Clinical trial NCT03003520
Conditions: Lymphoma, Large B-Cell, Diffuse
Keywords: Lymphoma Diffuse-large B-Cell Lymphoma Durvalumab Anti-PD-L1 Antibody MEDI4736 Immune Checkpoint Rituximab Cyclophosphamide Doxorubicin Vincristine Prednisone/Prednisolone Lenalidomide
Sponsor: Celgene
Start date: 2017-02-28; Completion date: 2022-04-24
Enrollment: 46 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase 2, two-arm, open-label study is designed to evaluate the safety, clinical activity, and predictive biomarkers of durvalumab in combination with R-CHOP or R2-CHOP, followed by durvalumab consolidation therapy in previously untreated subjects with high-risk diffuse large B-cell lymphoma (DLBCL). Induction treatment with R-CHOP (± lenalidomide) will last for a total of up to 6 to 8 treatment cycles (21 day cycles), and the total time on study treatment, including durvalumab consolidation, will last up to 12 months.

On 05-Sep-2017, the US FDA has issued a Partial Clinical Hold on this study resulting in the discontinuation of enrollment into Arm B (Durvalumab + Lenalidomide + R-CHOP). After the US FDA Partial Clinical Hold, new eligible participants have been enrolled in Arm A (Durvalumab + R-CHOP).

Detailed description:
This research study is conducted in participants with previously untreated, high-risk diffuse large B-cell lymphoma (DLBCL). Patients with high-risk DLBCL typically have insufficient therapeutic outcomes. Therefore, the addition of novel agents to the currently used induction therapy (R-CHOP) is a rational approach to improve therapeutic outcomes in this disease setting.

Based on pre-clinical and clinical observations, it is hypothesized that durvalumab will have activity in DLBCL because the PD 1/PD L1 pathway is involved in the pathophysiology of DLBCL. In particular, the addition of durvalumab may augment the anti-tumor activity of R-CHOP against high-risk DLBCL sub-types.

The safety of durvalumab has already been explored. However, as there is limited clinical experience with durvalumab in DLBCL, the study is divided into two stages:

* A Safety Run-in Stage to evaluate the safety of the treatment combinations until at least 10 subjects are included in each of the two treatment arms
* An Expansion Stage to analyze the clinical activity of the treatment combinations

Results posted following Primary Outcome Completion date are based on a database cut-off of August 2, 2018.

Arms: arm 1: On Day 1 of each 21-day cycle, participants received durvalumab 1125 mg intravenously (IV) followed by R-CHOP (IV rituximab 375 mg/m\^2, doxorubicin 50 mg/m\^2, vincristine 1.4 mg/m\^2 (maximum dose of 2.0 mg total), and cyclophosphamide 750 mg/m\^2); Participants also were administered daily oral or IV prednisone/prednisolone 100 mg from Day 1 to 5. Induction treatment continued for a total of 6-8 cycles.

Participants who achieve a complete response or partial response continue with consolidation therapy treatment consisting of durvalumab monotherapy 1500 mg by IV on Day 1 of each 28-day cycle for up to a total of 12 months. arm 2: Participants start the study on durvalumab in combination with R-CHOP (as described in Arm DUR + R-CHOP). Based on their DLBCL Cell-of-Origin subtype (test typically done between cycles 1 and 2), participants with ABC subtype continue the study taking durvalumab in combination with R2-CHOP. On Day 1 of each 21-day cycle, participants received durvalumab 1125 mg intravenously (IV) followed by R-CHOP. Participants were also administered daily oral or IV prednisone/prednisolone 100 mg from Day 1 to 5. In addition, a daily oral lenalidomide 15 mg was administered from Day 1 to 14 of each 21-day cycle. Induction treatment continued for a total of 6-8 cycles.

Participants who achieve a complete response or partial response continue with consolidation therapy treatment consisting of durvalumab monotherapy 1500 mg by IV on Day 1 of each 28-day cycle for up to a total of 12 months.

Enrollment into Arm B was discontinued.
Interventions: intervention 1: Durvalumab intervention 2: Rituximab intervention 3: Doxorubicin intervention 4: Vincristine intervention 5: Cyclophosphamide intervention 6: Prednisone intervention 7: Lenalidomide
Intervention descriptions: intervention 1: Durvalumab was supplied in single use vials as a liquid solution containing 500 mg (nominal) of durvalumab at a concentration of 50 mg/mL to be infused by intravenous (IV) injection.

Day 1 of each treatment cycle (Induction Period and Consolidation Period) started with the administration of IV durvalumab followed by a 2-hour observation period post infusion. intervention 2: Subsequent to durvalumab infusion, rituximab was administered by IV. Rituximab administration could be split over 2 consecutive days according to local clinical practice. Rapid infusion of rituximab was not allowed in this clinical study. intervention 3: A component of the CHOP therapy administered by IV. CHOP therapy was administered following rituximab. intervention 4: A component of the CHOP therapy administered by IV. CHOP therapy was administered following rituximab. intervention 5: A component of the CHOP therapy administered by IV. CHOP therapy was administered following rituximab. intervention 6: Prednisone was administered as an IV infusion or by mouth (PO) on Day 1, followed by PO administration on Days 2-5 of each cycle.

Prednisone could be given prior to other drugs of the CHOP therapy. It was administered after lenalidomide dosing in the R2-CHOP treatment arm. intervention 7: Lenalidomide was administered orally in capsule form on Days 1-14 of the DUR+R2-CHOP treatment arm only.

Protocol documents:
Prot_SAP_002.pdf: 
Official Title of Study: 
A Phase 2, Open-label, Multicenter Study to Evaluate the Safety and Clinical Activity of Durvalumab in 
Combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (R-CHOP) or with 
Lenalidomide plus R-CHOP (R2-CHOP) in Subjects With Previously Untreated, High-Risk Diffuse Large B-
Cell Lymphoma 
 
PROTOCOL(S) MEDI4736-DLBCL-001 
 
NCT Number: NCT03003520 
  
Document Date (Date in which document was last revised): October 25, 2019 


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Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
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TITLE PAGE
A PHASE 2, OPEN-LABEL, MULTICENTER STUDY TO 
EVALUATE THE SAFETY AND CLINICAL ACTIVITY 
OF DURVALUMAB IN COMBINATION WITH 
RITUXIMAB, CYCLOPHOSPHAMIDE, DOXORUBICIN, 
VINCRISTINE, PREDNISONE (R-CHOP) OR WITH 
LENALIDOMIDE PLUS R-CHOP (R2-CHOP) IN 
SUBJECTS WITH PREVIOUSLY-UNTREATED, 
HIGH-RISK DIFFUSE LARGE B-CELL LYMPHOMA
PROTOCOL NUMBER:
MEDI4736-DLBCL-001
DATE FINAL:
20 Jul 2016
Amendment 1
09 May 2017
Amendment 2
02 Jan 2018
Amendment 3
27 Feb 2018
Amendment 4
25 Oct 2019
EudraCT NUMBER:
2015-005173-20
IND NUMBER:
127058
SPONSOR NAME/ ADDRESS:
Celgene International II Sarl
Rue des Moulins 4
2108 Couvet
Switzerland
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or 
consultant for review by you, your staff, and ethics committee/institutional 
review board.  The information contained in this document is regarded as 
confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by 
law or regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.
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MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION
Contact Information:
Name:
Title:
 Clinical Research & Development
Address: Celgene International, Route de Perreux 1, CH-2017 Boudry, Switzerland
Phone:
Mobile:
E-mail:
Note: The back-up 24-hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls.
Back-up 24-hour Global Emergency Contact Call Center: 
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CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
 Clinical Research & Development
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.  
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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name:_______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from
Celgene representatives, the Declaration of Helsinki, International Council for 
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.
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COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:_______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed.
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PROTOCOL SUMMARY
Introduction
On 05 Sep 2017, a Partial Clinical Hold was placed to this study by the United States (US) Food 
and Drug Administration (FDA). The decision by the FDA was based on risks identified in other 
trials for pembrolizumab, an anti-programmed cell death-1 (PD-1) antibody, in patients with 
multiple myeloma in combination with immunomodulatory agents. As a result, enrollment 
continued into Arm A only and new subjects received induction therapy (durvalumab + R-
CHOP) after Cycle 1 regardless of diffuse large B-cell lymphoma (DLBCL) cell of origin (COO)
subtype. Enrollment into Arm B (durvalumab in combination with lenalidomide plus rituximab, 
cyclophosphamide, doxorubicin, vincristine, prednisone [R2-CHOP]) was discontinued. Subjects 
enrolled and treated in Arm B prior to the US FDA Partial Clinical Hold who were receiving 
clinical benefit, based on the discretion of the Investigator, could continue study treatment after 
being reconsented. 
Study enrollment was completed in March 2018.
The protocol-defined primary analysis was completed with a data cutoff date of 02 Aug 2018,
and the last subject’s last durvalumab dose occurred on 04 Mar 2019. Subsequently, the last 
durvalumab subject’s 90-day Safety Follow-up Visit was completed. At the time of the data 
cutoff date of the last 90-day Safety Follow-up Visit (06 Jun 2019), 30 subjects were in follow-
up. No subjects were on treatment with durvalumab or any other study treatments.
There are no further plans to evaluate long-term efficacy, including overall survival (OS), for the 
remaining subjects on study, and no additional statistical analysis on safety and efficacy will be 
performed. 
Therefore, the Follow-up Period will be discontinued, and data collection in the clinical database
will stop under this amendment. Subjects who received lenalidomide will continue to be 
followed for second primary malignancies (SPMs) as required by this study protocol 
(Section 3.1.3.1) 
. After stopping data collection in the clinical 
database, any SPM events will continue to be collected in the safety database.  
Study Title
A Phase 2, Open-label, Multicenter Study to Evaluate the Safety and Clinical Activity of 
Durvalumab in Combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, 
Prednisone (R-CHOP) or with Lenalidomide plus R-CHOP (R2-CHOP) in Subjects With 
Previously Untreated, High-Risk Diffuse Large B-Cell Lymphoma
Indication
Previously untreated, high-risk DLBCL.
Objectives

Primary Objective

To explore the clinical activity of durvalumab (MEDI4736) in combination with 
R-CHOP or R2-CHOP followed by durvalumab consolidation therapy in 
previously untreated subjects diagnosed with high-risk DLBCL
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
Secondary Objectives

To evaluate the safety and tolerability of durvalumab when given in combination 
with R-CHOP or R2-CHOP followed by durvalumab consolidation therapy

To identify and develop biomarkers of the tumor microenvironment and of the 
host immune system which are predictive of clinical response to durvalumab,
when administered in combination with R-CHOP or R2-CHOP, followed by 
durvalumab consolidation therapy that will be tested in further randomized 
clinical trials.  Examples of defined analytical methods that may be investigated 
include, but are not limited to:

PD-L1 immunohistochemistry (IHC)

Gene Expression Signatures

Exploratory Objective(s)

To examine the pharmacokinetic/pharmacodynamic (PK/Pd) relationship, and the 
mechanistic biomarkers for durvalumab when given in combination with 
R-CHOP or with R2-CHOP followed by durvalumab consolidation therapy.

To evaluate impact on endpoints related to clinical activity of durvalumab when 
given in combination with R-CHOP followed by durvalumab consolidation 
therapy.
Study Design
This Phase 2, two-arm, open-label study is designed to evaluate durvalumab in combination with 
R-CHOP (Arm A) or in combination with R2-CHOP (Arm B), followed by durvalumab 
consolidation therapy in previously untreated subjects with high-risk DLBCL (Figure 1).1
Induction treatment with R-CHOP will last for a total of up to 6 to 8 treatment cycles, and the 
total time on study treatment, including durvalumab consolidation, will last up to 12 months.
All subjects will be treated with durvalumab combined with R-CHOP during Cycle 1 of 
induction therapy. Based on their DLBCL COO subtype (ABC versus non-ABC) as determined 
by the NanoString Lymphoma subtyping test (LST) before start of Cycle 2, subjects will be 
allocated to one of two treatment arms1 from Cycle 2 onwards:
Induction Therapy (21-day cycles)
Arm A: Durvalumab in combination with R-CHOP
Durvalumab 1125 mg intravenously (IV) on Day 1 of each 21-day cycle in combination 
with 6 to 8 cycles R-CHOP (IV rituximab, doxorubicin, vincristine, and 
cyclophosphamide on Day 1; daily oral/IV prednisone/prednisolone from Day 1 to 5).
                                               
1 As a result of the US FDA Partial Clinical Hold, enrollment continued into Arm A only and new subjects received 
induction therapy (durvalumab + R CHOP) after Cycle 1 regardless of DLBCL COO subtype. Enrollment into 
Arm B (durvalumab in combination with lenalidomide plus rituximab, cyclophosphamide, doxorubicin, 
vincristine, prednisone [R2-CHOP]) was discontinued. Subjects enrolled and treated in Arm B prior to the US 
FDA Partial Clinical Hold who were receiving clinical benefit, based on the discretion of the Investigator, could
continue study treatment after being reconsented. 
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Arm B: Durvalumab in combination with R2-CHOP1
Durvalumab 1125 mg IV on Day 1 of each 21-day cycle in combination with 
6 to 8 cycles R2-CHOP (IV rituximab, doxorubicin, vincristine and cyclophosphamide on 
Day 1; daily oral/IV prednisone/prednisolone from Day 1 to 5; daily oral lenalidomide
15 mg from Day 1 to 14) from the cycle following COO determination until end of 
induction therapy (Cycle 6 or Cycle 8), or starting Cycle 1 if ABC subtype is identified 
prior to Cycle 1 Day 1 (C1D1).
Consolidation Therapy (28-day cycles) for subjects achieving a sufficient therapeutic 
response at end of the induction therapy. Note: In this study, a CR at the end of induction 
therapy is considered a sufficient therapeutic response. In addition, subjects achieving a PR 
at the end of induction therapy may continue on consolidation therapy based on the decision 
of the Investigator.
Arm A and Arm B:
Durvalumab 1500 mg IV on Day 1 of each 28-day cycle for up to a total of 12 months 
from C1D1.
All treatments will be administered until disease progression, unacceptable toxicity, or the 
completion of the treatment regimen.  Eligible subjects for whom the COO has already been 
identified as ABC subtype by the NanoString LST before starting study treatment, may have 
lenalidomide added starting at C1D1 onwards (Arm B). Subjects for whom the COO is 
determined as ABC only after Cycle 1 will be allocated to Arm B whenever the results become 
available, however, missed cycles of lenalidomide will not be made up. 1 Subjects for whom 
COO determination is inconclusive will continue treatment in study Treatment Arm A. Any 
newly enrolled subject with DLBCL of ABC COO subtype will continue induction therapy on 
Arm A (durvalumab + R-CHOP) after Cycle 1.
The study is divided into two stages:

A Safety Run-in Stage to evaluate the safety of the treatment combinations until at 
least 10 subjects are included. Following Partial Clinical Hold instituted by the US 
FDA which affects Arm B, the Safety Run-in Stage will evaluate safety of the 
treatment Arm A combinations when at least 10 subjects have been included into 
Arm A and have been treated for at least one cycle of study treatment or discontinued 
prematurely.

An Expansion Stage to analyze the clinical activity of the treatment combinations in 
up to a total of approximately 40 subjects in the efficacy evaluable population.
A Safety Review Committee (SRC), composed of the Celgene Medical Monitor, the Celgene 
Drug Safety Physician, as well as selected participating Principal Investigators, will evaluate the 
safety profile of treatment Arm A combination during the Safety Run-in Stage. The decision to 
initiate enrollment into the Expansion Stage will occur at the discretion of the Sponsor following 
the evaluation of the Safety Run-in Stage by the SRC. This review will take place after at least 10 
subjects have been enrolled into Arm A and have completed at least one cycle of study treatment 
or discontinued prematurely.  
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Protocol MEDI4736-DLBCL-001
Celgene International II Sàrl
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MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
The study will be conducted in compliance with International Council for Harmonisation (ICH) 
Good Clinical Practices (GCPs).
Study Population
The study population will consist of previously untreated subjects with high-risk DLBCL. In this 
study, high-risk DLBCL is defined as meeting both of the following two criteria:

Ann Arbor Stage 3-4 or Ann Arbor Stage 2 with bulky disease ≥7.0 cm

Intermediate-high or high International Prognostic Index (IPI) risk:
IPI ≥3 or National Comprehensive Cancer Network-IPI (NCCN-IPI) ≥4
This study is expected to be conducted in the US and Europe. Additional study sites located in 
other regions may be considered for participation as necessary.
Sample Size
Approximately 45 subjects are planned to be enrolled into this study (with approximately 
40 subjects in the efficacy evaluable population).
Study Duration for Subjects
The study consists of a Screening Period (up to 28 days before first dose of study treatment), a 
Treatment Period (up to a total of 12 months) and a Follow-up Period (up to 5 years after the last 
subject is enrolled). 
Follow-up for safety and efficacy begins after study treatments have completed or discontinued. 
For safety follow-up, subjects are followed for AEs, SPMs, and concomitant medications/ 
procedures for 90 days after the last durvalumab dose or 28 days after the last dose of other IPs, 
whichever is the later date. For efficacy follow-up, subjects are followed for disease progression,
or until death, lost to follow-up, or consent withdrawal, for up to 5 years after the last subject is 
enrolled, whichever occurs first.
Following completion of the last durvalumab subject’s 90-day safety follow-up (data cutoff date 
06 Jun 2019) and discontinuation of the Follow-up Period, subjects are no longer required to be 
followed for disease progression, safety, and can stop study participation under this amendment.
Subjects who received lenalidomide will continue to be followed for up to 5 years from the date 
of enrollment (C1D1) of the last subject and evaluated for the occurrence of SPMs.
Overview of Key Efficacy Assessments
The response to treatment will be assessed according to the 2014 International Working Group 
(IWG) Response Criteria for Non-Hodgkin’s Lymphoma (NHL) (Cheson, 2014).
Efficacy assessments will include:

Computed tomography (CT) scans

Fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans

Clinical findings (eg physical examination, constitutional symptoms)
Overview of Key Safety Assessments
Safety assessments will include:
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
Monitoring for adverse events (AE) including SPM

Physical examination

Vital signs

Body weight

Eastern Cooperative Oncology Group (ECOG) performance status

Hepatitis B virus (HBV) serology

Hematology laboratory parameters (complete blood count [CBC] with differential)

Serum chemistry laboratory parameters

Serum immunoglobulins

Cardiac function/left-ventricular ejection fraction (LVEF)

Electrocardiogram

Concomitant medications, therapies, and procedures

Pregnancy testing (for female subjects of childbearing potential [FCBP] only)
Statistical Methods
The Safety Run-in Stage will be used to determine the tolerability of the addition of durvalumab 
to the induction treatment with R-CHOP until at least 10 subjects have completed at least one 
cycle of study treatment or discontinued prematurely. Following Partial Clinical Hold instituted
by the US FDA which affects Arm B, the Safety Run-in Stage will evaluate safety of the 
treatment Arm A combinations when at least 10 subjects have been included into Arm A and 
have been treated for at least one cycle of study treatment or discontinued prematurely. Once 
treatment is confirmed to be tolerable, additional subjects will be enrolled for the Expansion 
Stage up to a total of approximately 40 subjects in the efficacy evaluable population.
The efficacy evaluable population is defined by all subjects who complete at least one cycle of 
their assigned treatment, have a baseline assessment by CT scan and have at least one post 
baseline tumor response assessment.
The primary efficacy analysis will evaluate the complete response rate (CRR) at the end of the 
induction therapy in the efficacy evaluable population in a comparative manner against historical 
control. The key secondary efficacy analysis will evaluate the rate of subjects who continue 
consolidation therapy out of all subjects in the efficacy evaluable population in a comparative 
manner against historical control.
If null hypothesis on primary endpoint is rejected, hypothesis testing on the key secondary
endpoint will be performed hierarchically without any type I error adjustment.
Analysis of secondary efficacy endpoints will include further analysis of response and 
progression data, and in particular those data related to biomarkers predictive of response to 
study treatment.
The statistical analysis of the safety profile of the study treatments will be observational in 
nature. 
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There is no interim analysis planned in this study.
The primary analysis for this study was completed (data cutoff date: 02 Aug 2018). No 
additional efficacy or safety statistical analyses are planned.
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TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
TABLE OF CONTENTS..........................................................................................................12
1.
INTRODUCTION..................................................................................................20
1.1.
Diffuse Large B-cell Lymphoma ............................................................................20
1.2.
Clinical and Biological Prognostic Factors..............................................................21
1.2.1.
International Prognostic Index (IPI) and National Comprehensive Cancer 
Network International Prognostic Index (NCCN-IPI)..............................................21
1.2.2.
Cell of Origin .........................................................................................................22
1.2.3.
Immune-checkpoint Inhibition................................................................................23
1.2.4.
PD-L1/PD-1 Pathway in B-cell Malignancies .........................................................23
1.3.
Compound Background ..........................................................................................24
1.3.1.
Durvalumab (MEDI4736).......................................................................................24
1.3.2.
Lenalidomide..........................................................................................................24
1.4.
Rationale ................................................................................................................25
1.4.1.
Rationale for Study Design.....................................................................................25
1.4.2.
Rationale for Backbone Therapy (R-CHOP, R2-CHOP).........................................25
1.4.3.
Rationale for Investigational Product......................................................................26
1.4.4.
Rationale for Dose, Schedule, and Regimen............................................................26
1.4.5.
Rationale for Biomarkers........................................................................................26
1.4.5.1.
Rationale for Potential Predictive Biomarkers.........................................................26
1.4.5.2.
Rationale for Pharmacodynamic Biomarker Assays................................................27
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................29
3.
OVERALL STUDY DESIGN ................................................................................32
3.1.
Study Design ..........................................................................................................32
3.1.1.
Screening Period.....................................................................................................32
3.1.2.
Treatment Period ....................................................................................................33
3.1.2.1.
Treatment Arms......................................................................................................33
3.1.3.
Follow-up Period....................................................................................................34
3.1.3.1.
Safety Follow-up ....................................................................................................34
3.1.3.2.
Efficacy (Long-term) Follow-up.............................................................................34
3.2.
Study Duration for Subjects....................................................................................36
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3.3.
End of Study...........................................................................................................36
4.
STUDY POPULATION.........................................................................................37
4.1.
Number of Subjects ................................................................................................37
4.2.
Inclusion Criteria....................................................................................................37
4.3.
Exclusion Criteria...................................................................................................40
5.
TABLE OF EVENTS.............................................................................................43
6.
PROCEDURES......................................................................................................48
6.1.
Screening Period.....................................................................................................48
6.2.
Treatment Period ....................................................................................................52
6.2.1.
End of Induction Treatment (EOI) ..........................................................................54
6.2.2.
End of Treatment....................................................................................................55
6.3.
Follow-up Period....................................................................................................57
6.3.1.
Safety Follow-up ....................................................................................................57
6.3.2.
Efficacy Follow-up.................................................................................................57
6.3.3.
Follow-up for Progression or Long-term Follow-up................................................58
6.4.
Efficacy Assessment...............................................................................................58
6.4.1.
Efficacy Assessments .............................................................................................58
6.4.2.
Imaging by CT Scans..............................................................................................59
6.4.3.
Imaging by FDG-PET Scans...................................................................................59
6.4.4.
Bone Marrow Biopsy and Aspirate .........................................................................60
6.5.
Safety Assessments.................................................................................................60
6.5.1.
Safety Run-in Stage................................................................................................61
6.5.2.
Safety Review Committee ......................................................................................61
6.6.
Pharmacokinetics (PK) ...........................................................................................62
6.7.
Immunogenicity......................................................................................................63
6.8.
Biomarkers, Pharmacodynamics and Pharmacogenomics .......................................63
6.8.1.
Tumor Tissue Biopsy..............................................................................................63
6.8.2.
Saliva and Blood Samples for Biomarker Assessments...........................................64
6.8.3.
Gene Expression Analysis/NanoString Technology ................................................64
6.9.
Subject Reported Outcomes or Quality of Life or Health Economics ......................65
6.10.
Assessments After Primary Endpoint Was Met.......................................................65
7.
DESCRIPTION OF STUDY TREATMENTS........................................................66
7.1.
Description of Investigational Product(s)................................................................66
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7.1.1.
Durvalumab............................................................................................................66
7.1.2.
Lenalidomide..........................................................................................................67
7.1.3.
Rituximab...............................................................................................................67
7.1.4.
Cyclophosphamide, Doxorubicin, Vincristine and Prednisone ................................67
7.2.
Treatment Administration and Schedule .................................................................68
7.2.1.
Optional Pre-phase Treatment.................................................................................68
7.2.2.
Pre-specify Post-Induction Radiotherapy ................................................................68
7.2.3.
Study Drug Treatment: ...........................................................................................68
7.2.3.1.
Criteria for stopping induction treatment and for starting consolidation 
treatment ................................................................................................................70
7.2.3.2.
Durvalumab (MEDI4736).......................................................................................70
7.2.3.3.
Lenalidomide..........................................................................................................71
7.2.3.4.
Rituximab...............................................................................................................72
7.2.3.5.
Cyclophosphamide .................................................................................................72
7.2.3.6.
Doxorubicin............................................................................................................73
7.2.3.7.
Vincristine..............................................................................................................73
7.2.3.8.
Prednisone..............................................................................................................73
7.2.4.
Required Criteria for Induction Treatment Cycles (Requalification Criteria)...........73
7.2.5.
Dose Modifications (Interruption/Reduction)..........................................................74
7.2.5.1.
General Dose Modification Guidelines ...................................................................75
7.2.5.2.
Dose Modification Guidelines for Durvalumab.......................................................75
7.2.5.3.
Dose Modifications Guidelines for R-CHOP ........................................................105
7.2.5.4.
Dose Modifications Guidelines for Lenalidomide .................................................106
7.2.6.
Overdose ..............................................................................................................109
7.3.
Method of Treatment Assignment.........................................................................109
7.4.
Packaging and Labeling........................................................................................109
7.5.
Investigational Product Accountability and Disposal ............................................109
7.6.
Investigational Product Compliance......................................................................110
8.
CONCOMITANT MEDICATIONS AND PROCEDURES..................................111
8.1.
Permitted/Recommended Concomitant Medications and Procedures.....................111
8.1.1.
Infection Prophylaxis............................................................................................111
8.1.2.
Venous Thromboembolism Prophylaxis (Lenalidomide).......................................111
8.1.3.
Nausea Prophylaxis ..............................................................................................112
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8.1.4.
Infusion Reaction Prophylaxis (Rituximab and Durvalumab)................................112
8.1.5.
Treatment of Early Anti-Tumor Response (Tumor Flare Reaction).......................112
8.1.6.
Urotoxicity Prophylaxis (Cyclophosphamide).......................................................112
8.2.
Prohibited Concomitant Medications and Procedures............................................113
8.3.
Required Concomitant Medications and Procedures..............................................114
8.3.1.
Mandatory Supportive Therapy.............................................................................114
8.3.2.
CNS Prophylaxis ..................................................................................................114
8.3.3.
TLS Prophylaxis...................................................................................................114
8.3.4.
Pneumocystis Jirovecii Prophylaxis ......................................................................114
8.3.5.
Neutropenia Prophylaxis.......................................................................................114
8.3.6.
Hepatitis B Virus Reactivation Prophylaxis ..........................................................115
9.
STATISTICAL CONSIDERATIONS ..................................................................116
9.1.
Overview..............................................................................................................116
9.2.
Study Population Definitions ................................................................................117
9.3.
Sample Size and Power Considerations.................................................................117
9.4.
Background and Demographic Characteristics......................................................118
9.5.
Subject Disposition...............................................................................................118
9.6.
Efficacy Analysis..................................................................................................118
9.7.
Safety Analysis.....................................................................................................119
9.7.1.
Adverse events .....................................................................................................119
9.7.2.
Laboratory Evaluations.........................................................................................119
9.8.
Interim Analysis ...................................................................................................120
9.9.
Other Topics.........................................................................................................120
9.9.1.
Safety Review Committee ....................................................................................120
9.9.2.
Steering Committee ..............................................................................................120
9.9.3.
Exploratory Analysis ............................................................................................120
10.
ADVERSE EVENTS............................................................................................121
10.1.
Monitoring, Recording and Reporting of Adverse Events .....................................121
10.2.
Evaluation of Adverse Events...............................................................................121
10.2.1.
Seriousness...........................................................................................................122
10.2.2.
Severity/Intensity..................................................................................................123
10.2.3.
Causality ..............................................................................................................123
10.2.4.
Duration ...............................................................................................................124
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10.2.5.
Action Taken........................................................................................................124
10.2.6.
Outcome...............................................................................................................124
10.3.
Abnormal Laboratory Values................................................................................124
10.4.
Pregnancy.............................................................................................................124
10.4.1.
Females of Childbearing Potential: .......................................................................125
10.4.2.
Male Subjects.......................................................................................................125
10.5.
Reporting of Serious Adverse Events....................................................................125
10.5.1.
Safety Queries ......................................................................................................126
10.6.
Expedited Reporting of Adverse Events................................................................126
10.7.
Adverse Events of Special Interest........................................................................127
10.7.1.
AESIs for Durvalumab .........................................................................................127
10.7.2.
AESIs for Lenalidomide .......................................................................................128
10.7.2.1.
Second Primary Malignancies...............................................................................128
10.7.2.2.
Deep Vein Thrombosis .........................................................................................128
10.7.2.3.
Tumor Flare Reaction / Pseudoprogression...........................................................129
10.7.3.
Other AESIs .........................................................................................................129
10.7.3.1.
Infusion-Related Reaction, Anaphylaxis and Allergic Reactions...........................129
10.7.3.2.
Tumor Lysis Syndrome ........................................................................................130
10.7.3.3.
Myelosuppression.................................................................................................130
10.8.
Celgene Drug Safety Contact Information: ...........................................................130
11.
DISCONTINUATIONS .......................................................................................131
11.1.
Treatment Discontinuation....................................................................................131
11.2.
Study Discontinuation ..........................................................................................131
12.
EMERGENCY PROCEDURES...........................................................................132
12.1.
Emergency Contact...............................................................................................132
12.2.
Emergency Identification of Investigational Products ...........................................132
13.
REGULATORY CONSIDERATIONS.................................................................133
13.1.
Good Clinical Practice..........................................................................................133
13.2.
Investigator Responsibilities .................................................................................133
13.3.
Subject Information and Informed Consent...........................................................134
13.4.
Confidentiality......................................................................................................134
13.5.
Protocol Amendments...........................................................................................134
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13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ..............................................................................................................134
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ..............135
13.8.
Termination of the Study ......................................................................................135
14.
DATA HANDLING AND RECORDKEEPING...................................................136
14.1.
Data/Documents ...................................................................................................136
14.2.
Data Management.................................................................................................136
14.3.
Record Retention..................................................................................................136
15.
QUALITY CONTROL AND QUALITY ASSURANCE......................................138
15.1.
Study Monitoring and Source Data Verification....................................................138
15.2.
Audits and Inspections..........................................................................................138
15.3.
Product Quality Complaint ...................................................................................138
16.
PUBLICATIONS .................................................................................................140
17.
REFERENCES.....................................................................................................141
18.
APPENDICES......................................................................................................146
Appendix A:
Table of Abbreviations ....................................................................................146
Appendix B:
Recommendations for Initial Evaluation, Staging, and Response 
Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano 
Classification........................................................................................................151
Appendix C:
Eastern Cooperative Oncology Group (ECOG) Performance Status.................155
Appendix D:
Cairo-Bishop Definitions of Tumor Lysis Syndrome .......................................156
Appendix E:
Lenalidomide Pregnancy Prevention Risk Management Plan ...........................157
Appendix F:
Prognostic Indexes for Patients With DLBCL (IPI and NCCN-IPI) and to 
Assess Risk of CNS Disease.................................................................................158
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LIST OF TABLES
Table 1:
Study Objectives.....................................................................................................29
Table 2:
Study Endpoints .....................................................................................................30
Table 3:
Schedule of Assessments ........................................................................................43
Table 4:
Tumor Tissue Biopsy Collection Time points for Biomarkers.................................63
Table 5:
Induction Treatment ...............................................................................................70
Table 6:
General Dose Modification and Toxicity Management Guidelines for 
Immune-mediated Adverse Events..........................................................................77
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific 
Immune-mediated Reactions...................................................................................79
Table 8:
General Dose Modification and Toxicity Management Guidelines for Non-
Immune-mediated Reactions.................................................................................102
Table 9:
Dose Modification and Toxicity Management Guidelines for Non-Immune-
mediated Adverse Events......................................................................................103
Table 10:
Dose Modification and Toxicity Management Guidelines for Infusion-
related Reactions ..................................................................................................105
Table 11:
Dose Modification Rules for Vincristine...............................................................106
Table 12:
Dose Reduction Levels for Vincristine..................................................................106
Table 13:
Lenalidomide Dose Modification Levels...............................................................106
Table 14:
Dose Modification Schedule for Lenalidomide-related Adverse Events ................107
Table 15:
Table of Abbreviations .........................................................................................146
Table 16:
Criteria for Involvement of Site ............................................................................151
Table 17:
Revised Criteria for Response Assessment............................................................152
Table 18:
Performance Status by Eastern Cooperative Oncology Group Scale......................155
Table 19:
Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome (LTLS) ...............156
Table 20:
Cairo-Bishop Definition of Clinical TLS ..............................................................156
Table 21:
Cairo-Bishop Grading System for TLS .................................................................156
Table 22:
International Prognostic Index ..............................................................................158
Table 23:
National Comprehensive Cancer Network- International Prognostic Index ...........158
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LIST OF FIGURES
Figure 1:
Study Design ..........................................................................................................35
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1.
INTRODUCTION 
Any questions regarding the protocol should be directed to the Celgene Medical Monitor or
designee.
Please refer to the Investigator’s Brochures (IBs) of lenalidomide and durvalumab for detailed 
information concerning the available pharmacology, toxicology, drug metabolism, clinical trials, 
and AE profiles of these Investigational Products (IP).
On 05 Sep 2017, a Partial Clinical Hold was placed to this study by the United States (US) Food 
and Drug Administration (FDA). The decision by the FDA was based on risks identified in other 
trials for pembrolizumab, an anti-programmed cell death-1 (PD-1) antibody, in patients with 
multiple myeloma in combination with immunomodulatory agents. As a result, enrollment 
continued into Arm A only and new subjects received induction therapy (durvalumab + R-
CHOP) after Cycle 1 regardless of diffuse large B-cell lymphoma (DLBCL) cell or origin (COO)
subtype. Enrollment into Arm B (durvalumab in combination with lenalidomide plus rituximab, 
cyclophosphamide, doxorubicin, vincristine, prednisone [R2-CHOP]) was discontinued. Subjects 
enrolled and treated in Arm B prior to the US FDA Partial Clinical Hold who were receiving 
clinical benefit, based on the discretion of the Investigator, may continue study treatment after 
being reconsented. 
Study enrollment was completed in March 2018.
The protocol-defined primary analysis was completed with a data cutoff date of 02 Aug 2018,
and the last subject’s last durvalumab dose occurred on 04 Mar 2019. Subsequently, the last 
durvalumab subject’s 90-day Safety Follow-up Visit was completed. At the time of the data 
cutoff date of the last 90-day Safety Follow-up Visit (06 Jun 2019), 30 subjects were in 
follow-up. No subjects were on treatment with durvalumab or any other study treatments.
There are no further plans to evaluate long-term efficacy, including overall survival, for the 
remaining subjects on study, and no additional statistical analysis on safety and efficacy will be 
performed. 
Therefore, the Follow-up Period will be discontinued, and data collection in the clinical database
will stop under this amendment. Subjects who received lenalidomide will continue to be 
followed for second primary malignancies (SPMs) as required by this study protocol 
(Section 3.1.3.1) 
. After stopping data collection in the clinical 
database, any SPM events will continue to be collected in the safety database.  
1.1.
Diffuse Large B-cell Lymphoma
Diffuse large B-cell lymphoma is a distinct histological type within mature B-cell non-Hodgkin’s 
lymphoma (NHL) that accounts for approximately 31% of all newly diagnosed malignant 
lymphomas (Armitage, 1998), and is characterized by large tumor cells and aggressive clinical 
behavior.
In most countries worldwide, the standard of care treatment for newly diagnosed DLBCL 
consists of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy 
in combination with the anti-CD20 monoclonal antibody rituximab (R-CHOP; Feugier, 2005; 
Ketterer, 2013). In a study comparing R-CHOP with CHOP as front-line therapy in elderly 
subjects with DLBCL, treatment with R-CHOP achieved a 5-year event-free survival (EFS) of 
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47%, a 5-year progression free survival (PFS) of 54%, and a 5-year overall survival (OS) of 58% 
(Feugier, 2005).
R-CHOP-21 (R-CHOP given in 21-day cycles) as the current standard of care in this disease 
setting has not been replaced by other treatment regimens including dose-intensified or dose-
dense regimens such as dose-intensive rituximab, doxorubicin, cyclophosphamide, vindesine, 
bleomycin, prednisone (R-ACVBD), dose-adjusted etoposide, prednisone, vincristine, 
cyclophosphamide, doxorubicin, rituximab (DA-EPOCH-R), rituximab, cyclophosphamide, 
doxorubicin, etoposide, vincristine, prednisone (R-CHOEP), dose dense regimens (R-CHOP-14; 
R-CHOP given in 14-day cycles), and rituximab, cyclophosphamide, vincristine, doxorubicin, 
dexamethasone, methotrexate cytarabine (R-HyperCVAD) (Ketterer, 2013; Micallef, 2011; 
Recher, 2011).
Considering the overall DLBCL population, approximately 50% to 60% of patients achieve a 
long-lasting complete response (CR) following R-CHOP and can be considered cured 
(Feugier, 2005; Micallef, 2011). In contrast, those 40% to 50% of DLBCL patients who are 
refractory or who progress or relapse following R-CHOP, have only limited treatment options 
and a poor overall clinical outcome, most of them dying within two years. Furthermore, DLBCL 
patients with an increased disease risk (Section 1.2) have a poorer outcome after R-CHOP 
therapy than the overall DLBCL patient population.
Therefore, patients who do not achieve a durable CR remain an unmet medical need and the 
evaluation of new treatment strategies is warranted.
1.2.
Clinical and Biological Prognostic Factors
1.2.1.
International Prognostic Index (IPI) and National Comprehensive Cancer 
Network International Prognostic Index (NCCN-IPI)
The IPI score (Appendix F) is an important prognostic tool developed utilizing clinical 
characteristics from more than 1,000 aggressive lymphoma patients treated with CHOP-like 
chemotherapy (The International Non-Hodgkin’s Lymphoma Prognostic Factors Project, 1993). 
Although developed in the pre-rituximab era, the IPI is still applicable and utilized today. Five 
clinical characteristics (age, lactic acid dehydrogenase [LDH], number of extra nodal sites, Ann 
Arbor stage, and ECOG performance status) are used to stratify patients into the following 4 risk 
categories:

