Clinical trial NCT02706405
Conditions: Diffuse Large B-Cell Lymphoma, Not Otherwise Specified Recurrent Diffuse Large B-Cell Lymphoma Recurrent Primary Mediastinal (Thymic) Large B-Cell Lymphoma Refractory Diffuse Large B-Cell Lymphoma Refractory High Grade B-Cell Lymphoma With MYC, BCL2, and BCL6 Rearrangements Refractory Primary Mediastinal (Thymic) Large B-Cell Lymphoma
Keywords: PD-L1 immunotherapy non-Hodgkin lymphoma
Sponsor: Fred Hutchinson Cancer Center
Start date: 2016-11-15; Completion date: 2021-05-28
Enrollment: 30 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This phase Ib trial studies whether anti-CD19-chimeric antigen receptor (CAR) lentiviral vector-transduced autologous T cells (JCAR014) and durvalumab are safe in combination and can work together in treating patients with non-Hodgkin lymphoma that has returned after a period of improvement (relapsed) or has not responded to previous treatment (refractory). JCAR014 is made of each patient's immune cells (T cells) that have a new gene added to them in a laboratory, which programs them to kill lymphoma cells. Durvalumab is a type of drug called a monoclonal antibody, targeted to PD-L1 that may help immune cells attack cancer cells more effectively and thus help JCAR014 work better.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the safety of JCAR014 in combination with durvalumab in adult patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL).

II. To determine the maximum tolerated dose (MTD) of durvalumab in combination with JCAR014.

III. To characterize the pharmacokinetic (PK) profile of JCAR014.

SECONDARY OBJECTIVES:

I. To assess the antitumor activity of JCAR014 in combination with durvalumab in R/R B-cell NHL.

II. To estimate the duration of response (DOR), progression-free survival (PFS), and overall survival (OS) in patients treated with JCAR014 in combination with durvalumab.

III. To characterize the PK profile of durvalumab. IV. To assess the immunogenicity of JCAR014 and durvalumab.

EXPLORATORY OBJECTIVE:

I. To assess the pharmacodynamic effects of JCAR014 and durvalumab in blood and within the tumor.

OUTLINE: This is a dose-escalation study of durvalumab administered with a single fixed dose of JCAR014. Patients are assigned to 1 of 2 treatment arms, listed as Groups 1 and 2 below.

LYMPHODEPLETING CHEMOTHERAPY: All patients receive cyclophosphamide and fludarabine intravenously (IV) for 3 days starting approximately on day -5 or day -4.

GROUP I: Patients receive JCAR014 IV over 20-30 minutes on day 0 and durvalumab IV over 60 minutes on day 21 (may occur as early as day 7) and then every 4 weeks for up to 10 doses in the absence of disease progression or unacceptable toxicity.

GROUP II: Patients receive durvalumab IV over 60 minutes on day -1, JCAR014 IV over 20-30 minutes on day 0, then up to 10 additional doses of durvalumab every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 30 days for 30 months, every 3 months for 12 months, then periodically for at least 15 years.

Arms: arm 1: Patients receive JCAR014 IV over 20-30 minutes on day 0 and durvalumab IV over 60 minutes on day 21 (may occur as early as day 7) and then every 4 weeks for up to 10 doses in the absence of disease progression or unacceptable toxicity.

Group 1 - early: start durvalumab no earlier than 7 days after JCAR014.

Group 1 Dose Level 2 is 750 mg Durvalumab, up to 2 x 106/kg CAR T cells arm 2: Patients receive JCAR014 IV over 20-30 minutes on day 0 and durvalumab IV over 60 minutes on day 21 (may occur as early as day 7) and then every 4 weeks for up to 10 doses in the absence of disease progression or unacceptable toxicity.

Group 1 - late: start durvalumab no earlier than 21 days after JCAR014

Group 1 Dose Level 1 is 225 mg Durvalumab, up to 2 x 106/kg CAR T cells

. arm 3: Patients receive JCAR014 IV over 20-30 minutes on day 0 and durvalumab IV over 60 minutes on day 21 (may occur as early as day 7) and then every 4 weeks for up to 10 doses in the absence of disease progression or unacceptable toxicity.

Group 1 - late: start durvalumab no earlier than 21 days after JCAR014

Group 1 Dose Level 2 is 750 mg Durvalumab, up to 2 x 106/kg CAR T cells arm 4: Patients receive durvalumab IV over 60 minutes on day -1, JCAR014 IV over 20-30 minutes on day 0, then up to 10 additional doses of durvalumab every 4 weeks in the absence of disease progression or unacceptable toxicity.

Group 2 Dose Level 1 is 7.5 mg Durvalumab, up to 2 x 106/kg CAR T cells arm 5: Patients receive durvalumab IV over 60 minutes on day -1, JCAR014 IV over 20-30 minutes on day 0, then up to 10 additional doses of durvalumab every 4 weeks in the absence of disease progression or unacceptable toxicity.

Group 2 Dose Level 2 is 22.5 mg Durvalumab, up to 2 x 106/kg CAR T cells arm 6: Patients receive durvalumab IV over 60 minutes on day -1, JCAR014 IV over 20-30 minutes on day 0, then up to 10 additional doses of durvalumab every 4 weeks in the absence of disease progression or unacceptable toxicity.

Group 2 Dose Level 3 is 75 mg Durvalumab, up to 2 x 106/kg CAR T cells arm 7: Patients receive durvalumab IV over 60 minutes on day -1, JCAR014 IV over 20-30 minutes on day 0, then up to 10 additional doses of durvalumab every 4 weeks in the absence of disease progression or unacceptable toxicity.

Group 2 Dose Level 4 is 225 mg Durvalumab, up to 2 x 106/kg CAR T cells arm 8: Patients receive durvalumab IV over 60 minutes on day -1, JCAR014 IV over 20-30 minutes on day 0, then up to 10 additional doses of durvalumab every 4 weeks in the absence of disease progression or unacceptable toxicity.

Group 2 Dose Level 5 is 750 mg Durvalumab, up to 2 x 106/kg CAR T cells
Interventions: intervention 1: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014 intervention 2: Cyclophosphamide intervention 3: Durvalumab intervention 4: Fludarabine
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
FRED HUTCHINSON CANCER RESEARCH CENTER  
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
PROTOCOL NO. 9457 
A Phase 1b study of JCAR014, autologous T cells engineered to express a 
CD19-specific chimeric antigen receptor, in combination with durvalumab 
(MEDI4736) for relapsed/refractory B-cell non-Hodgkin lymphoma  
Protocol No. 
FHCRC 9457 
Current Version: 
Previous Version: 
14 May 2021 
20 November 2020 
Study Team 
Investigators: 
Professional Title 
Telephone Number 
Jordan Gauthier, MD 
 (Principal Investigator) 
Assistant Professor, FHCRC 
206-667-2713
Alexandre V Hirayama, MD 
Post-Doctoral Research Fellow 
206-667-6909
Statistician: 
Vicky Wu 
Research Staff: 
Assistant Professor, FHCRC 
206-667-3358
Martha Kahugu 
Research Nurse 
206-667-7582
Alisa Bradford 
Research Coordinator 
206-667-2834
EMERGENCY (24-HOUR) PHONE:  206-598-8902 
IRO received 11/22/21
FHCRC IRB Approval  
DEC 22 2021 
Document Released Date


FHCRC Protocol No. 9457 
 
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PROTOCOL SYNOPSIS 
Protocol Number: FHCRC 9457 
Product Names: JCAR014 and durvalumab 
Title of Study: A Phase 1b study of JCAR014, autologous T cells engineered to express a CD19-specific chimeric 
antigen receptor, in combination with durvalumab (MEDI4736) for relapsed/refractory B-cell non-Hodgkin 
lymphoma 
 
Phase of Development: Phase 1b 
Study Objectives: 
Primary: 
• 
To evaluate the safety of JCAR014 in combination with durvalumab in adult patients with relapsed/refractory 
(R/R) B-cell non-Hodgkin lymphoma (NHL) 
• 
To determine the maximum tolerated dose (MTD) of durvalumab in combination with JCAR014 
• 
To characterize the pharmacokinetic (PK) profile of JCAR014 
Secondary: 
• 
To assess the antitumor activity of JCAR014 in combination with durvalumab in R/R B-cell NHL  
• 
To estimate the duration of response (DOR), progression-free survival (PFS), and overall survival (OS) in 
patients treated with JCAR014 in combination with durvalumab 
• 
To characterize the PK profile of durvalumab 
• 
To assess the immunogenicity of JCAR014 and durvalumab 
Exploratory: 
• 
To assess the pharmacodynamic effects of JCAR014 and durvalumab in blood and within the tumor  
Background: 
B-cell NHL: B-cell malignancies comprise a heterogeneous group of tumors including multiple NHL subtypes. 
Patients with B-cell NHL, including diffuse large B-cell lymphoma (DLBCL), commonly relapse or have 
refractory disease and remain incurable despite multi-modality treatments. 
The majority (> 95%) of B-cell lymphomas express the B-cell lineage marker CD19, a 95-kDa glycoprotein 
present on the surface of B cells from early development until differentiation into plasma cells. CD19 is an 
attractive immunotherapeutic target because it is present on the surface of most B-cell malignancies but not on 
most normal tissues. 
Approximately 30% of B-cell lymphomas have been shown to express programmed cell death ligand 1 (PD-L1), a 
protein involved in tumor immunosuppression of tumor-infiltrating lymphocytes and potentially of adoptively 
transferred T cells, such as chimeric antigen receptor (CAR)-modified T cells. Secretion of interferon gamma by 
CAR T cells may stimulate B-cell lymphomas to upregulate PD-L1 expression. In addition, B-cell lymphomas 
have a varying degree of infiltrating immune cells that also express PD-L1 and may contribute to the 
immunosuppressive microenvironment of the tumor. 
JCAR014: JCAR014 consists of autologous T cells that express a CAR composed of a murine-derived, CD19-
specific single-chain variable fragment (scFv) genetically fused to the 4-1BB and CD3ζ signaling endodomains. 
The JCAR014 cell product is prepared by modifying T cells ex vivo using a replication-incompetent, self-
inactivating lentiviral vector that encodes the CD19 CAR and a truncated human epidermal growth factor receptor 
(EGFRt) that facilitates analysis of transduction efficiency and in vivo tracking of transduced cells by flow 
cytometry. JCAR014 is administered intravenously (IV) in a 1:1 ratio of CD4+ and CD8+ CAR-expressing 
(EGFRt+) T cells. JCAR014 T cells exhibit CD19-specific tumor cell recognition, resulting in tumor cell lysis and 
CAR T cell cytokine secretion and proliferation. 
Durvalumab: Durvalumab is a human IgG1κ monoclonal antibody (mAb) that binds to PD-L1 and inhibits the 
binding of PD-L1 to programmed cell death protein 1 (PD-1) and CD80. Durvalumab contains a triple mutation in 
the constant domain of the IgG1 heavy chain that inhibits binding of complement protein C1q and the Fcγ receptors 


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involved in triggering effector function such as antibody-dependent cell-mediated cytotoxicity or phagocytosis. 
Durvalumab is administered by IV infusion. 
Study Purpose and Rationale: To date, JCAR014 has been studied in adult patients with CD19+ B-cell NHL and 
acute lymphoblastic leukemia (ALL) with encouraging results. The complete remission (CR) rate in ALL is > 90% 
and the overall response rate (CR and partial response [PR]) in NHL is approximately 67%. There is a need to 
improve the antitumor efficacy of this approach. Improvements in the expansion and persistence of CAR-T cells 
and in antitumor activity have been made by modifying the lymphodepleting chemotherapy regimen; however, 
expression of PD-L1 by the tumor, the lymphoma microenvironment, or the activated CAR-T cell mass may limit 
the antitumor activity of JCAR014. Preliminary data suggest that CAR-T cells, upon antigen stimulation, 
upregulate expression of PD-1 and PD-L1, thus becoming targets for suppression by PD-L1 expressed on the 
tumor, the tumor microenvironment, or by the CAR-T cell mass itself. 
In vitro studies have shown that durvalumab antagonizes the inhibitory effects of PD-L1 on primary human T cells, 
resulting in their restored proliferation and production of interferon gamma in response to T-cell receptor 
stimulation. Durvalumab has been evaluated in a total of 1883 patients with cancer, with evidence of antitumor 
activity and an acceptable safety profile when administered via IV infusion at 10 mg/kg every 2 weeks. More 
recently, a similar safety profile has been observed when administered at 20 mg/kg every 4 weeks. 
This Phase 1 study is intended to evaluate the safety, tolerability, in vivo expansion, and antitumor activity of 
CAR-T cells (JCAR014) in combination with a PD-L1 antagonist (durvalumab) in R/R B-cell NHL. 
Study Design: This is an open-label, single-center, Phase 1b study to determine the safety, PK, and antitumor 
activity of JCAR014 in combination with durvalumab in adult patients with R/R DLBCL (including transformed 
DLBCL and primary mediastinal B-cell lymphoma [PMBCL]). 
Patients will be enrolled into one of two treatment groups (Group 1 or Group 2). Within each group, durvalumab 
dose escalation/de-escalation will follow a modified toxicity probability interval (mTPI) algorithm, with a target 
dose-limiting toxicity (DLT) rate of 30% and an equivalence interval of 25%−35% (Appendix F). A dose level will 
be considered unsafe, with no additional patients enrolled at that dose level, if it has an estimated 95% or more 
probability of exceeding the target DLT rate of 30% (i.e., P[DLT > 30%|data] > 95%) with at least three patients 
treated at that dose level. Dose escalation in each group will occur independently according to the mTPI algorithm 
as applied to each group. 
Initial Study Design: 
Group 1 (first dose of durvalumab after JCAR014): 
Patients in Group 1 receive the first infusion of durvalumab after treatment with JCAR014. The first treated cohorts 
of patients in Group 1 received durvalumab no earlier than 21 days after the JCAR014 infusion (Group 1 – late). 
Patients in Group 1 receiving JCAR014 (up to 2 x 106 CAR-T cells/kg) are assessed for DLT from the time of the 
first durvalumab infusion until 28 days after the first durvalumab infusion. According to the mTPI algorithm, 
durvalumab at Dose Level 1 (225 mg, n = 3 evaluable) and Dose Level 2 (750 mg, n = 3 evaluable) were found to 
have acceptable safety. 
Group 2 (first dose of durvalumab before JCAR014): 
Patients in Group 2 receive the first dose of durvalumab 1 day prior to administration of JCAR014. DLTs in Group 
2 are assessed from the time of the pre-JCAR014 dose of durvalumab until 28 days after treatment with JCAR014 
(up to 2 x 106 CAR T cells/kg). According to the mTPI algorithm, durvalumab at Dose Level 1 (7.5 mg, n = 1 
evaluable), Dose Level 2 (22.5 mg, n = 1 evaluable), Dose Level 3 (75 mg, n = 3 evaluable), Dose Level 4 (225 
mg, n = 6 evaluable, including one DLT), and Dose Level 5 (750 mg, n = 6 evaluable, including one DLT) were 
found to have acceptable safety. 
In Group 1 and Group 2, patients subsequently receive durvalumab at approximately 28 day intervals at the current 
highest safe durvalumab dose level (750 mg) identified in dose escalation studies in either Group 1 or Group 2. 
Amended Study Design: 
Analyses of efficacy and pharmacodynamic data from patients previously treated in Group 1 (day 21 durvalumab 
start) and Group 2 (day -1 durvalumab start) indicated that durvalumab ≤ 750 mg starting no earlier than day 21 


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(Group 1 – late) may be superior to starting on day -1 (Group 2). Furthermore, data from the trial sponsor indicated 
that durvalumab 1500 mg is unlikely to provide an advantage in PD-L1 blockade compared to durvalumab 750 mg, 
suggesting that escalation to durvalumab 1500 mg in this trial may be unnecessary. Because JCAR014 CAR-T 
cells are declining in blood at day 21 after JCAR014 infusion, we elected to revise the protocol to add a cohort in 
Group 1 who receive durvalumab as early as 7 days after JCAR014 infusion (Group 1 – early) and nominate 750 
mg as the maximum durvalumab dose in all Groups. Patients in Group 1 – early receiving JCAR014 (up to 2 x 106 
CAR-T cells/kg) are treated in cohorts of 3 patients and assessed for DLT from the time of the first durvalumab 
infusion until 28 days after the first durvalumab infusion. Durvalumab dose de-escalation/re-escalation decisions 
follow the mTPI algorithm in cohorts of 3 patients. 
Amended groups: 
Group 1 – late: start durvalumab no earlier than 21 days after JCAR014. 
Group 1 – early: start durvalumab no earlier than 7 days after JCAR014. 
Group 2: start durvalumab one day prior to JCAR014. 
In all groups, patients subsequently receive durvalumab 750 mg at approximately 28 day intervals. 
If durvalumab 750 mg has acceptable safety in Group 1 – early (day 7 start) according to the mTPI algorithm, 
patients will then be treated alternately in Group 1 – early and Group 1 – late until 6 evaluable patients have been 
treated in each of the 3 groups: Group 2; Group 1 – late; Group 1 – early. The Steering Committee (SC) will then 
evaluate available safety, toxicity, efficacy, and pharmacodynamic data to determine which group/s should be 
subsequently expanded. Allocation of the subsequent patients will be alternated if more than one cohort is 
expanded. The maximum number of evaluable patients in the trial will be 42. 
Group 1 (post-JCAR014 treatment with durvalumab): 
 
Group 2 (pre-JCAR014 treatment with durvalumab): 
 
The study was gated such that the first six patients were treated with durvalumab at intervals of at least 2 weeks 
and subsequent patients were scheduled for treatment with durvalumab at intervals of at least 1 week. If a patient’s 
durvalumab infusion is delayed for clinical or logistical reasons, and JCAR014 cell manufacturing and/or 
lymphodepletion chemotherapy are in progress for the next patient planned for treatment with the same dose level 
of durvalumab, the 1 week interval between durvalumab infusions is not required. Patients may commence 
treatment with lymphodepletion and/or JCAR014 before durvalumab dose assignment. 
In both groups, JCAR014 may be dose de-escalated after review by the SC if the SC determines that the observed 
data indicate that dose de-escalation of JCAR014 is required. In this case, a separate group may be enrolled at a 


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stable dose of durvalumab (to be determined by the SC) and dose re-escalation of JCAR014 may occur via the 
mTPI algorithm. Enrollment in this group will commence after amendment to the protocol and discussion with the 
FDA. 
All eligible patients will undergo leukapheresis to enable JCAR014 production. Lymphodepleting chemotherapy 
(fludarabine [Flu] and cyclophospamide [Cy]) will be administered approximately Day -5 to Day -2 prior to 
JCAR014 administration, and will consist of either a single dose of cyclophosphamide 60 mg/kg administered on 
Day -5 and three daily doses of fludarabine 25 mg/m2/day on Days -4 to -2 or with concurrent cyclophosphamide 
(300 mg/m2/day) and fludarabine (30 mg/m2/day) on days -4 through -2. The first dose of durvalumab will be 
administered on Day -1 for patients in Group 2 only, and approximately day 7 or 21 for patients in Group 1. All 
patients will receive JCAR014 on Day 0. In both groups, durvalumab will be administered approximately every 4 
weeks for the greater of either 10 post-JCAR014 cycles or 4 cycles beyond identification of CR (for patients in 
whom studies demonstrating transition to CR occur late after JCAR014 infusion). Durvalumab cycles may be 
ceased if there is unacceptable toxicity, disease progression, or the patient or PI/designee determine it is not in the 
patient’s best interest to continue durvalumab. Patients with disease progression at restaging who have evidence of 
biological activity after durvalumab infusion that could be associated with subsequent antitumor effect (e.g., a 
mixed response, tumor stability, or evidence of JCAR014 expansion and/or persistence) may receive additional 
post-JCAR014 cycles of durvalumab up to the maximum number allowed for Group 1 or Group 2. 
The planned dose levels of durvalumab and JCAR014 (intermediate dose levels may be evaluated) are as follows: 
Dose Level 
 
Durvalumab 
 
JCAR014 
(Group 1 and Group 2) 
 
Group 1 
Group 2 
 
-1 
 
75 mg 
— 
 
— 
1 
 
225 mg 
7.5 mg 
 
Up to 2 x 106/kg CAR T cells 
2 
 
750 mg 
22.5 mg 
 
— 
3 
 
— 
75 mg 
 
— 
4 
 
— 
225 mg 
 
— 
5 
 
— 
750 mg 
 
— 
 
After the JCAR014 infusion, patients will be monitored for in vivo T-cell expansion/persistence and will have 
serum samples collected for cytokine profiling. Standard safety laboratory studies will be monitored until 12 
months post-JCAR014 infusion or 90 days after the final durvalumab infusion, whichever is longer. Safety and 
tolerability will be assessed from study entry until the end of treatment and primary follow-up (12 months post-
JCAR014 infusion or 90 days after last durvalumab infusion, whichever is longer). Long-term follow-up to assess 
delayed adverse events will begin after the primary follow-up and will continue for up to 15 years after the 
JCAR014 infusion. Toxicities will be graded using the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03, with the exception of cytokine release syndrome (CRS), which 
will be graded according to a system based on modified criteria (Davila 2014, Lee 2014). PK (in vivo expansion 
and persistence) will be assessed from the time of JCAR014 infusion until cells are no longer detectable by flow 
cytometry or quantitative polymerase chain reaction (qPCR). 
For a subset of patients with accessible tumor who consent to optional biopsies, a fresh tumor biopsy may be 
obtained prior to lymphodepleting chemotherapy, within the first 4 weeks after administration of JCAR014, and 
approximately within the first 4 weeks after the first post-JCAR014 administration of durvalumab. If biopsy within 
this period is not suitable for logistical, research or clinical reasons, biopsies may be completed at a different time. 
In the event of persistent mass, relapse or progression, a biopsy may be collected at that time point. These samples 
will be evaluated for the extent of JCAR014 migration and PD-1 and PD-L1 expression. Additional markers of 
immune cell phenotype and analysis of the tumor microenvironment may be explored in response to emerging data. 
Disease response will be determined by positron emission tomography (PET)/computed tomography (CT) at 
approximately 1, 2, 4, 6, 9, and 12 months after the JCAR014 infusion (at the end of the JCAR014 cycle, the end of 
the first post-JCAR014 durvalumab cycle, approximately every other durvalumab cycle until 6 months after the 
JCAR014 infusion, then every 3 months until 12 months after the JCAR014 infusion or 90 days after the last 
durvalumab dose, whichever is later). At the time of the 1-month post-JCAR014 response assessments (and at 


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other timepoints as clinically indicated until the patient achieves a CR), patients with bone marrow lymphoma at 
baseline may have repeat a bone marrow aspirate and biopsy that will be analyzed for lymphoma by flow 
cytometry; samples may also be analyzed for other exploratory endpoints. 
Patients may be eligible for retreatment with JCAR014 ± durvalumab if at least 3 months have elapsed since the 
last dose of durvalumab. Retreatment data will not be included in the dose-finding portion of the study. 
The SC, comprising the PI and/or designee and FHCRC statistician and medical director/s from Juno Therapeutics 
and MedImmune, will regularly assess the safety, PK, and efficacy of the combination of JCAR014 and 
durvalumab administration throughout the study. In addition, an independent Data Safety Monitoring Board 
(DSMB) will review cumulative study data approximately quarterly over the course of the study to evaluate safety, 
protocol conduct, and scientific validity and integrity of the trial. 
After the primary follow-up phase (12 months post-JCAR014 infusion or 90 days after the last durvalumab 
infusion, whichever is longer), patients will be asked to participate in long-term follow-up in accordance with Food 
and Drug Administration guidelines. 
Study Population: The target study population consists of adult patients with R/R B-cell NHL. 
Patients must meet all of the following criteria to be enrolled in this study: 
Inclusion Criteria: 
1) Male or female ≥ 18 years of age at the time of screening consent 
2) Relapsed or refractory, PET-positive DLBCL not otherwise specified (NOS), high grade B cell lymphoma 
with MYC and BCL2 and/or BCL6 rearrangements, PMBCL, or DLBCL transformed from indolent 
histology with one of the following: 
a) Persistent disease after first-line chemo-immunotherapy 
b) Relapse after first-line chemo-immunotherapy and not eligible for autologous hematopoietic stem cell 
transplant (HCT) 
c) Relapse or persistent disease after at least two lines of therapy or after autologous HCT 
3) Evidence of CD19 expression on any prior or current tumor specimen or a high likelihood of CD19 
expression based on disease histology 
4) Karnofsky performance status ≥ 60% 
5) Adequate organ function, defined as: 
a) Assessed by the Investigator to have adequate bone marrow function to receive lymphodepleting 
conditioning chemotherapy 
b) Serum creatinine < 1.5 x age-adjusted upper limit of normal (ULN) 
c) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 x ULN and total bilirubin 
≤ 2 x ULN 
d) Adequate pulmonary function, defined as CTCAE Grade ≤ 1 dyspnea and SaO2 ≥ 92% on room air. 
Patients with clinically significant pulmonary dysfunction, as determined by medical history and 
physical exam should undergo pulmonary function testing and must have a forced expiratory volume 
in 1 second (FEV1) of ≥ 50% of predicted value or diffusing capacity of the lung for carbon 
monoxide (DLCO; corrected) ≥ 40% of predicted value 
e) Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥ 35% as assessed by 
echocardiogram or multiple uptake gated acquisition (MUGA) 
6) Women of reproductive potential (defined as all women physiologically capable of becoming pregnant) 
must agree to use suitable methods of contraception for 90 days after the last dose of study therapy 
(durvalumab or JCAR014 infusion) 
7) Males who have partners of reproductive potential must agree to use an effective barrier contraceptive 


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method for 90 days after the last dose of study therapy (durvalumab or JCAR014) 
8) Ability to understand and provide informed consent 
 
Exclusion Criteria: 
1) Subjects with known active central nervous system (CNS) involvement by malignancy. Subjects with 
prior CNS disease that has been effectively treated will be eligible if treatment was completed at least 3 
months prior to enrollment and there is no evidence of disease or stable abnormalities on repeat imaging. 
2) Planned use of corticosteroids (> 10 mg/day prednisone or equivalent) or other systemic 
immunosuppression within 4 days prior to leukapheresis or within 72 hours prior to JCAR014 infusion. 
Topical and/or inhaled steroids are permitted. 
3) Prior treatment with any CD19 CAR T-cell therapy 
4) Prior allogeneic HCT 
5) Known active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection 
6) Pregnant or breastfeeding women 
7) Known exclusion criteria for leukapheresis, JCAR014, or durvalumab therapy 
8) Prior treatment with PD-1, PD-L1, cytotoxic T lymphocyte-associated protein 4 (CTLA-4) targeted 
therapy, or tumor necrosis factor receptor superfamily (TNFRSF) agonists including CD134 (OX40), 
CD27, CD137 (4-1BB), and CD357 (glucocorticoid-induced tumor necrosis factor receptor family-related 
protein [GITR]) 
9) Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel 
disease [e.g., ulcerative colitis, Crohn’s disease], celiac disease, or other serious chronic gastrointestinal 
conditions associated with diarrhea, autoimmune vasculitis, systemic lupus erythematosus, Wegener 
syndrome [granulomatosis with polyangitis], myasthenia gravis, Graves’ disease, rheumatoid arthritis, 
hypophysitis, uveitis, etc.) within 3 years prior to the planned start of treatment. The following are 
exceptions to this criterion: 
a) Vitiligo 
b) Alopecia 
c) Hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement 
d) Psoriasis not requiring systemic treatment 
e) Other conditions considered to be low risk of serious deterioration by the Principal Investigator (PI)  
10) History of any one of the following cardiovascular conditions within the past 6 months: Class III or IV 
heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, 
myocardial infarction, or unstable angina. History of other clinically significant cardiac disease that, in the 
opinion of the PI or designee, is a contraindication to lymphodepleting chemotherapy, JCAR014 infusion, 
or durvalumab infusion is also excluded. 
11) History or presence of clinically relevant CNS pathology, such as epilepsy, seizure, paresis, aphasia, 
stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, or psychosis. History of 
other organic brain syndrome that, in the opinion of the PI or designee, is a contraindication to 
lymphodepleting chemotherapy, JCAR014 infusion, or durvalumab infusion is also excluded. 
12) History of solid organ transplantation 
13) Uncontrolled infection 


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14) Receipt of live, attenuated vaccine within 28 days prior to the first dose of durvalumab (Note: enrolled 
patients should not receive live vaccine during the study and for 180 days after the last dose of 
durvalumab.)  
Test Product, Dose, and Mode of Administration: 
JCAR014 will be administered as an IV infusion and will consist of a single dose of 2 x 106/kg EGFRt+ T cells. 
Dose de-escalation to a lower dose of EGFRt+ T cells may be recommended by the SC based on ongoing safety 
evaluation. 
Durvalumab will be administered as an IV infusion at 7.5, 22.5, 75, 225, or 750 mg. Continued dosing at an every 
4 week (Q4W) interval is allowed after clearance of the DLT evaluation period. A maximum of 10 doses of 
durvalumab in Group 1 and 11 doses of durvalumab in Group 2 will be administered. Intermediate dose levels may 
be evaluated. 
Safety Assessments: Adverse events, serious adverse events, and laboratory abnormalities (type, frequency, and 
severity) will be collected. Adverse events of special interest will include CRS, neurological toxicity, macrophage 
activation syndrome (MAS), tumor lysis syndrome (TLS), hepatic function abnormalities, pneumonitis, infusion 
reactions, hypersensitivity reactions, colitis and other gastrointestinal disorders (diarrhea, enterocolitis), and other 
immune-related adverse events (irAEs), defined as adverse events of an immune nature (i.e., inflammatory) in the 
absence of a clear alternative etiology. DLTs will be assessed in Group 1 for 28 days after the first durvalumab 
administration and in Group 2 for 28 days after JCAR014 administration. 
DLT Definition: 
The following treatment-related (JCAR014 or durvalumab) events will be considered DLTs: 
1. 
Death within 4 weeks of the study treatment 
2. 
Grade ≥ 3 neurotoxicity of greater than 7 days duration 
3. 
Grade ≥ 3 neurotoxicity that does not revert to Grade 1 or baseline within 28 days 
4. 
Grade ≥ 3 seizures that do not resolve to grade ≤ 2 within 3 days 
5. 
Grade ≥ 4 cytokine release syndrome 
6. 
Grade 3 cytokine release syndrome that does not resolve to grade ≤ 2 within 7 days 
7. 
Grade ≥ 3 non-infectious colitis or non-infectious pneumonitis 
8. 
Grade ≥ 3 irAE or other grade ≥ 3 autoimmune toxicity (excluding B-cell aplasia) 
9. 
Any increase in aspartate transaminase (AST) or ALT > 3 x ULN and concurrent increase in total bilirubin > 2 
x ULN that is unrelated to CRS and has no other probable reason to explain the combination of increases 
10. Grade ≥ 3 allergic reaction to the JCAR014 infusion 
11. Any Grade 3 or 4 event deemed unexpected by the Investigator and considered a DLT upon evaluation by the 
SC 
Efficacy Assessments: PET/CT assessment of response will be performed at approximately 1, 2, 4, 6, 9, and 12 
months following the JCAR014 infusion. The Investigator’s assessment using Lugano criteria will be used to 
evaluate the protocol-specified response endpoints. 


