistry panel will include sodium, potassium, chloride, bicarbonate, glucose, BUN, AST, ALT, 
total bilirubin, total protein, thyroid stimulating hormone and magnesium will be tested at screening 
and on days, 1,8 and 15. Hematology panel includes complete blood count, including white blood 
cell count with differential (neutrophils, lymphocytes, eosinophils, basophils), red blood cell count, 
hemoglobin, hematocrit and platelet count will be tested at screening and days 1, 8 and 15.
Viral serologies will be tested at screening and include:

HIV antigen/antibody

Hepatitis B Panel (HBsAg, HBsAb, HBcAb and HBV DNA PCR if HBcAb is positive)

Hepatitis C Panel (HCV Ab and HCV PCR if HCV Ab is positive)
Leukocyte immunophenotyping (via flow cytometry/fluorescence-activated cell sorting) will be done 
at screening and prior to apheresis for manufacturing CAR-T cells.  This will determine the amount 
of B/T/NK cells and more specifically, the phenotypes and frequencies pre and post Duvelisib 
exposure. 
Electrocardiogram
All ECG’s will use a 12-lead tracing and performed during screening only.  ECG will measure PR 
interval, QRS interval, RR interval and QTc.  Additional ECG’s and other cardiac tests can be 
performed as clinically indicated.

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6. Data and Specimen Banking 
Blood samples will be obtained and used for medical research by the investigators of this study. Data 
and specimens from this study may be useful for other research being done by investigators at Emory 
or elsewhere. To help further science, Investigators may provide de-identified data and/or specimens to 
other researchers. Any information that could identify patients will not be included. If data or specimens 
are labeled with study ID, we will not allow other investigators to link that ID to identifiable information.
Samples and data collected under this protocol may be used to study lymphoma.  Access to stored 
samples will be limited to IRB-approved investigators. Samples and data will be stored using codes 
assigned by the investigators or their designees. Data will be kept in password-protected computers. 
Only investigators will have access to the samples and data.
All stored samples will be maintained in the laboratory to which it was sent initially for analysis. Study 
patients who request destruction of samples will be notified of compliance with such request and all 
supporting details will be maintained for tracking.
The results of some study tests and procedures will be used only for research purposes and will not be 
placed in patient’s medical record.  For this study, those items include: research blood collection. 
7. Tisagenlecleucel Apheresis Phase
7.1 Apheresis Collection
Patients will need to undergo leukapheresis within two (2) days of completion of the 8 to 15 day 
treatment of duvelisib. Apheresis will be performed at the Emory Center for Transplantation and Cell 
Therapy. Peripheral blood mononuclear cells will be collected for CAR-T cell manufacturing 
according to the standard of care. A single 2-4-hour leukapheresis will be performed on the COBE 
Optia with the intention of harvesting 3 x 109 white blood cells.  If patients are unable to collect the 
necessary amount required for manufacturing, they can undergo a second leukapheresis.  If patients 
are not able to collect enough product after the second leukapheresis, they will be considered 
unevaluable and replaced.  After apheresis, the quantity of CD27/CD28 double positive T cells, 
CD4/CD8 double negative gamma delta positive T cells and CD4/CD8 double negative gamma delta 
negative T cells will be measured via flow cytometry. CAR-T cell manufacturing will be provided by 
Novartis and are expected to be ready 4 weeks after collection. Failure of the incoming apheresis 
material or outgoing product to meet the commercial specifications will be discussed with Novartis 
on a case by case basis.
7.2 Chemotherapy post-apheresis
Chemotherapy will be allowed as a bridging therapy after apheresis at the provider’s discretion while 
the CAR T cells are being manufactured. Chemotherapy immediately prior to infusion of CAR-T cells 
for conditioning regimen (lymphodepleting) will be standard of care at the provider’s discretion.
7.3 Tisangenlecleucel Infusion
CAR-T infusion will be administered per the standard-of-care protocol at Winship Cancer Institute.  
Patients will remain hospitalized per the standard of care and adverse reactions (neurotoxicity, CRS) 
will be managed per the standard of care. 

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7.4 Post-Tisangenlecleucel Monitoring
Following, discharge from the hospital patients will be followed per routine practice for CAR-T patients 
in the clinic or in-patient hospital services. Data on performance status, vital signs, clinical exam and 
any history of adverse events will be captured by chart review of clinical notes on days 7,14, 28, 42 
and 90 post CAR-T (section 1.2, Table 2). Blood samples will be drawn on days 7,14, 28, 42 and 90 
post CAR-T draws hematology tests and the presence of CAR-T 19 cells with PCR and flow cytometry. 
8. Measurement of Effect
8.1 RECIST Criteria v 1.1
Although response is not the primary endpoint of this trial, patients with measurable disease will be 
assessed by RECIST criteria. For the purposes of this study, patients will be re-evaluated at 3 
months post CAR-T 19 infusion in comparison to a baseline scan.
8.1.1 Definitions 
Evaluable for objective response. Only those patients who have measurable disease present at 
baseline, have received one infusion of CAR T 19 therapy, and have had their disease re-
evaluated will be considered evaluable for response at 3 months (+/- 2 weeks) post CAR-T. 
These patients will have their response classified according to the definitions stated below. 
(Note: Patients who exhibit objective disease progression prior to the end of CAR T infusion will 
also be considered evaluable.) 
Evaluable Non-Target Disease Response. Patients who have lesions present at baseline that 
are evaluable but do not meet the definitions of measurable disease, have received at least 
one infusion of CAR T 19 infusion, and have had their disease re-evaluated will be considered 
evaluable for non-target disease. The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.
8.1.2. Disease Parameters:
Measurable disease. Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as ≥20 mm by chest x-ray or as ≥10 
mm with CT scan, MRI, or calipers by clinical exam. All tumor measurements must be recorded 
in millimeters (or decimal fractions of centimeters). 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. 
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, and abdominal masses (not followed by CT or MRI), are considered as non-
measurable. 

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Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred for selection 
as target lesions.
8.1.3. Methods for Evaluation of Measurable Disease:
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
Conventional CT: 
This guideline has defined measurability of lesions on CT scan based on the assumption that CT 
slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum 
size for a measurable lesion should be twice the slice thickness. 
Ideally, the same type of scanner should be used and the image acquisition protocol should be 
followed as closely as possible to prior scans. Body scans should be performed with breath-hold 
scanning techniques, if possible.
FDG-PET:
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-
PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans 
are needed to determine if there is truly progression occurring at that site (if so, the date of PD 
will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. The 
use of FDG-PET in this circumstance should be prospectively described in the protocol and 
supported by disease-specific medical literature for the indication. However, it must be 
acknowledged that both approaches may lead to false positive CR due to limitations of FDG-
PET and biopsy resolution/sensitivity. 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image.

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8.2 Evaluation of Disease:
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
8.3 Evaluation of Best Overall Response:
The best overall response is the best response recorded from the start of the treatment until 
repeat imaging at 90 days. The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria.
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
>4 wks. Confirmation**
CR
Non-CR/Non-
PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not 
evaluated
No
PR
>4 wks. Confirmation**
SD
Non-CR/Non-
PD/not 
evaluated
No
SD
Documented at least once >4 
wks. from baseline**
PD
Any
Yes or No
PD
Any
PD***
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR

See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**        Only for non-randomized trials with response as primary endpoint.
***      In exceptional circumstances, unequivocal progression in non-target lesions may be
            accepted as disease progression.
Note:  Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective progression 
even after discontinuation of treatment.