Low-risk (0-1)

Low-intermediate risk (2)

High-intermediate risk (3)

High-risk (4-5).
The NCCN-IPI scoring system (Appendix F) is an enhanced IPI score developed from clinical 
data of 1,650 patients with DLBCL treated during the rituximab era between 2000-2010 
(Zhou, 2014). Five predictors (age, LDH, sites of involvement, Ann Arbor stage, and ECOG 
performance status) were identified and a maximum of 8 points assigned, and patients are 
stratified into the following 4 risk groups as follows:
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
Low-risk (0-1)

Low-intermediate risk (2-3)

High-intermediate risk (4-5)

High-risk (6-8).
For this study, patients with either an IPI > 2 and/or NCCN-IPI > 3 will be considered to have 
high IPI risk. The PFS in this patient population is significantly lower with a 2-year PFS rate of 
approximately 60-65% compared with 85-90% in patients with low or low-intermediate IPI risk 
(Sehn, 2007).
1.2.2.
Cell of Origin
Diffuse large B-cell lymphoma is composed primarily of two biologically distinct patho-
physiologic entities (Alizadeh, 2000) derived from different cells of origin which can be 
classified by gene expression profiling (GEP): germinal center B-cell (GCB) type and ABC type.
Subsequently, an additional type III was identified by GEP (Rosenwald, 2002), which has since 
been renamed as unclassifiable type. In contrast, the less precise method of 
immunohistochemistry (IHC) results in grouping ABC and unclassifiable together as the 
non-GCB type and thus differentiates between GCB and non-GCB only. The Lymphoma/
Leukemia Molecular Profiling Project reported approximately 60% GCB and 40% non-GCB in 
240 newly diagnosed DLBCL subject biopsy samples examined by GEP (Fu, 2008; 
Lossos, 2004; Rosenwald, 2002).
The different DLBCL types have been reported to have different clinical outcomes with CHOP 
(Rosenwald, 2002) and R-CHOP (Fu, 2008) therapy. In the first-line setting with CHOP therapy, 
the 5-year OS rates for the GCB, unclassifiable, and ABC types were 60%, 39%, and 35%, 
respectively (Rosenwald, 2002). With R-CHOP, the 3-year EFS for GCB and non-GCB subtypes 
was 67% and 52%, respectively, and the 3-year OS was 85% and 69%, respectively (Fu, 2008). 
With R-CHOP and predominantly higher risk patients (IPI 0-1 = 21%, IPI 2-3 = 63%, and IPI 
4-5 = 15%), the median PFS for the ABC type was 1.5 years (Lenz, 2008).
Gene expression profiling on fresh tissue biopsy samples was considered a gold standard for the 
characterization of the COO in DLBCL. However, defining the COO via GEP is currently 
neither part of the routine diagnostic work-up in clinical practice, nor a practical method for 
subject selection in clinical trials due to the requirement of a fresh biopsy sample and the 
substantial time and technological expertise required to perform standard GEP and analysis.
In this clinical study, a GEP-based assay will be used to identify the COO. The NanoString 
Lymphoma subtyping test (LST) assay, which is based on the NanoString 20-gene assay for 
COO subtyping in DLBCL, will be used. The LST assay profiles formalin-fixed 
paraffin-embedded (FFPE) tissue using the previously reported 20-gene Lymph2Cx algorithm on 
the nCounter® Dx analysis platform. Although this assay is technically verified, it has not 
received marketing approval by a health authority beyond being Conformité Européenne (CE) 
marked in the European Union (EU).
The NanoString 20-gene assay was verified against the original COO model defined by Lenz 
(Lenz, 2008) using an independent cohort of 68 FFPE biopsies. In the validation cohort, the 
assay was found to be accurate with only one case with definitive COO that was incorrectly 
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assigned by NanoString. The assay was also found to be robust with > 95% concordance of COO 
assignment between two independent laboratories (Scott, 2014b). 
The NanoString LST assay is currently being utilized to identify ABC-type DLBCL for 
participation in a Celgene-sponsored Phase 3 study comparing the safety and efficacy of 
lenalidomide in combination with R-CHOP (R2-CHOP) to R-CHOP in patients with previously 
untreated ABC-DLBCL (NCT02285062).
1.2.3.
Immune-checkpoint Inhibition
The intratumoral microenvironment in B-cell lymphoma includes tumor-infiltrating lymphocytes 
(TILs) which are T-cells that appear to be specific for the malignant B-cell clone and, thus, have 
the capacity to control the growth of the lymphoma (Dunn, 2004, Gooden, 2011). However, 
these T-cells have been found to have decreased proliferative capacity and effector function 
(Gitelson, 2002, Hilchey, 2009), which could explain their inability to attack and eradicate the 
malignant B cells. Chronic and prolonged activation may cause some T-cells to become 
“exhausted” and other T-cells to acquire expression of inhibitory receptors (eg programmed cell 
death-1 [PD-1], programmed cell death ligand-1 [PD-L1]) and become suppressive cells 
(Zhi-Zhang, 2015), a phenomenon also known as “adaptive immune resistance” (Tumeh, 2014).
Engagement of TIL cell-surface receptors with these inhibitory ligands leads to a dysfunctional 
immune response, causes T-cell exhaustion, and facilitates tumor progression (Baitsch, 2012;
Crespo, 2013).
Novel monoclonal antibodies (mAbs) that block these inhibitory receptors have shown 
significant clinical activity across a number of tumor types (Wolchok, 2009; Hodi, 2010;
Robert, 2011; Brahmer, 2010; Topalian, 2012). Specifically, blockade of immune-checkpoint 
inhibitors such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), PD-1, and PD-L1 
have shown clinical activity not only in conventionally immune-responsive tumors such as 
melanoma and renal cell carcinoma but also in non-small cell lung cancer (Brahmer, 2010;
Brahmer, 2012; Topalian, 2012; Gordon, 2013) and prostate cancer (Harzstark, 2010). 
1.2.4.
PD-L1/PD-1 Pathway in B-cell Malignancies
A large French multicenter clinical trial demonstrated that high plasma levels of soluble PD-L1 
are a predictive biomarker associated with a poorer overall survival (OS) in DLBCL patients 
treated with R-CHOP (Rossille, 2014). These findings were confirmed in two additional 
databases in Australia and the U.S. and were found to be independent of IPI and other clinical 
factors (Fest, 2014).
Furthermore, it has been shown that PD-L1 expression on DLBCL cells is an independent 
(negative) prognostic factor for OS and that the number of PD-1 positive TILs is significantly 
associated with PD-L1 positivity of lymphoma cells and tumor infiltrating non-malignant 
stromal cells (Kiyasu, 2015). In addition, PD-1 expression in peripheral blood CD4+ and CD8+ 
T-cells were found to be markedly different between chronic lymphocytic leukemia (CLL)
disease stages when compared with healthy subjects (Novak, 2015).
A preclinical mantle-cell lymphoma (MCL) model demonstrated that PD-L1 expressed on MCL 
cells inhibited T-cell proliferation, impaired antigen-specific T-cell responses, and rendered 
MCL cells resistant to T-cell mediated cytolysis which could be reversed by blocking or 
knocking down tumor cell-associated PD-L1 (Wang, 2013). 
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
24
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
In clinical studies, nivolumab (Lesokhin, 2014) has shown single-agent activity in clinical 
studies in patients with DLBCL, follicular lymphoma (FL) and T-cell lymphomas.
1.3.
Compound Background 
1.3.1.
Durvalumab (MEDI4736)
Durvalumab (MEDI4736) is a human immunoglobulin (Ig) G1к monoclonal antibody (mAb) 
that blocks PD-L1 by inhibiting binding to its receptors, allowing T-cells to recognize and kill 
tumor cells. Durvalumab selectively binds to human PD-L1 with high affinity blocking its ability 
to bind to PD-1 and cluster of differentiation (CD) 80. The fragment crystallizable (Fc) domain 
of durvalumab contains a triple mutation in the constant domain of the IgG1 heavy chain that 
reduces binding to the complement component C1q and the Fcγ receptors responsible for 
mediating antibody-dependent cell-mediated cytotoxicity (ADCC) (Oganesyan, 2008; 
Ibrahim, 2015).
On 01 May 2017, the US FDA granted accelerated approval to durvalumab (IMFINZI™) for the 
treatment of patients with locally advanced or metastatic urothelial carcinoma patients who have 
disease progression during or following platinum-containing chemotherapy or who have disease 
progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing 
chemotherapy.
Please refer to the durvalumab IB for further information.
1.3.2.
Lenalidomide
Lenalidomide (Revlimid®) is a member of the class of immunomodulatory drugs (IMiD®) and 
has potent immuno-stimulatory, antiangiogenic, and pro-apoptotic activities in vitro.
In the US, lenalidomide has been approved for the treatment of patients with:

Multiple myeloma (MM) in combination with dexamethasone

Maintenance MM therapy following autologous hematopoietic stem cell transplantation

Transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic 
syndromes (MDS) associated with a deletion 5q abnormality with or without additional 
cytogenetic abnormalities

MCL whose disease has relapsed or progressed after two prior therapies, one of which 
included bortezomib
In Europe, lenalidomide has been approved for the treatment of patients with:

As combination therapy in patients with previously untreated MM who are not eligible 
for transplant

In combination with dexamethasone for patients with MM who have received at least one 
prior therapy

As maintenance monotherapy in the treatment of newly diagnosed patients with MM who 
have undergone autologous stem cell transplantation
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
25
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019

Transfusion-dependent anemia due to low- or intermediate-1-risk MDS associated with 
an isolated deletion 5q cytogenetic abnormality when other therapeutic options are 
insufficient or inadequate

Relapsed or refractory MCL
Please refer to the lenalidomide IB for further information.
1.4.
Rationale
1.4.1.
Rationale for Study Design
Patients with high-risk DLBCL typically have insufficient therapeutic outcomes. Therefore, the 
addition of novel agents to the currently used induction therapy (R-CHOP backbone) is a 
rationale approach to improve therapeutic outcomes in this disease setting.
1.4.2.
Rationale for Backbone Therapy (R-CHOP, R2-CHOP)
Treatment with R-CHOP is currently the most commonly used induction therapy for patients 
with previously untreated DLBCL.
Patients with non-GCB-DLBCL have a worse outcome than GCB-like DLBCL when treated 
with R-CHOP. Importantly, clinically meaningful improvements in CR rate and PFS were seen 
in two recent Phase 2 trials in patients with non-GCB-DLBCL who were treated with 
lenalidomide in combination with R-CHOP (R2-CHOP) when compared with historical 
R-CHOP-21 data (Nowakowski, 2015; Chiapella, 2012).
In the REAL07 Phase 2 study with R2-CHOP conducted by the Italian Lymphoma Study Group 
FIL (Chiapella, 2012; Vitolo, 2014), Overall Response Rate was 92% and the CR rate was 86%. 
The 2-year PFS was 81% (95% confidence interval [CI], 51% to 93%) in patients with non-GCB 
disease and 71% (95% CI, 51% to 93%) in those with GCB disease (HR 0.78, 95% CI, 0·21 to
2·90; p=0.705).
In a Phase 2 study with R2-CHOP conducted by the Mayo Clinic (Nowakowski, 2015), the 
overall response rate (ORR) was 98% with a CR rate of 80%. Event-free survival and overall 
survival (OS) rates at 24 months were 59% (95% CI, 48 to 74) and 78% (95% CI, 68 to 90), 
respectively.
In a historical comparison with patients treated with R-CHOP, the 24-month progression-free 
survival (PFS) and OS were 28% versus 64% and 46% versus 78% in non-GCB DLBCL versus 
GCB DLBCL, respectively, underlining the worse outcome of non-GCB-DLBCL patients who 
are treated with R-CHOP.
In contrast, no significant changes in outcome were noted in GCB-like DLBCL patients 
receiving R2-CHOP. When compared with patients treated with R-CHOP, there was no 
difference in 24-month PFS or OS for R2-CHOP patients on the basis of non-GCB and GCB 
subtype (60% versus 59% and 83% versus 75%, respectively).
Based on these promising Phase 2 results, in this study R-CHOP will be used as backbone 
therapy for patients with the non-ABC subtype whereas R2-CHOP will be used for patients with 
the ABC subtype. Following Partial Clinical Hold instituted by the US FDA rationale for 
backbone therapy has been changed. Any newly enrolled subject with ABC subtype will be 
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
26
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
treated with R-CHOP. Activated B-cell (ABC) subtype subjects already treated with R2-CHOP 
may continue study treatment if receiving clinical benefit, based on the discretion of the 
Investigator and after being reconsented. 
1.4.3.
Rationale for Investigational Product
Based on the described pre-clinical and clinical observations related to the PD-1/PD-L1 pathway, 
it is hypothesized that durvalumab will have activity in DLBCL. In particular, the addition of 
durvalumab may significantly augment the anti-tumor activity of R-CHOP against high-risk 
DLBCL subtypes.
The safety of durvalumab has already been explored and assessed in other hematology and 
oncology patient populations, and no dose limiting toxicity (DLT) has been defined to date. 
However, as there is limited clinical experience with durvalumab as monotherapy in DLBCL and 
none with durvalumab in combination with R-CHOP or R2-CHOP as first-line therapy of 
DLBCL, the design of this Phase 2 study includes a Safety Run-in Stage.
1.4.4.
Rationale for Dose, Schedule, and Regimen
The dosing schedule of 20 mg/kg once every 4 weeks (Q4W) for durvalumab was selected based 
on the safety analysis of doses (0.1, 0.3, 1, 3, and 10 mg/kg once every 2 weeks [Q2W]) 
administered in Study CD ON-MEDI4736-1108 and pharmacokinetics (PK) profile simulations 
for durvalumab administered using 10 mg/kg Q2W and 20 mg/kg Q4W schedules.
Population PK analysis indicated only minor impact of body weight on 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 was selected to approximate 10 mg/kg (based on median body weight of 75 kg).
Simulation results of 1,000 patients using body weights ranging from 40 to 120 kg demonstrated 
that body weight-based and fixed-dosing regimens yield similar median steady state PK 
concentrations with slightly less overall between-subject variability with the fixed-dosing 
regimen.
As it is therefore considered feasible to use a fixed-dosing regimen, and as a fixed-dosing 
approach is generally preferred by the prescribing community due to ease of use and reduced 
dosing errors, the current study will use a fixed dose of 1125 mg durvalumab Q3W (21-day 
cycles during induction therapy) and 1500 mg durvalumab Q4W (28-day cycles during 
consolidation therapy), both being equivalent to 20 mg/kg Q4W.
1.4.5.
Rationale for Biomarkers 
The key specific translational question in this study is whether the COO status or other 
biomarkers in DLBCL are associated with response to durvalumab in combination with either
R-CHOP or R2-CHOP.
1.4.5.1.
Rationale for Potential Predictive Biomarkers 
Durvalumab binds human PD-L1 with high affinity and blocks its ability to bind PD-1. This
restores immune activation with downstream effects on cytokine production, proliferation, cell 
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
27
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
survival, and transcription factors associated with effector T-cell function. Measurements of 
pharmacodynamic biomarkers, such as soluble PD-L1 saturation and immune cell activation 
status, could help with understanding the pharmacological effect of durvalumab and contribute to 
the decision of dose and schedule selection. In addition, a number of recent studies have reported 
correlation between several molecular markers, including expression level of PD-L1 in tumor 
and immune cells, gene expression patterns, neoantigen presentation and T cell clonality, and the 
clinical activity of immune checkpoint inhibitors (Topalian 2012; Herbst, 2014). More recent 
data indicates that a combination of elevated PD-L1 protein expression and elevated interferon 
[IFN]gene expression in pretreatment tumor biopsies may predict the best response to 
durvalumab monotherapy (Higgs, 2015, Higgs 2016).
Experience of durvalumab in solid tumors showed that greater responses were observed in 
subjects with PD-L1-positive, and a much lower rate of responses in subjects with PD-L1-
negative tumors (Segal, 2014). Thus, continued evaluation of these biomarkers and a broad
exploration of additional biomarkers related to immunological and disease factors are needed to 
help the identification of potential predictive biomarkers for the therapy.
The predictive biomarker data analysis will proceed in three stages. In the first stage, publically
available data, literature, and proprietary data assets of relevance will be analyzed to generate 
and refine predictive biomarker hypotheses. During the second stage, biomarker data will be 
analyzed as it is generated for this study and pre-specified hypotheses-related predictive 
biomarkers and immune mechanism of action will be tested. Lastly, after the biomarker, clinical 
and outcome data from the study is completed, final conclusions will be made on the pre-
specified hypotheses and hypotheses for testing in future studies will be defined.
1.4.5.2.
Rationale for Pharmacodynamic Biomarker Assays 
A key scientific objective of this clinical study is to evaluate the dynamic changes in the 
microenvironment of the tumor. While understanding the immunologic characteristics at baseline 
may be both predictive and prognostic, it will be extremely critical to understand the changes in 
the local immune system following treatment with durvalumab and the combination agents.
Biomarker analysis of durvalumab in non-small cell lung cancer (NSCLC) patients demonstrated 
a statistically significant increase in CD8+ infiltrating lymphocytes from on-treatment tumor 
samples compared with pre-treatment biopsies (Rizvi, 2015). Furthermore, durvalumab treatment 
induced IFNγ and effector T cell and Th-1 gene expression within NSCLC biopsies within 
8 weeks of treatment (Higgs, 2016), indicating a higher level of tumor microenvironment.
This data is consistent with the Pd effects observed in tumor biopsies from patients treated with 
atezolizumab (a PD-L1 inhibitor) and pembrolizumab (a PD-1 inhibitor). For pembrolizumab, 
increasing of CD8+ density at tumor or invasive margin after treatment is observed in responders 
while absent in progressors in melanoma, indicating that the CD8+ TILs were activated and 
targeting the tumor (Tumeh, 2014). Serial biopsy analyses for atezolizumab showed that 
increases in PD-L1 protein expression and genes indicative of activated T cells (eg granzyme, 
IFN) were more frequently observed in patients who respond to the therapy compared with the 
non-responders (Herbst, 2014). Notably, while pharmacodynamic response to durvalumab and 
atezolizumab can also be observed in the blood, circulating biomarkers have not been shown to
be correlated with response.
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
28
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Evaluation of on-treatment tumor samples is critical for identifying pharmacodynamic changes 
that are induced by durvalumab. These biomarker data will facilitate better understanding of the 
mechanism of action for durvalumab alone or in combination with other agents to facilitate 
future clinical study designs. The data may also allow new biomarker development to drive 
clinical decisions early in patients’ treatment and could reveal new targets/additional immune 
system pathways that may be targeted to improve therapeutic outcomes. 
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
29
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
2.
STUDY OBJECTIVES AND ENDPOINTS
Enrollment into Arm B (durvalumab in combination with lenalidomide plus rituximab, 
cyclophosphamide, doxorubicin, vincristine, prednisone [R2-CHOP]) was discontinued.  
Subjects enrolled and treated in Arm B prior to the US FDA Partial Clinical Hold who were 
receiving clinical benefit, based on the discretion of the Investigator, could continue study 
treatment after being reconsented. Any subject enrolled after the US FDA Partial Clinical Hold 
received induction therapy on Arm A (durvalumab + R-CHOP) after Cycle 1 regardless of 
DLBCL COO subtype.
After the last durvalumab subject’s 90-day safety follow-up (data cutoff date 06 Jun 2019), the
Follow-up Period will be discontinued. Subjects who received lenalidomide will continue to be 
followed for SPMs as required by this study protocol (Section 3.1.3.1) 
 
. 
Table 1:
Study Objectives
Primary Objective
The primary objective of the study is to explore the clinical activity of durvalumab (MEDI4736) in 
combination with R-CHOP or R2-CHOP followed by durvalumab consolidation therapy in previously 
untreated subjects diagnosed with high-risk DLBCL.
Secondary Objectives
The secondary objectives of the study are:

To evaluate the safety and tolerability of durvalumab when given in combination with R-CHOP 
or R2-CHOP followed by durvalumab consolidation therapy.

To identify and develop biomarkers of the tumor microenvironment and of the host immune 
system which are predictive of clinical response to durvalumab, when administered in 
combination with R-CHOP or R2-CHOP, followed by durvalumab consolidation therapy that 
will be tested in further randomized clinical studies.  Examples of defined analytical methods 
that will be investigated may include, but are not limited to:

PD-L1 IHC

Gene Expression Signatures
Exploratory Objective
The exploratory objectives of the study are:

To examine the pharmacokinetic/pharmacodynamic (PK/Pd) relationship, and the mechanistic 
biomarkers for durvalumab when given in combination with R-CHOP or with R2-CHOP 
followed by durvalumab consolidation therapy.

To evaluate impact on endpoints related to clinical activity of durvalumab when given in 
combination with R-CHOP followed by durvalumab consolidation therapy.
ABC = activated B-cell; CHOP = cyclophosphamide, doxorubicin, vincristine and prednisone; DLBCL = diffuse 
large B-cell lymphoma; IHC = immunohistochemistry; PD-L1 = programmed cell death-ligand 1; PK/Pd =
pharmacokinetic/pharmacodynamic; R-CHOP = Rituximab plus CHOP; R2-CHOP = Rituximab and lenalidomide 
plus CHOP.
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
30
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 2:
Study Endpoints
Endpoint
Name
Description
Timeframe
Primary Endpoint
Efficacy
Complete 
response rate 
(CRR) at end 
of induction 
therapy.
Subjects being in CR at the end of 
induction therapy
6 to 8 cycles (4 to 6 months) 
after the first dose of any IP
Key Secondary Endpoints
Efficacy
Rate of 
subjects who 
continue
consolidation 
therapy
Subjects being in CR/PR at the 
end of induction therapy and who 
continue into consolidation 
therapy
6 to 8 cycles of induction 
therapy and at least 1 cycle 
of consolidation therapy (4
to 6 months) after the first 
dose of any IP.
Secondary Endpoints
Biomarker
Clinical 
response to 
study treatment 
in biomarker-
defined 
subpopulations
Identification and development of 
biomarkers predictive of clinical 
response to study treatment
Defined analytical methods will 
be used in order to refine those
biomarkers to be tested in further 
randomized clinical studies
Tumor samples at baseline 
and during study treatment.
Peripheral blood samples 
collected at Screening and 
during study treatment.
Safety
TEAEs
Incidence of TEAE based on total 
events, percentage of subjects 
experiencing any specific TEAE 
and severity of the TEAE using 
the NCI-CTCAE criteria V4.03, 
and V3.0 for Tumor Flare 
Reaction.
From the first dose of any IP 
until 90 days after the last 
dose of durvalumab or 28 
days after the last dose of 
any other IP, whichever is 
later
Exploratory Endpoints
Efficacy
PFS at 
12 months
Subjects who have not 
experienced disease progression 
or death within 12 months after 
start of study treatment
12 months after the first 
dose of any IP
Efficacy
PFS at 
24 months
Subjects who have not 
experienced disease progression 
or death within 24 months after 
start of study treatment
24 months after the first 
dose of any IP
Efficacy
CRR at 
12 months
Subjects being in complete 
response (CR) at 12 months after 
start of study treatment
12 months after the first 
dose of any IP
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
31
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
Pharmacodynamic
and mechanistic
biomarkers of 
durvalumab
Pd
Biomarkers include but are not 
limited to gene and/or protein 
expression of analytes, such as 
individual sPD-L1 levels and 
immune cell activation in 
peripheral blood and immune cell 
activation in the tumor 
microenvironment, at baseline 
and at specified time points 
during treatment.
Before and during study 
treatment
Pharmacokinetics/ 
Pharmacodynamics
PK/Pd
Exploration of the PK/Pd
relationship of durvalumab when 
given in combination with 
R-CHOP and R2-CHOP as 
induction therapy as well as when 
administered as consolidation 
therapy
During study treatment
CR = Complete Response; CRR = Complete Response Rate; IP = Investigational Product; NCI-CTCAE; National 
Cancer Institute Common Terminology Criteria for Adverse Events; Pd = Pharmacodynamics; PFS = Progression-
free Survival; PK =Pharmacokinetics; R-CHOP = Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, 
Prednisone; R2-CHOP = Lenalidomide plus R-CHOP; sPD-L1 = soluble Programmed Cell Death-Ligand 1; TEAE 
= Treatment-emergent Adverse Events.
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
32
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
3.
OVERALL STUDY DESIGN
The study will be conducted in compliance with the International Council for Harmonisation
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good 
Clinical Practice (GCP) and applicable regulatory requirements.
3.1.
Study Design
This Phase 2, two-arm, open-label study is designed to evaluate durvalumab in combination with 
R-CHOP (Arm A) or in combination with R2-CHOP (Arm B), followed by durvalumab 
consolidation therapy in previously untreated subjects with high-risk DLBCL (Figure 1).2
Induction treatment with R-CHOP will last for a total of up to 6 to 8 treatment cycles, and the 
total time on study treatment, including durvalumab consolidation, will last up to 12 months.
The study is divided into two stages:

A Safety Run-in Stage to evaluate the safety of the treatment combinations (by a 
Safety Review Committee [SRC], see Section 6.5.2) until at least 10 subjects are 
included in the Safety Run-in (see Section 6.5.1). Following Partial Clinical Hold 
instituted by the US FDA which affects Arm B, the Safety Run-in Stage will evaluate 
safety of the treatment Arm A combinations when at least 10 subjects have been 
included into Arm A and have been treated for at least one cycle of study treatment or 
discontinued prematurely.

An Expansion Stage to analyze the clinical activity of the treatment combinations in 
up to approximately 40 total subjects in the efficacy evaluable population.
Approximately 45 subjects are planned to be enrolled into this study (with approximately 
40 subjects in the efficacy evaluable population). Subjects will be assigned into the appropriate
treatment arms dependent upon their COO status as determined by GEP.2
3.1.1.
Screening Period
The Screening Period begins once the subject signs the written informed consent form (ICF). 
During this period, the subjects will undergo assessments, according to Table 3 and Section 6.1
to determine whether the subject meets the eligibility criteria described in Section 4.2. 
All Screening assessments must be completed within 28 days prior to the first dose of IP
administered on C1D1. Subjects must undergo incisional or excisional biopsies of their 
lymphoma in order to evaluate their tumor microenvironments as well as other biomarkers. A 
core needle biopsy with multiple passes is acceptable but not preferred, due to the amount of 
tissue required needed to perform the necessary analyses. For subjects unable to provide fresh 
tissue samples, an archival diagnostic lymph node/tumor formalin fixed paraffin embedded 
                                               
2 As a result of the US FDA Partial Clinical Hold, enrollment continued into Arm A only and new subjects received 
induction therapy (durvalumab + R CHOP) after Cycle 1 regardless of DLBCL COO subtype. Enrollment into 
Arm B (durvalumab in combination with lenalidomide plus rituximab, cyclophosphamide, doxorubicin, 
vincristine, prednisone [R2-CHOP]) was discontinued. Subjects enrolled and treated in Arm B prior to the US 
FDA Partial Clinical Hold who were receiving clinical benefit, based on the discretion of the Investigator, could
continue study treatment after being reconsented.
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
33
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
(FFPE) biopsy obtained prior to signing informed consent may be acceptable for enrollment of a 
subject with poorly accessible tumor.
3.1.2.
Treatment Period
Eligible subjects with previously untreated, high-risk DLBCL will receive one cycle of induction 
therapy of durvalumab in combination with R-CHOP. Based on their DLBCL COO subtype 
(ABC versus non-ABC) as determined by the NanoString LST assay before start of Cycle 2, 
subjects will then be allocated to one of two treatment arms from Cycle 2 onwards (or the cycle 
following COO determination). Eligible subjects for whom the COO has already been identified 
as ABC subtype by NanoString LST assay before starting study treatment, may have 
lenalidomide added starting with C1D1 onwards. Subjects for whom COO determination is 
inconclusive will continue treatment in study Treatment Arm A. Subjects for whom the COO is 
determined as ABC only after Cycle 2 will be allocated to Arm B whenever the results become 
available, however, missed cycles of lenalidomide will not be made up. After the US FDA 
Partial Clinical Hold, enrollment of new subjects into Arm B was discontinued. If receiving 
clinical benefit at the discretion of the Investigator, subjects could continue treatment in Arm B 
after being reconsented. Any newly enrolled subject with DLBCL of ABC COO subtype after 
the US FDA Partial Clinical Hold could continue induction therapy on Arm A after Cycle 1.
Induction treatment will be administered until disease progression, unacceptable toxicity or the 
completion of induction treatment (6 to 8 cycles). Subjects completing the R-CHOP-based 
induction chemotherapy and achieving a CR (or a PR if the Investigator considers this to be a 
sufficient therapeutic response) will then receive consolidation therapy comprised of durvalumab 
monotherapy for up to a total of 12 months from the date of C1D1, ie, from the start of the 
induction treatment period (Figure 1). Subjects receiving lenalidomide will be followed for SPM 
for 5 years following enrollment (C1D1) of the last subject enrolled into Arm B (Figure 1).
3.1.2.1.
Treatment Arms 
Study treatment in both arms will be administered in 21-day cycles during the induction 
treatment and 28-day cycles during the consolidation treatment as follows:
Induction Therapy (21-day cycles)3
Arm A: Durvalumab in combination with R-CHOP
Durvalumab 1125 mg intravenously (IV) on Day 1 of each 21-day cycle in combination with 
6 to 8 cycles R-CHOP (IV rituximab, doxorubicin, vincristine and cyclophosphamide on 
Day 1; daily oral/IV prednisone/prednisolone from Day 1 to 5).
Arm B: Durvalumab in combination with R2-CHOP3
Durvalumab 1125 mg IV on Day 1 of each 21-day cycle in combination with 6 to 8 cycles 
R2-CHOP (IV rituximab, doxorubicin, vincristine and cyclophosphamide on Day 1; daily 
                                               
3 As a result of the US FDA Partial Clinical Hold, enrollment continued into Arm A only and new subjects received 
induction therapy (durvalumab + R CHOP) after Cycle 1 regardless of DLBCL COO subtype. Enrollment into 
Arm B (durvalumab in combination with lenalidomide plus rituximab, cyclophosphamide, doxorubicin, 
vincristine, prednisone [R2-CHOP]) was discontinued. Subjects enrolled and treated in Arm B prior to the US 
FDA Partial Clinical Hold who were receiving clinical benefit, based on the discretion of the Investigator, could
continue study treatment after being reconsented. 
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
34
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
oral/IV prednisone/prednisolone from Day 1 to 5; daily oral lenalidomide 15 mg from 
Day 1 to 14) from the cycle following COO determination until end of induction therapy 
(Cycle 6 or Cycle 8), or starting Cycle 1 if ABC subtype is identified prior to C1D1.
Consolidation Therapy (28-day cycles)
Arm A and Arm B: (Initiated following induction therapy and CR/PR)
Durvalumab 1500 mg IV on Day 1 of each 28-day cycle for up to a total of 12 months from 
C1D1 of induction therapy.
3.1.3.
Follow-up Period
The Follow-up Period will begin at study treatment completion or discontinuation.  
Once all study treatments have been discontinued, subjects will be followed for disease 
progression or until death, lost to follow-up, or consent withdrawal, for up to 5 years after the 
last subject is enrolled (C1D1), whichever occurs first.
Subjects receiving lenalidomide will be followed for up to 5 years from the date of enrollment 
(C1D1) of the last subject and evaluated for the occurrence of SPM.
3.1.3.1.
Safety Follow-up
All subjects will be followed for AEs and concomitant medications/procedures until 90 days 
after the last dose of durvalumab or 28 days after the last dose of any other IP, whichever is later.
Subjects who receive lenalidomide will, in addition to the above, be followed for SPM for up to 
5 years from the date of enrollment (C1D1) of the last subject to be treated with lenalidomide.
3.1.3.2.
Efficacy (Long-term) Follow-up
Subjects will continue to be followed for efficacy following study treatment completion or 
discontinuation for 5 years after the last subject is enrolled. This includes subjects who complete 
the full course of treatment, discontinue treatment due to progression or toxicity, as well as those 
who discontinue before progression to pursue a new anti-lymphoma therapy. 
Subjects will be followed for progression, and subsequent anti-lymphoma therapy according to 
the schedule described in Section 6.3.2. Therefore, efficacy assessments will continue at the 
protocol-specified time points until first progression or the start of a new anti-lymphoma therapy.
Following completion or discontinuation of durvalumab therapy per protocol for all subjects and 
completion of the last durvalumab subject’s 90-day Safety Follow-up Visit (data cutoff date 06 
Jun 2019), subjects are no longer required to be followed for disease progression, subsequent 
anti-lymphoma therapy, and overall survival. Follow-up procedures, efficacy assessments, 
central labs, imaging, AEs/SAEs and survival data will no longer be collected in the CRFs.  
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
35
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Figure 1:
Study Design
ABC = activated B-cell; COO = cell of origin; DLBCL = diffuse large B-cell lymphoma; IP = investigational product; LST = lymphoma subtyping test; R-CHOP = rituximab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone; SPM = second primary malignancy.
a Eligible subjects for whom the COO has already been identified as ABC subtype by gene expression profile before starting study treatment, may have lenalidomide added starting with Cycle 1 Day 1 
onwards (Arm B). 
b After the US FDA Partial Clinical Hold enrollment of new subjects into Arm B has been discontinued. If receiving clinical benefit at the discretion of the Investigator, subjects may continue treatment 
in Arm B after being reconsented. Any newly enrolled subject with DLBCL of ABC COO subtype after US FDA Partial Clinical Hold will continue induction therapy on Arm A after Cycle 1.
c Following completion or discontinuation of durvalumab therapy per protocol for all subjects and completion of the last durvalumab subject’s 90-day Safety Follow-up Visit (data cutoff date 06 Jun 
2019), subjects are no longer required to be followed for disease progression, subsequent anti-lymphoma therapy, and overall survival.
Non-ABC 
Subtype
ABCa, b
Subtype
Safety Run-in
Review safety from at 
least 10 subjects 
Go/No-Go Decision
Expansion Stage
Complete enrollment into 
the study (n=45)
End of Treatment
Treat until discontinuation for 
evidence of progression, 
death, unacceptable toxicity, 
subject/physician decision, or 
withdrawal of consent.
Follow-upc
Safety until 90 days after the 
last dose of durvalumab or 
28 days after the last dose of 
any other IP, whichever is 
later.
Response evaluation until 
progression, new disease 
therapy, or death, whichever 
is earlier. 
Subjects receiving 
lenalidomide will be followed 
for SPM for 5 years from last 
subject enrolled.
COO 
Analysis 
(NanoString 
LST assay)
Arm Ab
Durvalumab 12 months 
R-CHOP Cycle 2-6 or 8
Cycle 1:
Durvalumab 
+ R-CHOP a
Arm B
Durvalumab 12 months 
R-CHOP Cycle 2-6 or 8
Lenalidomide Cycle 2-6 or 8
Discontinued enrollment of new subjects
Screening
Eligibility Check
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
36
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
3.2.
Study Duration for Subjects
The study consists of a Screening Period (up to 28 days before first dose of study treatment), a 
Treatment Period (up to a total of 12 months from first dose) and a Follow-up Period (up to 
5 years after the last subject is enrolled).
3.3.
End of Study
The End of Study is defined as either the date of the last visit of the last subject to complete the 
post treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analysis, as pre-specified in the protocol, 
whichever is the later date.
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
37
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
4.
STUDY POPULATION
4.1.
Number of Subjects 
Approximately 45 subjects with previously untreated, high-risk DLBCL will be enrolled into this 
study (with approximately 40 subjects in the efficacy evaluable population). This study is 
expected to be conducted in the US and Europe. Additional study sites located in other regions 
may be considered for participation as necessary.
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is at least 18 years of age at the time of signing the informed consent form (ICF). 
2. Subject must understand and voluntarily sign an ICF prior to any study-related 
assessments/procedures being conducted. 
3. Subject is willing and able to adhere to the study visit schedule and other protocol 
requirements.
4. Subject has documented histologically confirmed CD20+ DLBCL of the below World 
Health Organization (WHO) sub-classifications:
a.
Not otherwise specified (NOS)
b. Associated with chronic inflammation
c.
Epstein-Barr virus positive (EBV+) of the elderly
d. T-cell/histiocyte-rich
5. Subject has high-risk disease defined as:
a.
Ann Arbor stage 3-4 or Ann Arbor stage 2 with bulky disease (tumor diameter 
≥7.0 cm)
and
b. Intermediate-high or high disease risk (IPI ≥3 or NCCN-IPI ≥4; see Appendix F).
6. Subject has bi-dimensionally measurable disease on cross-sectional imaging by CT with 
at least one (post-biopsy) nodal or extranodal lesion ≥2.0 cm in its longest dimension.
7. Subject has not received prior anti-lymphoma treatment. However, for subjects with 
bulky disease, systemic symptoms, compressive disease, or rapidly progressing 
adenopathies, pre-phase treatment with up to 100 mg/day prednisone, or equivalent, for a 
maximum of 7 days is permitted prior to beginning the Treatment Period, at the discretion 
of the Investigator. A washout period does not apply.
8. Subject is willing and able to undergo tumor/lymph node biopsy during the Screening 
Period, during treatment when clinically feasible, and at the time of disease progression 
from subjects who have achieved objective response (CR or partial response [PR]) to 
study treatment.
Note: An archival diagnostic lymph node/tumor formalin fixed paraffin embedded 
(FFPE) biopsy acquired by a surgical or core needle biopsy prior to signing informed 
consent may be acceptable for enrollment of a subject with poorly accessible tumor.
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
38
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
9. Subject is considered an appropriate candidate for induction therapy with 6 to 8 cycles of 
R-CHOP immuno-chemotherapy.
10. Subject has a performance status of 0-2 according to the Eastern Cooperative Oncology 
Group (ECOG) scale. 
11. Subject must fulfill the following laboratory requirements:
a.
Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 (1.5 x 109/L) unless secondary to 
bone marrow involvement by lymphoma (> 50%) as demonstrated by recent bone 
marrow aspiration and bone marrow biopsy. In the case of documented bone marrow 
involvement an ANC ≥1,000 cells/mm3 (1.0 x 109/L) is required.
b. Platelet count ≥ 75,000/mm3 (75 x 109/L) unless secondary to bone marrow 
involvement by lymphoma (> 50%) as demonstrated by recent bone marrow 
aspiration and bone marrow biopsy. In the case of documented bone marrow 
involvement a platelet count of ≥ 50,000/ mm3 (50 x 109/L) is required.
c.
Hemoglobin ≥ 10.0 g/dL (6.2 mmol/L) unless secondary to bone marrow involvement 
by lymphoma (> 50%) as demonstrated by recent bone marrow aspiration and bone 
marrow biopsy. In the case of documented bone marrow involvement a hemoglobin 
value of ≥9 g/dL is required.
d. Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) 
≤2.5 x upper limit of normal (ULN).  In the case of documented liver involvement by 
lymphoma, ALT/SGPT and AST/SGOT must be≤5.0 x ULN.
e.
Serum total bilirubin ≤2.0 mg/dL (34 µmol/L). In the case of Gilbert’s Syndrome, or 
documented liver or pancreatic involvement by lymphoma, serum total bilirubin must 
be ≤5.0 mg/dL (86 µmol/L).
f.
Calculated creatinine clearance of ≥40 mL/min by the Cockcroft-Gault formula. A 
24-hour urine collection may also be used for calculating the creatinine clearance 
value.
12. Females of childbearing potential (FCBP4) must:
a.
Have two negative pregnancy tests as verified by the Investigator prior to starting 
study therapy. She must agree to ongoing pregnancy testing during the course of the 
study, and after end of study treatment. This applies even if the subject practices true 
abstinence5 from heterosexual contact.
b. Either commit to true abstinence5 from heterosexual contact (which must be reviewed 
on a monthly basis and source documented) or agree to use, and be able to comply 
with, 2 effective measures of contraception without interruption. Contraception 
methods must include 1 highly effective and 1 additional effective (barrier) method of 
contraception from at least 28 days prior to starting investigational product, during 
the study therapy including dose interruptions, and for 1 year following the last dose 
                                               
