Clinical trial NCT02733042
Conditions: Lymphoma Leukemia, Lymphocytic, Chronic, B-Cell
Keywords: Lymphoma Chronic Lymphocytic Leukemia Durvalumab Anti-PD-L1 Antibody MEDI4736 Immune Checkpoint Lymphatic Disease B-Cell Malignancies Abscopal Effect Lenalidomide Bendamustine Rituximab Ibrutinib Lymphoma, B-Cell Lymphoma, Non Hodgkin, Hodgkin Disease Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, Follicular Lymphoma, Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, Small Lymphocytic Immune System Diseases Immunoproliferative Disorders Lymphoproliferative Disorders
Sponsor: Celgene
Start date: 2016-05-11; Completion date: 2022-08-21
Enrollment: 106 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study is designed to determine the recommended phase 2 dose (RP2D), and the safety, and efficacy of durvalumab as monotherapy and when given in combination with lenalidomide and rituximab; ibrutinib; or bendamustine and rituximab at the RP2D in adults with lymphoma or chronic lymphocytic leukemia (CLL).

Detailed description:
The study was to consist of 3 parts: dose-finding, dose-confirmation, and dose-expansion. In this study, 4 treatment arms were to be investigated:

* Arm A: durvalumab and lenalidomide ± rituximab
* Arm B: durvalumab and ibrutinib
* Arm C: durvalumab and rituximab ± bendamustine
* Arm D: durvalumab (monotherapy)

The study was to start with 3 dose-finding cohorts (Arms A, B, and C) and 1 dose-confirmation cohort (Arm D) in parallel. All treatment arms were to be open for enrollment at study start except in the US, where Arm D was to enroll depending on the availability of treatment slots and following the completion of assessment of responses from the combination therapy arms. For Arms A and C, prior to enrolling participants to receive all 3 drugs, the doublet combinations were to be evaluated. Once the doublet combinations were deemed tolerable, the eventual triplet combinations were to be tested.

On 05 September 2017, the US FDA issued a Partial Clinical Hold on the study Arm A. Following this Partial Clinical Hold no more participants were enrolled into study Arm A. Participants already enrolled and treated in Arm A who were receiving clinical benefit, based on the discretion of the investigator, could continue study treatment after being reconsented. Arm B and C completed dose confirmation. The dose expansion part of the study was not opened.

Arms: arm 1: Participants assigned to Arm A will receive:

* Durvalumab 1500 mg intravenous (IV) infusion on Day 1 of Cycles 1 through 13 (ie, 12 months) and
* Lenalidomide orally at assigned dose levels (10 mg, 15 mg or 20 mg) once daily on Days 1 to 21 of:

  * Cycles 1 through 13 in indolent non-Hodgkin's lymphoma (NHL) or
  * All cycles of treatment period until disease progression, unacceptable toxicity, or discontinuation for any other reason in aggressive NHL
* Rituximab 375 mg/m² IV infusion every week in Cycle 1 (Days 2, 8, 15, 22) and on Day 1 of Cycles 2 through 5.

All treatment cycles were 28 days. arm 2: Participants assigned to Arm B will receive:

* Durvalumab 1500 mg IV infusion on Day 1 of Cycles 1 through 13
* Ibrutinib orally at assigned dose levels (280 mg, 420 mg, or 560 mg) once daily until disease progression, unacceptable toxicity or discontinuation for any other reason.

All treatment cycles were 28 days. arm 3: Participants assigned to Arm C will receive:

* Durvalumab 1500 mg IV infusion on Day 1 of Cycles 1 through 13
* Rituximab 375 mg/m² IV infusion on Day 2 of Cycles 1 through 6 (for CLL the rituximab dose will be 375 mg/m² Cycle 1 first dose and 500 mg/m² for each subsequent dose)
* Bendamustine IV infusion at assigned dose levels (70 mg/m² or 90 mg/m²) on Days 1 and 2 of Cycles 1 through 6.

All treatment cycles were 28 days. arm 4: Participants assigned to Arm D will receive durvalumab 1500 mg IV infusion on Day 1 of Cycles 1 through 13. All treatment cycles were 28 days.
Interventions: intervention 1: Durvalumab intervention 2: Lenalidomide intervention 3: Rituximab intervention 4: Ibrutinib intervention 5: Bendamustine
Intervention descriptions: intervention 1: Administered as an IV infusion (250 mL) over approximately 1 hour in duration intervention 2: Administered orally intervention 3: Administered by intravenous infusion intervention 4: Administered orally intervention 5: Administered as a 30-minute intravenous infusion

Protocol documents:
SAP_002.pdf: 
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Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol MEDI4736-NHL-001
Celgene
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
AMENDMENT 1
A PHASE 1/2, OPEN-LABEL, MULTICENTER STUDY TO ASSESS THE SAFETY AND 
TOLERABILITY OF DURVALUMAB (ANTI-PD-L1 ANTIBODY) AS MONOTHERAPY 
AND IN COMBINATION THERAPY IN SUBJECTS WITH LYMPHOMA OR CHRONIC 
LYMPHOCYTIC LEUKEMIA
STUDY DRUG:
MEDI4736
PROTOCOL NUMBER:
MEDI4736-NHL-001
FINAL PROTOCOL DATE:
06 Nov 2015
PROTOCOL AMENDMENT No. 1 
DATE:
04 May 2017
PROTOCOL  AMENDMENT No 2 
DATE:
14 Dec 2017
Prepared by:
ICON Clinical Research
On behalf of
Celgene International II Sarl
Rue des Moulins 4
2108 Couvet
Switzerland
CONFIDENTIAL
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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Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol MEDI4736-NHL-001
Celgene
Confidential and Proprietary
3
Reason of the amendment
This statistical analysis plan (SAP) amendment details the Efficacy Evaluable Population in the 
case of subjects do not have a post-baseline response assessment before death. 
Efficacy Evaluable Population
Per SAP version 1.0, section 4.2.2, the Efficacy Evaluable Population is defined as follow:
Efficacy Evaluable (EE) Population (for the dose-finding, dose-confirmation, and
dose-expansion part) is defined as all subjects who complete at least 1 cycle of their assigned 
treatment, have baseline, and at least 1 post-baseline tumor response assessment. Subjects will 
be analyzed according to their initial treatment arm and dose level allocation.
Changed to 
Efficacy Evaluable (EE) Population (for the dose-finding, dose-confirmation, and 
dose-expansion part) is defined as all subjects who complete at least 1 cycle of their assigned 
treatment, have baseline, and at least 1 post-baseline tumor response assessment. 
A subject who died before Cycle 4 Day 1 (i.e. before the first IWG or IWCLL response 
assessment scheduled per protocol) and without having done any unscheduled post-baseline 
IWG or IWCLL response assessment will be included in the Efficacy Evaluable Population.
Subjects will be analyzed according to their initial treatment arm and dose level allocation.
Rational:
The first efficacy assessment is performed at Cycle 4 Day 1, any subject who died before and 
without having done any unscheduled post-baseline IWG or IWCLL response assessment cannot 
have a post baseline assessment and should not be excluded from the Efficacy Evaluable 
Population for that criterion.
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Prot_003.pdf: 
Official Title of Study: 
A PHASE 1/2, OPEN LABEL, MULTICENTER STUDY TO ASSESS THE SAFETY AND TOLERABILITY OF 
DURVALUMAB (ANTI-PD-L1 ANTIBODY) AS MONOTHERAPY AND IN COMBINATION THERAPY IN 
SUBJECTS WITH LYMPHOMA OR CHRONIC LYMPHOCYTIC LEUKEMIA 
 