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8.4. Assessment of Engraftment: 
Molecular studies (CAR-T 19 PCR) and immune phenotyping will be collected per the study protocol 
procedure.  All samples will be processed by the Winship Cancer Institute Laboratory.
9. Sharing of Results with Patients
In general, study staff will not provide any individual results to patients (ex. outcome trial results or 
results from patient’s samples studies). If something of urgent medical importance to the participating 
patients are found, the PI (or co-Is) will inform the patient, although we expect that this will be a very 
rare occurrence. Samples and data will only be used for research.
10. Study Timelines
10.1 Duration of therapy
We anticipate each individual patient’s duration of therapy to be approximately 5 months. In the 
absence of treatment delays due to adverse event(s), patients will be followed until any one of the 
following: 
• Death 
• Unacceptable toxicity 
• Symptomatic deterioration 
• Investigator’s decision to discontinue treatment 
• Patient decision to discontinue treatment 
• Patient withdraws consent 
• Lost to follow up 
In the event of a patient’s withdrawal, the Investigator will make every effort to complete the End of 
Treatment procedures specified in the Schedule of Events.
10.2 Duration of follow-up 
Patients will be followed for approximately 90 days after infusion of tisagenlecleucel product.
Patient records may be reviewed until death to assess progression and survival.  Survival information 
may be collected by clinic visit, email, or telephone after ending protocol treatment and until the study is 
terminated, the patient dies, or the patient is lost to follow-up.
A patient will be considered lost to follow-up if he/she fails to return for three scheduled visits and is 
unable to be contacted by the study site staff after three attempts at contact by phone.
The following actions must be taken if a patient fails to return to the clinic for a required study visit:
The site will attempt to contact the patient and reschedule the missed visit and counsel the participant 
on the importance of maintaining the assigned visit schedule and ascertain if the patient wishes to and/or 
should continue in the study.
Patients removed from study for unacceptable adverse event(s) will be followed until resolution or 
stabilization of the adverse event.
• Immunogenicity samples will be taken as per schedule of events 

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Patients who have not initiated a new antineoplastic regimen will have the following assessments:
 • Radiologic tumor assessments at 90 days
 • In case of a clinically significant AE, patient will be followed for safety until resolution or permanent 
sequelae of all toxicities attributable to study drug(s). If the patient discontinues study drug for a clinically 
significant AE, the patient will be followed until resolution of the AE or the event is considered to be 
stable and/or chronic. 
11. Inclusion and Exclusion Criteria
11.1 Inclusion Criteria

Patients must have a biopsy proven diagnosis of relapsed/refractory DLBCL or relapsed/refractory 
follicular lymphoma and be eligible to receive commercial tisagenlecleucel (Kymriah).

18 years of age or older

ECOG <2

Patients must have normal organ function as defined as:
o Serum Cr <2.0 mg/dL
o AST/ALT < 2x ULN
o Total Bilirubin <2.0 mg/dL

Patients with a hemoglobin >8 g/dL, platelet count >50K/mcl, an absolute neutrophil count (ANC) 
>1,000/mm3 and an absolute lymphocyte count (ALC) >300/mm3

Completion of all previous therapy (including surgery, radiotherapy, chemotherapy, immunotherapy, 
or investigational therapy) for the treatment of their DLBCL or relapsed/refractory follicular lymphoma 
≥ 2 weeks before the start of duvelisib.  There is no limit on how many previous lines of treatment a 
patient may have received. 

The effects of duvelisib on the developing human fetus are unknown.  For this reason, women of 
child-bearing potential (WOCBP) must have a negative serum or urine pregnancy test prior to 
starting therapy. WOCBP and men must agree to use highly effective contraception (hormonal or 
barrier method of birth control or abstinence) from enrollment into this study until at least 12 months 
after tisagenlecleucel infusion and until CAR-T cells are no longer present by qPCR on two 
consecutive tests (qPCR tests will be available upon request). 
o
A woman of childbearing potential (WOCBP) is a sexually mature woman who: 1) has not 
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally 
postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months. 
o
WOCBP must have a negative pregnancy test within 24 hours of leukapheresis, 
lymphodepletion (if performed) and tisagenlecleucel infusion (if lymphodepletion not 
performed). 
o
Should a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately.  
o
All men treated or enrolled on this protocol must agree to use highly effective contraception 
from enrollment into this study until at least 12 months after tisagenlecleucel infusion and 
until CAR-T cells are no longer present by qPCR on two consecutive tests (qPCR tests will 
be available upon request). 
The patient must be willing to comply with the fertility requirements and contraceptive options below:

Female patients identified as WOCBP must be willing to use two adequate barrier methods of 
contraception to prevent pregnancy or agree to abstain from heterosexual activity (total abstinence).

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
Total abstinence is permitted when this is in line with the usual practice and lifestyle of the patient.  
Periodic abstinence (i.e, calendar, ovulation, post-ovulation methods) and withdrawals are not 
acceptable forms of contraception.

Sterilization:
o
Female sterilization includes having had surgical bilateral oophorectomy and/or bilateral 
salpingectomy with or without a hysterectomy, a total hysterectomy, or bilateral tubal ligation 
at least six weeks before taking study treatment. In case of oophorectomy alone, patients are 
eligible only when the reproductive status of the woman has been confirmed by a follow-up 
hormone assessment.
o
Male sterilization with vasectomy must occur at least 6 months prior to screening. For female 
patients on the study, the vasectomized male partner should be the sole partner.

Use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception, 
or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of 
contraception that comparable efficacy (failure rate <1%). In case of oral contraception, the woman 
should be stable on the same pill for a minimum of 3 months prior to enrollment on the study.

Sexually active males must use a condom during intercourse from enrollment into this study until at 
least 12 months after tisagenlecleucel infusion and until CAR-T cells are no longer present by qPCR 
on two consecutive tests (qPCR tests will be available upon request). A condom is required of all 
sexually active male patients to prevent them from fathering a child AND to prevent delivery of study 
treatment via seminal fluid to their partner.
The patient must be willing to comply with the following requirements:

Patients must agree not to donate blood, sperm/ova or any other organs while taking protocol 
therapy and for at least 12 months after stopping treatment.

Willingness and ability of the patient to comply with scheduled visits, drug administration plan, 
protocol specified laboratory tests, other study procedures and study restrictions. 

Evidence of personally signed informed consent indicating that the subject is aware of the neoplastic 
nature of the disease and has been informed on the procedures to be followed, the experimental 
nature of the therapy, alternative, potential risks and discomforts, potential benefits and other 
pertinent aspects of study participation.
11.2 Exclusion criteria

Primary Central Nervous System Lymphoma

Patients with CNS Involvement of Lymphoma 

History of autoimmune disease, including but not limited to:
o Inflammatory Bowel Diseases (Crohn’s Disease, Ulcerative Colitis, Celiac Disease)
o Systemic Lupus Erythematosus
o Grave’s Disease
o Myasthenia Gravis
o Rheumatoid Arthritis
o Wegner’s Syndrome

Patients with history of drug reaction and eosinophilia systemic syndrome (DRESS) or toxic 
epidermal necrolysis (TEN)

History of Human Immunodeficiency Virus (HIV), active Hepatitis C Infection or active Hepatitis 
B infection as defined by:

Patients with a positive hepatitis B surface antigen [HBsAg] or hepatitis C antibody [HCV 
Ab] will be excluded

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
Patients with a positive hepatitis B core antibody (HBcAb) must have negative hepatitis B 
virus (HBV) deoxyribonucleic acid (DNA) to be eligible and must be periodically monitored 
for HBV reactivation by institutional guidelines

Patients with known active cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection (i.e., 
subjects with detectable viral load)

Patients with ongoing treatment for systemic bacterial, fungal or viral infection

Patients with history of immune or drug mediated colitis, hepatitis or pneumonitis

Patients with history or concurrent condition of interstitial lung disease of any severity and/or 
severely impaired lung function

Patients with previous treatment with a PI3K inhibitor

Patients currently on immunosuppressive therapy, including steroids

Previous CD 19 directed therapy

Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas 
or mitomycin C) prior to entering the study or those who have not recovered from adverse events 
due to agents administered more than 2 weeks earlier (i.e., have residual toxicities > Grade 1).

Patients receiving any other investigational drugs. 

Pregnant women are excluded from this study because duvelisib is agent with the potential for 
teratogenic or abortifacient effects.  Because there is an unknown but potential risk for adverse 
events in nursing infants secondary to treatment of the mother with duvelisib, breastfeeding should 
be discontinued if the mother is treated with duvelisib and breastfeeding should not be resumed until 
at least 1 month after last dose of duvelisib. 

Patients with history of chronic liver disease or veno-occlusive disease

Patients that are unable to receive prophylactic treatment for pneumocystis, herpes simplex virus 
(HSV), or herpes zoster “(VZV) at screening 

Patients with history of tuberculosis treatment within the 2 years prior to randomization

Patients with prior surgery or gastrointestinal dysfunction that may affect drug absorption (e.g., 
gastric bypass surgery, gastrectomy). Subjects with clinically significant medical condition of 
malabsorption, inflammatory bowel disease, chronic conditions which manifest with diarrhea, 
refractory nausea, vomiting or any other condition that will interfere significantly with drug absorption.

Concurrent administration of medications or foods that are strong inhibitors or inducers of 
cytochrome P450 3A (CYP3A). No prior use within 2 weeks before the start of study intervention

Administration of a live or live attenuated vaccine within 6 weeks of randomization
12. Local Number of Participants
We will be recruiting 20 patients at Winship.  We are expecting to have to enroll (consent) 30 patients 
to reach our recruitment goal of 20..  Patients will be registered after signing of the informed consent 
document and meeting all entry requirements.
13. Recruitment Methods
Investigators, nurses (CRNs), research coordinators (CRCs) and/or data managers review lists of 
patients who have DLBCL or relapsed/refractory follicular lymphoma and will determine if there are 
patients who might be eligible for the clinical trial. The CRN/CRC/data manager reviews accessible 
medical records to screen further for eligibility. The CRN/CRC reviews the eligibility with the 
physician.  
Patients will be identified by their treating physicians. Clinical care team at Winship will inform 
potential patients about the known benefits and potential risks of a clinical trial as well as other 
available treatment options.