4 A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not 
undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea 
following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had 
menses at any time in the preceding 24 consecutive months).
5 True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. In contrast, 
periodic abstinence (eg calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
39
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
of rituximab (according to the Rituxan Prescribing Information), 28 days following 
the last dose of lenalidomide, or 90 days after the last dose of durvalumab, whichever 
is latest. Cessation of contraception after this point should be discussed with a 
responsible physician. 
Note: Highly effective methods (defined as one that results in a low failure rate [ie,
less than 1% per year] when used consistently and correctly). The following are 
examples of highly effective and additional effective methods of contraception:
Highly effective methods:
i.
Intrauterine device (IUD). See Section 8.2 Prohibited Concomitant 
Medications and Procedures
ii.
Hormonal (birth control pills, injections, implants, levonorgestrel-releasing 
intrauterine system [IUS], medroxyprogesterone acetate depot injections, 
ovulation inhibitory progesterone-only pills [eg, desogestrel]). See Section 8.2
Prohibited Concomitant Medications and Procedures
iii.
Tubal ligation 
iv.
Partner’s vasectomy 
Additional effective methods: 
v.
Male condom 
vi.
Diaphragm
vii.
Cervical cap
c.
Agree to abstain from breastfeeding during study participation and for at least 28 days 
after the last dose of lenalidomide or 90 days after the last dose of durvalumab or 12 
months after the last dose of rituximab, whichever is longer.
d. Refrain from egg cell donation while taking durvalumab and for at least 28 days after 
the last dose of lenalidomide or 90 days after the last dose of durvalumab, whichever 
is longer. 
13. Male subjects must:
a.
Practice true abstinence5 (which must be reviewed on a monthly basis) or agree to use 
a condom (Appendix E) during sexual contact with a pregnant female or a female of 
childbearing potential while participating in the study, during dose interruptions and 
for at least 28 days after the last dose of lenalidomide or 90 days after the last dose of 
durvalumab, whichever is longer, even if he has undergone a successful vasectomy.
b. Agree to not donate semen or sperm during the IP therapy and for 28 days after the 
last dose of lenalidomide or 90 days after the last dose of durvalumab, whichever is 
longer.
14. All subjects must:
a.
Have an understanding that lenalidomide could have a potential teratogenic risk.
b. Agree to abstain from donating blood while taking lenalidomide therapy and for 28 
days after the last dose of lenalidomide therapy or 90 days after the last dose of
durvalumab, whichever is longer.
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
40
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
c.
Agree not to share lenalidomide with another person.
d. Agree to be counseled about pregnancy precautions and risk of fetal exposure.
4.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Subject has any significant medical condition, laboratory abnormality, or psychiatric 
illness that would prevent the subject from participating in the study.
2. Subject has any condition including the presence of laboratory abnormalities, which 
places the subject at unacceptable risk if he/she were to participate in the study.
3. Subject has any condition that confounds the ability to interpret data from the study.
4. The following WHO subcategories of DLBCL:
a.
Active central nervous system (CNS) or meningeal lymphoma
b. Primary cutaneous, leg type
c.
Primary mediastinal (thymic)
d. Lymphomatoid granulomatosis
e.
Anaplastic lymphoma kinase-positive (ALK)-positive lymphoma
f.
Plasmablastic lymphoma
g. Large B-cell lymphoma arising in HHV8 associated multicentric Castleman disease
h. Primary effusion lymphoma
i.
Intravascular large B-cell
j.
B-cell unclassifiable cases with features intermediate between DLBCL and Burkitt’s 
lymphoma
k. Unclassifiable cases with features intermediate between DLBCL and classical 
Hodgkin’s lymphoma.
5. Subject has evidence of composite DLBCL and Follicular Lymphoma (FL), or of 
transformed NHL.
6. Subjects with primary CNS lymphoma or secondary CNS involvement by lymphoma.  
Subjects will be evaluated to assess the status and risk of CNS disease. Risk evaluation of 
CNS involvement in selected subjects is found in Section 6.1 and the NCCN guidelines, 
Version 2 (2015), for DLBCL and NHL for risk evaluation of CNS involvement:
a.
Subjects with confirmed CNS involvement of DLBCL will not be eligible
b. For selected subjects at risk for occult CNS disease, the subject is required to have a 
negative cerebrospinal fluid (CSF) by cytology examination, routine studies to 
include cytology, and flow cytometric analysis. A brain/spinal CT or magnetic 
resonance imaging (MRI) during Screening will be required to rule out CNS disease 
only in subjects with neurological findings on exam or review of symptoms 
suspicious for CNS disease
c.
Lumbar puncture is required for selected subjects at risk for occult CNS
lymphomatous involvement
d. All subjects considered to be at high risk for CNS disease MUST be willing to 
receive CNS prophylaxis according to Section 8.3.2
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
41
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
7. Subject is seropositive for or has active viral infection with hepatitis B virus (HBV): 
a.
HBV surface antigen (HBsAg) positive
b. HBV surface antigen (HBsAg) negative, HBV surface antibody (anti-HBs) positive 
and/or HBV core antibody (anti-HBc) positive, and detectable viral DNA
Note: Subjects who are seropositive because of a successfully treated, prior infection are 
eligible (HBsAg negative, anti-HBs positive, and/or anti-HBc positive, but viral DNA 
negative). Subjects who are seropositive because of HBV vaccination are eligible (anti-
HBs positive, anti-HBc negative, and HBsAg negative).
8. Subject known to be seropositive for hepatitis C virus (HCV) with chronic hepatitis C, or 
subjects with an active hepatitis C infection requiring anti-viral medication (at time of 
enrollment).  
Note: HCV positive subjects who do not have active hepatitis C, and who are otherwise 
acceptable candidates for R-CHOP chemotherapy, as documented by the Investigator, 
are eligible.
9. Subject known to be seropositive for or active viral infection with human 
immunodeficiency virus (HIV).
10. Subject has undergone major surgery (excluding lymph node or bone marrow biopsy) 
within 28 days from signing the informed consent document, unless the subject is 
recovered.
11. Subject with a life expectancy < 6 months.
12. Subject has a history of other malignancies, unless the subject has been free of the disease 
for ≥ 5 years. Exceptions to the ≥ 5-year time limit include history of the following:
a.
Localized non-melanoma skin cancer
b. Carcinoma in situ of the cervix
13. Subject has a contraindication to any drug of the R-CHOP immune-chemotherapy 
regimen.
14. Left ventricular ejection fraction (LVEF) < 50% as assessed by multi gated acquisition 
scan (MUGA) or echocardiogram (2-D ECHO), or LVEF < local institutional normal 
limits for R-CHOP administration as assessed by echocardiography.
15. Subject has peripheral neuropathy ≥ Grade 2.
16. Subject with prior use of lenalidomide.
17. Subject with known allergy to thalidomide.
18. Subject with known sensitivity or allergy to murine products.
19. Subject with use of any investigational agent within 28 days or five half-lives, whichever 
is longer, prior to first dose of study drug treatment.
20. Subjects with a high risk of developing thromboembolic events, who are unwilling to 
take venous thromboembolism (VTE) prophylaxis.
21. Females who are pregnant or breastfeeding.
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
42
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
22. Subject having received any prior mAb against CTLA-4, PD-1, or PD-L1.  
23. Subject has received live, attenuated vaccine within 30 days prior to the first dose of 
durvalumab.
Note: Subjects, if enrolled, should not receive live vaccine during the study and for 
12 months after last dose of rituximab or until recovery of B-cells and for 120 days 
after last dose of durvalumab, whichever is longer.
24. Subject with active or prior documented autoimmune or inflammatory disorders 
(including inflammatory bowel disease [eg, colitis, Crohn’s disease], diverticulitis with 
the exception of a prior episode that has resolved or diverticulosis, celiac disease, irritable 
bowel disease, or other serious gastrointestinal chronic conditions associated with 
diarrhea; systemic lupus erythematosus; Wegener’s syndrome [granulomatosis with 
polyangiitis]; myasthenia gravis; Graves’ disease; rheumatoid arthritis; hypophysitis, 
uveitis; etc.) within the past 3 years prior to the start of treatment. The following are 
exceptions to this criterion:
a.
Subjects with vitiligo or alopecia.
b. Subjects with hypothyroidism (eg following Hashimoto syndrome) stable on hormone 
replacement.
c.
Subjects with psoriasis not requiring systemic treatment.
25. Subject with current or prior use of immunosuppressive medication within 28 days prior 
to the first dose of durvalumab. The following are exceptions to this criterion:
a.
Intranasal, inhaled, topical or local steroid injections (eg intra-articular injection);
b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone 
or equivalent;
c.
Steroids as premedication for hypersensitivity reactions (eg CT scan premedication).
26. Prior organ transplantation including allogeneic stem cell transplantation.
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
43
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
5.
TABLE OF EVENTS
Table 3:
Schedule of Assessments
EVENTS
Screening
INDUCTION
CONSOLIDATION
EOT 
(PD)
Safety FU
Efficacy 
FU j
Cycle
1
2
3
4
5
6
7
8
EOI 
1
2
3
4
5
6
7
8
9
IP 
+28d
Dur 
+90d
90d up 
to 2 
years 
from 
C1D1
Planned Day
-28 to-1
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
1
15
1
1
1
1
1
1
1
1
1
Window (± day)
2
1
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
7
2
2
2
2
2
2
2
2
7
7
14
14
Informed consent
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Inclusion / exclusion 
criteria
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Disease and medical 
history (including HIV 
/HCV)
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Prior cancer therapies
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Central Nervous System 
(CNS) Lymphoma 
evaluation
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Hepatitis B Virus (HBV) 
Local Testing
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Electrocardiogram
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
-
-
-
-
-
-
-
-
X
-
-
-
Left-ventricular ejection 
fraction
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
-
-
-
-
-
-
-
-
X
-
-
-
SAFETY ASSESSMENTS
Adverse Events
From signing ICF and until 90 days after the last dose of durvalumab or 28 days after the last dose of any other IP
Assessment of Second 
Primary Malignancy 
(SPM)
From signing ICF for up to 90 days after the last dose of durvalumab and up to 5 years after enrollment (C1D1) of the last subject to receive lenalidomide
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
44
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 3:
Schedule of Assessments (Continued)
EVENTS
Screening
INDUCTION
CONSOLIDATION
EOT 
(PD)
Safety FU
Efficacy 
FU j
Cycle
1
2
3
4
5
6
7
8
EOI 
1
2
3
4
5
6
7
8
9
IP 
+28d
Dur 
+90d
90d up 
to 2 
years 
from 
C1D1
Planned Day
-28 to-1
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
1
15
1
1
1
1
1
1
1
1
1
Window (± day)
2
1
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
7
2
2
2
2
2
2
2
2
7
7
14
14
Prior/ Concomitant 
Medications/ Procedures/ 
Hospitalizations
From signing ICF and until 90 days after the last dose of durvalumab or 28 days after the last dose of any other IP
Physical examination
X
X
a
X
X
X
X
X
X
X
X
X
-
X
-
X
-
X
-
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG performance status
X
X
-
-
X
-
X
-
X
-
X
-
X
-
X
-
X
-
X
X
X
X
X
X
X
X
X
X
X
X
-
Vital signs
X
X
X
X
X
X
X
X
X
X
X
-
X
-
X
-
X
-
X
X
X
X
X
X
X
X
X
X
X
X
-
Hematology laboratory
X
Xb
X
X
X
X
X
X
X
X
X
-
X
-
X
-
X
-
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry laboratory
X
Xb
X
X
X
X
X
X
X
X
X
-
X
-
X
-
X
-
X
X
X
X
X
X
X
X
X
X
X
X
X
Requalification Criteria
-
-
-
-
X
-
X
-
X
-
X
-
X
-
X
-
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Coagulation
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
-
-
-
-
-
-
-
-
X
-
-
-
Urinalysis
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
-
-
-
Quantitative 
immunoglobulins
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
-
-
-
-
-
-
-
-
X
-
-
-
Thyroid function tests
X
X
-
-
X
-
X
-
X
-
X
-
X
-
X
-
X
-
X
X
X
X
X
X
X
X
X
X
-
-
-
Constitutional symptoms
X
X
-
-
X
-
X
-
X
-
X
-
X
-
X
-
X
-
X
X
X
X
X
X
X
X
X
X
-
-
-
Tumor Lysis prophylaxis
-
X
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
PREGNANCY
Pregnancy Testing - All 
FCBP
X
X
X
c
-
X
-
X
-
X
-
X
-
X
-
X
-
X
-
X
X
X
X
X
X
X
X
X
X
X
X
-
Lenalidomide Counseling 
- All FCBP (up to COO 
identification and 
stratification)
X
X
-
-
X
-
X
-
X
-
X
-
X
-
X
-
X
-
X
-
-
-
-
-
-
-
-
-
-
-
-
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
45
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 3:
Schedule of Assessments (Continued)
EVENTS
Screening
INDUCTION
CONSOLIDATION
EOT 
(PD)
Safety FU
Efficacy 
FU j
Cycle
1
2
3
4
5
6
7
8
EOI 
1
2
3
4
5
6
7
8
9
IP 
+28d
Dur 
+90d
90d up 
to 2 
years 
from 
C1D1
Planned Day
-28 to-1
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
1
15
1
1
1
1
1
1
1
1
1
Window (± day)
2
1
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
7
2
2
2
2
2
2
2
2
7
7
14
14
Arm B Pregnancy Testing 
- for FCBP with Regular 
or No Menstrual Cycles
Xd
Weekly during first 28 days; every cycle on Day 1 thereafter
End of lenalidomide and 28 days after the last dose of 
lenalidomide
Arm B Pregnancy Testing 
- for FCBP with Irregular 
Menstrual Cycles
Xd
Weekly during first 28 days; every cycle on Days 1 and 14 thereafter
End of lenalidomide and 14 and 28 days after the last dose of 
lenalidomide
Birth Control
up to 12 months after the last dose of rituximab
BIOMARKERS
Tumor Biopsy
X
-
-
-
X
e
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
f
-
-
-
Submit Lymph Node / 
Tumor Biopsy to Central 
Laboratory
X
-
-
-
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
-
-
-
Saliva Samples for 
Biomarkers
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
PBMC isolation for 
biomarkers
X
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
-
-
-
X
-
-
-
Whole blood biomarker 
for immunophenotyping
X
X
X
X
X
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Serum samples for 
biomarkers (ie sPD-L1)
X
X
-
-
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
-
-
-
Plasma samples 
(cytokines/ soluble factors; 
circulating tumor DNA)
X
X
X
X
X
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
-
-
-
EFFICACY ASSESSMENTS
FDG-PET scang
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
-
-
-
-
-
-
-
-
X
-
-
-
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
46
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 3:
Schedule of Assessments (Continued)
EVENTS
Screening
INDUCTION
CONSOLIDATION
EOT 
(PD)
Safety FU
Efficacy 
FU j
Cycle
1
2
3
4
5
6
7
8
EOI 
1
2
3
4
5
6
7
8
9
IP 
+28d
Dur 
+90d
90d up 
to 2 
years 
from 
C1D1
Planned Day
-28 to-1
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
1
15
1
1
1
1
1
1
1
1
1
Window (± day)
2
1
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
7
2
2
2
2
2
2
2
2
7
7
14
14
CT Scan (neck, chest, 
abdomen and pelvis)
X
-
-
-
-
-
-
Xh
-
Xh
-
-
-
-
-
-
-
-
X
Every 3 months (± 1 week) up to PD
X
Every 3 months (± 1 
week) up to PD
Response Assessment
(Cheson, 2014)
-
-
-
-
-
-
-
Xh
-
Xh
-
-
-
-
-
-
-
-
X
Every 3 months (± 1 week) up to PD
X
Every 3 months (± 1 
week) up to PD
Bone marrow biopsy and 
aspirate
Xi
Within 28 days of a suspected CR, except in subjects with no evidence of lymphomatous marrow involvement at baseline
-
-
-
Progression and Survival 
follow-up
for up to 5 years after the last subject is enrolled
Subsequent Anti-
lymphoma
therapy
See Section 6.3.2 for more details
PHARMACOKINETICS
PK analysis
-
X
X
X
X
X
-
-
X
X
-
-
X
-
-
-
X
-
X
X
X
X
X
X
-
X
-
X
-
-
-
Immunogenicity (ADA)
-
X
-
-
X
-
-
-
X
-
-
-
X
-
-
-
X
-
-
X
-
X
-
X
-
X
-
X
-
-
-
TREATMENT
Dispense Study Drug
-
X
-
-
X
-
X
-
X
-
X
-
X
-
X
-
X
-
X
X
X
X
X
X
X
X
X
-
-
-
-
Drug Accountability
-
-
-
-
X
-
X
-
X
-
X
-
X
-
X
-
X
-
X
X
X
X
X
X
X
X
X
X
-
-
-
ADA = anti-drug antibodies; C = cycle; CNS = central nervous system; COO = cell of origin; CR = complete response; CT = computed tomography; D = day; Dur = durvalumab; 
ECOG= Eastern Cooperative Oncology Group; EOI = end of induction; EOT = end of treatment (day of last durvalumab planned dosing); FCBP = female of child-bearing 
potential; FDG-PET = fluorodeoxyglucose-positron emission tomography; FU = Follow-up; HCV = hepatitis C virus; HBV = hepatitis B virus; HIV = Human Immunodeficiency 
Virus; ICF = informed consent form; IP = investigational product; PBMC = peripheral blood mononuclear cell; PD = progressive disease; PD-L1 = programmed cell death-ligand 
1; PK = pharmacokinetics; SPM = second primary malignancy,
a If performed within 72 hours of Cycle 1 Day 1 examination do not need to be repeated at Cycle 1 Day 1.
b Safety laboratory assessments performed during Screening within 7 days of the first study treatment will not need to be repeated for Cycle 1 Day 1.
c Once during day -10 to -14, and within 24h prior to first lenalidomide dose.
d Once during day -10 to -14, and within 24h prior to C1D1, see Section 6 for more details.
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
47
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
e Either at C2D14 (± 7 days), C3D14 (± 7 days).
f PD ± 14 days.
g Imaging by FDG-PET scan will be performed also following a CR, see Section 6.4.3 for more details.
h Every 3 months (± 1 week). Or after 50% of induction treatment (between C3D15 and C4D1 for 6×R-CHOP; between C4D15 and C5D1 for 8×R-CHOP). See 
Section 6.4.2 for more details.
i ± 12weeks. Not necessary if PET (-), see Section 6.4.4 for more details.
j Following completion or discontinuation of durvalumab therapy per protocol for all subjects and completion of the last durvalumab subject’s 90-day Safety Follow-up 
Visit (data cutoff date 06 Jun 2019), subjects are no longer required to be followed for disease progression, subsequent anti-lymphoma therapy, and overall survival.
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
48
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
6.
PROCEDURES
After the US FDA Partial Clinical Hold, enrollment continued into Arm A only and new subjects 
received induction therapy (durvalumab + R CHOP) after Cycle 1 regardless of DLBCL COO 
subtype. Enrollment into Arm B (durvalumab in combination with lenalidomide plus rituximab, 
cyclophosphamide, doxorubicin, vincristine, prednisone [R2-CHOP]) was discontinued.  This 
study continued enrollment into treatment Arm A. Subjects enrolled and treated in Arm B prior 
to the US FDA Partial Clinical Hold who were receiving clinical benefit, based on the discretion 
of the Investigator, could continue study treatment after being reconsented. 
Any questions regarding the protocol should be directed to the Celgene Medical Monitor or 
designee.
In the procedures section, assessments performed on C1D1 will always refer to the start of the 
initial R-CHOP treatment.  For instances when C1D1 is in reference to the start of the 
consolidation drug treatment, this will be explicitly stated.
The Informed consent must be obtained prior to beginning any study assessments solely for the 
purpose of this study. Standard of care assessments performed prior to signing the ICF (as 
described in the protocol) may be used for this study, assuming they meet the protocol 
requirements and following discussion with the Celgene medical monitor or designee. The 
subject may withdraw consent at any time for all or certain aspects of the study as follows: 

Withdraw consent for study treatment, but allow Follow-up Period assessments and 
data collection on subsequent anti-lymphoma therapy and disease progression or 
death.

Withdraw consent for study treatment and Follow-up Period assessments, but allow 
data collection on subsequent anti-lymphoma therapy and death.

Withdraw all consent.
6.1.
Screening Period
Screening evaluations will be performed for all subjects to determine study eligibility. These 
evaluations must be completed within 28 days of first dose of study induction treatment (C1D1) 
unless otherwise noted. Screen failed subjects may be re-screened under exceptional 
circumstances and will be subject to the Medical Monitor agreement.
Inclusion/exclusion criteria must be reviewed prior to treatment assignment. Waivers to the 
protocol will not be granted during the conduct of this study under any circumstances. The 
following will be performed at Screening as specified in the Table of Events (Table 3), initiating 
once the informed consent has been obtained:

Inclusion/Exclusion criteria will be evaluated for subject eligibility during the 
28 day Screening period.

Disease history of DLBCL will include specific information regarding diagnosis, 
staging and histology, and grade.
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
49
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019

Prior cancer therapies: All subjects will be evaluated for any prior cancer 
treatments that may have been received. Any treatments related to DLBCL will result 
in exclusion from the study.

Complete medical history will be obtained by the Investigator or qualified designee.  
The medical history will be general enough to document common comorbid 
conditions as well as specific enough to confirm any condition against the eligibility 
criteria, and will document whether the identified conditions are active or inactive at 
the time of enrollment. Relevant medical history (including HIV and HCV infection)
findings will be recorded within the source document and the case report form (CRF).  
Medical and medication history will be assessed in relation to the eligibility criteria as 
listed in Section 4.2.

Demographics will include date of birth or age, sex, race, and ethnicity (if allowed 
by local regulations).

Prior and concomitant medications and procedures will include all medications 
and procedures including transfused blood products (packed red blood cells, platelets, 
etc.), occurring ≤ 28 days before Screening and ongoing during Screening.

Bone Marrow Biopsy and aspirate will be performed within 12 weeks prior C1D1.
Note: If the screening FDG-PET demonstrates the bone marrow to be FDG-negative, 
no bone marrow biopsy (BMB)/aspirate is required.

ECOG Performance Status (Oken, 1982) will be scored according to Appendix C.

Physical examination including evaluation of lymph nodes, spleen, liver, heart, lung, 
abdomen, neurological status, and skin will be performed. Physical examination
performed within 72 hours of C1D1 do not need to be repeated at C1D1.

Vital signs will include height (Screening only), weight, body surface area (BSA), 
blood pressure, pulse, pulse oximetry, and body temperature. 

Safety laboratory analyses will be performed at a designated Central Laboratory,
according to the Schedule of Assessments (Table 3). Central laboratory results must 
be used during Screening to evaluate subject eligibility, and may be repeated within 
the Screening window, if necessary. However, if for any reason Screening central 
laboratory results become unavailable following collection of the samples (eg
hemolyzed samples), local laboratory results may be used after discussion with and 
approval of the Celgene Medical Monitor. Safety laboratory assessments performed 
during Screening within 7 days of the first study treatment will not need to be 
repeated for C1D1. Refer to the Laboratory Manual for sample handling, storage, and 
shipment instructions.

Hematology laboratories: Complete blood count (CBC) with absolute 
differential will include hematocrit, hemoglobin, white blood cell count (WBC) 
with differential, and platelet count.

Serum chemistry laboratories: will include albumin, alkaline phosphatase, 
alanine aminotransferase (ALT/SGPT), amylase, aspartate transaminase 
(AST/SGOT), bilirubin, calcium, chloride, creatinine, gamma glutamyl 
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
50
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
transferase, glucose, lactic acid dehydrogenase (LDH), lipase, phosphorous, 
potassium, sodium, total protein, serum urea/blood urea nitrogen (BUN), and uric 
acid.
Calculated creatinine clearance (CrCl) will be estimated by central laboratory
using the Cockcroft-Gault formula:
CrCl (mL/min) = ((140 – age) (weight [kg])) / (72 (serum creatinine [mg/dL])); 
for females, the formula is multiplied by 0.85 (Cockcroft, 1976).
Alternatively, the CrCl can be calculated with a 24-hour urine collection.

Coagulation tests will include prothrombin time, international normalized ratio 
(INR) and partial thromboplastin time (PTT or activated PTT).

Urinalysis (a urine dipstick may be used). The urinalysis will include color, 
appearance, specific gravity, pH, glucose, ketones, blood, bilirubin, and protein.  
A microscopic examination will be performed if urinalysis result is abnormal.
Additional urinalyses will be performed as considered clinically necessary.

A Tumor Biopsy will be required of all subjects during Screening. Please refer to 
Section 6.8 for details.

Local Pathology review: Anonymized reports should be submitted, as well as 
locally stained slides.

Gene expression profile (GEP) analysis to determine COO will be performed on 
all subjects. Genomic subtype analysis is not necessary for determination of 
eligibility but must be performed prior to the start of Cycle 2 for each subject.

Tumor biopsies will also be used for other biomarker analysis as described in
Section 6.8.

Biomarker saliva and blood sample(s): Saliva and blood samples will be collected 
at Screening for pharmacogenomics and Pd analyses as outlined in the Biomarker 
Collection Schedule (Table 3) and Section 6.8.

Quantitative immunoglobulins including IgG, IgA, and IgM will be measured.

Hepatitis B virus (HBV) testing (assessed locally) will include hepatitis B surface 
antigen (HBsAg), antibody to the hepatitis B surface antigen (anti-HBs), and antibody 
to the hepatitis B core antigen (anti-HBc). For subjects with previous HBV infection 
which is inactive at the time of Screening, viral DNA levels may be measured (see 
Section 4.3, Number 7).

Thyroid function tests: Assessments of thyroid stimulating hormone (TSH), fT4, 
and fT3 will be performed.

Central nervous system (CNS) lymphoma evaluation and CNS prophylaxis: CNS 
evaluation will be performed in selected patients to be at high risk for CNS 
involvement by lymphoma. Central nervous system involvement should be ruled out 
if any of the following involvement or criteria are observed: paranasal sinus, 
testicular, epidural, bone marrow, kidney or adrenal gland, DLBCL, concurrent 
expression of MYC and BCL-2 protein (ie, double expressing lymphoma [DEL]), 
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
51
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
double hit lymphoma (DHL)/ triple hit lymphoma (THL) by FISH/cytogenetics 
analysis, or ≥2 extranodal sites and elevated LDH. If a subject has evidence of CNS 
disease on evaluation of spinal fluid and /or neuroimaging studies (performed if a 
subject has any review of symptoms and / or neurological findings suspicious for 
CNS involvement), the subject would be excluded from enrolling in this study.

In addition to routine CSF evaluation, flow cytometric analysis to rule out 
lymphomatous involvement is required.

Subjects at high-risk for developing secondary CNS disease (as described above) 
must also receive prophylactic chemotherapy according to NCCN guidelines or 
institutional standards. Refer to Section 8.3.2 for required and permitted 
concomitant CNS prophylaxis treatment.

Echocardiogram (2-D ECHO) or multi gated acquisition scan (MUGA) for 
assessment of LVEF. The MUGA is the preferred method for LVEF evaluation over 
the use of an ECHO.

12-lead Electrocardiogram (ECG) will be performed to assess heart electrical 
function. If an ECG was performed as standard of care within 28 days of dosing, 
those data may be used to fulfill the eligibility requirement.

Pregnancy testing is applicable to all subjects who are females of childbearing 
potential. For FCBP, 2 pregnancy tests must be performed (medically supervised; 
urine tests are provided and are the preferred method; if other test method [blood] is 
used, the minimum sensitivity required is 25 mIU/mL): (1) one during Screening 
Period (between Day- 10 and -14) and (2) one within 24 hours prior to the start of 
lenalidomide (refer also Section 6.2 for FCBP with COO unknown at C1D1). 
Negative results are required for IP administration. Please refer to the Pregnancy 
Prevention Plan located in Appendix E for further details.

Lenalidomide Counseling about pregnancy precautions and the potential risks of 
fetal exposure to lenalidomide MUST be conducted for all subjects assigned to 
receive lenalidomide (Treatment Arm B) prior to receiving any IP. During 
counseling, subjects must be reminded to not share study drug and to not donate 
blood. Please consult the Lenalidomide Pregnancy Prevention Risk Management Plan 
(Appendix E) for details.

Constitutional symptom review includes assessing subject for the presence of 
documentation B-symptoms (fever, weight loss, and night sweats).

Tumor Evaluation:  Integrated FDG-PET/CT is preferred for response assessment.  
The imaging modality (the same imaging modality [eg CT, MRI] and technique [eg
the use of contrast, slice thickness for scans]) used at Screening should be used 
consistently throughout the study for all further assessments.

Imaging by Computed Tomography (CT) scan:  All subjects are required to 
undergo a CT scan, with contrast, of the neck, chest, abdomen and pelvis during 
Screening. Tumor evaluations performed as part of the standard of care up to 
28 days prior to C1D1 can be accepted as the baseline tumor evaluation. See
Section 6.4.1 for further details.
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
52
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019

Imaging by FDG-PET: All subjects are required to undergo a FDG-PET scan 
during Screening. See Section 6.4.1 for further details.

The assessment period for Adverse Events (AEs) and SPMs begins when the subject 
signs the informed consent form. See Section 10 for further details.

Pre-specify Post-Induction Radiotherapy if applicable. If the Investigator intends 
to administer radiotherapy post-induction (Section 7.2.2), this must be specified prior 
to enrollment of the subject through the Integrated Response Technology (IRT).
6.2.
Treatment Period
Subjects will begin treatment following the confirmation of eligibility. Treatment will start on 
C1D1 and must start within 28 days of signing the informed consent form (ICF). For all 
subsequent visits, an administrative window of ± 2 days for Day 1 visits of each cycle and 
± 1 day for scheduled interim study visits (eg Cycle Day 8 and Day 15 visits) are allowed unless 
otherwise noted.  
The treatment period referred to in this section includes both the induction and the consolidation 
study drug treatments. Treatment cycles are 21 days in length during the induction treatment 
period and 28 days in length during the consolidation treatment period and will occur as 
described in Section 7.2.
Study visits and subject assessments will be performed at the frequency specified in the Schedule 
of Assessments (Table 3). Scheduled assessments should be performed prior to dosing on the 
scheduled visit day, unless otherwise specified (ie, PK, Pd). 
Unscheduled assessments may be performed as clinically indicated, and those visits should be 
recorded in the subject’s source documents and CRF.
The following evaluations will be performed as specified in the Table of Events (Table 3):

Concomitant Medications and Procedures will be collected from signing of 
informed consent through 90 days after the last dose of durvalumab or 28 days after 
the last dose of any other IP, whichever is later. This will include all recent and 
current medications and procedures, including transfused blood products (packed red 
blood cells, platelets, etc.).

Bone Marrow Biopsy and aspirate will be performed to confirm a CR (within 
28 days for confirmation of a suspected CR), except in subjects with no evidence of 
lymphomatous marrow involvement performed during Screening.
Note: If a FDG-PET-CT is performed and confirms FDG-negative CR, no bone 
marrow biopsy (BMB)/aspirate is required. 

ECOG Performance Status will be performed on Day 1 of each cycle and scored 
according to Appendix C.

Physical examination: Documentation of any enlargement of the lymph nodes, 
spleen and/or liver should be recorded in the source document and CRF.

Vital signs
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Protocol MEDI4736-DLBCL-001
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
Safety laboratory tests (Hematology and Serum Chemistry) will be performed at the 
designated central laboratory during Day 1 of every cycle, weekly during cycle 1 
(Days 1, 8 and 15), at Day 15 of Cycles 1-4 during the induction treatment and EOT.

An On-treatment Tumor Biopsy is required when clinically feasible during Cycle 2 
(C2D14 ±7 days) or during Cycle 3 (C3D14 ±7 days). The collection of tumor tissue 
is also required for all subjects at the time of disease progression following an 
objective response (PR or CR). See Section 6.8.1.

Thyroid function tests: on Day 1 of each treatment cycle.

Pregnancy test is required for all FCBP on Day 1 of each treatment cycle. See also 
Appendix E for details.

For all FCBP for whom COO results are pending and or determined as ABC 
before C1D8, and to respect the pre-lenalidomide dosing rules (explained in 
Section 6.1: one test between Day -10 and -14 and one test within 24 hours prior 
to the start of lenalidomide) a test must be performed, for example on C1D8 (or 
between Day -10 and -14 from C2D1) and within 24 hours prior C2D1.

FCBP in Arm B with regular or no menstrual cycles must agree to have 
pregnancy tests weekly for the first 28 days of study participation and then every 
28 days while taking lenalidomide, at study discontinuation, and at Day 28 
following the last dose of lenalidomide.

FCBP in arm B with irregular menstrual cycles must agree to have pregnancy 
tests between Day -10 and -14 prior to the start of lenalidomide, weekly for the 
first 28 days of study participation and then every 14 days while taking 
lenalidomide, at study discontinuation, and at Days 14 and 28 following the last 
dose of lenalidomide.

Lenalidomide Counseling will be conducted on Day 1 of each treatment cycle 
during the induction treatment period, and at end of induction (EOI) for all subjects
assigned to receive treatment with lenalidomide (Treatment Arm B). See Appendix E
for details.

Constitutional Symptom Review on Day 1 of each treatment cycle.

Tumor Evaluation: Integrated FDG-PET/CT is preferred for response assessment.  
The imaging modality (the same imaging modality [eg CT, MRI] and technique [eg
the use of contrast, slice thickness for scans]) used at Screening should be used 
consistently throughout the study for all further assessments.

Imaging by CT scan:  All subjects are required to undergo a CT scan, with 
contrast, of the neck, chest, abdomen and pelvis every 3 months (±1 week) for the 
first 2 years. During induction treatment, it is acceptable to perform the scans at 
12 week intervals. It is also acceptable to perform the scans after 50% of 
induction treatment (between C3D15 and C4D1 for 6xR-CHOP schedule; 
between C4D15 and C5D1 for 8xR-CHOP schedule). See Section 6.4.1 for 
further details.
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Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
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
Imaging by FDG-PET will be performed following a CR. Further evaluation by 
FDG-PET scans are optional, except PET scan at the end of induction, and may 
be performed according to the scheduled CT scans to align with the efficacy 
response. See Section 6.4.1 for further details.

Efficacy Response will be assessed locally along with the CT scan schedule until PD 
or premature discontinuation from the study and documented in the CRFs based on
the 2014 International Working Group Response Criteria for Non-Hodgkin’s 
Lymphoma (Cheson, 2014) according to the Schedule of Assessments (Table 3).

Pharmacokinetic Analysis will be performed on blood samples collected according 
to the schedule described in Section 6.6. 

Biomarker blood sample(s): Samples for biomarker analyses will be collected as 
outlined in the Schedule of Assessments (Table 3) and Section 6.8.

Immunogenicity blood samples will be collected as outlined in Section 6.7.

Study Drug Administration and Accountability:  Study drug will be administered 
at the Day 1 visit of each cycle. Intravenous treatments will be administered at the 
clinic and oral drugs will be provided to the subject for treatment as prescribed.  
Starting C2D1, study drug accountability will be performed and treatment compliance 
assessed.

Adverse events and SPMs (refer to Section 10).
6.2.1.
End of Induction Treatment (EOI)
Assessments will be performed at the end of the induction treatment period according to the 
Schedule of Assessments (Table 3) once a subject has completed or prematurely discontinued the 
induction treatment period. For subjects continuing on to the consolidation phase, the end of the 
induction treatment will initiate the start of consolidation treatment, therefore the end of 
induction visit will coincide with the first cycle visit (C1D1) for the consolidation treatment 
period.
In instances where the subject has prematurely discontinued from study treatment, the end of 
induction treatment will correspond with the end of study treatment (EOT) and only the EOT
visits assessments will be performed

Concomitant Medications and Procedures

Bone Marrow Biopsy and Aspirate as necessary (see Section 6.4.4)

ECOG Performance Status

Physical examination

Vital signs

Safety Laboratories: Hematology, Serum Chemistry, and coagulation tests.

Quantitative Immunoglobins

Thyroid Function Tests
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Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
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
A 2D-ECHO or MUGA 

A 12-Lead ECG

Pregnancy testing is required for all FCBP.

Lenalidomide Counseling for all subjects assigned to receive treatment with 
lenalidomide (Treatment Arm B). See Appendix E for details.

Constitutional Symptoms

Tumor Evaluations: 

Imaging by CT scan:  All subjects completing the induction treatment regimen 
should have a CT scan at the end of the induction treatment:
o
For subjects treated with 8 cycles of induction therapy, the end of induction 
CT scan should be done 6 months after C1D1.
o
For subjects treated with 6 cycles of induction therapy, the end of induction 
CT scan can be done before 6 months after C1D1, however, the subsequent 
CT scan should be performed at 9 months from C1D1. See Section 6.4.1 for 
further details.

Imaging by FDG-PET will be performed at the end of the induction treatment, 
but before the start of the consolidation treatment. See Section 6.4.1 for further 
details.

Assessment of Efficacy Response and decision to continue in consolidation phase
(see Section 7.2.3.1).

Pharmacokinetic Analysis will be performed on blood samples collected according 
to the schedule described in Section 6.6. Collection of blood samples for PK analysis 
will be performed at the end of induction treatment for all subjects.

Biomarker blood sample(s): Blood samples for biomarker analyses will be collected 
as outlined in the Schedule of Assessments (Table 3) and Section 6.8.

Study drug administration and accountability

Adverse Events and SPMs (refer to Section 10)
6.2.2.
End of Treatment
An end of treatment (EOT) evaluation will be performed for subjects who completed the study 
treatment (the day of last durvalumab planned dosing) or who were withdrawn from treatment 
for any reason as soon as possible after the decision to permanently discontinue the subject from 
study treatment is made. 
The following evaluations will be performed as specified in the Table of Events (Table 3):

Concomitant medications and procedures will continue to be collected at EOT 
visit and through 90 days after the last dose of durvalumab or 28 days after the last 
dose of any other IP, whichever is later.