The “FUSION NHL-001” Study 
 
PROTOCOL(S) MEDI4736-NHL-001 
 
NCT Number: NCT02733042 
  
Document Date (Date in which document was last revised): April 22, 2020 


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
1
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr2020
TITLE PAGE
A PHASE 1/2, OPEN LABEL, MULTICENTER STUDY 
TO ASSESS THE SAFETY AND TOLERABILITY OF
DURVALUMAB (ANTI-PD-L1 ANTIBODY) AS 
MONOTHERAPY AND IN COMBINATION THERAPY 
IN SUBJECTS WITH LYMPHOMA OR CHRONIC 
LYMPHOCYTIC LEUKEMIA
The “FUSION NHL-001” Study
PROTOCOL NUMBER:
MEDI4736-NHL-001
ORIGINAL DATE:
06 Nov 2015
AMENDMENT No. 1 DATE:
04 May 2017
AMENDMENT No. 2 DATE:
14 Dec 2017
AMENDMENT No. 3 DATE:
12 Sep 2019
AMENDMENT No. 4 DATE:
22 April 2020
EudraCT NUMBER:
2015-003516-21
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.
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
2
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr2020
MEDICAL MONITORS / EMERGENCY CONTACT INFORMATION 
Contact Information: 
Name :
Title: 
Address: Route de Perreux, Boudry, Switzerland
Phone: 
Mobile Phone: 
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(s) or designee 
for emergency calls.
Back-up 24-hour Global Emergency Contact Call Center: 
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
3
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr2020
CELGENE THERAPEUTIC AREA HEADS SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
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.  
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
4
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr2020
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.
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
5
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr2020
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.
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
6
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr2020
PROTOCOL SUMMARY
On 05 Sep 2017, a Partial Clinical Hold was placed on 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-PD-1 antibody, pembrolizumab, in patients with multiple myeloma in 
combination with immunomodulatory agents. As a result, enrollment into Arm A (durvalumab 
plus lenalidomide with or without rituximab) was discontinued. Subjects already enrolled and 
treated in Arm A who are receiving clinical benefit, based on the discretion of the investigator, 
may continue study treatment after being reconsented.
In December 2017, Celgene stopped enrollment and discontinued the dose expansion part of the 
study.
Following completion or discontinuation of durvalumab therapy per protocol for all subjects 
(n=106), and completion of the primary analysis (data cutoff date 06 Mar 2019, defined as last 
durvalumab subject’s 90-day Safety Follow-up Visit), there are no further plans to evaluate long-
term efficacy, including overall survival for the remaining subjects on study. Therefore, the
Follow-up Period will be discontinued, and data collection will stop under this amendment. No 
additional statistical analysis on safety and efficacy will be performed. 
At the time of primary analysis data cutoff, 36 subjects were in follow-up. There were 13 
subjects on ibrutinib treatment (Arm B), and no subjects on treatment with lenalidomide or 
bendamustine. Subjects who continue ibrutinib on-study will be treated per investigator’s 
medical judgement and standard of care at the investigative site or discontinue study to receive 
ibrutinib commercially as standard of care treatment (off-study). 
Subjects who received lenalidomide will continue to be followed for second primary 
malignancies (SPMs) as required by 
After stopping data collection in the 
clinical database, any SPM events will continue to be collected in the safety database. 
Study Title
A Phase 1/2, open label, multicenter study to assess the safety and tolerability of durvalumab 
(anti-PD-L1 antibody) as monotherapy and in combination therapy in subjects with lymphoma or 
chronic lymphocytic leukemia (MEDI4736-NHL-001). The “FUSION NHL-001” Study.
Indication
Relapsed/refractory (R/R) lymphoma or R/R chronic lymphocytic leukemia (CLL) previously 
treated with at least one systemic therapy. 
Objectives
Arm A is discontinued to the enrollment of new subjects. Only those subjects already 
enrolled and treated in Arm A who are receiving clinical benefit, based on the discretion of 
the investigator, may continue study treatment after being reconsented.
Primary: 
Dose finding part (Phase 1):
To assess the safety and tolerability of durvalumab when given in combination with 
lenalidomide and rituximab; ibrutinib; or bendamustine and rituximab to determine the
recommended Phase 2 doses (RP2Ds) of each combination.
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
7
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr2020
Dose confirmation part (Phase 1):
To assess the safety of durvalumab as monotherapy and when given in combination with 
lenalidomide and rituximab; ibrutinib; or bendamustine and rituximab at the RP2D 
Dose expansion part (Phase 2):
To evaluate the preliminary efficacy of durvalumab when given in combination with 
lenalidomide and rituximab; ibrutinib; or bendamustine and rituximab in subjects with 
lymphoma or CLL
Secondary: 
Dose finding and confirmation parts (Phase 1):
To make a preliminary assessment of antitumor activity of durvalumab as monotherapy and 
when given in combination with lenalidomide and rituximab; ibrutinib; or bendamustine and 
rituximab in subjects with lymphoma or CLL
Dose expansion part (Phase 2):
To assess the safety of durvalumab when given in combination with lenalidomide and rituximab; 
ibrutinib; or bendamustine and rituximab in subjects with lymphoma or CLL
All parts (Phase 1/2)
To characterize the pharmacokinetics (PK) of durvalumab as monotherapy and when given in 
combination
To characterize the PK of lenalidomide and ibrutinib when given in combination with 
durvalumab
To determine the pharmacodynamic (Pd) effects of durvalumab as monotherapy 
Exploratory: 
To explore population PK analyses including the influence of intrinsic and extrinsic factors that 
may influence durvalumab exposures
To determine the immunogenicity of durvalumab as monotherapy and when given in 
combination
To explore PK/Pd relationship, explore pharmacodynamic mechanistic biomarkers for 
durvalumab and other combination agents in the study
To explore host immune and tumor molecular markers predictive of response to durvalumab and 
other agents when given in combination
To explore minimal residual disease (MRD) and its correlation with clinical outcome
To explore the abscopal effect (ie, immune-mediated tumor response outside the radiation field) 
of involved field radiation therapy when given in combination with durvalumab
Study Design
The study will be conducted in compliance with International Council for Harmonisation (ICH) 
Good Clinical Practices (GCPs).
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
8
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr2020
This is a multicenter, open label, Phase 1/2 study assessing the safety, tolerability, PK, PD, and 
preliminary efficacy of durvalumab as monotherapy and when given in combination in select 
subtypes of R/R lymphoma or R/R CLL. 
The study will consist of 3 parts: dose finding, dose confirmation, and dose expansion.  Four 
treatment arms will be investigated: 

Arm A (durvalumab and lenalidomide ± rituximab): discontinued to the enrollment 
of new subjects. Only those subjects already enrolled and treated who are 
receiving clinical benefit, based on the discretion of the investigator, may 
continue study treatment after being reconsented.

Arm B (durvalumab and ibrutinib)

Arm C (durvalumab and rituximab ± bendamustine)