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Some of the patients recruited for this protocol will be patients being treated at Emory and under the 
care of one or more of the study investigators. Some potential patients will be identified by their 
community treating physician and referred to Emory for possible participation in the clinical trial.
No incentives are provided to patients for trial participation.
Study personnel will notify Winship Central Subject Registration (WCSR) by email at 
winshipcsr@emory.edu, once a patient has been consented for a trial. 
Email notification must be done within 24 hours after consent has been obtained and it will include 
scanned copies of:

Signed patient consent form

HIPAA authorization form
     Emory Research Management System (ERMS; https://erms.emory.edu) Enrollment Fax     
Cover 
The WCSR will enter the subject into the OnCore Research Management System, which is the 
system of record for Winship Cancer Institute Clinical Trials.
14. Withdrawal of Patients
All study patients have the right to withdraw from the study at any time.  The reasons for withdrawal 
must be documented in the case report form.  Final study evaluations will be done at the time of 
withdrawal. The following are examples of early withdrawal from the study:

Patient withdrawal of consent at any time

Any medical condition that the primary investigator or sponsor believes may jeopardize the 
patient’s health or safety if they continue in the study

Non-compliance (frequent missed visit, doses)

Pregnancy

Rapid progression of disease (ie: increasing/symptomatic lymphadenopathy) that would require 
alternative treatment prior to CAR T cell leukapheresis 

Termination of the study by the primary investigator, sponsor or FDA
15. Risks to Participants

Additional blood draws - The physical risk of drawing blood is local pain and bruising at the site of 
venipuncture. Qualified phlebotomists or designee will draw blood samples. Care will be taken to 
obtain these specimens in a safe and hygienic manner. A small number of people experience 
lightheadedness or fainting. There is a slight risk of infection. To minimize these risks, attempts will 
be made to draw study blood samples at the same time as blood draws needed for routine clinical 
care are obtained. Repeated blood drawing may be associated with iron deficiency anemia.

Data security- Subjects will be asked to provide personal health information (PHI). All attempts will 
be made to keep this PHI confidential within the limits of the law. However, there is a chance that 
unauthorized persons will see the subjects’ PHI. All records will be kept in a locked file cabinet or 
maintained in a locked room at the participating sites. Electronic files will be password protected 
behind an academic institutional firewall. Only people who are involved in the conduct, oversight, 
monitoring, or auditing of this study will be allowed access to the PHI that is collected. Any 

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publications from this study will not use information that will identify subjects. Organizations that may 
inspect and/or copy research records maintained at the participating sites for quality assurance and 
data analysis include groups such as the National Cancer Institute (NCI) and Food and Drug 
Administration (FDA).
16. Potential Benefits to Participants
There is no guarantee of benefit to subjects who enroll in this protocol.
17. Data Management and Confidentiality
17.1 Source Documents:
Source data is all information, original records of clinical findings, observations, or other activities in 
a clinical trial necessary for the reconstruction and evaluation of the trial.  Examples include medical 
records (hospital records, office charts), laboratory results, imaging scans and reports, EKG’s, 
patient diaries, videos, photographs, pharmacy dispensing, and other records, investigator or patient 
completed questionnaires involved in the clinical trial. 
17.2 Case Report Forms:
The case report form (CRF) will be the primary data collection instrument for the study.  All data 
requested on the CRF will be recorded and all entries will be recorded into an electronic data capture 
system by authorized personnel.   The principal investigator is responsible for assuring that the data 
entered into the CRF are complete, accurate and that entries are updated in a timely fashion.  Data 
will be entered in the clinical management system - Online Collaborative Research Environment 
(ONCORE)- per Winship SOP 4.2 Data Completion Metrics.  OnCore will be used to record all study 
related information for all registered subjects, including their assigned patient ID and assigned dose 
cohort. All data submitted must be accompanied by supporting source documents, where applicable 
and as outlined in the protocol-specific monitoring plan.  Data completion will be reviewed monthly. 
In situations where there are significant delays of data completion, the Associate Director of Clinical 
Research or the Director of Clinical Trials may temporarily suspend enrollment. 
All data must be entered in the timeframe required at each site, but no later than 30 days following 
registration and each visit completion. All queries are to be resolved within 4 weeks of issue. The 
coordinating center multi-site coordinator will provide OnCore training and request access to the 
appropriate staff at the participating site.
17.3 Data Retention:
All study documents will be retained for at least two years after the last approval of a marketing 
application in their country and until there are no pending or contemplated marketing applications in 
their country.
17.4. Transmission of Data:
. Emory University will cover the cost of shipment of blood samples. All patient samples for T-cell 
phenotyping will be analyzed at Emory University to ensure uniform analysis.  Clinical data (ORR 
and rates of CRS, neurotoxicity, ICU transfers) will be captured with chart review at both Emory 
University.  Data will be uploaded onto OnCore.  

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17.5 Statistical Plan:
17.5.1 Study Design Endpoints
This is pilot study to examine if exposure to a dual PI3K delta and gamma inhibitor before CAR T 
cell leukapheresis leads to decreases in manufacturing time and enhanced expression of 
CD27/CD28+ T cells.   Patients who receive at least 75% (23/28 doses) of duvelisib will be evaluable 
for final analysis.   Patients who do not receive 75% of doses will be considered unevaluable and 
replaced.  Patients who do not undergo leukapheresis within two (2) days of completion of the 8 to 
15 days of duvelisib will be considered unevaluable and replaced. All patients with any exposure to 
duvelisib will for evaluable for toxicity (please see section 13.3 on grading of toxicities).
17.5.2 Analysis of Primary Endpoints
All patients that complete >75% of planned duvelisib doses and undergo leukapheresis within 2 
weeks of duvelisib treatment completion will be included in the final analysis of the primary endpoint. 
The primary endpoint of the study to estimate the fold-change increase in CD27/CD28 double 
positive T cells following in vivo exposure to duvelisib from baseline to day 15.  Our in vitro studies 
have shown that culturing DLBCL patients’ T cells with 14 days of duvelisib increased the amount of 
CD27/CD28 double positive T cells from 12.2% to 32.7% (Petersen, et al, supplemental data). 
However, there are currently no in vivo background data to benchmark the expected fold-change 
CD27/CD28 double positive T cells over a 14-day window. Therefore, with 20 patients, this pilot 
study will be based on estimation on the fold change increase only and will not include a formal 
evaluation of the change against a null unpromising fold-change.  However, we will consider this 
study promising if there is at least a two-fold increase in CD27+/CD28+ in at least 75% of patients.  
17.5.3 Analysis of Secondary Endpoints
1).  Descriptive statistics will be used to calculate the proportion of patients that completed at least 
75% of duvelisib doses as documented by the patient pill diaries.  The proportion along with an exact 
95% confidence interval will be reported.
2). Descriptive statistics will be used to calculate the median manufacturing time from the 10 patients 
that completed at least 75% of duvelisib doses.  The median will be reported along with the minimum 
and maximum manufacturing times.
3).  A Wilcoxon signed-rank test will evaluate the change in proportion of CD27+/CD28+ and CD4-
/CD8- T cells at baseline and at day 15
4). Descriptive statistics will be used to calculate the in vivo expansion and persistence of CAR-T 
19 cells post infusion as measured by serial CAR-T 19 PCR measurements. 
5). The ORR (complete response or partial response) will be summarized along with an exact 95% 
confidence interval. Disease response will be based on the RECIST criteria (version 1.1). Please 
see section 8.2 on the definitions of disease response.