ECOG performance status
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Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
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
Physical examination

Vital signs

Safety laboratory tests: Hematology, Serum Chemistry, coagulation and urinalysis.

A post treatment Tumor Biopsy will be required at the time of disease progression 
(within 14 days) from subjects who previously achieved an objective response 
(CR/PR). For subjects who have experienced disease progression without 
experiencing an objective response, a tumor biopsy at discontinuation is optional.

Quantitative immunoglobulins 

Thyroid function tests

A 2-D ECHO or MUGA 

A 12-Lead ECG 

Pregnancy testing is required for all FCBP at the EOT visit. All FCBP in Arm B, 
with regular or no menstrual cycles must have pregnancy tests at treatment 
discontinuation and at Day 28 following lenalidomide discontinuation. If menstrual 
cycles are irregular, the pregnancy testing must occur at treatment discontinuation 
and at Days 14 and 28 following lenalidomide discontinuation. See Appendix E for 
details.

Constitutional symptom review

Tumor Evaluations:  FDG-PET/CT 

Imaging by CT scan

Imaging by FDG-PET will be performed unless a FDG-PET confirmed CR was 
previously documented in an earlier cycle.  

Efficacy response 

Immunogenicity blood samples

Pharmacokinetic Analysis according to the schedule described in Section 6.6.  

Biomarker blood sample(s): Blood samples for biomarker analyses will be collected 
as outlined in the Schedule of Assessments (Table 3) and Section 6.8.

Study drug accountability:  All final accountability of study drugs will be 
performed at the EOT visit.

Adverse events and SPMs (refer to Section 10)

Subsequent anti-lymphoma/anticancer treatments status
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
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6.3.
Follow-up Period 
6.3.1.
Safety Follow-up
All subjects will have a safety follow-up visit at 28 days and 90 days after last dose of study 
treatment, whichever is later for AE reporting, as well as serious adverse events (SAEs) made 
known to the Investigator at any time thereafter that are suspected of being related to IP, as 
described in Section 10.1.
The following evaluations will be performed as specified in the Table of Events (Table 3):

Concomitant medications and procedures will continue to be collected through 90 
days after the last dose of durvalumab or 28 days after the last dose of any other IP, 
whichever is later.

ECOG performance status

Physical examination

Vital signs

Safety laboratory tests: Hematology, Serum Chemistry.

Pregnancy testing is required for all females of childbearing potential (FCBP).
FCBP in Arm B with regular or no menstrual cycles must have pregnancy tests at 
treatment discontinuation and at Day 28 following lenalidomide discontinuation. If 
menstrual cycles are irregular, the pregnancy testing must occur at treatment 
discontinuation and at Days 14 and 28 following lenalidomide discontinuation.
Pregnancy tests will be performed for all FCBP 90 days after the last dose of 
durvalumab.

Adverse events including SPMs will be assessed up to 90 days after last dose of 
durvalumab. Adverse events will be graded according to the NCI-CTCAE version 
4.03 unless otherwise specified in this document. Subjects treated with lenalidomide 
during any stage of the study will continued to be followed for SPM for up to 5 years 
after enrollment (C1D1) of the last subject to receive lenalidomide as part of their 
study treatment.
6.3.2.
Efficacy Follow-up
The Follow-up Period begins once all study treatments have been discontinued or have
completed the full course of treatment as per protocol and contact or visits will be performed 
every 90 days (±14 days) post last dose of study treatment until disease progression. This 
includes subjects who discontinue treatment due to toxicity, as well as those who discontinue 
before progression to receive a new anti-lymphoma therapy.  
Subjects will be followed for disease progression, and subsequent anti-lymphoma treatments.  
Efficacy assessments will continue at the protocol specified time points until disease progression, 
withdrawal of consent, or the initiation of a subsequent anti-lymphoma treatment.
In addition, physical examination for lymphadenopathy and organomegaly, and CBC with 
differential and serum chemistry including LDH test, will be repeated at the same time with the 
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Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
58
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
efficacy assessments according to the schedule described in Table 3 up to two years after C1D1.
Survival status of the subject will be documented and for deceased subjects, the date and cause 
of death will be documented in the CRFs, when available.
Following the documented disease progression, subjects will be followed for subsequent 
anti-lymphoma therapy every 6 months (±1 month) until withdrawal of ICF, or up to 24 months 
from the subject’s last durvalumab dose, by contact with the subject or subject’s caregiver.
6.3.3.
Follow-up for Progression or Long-term Follow-up 
After the end of treatment visit, all subjects will continue to be followed for disease progression
for up to 5 years after the last subject is enrolled (C1D1) or until death, lost to follow-up, consent 
withdrawal, or the End of Study whichever occurs first according to the Table 3. Subsequent
anti-lymphoma therapies should be collected at the same time schedule.
Following completion or discontinuation of durvalumab treatment per protocol for all subjects, 
and completion of last durvalumab subject’s 90-day Safety Follow-up Visit (data cutoff date 06 
Jun 2019), subjects are no longer required to be followed for disease progression, subsequent 
anti-lymphoma therapy, and overall survival. Follow-up procedures, efficacy assessments, 
central labs, imaging, AEs/SAEs and survival data will no longer be collected in the case report 
forms (CRFs).  
6.4.
Efficacy Assessment
Efficacy response assessments will be performed throughout the study treatment period and 
during the follow-up period for subjects until they have discontinued the treatment for disease 
progression or withdrawn consent from the study for further evaluation. Efficacy response 
assessment for this study will be based on the 2014 IWG Response Criteria for lymphoma
(Cheson, 2014; Appendix B).
Tumor assessments will be performed by the Investigator. There is no central radiology review 
in this clinical study. However, tumor assessment data including images should be made 
available to the Celgene Medical Monitor or designee upon request. Once a subject has 
experienced confirmed progression, no further scans are required.
6.4.1.
Efficacy Assessments 
Integrated FDG-PET/CT is preferred for response assessment, however, CT scans are required 
for all tumor assessment and FDG-PET scans are required at Screening and for confirmation of 
CR. The imaging modality (eg CT, MRI and technique for example, use of contrast, slice 
thickness for scans) used at Screening should be used consistently throughout the study for all 
further assessments.
Scans previously acquired as standard of care within 28 days prior to C1D1 may be used to 
fulfill the Screening requirement. Fields missing from archival scans may be imaged separately 
during Screening and the complete set of scans may be used together to fulfill Screening 
requirements.
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
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6.4.2.
Imaging by CT Scans 
Subjects are required to undergo contrast-enhanced CT scan of the neck, chest, abdomen and 
pelvis as the required imaging modality for this study. An integrated FDG-PET/CT is the 
preferred modality. Imaging by CT scan without contrast or magnetic resonance imaging (MRI) 
may be used only when CT with contrast is medically contraindicated or when the frequency of 
CT scans exceeds local standards. Ultrasound is not an acceptable imaging modality for this 
study.
Computed tomography scans will be performed until disease progression at the following 
intervals:

Screening (within 28 days of C1D1).

Every 3 months (± 1 week) starting C1D1 for the first 2 years.
Note: During induction treatment, it is acceptable to perform the scans at 12 week 
intervals to align with the treatment cycles

During induction treatment, it is also acceptable to perform the scans as described 
below:

Interim Staging after 50% of induction therapy was administered
For subjects treated with 8 cycles of R(2)-CHOP: between C4D15 and C5D1
For subjects treated with 6 cycles of R(2)-CHOP: between C3D15 and C4D1

Final Staging (EOI) after 100% of induction therapy was administered
For subjects treated with 8 cycles of R(2)-CHOP: after C8D15
For subjects treated with 6 cycles of R(2)-CHOP: after C6D15
Note: the next CT scan after EOI should be performed at 9 months, independently of the 
number of cycles in induction, then every 3 months until 2 years after C1D1.
Following completion of treatment or discontinuation of treatment for any reason other than 
disease progression, the CT scan assessment will continue until disease progression, subsequent 
anti-lymphoma treatment or withdrawal of consent in the Follow-up period based on the 
schedule above. Unscheduled tests may be ordered at any time as clinically indicated.
After 2 years, CT scans are no longer required per protocol, however assessments may be 
continued according to local clinical practice.
Following completion of the last durvalumab subject’s 90-day safety follow-up (data cutoff date 
06 Jun 2019) and discontinuation of the Follow-up Period, the CT scan assessments are no 
longer required to be performed and collected in the CRFs.
6.4.3.
Imaging by FDG-PET Scans
A FDG-PET scan (either as part of the integrated PET/CT or as a separate scan) using 
18F-fluorodeoxyglucose (18F-FDG) is required of all subjects at Screening. Follow-up scans 
will be performed to confirm a CR. A FDG-PET is to be performed at the end of the induction 
treatment, but before the start of the consolidation treatment.
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
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MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Confirmation of a CR during the induction period will be performed on Day 1 of the following 
cycle prior to the subsequent study treatment. This FDG-PET confirmatory scan is acceptable if 
performed up to 3 days prior to next treatment. Further evaluation by PET scans are optional and 
may be performed according to the scheduled CT scans to align with the efficacy response. 
A FDG-PET scan is to be performed at the following intervals: 

During Screening for a baseline image (within 28 days of C1D1).

Any time during the study treatment (within 14 days following demonstration of CR
by CT scan alone) to confirm CR.

End of induction treatment unless a FDG-PET-confirmed CR was previously 
documented in an earlier cycle.

End of treatment unless a FDG-PET-confirmed CR was previously documented in an 
earlier cycle.

The FDG-PET scans are optional at all other response assessment time points.
A positive FDG-PET scan is determined visually by comparing the intensity of the suspected 
area of malignancy to the intensity of activity in the mediastinal blood pool (Appendix B).
A dedicated contrast-enhanced CT scan may be required in addition to the FDG-PET to define 
the extent of disease in special situations, such as in the setting of lymphadenopathy close to 
bowel or if there is compression or thrombosis of blood vessels.
6.4.4.
Bone Marrow Biopsy and Aspirate 
Bone marrow biopsy (BMB) and aspirate (BMA) will be performed for diagnosis and efficacy 
assessments at:

Screening
Note: if a bone marrow sample was collected within 12 weeks of C1D1, that sample 
can be used.

Within 28 days of a suspected CR. This sample is necessary for confirmation of the
CR, except in subjects with no evidence of lymphomatous marrow involvement 
performed during Screening.
Note: If an FDG-PET is performed and confirms FDG-negative CR, no BMB/aspirate 
is required to confirm CR.
Neither BMB nor BMA samples are acceptable for the confirmation of the diagnosis or the 
determination of COO by the NanoString assay and should not be submitted to the Central 
Laboratory.
6.5.
Safety Assessments
Safety assessments include monitoring for AEs; physical examination; vital signs and body 
weight measurement; ECOG performance status; HBV screening; hematology (CBC with 
differential and platelets); serum chemistry; urinalysis; coagulation; serum immunoglobulins; 
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Protocol MEDI4736-DLBCL-001
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61
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concomitant medications and procedures; pregnancy testing (for FCBP only); cardiac function
and ECG.
Safety assessments will be performed during Screening and will be repeated weekly during 
Cycle 1, bi-weekly during Cycles 2 through 4, and once every 3 weeks during the induction 
treatment period and once every 4 weeks during the consolidation treatment period.
The assessment period for AEs begins when the subject signs the ICF. Adverse Events 
(including SPMs) will be assessed throughout the study until 90 days after the last dose of 
durvalumab or 28 days after the last dose of any other IP, whichever is later. Subjects treated 
with lenalidomide during any stage of the study will continued to be followed for SPM for up to 
5 years after enrollment (C1D1) of the last subject to receive lenalidomide as part of their study 
treatment.
Adverse events will be graded according to the National Cancer Institute-Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) version 4.03 unless otherwise specified in this 
document.
Tumor flare reaction (pseudoprogression) will be graded according to NCI-CTCAE version 3.0
(Table 9).
Tumor lysis syndrome will be assessed according to the Cairo-Bishop index (Appendix D).
Definitions for AEs and SAEs are found in Section 10.
6.5.1.
Safety Run-in Stage
This study includes a Safety Run-in Stage to evaluate the safety of the treatment combinations 
until at least 10 subjects are included. Following Partial Clinical Hold instituted by the US FDA 
which affects Arm B, the Safety Run-in Stage will evaluate safety of the treatment Arm A 
combinations when at least 10 subjects have been included into Arm A and have been treated for
at least one cycle of study treatment or discontinued prematurely.
The decision to continue enrollment into the Expansion Stage will occur at the discretion of the 
Sponsor following the evaluation of the Safety Run-in Stage by the SRC. This review will take 
place after at least 10 subjects have been enrolled into Arm A and have completed at least one 
cycle of study treatment or discontinued prematurely.
The Expansion Stage will start once study treatment is confirmed to be tolerable during the 
Safety Run-in Stage. Additional subjects up to the total sample size will be enrolled in the 
expansion phase to evaluate clinical activity as well as to further define the safety profile of the 
study treatments.
6.5.2.
Safety Review Committee
A SRC will be convened to evaluate the safety profile and tolerability of the Safety Run-in Stage
as well as potentially other safety data in this clinical study.
Following data review by the Sponsor and the SRC, it may be decided to proceed with only one 
treatment arm or to extend the Safety Run-in Stage with more subjects. Following Partial 
Clinical Hold instituted by the US FDA which affects Arm B, the Safety Run-in Stage will 
evaluate safety of the treatment Arm A combinations when at least 10 subjects have been 
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included into Arm A and have been treated for at least one cycle of study treatment or 
discontinued prematurely.
The SRC will continue to review safety data regularly throughout all phases of the study and 
make recommendations about study continuation and dose modifications for the IPs as 
appropriate. The SRC will also be informed about any relevant safety data available from other 
durvalumab studies. 
The SRC membership will be comprised of Investigators who are participating in the study and 
who have sufficient experience in early phase clinical studies in lymphoma, as well as the 
Celgene Medical Monitor and Drug Safety Physician. Other study team members (eg study 
statistician, clinical research scientist or trial safety manager) may also participate in SRC 
meetings as needed.
Operational details for the SRC will be detailed in a separate SRC charter.
6.6.
Pharmacokinetics (PK)
Blood collections for pharmacokinetic analysis of durvalumab blood levels are mandatory and 
will be performed on all subjects enrolled according to the sample collection schedule as outlined 
below.
During PK sampling days, dosing and sample collection information including dosing date, 
dosing time (24-hour clock; eg, 2:00 pm = 1400), and actual PK blood sampling time (24-hour 
clock) should be accurately documented on the appropriate CRF pages. All the sampling 
timepoints are relative to the durvalumab treatment administration schedule. For subjects on 
Treatment Arm B, the first sample collection of any visit treatment during induction therapy 
should precede lenalidomide dosing for that day.
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EDMS Doc. Number: 24223666 - 20700003
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6.7.
Immunogenicity 
Blood samples for immunogenicity analysis will be collected from all subjects. Samples will be 
collected between 5 and 30 minutes prior to administration of durvalumab.
On immunogenicity sampling days, dosing and sample collection information including dosing 
date, dosing time (24-hour clock), and actual immunogenicity blood sampling time (24-hour 
clock) should be accurately documented on the appropriate CRF pages.
Samples will be collected on Day 1 of Cycle 1 and Cycle 2, and then every second cycle (Day 1 
of Cycles 4, 6 and 8 [if applicable] of induction treatment and Day 1 of cycles 2, 4, 6 and 8 of 
consolidation treatment) until the end of durvalumab treatment, and the EOT visit (−30 to −5 
minutes prior to the very last dose of durvalumab). 
6.8.
Biomarkers, Pharmacodynamics and Pharmacogenomics
6.8.1.
Tumor Tissue Biopsy
The collection of tumor tissue is mandatory.
Table 4:
Tumor Tissue Biopsy Collection Time points for Biomarkers
Timepoints
Window
Requirement
Screeninga
Mandatory
During Treatment
C2D14 (±7 days) or
C3D14 (±7 days)
Required when clinically feasible
At time of PD in subjects who 
achieved a response (CR/PR)
Within 14 days of 
documented PD
Mandatory
Any available archival sample 
collected prior to study entry or 
unscheduled sample collected 
during the study
If available, submit to the Central 
Laboratory (strongly recommended)
CR = complete response, PD = progressive disease, PR = partial response
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aIt is required to submit Local Pathology reports (anonymized) associated with these tissue and diagnosis to Central 
Laboratory. For subjects with a poorly accessible tumor, an archival diagnostic lymph node/tumor FFPE biopsy 
sample, acquired by a surgical or core needle biopsy prior to signing the informed consent form, may be 
acceptable for enrollment.
Due to the required amount of tissue needed to perform the necessary analyses, tumor biopsies 
collected by tumor excision or incision are strongly preferred, however core needle biopsies 
(4 passages preferred) are acceptable if a surgical biopsy is not clinically feasible.
Other commonly used devices (eg, endoscopy forceps or grasp biopsy) are also acceptable 
provided they yield an equivalent amount of tumor tissue.
Material from a fine needle aspiration is not acceptable.
Tissue will be formalin fixed and submitted to the Central Laboratory in order to evaluate the 
tumor microenvironment as well as to identify predictive/Pd biomarkers.
In addition, it is strongly recommended to submit to the Central Laboratory any archival tumor 
biopsy samples collected prior to study entry or during the study at time points other than 
described above for biomarker analysis.
Note: Neither BMB nor BMA samples are acceptable for the confirmation of the diagnosis or the 
determination of COO by the NanoString assay and should not be submitted to the Central 
Laboratory.
Refer to the Laboratory Manual for a summary of tumor tissue specific assessments and material 
to be provided, sample collection and processing instructions.  
6.8.2.
Saliva and Blood Samples for Biomarker Assessments
Saliva, whole blood, and whole-blood derived sample specimens will be collected and analyzed 
to evaluate protein, nucleic acid and cellular biomarkers that relate to durvalumab, combination 
treatment and disease status according to the schedule presented in Table 3.
A saliva sample will be collected at Screening. Blood samples for biomarker analyses will be 
collected from all subjects to assess Pd, predictive, and/or disease-related markers. Biomarker 
blood samples will be collected during induction and consolidation treatments, according to the 
collection schedule described in Table 3. Samples are to be collected prior to treatment. Details 
for sample collection, processing, storage, and shipment will be provided in the Laboratory 
Manual.
6.8.3.
Gene Expression Analysis/NanoString Technology 
Gene expression profiling will be performed on NanoString’s nCounter® Analysis System with 
formalin-fixed paraffin-embedded (FFPE) biopsy material obtained during screening to identify 
the COO subtype for each eligible subject. Bone marrow tumor specimens (BMB or BMA) are 
not acceptable for this analysis.
The NanoString LST assay, which is based on the NanoString 20-gene assay for cell of origin 
subtyping in DLBCL, will be used in this current study. The LST assay profiles FFPE tissue 
using the previously reported 20-gene Lymph2Cx algorithm on the nCounter Dx analysis 
platform.
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
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MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
The NanoString 20-gene assay was verified against the original COO model defined by Lenz
(Lenz, 2008) using an independent cohort of 68 FFPE biopsies. In the validation cohort the assay 
was accurate and robust, with > 95% concordance of COO assignment between two independent 
laboratories (Scott, 2014b).   
6.9.
Subject Reported Outcomes or Quality of Life or Health Economics
Not applicable.
6.10.
Assessments After Primary Endpoint Was Met
Once the study has sufficient events for analysis of the primary endpoint of PFS, subjects will 
continue to be followed for subsequent anti-lymphoma treatments, including responses, and for 
the occurrence of any SPM.
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
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7.
DESCRIPTION OF STUDY TREATMENTS
This Phase 2, two-arm, open-label study is designed to evaluate durvalumab in combination with 
R-CHOP or in combination with R2-CHOP followed by durvalumab consolidation therapy in 
previously untreated subjects with high-risk DLBCL.
Subjects meeting the study eligibility criteria receive one cycle of induction therapy of 
durvalumab in combination with R-CHOP. Based on their DLBCL Cell-of-Origin subtype (ABC 
versus non-ABC) as determined by the NanoString LST assay before start of Cycle 2, subjects 
will then be allocated to one of two treatment arms from Cycle 2 onwards (or the cycle following 
COO determination). As a result of the US FDA Partial Clinical Hold, enrollment continued into 
Arm A only and new subjects received induction therapy (durvalumab + R CHOP) after Cycle 1 
regardless of DLBCL COO subtype. Enrollment into Arm B (durvalumab in combination with 
R2-CHOP) was discontinued. Subjects enrolled and treated in Arm B prior to the US FDA 
Partial Clinical Hold who were receiving clinical benefit, based on the discretion of the 
Investigator, could continue study treatment after being reconsented. 
Induction treatment will be administered until disease progression, unacceptable toxicity or the 
completion of induction treatment (6 to 8 cycles). Subjects completing induction treatment and 
achieving a CR (or a PR, see details on Section 7.2.3.1) will receive consolidation therapy 
comprised of durvalumab monotherapy for up to a total of 12 months from C1D1.
7.1.
Description of Investigational Product(s)
Investigational product supply will be managed by IRT. All IPs must be stored in accordance 
with the product label in a secured area to prevent unauthorized access. The IP will be labeled as 
per local regulations.
Required medications for neutropenia will be selected by the Investigator according to local 
practice and provided by the investigative site.
Recommended medications such as aspirin and allopurinol, if used, will be selected by the 
Investigator according to local practice and provided by the investigative site.
7.1.1.
Durvalumab
Durvalumab will be supplied by Celgene in single use vials in single count cartons. Each 10R 
(10 mL) vial will be supplied as a vialed liquid solution containing 500 mg (nominal) of 
durvalumab at a concentration of 50 mg/mL. Durvalumab should be stored in accordance with 
the product label.
Site will supply IV infusion bags with dilution solution and infusion lines with appropriate 
filters:

IV infusion bags of normal saline (0.9% [w/v] sodium chloride injection, 250 mL 
size) or dextrose (5% [w/v] dextrose injection, 250 mL). Saline or dextrose bags must 
be latex-free and can be made of polypropylene, polyethylene, polyolefin 
copolymers, or polyvinyl chloride. Infusion lines should contain a 0.2 to 0.22 μm 
in-line filter.  
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
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MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019

Since the compatibility of durvalumab with other IV medications and solutions, other 
than normal saline and dextrose, is not known, the durvalumab solution should not be 
infused through an IV line in which other solutions or medications are being 
administered.
For additional information on supplies, preparation and storage, please refer to the Pharmacy 
Manual.
7.1.2.
Lenalidomide
Lenalidomide will be supplied by Celgene in appropriate strengths for oral administration. 
Investigational product will contain a 14-day supply of lenalidomide. Lenalidomide should be 
stored in accordance to the product label. 
For additional information on preparation and storage please refer to the Pharmacy Manual, the 
Summary of Product Characteristics, or the IB. 
No newly enrolled subjects are to be treated with the combination of durvalumab, R-CHOP plus 
lenalidomide. Only those subjects currently enrolled and receiving clinical benefit, based on the 
discretion of the Investigator, are eligible to remain on treatment following reconsent.
7.1.3.
Rituximab
Celgene will provide commercial supplies, for countries where rituximab is designated as 
investigational product, labeled appropriately for investigational use as per the regulations of the 
relevant country health authority.  Subjects enrolled in countries where rituximab is not 
designated as investigational product, should obtain commercially available product through 
their local hospital pharmacy or licensed distributer.
Depending on local authorization, this protocol allows the use of:

Rituximab IV standard infusion time

Rituximab IV generics

Rituximab Subcutaneous (1400 mg/11.7 mL fixed dose; Hoffman-La Roche, 2016; 
Lugtenburg, 2015) 
The protocol does not allow the use of rituximab IV rapid infusion or other CD20 antibodies (eg
obinutuzumab, ofatumumab).
Please refer to the locally approved rituximab label or Pharmacy Manual for preparation, 
administration, or storage information, as well as for further information on rituximab including 
warnings, precautions, contraindications, and guidance on pregnancy prevention.
7.1.4.
Cyclophosphamide, Doxorubicin, Vincristine and Prednisone
The CHOP treatment regimen, will be administered to all subjects as a combination 
chemotherapy treatment of the following drugs: cyclophosphamide, doxorubicin, vincristine and 
prednisone/prednisolone.  
Celgene will provide commercial supplies, for countries where cyclophosphamide, doxorubicin, 
vincristine, and prednisone or prednisolone are designated as investigational product, labeled 
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
68
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
appropriately for investigational use as per the regulations of the relevant country health 
authority. For subjects enrolled in countries where cyclophosphamide, doxorubicin, vincristine, 
and prednisone or prednisolone are not designated as investigational product, commercially 
available product should be obtained through a local hospital pharmacy or licensed distributer.
Please refer to the locally approved product/prescribing information, the Summary of Product 
Characteristics or the IB for further information on cyclophosphamide, doxorubicin, vincristine 
and prednisone therapies including warning, precautions, and contraindications.
7.2.
Treatment Administration and Schedule
Information regarding prohibited, required, or recommended prophylactic treatments can be 
found in Section 8.
7.2.1.
Optional Pre-phase Treatment
Subjects with bulky disease (defined for this study as having one lesion with at least one 
diameter ≥ 7.0 cm), systemic symptoms, compressive disease, elevated bilirubin due to 
lymphoma, or rapidly progressing adenopathies may at the discretion of the Investigator receive
pre-phase treatment with 100 mg/day prednisone, or equivalent, for a maximum of 7 days prior 
to beginning the Treatment Period.
A washout period is not required. Pre-phase treatment may be immediately followed by 
prednisone as part of R-CHOP, and then a corticosteroid taper is allowed. However, the 
Screening PET, CT, lymph node biopsy, and bone marrow biopsy (and if applicable, also the 
bone marrow aspirate) should be completed before initiating corticosteroids.
Pre-phase treatment with vincristine or any other chemotherapy is prohibited.
7.2.2.
Pre-specify Post-Induction Radiotherapy
The Investigator may prospectively choose to give local radiotherapy after study chemotherapy 
for the treatment of a particular site of bulky disease or a large mass. In the case of consolidation 
treatment, bulky disease is defined as one lesion with at least one diameter ≥ 7.0 cm. However, 
the decision to treat and the location to be treated must be determined during the Screening 
Period, source documented, and registered in the IRT.
7.2.3.
Study Drug Treatment6:
Subjects who are eligible to participate in this study will receive one cycle of induction therapy 
of durvalumab in combination with R-CHOP. Subjects will then be allocated to one of two 
treatment arms from Cycle 2 onwards (or the cycle following COO determination) based on their 
DLBCL COO subtype. Eligible subjects for whom the COO has already been identified as ABC 
                                               
6 As a result of the US FDA Partial Clinical Hold, enrollment continued into Arm A only and new subjects received
induction therapy (durvalumab + R CHOP) after Cycle 1 regardless of DLBCL COO subtype. Enrollment into 
Arm B (durvalumab in combination with lenalidomide plus rituximab, cyclophosphamide, doxorubicin, 
vincristine, prednisone [R2-CHOP]) was discontinued. Subjects enrolled and treated in Arm B prior to the US 
FDA Partial Clinical Hold who were receiving clinical benefit, based on the discretion of the Investigator, could
continue study treatment after being reconsented. 
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
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subtype by NanoString LST assay before starting study treatment may have lenalidomide added 
starting with C1D1 onwards:

Arm A:
Durvalumab in combination with R-CHOP

Arm B7:
Durvalumab in combination with lenalidomide and R-CHOP
The induction period will last for either 6 or 8 cycles at the discretion of the treating Investigator,
or until unacceptable toxicity, disease progression, or withdrawal of consent.
Subjects for whom COO determination is inconclusive will continue treatment in study 
Treatment Arm A. Subjects for whom the COO is determined as ABC only after Cycle 2 will be 
allocated to Arm B whenever the results become available, however, missed cycles will not be 
made up. After the US FDA Partial Clinical Hold enrollment of new subjects into Arm B has 
been discontinued. If receiving clinical benefit at the discretion of the Investigator, subjects may 
continue treatment in Arm B after being reconsented. Any newly enrolled subject with DLBCL 
of ABC COO subtype after the US FDA Partial Clinical Hold will continue induction therapy on 
Arm A after Cycle 1.
Subjects tolerating treatment and achieving a CR (or PR, see Section 7.2.3.1) will continue 
consolidation treatment up to a total of 12 months from C1D1 as follows:

Arm A+B: Durvalumab monotherapy
More detailed information regarding the administration and schedule of the study treatments is 
found in the following sections.  
Dosing Sequence:
The following sequence of study treatment administration should be followed for each induction 
treatment cycle:
1. Durvalumab: Day 1 of each cycle should start with the administration of IV durvalumab 
followed by a 2-hour observation period post infusion.
2. Subsequently, rituximab is administered. Rituximab administration may be split over 
2 consecutive days according to local clinical practice. Rapid infusion of rituximab is not 
allowed in this clinical study.
3. This is followed by the administration of the CHOP chemotherapy.
4. This is followed by lenalidomide (Arm B only, ie from C2D1 onwards).
The method of administration, the dose and the timing of each study treatment drug is outlined 
below in Table 5.
                                               
7 As a result of the US FDA Partial Clinical Hold, enrollment continued into Arm A only and new subjects received 
induction therapy (durvalumab + R CHOP) after Cycle 1 regardless of DLBCL COO subtype. Enrollment into 
Arm B (durvalumab in combination with lenalidomide plus rituximab, cyclophosphamide, doxorubicin, 
vincristine, prednisone [R2-CHOP]) was discontinued. Subjects enrolled and treated in Arm B prior to the US 
FDA Partial Clinical Hold who were receiving clinical benefit, based on the discretion of the Investigator, could
continue study treatment after being reconsented. 
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
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Table 5:
Induction Treatment
Drug
Dose
Route of 
Administration
Dosing Days
(21-day 
cycle)
Dosing 
sequence
(Cycle Day 1)
Durvalumab
1125 mg
IV
1
1
Rituximab 
375 mg/m2
IV
1
2
Cyclophosphamide 
750 mg/m2
IV
1
3
Doxorubicin 
50 mg/m2
IV
1
Vincristine 
1.4 mg/m2
(up to 2.0 mg 
total)
IV
1
Prednisone / Prednisolone
a
100 mg
IV/ PO
1-5
Lenalidomide
From C2D1; Arm B only
(discontinued enrollment 
of new subjects)
15 mg 
PO
1-14
4
CHOP = cyclophosphamide, doxorubicin, vincristine and prednisone; IV = intravenous; PO = per os, oral 
administration.
a Prednisone/Prednisolone may be administered as an IV infusion or PO on Day 1 followed by PO administration on 
Days 2-5 of each cycle. Prednisone should be administered after lenalidomide dosing. For subjects on Treatment 
Arm A, prednisone may be given before the other drugs of the CHOP chemotherapy.
7.2.3.1.
Criteria for stopping induction treatment and for starting consolidation 
treatment
During and at the end of the induction treatment, the Investigator may initiate new anti-
lymphoma therapy if study treatment is discontinued because of an insufficient therapeutic 
response to the first-line induction therapy.
Subjects with a CR after the end of induction therapy will continue on consolidation treatment 
with durvalumab.
Subjects achieving a PR at the end of the induction treatment may be allowed to continue with 
consolidation therapy with durvalumab if the Investigator considers this to be clinically justified.
Subjects with a SD or PD after the end of induction therapy will discontinue the study treatment.
7.2.3.2.
Durvalumab (MEDI4736)
Durvalumab will be administered to all subjects, initiating on C1D1 for 6 to 8 cycles of 21-days
per cycle during the induction treatment at a fixed dose of 1125 mg as an IV infusion.  
During the consolidation treatment stage, durvalumab will be administered to all subjects as an 
IV infusion at 1500 mg on Day 1 of each 28-day cycle for up to a total of 12 months from C1D1
or until unacceptable toxicity, disease progression, or withdrawal of consent. 
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
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Durvalumab infusion will be administered before the IV infusion of any of the other study 
medications on Day 1. Please refer to the Pharmacy Manual for dose preparation and 
administration guidance.
Durvalumab treatment should be administered on Day 1 of each cycle without any drug hold 
unless approved by the Celgene Medical Monitor.
Note: Special monitoring requirements are associated with each infusion of durvalumab, both 
during and after the infusion:

Subjects will have their temperature, blood pressure and pulse measured before, 
during and after the infusion at the following times (based on a 60-minute infusion):

At the beginning of the infusion (at 0 minutes)

At 30 minutes during the infusion (±5 minutes)

At the end of the infusion (at 60 minutes ±5 minutes)

In the 2-hour observation period post-infusion: every 30 minutes (±5 minutes) 
after the infusion (ie, 90, 120, 150, and 180 minutes from the start of the infusion) 

If the infusion takes longer than 60 minutes, then temperature, blood pressure and 
pulse measurements should be collected every 30 minutes (±5 minutes) and as 
described above or more frequently if clinically indicated.
Dose modifications will be performed according to criteria found in Table 6, Table 7,
Table 8, Table 9 and Table 10. The dose may also be interrupted for toxicities not listed in those 
tables according to the clinical judgment of the Investigator. Refer to the SmPC or the IB for 
further information including warning, precautions, and contraindications.
7.2.3.3.
Lenalidomide
No new subjects are to be treated with the combination of durvalumab, R-CHOP plus 
lenalidomide. Only those subjects currently enrolled and receiving clinical benefit, based on the 
discretion of the Investigator, are eligible to remain on treatment following reconsent.
Lenalidomide treatment will be initiated for subjects allocated to Treatment Arm B during the 
induction treatment from Cycle 2 onwards (or the cycle following COO determination). 
Treatment will begin on C2D1 at a dose of 15 mg oral administration (PO) once daily for 
14 days of 21-days per cycle for 6 to 8 cycles. Eligible subjects for whom the COO has already 
been identified as ABC subtype by NanoString LST assay before starting study treatment, may 
have lenalidomide added starting with C1D1 onwards.8
On Day 1 of every cycle, lenalidomide will be administered in the clinic after the administration 
of durvalumab and R-CHOP. For subsequent dosing days, subjects should be instructed to take 
lenalidomide at approximately the same time each day as the Day 1 dosing for that cycle. There 
                                               
8 As a result of the US FDA Partial Clinical Hold, enrollment continued into Arm A only and new subjects received 
induction therapy (durvalumab + R CHOP) after Cycle 1 regardless of DLBCL COO subtype. Enrollment into 
Arm B (durvalumab in combination with lenalidomide plus rituximab, cyclophosphamide, doxorubicin, 
vincristine, prednisone [R2-CHOP]) was discontinuedSubjects enrolled and treated in Arm B prior to the US FDA 
Partial Clinical Hold who were receiving clinical benefit, based on the discretion of the Investigator, could
continue study treatment after being reconsented. 
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
72
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
is no requirement for taking lenalidomide with or without food, or with or without certain types 
of foods or liquids.
A 7-day rest period following the 14 days of dosing (Days 15-21 of each induction cycle) is 
mandatory. The rest period may be extended for toxicity as needed (Section 7.2.5.4).
If a subject misses a dose of lenalidomide and it is within 12 hours of their normal dosing time, 
the subject should be instructed to make up the missed dose, and to then take their next dose 
according to their regular schedule. Lenalidomide concentration is low at 12 hours post dose, 
therefore making up a missed dose and then resuming regular dosing with a greater than or equal 
to (≥) 12-hour interval between the two doses will not cause considerable drug accumulation.
Dose modifications will be performed according to criteria found in Table 13. The dose may also 
be modified for toxicities not listed in those tables based on the clinical judgment of the 
Investigator. Once a dose is reduced, re-escalation is not permitted. Refer to the Summary of 
Product Characteristics or the IB for further information including warning, precautions, and 
contraindications.
7.2.3.4.
Rituximab 
Rituximab will be administered at 375 mg/m2 BSA on Day 1 of each 21-day cycle for 6 to 8 
cycles as part of the R-CHOP treatment regimen. 
All dosage calculations for rituximab will be based on the subject’s BSA, using actual weight for 
calculations. This will be determined during the Screening Visit or on the first day of IP 
administration in Cycle 1 and will be calculated using the subject’s height and weight according 
to local pharmacy practice.
It is acceptable to use dose banding for rituximab or BSA capping at 2.0 mg/m2 as per local 
practice.
Furthermore, it is up to the discretion of the Pharmacist and Investigator whether BSA will be 
recalculated for each cycle of rituximab, or whether the BSA calculated prior to the first dose of 
rituximab will be used throughout the study. If BSA is recalculated, the same calculation method 
should be used throughout the study per subject.
Preparation, infusion rate, dose modification, and premedication should be performed according
to local approved rituximab prescribing guidelines. Rituximab administration may be split over 
2 consecutive days according to local clinical practice. Rapid infusion of rituximab is not 
allowed in this clinical study. Refer to approved product/prescribing information, Summary of 
Product Characteristics or the IB for further information, including warning, precautions, and 
contraindications.
7.2.3.5.
Cyclophosphamide 
Cyclophosphamide will be administered at 750 mg/m2 BSA on Day 1 of each 21-day cycle for 6 
to 8 cycles as part of the R-CHOP treatment regimen.
The cyclophosphamide dose may not be modified. Preparation and infusion rate are according to 
the package insert and local practice.
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
73
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Urotoxicity including hemorrhagic cystitis, pyelitis, ureteritis, and haematuria have been 
reported with cyclophosphamide therapy. Prior, during and immediately after the administration, 
adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the 
risk of urinary tract toxicity. Adequate treatment with mesna and/or strong hydration to force 
diuresis can markedly reduce the frequency and severity of bladder toxicity. Please refer to the 
cyclophosphamide prescribing information, the Summary of Product Characteristics or the IB for 
further details.
7.2.3.6.
Doxorubicin
Doxorubicin will be administered at 50 mg/m2 BSA on Day 1 of each 21-day cycle for 6 to 8 
cycles as part of the R-CHOP treatment regimen.
The doxorubicin dose may not be modified. No other anthracycline may be substituted for 
doxorubicin. Liposomal doxorubicin is not permitted. Preparation and infusion rate are according 
to the package insert and local practice. Refer to approved product/prescribing information, the 
Summary of Product Characteristics or the IB for further information including warning, 
precautions and contraindications.
7.2.3.7.
Vincristine
Vincristine will be administered at 1.4 mg/m2 BSA (recommended capping at 2 mg absolute 
dose) on Day 1 of each 21-day cycle for 6-8 cycles as part of the R-CHOP treatment regimen.
The vincristine dose may be modified according to Table 11 and Table 12. Preparation and 
infusion rate are according to the package insert and local practice. Refer to approved 
product/prescribing information, the Summary of Product Characteristics or the IB for further 
information including warning, precautions and contraindications.
7.2.3.8.
Prednisone
The prednisone start dose is a flat 100 mg PO or intravenous (IV) dose. Subsequent doses may 
be reduced for medical reasons at Investigator discretion.
Subjects should be instructed to take prednisone in the morning on scheduled dosing days. For 
subjects on Treatment Arm A, prednisone may be given before the other drugs of the CHOP 
chemotherapy.
In countries where prednisone is not available it will be acceptable to substitute prednisolone on 
a 1:1 basis for prednisone. It is also acceptable to administer the prednisone or prednisolone by 
IV rather than PO on Day 1 of the cycle for convenience. Refer to approved product/prescribing 
information, the Summary of Product Characteristics or the IB for further information including 
warning, precautions and contraindications.
7.2.4.
Required Criteria for Induction Treatment Cycles (Requalification Criteria)
All subjects who have met the Screening requirements and are not experiencing AEs requiring a 
dose hold or which the treating Investigator considers to compromise the safety of the study 
subject, are eligible to receive study treatment on C1D1.
Subsequent cycles with induction treatment may begin on the next scheduled Day 1 if all of the 
following Requalification Criteria are met:
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EDMS Doc. Number: 24223666 - 20700003
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Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
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
ANC ≥1,000 cells/mm³ (1.0 x 109/L), unless secondary to lymphoma bone marrow 
involvement per Investigator assessment.