Arm D (durvalumab monotherapy)
The study will start with 3 dose finding cohorts (Arms A, B, and C) and 1 dose confirmation 
cohort (Arm D) in parallel. 
All treatment arms will open for enrollment at study start except in the US, where Arm D will 
enroll depending on the availability of treatment slots and following the completion of 
assessment of responses from the combination therapy arms (ie, Arms A, B, and C).
Please see the following figure for the overall study design and table for the eligible histologies.
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
9
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
If DLT ≤ 0/3 or 1/6
Confirm 
antitumor activity
Confirm 
RP2D 
If DLT ≥ 2/3 or 2/6
If DLT ≤ 0/3 or 1/6
If DLT ≥ 2/3 or 2/6
Confirm 
RP2D 
If DLT ≥ 2/3 or 2/6
Confirm 
antitumor activity
Confirm 
antitumor activity
Overall Study Design
ARM A   
R/R B-cell 
NHL
discontinued 
to the 
enrollment of 
new subjects
DOSE FINDING
(Determine preliminary RP2D based on 3 + 3 design)
DL 1: Durvalumab + 
Lenalidomide 20 mg
DL 2: Durvalumab+ Lenalidomide 
20 mg+ Rituximaba  
DL -1A: Durvalumab +    
Lenalidomide 10 mg 
If DLT ≥ 2/3 or 2/6
ARM B    
R/R B-cell 
NHL/CLL
DL 1 c: Durvalumab
+ Ibrutinib 420 mg
If DLT ≤ 0/3 or 1/6
If DLT ≤ 0/3 or 1/6
DL 2: Durvalumab+ 
Ibrutinib 560 mg 
(NHL only)
DL -1: Durvalumab + 
Ibrutinib 280 mg
If DLT ≥ 2/3 or 2/6
DL 1: Durvalumab + 
Rituximab
DL 2 c: Durvalumab + 
Bendamustine 70 mg/m2 + 
Rituximab
ARM D 
Durvalumab 
monotherapy
DL 3: Durvalumab + 
Bendamustine 90 mg/m2+ 
Rituximab (NHL only)
No dose finding cohort
Confirm 
RP2D 
R/R CLL/SLL, MCL
R/R CLL/SLL, MCL
R/R CLL/SLL, FL, 
DLBCL
R/R CLL/SLL, FL, 
DLBCL
R/R CLL/SLL, 
DLBCL, MCL, FL, 
HL
Abbreviations: CLL = chronic lymphocytic leukemia; DL = dose level; DLT = dose limiting toxicity; DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; HL = 
Hodgkin lymphoma; MCL = mantle cell lymphoma; NHL = non-Hodgkin lymphoma; RP2D = recommended phase 2 dose; R/R = relapsed/refractory; SLL = small lymphocytic
lymphoma; SRC = safety review committee; US = United States.
a Arm A DL 2 and -1B (discontinued to the enrollment of new subjects): Rituximab 375 mg/m2on Cycle 1 Days 2, 8, 15, 22 and then on Day 1 of every 28-day cycle from Cycles 2-5.
b Arm A DL -2 and DL -3 (discontinued to the enrollment of new subjects): Rituximab 375 mg/m2on Cycle 1 Day 2 and then on Day 1 of every 28-day cycle from Cycles 2 through 8.
c Arm B DL 1 and Arm C DL 2: These dose levels will be the highest dose levels tested in subjects with CLL/SLL before opening CLL/SLL dose confirmation cohorts.
d Arm A dose confirmation and dose expansion cohorts are discontinued and will not enroll new subjects. In addition, the add-on combination treatment with lenalidomide ± rituximab is 
no longer allowed
Notes:  Durvalumab will be administered at a fixed dose of 1500 mg once every 4 weeks.  All treatment arms will be open for enrollment at study start. Arm D will not be open for
enrollment at the study start in the US, where Arm D will enroll depending on treatment slot availability and following the completion of an assessment of responses from the combination 
therapy arms (ie, Arms A, B, and C).  Arm A is discontinued to the enrollment of new subjects. Only those subjects already enrolled and treated in Arm A who are receiving 
clinical benefit based on the discretion of the investigator, may continue study treatment after being reconsented.
DOSE EXPANSION
(Confirm efficacy in specific histology)
DOSE CONFIRMATION          
(Confirm RP2D and seek preliminary 
signal in specific histology)
Note for Arm D: At the time of disease 
progression, the investigator may add study 
treatments previously investigated with durvalumab 
(eg, rituximab ± either lenalidomided or 
bendamustine; or ibrutinib) once a dose level for 
that combination therapy is deemed tolerable) or 
involved-field radiation to a single involved nodal 
site (ie, to evaluate for abscopal antitumor effect) 
for subjects who meet the criteria in Section 3.1.2
ARM C    
R/R B-cell 
NHL/CLL
DL -2: Durvalumab+ 
Lenalidomide 15 mg+ 
Rituximabb
DL -1B: Durvalumab+ 
Lenalidomide 10 mg+ Rituximaba
DL -3: Durvalumab + 
Lenalidomide 10 mg+ 
Rituximabb
If DLT ≤ 
0/3 or 1/6
Confirm 
RP2D 
R/R FL, DLBCLd
R/R FL, DLBCL d
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
10
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Eligible Histologies per Treatment Arm and Part of the Study
Treatment Arm
Dose Finding (RP2D)
Dose Finding
Evaluation of the Safety of RP2D in Specific Histology and Preliminary 
Signal Seeking
Dose Confirmation
ab
Preliminary Efficacy
Dose Expansionabe
Arm A
c
(Durvalumab + 
Lenalidomide ±
Rituximab)
Discontinued to 
the enrollment 
of new subjects
R/R B-cell NHL
N = 6-30
R/R FL N = 10d
R/R DLBCL N = 10d
R/R FL N = 15d
R/R DLBCL N = 15d
Arm B
(Durvalumab + 
Ibrutinib)
R/R B-cell 
NHL/ CLL
N = 6-12
R/R CLL/SLL N = 10
R/R MCL N = 10
R/R CLL/SLL N = 15
R/R MCL N = 15
Arm C
(Durvalumab + 
Rituximab ±
Bendamustine)
R/R B-cell 
NHL/ CLL
N = 3-18
R/R CLL/SLL N = 10
R/R FL N = 10
R/R DLBCL N = 10 
R/R CLL/SLL N =15
R/R FL N = 15
R/R DLBCL N = 15
Arm D
(Durvalumab)
No dose finding
R/R CLL/SLL
R/R DLBCL
R/R FL 
R/R MCL
R/R HL
N = 30 (5-10 subjects in 
each histology)
Not planned
Abbreviations: CLL = chronic lymphocytic leukemia; DLBCL = diffuse large B-cell lymphoma; FL = follicular 
lymphoma; HL = Hodgkin lymphoma; MCL = mantle cell lymphoma; NHL = non-Hodgkin lymphoma; N = 
number of subjects; RP2D = recommended Phase 2 dose; R/R = relapsed/refractory; SLL = small lymphocytic 
lymphoma.
a Subjects with FL Grade 3b may be enrolled into DLBCL cohorts but are excluded from FL cohorts.
b Subjects with DLBCL not otherwise specified or T-cell/histiocyte rich large B-cell lymphoma will be eligible for 
the dose confirmation and expansion DLBCL cohorts.
c Arm A will exclude subjects with CLL/SLL.
d Arm A dose confirmation and dose expansion cohorts are discontinued and will not enroll new subjects.
e Celgene decided to not continue with the dose expansion part of the study. 
In the dose finding part (Phase 1), a preliminary RP2D will be established for each durvalumab 
combination treatment using a 3 + 3 design (Storer, 1989).  For Arms A and C, prior to enrolling 
subjects to receive all 3 drugs, the doublet combinations (ie, Arm A: durvalumab and 
lenalidomide and Arm C: durvalumab and rituximab) will be evaluated.  Once the doublet 
combinations are deemed tolerable, the eventual triplet combinations will be tested.  The 
durvalumab starting dose is fixed in each of these arms.  Three to 6 subjects will be evaluated in 
each dose finding cohort; therefore, approximately 15 to 60 (DLT evaluable) subjects with B-cell 
non-Hodgkin lymphoma (NHL) or CLL are anticipated to be enrolled in the dose finding part (6 
to 30 subjects in Arm A; 6 to 12 subjects in Arm B; and 3 to 18 subjects in Arm C).  Subjects 
with CLL/small lymphocytic lymphoma (SLL) will not be eligible for Arm A.  The final number 
of subjects will depend on the number of dose levels tested and the number of dose limiting 
toxicities (DLTs) observed within each cohort. 
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
11
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
A safety review committee (SRC) whose members include the sponsor’s medical monitor, drug 
safety physician, and a subset of investigators will determine a preliminary RP2D for each 
combination treatment arm (except Arm D) based on the assessment of the safety, available PK 
and Pd data, and preliminary efficacy information as needed. 
In the dose confirmation part (Phase 1), once the preliminary RP2D is established, each 
combination treatment arm will enroll approximately 10 subjects with each prespecified disease 
histology (7 cohorts of 10 subjects) into Arms A, B, and C to confirm the tolerability and safety 
of the RP2D and identify the strongest antitumor signal in those histologies. The Arm D dose 
confirmation cohort will be open at study start and enroll a total of approximately 30 subjects 
into up to 5 cohorts.  In total, approximately 100 subjects are anticipated to enroll in the dose 
confirmation part.
If a promising antitumor signal is detected in any dose confirmation cohort, that cohort will 
expand and enroll approximately 15 additional subjects to further assess the efficacy in the dose 
expansion part (Phase 2).  In total, approximately 105 subjects are anticipated to enroll in the 
dose expansion part.
Study Population
Eligible subjects must have previously received treatment with at least one systemic therapy and 
currently have relapsed or refractory lymphoma or CLL (high risk) requiring therapeutic 
intervention.  Subjects with lymphoma must have at least 1 measurable lesion by computed 
tomography (CT) scan (≥ 2 cm in the longest dimension).  Subjects with CLL must be in need of 
treatment as defined by modified International Workshop on Chronic Lymphocytic Leukemia 
(IWCLL) Guidelines for the Diagnosis and Treatment of CLL (Hallek, 2008); (Appendix H).  
All subjects must have adequate liver, renal, and bone marrow function as defined in Section 4. 
Length of Study
The entire study is anticipated to last approximately 6 years and will consist of 3 periods:
Screening, Treatment, and Follow-up.  
During the Screening Period, lasting up to 28 days from the time of signing informed consent to
first dose administered, subjects will undergo assessments to determine their eligibility.  
Subjects who qualify for enrollment into the study will enter the Treatment Period, during which 
subjects will receive investigational product(s) (IP[s]) at a predetermined dose and schedule for 
up to 13 cycles (in Arm A [only subjects with indolent NHL], Arm C, and Arm D); disease 
progression (in Arm A [subjects with aggressive NHL] and Arm B); or discontinuation treatment 
due to unacceptable toxicity or other reasons.  
Once subjects complete the Treatment Period, they will enter into the Safety Follow-up Period.  
All subjects will be followed for adverse events (AEs) (including second primary malignancies 
[SPMs]) and concomitant medications/ procedures for 90 days after the last dose of durvalumab 
or 28 days after the last dose of other IPs, whichever is the later date.  
Subjects who have received lenalidomide (ie, subjects in Arm A or subjects in Arm D who have
received lenalidomide as additional treatment at the time of progression) will be followed for 
SPMs for up to 5 years from the last subject’s first lenalidomide dose. 
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
12
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
In the Efficacy Follow-up Period, subjects will be followed for first progression, subsequent 
antilymphoma/CLL therapy, and overall survival.  In Arms A (indolent NHL: follicular 
lymphoma [FL] or marginal zone lymphoma [MZL]), C, and D, subjects will be followed for 
24 months after their last durvalumab dose.   In Arms A (aggressive NHL) and B, subjects will 
be followed for 24 months after their last durvalumab dose or their disease progression, 
whichever date occurs later.
The End of Trial 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 prespecified in the protocol
(whichever is the later date).
Study Treatments
Subjects will be assigned to 1 of the 4 treatment arms based on the investigator’s choice led by
the subject’s eligibility, prior antilymphoma/CLL therapy, and treatment arm/slot availability. 
Arm A is discontinued to the enrollment of new subjects, and only subjects already 
enrolled and treated in Arm A who are receiving clinical benefit, based on the discretion of 
the investigator, may continue study treatment after being reconsented. In addition, the 
add-on combination treatment with lenalidomide ± rituximab is no longer allowed.*
During each 28-day treatment cycle, subjects will receive durvalumab (intravenous [IV]) 
infusion on Day 1 of Cycles 1 through 13 at a fixed dose of 1500 mg every 4 weeks in 
combination with: 

Arm A: Lenalidomide orally [PO]) once daily on Days 1 to 21 (inclusive) of each cycle 
for 12 months (Cycles 1 through 13) in indolent lymphoma histologies (eg, follicular 
lymphoma [FL] or marginal zone lymphoma [MZL]) or until disease progression in 
aggressive lymphoma histologies (eg, diffuse large B-cell lymphoma [DLBCL]) ±
rituximab (IV) infusion:

Rituximab Schedule 1 (dose levels 2 and -1B): on Days 2, 8, 15 and 22 of Cycle 1 
and on Day 1 of Cycles 2 through 5 or

Rituximab Schedule 2 (dose levels -2 and -3): on Day 2 of Cycle 1 and on Day 1
of Cycles 2 through 8.

Arm B: Ibrutinib (PO) continuous, once daily until disease progression, unacceptable 
toxicity, starts new therapy, or discontinuation for any other reason, ie, subject withdraws 
consent or discontinues per investigator’s discretion.

Arm C: Rituximab (IV) infusion on Day 2 of Cycles 1 through 6 ± bendamustine (IV) 
infusion on Days 1 and 2 of Cycles 1 through 6.   Bendamustine may be stopped after 4 
cycles if the subject experiences a cumulative toxicity related to bendamustine and there 
is no clinical evidence of a favorable benefit to risk ratio for continuation of 
bendamustine treatment per the investigator’s medical judgment.  