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Pharmacokinetics and Biomarker Assessments: 
1. 
PK assessment of JCAR014 cells by flow cytometry and JCAR014 transgene DNA by PCR in blood and bone 
marrow 
2. 
PK assessment of durvalumab 
3. 
Quantification of anti-drug antibodies (ADAs) directed against durvalumab 
4. 
Quantification of ADAs directed against JCAR014 
5. 
Assessment of cellular immune responses against JCAR014 
6. 
Characterization of JCAR014 cells and other immune cells in the blood by flow cytometry 
7. 
Quantification of PD-L1 on JCAR014 cells by immunohistochemistry and flow cytometry 
8. 
Quantification of soluble PD-L1 in serum 
9. 
Assessment of soluble proteins (e.g., cytokines and chemokines) in the blood 
10. Evaluation of tumor biopsies for CD19 and PD-L1 expression, presence of JCAR014, and attributes of tumor 
and tumor microenvironment (e.g., presence of regulatory T cells, expression of tumor immune checkpoint 
markers) 
11. Assessment of replication-competent lentivirus (RCL) 
Statistical Methods: 
The target toxicity rate for the MTD is 30%. An mTPI method will be used to guide dose escalation, and the MTD 
for each group will be estimated using isotonic regression based on the DLT evaluable analysis set. The DLT 
evaluable analysis set includes all patients who have received JCAR014 cell product that conforms to dose or 
composition standards and full infusion of the first dose of durvalumab, and who have either experienced a DLT or 
were followed for the full DLT evaluation period. 
Analysis of other primary, secondary, and exploratory endpoints will be descriptive based on the appropriate 
analysis set and may include summary statistics such as means, standard deviations, and 95% confidence intervals, 
if applicable. Kaplan-Meier curves and median time-to-event data will be presented for time-to-event variables 
(e.g., DOR, PFS, and OS), if appropriate. 
Adverse events and laboratory abnormalities will be described and summarized. 
Analyses will be performed for each group separately. 
Sample size: A maximum sample size of 42 is planned for Group 1 and Group 2 combined. The SC may decide to 
further increase the sample size beyond 21 per group by adding additional patients. If a third group is enrolled, a 
maximum sample size of 63 is allowed for the trial. 
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ..............................................................................................................2 
TABLE OF CONTENTS ............................................................................................................10 
LIST OF FIGURES .....................................................................................................................15 
LIST OF TABLES .......................................................................................................................15 
LIST OF APPENDICES .............................................................................................................15 
LIST OF ABBREVIATIONS .....................................................................................................16 
1. 
BACKGROUND ..............................................................................................................20 
1.1 
B-Cell Non-Hodgkin Lymphoma ..........................................................................20 
1.2 
CD19 as a Drug Target in B-Cell Non-Hodgkin Lymphoma ................................20 
1.3 
PD-L1 as a Drug Target in B-Cell Non-Hodgkin Lymphoma ..............................21 
1.4 
Adoptive CAR T-Cell Therapy for B-Cell Non-Hodgkin Lymphoma ..................22 
1.5 
Investigational Drug Products................................................................................23 
1.5.1 
JCAR014 ...............................................................................................23 
1.5.1.1 
Description of JCAR014 Drug Product .........................................23 
1.5.1.2 
Clinical Experience with JCAR014 ...............................................24 
1.5.2 
Durvalumab (MEDI4736) .....................................................................25 
1.5.2.1 
Description of Durvalumab Investigational Product .....................25 
1.5.2.2 
Nonclinical Experience with Durvalumab .....................................25 
1.5.2.3 
Clinical Experience with Durvalumab ...........................................26 
2. 
STUDY PURPOSE AND RATIONALE .......................................................................28 
2.1 
Rationale for Combination of JCAR014 with Durvalumab ..................................28 
2.2 
JCAR014 Dose Rationale ......................................................................................29 
2.3 
Rationale for Lymphodepleting Chemotherapy.....................................................30 
2.4 
Durvalumab Dose Rationale ..................................................................................31 
2.5 
Rationale for Dosing Schedules with JCAR014 and Durvalumab ........................31 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................32 
4. 
STUDY DESIGN AND INVESTIGATIONAL PLAN .................................................33 
4.1 
Overall Study Design .............................................................................................33 
4.2 
Dose Escalation Scheme ........................................................................................38 
4.3 
Dose-Limiting Toxicity Criteria ............................................................................38 
4.4 
Protocol Enrollment ...............................................................................................38 
4.5 
Removal of Patients from Study ............................................................................38 
4.5.1 
Patient Withdrawal from Further Study Treatment ..............................38 
4.5.2 
Patient Withdrawal from Study .............................................................39 
4.5.3 
Termination of the Study ......................................................................39 


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4.5.4 
Replacement of Study Patients .............................................................39 
5. 
STUDY POPULATION ..................................................................................................40 
5.1 
Criteria for Screening .............................................................................................40 
5.1.1 
Inclusion Criteria ...................................................................................40 
5.1.2 
Exclusion Criteria..................................................................................40 
5.2 
Criteria for Leukapheresis and Pre-therapy Evaluation .........................................40 
5.2.1 
Inclusion Criteria ...................................................................................40 
5.2.2 
Exclusion Criteria..................................................................................41 
5.3 
Criteria for JCAR014 and Durvalumab Therapy ...................................................42 
5.3.1 
Inclusion Criteria ...................................................................................42 
5.3.2 
Exclusion Criteria..................................................................................42 
5.4 
Reproductive Potential and Contraception Requirements .....................................43 
6. 
STUDY TREATMENTS .................................................................................................43 
6.1 
Leukapheresis ........................................................................................................43 
6.2 
Lymphodepleting Chemotherapy...........................................................................44 
6.3 
JCAR014 Treatment ..............................................................................................44 
6.3.1 
Criteria for Withholding JCAR014 or Durvalumab Treatment ............44 
6.3.2 
JCAR014 Administration ......................................................................44 
6.3.3 
Acute Infusion Reactions ......................................................................44 
6.4 
Durvalumab Treatment ..........................................................................................44 
6.4.1 
Durvalumab Drug Product ....................................................................45 
6.4.2 
Durvalumab Preparation and Administration .......................................45 
6.5 
Recommended Supportive Care, Additional Treatment, and Monitoring .............46 
6.6 
Concomitant Medications ......................................................................................46 
7. 
POTENTIAL RISKS AND MANAGEMENT OF TREATMENT TOXICITIES ....47 
7.1 
Cytokine Release Syndrome ..................................................................................47 
7.2 
Neurologic Toxicities.............................................................................................50 
7.3 
Macrophage Activation Syndrome ........................................................................50 
7.4 
Infusion Reactions .................................................................................................50 
7.5 
Tumor Lysis Syndrome..........................................................................................51 
7.6 
B-Cell Aplasia ........................................................................................................52 
7.7 
Persistent Uncontrolled T-cell Proliferation ..........................................................52 
7.8 
Replication-Competent Lentivirus .........................................................................53 
7.9 
Immune-Related Adverse Events ..........................................................................53 
7.9.1 
Hepatic Function Abnormalities ...........................................................54 
7.9.2 
Pneumonitis ...........................................................................................54 


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7.9.3 
Infusion Reactions .................................................................................54 
7.9.4 
Hypersensitivity Reactions ...................................................................54 
7.9.5 
Gastrointestinal Disorders .....................................................................55 
7.9.6 
Nephritis ................................................................................................55 
7.10 
Management of Other Toxicities ...........................................................................55 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..........................................................56 
8.1 
Schedule of Events .................................................................................................56 
8.1.1 
Patient Enrollment .................................................................................56 
8.1.2 
Screening ...............................................................................................56 
8.1.3 
Pre-Treatment Evaluation for Study Therapy .......................................57 
8.1.4 
Administration of Lymphodepleting Chemotherapy ............................58 
8.1.5 
Evaluations on the Day of Durvalumab Administration Prior to 
JCAR014 Administration (Day -1; Group 2 Only) ...............................58 
8.1.6 
Evaluations on the Day of JCAR014 Infusion (Day 0; Groups 1 and 
2) ...........................................................................................................59 
8.1.7 
Evaluations after the JCAR014 Infusion and prior to the First Post-
JCAR014 Durvalumab Infusion (Groups 1 and 2) ...............................60 
8.1.8 
Evaluation on the Day of each Post-JCAR014 Durvalumab 
Administration (Groups 1 and 2) ..........................................................61 
8.1.9 
Post-Infusion Evaluations during Cycles of Durvalumab 
Administration ......................................................................................62 
8.1.9.1 
First Post-JCAR014 Durvalumab Cycle (Groups 1 and 2) ............62 
8.1.9.2 
Subsequent Durvalumab Cycles (Groups 1 and 2) ........................63 
8.1.10 
Restaging Studies and Response Assessment .......................................64 
8.1.11 
Follow-Up Evaluations .........................................................................65 
8.1.12 
Retreatment ...........................................................................................65 
8.1.13 
Long-Term Follow-Up ..........................................................................66 
8.1.14 
Death .....................................................................................................66 
8.2 
Efficacy Assessments.............................................................................................66 
8.3 
Safety Assessments ................................................................................................66 
8.3.1 
Physical Examination ............................................................................66 
8.3.2 
Clinical Laboratory Evaluation .............................................................67 
8.3.3 
Routine Neurological Examination .......................................................67 
8.3.4 
Formal Neuropsychological Tests ........................................................67 
8.3.5 
Vital Signs .............................................................................................68 
8.3.6 
CSF Examination and CNS Symptom Assessment ..............................68 
8.3.7 
Karnofsky Performance Status ..............................................................68 


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8.3.8 
MUGA/Echocardiogram .......................................................................69 
8.3.9 
Electrocardiogram .................................................................................69 
8.4 
Research Assessments ...........................................................................................69 
8.4.1 
Pharmacokinetic Assessments ..............................................................69 
8.4.2 
RCL Testing  .........................................................................................70 
8.4.3 
Immunogenicity Assessments ...............................................................70 
8.4.4 
Biomarker Assessments ........................................................................70 
9. 
ADVERSE EVENT REPORTING ................................................................................71 
9.1 
Definitions..............................................................................................................71 
9.1.1 
Adverse Event .......................................................................................71 
9.1.2 
Serious Adverse Event ..........................................................................71 
9.1.3 
Adverse Events of Special Interest .......................................................72 
9.2 
Clinical Laboratory Abnormalities and Other Abnormal Assessments .................73 
9.3 
Assessment of Adverse Events and Serious Adverse Events ................................74 
9.3.1 
Grading and Intensity of Adverse Events .............................................74 
9.3.2 
Relationship to Study Drug ...................................................................74 
9.3.3 
Adverse Event Collection and Reporting ..............................................74 
9.3.3.1 
Non-Serious Adverse Event Reporting ..........................................75 
9.3.3.2 
Serious Adverse Event Reporting ..................................................75 
9.3.4 
Death .....................................................................................................75 
9.3.5 
Pregnancy ..............................................................................................76 
9.4 
IRB Reporting Requirements .................................................................................76 
9.5 
FDA Reporting Requirements ...............................................................................76 
9.6 
Steering Committee ...............................................................................................77 
9.7 
Data Safety Monitoring Plan .................................................................................77 
9.7.1 
Definition of Risk Level........................................................................77 
9.7.2 
Monitoring and Personnel Responsible for Monitoring .......................78 
9.7.3 
Data Safety Monitoring Board ..............................................................78 
10. 
STATISTICAL PLAN .....................................................................................................79 
10.1 
General Considerations ..........................................................................................79 
10.2 
Analysis Sets ..........................................................................................................79 
10.2.1 
Screened Analysis Set ...........................................................................79 
10.2.2 
Enrolled Analysis Set ............................................................................79 
10.2.3 
All Treated Analysis Set .......................................................................79 
10.2.4 
DLT Evaluable Analysis Set .................................................................79 
10.2.5 
Efficacy Evaluable Analysis Set ...........................................................79 


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10.2.6 
Pharmacokinetic Evaluable Set .............................................................79 
10.3 
Planned Analyses ...................................................................................................80 
10.3.1 
Patient Disposition and Baseline Characteristics ..................................80 
10.3.2 
Primary Endpoints .................................................................................80 
10.3.3 
Secondary Endpoints .............................................................................81 
10.3.4 
Exploratory Endpoints ..........................................................................81 
10.3.5 
Safety Analysis .....................................................................................81 
10.3.5.1 
Adverse Events ..............................................................................81 
10.3.5.2 
Laboratory Data .............................................................................82 
10.4 
Sample Size Considerations ...................................................................................82 
10.5 
Timing of Analyses ................................................................................................82 
11. 
DATA MANAGEMENT .................................................................................................83 
11.1 
Data Collection System..........................................................................................83 
11.2 
Data Quality ...........................................................................................................83 
12. 
STUDY ADMINISTRATION ........................................................................................83 
12.1 
Regulatory and Ethical Considerations ..................................................................83 
12.1.1 
Trial Conduct ........................................................................................83 
12.1.2 
Institutional Review Board Approval ...................................................83 
12.1.3 
Institutional Biosafety Committee Approvals .......................................84 
12.1.4 
Patient Informed Consent ......................................................................84 
12.2 
Investigator Obligations .........................................................................................85 
12.2.1 
Investigator Responsibilities .................................................................85 
12.3 
Site Audits and Regulatory Inspections .................................................................85 
12.4 
Public Notification of Study Conduct ....................................................................85 
12.5 
Study Termination .................................................................................................85 
12.6 
Records ..................................................................................................................86 
12.7 
Confidentiality of Information ...............................................................................86 
13. 
REFERENCES .................................................................................................................87 
 


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LIST OF FIGURES 
Figure 1: Study Schema for Patients in Group 1 (Post-JCAR014 Treatment with 
Durvalumab) ..............................................................................................34 
Figure 2: Study Schema for Patients in Group 2 (Pre-JCAR014 Treatment with 
Durvalumab) ..............................................................................................34 
Figure 3: Recommended Management of CRS ..........................................................................49 
 
LIST OF TABLES 
Table 1: Summary of Durvalumab Data and Guidance for Investigator ....................................25 
Table 2: Study Objectives and Endpoints ...................................................................................32 
Table 3: Planned Dose Levels for Durvalumab and JCAR014 ..................................................36 
Table 4: IV Bag Specifications for each Durvalumab Dose Level .............................................45 
Table 5: Grading Criteria for CRS ..............................................................................................48 
Table 6: Analytes for Clinical Laboratory Evaluation ................................................................67 
Table 7: Karnofsky Performance Status Scale Definitions Rating (%) Criteria .........................68 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Evaluations .............................................................................92 
Appendix B 
Blood Volume Collection for Research Laboratory Evaluations ..............98 
Appendix C 
Response Criteria for Non-Hodgkin Lymphoma .....................................100 
Appendix D 
Mini Mental State Examination ...............................................................101 
Appendix E 
Long-Term Follow-Up.............................................................................105 
Appendix F 
Modified Toxicity Probability Interval Decision Table...........................106 
Appendix G 
Durvalumab Dosing Modification for Toxicity Management .................107 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation or Term 
Definition/Explanation 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
ALL 
acute lymphoblastic leukemia 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
CAR 
chimeric antigen receptor 
CBC 
complete blood count 
CCO 
Clinical Coordinators Office 
CFR 
Code of Federal Regulations 
CL 
clearance 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum concentration 
CMC 
Chemistry, Manufacturing, and Controls 
CNS 
central nervous system 
CPF 
Cell Processing Facility 
CR 
complete response or complete remission 
CRA 
Clinical Research Associate 
CRF 
case report form 
CRM 
continuous reassessment method 
CRP 
C-reactive protein 
CRS 
cytokine release syndrome 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
Cell Therapy Laboratory 
CTLA-4 
cytotoxic T lymphocyte-associated protein 4 
Cy/Flu 
cyclophosphamide + fludarabine 
DCR-24w 
disease control rate at 24 weeks 
DLBCL 
diffuse large B-cell lymphoma 
DLCO 
diffusing capacity of the lung for carbon monoxide 


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Abbreviation or Term 
Definition/Explanation 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
EDC 
electronic data capture 
EEG 
electroencephalogram 
EGFR 
epidermal growth factor receptor 
EGFRt 
truncated epidermal growth factor receptor 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
FHCRC 
Fred Hutchinson Cancer Research Center 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
HCC 
hepatocellular carcinoma 
HCT 
hematopoietic stem cell transplant 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
IBC 
Institutional Biosafety Committee 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICU 
intensive care unit 
IFNγ 
interferon gamma 
IHC 
immunohistochemistry 
IL-6 
interleukin 6 
IND 
Investigational New Drug 
IP 
investigational product 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
IRO 
Institutional Review Office 


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Abbreviation or Term 
Definition/Explanation 
IV 
intravenous(ly) 
LDH 
lactate dehydrogenase 
LTFU 
long-term follow-up 
LVEF 
left ventricular ejection fraction 
mAb 
monoclonal antibody 
MAS 
macrophage activation syndrome 
MHC 
major histocompatibility complex 
MMSE 
Mini Mental State Examination 
MTD 
maximum tolerated dose 
mTPI 
modified toxicity probability interval 
MUGA 
multiple uptake gated acquisition 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin lymphoma 
NIH 
National Institutes of Health 
NOAEL 
no-observed-adverse-effect level 
NOS 
not otherwise specified 
NSCLC 
non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PCP 
pneumocystis pneumonia 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed cell death ligand 1 
PD-L2 
programmed cell death ligand 2 
P[DLT] 
probability of dose-limiting toxicity 
PET 
positron emission tomography 
PFS 
progression-free survival 
PI 
Principal Investigator 
PK 
pharmacokinetic(s) 


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Abbreviation or Term 
Definition/Explanation 
PMBCL 
primary mediastinal B-cell lymphoma 
PO 
per os 
PR 
partial response 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
Q28D 
every 28 days 
qPCR 
quantitative polymerase chain reaction 
R/R 
relapsed/refractory 
RCL 
replication-competent lentivirus 
SAE 
serious adverse event 
SCCA 
Seattle Cancer Care Alliance 
SCCHN 
squamous cell carcinoma of the head and neck 
scFv 
single-chain variable fragment 
sCRS 
severe cytokine release syndrome 
SEM 
standard error of the mean 
SC 
Steering Committee 
SNP 
single nucleotide polymorphism 
SOP 
standard operating procedure 
TCR 
T-cell receptor 
TIL 
tumor-infiltrating lymphocyte 
TLS 
tumor lysis syndrome 
Tmax 
time to peak concentration 
TNBC 
triple-negative breast cancer 
TNFα 
tumor necrosis factor alpha 
ULN 
upper limit of normal 
UPN 
Unique Patient Number 
 


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1. 
BACKGROUND 
1.1 
B-Cell Non-Hodgkin Lymphoma 
It is estimated that approximately 72,000 new cases of non-Hodgkin lymphoma (NHL) will be 
diagnosed and approximately 20,000 patients will die of their disease in 2015 (Siegel 2015).  In 
the United States, approximately 85% of NHL cases are categorized as B-cell lymphomas and 
15% are categorized as T/NK-cell lymphomas (NCCN 2014).  The most common histologic type 
of lymphoma is diffuse large B-cell lymphoma (DLBCL), representing approximately 30% of 
the annual incidence of NHL.  The addition of anti-CD20 antibody therapy with rituximab to 
standard CHOP chemotherapy has improved the outcome for patients with DLBCL (Coiffier 
2002).  The goal of treatment is to obtain a complete remission (CR) as demonstrated by a 
negative positron emission tomography (PET) scan.  Patients with advanced stage disease 
usually receive six to eight cycles of R-CHOP or six cycles of dose-adjusted EPOCH-R.  Patients 
who fail to achieve a PET-negative CR or those who relapse following CR are treated with 
salvage therapy with plans for high-dose chemotherapy and autologous hematopoietic cell 
transplantation (HCT) for those who respond to the salvage regimen.  High-dose therapy with 
HCT can cure 20% to 50% of chemotherapy-responsive patients and is considered the standard 
of care for patients responding to salvage chemotherapy who are medically fit for transplant.  
Unfortunately, patients who relapse early after primary therapy with a regimen containing 
rituximab have a worse prognosis even with salvage high-dose therapy and autologous HCT 
(Gisselbrecht 2010). 
Patients who are unable to undergo autologous HCT or those who relapse following autologous 
HCT have a poor prognosis with a median survival of 6 to 12 months.  Allogeneic HCT may be 
considered in patients who have appropriate donors and chemotherapy-sensitive disease that can 
be rendered into CR or near CR prior to the transplant (Rezvani 2008).  Evidence for a graft-
versus-lymphoma effect for DLBCL is more limited, perhaps because Class I major 
histocompatibility complex (MHC) is absent on a high proportion of DLBCL (Challa-Malladi 
2011), and long-term survival is achieved in only 30% to 40% of patients who have minimal 
disease at the time of allogeneic HCT.  Thus, patients with relapsed aggressive lymphoma who 
have previously had an autologous HCT or those medically unable to receive autologous HCT 
have a poor prognosis and are in need of novel treatments. 
1.2 
CD19 as a Drug Target in B-Cell Non-Hodgkin Lymphoma 
CD19 is a 95-kDa glycoprotein present on B cells from early development until differentiation 
into plasma cells (Stamenkovic 1988).  It is a member of the immunoglobulin superfamily and a 
component of a B-cell surface signal transduction complex that positively regulates signal 
transduction through the B-cell receptor (Stamenkovic 1988, Brentjens 2011).  CD19 is an 
attractive therapeutic target because it is expressed homogeneously by most B-cell malignancies, 
including B-cell NHL (Li 1993, Li 1996, Davila 2012).  Importantly, the CD19 antigen is not 
expressed on hematopoietic stem cells or on any normal tissue apart from those of the B-cell 
lineage. 


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1.3 
PD-L1 as a Drug Target in B-Cell Non-Hodgkin Lymphoma 
Programmed cell death protein 1 (PD-1, or CD279) is a member of the immunoglobulin 
superfamily of molecules involved in regulation of T-cell activation.  It is found mainly on 
activated T cells where its engagement inhibits activation, resulting in downstream effects on 
cytokine production, proliferation, cell survival, and transcription factors associated with effector 
T-cell function (Freeman 2000, Carter 2002, Bennett 2003, Saunders 2005, Nurieva 2006, Fife 
2008). 
PD-1 has two ligands.  The first, programmed cell death ligand 1 (PD-L1), is constitutively 
expressed on many hematopoietic cells, but may be up-regulated in hematopoietic and non-
hematopoietic cells.  Regulation of PD-L1 is mediated, in part, by type I and type II interferons. 
The second, programmed cell death ligand 2 (PD-L2), was identified in 2001 (Latchman 2001, 
Tseng 2001).  Its expression is far more restricted and is confined to hematopoietic cells. 
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling T-
cell activation.  PD-L1 acts at multiple sites in the body to help regulate normal immune 
responses and is utilized by tumors to help evade detection and elimination by the host immune 
system tumor response.  In the lymph nodes, PD-L1 on antigen-presenting cells binds to PD-1 or 
CD80 on activated T cells and delivers an inhibitory signal to the T cell (Keir 2008, Park 2010).  
This results in reduced T-cell activation and fewer activated T cells in circulation.  In the tumor 
microenvironment, PD-L1 expressed on tumor cells and infiltrating immune cells binds to PD-1 
and CD80 on activated T cells reaching the tumor.  Binding of PD-L1 to PD-1 delivers an 
inhibitory signal to those T cells, preventing them from killing target cancer cells and protecting 
the tumor from immune elimination (Zou 2008). 
Approximately 30% of B-cell lymphomas have been shown to express PD-L1 (Andorsky 2011).  
Additionally, B-cell lymphomas have a varying degree of infiltrating immune cells that also 
express PD-L1 and contribute to the immunosuppressive microenvironment of the tumor 
(Myklebust 2013).  A significant frequency of primary mediastinal B-cell lymphomas have 
genomic rearrangements associated with overexpression of PD-L1 transcripts (Twa 2014).  High 
levels of soluble PD-L1 have also been associated with poor overall survival in DLBCL 
suggesting that targeting this axis may have therapeutic utility (Rossille 2014). 
One published report (Andorsky 2011), as well as immunohistochemistry (IHC) studies 
conducted by Ventana/MedImmune, demonstrate expression of PD-L1 in a subset of NHL 
patient tumor biopsies.  Andorsky et al. reported that PD-L1 is expressed by tumor cells in 
approximately 30% of the NHL biopsies analyzed.  A more complete analysis was performed by 
MedImmune/Ventana.  In this study, a series of 84 formalin-fixed, paraffin-embedded biopsy 
sections from NHL patients were analyzed by IHC for the expression of PD-L1.  The majority of 
samples, 46, were of the DLBCL subtype, 18 were of the follicular lymphoma (FL) subtype, and 
the remaining 20 were of the mantle cell lymphoma (MCL) subtype.  The percentage of tumor 
cells demonstrating PD-L1−specific staining of the cell membrane was estimated by visual 
inspection in DLBCL and MCL samples, but not FL samples, as it was not possible to 


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distinguish FL cells from normal infiltrating lymphocytes.  Where PD-L1 staining on tumor cell 
membranes was identified, staining intensity was scored between 1 (low) and 3 (high).  The 
percentage of infiltrating lymphocytes demonstrating PD-L1−specific staining of the cell 
membrane was estimated by visual inspection in all samples. 
In the 46 DLBCL samples, 32 samples (70%) demonstrated PD-L1 staining on ≥ 5% of tumor 
cells.  The mean percentage of PD-L1−expressing tumor cells within these 32 samples (± 
standard error of the mean [SEM]) was 27% ± 5%, with a range of 5%-100%.  The intensity of 
staining varied across the 32 positive samples, with 38% of samples demonstrating high intensity 
staining.  There was no correlation between the percentage of tumor cells expressing PD-L1 and 
the intensity of staining.  PD-L1 was also detected on ≥ 5% of infiltrating lymphocytes in 40 of 
the 46 samples (87%).  The mean percentage of PD-L1−expressing infiltrating lymphocytes in 
these 40 samples was 57% ± 4%, with a range of 5%-100%.  In general, samples with high 
tumoral expression of PD-L1 also demonstrated high levels of infiltrating lymphocyte PD-L1 
expression; however, there was a subset of samples that demonstrated high expression on 
infiltrating lymphocytes in the absence of notable tumoral expression. 
The percentage of MCL samples demonstrating PD-L1 expression on ≥ 5% tumor cells was only 
10% (2 of 20), notably lower than that in the DLBCL samples.  The mean percentage of PD-
L1−expressing cells in these two positive samples was 5% ± 1%, also lower than that observed 
in the DLBCL samples.  In contrast, 100% of the MCL samples demonstrated PD-L1 expression 
on ≥ 5% infiltrating lymphocytes; however, the mean percentage of PD-L1−positive infiltrating 
lymphocytes across the samples was also lower in the MCL samples (13.3% ± 3%; range, 5%-
60%). 
Seventeen of 18 FL samples (94%) demonstrated PD-L1 expression on ≥ 5% infiltrating 
lymphocytes, and the mean percentage of PD-L1−expressing infiltrating lymphocytes in these 
samples was more comparable to that observed in the DLBCL samples (35% ± 6%; range, 
5%-80%). 
Of the 84 NHL samples examined, 75 (89%) demonstrated PD-L1 expression on greater than 5% 
of tumor cells or infiltrating lymphocytes.  These data suggest that the expression of PD-L1 is a 
common feature of NHL tumors.  
1.4 
Adoptive CAR T-Cell Therapy for B-Cell Non-Hodgkin Lymphoma 
CD19-specific chimeric antigen receptors (CARs) are single chain variable fragments (scFv) 
from CD19-specific monoclonal antibodies (mAbs) fused to a transmembrane domain and 
cytoplasmic signaling domains.  The CAR is expressed on the T-cell surface and redirects the 
transfected T cells to recognize CD19-expressing lymphoma cells, leading to tumor cell lysis, 
cytokine secretion, and T-cell proliferation (Sadelain 2013).  In clinical studies, CD19-targeted 
CARs have demonstrated encouraging activity in adult and pediatric patients with 
relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (ALL), B-cell NHL, and chronic 


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lymphocytic leukemia (CLL) (Kalos 2011, Porter 2011, Davila 2014, Maude 2014, 
Kochenderfer 2015, Lee 2015). 
Recent studies in B-cell NHL demonstrating activity of CD19-targeted CAR T cells have 
employed T-cell products that are unselected for T-cell subsets (Kochenderfer 2014b, Schuster 
2014, Kochenderfer 2015).  JCAR014 differs from these products in that it consists of CD4+ and 
CD8+ CD19-targeted CAR T cells administered in a 1:1 ratio.  It is known that CD4+ T cells 
enhance CD8+ effector T-cell persistence, memory formation, and trafficking to antigen-rich 
tissues.  Activated CD8+ T cells have also shown poor survival in the absence of CD4+ T-cell 
help, and CD4+ T-cell help is required during recall expansion of memory CD8+ T cells (Toes 
1999, Bos 2010).  Likewise, CAR+ CD4+ T cells enhance CAR+ CD8+ cytolytic effector T-cell 
function both in vitro and in vivo (Adusumilli 2014).  Thus, since JCAR014 is enriched with 
CD4+ and CD8+ CD19-targeted CAR T cells, persistence, trafficking to the tumor, and 
antitumor activity may be improved and more reproducible compared to unselected CAR T-cell 
investigational drug products. 
Emerging data indicate that in vivo expansion of CD19-targeted CAR T cells strongly correlates 
with antitumor response (Gardner 2014, Kochenderfer 2014b, Schuster 2014, Turtle 2015).  The 
antitumor activity of CAR T cells in NHL has been lower than that observed in ALL patients.  
The effect of the tumor microenvironment or bone marrow lymphoma involvement (i.e., more 
accessible target antigen) on CAR-T cell expansion and function may be important for antitumor 
activity in NHL. 
1.5 
Investigational Drug Products 
1.5.1 JCAR014 
1.5.1.1 
Description of JCAR014 Drug Product 
JCAR014 consists of autologous T cells that express a CAR composed of a murine-derived, 
CD19-specific scFv genetically fused via a modified IgG4 hinge spacer and a CD28 
transmembrane domain to the 4-1BB and CD3ζ signaling endodomains.  The JCAR014 cell 
product is prepared by modifying T cells ex vivo using a replication-incompetent, self-
inactivating lentiviral vector that encodes the CD19 CAR and a truncated human epidermal 
growth factor receptor (EGFRt) downstream of a T2A ribosomal skip element.  Expression of 
EGFRt allows accurate measurement of transduction efficiency, selection, and in vivo tracking 
of transduced cells by flow cytometry.  JCAR014 is administered intravenously (IV) in a 1:1 
ratio of CD4+ and CD8+ CAR-expressing (EGFRt+) T cells. 
The methods employed to derive CD19 CAR T cells from the patient’s CD8+ and CD4+ T cells 
enriched from peripheral blood mononuclear cells (PBMCs), and release tests of the cell 
products prior to infusion are outlined in the Chemistry, Manufacturing and Controls (CMC) 
section of the Investigational New Drug (IND) application to the Food and Drug Administration 
(FDA).  Modifications to the CMC section during the course of the study will be submitted for 
FDA review. 


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1.5.1.2 
Clinical Experience with JCAR014 
JCAR014 is currently being evaluated in a first-in-human Phase 1/2 trial in adult patients with 
relapsed or refractory CD19+ ALL, CLL, and NHL (2639 study; ClinicalTrials.gov 
#NCT01865617).  This trial is the first clinical trial in which patients with CD19+ B-cell 
malignancies receive T cells composed of a defined composition of CD8+ and CD4+ T cells 
engineered to express a CD19-specific CAR.  The cell product for infusion is formulated in a 1:1 
ratio of CD8+:CD4+ CAR+ T cells and infused at one of three dose levels (2 x 105, 2 x 106, or 2 
x 107 CAR T cells/kg) after lymphodepleting chemotherapy.  Different lymphodepleting 
chemotherapy regimens have been sequentially evaluated; cyclophosphamide (2 to 4 g/m2) plus 
etoposide (100 to 200 mg/m2/d for 3 days), cyclophosphamide alone (2 to 4 g/m2), 
cyclophosphamide (30 to 60 mg/kg) plus fludarabine (25 mg/m2/d for 3 to 5 days), and 
concurrent cyclophosphamide (300 mg/m2/day) and fludarabine (30 mg/m2/day) on each of 3 
days. 
We reported data from patients treated with JCAR014, which demonstrated elimination of 
marrow disease by flow cytometry in 93% of patients with B-ALL, and a complete response rate 
in NHL of 64% after treatment with lymphodepletion containing cyclophosphamide and 
fludarabine and JCAR014 at 2 x 106 CAR-T cells/kg (Turtle et al, J Clin Invest, 2016; Turtle et 
al, Sci Trans Med, 2016).  At ASH 2016, we presented response data in high-risk CLL patients, 
showing 25% CR in patients who received cyclophosphamide and fludarabine and JCAR014 at ≤ 
2 x 106 CAR-T cells/kg (Turtle et al, ASH abstract #56, 2016). 
At ASH 2016, we also reported toxicity data from 133 patients with B-ALL, NHL or CLL who 
received lymphodepletion chemotherapy followed by JCAR014 (Turtle et al, ASH abstract 
#1852, 2016).  Ninety-five of 133 patients (71%) developed CRS, which was grade ≥ 4 in 8%. 
Neurologic toxicity occurred in 40% of patients and was grade ≥ 3 in 21%. Six patients (4.5%) 
died of complications related to severe CRS and/or neurologic toxicity.  Only 1 of these patients 
died after receiving a regimen of cyclophosphamide and fludarabine lymphodepletion and CAR-
T cells at a dose level that is now recommended for their disease status. 
Among NHL patients in the cohort reported at ASH 2016 (Turtle et al, ASH abstract #1852, 
2016), 58% developed grade 1-3 CRS and 6% developed grade 4 CRS.  Two NHL patients died 
of complications related to CRS and/or neurotoxicity.  Both patients received JCAR014 at 2 x 
107 CAR-T cells/kg. One patient died from gastrointestinal bleeding and complications of CRS 
23 days after receiving JCAR014, and a second developed neurotoxicity and an intracranial 
hemorrhage and died 13 days after the JCAR014 infusion.  A JCAR014 dose of 2x107 CAR-T 
cells/kg was deemed excessively toxic for a first JCAR014 infusion. 
In NHL patients treated with cyclophosphamide and fludarabine followed by JCAR014 at 2 x 
106 CAR-T cells/kg (n = 42), grade 1-2 CRS occurred in 26 patients (62%), no patients 
developed grade 3 CRS, and only one developed grade 4 CRS. Ten patients (23%) had grade 1-2 
neurotoxicity, 3 (7%) had grade 3 neurotoxicity, and none had grade 4 neurotoxicity. 
Neurotoxicity was reversible and no NHL patients died after receiving this regimen. Therefore, 


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cyclophosphamide and fludarabine lymphodepletion followed by JCAR014 at 2 x 106 CAR-T 
cells/kg is a regimen with acceptable toxicity in NHL patients. 
1.5.2 Durvalumab (MEDI4736) 
1.5.2.1 
Description of Durvalumab Investigational Product 
Durvalumab is a human IgG1κ mAb that binds to PD-L1 and inhibits the binding of PD-L1 to 
PD-1 and CD80.  Durvalumab contains a triple mutation in the constant domain of the IgG1 
heavy chain that inhibits binding of complement protein C1q and the Fcγ receptors involved in 
triggering effector function such as antibody-dependent cell-mediated cytotoxicity or 
phagocytosis.  Durvalumab is administered by IV infusion. 
A summary of durvalumab product information is provided in Table 1. 
Table 1: 
Summary of Durvalumab Data and Guidance for Investigator 
Category 
Description 
Investigational product: 
Durvalumab, a human IgG1κ mAb directed against PD-L1, and with reduced 
binding to C1q and the Fcγ receptors 
Therapeutic indication: 
Durvalumab is being developed for the treatment of patients with advanced solid 
tumors and hematologic malignancies 
Dosage forms and strengths: 
Durvalumab is formulated at 50 mg/mL. The investigational product is supplied 
as a vialed liquid solution in clear 10R glass vials closed with an elastomeric 
stopper and a flip-off cap overseal. Each vial contains 500 mg (nominal) of active 
investigational product at a concentration of 50 mg/mL 
Method of administration: 
The product is to be diluted with 0.9% (w/v) saline for IV infusion. 
1.5.2.2 
Nonclinical Experience with Durvalumab 
Durvalumab has shown the following activity as an anti−PD-L1 molecule: 
• Durvalumab binds to PD-L1 and blocks its interaction with PD-1 and CD80. 
• Durvalumab can relieve PD-L1−mediated suppression of human T-cell activation in vitro. 
• Durvalumab inhibits tumor growth in a xenograft model via a T-cell−dependent mechanism. 
• A surrogate anti-mouse PD-L1 antibody resulted in improved survival in a syngeneic tumor 
model as monotherapy and resulted in complete tumor regression in > 50% of treated mice 
when given in combination with chemotherapy. 
• In the same study, anti-mouse PD-L1 antibody-treated mice were completely tumor-free 3 
months after tumor implantation and demonstrated long-term immunity during re-challenge. 
• In a subsequent study in the same syngeneic model, the combination of an anti-mouse PD-L1 
antibody and anti−CTLA-4 antibody resulted in complete tumor regression in all treated 
mice. 


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• Prevalence of PD-L1 expression on the surface of human tumors, ranging from 
approximately 0% to 35%, was demonstrated in a broad survey of samples derived from 
solid tumor types of interest. 
The cynomolgus monkey is considered to be the only relevant nonclinical species for evaluation 
of local and systemic toxicities of durvalumab.  This is based on similar binding and potency of 
durvalumab against human and cynomolgus monkey PD-L1 and lack of binding to rodent PD-
L1.  To underscore the pharmacological relevance of the cynomolgus monkey, durvalumab was 
found to suppress soluble PD-L1 in serum and fully occupy membrane PD-L1 on various 
leukocyte subsets at doses ≥ 0.1 mg/kg (lowest dose tested), with a dose-related duration of 
suppression and occupancy. 
In general, IV administration of durvalumab to cynomolgus monkeys in nonclinical safety 
studies was not associated with adverse effects that were considered of relevance to humans.  
Adverse findings in the non-Good Laboratory Practice (GLP) pharmacokinetic 
(PK)/pharmacodynamic and dose range-finding study (four doses over 5 weeks) and a GLP 4-
week repeat-dose toxicity study were consistent with anti-drug antibody (ADA)-associated 
morbidity and mortality in individual animals.  Similar observations have been reported by 
MedImmune in cynomolgus monkeys administered human mAbs unrelated to durvalumab.  
Given that immunogenicity of human mAbs and consequent ADA-mediated adverse effects in 
nonclinical species are generally not predictive of responses in humans, the observed ADA-
associated morbidity and mortality in these studies were not taken into consideration for the 
determination of the no-observed-adverse-effect level (NOAEL) of durvalumab.  Based on the 
lack of any other treatment-related adverse effects, the NOAELs for durvalumab in these studies 
were considered to be the 100 mg/kg dose for the non-GLP dose range-finding study, and the 
200/100 mg/kg dose (200 mg/kg loading dose followed by four weekly doses of 100 mg/kg) in 
the GLP 4-week repeat-dose toxicity study.  Finally, in the pivotal 3-month GLP toxicity study, 
IV administration of durvalumab to cynomolgus monkeys was not associated with any treatment-
related adverse effects.  Therefore, the NOAEL for durvalumab in this study was considered to 
be the 200/100 mg/kg dose (200 mg/kg loading dose followed by 13 weekly doses of 100 
mg/kg), the highest dose tested.  In addition to the in vivo toxicology data, no unexpected 
membrane binding of durvalumab was observed in GLP tissue cross-reactivity studies using 
normal human and cynomolgus monkey tissues. 
1.5.2.3 
Clinical Experience with Durvalumab 
A total of 1,883 subjects have been enrolled and treated in 30 ongoing durvalumab clinical 
studies, including 20 sponsored and 10 collaborative studies.  Of the 1,883 subjects, 1,279 
received durvalumab monotherapy and 440 received durvalumab in combination with other 
agents.  No studies have been completed and none were terminated prematurely due to toxicity. 
Data from the largest clinical study to date, Study CD-ON-MEDI4736-1108, examining 
durvalumab monotherapy across numerous types of advanced solid tumors, are presented below.  
Data from other ongoing studies are presented in the durvalumab Investigator’s Brochure. 