Platelet count ≥ 75000 cells/mm³ (75 x 109/L), unless secondary to lymphoma bone 
marrow involvement per Investigator assessment.

All other toxicities have resolved to ≤ Grade 2.

A 7-day rest period has elapsed following the last dose of lenalidomide.
7.2.5.
Dose Modifications (Interruption/Reduction)
The guidelines for dose modifications and toxicity management are provided in the following 
sections. These guidelines prepared by the Sponsor are intended to assist the clinical judgment of 
Investigator in the appropriate medical management of these toxicities and should only be 
applied to those events related to the study treatments. Dose modifications must be recorded in 
the Study Drug Record case report form (CRF).
Dose modifications are permitted in any cycle for appropriate management of AEs. Dose 
reductions are allowed for lenalidomide and vincristine. No dose reductions are allowed for 
durvalumab or the other drugs of the R-CHOP regimen. Nonetheless, treatment may be 
interrupted or discontinued, or the infusion rate for any IV treatment may be changed at the 
discretion of the Investigator for severe infusion or allergic reactions, or other toxicities.
If the requalification criteria for subsequent treatments are not met (after the rest period has 
elapsed) on Day 1 of the new cycle, the subject will be evaluated every 7 days for 14 days. 
If the requalification criteria are met within 14 days, lenalidomide may be resumed or the 
Investigator may continue treatment without lenalidomide, if clinically appropriate.
Dose interruptions lasting beyond 21 days (> one cycle) should be discussed with the Celgene 
Medical Monitor.
Toxicity delays due to any drugs included in the R-CHOP regimen are allowed up to a maximum 
of two 14-day delays over the 6 to 8 cycle treatment duration. Should a delay be required for any 
one of the R-CHOP drugs, then the R-CHOP treatment must be delayed, with the exception of 
vincristine as described below.
If the criteria for the next treatment cycle are adequately met, but the subject develops peripheral 
neuropathy due to vincristine (Table 11), the Investigator may choose to skip the vincristine for 
the current cycle and resume vincristine on the defined R-CHOP schedule at the start of the next 
cycle. In this case, the skipped vincristine dose is not made up. If the subject cannot tolerate the 
lowest level of vincristine, it is acceptable to continue with the study drug treatment without 
vincristine.
If the requalification criteria are fulfilled, but the subject develops toxicity as described due to 
toxicities attributed to lenalidomide, durvalumab and R-CHOP should continue during the 
lenalidomide dose hold. If the requalification criteria are fulfilled, but the subject develops 
toxicity as described due to toxicities attributed durvalumab, R-CHOP should continue during 
the durvalumab dose hold. There is no maximum delay limit for lenalidomide which may be 
resumed later if the treatment criteria are met. Skipped doses of lenalidomide may not be made 
up and rest periods must be observed. 
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
75
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Subjects can discontinue any of the treatment regimens (durvalumab, lenalidomide or R-CHOP), 
and remain on study until completion of the scheduled consolidation treatment according to the 
following guidelines:

If subjects discontinue durvalumab treatment, they may continue to receive the 
complete regimen of either R-CHOP or R2-CHOP during induction treatment.

If the lowest dose of lenalidomide is not tolerated the subject will discontinue 
lenalidomide treatment. Subjects can remain on other remaining treatments should 
lenalidomide be discontinued.

If R-CHOP is discontinued, subjects may continue on durvalumab with or without 
lenalidomide until all scheduled treatments have been administered and then proceed 
into the durvalumab consolidation treatment.
Lenalidomide may be resumed once the requalification criteria are met; however, skipped doses 
of lenalidomide may not be made up, and the 7-day rest period requirement of each cycle must 
be observed.
Durvalumab treatment should be administered on Day 1 of each cycle without any drug hold 
unless discussed with and approved by the Celgene Medical Monitor.
Durvalumab and lenalidomide may be continued during the induction for the remaining protocol 
defined treatment period, if R-CHOP is discontinued, provided the above treatment criteria are 
otherwise met, and rest periods are observed.
7.2.5.1.
General Dose Modification Guidelines
Subjects will be evaluated for AEs at each visit using the NCI-CTCAE version 4.03 as a guide 
for severity grading, with the exception of TLS which will be graded according to the Cairo-
Bishop index which can be found in Appendix D (Cairo, 2004) and TFR which will be graded 
using NCI-CTCAE Version 3.0.
Dose modifications will not be required for AEs that are clearly not attributable to IPs (such as 
an accident) or for laboratory abnormalities that are not determined to be clinically significant. If 
an AE occurs, the Investigator should assess whether the AE is attributable to any of the IPs. If 
the AE is attributable to any IP based on the Investigator’s clinical judgment, then the 
Investigator will follow the dose modification guidelines for that causative IP(s) provided in 
Section 7.2.5.
7.2.5.2.
Dose Modification Guidelines for Durvalumab
Based on the mechanism of action of durvalumab leading to T-cell activation and proliferation, 
there is the possibility of observing immune-mediated AEs (imAEs) during the conduct of this 
study. Potential imAEs may be similar to those seen with the use of ipilimumab, BMS-936558, 
and BMS-936559 and may include immune-mediated enterocolitis, dermatitis, hepatitis, and 
endocrinopathies (Hodi, 2010; Brahmer, 2012; Topalian, 2012). Subjects should be monitored
for signs and symptoms of imAEs. In the absence of an alternate etiology (eg infection or disease 
progression), an immune-mediated etiology should be considered for signs or symptoms of 
enterocolitis, dermatitis, hepatitis, and endocrinopathy.  
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
76
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Dose reductions of durvalumab are not permitted. Dose modifications (ie, dose interruption, dose 
hold, or infusion rate modification) of durvalumab may be required in the event of treatment-
related toxicity as described in Table 6, Table 8, Table 9, and Table 10.
In addition to the dose modifications shown in Table 6, Table 8, Table 9, and Table 10, it is 
recommended that management of imAEs follow the guidelines outlined for ipilimumab 
(Weber, 2012). These guidelines recommend the following:
1. Subjects 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-mediated.
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 immunosuppressive therapies should be considered for events not 
responding to systemic steroids (eg infliximab, mycophenolate, etc).
If the Investigator has any question in regards to an AE being an imAE, the Investigator should 
immediately contact the Celgene Medical Monitor.
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
77
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 6:
General Dose Modification and Toxicity Management Guidelines for Immune-mediated Adverse Events
Immune-mediated Adverse Events – General Considerations
Dose Modifications
Toxicity Management
Immune-
mediated 
Adverse Events 
(Overall 
Management 
For toxicities 
not noted 
below)
Drug administration modifications of study drug/study regimen 
will be made to manage potential immune-mediated AEs based 
on severity of treatment-emergent toxicities graded per NCI 
CTCAE v4.03.
In addition to the criteria for permanent discontinuation of study 
drug/study 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/study regimen

Recurrence of a previously experienced Grade 3 treatment-
related AE following resumption of dosing
It is recommended that management of immune-mediated adverse 
events (imAEs) follows the guidelines presented in this table:
-
It is possible that events with an inflammatory or immune 
mediated mechanism could occur in nearly all organs, some of 
them not noted specifically in these guidelines.
-
Whether specific immune-mediated events (and/or laboratory 
indicators of such events) are noted in these guidelines or not, 
patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression, concomitant 
medications, and infections) to a possible immune-mediated 
event. In the absence of a clear alternative etiology, all such 
events should be managed as if they were immune related. 
General recommendations follow.
-
Symptomatic and topical therapy should be considered for 
low-grade (Grade 1 or 2, unless otherwise specified) events.
-
For persistent (>3 to 5 days) low-grade (Grade 2) or severe 
(Grade ≥3) events, promptly start prednisone 1 to 2 mg/kg/day 
PO or IV equivalent.
-
Some events with high likelihood for morbidity and/or mortality 
– eg, myocarditis, or other similar events even if they are not 
currently noted in the guidelines – should progress rapidly to 
high dose IV corticosteroids (methylprednisolone at 2 to 
4 mg/kg/day) even if the event is Grade 2, and if clinical 
suspicion is high and/or there has been clinical confirmation. 
Consider, as necessary, discussing with the Sponsor’s medical 
monitor, and promptly pursue specialist consultation.
-
If symptoms recur or worsen during corticosteroid tapering 
(28 days of taper), increase the corticosteroid dose (prednisone 
dose [eg, up to 2 to 4 mg/kg/day PO or IV equivalent]) until
stabilization or improvement of symptoms, then resume 
corticosteroid tapering at a slower rate (>28 days of taper).
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. Study drug/study regimen can be 
resumed once event stabilizes to Grade ≤1 after 
completion of steroid taper.
Subjects with endocrinopathies who may 
require prolonged or continued steroid 
replacement can be retreated with study 
drug/study regimen on the following 
conditions: 
1.
The event stabilizes and is controlled
2.
The patient is clinically stable as per 
Investigator or treating physician’s 
clinical judgement
3.
Doses of prednisone are at 
≤10 mg/day or equivalent
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
78
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 6:
General Dose Modification and Toxicity Management Guidelines for Immune-mediated Adverse Events
(Continued)
Immune-mediated Reactions
Dose Modifications
Toxicity Management
Grade 3
Depending on the individual toxicity, study 
drug/study regimen may be permanently 
discontinued. Please refer to guidelines below.
-
More potent immunosuppressives such as TNF inhibitors 
(eg, infliximab) (also refer to the individual sections of the 
imAEs for specific type of immunosuppressive) should be 
considered for events not responding to systemic steroids. 
Progression to use of more potent immunosuppressives should 
proceed more rapidly in events with high likelihood for 
morbidity and/or mortality – eg, myocarditis, or other similar 
events even if they are not currently noted in the guidelines –
when these events are not responding to systemic steroids.
-
With long-term steroid and other immunosuppressive use, 
consider need for Pneumocystis jirovecii pneumonia (PJP, 
formerly known as Pneumocystis carinii pneumonia) 
prophylaxis, gastrointestinal protection, and glucose monitoring.
-
Discontinuation of study drug/study regimen is not mandated for 
Grade 3/Grade 4 inflammatory reactions attributed to local tumor 
response (eg, inflammatory reaction at sites of metastatic disease 
and lymph nodes). Continuation of study drug/study regimen in 
this situation should be based upon a benefit-risk analysis for 
that patient.
Grade 4
Permanently discontinue study drug/study 
regimen 
Note: For Grade ≥3 asymptomatic amylase or lipase levels, hold 
study drug/study regimen, and if complete work up shows no 
evidence of pancreatitis, study drug/study regimen may be 
continued or resumed.
Note: Study drug/study regimen should be permanently 
discontinued in Grade 3 events with high likelihood for morbidity 
and/or mortality – eg, myocarditis, or other similar events even if 
they are not currently noted in the guidelines. Similarly, consider 
whether study drug/study regimen should be permanently 
discontinued in Grade 2 events with high likelihood for morbidity 
and/or mortality – eg, myocarditis, or other similar events even if 
they are not currently noted in the guidelines – when they do not 
rapidly improve to Grade <1 upon treatment with systemic 
steroids and following full taper.
Note: There are some exceptions to permanent discontinuation of 
study drug for Grade 4 events (i.e., hyperthyroidism, 
hypothyroidism, Type 1 diabetes mellitus)
AE = adverse event; CTC = Common Terminology Criteria; imAE = immune-mediated adverse event; IV = intravenous; NCI-CTCAE = National Cancer 
Institute Common Terminology Criteria for Adverse Events; PO = by mouth; TNF-α = tumor necrosis factor-alpha
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
79
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions
AE
CTC 
Grade/Severity
a
Dose Modifications
Toxicity Management
Pneumonitis/ 
Interstitial Lung 
Disease (ILD)
Any Grade
General Guidance
-
Monitor subjects for signs and symptoms of pneumonitis or ILD (new 
onset or worsening shortness of breath or cough).  Subjects should be 
evaluated with imaging and pulmonary function tests including other 
diagnostic procedures 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
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 will be 
based upon treating physician’s 
clinical judgment and after 
completion of steroid taper.
For Grade 2 (Mild to Moderate New Symptoms)
-
Monitor symptoms daily and consider hospitalization
-
Promptly start systemic steroids (eg, prednisone 1-2mg/kg/day PO or IV 
equivalent)
-
Reimaging as clinically indicated
-
If no improvement within 3-5 days, additional workup 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 methylprednisolone at 
2-4 mg/kg/day, promptly start immunosuppressive therapy such as TNF-α 
inhibitors (eg, infliximab at 5 mg/kg every 2 weeks). 
Note: It is important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab
-
Once improving, gradually taper steroids over ≥ 28 days and consider 
prophylactic antibiotics, antifungal or anti PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related infections [Category 2B 
recommendation]). a
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
80
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
CTC 
Grade/Severitya
Dose Modifications
Toxicity Management
Pneumonitis/ 
Interstitial Lung 
Disease (ILD)
-
Consider pulmonary and infectious disease consult
-
Consider as necessary discussing with the Sponsor’s 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 
[eg 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 to 4 mg/kg/day or 
equivalent
-
Obtain pulmonary and infectious disease consult; consider, as necessary, 
discussing with Sponsor’s medical monitor. Hospitalize the subject
-
Supportive Care (oxygen, etc.)
-
If no improvement within 3-5 days, additional workup should be 
considered and prompt treatment with additional immunosuppressive 
therapy such as TNF-α inhibitors (eg infliximab at 5 mg/kg every 2 
weeks’ dose) started
Note: rule out sepsis and refer to infliximab label for general guidance 
before using infliximab 
-
Once the patient is improving, gradually taper steroids over ≥28 days and 
consider prophylactic antibiotics, antifungals and in particular, anti-PJP 
treatment (please refer to current NCCN guidelines for treatment of 
cancer-related infections [Category 2B recommendation]). a
Diarrhea/ Colitis
Any Grade
General Guidance
-
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)
-
Subjects should be thoroughly evaluated to rule out any alternative 
etiology (eg disease progression, other medications, infections including 
testing for clostridium difficile toxin, etc.)
-
Steroids should be considered in the absence of clear alternative etiology, 
even for low grade events, in order to prevent potential progression to 
higher grade event
-
Use analgesics carefully; analgesics may mask symptoms of perforation 
and peritonitis
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
81
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
CTC 
Grade/Severitya
Dose Modifications
Toxicity Management
Diarrhea/ Colitis
Grade 1 
(Diarrhea: stool 
frequency of < 4 over 
baseline per day) 
(Colitis: 
asymptomatic; 
clinical or diagnostic 
observations only) 
No dose modification
For Grade 1 diarrhea: 
-
Close monitoring for worsening symptoms
-
Consider symptomatic treatment including hydration, electrolyte 
replacement, dietary changes (eg American Dietetic Association colitis 
diet), and loperamide. Use of probiotics as per treating physician’s clinical 
judgment
Grade 2
(Diarrhea: stool 
frequency of 4-6 over 
baseline per day) 
(Colitis: abdominal 
pain; mucus or blood
in stool) 
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 study 
drug/study regimen can be 
resumed after completion of 
steroid taper
For Grade 2 diarrhea: 
-
Consider symptomatic treatment including hydration, electrolyte 
replacement, dietary changes (eg American Dietetic Association colitis 
diet), and loperamide and/or budesonide 
-
Promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent 
-
If event is not responsive within 3-5 days or worsens despite prednisone at 
1-2 mg/kg/day PO or IV equivalent, GI consult should be obtained for 
consideration of further workup 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 3-5 days despite 2-4 mg/kg IV 
methylprednisolone, promptly start immunosuppressives such as 
(infliximab at 5 mg/kg once every 2 weeks) b Caution: It is important to 
rule out bowel perforation and refer to infliximab label for general 
guidance before using infliximab  
-
Consider, as necessary, discussing with Sponsor’s medical monitor if no 
resolution to ≤ Grade 1 in 3-4 days
-
Once improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals and anti-PJP treatment (please refer to 
current NCCN guidelines for treatment of cancer-related infections
[Category 2B recommendation]). a
1.0
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11.0
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Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
82
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
CTC 
Grade/Severitya
Dose Modifications
Toxicity Management
Diarrhea/ Colitis
Grade 3 or 4 
(Grade 3 diarrhea: 
stool frequency of 
≥7 over baseline 
per day; 
(Grade 4 diarrhea: 
life threatening 
consequences)
(Grade 3 colitis: 
severe abdominal 
pain, change in 
bowel habits, 
medical 
intervention indi-
cated, peritoneal 
signs;
(Grade 4 colitis: 
life-threatening 
consequences, 
urgent intervention 
indicated)
Grade 3
Permanently discontinue study 
drug/study regimen. for Grade 3 if 
toxicity does not improve to Grade 
≤1 within 14 days; study 
drug/study regimen can be 
resumed after completion of 
steroid taper.
Grade 4
Permanently discontinue 
study drug/study regimen.
For Grade 3 or 4 diarrhea:
-
Promptly initiate empiric IV methylprednisolone 2 to 4 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 3-5 days of IV methylprednisolone 2 to 
4 mg/kg/day or equivalent, promptly start further immunosuppressives 
(eg, infliximab at 5 mg/kg once every 2 weeks)
-
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 ≥28 days and consider 
prophylactic antibiotics, antifungals and anti-PJP treatment (please refer to 
current NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation]).a
Hepatitis 
(Elevated LFTs)
Infliximab 
should not be 
used for 
management of 
Immune Related
Hepatitis
Any Grade
General Guidance
-
Monitor and evaluate liver function test: AST, ALT, ALP and total 
bilirubin 
-
Evaluate for alternative etiologies (eg viral hepatitis, disease progression, 
concomitant medications)
1.0
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
83
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
CTC 
Grade/Severitya
Dose Modifications
Toxicity Management
Hepatitis 
(Elevated LFTs)
Infliximab 
should not be 
used for 
management of 
Immune Related
Hepatitis
Grade 1 
(AST or ALT >
ULN and <3.0 x 
ULN
and/or TB > 1.5 x 
ULN and <3.0 x 
ULN)
No dose modification
Upon worsening, treat as 
Grade 2 event
For Grade 1 AST or ALT and/or TB elevation       
Continue LFT monitoring per protocol
Grade 2 
(AST or 
ALT >3.0×ULN 
and ≤5.0×ULN 
and/or 
TB >1.5×ULN and   
≤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 toxicity improves to ≤ Grade 1 
or baseline, resume study 
drug/study regimen after 
completion of steroid taper
For Grade 2 AST or ALT and or TB elevation: 
-
Regular and frequent checking of LFTs (eg every 1-2 days) until elevations 
of these are improving or resolved
-
If no resolution to ≤ Grade 1 in 1-2 days, consider, as necessary, discussing 
with Sponsor’s medical monitor.If event is persistent (> 3-5 days) or 
worsens, promptly start prednisone 1-2 mg/kg/day PO or IV equivalent
-
If still no improvement within 3-5 days despite 1-2 mg/kg/day of 
prednisone PO or IV equivalent, consider additional workup and prompt 
treatment with IV methylprednisolone 2-4 mg/kg/day started
-
If still no improvement within 3-5 days despite 2-4 mg/kg/day of IV 
methylprednisolone, promptly start immunosuppressives (mycophenolate 
mofetil) b. Discuss with Sponsor’s medical monitor if mycophenolate 
mofetil is not available.  Infliximab should NOT be used
-
Once improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals and anti-PJP treatment (please refer to 
current NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation] ).a
Grade 3 
(AST or 
ALT >5.0×ULN 
and ≤20.0×ULN 
and/or TB 
>3.0×ULN and 
≤10.0×ULN)
For elevations in transaminases 
≤8 X ULN, or elevations in 
bilirubin ≤5X ULN 
-
Hold study drug/study 
regimen dose until 
resolution to ≤Grade 1 or 
baseline   
For Grade 3 or 4 AST or ALT and/or TB elevation:
-
Promptly initiate empiric IV methylprednisolone at 1-4 mg/kg/day or 
equivalent 
-
If still no improvement within 3-5 days despite 1-4 mg/kg/day 
methylprednisolone IV or equivalent, promptly start treatment with 
immunosuppressive therapy (mycophenolate mofetil).  Discuss with 
Sponsor’s medical monitor if mycophenolate motefil is not available. 
Infliximab should NOT be used
PLEASE 
SEE section
immediately 
below this 
section to 
find
guidance for
management 
of “Hepatitis 
(elevated 
LFTs)” in
HCC 
patients
1.0
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
84
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
CTC 
Grade/Severitya
Dose Modifications
Toxicity Management
Hepatitis 
(Elevated LFTs)
Infliximab 
should not be 
used for 
management of 
Immune Related
Hepatitis
-
Resume study drug/study 
regimen if elevations 
downgrade ≤ Grade 1 or 
baseline within 14 days and 
after completion of steroid 
taper
-
Permanently discontinue 
study drug/study regimen if 
the elevations do not
downgrade to ≤ Grade 1 or 
baseline within 14 days 
For elevations in transaminase 
> 8X ULN or elevations in 
bilirubin > 5X ULN, discontinue 
study drug/study regimen
Permanently discontinue study 
drug/study regimen for any 
case meeting Hy’s law (ALT 
and/or AST > 3X ULN and 
bilirubin > 2X ULN criteria
without initial findings of 
cholestasis [ie, elevated ALP] 
and in the absence of any 
alternative cause
b)
-
Perform hepatology consult, abdominal workup, and imaging as 
appropriate.
-
Once improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals and anti-PJP treatment (please refer to 
current NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation]). a
Grade 4 
(AST or 
ALT >20×ULN 
and/or 
TB >10×ULN)
Permanently discontinue study 
drug/study regimen 
PLEASE 
SEE section
immediately 
below this 
section to 
find
guidance for
management 
of “Hepatitis 
(elevated 
LFTs)” in
HCC 
patients 
1.0
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1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
85
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
CTC 
Grade/Severitya
Dose Modifications
Toxicity Management
Hepatitis 
(Elevated LFTs)
Infliximab should not 
be used for 
management of 
Immune Related
Hepatitis
See instructions at 
bottom of shaded area 
if transaminase rise is 
not isolated but (at any 
time) occurs in setting 
of either increasing 
bilirubin or signs of 
DILI/liver 
decompensation
Any Grade
General Guidance
For Any Grade:
−
Monitor and evaluate liver function test: AST, ALT, ALP, and TB.
−
Evaluate for alternative etiologies (eg, viral hepatitis, disease progression, 
concomitant medications, worsening of liver cirrhosis [eg, portal vein 
thrombosis]).
−
For HBV+ patients: evaluate quantitative HBV viral load, quantitative HBsAg, 
or HBeAg
−
For HCV+ patients: evaluate quantitative HCV viral load
−
Consider consulting hepatologist/Infectious disease specialist regarding 
change/implementation in/of antiviral medications for any patient with an 
elevated HBV viral load >2000 IU/ml
−
Consider consulting hepatologist/Infectious disease specialist regarding 
change/implementation in/of antiviral HCV medications if HCV viral load 
increased by ≥2-fold
−
For HCV+ with HBcAB+: Evaluate for both HBV and HCV as above
Grade 1
(Isolated AST or 
ALT >ULN and 
≤5.0×ULN, 
whether normal or 
elevated at 
baseline) 
-
No dose modifications.
-
If ALT/AST elevations 
represents significant 
worsening based on 
Investigator assessment, then 
treat as Grade 2 event.
For all grades, see instructions at 
bottom of shaded area if 
transaminase rise is not isolated but 
(at any time) occurs in setting of 
either increasing bilirubin or signs 
of DILI/liver decompensation
THIS section
provides guidance
only for
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
ti
t
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
86
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
CTC 
Grade/Severitya
Dose Modifications
Toxicity Management
Hepatitis 
(Elevated LFTs)
Infliximab should not 
be used for 
management of 
Immune Related
Hepatitis
See instructions at 
bottom of shaded area 
if transaminase rise is 
not isolated but (at any 
time) occurs in setting 
of either increasing 
bilirubin or signs of 
DILI/liver 
decompensation
Grade 2
(Isolated AST or 
ALT >5.0×ULN 
and ≤8.0×ULN, if 
normal at 
baseline)
(Isolated AST or 
ALT 
>2.0×baseline and 
≤12.5×ULN, if 
elevated >ULN at 
baseline)
-
Hold study drug/study regimen 
dose until Grade 2 resolution to 
Grade ≤1 or baseline.
-
If toxicity worsens, then treat as 
Grade 3 or Grade 4.
If toxicity improves to Grade ≤1 or 
baseline, resume study drug/study 
regimen after completion of steroid 
taper.
For Grade 2:
−
Regular and frequent checking of LFTs (eg, every 1 to 3 days) until elevations of 
these are improving or resolved.
−
Recommend consulting hepatologist; consider abdominal ultrasound, including 
Doppler assessment of liver perfusion.
−
Consider, as necessary, discussing with Sponsor’s medical monitor.
−
If event is persistent (>3 to 5 days) or worsens, and Investigator suspects toxicity to 
be immune-mediated AE, recommend to start prednisone 1 to 2 mg/kg/day PO or 
IV equivalent.
−
If still no improvement within 3 to 5 days despite 1 to 2 mg/kg/day of prednisone 
PO or IV equivalent, consider additional workup and treatment with IV 
methylprednisolone 2 to 4 mg/kg/day.
−
If still no improvement within 3 to 5 days despite 2 to 4 mg/kg/day of IV 
methylprednisolone, consider additional abdominal workup (including liver biopsy) 
and imaging (i.e., liver ultrasound), and consider starting immunosuppressives (i.e., 
mycophenolate mofetil)a. Discuss with Sponsor’s medical monitor if 
mycophenolate mofetil is not available. Infliximab should NOT be used.
Grade 3
(Isolated AST or 
ALT >8.0×ULN 
and ≤20.0×ULN, 
if normal at 
baseline)
(Isolated AST or 
ALT >12.5×ULN 
and ≤20.0×ULN, 
if elevated >ULN 
at baseline)
-
Hold study drug/study regimen 
dose until resolution to Grade ≤1 
or baseline
-
Resume study drug/study 
regimen if elevations downgrade 
to Grade ≤1 or baseline within 
14 days and after completion of 
steroid taper.
-
Permanently discontinue study 
drug/study regimen if the 
elevations do not downgrade to 
Grade ≤1 or baseline within 
14 days
-
Permanently discontinue study 
drug/study regimen for any case 
meeting Hy’s law criteria, in the 
absence of any alternative 
cause.b
For Grade 3:
−
Regular and frequent checking of LFTs (eg, every 1-2 days) until elevations of 
these are improving or resolved.
−
Consult hepatologist (unless Investigator is hepatologist); obtain abdominal 
ultrasound, including Doppler assessment of liver perfusion; and consider liver 
biopsy.
−
Consider, as necessary, discussing with Sponsor’s medical monitor.
−
If Investigator suspects toxicity to be immune-mediated, promptly initiate empiric 
IV methylprednisolone at 1 to 4 mg/kg/day or equivalent.
−
If no improvement within 3 to 5 days despite 1 to 4 mg/kg/day methylprednisolone 
IV or equivalent, obtain liver biopsy (if it has not been done already) and promptly 
start treatment with immunosuppressive therapy (mycophenolate mofetil). Discuss 
with Sponsor’s medical monitor if mycophenolate motefil is not available. 
Infliximab should NOT be used.
−
Once the patient is improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP treatment (refer to current 
THIS section
provides guidance
only for
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
ti
t
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
87
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-Mediated Reactions (Continued)
AE
CTC Grade/Severitya
Dose Modifications
Toxicity Management
Hepatitis 
(Elevated LFTs)
Infliximab should not 
be used for 
management of 
Immune Related
Hepatitis
See instructions at 
bottom of shaded area 
if transaminase rise is 
not isolated but (at any 
time) occurs in setting 
of either increasing 
bilirubin or signs of 
DILI/liver 
decompensation
NCCN guidelines for treatment of cancer-related infections [Category 2B 
recommendation]).a
Grade 4
(Isolated AST or ALT 
>20×ULN,  whether 
normal or elevated at 
baseline)
Permanently discontinue 
study drug/study regimen.
For Grade 4:
Same as above  (except would recommend obtaining liver biopsy early)
If transaminase rise is not isolated but (at any time) occurs in setting of either increasing total/direct bilirubin (≥1.5×ULN, if normal at baseline; or 2×baseline, if 
>ULN at baseline) or signs of DILI/liver decompensation (eg, fever, elevated INR):
-
Manage dosing for Grade 1 transaminase rise as instructed for Grade 2 transaminase rise
-
Manage dosing for Grade 2 transaminase rise as instructed for Grade 3 transaminase rise
Grade 3-4: Permanently discontinue study drug/study regimen
THIS section
provides guidance
only for
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
ti
t
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
88
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
CTC 
Grade/Severitya
Dose Modifications
Toxicity Management
Nephritis or 
Renal 
Dysfunction 
(Elevated Serum 
Creatinine)
Any Grade
General Guidance
-
Consult with Nephrologist
-
Monitor for signs and symptoms that may be related to changes in renal 
function (eg, routine urinalysis, elevated serum BUN and creatinine, 
decreased creatinine clearance, electrolyte imbalance, decrease in urine 
output, proteinuria, etc.) 
-
Subjects should be thoroughly evaluated to rule out any alternative 
etiology (eg, disease progression, infections etc.)
-
Steroids should be considered in the absence of clear alternative etiology 
even for low grade events (Grade 2), in order to prevent potential 
progression to higher grade event
Grade 1:
Serum Creatinine 
> 1-1.5 x baseline;  
> ULN-1.5 x ULN
No dose modification
For Grade 1: 
Monitor serum creatinine weekly and any accompanying symptom
-
If creatinine returns to baseline, resume its regular monitoring per study 
protocol.
-
Upon worsening treat according to severity 
-
Consider symptomatic treatment including hydration, electrolyte 
replacement, diuretics, etc.
Grade 2 
Serum Creatinine 
> 1.5-3.0 x
baseline; 
> 1.5 x-3.0 x ULN
Hold study drug/study regimen 
until resolution to ≤Grade 1 or 
baseline
-
If toxicity worsens then treat
as Grade 3 or Grade 4
-
If toxicity improves to 
≤Grade 1 or baseline then 
resume study drug/study 
regimen after completion of 
steroid taper   
For Grade 2: 
-
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 PO or IV equivalent
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
89
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
CTC 
Grade/Severitya
Dose Modifications
Toxicity Management
Nephritis or 
Renal 
Dysfunction 
(Elevated Serum 
Creatinine)
-
If event is not responsive within 3-5 days or worsens despite prednisone at 
1-2 mg/kg/day PO 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 ≥28 days and consider 
prophylactic antibiotics, antifungals and anti-PJP treatment (please refer to 
current NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation] ).a
-
Once serum creatinine returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per study protocol
Grade 3 or 4 
Grade 3: 
Serum Creatinine 
> 3.0 x baseline; 
> 3.0-6.0 x ULN
Grade 4: 
Serum Creatinine 
> 6.0 x ULN)
Permanently discontinue IP/study 
regimen
For Grade 3-4: 
-
Carefully monitor serum creatinine on daily basis
-
Consult nephrologist and consider renal biopsy if clinically indicated
-
Promptly start prednisone 1-2 mg/kg/day PO or IV equivalent 
-
If event is not responsive within 3-5 days or worsens despite prednisone at 
1-2 mg/kg/day PO or IV equivalent, additional workup should be 
considered and prompt treatment with IV methylprednisolone 
2-4 mg/kg/day started
-
Once improving, gradually taper steroids over ≥ 28 days and consider 
prophylactic antibiotics, antifungals and anti-PJP treatment (please refer to 
current NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation]). a
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
90
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
CTC 
Grade/Severitya
Dose Modifications
Toxicity Management
Rash (excluding 
bullous skin 
formations)
Grade of Skin Rash 
General Guidance
-
Monitor for signs and symptoms of dermatitis (rash and pruritus) 
-
**IN THE EVENT OF ANY BULLOUS FORMATION, THE 
SPONSOR’S MEDICAL MONITOR SHOULD BE CONTACTED 
AND STUDY DRUG DISCONTINUED**
Grade 1 
No dose modification
For Grade 1:
-
Consider symptomatic treatment including oral antipruritics (eg,
diphenhydramine or hydroxyzine) and topical therapy (eg, urea cream)
Grade 2
If persistent (> 1-2 weeks) at 
Grade 2, hold scheduled study 
drug/study regimen until 
resolution to ≤ Grade 1 or baseline 
-
If toxicity worsens then treat 
as Grade 3 
-
If toxicity improves to Grade 
≤1 or baseline then resume 
study drug/study regimen
after completion of steroid 
taper
For Grade 2:
-
Obtain dermatology consult 
-
Consider symptomatic treatment including oral antipruritics (eg,
diphenhydramine or hydroxyzine) and topical therapy (eg, 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 study medical monitor and promptly start 
systemic steroids at 1-2 mg/kg/day PO or IV equivalent  
-
Consider skin biopsy if persistent for > 1-2 weeks or subject experiences 
recurrence
Grade 3
Hold study drug/study regimen 
until resolution to ≤Grade 1 or 
baseline
-
If rash does not improve to 
≤Grade 1 or baseline within 
30 days, then permanently 
discontinue Study drug/study 
regimen
For Grade 3 or 4:
-
Consult dermatologist 
-
Promptly initiate empiric IV methylprednisolone 1-4 mg/kg/day or 
equivalent
-
Consider hospitalization
-
Monitor extent of rash (Rule of Nines)
-
Consider skin biopsy (preferably more than 1) as clinically feasible.
-
Once improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals and anti-PJP treatment (please refer to 
current NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation]). a
-
Consider, as necessary, discussing with Sponsor’s medical monitor
Grade 4
Permanently discontinue study 
drug/study regimen 
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
91
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
CTC 
Grade/Severitya
Dose Modifications
Toxicity Management
Endocrinopathy 
(eg,
hyperthyroidism, 
hypothyroidism, 
Type 1 diabetes 
mellitus, 
hypophysitis, 
hypopituitarism, 
and adrenal 
insufficiency; 
exocrine event of 
amylase/lipase 
increased also 
included in this 
section)
Any Grade 
(depending on the 
type of 
endocrinopathy, 
refer to NCI
CTCAE v4.03 for 
defining the CTC 
grade/severity)
General Guidance
-
Consider consulting an endocrinologist for endocrine events.
-
Consider, as necessary, discussing with Sponsor’s medical monitor.
-
Monitor patients for signs and symptoms of endocrinopathies. Non-
specific symptoms include headache, fatigue, behaviour changes, changed 
mental status, vertigo, abdominal pain, unusual bowel habits, polydipsia, 
polyuria, hypotension, and weakness.
-
Patients should be thoroughly evaluated to rule out any alternative 
etiology (eg, disease progression including brain metastases, or 
infections).
-
Depending on the suspected endocrinopathy, monitor and evaluate thyroid 
function tests: TSH, free T3 and free T4 and other relevant endocrine and 
related labs (eg, blood glucose and ketone levels, HgA1c).
-
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 a patient experiences an AE that is thought to be possibly of 
autoimmune nature (eg, thyroiditis, pancreatitis, hypophysitis, or diabetes 
insipidus), the Investigator should send a blood sample for appropriate 
autoimmune antibody testing.
Grade 1
No dose modification
For Grade 1: (including those with asymptomatic TSH elevation):
-
Monitor patient with appropriate endocrine function tests.
-
For suspected hypophysitis/hypopituitarism, consider consultation of an 
endocrinologist to guide assessment of early-morning ACTH, cortisol, 
TSH and free T4; also consider gonadotropins, sex hormones, and 
prolactin levels, as well as cosyntropin stimulation test (though it may not 
be useful in diagnosing early secondary adrenal insufficiency).
-
If TSH < 0.5 × LLN, or TSH >2 × ULN, or consistently out of range in 2 
subsequent measurements, include free T4 at subsequent cycles as 
clinically indicated and consider consultation of an endocrinologist.
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
92
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
CTC 
Grade/Severitya
Dose Modifications
Toxicity Management
Endocrinopathy 
(eg,
hyperthyroidism, 
hypothyroidism, 
Type 1 diabetes 
mellitus, 
hypophysitis, 
hypopituitarism, 
and adrenal 
insufficiency; 
exocrine event of 
amylase/lipase 
increased also 
included in this 
section
Grade 2
For Grade 2 endocrinopathy other 
than hypothyroidism and Type 1 
diabetes mellitus, hold study 
drug/study regimen dose until 
patient is clinically stable.
If toxicity worsens, then treat as 
Grade 3 or Grade 4.
Study drug/study regimen can be 
resumed once event stabilizes and 
after completion of steroid taper
Subjects with endocrinopathies 
who may require prolonged or 
continued steroid replacement (eg, 
adrenal insufficiency) can be 
retreated with study drug/study 
regimen on the following 
conditions:
1.
The event stabilizes and is 
controlled.
2.
The patient is clinically stable 
as per Investigator or treating 
physician’s clinical 
judgement.
Doses of prednisone are 
≤10 mg/day or equivalent
For Grade 2 (including those with symptomatic endocrinopathy):
−
Consult endocrinologist to guide evaluation of endocrine function and, as 
indicated by suspected endocrinopathy and as clinically indicated, 
consider pituitary scan.
−
For all patients with abnormal endocrine work up, except those with 
isolated hypothyroidism or Type 1 DM, and as guided by an 
endocrinologist, consider short-term corticosteroids (eg, 1 to 2 mg/kg/day 
methylprednisolone or IV equivalent) and prompt initiation of treatment 
with relevant hormone replacement (eg, hydrocortisone, sex hormones).
−
Isolated hypothyroidism may be treated with replacement therapy, without 
study drug/study regimen interruption, and without corticosteroids.
−
Isolated Type 1 diabetes mellitus (DM) may be treated with appropriate 
diabetic therapy, without study drug/study regimen interruption, and 
without corticosteroids.
−
Once patients on steroids are improving, gradually taper 
immunosuppressive steroids (as appropriate and with guidance of 
endocrinologist) over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (please refer to current NCCN 
guidelines for treatment of cancer-related infections [Category 2B 
recommendation]). a
- For patients with normal endocrine workup (laboratory assessment or MRI 
scans), repeat laboratory assessments/MRI as clinically indicated.
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
93
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
CTC 
Grade/Severitya
Dose Modifications
Toxicity Management
Endocrinopathy 
(eg,
hyperthyroidism, 
hypothyroidism, 
Type 1 diabetes 
mellitus, 
hypophysitis, 
hypopituitarism, 
and adrenal 
insufficiency; 
exocrine event of 
amylase/lipase 
increased also 
included in this 
section
Grade 3 or 4
For Grade 3 or 4 endocrinopathy 
other than hypothyroidism and 
Type 1 diabetes mellitus, hold 
study drug/study regimen dose 
until endocrinopathy symptom(s) 
are controlled. 
Study drug/study regimen can be 
resumed once event stabilizes and 
after completion of steroid taper.
Patients with endocrinopathies 
who may require prolonged or 
continued steroid replacement (eg, 
adrenal insufficiency) can be 
retreated with study drug/study 
regimen on the following
conditions:
1.
The event stabilizes and is 
controlled.
2.
The patient is clinically stable 
as per Investigator or treating 
physician’s clinical 
judgement.
Doses of prednisone are 
≤10 mg/day or equivalent.
For Grade 3 or 4:
−
Consult endocrinologist to guide evaluation of endocrine function 
and, as indicated by suspected endocrinopathy and as clinically 
indicated, consider pituitary scan. Hospitalization recommended.
−
For all patients with abnormal endocrine work up, except those with 
isolated hypothyroidism or Type 1 DM, and as guided by an 
endocrinologist, promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent, as well as relevant hormone replacement 
(eg, hydrocortisone, sex hormones).
−
For adrenal crisis, severe dehydration, hypotension, or shock, 
immediately initiate IV corticosteroids with mineralocorticoid 
activity.
−
Isolated hypothyroidism may be treated with replacement therapy, 
without study drug/study regimen interruption, and without 
corticosteroids.
−
Isolated Type 1 diabetes mellitus may be treated with appropriate 
diabetic therapy, without study drug/study regimen interruption, and 
without corticosteroids.
−
Once patients on steroids are improving, gradually taper 
immunosuppressive steroids (as appropriate and with guidance of 
endocrinologist) over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (please refer to current NCCN 
guidelines for treatment of cancer-related infections [Category 2B 
recommendation]). a
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
94
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
CTC 
Grade/Severitya
Dose Modifications
Toxicity Management
Neurotoxicity 
(including but not 
limited to limbic 
encephalitis. 
autonomic 
neuropathy, 
excluding 
myasthenia 
gravis and 
Guillain-Barre 
Syndrome)  
Any Grade 
(depending on the 
type of 
neurotoxicity, refer 
to NCI CTCAE 
v4.03 for defining 
the CTC 
grade/severity)
General Guidance
For Any Grade:
-
Patients should be evaluated to rule out any alternative etiology (eg, disease 
progression, infections, metabolic syndromes, or medications).
-
Monitor patient for general symptoms (headache, nausea, vertigo, behavior 
change, or weakness).
-
Consider appropriate diagnostic testing (eg, electromyogram and nerve 
conduction investigations).
-
Perform symptomatic treatment with neurological consult as appropriate
Grade 1
No dose modifications
See “Any Grade” recommendations above
Grade 2
For acute motor neuropathies or 
neurotoxicity, hold study drug/study 
regimen dose until resolution to ≤Grade 1
For sensory neuropathy/ neuropathic pain, 
consider holding study drug/study regimen 
dose until resolution to ≤ Grade 1
If toxicity worsens then treat as Grade 3 or 
Grade 4 Study drug/study regimen can be 
resumed once event stabilizes to Grade ≤1 
and after completion of steroid taper   
For Grade 2:
- Consider, as necessary, discussing with the Sponsor’s medical monitor
- Obtain Neurology Consult 
- Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (eg gabapentin, duloxetine, etc.)
- Promptly start systemic steroids prednisone 1-2 mg/kg/day PO or IV 
equivalent 
- If no improvement within 3-5 days despite 1-2 mg/kg/day prednisone 
PO or IV equivalent consider additional workup and promptly treat 
with additional immunosuppressive therapy (eg IVIG)
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.
For Grade 4:
- Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4:
- Consider, as necessary, discussing with the Sponsor’s medical monitor
Obtain Neurology Consult
- Consider hospitalization
- Promptly initiate empiric IV methylprednisolone 1-2 mg/kg/day or 
equivalent
- If no improvement within 3-5 days despite IV corticosteroids, 
consider additional workup and promptly treat with additional 
immunosuppressants (eg IVIG) 
- Once stable, gradually taper steroids over ≥28 days
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
95
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
CTC 
Grade/Severitya
Dose Modifications
Toxicity Management
Peripheral 
neuromotor 
syndromes, such 
as Guillain-Barre 
and myasthenia 
gravis
Any Grade
General Guidance
- The prompt diagnosis of immune-mediated peripheral neuromotor 
syndromes is important, since certain subjects 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
- Subjects should be evaluated to rule out any alternative etiology (eg
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 subjects 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 (eg 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 
- Subjects requiring treatment should be started with IVIG and 
followed by plasmapheresis if not responsive to IVIG 
Grade 1
No dose modification
For Grade 1
-
Consider, as necessary, discussing with the Sponsor’s medical monitor.
Care should be taken to monitor subjects for sentinel symptoms of a 
potential decompensation as described above
-
Obtain a neurology consult 
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
96
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
CTC 
Grade/Severitya
Dose Modifications
Toxicity Management
Peripheral 
neuromotor 
syndromes, such 
as Guillain-Barre 
and myasthenia 
gravis
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
For Grade 2 
- Consider, as necessary, discussing with the Sponsor’s medical monitor. Care 
should be taken to monitor subjects for sentinel symptoms of a potential 
decompensation as described above
- Obtain a neurology consult 
- Sensory neuropathy/neuropathic pain may be managed by appropriate 
medications (eg 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.
- Subjects 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 subject.
- 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
Subjects requiring treatment should be started with IVIG and followed by 
plasmapheresis if not responsive to IVIG
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 or autonomic 
instability
For Grade 3 or 4
- Consider, as necessary, discussing with the Sponsor’s medical monitor.
Recommend hospitalization
- Monitor symptoms and obtain neurological consult
MYASTHENIA GRAVIS
- Steroids may be successfully used to treat myasthenia gravis.  It should 
typically be administered in a monitored setting under supervision of a 
consulting neurologist.
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
97
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
CTC 
Grade/Severitya
Dose Modifications
Toxicity Management
Peripheral 
neuromotor 
syndromes, such 
as Guillain-Barre 
and myasthenia 
gravis
Grade 4
Permanently discontinue study 
drug/study regimen 
- Subjects unable to tolerate steroids may be candidates for treatment with 
plasmapheresis or IVIG.
- 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: 
Subjects requiring treatment should be started with IVIG and followed by 
plasmapheresis if not responsive to IVIG
Myocarditis
Any Grade
General Guidance
Discontinue drug permanently if 
biopsy-proven immune-mediated 
myocarditis
For Any Grade:
−
The prompt diagnosis of immune-mediated myocarditis is important, 
particularly in patients with baseline cardiopulmonary disease and 
reduced cardiac function. 
−
Consider, as necessary, discussing with the Sponsor’s medical 
monitor.
−
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 (eg, pulmonary embolism, congestive heart failure, 
malignant pericardial effusion). A Cardiology consultation should be 
obtained early, with prompt assessment of 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 (eg, disease progression, other medications, or infections)
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
98
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
CTC 
Grade/Severitya
Dose Modifications
Toxicity Management
Myocarditis
Grade 1
(asymptomatic with 
laboratory (eg, 
BNP) or cardiac 
imaging 
abnormalities)
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.
For Grade 1 (no definitive findings):
-
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
(Grade 2: 
Symptoms with 
mild to moderate 
activity or exertion)
(Grade 3: Severe 
with symptoms at 
rest or with 
minimal activity or 
exertion; 
intervention 
indicated)
(Grade 4: Life-
threatening 
consequences; 
urgent intervention 
indicated (eg, 
continuous IV 
therapy or 
mechanical 
hemodynamic 
support)
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.
For Grade 2-4:
−
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 (eg, oxygen).
−
If no improvement within 3 to 5 days despite IV methylprednisolone 
at 2 to 4 mg/kg/day, promptly start immunosuppressive therapy such 
as TNF inhibitors (eg, infliximab at 5 mg/kg every 2 weeks). Caution: 
It is important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab.
−
Once the patient is improving, gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, antifungals, or anti-PJP 
treatment (please refer to current NCCN guidelines for treatment of 
cancer-related infections [Category 2B recommendation]). a
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
99
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-Mediated Reactions (Continued)
AE
CTC 
Grade/Severitya
Dose Modifications
Toxicity Management
Myositis/
Polymyositis 
(“Poly/myositis”)
Any Grade
General Guidance
For 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 Sponsor’s medical monitor.
−
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 (eg, disease progression, other medications, or infections)
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
100
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-Mediated Reactions (Continued)
AE
CTC 
Grade/Severitya
Dose Modifications
Toxicity Management
Myositis/
Polymyositis 
(“Poly/myositis”)
Grade 1
(mild pain)
No dose modifications.
For Grade 1:
−
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 Sponsor’s medical monitor.
Grade 2
(moderate pain 
associated with 
weakness; pain 
limiting 
instrumental 
activities of daily 
living [ADLs])
- 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.
For Grade 2:
−
Monitor symptoms daily and consider hospitalization.
−
Obtain Neurology consult, and initiate evaluation.
−
Consider, as necessary, discussing with the Sponsor’s medical monitor.
−
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 (eg, 
prednisone 1 to 2 mg/kg/day PO or IV equivalent); if no improvement 
within 3 to 5 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 3 to 5 days, consider start of immunosuppressive 
therapy such as TNF inhibitors (eg, infliximab at 5 mg/kg every 2 
weeks). Caution: It is important to rule out sepsis and refer to 
infliximab label for general guidance before using infliximab.
−
Once the patient is improving, gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, antifungals, or anti-PJP treatment 
(please refer to current NCCN guidelines for treatment of cancer-
related infections [Category 2B recommendation]).a
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
101
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 7:
Dose Modification and Toxicity Management Guidelines for Specific Immune-Mediated Reactions (Continued)
AE
CTC Grade/Severitya
Dose Modifications
Toxicity Management
Grade 3 or 4
(pain associated with 
severe weakness; limiting 
self-care ADLs)
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.
For Grade 3 or 4 (severe or life-threatening events):
−
Monitor symptoms closely; recommend hospitalization.
−
Obtain Neurology consult, and complete full evaluation.
−
Consider, as necessary, discussing with the Sponsor’s medical 
monitor.
−
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 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors (eg, infliximab 
at 5 mg/kg every 2 weeks). Caution: It is important to rule out 
sepsis and refer to infliximab label for general guidance before 
using infliximab.
−
Consider whether patient may require IVIG, plasmapheresis.
Once the patient is improving, gradually taper steroids over ≥28 days and 
consider prophylactic antibiotics, antifungals, or anti-PJP treatment (please 
refer to current NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation]).a
AChE= Acetylcholine esterase; ACTH= Adrenocorticotropin; ADL= Activities of daily living; AE= Adverse event; ALP= Alkaline phosphatase test; ALT=
Alanine aminotransferase; AST= Aspartate aminotransferase; BNP= Brain natriuretic Peptide; BUN= Blood urea nitrogen; CT= Computed tomography; 
CTCAE= Common Terminology Criteria for Adverse Events; DILI= Drug-induced liver injury; ECG= Electrocardiography; HBcAb= Hepatitis B Antibody; 
HBeAg= Hepatitis B Antigen; HBsAg= Hepatitis B Australian Antigen; HBV= Hepatitis B Virus; HCC= Hepatocellular Carcinoma; HCV= Hepatitis C virus; 
HgA1c= Hemoglobin A1c test; IP= Investigational Product; ILD= Interstitial lung disease; imAE= immune-mediated adverse event; IG= Immunoglobulin; IV=
Intravenous; GI= Gastrointestinal; LDH= Lactic acid dehydrogenase; LFT= Liver function tests; LLN= Lower limit of normal; MRI  Magnetic resonance 
imaging; NCI= National Cancer Institute; NCCN= National Comprehensive Cancer Network; PJP= Pneumocystis jirovecii pneumonia (formerly known as 
Pneumocystis carinii pneumonia); PO= By mouth; T3= Triiodothyronine; T4= Thyroxine; TB= Total bilirubin; TNF= Tumor necrosis factor; TSH= Thyroid-
stimulating hormone; ULN= Upper limit of normal.
a ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD.
b FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation.
1.0
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11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
102
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 8:
General Dose Modification and Toxicity Management Guidelines for Non-Immune-mediated Reactions
Non-immune-mediated Reactions
CTC 
Grade/Severity
a
Dose Modification
Toxicity Management
Any Grade
Note: dose modifications are not required for adverse events not deemed to be 
related to study treatment (ie. events due to underlying disease) or for laboratory 
abnormalities not deemed to be clinically significant.
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. 
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 Sponsor) 
Treat accordingly as per institutional standard 
AE = Adverse Events; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse Events.
a Grade according to NCI-CTCAE version 4.03
1.0
Approved
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11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
103
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 9:
Dose Modification and Toxicity Management Guidelines for Non-Immune-
mediated Adverse Events
AE
Toxicity Grade
Dose Modification
Toxicity Management
Any Grade
Note: dose modifications are not required for adverse events not considered to be related to 
IP/regimen (i.e. events due to underlying disease) or for laboratory abnormalities not considered 
to be clinically significant.
Neutropenia
(unless 
secondary to 
lymphomatou
s/CLL bone 
marrow 
involvement)
Grade 3 
(ANC < 1000 
cells/mm³ 
[1x109/L])
- Hold IP/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 
IP/study regimen administration at next 
scheduled dose. Otherwise, discontinue 
IP/study regimen
- Monitor CBC with 
differential at least weekly
-
Use of growth factors (G-
CSF, GM-CSF) is 
permitted as per ASCO or 
- ESMO Guidelines
Grade 4 
(ANC 
< 500 cells/mm³ 
[0.5x109/L])
- Decision to discontinue would be based 
on accompanying clinical 
signs/symptoms and as per 
Investigator’s clinical judgment and in 
consultation with the Sponsor
- Monitor CBC with 
differential at least weekly
-
Use of growth factors (G-
CSF, GM-CSF) is 
permitted as per ASCO or 
ESMO Guidelines
Thrombocyto
penia
(unless 
secondary to 
lymphomatou
s/CLL bone 
marrow 
involvement)
Grade 3
(Platelets 
< 50,000 cells 
/mm³ 
[50×109/L])
- Hold IP/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 
IP/study regimen administration at next 
scheduled dose. Otherwise, discontinue 
IP/study regimen
- Monitor CBC with 
differential at least weekly
- Platelet transfusion is 
permitted as per ASCO 
Guidelines
Grade 4
(Platelets < 
25,000 
cells /mm³ 
[25x109/L])
- Decision to discontinue would be based 
on accompanying clinical 
signs/symptoms and as per 
Investigator’s clinical judgment and in 
consultation with the Sponsor
- Monitor CBC with 
differential at least weekly
- Platelet transfusion is 
permitted as per ASCO 
Guidelines
Stevens-
Johnson 
Syndrome or 
toxic 
epidermal 
necrosis
- Discontinue all the agents
1.0
Approved
930191714
11.0
v
Approved
1.0
v


EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
104
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 9:
Dose Modification and Toxicity Management Guidelines for Non-Immune-
mediated Adverse Events (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Venous 
thrombosis/ 
embolism
Grade 3 or 4
- If Grade 3, hold durvalumab 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 
durvalumab administration at next 
scheduled dose. Otherwise, discontinue 
durvalumab
- If Grade 4, discontinue durvalumab
- Start anticoagulation 
treatment
Early 
anti-tumor 
response (eg
pseudotumor 
progression or 
flare reaction)
Grade 1 or 2
- Continue IP/regimen
- At the Investigator’s 
discretion may initiate 
therapy with NSAIDs, 
limited duration 
corticosteroids, and/or 
narcotics
Grade 3 or 4
- Hold IP/regimen 
- If symptoms resolve to ≤ Grade 1, 
resume the IP/regimen
- Initiate therapy with 
NSAIDs, corticosteroids, 
and/or narcotics
Grade 3 or 4
- Hold IP/regimen 
- If symptoms resolve to ≤ Grade 1, 
resume the IP/regimen
- Initiate therapy with 
NSAIDs, corticosteroids, 
and/or narcotics
Other AEs
(continued)
Grade 3 or 4
For Grade 3
- Hold durvalumab 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 
IP/study regimen administration at next 
scheduled dose. Otherwise, discontinue 
IP/study regimen
For Grade 4
- Discontinue IP/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 Sponsor)
- Treat accordingly as per 
local/institutional 
guidelines
AE = adverse event; ANC = absolute neutrophil count; ASCO = American Society of Clinical Oncology; CBC = 
complete blood count; CLL = chronic lymphocytic leukemia; ESMO = European Society of Medical Oncology; 
G CSF = granulocyte-colony stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; IP = 
investigational product; L = liter; mm = millimeter; NSAID = non-steroidal anti-inflammatory drug; 
1.0
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1.0
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
105
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 10:
Dose Modification and Toxicity Management Guidelines for Infusion- related 
Reactions
Toxicity
Severity
Dose Modification
Toxicity Management
Infusion- related 
Reactions
Any
Grade
General Guidance
- Management per institutional 
standard at the discretion of 
Investigator
- Monitor subjects for signs and 
symptoms of infusion-related 
reactions (eg 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 (eg generalized 
urticaria, angioedema, wheezing, 
hypotension, tachycardia)
Grade 1
- The infusion rate of study 
drug/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 for durvalumab
- Pre-medicate prior to rituximab 
doses
- Steroids should not be used for 
routine premedication of ≤Grade 2 
infusion reactions 
Grade 2
- The infusion rate of study 
drug/regimen may be decreased 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 
or 4
- Permanently discontinue 
durvalumab or study drug regimen
For Grade 3 or 4:
- Manage severe infusion-related 
reactions per institutional 
standards (eg IM epinephrine, 
followed by IV diphenhydramine 
and ranitidine, and IV 
glucocorticoid)
IM = intramuscular; IP = investigational product; IV = intravenous.
7.2.5.3.
Dose Modifications Guidelines for R-CHOP
Dose reductions of the R-CHOP regimen or any of the drugs included in the treatment regimen 
are not allowed except for vincristine as described in Table 12.
Should there be a treatment-related AE requiring interruption of R-CHOP administration on 
Day 1 of any scheduled treatment cycle (R-CHOP is scheduled for 6 to 8 cycles), the infusion 
will be held until resolution of the AE. If the events resolve adequately by Day 7 of a cycle, 
R-CHOP can be administered up to Day 8 of the cycle. However, if the AEs do not resolve by 
1.0
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Approved
1.0
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
Celgene International II Sarl
Confidential and Proprietary
106
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Day 8 of the cycle, R-CHOP will be held until Day 1 of the next cycle. Any missed doses of 
R-CHOP will not be made up at a later time. 
Table 11:
Dose Modification Rules for Vincristine
NCI-CTCAE
Toxicity Grade
Action Required
Peripheral neuropathy
Newly developed ≥ Grade 3 
(applies only to those neuropathies 
which begin or worsen while on 
study)

Hold (interrupt dose)

When the toxicity resolves to ≤ Grade 2 or to baseline, 
restart at the next lower dose level
NCI-CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.
Table 12:
Dose Reduction Levels for Vincristine
Starting Dose
1.4 mg/m2 (maximum of 2.0 mg total)
Level –1 Dose
1.0 mg max
7.2.5.4.
Dose Modifications Guidelines for Lenalidomide
No newly enrolled subjects are to be treated with the combination of durvalumab, R-CHOP plus 
lenalidomide. Only those subjects currently enrolled and receiving clinical benefit, based on the 
discretion of the Investigator, are eligible to remain on treatment following reconsent.
Dose modifications (interruption and dose reduction) of lenalidomide are allowed for AEs 
associated with known lenalidomide-related toxicities. Treatment-related AEs and the severity 
which require protocol-defined dose modifications of lenalidomide are found in Table 14. 
The dose of lenalidomide may be reduced successively by one level from the starting dose 
according to Table 13. No more than one dose level reduction per cycle is permitted unless 
discussed with and approved after consultation with the Celgene Medical Monitor. No dose 
re-escalation of lenalidomide is permitted at any time during the study treatment. In addition, if a 
subject continues to experience unacceptable toxicity at the lowest dose level allowed, 
lenalidomide will be discontinued permanently.  
Table 13:
Lenalidomide Dose Modification Levels 
Dose
a
Induction Treatment
Once Daily on Days 1-14 of 21-day Cycle
Level 1
15 mg
Level −1
10 mg
Level −2
5 mg
Level −3
2.5 mg
Level −4
Discontinue
a Once a subject's dose has been reduced, no dose re-escalation will be permitted
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Table 14:
Dose Modification Schedule for Lenalidomide-related Adverse Events
Dose Modifications 
(Interruption/Reduction)
NCI-CTCAE (v 4.03)
Toxicity Grade
Action Required
Neutropeniaa
Sustained (≥ 7 days) Grade 3 
OR
≥ Grade 3 associated with 
fever (temperature ≥ 38.5°C)
OR 
Grade 4 

Withhold dose

Monitor CBC at least every seven days

If neutropenia has resolved to ≤ Grade 2 on first occurrence, 
restart at the same dose level

If neutropenia has resolved to ≤ Grade 2 on subsequent 
occurrences, restart at the next lower dose level
Thrombocytopenia a
≥ Grade 3 (platelet count 
< 50,000 cells/mm³ 
[50x109/L])

Withhold dose

Monitor CBC at least every seven days

If thrombocytopenia resolves to ≤ Grade 2 on first occurrence, 
restart at the same dose level

If thrombocytopenia resolves to ≤ Grade 2 on subsequent 
occurrences, restart at next lower dose level
Rash
Grade 2 or 3 
non-desquamating (blistering)
------------
Desquamating (blistering) 
≥Grade 3 
OR
Non-desquamating Grade 4

Determine causative investigational product and if attributable to 
lenalidomide then: 

Hold dose; administer antihistamines or short course of ≤ 20 mg 
prednisone (or equivalent)

When toxicity resolves to ≤ Grade 1, restart at the same dose level
-----------------

Determine causative investigational product and if attributable to 
lenalidomide then: 

Discontinue lenalidomide
Allergic reaction or 
hypersensitivity
Grade 2

Determine causative investigational product and if attributable to 
lenalidomide then: 

Withhold dose.  Follow at least every seven days
------------
Grade 3-4

When the toxicity resolves to ≤ Grade 1, restart lenalidomide at 
next lower dose level
-----------------

Discontinue lenalidomide
Constipation
Grade 1-2
-----------------
≥ Grade 3

Initiate bowel regimen and maintain dose level
-----------------

Withhold dose.  Follow at least every seven days 

When the toxicity resolves to ≤ Grade 2, restart at same dose level
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Table 14:
Dose Modification Schedule for Lenalidomide-related Adverse Events
(Continued)
Dose Modifications 
(Interruption/Reduction)
NCI-CTCAE (v 4.03)
Toxicity Grade
Action Required
Venous 
thrombosis/embolism
≥ Grade 3

Withhold dose and start therapeutic anticoagulation; restart at the 
same dose level at Investigator’s discretion  
Tumor Lysis Syndrome 
Grading is per Cairo-Bishop, 
and not per NCI-CTCAE, for 
TLS only
Lab TLS or Grade 1 TLS
-----------------
Grade 2-4

Continue lenalidomide at the same dose level, OR at the 
Investigator’s discretion, continue lenalidomide and reduce dose 
by one level

Provide vigorous IV hydration and appropriate medical 
management according to the local standard of care, until 
electrolyte abnormalities are corrected.  Rasburicase therapy is 
appropriate (if approved by the local Health Authority) as needed 
to reduce hyperuricemia

Hospitalization will be at Investigator’s discretion
-----------------

Withhold dose

When symptoms resolve to Grade 0, restart at same dose level

If lenalidomide is resumed prior to the start of the subsequent 
cycle, a chemistry test should be performed every other day for 
the first week following re-initiation of lenalidomide
AST or ALT > 3 x ULN

Withhold lenalidomide dose; re-test at least weekly until AST or 
ALT < 2.5 x ULN or return to baseline

If the event is considered related to lenalidomide, restart 
lenalidomide at next lower dose level

If the event is considered NOT related to lenalidomide, restart at 
the same dose level of lenalidomide

For subjects with Gilbert’s syndrome or liver involvement, 
consult the Celgene Medical Monitor regarding dose reductions 
Bilirubin > 3 x ULN

Withhold lenalidomide dose; re-test at least weekly until bilirubin 
< 1.5 x ULN

If the event is considered related to lenalidomide, restart 
lenalidomide at next lower dose level 

If the event is considered NOT related to lenalidomide, restart at 
the same dose of lenalidomide

For subjects with Gilbert’s syndrome or liver involvement, 
consult the Celgene Medical Monitor regarding dose reductions
Other lenalidomide related 
non-hematologic AEs 
≥Grade 3

Withhold dose

When the AE resolves to ≤ Grade 2, restart at the same or next 
lower dose level per the Investigator’s discretion
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AE = adverse event, ALT = alanine transaminase; AST = aspartate transaminase; CBC = complete blood count, 
NCI-CTCAE = National Cancer Institute Common Terminology Criteria for AE, Lab = laboratory, TLS = tumor 
lysis syndrome; ULN = upper limit of normal
a Unless secondary to lymphoma bone marrow involvement per Investigator assessment.
7.2.6.
Overdose
Overdose, as defined for this protocol, refers to durvalumab, lenalidomide, rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone/prednisolone. On a per-dose basis, 
an overdose is defined as the following amount over the protocol-specified dose of these drug(s) 
assigned to a given subject, regardless of any associated AEs or sequelae:

PO:
any amount over the protocol-specified dose

IV:
10% over the protocol-specified dose
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency. On an infusion rate basis, an overdose is defined as any 
rate faster than the protocol-specified rate.
Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the CRF. See Section 10 for the 
reporting of AEs associated with overdose.
7.3.
Method of Treatment Assignment
Interactive response technology will be employed to manage subject medications.
7.4.
Packaging and Labeling
The label(s) for IP will include Sponsor name, address and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, lot 
number, expiry date (where applicable), medication identification/kit number, dosing 
instructions, storage conditions, and required caution statements and/or regulatory statements as 
applicable. Additional information may be included on the label as applicable per local 
regulations.
7.5.
Investigational Product Accountability and Disposal 
The Investigator(s) or designee is responsible for taking an inventory of each shipment of 
investigational product received and comparing it with the accompanying shipping 
order/packaging slip. The Investigator(s) will verify the accuracy of the information on the 
shipping order/packaging slip and call IRT to register receipt at the site of the investigational 
product.  
At the study site, investigational product will be stored in a locked, safe area to prevent 
unauthorized access and should be stored as directed on the product label.
An accurate accounting of the dispensing and return of investigational product for each study 
subject will be maintained in source documents on an ongoing basis by a member of the study 
site staff. Additionally, if any investigational product is lost or damaged or if the study subject 
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misses a dose, this information should be documented in the study subject’s CRF and source 
documents.  
Celgene will instruct the Investigator on the return, disposal, and/or destruction of unused 
investigational product.
7.6.
Investigational Product Compliance
For the oral medications of lenalidomide and prednisone/prednisolone, study personnel will 
review the dosing instructions with the subject prior to dispensing investigational product. The 
subject will be instructed to return the investigational product container, including any unused 
investigational product, to the site at the end of the applicable treatment cycle. To monitor 
treatment compliance, the subject will be interviewed at each applicable visit regarding whether 
they took their medication, and reconciliation of capsules/tablets will be done upon return of the 
investigational product container. Subject compliance will be noted in the source records and on 
the appropriate CRFs based upon the interview and capsule/tablet count. 
For the IV medications of durvalumab, rituximab, cyclophosphamide, doxorubicin and 
vincristine, the planned administered dosage will be recorded in the source records and on the 
appropriate CRFs.
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Protocol MEDI4736-DLBCL-001
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8.
CONCOMITANT MEDICATIONS AND PROCEDURES
Over the course of this study, additional medications may be required to manage aspects of the 
disease state of the subjects, including side effects from study treatments or disease progression. 
Supportive care, including but not limited to anti-emetic medications, may be administered at the 
discretion of the Investigator. 
All concomitant treatments, including blood and blood products, used from 28 days prior to first 
dose of IP until 90 days after the last dose of durvalumab or 28 days after the last dose of any 
other IP, whichever is later, must be reported on the CRF. 
For subjects who are treated with lenalidomide in this study (Arm B: durvalumab in combination 
with lenalidomide and R-CHOP), please refer to the lenalidomide prescribing information, the 
Summary of Product Characteristics or the IB for potential drug interactions. In particular, 
caution should be exercised with the concomitant use of digoxin and statins. Although the 
coadministration of lenalidomide with the P-glycoprotein inhibitors quinidine or temsirolimus 
had no clinically relevant effect on the pharmacokinetics of lenalidomide, the concomitant use of 
P-glycoprotein inhibitors (eg verapamil, cyclosporin A, reserpine, quinidine, yohimbine, 
tamoxifen, toremifena) should be considered carefully.
For information regarding other drugs that may interact with IP and affect its metabolism, 
pharmacokinetics, or excretion, please see the IBs and/or local package inserts.
8.1.
Permitted/Recommended Concomitant Medications and Procedures
Investigators may prescribe concomitant medications or treatments necessary to provide 
adequate supportive care except for those medications identified as “prohibited” as listed in 
Section 8.2.
Specifically, subjects should receive full supportive care during the study, including but not 
limited to, transfusions of blood and blood products, treatment with antibiotics, antiemetics, 
antidiarrheals, analgesics, and other treatments considered necessary based on the clinical 
judgment of the treating physician, and in accordance with institutional standards.
8.1.1.
Infection Prophylaxis
Investigators may use their discretion in administering infection prophylaxis for subjects 
regarded to be at high risk (including but not limited to: acyclovir or similar drug for herpes 
zoster). Monitoring of subjects for fever, neutropenia and infections and treatment with 
appropriate anti-infective therapy should be instituted as clinically indicated.  
8.1.2.
Venous Thromboembolism Prophylaxis (Lenalidomide)
It is not known whether prophylactic anticoagulation therapy prescribed in conjunction with 
lenalidomide may lessen the potential for venous thromboembolism (VTE). The decision to take 
prophylactic measures should be made carefully after an assessment of an individual subject’s 
underlying risk factors.
As reference information, for subjects receiving lenalidomide in open-label trials, it is strongly 
recommended that subjects at risk for VTE receive either aspirin (70 – 325 mg PO daily) or 
another prophylaxis agent while on lenalidomide. In those subjects with a high risk of VTE, it is 
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strongly recommended that the subject receive prophylactic anticoagulation therapy with low 
molecular weight heparin, or heparin (dose recommended for the prophylaxis of deep vein 
thrombosis/ pulmonary embolism per the package insert), or warfarin (to maintain an INR of 
2.0). The choice of VTE prophylaxis agent relies upon the Investigator’s discretion and should 
be tailored to the subject’s individual risk/benefit profile by taking into account the individual 
thrombotic risk, bleeding risk, and the quality of compliance with the VTE prophylaxis. 
8.1.3.
Nausea Prophylaxis
Premedication with an antiemetic is recommended according to local practice.
8.1.4.
Infusion Reaction Prophylaxis (Rituximab and Durvalumab)
Premedication consisting of acetaminophen and an antihistamine should be administered before 
each rituximab infusion (see package insert or where applicable refer to the instruction in the 
Pharmacy Manual). Steroids may also be administered before the start of the rituximab infusion 
according to institutional practice. Surveillance measures during and after infusion of rituximab 
should be applied as recommended by the manufacturer/current guidelines.
Subjects who experienced Grade 3 or higher allergic reactions should not be re-challenged but 
premedication with antihistamines, antipyretics and corticosteroids for subjects with a history of 
Grade 1 or 2 infusion reactions should be considered for durvalumab.
General guidelines for dose modification due to infusion reactions are found in Table 10.
8.1.5.
Treatment of Early Anti-Tumor Response (Tumor Flare Reaction)
Early anti-tumor response (eg pseudotumor progression, tumor flare reaction) is defined as a 
sudden increase in the size of the disease bearing sites, including the lymph nodes, spleen and/or 
the liver often accompanied by a low-grade fever, tenderness and swelling, diffuse rash and in 
some cases, an increase in the peripheral blood lymphocyte counts. Treatment is based on the 
clinical judgment of the Investigator. TFR will be graded using NCI-CTCAE Version 3.0. 
Symptomatic treatment of Grade 1 and 2 events with non-steroidal anti-inflammatory drugs 
(NSAIDs) (ie, ibuprofen), corticosteroids, and/or narcotic analgesics for pain management is 
recommended, without an interruption in study drug administration.
In the event of a ≥ Grade 3 early anti-tumor response, it is recommended that IP should be 
interrupted, as indicated, and the event treated with corticosteroids, NSAIDs, narcotic analgesics, 
and or antihistamines. Refer to Table 9 for further instructions and dose modifications for 
Grade 3 and 4 events.
8.1.6.
Urotoxicity Prophylaxis (Cyclophosphamide)
Urotoxicity including hemorrhagic cystitis, pyelitis, ureteritis, and haematuria have been 
reported with cyclophosphamide therapy. Prior, during and immediately after the administration, 
adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the 
risk of urinary tract toxicity. Adequate treatment with mesna and/or strong hydration to force 
diuresis can markedly reduce the frequency and severity of bladder toxicity. Please refer to the 
cyclophosphamide prescribing information for further details.
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8.2.
Prohibited Concomitant Medications and Procedures
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the Investigator.
The following medications are considered prohibited concomitant medications during the study.  
The Sponsor must be notified if a subject receives any of these during the study:

Any investigational anti-cancer therapy.

Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for 
cancer treatment.

Concurrent Radiotherapy with the exception of post-induction radiotherapy if 
prespecified during the screening period (Section 7.2.2). Response-adapted 
radiotherapy is not permitted.

Concurrent use of hormones or high dose corticosteroids as anti-cancer therapy is 
prohibited. However, these treatments may be permitted for treating AEs, certain 
chronic conditions, and/or other non-cancer-related conditions as clinically necessary 
(eg insulin for diabetes and hormone replacement therapy).

Based on the observation in subjects with multiple myeloma who had an increased 
risk of venous thromboembolism when treated with lenalidomide in combination with 
dexamethasone, combined oral contraceptive pills are not recommended in this 
clinical study. If a subject is already using combined oral contraception at study entry, 
she should switch to one of the highly effective methods listed in Section 4.2 , 
however, the risk of venous thromboembolism continues to be increased for 
4 to 6 weeks after discontinuing combined oral contraception.

Copper-releasing intrauterine devices are generally not recommended due to the 
potential risks of infection at the time of insertion and menstrual blood loss which 
may compromise patients with neutropenia or thrombocytopenia.

Immunosuppressive medications including, but not limited to systemic corticosteroids 
at doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, 
azathioprine, and tumor necrosis factor alpha (TNF-α) inhibitors.
Note: Use of immunosuppressive medications for the management of IP-related AEs 
or in subjects with contrast allergies is acceptable. In addition, use of inhaled and 
intranasal corticosteroids is permitted

Live attenuated vaccines during the study and for 12 months after last dose of 
rituximab or until recovery of B-cells and for 120 days after last dose of durvalumab, 
whichever is longer.

Herbal and natural remedies are to be avoided.