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6). The 90 day PFS and OS will be estimated using the Kaplan-Meier method and calculated with 
corresponding 95% confidence intervals. Please see section 8.3 on the definitions of progressive 
disease.
7). Descriptive statistics will be used to calculate the frequency of ICU transfers due to CRS and/or 
neurotoxicity.  Descriptive statistics will also be used to calculate the frequency of administration of 
tocilizumab and/or corticosteroids use for CRS and/or neurotoxicity.
8). Descriptive statistics will be used to assess the frequency of all grade toxicities as defined by 
CTCAE (version 5.0).
17.5.4 Demographics and Baseline Characteristics
Summary statistics and frequencies for the following characteristics will be collected:

ECOG

Race

Age

Sex

Past Medical History

Current Medication List

Number type, dose and dates of prior treatments

Prior autologous stem cell transplant (ASCT)

Molecular Subgroup (Activated B cell vs Germinal Center)

BCL-2 alterations/overexpression

BCL-6 alterations/overexpression

C-MYC alterations/overexpression

Double/Triple Hit Status

Disease Stage

History of lymphoma bone marrow involvement
17.5.5 Safety Analysis 
Adverse event data will be described and graded per the NCI CTCAE 5.0 guidelines. For each 
adverse event, information to be collected includes event description, time of onset, clinician 
assessment of severity, relationship to study product (assessed only by those with the training and 
authority to make a diagnosis), current correlate laboratory values (regardless of hematologic or 
non-hematologic etiology), treatment of AE and time of resolution/stabilization of the event. 
Regardless of relationship, all AEs will be recorded with start dates occurring any time after patient 
receives any duvelisib. At each study visit, the investigator will inquire about the occurrence of 
AE/SAEs since the last visit. Events will be followed for outcome information until resolution or 
stabilization.
Any medical condition that is present at the time that the participant is screened will be considered 
as baseline and not reported as an AE. However, if the study participant’s condition deteriorates at 
any time during the study, it will be recorded as an AE. Changes in the severity of an AE will be 
documented to allow an assessment of the duration of the event at each level of severity to be 
performed. AEs characterized as intermittent require documentation of onset and duration of each 
episode.

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The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables 
will be reviewed to determine toxicity patterns. Adverse events will be summarized and described 
within each cohort. They will initially be reviewed regardless of attribution, but also whether they are 
possibly, probably, or definitely related to treatment. In addition, we will review all adverse event data 
that are graded as 3, 4, or 5 and classified as either “unrelated” or “unlikely to be related” to study 
treatment in the event of an actual relationship developing. The incidence of severe adverse events 
or toxicities will be described. We will assess the proportion of patients who experience grade 3 or 
higher non-hematologic toxicity. To assess tolerability, we will also capture the proportion of patients 
who go off treatment due to adverse events. 
17.6 Data/Specimens:
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. Therefore, the study protocol, documentation, data, and all other 
information generated will be held in strict confidence. No information concerning the study or the data 
will be released to any unauthorized third party without prior written approval of the Principal Investigator. 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by local IRB and Institutional regulations.
Data and/or data forms will be submitted in the clinical management system - Online Collaborative 
Research Environment (ONCORE)- per Winship SOP 4.2 Data Completion Metrics. All information in 
original records and certified copies of original records or clinical findings, observations, or other 
activities necessary for the reconstruction and evaluation of the trial is considered source data. Source 
data are contained in source documents, which can be original records or certified copies of hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects' diaries of evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the 
laboratories, and at medico-technical departments involved in the clinical trial. Case Report Forms 
(CRFs) - Source data may be collected in the source documents or entered directly onto the case report 
forms.
All documentation of adverse events, records of study drug receipt and dispensation, and all IRB 
correspondence will be maintained for at least 2 years after the investigation is completed.
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be stored. This will not include the participant’s contact or identifying information. Rather, individual 
participants and their research data will be identified by a unique study identification number. The study 
data entry and study management systems used by clinical sites and research staff will be secured and 
password protected. At the end of the study, all study databases will be de-identified and archived.
Samples and data collected under this protocol may be used to study DLBCL and relapsed/refractory 
follicular lymphoma. Access to stored samples will be limited to IRB-approved investigators. Samples 
and data will be stored using codes assigned by the investigators or their designees. Data will be kept 
in password-protected computers. Only investigators will have access to the samples and data.
All stored samples will be maintained in the laboratory to which it was sent initially for analysis. 
Study participants who request destruction of samples will be notified of compliance with such 
request and all supporting details will be maintained for tracking.

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18 Provisions to Monitor the Data to Ensure the Safety of Participants
18.1 Definition of Adverse Events (AE):
The ICH defines an adverse event as any unfavorable and unintended sign, including laboratory 
findings, symptoms or diseases temporally associated with the use of an investigational product. 
Adverse event severity will be graded per the using the CTCAE version 5 for toxicity and adverse event 
reporting.  
Any adverse events, either observed by the investigator or reported by the patient, should be 
documented, including the intensity and duration of the AE, what steps were taken in regard to duvelisib 
and the outcome.
The principal investigator must review any laboratory abnormality for clinical significance.  If the 
abnormality is deemed to be clinically significant, then the adverse event will be reported along with 
the actions taken in regard to study treatment and the outcome of the event. All AE’s will began 
recording at the beginning of enrollment until withdrawal and/or completion of the clinical trial.
18.2 Definition of Serious Adverse Events (SAE):
A serious adverse event (SAE) is any adverse event, occurring at any time or dose that:

Results in death

Is life-threatening 

Requires prolonged inpatient hospitalization or prolongation of an existing hospitalization 

Results in persistent of significant disability/incapacity 

Is a congenital anomaly/birth defect or

Considered to be a serious medical event by the investigator (may jeopardize the patient or 
require intervention to prevent one of the outcomes listed in the above definitions)
Any event that does not meet the above criteria should be consider a non-SAE.  For any event that 
meets the above criteria, an SAE report should be completed detailing the start and stop 
dates of the SAE, relationship to the study drug, the measures taken and outcome.
18.3 Classification of an Adverse Event
Severity of Event
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity. 
•
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities. 
•
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning.
•
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or incapacitating.  
Of note, the term “severe” does not necessarily equate to “serious”.
Relationship to Study Intervention

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All adverse events (AEs) must have their relationship to study intervention assessed by the clinician 
who examines and evaluates the participant based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories below. In a 
clinical trial, the study product must always be suspect. 
•
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary.
•
Probably Related – There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs 
within a reasonable time after administration of the study intervention, is unlikely to be attributed 
to concurrent disease or other drugs or chemicals, and follows a clinically reasonable response 
on withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition.
•
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate.
•
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant treatments).
•
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician.
Efforts will be made to associate all AEs with a particular study intervention. AE collection for duvelisib 
will occur from the time of enrollment until 15 days post duvelisib treatment and followed until resolution 
or stabilization. AE collection for tisagenlecleucel will occur from the time of CAR-T infusion until 90 post 
CAR-T cell infusion.  
18.4 Adverse Event and Serious Adverse Event Reporting 
Expectedness 
The principal investigator will be responsible for determining whether an adverse event (AE) is expected 
or unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event 
is not consistent with the risk information previously described for the study intervention.
Adverse Event Reporting 
From the time of enrollment until 90 post CAR-T cell infusion following cessation of study treatment all 
adverse events, that begin or worsen after informed consent, must be recorded by the investigator or 
designee at each examination on the Adverse Event case report forms (CRF)/worksheets.  All serious 

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adverse events collected during this time frame will also be reported to both the study supporter Secura 
Bio (email to securabio@parexel.com) and cell manufacturer (Novartis)..
The investigator will make every attempt to follow all subjects with serious and non-serious adverse 
events for outcome.  Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF/worksheet.
Adverse events will be assessed and graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0. Grade 1 to 5 will be used to characterize the severity of the Adverse Event. 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, and life-
threatening, death related to the AE corresponding respectively to Grades 1 - 5, will be used. Information 
about any deaths (related to an Adverse Event or not) will also be collected through a Death form (or 
EOT/SEC/Survival Information in NOVDD). The occurrence of adverse events should be sought by non-
directive questioning of the patient (patient) during the screening process after signing informed consent 
and at each visit during the study. Adverse events also may be detected when they are volunteered by 
the patient (patient) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated to 
determine: 
1. The severity grade (CTCAE Grade 1-5) 
2. Its duration (Start and end dates)  
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
investigational treatment, Yes, the study treatment (non-investigational), Yes, both and/or 
indistinguishable) 
4. Action taken with respect to study or investigational treatment (none, dose adjusted, temporarily 
interrupted, permanently discontinued, unknown, not applicable) 
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 13.2 and which 
seriousness criteria have been met (include for NCDS trials) 
Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, recovered/resolved 
with sequelae, fatal, unknown)  
 
If the event worsens the event should be reported a second time in the CRF noting the start date when 
the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a lower grade 
is determined a new entry for this event should be reported in the CRF noting the start date when the 
event improved from having been Grade 3 or Grade 4.  All adverse events should be treated 
appropriately. If a concomitant medication or non-drug therapy is given, this action should be recorded 
on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged to be 
permanent, and assessment should be made at each visit (or more frequently, if necessary) of any 
changes in severity, the suspected relationship to the study treatment, the interventions required to 
treat it, and the outcome. Laboratory abnormalities that constitute an Adverse event in their own right 
(are considered clinically significant, induce clinical signs or symptoms, require concomitant therapy 
or require changes in study treatment), should be recorded on the Adverse Events CRF.
A Grade 3 or 4 event (severe) as per CTCAE does not automatically indicate a SAE unless it meets 
the definition of serious as defined below and/or as per investigator’s discretion. A dose hold or 
medication for the lab abnormality may be required by the protocol in which case the lab abnormality 