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Study CD-ON-MEDI4736-1108 
Study CD-ON-MEDI4736-1108 is a Phase 1/2, first-in-human, multicenter, open label, dose-
escalation, and dose-expansion study to determine the MTD or optimal biologic dose, safety, PK, 
immunogenicity, and antitumor activity of durvalumab in adult patients with advanced solid 
tumors refractory to standard therapy or for which no standard therapy exists.  A total of 736 
subjects with advanced solid tumors have been treated in Study CD-ON-MEDI4736-1108. Of 
these subjects, 694 have received durvalumab at 10 mg/kg every 2 weeks (Q2W), either in the 
dose-escalation or dose-expansion phase of the study.  The 10 mg/kg Q2W cohort comprises 
subjects with non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and 
neck (SCCHN), gastroesophageal cancer, hepatocellular carcinoma (HCC), pancreatic 
adenocarcinoma, triple-negative breast cancer (TNBC), bladder cancer, uveal melanoma, and 
advanced cutaneous melanoma.  Subjects in the 10 mg/kg Q2W dose cohort were exposed to a 
median of six doses of durvalumab (range, 1–27). 
The safety profile of durvalumab as monotherapy and combined with other anticancer agents 
was consistent with the pharmacology of the target and other agents in the immune checkpoint 
inhibitor class.  The safety profile of durvalumab monotherapy in the 694 subjects with advanced 
solid tumors treated at 10 mg/kg Q2W in Study CD-ON-MEDI4736-1108 has been broadly 
consistent with that of the overall 1,279 subjects who have received durvalumab monotherapy 
(not including subjects treated with blinded investigational product) across the clinical 
development program.  No tumor types appeared to be associated with unique adverse events 
(AEs).  The majority of treatment-related AEs were manageable with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity.  As of 07 May 2015, among the 694 subjects 
treated with durvalumab 10 mg/kg Q2W in Study CD-ON-MEDI4736-1108, a total of 378 
subjects (54.5%) experienced a treatment-related AE, with the most frequent (occurring in ≥ 5% 
of subjects) being fatigue (17.7%), nausea (8.6%), diarrhea (7.3%), decreased appetite (6.8%), 
pruritus (6.3%), rash (6.1%), and vomiting (5.0%).  A majority of the treatment-related AEs were 
Grade 1 or Grade 2 in severity with ≥ Grade 3 events occurring in 65 subjects (9.4%). Six 
subjects had treatment-related Grade 4 AEs (upper gastrointestinal hemorrhage, increased 
aspartate aminotransferase [AST], dyspnea, neutropenia, colitis, diarrhea, and pneumonitis) and 
one subject had a treatment-related Grade 5 event (pneumonia).  Treatment-related serious 
adverse events (SAEs) that occurred in ≥ 2 subjects were colitis and pneumonitis (three subjects 
each).  A majority of the treatment-related SAEs were ≥ Grade 3 in severity and resolved with or 
without sequelae.  Adverse events that resulted in permanent discontinuation of durvalumab 
were considered treatment-related in 18 subjects (2.6%), with colitis being the most frequent 
treatment-related AE resulting in discontinuation (three subjects).  A majority of the treatment-
related AEs resulting in discontinuation of durvalumab were ≥ Grade 3 in severity and resolved 
with or without sequelae. 
Partial efficacy data are available for Study CD-ON-MEDI4736-1108.  Tumor assessments were 
based on RECIST v1.1 (Eisenhauer 2009).  A total of 456 of 694 subjects with advanced solid 


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tumors treated with durvalumab 10 mg/kg Q2W were evaluable for response (defined as having 
≥ 24 weeks of follow-up, measurable disease at baseline, and at least one follow-up scan, or 
discontinued due to disease progression or death without any follow-up scan).  In PD-
L1−unselected patients, the objective response rate (ORR), based on investigator assessment per 
RECIST v1.1, ranged from 0% in uveal melanoma to 20.0% in bladder cancer, and the disease 
control rate at 24 weeks (DCR-24w) ranged from 4.2% in TNBC to 39.1% in advanced 
cutaneous melanoma.  PD-L1 status was known for 383 of the 456 response-evaluable subjects. 
Across the PD-L1−positive tumors, ORR was > 10% for bladder cancer, advanced cutaneous 
melanoma, HCC (33.3% each); NSCLC (26.7%); and SCCHN (18.2%).  Moreover, in the PD-
L1−positive subset, DCR-24w was > 10% in advanced cutaneous melanoma (66.7%), NSCLC 
(36.0%), HCC and bladder cancer (33.3% each), and SCCHN (18.2%). 
As of 09 February 2015, PK data were available for 378 subjects in the dose-escalation and dose-
expansion phases of Study CD-ON-MEDI4736-1108 following treatment with durvalumab 0.1 
to 10 mg/kg Q2W or 15 mg/kg every 3 weeks (Q3W).  The maximum observed concentration 
(Cmax) increased in an approximately dose-proportional manner over the dose range of 0.1 to 15 
mg/kg.  The area under the concentration-time curve from 0 to 14 days (AUC0-14) increased in a 
greater than dose-proportional manner over the dose range of 0.1 to 3 mg/kg and increased dose-
proportionally at ≥ 3 mg/kg.  These results suggest that durvalumab exhibits nonlinear PK, likely 
due to saturable target-mediated clearance (CL), at doses < 3 mg/kg and approaches linearity at 
doses ≥ 3 mg/kg.  Near complete target saturation (soluble programmed cell death ligand 1 [sPD-
L1] and membrane bound) is expected with durvalumab ≥ 3 mg/kg Q2W. Exposures after 
multiple doses showed accumulation consistent with PK parameters estimated from the first 
dose.  Of the 338 subjects for whom ADA were available, 8 were detected ADA-positive, with 
an impact on PK/pharmacodynamics in one subject. 
2. 
STUDY PURPOSE AND RATIONALE 
2.1 
Rationale for Combination of JCAR014 with Durvalumab 
CD19-targeted CAR T cells have been tested in adult patients with CD19+ B-cell NHL with a 
high overall response rate, but a lower than desirable rate of complete remission.  While changes 
to the conditioning regimen or to the CAR T-cell product may improve the expansion and 
persistence of CAR T cells, expression of checkpoint proteins may decrease the function of the 
modified T cells, thereby limiting antitumor activity. 
PD-L1 is expressed in lymphoma, both on the tumor and in the tumor microenvironment, and 
likely plays a role in tumor-associated immunosuppression (Andorsky 2011). 
Immunohistochemical studies conducted by MedImmune suggest that PD-L1 expression is a 
common feature of NHL tumors, with expression being found on greater than 5% of tumor cells 
or infiltrating lymphocytes in 75 of 84 (89%) NHL samples examined.  Evidence also exists that 
PD-L1 is upregulated in response to IFNγ (Chen 2012, Abiko 2015).  As such, PD-L1 expression 
may be induced or further upregulated on tumor cells and other infiltrating cells at the site of 
CAR T-cell action due to secretion of IFNγ by activated CAR-T cells.  Expression of PD-L1 by 


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lymphoma cells may play a role in tumor-associated immunosuppression within the tumor 
microenvironment. 
Blockade of the PD-1/PD-L1 axis has been explored in NHL (Lesokhin 2014).  Preliminary 
results of a Phase 1 study of the PD-1 antagonist mAb nivolumab in NHL showed that PD-1 
inhibition had an acceptable safety profile at similar dose levels (1 and 3 mg/kg) used for the 
treatment of solid tumors.  Among 29 treated patients with B-cell NHL, 72% experienced drug-
related AEs, including two patients (7%) with SAEs of pneumonitis.  The clinical study included 
11 patients with DLBCL, and evidence of clinical activity was observed.  One patient achieved a 
CR and three additional patients achieved a partial response (PR).  Progression-free survival 
(PFS) at 24 weeks was 24% for the cohort of patients with DLBCL. 
It is well established that tumor-infiltrating lymphocytes (TILs) express PD-1, and preliminary 
data collected at Juno also suggest that CAR-T cells, upon stimulation through the CAR, 
upregulate expression of PD-1 and PD-L1, but not PD-L2.  Thus, both TILs and CARs are 
targets of suppression by PD-L1.  With these data in mind, CAR-T cells given in combination 
with agents that block T-cell suppression through the PD-1 pathway may have enhanced 
antitumor activity due to improved expansion of CAR-T cells and prolonged duration of CAR-T 
cell persistence and function. 
Monoclonal blocking antibodies to PD-1 or PD-L1 have been shown to be safe and effective in 
patients with various cancers, and may be useful in reversing the PD-L1−mediated 
immunosuppression in patients treated with CAR-T cells.  Durvalumab is a human IgG1κ mAb 
that binds to PD-L1 and inhibits the binding of PD-L1 to PD-1.  In vitro studies have shown that 
durvalumab antagonizes the inhibitory effects of PD-L1 on primary human T cells, resulting in 
their enhanced proliferation and production of IFNγ in response to T-cell receptor stimulation. 
Thus, blockade of the PD-1/PD-L1 axis with durvalumab may improve the antitumor activity of 
JCAR014 in patients with aggressive NHL lymphoma by both blocking suppression of the CAR-
T cells as well as reinvigorating exhausted CAR-T cells and TILs.  This Phase 1 study is 
intended to evaluate the safety, tolerability, in vivo expansion, and antitumor activity of CAR-T 
cells (JCAR014) in combination with a PD-L1 antagonist (durvalumab) in R/R B-cell NHL. 
2.2 
JCAR014 Dose Rationale 
This trial will employ lymphodepleting chemotherapy with cyclophosphamide and fludarabine 
prior to CAR-T cell administration.  In the 2639 study, JCAR014 has been generally tolerated as 
monotherapy at dose levels ranging from 2 x 105 to 2 x 106 CAR+ T cells/kg in 14 patients with 
NHL conditioned with cyclophosphamide and fludarabine (see Section 1.5.1.2); toxicity was 
encountered in three of six patients treated with 2 x 107 CAR+ T cells/kg, which exceeded the 
MTD.  Antitumor activity has been observed in patients with NHL at all doses of JCAR014 
tested. 


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2.3 
Rationale for Lymphodepleting Chemotherapy 
Clinical trials of T-cell therapy for melanoma at the National Cancer Institute (NCI) 
demonstrated that administering lymphodepleting chemotherapy such as fludarabine and 
cyclophosphamide, or fludarabine, cyclophosphamide, and total body irradiation, prior to the 
transfer of 1010 to 1011 polyclonal melanoma-specific T cells improved the survival of a subset of 
the transferred T cells and antitumor efficacy (Dudley 2002, Dudley 2005, Dudley 2008).  The 
size of the T-cell pool is subject to homeostatic regulation, and the induction of lymphopenia 
results in less competition for cytokines such as IL-15 and IL-7 that promote lymphocyte 
proliferation and survival, and thus leads to the proliferation of residual T cells including those 
that are adoptively transferred.  Lymphodepleting chemotherapy may also eliminate CD4+ 
CD25+ regulatory T cells, and activate antigen-presenting cells that may promote the function of 
transferred T cells.  Studies in murine models subsequently confirmed the human data indicating 
that lymphodepletion improves the persistence and antitumor efficacy of transferred effector T 
cells (Wrzesinski 2007). 
Data have been presented for over 50 patients with NHL who were treated with three different 
CD19-targeted CAR-T cell products; however, there is no consensus on the optimal 
lymphodepleting chemotherapy regimen to use.  
Encouraging antitumor activity has been observed in 11 patients with NHL who received 
lymphodepleting chemotherapy with a combination of high doses of cyclophosphamide (60 to 
120 mg/kg) and fludarabine (25 mg/m2/day for 5 days) (Kochenderfer 2015).  However, 
significant cardiac toxicity, neurotoxicity, and death were reported at the highest CAR-T cell 
dose level (5 x 106 CAR+ T cells/kg).  When the CAR-T cell dose was reduced to 1 x 106 CAR+ 
T cells/kg and a lower dose regimen of cyclophosphamide (300 mg/m2/day for 3 days) and 
fludarabine (30 mg/m2/day for 3 days) was used, the severe cardiac and neurotoxicity was 
eliminated, and although transient neurotoxicity (aphasia and ataxia) was still evident, 
encouraging antitumor activity was observed (Kochenderfer 2014a). 
Current data with JCAR014 show improved CAR-T cell expansion, persistence, and antitumor 
activity in patients conditioned with high-dose cyclophosphamide (60 mg/kg) and fludarabine 
(25 mg/m2/day for 3 to 5 days) compared with those treated with cyclophosphamide alone or in 
combination with etoposide (see Section 1.5.1.2).  However, similar to the data presented by 
Kochenderfer et al., cardiac toxicity, neurotoxicity, and death were observed with high cell doses 
(2 x 107 CAR+ T cells/kg).  Current data in 14 patients support the tolerability of monotherapy at 
doses of 2 x 105 (n = 3) and 2 x 106 CAR+ T cells/kg (n = 11) after Cy/Flu conditioning.  CAR-T 
cell expansion was also observed in a small number of patients who were retreated with a second 
dose of JCAR014 after Cy/Flu conditioning, whereas no appreciable expansion was observed in 
patients retreated with JCAR014 after conditioning with regimens other than cyclophosphamide 
and fludarabine (personal communication, Turtle et al). 


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2.4 
Durvalumab Dose Rationale 
The dose level and treatment schedule for durvalumab (up to 20 mg/kg Q4W) is based on a safe 
dose established in Study CD-ON-MEDI4736-1108, a Phase 1/2 study to evaluate the safety, 
tolerability, and PK of durvalumab in patients with advanced solid tumors (see Section 1.5.2.3). 
To our knowledge, anti−PD-L1 antibodies have not previously been administered in combination 
with CAR-T cells, such as JCAR014, in human patients.  Inhibition of PD-L1 prior to the 
administration of JCAR014 has the potential to affect the proliferative rate and adverse event 
profile of JCAR014. Similarly, the stimulation of CAR-T cells and the secretion of cytokines 
have the potential to affect the adverse event profile of durvalumab due to the activation of 
endogenous TILs upon lifting checkpoint inhibition. Thus, the combination of JCAR014 and 
durvalumab has the potential to cause both immune-related adverse events (irAEs), defined as 
AEs of an immune nature (i.e., inflammatory) in the absence of a clear alternative etiology, as 
well as AEs unique to JCAR014 or the combination. 
A fixed dosing regimen will be used for this study and is based on a population PK model that 
was developed for durvalumab using monotherapy data from Study CD-ON-MEDI4736-1108 
(292 patients; dose regimens = 0.1 to 10 mg/kg Q2W or 15 mg/kg every 3 weeks).  Population 
PK analysis indicated only a minor impact of body weight on the PK of durvalumab (coefficient 
of ≤ 0.5).  The impact of body weight-based (10 mg/kg Q2W) and fixed dosing (750 mg Q2W) 
of durvalumab was evaluated by comparing predicted steady state PK concentrations (5th, 
median, and 95th percentiles) using the population PK model.  A fixed dose of 750 mg and 1500 
mg was selected to approximate 10 mg/kg and 20 mg/kg, respectively (based on median body 
weight of approximately 75 kg).  A total of 1000 patients were simulated using a body weight 
distribution of 40 to 120 kg.  Simulation results demonstrated that body weight-based and fixed 
dosing regimens yield similar median steady state PK concentrations with slightly less overall 
between-patient variability with fixed dosing regimen. 
The proposed initial durvalumab dose level in Group 1 will utilize a dose of durvalumab 
equivalent to that shown to have an acceptable safety profile (225 mg or 3 mg/kg IV Q4W) and 
approximately one order of magnitude below the recommended dose (1500 mg or 20 mg/kg 
Q4W).  A further 1.5 order of magnitude reduction in the initial durvalumab dose level in Group 
2 to 7.5 mg Q4W (equivalent to ~0.1 mg/kg) is planned in order to start below a dose that would 
provide maximal inhibition of PD-L1 throughout the interval of dosing.  Dose escalation will 
then follow a modified toxicity probability interval (mTPI) scheme with careful safety 
monitoring. 
2.5 
Rationale for Dosing Schedules with JCAR014 and Durvalumab 
In vitro studies have shown that durvalumab antagonizes the inhibitory effects of PD-L1 on 
primary human T cells, resulting in their enhanced proliferation and production of IFNγ. Thus, 
blockade of the PD-1/PD-L1 axis with durvalumab may be able to improve the antitumor activity 
of CAR-T cells such as JCAR014 in patients with aggressive NHL lymphoma by either 


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reinvigorating exhausted CAR-T cells or blocking suppression of the CAR-T cells that are 
subsequently infused. 
After treatment with CAR-T cells, most patients with lymphoma have a partial response and, 
although CAR-T cells may persist, the cells decline in number in the peripheral blood and fail to 
mediate further resolution of the lymphoma.  Administration of a PD-L1 inhibitor after treatment 
with JCAR014 (Group 1) may reverse the suppression of the CAR-T cells that may have 
occurred from PD-L1 expression on the tumor, or on cells in the tumor microenvironment, 
including the CAR-T cells.  Administering a PD-L1 inhibitor prior to treatment with JCAR014 
(Group 2) may prevent the induction of suppression of the CAR-T cells at the tumor site or by 
the tumor microenvironment, resulting in superior antitumor efficacy. 
3. 
STUDY OBJECTIVE AND ENDPOINTS 
The objectives and corresponding endpoints for the study are presented in Table 2. 
Table 2: 
Study Objectives and Endpoints 
Objective 
Endpoint(s) 
Primary 
• 
To evaluate the safety of JCAR014 in combination 
with durvalumab in adult patients with R/R B-cell 
NHL 
• 
Type, frequency, and severity of AEs and laboratory 
abnormalities 
• 
DLT rates 
• 
To determine the maximum tolerated dose (MTD) 
of durvalumab in combination with JCAR014 
• 
MTD estimated per isotonic regression 
• 
To characterize the PK profile of JCAR014  
• 
Maximum concentration (Cmax), time to maximum 
concentration (Tmax), area under the curve (AUC), 
and other relevant PK parameters of JCAR014 
Secondary 
• 
To assess the antitumor activity of JCAR014 in 
combination with durvalumab in R/R B-cell NHL  
• 
Rate of CR, rate of PR, and objective response rate 
(ORR, defined as the proportion of patients with a 
best response of either CR or PR) by Investigator 
assessment using Lugano criteria 
• 
To estimate the duration of response (DOR), PFS, 
and overall survival (OS) in patients treated with 
JCAR014 in combination with durvalumab 
• 
DOR, defined as the time from first response to 
progressive disease (PD) or death 
• 
PFS, defined as the time from date of first study 
treatment (JCAR014 or durvalumab) to PD or death 
• 
OS, defined as the time from date of first study 
treatment to death 
• 
To characterize the PK profile of durvalumab 
• 
Cmax, Tmax, AUC, and other relevant PK 
parameters of durvalumab 


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Objective 
Endpoint(s) 
• 
To assess the immunogenicity of JCAR014 and 
durvalumab 
• 
Measurement of antibodies and cellular immune 
responses to JCAR014 and ADAs directed against 
durvalumab 
Exploratory 
• 
To assess the pharmacodynamic effects of JCAR014 
and durvalumab in blood and within the tumor 
• 
B-cell depletion in circulation, profile of soluble 
circulating proteins such as cytokines and 
chemokines, and changes in the level of detectable 
soluble PD-L1 in serum 
• 
Assessment by immunohistochemistry and/or gene 
expression of changes in the phenotype of tumor 
cells (e.g., expression of PD-L1) and of the tumor 
microenvironment (e.g., infiltration by CAR-T cells) 
assessed in biopsies 
• 
Assessment of the phenotype and/or genetic profile 
of endogenous immune cells and CAR-T cells in 
blood  
• 
Evaluations may be made pre-JCAR014 and post- 
JCAR014 and/or pre-durvalumab and post-
durvalumab 
 
4. 
STUDY DESIGN AND INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This is an open-label, single-center, Phase 1b study to determine the safety, PK, and antitumor 
activity of JCAR014 in combination with durvalumab in adult patients with R/R DLBCL 
(including transformed DLBCL and primary mediastinal B-cell lymphoma [PMBCL]).  
Patients will be enrolled into one of two treatment groups (Group 1 or Group 2).  Within each 
group, dose escalation/de-escalation of durvalumab will follow a modified toxicity probability 
interval (mTPI) algorithm (Ji 2010) with a target DLT rate of 30% and an equivalence interval of 
25%−35%.  A dose level will be considered unsafe, with no additional patients enrolled at that 
dose level, if it has an estimated 95% or more probability of exceeding the target DLT rate of 
30% (i.e., P[DLT>30%|data] > 95%) with at least three patients treated at that dose level.  Dose 
escalation in each group will occur independently according to the mTPI algorithm as applied to 
each group. 
Initial Study Design: 
Group 1 (first dose of durvalumab after JCAR014): 
Patients in Group 1 receive the first infusion of durvalumab after treatment with JCAR014.  The 
first treated cohorts of patients in Group 1 received durvalumab no earlier than 21 days after the 
JCAR014 infusion (Group 1 – late).  Patients in Group 1 receiving JCAR014 (up to 2 x 106 
CAR-T cells/kg) are assessed for DLT (see Section 4.3) from the time of the first durvalumab 


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infusion until 28 days after the first durvalumab infusion.  According to the mTPI algorithm, 
durvalumab at Dose Level 1 (225 mg, n = 3 evaluable) and Dose Level 2 (750 mg, n = 3 
evaluable) were found to have acceptable safety. 
Group 2 (first dose of durvalumab before JCAR014): 
Patients in Group 2 receive the first dose of durvalumab 1 day prior to administration of 
JCAR014. DLTs in Group 2 are assessed from the time of the pre-JCAR014 dose of durvalumab 
until 28 days after treatment with JCAR014 (up to 2 x 106 CAR T cells/kg).  According to the 
mTPI algorithm, durvalumab at Dose Level 1 (7.5 mg, n = 1 evaluable), Dose Level 2 (22.5 mg, 
n = 1 evaluable), Dose Level 3 (75 mg, n = 3 evaluable), Dose Level 4 (225 mg, n = 6 evaluable, 
including one DLT), and Dose Level 5 (750 mg, n = 6 evaluable, including one DLT) were 
found to have acceptable safety. 
In Group 1 and Group 2, patients subsequently receive durvalumab at approximately 28 day 
intervals at the current highest safe durvalumab dose level (750 mg) identified in dose escalation 
studies in either Group 1 or Group 2. 
Amended Study Design: 
Analyses of efficacy and pharmacodynamic data from patients previously treated in Group 1 
(day 21 durvalumab start) and Group 2 (day -1 durvalumab start) indicated that durvalumab ≤ 
750 mg starting no earlier than day 21 (Group 1 – late) may be superior to starting on day -1 
(Group 2).  Furthermore, data from the trial sponsor indicated that durvalumab 1500 mg is 
unlikely to provide an advantage in PD-L1 blockade compared to durvalumab 750 mg, 
suggesting that escalation to durvalumab 1500 mg in this trial may be unnecessary.  Because 
JCAR014 CAR-T cells are declining in blood at day 21 after JCAR014 infusion, we elected to 
revise the protocol to add a cohort in Group 1 who receive durvalumab as early as 7 days after 
JCAR014 infusion (Group 1 – early) and nominate 750 mg as the maximum durvalumab dose in 
all Groups.  Patients in Group 1 – early receiving JCAR014 (up to 2 x 106 CAR-T cells/kg) are 
treated in cohorts of 3 patients and assessed for DLT from the time of the first durvalumab 
infusion until 28 days after the first durvalumab infusion.  Durvalumab dose de-escalation/re-
escalation decisions follow the mTPI algorithm in cohorts of 3 patients. 
Amended groups: 
Group 1 – late: start durvalumab no earlier than 21 days after JCAR014. 
Group 1 – early: start durvalumab no earlier than 7 days after JCAR014. 
Group 2: start durvalumab one day prior to JCAR014. 
In all groups, patients subsequently receive durvalumab 750 mg at approximately 28 day 
intervals. 
If durvalumab 750 mg has acceptable safety in Group 1 – early (day 7 start) according to the 
mTPI algorithm, patients will then be treated alternately in Group 1 – early and Group 1 – late 
until 6 evaluable patients have been treated in each of the 3 groups: Group 2; Group 1 – late; 


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Group 1 – early.  The Steering Committee (SC) will then evaluate available safety, toxicity, 
efficacy, and pharmacodynamic data to determine which group/s should be subsequently 
expanded.  Allocation of the subsequent patients will be alternated if more than one cohort is 
expanded.  The maximum number of evaluable patients in the trial will be 42. 
Study schematics for patients treated in Group 1 and Group 2 are provided in Figure 1 and 
Figure 2, respectively. 
Figure 1: 
Study Schema for Patients in Group 1 (Post-JCAR014 Treatment 
with Durvalumab) 
 
Figure 2: 
Study Schema for Patients in Group 2 (Pre-JCAR014 Treatment with 
Durvalumab) 
 
In both groups, JCAR014 may be dose de-escalated after review by the SC if the SC determines 
that the observed clinical safety data indicate that dose de-escalation of JCAR014 is required.  In 
this case, a separate group may be enrolled at a stable dose of durvalumab (to be determined by 
the SC) and dose re-escalation of JCAR014 may occur via the mTPI algorithm.  Enrollment in 
this group will commence after amendment to the protocol and discussion with the FDA. 
All eligible patients will undergo leukapheresis to enable JCAR014 production.  
Lymphodepleting chemotherapy will be administered prior to JCAR014 administration, and will 
consist of either a single dose of cyclophosphamide 60 mg/kg administered on Day -5 and three 
daily doses of fludarabine 25 mg/m2/day on Days -4 to -2 or concurrent cyclophosphamide (300 
mg/m2/day) and fludarabine (30 mg/m2/day) on days -4 through -2.  The first dose of durvalumab 
will be administered on Day -1 for patients in Group 2 only, and approximately day 7 or 21 for 
patients in Group 1. All patients will receive JCAR014 on Day 0.  In both groups, durvalumab 


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will be administered approximately every 4 weeks for the greater of either 10 post-JCAR014 
cycles or 4 cycles beyond identification of CR (for patients in whom studies demonstrating 
transition to CR occur late after JCAR014 infusion).  Durvalumab cycles may be ceased if there 
is unacceptable toxicity, disease progression, or the patient or PI/designee determine it is not in 
the patient’s best interest to continue durvalumab.  Patients with disease progression at restaging 
who have evidence of biological activity after durvalumab infusion that could be associated with 
subsequent anti-tumor effect (e.g. a mixed response, tumor stability, or evidence of JCAR014 
expansion and/or persistence) may receive additional post-JCAR014 cycles of durvalumab up to 
the maximum number allowed for Group 1 or Group 2. 
The planned dose levels for durvalumab and JCAR014 are listed in Table 3.  Intermediate doses 
may be evaluated upon recommendation by the SC. 
Table 3: 
Planned Dose Levels for Durvalumab and JCAR014 
Dose Level 
 
Durvalumab 
 
 
JCAR014 
(Group 1 and Group 2) 
Group 1 
Group 2 
-1 
75 mg 
— 
— 
1 
225 mg 
7.5 mg 
Up to 2 x 106/kg CAR-T cells 
2 
750 mg 
22.5 mg 
— 
3 
— 
75 mg 
— 
4 
— 
225 mg 
— 
5 
— 
750 mg 
— 
After the JCAR014 infusion, patients will be monitored for in vivo T-cell expansion/persistence 
and will have serum samples collected for cytokine profiling.  Standard safety laboratory studies 
will be monitored until 12 months post-JCAR014 infusion or 90 days after the final durvalumab 
infusion, whichever is longer.  Safety and tolerability will be assessed from study entry until the 
end of treatment and primary follow-up (12 months post-JCAR014 infusion or 90 days after the 
last durvalumab infusion, whichever is longer).  Long-term follow-up to assess delayed AEs will 
begin after the primary follow-up and will continue for up to 15 years after the JCAR014 
infusion.  Toxicities will be graded using the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03, with the exception of CRS, which will be graded according to a 
system based on modified criteria (Davila 2014, Lee 2014).  PK (in vivo expansion and 
persistence) will be assessed from the time of JCAR014 infusion until cells are no longer 
detectable by flow cytometry or quantitative polymerase chain reaction (qPCR).  
For a subset of patients with accessible tumor who consent to optional biopsies, a fresh tumor 
biopsy may be obtained prior to lymphodepleting chemotherapy, within the first 4 weeks after 
administration of JCAR014, and approximately within the first 4 weeks after the first post-
JCAR014 administration of durvalumab.  If biopsy within this period is not suitable for 


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logistical, research or clinical reasons, biopsies may be completed at a different time.  In the 
event of persistent mass, relapse or progression, a biopsy may be collected at that time point.  
These samples will be evaluated for the extent of JCAR014 migration and PD-1 and PD-L1 
expression.  Additional markers of immune cell phenotype and analysis of the tumor 
microenvironment may be explored in response to emerging data. 
Disease response will be determined by positron emission tomography (PET)/computed 
tomography (CT) at approximately 1, 2, 4, 6, 9, and 12 months after the JCAR014 infusion (at 
the end of the JCAR014 cycle, the end of the first post-JCAR014 durvalumab cycle, 
approximately every other durvalumab cycle until 6 months after the JCAR014 infusion, then 
every 3 months until 12 months after the JCAR014 infusion or 90 days after the last durvalumab 
dose, whichever is later).  At the time of the 1-month post-JCAR014 response assessments, 
patients with bone marrow lymphoma at baseline may have a repeat bone marrow aspirate and 
biopsy that will be analyzed for lymphoma by flow cytometry; samples may also be analyzed for 
other exploratory endpoints.  Bone marrow and aspirates may be collected and analyzed at other 
timepoints as clinically indicated until the patient achieves a CR. 
Patients may be eligible for retreatment with JCAR014 at the same cell dose ± durvalumab at or 
below the highest tested safe dose if at least 3 months have elapsed since the last dose of 
durvalumab.  Subjects undergoing retreatment will follow the same assessment schedule; 
however, durvalumab-related assessments will not be conducted in subjects who receive 
retreatment with JCAR014 only.  Retreatment data will not be included in the dose-finding 
portion of the study.  
After the primary follow-up phase (12 months post-JCAR014 infusion or 90 days after the last 
durvalumab infusion, whichever is longer), patients will be asked to participate in long-term 
follow-up in accordance with Food and Drug Administration guidelines. 
4.2 
Dose Escalation Scheme 
Dose escalation will follow the mTPI decision table in Appendix F. The PI or designee will 
submit an updated list of treated subjects and DLT events to FHCRC Statistics, who will then 
confirm the assigned durvalumab dose and treatment group. 
4.3 
Dose-Limiting Toxicity Criteria 
The following treatment-related (JCAR014 or durvalumab) events will be considered DLTs: 
1. 
Death within 4 weeks of the study treatment 
2. 
Grade ≥ 3 neurotoxicity of greater than 7 days duration 
3. 
Grade ≥ 3 neurotoxicity that does not revert to Grade 1 or baseline within 28 days 
4. 
Grade ≥ 3 seizures that do not resolve to grade ≤ 2 within 3 days 
5. 
Grade ≥ 4 cytokine release syndrome (grading is shown in Table 5) 


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6. 
Grade 3 cytokine release syndrome that does not resolve to grade ≤ 2 within 7 days 
7. 
Grade ≥ 3 non-infectious colitis or non-infectious pneumonitis 
8. 
Grade ≥ 3 irAE or other grade ≥ 3 autoimmune toxicity (excluding B-cell aplasia) 
9. 
Any increase in aspartate transaminase (AST) or ALT > 3 x ULN and concurrent increase 
in total bilirubin > 2 x ULN that is unrelated to CRS and has no other probable reason to 
explain the combination of increases 
10. 
Grade ≥ 3 allergic reaction to the JCAR014 infusion  
11. 
Any Grade 3 or 4 event deemed unexpected by the Investigator and considered a DLT 
upon evaluation by the Steering Committee 
4.4 
Protocol Enrollment 
Enrollment is expected to take approximately 18 to 24 months.  Study treatment with initial 
follow-up is expected to be approximately 15 months.  All patients who receive treatment with 
JCAR014 will be followed for up to 15 years after the JCAR014 dose for safety evaluations (see 
Section 8.1.13).  The anticipated duration of the study is approximately 3 years. 
4.5 
Removal of Patients from Study 
4.5.1 
Patient Withdrawal from Further Study Treatment 
Patients who receive JCAR014 and/or durvalumab and are subsequently withdrawn from further 
study treatment (e.g., due to toxicity) will not be withdrawn from the study.  They will remain on 
study and continue to have all scheduled follow-up evaluations per the Schedule of Events (see 
Appendix A).  A patient’s treatment may be discontinued for any of the following reasons: 
• CR 
• Undetectable levels of JCAR014 (< 10 copies/µg DNA in blood by PCR) on two consecutive 
evaluations  
• Progressive disease 
• AE 
• Investigator decision 
• Patient decision 
• Other 
Patients who receive treatment with JCAR014 and/or durvalumab, achieve a CR, and then 
relapse may be eligible for retreatment (see Section 8.1.12). 
4.5.2 
Patient Withdrawal from Study 
A patient may be discontinued from the study for any of the following reasons: 


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• Patient did not receive any study therapy (JCAR014 or durvalumab) 
• Patient withdrawal of consent 
• Study termination by the Principal Investigator (PI), the FHCRC Institutional Review Board 
(IRB), or the FDA 
• Lost to follow-up 
• Death 
• Other 
Patients who are withdrawn from the study because of failure to generate a JCAR014 dose that 
meets the required quality control and criteria for product release may re-enroll in the study at a 
later time provided that the patient meets all eligibility criteria. 
4.5.3 
Termination of the Study 
The study may be terminated at any time by the PI, the study Sponsor, the FHCRC IRB, or the 
FDA. 
4.5.4 
Replacement of Study Patients 
Patients who are enrolled for leukapheresis and/or treatment with lymphodepleting 
chemotherapy, JCAR014, and durvalumab, but do not receive at least one dose of JCAR014 or 
durvalumab will be replaced.  In addition, patients enrolled in the dose-escalation phase who do 
not complete the DLT evaluation period for reasons other than DLT will be considered non-
evaluable and will be replaced with another patient at the same dose level. 
5. 
STUDY POPULATION 
The target study population consists of adult patients with R/R DLBCL.  Patients must meet all 
of the inclusion and exclusion criteria to be enrolled in this study. 
5.1 
Criteria for Screening 
5.1.1 
Inclusion Criteria  
1) Male or female ≥ 18 years of age at the time of screening consent 
2) Relapsed or refractory DLBCL, not otherwise specified (NOS); high grade B-cell 
lymphoma with MYC and BCL2 and/or BCL6 rearrangements; primary mediastinal B-
cell lymphoma (PMBCL); or DLBCL transformed from indolent histology with one of 
the following: 
a) Persistent disease after first-line chemo-immunotherapy 
b) Relapse after first-line chemo-immunotherapy and not eligible for autologous 
hematopoietic stem cell transplant (HCT) 