Prophylactic treatment for CNS disease with IV drugs is not permitted during the 
course of the study treatment period.
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8.3.
Required Concomitant Medications and Procedures
8.3.1.
Mandatory Supportive Therapy
Appropriate pre-infusion medications according to the package insert or institutional standards is 
required prior to administration of intravenous study treatments.
8.3.2.
CNS Prophylaxis
Subjects at high risk for CNS involvement, as defined in the NCCN guidelines and CNS 
evaluation in Section 6.1 must receive CNS lymphoma prophylaxis treatment with intrathecal 
drugs (eg methotrexate, cytarabine) as per NCCN guidelines or per institutional standards.
Prophylactic treatment for CNS disease with IV drugs is not permitted during the course of the 
study treatment period.  
8.3.3.
TLS Prophylaxis
Treatment with allopurinol (or equivalent as per institutional guidelines) and hydration for TLS 
prophylaxis is required during the first week of study treatment and should initiate at least 3 days 
prior to the first study drug treatment (C1D1). Hydration levels should be adjusted according to 
age and clinical status. To monitor for TLS, the subjects will have close monitoring of blood 
chemistry during the first few cycles and additionally as clinically indicated.
Tumor lysis syndrome will be monitored by blood chemistry laboratory analysis and assessed by 
the Cairo-Bishop Grading system (Appendix D). The assessment includes both laboratory tumor 
lysis syndrome (LTLS) and clinical TLS criteria. Subjects experiencing LTLS or clinical TLS 
should receive appropriate medical management according to the institutional standard of care.
8.3.4.
Pneumocystis Jirovecii Prophylaxis
Pneumocystis jirovecii prophylaxis is required (including but not limited to 
trimethoprim/sulfamethoxazole) and should follow local practice.
8.3.5.
Neutropenia Prophylaxis
All subjects allocated to Arm B should receive neutropenia prophylaxis with G-CSF.
For subjects allocated to Treatment Arm A, primary neutropenia prophylaxis with G-CSF should 
follow local practice. 
Both G-CSF and pegylated G-CSF are allowed. Other growth factors (eg erythropoietin) may be 
prescribed at any time during the Treatment and Follow-up Periods at the Investigator’s 
discretion once a subject has experienced cytopenic or myelosuppressive events.
Granulocyte colony stimulating factor is recommended to be used to mitigate the duration of 
neutropenia for any subject requiring a dose modification due to neutropenia. Growth factors or 
transfusions of blood or blood products cannot be administered during the Screening period to 
increase a subject’s blood values in order to meet entry criteria.
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8.3.6.
Hepatitis B Virus Reactivation Prophylaxis
In subjects with prior HBV infection, HBV reactivation may occur during or after rituximab 
treatment even if HBV-DNA is undetectable. Reactivation cases have also been reported from 
worldwide postmarketing experience with lenalidomide and are considered to be at least possibly 
related to lenalidomide.
For subjects with evidence of prior HBV exposure (positive for anti-HBs and/or anti-HBc with 
or without detectable HBV-DNA), liver disease experts should be consulted before start of 
rituximab or lenalidomide treatment. Such subjects should be monitored for clinical and 
laboratory signs of hepatitis (eg elevation in liver enzymes) and/or HBV reactivation during and 
following rituximab or lenalidomide treatment and managed following local medical standards to 
prevent HBV reactivation. In case of any suspicion for HBV reactivation, HBV DNA should be 
repeated at any time during the study in consultation with a hepatologist.
In subjects who develop HBV reactivation during the study treatment, the study treatment should 
be immediately discontinued. In subjects who develop HBV reactivation during or after the study
treatment, appropriate HBV treatment (eg lamivudine) should be instituted as per local medical 
practice and locally approved product/prescribing information.
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9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
This Phase 2, two-arm, open-label study is designed to evaluate the clinical activity, safety, and 
tolerability of durvalumab in combination with R-CHOP or in combination with R2-CHOP 
followed by durvalumab consolidation therapy in previously untreated subjects with high-risk 
DLBCL within each COO subtype (non-ABC and ABC). It is also intended to identify 
biomarkers that predict response to the study treatment.
The study is divided into a Safety Run-in Stage to evaluate the safety of the treatment 
combinations until at least 10 subjects have completed at least one cycle of study treatment or 
discontinued prematurely followed by an Expansion Stage (to complete study enrollment) to 
analyze the clinical activity of the treatment combinations in up to approximately 40 total 
subjects in the efficacy evaluable population.
Following Partial Clinical Hold instituted by the US FDA which affects Arm B, the Safety Run-
in Stage will evaluate safety of the treatment Arm A combinations when at least 10 subjects have 
been included into Arm A and have been treated for at least one cycle of study treatment or 
discontinued prematurely.
The primary objective of this study is to assess the clinical activity of durvalumab in 
combination with R-CHOP or in combination with R2-CHOP in previously untreated subjects 
diagnosed with high-risk DLBCL.
The secondary objectives are: 

To examine the safety and tolerability of durvalumab when given in combination with 
R-CHOP or R2-CHOP followed by durvalumab consolidation in the treatment of 
previously untreated subjects with high-risk DLBCL

To identify and develop biomarkers of the tumor microenvironment and of the host 
immune system which are predictive of clinical response to durvalumab, when 
administered in combination with R-CHOP or R2-CHOP, followed by durvalumab 
consolidation therapy that will be tested in further randomized clinical trials.  
Examples of defined analytical methods that may be investigated include, but are not 
limited to:

PD-L1 IHC

Gene Expression Signatures
The primary efficacy analysis will evaluate the complete response rate (CRR) at the end of the 
induction therapy in the efficacy evaluable population in a comparative manner against historical 
control.
The key secondary efficacy analysis will evaluate the rate of subjects who continue consolidation 
therapy out of all subjects in the efficacy evaluable population in a comparative manner against 
historical control.
If null hypothesis on primary endpoint is rejected, hypothesis testing on the key secondary 
endpoint will be performed hierarchically without any type I error adjustment.
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Analysis of other secondary efficacy endpoints will include further analysis of response and 
progression data and correlative evaluation of biomarkers (as described in Section 6.8) as
predictive with clinical responsiveness. 
The statistical analysis of the safety profile will be observational in nature.
On 05 Sep 2017, a Partial Clinical Hold was placed to this study by US FDA. The decision by 
the FDA was based on risks identified in other trials for pembrolizumab, an anti-programmed 
cell death-1 (PD-1) antibody, in patients with multiple myeloma in combination with 
immunomodulatory agents. As a result of the US FDA Partial Clinical Hold, enrollment 
continued into Arm A only and new subjects received induction therapy (durvalumab + 
R-CHOP) after Cycle 1 regardless of DLBCL COO subtype. Enrollment into Arm B 
(durvalumab in combination with [R2-CHOP]) was discontinued. Subjects enrolled and treated 
in Arm B prior to the US FDA Partial Clinical Hold who were receiving clinical benefit, based 
on the discretion of the investigator, could continue study treatment after being reconsented. 
9.2.
Study Population Definitions
The statistical analysis populations are defined as follows.

Safety Population:  All subjects who take at least one dose of IP. Reporting done on 
Safety Population will be done against actual treatment received.

Efficacy Evaluable Population:  All subjects who complete at least one cycle of their 
assigned treatment, have a baseline assessment by CT scan and have at least one 
post-baseline tumor response assessment. Reporting done on Efficacy Evaluable 
Population will be done against planned treatment.

Pharmacokinetic (PK) Population:  All subjects who receive at least one dose of IP 
and have at least one measurable plasma concentration. Reporting done on PK 
Population will be done against actual treatment received.

Biomarker Evaluable Population:  All subjects who receive at least one dose of IP and 
have at least one post-dose biomarker assessment. Reporting done on Biomarker 
Evaluable Population will be done against actual treatment received.
9.3.
Sample Size and Power Considerations
The total sample size for the study is estimated to be approximately 45 subjects enrolled (with 
approximately 40 subjects in the efficacy evaluable population).
Assuming historical control data of 55% for the complete response rate at the end of the 
induction therapy in the efficacy evaluable population when treated with R-CHOP and 75% for 
the complete response rate at the end of the induction when durvalumab is added to R-CHOP, 
40 subjects would provide ~71% power to reject the null hypothesis that the complete response 
rate at the end of the induction therapy in the efficacy evaluable population is less than 55%. If 
null hypothesis on the primary endpoint is rejected, hypothesis testing on the rate of subjects who 
continue consolidation therapy in the efficacy evaluable population will be performed 
hierarchically without any type I error adjustment. Assuming that the rate of subjects who 
continue consolidation when durvalumab is added to R-CHOP is at 85%, 40 subjects would 
provide in this hierarchical testing strategy ~43% power to reject the null hypothesis that the rate 
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of subjects who continue consolidation therapy in the efficacy evaluable population is less than 
70%.
9.4.
Background and Demographic Characteristics
Subject’s age, height, weight, and baseline characteristics will be summarized using descriptive 
statistics, while sex, race and other categorical variables will be provided using frequency 
tabulations. Medical history data will be summarized using frequency tabulations by MedDRA 
system organ class and preferred term.
9.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent for both Treatment 
and Follow-up Periods. A summary of subjects enrolled by site will be provided. Protocol 
deviations will be summarized using frequency tabulations.
9.6.
Efficacy Analysis
The clinical activity of the study treatments will be evaluated from a baseline assessment 
collected during Screening prior to the start of treatment, until a subject meets the criteria for 
disease progression.
All efficacy evaluable subjects will be included for efficacy analysis.
Efficacy analysis will be performed for each treatment arm by combining data from both the 
Safety Run-in Stage and the Expansion Stage of the study. Subgroup analysis for efficacy 
evaluation will be summarized. This includes sex, age category and prognostic risk criteria for 
each treatment arm.
The primary endpoint of this study is the complete response rate at the end of the induction 
therapy. The key secondary endpoint is the rate of subjects who continue consolidation therapy 
out of all subjects.
The CRR and the rate of subjects who continue consolidation therapy will be summarized using 
count and percentage. The 95% confidence 2-sided confidence interval will be based on the 
Clopper-Pearson approach. Null hypothesis for the primary endpoint will be rejected if the lower 
limit of the confidence interval for the complete response rate at the end of the induction therapy 
in the efficacy evaluable population is above 55%. If null hypothesis for the primary endpoint is 
rejected, then hypothesis testing can be performed on the key secondary endpoint without any 
type I error adjustment. Null hypothesis for the key secondary endpoint will be rejected if the 
lower limit of the confidence interval for the rate of subjects who continue consolidation therapy 
out of all subjects in the efficacy evaluable population is above 70%.
The secondary efficacy endpoint will consist of an analysis of clinical responses to study 
treatment in biomarker-defined subpopulations. Clinical responses will be assessed for potential 
relationship to biomarker positive subjects and biomarker negative subjects. Other efficacy 
analyses included in the exploratory analysis will include PFS rate at 12 months, PFS rate at 24 
months, CR rate at end of treatment (12 months). Progression-free survival is calculated as the 
time from C1D1 to the first documented progression or death due to any cause during the entire 
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efficacy evaluation period. The PFS from first dose of any IP to 12 or 24 months after the first 
dose of any IP will be summarized from Kaplan-Meier method and its 95% confidence interval 
will also be provided.
9.7.
Safety Analysis
Safety analysis will include all subjects in the Safety population. Investigational product 
exposure will be summarized for each treatment arm including duration of IP, total dose taken, 
and dose reductions.  
Adverse events, vital sign measurements, clinical laboratory measurements, physical 
examination and concomitant medications will be summarized by treatment arm and for all 
subjects combined.
9.7.1.
Adverse events
Adverse events will be coded according to Medical Dictionary for Regulatory Activities 
(MedDRA) and graded according to NCI-CTCAE version 4.03 with the exception of the 
evaluation of TFR which will be graded according to NCI-CTCAE version 3.0. The incidence 
rates of AEs will be tabulated by system organ class and preferred term. The incidence of AEs 
will also be tabulated by severity within each system organ class and preferred term. The most 
severe grade of each preferred term and AE of special interest (Section 10.7) for a subject will be 
utilized for summaries of AEs by NCI-CTCAE grade.
Subsets of AEs to be summarized include AEs of special interest (AESI), SAEs, suspected 
treatment-related AEs, AEs that resulted in withdrawal of investigational product and AEs that 
resulted in death. 
All AEs with corresponding attributes will be displayed in a by-subject listing. AEs leading to 
death or to discontinuation from treatment, events classified as NCI-CTCAE grade 3 or higher, 
suspected treatment-related events, and SAEs will also be displayed in separate by-subject 
listings.  
9.7.2.
Laboratory Evaluations
Summaries of laboratory data will be based on observed data and will be reported using 
conventional units. Baseline, raw values, and changes from baseline will be summarized using 
descriptive statistics for each laboratory test specified in the study protocol at each post-baseline 
visit by treatment arm.
Laboratory data will be graded according to NCI-CTCAE severity grade. For variables for which 
an NCI-CTCAE grade does not exist, the frequency of subjects with values below, within, and 
above the normal ranges pretreatment and during treatment will be summarized by treatment 
arm.
The frequencies of the worst severity grade observed during treatment will be displayed in cross-
tabulations by baseline status for each treatment arm. Shift tables will be presented showing the 
change in severity grade from baseline to each post-baseline visit and to the maximum 
post-baseline grade during the induction phase and consolidation phase.
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9.8.
Interim Analysis
No formal interim analysis planned in this study. 
Primary analysis was run as planned based on the 02 Aug 2018 data cutoff, therefore, following 
the decision to discontinue the Follow-up Period and stop the follow-up data collection in the 
clinical database, no additional efficacy or safety statistical analyses will be performed after the 
primary analysis.
9.9.
Other Topics
The PK and Pd/ biomarker analysis will be specified in separate analysis plan.
9.9.1.
Safety Review Committee 
A SRC will be convened to evaluate the safety profile and tolerability of the Safety Run-in Stage
as well as potentially other safety data in this clinical study, see Section 6.5.2.
9.9.2.
Steering Committee 
The conduct of this study will be overseen by a global scientific steering committee (GSSC), 
presided over by the coordinating Principal Investigator(s) and if possible the lead Investigators 
from each country participating in this study. The GSSC will serve in an advisory capacity to the 
Sponsor. Operational details for the GSSC will be detailed in a separate GSSC charter.
9.9.3.
Exploratory Analysis 
Planned exploratory analyses include:

PFS at 12 months;

PFS at 24 months;

CR rate at 12 months;

The PK/Pd relationship for durvalumab when given in combination with R-CHOP or 
with R2-CHOP followed by durvalumab consolidation;

Pharmacodynamic and mechanistic biomarkers for durvalumab and lenalidomide 
when given in combination with R-CHOP or with R2-CHOP followed by durvalumab 
consolidation therapy will be explored
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10.
ADVERSE EVENTS
10.1.
Monitoring, Recording and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE. A diagnosis or syndrome should be recorded on 
the AE page of the CRF rather than the individual signs or symptoms of the diagnosis or 
syndrome. 
Abuse, withdrawal, sensitivity or toxicity to an investigational product should be reported as an 
AE. Overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported on the overdose CRF (See Section 7.2.6 for the definition of an overdose). Any sequela 
of an accidental or intentional overdose of an investigational product should be reported as an 
AE on the AE CRF. If the sequela of an overdose is an SAE, then the sequela must be reported 
on an SAE report form and on the AE CRF. The overdose resulting in the SAE should be 
identified as the cause of the event on the SAE report form and CRF but should not be reported 
as an SAE itself.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary. There is no known specific antidote for durvalumab, 
lenalidomide, rituximab, cyclophosphamide, vincristine, doxorubicin or prednisone overdose. 
Actual treatment should depend on the severity of the clinical situation and the judgment and 
experience of the treating physician.
All subjects will be monitored for AEs during the study. Assessments may include monitoring of 
any or all of the following parameters:  the subject’s clinical symptoms, laboratory, pathological, 
radiological or surgical findings, physical examination findings, or findings from other tests 
and/or procedures.
All AEs will be recorded by the Investigator from the time the subject signs informed consent 
until 90 days after the last dose of durvalumab or 28 days after the last dose of any other IP, 
whichever is later, as well as those SAEs made known to the Investigator at any time thereafter 
that are suspected of being related to IP. AEs and SAEs will be recorded on the AE page of the 
CRF and in the subject’s source documents. All SAEs must be reported to Celgene Drug Safety 
within 24 hours of the Investigator’s knowledge of the event by facsimile, or other appropriate 
method, using the SAE Report Form, or approved equivalent form. 
Following completion of the last durvalumab subject’s 90-day Safety Follow-up Visit (data 
cutoff date 06 Jun 2019), AEs and SAEs are no longer required to be collected in the CRFs.      
10.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all AEs as to: 
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10.2.1.
Seriousness 
An SAE is any AE occurring at any dose that:

Results in death

Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE)

Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay)

Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect

Constitutes an important medical event
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Events not considered to be SAEs are hospitalizations for:

A standard procedure for protocol therapy administration. However, hospitalization 
or prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE

Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition

The administration of blood or platelet transfusion as routine treatment of studied 
indication. However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE

A procedure for protocol/disease-related investigations (eg surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling). However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable 
SAE

Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE

A procedure that is planned (ie, planned prior to start of treatment on study); must be 
documented in the source document and the CRF. Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE

An elective treatment of or an elective procedure for a pre-existing condition, 
unrelated to the studied indication, that has not worsened from baseline

Emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above
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If an AE is considered serious, both the AE page/screen of the CRF and the SAE Report Form 
must be completed.
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to the IP, action taken regarding the IP, and outcome.
10.2.2.
Severity/Intensity
For both AEs and SAEs, the Investigator must assess the severity/intensity of the event. 
The severity/intensity of AEs will be graded based upon the subject’s symptoms according to the 
current active minor version of the Common Terminology Criteria for Adverse Events (CTCAE, 
Version 4.03); 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40. However, 
TFR will be graded using NCI-CTCAE version 3.0.
AEs that are not defined in the CTCAE should be evaluated for severity/intensity according to 
the following scale:
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be needed; no 
or minimal medical intervention/therapy required
Grade 3 = Severe – marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalization is possible
Grade 4 = Life-threatening – extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable
Grade 5 = Death - the event results in death
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache). This criterion is not the same as “serious” which is based 
on subject/event outcome or action criteria associated with events that pose a threat to a subject’s 
life or functioning.  
Seriousness, not severity, serves as a guide for defining regulatory obligations.
10.2.3.
Causality
The Investigator must determine the relationship between the administration of the IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
a causal relationship of the adverse event to IP administration is unlikely 
or remote, or other medications, therapeutic interventions, or underlying 
conditions provide a sufficient explanation for the observed event.
Suspected:
there is a reasonable possibility that the administration of IP caused the 
adverse event. ‘Reasonable possibility’ means there is evidence to 
suggest a causal relationship between the IP and the adverse event.
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Causality should be assessed and provided for every AE/SAE based on currently available 
information. Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP 
that has not been manufactured or provided by Celgene, please provide the name of the 
manufacturer when reporting the event.
10.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
10.2.5.
Action Taken
The Investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(eg discontinuation, interruption, or dose reduction of IP, as appropriate) and report if 
concomitant and/or additional treatments were given for the event. 
10.2.6.
Outcome
The Investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE).
10.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:

results in discontinuation from the study

requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention; or

is judged to be of significant clinical importance, for example, one that indicates a 
new disease process and/or organ toxicity, or is an exacerbation or worsening of an 
existing condition
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the CRF. If the abnormality was not a 
part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. If 
possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg record thrombocytopenia rather than decreased platelets).
10.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject of childbearing 
potential or partner of childbearing potential of a male subject are immediately reportable events.  
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The exposure of any pregnant female (eg caregiver, Pharmacist, study coordinator or monitor) to 
lenalidomide is also an immediately reportable event.
10.4.1.
Females of Childbearing Potential:
Pregnancies and suspected pregnancies (including elevated β-subunit of human chorionic 
gonadotropin (β-hCG) or positive pregnancy test in a female subject of childbearing potential 
regardless of disease state) occurring while the subject is on IP, or within 90 days after the last 
dose of durvalumab, 12 months after the last dose of rituximab, or 28 days after last dose of
lenalidomide, are considered immediately reportable events.
Investigational product is to be discontinued immediately (please also see Section 11.1) and the 
subject instructed to return any unused portion of lenalidomide or prednisone/prednisolone to the 
Investigator.  The pregnancy, suspected pregnancy, or positive pregnancy test must be reported to 
Celgene Drug Safety immediately by email, phone or facsimile, or other appropriate method, 
using the Pregnancy Initial Report Form, or approved equivalent form.  
The female subject should be referred to an obstetrician-gynecologist, preferably one 
experienced in reproductive toxicity for further evaluation and counseling.
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.
If the outcome of the pregnancy was abnormal (eg spontaneous abortion), the Investigator should 
report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the SAE Report 
Form, or approved equivalent form.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to any IP should also be reported to Celgene Drug Safety by 
facsimile, or other appropriate method, within 24 hours of the Investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form.
10.4.2.
Male Subjects
If a female partner of a male subject taking IP becomes pregnant, the male subject taking IP 
should notify the Investigator, and the pregnant female partner should be advised to call their 
healthcare provider immediately.  
10.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the CRF. All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event by facsimile, 
or other appropriate method (eg via email), using the SAE Report Form, or approved equivalent 
form. This instruction pertains to initial SAE reports as well as any follow-up reports.
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The Investigator is required to ensure that the data on these forms is accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study 
(from the time the subject signs informed consent until 90 days after the last dose of durvalumab 
or 28 days after the last dose of any other IP, whichever is later) or any SAE made known to the 
Investigator at any time thereafter that are suspected of being related to IP. Serious adverse 
events occurring prior to treatment (after signing the ICF) will be captured.
The SAE report should provide a detailed description of the SAE and include a concise summary 
of hospital records and other relevant documents. If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
Safety as soon as these become available. Any follow-up data should be detailed in a subsequent 
SAE Report Form, or approved equivalent form, and sent to Celgene Drug Safety.  
Where required by local legislation, the Investigator is responsible for informing the Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event. The Investigator must keep copies of all SAE 
information on file including correspondence with Celgene and the IRB/EC.
10.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail. The response time is expected to be no more than five (5) business 
days. Urgent queries (eg missing causality assessment) may be handled by phone.
10.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to durvalumab or lenalidomide based on the IB.
In the US, all suspected unexpected serious adverse reactions (SUSARs) will be reported in an 
expedited manner in accordance with 21 CFR 312.32.
For countries within the European Economic Area (EEA), Celgene or its authorized 
representative will report in an expedited manner to Regulatory Authorities and Ethics 
Committees concerned, suspected unexpected SUSARs in accordance with Directive 
2001/20/EC and the Detailed Guidance on collection, verification and presentation of adverse 
reaction reports arising from clinical trials on investigational products for human use 
(ENTR/CT3) and also in accordance with country-specific requirements. 
For the purpose of regulatory reporting in the EEA, Celgene Drug Safety will determine the 
expectedness of events suspected of being related to the other components of the study treatment
(ie, rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone/prednisolone,) based on 
the EU Summary of Product Characteristics (SmPC). Any SAE that is suspected of being related 
to local Involved-Field Radiation Therapy (IFRT) alone will not be assessed for expectedness or 
reported in an expedited manner.
Events of disease progression for the disease under study (including deaths due to disease 
progression for indications that are considered to be fatal) will be assessed as expected adverse 
events and will not be reported as expedited safety reports to regulatory authorities.
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Celgene or its authorized representative shall notify the Investigator of the following information 
(in Japan, Celgene KK shall notify the Heads of the Institutes in addition to the Investigators):

Any AE suspected of being related to the use of IP(s) in this study or in other studies 
that is both serious and unexpected (ie, SUSAR)

Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity

In Japan, measures taken in foreign countries to ensure subject safety, study reports 
that indicate potential risk of cancer, etc, or SAE report according to the local 
regulations
Where required by local legislation, the Investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects.
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC. (See Section 14.3 for record retention 
information).
10.7.
Adverse Events of Special Interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid 
communication by the Investigator to the Sponsor. An AESI may be serious or non-serious. 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. These AESIs are 
being closely monitored in clinical studies with durvalumab monotherapy and combination 
therapy.
An imAE is defined as an adverse event that is associated with drug exposure and is consistent 
with an immune-mediated mechanism of action and where there is no clear alternate etiology. 
Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to support 
an imAE diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin, or other etiologic causes of the imAE.
If the Investigator has any questions in regard to an adverse event (AE) being an imAE, the 
Investigator should promptly contact the Medical Monitor.
10.7.1.
AESIs for Durvalumab
The AESIs reported for durvalumab are AEs that include, but are not limited to, events with a 
potential inflammatory or immune-mediated mechanism that may require more frequent 
monitoring and/or interventions such as corticosteroids, immunosuppressants, and/or endocrine 
therapy. Early recognition of signs and symptoms potentially related to an inflammatory or 
immune-mediated mechanism is important for proper management of toxicities.
The AESIs observed with anti PD-L1/PD-1 agents such as durvalumab include diarrhea/colitis, 
pneumonitis/ILD, hepatitis and increases in transaminases, endocrinopathies, dermatitis/rash and 
pruritus, nephritis and increases in serum creatinine, neuromuscular toxicity such as myasthenia 
gravis and Guillain-Barre, and pancreatitis. These are described below in more detail.
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For guidance on identifying, evaluating, and treating AESIs see the toxicity management 
guidelines (Table 6, Table 7, Table 8, Table 9, Table 10).
Further information on these AESIs (eg, presenting symptoms) can be found in the current 
version of the durvalumab Investigator’s Brochure.
10.7.2.
AESIs for Lenalidomide
The AESIs defined for lenalidomide in this study are Second Primary Malignancies (SPM), Deep 
Vein Thrombosis (DVT), and Tumor Flare Reaction (TFR). These AESIs are described below in 
more detail.
Further information on the AESIs for lenalidomide can be found in the current version of the 
lenalidomide IB and in the lenalidomide prescribing information.
10.7.2.1.
Second Primary Malignancies 
Second primary malignancies will be monitored as events of interest and must be reported as 
serious adverse events regardless of the treatment arm the subject is in and must be considered as 
“Important Medical Events” if no other serious criteria apply. This includes any second primary 
malignancy, regardless of causal relationship to IP (study drugs), occurring at any time for the 
duration of the study, from the time of signing the ICF for at least until: 

90 days after last dose of study treatment; or

Up to 5 years from last subjects’ first lenalidomide dose in the study, whichever is the 
later date for an individual subject
as well as, those SPMs made known to the Investigator at any time thereafter that are suspected 
of being related to any IP.
These events must also be documented in the appropriate page(s) of the CRF (ie, AE and SPM 
CRF) and subject’s source documents. Documentation on the diagnosis of the second primary 
malignancy must be provided at the time of reporting as a serious adverse event (eg any 
confirmatory histology or cytology results, x-rays, CT scans, etc). 
Following completion of the last durvalumab subject’s 90-day Safety Follow-up Visit (data 
cutoff date 06 Jun 2019), SPMs will no longer be collected in the CRFs. Subjects who received 
lenalidomide will continue to be followed for SPMs as required by this study protocol 
(Section 3.1.3.1) 
. Investigators will continue to record SPMs in the 
subject’s source documents and report SPM events to Celgene Drug Safety. After stopping data 
collection in the clinical database, any SPM events will continue to be collected in the safety 
database.  
10.7.2.2.
Deep Vein Thrombosis
Factors known to increase thrombotic risk in cancer patients in general, not necessarily those 
receiving lenalidomide, include but are not limited to the underlying disease, family history, age, 
obesity, immobilization, hormonal therapy, central venous catheter, recent DVT, and 
doxorubicin (Zhou, 2010; Park, 2012; Lyman 2013).
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Although available data with lenalidomide monotherapy in lymphoma patients show a lower 
incidence of VTE compared with lenalidomide in combination with dexamethasone in multiple 
myeloma subjects, it is recommended that all subjects at risk for thromboembolic events receive 
anti-thrombotic prophylaxis (see Section 8.1.2), and all subjects will be closely monitored for 
VTE.
10.7.2.3.
Tumor Flare Reaction / Pseudoprogression
Tumor flare reaction is an adverse effect of lenalidomide typically occurring in the first cycle 
(Chanan-Khan, 2008a; Witzig, 2009). It is important to note that the increased lymphadenopathy 
seen in TFR may mimic PD. Therefore, careful monitoring and evaluation to differentiate TFR 
from PD is necessary for addressing treatment of individual subjects including making decisions 
to discontinue treatment (Chanan-Khan, 2008b). There are currently no laboratory or
radiological tests that distinguish TFR from PD. The distinction may be made on clinical 
grounds, incorporating observations such as timing of the event relative to the start of 
lenalidomide, associated physical findings, laboratory findings, and pace of disease before and 
after institution of lenalidomide treatment. Also, in case of TFR, inflammation and edema may 
reduce or disappear after short term treatment with NSAIDs and/or corticosteroids.
Management of TFR is described in Section 8.1.5.
10.7.3.
Other AESIs
Other AESIs defined in this study are Infusion-Related Reactions and Allergic Reactions, Tumor 
Lysis Syndrome (TLS), and Myelosuppression. These AESIs can be related to any of the study 
treatments including backbone therapy with rituximab, cyclophosphamide, doxorubicin, 
vincristine, and prednisone.
These AESIs are described below in more detail.
10.7.3.1.
Infusion-Related Reaction, Anaphylaxis and Allergic Reactions
With the administration of monoclonal antibodies, major safety concerns associated with 
immunogenicity include serious allergic reactions and anaphylaxis, cytokine-release syndrome, 
infusion-related reactions, and delayed hypersensitivity associated to immune complex disease, 
which can potentially be severe or life-threatening leading to death.
Adverse reactions that occur during or shortly after infusion may include fever, chills, 
hypotension, dyspnea, tachycardia, cyanosis, respiratory failure, urticaria and pruritus, 
angioedema, hypotonia, arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, headache, 
hypertension rash, headache, flushing, sweating, myalgia, nausea, vomiting, unresponsiveness, 
and hemodynamic instability. The typical onset can be within 30 minutes to 2 hours after the 
initiation of drug infusion, although symptoms may be delayed for up to 24 hours. The majority 
of reactions occur after the first or second exposure to the agent, but between 10% and 30% 
occur during subsequent treatments (Lenz, 2007).
Anaphylaxis is a systemic, immediate hypersensitivity reaction that is mediated by interactions 
between factors released from IgE and mast cells; these interactions result in an antigen/antibody 
reaction. Clinical manifestations of acute allergic reactions may range from localized skin 
reactions at the injection site to AEs, which can include, but are not limited to, those events 
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similar to infusion-related reactions to severe reactions including anaphylaxis and drug 
hypersensitivity syndromes. These reactions may be more common with higher rates of infusion, 
and in patients with a history of allergies.
Patients should be closely monitored during and after infusions. Severe hypersensitivity reactions 
should be managed according to standard clinical practice, and medical equipment and staff 
trained to treat acute anaphylactic reactions must be immediately available at all sites that 
perform mAb infusions.
10.7.3.2.
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) is a well-known constellation of metabolic abnormalities resulting 
from spontaneous or treatment-related tumor necrosis or fulminant apoptosis. The metabolic 
abnormalities include: hyperkalemia, hyperuricemia and hyperphosphatemia with secondary 
hypocalcaemia with risk of renal failure. TLS has been reported in subjects receiving rituximab 
plus lenalidomide and rituximab plus chemotherapy.
The presence of known risk factors such as bulky disease, pre-existing (moderate) renal 
insufficiency, high ALC and high uric acid levels (> 8 mg/ dL) prior to therapy are known to 
increase the likelihood of TLS. Early identification of subjects at risk and the prevention of TLS 
development with the initiation of preventive measures, as well as the careful monitoring for 
early signs of laboratory TLS and the prompt initiation of supportive care are critical to prevent 
potentially life-threatening metabolic derangements (Cairo, 2010).
Management of TLS is described in Section 8.3.3.
10.7.3.3.
Myelosuppression
Myelosuppression is the major toxicity of rituximab plus cyclophosphamide, doxorubicin, 
vincristine, and prednisone (R-CHOP) regimen in the treatment of diffuse large B-cell 
lymphoma and can present as decrease in the WBC count, decrease in the platelet count, 
decrease in the hemoglobin concentration, or any combination of those.
Particularly neutropenia and febrile neutropenia (FN) are serious hematologic toxicities of 
chemotherapy containing myelotoxic agents, and prolonged FN may increase disease-related 
morbidity and mortality.
Management of myelosuppression is described in Table 9. Please also refer to Section 8.3.5 for 
the use of neutropenia prophylaxis with G-CSF.
10.8.
Celgene Drug Safety Contact Information:
For Celgene Drug Safety contact information, please refer to the Serious Adverse Event Report 
Form Completion Guidelines or to the Pregnancy Report Form Completion Guidelines.
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11.
DISCONTINUATIONS
11.1.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product(s):

Treatment was completed per protocol

Adverse event(s)

Pregnancy (please also see Section 10.4.1)

Disease progression

Protocol violation

Withdrawal of consent

Lost to follow up

Death

Other (to be specified on the CRF)
The reason for discontinuation of treatment should be recorded in the CRF and in the source 
documents.
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor. However, prior to discontinuing 
a subject, the Investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion.
11.2.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
study:

Disease progression

Adverse event

Protocol violation

Withdrawal of consent

Screen failure

Lost to follow up

Death

Other (to be specified on the CRF)
The reason for study discontinuation should be recorded in the CRF and in the source 
documents.
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12.
EMERGENCY PROCEDURES
12.1.
Emergency Contact
In emergency situations, the Investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page). This global 
Emergency Call Center is available 24 hours a day and 7 days a week. The representatives are 
responsible for obtaining your call-back information and contacting the on-call Celgene/contract 
research organization Medical Monitor, who will then contact you promptly.
Note: The back-up 24-hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls. 
12.2.
Emergency Identification of Investigational Products
This is an open-label study; therefore, IP will be identified on the package labeling.
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13.
REGULATORY CONSIDERATIONS
13.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative, 
and Investigator abide by Good Clinical Practice (GCP), as described in ICH Guideline E6 and 
in accordance with the general ethical principles outlined in the Declaration of Helsinki. The 
study will receive approval from an IRB/EC prior to commencement. The Investigator will 
conduct all aspects of this study in accordance with applicable national, state, and local laws of 
the pertinent regulatory authorities.
13.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations. Celgene staff or an authorized representative will evaluate and approve all 
Investigators who in turn will select their staff.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of Celgene information. The Investigator should maintain 
a list of Sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an informed consent 
form (ICF) and are screened for entry into the study. Subjects who fail Screening must have the 
reason(s) recorded in the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg
medical records, office charts, hospital charts, and study-related charts) for source data 
verification. The Investigator must ensure timely and accurate completion of CRFs and queries.
The information contained in the protocol and amendments (with the exception of the 
information provided by Celgene on public registry websites) is considered Celgene confidential 
information. Only information that is previously disclosed by Celgene on a public registry 
website may be freely disclosed by the Investigator or its institution, or as outlined in the Clinical 
Trial Agreement. Celgene protocol, amendment and IB information is not to be made publicly 
available (for example on the Investigator’s or their institution’s website) without express written 
approval from Celgene. Information proposed for posting on the Investigator’s or their 
institution’s website must be submitted to Celgene for review and approval, providing at least 5 
business days for review.
At the time results of this study are made available to the public, Celgene will provide 
Investigators with a summary of the results that is written for the lay person. The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.
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13.3.
Subject Information and Informed Consent
The Investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date. The original ICF signed and dated by the study subject and by the person 
consenting the study subject prior to the study subject’s entry into the study, must be maintained 
in the Investigator’s study files and a copy given to the study subject. In addition, if a protocol is 
amended and it impacts on the content of the informed consent, the ICF must be revised. Study 
subjects participating in the study when the amended protocol is implemented must be 
reconsented with the revised version of the ICF. The revised ICF signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the Investigator’s 
study files and a copy given to the study subject.
13.4.
Confidentiality
Celgene affirms the subject's right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Celgene requires 
the Investigator to permit Celgene's representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual.
13.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene Clinical Research 
Physician/Medical Monitor. Amendments will be submitted to the IRB/EC for written approval.
Written approval must be obtained before implementation of the amended version occurs. The 
written signed approval from the IRB/EC should specifically reference the Investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/IEC approval but will be submitted to the IRB/IEC 
for information purposes.
13.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF, and any other appropriate documents will 
be submitted to the IRB/EC with a cover letter or a form listing the documents submitted, their 
dates of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is 
sought. If applicable, the documents will also be submitted to the authorities in accordance with 
local legal requirements.
IP can only be supplied to an Investigator by Celgene or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
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Celgene or its authorized representative. This documentation must also include a list of the 
members of the IRB/EC and their occupation and qualifications. If the IRB/EC will not disclose 
the names, occupations and qualifications of the committee members, it should be asked to issue 
a statement confirming that the composition of the committee is in accordance with GCP. For 
example, the IRB General Assurance Number may be accepted as a substitute for this list. 
Formal approval by the IRB/EC should mention the protocol title, number, amendment number 
(if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICF should also be revised.
The Investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the Investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and the 
IRB/EC prior to use.  
13.7.
Ongoing Information for Institutional Review Board/ Ethics 
Committee
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC:

Information on serious or unexpected adverse events as soon as possible

Periodic reports on the progress of the study

Deviations from the protocol or anything that may involve added risk to subjects
13.8.
Termination of the Study
Celgene reserves the right to terminate this study prematurely at any time for reasonable medical  
or administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg IRB/EC, regulatory authorities, etc).
In addition, the Investigator or Celgene has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such as:

Unsatisfactory enrollment

GCP noncompliance

Inaccurate or incomplete data collection

Falsification of records

Failure to adhere to the study protocol
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14.
DATA HANDLING AND RECORDKEEPING 
14.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of CRFs or CD-ROM.
There will be no analysis of data generated after the last durvalumab subject’s 90-day Safety 
Follow-up Visit date (data cutoff date 06 Jun 2019). Any data generated after this data cutoff 
date will be maintained in the source documents and will not need to be entered in the CRFs.
14.2.
Data Management
Data will be collected via CRF and entered into the clinical database per Celgene standard 
operative procedures (SOPs). This data will be electronically verified through use of 
programmed edit checks specified by the clinical team. Discrepancies in the data will be brought 
to the attention of the clinical team, and investigational site personnel, if necessary. Resolutions 
to these issues will be reflected in the database. An audit trail within the system will track all 
changes made to the data.
There will be no analysis of data generated after the last durvalumab subject’s 90-day Safety 
Follow-up Visit date (data cutoff date 06 Jun 2019). Any data generated after this data cutoff 
date will be maintained in the source documents and will not need to be entered in the CRFs.
14.3.
Record Retention
Essential documents must be retained by the Investigator according to the period of time outlined 
in the clinical trial agreement. The Investigator must retain these documents for the time period 
described above or according to local laws or requirements, whichever is longer. Essential 
documents include, but are not limited to, the following:

Signed ICFs for all subjects;

Subject identification code list, Screening log (if applicable), and enrollment log;

Record of all communications between the Investigator and the IRB/EC;

Composition of the IRB/EC;

Record of all communications between the Investigator, Celgene, and their authorized 
representative(s);

List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures;

Copies of CRFs (if paper) and of documentation of corrections for all subjects;
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
IP accountability records;

Record of any body fluids or tissue samples retained;

All other source documents (subject records, hospital records, laboratory records, 
etc.); 