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would still, by definition, be an adverse event and must be reported as such. Any serious adverse 
event, or follow up to a serious adverse event, including death due to any cause whether or not related 
to the study drug, must be submitted on an SAE form and assessed by PI in order to determine 
reporting criteria to regulatory authorities, IRB, DSMC, or Sponsor. All SAEs will be followed until 
satisfactory resolution or until the site investigator deems the event to be chronic or the adherence to 
be stable. Other supporting documentation of the event may be requested by the study sponsor and 
should be provided as soon as possible. The study sponsor will be responsible for notifying FDA of 
any unexpected fatal or life-threatening suspected adverse reaction as soon as possible but in no case 
later than 7 calendar days after the sponsor's initial receipt of the information.
All patients with serious adverse events must be followed up for outcome.
Any additional information for the SAE including complications, progression of the initial SAE, and 
recurrent episodes must be reported as follow-up to the original episode within 24 hours of the 
investigator receiving the follow-up information.  An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one should be reported separately 
as a new event. Any SAEs experienced after the reporting period described above should only be 
reported to FDA/IRB if the investigator suspects a causal relationship to the study treatment.   
Information about all SAEs is collected and recorded on the Serious Adverse Event Report Form; 
all applicable sections of the form must be completed in order to provide a clinically thorough report. 
The investigator must assess and record the relationship of each SAE to each specific study treatment 
(if there is more than one study treatment), complete the SAE Report Form, and submit the completed 
form.  Each reoccurrence, complication, or progression of the original event should be reported as a 
follow-up to that event regardless of when it occurs. The follow-up information should describe whether 
the event has resolved or continues, if and how it was treated, whether the blind was broken or not, 
and whether the patient continued or withdrew from study participation. 
SAEs thought to be related to Duvelisib should be reported to Secura Bio at 844-9-SECURA
Due to possible increased potency and increased toxicity risk-profile of tisagenlecleucel manufactured 
from the mononuclear cell apheresis product collected following treatment with duvelisib, all SAE that 
are collected will be reported to Novartis within 24 hours according to the following Table:

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Interventional Clinical Trial WITH Tisagenlecleucel
Collection by Sponsor
Transfer to Novartis

All SAEs

All non-serious AEs

All reports of drug exposure during 
pregnancy and pregnancy outcome. 
Pregnancy and pregnancy outcome 
should also be collected for the female 
partner of any male patient who was 
treated with tisagenlecleucel, provided 
consent has been obtained from the 
female partner.

All reports of abuse and misuse of an 
investigational medicinal product, other 
medication errors and uses outside of 
what is foreseen in the protocol 
(irrespective if a clinical event has 
occurred). 
Within 24 hours of awareness, transfer 
the following safety events: 

All collected SAEs in patients exposed to 
tisagenlecleucel

All collected reports of tisagenlecleucel 
exposure during pregnancy and 
pregnancy outcome. All collected reports 
of pregnancy and pregnancy outcome of 
the female partner of any male patient 
who was treated with tisagenlecleucel, 
provided consent has been obtained from 
the female partner.

All collected reports of abuse and misuse 
of tisagenlecleucel.
In particular, any episode of CRS or neurotoxicity grade 2 or greater observed within the first 100 
days after tisagenlecleucel infusion will be reported to Novartis. 
18.5 Definition of unanticipated problems (UP) and reporting requirements
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks 
to participants or others to include, in general, any incident, experience, or an outcome that meets all 
the following criteria:  Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the participant population being 
studied; Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and Suggests that the research places participants or others at a 
greater risk of harm (including physical, psychological, economic, or social harm) than was previously 
known or recognized.  This study will use the OHRP definition of unanticipated problems. Incidents or 
events that meet the OHRP criteria for UPs require the creation and completion of a UP report form. It 
is the site investigator’s responsibility to report UPs to their IRB and to the DCC/study sponsor. The UP 
report will include the following information:  Protocol identifying information: protocol title and number, 
PI’s name, and the IRB project number; A detailed description of the event, incident, experience, or 
outcome; An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP; A description of any changes to the protocol or other corrective actions that have 
been taken or are proposed in response to the UP. This assessment will be provided to the Emory 
University IRB.  If the Emory IRB determines an event is a UP it will notify the appropriate regulatory 
agencies and institutional officials. 
18.6 The Data and Safety Monitoring Committee (DSMC)

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The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will provide 
oversight for the conduct of this study. The DSMC functions independently within Winship Cancer 
Institute to conduct internal monitoring functions to ensure that research being conducted by Winship 
Cancer Institute Investigators produces high-quality scientific data in a manner consistent with good 
clinical practice (GCP) and appropriate regulations that govern clinical research. Depending on the risk 
level of the protocol as determined by CTRC, the DSMC review may occur every 6 months or annually. 
Subsequent monitoring will occur in routine intervals per the Winship Data and Safety Monitoring Plan 
(DSMP).  The DSMC will review pertinent aspects of the study to assess subject safety, compliance with 
the protocol, data collection, and risk-benefit ratio. Specifically, the Winship Cancer Institute Internal 
Monitors assigned to the DSMC may verify informed consent, eligibility, data entry, accuracy and 
availability of source documents, AEs/SAEs, and essential regulatory documents. Following the 
monitoring review, monitors will provide a preliminary report of monitoring findings to the PI and other 
pertinent individuals involved in the conduct of the study. The PI is required to address and respond to 
all the deficiencies noted in the preliminary report. Prior to the completion of the final summary report, 
monitors will discuss the preliminary report responses with the PI and other team members (when 
appropriate). A final monitoring summary report will then be prepared by the monitor. Final DSMC review 
will include the final monitoring summary report with corresponding PI response, submitted CAPA (when 
applicable), PI Summary statement, and available aggregate toxicity and safety data.  The DSMC will 
render a recommendation and rating based on the overall trial conduct. The PI is responsible for 
ensuring that instances of egregious data insufficiencies are reported to the IRB. Continuing Review 
submissions will include the DSMC recommendation letter. Should any revisions be made to the 
protocol-specific monitoring plan after initial DSMC approval, the PI will be responsible for notifying the 
DSMC of such changes. The Committee reserves the right to conduct additional audits if necessary.  
18.7 Multisite Monitoring Plan 
 At the time of study initiation at a non-Emory site, the Emory Sponsor, Winship regulatory specialist, 
and Winship research coordinators will perform a site initiation teleconference. During this 
teleconference, the Emory team will review the study, enrollment, reporting, and regulatory compliance. 
The participating site will have internal monitoring meetings. These meetings, which will include the 
participating site investigator, the clinical research coordinator and the regulatory affairs coordinator, will 
meet at least on a monthly basis to review and discuss study data to ensure subject safety. The research 
coordinators will maintain a spreadsheet which will be de-identified and will summarize all the patient 
data for subjects actively being treated on the trial as well as a roadmap detailing pending 
tests/treatments for each individual subject. The spreadsheet will be shared with the Emory PI via e-
mail.  Multi-Site Winship’s MSC will perform an on-site or remote monitoring visit within the first three 
months of enrollment of the first subject. Quarterly monitoring visits will occur (once annually onsite and 
three times remotely) until subject follow-up is terminated. Monthly reviews of data in OnCore will be 
conducted to ensure compliance or identify discrepancies. 
At least monthly teleconferences between Emory PI and participating site Teleconferences will be 
conducted at least once monthly between the PI at Emory and the research team at the participating 
site(s). The purpose of the meetings is to discuss the enrollment, regulatory updates, monitor toxicities, 
and evaluate the progress of the trial. Scheduled teleconferences may stop after all patients have 
completed assigned protocol therapy. The PI at Emory will communicate with participating sites via 
monthly email. The minutes from the teleconference will be maintained in the regulatory binder for the 
study. In addition, electronic copies will be sent via email to the principal investigators at each site.  
19. Provisions to Protect the Privacy Interests of Participants