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c) Relapse or persistent disease after at least two lines of therapy or after autologous 
HCT 
3) Ability to understand and provide informed consent 
 
5.1.2 
Exclusion Criteria  
1) Subjects with known active central nervous system (CNS) involvement by malignancy. 
Subjects with prior CNS disease that has been effectively treated will be eligible if 
treatment was completed at least 3 months prior to enrollment and there is no evidence of 
disease or stable abnormalities on repeat imaging 
2)  Planned use of corticosteroids (> 10 mg/day prednisone or equivalent) or other systemic 
immunosuppression within 4 days prior to leukapheresis. Topical and/or inhaled steroids 
are permitted. 
3) Prior treatment with any CD19 CAR-T cell therapy 
4) Prior allogeneic HCT 
5) Known active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection 
6) Pregnant or breastfeeding women 
7) Known exclusion criteria for leukapheresis, JCAR014, or durvalumab therapy 
 
5.2 
Criteria for Leukapheresis and Pre-therapy Evaluation 
5.2.1 
Inclusion Criteria 
1) Screening evaluation appropriate for leukapheresis and T-cell collection 
2) Evidence of CD19 expression on any prior or current tumor specimen or a high 
likelihood of CD19 expression based on disease histology  
5.2.2 
Exclusion Criteria  
1) Subjects with known active central nervous system (CNS) involvement by malignancy. 
Subjects with prior CNS disease that has been effectively treated will be eligible if 
treatment was completed at least 3 months prior to enrollment and there is no evidence of 
disease or stable abnormalities on repeat imaging 
2) Prior treatment with PD-1, PD-L1, cytotoxic T lymphocyte-associated protein 4 
(CTLA-4) targeted therapy, or tumor necrosis factor receptor superfamily (TNFRSF) 
agonists including CD134 (OX40), CD27, CD137 (4-1BB), and CD357 (glucocorticoid-
induced tumor necrosis factor receptor family-related protein [GITR]) 


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3) Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [e.g., ulcerative colitis, Crohn’s disease], celiac disease, or 
other serious chronic gastrointestinal conditions associated with diarrhea, autoimmune 
vasculitis, systemic lupus erythematosus, Wegener syndrome [granulomatosis with 
polyangitis], myasthenia gravis, Graves’ disease; rheumatoid arthritis, hypophysitis, 
uveitis, etc.) within 3 years prior to the planned start of treatment.  The following are 
exceptions to this criterion: 
a) Vitiligo 
b) Alopecia 
c) Hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone 
replacement 
d) Psoriasis not requiring systemic treatment 
e) Other conditions considered to be low risk of serious deterioration by the PI 
4) History of any one of the following cardiovascular conditions within the past 6 months: 
Class III or IV heart failure as defined by the New York Heart Association (NYHA), 
cardiac angioplasty or stenting, myocardial infarction, or unstable angina.  History of 
other clinically significant cardiac disease that, in the opinion of the PI or designee, is a 
contraindication to lymphodepleting chemotherapy, JCAR014 infusion, or durvalumab 
infusion is also excluded. 
5) History or presence of clinically relevant CNS pathology, such as epilepsy, seizure, 
paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar 
disease, or psychosis.  History of other organic brain syndrome that in the opinion of the 
PI or designee is a contraindication to lymphodepleting chemotherapy, JCAR014 
infusion or durvalumab infusion 
6) History of solid organ transplantation 
 
5.3 
Criteria for Lymphodepletion Chemotherapy, JCAR014 and Durvalumab Therapy 
5.3.1 
Inclusion Criteria 
1) Successful collection of T cells for JCAR014 manufacturing 
2) Documentation of CD19 expression on any prior or current tumor biopsy 
3) Internal review of histology 
4) Detectable PET-positive disease 
5) Karnofsky performance status ≥ 60% 
6) Adequate organ function, defined as: 
a) Assessed by the Investigator to have adequate bone marrow function to receive 
lymphodepleting conditioning chemotherapy 


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b) Serum creatinine < 1.5 x age-adjusted ULN 
c) ALT and AST < 3 x ULN and total bilirubin ≤ 2 x ULN 
d) Adequate pulmonary function, defined as CTCAE Grade ≤ 1 dyspnea and SaO2 ≥ 
92% on room air.  Patients with clinically significant pulmonary dysfunction, as 
determined by medical history and physical exam should undergo pulmonary function 
testing and must have a forced expiratory volume in 1 second (FEV1) ≥ 50% of 
predicted value or diffusing capacity of the lung for carbon monoxide (DLCO; 
corrected) ≥ 40% of predicted value 
e) Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥ 35% 
as assessed by echocardiogram (ECHO) or multiple uptake gated acquisition 
(MUGA) 
7) Women of reproductive potential (defined as all women physiologically capable of 
becoming pregnant) must agree to use suitable methods of contraception for 90 days after 
the last dose of study therapy (durvalumab or JCAR014) 
8) Males who have partners of reproductive potential must agree to use an effective barrier 
contraceptive method for 90 days after the last dose of study therapy (durvalumab or 
JCAR014) 
5.3.2 
Exclusion Criteria 
1) Subjects with known active CNS involvement by malignancy.  Subjects with prior CNS 
disease that has been effectively treated will be eligible if treatment was completed at 
least 3 months prior to enrollment and there is no evidence of disease or stable 
abnormalities on repeat imaging. 
2) Uncontrolled infection 
3) Receipt of live, attenuated vaccine within 28 days prior to the first dose of durvalumab 
(Note: enrolled patients should not receive live vaccine during the study and for 180 days 
after the last dose of durvalumab) 
4) Planned use of corticosteroids (> 10 mg/day prednisone or equivalent) or other systemic 
immunosuppression is not permitted within 72 hours prior to JCAR014 infusion.  Topical 
and/or inhaled steroids are permitted. 
 
5.4 
Reproductive Potential and Contraception Requirements 
Any female patient who does not meet at least one of the following criteria will be considered to 
have reproductive potential: 
• Post-menopausal for at least 12 consecutive months (i.e., no menses), or 
• Undergone a sterilization procedure (hysterectomy, salpingectomy, or bilateral 
oophorectomy; tubal ligation is not considered a sterilization procedure) 


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Pregnancy test for females of reproductive potential must be negative within 14 days before 
leukapheresis and within 28 days before lymphodepleting chemotherapy. 
Female patients with reproductive potential who are not sexually abstinent and male patients 
who are sexually active with females of reproductive potential must agree to use a suitable 
method of contraception for the duration of the study (from screening through 90 days after the 
last dose of study therapy [durvalumab or JCAR014]), for example: 
• Condom with spermicidal agent 
• Diaphragm or cervical cap with spermicidal agent 
• Intrauterine device 
• Hormonal contraceptives in combination with either a condom, diaphragm, or cervical cap 
 
6. 
STUDY TREATMENTS 
Minor variations to the outlined schedules for logistical or clinical reasons are permissible. 
6.1 
Leukapheresis 
Following enrollment on the study, a leukapheresis collection will be performed on each patient 
to obtain PBMCs for the production of the JCAR014 investigational product.  The leukapheresis 
will be performed by the Seattle Cancer Care Alliance (SCCA) Apheresis Unit using standard 
operating procedures (SOPs) for obtaining PBMCs.  If a technical issue arises during the 
procedure or in the immediate processing of the product such that it cannot be used for JCAR014 
production, the patient may undergo a second collection procedure. 
Patients ineligible for a vein-to-vein apheresis may elect to have a percutaneous central venous 
access catheter inserted to support this collection. 
The leukapheresis product will be delivered to the Cell Processing Facility (CPF) at the FHCRC 
or the Cell Therapy Laboratory (CTL) at the SCCA.  CAR-T cell manufacturing will be 
conducted in accordance with the IND.  A portion of the cells at any point in manufacturing may 
be collected for research. 
Quality control and release testing will be performed on the CAR-T cell product prior to its 
release for patient infusion. 
6.2 
Lymphodepleting Chemotherapy 
Patients will either be treated with a single dose of cyclophosphamide (60 mg/kg) followed by 
fludarabine (25 mg/m2/day for 3 days) or with concurrent cyclophosphamide (300 mg/m2/day) 
and fludarabine (30 mg/m2/day) for 3 days prior to treatment with JCAR014.  Refer to the most 
recent package inserts for specific details on administration of these agents.  Dose reduction is 
permissible at the discretion of the PI or designee. 


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6.3 
JCAR014 Treatment 
JCAR014 should be administered at least 36 hours and preferably within 96 hours after 
completion of lymphodepleting chemotherapy.  However, the JCAR014 infusion may be delayed 
to allow for resolution of AEs related to the disease, lymphodepleting chemotherapy, and 
durvalumab infusion, or for other factors. 
Within a day of scheduled JCAR014 infusion the patient should undergo a clinical evaluation 
and determination of suitability to proceed with JCAR014 administration. Patients deemed not 
suitable for JCAR014 administration may receive JCAR014 with or without lymphodepletion 
chemotherapy at a later time if the clinical and/or laboratory contraindication to infusion 
subsequently improves. Discussion with the protocol PI or designee is required. 
 
6.3.1 
JCAR014 Administration 
JCAR014 will be provided as a single cell product at the assigned cell dose.  The JCAR014 
infusion should be administered IV over approximately 20 to 30 minutes.  All patients will be 
monitored during each T-cell infusion with vital signs and O2 saturation being recorded before, 
during, and after the infusion (see Section 8.3.5).  
6.3.2 
Acute Infusion Reactions 
Acute infusion reactions may occur with administration of JCAR014 or durvalumab.  Guidelines 
for the treatment of acute infusion reactions are provided in Section 7.4. 
6.4 
Durvalumab Treatment 
Durvalumab will be administered as an IV infusion at the assigned dose.  Continued dosing at an 
approximately Q4W interval is allowed after clearance of the DLT evaluation period. 
Within a day of scheduled durvalumab infusion the patient should undergo a clinical evaluation 
and clinical determination for suitability to proceed with durvalumab administration. Patients 
deemed not suitable for durvalumab administration may receive durvalumab with or without 
lymphodepletion chemotherapy at a later time if the clinical and/or laboratory contraindication to 
infusion subsequently improves. Discussion with the protocol PI or designee is required. 
6.4.1 
Durvalumab Drug Product 
Durvalumab will be supplied as a 500 mg vial solution for infusion after dilution.  The solution 
contains 50 mg/mL durvalumab, 26 mM histidine/histidine-hydrochloride, 275 mM trehalose 
dihydrate, and 0.02% (w/v) polysorbate 80; it has a pH of 6.0.  The nominal fill volume is 10 
mL.  Durvalumab must be stored at 2°C to 8°C (36°F to 46°F). 


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6.4.2 
Durvalumab Preparation and Administration 
The dose of durvalumab for administration must be prepared by the Investigator’s or site’s 
designated investigational product (IP) manager using aseptic technique.  Total time from needle 
puncture of the vial to the start of administration should not exceed:  
• 24 hours at 2°C to 8°C (36°F to 46°F) 
• 4 hours at room temperature 
Durvalumab will be administered using an IV bag containing 0.9% (w/v) saline, with a final in-
bag concentration ranging from 0.15 mg/mL to 20 mg/mL, and delivered through an IV 
administration set with a 0.2 µm or 0.22 µm in-line filter. 
The IV bag size should be selected such that a final durvalumab in-bag concentration of 0.15 
mg/mL to 20 mg/mL is achieved.  The volumes of durvalumab, syringe accuracy, and acceptable 
bag volumes for each dose level are provided in Table 4. 
Table 4: 
IV Bag Specifications for each Durvalumab Dose Level 
Durvalumab dose  
(mg) 
Durvalumab volume  
(mL) 
Syringe accuracy  
(mL) 
Acceptable IV bag sizes 
(mL) 
7.5 
0.15 
0.01 
50 
22.5 
0.45 
0.01 
50-100 
75 
1.5 
0.1 
50-500 
225 
4.5 
0.1 
50-1000 
750 
15 
0.5 
50-1000 
A volume of IV bag diluent equal to the determined volume of durvalumab must be removed 
from the bag prior to addition of durvalumab.  The determined volume of durvalumab is then 
added to the IV bag, and the bag is mixed by gentle inversion to ensure homogeneity of the dose 
in the bag.  No incompatibilities between durvalumab and polyvinylchloride or polyolefin have 
been observed. 
The standard infusion time is 1 hour; however, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature.  In the event that either preparation 
time or infusion time exceeds the specified time limits, a new dose must be prepared from new 
vials to ensure the patient receives the intended durvalumab dose.  Durvalumab does not contain 
preservatives, and any unused portion must be discarded. 


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6.5 
Recommended Supportive Care, Additional Treatment, and Monitoring 
Prophylactic treatment/measures are strongly recommended for patients at risk for tumor lysis 
syndrome (TLS) according to institutional or clinical standards.  Supportive care for the 
management of CRS is detailed in Section 7.1. 
The use of red blood cells and platelet transfusions, and/or colony-stimulating factors is 
permitted according to institutional or clinical standards. 
The use of prophylactic or empiric anti-infective agents (e.g., trimethoprim/sulfmethoxazole for 
pneumocystis pneumonia [PCP] prophylaxis, broad spectrum antibiotics, antifungals, or antiviral 
agents for febrile neutropenia) is permitted according to institutional standards. 
Prophylactic anti-seizure medication should be considered in some patients (see Section 7.2). 
Hospitalization may be required after study treatment to manage any treatment-associated 
toxicities.  Patients who do not have adequate support outside of the hospital or do not have 
reliable transportation to the clinic for scheduled evaluation or emergencies should be considered 
for hospitalization for the first 7 days of treatment in each cycle. 
6.6 
Concomitant Medications 
Prescription medications taken by the patient at the time of a protocol-related AE that occurs 
from the time of informed consent until initiation of lymphodepleting chemotherapy will be 
recorded.  All medications taken from the time of lymphodepleting chemotherapy until 30 days 
after the last dose of study therapy (durvalumab or JCAR014) will be recorded.  From 30 days to 
12 months after the the last dose of study therapy, only concomitant medications used at the time 
of JCAR014-related or durvalumab-related AEs will be recorded.  Patients should be 
discouraged from use of illicit drugs, herbal remedies, self-prescribed drugs, tobacco products, or 
excessive alcohol at any time during the clinical study. 
Vaccination with a killed vaccine is permitted at any time with consultation with the medical 
monitor. 
7. 
POTENTIAL RISKS AND MANAGEMENT OF TREATMENT TOXICITIES 
Administration of durvalumab is expected to enhance the persistence and activity of JCAR014 T 
cells.  Similarly, cytokines released in response to JCAR014 administration may activate 
endogenous T cells, thus potentiating the immune-related adverse events associated with 
administration of immune therapies such as durvalumab.  Thus, administration of the two agents 
in combination could exacerbate the adverse events expected from each agent alone. 
A summary of potential risks and management of treatment toxicities is provided in the sections 
below. 


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7.1 
Cytokine Release Syndrome 
Administration of CAR-T cells such as JCAR014 may be associated with CRS.  CRS may be 
characterized by high fever, fatigue, nausea, headache, dyspnea, tachycardia, rigors, hypotension, 
hypoxia, myalgia/arthralgia, anorexia, and neurologic abnormalities (e.g., altered mental status, 
aphasia, altered level of consciousness, and seizures or seizure-like activity).  A modification of 
the CTCAE CRS grading scale has been established to better reflect JCAR014-associated CRS 
(Lee 2014), as detailed in Table 5. 
If a patient becomes febrile or develops symptoms of CRS, cytokine and biomarker levels, serum 
ferritin, C-reactive protein (CRP), and/or markers of tumor lysis syndrome (e.g., chemistry, uric 
acid, lactate dehydrogenase [LDH]) may be measured, and persistence and/or phenotype of the 
transgene-expressing cells may be evaluated, as clinically indicated. 
Any patient who develops clinical evidence of symptoms related to CRS will have a work-up to 
exclude infection or other causes, as clinically appropriate.  Initial treatment should consist of 
supportive measures as dictated by the clinical and laboratory findings, and may include fluid 
replacement, medications to support blood pressure, antipyretics, oxygen supplementation, anti-
seizure medications, and broad-spectrum antibiotics if infection cannot be excluded as a potential 
etiology for the signs and symptoms.   
Grade ≥ 3 CRS (severe CRS; sCRS) and/or Grade 2 CRS with progressive symptoms and signs 
may be treated with tocilizumab 4-8 mg/kg IV with or without corticosteroids (e.g., 
dexamethasone 10 mg IV every 6 to 24 hours). An algorithm for management of CRS is shown 
in Figure 3.  Other cytokine-directed therapies may be considered after discussion with the PI. 
 


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Table 5: 
Grading Criteria for CRS 
Grade 
Description of Symptoms 
1: Mild 
Not life-threatening, require only symptomatic treatment such as antipyretics and anti-
emetics (e.g., fever, nausea, fatigue, headache, myalgia, malaise) 
2: Moderate 
Require and respond to moderate intervention: 
• 
Oxygen requirement < 40%, or 
• 
Hypotension responsive to fluids or low dose of a single vasopressor, or 
• 
Grade 2 organ toxicity (by CTCAE v4.03) 
3: Severe 
Require and respond to aggressive intervention: 
• 
Oxygen requirement ≥ 40%, or 
• 
Hypotension requiring high dose of a single vasopressor (e.g., norepinephrine ≥ 20 
µg/min, dopamine ≥ 10 µg/kg/min, phenylephrine ≥ 200 µg/min, or epinephrine ≥ 
10 µg/min), or 
• 
Hypotension requiring multiple vasopressors (e.g., vasopressin + one of the above 
agents, or combination vasopressors equivalent to ≥ 20 µg/min norepinephrine), or 
• 
Grade 3 organ toxicity or Grade 4 transaminitis (by CTCAE v4.03) 
4: Life-threatening 
Life-threatening: 
• 
Requirement for ventilator support, or 
• 
Grade 4 organ toxicity (excluding transaminitis) 
5: Fatal 
Death 
Adapted from Lee et al., 2014 (Lee 2014) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 3: Recommended Management of CRS 
 
 


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7.2 
Neurologic Toxicities 
Therapy with JCAR014 can be associated with neurologic toxicities, such as delirium, seizures, 
and/or focal neurologic deficits, which can preceed, accompany, or follow signs of CRS or occur 
in the absence of CRS. 
For patients who have mild neurologic manifestations, symptomatic care and levetiracetam are 
recommended.  Discussion with the PI or designee is recommended.  For patients with 
worsening neurologic changes, the addition of corticosteroids should be considered (e.g., 
dexamethasone 10 mg IV every 6 to 24 hours).  Tocilizumab (4-8 mg/kg IV) or other cytokine-
directed therapies may be used based on clinical judgment; at this time, it is unclear if these 
approaches are of benefit to patients with neurotoxicity.  Cerebrospinal fluid (CSF) assessments 
and CNS imaging should be considered if clinically indicated (see Section 8.3.6). 
Levetiracetam (500 mg bid PO starting dose) or other anti-seizure medication should be 
considered prophylactically prior to treatment with JCAR014 for patients with a history of CNS 
irradiation or other intensive CNS-directed therapy.  Levetiracetam or other anti-seizure 
medication should also be considered at the first appearance of symptoms consistent with CRS or 
neurologic toxicity (e.g., confusion, word-finding difficulties, disorientation). The use of 
continuous electroencephalogram (EEG) monitoring may be considered based on the patient’s 
risk of toxicity and his/her clinical status.  
7.3 
Macrophage Activation Syndrome 
Macrophage activation syndrome (MAS) is a serious disorder potentially associated with 
uncontrolled activation and proliferation of CAR-T cells and subsequent activation of 
macrophages.  MAS is typically characterized by high-grade, non-remitting fever, cytopenias, 
and hepatosplenomegaly.  Laboratory abnormalities found in MAS include elevated 
inflammatory cytokine levels, serum ferritin, soluble IL-2 receptor (sCD25), triglycerides, and 
decreased circulating NK cells.  Other findings include variable levels of transaminases, signs of 
acute liver failure, coagulopathy, and disseminated intravascular coagulopathy.  While there are 
no definitive diagnostic criteria for MAS, it is typically diagnosed using published criteria for 
hemaphagocytic lymphohistiocytosis (Schulert 2015). 
Patients treated with JCAR014 should be monitored for MAS, and cytokine-directed therapy or 
corticosteroids should be considered as clinically indicated. 
7.4 
Infusion Reactions 
Administration of JCAR014 and durvalumab may cause infusion reactions.  Possible risks 
associated with IV administration of JCAR014 and durvalumab are infection, redness, swelling, 


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pain, and induration at the administration site.  Examples of other potential symptoms and signs 
associated with infusion reactions and their initial management are listed below: 
• Fever, chills, and temperature elevations > 38.3°C may be managed with acetaminophen 650 
mg PO every 4 to 6 hrs. All patients who develop fever or chills should have a blood culture 
drawn. 
• Headache may be managed with acetaminophen. 
• Nausea and/or vomiting may be managed with diphenhydramine 25 to 50 mg IV or other 
antiemetics (excluding corticosteroids). 
• Hypotension should be managed initially by fluid administration. 
• Hypoxemia should be managed initially with supplemental oxygen. 
If the following signs appear during infusion of JCAR014, the infusion should be paused and the 
patient assessed.  If assessment by the PI or designee indicates that the patient’s condition is 
stable, then the infusion may be resumed. 
• Systolic blood pressure < 80 mmHg OR > 30 mmHg fall from baseline 
• Heart rate > 140/min OR increase from baseline > 40/min (confirmed by palpation or 
electrocardiogram [ECG]) 
• Respiratory rate > 35/min OR increase from baseline of > 10/min 
• Arterial O2 saturation < 88% on air OR fall from baseline > 5% 
If a JCAR014 infusion is terminated due to acute toxicity, the residual T cells should be returned 
to FHCRC Therapeutic Products Program Quality Control Department for analysis.  
Investigation of possible causes of observed signs should proceed and, if necessary, additional 
medical treatment will be instituted. 
Patients requiring discontinuation of the JCAR014 infusion may be eligible for re-treatment if 
the cause is deemed not related to the JCAR014 infusion. 
Guidelines for the management of infusion reactions deemed related to durvalumab 
administration are provided in Appendix G. 
7.5 
Tumor Lysis Syndrome 
Both lymphodepleting conditioning chemotherapy and JCAR014 may cause TLS in patients with 
high lymphoma burden.  All patients will be considered at risk for TLS and should receive 
allopurinol prophylaxis before chemotherapy begins, unless contraindicated.  Allopurinol should 
be continued for as long as the medical team determines appropriate after the JCAR014 infusion. 
Patients may receive additional hydration and urine alkalinization for the first 2 weeks after 
JCAR014 infusion. 


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If TLS develops, as defined by the Cairo Bishop criteria (Coiffier 2008), the Attending Physician 
will direct patient management with guidance from the study staff (Howard 2011).  Conservative 
therapy, including allopurinol, urinary alkalinization, and IV fluid hydration may be instituted 
immediately for suspected TLS.  Hyperkalemia may be treated with potassium-binding resins, 
diuresis, or insulin/dextrose therapy.  Hyperphosphatemia may be treated with phosphate-binding 
resins.  In severe cases, rasburicase (in non-G6PD-deficient individuals) or renal dialysis may be 
necessary. 
7.6 
B-Cell Aplasia 
B-cell aplasia is an expected potential off-tumor, on-target toxicity associated with 
administration of CD19-targeted CAR-T cells.  Prolonged B-cell aplasia has been observed in 
other CD19-directed CAR-T cell programs (Davila 2013, Grupp 2013). Serum immunoglobulin 
levels will be obtained from all patients prior to and at various timepoints following JCAR014 
treatment.  Hypogammaglobulinemic patients (serum IgG < 400 mg/dL) should be considered 
for intravenous immunoglobulin replacement therapy according to institutional guidelines. 
The following should be considered for infection prophylaxis, as clinically indicated: 
1) Antibiotic: while neutropenic 
2) Antifungal: start fluconazole on the day of JCAR014 infusion and continue for 
approximately 21 days after JCAR014 infusion  
3) Antiviral: start before chemotherapy and continue for at least 3 months after JCAR014 
infusion 
4) Pneumocystis jiroveci pneumonia (PJP) prophylaxis: start approximately day 21 after 
JCAR014 infusion and continue for at least 3 months after JCAR014 infusion 
7.7 
Persistent Uncontrolled T-cell Proliferation 
In the unlikely event that clinically significant uncontrolled and persistent proliferation of 
JCAR014 T cells occurs in a study patient, initial therapy may involve treatment with 
corticosteroids. Anti-lymphocyte globulin, cytotoxic drugs, or administration of anti-EGFR 
monoclonal antibody (cetuximab), which has been shown to eliminate EGFRt+ CD19 CAR-T 
cells in murine models, may be considered in serious cases.  If an increase in CAR-T cells to 
greater than 10% of T cells at more than 3 months after the CAR-T cell infusion is observed, an 
analysis for clonal expansion by deep sequencing of the T-cell receptor (TCR) beta gene 
(Adaptive Biotechnology) may be conducted.  All patients will be monitored for evidence of 
unexpected JCAR014 expansion and the emergence of a new malignancy, particularly of T-cell 
origin. 


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7.8 
Replication-Competent Lentivirus 
Per the FDA guidelines (Food and Drug Administration 2000, Food and Drug Administration 
2006), all patients will be followed in this study for replication-competent lentivirus (RCL) and 
vector sequences for up to 15 years following the last dose of JCAR014. 
7.9 
Immune-Related Adverse Events 
Based on the mechanism of action of durvalumab leading to T-cell activation and proliferation, 
there is the possibility of observing immune-related adverse events (irAEs) with JCAR014 and 
durvalumab combination therapy.  Potential irAEs may be similar to those seen with the use of 
ipilimumab, nivolumab, or the combination thereof and may include immune-mediated 
pneumonitis/interstitial lung disease, diarrhea/enterocolitis, hepatitis, nephritis or renal 
dysfunction, rash, endocrinopathy, neurotoxicity, or peripheral neuromotor syndrome (Hodi 
2010, Brahmer 2012, Topalian 2012, Wolchok 2013).  Patients should be monitored for signs 
and symptoms of irAEs.  In the absence of an alternate etiology (e.g., infection or disease 
progression), an immune-mediated etiology should be considered.  In addition to the dose 
modifications shown in Appendix G, it is recommended that management of irAEs follow the 
guidelines outlined for ipilimumab (Weber 2012).  The following guidelines are recommended 
for events considered related to durvalumab: 
1. 
Patients should be evaluated to identify any alternative etiology. 
2. 
In the absence of clear alternative etiology, all events of an inflammatory nature should 
be considered to be immune-related. 
3. 
Symptomatic and topical therapy should be considered for low-grade events. 
4. 
Systemic corticosteroids should be considered for a persistent low-grade event or for a 
severe event. 
5. 
More potent immunosuppressives (e.g., infliximab, mycophenolate mofetil) should be 
considered for events not responding to systemic steroids. 
If the Investigator has any question in regards to an AE being an irAE, the Investigator should 
contact the Juno medical monitor.  Treatment modifications will not be required for AEs that are 
clearly not attributed to durvalumab (such as an accident) or for laboratory abnormalities that are 
not deemed to be clinically significant. 
Following the DLT evaluation period, individual patient treatments may be interrupted or 
delayed based on toxicities observed during each subsequent 28-day period of treatment.  
General guidelines regarding treatment modification for irAEs deemed related to durvalumab are 
provided in Appendix G. 


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7.9.1 
Hepatic Function Abnormalities 
Hepatic function abnormalities meeting the definition of Hy’s law (i.e., any increase in ALT or 
AST to greater than or equal to 3 x ULN and concurrent increase in total bilirubin to greater than 
2 x ULN with no probable reason to explain the combination of increases) and considered related 
to either durvalumab alone or durvalumab in combination with JCAR014 is considered an 
adverse event of special interest (AESI).  Concurrent findings are those that derive from a single 
blood draw or from separate blood draws taken within 8 days of each other.  Follow-up 
investigations and inquiries will be initiated promptly to determine whether the findings are 
reproducible and/or whether there is objective evidence that clearly supports causation by a 
disease (e.g., cholelithiasis and bile duct obstruction with distended gallbladder, lymphoma, or 
hypotensive episode during CRS) or a medication or agent other than the investigational product 
(e.g., lymphodepleting chemotherapy).  Guidelines for management of patients with hepatic 
function abnormalities deemed related to durvalumab are provided in Appendix G. 
Hepatic abnormalities considered related to durvalumab and potentially meeting the definition of 
Hy’s law will be reported as SAEs (see Section 9.3.3.2). 
7.9.2 
Pneumonitis 
Adverse events of pneumonitis are also of special interest, as pneumonitis has been observed 
with anti−PD-1 and anti−PD-L1 mAbs, including durvalumab.  Immune-mediated pneumonitis 
is characterized by inflammation focally or diffusely affecting the lung parenchyma that may be 
the result of effects of checkpoint inhibitors against the normal lung parenchyma (Chow 2013).  
Presentations of pneumonitis range from asymptomatic lung infiltrates to those that mimic severe 
bacterial pneumonia and can be fatal.  For symptomatic patients, complaints and findings may 
include dyspnea, cough, tachypnea, pleuritic chest pain, and hypoxia.  Initial work-up should 
include high-resolution CT scan, ruling out infection, and pulse oximetry.  Pulmonary 
consultation is highly recommended.  Guidelines for management of patients with pneumonitis 
deemed related to durvalumab are provided in Appendix G. 
7.9.3 
Infusion Reactions 
Infusion-related reactions to durvalumab are of special interest and are defined, for the purpose 
of this protocol, as all AEs occurring from the start of investigational product infusion up to 24 
hours after the infusion start time.  Guidelines for management of patients with infusion 
reactions deemed related to durvalumab are provided in Appendix G. 
7.9.4 
Hypersensitivity Reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti−PD-
L1 and anti−PD-1 therapy (Brahmer 2012).  As with the administration of any foreign protein 
and/or other biologic agents, reactions following the infusion of mAbs can be caused by various 
mechanisms, including acute anaphylactic (immunoglobulin E-mediated) and anaphylactoid 
reactions against the mAb, and serum sickness.  Acute allergic reactions may occur, may be 


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severe, and may result in death.  Acute allergic reactions may include hypotension, dyspnea, 
cyanosis, respiratory failure, urticaria, pruritus, angioedema, hypotonia, urticaria, arthralgia, 
bronchospasm, wheeze, cough, dizziness, fatigue, headache, hypertension, myalgia, vomiting, 
and unresponsiveness. 
Guidelines for management of patients with hypersensitivity (including anaphylactic reaction) 
and infusion-related reactions deemed related to durvalumab are provided in Appendix G. 
7.9.5 
Gastrointestinal Disorders 
Diarrhea, colitis, enterocolitis, and pancreatitis are gastrointestinal irAEs that have been reported 
with durvalumab.  Mild to severe diarrhea is the most frequently observed sign/symptom 
potentially associated with immune-mediated colitis, and may be accompanied by other signs 
and symptoms, including changes in bowel habits from baseline, abdominal pain, 
nausea/vomiting, or hematochezia.  In severe cases, patients may experience significant 
dehydration, fever, peritoneal signs, bowel perforation, or ileus (Kaehler 2010).  Immune-
mediated pancreatitis, an important potential risk, is an inflammatory condition of the pancreas 
that typically manifests initially as asymptomatic elevations of amylase and lipase in patients 
treated with immune-checkpoint inhibitors.  Clinical presentation frequently includes low-grade 
abdominal pain with accompanying fever and malaise (Di Giacomo 2010, Weber 2012).  
Guidelines for the management of patients with gastrointestinal disorders deemed related to 
durvalumab are in Appendix G. 
7.9.6 
Nephritis 
The major clinical syndromes produced by immune-mediated renal injury include nephrotic 
syndrome, rapidly progressive glomerulonephritis, and acute renal failure (Cunard 2003).  In 
association to immune-checkpoint inhibitors, two different forms of ipilimumab-induced renal 
damage are reported, acute kidney injury due to predominant acute granulomatous 
tubulointerstitial nephritis and nephrotic syndrome in lupus nephritis (Izzedine 2014).  Signs and 
symptoms include increase in serum creatinine, decrease in urine output, peripheral edema, 
hematuria, and loss of appetite.  Subjects should be monitored for elevated serum creatinine prior 
to and periodically during treatment. 
7.10 
Management of Other Toxicities 
If a new onset CTCAE v4.03 Grade ≥ 3 toxicity is observed following study treatment, the 
patient will receive investigation and medical treatment appropriate for the physiological 
abnormalities. 
Grade ≥ 3 toxicity that is attributed to the JCAR014 infusion, is unresponsive to supportive 
measures, or persists for > 7 days may be treated with corticosteroids (e.g., dexamethasone 10 
mg IV every 4 to 12 hours), tocilizumab, or other cytokine-directed therapy after discussion with 
the PI or designee. 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
Schedule of Events 
A tabular schedule of events is provided in Appendix A.  The proposed days of all treatments 
and assessments are approximate and may vary due to scheduling, clinical or other factors. 
Results of tests and procedures previously conducted as standard of care may be used for 
research purposes if conducted within the protocol-defined window. 
8.1.1 
Patient Enrollment 
Eligible patients will be identified and registered into the system by the Clinical Coordinator’s 
Office (CCO; Intake Office) and assigned a UPN (Unique Patient Number).  The CCO will 
register the patient for the protocol through the Data Management Office. 
Patients will initially sign a consent for screening and undergo eligibility blood tests.  Eligible 
patients will then sign a consent for and undergo leukapheresis and restaging.  Enrollment to the 
therapy portion of the study occurs at the conclusion of the pre-T-cell work-up when data are 
reviewed for all inclusion and exclusion criteria for therapy by the Immunotherapy attending 
physician and the patient signs consent for therapy. 
A study number will be allocated to each patient and a log of enrolled patients will be 
maintained.   
8.1.2 
Screening 
The following events will occur during the screening period: 
1) Informed consent for screening 
2) Medical history, including: 
a) Clinical and pathologic data at diagnosis and at the time of enrollment on the study 
b) Prior therapies and response to therapy 
3) Height and weight 
4) Physical examination 
5) Karnofsky performance status 
6) Recording of concomitant medications (see Section 6.6) 
7) Safety laboratory evaluation: 
a) Complete blood count (CBC), differential, and platelet count 
b) Hepatic function panel with LDH and renal function panel with Mg 
c) Puget Sound Blood Center Recipient/Donor Battery Panel 


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d) Pregnancy test for females of reproductive potential 
e) ABO blood typing and antibody screen 
8) Collection of blood samples for research evaluations (see Appendix A and Appendix B) 
 