Arm D: Durvalumab monotherapy arm. At the time of disease progression, the
investigator may add study treatments previously investigated with durvalumab in this 
protocol (ie, lenalidomide ± rituximab*; bendamustine ± rituximab; rituximab; or 
ibrutinib) once a tolerable dose level is confirmed for that combination, or subjects can 
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
13
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
receive involved-field radiation to a single involved nodal site (ie, to evaluate for a 
systemic abscopal antitumor effect) if they meet the criteria defined in Section 3.1.2.  
Prior to addition of another therapy to durvalumab, the investigator must consult with the 
sponsor’s medical monitor.
Treatment arms and dose levels for each arm are described and tabulated in Section 7 and 9.3.
Overview of Key Efficacy Assessments
Disease response to treatment in lymphoma is determined by the Lugano Classification 
(Cheson 2014) and in CLL by the modified IWCLL Response Criteria (Hallek, 2008; 
Hallek, 2012; Hallek, 2013) including a careful review of laboratory assessments (eg, complete 
blood counts with differential, bone marrow/tumor biopsy assessments, immunophenotyping of 
blood for circulating CLL cells) and imaging studies (eg, CT or fluorodeoxyglucose-positron 
emission tomography [FDG-PET] scan) as well as clinical findings (eg, physical examination, 
constitutional symptoms). 
Integrated FDG-PET with CT (FDG-PET-CT) is preferred for response assessment of FDG-avid 
lymphomas (eg, DLBCL, Hodgkin lymphoma [HL], or FL), while dedicated CT scan alone is 
preferred for FDG-non-avid and variably FDG-avid histologies (eg, CLL/SLL, or MZL).
Overview of Key Safety Assessments
Safety assessments include monitoring for AEs; physical examination; vital signs and body 
weight measurement; Eastern Cooperative Oncology Group (ECOG) performance status; 
hepatitis B virus (HBV) screening; hematology (complete blood count [CBC] with differential 
and platelets); serum chemistry; urinalysis; serum immunoglobulins; concomitant medications, 
therapies, and procedures; pregnancy testing (for female subjects of childbearing potential 
[FCBP] only); and electrocardiogram.
Safety assessments will be performed during screening and will be repeated weekly in Cycle 1, 
bi-weekly in Cycles 2 through 4 in Arms A, B, D or Cycles 2 through 6 in Arm C, and once 
every 4 weeks thereafter for all arms. For subjects continuing on ibrutinib, assessments will be 
performed per the investigator’s discretion following standard of care.
The investigator remains responsible to monitor safety, record adverse events (AEs)/serious 
adverse events (SAEs)/second primary malignancies(SPMs) in source documents, and report 
SAEs and SPMs to Celgene Drug Safety.
Overview of Pharmacokinetic Assessments
Serum or plasma samples will be collected to assay concentrations of durvalumab and other 
combination agents (ie, lenalidomide or ibrutinib). 
Overview of Biomarker Assessments
Pharmacodynamic markers for durvalumab and other combination agents will be measured, such 
as soluble programmed cell death ligand 1 (sPD-L1) levels for durvalumab and proliferation of 
immune cell subsets, and soluble cytokines and chemokines. 
Exploratory biomarkers predictive of response or disease/mechanistic related will be measured 
including, but not limited to PD-L1 protein levels, immune cell subsets, and other markers that 
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
14
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
may be associated with immune status, gene signature related to immune-related pathways or 
cell of origins, T-cell receptor clonality, neoantigen assessments, or genetic alterations.
Overview of Immunogenicity Assessments
Blood samples for immunogenicity will be collected from all subjects.  Antidrug antibody 
(ADA) for durvalumab will be explored using these samples.
Statistical Methods
There are 3 treatment arms in the dose finding part, ie, Arm A (discontinued to the enrollment of 
new subjects), Arm B, and Arm C. The standard 3 + 3 design will be used to identify the 
maximum tolerated dose (MTD) and preliminary RP2D in each treatment arm.  The sample size 
for the dose finding part (Phase 1) is expected to range from approximately 15 to 60 (DLT 
evaluable) subjects. The final number of subjects will depend on the number of dose levels 
studied and number of DLTs observed within each cohort.
The planned sample size for the dose confirmation (Phase 1) and dose expansion (Phase 2) parts
is based on clinical, empirical, and practical considerations traditionally used for Phase 1/2 
studies. Please see Section 9.3 for further details.
Should the stopping rules described in Table 34 for the dose confirmation part be fulfilled, the 
SRC for that cohort and global scientific steering committee (GSSC) will be consulted to 
determine whether the clinical trial should completely stop further enrollment of subjects with a 
particular histology (ie, not advance to the dose expansion part), temporarily halt enrollment and 
await maturation of efficacy data to examine for example durability of responses, or enroll 
additional subjects either in the dose confirmation part or by formally advancing to the dose 
expansion part.
For the efficacy analysis, in order to make use of all available data, the data from the dose 
expansion and dose confirmation parts will be pooled together for a particular histology for the 
evaluation of treatment efficacy. A total of approximately 25 subjects in a particular treatment 
arm and subject histology cohort will provide a moderate estimate of the response rate with 95% 
confidence interval (CI) no wider than ± 20%. Efficacy analyses will also be performed 
separately for the dose confirmation part and the dose expansion part as well.
The safety analysis will include all subjects in the safety population. 
All analyses will use descriptive statistics.
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
15
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................25
1.1.
Disease Background ...............................................................................................25
1.1.1.
Non-Hodgkin Lymphoma and CLL ........................................................................25
1.1.2.
Hodgkin Lymphoma...............................................................................................26
1.2.
Compound Background ..........................................................................................26
1.2.1.
Durvalumab (MEDI4736).......................................................................................26
1.2.2.
Lenalidomide..........................................................................................................27
1.2.3.
Ibrutinib..................................................................................................................28
1.2.4.
Bendamustine.........................................................................................................28
1.2.5.
Rituximab...............................................................................................................28
1.3.
Rationale ................................................................................................................29
1.3.1.
Immune-checkpoint Inhibition................................................................................29
1.3.2.
Study Rationale and Purpose ..................................................................................30
1.3.3.
Rationale for the Study Design ...............................................................................31
1.3.4.
Rationale for Dose, Schedule, and Regimen Selection ............................................32
1.3.5.
Rationale for Choice of Combination Compounds ..................................................33
1.3.5.1.
Rituximab and Lenalidomide..................................................................................33
1.3.5.2.
Ibrutinib..................................................................................................................34
1.3.5.3.
Bendamustine and Rituximab .................................................................................34
1.3.5.4.
Local Involved Field Radiation Therapy.................................................................34
1.3.6.
Rationale for Pharmacodynamics and Potential Predictive Biomarkers ...................35
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................37
3.
OVERALL STUDY DESIGN ................................................................................43
3.1.
Study Design ..........................................................................................................43
3.1.1.
Potential Pseudoprogression ...................................................................................47
3.1.2.
Criteria for Adding Combination Agent or Local Involved Field Radiation 
Therapy to Durvalumab Monotherapy at the time of Progression (Arm D)..............47
3.2.
Study Duration for Subjects....................................................................................48
3.2.1.
Screening Period.....................................................................................................49
3.2.2.
Treatment Period ....................................................................................................50
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
16
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
3.2.3.
Follow-up Period....................................................................................................51
3.3.
End of Trial ............................................................................................................52
4.
STUDY POPULATION.........................................................................................53
4.1.
Number of Subjects ................................................................................................53
4.2.
Inclusion Criteria....................................................................................................55
4.3.
Exclusion Criteria...................................................................................................61
5.
TABLE OF EVENTS.............................................................................................65
6.
PROCEDURES......................................................................................................94
6.1.
Screening Period.....................................................................................................94
6.2.
Treatment Period ....................................................................................................98
6.2.1.
End of Treatment..................................................................................................102
6.3.
Follow-up Period..................................................................................................104
6.3.1.
Safety Follow-up ..................................................................................................104
6.3.2.
Efficacy (Long Term) Follow-Up .........................................................................104
6.4.
Efficacy Assessments ...........................................................................................104
6.4.1.
Efficacy Assessments in Lymphoma.....................................................................105
6.4.1.1.
CT Scans of the Neck, Chest, Abdomen, and Pelvis (Lymphoma) ........................105
6.4.1.2.
FDG-PET-CT Scan (Whole Body) (Lymphoma) ..................................................106
6.4.1.3.
Bone Marrow Biopsy and Aspirate (Lymphoma)..................................................106
6.4.1.4.
Minimal Residual Disease (MCL and FL).............................................................107
6.4.2.
Efficacy Assessments in CLL ...............................................................................107
6.4.2.1.
CT Scans of the Neck, Chest, Abdomen, and Pelvis (CLL)...................................108
6.4.2.2.
Bone Marrow Biopsy and Aspirate (CLL) ............................................................108
6.4.2.3.
Minimal Residual Disease (Immunophenotyping of Blood for Circulating 
CLL Cells by Multiparameter Flow Cytometry) (CLL).........................................108
6.5.
Safety Assessments...............................................................................................109
6.6.
Pharmacokinetics..................................................................................................109
6.6.1.
Pharmacokinetics of Durvalumab (All Arms) .......................................................109
6.6.2.
Pharmacokinetics of Lenalidomide (Arm A Only) ................................................110
6.6.3.
Pharmacokinetics of Ibrutinib (Arm B only) .........................................................111