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Patients will be assured of their voluntary participation in the study, their choice to answer or not 
answer any question, and the protocol for maintaining confidentiality.
Patient confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to patients. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No information 
concerning the study or the data will be released to any unauthorized third party without prior written 
approval of the sponsor.
The study monitor, other authorized representatives of the sponsor, representatives of the IRB or 
pharmaceutical company supplying study product may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) 
and pharmacy records for the patients in this study. The clinical study site will permit access to such 
records.
The study patient’s contact information will be securely stored at each clinical site for internal use during 
the study. At the end of the study, all records will continue to be kept in a secure location for as long a 
period as dictated by local IRB and Institutional regulations.
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted and stored. This will not include the participant’s contact or identifying information. 
Rather, individual participants and their research data will be identified by a unique study identification 
number. The study data entry and study management systems used by clinical sites and research staff 
will be secured and password protected. At the end of the study, all study databases will be de-identified 
and archived.
20. Economic Burden to Participants
The study sponsor, supporter (Secura Bio), and cell manufacturer (Novartis) will not pay for certain 
items and services the subject may receive in this study.  Patients will have to pay for the items or 
services for which the study sponsor does not pay. The sponsor will not pay for regular medical care. 
If subjects have insurance, Emory will submit claims to the insurance for items and services that the 
sponsor does not cover.  Emory will send in only those claims for items and services that it reasonably 
believes the insurance will pay and that the sponsor, supporter, or cell manufacturer has not paid. The 
actual amount that participants have to pay depends on whether or not they have health insurance and 
whether or not that insurance will pay for any research study costs. Generally, insurance companies 
will not pay for items and services that are required just for a research study. Some insurance 
companies will not pay for regular medical treatment or treatment for complications if in a study.  If a 
patient does not have insurance, Emory will review that particular case as part of its program for low-
income patient care.  The standard policies of that program will apply.  The program will figure out if 
patients have to pay any costs for taking part in the study and what those costs will be.
21. Consent Process
The initial informed consent discussion will occur in Winship Cancer. At Winship Cancer Institute, the 
informed consent is an ongoing, interactive process rather than a one-time information session. The 
consent form document is designed to begin the informed consent process, which provides the patient 
with ongoing explanations that will help them make educational decisions about whether to begin or 

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continue participating in the trial. The research team knows that a written document alone may not 
ensure that the patient fully understands what participation means. Therefore, the research team will 
discuss with the patient the trial's purpose, procedures, risks and potential benefits, and their rights as 
a patient. The team will continue to update the patient on any new information that may affect their 
situation.
Consent will be obtained prior to any research-driven procedures. The investigator will assess the 
patient’s capacity during his/her encounters with him or her. The investigator will give the person 
providing consent adequate opportunity to read the consent document before it is signed and dated.
It will be explained to prospective patients what the study involves research, the purpose of the research, 
the expected duration of participation, as well as the approximate number of patients to be enrolled. The 
study procedures, and identification of research procedures vs. non-research will also be thoroughly 
discussed. It will be explained to patients that participation is voluntary and that the patient may 
discontinue at any time.
Refusal to participate or withdraw will not involve a penalty or loss of benefits to which the patient is 
otherwise entitled. Refusal will in no way affect the patient’s future care. The patient will also be told of 
the possible consequences of the decision to withdraw from the research, and procedures for orderly 
termination of participation.
Any significant new findings developed during the course of the research that may affect the patient’s 
willingness to continue to participate will be provided. Also explained will be anticipated circumstances 
under which the patient’s participation may be terminated by the investigator without the patient's 
consent.
Prospective patients will be provided with a description of any reasonably foreseeable risks or 
discomforts as well as a description of any benefits to the patient or to others that might be reasons 
expected from the research. Alternative procedures or courses of treatment will also be thoroughly 
discussed.
Prospective patients will also be given detailed information describing the extent to which confidentiality 
of records identifying the participant will be maintained and what records may be examined by the 
research staff, IRBs, sponsor, their representatives, and possibly the FDA or OHRP.
Also communicated to the patient will be an explanation that emergency medical care will be arranged 
for a study-related illness or injury, and an explanation of whether funds are set aside to pay for this care 
and/or compensation, and if so by whom (e.g., sponsor, supporter, subject, or insurer). The participant 
is told the source of the study's funding.
All participants will be told of any additional costs that may result from participation in the research.
Non-English-Speaking Patients  
A certified translator/interpreter will be present during the consenting process and all questions and 
concerns will be answered by the treating physician. 
A short form in that specific language will be used. A certified translator/interpreter will be present during 
the consenting process and this will be documented. We will use what's available on Emory IRB website. 
For the languages that are not available, we will have the short form translated to that language and 
submit the IRB for review and approval prior to use. Process to Document Consent in Writing: Winship 
SOP 2.1:  ”Obtaining Informed consent for Interventional clinical trial” will be followed.
22. Setting
This pilot trial will be conducted at Emory University. Potential patients will be identified in 
hematology clinics, multidisciplinary cancer clinic and multidisciplinary tumor board at Emory 
University. 

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23.   Resources Available
Emory University was founded in 1836 and is a national center for teaching, research, and service. 
Emory University has been named as one of the nation’s top 25 universities for more than a decade by 
the U.S. News and World Report. Emory University research partners include the Georgia Institute of 
Technology, the University of Georgia, Morehouse School of Medicine, the US Centers for Disease 
Control and Prevention, Children's Healthcare of Atlanta, and the Georgia Clinical and Translational 
Science Alliance (GACTSA). Emory University researchers received $734 million from external funding 
agencies in fiscal year 2018, including approximately $441 million in funding from federal agencies, $359 
million of this from the National Institutes of Health (NIH).
Winship Cancer Institute (Winship) is Georgia's first and only National Cancer Institute (NCI)-
designated Comprehensive Cancer Center (P30CA138292) and is dedicated to the integration of 
innovative clinical and basic science research with outstanding patient care for the prevention, treatment 
and control of cancer. First designated in 2009, Winship’s NCI designation was renewed in 2012 and 
2016, achieving an “outstanding” rating. Winship earned the prestigious Comprehensive Cancer Center 
designation from the NCI in 2016, after demonstrating that its outstanding programs are reducing the 
cancer burden on the state of Georgia through research conducted in its laboratories, its clinical trial 
program, and its population-based science. The institutional support for Winship was rated as 
‘exceptional’ by the review panel.
The Winship Clinic Building C houses the primary offices and clinical space for cancer services 
including the medical oncology, hematology, and surgical oncology clinics, the radiation oncology 
program, and the Winship Ambulatory Infusion Center.  In summer 2017, Emory Healthcare completed 
the expansion of Emory University Hospital Tower on Clifton Road. This nine-floor facility adds 144 
inpatient beds to the hospital, of which more than 80% are dedicated to cancer care. The hospital 
expansion also accommodates cancer patient-specific intensive care units, an expanded BMT Unit with 
peri-transplant clinics to facilitate continuity of care, and a 24-hour cancer urgent care center, which 
serves as both a triage facility and short stay treatment center for patients with cancer-related medical 
concerns. 
The Winship Phase I Unit, on the fourth floor of the Emory University Hospital Tower, is the largest unit 
in Georgia dedicated to the earliest and most critical phase of new cancer therapy evaluation. There is 
space for 15 private treatment bays, four clinic rooms, its own lab for doing patient blood work, a 
dedicated secure medication room, computer workspace for research and other support staff, and a 
"fast track" bay with three chairs for rapid use in patients who, for example, might need only a research 
lab test done.
24.   References
1). National Cancer Institute. NHL-Diffuse Large B Cell Lymphoma. 
https://seer.cancer.gov/statfacts/html/dlbcl.html. 
2). Galaznik A, Huelin R, Stokes M, et al. Systematic review of therapy used in relapsed or 
refractory diffuse large B-cell lymphoma and follicular lymphoma. Future Sci OA. 
2018;4(7):FSO322. Published 2018 Jul 19. doi:10.4155/fsoa-2018-0049
3). National Comprehensive Cancer Network. B Cell Lymphomas. Version 2.2019. 
https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf.
4). Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: 
results from the international SCHOLAR-1 study [published correction appears in Blood. 2018 Feb 
1;131(5):587-588]. Blood. 2017;130(16):1800–1808. doi:10.1182/blood-2017-03-769620