8.1.3 
Pre-Treatment Evaluation for Study Therapy 
The following events will occur: 
1) Informed consent for leukapheresis and restaging 
2) The patient will undergo leukapheresis 
3) Confirmation of diagnosis by internal pathology review of initial or subsequent biopsy or 
other pathologic material at the FHCRC/SCCA 
4) Collection of archived tissue from most recent tumor biopsy (block or slides), if available 
5) Updated medical history 
6) Physical examination, including neurologic exam 
7) Baseline chest x-ray 
8) Baseline ECG 
9) MUGA or cardiac ECHO 
10) Mini Mental State Examination (MMSE; see Appendix D) 
11) Baseline neuropsychological testing 
12) Assessment of AEs (see Section 9.3.3) 
13) Recording of concomitant medications (see Section 6.6)  
14) Safety laboratory evaluations: 
a) CBC, differential, and platelet count 
b) Hepatic function panel with LDH and renal function panel with Mg 
c) Uric acid 
d) Serum ferritin 
e) CRP 
f) Prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, and D-dimer 
g) Human leukocyte antigen (HLA) typing will be initiated if results from previous test 
are not available 
h) Pregnancy test for females of reproductive potential within 14 days before 
leukapheresis and within 28 days before initiation of lymphodepleting chemotherapy 


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i) Thyroid stimulating hormone (TSH), Free T3, Free T4 
15)  Quantitative IgG 
16)  Collection of blood and biopsy samples for research evaluations (see Appendix A and 
Appendix B). If biopsies are performed for clinical reasons, additional samples may be 
collected for research. 
a) Fresh tumor biopsy in patients who consent to optional biopsies  
17) Restaging 
a) Bone marrow aspirate and biopsy (may be omitted in patients who have had a marrow 
aspirate and biopsy within 30 days before the scheduled JCAR014 infusion AND 
have not received antitumor therapy in the interim) 
b) Diagnostic-quality CT scan and a PET scan (may be omitted in patients who have had 
recent imaging within 30 days before the scheduled JCAR014 infusion AND who 
have not received antitumor therapy in the interim) 
 
8.1.4 
Administration of Lymphodepleting Chemotherapy 
Patients will receive lymphodepleting chemotherapy with either a single dose of 
cyclophosphamide 60 mg/kg (administered on Day -5) and fludarabine 25 mg/m2 daily for 3 
days (administered on Days -4, -3, and -2) or with concurrent cyclophosphamide (300 
mg/m2/day) and fludarabine (30 mg/m2/day (days -4 through -2). Alteration in the timing of 
chemotherapy is permissible for clinical or logistical reasons. 
The following events will occur: 
1) Informed consent for therapy 
2) Safety laboratory evaluations daily during lymphodepleting chemotherapy: 
a) CBC, differential, and platelet count 
b) Hepatic function panel with LDH and renal function panel with Mg 
c) Uric acid 
3) Assessment of AEs (see Section 9.3.3) 
4) Recording of concomitant medications (see Section 6.6) 
5) Administration of allopurinol for TLS prophylaxis, as clinically appropriate 
 


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8.1.5 
Evaluations on the Day of Durvalumab Administration Prior to JCAR014 
Administration (Day -1; Group 2 Only) 
Patients in Group 2 will receive durvalumab on the day prior to JCAR014 administration.  The 
following evaluations will occur at this visit: 
1) Weight prior to the start of the durvalumab infusion  
2) Physical examination prior to the start of the durvalumab infusion.  If there is clinical 
suspicion of neurologic dysfunction, a neurologic examination should be performed. 
3) ECG prior to the start of the durvalumab infusion  
4) Safety laboratory evaluations prior to durvalumab infusion: 
a) CBC, differential, and platelets  
b) Hepatic function panel with LDH and renal function panel with Mg  
c) Uric acid 
5) Collection of blood samples for research evaluations prior to and after durvalumab 
infusion (see Appendix A and Appendix B) 
6) Evaluation of vital signs, including O2 saturation, before, during, and after the infusion 
(see Section 8.3.5) 
7) Assessment of AEs (see Section 9.3.3) 
8) Recording of concomitant medications (see Section 6.6) 
 
8.1.6 
Evaluations on the Day of JCAR014 Infusion (Day 0; Groups 1 and 2) 
The following evaluations will occur for patients in both groups on Day 0, the day of JCAR014 
infusion: 
1) Weight prior to the start of the JCAR014 infusion 
2) Physical examination prior to the start of the JCAR014 infusion.  If there is clinical 
suspicion of neurologic dysfunction, a neurologic examination should be performed. 
3) Karnofsky performance status prior to the start of the JCAR014 infusion  
4) ECG prior to the start of the JCAR014 infusion (patients in Group 1 only) 
5) MMSE prior to the start of the JCAR014 infusion (Appendix D) 
6) Safety laboratory evaluations prior to JCAR014 infusion: 
a) CBC, differential, and platelets  
b) Hepatic function panel with LDH and renal function panel with Mg  
c) Uric acid 


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d) Serum ferritin 
e) CRP 
f) PT, PTT, fibrinogen, and D-dimer 
7) Collection of blood samples for research evaluations prior to JCAR014 infusion (see 
Appendix A and  Appendix B) 
8) Evaluation of vital signs, including O2 saturation, before, during, and after the infusion 
(see Section 8.3.5) 
9) Assessment of AEs (see Section 9.3.3) 
10)  Recording of concomitant medications (see Section 6.6) 
 
8.1.7 
Evaluations after the JCAR014 Infusion and prior to the First Post-JCAR014 
Durvalumab Infusion (Groups 1 and 2) 
The following evaluations will be performed between the JCAR014 infusion and the first post-
JCAR014 durvalumab infusion. If no durvalumab is given, evaluations should be performed until 
6 weeks after JCAR014 administration:  
1) Physical examination 1 day after the JCAR014 infusion, twice weekly for the first 2 
weeks after JCAR014 infusion, then at least weekly.  If there is clinical suspicion of 
neurologic dysfunction, a neurologic examination should be performed. 
2) MMSE on approximately Day 7 and Day 14 after JCAR014 infusion 
3) Assessment of AEs (see Section 9.3.3) 
4) Recording of concomitant medications (see Section 6.6) 
5) Safety laboratory evaluations twice weekly for the first 2 weeks after JCAR014 infusion 
and then at least weekly: 
a) CBC, differential, and platelets (a CBC with differential should be drawn 
concurrently with JCAR014 persistence samples) 
b) Hepatic function panel with LDH and renal function panel with Mg  
c) Uric acid 
d) Serum ferritin 
e) CRP 
f) PT, PTT, fibrinogen, and D-dimer 
If patients become febrile or develop symptoms of CRS or TLS between the indicated 
timepoints, serum ferritin, CRP, or tumor lysis markers (e.g., chemistry, uric acid, LDH) 
may be measured at additional times, as clinically indicated. 


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6) Collection of blood and biopsy samples for research evaluations (see Appendix A and 
Appendix B). If biopsy or sampling of tissues is performed for clinical indications, then 
additional tissue may be obtained during the same procedure for research studies. The 
planned procedure should be discussed with the PI. 
a) If patients become febrile or develop possible signs of toxicity between the indicated 
timepoints, the persistence of transferred T cells and serum/plasma biomarkers may 
be measured at additional times, as clinically indicated. Samples may be 
cryopreserved for future analyses. 
b) For patients who consented to optional biopsies, a fresh tumor biopsy may be 
performed within the first 4 weeks after the JCAR014 infusion for research 
evaluations. Variation in timing of the biopsy due to logisitical or clinical reasons is 
acceptable. In the event of persistent mass, relapse or progression, a biopsy may be 
collected at that time point. 
7) Restaging: 
a) CT and PET scans (see Section 8.1.10) 
b) Bone marrow aspirate and biopsy, if applicable (see Section 8.1.10) 
 
8.1.8 
Evaluation on the Day of each Post-JCAR014 Durvalumab Administration 
(Groups 1 and 2) 
The following evaluations will occur on the day of each post-JCAR014 durvalumab infusion 
(e.g., approximately Days 28, 56, 84; first infusion may occur as early as Day 7 in Group 1): 
1) Weight prior to the start of the durvalumab infusion  
2) Physical examination prior to the start of the durvalumab infusion.  If there is clinical 
suspicion of neurologic dysfunction, a neurologic examination should be performed. 
3) Karnofsky performance status prior to the start of the durvalumab infusion 
4) ECG prior to the start of the durvalumab infusion (first and third post-JCAR014 
durvalumab cycles only) 
5) MMSE (first post-JCAR014 durvalumab cycle only) (Appendix D)  
6) Safety laboratory evaluations prior to durvalumab infusion: 
a) CBC, differential, and platelets  
b) Hepatic function panel with LDH and renal function panel with Mg  
c) Uric acid 
d) Serum ferritin 
e) CRP  


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f) PT, PTT, fibrinogen, and D-dimer 
g) Quantitative IgG 
7) Collection of blood samples for research evaluations prior to and after durvalumab 
infusion (see Appendix A and Appendix B).  
8) Evaluation of vital signs, including O2 saturation, before, during, and after the infusion 
(see Section 8.3.5) 
9) Assessment of AEs (see Section 9.3.3) 
10) Recording of concomitant medications (see Section 6.6) 
 
8.1.9 
Post-Infusion Evaluations during Cycles of Durvalumab Administration 
8.1.9.1 
First Post-JCAR014 Durvalumab Cycle (Groups 1 and 2) 
Post-infusion evaluations during the first post-JCAR014 cycle of durvalumab will include the 
following: 
1) Physical examination 1 day after the durvalumab infusion, twice weekly for the first 2 
weeks after durvalumab infusion, then at least weekly.  If there is clinical suspicion of 
neurologic dysfunction, a neurologic examination should be performed. 
2) MMSE approximately 7 and 14 days after durvalumab infusion 
3) Assessment of AEs (see Section 9.3.3) 
4) Recording of concomitant medications (see Section 6.6) 
5) Safety laboratory evaluations twice weekly for the first 2 weeks after durvalumab 
infusion and then at least weekly: 
a) CBC, differential, and platelets  
b) Hepatic function panel with LDH and renal function panel with Mg  
c) Uric acid 
d) Serum ferritin 
e) CRP 
f) PT, PTT, fibrinogen, and D-dimer 
If patients become febrile or develop symptoms of CRS or TLS between the indicated 
timepoints, serum ferritin, CRP, tumor lysis markers (e.g., chemistry, uric acid, LDH) 
may be measured at additional times, as clinically indicated. 


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6) Collection of blood and biopsy samples for research evaluations (see Appendix A and 
Appendix B). If biopsy or sampling of tissues is performed for clinical indications, then 
additional tissue may be obtained during the same procedure for research studies.  The 
planned procedure should be discussed with the PI. 
a) If patients become febrile or develop possible signs of toxicity between the indicated 
timepoints, the persistence of transferred T cells and serum/plasma biomarkers may 
be measured at additional times, as clinically indicated. Samples may be 
cryopreserved for future analyses. 
b) For patients who consented to optional biopsies, a fresh tumor biopsy may be 
performed approximately  within the first 4 weeks after the durvalumab infusion for 
research evaluations. Variation in timing of the biopsy due to logisitical or clinical 
reasons is acceptable. In the event of persistent mass, relapse or progression, a biopsy 
may be collected at that time point. 
7) Restaging 
a) CT and PET scans (see Section 8.1.10) 
b) Bone marrow aspirate and biopsy, if applicable (see Section 8.1.10) 
8) Quantitative IgG prior to the subsequent dose of durvalumab as clinically indicated. 
8.1.9.2 
Subsequent Durvalumab Cycles (Groups 1 and 2) 
The following post-infusion evaluations will be performed in subsequent durvalumab cycles: 
1) Physical examination approximately every 2 weeks.  If there is clinical suspicion of 
neurologic dysfunction a neurologic examination should be performed.  
2) Assessment of AEs (see Section 9.3.3) 
3) Recording of concomitant medications 
4) Safety laboratory evaluations approximately every 2 weeks 
a) CBC, differential, and platelet count 
b) Hepatic function panel with LDH and renal function panel 
c) Uric acid 
d) Serum ferritin 
e) CRP 
f) PT, PTT, fibrinogen, and D-dimer 
5) Collection of blood and biopsy samples for research evaluations (see Appendix A and 
Appendix B). If biopsy or sampling of tissues is performed for clinical indications, then 
additional tissue may be obtained during the same procedure for research studies. The 
planned procedure should be discussed with the PI. 


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a) If patients become febrile or develop possible signs of toxicity between the indicated 
timepoints, the persistence of transferred T cells and serum/plasma biomarkers may 
be measured at additional times, as clinically indicated. Samples may be 
cryopreserved for future analyses. 
b) For patients who consented to optional biopsies, a fresh tumor biopsy may be 
performed approximately  within the first 4 weeks after the durvalumab infusion for 
research evaluations. Variation in timing of the biopsy due to logisitical or clinical 
reasons is acceptable. In the event of persistent mass, relapse or progression, a biopsy 
may be collected at that time point. 
6) Restaging scans (see Section 8.1.10) should be coordinated to occur approximately 4 
weeks after treatment with durvalumab and prior to the next cycle. 
If clinically indicated, such as in the event of JCAR014 expansion and persistence with 
JCAR014-related toxicity, clinical assessments and safety laboratory evaluations may be 
performed in these subsequent cycles of durvalumab with the same frequency recommended in 
the first post-JCAR014 durvalumab cycle (see Section 8.1.9.1). 
Post-infusion evaluations including physical examination, scans, and laboratory evaluations may 
be performed at an outside facility.  Blood samples for research evaluations may be collected at 
an outside facility and shipped to Fred Hutchinson Cancer Research Center. 
8.1.10 
Restaging Studies and Response Assessment 
The following evaluations will be performed for restaging and assessment of response: 
1) A PET scan and a CT scan (preferably diagnostic quality) of the neck, chest, abdomen, 
and pelvis should be obtained approximately 1, 2, 4, 6, 9, and 12 months after the 
JCAR014 infusion.  Scans should be performed until 12 months after JCAR014 or 90 
days after the last dose of durvalumab, whichever is longer.  This will result in restaging 
scans at the following timepoints relative to durvalumab: 
a) Prior to the first dose of durvalumab in Group 1 – late (may occur after first dose of 
durvalumab in the case of patients receiving durvalumab in Group 1 – early) and prior 
to the second dose of durvalumab in Group 2 
b) Approximately 4 weeks after the first post-JCAR014 durvalumab dose 
c) Approximately every other durvalumab cycle until 6 months post-JCAR014, then 
every 3 months until 12 months post-JCAR014 or 90 days after the last dose of 
durvalumab, whichever is later 
PET and CT scans may be performed before first dose of durvalumab in Group 1 – early. 
PET and CT scans are not required if progressive disease has been documented on 
previous imaging.  PET scans are not required for patients with documented CR unless 
progression is suspected on CT, in which case, a PET scan should be performed. 


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2) Bone marrow aspirate and biopsy may be done at the time of the 1-month post-JCAR014 
restaging assessment, and at other timepoints as clinically indicated, in patients with 
lymphoma involvement documented at baseline until the patient achieves a CR. 
The Lugano Classification (as detailed in Appendix B) will be used to define tumor response. 
Evaluation of tumor response may be discontinued in patients who proceed to other antitumor 
therapies. 
8.1.11 
Follow-Up Evaluations 
The following evaluations will occur every 30 days for the first 3 months following 
administration of the last dose of study therapy (durvalumab or JCAR014) and then every 3 
months until 12 months after JCAR014 or 90 days after the last dose of durvalumab, whichever 
is longer: 
1) Physical examination.  If there is clinical suspicion of neurologic dysfunction, a 
neurologic examination should be performed. 
2) ECG at 1 month after the last dose of study therapy (durvalumab or JCAR014)  
3) Neuropsychological testing at approximately 2 months after JCAR014 administration 
4) Assessment of AEs 
5) Recording of concomitant medications (see Section 6.6) 
6) Safety laboratory evaluations: 
a) CBC, differential, and platelet count 
b) Hepatic function panel with LDH and renal function panel with Mg 
c) Quantitative IgG, if clinically indicated 
7) Collection of blood and biopsy samples for research evaluations (see Appendix A and 
Appendix B). If biopsy or sampling of tissues is performed for clinical indications, then 
additional tissue may be obtained during the same procedure for research studies. The 
planned procedure should be discussed with the PI. 
a) If patients become febrile or develop possible signs of toxicity between the indicated 
timepoints, the persistence of transferred T cells and serum/plasma biomarkers may 
be measured at additional times, as clinically indicated. Samples may be 
cryopreserved for future analyses. To evaluate re-expansion of JCAR014 and/or 
toxicity, research biomarker and/or T cell persistence samples may also be collected 
from patients who are planned for or have received subsequent treatment with a 
different CAR-T cell product. 
During the follow-up period, physical examination, scans, and laboratory evaluations may be 
performed at an outside facility.  Blood samples for research evaluations may be collected at an 
outside facility and shipped to Fred Hutchinson Cancer Research Center. 


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8.1.12 
Retreatment 
Patients may be eligible for retreatment with JCAR014 ± durvalumab if at least 3 months have 
elapsed since the last dose of durvalumab.  Patients may be treated with the highest tested doses 
determined to be safe; the schedule of evaluations will follow the primary treatment schedule.  
Durvalumab-related assessments will not be conducted in patients who receive retreatment with 
JCAR014 only. 
8.1.13 
Long-Term Follow-Up 
Enrolled patients who receive JCAR014 will be asked to participate in long-term follow-up 
(LTFU) for a minimum of 15 years according to the guidelines set forth by the FDA’s Biologic 
Response Modifiers Advisory Committee that apply to gene transfer studies (see Appendix E). 
8.1.14 
Death 
Death is an expected outcome during this study due to the nature of the disease being treated.  
All deaths must be reported.  
During the informed consent process, the patient may be informed that in the event of their 
death, their next of kin may be asked if they consent to an autopsy being performed on the 
patient.  Autopsy reports may be collected.  The cause of death will be recorded if available. 
If an autopsy is performed, tissue samples should be collected where feasible for evaluation of 
the presence of JCAR014 cells in brain, liver, kidney, lungs, bone marrow, blood, heart, 
reproductive organs, and any sites of disease. 
8.2 
Efficacy Assessments 
Treatment response will be assessed by radiographic tumor evaluation at protocol-specified 
timepoints by diagnostic quality CT scans (chest, neck, abdomen, and pelvis) and PET scans, 
where feasible (see Section 8.1.10).  Disease response will be determined using the Investigator’s 
assessment according to the “Recommendations for Initial Evaluation, Staging, and Response 
Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification” (Cheson 
2014) as described in Appendix C.  Evaluation of tumor response may be discontinued in 
patients who proceed to other antitumor therapies. 
8.3 
Safety Assessments 
Safety will be monitored by physical examination, laboratory evaluation, neurologic 
examination, as well as by collecting appropriate AEs.  Details for AE collection and reporting 
are provided in Section 9.3.3. 


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8.3.1 
Physical Examination 
A physical examination should include assessments of the following body parts/systems: 
abdomen, extremities, heart, lungs, and routine neurological examination.  In addition, symptom-
directed exams should be performed. 
8.3.2 
Clinical Laboratory Evaluation 
Screening and other laboratory evaluations (see Table 6) will be performed according to 
Appendix A.  Additional assessments should be performed between scheduled study visits as 
clinically required in order to diagnose and monitor AEs or expected events.  The Investigator 
will assess the clinical significance of each applicable laboratory value that falls outside of the 
institutional reference range.  This decision should be based upon the nature and degree of the 
observed laboratory abnormality.  Values that are considered by the Investigator to be clinically 
significant and/or related to JCAR014 and/or durvalumab will be noted.  The Investigator may 
choose to repeat any abnormal test once in order to rule out laboratory or sample collection error.  
Table 6: 
Analytes for Clinical Laboratory Evaluation 
Laboratory Panel 
Analytes 
Hepatic function panel 
Albumin, total and direct bilirubin, alkaline phosphatase, ALT (SGPT), AST 
(SGOT), lactate dehydrogenase (LDH) 
Renal function panel 
Sodium, chloride, potassium, CO2, anion gap, glucose, blood urea nitrogen (BUN), 
creatinine, albumin, calcium, phosphate, magnesium, GFR 
CBC with differential and 
platelet count 
WBC, RBC, hemoglobin, hematocrit, MCV, MCH, MCHC, platelet count, RDW-
CV, % neutrophils, % lymphocytes, % eosinophils, % basophils, % immature 
granulocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils, 
immature granulocytes 
Coagulation 
PT, PTT, fibrinogen, and D-dimer 
PSBC recipient/donor 
battery panel 
HBsAg; anti-HIV-1, 2; anti-HBc; anti-HTLV-1, 2; anti-HCV 
Inflammatory markers 
CRP, ferritin 
Immunoglobulins 
IgG 
 
8.3.3 
Routine Neurological Examination 
A routine neurological exam should include, at minimum, a physical exam to assess cranial 
nerves, motor and sensory function, and coordination and balance.  In addition, the Mini Mental 
Status Examination (MMSE; see Appendix D) will be administered pre-treatment and at 
timepoints post-JCAR014 infusion and post-durvalumab infusion (see Appendix A).  The 
MMSE may be administered by an appropriately trained provider (i.e., physician, nurse, study 
personnel); a neurologist is not required. 


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8.3.4 
Formal Neuropsychological Tests 
A formal neuropsychological test will be conducted pre-treatment and at approximately 2 months 
after JCAR014 administration.  This evaluation will be performed by appropriately trained 
personnel and will include, at minimum, evaluation of information processing, attention, verbal 
fluency, executive function, and memory. Formal neuropsychological testing will be conducted 
in English-speaking subjects only. 
8.3.5 
Vital Signs 
Vital signs include temperature, respiratory rate, heart rate, blood pressure, and SaO2 by pulse 
oximetry.  On the days of JCAR014 or durvalumab administration, vital signs, including SaO2, 
should be measured at approximately the following times:   
• Prior to the start of infusion 
• Every 15 minutes (± 5 minutes) during the infusion 
• Within 5 minutes after the end of infusion 
• 30 minutes after the end of the infusion 
• 60 minutes after the end of the infusion 
• 2 hours after the end of the infusion 
 
8.3.6 
CSF Examination and CNS Symptom Assessment 
CSF assessments and CNS imaging should be performed as clinically indicated (e.g., if new 
CNS symptoms occur, or if clinical signs or suspicion of CNS lymphoma exist).  CSF will be 
analyzed for cell count and differential cytology, and where feasible for the presence of 
JCAR014.  CSF cultures (bacterial, fungal, viral) should be performed as clinically indicated for 
suspicion of infection. 
8.3.7 
Karnofsky Performance Status 
Karnofsky performance status (see Table 7) will be used to evaluate patient eligibility at 
screening and will be assessed throughout the study at timepoints specified in Appendix A. 
 
 
 


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Table 7: Karnofsky Performance Status Scale Definitions Rating (%) Criteria 
Description 
Score 
Criteria 
• 
Able to carry on normal 
activity and to work 
• 
No special care needed 
100 
Normal, no complaints; no evidence of disease 
90 
Able to carry on normal activity; minor signs of symptoms of disease 
80 
Normal activity with efforts; some signs or symptoms of disease 
• 
Unable to work 
• 
Able to live at home and 
care for most personal needs 
• 
Varying amount of 
assistance needed 
70 
Cares for self; unable to carry on normal activity or do active work 
60 
Requires occasional assistance, but is able to care for most of 
personal needs 
50 
Requires considerable assistance and frequent medical care 
• 
Unable to care for self 
• 
Requires equivalent of 
institutional or hospital care 
• 
Disease may be progressing 
rapidly 
40 
Disabled; requires special care and assistance 
30 
Severely disabled; requires special care and assistance 
20 
Very sick; hospital admission necessary; active supportive treatment 
necessary 
10 
Moribund; fatal processes progressing rapidly 
0 
Dead 
 
8.3.8 
MUGA/Echocardiogram 
An assessment of LVEF will be performed by ECHO or MUGA to assess the cardiac function of 
the patient and to confirm study eligibility. 
8.3.9 
Electrocardiogram 
A standard 12-lead ECG should be obtained. 
8.4 
Research Assessments 
Peripheral blood, bone marrow biopsies and aspirates, and tumor biopsies may be collected for 
these biomarker studies.  The volumes and timepoints for collection of these evaluations are 
listed in Appendices A and Appendix B. 
8.4.1 
Pharmacokinetic Assessments 
Assessment of JCAR014 PK will be determined by quantitative PCR (qPCR) to detect the 
JCAR014 transgene and/or by flow cytometry to enumerate the number and immunophenotype 
of JCAR014 cells.  Peripheral blood and bone marrow will be collected as indicated in Appendix 
A. 
Assessment of durvalumab PK will be determined by a validated immunoassay on serum 
samples. 


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8.4.2 
RCL Testing 
In accordance with FDA guidelines (Food and Drug Administration 2000, Food and Drug 
Administration 2006), peripheral blood samples will be tested for RCL during screening and at 3, 
6, and 12 months following the JCAR014 infusion.  Additional blood samples will be collected 
annually for up to 15 years following JCAR014 administration (see Appendix E)  
8.4.3 
Immunogenicity Assessments 
Humoral immune responses to JCAR014 will be assessed in selected patients.  Samples from 
patients who have two consecutive negative assays for JCAR014 persistence or who have 
recovered endogenous B cells will be prioritized for humoral immune response analysis. 
Humoral responses will be evaluated by testing plasma in an anti-therapeutic antibody (ATA) 
assay in which binding to the extracellular region of JCAR014 is measured in patients who have 
B cell recovery or undetectable levels of JCAR014. Cellular immune responses to JCAR014 will 
be considered in patients who have two consecutive negative assays for JCAR014 or who have 
recovered endogenous B cells.  Cellular responses to JCAR014 will be evaluated by assessing 
reactivity of patient peripheral T cells to JCAR014.  Peripheral blood will be collected for these 
studies at the timepoints indicated in Appendix A. 
The levels of ADA directed against durvalumab will be assessed using a validated immunoassay 
in serum samples. 
8.4.4 
Biomarker Assessments 
Biomarker assessments may include immunophenotypic evaluation of JCAR014 and endogenous 
immune cell subsets, characterization of tumor and tumor microenvironment, assessment of 
serum biomarkers associated with CRS and immune cell function, and pharmacodynamic 
markers of therapeutic activity.  Peripheral blood, lymphoma and bone marrow biopsies, bone 
marrow aspirates, and CSF (only if lumbar puncture indicated for clinical purposes) will be 
collected for these evaluations.  Assays will be prioritized based on availability of tissue and the 
clinical situation.  
Flow cytometry may be used to determine the phenotype of JCAR014 cells and to enumerate 
immune cell subsets in the blood, bone marrow, and CSF (if applicable).  These studies aim to 
identify cellular markers correlated with JCAR014 function as well as safety and efficacy.  As 
one component of this analysis, the absence of normal B cells in blood or bone marrow, if 
obtained, will be determined by flow cytometry as a pharmacodynamic marker of JCAR014 
activity. 
Serum/plasma biomarkers may be measured as a marker of immune activation.  Potential 
correlations between cytokine production and efficacy and severity of CRS will be assessed.  
Single nucleotide polymorphism (SNP), targeted mutational analysis, whole exome/genome 
sequencing, and/or gene expression analysis (e.g., RNA-Seq) may be conducted on JCAR014 
cells pre-treatment, or isolated from peripheral blood and bone marrow aspirates post-treatment, 


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as well as tumor cells isolated from lymph node biopsies, in order to identify markers or 
signatures correlating with clinical response.  T-cell receptor repertoire may also be assessed 
through sequencing analysis of the peripheral blood. 
Soluble PD-L1 levels before and after treatment with durvalumab will be measured in serum 
samples. 
The presence and distribution of specific cellular elements within the tumor and the tumor 
microenvironment may be assessed by immunohistochemistry on tumor biopsies to correlate the 
presence of these factors with response, duration of response, and/or JCAR014 persistence and 
function.  Analyses to detect lymphoma cells in the peripheral blood may be performed. 
Lymphoma biopsy specimens may be collected for immunohistochemical evaluation of 
JCAR014 infiltration and prevalence, markers of JCAR014 phenotype and function, and location 
of JCAR014 relative to CD19+ tumor cells.  Immunoregulatory pathways operative in the tumor 
microenvironment may influence the fate and function of adoptively transferred JCAR014 T 
cells.  The data collected in these biomarker assessments may be used in aggregate to elucidate 
relationships between CAR T-cell function, persistence and efficacy, and molecules present in 
the tumor microenvironment. 
9. 
ADVERSE EVENT REPORTING 
9.1 
Definitions 
9.1.1 
Adverse Event 
An adverse event (AE) is the development of any untoward medical occurrence or the clinical 
deterioration of a pre-existing medical condition in a patient or clinical study patient 
administered a medicinal product (e.g., JCAR014 and/or durvalumab). 
9.1.2 
Serious Adverse Event 
A serious adverse event (SAE) is defined as an AE occurring at any dose that meets one or more 
of the following criteria: 
• Results in death 
• Is life-threatening 
An AE or adverse reaction is considered “life-threatening” if, in view of the Investigator, its 
occurrence places the patient at immediate risk of death.  It does not include an event that, 
had it occurred in a more severe form, might have caused death. 
• Requires inpatient hospitalization or prolongation of an existing hospitalization (see NOTE 
below) 
• Results in a persistent or significant disability/incapacity 
• Is a congenital anomaly or birth defect 


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• Is an important medical event, as determined by the Investigator that may jeopardize the 
patient or may require medical intervention to prevent one of the outcomes listed above.   
For reporting purposes, any suspected transmission via a medicinal product of an infectious 
agent is also considered a SAE and may be subject to expedited reporting requirements in 
some countries.  Any organism, virus or infectious particle (for example prion protein 
transmitting transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. 
NOTE: 
The following hospitalizations are not considered SAEs in this study: 
• Admission to the hospital for social or situational reasons (e.g., no place to stay, live too far 
away to come for hospital visits) 
• Hospitalization at the discretion of the Investigator for administration of study therapy 
(JCAR014 or durvalumab) or for ease of clinical monitoring 
• Hospitalization for elective or pre-planned treatment for a pre-existing condition that is 
unrelated to the condition under study and has not worsened since signing informed consent 
 
9.1.3 
Adverse Events of Special Interest 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
the further understanding of the investigational product and which should be closely monitored.  
An AESI may be serious or nonserious.  The rapid reporting of AESIs allows ongoing 
surveillance of these events in order to characterize and understand them in association with the 
use of this investigational product. 
AESIs for durvalumab include, but are not limited to, events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants, and/or hormone replacement therapy.  
These AESIs are being closely monitored in clinical studies with durvalumab monotherapy and 
combination therapy.  An immune-related adverse event (irAE) is defined as an adverse event 
that is associated with drug exposure, is consistent with an immune-mediated mechanism of 
action, and where there is no clear alternate aetiology.  Serologic, immunologic, and histologic 
(biopsy) data, as appropriate, should be used to support an irAE diagnosis.  Appropriate efforts 
should be made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of 
the irAE.  
If the Investigator has any questions in regards to an AE being an irAE, the Investigator should 
promptly contact the Juno Medical Director. 
The following AEs are considered AESIs: 


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• Colitis 
• Pneumonitis 
• ALT/AST increases / hepatitis / hepatotoxicity  
• Neuropathy / neuromuscular toxicity (i.e., events of encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis) 
• Endocrinopathy (i.e., events of hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism) 
• Dermatitis 
• Nephritis 
• Pancreatitis or laboratory abnormalities suggestive of pancreatitis, e.g., increased serum 
lipase, increased serum amylase 
Further information on these risks (e.g., presenting symptoms) can be found in the current 
version of the durvalumab Investigator Brochure.  More specific guidelines for their evaluation 
and treatment are described in detail in Appendix G. 
9.2 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
Laboratory abnormalities (e.g., clinical chemistry, hematology, and urinalysis) and other 
abnormal assessment findings (e.g., ECG or vital signs) that meet at least one of the following 
criteria should be recorded as an AE or SAE: 
• Investigator determines it is clinically significant  
• Requires medical or surgical intervention  
• Leads to product discontinuation, delay or interruption 
• Associated with clinical signs and/or symptoms 
Laboratory abnormalities without clinical significance should not be recorded as AEs or SAEs. 
Whenever possible, the clinical diagnosis, rather than the laboratory result, should be reported by 
the Investigator (e.g., anemia versus low hematocrit).  
Clinically significant abnormal laboratory values occurring during the study will be followed 
until repeat tests return to normal, stabilize, or are no longer clinically significant. 
9.3 
Assessment of Adverse Events and Serious Adverse Events 
Each AE and SAE is to be evaluated for duration, severity, and causal relationship with 
JCAR014 and durvalumab. 


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9.3.1 
Grading and Intensity of Adverse Events 
The NCI CTCAE, version 4.03 (http://ctep.cancer.gov/reporting/ctc.html) will be used for 
grading and analysis of all AEs, with the exception of CRS, which will be graded according to 
the criteria outlined in Section 7.1.  If CTCAE criteria do not exist for a given event, the 
Investigator should use one of the following: 
• Grade 1: Mild – An event that is usually transient in nature and generally not interfering with 
activities, the AE is generally easily tolerated, does not require treatment. 
• Grade 2: Moderate – An event that produces discomfort sufficient to interfere with some 
aspect of the patient’s usual activity and may require medical intervention. 
• Grade 3: Severe – An event that results in discomfort or disability which is incapacitating 
and preventing most normal daily activities and requires medical intervention and/or close 
follow up.  
• Grade 4: Life-threatening – An event that could reasonably result in a potential threat to life. 
• Grade 5: Fatal – The AE results in death. 
 
9.3.2 
Relationship to Study Drug 
To ensure that investigative treatment-related conditions are distinguished from disease-related 
conditions, attribution of causality will be established in grading AEs. For each event, the 
Investigator or designee, in conjunction with data from the physician, research nurse, or other 
provider who examined and evaluated the research participant, will assign the attribution.   
Attribution of AEs to study therapy (JCAR014 and/or durvalumab) should be determined using 
the following criteria: 
• No (not related): 
The time course between administration of study therapy and the occurrence or worsening of 
the AE likely rules out a causal relationship and/or another cause (concomitant drugs, 
therapies, complications, etc.) is suspected and more plausible. 
• Yes (related): 
The time course between administration of study therapy and the occurrence of or worsening 
of the AE is consistent with a causal relationship, and no other cause is likely. 
9.3.3 
Adverse Event Collection and Reporting 
Whenever possible, AEs should be recorded as a diagnosis rather than listing of signs and 
symptoms.  If an observed or reported sign or symptom is not considered a component of a 
disease or syndrome by the Investigator, it should be recorded as a separate AE.  While CRS will 


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be collected as an AE, the individual signs and symptoms of CRS will be collected separately for 
analysis.  
9.3.3.1 
Non-Serious Adverse Event Reporting 
From the time of initial consent up to initiation of lymphodepleting conditioning chemotherapy, 
AEs will not be recorded unless they are related to study procedures, or ongoing at the start of 
lymphodepleting chemotherapy. 
All Grade 3 or greater AEs will be collected during and for 48 hours after leukapheresis. 
All AEs that begin between the first dose of lymphodepleting conditioning chemotherapy and 30 
days after the final dose of study treatment (JCAR014 or durvalumab) will be collected and 
recorded. 
All AEs considered related to either JCAR014 or durvalumab should be collected and recorded 
until 12 months after JCAR014 infusion or 90 days after the final durvalumab infusion, 
whichever is longer.  
The collection of AEs will stop at the commencement of new systemic antitumor therapy.  
9.3.3.2 
Serious Adverse Event Reporting 
From the time of initial informed consent up to initiation of lymphodepleting chemotherapy, only 
protocol-related SAEs will be collected.  All SAEs that occur after initiation of lymphodepleting 
chemotherapy up to 30 days following the final dose of study therapy (JCAR014 or durvalumab) 
must be collected and reported to Juno Therapeutics.  After the 30 day post-treatment timeline, 
only SAEs considered related to study therapy (JCAR014 or durvalumab) must be reported to 
Juno Therapeutics. 
All SAEs must be followed until the SAE has resolved or until the condition becomes chronic in 
nature, stabilizes (in the case of persistent impairment), or the patient dies. 
All follow-up information must be submitted to Juno Therapeutics.  Serious adverse events must 
also be reported to the reviewing IRB per IRB requirements (see Section 9.4); a copy of that 
report must be retained at the site and filed in the study files in accordance with the requirements 
of that institution. 
Serious adverse events will be reported to the FDA and to the National Institutes of Health (NIH) 
Office of Biotechnology Biosafety Program within the appropriate reporting timelines in 
accordance with Federal Regulations (i.e., 21 CFR §312.32) and the NIH Guidelines for 
Research Involving Recombinant or Synthetic Nucleic Acid Molecules, respectively. 