6.7.
Immunogenicity....................................................................................................111
6.8.
Biomarkers, Pharmacodynamics, Pharmacogenomics...........................................112
6.8.1.
Tumor Tissue Biopsy for Biomarker Assessments (Lymphoma)...........................112
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
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MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
6.8.2.
Bone Marrow Biopsy and Aspirate for Biomarker Assessments............................113
6.8.3.
Saliva and Blood Samples for Biomarker Assessments.........................................114
7.
DESCRIPTION OF STUDY TREATMENTS......................................................115
7.1.
Description of Investigational Product(s)..............................................................115
7.1.1.
Durvalumab..........................................................................................................115
7.1.2.
Lenalidomide........................................................................................................115
7.1.3.
Rituximab.............................................................................................................115
7.1.4.
Ibrutinib................................................................................................................116
7.1.5.
Bendamustine.......................................................................................................116
7.1.6.
Local Involved Field Radiation Therapy...............................................................116
7.2.
Treatment Administration and Schedule ...............................................................116
7.2.1.
Dose Finding Cohorts (Phase 1)............................................................................117
7.2.1.1.
Arm A: Durvalumab and Lenalidomide ± Rituximab (Discontinued to the 
Enrollment of New Subjects)................................................................................117
7.2.1.2.
Arm B: Durvalumab and Ibrutinib ........................................................................120
7.2.1.3.
Arm C: Durvalumab and Rituximab ± Bendamustine ...........................................121
7.2.1.4.
Arm D: Durvalumab Monotherapy .......................................................................123
7.2.2.
Definition of DLT Evaluation Period....................................................................123
7.2.3.
Definition of Dose Limiting Toxicity (DLT).........................................................123
7.2.4.
Definition of a Subject Evaluable for DLTs ..........................................................124
7.2.5.
Definition of Non-Tolerated Dose (NTD).............................................................124
7.2.6.
Definition of Maximum Tolerated Dose (MTD) ...................................................124
7.2.6.1.
Determination of Preliminary RP2D .....................................................................124
7.2.6.2.
Evaluation of Alternate Treatment Schedules........................................................125
7.2.7.
Safety Review Committee ....................................................................................125
7.2.8.
Dose Confirmation Cohorts (Phase 1)...................................................................125
7.2.8.1.
Arm D ..................................................................................................................126
7.2.9.
Dose Expansion Cohorts (Phase 2) .......................................................................126
7.2.10.
Dose Modifications (Interruption/Reduction)........................................................127
7.2.10.1.
General Dose Modification Guidelines .................................................................127
7.2.10.2.
Dose Modification for Durvalumab ......................................................................127
7.2.10.3.
Dose Modification for Lenalidomide (Discontinued to the Enrollment of 
New Subjects) ......................................................................................................128
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EDMS Doc. Number: 24715418 - 20540270
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Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
18
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
7.2.10.4.
Dose Modification for Rituximab .........................................................................129
7.2.10.5.
Dose Modification for Ibrutinib ............................................................................130
7.2.10.6.
Dose Modification for Bendamustine....................................................................131
7.2.10.7.
Dose Modification and Toxicity Management Guidelines.....................................131
7.3.
Method of Treatment Assignment.........................................................................177
7.4.
Overdose ..............................................................................................................177
7.5.
Packaging and Labeling........................................................................................177
7.6.
Investigational Product Accountability and Disposal ............................................177
7.7.
Investigational Product Compliance......................................................................178
8.
CONCOMITANT MEDICATIONS AND PROCEDURES..................................179
8.1.
Permitted/Recommended Concomitant Medications and Procedures.....................179
8.1.1.
Growth Factors and Transfusions for Cytopenia (All Arms) .................................179
8.1.2.
Infection Prophylaxis (All Arms)..........................................................................179
8.1.3.
Venous Thromboembolism Prophylaxis (Lenalidomide).......................................180
8.1.4.
Nausea Prophylaxis (Bendamustine).....................................................................180
8.1.5.
Infusion Reaction Prophylaxis (Rituximab, Bendamustine, Durvalumab) .............180
8.1.6.
Early Antitumor Response (eg, Pseudoprogression, Flare Reaction) 
Treatment (All Arms) ...........................................................................................180
8.1.7.
Tumor Lysis Syndrome Prophylaxis or Treatment (All Arms) ..............................181
8.1.8.
Progressive Multifocal Leukoencephalopathy (Rituximab) ...................................181
8.2.
Prohibited Concomitant Medications and Procedures............................................181
8.2.1.
Prohibited Concomitant Medications for Arm B Only (Ibrutinib)..........................182
8.2.2.
Prohibited Concomitant Medications for Arm C Only (Bendamustine).................183
8.3.
Required Concomitant Medications and Procedures..............................................183
8.3.1.
Hepatitis B Virus Reactivation Prophylaxis ..........................................................183
9.
STATISTICAL CONSIDERATIONS ..................................................................184
9.1.
Overview..............................................................................................................184
9.2.
Study Population Definitions ................................................................................184
9.3.
Sample Size and Power Considerations.................................................................185
9.3.1.
Dose Finding Part (Phase 1)..................................................................................185
9.3.1.1.
Arm A (Discontinued to the Enrollment of New Subjects)....................................186
9.3.1.2.
Arm B ..................................................................................................................187
9.3.1.3.
Arm C ..................................................................................................................188
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9.3.2.
Dose Confirmation Part (Phase 1).........................................................................189
9.3.3.
Dose Expansion Part (Phase 2) .............................................................................191
9.4.
Background and Demographic Characteristics......................................................191
9.5.
Subject Disposition...............................................................................................192
9.6.
Efficacy Analysis..................................................................................................192
9.7.
Safety Analysis.....................................................................................................193
9.8.
Interim Analysis ...................................................................................................193
9.9.
Other Topics.........................................................................................................193
9.9.1.
Steering Committee ..............................................................................................194
9.9.2.
Exploratory Analysis ............................................................................................194
10.
ADVERSE EVENTS............................................................................................195
10.1.
Monitoring, Recording and Reporting of Adverse Events .....................................195
10.2.
Evaluation of Adverse Events...............................................................................196
10.2.1.
Seriousness...........................................................................................................196
10.2.2.
Severity/Intensity..................................................................................................197
10.2.3.
Causality ..............................................................................................................198
10.2.4.
Duration ...............................................................................................................198
10.2.5.
Action Taken........................................................................................................198
10.2.6.
Outcome...............................................................................................................198
10.3.
Abnormal Laboratory Values................................................................................198
10.4.
Pregnancy.............................................................................................................199
10.4.1.
Females of Childbearing Potential ........................................................................199
10.4.2.
Male Subjects.......................................................................................................200
10.5.
Reporting of Serious Adverse Events....................................................................200
10.5.1.
Safety Queries ......................................................................................................201
10.6.
Expedited Reporting of Adverse Events................................................................201
10.7.
Adverse Events of Special Interest........................................................................201
10.7.1.
Second Primary Malignancies (SPMs)..................................................................202
11.
DISCONTINUATIONS .......................................................................................203
11.1.
Treatment Discontinuation....................................................................................203
11.2.
Study Discontinuation ..........................................................................................203
12.
EMERGENCY PROCEDURES...........................................................................204
12.1.
Emergency Contact...............................................................................................204
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12.2.
Emergency Identification of Investigational Products ...........................................204
13.
REGULATORY CONSIDERATIONS.................................................................205
13.1.
Good Clinical Practice..........................................................................................205
13.2.
Investigator Responsibilities .................................................................................205
13.3.
Subject Information and Informed Consent...........................................................206
13.4.
Confidentiality......................................................................................................206
13.5.
Protocol Amendments...........................................................................................206