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5). Armitage, JO, Gascoyne RD, Lunning MA, Cavalli, F. Non-Hodgkin Lymphoma. Lancet. 2017 
Jul 15;390(10091):298-310. doi: 10.1016/S0140-6736(16)32407-2. 
6). Schuster SJ, Svoboda J, Chong EA, et al. Chimeric Antigen Receptor T Cells in Refractory B-
Cell Lymphomas. N Engl J Med. 2017;377(26):2545–2554. doi:10.1056/NEJMoa1708566
7). Brudno, JN,  Kochenderfer, JN. Chimeric antigen receptor T-cell therapies for lymphoma.  Nat 
Rev Clin Oncol. 2018 Jan;15(1):31-46. doi: 10.1038/nrclinonc.2017.128. Epub 2017 Aug 31.
8). Levine BL, Miskin J, Wonnacott K, Keir C. Global Manufacturing of CAR T Cell Therapy. Mol 
Ther Methods Clin Dev. 2016;4:92–101. Published 2016 Dec 31. doi:10.1016/j.omtm.2016.12.006
9). Fraietta JA, Lacey SF, Orlando EJ, et al. Determinants of response and resistance to CD19 
chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med. 
2018;24(5):563–571. doi:10.1038/s41591-018-0010-1
10). Cantley, LC. The Phosphoinositide 3-Kinase Pathway. Science (80- ). 2002;296(May):1655-
1658. doi:10.1126/science.296.5573.1655. 
11). Cantley, LC. Obesity, Diabetes, and Cancer: The PI3K Connection. Lecture presented at: 
2013 Breakthrough Prize in Medicine Symposium. December 13, 2013
12). Okkenhaug K. Signaling by the phosphoinositide 3-kinase family in immune cells. Annu Rev 
Immunol. 2013;31:675–704. doi:10.1146/annurev-immunol-032712-095946
13). Vanhaesebroeck B., Guillermet-Guibert J., Graupera M., Bilanges B. (2010). The emerging 
mechanisms of isoform-specific PI3K signalling. Nat. Rev. Mol. Cell Biol.11, 329–341. 
10.1038/nrm288
14). van der Windt GJ, O'Sullivan D, Everts B, et al. CD8 memory T cells have a bioenergetic 
advantage that underlies their rapid recall ability. Proc Natl Acad Sci U S A. 2013;110(35):14336–
14341. doi:10.1073/pnas.1221740110
15). Vangapandu HV, Jain N, Gandhi V. Duvelisib: a phosphoinositide-3 kinase δ/γ inhibitor for 
chronic lymphocytic leukemia. Expert Opin Investig Drugs. 2017;26(5):625–632. 
doi:10.1080/13543784.2017.1312338
16). Petersen CT, Hassan M, Morris AB, et al. Improving T-cell expansion and function for 
adoptive T-cell therapy using ex vivo treatment with PI3Kδ inhibitors and VIP antagonists. Blood 
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17). Finlay DK, Rosenzweig E, Sinclair LV, et al. PDK1 regulation of mTOR and hypoxia-inducible 
factor 1 integrate metabolism and migration of CD8+ T cells. J Exp Med. 2012;209(13):2441–2453. 
doi:10.1084/jem.20112607
18). Rolf J., Zarrouk M., Finlay D. K., Foretz M., Viollet B., Cantrell D. A. (2013). AMPKalpha1: a 
glucose sensor that controls CD8 T-cell memory.Eur. J. Immunol.43 889–896. 
10.1002/eji.201243008
19). Hukelmann JL, Anderson KE, Sinclair LV, et al. The cytotoxic T cell proteome and its shaping 
by the kinase mTOR. Nat Immunol. 2015;17(1):104–112. doi:10.1038/ni.3314
20). Salmond, RJ. mTOR Regulation of Glycolytic Metabolism in T cells. Front Cell Dev Biol. 2018; 
6: 122.
21). Zhao Y, Niu C, Cui J. Gamma-delta (γδ) T cells: friend or foe in cancer development? 
[published correction appears in J Transl Med. 2018 May 8;16(1):122]. J Transl Med. 2018;16(1):3. 
Published 2018 Jan 10. doi:10.1186/s12967-017-1378-2
22). Landmeier S, Altvater B, Pscherer S, et al. Activated human gammadelta T cells as 
stimulators of specific CD8+ T-cell responses to subdominant Epstein Barr virus epitopes: potential 
for immunotherapy of cancer. J Immunother. 2009;32(3):310–321. 
doi:10.1097/CJI.0b013e31819b7c30
23). Zou C, Zhao P, Xiao Z, Han X, Fu F, Fu L. γδ T cells in cancer immunotherapy. Oncotarget. 
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24). Capsomidis A, Benthall G, Van Acker HH, Fisher J, Kramer AM, Abeln Z, et al. Chimeric 
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25). Jensen MC, Riddell SRDesign and implementation of adoptive therapy with chimeric antigen 
receptor-modified T cells. 24329794 Immunological reviews, 2014 Jan. : 257(1)127-44
26). Mackall, CL, Fleisher TA, Brown MR, Magrath IT et al. Lymphocyte depletion during treatment 
with intensive chemotherapy for cancer. Blood. 1994 Oct 1;84(7):2221-8.
27). Klebanoff CA, Scott CD, Leonardi AJ, et al. Memory T cell-driven differentiation of naive cells 
impairs adoptive immunotherapy. J Clin Invest. 2015;126(1):318–334. doi:10.1172/JCI81217
28). Gattinoni L, Lugli E, Ji Y, et al. A human memory T cell subset with stem cell-like 
properties. Nat Med. 2011;17(10):1290–1297. Published 2011 Sep 18. doi:10.1038/nm.2446
29). Gattinoni L, et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ 
memory stem cells. Nat. Med. 2009;15:808–813
30). Klebanoff CA, Gattinoni L, Torabi-Parizi P, et al. Central memory self/tumor-reactive CD8+ T 
cells confer superior antitumor immunity compared with effector memory T cells. Proc Natl Acad 
Sci U S A. 2005;102(27):9571–9576. doi:10.1073/pnas.0503726102
31). Fraietta JA, Lacey SF, Orlando EJ, et al. Determinants of response and resistance to CD19 
chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med. 
2018;24(5):563–571. doi:10.1038/s41591-018-0010-1
32). Funk CR, Petersen CT, Jagirdar N, et al. Oligoclonal T Cells Transiently Expand and Express 
Tim-3 and PD-1 Following Anti-CD19 CAR T Cell Therapy: A Case Report. Int J Mol Sci. 
2018;19(12):4118. Published 2018 Dec 19. doi:10.3390/ijms19124118
33). Stock S, Schmidt P, Schmitt A, et al. Idelalisib for optimized CD19-specific chimeric antigen 
receptor T cells in chronic lymphocytic leukemia patients. Int J Cancer. 2019. 
doi:10.1002/ijc.32201.
34). Greenwell I.B., Ip A., Cohen J.B. PI3K Inhibitors: Understanding Toxicity Mechanisms and 
Management. Oncology (Williston Park) 2017;31:821–828
35). Flinn IW, O'Brien S, Kahl B, et al. Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically 
active in advanced hematologic malignancies. Blood. 2018;131(8):877–887. doi:10.1182/blood-
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36). Flinn IW, Hillmen P, Montillo M, et al. The phase 3 DUO trial: duvelisib vs ofatumumab in 
relapsed and refractory CLL/SLL. Blood. 2018;132(23):2446–2455. doi:10.1182/blood-2018-05-
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37).  Horwitz SM, Koch R, Porcu P, et al. Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 
trial and preclinical models of T-cell lymphoma. Blood. 2018;131(8):888–898. doi:10.1182/blood-
2017-08-802470

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APPENDIX A PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence of 
disease.
0
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction.
90
Able to carry on normal activity; minor 
signs or symptoms of disease.
80
Normal activity with effort; some signs 
or symptoms of disease.
1
Symptoms, 
but 
ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work).
70
Cares for self, unable to carry on normal 
activity or to do active work.
60
Requires occasional assistance, but is 
able to care for most of his/her needs.
2
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but unable 
to carry out any work activities.  Up 
and about more than 50% of waking 
hours.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours.
30
Severely 
disabled, 
hospitalization 
indicated.  Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% 
bedridden. 
 
Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair. 10
Moribund, fatal processes progressing 
rapidly.
5
Dead.
0
Dead.
As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., 
Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 
1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair

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APPENDIX B: POTENT INHIBITORS AND INDUCERS AND SENSITIVE 
CLINICAL SUBSTRATES OF CYP3A
Effect on CYP3A
 Drug Class 
Medications
Antibiotics
chloramphenicol, ciprofloxacin, 
clarithromycin, erythromycin,telithromycin
Antiemetic
aprepitant
Antifungals
ketoconazole, fluconazole, itraconazole, 
posaconazole, voriconazole
Antiviral protease inhibitors
amprenavir, atazanavir, boceprevir, 
cobicistat, darunavir, elvitegravir, 
fosamprenavir, indinavir, lopinavir, 
nelfinavir, ritonavir, saquinavir, telaprevir, 
tenofovir, tipranavir
Calcium-channel blockers
diltiazem, mibifradil, verapamil
Foods/herbs
grapefruit, grapefruit juice, Seville oranges
Serotonin antagonist
nefazodone
Tyrosine kinase inhibitor
imatinib
Moderate to Strong 
CYP3A Inhibitors
Vasopressin antagonist
conivaptan
Antibiotics
nafcillin, rifampin
Anticonvulsants
carbamazepine, phenobarbital, phenytoin
Antiviral reverse transcriptase 
inhibitors
efavirenz, etravirine
Endothelin receptor antagonist
bosentan
Foods/herbs
St. John’s wort
Moderate to Strong 
CYP3A Inducers
Wakefulness-promoting agent
modafinil
Sensitive Substrates
Moderately Sensitive Substrates
CYP3A
alfentanil, avanafil, buspirone, 
conivaptan, darifenacin, darunavir(f), 
ebastine, everolimus, ibrutinib, 
lomitapide, lovastatin(g), midazolam, 
naloxegol, nisoldipine, saquinavir(f), 
alprazolam, aprepitant, 
atorvastatin(c), colchicine, 
eliglustat(e), pimozide, rilpivirine, 
rivaroxaban, tadalafil