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9.3.4 
Death 
Any death from the time the patient provides informed consent through 8 weeks after the final 
dose of study therapy (JCAR014 or durvalumab) should be reported as an SAE (Section 9.3.3.2).  
Deaths that occur more than 8 weeks after the final dose of study therapy (JCAR014 or 
durvalumab) will be reported as SAEs only if considered related to JCAR014 or durvalumab.  
If the patient’s death is not related to progression of disease, the cause of death will be evaluated 
to determine if it was related to JCAR014 or durvalumab treatment. 
9.3.5 
Pregnancy 
To ensure patient safety, each pregnancy occurring in a female patient or in the female partner of 
a male patient from the time of consent until 90 days after the final study treatment must be 
recorded.  If the pregnancy is discovered following initiation of study therapy (JCAR014 or 
durvalumab), the pregnancy should be followed to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications.   
9.4 
IRB Reporting Requirements 
Definitions associated with reportable events and reporting requirements can be found on the 
FHCRCs Institutional Review Office (IRO) extranet website.  
The FHCRC PI and study personnel should meet regularly (in person or via teleconference) to 
review all reported events. The FHCRC IRB and IND Sponsor will be notified of reportable 
events by the FHCRC PI or study nurse according to current FHCRC IRB reporting obligations.  
Reporting of unanticipated adverse effects to the FDA will be the responsibility of the sponsor 
(see Section 9.5) 
Classification of an event as serious or non-serious determines the reporting procedures to be 
followed by the site for reporting the event to the Sponsor.  
PI to Sponsor reporting requirements for adverse events are summarized below: 
Classification 
Reporting Time* 
Reporting Action 
SAE 
Fatal or life-
threatening 
Within 24 hours of 
study team awareness 
Email notification to Sponsor & 
PI 
All other SAEs 
Within 2 business days 
of study team 
awareness 
Email notification to Sponsor & 
PI 
*In Title 21 CFR 312.64 the term “Immediate” is interpreted by the immunotherapy program in the Reporting Time column  


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9.5 
FDA Reporting Requirements 
As a study conducted under IND regulations, we will comply with the FDA regulations 
regarding safety reporting 21 CFR §312.32 including the following requirements: 
• A sponsor must promptly review all information relevant to the safety of the drug 21 CFR 
§312.32 (b). 
• A sponsor must notify the FDA in an IND safety report of potential serious risks, as soon as 
possible but in no case later than 15 calendar days after the sponsor determines that the 
information qualifies for reporting under 21 CFR §312.32 (c)(1).  Information that is required 
to be reported includes, but is not limited to, (a) serious and unexpected adverse reactions 
and (b) an increased rate of occurrence of serious suspected adverse reactions.  
• The IND safety report must be completed and sent to the FDA in a narrative format, on FDA 
Form 3500A, or an electronic format. 
• A sponsor must also notify the 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 21 CFR §312.32 (c)(2). 
9.6 
Steering Committee 
The Steering Committee (SC), comprising the PI and/or designee and IND Sponsor, and 
representatives (medical director/s-) from Juno Therapeutics and MedImmune and statistician 
from FHCRC, will act in an advisory capacity to the PI/Sponsor throughout the trial, as needed. 
The decision to proceed to Group 2 will be made in consultation with the SC. The PI and IND 
Sponsor may override the algorithm’s allocation of a patient to a particular dose level or 
schedule. 
9.7 
Data Safety Monitoring Plan 
9.7.1 
Definition of Risk Level 
This Phase 1b trial involves genetic modification of somatic cells and requires an IND.  At the 
FHCRC, this type of trial requires independent monitoring twice each year through the Clinical 
Research Support Office at the FHCRC, and through an independent Data Safety Monitoring 
Board (Section 9.7.3). 
Institutional support of trial monitoring will be in accordance with the FHCRC/University of 
Washington Cancer Consortium Institutional Data and Safety Monitoring Plan.  Under the 
provisions of this plan, FHCRC Clinical Research Support coordinates data and compliance 
monitoring conducted by consultants, contract research organizations, or FHCRC employees 
unaffiliated with the conduct of the study.  Independent monitoring visits occur at specified 
intervals determined by the assessed risk level of the study and the findings of previous visits per 
the institutional DSMP. 


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In addition, protocols are reviewed at least annually and as needed by the Consortium Data and 
Safety Monitoring Committee (DSMC), FHCRC Scientific Review Committee (SRC) and the 
FHCRC/University of Washington Cancer Consortium Institutional Review Board (IRB).  The 
review committees evaluate accrual, adverse events, stopping rules, and adherence to the 
applicable data and safety monitoring plan for studies actively enrolling or treating patients.  The 
IRB reviews the study progress and safety information to assess continued acceptability of the 
risk-benefit ratio for human subjects.  Approval of committees as applicable is necessary to 
continue the study. 
The trial will comply with the standard guidelines set forth by these regulatory committees and 
other institutional, state and federal guidelines. 
9.7.2 
Monitoring and Personnel Responsible for Monitoring 
The PI and IND Sponsor are responsible for every aspect of the design, conduct, and final 
analysis of the protocol.  Regulations defining the responsibilities for assessment and reporting 
of AEs, SAEs, and unexpected AEs are defined by the Code of Federal Regulations: 21 CFR 
312.32 and CTCAE Version 4.03 published by the Cancer Therapy Evaluation Program (CTEP), 
a division of the NCI/NIH. 
This clinical study will rely upon the monitoring of the trial by the PI in conjunction with Study 
Physician(s), Physician Assistant(s) (PA), or Nurse Practitioner(s), Research Nurse(s), Research 
Coordinator(s), statistician, and an independent Study Monitor assigned by the FHCRC Clinical 
Research Support Office (CRS).  Juno Therapeutics will perform targeted data verification of 
key study safety and outcome measures. 
Continuous monitoring of the data and safety of this study should be performed by the Protocol 
Management Team (PMT), which consists of the PI and study personnel.  Monitoring by the 
PMT should be performed at least monthly or more often if necessitated by the development of 
AEs, and should include review of the data on enrolled patients.  The PMT will be responsible 
for implementation of the stopping rules for safety if necessary. 
A case report form (CRF) should be completed for every patient who is registered for 
participation in the study.  The PI or a Co-Investigator will sign and date the indicated places of 
the CRF.  This signature will indicate that thorough inspection of the data therein has been made, 
and will certify the contents of the form. 
9.7.3 
Data Safety Monitoring Board 
The study will be monitored by the Immunotherapy Integrated Research Center (IIRC) DSMB.  
The DSMB will be responsible for safeguarding the interests of trial participants and assessing 
the safety and efficacy of the interventions during the trial.  This responsibility will be exercised 
by providing recommendations about stopping or continuing the trial.  To contribute to 
enhancing the integrity of the trial, the DSMB may also formulate recommendations relating to 


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the selection, recruitment and retention of participants and their management; adherence to 
protocol-specified regimens; and the procedures for data management and quality control.  
The DSMB will be advisory to the study Sponsor and the PI, who will be responsible for prompt 
review of the DSMB recommendations to guide decisions regarding continuation or termination 
of the trial and whether amendments to the protocol or changes in study conduct are required. 
The DSMB is an independent, multidisciplinary group consisting of clinical experts and a 
statistician who collectively have experience in leukemia, lymphoma, hematology, biostatistics, 
and the conduct and monitoring of clinical trials.  The DSMB will meet approximately every 6 
months to review data. The current members are listed in the IIRC DSMB charter. 
10. 
STATISTICAL PLAN 
10.1 
General Considerations 
Results will be presented by dose level for each group separately using descriptive statistics.  Data 
will be combined for all patients regardless of disease histology.  Subgroup analyses by disease 
histology may be performed if the sample size in each subgroup is sufficient. 
Data from retreated patients will be summarized separately. 
10.2 
Analysis Sets 
10.2.1 
Screened Analysis Set 
The Screened analysis set will include all patients who have signed informed consent for 
screening. 
10.2.2 
Enrolled Analysis Set 
The Enrolled analysis set will include all patients who meet all inclusion/exclusion criteria for 
leukapheresis and restaging, who are enrolled, and who undergo leukapheresis. 
10.2.3 
All Treated Analysis Set 
The All Treated analysis set will include all patients who have received at least one dose of 
JCAR014 or one infusion of durvalumab. 
10.2.4 
DLT Evaluable Analysis Set 
The DLT evaluable analysis set includes all patients who have received JCAR014 cell product 
that conforms to dose or composition standards and full infusion of the first dose of durvalumab, 
and who have either experienced a DLT or were followed for the full DLT evaluation period.  
Patients with JCAR014 levels < 10 copies/µg DNA in blood by PCR at time of durvalumab 
administration in Group 1 will not be DLT-evaluable unless a DLT is experienced or JCAR014 
cell expansion after durvalumab administration is clinically significant as determined by the SC. 
10.2.5 
Efficacy Evaluable Analysis Set 
The Efficacy Evaluable (EE) analysis set includes all patients who have received JCAR014 cell 
product that conforms to dose or composition standards and a full infusion of durvalumab on 


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Day 7-21 (Group 1) or Day-1 (Group 2), and who had at least one post-baseline disease 
assessment. 
10.2.6 
Pharmacokinetic Evaluable Set 
The PK analysis set includes patients who have received JCAR014 (for analysis of JCAR014 
PK) or durvalumab (for analysis of durvalumab PK) and who have the necessary baseline and 
on-study PK measurements to provide interpretable results for the specific parameters of interest. 
10.3 
Planned Analyses 
10.3.1 
Patient Disposition and Baseline Characteristics 
An accounting of patients by disposition will be tabulated for each analysis set.  Descriptive 
summaries of demographics and baseline characteristics will be presented for each analysis set. 
Available demographic and baseline information on such patients will be listed and summarized. 
10.3.2 
Primary Endpoints 
Analyses of the primary endpoints will be as follows: 
1) Type, frequency, and severity of AEs and laboratory abnormalities 
All AEs will be listed and summarized (see Section 10.3.5.1 for details).  Summaries of 
laboratory data will include, at a minimum, treatment-emergent laboratory abnormalities (see 
Section 10.3.5.2 for details).  Summaries of AEs and laboratory abnormalities will be based 
on the All Treated analysis set. 
2) DLT rates 
Observed DLT rates and AEs will be summarized based on the DLT Evaluable analysis set.  
Final DLT rates at each dose level will be estimated by isotonic regression (Ji 2010). 
The target toxicity rate for the MTD is 30%.  The weighted least squares regression model 
will assume monotonic non-decreasing DLT rates with increasing dose and use the empirical 
(observed) DLT rates at each dose level as responses and dose level sample sizes as weights, 
along with the pool adjacent violators algorithm (PAVA) to estimate the DLT rate at each 
dose level using available software (e.g., Cytel EAST or the function pava() from the R 
package ‘ISO’).  Given the DLT estimates for each dose level, the MTD will be selected 
from all tried dose levels that have not been previously declared to be unsafe (i.e., 
P[DLT>30% data] > 95%) or unacceptably toxic according to the mTPI decision table (i.e., 
DU decision).  With this constraint, the MTD will be determined as the dose level with the 
DLT estimate closest to the target toxicity level of 30%.  In the case of dose levels with 
estimated toxicity of equal distance (tied dose levels) from the target toxicity of 30%, the 
following approach will be used (Ji 2010): 


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− Among all tied dose levels, the highest dose level with target toxicity ≤ 30% will be 
selected.  For example, if one dose level has an estimated toxicity of 28% and the other 
has an estimated toxicity of 32%, the dose level with the estimated toxicity of 28% will 
be chosen as the MTD. 
− If all tied dose levels have estimated toxicity > 30%, the lowest dose level will be 
selected. For example, if two dose levels have estimated toxicity of 32%, the lower dose 
level will be selected as the MTD. 
3) Maximum concentration (Cmax), time to peak concentration (Tmax), area under the curve 
(AUC), and other relevant PK parameters of JCAR014 in blood and bone marrow 
The PK profile of JCAR014 cells in blood, bone marrow, and CSF (in patients with samples) 
will be characterized, including Cmax, Tmax, AUC, and other relevant PK parameters.  
Expansion of JCAR014 in the blood will be determined (Cmax/Cpost-dose Day 2), along with the 
persistence of JCAR014 in the blood and bone marrow, based on both the qPCR assay (time 
above the lower limit of quantification) and flow cytometry (time above threshold JCAR014 
level; see Section 8.4.1). 
10.3.3 
Secondary Endpoints 
Definitions for secondary endpoints are provided in Section 0. 
1) CR, PR, and OR rates 
The rates of CR, PR, and OR will be summarized along with the 2-sided 95% exact Clopper-
Pearson confidence intervals based on the EE analysis sets.  In addition, ORR will be 
presented based on the All Treated analysis set, where patients with non-evaluable response 
will be treated as non-responders. 
2) DOR, PFS, and OS 
If a patient does not have an event for the DOR or PFS analyses, the patient will be censored 
at the date of the last adequate disease assessments on or prior to the earliest censoring event. 
The censoring reason can include ongoing follow-up, discontinuation or completion of the 
study, receipt of another anticancer treatment, and at least two consecutive missed scheduled 
disease assessments.  For assessment of OS, data from surviving patients will be censored at 
the last time that the patient is known to be alive. 
Kaplan-Meier (KM) methodology will be used to analyze DOR, PFS, and OS. 
10.3.4 
Exploratory Endpoints 
The exploratory endpoints of the study are listed in Section 0; details of the exploratory analyses 
are provided in the statistical analysis plan (SAP). 


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10.3.5 
Safety Analysis 
10.3.5.1 
Adverse Events 
All AEs will be listed.  The focus of AE summarization will be on treatment-emergent AEs 
(TEAEs).  A TEAE is defined as an AE that occurs after the first study therapy infusion 
(JCAR014 or durvalumab) until 30 days after the final dose of study therapy, or an AE leading to 
discontinuation of study therapy.  Any AE occurring after the initiation of another anticancer 
treatment will not be considered a TEAE. 
Reporting of AEs will be based on the Medical Dictionary for Regulatory Activities (MedDRA) 
and CTCAE version 4.03.  TEAEs will be summarized by system organ class (SOC), preferred 
term, and severity.  A patient who reports multiple occurrence of TEAEs within the same SOC 
and preferred term is counted only once using the maximum severity grade for summaries.  In 
addition, TEAEs will be summarized by treatment cycle. 
10.3.5.2 
Laboratory Data 
All laboratory data will be listed.  The focus of laboratory data summarization (including 
hematology, serum chemistry) will be on treatment-emergent laboratory abnormalities.  A 
treatment-emergent laboratory abnormality is defined as an abnormality that, compared to 
baseline, worsens by at least one grade within 30 days after the final dose of study therapy 
(JCAR014 or durvalumab).  The baseline value is defined as the last available recorded value on 
or prior to the date of the first dose of study therapy. In addition, laboratory abnormalities will be 
summarized by treatment cycle. 
If baseline data are missing, then any graded abnormality (i.e., an abnormality that is Grade ≥ 1 
in severity) will be considered treatment-emergent.  Hematological and serum biochemistry data 
will be graded according to CTCAE version 4.03, when applicable.  Grade 0 includes all non-
missing values that do not meet the criteria for an abnormality of at least Grade 1.  Grade 5 will 
not be used.  Some laboratory tests have criteria for both increased and decreased levels; 
analyses for each direction (i.e., increased, decreased) will be presented separately. 
10.4 
Sample Size Considerations 
A maximum sample size of 42 is planned for Group 1 and Group 2 combined.  The SC may 
decide to further increase the sample size beyond 21 per group by adding additional patients.  If a 
third group is enrolled, a maximum sample size of 63 is allowed for the trial. 
10.5 
Timing of Analyses 
Data will be reviewed on a continual basis to evaluate DLT and antitumor activity to inform dose 
allocation.  Dose allocation may stop early if all doses are either unsafe or ineffective.  
Interim data may be analyzed and presented at scientific meetings. 


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The final analysis will occur when the study stopping criteria have been met and the follow-up 
period is complete, approximately 12 months after the last patient has come off treatment. 
11. 
DATA MANAGEMENT 
11.1 
Data Collection System 
An EDC system provided by Juno Therapeutics will be used for data collection.  The EDC 
system will be a fully validated, secure system that conforms to 21 CFR Part 11 requirements.  
Access to the EDC system is role-based, and login credentials will be provided only after 
completion of the assigned role-based training. 
11.2 
Data Quality 
Study site personnel will enter data into the CRFs in the EDC system.  An independent monitor 
assigned through Clinical Research Support will perform regular monitoring of patient data per 
CRS policies. In addition, a Juno Therapeutics Clinical Research Associate (CRA) or designee 
will verify specific predetermined data points recorded in the CRFs with the source documents. 
To ensure complete and accurate data, automated data validation checks programmed within the 
EDC system will flag missing and non-conformant data during data entry.  Data review by the 
investigators and by the Juno Therapeutics project team may result in additional questions.  
Items flagged by the automated data validation checks and by the project team will appear as 
electronic queries on the applicable CRF in the EDC system for a specified user role to resolve.  
All data entry and subsequent data changes are logged in an audit trail in the EDC system. 
Following database lock, an electronic copy of the final patient casebook will be provided to the 
study site for archival. 
12. 
STUDY ADMINISTRATION 
12.1 
Regulatory and Ethical Considerations 
12.1.1 
Trial Conduct 
This study is conducted by FHCRC in collaboration with Juno Therapeutics and MedImmune.  
Juno Therapeutics is funding the study, will undertake research investigations and will provide 
Durvalumab on behalf of MedImmune.  MedImmune will undertake research investigations on 
this study.  The IND Sponsor is Stanley Riddell, MD.  The study will be conducted in 
compliance with the protocol approved by the Institutional Review Board, and according to 
Good Clinical Practice (GCP) standards any other applicable Federal, state, and/or local 
regulatory requirements.  No deviation from the protocol will be implemented without the prior 
review and approval of the IRB except where it may be necessary to eliminate an immediate 
hazard to a patient.  In such case, the deviation will be reported to the IRB as soon as possible. 


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12.1.2 
Institutional Review Board Approval 
It is the responsibility of the Investigator to ensure that the FHCRC IRB has reviewed and 
approved this protocol prior to initiating the study.  The IRB must also review and approve the 
informed consent form (ICF), other written information provided to the patient, and all patient 
materials that may be used. 
If the protocol, Investigator’s Brochure, or ICF are amended during the study, the Investigator is 
responsible for ensuring that the IRB has reviewed and approved these amended documents and 
the study Sponsor has been notified.  In addition, IRB approval of the amended documents must 
be obtained before implementation and before new patients are consented to participate in the 
study using the amended version of the ICF. 
12.1.3 
Institutional Biosafety Committee Approvals 
JCAR014 consists of autologous T cells that have been manipulated via genetic modification in 
vitro to express a CAR directed against the CD19 cell surface marker.  Since neither the patient’s 
source material nor the final investigational drug product has been tested for the presence of 
communicable diseases in accordance with the provisions in 21 CFR §1271.90(a)(1), the 
JCAR014 investigational drug product should be handled according to institutional procedures 
for materials that may contain infectious materials (e.g., BioSafety Level 1 or 2).  
It is the responsibility of the Investigator to ensure that the appropriate Institutional Biosafety 
Committee (IBC) has reviewed and approved this protocol and any other required materials prior 
to initiating the study if required per institutional policy.  
12.1.4 
Patient Informed Consent 
Patients will be seen at the Seattle Cancer Care Alliance or the Fred Hutchinson Cancer Research 
Center (FHCRC) for consideration of treatment options for their disease.  The protocol will be 
discussed thoroughly with the patient and other family members if appropriate, and all known 
and potential risks to the patient will be described.  The procedure and alternative forms of 
therapy will be presented as objectively as possible, and the risks and hazards of the procedure 
explained to the patient.  A summary of the clinic visit detailing what was covered will be 
dictated for the medical record.  
Consent from the patient will be obtained using forms approved by the FHCRC IRB.  Each 
informed consent form will be appropriately signed and dated by the patient or the patient’s 
legally authorized representative and the person conducting the consent discussion, and also by 
an impartial witness if required by the IRB or local requirements.  The process of obtaining the 
informed consent will be in compliance with all federal regulations, International Conference of 
Harmonisation (ICH) requirements (ICH E6 4.8) and local laws. 
If the ICF is amended during the study, the Investigator must follow all applicable regulatory 
requirements pertaining to approval of the amended ICF by the IRB.  The investigative site must 


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use the amended ICF for all new patients and repeat the consent process with the amended ICF 
for any ongoing patients. 
12.2 
Investigator Obligations 
12.2.1 
Investigator Responsibilities 
The Investigator is responsible for ensuring that all study site personnel, including 
subinvestigators and other responsible study staff members, conduct the study in compliance 
with the Declaration of Helsinki and the ICH E6 Guideline for GCP, including the archiving of 
essential documents. 
The Investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, Subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, 
Part 50, 1998, and 21 CFR, Part 56, 1998. 
The Investigator, subinvestigators, and study staff will comply with 21 CFR, Part 54, 1998, 
providing documentation of any financial conflict of interest.   
If necessary to amend either the protocol or the study ICF, the Investigator will be responsible 
for ensuring that the IRB reviews and approves the amended documents, and that patients are 
informed of applicable changes and updates.  In accordance with applicable regulatory 
requirements, the Investigator is solely obligated to inform the IRB of progress of the study and 
notify the IRB of study closure. 
12.3 
Site Audits and Regulatory Inspections 
Representatives of regulatory authorities, Juno Therapeutics, or the IRB may conduct inspections 
or audits of the clinical study.  The Investigator agrees to provide to representatives of a 
regulatory agency or Juno access to records, facilities, and personnel for the effective conduct of 
any inspection or audit. 
12.4 
Public Notification of Study Conduct 
Consistent with Section 113 of the Food and Drug Modernization Act of 1997 (FDAMA) and 
with requirements of the International Committee of Medical Journal Editors (ICMJE) as a 
condition of consideration for publication of study results, this protocol will be listed at the 
ClinicalTrials.gov website per the US FDA requirement and information at the website relating 
to study design and conduct will be appropriately updated during the course of the study. 
12.5 
Study Termination 
Upon completion or early termination of the study, the following activities, when applicable, 
must be conducted by the Investigator: 
• Data clarifications and/or resolutions; 


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• Accounting, reconciliation, and final disposition of used and unused study drug; and 
• Review of site study records for completeness. 
If the study is suspended or terminated for safety reasons, the Investigator will promptly inform 
the regulatory authorities of the suspension or termination of the study and the reasons for the 
action.  The Investigator is also responsible for promptly informing the IRB and providing the 
reasons for the suspension or termination of the study. 
12.6 
Records  
The medical record containing information regarding treatment of the patient will be maintained 
as a confidential document, within the guidelines of the FHCRC, the University of Washington 
Medical Center, and the SCCA.  The investigators will ensure that data collected conform to all 
established guidelines for coding collection, key entry, and verification.  Each patient is assigned 
a unique patient number to assure patient confidentiality.  Patients will not be referred to by 
name or by any other personal identifier in any publication or external presentation.  The Clinical 
Statistics Departments at FHCRC maintain a patient database to allow storage and retrieval of 
subject data collected from a wide variety of sources.  The licensed medical records departments, 
affiliated with the institution where the patient receives medical care, maintains all original 
inpatient and outpatient chart documents. 
The primary research records are kept in access controlled office spaces or password-protected 
computer-based applications; records will be retained, at a minimum, for the duration of time 
that durvalumab is commercially available in any region plus an additional 15 years.  
Information gathered from this study regarding patient outcomes and adverse events may be 
made available to the FDA, NIH, and Juno Therapeutics.  All precautions to maintain 
confidentiality of medical records will be taken. 
12.7 
Confidentiality of Information 
Patients’ names will remain confidential and will not be included in the database.  All study 
findings will be stored in electronic databases.  The Investigator will maintain a personal patient 
identification list (patient and treatment numbers with the corresponding patient names) to enable 
records to be identified. 


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13. 
REFERENCES 
1.  Abiko K, Matsumura N, Hamanishi J, et al. IFN-gamma from lymphocytes induces PD-L1 
expression and promotes progression of ovarian cancer. Br J Cancer 2015;112(9):1501-
1509. 
2.  Adusumilli PS, Cherkassky L, Villena-Vargas J, et al. Regional delivery of mesothelin-
targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor 
immunity. Science Translational Medicine 2014;6(261):261ra151. 
3.  Andorsky DJ, Yamada RE, Said J, et al. Programmed death ligand 1 is expressed by non-
hodgkin lymphomas and inhibits the activity of tumor-associated T cells. Clin Cancer 
Res 2011;17(13):4232-4244. 
4.  Bennett F, Luxenberg D, Ling V, et al. Program death-1 engagement upon TCR activation 
has distinct effects on costimulation and cytokine-driven proliferation: attenuation of 
ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses. J Immunol 
2003;170(2):711-718. 
5.  Bos R and Sherman LA. CD4+ T-cell help in the tumor milieu is required for recruitment and 
cytolytic function of CD8+ T lymphocytes. Cancer Res 2010;70(21):8368-8377. 
6.  Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in 
patients with advanced cancer. N Engl J Med 2012;366(26):2455-2465. 
7.  Brentjens RJ, Rivière I, Park JH, et al. Safety and persistence of adoptively transferred 
autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-
cell leukemias. Blood 2011;118(18):4817-4828. 
8.  Carter L, Fouser LA, Jussif J, et al. PD-1:PD-L inhibitory pathway affects both CD4(+) and 
CD8(+) T cells and is overcome by IL-2. Eur J Immunol 2002;32(3):634-643. 
9.  Challa-Malladi M, Lieu YK, Califano O, et al. Combined genetic inactivation of beta2-
Microglobulin and CD58 reveals frequent escape from immune recognition in diffuse 
large B cell lymphoma. Cancer Cell 2011;20(6):728-740. 
10.  Chen J, Feng Y, Lu L, et al. Interferon-gamma-induced PD-L1 surface expression on human 
oral squamous carcinoma via PKD2 signal pathway. Immunobiology 2012;217(4):385-
393. 
11.  Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano 
classification. J Clin Oncol 2014;32(27):3059-3068. 
12.  Chow LQ. Exploring novel immune-related toxicities and endpoints with immune-
checkpoint inhibitors in non-small cell lung cancer. Am Soc Clin Oncol Educ Book 2013. 
13.  Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult 
tumor lysis syndrome: an evidence-based review. J Clin Oncol 2008;26(16):2767-2778. 
14.  Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with 
CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 
2002;346(4):235-242. 
15.  Cunard R and Kelly CJ. 18. Immune-mediated renal disease. J Allergy Clin Immunol 
2003;111(2 Suppl):S637-644. 
16.  Davila ML, Brentjens R, Wang X, et al. How do CARs work? Early insights from recent 
clinical studies targeting CD19. Oncoimmunology 2012;1(9):1577-1583. 
17.  Davila ML, Kloss CC, Gunset G, et al. CD19 CAR-targeted T cells induce long-term 
remission and B Cell Aplasia in an immunocompetent mouse model of B cell acute 
lymphoblastic leukemia. Plos One 2013;8(4):e61338. 


FHCRC Protocol No. 9457 
 
14 May 2021 
88 
 
18.  Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T 
cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 
2014;6(224):224ra225. 
19.  Di Giacomo AM, Biagioli M and Maio M. The emerging toxicity profiles of anti-CTLA-4 
antibodies across clinical indications. Semin Oncol 2010;37(5):499-507. 
20.  Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in 
patients after clonal repopulation with antitumor lymphocytes. Science 
2002;298(5594):850-854. 
21.  Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-
myeloablative but lymphodepleting chemotherapy for the treatment of patients with 
refractory metastatic melanoma. J Clin Oncol 2005;23(10):2346-2357. 
22.  Dudley ME, Yang JC, Sherry R, et al. Adoptive Cell Therapy for Patients With Metastatic 
Melanoma: Evaluation of Intensive Myeloablative Chemoradiation Preparative 
Regimens. J Clin Oncol 2008. 
23.  Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-247. 
24.  Fife BT and Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the 
CTLA-4 and PD-1 pathways. Immunol Rev 2008;224:166-182. 
25.  Food and Drug Administration. Guidance for Industry:  Gene Therapy Clinical Trials — 
Observing Subjects for Delayed Adverse Events.  2006. 
26.  Food and Drug Administration. Guidance for Industry: Supplemental Guidance on Testing 
for Replication Competent Retrovirus in Retroviral Vector Based Gene Therapy Products 
and During Follow-up of Patients in Clinical Trials Using Retroviral Vectors.  2000. 
27.  Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by 
a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp 
Med 2000;192(7):1027-1034. 
28.  Gardner RA, Park JR, KellySpratt KS, et al. T Cell Products of Defined CD4:CD8 
Composition and Prescribed Levels of CD19-CAR/EGFRt Transgene Expression 
Mediate Regression of Acute Lymphoblastic Leukemia in the Setting of Post-Allo-HSCT 
Relapse. Presented at the 56th Annual Meeting of the American Society of Hematology. 
2014; San Francisco, CA. 
29.  Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation 
for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 2010;28(27):4184-
4190. 
30.  Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute 
lymphoid leukemia. New England Journal of Medicine 2013;368(16):1509-1518. 
31.  Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients 
with metastatic melanoma. N Engl J Med 2010;363(8):711-723. 
32.  Howard SC, Jones DP and Pui CH. The tumor lysis syndrome. N Engl J Med 
2011;364(19):1844-1854. 
33.  Izzedine H, Gueutin V, Gharbi C, et al. Kidney injuries related to ipilimumab. Invest New 
Drugs 2014;32(4):769-773. 
34.  Ji Y, Liu P, Li Y, et al. A modified toxicity probability interval method for dose-finding 
trials. Clin Trials 2010;7(6):653-663. 
35.  Kaehler KC, Piel S, Livingstone E, et al. Update on immunologic therapy with anti-CTLA-4 
antibodies in melanoma: identification of clinical and biological response patterns, 


FHCRC Protocol No. 9457 
 
14 May 2021 
89 
 
immune-related adverse events, and their management. Semin Oncol 2010;37(5):485-
498. 
36.  Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent 
antitumor effects and can establish memory in patients with advanced leukemia. Sci 
Transl Med 2011;3(95):95ra73. 
37.  Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. 
Annu Rev Immunol 2008;26:677-704. 
38.  Kochenderfer JN, Dudley ME, Kassim S, et al. Chemotherapy-Refractory Diffuse Large B-
Cell Lymphoma and Indolent B-Cell Malignancies Can Be Effectively Treated With 
Autologous T Cells Expressing an Anti-CD19 Chimeric Antigen Receptor. Journal of 
Clinical Oncology 2015;33(6):540-549. 
39.  Kochenderfer JN, Kassim SH, Somerville R, et al. Treatment of Chemotherapy-Refractory 
B-Cell Malignancies with Anti-CD19 Chimeric Antigen Receptor T Cells. Presented at 
the Annual Meeting of the American Society of Gene and Cell Therapy. 2014a; New 
Orleans, LA. 
40.  Kochenderfer JN, Somerville R, Lu L, et al. Anti-CD19 CAR T Cells Administered after 
Low-Dose Chemotherapy Can Induce Remissions of Chemotherapy-Refractory Diffuse 
Large B-Cell Lymphoma. Presented at the 56th Annual Meeting of the American Society 
of Hematology. 2014b; San Francisco, CA. 
41.  Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T 
cell activation. Nat Immunol 2001;2(3):261-268. 
42.  Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of 
cytokine release syndrome. Blood 2014;124(2):188-195. 
43.  Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric 
antigen receptors for acute lymphoblastic leukaemia in children and young adults: a 
phase 1 dose-escalation trial. Lancet 2015;385(9967):517-528. 
44.  Lesokhin AM, Ansell SM, Armand P, et al. Preliminary Results of a Phase I Study of 
Nivolumab (BMS-936558) in Patients with Relapsed or Refractory Lymphoid 
Malignancies. 56th Annual Meeting of the American Society of Hematology (2014), San 
Francisco, CA. 
45.  Li YS, Hayakawa K and Hardy RR. The regulated expression of B lineage associated genes 
during B cell differentiation in bone marrow and fetal liver. Journal of Experimental 
Medicine 1993;178(3):951-960. 
46.  Li YS, Wasserman R, Hayakawa K, et al. Identification of the earliest B lineage stage in 
mouse bone marrow. Immunity 1996;5(6):527-535. 
47.  Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained 
remissions in leukemia. New England Journal of Medicine 2014;371(16):1507-1517. 
48.  Myklebust JH, Irish JM, Brody J, et al. High PD-1 expression and suppressed cytokine 
signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T 
cells. Blood 2013;121(8):1367-1376. 
49.  NCCN. NCCN Guidelines: Non-Hodgkin's Lymphomas. NCCN Clinical Practice 
Guidelines in Oncology 2014;1.2014. 
50.  Nurieva R, Thomas S, Nguyen T, et al. T-cell tolerance or function is determined by 
combinatorial costimulatory signals. EMBO J 2006;25(11):2623-2633. 
51.  Park JJ, Omiya R, Matsumura Y, et al. B7-H1/CD80 interaction is required for the induction 
and maintenance of peripheral T-cell tolerance. Blood 2010;116(8):1291-1298. 