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ..............................................................................................................206
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ..............207
13.8.
Termination of the Study ......................................................................................207
14.
DATA HANDLING AND RECORDKEEPING...................................................208
14.1.
Data/Documents ...................................................................................................208
14.2.
Data Management.................................................................................................208
14.3.
Record Retention..................................................................................................208
15.
QUALITY CONTROL AND QUALITY ASSURANCE......................................210
15.1.
Study Monitoring and Source Data Verification....................................................210
15.2.
Audits and Inspections..........................................................................................210
16.
PUBLICATIONS .................................................................................................211
17.
REFERENCES.....................................................................................................212
18.
APPENDICES......................................................................................................220
Appendix A:  Table of Abbreviations......................................................................................220
Appendix B:  Recommendations for Initial Evaluation, Staging, and Response 
Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano 
Classification........................................................................................................226
Appendix C:  Guidelines for the Diagnosis and Treatment Response of Chronic 
Lymphocytic Leukemia: International Workshop on Chronic Lymphocytic 
Leukemia..............................................................................................................230
Appendix D:  Cairo-Bishop Definitions of Tumor Lysis Syndrome.........................................232
Appendix E:  Grading Scale for Hematologic Toxicity in Chronic Lymphocytic 
Leukemia Studies .................................................................................................233
Appendix F:  Lenalidomide Pregnancy Prevention Risk Management Plan .............................234
Appendix G:  Inhibitors or Inducers of CYP3A.......................................................................235
Appendix H:  Criteria for Initiating Treatment in Subjects with CLL (Adopted and 
Modified from the IWCLL Guidelines for CLL Section 4)....................................237
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Appendix I:  Modified Cumulative Illness Rating Scale (CIRS) ..............................................238
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LIST OF TABLES
Table 1:
Study Objectives.....................................................................................................37
Table 2:
Study Endpoints .....................................................................................................39
Table 3:
Eligible Histologies per Treatment Arm and Part of the Study ................................54
Table 4:
Eligible B-cell Non-Hodgkin Lymphoma Histologies (Based on the 2008 
WHO Lymphoma Classification) for Phase 1 Dose Finding Cohorts.......................54
Table 5:
Eligible Hodgkin Lymphoma Histologies (Based on the 2008 WHO 
Lymphoma Classification) for Arm D Dose Confirmation Cohort...........................55
Table 6:
Eligible Laboratory Values .....................................................................................57
Table 7:
Table of Events – Arm A - Durvalumab and Lenalidomide ± Rituximab.................65
Table 8:
Table of Events – Arm B - Durvalumab and Ibrutinib.............................................73
Table 9:
Table of Events – Arm C – Durvalumab and Rituximab ± Bendamustine ...............81
Table 10:
Table of Events – Arm D – Durvalumab Monotherapy ...........................................87
Table 11:
Performance Status by Eastern Cooperative Oncology Group Scale........................95
Table 12:
Pharmacokinetic Sample Collection Timepoints (All Arms) .................................110
Table 13:
Pharmacokinetic Sample Collection Timepoints (Arm A Only) ............................110
Table 14:
Pharmacokinetic Sample Collection Timepoints (Arm B only) .............................111
Table 15:
Immunogenicity Sample Collection Timepoints....................................................111
Table 16:
Tumor Tissue Biopsy Collection Timepoints for Biomarkers................................112
Table 17:
Bone Marrow Biopsy and Aspirate Collection Timepoints for Biomarkers -
CLL......................................................................................................................113
Table 18:
Bone Marrow Biopsy and Aspirate Collection Timepoints for Biomarkers -
Lymphoma ...........................................................................................................113
Table 19:
Planned Dose Finding Cohorts..............................................................................117
Table 20:
Dose Finding: Arm A Dose Levels (Discontinued to the Enrollment of New 
Subjects)...............................................................................................................118
Table 21:
Dose Finding: Arm B Dose Levels .......................................................................121
Table 22:
Dose Finding: Arm C Dose Levels .......................................................................122
Table 23:
Planned Dose Confirmation Cohorts.....................................................................125
Table 24:
Planned Dose Expansion Cohorts .........................................................................126
Table 25:
Lenalidomide Dose Modification Levels for Subjects Initiating Treatment at 
20 mg Based on Pretreatment Creatinine Clearance ≥ 60 mL/min.........................128
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Table 26:
Lenalidomide Dose Modification Levels for Subjects Initiating Treatment at 
10 mg Based on Pretreatment Creatinine Clearance ≥ 40 mL/min and < 60 
mL/min (Dose Confirmation and Expansion Parts Only) ......................................129
Table 27:
Ibrutinib Dose Modification Levels - NHL ...........................................................130
Table 28:
Ibrutinib Dose Modification Levels - CLL............................................................130
Table 29:
Bendamustine Dose Modification Levels..............................................................131
Table 30:
General Dose Modification and Toxicity Management Guidelines for 
Immune-mediated Adverse Events........................................................................132
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific 
Immune-mediated Reactions.................................................................................135
Table 32:
Dose Modification and Toxicity Management Guidelines for NON Immune-
mediated Reactions...............................................................................................166
Table 33:
Dose Modification and Toxicity Management Guidelines for Infusion-
related Reactions ..................................................................................................176
Table 34:
Dose Confirmation Part Stopping Rules for Efficacy ............................................190
Table 35:
Dose Expansion Part Sample Size.........................................................................191
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LIST OF FIGURES
Figure 1:
Mechanism of Action of Durvalumab (MEDI4736; an Anti-PD-L1 
Antibody) ...............................................................................................................27
Figure 2:
Overall Study Design..............................................................................................44
Figure 3:
Overall Study Flow.................................................................................................49
Figure 4:
Arm A Dose Finding Flow Chart..........................................................................187
Figure 5:
Arm B Dose Finding Flow Chart ..........................................................................188
Figure 6:
Arm C Dose Finding Flow Chart ..........................................................................189
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1.
INTRODUCTION
1.1.
Disease Background 
Lymphoid neoplasms originate from cells that normally develop into B lymphocytes 
(lymphocytes or plasma cells) or T lymphocytes (cytotoxic T lymphocytes, helper T 
lymphocytes, or regulatory T lymphocytes).  
In the 2008 World Health Organization (WHO) classification of lymphoid neoplasms 
(Swerdlow, 2008), the diagnosis of the various lymphoid neoplasms depends not on the anatomic 
location of tumor cells, but rather on the cell of origin of the tumor, as judged by morphology, 
immunophenotype, and genetic findings.  As a result, several entities previously considered 
distinct are now grouped together under single diagnostic categories (eg, chronic lymphocytic 
leukemia [CLL] and small lymphocytic lymphoma [SLL]).
1.1.1.
Non-Hodgkin Lymphoma and CLL
Non-Hodgkin Lymphoma (NHL) is a heterogeneous group of lymphoproliferative neoplasm 
with differing patterns of behavior and responses to treatment (Armitage, 1993). Currently, the 
WHO Lymphoma Classification scheme is utilized to define specific subtypes of lymphoma and 
subdivides them based on cell of origin (B, T or natural killer [NK]) and whether they are 
derived from precursor lymphocytes versus mature lymphocytes (Swerdlow, 2008).  Most (ie, 
80% to 90%) NHLs are of B-cell origin.  In the United States (US), 80-85% of lymphomas are 
diagnosed as B-cell lymphomas and 15% to 20% as T-cell lymphomas. Natural killer-cell 
lymphomas are very rare. 
The pathogenesis of lymphomas represents a complex process involving the accumulation of 
multiple genetic lesions affecting proto-oncogenes and tumor suppressor genes.  The lymph node 
microenvironment, which includes stromal cells, macrophages, regulatory T-cells, and the lymph 
node vasculature, has been implicated in the promotion of lymphomagenesis (Coupland, 2011).
In 2015, it is estimated that there will be 71,850 new cases of NHL and an estimated 19,790 
people will die from this disease annually in the US (Siegel, 2015).   
Chronic lymphocytic leukemia is the most common leukemia in North America and Europe with 
an incidence of 4.0 cases per 100,000 persons per year and has a median age of diagnosis of 72
years.  It consists of an accumulation of mature B-cells typically cluttering in marrow, blood and 
lymphoid organs with a unique cluster of differentiation (CD) 19+, CD5+, and CD23+
phenotype. The etiology of CLL is unknown and its pathogenesis is not clearly understood, 
however it is likely that the following factors play a significant role: accumulation of genomic 
events over time, chronic antigen stimulation, and age-related changes in immunosurveillance 
and in the tumor microenvironment.
Chronic lymphocytic leukemia is a heterogeneous disease with a variable disease course from 
indolent disease (at times requiring little to no therapy) to aggressive disease (fatal disease poorly 
responsive to aggressive therapeutic intervention). Prognostic factors in CLL include clinical, 
serum, genetic, as well as cytogenetic markers.
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1.1.2.
Hodgkin Lymphoma 
Hodgkin lymphoma (HL), formerly called Hodgkin’s disease, arises from germinal center or 
post-germinal center B-cells. Hodgkin lymphoma has a unique cellular composition, containing a 
minority of neoplastic cells (Reed-Sternberg cells and their variants) in an inflammatory 
background. It is separated from the other B-cell lymphomas based on its unique 
clinicopathologic features. 
Hodgkin lymphoma is a B-cell lymphoma that accounts for approximately 10% of all 
lymphomas in economically advanced countries.  This amounts to approximately 9,050 new 
cases and about 1,150 deaths due to HL in the US annually (Siegel, 2015).  The incidence in 
Europe is approximately 2.4 cases per 100,000 persons (Sant, 2010; Smith, 2011).  
The treatment of patients with HL is primarily guided by the clinical stage of disease as 
determined by the Cotswolds classification (Lister, 1989).  While the majority of treated patients 
will be cured of their lymphoma, treatment-related toxicities have become a contributing cause 
of mortality later in life.  As such, the selection of therapy must balance the desire to maintain a 