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simvastatin(g), sirolimus, tacrolimus, 
tipranavir(f), triazolam, vardenafil
budesonide, dasatinib, 
dronedarone, eletriptan, 
eplerenone, felodipine, indinavir(f), 
lurasidone, maraviroc, quetiapine, 
sildenafil, ticagrelor, tolvaptan
 

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APPENDIX C 
Drug Diary
Record all medications taken during this cycle for example prescriptions and over the counter 
including vitamins.
If you have any questions, please call: ________________________
Study ID:
[Drug] Pill Diary
 Patient Initials: ___          Patient ID: _____                  Cycle: _____                                                                
Instructions:
 
 
 
 
 
 
 
 
 
Planned Daily Dose: __mg
 
REMINDERS:
1. 
2.
Day
Date 
Time
# of Tablets taken
Comments
1
 
 
 
2
 
 
 
3
 
 
 
4
 
 
 
5
 
 
 
6
 
 
 
7
 
 
 
8
 
 
 
9
 
 
 
10
 
 
 
Name 
of 
 Medication
Why did you take the 
medication?
Date
 Medication
 Started
Date  
Medication 
Stopped

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APPENDIX D: Procedure protocol for analysis of T cells and Correlate 
Studies Sample Collection Process 
Procedure Protocol for Analysis of T-Cells and PMBCs for Winship Protocol #CTL019CUSO3T 
(Duvelisib Exposure to Enhance Immune Profiles of T Cells in Patients with Diffuse Large B Cell 
Lymphoma (DEEP T CELLS)
PBMC Cryopreservation with CryoStor Media (on days per schema below):
1. Suspend cells to be cryopreserved using mechanical or enzymatic dissociation.
2. Centrifuge cells to obtain cell pellet.
3. Remove supernatant.
Note: Remove as much culture medium as possible to reduce dilution of the CryoStor medium.
4. Isolation – Add cold (2–8 °C) CryoStor medium to a cell concentration range of 0.5–10x106 cells/ml
for standard cell culture protocols. A higher cell concentration is possible with testing.
Note: CryoStor media contain DMSO, no additives are necessary.
5. Pre-freeze – Incubate cell suspension at 2–8 °C for ~10 minutes.
6. Nucleation – Lower sample temperature to –80 °C.
a. Use a controlled rate freezer (–1 °C /minute) or similar procedure for most mammalian cell
systems.
b. The freezer should be pre-cooled to 2–8 °C.
c. Ice nucleation within the sample (seeding) should be initiated at approximately –5 °C using
a liquid nitrogen burst program setting on the controlled rate freezer or mechanical agitation
(flick or tap) of the cryovial/sample container after 15–20 minutes at –80 °C.
Alternative Nucleation Procedures – cells can be frozen using stepwise freezing procedures.
Stepwise freezing procedures include:
a. 2 hours at –20 °C followed by 2 hours at –80 °C or
b. 3–4 hours at –80 °C in an isopropanol freezing container. The isopropanol container should be 
pre-cooled to 2–8 °C
Ice nucleation – mechanical agitation (flick or tap) of the cryovial/sample container after 15–20 
minutes at –80 °C.
7. Storage – Store the samples at liquid nitrogen temperatures (below –130 °C).
Note: Sample storage at –80 °C is only recommended.
8. Thawing - Thaw samples quickly in a 37 °C water bath. Sample should be thawed with gentle swirling 
of the sample until all visible ice has melted. Thaw time for a 1 ml sample in a cryovial is ~3 minutes. 
Note: DO NOT allow sample to warm above chilled temperatures (0–10 °C). Cryovials should be cool 
to the touch when removed from the water bath. Passive thaw is not recommended.
9. Dilute cell/CryoStor mixture immediately with appropriate culture medium. This can be performed in 
a single step. The dilution medium should be between 20–37 °C. A dilution ratio of 1:10 (sample: 
medium) or greater is recommended.
10. Plate cells appropriately.
11. Culture the cells or use immediately.
CAR-T PCR (on days per schema below)
Peripheral blood will be sent to Novartis for PCR analysis. Overnight shipment will occur directly from 
each clinical site to Novartis for analysis.   
Collection for Correlate Whole Blood/T-cell Studies (on days per schema below)

Protocol Title: Duvelisib Exposure to Enhance Immune Profiles of T Cells in Patients with Diffuse 
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Additional sample collection along with T-cell immunophenotyping samples per schema below for 
biomarker correlative studies and tissue banking: 
- PBMC Immunophenotyping in 1x 10mL BD EDTA top tube (CyTOF) 
- T-cell and PBMC RNA Analysis/Phenotyping in 2x 10cc (Nanostring)
All samples will be processed per manufacture protocols (CPT Tubes: Becton Dickinson, CyTOF 
MaxPar Direct Immune Profiling: Fluidigm, Nanostring Panels: Nanostring Technologies). Remaining 
serum, PBMCs, and T-cells will be centrally banked at Emory University. 

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APPENDIX E Abbreviations and definition of terms
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or special term
Explanation
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse event of special interest
ALK
Anaplastic lymphoma kinase
ALT
Alanine aminotransferase
APF12
Proportion of patients alive and progression free at 12 months from randomization
AST
Aspartate aminotransferase
BoR
Best objective response
BP
Blood pressure
C
Cycle
CD
Cluster of differentiation
CI
Confidence interval
CL
Clearance
Cmax
Maximum plasma concentration
Cmax,ss
Maximum plasma concentration at steady state
CR
Complete response
CSA
Clinical study agreement
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
CTLA-4
Cytotoxic T–lymphocyte-associated antigen 4
Ctrough,ss
Trough concentration at steady state
CXCL
Chemokine (C-X-C motif) ligand
DoR
Duration of response
EC
Ethics Committee, synonymous to Institutional Review Board and Independent 
Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group

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Abbreviation or special term
Explanation
eCRF
Electronic case report form
EDoR
Expected duration of response
EGFR
Epidermal growth factor receptor
EU
European Union
FAS
Full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
Gastrointestinal
GMP
Good Manufacturing Practice
hCG
Human chorionic gonadotropin
HIV
Human immunodeficiency virus
HR
Hazard ratio
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IFN
Interferon
IgE
Immunoglobulin E
IgG
Immunoglobulin G
IHC
Immunohistochemistry
IL
Interleukin
ILS
Interstitial lung disease
IM
Intramuscular
IMT
Immunomodulatory therapy
IP
Investigational product 
irAE
Immune-related adverse event
IRB
Institutional Review Board
irRECIST
Immune-related Response Evaluation Criteria in Solid Tumors
ITT
Intent-to-Treat
IV
Intravenous
IVRS
Interactive Voice Response System

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Abbreviation or special term
Explanation
IWRS
Interactive Web Response System
mAb
Monoclonal antibody
MDSC
Myeloid-derived suppressor cell
MedDRA
Medical Dictionary for Regulatory Activities
MHLW
Minister of Health, Labor, and Welfare
miRNA
Micro-ribonucleic acid
MRI
Magnetic resonance imaging
NCI
National Cancer Institute
NE
Not evaluable
NSCLC
Non–small-cell lung cancer
OAE
Other significant adverse event
ORR
Objective response rate
OS
Overall survival
PBMC
Peripheral blood mononuclear cell
PD
Progressive disease
PDx
Pharmacodynamic(s)
PFS
Progression-free survival
PFS2
Time to second progression
PGx
Pharmacogenetic research
PK
Pharmacokinetic(s)
PR
Partial response
q2w
Every 2 weeks
q3w
Every 3 weeks
q4w
Every 4 weeks
q6w
Every 6 weeks
q8w
Every 8 weeks
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
RNA
Ribonucleic acid
RR
Response rate
RT-QPCR
Reverse transcription quantitative polymerase chain reaction

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Abbreviation or special term
Explanation
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Safety analysis set
SCLC
Small cell lung cancer
SD
Stable disease
SNP
Single nucleotide polymorphism
SoC
Standard of Care
T3
Triiodothyronine
T4
Thyroxine
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
US
United States
WBDC
Web-Based Data Capture
WHO
World Health Organization