FHCRC Protocol No. 9457 
 
14 May 2021 
90 
 
52.  Porter DL, Levine BL, Kalos M, et al. Chimeric antigen receptor-modified T cells in chronic 
lymphoid leukemia. New England Journal of Medicine 2011;365(8):725-733. 
53.  Rezvani AR, Norasetthada L, Gooley T, et al. Non-myeloablative allogeneic haematopoietic 
cell transplantation for relapsed diffuse large B-cell lymphoma: a multicentre experience. 
Br J Haematol 2008;143(3):395-403. 
54.  Rossille D, Gressier M, Damotte D, et al. High level of soluble programmed cell death 
ligand 1 in blood impacts overall survival in aggressive diffuse large B-Cell lymphoma: 
results from a French multicenter clinical trial. Leukemia 2014;28(12):2367-2375. 
55.  Sadelain M, Brentjens R and Riviere I. The basic principles of chimeric antigen receptor 
design. Cancer Discovery 2013;3(4):388-398. 
56.  Saunders PA, Hendrycks VR, Lidinsky WA, et al. PD-L2:PD-1 involvement in T cell 
proliferation, cytokine production, and integrin-mediated adhesion. Eur J Immunol 
2005;35(12):3561-3569. 
57.  Schulert GS and Grom AA. Pathogenesis of Macrophage Activation Syndrome and Potential 
for Cytokine-Directed Therapies. Annual Review of Medicine 2015;66:145-159. 
58.  Schuster SJ, Svoboda J, Nasta SD, et al. Phase IIa Trial of Chimeric Antigen Receptor 
Modified T Cells Directed Against CD19 (CTL019) in Patients with Relapsed or 
Refractory CD19+ Lymphomas. Presented at the 56th Annual Meeting of the American 
Society of Hematology. 2014; San Francisco, CA. 
59.  Siegel RL, Miller KD and Jemal A. Cancer Statistics 2015. Cancer: A Cancer Journal for 
Physicians 2015;65(1):5-29. 
60.  Stamenkovic I and Seed B. CD19, the earliest differentiation antigen of the B cell lineage, 
bears three extracellular immunoglobulin-like domains and an Epstein-Barr virus-related 
cytoplasmic tail. Journal of Experimental Medicine 1988;168(3):1205-1210. 
61.  Toes RE, Ossendorp F, Offringa R, et al. CD4 T cells and their role in antitumor immune 
responses. Journal of Experimental Medicine 1999;189(5):753-756. 
62.  Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-
PD-1 antibody in cancer. N Engl J Med 2012;366(26):2443-2454. 
63.  Tseng SY, Otsuji M, Gorski K, et al. B7-DC, a new dendritic cell molecule with potent 
costimulatory properties for T cells. J Exp Med 2001;193(7):839-846. 
64.  Turtle CJ, Berger C, Sommermeyer D, et al. Immunotherapy with CD19-specific chimeric 
antigen receptor (CAR)-modified T cells of defined subset composition. Annual Meeting 
of the American Society for Clinical Oncology (2015), Chicago, IL. 
65.  Twa DD, Chan FC, Ben-Neriah S, et al. Genomic rearrangements involving programmed 
death ligands are recurrent in primary mediastinal large B-cell lymphoma. Blood 
2014;123(13):2062-2065. 
66.  Weber JS, Kahler KC and Hauschild A. Management of immune-related adverse events and 
kinetics of response with ipilimumab. J Clin Oncol 2012;30(21):2691-2697. 
67.  Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced 
melanoma. N Engl J Med 2013;369(2):122-133. 
68.  Wrzesinski C, Paulos CM, Gattinoni L, et al. Hematopoietic stem cells promote the 
expansion and function of adoptively transferred antitumor CD8 T cells. J Clin Invest 
2007;117(2):492-501. 
69.  Zou W and Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat 
Rev Immunol 2008;8(6):467-477. 
70. Turtle CJ, Laïla-Aïcha Hanafi, Carolina Berger et al. CD19 CAR–T cells of defined CD4+: 


FHCRC Protocol No. 9457 
 
14 May 2021 
91 
 
CD8+ composition in adult B cell ALL patients. J Clin Invest, 2016; 126(6): 2123–2138. 
71. Turtle CJ, Laïla-Aïcha Hanafi, Carolina Berger et al. Immunotherapy of non-Hodgkin’s 
lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen 
receptor–modified T cells. Sci Trans Med, 2016; 8 (355). 


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Appendix A 
Schedule of Evaluations 
Table A-1:  Schedule of Evaluations  
Assessment 
Protocol 
Section 
Screening 
Pretreatment 
Evaluation 
Days  
-5 
to -2 
Day 
-1b 
JCAR014 
Treatment Cycle 
First Post-JCAR014 
Durvalumab Cycle 
Subsequent Durvalumab 
Cyclesa 
Follow-Up 
Evaluationsc 
Day 
0 
Post-JCAR014 
Assessments 
(Days 1 to 27) 
Day 
21-
28f 
Post 
Durvalumab 
Assessments 
Durvalumab 
Infusion 
(Approximately 
Days 56, 84, etc.) 
Post-
Durvalumab 
Assessments 
I/E criteria 
5 
X 
X 
 
 
 
 
 
 
 
 
 
Confirm diagnosis 
 
 
X 
 
 
 
 
 
 
 
 
 
Medical historyd 
 
X 
X 
 
 
 
 
 
 
 
 
 
Height/weighte 
 
X 
 
 
X 
X 
 
X 
 
X 
 
 
Physical exam 
8.3.1 
X 
X 
 
X 
X 
Day 1, twice 
weekly for first 
2 weeks, then 
weekly 
X 
1 day post-
infusion, twice 
weekly for first 
2 weeks, then 
weekly 
X 
Approx every 
2 weeks 
X 
Vitals including 
O2 sat 
8.3.5 
 
X 
 
Xg 
Xg 
 
Xg 
 
Xg 
 
 
Karnofsky 
performance status 
8.3.7 
 
X 
 
 
X 
 
X 
 
X 
 
 
Chest x-ray 
 
 
X 
 
 
 
 
 
 
 
 
 
12-lead ECGh 
8.3.9 
 
X 
 
Xh 
Xh,n 
 
Xh 
 
Xh,o 
 
1 month after 
the last dose of 
study therapy 
(JCAR014 or 
durvalumab) 
MUGA/ECHO 
8.3.8 
 
X 
 
 
 
 
 
 
 
 
 
CT/PET scani 
8.1.10 
 
Xj 
 
 
 
Approximately 1, 2, 4, 6, 9, and 12 months after the JCAR014 infusion (see Section 8.1.10) 
Pregnancy test 
 
Xk 
Xk 
 
 
 
 
 
 
 
 
 
HLA typing 
 
 
Xp 
 
 
 
 
 
 
 
 
 


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93 
 
Assessment 
Protocol 
Section 
Screening 
Pretreatment 
Evaluation 
Days  
-5 
to -2 
Day 
-1b 
JCAR014 
Treatment Cycle 
First Post-JCAR014 
Durvalumab Cycle 
Subsequent Durvalumab 
Cyclesa 
Follow-Up 
Evaluationsc 
Day 
0 
Post-JCAR014 
Assessments 
(Days 1 to 27) 
Day 
21-
28f 
Post 
Durvalumab 
Assessments 
Durvalumab 
Infusion 
(Approximately 
Days 56, 84, etc.) 
Post-
Durvalumab 
Assessments 
Leukapheresis 
6.1 
 
X 
 
 
 
 
 
 
 
 
 
Allopurinol 
prophylaxis 
7.5 
 
 
Xm 
 
 
 
 
 
 
 
 
Lymphodepleting 
chemotherapy 
6.2 
 
 
X 
 
 
 
 
 
 
 
 
JCAR014 admin 
6.3 
 
 
 
 
X 
 
 
 
 
 
 
Durvalumab 
admin 
6.4 
 
 
 
X 
 
 
X 
 
X 
 
 
AEs 
9.3.3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con meds 
5.6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurological exam 
7.3.3 
 
X 
 
Xr 
Xr 
Xr 
Xr 
Xr 
Xr 
Xr 
Xr 
MMSE 
Appendix 
D 
 
X 
 
 
X 
Approx Day 7 
and Day 14 
X 
Approx 7 and 
14 days after 
durvalumab 
infusion 
 
 
 
Neuropsychologic
al test 
8.3.4 
 
X 
 
 
 
 
 
 
 
 
2 months after 
JCAR014 
infusion 


FHCRC Protocol No. 9457 
 
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94 
 
Assessment 
Protocol 
Section 
Screening 
Pretreatment 
Evaluation 
Days  
-5 
to -2 
Day 
-1b 
JCAR014 
Treatment Cycle 
First Post-JCAR014 
Durvalumab Cycle 
Subsequent Durvalumab 
Cyclesa 
Follow-Up 
Evaluationsc 
Day 
0 
Post-JCAR014 
Assessments 
(Days 1 to 27) 
Day 
21-
28f 
Post 
Durvalumab 
Assessments 
Durvalumab 
Infusion 
(Approximately 
Days 56, 84, etc.) 
Post-
Durvalumab 
Assessments 
CBC, differential, 
platelet count 
8.3.2 
X 
X 
X 
X 
X 
Twice weekly 
for first 2 
weeks, then at 
least weekly 
X 
Twice weekly 
for first 2 
weeks, then at 
least weekly 
X 
Approx every 
2 weeks 
X 
Hepatic function 
with LDH; renal 
function with Mg 
8.3.2 
X 
X 
X 
X 
X 
X 
X 
X 
Uric acid 
8.3.2 
 
X 
X 
X 
X 
X 
X 
 
Serum ferritin 
8.3.2 
 
X 
 
 
X 
X 
X 
 
CRP 
8.3.2 
 
X 
 
 
X 
X 
X 
 
PT, PTT, 
fibrinogen, and D-
dimer 
8.3.2 
 
X 
 
 
X 
X 
X 
 
Quantitative IgG 
8.3.2 
 
X 
 
 
 
 
X 
 
Xt 
 
Approximately 
monthlyt 
PSBC recipient 
donor battery 
panel 
8.3.2 
X 
 
 
 
 
 
 
 
 
 
 
ABO blood 
typing; antibody 
screen 
 
X 
 
 
 
 
 
 
 
 
 
 
Research Assessments 
Collection of 
archived tumor 
biopsy sample (if 
applicable) 
8.4.4 
 
X 
 
 
 
 
 
 
 
 
 
Fresh tumor 
biopsy (consenting 
patients only) 
8.4.4 
 
X 
 
 
 
Within the first 
4 weeks after 
JCAR014w 
 
Within the first 
4 weeks after 
durvalumabw 
 
 
 
BMA/BMBl 
8.1.10 
 
Xq 
 
 
 
 


FHCRC Protocol No. 9457 
 
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95 
 
Assessment 
Protocol 
Section 
Screening 
Pretreatment 
Evaluation 
Days  
-5 
to -2 
Day 
-1b 
JCAR014 
Treatment Cycle 
First Post-JCAR014 
Durvalumab Cycle 
Subsequent Durvalumab 
Cyclesa 
Follow-Up 
Evaluationsc 
Day 
0 
Post-JCAR014 
Assessments 
(Days 1 to 27) 
Day 
21-
28f 
Post 
Durvalumab 
Assessments 
Durvalumab 
Infusion 
(Approximately 
Days 56, 84, etc.) 
Post-
Durvalumab 
Assessments 
As clinically indicated at the time of restaging in patients with bone marrow lymphoma at 
baseline until patient achieves a CR 
B-cell 
reconstitution 
8.4.4 
 
X 
 
 
 
Approx Day 14 
X 
Approx 14 days 
post-infusion 
X 
 
Approx 1, 2, 3, 
4, 5, 6, 9, and 12 
months after the 
JCAR014   
infusion 
T-cell subset 
screening 
8.1.2 
X 
 
 
 
 
 
 
 
 
 
 
T-cell persistences 
8.4.1 
 
 
 
 
X 
Approx 5, 7, 11, 
14, 21 days 
post-infusion 
X 
Approx 5, 7, 
11, 14, 21 days 
post-infusion 
X 
Approx 14 
days post-
infusion 
Approx 1, 2, 3, 
4, 5, 6, 9, and 12 
months after the 
JCAR014 
infusion 
Serum 
biomarkerss,u 
8.4.4 
 
X 
 
X 
X 
Approx 1, 4, 5, 
7, 11, 14, 21 
days post-
infusion 
X 
Approx 1, 4, 5, 
7, 11, 14, 21 
days post-
infusion 
X 
Approx 1 month 
after the last 
durvalumab 
infusion 
RCL testing by 
VSVG qPCR 
8.4.2 
 
X 
 
 
 
 
 
 
Approximately 3, 6, and 12 months after the 
JCAR014 infusion (see Section 8.4.2) 
JCAR014 humoral 
and cellular 
immune responseu 
8.4.3 
 
X 
 
 
 
Approx 14 days 
post infusion 
X 
Approx 14 days 
post infusion 
X 
Approx 14 
days post 
infusion 
Approx 1 and 2 
months after 
JCAR014 
infusion (if no 
post-JCAR014 
durvalumab 
administered) 
Endothelial 
activation studies 
8.4.4 
 
X 
 
 
X 
Approx 1 and 7 
days post-
infusion 
 
 
 
 
 


FHCRC Protocol No. 9457 
 
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Assessment 
Protocol 
Section 
Screening 
Pretreatment 
Evaluation 
Days  
-5 
to -2 
Day 
-1b 
JCAR014 
Treatment Cycle 
First Post-JCAR014 
Durvalumab Cycle 
Subsequent Durvalumab 
Cyclesa 
Follow-Up 
Evaluationsc 
Day 
0 
Post-JCAR014 
Assessments 
(Days 1 to 27) 
Day 
21-
28f 
Post 
Durvalumab 
Assessments 
Durvalumab 
Infusion 
(Approximately 
Days 56, 84, etc.) 
Post-
Durvalumab 
Assessments 
Plasma 
biomarkerss,u 
8.4.4 
 
X 
 
X 
X 
Approx 1, 4, 5, 
7, 11, 14, 21 
days post-
infusion 
X 
Approx 1, 4, 5, 
7, 11, 14, 21 
days post-
infusion 
X 
Approx 14 
days post 
infusion 
Approx 1 month 
after the last 
durvalumab 
infusion 
IgH sequencingu 
8.4.4 
 
X 
 
 
 
Approx Day 14 
X 
Approx 14 days 
post-infusion 
X 
 
Approx 1, 2, 3, 
4, 5, 6, 9, and 12 
months after the 
JCAR014   
infusion 
Durvalumab 
humoral immune 
responseu,z 
8.4.3 
 
 
 
X 
 
 
X 
 
Day 0 of 4th, and 
7th infusions 
 
Approx 90 days  
after the last 
durvalumab 
infusion 
Durvalumab PKv,u 
8.4.1 
 
 
 
X 
 
Approx 14 days 
post-infusionx 
X 
Approx 14 days 
post-infusiony 
Day 0 of 3rd, 4th, 
and 7th infusions 
 
Approx 90 days  
after the last 
durvalumab 
infusion 
Soluble PD-L1u,z 
8.4.4 
 
X 
 
X 
 
Approx 14 days 
post-infusionx 
X 
Approx 14 days 
post-infusiony 
Day 0 of 2nd, and 
4th infusions 
 
 
Additional 
optional 
Pharmacogenetic, 
Immunogenicity 
and Biomarker 
Research 
Laboratory 
Evaluations in 
Blood, BMB, 
BMA, and Tumor 
Tissue  
(archival or fresh)s 
8.4.1 
8.4.2 
8.4.3 
Details regarding the timepoints at which samples will be collected for these assays will be provided in a separate laboratory 
sample handling document. 


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NOTE: The proposed days of all treatments and assessments are approximate and may vary due to scheduling, clinical or other factors. 
a 
If JCAR014-related toxicity is observed during the first durvalumab cycle due to re-expansion of the CAR T cells, the schedule of assessments listed for the 
first durvalumab cycle may be followed 
b 
Patients in Group 2 only 
c 
Follow-up visits should be scheduled every 30 days for the first 3 months after the final dose of study therapy (durvalumab or JCAR014), then every 3 
months up to 12 months after the JCAR014 infusion or 3 months after the final durvalumab infusion, whichever is later 
d 
Medical history to include hematologic, histologic, and genetic findings at diagnosis and time of enrollment as well as prior therapies and response to 
therapy 
e 
Height required only at Screening 
f 
May occur as early as Day 7 for patients in Group 1 – early. Durvalumab infusion days for subsequent durvalumab cycles will be adjusted accordingly. 
g 
Vital signs, including O2 sat, obtained before the start of infusion; every 15 ± 5 min during infusion; within 5 min after the end of infusion; and 30 min, 
60 min, and 2 hours after the end of infusion 
h 
On days of JCAR014 or durvalumab administration, ECGs are to be obtained prior to infusion 
i 
Diagnostic CT/PET scan to include neck chest, abdomen and pelvis, as clinically indicated by disease and status and according to the protocol.  Staging 
evaluations may be ceased if the patient proceeds to other antitumor therapy (see Section 8.1.10) 
j 
May be omitted in patients with imaging within 30 days before scheduled JCAR014 infusion who have not receive antitumor therapy since prior imaging 
k 
Pregnancy tests to be conducted within 14 days before leukapheresis and within 28 days before initiation of lymphodepleting chemotherapy 
l 
Bone marrow aspirates/biopsies should be sent for pathology analysis as clinically indicated.  A 5-10 mL aliquot of the bone marrow aspirate in sodium 
heparin should be sent to the Turtle Lab for research.  Fresh research bone marrow biopsy samples may be collected if requested by the PI or archived tissue 
may be used.  
m 
May begin prior to lymphodepleting chemotherapy per standard institutional practice 
n 
Patients in Group 1 only 
o 
Third post-JCAR014 durvalumab cycle only 
p 
Does not need to be repeated if results from previous test are available 
q 
Not required for patients who have had a marrow aspirate and biopsy within 30 days before the scheduled JCAR014 infusion AND have not received 
antitumor therapy in the interim 
r 
A neurologic examination should be performed if there is clinical suspicion of neurologic dysfunction 
s 
May be evaluated at additional timepoints if clinically indicated 
t 
Quantitative IgG to be measured approximately monthly (on days of durvalumab infusion as applicable) until levels are normal without IVIG replacement, 
as clinically indicated.   
u 
Samples may be archived and assays performed in selected patients only. 
v 
Pre and post durvalumab PK samples should be collected 
w 
Biopsy may also be performed at a different timepoint if there is a persistent mass, progression or relapse 
x 
Patients in Group 2 only 
y 
Patients in Group 1 only 
z 
Pre durvalumab infusion sample 


FHCRC Protocol No. 9457 
 
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Appendix B 
Maximum Blood Volume Collection for Research Laboratory 
Evaluations 
Time 
Volume (mL)b,c 
Sodium heparin 
EDTA 
Citrate  
Serum separator 
Screening 
30 – d 
0 
0 
0 
Pretreatment evaluation 
55 – g, i 
11 – j 
15 – i, k 
10 – f, h, i 
Day -1 – l 
0 
0 
0 
15 - f 
JCAR014 Treatment Cycle 
Day 0 pre-infusion 
35 – e, i 
0 
15 – i, k 
5 - f 
Day 1 
15 – i 
0 
15 – i, k 
5 - f 
Day 4 
15 - i 
0 
5 – i 
5 – f 
Day 5 
20 – e 
0 
5 – i 
5 – f 
Day 7 
20 – e 
0 
15 – i, k 
5 – f 
Day 11 
20 – e 
0 
5 – i 
5 – f 
Day 14 
75 – e, i 
11 – j 
5 – i 
7.5 – f, h 
Day 21 
20 – e 
0 
5 – i 
5 – f 
Day 28 – a, m 
75 – e, i 
11 – j 
5 – i 
15 – f, h, i 
First Post-JCAR014 Durvalumab Cycle 
Day 1 
15 – i 
0 
5 – i 
5 – f 
Day 4 
15 – i 
0 
5 – i 
5 – f 
Day 5 
20 – e 
0 
5 – i 
5 – f 
Day 7 
20 – e 
0 
5 – i 
5 – f 
Day 11 
20 – e 
0 
5 – i 
5 - f 
Day 14 
75 – e, i 
11 – j 
5 – i 
7.5 – f, h 
Day 21 
20 – e 
0 
5 – i 
5 – f 
Day 28 – a 
65 – e, i 
11 – j 
5 – i 
15 – f, h, n 
Subsequent Durvalumab Cycles 
Day 14 
30 – e, i 
0 
5 – i 
5 – f, h 
Day 28 – a 
75 – e, i 
11 – j 
5 – i 
5 – f, h 


FHCRC Protocol No. 9457 
 
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Time 
Volume (mL)b,c 
Sodium heparin 
EDTA 
Citrate  
Serum separator 
Third, and Seventh Durvalumab Cycles 
Day 0 
75 – e, i 
11 – j 
5 – i 
7.5 – f, h 
Fourth Durvalumab Cycles 
Day 0 
75 – e, i 
11 – j 
5 – i 
17.5 – f, h, i 
Last Durvalumab Cycle 
Day 90 
35 – e, i 
5 – j 
5 – i 
7.5 – f, h 
Follow-Up Evaluations 
Day 60 
55 – e, i 
11 – j 
5 – i 
10 – f, h 
Day 90 
35 – e, g, i 
11 – j 
5 – i 
5 - i 
Day 120 
35 – e, i 
11 – j 
5 – i 
5 - i 
Day 150 
35 – e, i 
11 – j 
5 – i 
5 – i 
Day 180 
35 – e, g, i 
11 – j 
5 – i 
5 – i 
Day 270 
35 – e, i 
11 – j 
5 – i 
5 – i 
Day 365 
35 – e, g, i 
11 – j 
5 – i 
5 - i 
 
a 
Additional Day 0 pre-infusion samples may be drawn if there is a significant delay in 
administration of the first post-JCAR014 durvalumab infusion. 
b 
Sample volumes reflect all assays expected for each visit day. If visit days are combined or 
not conducted, volumes will be revised accordingly in order to avoid duplication in sample 
collection. 
c 
If multiple samples are collected at one time point, the first sample of the day will be used, 
unless there is a suspected problem with the first sample. Late-night samples may be 
counted as the next calendar day, as per inpatient standard. 
d 
T-cell subset screening. 
e 
T-cell persistence. 
f 
Serum biomarkers, and durvalumab/ soluble PD-L1 assays (as specified in Appendix A). 
g 
RCL testing by VSVG QPCR. 
h 
JCAR014 humoral immune response. 
i 
Optional archive/additional research studies. 
j 
B-cell persistence and IgH sequencing (MRD tracking). 
k 
Endothelial activation studies. 
l 
Patients in Group 2 only. 
m 
May occur as early as Day 7 for patients in Group 1 – early. 
n 
Patients in Group 1 only. 


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Appendix C 
Response Criteria for Non-Hodgkin Lymphoma 
 
Response 
PET-CT-Based Criteria (Cheson 2014) 
Complete response (CR) 
Score 1, 2, or 3a with or without residual mass 
No evidence of FDG-avid disease in marrow 
Partial response (PR) 
Score 4 or 5a with reduced uptake compared with baseline and residual masses 
of any size 
Bone marrow with residual uptake higher than in normal marrow but reduced 
compared with baseline (Diffuse uptake compatible with reactive changes from 
chemotherapy allowed).  If there are persistent focal changes in marrow in the 
context of a nodal response, should consider further evaluation with MRI, 
biopsy, or interval scan. 
Stable disease (SD) 
Score 4 or 5a with no significant change in FDG uptake from baseline 
Bone marrow unchanged from baseline 
Progressive disease (PD) 
Score 4 or 5a with an increase in intensity of uptake from nadir 
New FDG-avid foci consistent with lymphoma (may need biopsy or repeat 
scan if uncertain about etiology of foci) 
a 
Based on the Deauville 5-point Scale: 1 = no uptake; 2 = uptake ≤ mediastinum; 3 = uptake > mediastinum ≤ 
liver; 4 = moderately increased uptake > liver; 5 = markedly increased uptake > liver and/or new lesions related 
to lymphoma; X = new areas of uptake unlikely to be related to lymphoma 


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Appendix D 
Mini Mental State Examination 
 


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Appendix E 
Long-Term Follow-Up 
Study participants should be asked to participate in long term follow-up, as directed by the FDA 
Guidance for Industry – Gene Therapy Clinical Trials: Observing Patients for Delayed Adverse 
Events (http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformati  
on/Guidances/CellularandGeneTherapy/ucm072957.htm#5). 
Long term follow-up should commence approximately 1 year after the JCAR014 infusion.  The 
planned recommendations for follow-up are as follows: 
Years 1 - 15: 
1. 
Recommendation that patients undergo at least annual history and physical examination 
with their primary physician: 
− Adverse event screening guidance for the primary physician in the form of a gene 
therapy LTFU-directed screening survey may be available. 
− A request for the study team to be notified of all new malignancies and unexpected 
illnesses. 
− The primary physician may be provided with a blood draw courier kit to enable 
samples to be returned to the Turtle Lab for archival purposes, and for analysis for 
transgene and vector persistence, and RCL, as dictated by studies of transferred T cell 
persistence. 
2. 
A phone call survey or questionnaire to the participant may be used to screen for adverse 
events, and the patient may be offered the opportunity to return to FHCRC for an annual 
LTFU clinic visit. 
3. 
Compliance with 21 CFR 312.32 in adverse event reporting. 
4. 
Research studies: 
− Evaluation for transgene vector sequence by PCR of PBMC every 6 months for Years 
1 to 5 and every year for Years 6-15 until the transgene becomes undetectable. 
− Annual testing of PBMC for RCL by VSVG qPCR.  If there is no evidence of 
transgene persistence, RCL assays may be suspended after 1 year and samples may be 
archived. 
5. 
Survival data and results from any available disease response evaluations (i.e., imaging 
studies [CT, PET/CT, MRI], bone marrow examinations, etc.) performed by the treating 
physician as standard of care may be collected.


FHCRC Protocol No. 9457 
 
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Appendix F 
Modified Toxicity Probability Interval Decision Table 
Number of patients treated at current dose 
Number of toxicities 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
0 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
1 
D 
S 
S 
S 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
2 
 
DU 
D 
S 
S 
S 
S 
S 
S 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
3 
 
 
DU DU 
D 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
4 
 
 
 
DU DU DU 
D 
D 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
5 
 
 
 
 
DU DU DU DU DU 
D 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
E 
E 
E 
E 
E 
6 
 
 
 
 
 
DU DU DU DU DU DU 
D 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
E 
7 
 
 
 
 
 
 
DU DU DU DU DU DU DU 
D 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
8 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU 
D 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
9 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU DU DU 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
10 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU DU DU DU 
D 
S 
S 
S 
S 
S 
S 
S 
S 
11 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU DU DU DU DU DU 
S 
S 
S 
S 
S 
S 
12 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU 
S 
S 
S 
13 
 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU 
S 
14 
 
 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU 
15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU 
16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU 
17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU DU DU DU DU DU 
18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU DU DU DU DU 
19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU DU DU DU 
20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU DU DU 
21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU DU 
22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU 
23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU 
24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU 
25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU 
D, de-escalate to the next lower dose level; E, escalate to the next higher dose level; DU, current dose is unacceptably toxic; S, stay at the current dose level 
Target toxicity (%) = 30%; Sample size = 30 


FHCRC Protocol No. 9457 
 
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Appendix G 
Durvalumab Dosing Modification for Toxicity Management 
The following tables provide suggested management for toxicities that could be implemented at 
the discretion of the treating physician. 
Table G-1 
Durvalumab Treatment Modification and Toxicity Management Guidelines for 
Immune-related Adverse Events 
Table G-2 
Durvalumab Treatment Modification and Toxicity Management Guidelines for 
Infusion-related Reactions 
Table G-3 
Durvalumab Treatment Modification and Toxicity Management Guidelines for 
Non-immune-mediated Reactions 


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Table G-1 
Durvalumab Treatment Modification and Toxicity Management Guidelines (TMGs) for Durvalumab  
Dose Modifications 
Toxicity Management 
Immune-related 
adverse events 
(overall 
management for 
toxicities not 
noted below) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug administration modifications of study drug/study regimen will 
be made to manage potential irAEs based on severity of treatment-
emergent toxicities graded per NCI CTCAE v4.03. 
In addition to the criteria for permanent discontinuation of study 
drug/regimen based on CTC grade/severity (table below), 
permanently discontinue study drug/study regimen for  the following 
conditions:  
• Inability to reduce corticosteroid to a dose of ≤ 10 mg of 
prednisone per day (or equivalent) within 12 weeks after last dose 
of study drug/regimen 
• Recurrence of a previously experienced Grade 3 treatment-related 
AE following resumption of dosing. 
It is recommended that management of irAEs follow the 
guidelines presented in this table: 
• Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, concomitant 
medications, infections, etc.) 
• In the absence of a clear alternative etiology, all events 
should be considered potentially immune-related 
• Symptomatic and topical therapy should be considered for 
low-grade (Grade 1 or 2, unless otherwise specified) events  
• For persistent  (more than 3 to 5 days) low-grade (Grade 2)  
or severe (Grade ≥3) events, promptly start prednisone PO 
1-2 mg/kg/day or IV equivalent  
• If symptoms recur or worsen during corticosteroid tapering 
(≥ 4 weeks of taper), increase the corticosteroid dose 
(prednisone dose [e.g., up to 2-4 mg/kg/day or IV 
equivalent]) until stabilization or improvement of symptoms, 
then resume corticosteroid tapering at a slower rate  
 
• More potent immunosuppressives – (refer to individual 
sections of the irAE for specific type of immunosuppressive) 
should be considered for events not responding to systemic 
steroids 
• Discontinuation of study drug is not mandated for 
Grade 3/Grade 4 inflammatory reactions attributed to local 
tumour response (e.g., inflammatory reaction at sites of 
metastatic disease, lymph nodes, etc.). Continuation of study 
drug in this situation should be based upon a benefit/risk 
analysis for that patient  
 
 
Grade 1 
No dose modification 
   
 
Grade 2 
Hold study drug/study regimen dose until 
Grade 2 resolution to ≤ Grade 1 
• If toxicity worsens, then treat as Grade 3 or 
Grade 4 
• If toxicity improves to ≤ Grade 1, then treat 
at next scheduled treatment date 
Grade 3 
Depending on the individual toxicity, may 
permanently discontinue study drug/study 
regimen. Please refer to guidelines below 
Grade 4 
Permanently discontinue study drug/study 
regimen  
Note:  For Grade 3 and above asymptomatic amylase or lipase levels, 
hold study drug/regimen and if complete work-up shows no evidence 
of pancreatitis, may continue or resume study drug/regimen 


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Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Pneumonitis/ILD 
Grade of pneumonitis 
(CTCAE v4.03)  
Any grade 
• Monitor patients for signs and symptoms of pneumonitis or ILD (new onset or 
worsening shortness of breath or cough).  Patients should be evaluated with 
imaging and pulmonary function tests, including other diagnostic procedures 
as described below 
• Suspected pneumonitis should be confirmed with radiographic imaging and 
other infectious and disease-related aetiologies excluded, and managed as 
described below 
• Initial work-up may include clinical evaluation, monitoring of oxygenation 
via pulse oximetry (resting and exertion), laboratory work-up and high-
resolution CT scan.  
• Consider pulmonary and infectious disease consult 
Grade 1  
(Asymptomatic, 
clinical or diagnostic 
observations only, 
intervention not 
indicated) 
No dose modification required; however, 
consider holding study drug/study 
regimen dosing as clinically appropriate 
and during diagnostic work-up for other 
etiologies 
For Grade 1 (radiographic changes only): 
• Monitor and closely follow up in 2-4 days for clinical symptoms, pulse 
oximetry (resting and exertion), and laboratory work-up and then as clinically 
indicated 
• Consider pulmonary and  infectious disease consult 
Grade 2  
(Symptomatic, 
medical intervention 
indicated, limiting 
instrumental ADL)  
 Hold study drug/study regimen dose until 
Grade 2 resolution to ≤ Grade 1 
• If  toxicity worsens, then treat as Grade 
3 or Grade 4  
• If toxicity improves to ≤ Grade 1, then 
the decision to reinitiate study 
drug/regimen at next scheduled 
treatment date will be based upon 
treating physician’s clinical judgment.  
  
For Grade 2 (mild to moderate new symptoms): 
• Monitor symptoms daily and consider hospitalization 
• Promptly start systemic steroids (e.g., prednisone 1-2 mg/kg/day or IV 
equivalent) 
• Reimaging as clinically indicated, consider Chest CT with contrast and repeat 
in 3-4 weeks 
• If no improvement within 2-3 days, additional work-up should be considered 
and prompt treatment with IV methylprednisolone 2-4 mg/kg/day started  
• If still no improvement within 3-5 days despite IV methylprednisone at 
2-4/g/kg/day, promptly start immunosuppressive therapy (e.g. infliximab at 
5 mg/kg IV, may be repeated at 2 and 6 weeks after initial doses at the 
discretion of the treating provider).  Caution: Important to rule out sepsis and 
refer to infliximab label for general guidance before using infliximab  
• Once improving, gradually taper steroids over ≥ 4 weeks  and consider 
prophylactic antibiotics, antifungal, or anti-PCP treatment (refer to current  


FHCRC Protocol No. 9457 
 
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110 
 
 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
NCCN guidelines for treatment of  cancer-related infections (Category 2B 
recommendation)1 
• Consider pulmonary and infectious disease consult 
- Consider as necessary discussing with Juno medical monitor 
Grade 3 or 4  
(Grade 3: Severe 
symptoms; limiting 
self-care ADL; 
oxygen indicated  
 
Grade 4: life-
threatening 
respiratory 
compromise, urgent 
intervention indicated 
[e.g., tracheostomy or 
intubation])  
Permanently discontinue study drug/study 
regimen 
 
For Grade 3 or 4 (severe or new symptoms, new/worsening hypoxia, life-
threatening):  
• Promptly initiate empiric IV methylprednisolone 1-4 mg/kg/day or equivalent  
• Obtain pulmonary and infectious disease  consult 
• Hospitalize the patient 
• Supportive care (oxygen, etc.) 
• If no improvement within 2-3 days, additional work-up should be considered 
and prompt treatment with additional immunosuppressive therapy (e.g. 
infliximab at 5 mg/kg IV, may be repeated at 2 and 6 weeks after initial doses 
at the discretion of the treating provider) started.  Caution: rule out sepsis and 
refer to infliximab label for general guidance before using infliximab  
• Once improving, gradually taper steroids over ≥ 4 weeks  and consider 
prophylactic antibiotics, antifungals, and in particular, anti-PCP treatment 
(refer to current  NCCN guidelines for treatment of  cancer-related infections 
(Category 2B recommendation)2 
Diarrhea/ 
Enterocolitis 
Grade of diarrhea 
(CTCAE v4.03) 
Any grade 
 
• 
Monitor for symptoms that may be related to diarrhea/enterocolitis 
(abdominal pain, cramping, or changes in bowel habits, such as increased 
frequency over baseline or blood in stool) or related to bowel perforation 
(such as sepsis, peritoneal signs, and ileus)  
• 
Permanently discontinue study drug for any grade of intestinal perforation 
• Patients should be thoroughly evaluated to rule out any alternative etiology 
(e.g., disease progression, other medications, infections including testing for 
clostridium difficile toxin, etc.) 
• Steroids should be considered in the absence of a clear alternative etiology, 
even for low-grade events, in order to prevent potential progression to higher-
grade event 
 
1 ASCO Educational Book 2015. Michael Pestow MD. “Managing Immune Checkpoint Blocking Antibody Side Effects” Section on Hepatotoxicity page 78 
2 ASCO Educational Book 2015. “Managing Immune Checkpoint Blocking Antibody Side Effects” 


FHCRC Protocol No. 9457 
 
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111 
 
 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
• Use analgesics carefully; they can mask symptoms of perforation and 
peritonitis 
Grade 1 diarrhea  
(stool frequency of 
< 4 over baseline per 
day)  
No dose modification 
For Grade 1 diarrhea:  
• Close monitoring for worsening symptoms 
• Consider symptomatic treatment, including hydration, electrolyte 
replacement, dietary changes (e.g., American Dietetic Association colitis 
diet), loperamide and other supportive measures . Use of probiotics as per 
treating physician’s clinical judgment. 
• If symptoms persist consider checking lactoferrin; if positive treat as Grade 2 
below. If negative and no infection, continue Grade 1 management. 
Grade 2 diarrhea 
(stool frequency of 
4-6 over baseline per 
day)  
Hold study drug/study regimen until 
resolution to ≤ Grade 1 
• If  toxicity worsens, then treat as 
Grade 3 or Grade 4 
• If toxicity improves to ≤ Grade 1 then 
treat at next scheduled treatment date 
For Grade 2 diarrhea:  
• Consider symptomatic treatment including hydration, electrolyte replacement, 
dietary changes (e.g., American Dietetic Association colitis diet), and 
loperamide and/or budesonide  
• Promptly start prednisone 1-2 mg/kg/day or IV equivalent  
• If event is not responsive within 2-3 days or worsens despite prednisone at 
1-2 mg/kg/day or IV equivalent, GI consult should be obtained for 
consideration of further work-up, such as imaging and/or colonoscopy to 
confirm colitis and rule out perforation, and prompt treatment with IV 
methylprednisolone 2-4 mg/kg/day started 
• If still no improvement within 2-3 days despite 1-2 mg/kg IV 
methylprednisolone, promptly start immunosuppressives (e.g. infliximab at 
5 mg/kg IV, may be repeated at 2 and 6 weeks after initial dose at the 
discretion of the treating provider)3.  Caution: Important to rule out bowel 
perforation and refer to infliximab label for general guidance before using 
infliximab   
• Consult Juno medical monitor if no resolution to ≤ Grade 1 in 3-4 days 
• Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current  


FHCRC Protocol No. 9457 
 
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Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
NCCN guidelines for treatment of  cancer-related infections [Category 2B 
recommendation]) 
Grade 3 or 4 diarrhea  
 
(Grade 3: stool 
frequency of ≥ 7 over 
baseline per day 
 
Grade 4: life-
threatening 
consequences) 
Hold study drug/study regimen until 
resolution to Grade ≤1; study drug/study 
regimen can be resumed after completion 
of steroid taper. Permanently discontinue 
study drug/study regimen for Grade 3 if 
toxicity does not improve to Grade ≤1 
within 14 days.  
 