high rate of cure and the need to minimize long-term complications.
Recent major advances in the therapeutic field have been the results of treatment strategies 
utilizing agents that target unique antigens (eg, anti-CD30-drug immunoconjugate [brentuximab 
vedotin], check-point inhibition via anti-programmed cell death-1 (anti-PD-1) monoclonal 
antibodies [nivolumab, pembrolizumab, and pidilizumab]) which have antitumor activity in 
patients with R/R HL. Although these novel agents appear to prolong patient survival, they are 
not curative.  
Despite the progress in treatment outcomes for lymphoma or CLL, largely secondary to the 
addition of novel targeted or biologic-based therapies in recent years, a high percentage of 
patients experience R/R disease.  Overall, lymphoma or CLL remains mostly incurable in the 
majority of patients treated with conventional therapies.  New therapies are urgently needed to 
treat R/R lymphoma or CLL patients.
1.2.
Compound Background 
1.2.1.
Durvalumab (MEDI4736)
Durvalumab (MEDI4736) is a human immunoglobulin (Ig) G1к monoclonal antibody (mAb)
that blocks programmed cell death ligand-1 (PD-L1) by binding to its receptors, allowing T-cells 
to recognize and kill tumor cells as illustrated in Figure 1.  Durvalumab selectively binds to 
human PD-L1 with high affinity and blocks its ability to bind to programmed cell death-1 (PD-1) 
and cluster of differentiation (CD80).  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 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.
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Please refer to the Durvalumab Investigator’s Brochure (IB) for detailed information concerning 
the available pharmacology, toxicology, drug metabolism, clinical studies, and adverse event 
profile of investigational product (IP).
Figure 1:
Mechanism of Action of Durvalumab (MEDI4736; an Anti-PD-L1 Antibody)
PD-L1 inhibits cancer immunity (Zou, 2008)
Durvalumab binds to PD-L1 and allows T-cells to recognize and kill tumor cells (Segal, 2014)
Durvalumab is a selective, high affinity human IgG mAb that blocks PD-L1 binding to PD-1 (IC50 0.1 nM) and 
CD80 (IC50 0.04 nM) (Segal, 2015)
1.2.2.
Lenalidomide
Lenalidomide (Revlimid®) is a member of a class of pharmaceutical compounds known as 
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 MM in combination 
with dexamethasone and in monotherapy as maintenance following autologous stem cell 
transplantation; transfusion-dependent anemia due to low- or intermediate-1-risk MDS 
associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities; 
and mantle cell lymphoma (MCL) whose disease has relapsed or progressed after 2 prior 
therapies, one of which included bortezomib.
In Europe, lenalidomide has been approved as monotherapy for maintenance treatment of 
patients with newly diagnosed MM who have undergone autologous stem cell transplantation; as 
combination treatment of patients with previously untreated MM who are not eligible for 
transplant; in combination with dexamethasone for the treatment of patients with MM who have 
received at least one prior therapy; transfusion-dependent anemia due to low- or intermediate-1-
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risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic 
options are insufficient or inadequate; and relapsed or refractory (R/R) MCL.
Please refer to the Lenalidomide Investigator’s Brochure for detailed information concerning the 
available pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile 
of the IP.
1.2.3.
Ibrutinib
Ibrutinib (Imbruvica®) is an inhibitor of Bruton’s tyrosine kinase (BTK).  Bruton’s tyrosine 
kinase is a non-receptor tyrosine kinase with restricted cellular expression largely limited to 
B-lymphocytes, monocytes and mast cells or basophils.  Bruton’s tyrosine kinase is a critical 
component of the B-cell receptor signaling network and is crucial for B-cell development.  
In the US, ibrutinib has been approved for the treatment of patients with MCL who have 
received at least one prior therapy; CLL/SLL; CLL/SLL with 17p deletion; Waldenstrom’s 
macroglobulinemia; and marginal zone lymphoma who require systemic therapy and have 
received at least one prior anti-CD20 based therapy.
In Europe, ibrutinib has been approved for the treatment of patients with R/R MCL; previously 
untreated CLL; CLL who have received at least one prior therapy as a single agent or in 
combination with bendamustine and rituximab; and Waldenstrom’s macroglobulinemia who 
have received at least one prior therapy, or in first line for patients unsuitable for 
chemoimmunotherapy.
Ibrutinib is currently being studied in multiple histologies as monotherapy or in combination 
therapy.
1.2.4.
Bendamustine
Bendamustine (Treanda®, Bendeka®, Levact®) is an alkylating drug whose mechanisms of action 
involve induction of apoptosis through activation of DNA-damage stress responses, inhibition of 
mitotic checkpoints, and induction of mitotic catastrophe (Leoni, 2008).  
In the US, bendamustine has been approved for the treatment of patients with CLL (efficacy 
relative to first line therapies other than chlorambucil has not been established) and indolent 
B-cell NHL that has progressed during or within 6 months of treatment with rituximab or a 
rituximab-containing regimen.
In Europe, bendamustine has been approved for the treatment of patients with CLL for whom 
fludarabine combination chemotherapy is not appropriate and indolent B-cell NHL that has 
progressed during or within 6 months of treatment with rituximab or a rituximab-containing 
regimen as well as front-line treatment of MM in combination with prednisone for patients older 
than 65 years of age.  
1.2.5.
Rituximab
Rituximab (Rituxan®, MabThera®) is a cytolytic, chimeric murine/human monoclonal antibody 
directed against the CD20 cell-surface molecule present (CD20+) in normal B lymphocytes and 
B-cell CLL and in most forms of non-Hodgkin B-cell lymphomas.  
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In the US, rituximab has been approved for the treatment of patients with R/R low grade or 
follicular lymphoma (FL), CD20+, B-cell NHL as single agent; for the treatment of patients with 
previously untreated FL, CD20+, B-cell NHL in combination with first line chemotherapy; for 
the treatment of patients who have achieved a complete or partial response to rituximab in 
combination with chemotherapy, as single agent maintenance therapy; for the treatment of 
patients non progressing (including stable disease), low grade, CD20+, B-cell NHL as a single 
agent after first line cyclophosphamide, vincristine, and prednisone chemotherapy; for the 
treatment of patients with previously untreated diffuse large B-cell lymphoma (DLBCL), CD20+ 
NHL in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) 
chemotherapy or other anthracycline-based chemotherapy regimens; and for the treatment of 
patient with previously untreated and previously treated CD20+ CLL.
In Europe, rituximab has been approved for the treatment of patients with previously untreated 
stage 3 and 4 FL in combination chemotherapy; for the treatment of patients with FL patients 
responding to induction therapy; for the treatment of patients with stage 3 and 4 FL who are 
chemoresistant or are in their second or subsequent relapse after chemotherapy; for the treatment 
of patients with CD20+ DLBCL NHL in combination with CHOP chemotherapy; and for the 
treatment of patients with previously untreated and R/R CLL.
Rituximab has been also approved for non oncology indications (ie, rheumatoid arthritis, 
granulomatosis with polyangiitis and microscopic polyangiitis) in the US and Europe.
1.3.
Rationale
1.3.1.
Immune-checkpoint Inhibition
Tumor-infiltrating lymphocytes (TILs) have the capacity to control the growth of many types of 
cancers (Gooden, 2011).  Most tumors show infiltration by TILs, but tumors modulate the local 
microenvironment through expression of inhibitory molecules.  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).  It is increasingly 
appreciated that cancers are recognized by the immune system, and under some circumstances, 
the immune system may control or even eliminate tumors (Dunn, 2004).   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).  
Pembrolizumab and nivolumab are both PD-1 blocking antibodies and the first in the anti-PD-1 
pathway family of checkpoint inhibitors to gain regulatory approval from the US FDA and 
European Commission for melanoma and non-small cell lung cancer (NSCLC).  Nivolumab has 
also been approved for melanoma in combination therapy with ipilimumab, another checkpoint 
inhibitor (anti-CTLA-4 antibody).  Both anti-PD-1 antibodies (nivolumab and pembrolizumab) 
have gained approvals for additional indications from the US FDA and/or the European 
Commission (ie, nivolumab for renal cell carcinoma from the FDA and European Commission;
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pembrolizumab for head and neck squamous cell carcinoma from the FDA; nivolumab and 
pembrolizumab for classical HL from the FDA and European Commission).  
In Japan, both pembrolizumab and nivolumab have been approved for melanoma and non-small 
cell lung cancer.  Nivolumab has also been approved for renal cell carcinoma and classical HL in 
Japan.
Atezolizumab, an anti-PD-L1 antibody, has been approved by the US FDA for the treatment of 
patients with locally advanced, or metastatic urothelial carcinoma whose disease has worsened 
during, or following platinum-containing chemotherapy, or within 12 months of receiving 
platinum-containing chemotherapy, either neoadjuvant or adjuvant surgical treatment as well as 
for the treatment of patients with metastatic NSCLC who have disease progression during or 
following platinum-containing chemotherapy, and have progressed on an appropriate FDA 
approved targeted therapy if their tumor has epidermal growth factor receptor (EGFR) or 
anaplastic lymphoma kinase (ALK) gene abnormalities. 
Several anti-PD-1 and anti-PD-L1 antibodies are currently being studied in multiple other 
oncologic and hematologic indications either as monotherapy or in combination therapy.
1.3.2.
Study Rationale and Purpose
Lymphoma/CLL is comprised of multiple histologies. It is hypothesized that durvalumab will 
have activity in multiple indications based on known expression pattern of PD-L1/PD-1, 
available preclinical data, and recent clinical data utilizing nivolumab (Ansell, 2015) or 
pembrolizumab (Moskowitz, 2014) in R/R classical HL and promising early data of pidilizumab 
alone or in combination with rituximab (Westin, 2014) in DLBCL or FL, respectively; also 
nivolumab monotherapy (Lesokhin, 2014) has shown antitumor activity in DLBCL, FL, and T-
cell lymphomas.    
The programmed cell death-1 (PD-1) plays an important role in the regulation of the immune 
response.  The PD-1 receptor, in conjunction with receptor ligands PD-L1 and PD-L2, functions 
to regulate the immune system primarily by down regulating signals of the T-cell receptor.  PD-
L1 expressed on tumor cells binds to PD-1 on T-cells which leads to down-regulation of T-cell 
activity and allows tumor cells to evade the immune response.  
Based on in vitro studies, an antibody that blocks the interaction between PD-L1 and its 
receptors can relieve PD-L1-dependent immunosuppressive effects and enhance the cytotoxic 
activity of antitumor T-cells (Blank, 2007). The levels of tumor-infiltrating lymphocytes, and 
more specifically cytotoxic T-cells, have been correlated with improved prognosis in a number 
of cancers including colorectal, melanoma, and lung (Galon, 2006; Clemente, 1996; Dieu-
Nosjean, 2008, Hodi 2010). Based on these findings, an anti-PD-L1 antibody could be used 
therapeutically to enhance antitumor immune responses in multiple forms of cancer. Results of 
several preclinical studies using mouse myeloma models support this hypothesis (Gorgun, 2015; 
Hirano, 2005; Iwai, 2002; Kearl, 2013; Okudaira, 2009; Zhang, 2008). In these studies, 
antibodies directed against PD-L1 or its receptor, PD-1, demonstrated antitumor activity by 
inducing anti-MM immune responses. In addition to the limited aforementioned clinical data in 
NHL with agents that inhibit PD-1, there are several other preclinical and prognostic 
observations in various lymphoma subtypes that lead us to believe that PD-1/PD-L1 inhibition 
may prove to be efficacious:
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
Two recently published Blood journal articles describing PD-L1/PD-1-mediated CD8 
T-cell dysfunction in the context of aging-related immune defects in a CLL mouse 
model which replicates human T-cell defects (McClanahan, 2015; McClanahan, 
2015a) and that utilizing the same murine CLL mouse model that in vivo PD-L1 
blockade normalizes T-cell and myeloid cell populations and immune effector 
functions and prevents CLL development following adoptive transfer.