All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
The Investigator must notify Celgene if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified period.
The Investigator must obtain approval in writing from Celgene prior to destruction of any 
records. If the Investigator is unable to meet this obligation, the Investigator must ask Celgene 
for permission to make alternative arrangements. Details of these arrangements should be 
documented. 
All study documents should be made available if required by relevant health authorities. 
Investigator or institution should take measures to prevent accidental or premature destruction of 
these documents.
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15.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and SOPs.
15.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study. All aspects of the study are reviewed with the Investigator and the staff at a study 
initiation visit and/or at an Investigators’ Meeting. Prior to enrolling subjects into the study, a 
Celgene representative will review the protocol, CRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the Investigator. Monitoring will 
include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone. During monitoring visits, the facilities, 
investigational product storage area, CRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Celgene representative in accordance with the 
Study Monitoring Plan.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the CRFs against the appropriate source documentation. Any resulting 
discrepancies will be reviewed with the Investigator and/or his/her staff. Any necessary 
corrections will be made directly to the CRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified. Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
15.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene. Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, CRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (eg Food and Drug Administration 
[FDA] and European Medicines Agency [EMA]) and company authorized representatives. The 
Investigator should make every effort to be available for the audits and/or inspections. If the 
Investigator is contacted by any regulatory authority regarding an inspection, he/she should 
contact Celgene immediately.
15.3.
Product Quality Complaint
A Product Quality Complaint (PQC) is any written, electronic, or oral communication that 
alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, 
purity, or performance of any drug product manufactured by or on behalf of Celgene Corporation 
after it is released for distribution.  PQCs may reduce the usability of the product for its intended 
function or affect performance of the product and therefore pose a significant risk to the patient.  
Examples of PQCs include (but are not limited to): mixed product, mislabeling, lack of effect, 
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seal/packaging breach, product missing/short/overage, contamination, suspected falsified, 
tampered, diverted or stolen material, and general product/packaging damage. If you become 
aware of a suspected PQC, you are obligated to report the issue immediately.  You can do so by 
emailing 
 or by contacting the Celgene Customer Care Center 
.
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16.
PUBLICATIONS
As described in Section 13.2, all protocol- and amendment-related information, with the 
exception of the information provided by Celgene on public registry websites, is considered 
Celgene confidential information and is not to be used in any publications. Celgene protocol-
related information proposed for use in a publication must be submitted to Celgene for review 
and approval, and should not be utilized in a publication without express written approval from 
Celgene, or as described in the Clinical Trial Agreement.  
Celgene will ensure Celgene-sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results. At a minimum, this applies to 
results from all Phase 3 clinical studies, and any other study results of significant medical 
importance. This also includes results relating to investigational medicines whose development 
programs have been discontinued.
Study results may also be presented at one or more medical congresses, and may be used for 
scientific exchange and teaching purposes. Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.
Eligibility for external authorship, as well as selection of first authorship, will be based on 
several considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable) and contribution to abstract, presentation and/or publication development.
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17.
REFERENCES
Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, et al. Distinct types of 
diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000; 
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18.
APPENDICES
Appendix A: Table of Abbreviations
Table 15:
Table of Abbreviations
Abbreviation or 
Specialist Term
Explanation
ABC
Activated B-cell
ADA
Anti-drug antibodies
ADCC
Antibody-dependent cell-mediated cytotoxicity
ADL
Activity of daily life
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil count
anti-HBc
Antibody to the hepatitis B core antigen
Anti-HBs
HBV surface antibody
ASCO
American Society of Clinical Oncology
ASCT
Autologous stem cell transplant
AST
Aspartate aminotransferase (SGOT)
β-hCG
β-subunit of human chorionic gonadotropin
BMA
Bone marrow aspirate
BMB
Bone marrow biopsy
BSA
Body surface area
BUN
Blood urea nitrogen
C
Cycle
CBC
Complete blood count
CHOP
Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone
CI
Confidence interval
CLL
Chronic lymphocytic leukemia
CNS
Central nervous system
COO
Cell of origin
CR
Complete response
CrCl
Creatinine clearance
CRF
Case report form
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Table 15:
Table of Abbreviations (Continued)
Abbreviation or 
Specialist Term
Explanation
CSF
Cerebrospinal fluid
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA
Cytotoxic T-lymphocyte-associated antigen
D
Day
DEL
Double-expressor lymphoma
DHL
Double-hit lymphoma
DLBCL
Diffuse large B-cell lymphoma
DLT
Dose-limiting toxicity
EBV
Epstein-Barr virus
EC
Ethics Committee
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EEA
European Economic Area
EFS
Event-free survival
EOI
End of infusion
EOT
End of treatment
ESMO
European Society for Medical Oncology
FCBP
Female subjects of childbearing potential
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
FFPE
Formalin-fixed paraffin-embedded
FL
Follicular lymphoma
GCB
Germinal center B-cell
G-CSF
Granulocyte-Colony stimulating factor
GEP
Gene expression profiling
GCP
Good Clinical Practice
GM-CSF
Granulocyte Macrophage-Colony stimulating factor
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Table 15:
Table of Abbreviations (Continued)
Abbreviation or 
Specialist Term
Explanation
GSSC
Global scientific steering committee
HBsAg
HBV surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
IHC
Immunohistochemistry
imAE
Immune-mediated adverse event
IMiD
Immunomodulatory drug
IND
Investigational New Drug
INR
International normalized ratio
IP
Investigational Product
IPI
International Prognostic Index
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
Intravenous
IWG
International Working Group
LDH
Lactic acid dehydrogenase
LST
Lymphoma subtyping test
LTLS
Laboratory tumor lysis syndrome
LVEF
Left ventricular ejection fraction
mAb
Monoclonal antibody
MCL
Mantle cell lymphoma
MDS
Myelodysplastic syndromes
MedDRA
Medical Dictionary for Regulatory Activities
MM
Multiple myeloma
MRI
Magnetic resonance imaging
MUGA
Multi gated acquisition scan
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Table 15:
Table of Abbreviations (Continued)
Abbreviation or 
Specialist Term
Explanation
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NHL
Non-Hodgkin’s Lymphoma
NOS
Not otherwise specified
NSAID  
Non-steroidal anti-inflammatory drug  
NSCLC
Non-small cell lung cancer
ORR
Overall response rate
OS
Overall survival
PBMC
Peripheral Blood Mononuclear Cell
PD
Progressive Disease
Pd
Pharmacodynamic(s)
PD-1
Programmed cell death-1
PD-L1
Programmed cell death-ligand 1
PET
Positron emission tomography
PFS
Progression-free survival
PK
Pharmacokinetics
PO
Oral administration
PR
Partial response
PTT
Partial thromboplastin time
Q2W
Once every 2 weeks
Q4W
Once every 4 weeks
R-CHOP
Rituximab plus CHOP
R2-CHOP
Lenalidomide plus R-CHOP
SAE
Serious adverse event
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SmPC
Summary of Product Characteristics
SOP
Standard operating procedure
SPM
Second primary malignancies
SRC
Safety Review Committee
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Table 15:
Table of Abbreviations (Continued)
Abbreviation or 
Specialist Term
Explanation
SUSAR
Suspected unexpected serious adverse reaction
THL
Triple-hit lymphoma
TIL
Tumor-infiltrating lymphocytes
TLS
Tumor lysis syndrome
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
US
United States 
VTE
Venous thromboembolism
WBC
White blood cell count
WHO
World Health Organization
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Appendix B: Recommendations for Initial Evaluation, Staging, and Response 
Assessment of Hodgkin and Non-Hodgkin Lymphoma: The 
Lugano Classification
The guidelines for Recommendations for Initial Evaluation, Staging, and Response Assessment 
of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification are outlined in a report 
(Cheson, 2014).
Table 16:
Criteria for Involvement of Site
Tissue Site
Clinical
FDG Avidity
Test
Positive Finding
Lymph nodes
Palpable
FDG-avid 
histologies
Nonavid disease
PET-CT
                   
CT
Increase FDG uptake
Unexplained node 
enlargement
Spleen
Palpable
FDG-avid 
histologies
Nonavid disease
PET-CT
                   
CT
Diffuse update, solitary 
mass, military lesions, 
nodules > 13 cm in 
vertical length, mass, 
nodules
Liver
Palpable
FDG-avid 
histologies
Nonavid disease
PET-CT
                   
CT
Diffuse update, mass           
Nodules                        
CNS
Signs, symptoms
CT
MRI
CSF 
assessmen
t
Mass lesion(s)
Leptomeningeal 
infiltration, mass lesions
Cytology, flow cytometry
Other (eg skin, 
lung, GI tract, 
bone, bone 
marrow)
Site dependent
PET-CTa, 
biopsy
Lymphoma involvement
CSF = cerebrospinal fluid; CT = computed tomography; FDG = fluorodeoxyglucose; MRI = magnetic resonance 
imaging; PET = positron emission tomography.
a PET-CT is adequate for determination of bone marrow involvement and can be considered highly suggestive for 
involvement of other extralymphatic sites. Biopsy confirmation of those sites can be considered if necessary.
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Table 17:
Revised Criteria for Response Assessment
Response and 
site
PET-CT based response
CT-based response
Complete
Complete metabolic response
Complete radiologic response (all 
of the following)
Lymph nodes and 
extralymphatic sites
Score 1, 2, or 3a with or without a residual 
mass on 5PSb
It is recognized that in Waldeyer's ring or 
extranodal sites with high physiologic uptake 
or with activation within spleen or marrow (eg
with chemotherapy or myeloid colony-
stimulating factors), uptake may be greater 
than normal mediastinum and/or liver. In this 
circumstance, complete metabolic response 
may be inferred if uptake at sites of initial 
involvement is no greater than surrounding 
normal tissue even if the tissue has high 
physiologic uptake
Target nodes/nodal masses must regress 
to ≤ 1.5 cm in LDi
No extralymphatic sites of disease
Non-measured 
lesion
Not applicable
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in marrow
Normal by morphology; if 
indeterminate, IHC negative
Partial 
Partial metabolic response
Partial remission (all of the 
following)
Lymph nodes and 
extralymphatic sites
Score 4 or 5b with reduced uptake compared 
with baseline and residual mass(es) of any size
At interim, these findings suggest responding 
disease
At end of treatment, these findings indicate 
residual disease
≥ 50% decrease in sum of perpendicular 
diameters (SPD) of up to 6 target 
measurable nodes and extranodal sites 
When a lesion is too small to measure 
on CT, assign 5 mm × 5 mm as the 
default value
When no longer visible, 0 × 0 mm
For a node > 5 mm × 5 mm, but smaller 
than normal, use actual measurement 
for calculation
Non-measured 
lesion
Not applicable
Absent/normal, regressed, but no 
increase
Organ enlargement
Not applicable
Spleen must have regressed > 50% in 
length beyond normal
New lesions
None
None
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Table 17:
Revised Criteria for Response Assessment (Continued)
Response and 
site
PET-CT based response
CT-based response
Bone marrow
Residual uptake higher than uptake in normal 
marrow but reduced compared with baseline 
(diffuse uptake compatible with reactive 
changes from chemotherapy allowed).  If there 
are persistent focal changes in the marrow in 
the context of a nodal response, consideration 
should be given to further evaluation with 
MRI or biopsy or an interval scan
Not applicable
No response or 
stable disease
No metabolic response
Stable disease
Target nodes/nodal 
masses, extranodal 
lesions
Score 4 or 5b with no significant change in 
FDG uptake from baseline at interim or end of 
treatment
< 50% decrease from baseline in SPD 
of up to 6 dominant measurable nodes 
and extranodal sites; no criteria for 
progressive disease are met
Non-measured 
lesion
Not applicable
No increase consistent with progression
Organ enlargement
Not applicable
No increase consistent with progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable
Progressive 
disease
Progressive metabolic response
Progressive disease requires at 
least 1 of the following
Individual target 
nodes/nodal masses
Score 4 or 5b with an increase in intensity of 
uptake from baseline and/or
PPD progression:
Extranodal lesions
New FDG-avid foci consistent with lymphoma 
at interim or end-of-treatment assessment
An individual node/lesion must be 
abnormal with:
LDi  > 1.5 cm and 
Increase by ≥ 50% from PPD nadir and  
An increase in LDi or SDi from nadir
0.5 cm for lesions ≤ 2 cm
1.0 cm for lesions > 2 cm
In the setting of splenomegaly, the 
splenic length must increase by > 50% 
of the extent of its prior increase 
beyond baseline (eg a 15 cm spleen 
must increase to > 16 cm).  If no prior 
splenomegaly, must increase by at least 
2 cm from baseline
New or recurrent splenomegaly
Non-measured 
lesions
None
New or clear progression of preexisting 
non-measured lesions
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Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
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MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Table 17:
Revised Criteria for Response Assessment (Continued)
Response and 
site
PET-CT based response
CT-based response
New lesions
New FDG-avid foci consistent with lymphoma 
rather than another etiology (eg infection, 
inflammation).  If uncertain regarding etiology 
of new lesions, biopsy or interval scan may be 
considered
Regrowth of previously resolved 
lesions
A new node > 1.5 cm in any axis
A new extranodal site > 1.0 cm in any 
axis, if < 1.0 cm in any axis, its 
presence must be unequivocal and must 
be attributable to lymphoma
Assessable disease of any size 
unequivocally attributable to lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
5PS = 5-point scale; CT = computed tomography; FDG = fluorodeoxyglucose; GI = gastrointestinal; IHC = 
immunohistochemistry; LDi = longest transverse diameter of a lesion; MRI = magnetic resonance imaging; PET = 
positron emission tomography; PPD = cross product of the LDi and perpendicular diameter; SDi = shortest axis 
perpendicular to the LDi; SPD = sum of the product of the perpendicular diameters for multiple lesions.
a A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of 
an interim scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to 
consider a score of 3 as inadequate response (to avoid undertreatment). 
Measured dominant lesions: Up to six of the largest dominant nodes, nodal masses, and extranodal lesions 
selected to be clearly measurable in two diameters. Nodes should preferably be from disparate regions of the 
body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include 
those in solid organs (eg liver, spleen, kidneys, and lungs), GI involvement, cutaneous lesions, or those noted 
on palpation. Non-measured lesions: Any disease not selected as measured, dominant disease and truly 
assessable disease should be considered not measured. These sites include any nodes, nodal masses, and 
extranodal sites not selected as dominant or measurable or that do not meet the requirements for measurability 
but are still considered abnormal, as well as truly assessable disease, which is any site of suspected disease 
that would be difficult to follow quantitatively with measurement, including pleural effusions, ascites, bone 
lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed 
by imaging. In Waldeyer’s ring or in extranodal sites (eg GI tract, liver, bone marrow), FDG uptake may be 
greater than in the mediastinum with complete metabolic response, but should be no higher than surrounding 
normal physiologic uptake (eg with marrow activation as a result of chemotherapy or myeloid growth factors).
b PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, 
uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake 
unlikely to be related to lymphoma.
Source: Cheson, 2014
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MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Appendix C: Eastern Cooperative Oncology Group (ECOG) Performance 
Status 
ECOG Performance Status (Oken, 1982) will be scored according to Table 18. 
Table 18:
Performance Status by Eastern Cooperative Oncology Group Scale
Score
Description
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, eg, light housework, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair.
5
Dead.
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
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Appendix D: Cairo-Bishop Definitions of Tumor Lysis Syndrome
Table 19:
Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome (LTLS)
Laboratory Parameter
Laboratory Result
Uric Acid
≥ 476 μmol/L (≥ 8.0 mg/dL) or 25% increase from baseline
Potassium
≥ 6.0 mmol/L (≥ 6.0 mEq/L) or 25% increase from baseline
Phosphorous
≥1.45 mmol/L (≥ 4.5 mg/dL) or 25 % increase from baseline
Calcium
≤ 1.75 mmol/L (≤ 7.0 mg/dL) or 25% decrease from baseline
Laboratory tumor lysis syndrome (LTLS) is defined as either a 25% change or level above or below normal, as 
defined above, for any two or more serum values of uric acid, potassium, phosphate, and calcium within 3 days 
before or 7 days after the initiation of chemotherapy.  This assessment assumes that a subject has or will receive 
adequate hydration (± alkalinization) and a hypouricemic agent(s).
Table 20:
Cairo-Bishop Definition of Clinical TLS
The presence of laboratory TLS and one or more of the following criteria:
1.
Creatinine: ≥ 1.5 ULN (age > 12 years or age adjusted)
2.
Cardiac arrhythmia / sudden death
3.
Seizurea
ULN = upper limit of normal. 
a Not directly attributable to a therapeutic agent.
Table 21:
Cairo-Bishop Grading System for TLS
Grade
LTLS
Creatinine
Cardiac Arrhythmia
Seizure
0
-
≤ 1.5 × ULN
None
None
1
+
1.5 × ULN
Intervention not 
indicated
None
2
+
> 1.5 – 3.0 × ULN
Non-urgent medical 
intervention indicated
One brief generalized seizure; seizure(s) 
well controlled or infrequent; focal motor 
seizures not interfering with ADL
3
+
> 3.0 – 6.0 × ULN
Symptomatic and 
incompletely 
controlled medically or 
controlled with device
Seizure in which consciousness is altered; 
poorly controlled seizure disorder; 
breakthrough generalized seizures despite 
medical intervention
4
+
> 6.0 × ULN
Life-Threatening
Seizures of any kind that are prolonged, 
repetitive, or difficult to control
5
+
Deatha
Deatha
Deatha
ADL= activities of daily living; LTLS = laboratory tumor lysis syndrome; TLS= tumor lysis syndrome; ULN = 
upper limit of normal.  
a Probably or definitely attributable to clinical TLS.
Source: Cairo, 2004
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EDMS Doc. Number: 24223666 - 20700003
Durvalumab (MEDI4736)
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Appendix E: Lenalidomide Pregnancy Prevention Risk Management Plan
The Pregnancy Prevention Risk Management Plan is a standalone document.
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Durvalumab (MEDI4736)
Protocol MEDI4736-DLBCL-001
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MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
Appendix F: Prognostic Indexes for Patients With DLBCL (IPI and 
NCCN-IPI) and to Assess Risk of CNS Disease
Table 22:
International Prognostic Index
All Patients
International; Index
a
Age
> 60
Low Risk
0-1
Serum LDH 
> normal
Low-Intermediate-risk 
2
Performance Status
> 1
High-Intermediate-risk
3
Stage 
III or IV
High-Risk
4 or 5
Extranodal involvement
> 1 site
IPI = International Prognostic Index, LDH = Lactic acid dehydrogenase, NCCN-IPI = National Comprehensive 
Cancer Network- International Prognostic Index
a The international Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive 
non-Hodgkins’s lymphoma.  N Engl J Med 1993; 329:987-994
Table 23:
National Comprehensive Cancer Network- International Prognostic Index
NCCN-IPI
(Zhou, 2014)
Age, years
Risk Group
> 40 to ≤60
1
Low
0-1
> 60 to < 75
2
Low-Intermediate
2-3
≥75
3
High-Intermediate
4-5
LDH, normalized
(ratio to the institutional 
upper limit of normal)
High
≥6
> 1 to ≤3
1
> 3
2
Ann Arbor stage III-IV
1
Extranodal disease
in major organs:
bone marrow, CNS, liver/GI 
tract, or lung
1
Performance Status ≥2
1
LDH = Lactic acid dehydrogenase, NCCN-IPI = National Comprehensive Cancer Network- International Prognostic 
Index
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EDMS Doc. Number: 24223666 - 20700003
Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
UserName: 
Title:  
Date: Wednesday, 30 October 2019, 11:06 AM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
 ================================================
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EDMS Doc. Number: 24223666 - 21892028
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
3
MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019
1.
JUSTIFICATION FOR AMENDMENT
The purpose of Protocol Amendment 4 is to close the study, discontinue the Follow-up Period,
and stop data collection in the clinical database.  
The protocol-defined primary analysis was completed with a data cutoff date of 02 Aug 2018,
and the last subject’s last durvalumab dose occurred on 04 Mar 2019. Subsequently, the last 
durvalumab subject’s 90-day Safety Follow-up Visit was completed. At the time of the data 
cutoff date of the last 90-day Safety Follow-up Visit (06 Jun 2019), 30 subjects were in 
follow-up. No subjects were on treatment with durvalumab or any other study treatments.
There are no further plans to evaluate long-term efficacy, including overall survival, for the 
remaining subjects on study, and no additional statistical analysis on safety and efficacy will be 
performed. 
Therefore, the Follow-up Period will be discontinued, and data collection in the clinical database
will stop under this amendment. Subjects who received lenalidomide will continue to be 
followed for second primary malignancies (SPMs) as required by this study protocol 
(Section 3.1.3.1) 
. After stopping data collection in the clinical 
database, any SPM events will continue to be collected in the safety database.  
Significant changes included in this amendment are summarized below:

Discontinuation of Follow-up Period, assessments and data collection 
Subjects who completed or discontinued durvalumab per protocol are no longer required to be 
followed for disease progression, subsequent anti-lymphoma therapy, and overall survival.
Follow-up procedures, efficacy assessments, central labs, imaging, adverse events/serious 
adverse events (AEs/SAEs), and survival data collection can stop and will not be collected in the 
case report forms (CRFs). 
Revised Sections:  Protocol Summary, Section 1, Section 2, Section 3.1.3.2, Figure 1, Table 3, 
Section 6.3.3, Section 6.4.2, and Section 10.1.

Second Primary Malignancies (SPMs) data collection
Collection and monitoring of SPMs will continue as events of interest and will be reported as 
SAEs for those who received lenalidomide. For SAE reporting, SPMs are considered “Important 
Medical Events” if no other serious criteria apply. The SPM events will continue to be 
documented in the subject’s source documents, reported as SAEs to Celgene Drug Safety and 
collected in the safety database. It is no longer required to collect SPMs in the clinical database, 
ie, AE and SPM CRFs.
Revised Section: Protocol Summary, Section 1, Section 2, and Section 10.7.2.1.
Other changes included in this amendment are summarized below:

Editorial updates. – Protocol Summary, Table 4, Section 7, Section 7.2.5.2, and 
Section 9.1.

Provided background, enrollment completion update, and purpose of protocol 
amendment 4. – Protocol Summary and Section 1.
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EDMS Doc. Number: 24223666 - 21892028
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
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MEDI4736-DLBCL-001 Amendment 4 Final: 25 Oct 2019

Specified no additional efficacy or safety analyses will be performed after the primary 
analysis (data cutoff date 02 Aug 2018). – Protocol Summary and Section 9.8.

Any data generated after the last durvalumab subject’s 90-day Safety Follow-up Visit 
(data cutoff date 06 Jun 2019) will be maintained in the source documents and not 
required to be entered in the clinical database. – Section 14.1 and Section 14.2.

Removed Health Canada. Protocol was not opened for enrollment in Canada. –
Section 15.2.
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EDMS Doc. Number: 22546740 - 21892028
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
3
MEDI4736-DLBCL-001 Amendment 3 Final: 27 Feb 2018
1.
JUSTIFICATION FOR AMENDMENT
Protocol Amendment 3 is written to implement changes to the study as communicated in an
investigator letter.to all participating sites on 16 Jan 2018. As announced, following the Partial 
Clinical Hold instituted by the United States (US) Food and Drug Administration (FDA) in 
September 2017, Celgene in collaboration with AstraZeneca/MedImmune has decided to modify 
this study to include a total sample size of approximately 40 subjects in the efficacy evaluable 
population and to change the study primary endpoint to the rate of subjects with Complete 
Response at the end of the induction therapy with durvalumab + rituximab, cyclophosphamide, 
doxorubicin, vincristine, prednisone (R-CHOP).
Significant changes included in this amendment are summarized below:

Protocol Summary and Sections 3.1 (Study Design), 4.1 (Number of Subjects), 9.1 
(Statistical Considerations – Overview) and 9.3 (Sample Size and Power 
Considerations): references to sample size have been updated to “approximately 
45 subjects are planned to be enrolled into this study (with approximately 40 subjects 
in the efficacy evaluable population.)”

Protocol Summary and Sections 2 (Study Objectives and Endpoints, Table 2: Study 
Endpoints), 3.1 (Study Design), 4.1 (Number of Subjects), 9.1 (Statistical 
Considerations – Overview), 9.3 (Sample Size and Power Considerations), 9.6 
(Efficacy Analysis) and 9.9.3 (Exploratory Analysis): changes into the listed sections 
have been implemented to modify the primary endpoint to the complete response rate 
at the end of the induction therapy, to add as the key secondary endpoint the rate of 
subjects who continue consolidation therapy out of all subjects in the efficacy 
evaluable population and to move the progression-free survival (PFS) at 24 months 
from the primary to an exploratory endpoint in the study.
Other changes included in this amendment are summarized below:

Protocol Section 2 (Study Objectives and Endpoints, Table 1), Section 3.1.2 
(Treatment Period) and 7.2.3 (Study Drug Treatment): removed non-ABC DLBCL 
and ABC DLBCL as following the US FDA Partial Clinical Hold, all newly enrolled 
subjects are to be assigned to Arm A regardless of cell of origin (COO) diffuse large 
B-cell lymphoma (DLBCL), ABC or non-ABC subtype.  

Protocol Section 10.7.1 (AESIs for Durvalumab): the adverse events of special 
interest (AESIs) listed have been replaced by the following statement “Further 
information on these AESIs (eg, presenting symptoms) can be found in the current 
version of the durvalumab Investigator’s Brochure.”

Correction of typographical errors and updated tables and table footnotes consistently 
with the revised text throughout the document.
Approved
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EDMS Doc. Number: 22442198 - 21892028
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
3
MEDI4736-DLBCL-001 Amendment 2 Final: 02 Jan 2018
1.
JUSTIFICATION FOR AMENDMENT
Protocol Amendment 2 is written to address protocol deficiencies consequent to the Partial 
Clinical Hold instituted to this study by the United States (US) Food and Drug Administration 
(FDA) on 05 Sep 2017 and to include updates to Durvalumab Toxicity Management Guidelines
as per Durvalumab Investigator’s Brochure (IB) Edition 12, dated 03 Nov 2017. 
Significant changes included in this amendment are summarized below.

Protocol Summary and Section 1 (Introduction): Added the following statement to 
describe changes to the study following partial clinical hold placed by the US FDA: 
“On 05 Sep 2017, a Partial Clinical Hold was placed to this study by the United 
States (US) Food and Drug Administration (FDA). The decision by the FDA was 
based on risks identified in other trials for an anti-programmed cell death-1 (PD-1) 
antibody, pembrolizumab, in patients with multiple myeloma in combination with 
immunomodulatory agents. Enrollment into Arm B (durvalumab in combination with 
lenalidomide plus rituximab, cyclophosphamide, doxorubicin, vincristine, 
prednisone [R2-CHOP]) has been discontinued. This study will continue enrollment 
into Arm A. Subjects enrolled and treated in Arm B prior to the US FDA Partial 
Clinical Hold who are receiving clinical benefit, based on the discretion of the 
investigator, may continue study treatment after being reconsented. Any newly 
enrolled subject after the US FDA Partial Clinical Hold will continue induction 
therapy on Arm A (durvalumab + R-CHOP) after Cycle 1 regardless of diffuse large 
B-cell lymphoma (DLBCL) cell of origin (COO) subtype.”

Protocol Summary and Section 2 (Study objectives), Added as exploratory objective: 
To evaluate impact on endpoints related to clinical activity of durvalumab when 
given in combination with R-CHOP followed by durvalumab consolidation.”

Protocol Summary, Section 2 (Study objectives), Section 3.1 (Study Design), 
Section 6 (Procedures), section 7 (description of study treatments), Section 7.2.3.3 
(Lenalidomide) and Section 9 (Statistical Considerations): Added as introductory 
statement and as footnote 1,2,3,6 and 7 for clarification: “Enrollment into Arm B 
(durvalumab in combination with lenalidomide plus rituximab, cyclophosphamide, 
doxorubicin, vincristine, prednisone [R2-CHOP]) has been discontinued.  Subjects 
enrolled and treated in Arm B prior to the US FDA Partial Clinical Hold who are 
receiving clinical benefit, based on the discretion of the investigator, may continue 
study treatment after being reconsented. Any newly enrolled subject after the US 
FDA Partial Clinical Hold will continue induction therapy on Arm A (durvalumab + 
R-CHOP) after Cycle 1 regardless of DLBCL COO subtype.”

Section 3.1.2 (Treatment Period), Figure 1 (Study Design) and section 7.2.3 (Study 
Drug Treatment): Added as statement and as footnotes into Figure 1: “After the US 
FDA Partial Clinical Hold enrollment of new subjects into Arm B has been 
discontinued. If receiving clinical benefit at the discretion of the investigator, 
subjects may continue treatment in Arm B after being reconsented. Any newly 
enrolled subject with DLBCL of ABC COO subtype after the US FDA Partial 
Clinical Hold will continue induction therapy on Arm A after Cycle 1.”
Approved
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EDMS Doc. Number: 22442198 - 21892028
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
4
MEDI4736-DLBCL-001 Amendment 2 Final: 02 Jan 2018

Protocol Summary, Section 3.1 (Study Design), Section 6.5.1 (Safety Run-in Stage), 
Section 6.5.2 (Safety Review Committee) and Section 9.1 (Statistical Considerations 
Overview): Changes to the Safety run-in stage definition and addition of a statement
for the Safety Run-in assessment of only Arm A: “Following Partial Clinical Hold 
instituted by the US FDA which affects Arm B, the Safety Run-in Stage will evaluate 
safety of the treatment Arm A combinations when at least 10 subjects have been 
included into Arm A and have been treated for at least one cycle of study treatment 
or discontinued prematurely.”

Protocol Summary and Section 9 (Statistical considerations): Clarifications added to 
statistical considerations as enrollment into Arm B has been discontinued. Sample 
size and power considerations reviewed following Partial Clinical Hold instituted by 
the US FDA with continuation of the study with all patients DLBCL ABC COO and 
non-ABC COO assigned to arm A.

Section 1.3.1 (Durvalumab): Added information on new approval of durvalumab for 
the treatment of patients with locally advanced metastatic urothelial carcinoma.

Section 1.4.2 (Rationale for Backbone Therapy (R-CHOP, R2-CHOP)): Added the 
following statement for clarification of changes in backbone therapy after US FDA 
Partial Clinical Hold: “Following Partial Clinical Hold instituted by the US FDA 
rationale for backbone therapy has been changed. Any newly enrolled subject with 
ABC subtype will be treated with R-CHOP. Activated B-cell (ABC) subtype subjects 
already treated with R2-CHOP may continue study treatment if receiving clinical 
benefit, based on the discretion of the investigator and after being reconsented.” 

Section 7.1.2 (Lenalidomide), Section 7.2.5.4 (Dose Modifications Guidelines for 
Lenalidomide) and 7.2.3.3 (Study treatment - lenalidomide): Added as clarification: 
“No newly enrolled subjects are to be treated with the combination of durvalumab, 
R-CHOP plus lenalidomide. Only those subjects currently enrolled and receiving 
clinical benefit, based on the discretion of the investigator, are eligible to remain on 
treatment following reconsent.”

Section 7.2.5 (Dose Modifications (Interruption/Reduction)): Added for clarification 
in case of durvalumab dose hold “If the requalification criteria are fulfilled, but the 
subject develops toxicity as described due to toxicities attributed durvalumab, R-
CHOP should continue during the durvalumab dose hold.”

Section 7.2.5.2 (Dose Modification Guidelines for Durvalumab): Updates to the 
Dose Modification and Toxicity Management Guidelines as per the Durvalumab 
Toxicity Management Guidelines (TMGs) dated 01 Nov 2017: Updates
implemented to Table 6 (General Dose Modification and Toxicity Management 
Guidelines for Immune-mediated Adverse Events), Table 7 (Dose Modification and 
Toxicity Management Guidelines for Specific Immune-mediated Reactions), Table 8
(General Dose Modification and Toxicity Management Guidelines for Non-Immune-
mediated Reactions), Table 9 (Dose Modification and Toxicity Management 
Guidelines for Non-Immune-mediated Adverse Events) and Table 10 (Dose 
Modification and Toxicity Management Guidelines for Infusion-Related Reactions). 
Approved
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EDMS Doc. Number: 22442198 - 21892028
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
5
MEDI4736-DLBCL-001 Amendment 2 Final: 02 Jan 2018

Section 7.2.5.2 (Dose Modification Guidelines for Durvalumab), Table 6 (General 
Dose Modification and Toxicity Management Guidelines for Immune-mediated
Adverse Events) and Appendix A (Table of Abbreviations): the term imAE 
(immune-mediated adverse event) is replacing previous term irAE (immune-related 
adverse event).
Approved
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EDMS Doc. Number: 22077992 - 21892028
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
1
MEDI4736-DLBCL-001 Amendment 1.1 US Final: 03 Aug 2017
1.
JUSTIFICATION FOR AMENDMENT
 It is now noted in the protocol that, prior to beginning consolidation therapy 
with single-agent durvalumab, subjects who achieve only a partial response (PR) will be re-
consented after initial induction therapy.
Updated Section(s): 
Protocol Summary (Study Design), Section 3.1.2, Section 5 (Table of Events), Section 6.2.1, 
Section 7.2.3.1: Updated to specify subjects achieving a PR at end of induction may continue 
onto consolidation therapy based on the decision of the Investigator and after being re-consented 
for the consolidation treatment phase.
Approved
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EDMS Doc. Number: 21890444 - 21892028
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
3
MEDI4736-DLBCL-001 Amendment 1 Final: 09 May 2017
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in the amendment are summarized below.
The following changes were made to the study protocol and the associated sections of the 
Protocol Summary:

Section 4.2: Update of inclusion criterion 11 (c and d) for liver enzymes and 
hemoglobin.
Rationale for change: The laboratory entry criteria were tightened in order to 
reduce the risk for additive or synergistic toxicity of compounds of the study 
treatment.

Section 4.2: Update of inclusion criteria 12, 13 and 14 to:
o
Clarify highly effective methods for contraception,
o
Clarify timelines for subjects to abstain from breastfeeding, egg cell donation, 
blood and semen donation, 
o
Clarify the requirement for subjects to understand and follow the overall 
lenalidomide standard pregnancy and counseling plan.

Section 4.3: Update of exclusion criteria 8 and 9 to clarify that subjects known to be 
seropositive for hepatitis C virus (HCV) and human immunodeficiency virus (HIV) 
are excluded.

Sections 4.3 (exclusion criterion 23) and 8.2: Update of the duration of avoidance of 
use of live attenuated vaccines is from 30 days prior to the first dose of durvalumab, 
until 12 months after last dose of rituximab or until recovery of B-cells and for 120 
days after last dose of durvalumab, whichever is longer.
Rationale for change: Live attenuated vaccines during and after study treatment 
should be avoided because the effects of the study backbone therapy, namely B-cell 
depletion by rituximab, and the PD-L1 inhibitor durvalumab, on such vaccination 
have not been evaluated. In order to not put study subjects at risk, live attenuated 
vaccines are not permitted during the defined periods of study participation and 
treatment.

Section 6 (Procedures): Clarification of the following assessments:
o
Safety run-in stage: Clarification by inserting a new section (6.5.1.).
Approved
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Approved
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EDMS Doc. Number: 21890444 - 21892028
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
4
MEDI4736-DLBCL-001 Amendment 1 Final: 09 May 2017
o
Safety review committee: Clarification by inserting a new section (6.5.2.).
o
Pregnancy testing and lenalidomide counseling: Clarification following 
lenalidomide counseling document.

Section 7.2 (Treatment Administration and Schedule):
o
Section 7.2.3.1. Criteria for stopping induction treatment and for starting 
consolidation treatment: Clarification of stopping criteria and rules.
o
Sections 7.2.3.5 and 8.1.6: Addition of special considerations regarding urinary 
tract toxicity of cyclophosphamide (hemorrhagic cystitis, pyelitis, ureteritis, 
hematuria).
Rationale for change: Addition of specific details to support the risk-benefit 
assessment of the Investigator regarding cyclophosphamide as part of the R-
CHOP backbone therapy in this study.

Section 8:
o
Addition of information related to the Summary of Product Characteristics 
(SmPC) about lenalidomide interaction with digoxin, statins, and P-glycoprotein 
(P-gp) inhibitors.
Rationale for change: Addition of specific details on drug-drug interactions 
related to lenalidomide to support the risk-benefit assessment of the 
Investigator.
o
Section 8.2 Prohibited Concomitant Medications and Procedures: Update to 
include information about risk of venous thromboembolism in subjects treated 
with lenalidomide in combination with dexamethasone, to note that combined 
oral contraceptive pills are not recommended in this clinical study and that 
Copper-releasing intrauterine devices are generally not recommended due to
risks of infection.
o
Section 8.3.6. Hepatitis B virus reactivation prophlylaxis as required (previously 
recommended). A hepatologist will be consulted and HBV DNA will be 
repeated in case of any elevation in liver enzymes of subjects who are treated 
with rituximab or lenalidomide. If liver enzymes are increased, a hepatologist 
should be consulted for further clarification (eg, hepatitis DNA PCR) and to 
decide on further treatment.

Section 10 (Adverse Events):
o
Section 10.7.1 AESIs (adverse events of special interest) durvalumab: New 
section to define AESIs.
o
Section 10.7.2 AESIs lenalidomide: New section to define AESIs.

Section 11 (Adverse Events): Addition of pregnancy as event for treatment 
discontinuation.
Rationale for change: Addition of pregnancy as a specific reason for 
discontinuing treatment with investigational product.
Approved
2.0
v
Approved
1.0
v


EDMS Doc. Number: 21890444 - 21892028
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
5
MEDI4736-DLBCL-001 Amendment 1 Final: 09 May 2017
In addition, some aspects of the original protocol version were clarified, spelling, formatting and
punctuation errors were corrected, and various abbreviations and acronyms were spelled out.
This amendment includes several other minor clarifications and corrections:

Section 1.3.2: Addition of the US approval for lenalidomide for:
o
Maintenance multiple myeloma therapy following autologous hematopoietic 
stem cell transplantation

Section 1.3.2: Addition of the EU approvals for lenalidomide for:
o
Maintenance treatment of newly diagnosed patients with MM who have 
undergone autologous stem cell transplantation,
o
Relapsed or refractory mantle-cell lymphoma (MCL).

Section 1.4.5.2: Update of the rationale for Pd biomarker assay.

Section 4.2: Update of inclusion criterion 8 to clarify that the on-treatment tumor 
biopsy is also required if clinically feasible in order to align with other sections of 
the study protocol.

Section 4.2: Update of inclusion criterion 13 in order to align with the rituximab 
package insert or SmPC.

Section 4.3: Update of exclusion criterion 4j to correct a spelling mistake (Burkitt’s 
lymphoma).

Section 4.3: Addition of exclusion criterion 26 (“prior organ transplantation 
including allogeneic stem cell transplantation”).
Rationale for change: Transplantation of allogeneic organs or stem cells resemble a 
medical condition that carries an increased risk for immune reactions including 
host-versus-graft and graft-versus-host reactions. In order to not put study subjects 
at risk, prior organ or allogeneic stem cell transplantation is not permitted.

Section 5 (Table of Events): Revision of Table 3 (Schedule of Assessments) to 
update and clarify all assessment time points, particularly for PK and biomarkers.

Section 6 (Procedures): Clarification of the following assessments:
o
Bone Marrow Biopsy: If screening FDG-PET demonstrates the bone marrow to 
be FDG-negative, no bone marrow biopsy (BMB)/aspirate is required.
o
Tumor Biopsy: Anonymized reports should be submitted, as well as locally 
stained slides.
o
Hepatitis B virus (HBV) serology to be assessed locally.
o
CT Scan schedule: It is also acceptable to perform the scans after that 50% of 
induction treatment was provided.
o
Bone Marrow biopsy and Aspirate: Samples not to be send to central laboratory.
o
Safety Assessments: Addition of NCI-CTCAE version 3.0 for TFR grading.
Approved
2.0
v
Approved
1.0
v


EDMS Doc. Number: 21890444 - 21892028
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-DLBCL-001
Celgene International II Sàrl
Confidential and Proprietary
6
MEDI4736-DLBCL-001 Amendment 1 Final: 09 May 2017
o
Pharmacokinetics: Addition of PK time points during induction therapy (C6D1,
C8D1) and consolidation therapy (C4D1, C6D1, C8D1).
o
Biomarkers: Removal of the Aiolos and Ikaros sampling and analysis;
Clarification and new timelines window for the tumor biopsies.

Section 7.1 (Description of Investigational Products):
o
Section 7.1.1 (durvalumab): Update as per new IB version 10.
o
Section 7.1.3 (rituximab): Clarification that rituximab IV standard infusion 
time, rituximab IV generics and rituximab subcutaneous are acceptable.

Section 7.2 (Treatment Administration and Schedule):
o
Section 7.2.2. Pre-specify Post-Induction Radiotherapy: Clarification that 
subjects with bulky disease are allowed to receive radiotherapy after induction 
treatment if planned before start of treatment.
o
Section 7.2.5.2: Update to Durvalumab Treatment Modification and Toxicity
Management Guidelines (Table 6, Table 7, Table 8, Table 9, Table 10).
o
Section 7.2.3.1: Subjects achieving a PR at the end of the induction treatment 
may be allowed to continue with consolidation therapy with durvalumab if the 
Investigator considers this to be clinically justified.

Section 9 (Statistical considerations): Several clarifications.
Approved
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Approved
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