Permanently discontinue study drug for 
1) Grade 3 colitis in patients treated with 
CTLA-4 inhibitors or 2) Any grade large 
intestine perforation/Intestinal perforation 
in any patient treated with ICI. 
 
For Grade 3 or 4 diarrhea: 
• Promptly initiate empiric IV methylprednisolone 1-2 mg/kg/day or equivalent  
• Monitor stool frequency and volume and maintain hydration   
• Urgent GI consult and imaging and/or colonoscopy as appropriate 
• If still no improvement within 2 days continue steroids and, promptly start 
further immunosuppressives agents (e.g. infliximab at 5 mg/kg 5 mg/kg IV, 
may be repeated at 2 and 6 weeks after initial dose at the discretion of the 
treating provider) 
•  Caution: Ensure GI consult to rule out bowel perforation and refer to 
infliximab label for general guidance before using infliximab 
• Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current  
NCCN guidelines for treatment of cancer-related infections [Category 2B 
recommendation]) 
Hepatitis (elevated 
LFTs) 
Infliximab should 
not be used for 
management of 
immune-related 
hepatitis 
Grade of LFT 
elevation (CTCAE 
v4.03) 
Any grade 
  
• Monitor and evaluate liver function tests: AST, ALT, ALP, and total bilirubin  
• Evaluate for alternative etiologies (e.g., viral hepatitis, disease progression, 
concomitant medications)  
Grade 1  
(AST or ALT > ULN 
to 3 × ULN and/or 
TB > ULN to 1.5 × 
ULN) 
No dose modification 
If it worsens, treat as Grade 2 event 
For Grade 1 AST or ALT and/or TB elevation:     
•   Continue LFT monitoring per protocol   


FHCRC Protocol No. 9457 
 
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113 
 
 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Grade 2  
(AST or ALT > 3 to 
5 × ULN and/or TB 
>1.5-3.0 × ULN) 
Hold study drug/study regimen dose until 
Grade 2 resolution to ≤ Grade 1 
• If toxicity worsens, then treat as Grade 
3 or Grade 4 
• If improves to ≤ Grade 1, then treat at 
next scheduled treatment date 
For Grade 2 AST or ALT and/or TB elevation:  
• Regular and frequent checking of LFTs (e.g., every 1-2 days) until elevations 
of these are improving or resolved.   
• If no resolution to ≤ Grade 1 in 1-2 days, discuss with Juno medical monitor. 
• If event is persistent (> 2-3 days) or worsens, promptly start prednisone 
1-2 mg/kg/day or IV equivalent.  
• If still no improvement within 2-3 days despite 1-2 mg/kg/day of prednisone 
or IV equivalent, consider additional work-up and prompt treatment with IV 
methylprednisolone 2-4 mg/kg/day started. 
• If still no improvement within 2-3 days despite 1-2 mg/kg/day of IV 
methylprednisolone, promptly start immunosuppressives (mycophenolate 
mofetil 0.5-1g every 12 hours then taper in consultation with hepatology 
consult)).3  Discuss with Juno medical monitor if mycophenolate mofetil is 
not available.  Infliximab should NOT be used. 
• Once improving, gradually taper steroids over ≥ 4 weeks  and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current  
NCCN guidelines for treatment of  cancer-related infections [Category 2B 
recommendation]) 
Grade 3 
(AST or ALT >5 to 
20 × ULN and/or TB 
> 3.0 to 10 × ULN) 
For elevations in transaminases ≤ 8 × 
ULN, or elevations in bilirubin ≤ 5 × 
ULN  
• Hold study drug/study regimen dose 
until resolution to ≤ Grade 1 or 
baseline   
• Resume study drug/study regimen 
administration at the next scheduled 
dose if elevations downgrade to 
≤ Grade 1 or baseline within 14 days 
• Permanently discontinue study 
drug/study regimen if the elevations 
For Grade 3 or 4 AST or ALT and/or TB elevation: 
• Promptly initiate empiric IV methylprednisolone at 1-2 mg/kg/day or 
equivalent  
• If still no improvement within 2-3 days despite 1-2 mg/kg/day 
methylprednisolone IV or equivalent, promptly start treatment with 
immunosuppressive therapy (mycophenolate mofetil 0.5-1g every 12 hours 
then taper in consultation with hepatology consult). Discuss with Juno 
medical monitor if mycophenolate is not available. Infliximab should NOT 
be used. 
• Hepatology consult, abdominal workup, and imaging as appropriate 
 
3 ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects”, page 78 Section on Hepatotoxicity 


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Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
do not downgrade to ≤ Grade 1 or 
baseline within 14 days  
For elevations in transaminases > 8 × 
ULN or elevations in bilirubin > 5 × 
ULN, discontinue study drug/study 
regimen  
• Permanently discontinue study 
drug/study regimen for any case 
meeting Hy’s law criteria (ALT > 3 × 
ULN + bilirubin > 2 × ULN without 
initial findings of cholestasis (i.e., 
elevated ALP) and  in the absence of 
any alternative cause4 
• Once improving, gradually taper steroids over ≥ 4 weeks  and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current  
NCCN guidelines for treatment of cancer-related infections [Category 2B 
recommendation]) 
Grade 4  
(AST or ALT > 20 × 
ULN and/or TB > 10 
× ULN)  
Permanently discontinue study drug/study 
regimen  
Nephritis or renal 
dysfunction 
(elevated serum 
creatinine)  
Grade of elevated 
serum creatinine 
(CTCAE v4.03) 
 
Any grade  
 
• Consult with Nephrologist 
• Monitor for signs and symptoms that may be related to changes in renal 
function (e.g., routine urinalysis, elevated serum BUN and creatinine, 
decreased creatinine clearance, electrolyte imbalance, decrease in urine 
output, proteinuria, etc.)  
• Patients should be thoroughly evaluated to rule out any alternative etiology 
(e.g., disease progression, infections, etc.) 
• Steroids should be considered in the absence of a clear alternative etiology 
even for low-grade events (Grade 2) in order to prevent potential progression 
to higher-grade event 
 
4 FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation 


FHCRC Protocol No. 9457 
 
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Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Grade 1 (serum 
creatinine > 1-1.5 × 
baseline;  > ULN to 
1.5 × ULN)  
No dose modification 
For Grade 1 elevated creatinine:  
• Monitor serum creatinine weekly and any accompanying symptom 
− If creatinine returns to baseline, resume its regular monitoring per study 
protocol. 
− If it worsens, depending on the severity, treat as Grade 2 or Grade 3 or 4  
• Consider symptomatic treatment, including hydration, electrolyte 
replacement, diuretics, etc. 
Grade 2 (serum 
creatinine > 1.5-3.0 × 
baseline; > 1.5× to 
3.0× ULN) 
 
Hold study drug/study regimen until 
resolution to ≤ Grade 1 
• If  toxicity worsens, then treat as 
Grade 3 or Grade 4 
• If toxicity improves to ≤ Grade 1, then 
treat at next scheduled treatment date 
For Grade 2 elevated creatinine:  
• Consider symptomatic treatment, including hydration, electrolyte 
replacement, diuretics, etc.  
• Carefully monitor serum creatinine every 2-3 days and as clinically warranted 
• Consult Nephrologist and consider renal biopsy if clinically indicated 
• If event is persistent (> 3-5 days) or worsens, promptly start  prednisone 
1-2 mg/kg/day or IV equivalent  
• If event is not responsive within 3-5 days or worsens despite prednisone at 
1-2 mg/kg/day or IV equivalent, additional workup should be considered and 
prompt treatment with IV methylprednisolone at 2-4 mg/kg/day started.  
• Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current  
NCCN guidelines for treatment of cancer-related infections [Category 2B 
recommendation]).  
• When event returns to baseline, resume study drug/study regimen and routine 
serum creatinine monitoring per study protocol. 
Grade 3 or 4  
(Grade 3: serum 
dreatinine > 3.0 × 
baseline; > 3.0-6.0 × 
ULN 
Grade 4: serum 
creatinine > 6.0 × 
ULN)  
Permanently discontinue study drug/study 
regimen 
• Carefully monitor serum creatinine on daily basis 
• Consult Nephrologist and consider renal biopsy if clinically indicated 
• Promptly start prednisone 1-2 mg/kg/day or IV equivalent  
• If event is not responsive within 3-5 days or worsens despite prednisone at 
1-2 mg/kg/day or IV equivalent, additional work-up should be considered and 
prompt treatment with with an immunosuppressive in consultation with a 
nephrologist 


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Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
• Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current  
NCCN guidelines for treatment of cancer-related infections [Category 2B 
recommendation]  
Rash (excluding 
bullous skin 
formations) 
Grade of skin rash  
(Refer to CTCAE 
v4.03 for definition 
of severity/grade 
depending on type of 
skin rash)  
Any grade 
 
Monitor for signs and symptoms of dermatitis (rash and pruritus)  
• 
Hold study drug if Stevens-Johnson Syndrome (SJS), Toxic Epidermal 
Necrolysis (TEN), or other severe cutaneous adverse reaction (SCAR) is 
suspected  
• 
Permanently discontinue study drugs if SJS, TEN or SCAR is confirmed 
 
Grade 1  
No dose modification 
For Grade 1: 
• Consider symptomatic treatment, including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) and topical therapy (e.g., urea cream) 
Grade 2 
For persistent (> 1 week) Grade 2 events, 
hold scheduled study drug/study regimen 
until resolution to ≤ Grade 1 or baseline  
• If  toxicity worsens, then treat as 
Grade 3  
• If  toxicity improves, then resume 
administration at next scheduled dose 
For Grade 2: 
• Obtain dermatology consult  
• Consider symptomatic treatment, including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) and topical therapy (e.g., urea cream) 
• Consider moderate-strength topical steroid  
• If no improvement of rash/skin lesions occurs within 3-5 days or is worsening 
despite symptomatic treatment and/or use of moderate-strength topical steroid, 
discuss with Juno medical monitor and promptly start systemic steroids 
prednisone 1-2 mg/kg/day or IV equivalent   
• Consider skin biopsy if persistent for > 1 week or recurs 
Grade 3 
If toxicity improves to Grade ≤1 or 
baseline, then resume drug/study regimen 
after completion of steroid taper.  
• 
If toxicity worsens, then treat as 
Grade 4. 
For Grade 3 or 4: 
• Consult dermatology  
• Promptly initiate empiric IV methylprednisolone 1 to 2 mg/kg/day or 
equivalent  
• Consider hospitalization 
• Monitor extent of rash [Rule of Nines] 
• Consider skin biopsy (preferably more than 1) as clinically feasible 
Grade 4 
Permanently discontinue study drug/study 
regimen  


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Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
• Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current 
NCCN guidelines for treatment of  cancer-related infections [Category 2B 
recommendation]) 
• Discuss with Juno medical monitor 
Endocrinopathy 
(e.g., 
hyperthyroidism, 
hypothyroidism, 
hypopituitarism, 
adrenal 
insufficiency, etc.) 
Any grade  
(Depending on the 
type of 
endocrinopathy, refer 
to CTCAE v4.03 for 
defining the CTC 
grade/severity)  
 
• Consult endocrinologist 
• Monitor patients for signs and symptoms of endocrinopathies.  Non-specific 
symptoms include headache, fatigue, behavior changes, changed mental 
status, vertigo, abdominal pain, unusual bowel habits, hypotension, and 
weakness. 
• Patients should be thoroughly evaluated to rule out any alternative etiology 
(e.g., disease progression including brain metastases, infections, etc.) 
• Monitor and evaluate thyroid function tests: TSH, free T3 and free T4 and 
other relevant endocrine labs depending on suspected endocrinopathy.  
• If a patient experiences an AE that is thought to be possibly of autoimmune 
nature (e.g., thyroiditis, pancreatitis, hypophysitis, diabetes insipidus), the 
investigator should send a blood sample for appropriate autoimmune antibody 
testing  
• Investigators should ask subjects with endocrinopathies who may require 
prolonged or continued hormonal replacement, to consult their primary care 
physicians or endocrinologists about further monitoring and treatment after 
completion of the study. 
Grade 1 
(Depending on the 
type of 
endocrinopathy, refer 
to CTCAE v4.03 for 
defining the CTC 
Grade 1) 
No dose modification 
For Grade 1 (including those with asymptomatic TSH elevation): 
• Monitor patient with appropriate endocrine function tests 
• If TSH < 0.5 × LLN, or TSH > 2 × ULN or consistently out of range in two 
subsequent measurements, include FT4 at subsequent cycles as clinically 
indicated and consider endocrinology consult. 
Grade 2  
(Depending on the 
type of 
endocrinopathy, refer 
For Grade 2 endocrinopathy other than 
hypothyroidism, hold study drug/study 
regimen dose until patient is clinically 
stable 
For Grade 2 (including those with symptomatic endocrinopathy): 
• Isolated Type 1 diabetes mellitus may be treated with appropriate diabetic 
therapy and without corticosteroids. Only hold study drug/study regimen in 


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Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
to CTCAE v4.03 for 
defining the CTC 
Grade 2) 
  
• If toxicity worsens, then treat as Grade 
3 or Grade 4  
• If toxicity improves to ≤ Grade 1, then 
treat at next scheduled treatment date 
 
setting of hyperglycemia when diagnostic workup is positive for diabetic 
ketoacidosis. 
• Isolated hypothyroidism may be treated with replacement therapy without 
treatment interruption and without corticosteroids 
• Initiate hormone replacement as needed for management 
• Evaluate endocrine function, and as clinically indicated, consider pituitary 
scan 
• For patients with abnormal endocrine work-up, except for those with isolated 
hypothyroidism, consider short-term corticosteroids (e.g., 1-2 mg/kg/day 
methylprednisolone or IV equivalent) and prompt initiation of treatment with 
relevant hormone replacement (e.g., levothyroxine, hydrocortisone, or sex 
hormones).  
• Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current 
NCCN guidelines for treatment of cancer-related infections [Category 2B 
recommendation]) 
- For patients with normal endocrine work-up (lab or MRI scans), repeat 
labs/MRI as clinically indicated. 
Grade 3 or 4 
(Depending on the 
type of 
endocrinopathy, refer 
to CTCAE v4.03 for 
defining the CTC 
grade/severity 3 or 4)  
For Grade 3 or 4 endocrinopathy other 
than hypothyroidism, hold study 
drug/study regimen dose until 
endocrinopathy symptom(s) are 
controlled 
Resume study drug/study regimen     
administration if ≤ Grade 1 at the next 
scheduled dose 
For Grade 3 or 4: 
• Consult endocrinologist 
• Isolated Type 1 diabetes mellitus may be treated with appropriate diabetic 
therapy and without corticosteroids. Only hold study drug/study regimen in 
setting of hyperglycemia when diagnostic workup is positive for diabetic 
ketoacidosis. 
• Isolated hypothyroidism may be treated with replacement therapy without 
treatment interruption and without corticosteroids 
• Promptly initiate empiric IV methylprednisolone 1-2 mg/kg/day or equivalent 
• Administer hormone replacement therapy as necessary. 
• For adrenal crisis, severe dehydration, hypotension, or shock: immediately 
initiate IV corticosteroids with mineralocorticoid activity 
• Once improving, gradually taper immunosuppressive steroids over ≥ 4 weeks 
and consider prophylactic antibiotics, antifungals, and anti-PCP treatment  


FHCRC Protocol No. 9457 
 
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Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
• (refer to current NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation]) 
• Discuss with Juno medical monitor 
Amylase/Lipase 
increased 
Grade 1 
None 
• 
For modest asymptomatic elevations in serum amylase and lipase, 
corticosteroid treatment is not indicated as long as there are no other signs or 
symptoms of pancreatic inflammation.  
• 
If isolated elevation of enzymes without evidence of pancreatitis, continue 
immunotherapy.  
• 
Assess for signs/symptoms of pancreatitis   
• 
Consider appropriate diagnostic testing (e.g, abdominal CT with contrast, 
MRCP if clinical suspicion of pancreatitis and no radiologic evidence on CT)   
• 
Consider other causes of elevated amylase/lipase   
• 
If evidence of pancreatitis, manage according to pancreatitis 
recommendations 
 
Grade 2, 3 or 4 
 
In consultation with relevant pancreatic 
specialist consider continuing study 
drug/study regimen if no 
clinical/radiologic evidence of 
pancreatitis ± improvement in 
amylase/lipase. 
 
Acute Pancreatitis 
Grade 1 
None 
• 
Consider gastroenterology referral 
 
 
Grade 2 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. Consider 
resumption of study drug/study regimen 
if no clinical/radiologic evidence of 
pancreatitis ± improvement in 
amylase/lipase in consultation with 
relevant pancreatic specialist 
 
• 
Promptly start systemic steroids prednisone 1 to 2 mg/kg/day PO or IV 
equivalent –  
• 
IV hydration 
• 
Consider gastroenterology referral 
 
 


FHCRC Protocol No. 9457 
 
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Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
Grade 3 or 4 
Permanently discontinue study drug/study 
regimen 
 
• 
Promptly start systemic steroids prednisone 1 to 2 mg/kg/day PO or IV 
equivalent –  
• 
IV hydration 
• 
Consider gastroenterology referral 
 
Immune-mediated 
neurotoxicity (to 
include, but not 
limited to, limbic 
encephalitis, 
autonomic 
neuropathy, 
excluding 
Myasthenia Gravis 
and Guillain-Barre)   
 
Grade of 
neurotoxicity  
(Depending on the 
type of neurotoxicity, 
refer to CTCAE 
v4.03 for defining the 
CTC grade/severity) 
 
Any grade  
 
• Patients should be evaluated to rule out any alternative etiology (e.g., disease 
progression, infections, metabolic syndromes, and medications, etc.)  
• Monitor patient for general symptoms (headache, nausea, vertigo, behavior 
change, or weakness) 
• Consider appropriate diagnostic testing (e.g., electromyogram and nerve 
conduction investigations) 
• Symptomatic treatment with neurological consult as appropriate 
• For transverse myelitis, permanently discontinue for any grade. 
Grade 1 
 No dose modifications 
See “Any grade” recommendations above. 
Grade 2 
• 
Permanently discontinue study 
drug/study regimen if Grade 2 imAE 
does not resolve to Grade ≤1 within 
30 days 
If toxicity worsens, then treat as Grade 3 
or Grade 4  
 
• Discuss with the Juno medical monitor  
• Obtain Neurology consult  
• Sensory neuropathy/neuropathic pain may be managed by appropriate 
medications (e.g., gabapentin, duloxetine, etc.) 
• Promptly start systemic steroids prednisone 1-2 mg/kg/day or IV equivalent  
• If no improvement within 2-3 days despite 1-2 mg/kg/day prednisone or IV 
equivalent, consider additional work-up and promptly treat with additional 
immunosuppressive therapy (e.g., IVIgG or other immunosuppressive 
depending on the specific imAE)  
 


FHCRC Protocol No. 9457 
 
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Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
Grade 3 
• Permanently discontinue study 
drug/study regimen  
For Grade 3 or 4: 
• Discuss with Juno medical monitor 
• Obtain Neurology consult 
• Consider hospitalization 
• Promptly initiate empiric IV methylprednisolone 1-2 mg/kg/day or equivalent  
• If no improvement within 2-3 days despite IV corticosteroids, consider 
additional work-up and promptly treat with additional immunosuppressants 
(e.g., IVIgG or other immunosuppressive depending on the specific imAE)  
• Once stable, gradually taper steroids over ≥ 4 weeks 
Grade 4 
 
• Permanently discontinue study 
drug/study regimen 
Immune-mediated 
peripheral 
neuromotor 
syndromes, such as 
Guillain-Barre and 
Myasthenia Gravis 
 
Any grade 
• The prompt diagnosis of immune-mediated peripheral neuromotor syndromes 
is important, since certain patients may unpredictably experience acute 
decompensations which can result in substantial morbidity or in the worst 
case, death. Special care should be taken for certain sentinel symptoms which 
may predict a more severe outcome, such as prominent dysphagia, rapidly 
progressive weakness, and signs of respiratory insufficiency or autonomic 
instability 
• Patients should be evaluated to rule out any alternative etiology (e.g., disease 
progression, infections, metabolic syndromes, and medications, etc.). It should 
be noted that the diagnosis of immune-mediated peripheral neuromotor 
syndromes can be particularly challenging in patients with underlying cancer, 
due to the multiple potential confounding effects of cancer (and its treatments) 
throughout the neuraxis.  Given the importance of prompt and accurate 
diagnosis, it is essential to have a low threshold to obtain a neurological 
consult 
• Neurophysiologic diagnostic testing (e.g., electromyogram and nerve 
conduction investigations, and “repetitive stimulation” if myasthenia is 
suspected) are routinely indicated upon suspicion of such conditions and may 
be best facilitated by means of a neurology consultation  
• Important to consider that the use of steroids as the primary treatment of 
Guillain-Barre is not typically considered effective.  Patients requiring 
treatment should be started with IVIG and followed by plasmapheresis if not 
responsive to IVIgG  
Grade 1 
No dose modification 
• Discuss with the Juno medical monitor 


FHCRC Protocol No. 9457 
 
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Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
• Care should be taken to monitor patients for sentinel symptoms of a potential 
decompensation as described above 
• Obtain a neurology consult unless the symptoms are very minor and stable 
Grade 2 
Hold study drug/study regimen dose until 
resolution to ≤ Grade 1 
Permanently discontinue study drug/study 
regimen if it does not resolve to 
≤ Grade 1 within 30 days or if there are 
signs of respiratory insufficiency or 
autonomic instability 
 
Grade 2  
• Discuss with the Juno medical monitor  
• Care should be taken to monitor patients for sentinel symptoms of a potential 
decompensation as described above 
• Obtain a Neurology consult  
• Sensory neuropathy/neuropathic pain may be managed by appropriate 
medications (e.g., gabapentin, duloxetine, etc.) 
• MYASTHENIA GRAVIS 
− Steroids may be successfully used to treat Myasthenia Gravis. Important 
to consider that steroid therapy (especially with high doses) may result in 
transient worsening of myasthenia and should typically be administered in 
a monitored setting under supervision of a consulting neurologist. 
− Patients unable to tolerate steroids may be candidates for treatment with 
plasmapheresis or IVIG.  Such decisions are best made in consultation 
with a neurologist, taking into account the unique needs of each patient. 
− If Myasthenia Gravis-like neurotoxicity present, consider starting 
acetylcholine esterase (AChE) inhibitor therapy in addition to steroids. 
Such therapy, if successful, can also serve to reinforce the diagnosis. 
• GUILLAIN-BARRE:  
− Important to consider that the use of steroids as the primary treatment of 
Guillain-Barre is not typically considered effective. Patients requiring 
treatment should be started with IVIG and followed by plasmapheresis if 
not responsive to IVIgG. 
Grade 3 
Hold study drug/study regimen dose until 
resolution to ≤ Grade 1 
Permanently discontinue study drug/study 
regimen if Grade 3 irAE does not 
resolve to ≤ Grade 1 within 30 days or 
if there are signs of respiratory 
insufficiency or autonomic instability 
For severe or life threatening (Grade 3 or 4) events:  
• Discuss with Juno medical monitor 
• Recommend hospitalization 
• Monitor symptoms and obtain neurological consult 
• MYASTHENIA GRAVIS 


FHCRC Protocol No. 9457 
 
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Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Grade 4 
Permanently discontinue study drug/study 
regimen  
− Steroids may be successfully used to treat Myasthenia Gravis.  It should 
typically be administered in a monitored setting under supervision of a 
consulting neurologist. 
− Patients unable to tolerate steroids may be candidates for treatment with 
plasmapharesis or IVIgG. 
− If Myasthenia Gravis-like neurotoxicity present, consider starting 
acetylcholine esterase (AChE) inhibitor therapy in addition to steroids. 
Such therapy, if successful, can also serve to reinforce the diagnosis. 
• GUILLAIN-BARRE:  
− Important to consider that the use of steroids as the primary treatment of 
Guillain-Barre is not typically considered effective. Patients requiring 
treatment should be started with IVIG and followed by plasmapheresis if 
not responsive to IVIgG 
Myocarditis 
Any Grade 
Discontinue drug permanently if biopsy 
proven immune-mediated myocarditis 
 
• The prompt diagnosis of immune-mediated myocarditis is important, 
particularly in patients with baseline cardiopulmonary disease and reduced 
cardiac function 
• Consider, discussing with the study physician, as needed 
• Monitor patients for signs and symptoms of myocarditis (new onset or 
worsening chest pain, arrhythmia, shortness of breath, peripheral edema). As 
some symptoms can overlap with lung toxicities, simultaneously evaluate for 
and rule out pulmonary toxicity as well as other causes (e.g., pulmonary 
embolism, congestive heart failure, malignant pericardial effusion). Consult a 
cardiologist early, to promptly asses whether and when to complete a cardiac 
biopsy, including any other diagnostic procedures. 
• Initial work-up should include clinical evaluation, BNP, cardiac enzymes, 
ECG, echocardiogram (ECHO), monitoring of oxygenation via pulse oximetry 
(resting and exertion), and additional laboratory work-up as indicated. Spiral 
CT or cardiac MRI can complement ECHO to assess wall motion 
abnormalities when needed. 
• Patients should be thoroughly evaluated to rule out any alternative etiology 
(e.g., disease progression, other medications, or infections)medications, or 
infections) 
 


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Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
Grade 1 
No dose modifications required unless 
clinical suspicion is high, in which case 
hold study drug/study regimen dose 
during diagnostic work-up for other 
etiologies. If study drug/study regimen is 
held, resume after complete resolution to 
Grade 0. 
• Monitor and closely follow up in 2 to 4 days for clinical symptoms,  BNP, 
cardiac enzymes, ECG, ECHO, pulse oximetry (resting and exertion), and 
laboratory work-up as clinically indicated. 
• Consider using steroids if clinical suspicion is high. 
 
Grade 2, 3, or 4 
If Grade 2 -- Hold study drug/study 
regimen dose until resolution to Grade 0. 
If toxicity rapidly improves to Grade 0, 
then the decision to reinitiate study 
drug/study regimen will be based upon 
treating physician’s clinical judgment and 
after completion of steroid taper. If 
toxicity does not rapidly improve, 
permanently. discontinue study 
drug/study regimen. 
 
If Grade 3-4, permanently discontinue 
study drug/study regimen. 
• Monitor symptoms daily, hospitalize. 
• Promptly start IV methylprednisolone 2 to 4 mg/kg/day or equivalent after 
Cardiology consultation has determined whether and when to complete 
diagnostic procedures including a cardiac biopsy. 
• Supportive care (e.g., oxygen). 
• If no improvement within 2-3 days despite IV methylprednisolone at 2 to 
4 mg/kg/day, promptly start immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab at 5 mg/kg IV, may be repeated at 2 and 6 weeks 
after initial dose at the discretion of the treating provider). Caution: It is 
important to rule out sepsis and refer to infliximab label for general guidance 
before using infliximab. Infliximab is contraindicated for patients who have 
heart failure. 
 


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Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Myositis/Polymyos
itis 
 
Any Grade 
 
• Monitor patients for signs and symptoms of poly/myositis. Typically, muscle 
weakness/pain occurs in proximal muscles including upper arms, thighs, 
shoulders, hips, neck and back, but rarely affects the extremities including 
hands and fingers; also difficulty breathing and/or trouble swallowing can 
occur and progress rapidly. Increased general feelings of tiredness and fatigue 
may occur, and there can be new-onset falling, difficulty getting up from a 
fall, and trouble climbing stairs, standing up from a seated position, and/or 
reaching up. 
• If poly/myositis is suspected, a Neurology consultation should be obtained 
early, with prompt guidance on diagnostic procedures. Myocarditis may co-
occur with poly/myositis; refer to guidance under Myocarditis. Given 
breathing complications, refer to guidance under Pneumonitis/ILD.  
Given possibility of an existent (but previously unknown) autoimmune 
disorder, consider Rheumatology consultation. 
• Consider, as necessary, discussing with the study physician. 
• Initial work-up should include clinical evaluation, creatine kinase, aldolase, 
LDH, BUN/creatinine, erythrocyte sedimentation rate or C-reactive protein 
level, urine myoglobin, and additional laboratory work-up as indicated, 
including a number of possible rheumatological/antibody tests (i.e., consider 
whether a rheumatologist consultation is indicated and could guide need for 
rheumatoid factor, antinuclear antibody, anti-smooth muscle, antisynthetase 
[such as anti-Jo-1], and/or signal-recognition particle antibodies). 
Confirmatory testing may include electromyography, nerve conduction 
studies, MRI of the muscles, and/or a muscle biopsy. Consider Barium 
swallow for evaluation of dysphagia or dysphonia. 
• Patients should be thoroughly evaluated to rule out any alternative etiology 
(e.g., disease progression, other medications, or infections). 
 
 
Grade 1 
None 
• Monitor and closely follow up in 2 to 4 days for clinical symptoms and initiate 
evaluation as clinically indicated. 
• Consider Neurology consult. 
• Consider, as necessary, discussing with the study physician. 
 


FHCRC Protocol No. 9457 
 
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Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
Grade 2 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
 
Permanently discontinue study drug/study 
regimen if it does not resolve to Grade ≤1 
within 30 days or if there are signs of 
respiratory insufficiency. 
• Monitor symptoms daily and consider hospitalization. 
• Obtain Neurology consult, and initiate evaluation. 
• Consider, as necessary, discussing with the study physician. 
• If clinical course is rapidly progressive (particularly if difficulty breathing 
and/or trouble swallowing), promptly start IV methylprednisolone 2 to 
4 mg/kg/day systemic steroids along with receiving input from Neurology 
consultant  
• If clinical course is not rapidly progressive, start systemic steroids (e.g., 
prednisone 1 to 2 mg/kg/day PO or IV equivalent); if no improvement within 
2-3 days, continue additional work up and start treatment with IV 
methylprednisolone 2 to 4 mg/kg/day 
• If after start of IV methylprednisolone at 2 to 4 mg/kg/day there is no 
improvement within 2-3 days, consider starting another immunosuppressive 
therapy such as TNF inhibitors (e.g., infliximab at 5 mg/kg IV, may be 
repeated at 2 and 6 weeks after initial dose at the discretion of the treating 
provider). Caution: It is important to rule out sepsis and refer to infliximab 
label for general guidance before using infliximab. 
 
 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study drug/study 
regimen if Grade 3 imAE does not 
resolve to Grade ≤1 within 30 days or if 
there are signs of respiratory 
insufficiency. 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
 
 
• Monitor symptoms closely; recommend hospitalization. 
• Obtain Neurology consult 
• Consider discussing with the study physician, as necessary. 
• Promptly start IV methylprednisolone 2 to 4 mg/kg/day systemic steroids 
along with receiving input from Neurology consultant. 
• If after start of IV methylprednisolone at 2 to 4 mg/kg/day there is no 
improvement within 2-3 days, consider start of immunosuppressive therapy 
such as TNF inhibitors (e.g., infliximab at 5 mg/kg may be repeated at 2 and 6 
weeks after initial dose at the discretion of the treating provider). Caution: It is 
important to rule out sepsis and refer to infliximab label for general guidance 
before using infliximab. 
• Consider whether patient may require IV IG, plasmapheresis. 
 


FHCRC Protocol No. 9457 
 
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Table G-2 
Durvalumab Treatment Modification and Toxicity Management Guidelines for Infusion-Related Reactions 
Severity 
Grade 
Dose Modifications 
Toxicity Management 
Any Grade 
 
• Management per institutional standard at the discretion of investigator 
• Monitor patients for signs and symptoms of infusion-related reactions (e.g., 
fever and/or shaking chills, flushing and/or itching, alterations in heart rate 
and blood pressure, dyspnea or chest discomfort, skin rashes, etc.) and 
anaphylaxis (e.g., generalized urticaria, angioedema, wheezing, hypotension, 
tachycardia, etc.) 
Grade 1 
The infusion rate of study drug/study regimen may be 
decreased by 50% or temporarily interrupted until 
resolution of the event 
For Grade 1 or Grade 2: 
• Acetaminophen and/or antihistamines may be administered per institutional 
standard at the discretion of the investigator  
• Consider premedication per institutional standard prior to subsequent doses 
Grade 2 
 
The infusion rate of study drug/study regimen may be 
decreased by 50% or temporarily interrupted until 
resolution of the event (up to 4 hours). 
Subsequent infusions may be given at 50% of the initial 
infusion rate 
Grade 3/4 
Permanently discontinue study drug/study regimen 
For Grade 3 or 4: 
• Manage severe infusion-related reactions per institutional standards (e.g., IM 
epinephrine, followed by IV diphenhydramine and famotidine, and IV 
glucocorticoid) 
 


FHCRC Protocol No. 9457 
 
14 May 2021 
128 
 
Table G-3 
Durvalumab Treatment Modification and Toxicity Management Guidelines for Non-Immune-Mediated Reactions 
CTC Grade/Severity 
Dose Modification  
Toxicity Management  
Any grade 
Note: Dose modifications are not required for adverse events not deemed to be related to study 
treatment (i.e., events due to underlying disease) or for laboratory abnormalities not deemed to 
be clinically significant. Any durvalumab-related adverse event ≥ Grade 2 resulting in holding of 
durvalumab, please discuss with Juno medical monitor. 
Treat accordingly as per institutional 
standard  
1 
No dose adjustment  
Treat accordingly as per institutional 
standard  
2 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline 
Treat accordingly as per institutional 
standard  
3 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline 
For AEs that downgrade to ≤ Grade 2 within 7 days or resolve to ≤ Grade 1 or baseline within 
14 days, resume study drug/study regimen administration at next scheduled dose. Otherwise, 
discontinue study drug/study regimen 
Treat accordingly as per institutional 
standard  
 
 
4 
Discontinue study drug/study regimen (note for Grade 4 labs, decision to discontinue would be 
based on accompanying clinical signs/symptoms and as per Investigator’s clinical judgment and 
in consultation with the Juno medical monitor)  
Treat accordingly as per institutional 
standard