A large French multicenter clinical trial demonstrated that high levels of plasma 
soluble PD-L1 are associated with a poorer prognosis (ie, overall survival [OS]) in 
DLBCL patients treated with R-CHOP and are a patient predictive biomarker; use of 
PD-1 axis inhibitors may prove to be effective in this subgroup of DLBCL patients 
(Rossille, 2014).

PD-1 expression in peripheral blood CD4+ and CD8+ T-cells were found to be 
markedly different between CLL disease stages when compared with healthy 
subjects; highest numbers of both CD8+ PD-1+ and CD4+PD-1+ cells were present 
in R/R CLL patients (Novak, 2015).

A preclinical 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). 
In this current trial a diverse group of lymphoma histologies (eg, R/R CLL and B-NHL) will be 
evaluated in both durvalumab monotherapy and durvalumab combination therapy arms in an 
attempt to determine dose finding/ safety, but also which lymphoma histology and treatment 
arms show the strongest antitumor signals which will lead to additional clinical trials. 
1.3.3.
Rationale for the Study Design
The safety of durvalumab has already been explored and assessed in other hematology and 
oncology patient populations. No dose limiting toxicity has been defined to date. Dosing was 
originally based on weight and ranged up to 10 mg/kg once every 2 weeks (Q2W) and 20 mg/kg 
once every 4 weeks (Q4W). Pharmacokinetic analysis demonstrated that fixed dosing had 
equivalent variability to weight based dosing.  Based on an average weight of 75 kg, a fixed dose 
of 1500 mg Q4W is now being explored as a dose that provides continuous plasma concentration 
of antibody above the threshold needed for in vitro activity. The dose of 1500 mg Q4W is the 
recommended Phase 2 dose (RP2D) across the durvalumab clinical program (for ongoing or 
planned studies in both solid tumors and hematologic malignancies).  Over 1000 patients with 
solid tumors and myelodysplastic syndrome were treated at a dose schedule equivalent to 
1500 mg Q4W (ie, 10 mg/kg Q2W or 20 mg/kg Q4W which show similar exposure levels based 
on the area under the curves steady state), and available safety data support this as an appropriate 
dose for durvalumab in this study.  Please refer to the Durvalumab IB for further information and 
Section 1.3.4.
There is no prior clinical experience with durvalumab monotherapy in lymphoma/CLL or in 
combination with lenalidomide, bendamustine, ibrutinib, or rituximab.  A parallel dose-
finding/confirmation or expansion design was selected to confirm the safety of the 1500 mg 
Q4W durvalumab dose as monotherapy and for selected durvalumab combination regimens in 
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R/R population of lymphoma and CLL patients.  A standard 3 + 3 dose finding trial design will 
be used to evaluate the safety and establish the RP2D of each combination.
Once the RP2D for each combination is established, treatment arms of interest may be expanded 
to obtain additional safety, pharmacokinetics (PK), pharmacodynamics (Pd) and efficacy data in 
specific lymphoma histologies and CLL, and thereby to guide future development.
1.3.4.
Rationale for Dose, Schedule, and Regimen Selection
The dose and schedule for durvalumab monotherapy (20 mg/kg Q4W) were selected based on 2 
sets of data: (i) the safety analysis of doses (0.1, 0.3, 1, 3, and 10 mg/kg Q2W) administered in 
Study CD-ON-MEDI4736-1108 (a Phase 1/2 study to evaluate the safety, tolerability, and PK of  
durvalumab IV given as monotherapy in subjects with advanced solid tumors); and (ii) PK 
profile simulations for durvalumab administered using 10 mg/kg Q2W and 20 mg/kg Q4W 
schedules.
Safety and PK characteristics of the studied dose and schedule 10 mg/kg Q2W:
After evaluation of the PK data from subjects enrolled in Study CD-ON-MEDI4736-1108, 
durvalumab exhibited nonlinear (dose dependent) PK consistent with target-mediated drug 
disposition.  Linear PK was observed at doses of 3 mg/kg and higher and is consistent with near 
complete target suppression, as reflected in target trough plasma concentrations of drug 
> 100 ug/mL. This trough concentration is supported by soluble PD-L1 (sPD-L1) suppression 
data. Furthermore, the 10 mg/kg Q2W dose was not associated with any dose limiting toxicities 
(DLTs) in the dose escalation portion and was, therefore, selected for further evaluation in the 
dose expansion portion of Study CD-ON-MEDI4736-1108.
Extrapolation of dose and schedule of 10 mg/kg Q2W to 20 mg/kg Q4W through population PK 
modeling:
A population PK model was developed using durvalumab monotherapy data from Phase 1 of 
Study CD-ON-MEDI4736-1108 (N = 292; doses = 0.1 to 10 mg/kg Q2W or 15 mg/kg once 
every 3 weeks; solid tumors) (Fairman, 2014). This population PK model adequately described 
monotherapy PK data and was utilized to predict expected PK exposures following 20 mg/kg
Q4W dosing regimens (since none of the monotherapy studies explored Q4W regimens).  
Pharmacokinetic simulations indicate that a similar overall exposure as represented by area under 
the curves steady state (AUCss) (4 weeks) is expected following both 10 mg/kg Q2W and
20 mg/kg Q4W regimens. However, median maximum plasma concentration (Cmax) at steady 
state is expected to be higher with 20 mg/kg Q4W (~1.5 fold) and median trough concentration 
at steady state is expected to be higher with 10 mg/kg Q2W (~1.25 fold). 
Justification for fixed dosing over weight-based dosing:
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).  A 
total of 1000 patients were simulated using body weight distribution of 40 to 120 kg. Simulation 
results demonstrate that body weight-based and fixed-dosing regimens yield similar median 
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steady state PK concentrations with slightly less overall between-subject variability with the 
fixed- dosing regimen.  
Similar findings have been reported by others (Ng, 2006; Wang, 2009; Zhang, 2012; Narwal, 
2013). Wang and colleagues (Wang, 2009 ) investigated 12 monoclonal antibodies and found 
that fixed and body size-based dosing perform similarly, with fixed dosing being better for 7 of 
12 antibodies. In addition, they (Zhang, 2012) investigated 18 therapeutic proteins and peptides 
and showed that fixed dosing performed better for 12 of 18 proteins in terms of reducing the 
between-subject variability in PK/Pd parameters.
A fixed-dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar pharmacokinetic exposure and variability, 
we considered it feasible to switch to fixed-dosing regimens. Based on average body weight of 
75 kg, a fixed dose 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) is the RP2D for 
this study.
Please refer to the Durvalumab IB for further information.
1.3.5.
Rationale for Choice of Combination Compounds
1.3.5.1.
Rituximab and Lenalidomide
Lenalidomide has pleiotropic activities including a capacity to activate NK cells, to increase T-
cell proliferation and function, and to enhance macrophage-mediated ADCC of rituximab-coated 
tumor cells.  The main molecular target of lenalidomide is the E3 ubiquitin ligase cereblon that 
was recently shown to trigger induction of cytokine production by T-cells.  Follicular lymphoma
infiltrating CD4+ and CD8+ tumor induced immunosuppression in the context of increased 
expression of B7- related inhibitory ligands (including PD-L1) down-regulates activated Rho-
GTPases RhoA, Rac1, and Cdc42, key regulators of T-cell synapse actin dynamics.  T-cells 
display immunological synapse dysfunction with impaired F-actin polymerization and reduced 
effector function.  Lenalidomide can repair the Rho A mediated T-cell synapse defect present in 
cancer patients thereby restoring T-cell functions and potentially enabling the effect of 
immunotherapies (Greaves, 2013; Ramsay, 2013; Gribben, 2015). 
Lenalidomide clinical trials with registration intent are ongoing with the combination of 
lenalidomide and rituximab in relapsed, refractory and first line FL, based on Phase 2 results 
suggesting that this combination may be a reasonable alternative to traditional chemo-
immunotherapy (Fowler, 2014; Leonard, 2015)
Preclinical studies with respect to MM have demonstrated that lenalidomide enhances immune 
checkpoint blockade (ie, anti- PD-1/PD-L1) induced immune response in patient-derived 
primary myeloma cells; this may represent a novel immune-based therapeutic strategy to treat 
MM and other B-cell neoplasms (Gorgun, 2015). Other studies demonstrate that lenalidomide 
reduced PD-L1 expression on myeloma cells (Benson, 2010), and that lenalidomide exposure 
resulted in a decrease in the expression of PD-1 on T-cells and induced amplified responses to 
myeloma vaccine (Luptakova, 2013).
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1.3.5.2.
Ibrutinib
Ibrutinib is a covalent BTK inhibitor which affects 3 key neoplastic B-cell processes: a) inhibits 
proliferation/survival; b) inhibits adhesion; and c) modulates chemotaxis. It is US FDA 
approved for patients with 17p-deletion CLL and for CLL or MCL patients who have received at 
least one prior therapy. Ibrutinib has also demonstrated preferential clinical response activity in 
activated B-cell-like versus germinal center B-cell like DLBCL in a monotherapy clinical trial of 
relapsed DLBCL (Wilson, 2015) as well as moderate single-agent activity in R/R FL 
(Fowler, 2012). Recently, Stanford University investigators demonstrated that the combination 
of anti-PD-L1 antibodies and ibrutinib suppressed tumor growth in mouse models of lymphoma 
insensitive to ibrutinib and enhanced antitumor T-cell immune responses, based in part on the 
ability of ibrutinib to inhibit interleukin-2-inducible T-cell kinase and thus potentially enhance 
T helper 1 based immune responses (Sagiv-Barfi, 2015). These findings, along with ibrutinib’s 
favorable toxicity profile, make it a good choice to study in combination with durvalumab in a 
variety of lymphoma histologies. 
1.3.5.3.
Bendamustine and Rituximab
Bendamustine is an alkylating agent which structure also shows similarities to purine analogues. 
It has antitumor activity in both hematologic and solid tumors. The combination of 
bendamustine and rituximab is highly utilized clinically to treat FL, CLL/SLL, and MCL around 
the world. 
Of interest, a Phase 2 multicenter study of bendamustine and rituximab in older patients with 
previously untreated DLBCL (N = 23) demonstrated an overall response rate of 93% (complete 
response [CR] rate of 60%) in 15 evaluable patients with a time to progression of 7.4 months 
(Spina, 2014); in addition, 2 small clinical trials of bendamustine and rituximab in R/R DLBCL 
demonstrated an overall response rate (ORR) of 50 to 60% and a median progression-free 
survival (PFS) of approximately 7 months (Arcari, 2014; Ohmachi, 2013).  Bendamustine has 
also been used in R/R FL, MCL, and other indolent lymphomas (Rummel, 2005) as well as CLL 
(Fischer, 2011).
It may seem counterintuitive to use bendamustine in a trial initializing an anti PD-L1 monoclonal 
antibody. The use of rituximab maintenance therapy following bendamustine plus rituximab 
induction in lymphoma has been shown to be associated with sustained CD4 lymphopenia 
(Yutaka, 2015); however, it appears that fludarabine and rituximab based therapy (without 
rituximab maintenance) in low grade lymphoma appears to result in an even longer recovery 
time for circulating T-cells in peripheral blood (Czuczman, 2005).  The correlation of T-cell 
subsets between blood versus marrow/nodal compartments and their changes following exposure 
to durvalumab is unknown and is part of the correlative studies on this trial. It may be 
hypothesized that T-cells within the tumor/marrow microenvironment may still be present and 
responsive to agents targeting the PD-1/PD-L1 axis (even if they are significantly decreased or 
even absent in peripheral blood).
1.3.5.4.
Local Involved Field Radiation Therapy
The addition of other antilymphoma/CLL agents (ie, those shown to be safe in combination with 
durvalumab [Arms A, B, or C]) or “involved-field” radiation therapy (IFRT) (to evaluate for 
possible abscopal effect) at the time of progressive lymphoma or CLL is allowed as an option in 
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this study.  B-cell lymphoma is a highly radiosensitive disease.  The potential value of 
combining durvalumab with other agents used in the treatment of lymphoma or CLL is discussed 
in this section and is self-explanatory.  However, the potential benefit of the combination of a 
check-point inhibitor plus IFRT requires further elucidation.
Immunologic responses to localized radiation therapy leading to systemic antitumor effects in 
non-radiated tumor sites (called the abscopal effect) is very rare event and largely reported as 
case studies in the past (Reynders, 2015). Theoretically, recent advances in the field of immune-
oncology indicates that significant increase in the incidence of “abscopal” effects may become 
reality when immune checkpoint inhibitors are combined with limited field radiation therapy 
(Almo, 2014).
A review on this topic describes the critical role of radiation therapy (with appropriate dose and 
fraction [not known]) causes an “in situ” vaccination by inducing tumor “neoantigen” release for 
dendtritic cross-presentation; if this occurs in the setting of immune check-point blocked 
immunotherapy (eg, anti-PD-L1), the tumor-specific immune response is triggered/enhanced and 
can lead to a systemic antitumor activity in the host. It is unknown which regimen of radiation 
therapy is optimal in maximizing this abscopal effect, but it is suggested that hypofractionated 
radiation therapy may be better than conventional or hyper-fractionated techniques (Teng, 2015).
Therefore, for subjects enrolled in all study arms, at time of progressive lymphoma or CLL, 
IFRT (to evaluate for possible abscopal effect) is allowed.  
1.3.6.
Rationale for Pharmacodynamics and 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 
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. 
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 NSCLC patients demonstrated a statistically 
significant increase in CD8+ infiltrating lymphocytes from on-treatment tumor samples 
compared with pretreatment biopsies (Rizvi, 2015).  Furthermore, durvalumab treatment induces 
IFNγ and effector T-cell and type 1 T-helper (Th-1) cell gene expression within the NSCLC 
biopsies within 4 to 8 weeks of treatment (Higgs, 2016), indicating a more inflamed tumor 
microenvironment.  This data is consistent with the pharmacodynamic effects observed in tumor 
biopsies from patients treated with atezolizumab (PD-L1 inhibitor) and pembrolizumab (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, IFNγ) were more frequently observed in patients who respond to 
the therapy compared with the non-responders (Herbst, 2014).  Notably, while pharmacodynamic 
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response to durvalumab and atezolizumab can also be observed in the blood, circulating 
biomarkers have not been shown to be correlated with response.
Evaluation of on-treatment tumor samples is critical for identifying pharmacodynamics 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 will also allow new biomarker development to drive 
clinical decisions early in patient treatment and reveal new targets/additional immune system 
pathways that may be targeted to improve therapeutic outcomes.
Pretreatment biopsies will be used to assess biomarkers that may be predictive of response to 
durvalumab combination therapies.  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.
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 IFNγ gene expression in pretreatment tumor 
biopsies may predict the best response to durvalumab monotherapy (Higgs, 2015; Higgs, 2016). 
Non-Hodgkin lymphoma is a heterogeneous patient population with multiple diseases. 
Genetic/cytogenetic changes have been shown to be associated with disease prognosis.  Gene 
expression signatures related to cell of origin or other disease mechanism may define disease 
subtypes with differential response.  Baseline disease specific biomarkers such as genetics/gene 
expression signatures will be measured in the study. The samples collected in the study may be 
utilized for unbiased genetic/genomic analysis to understand disease or mechanism of action for 
single or combination therapies.
Multi-color flow cytometry techniques will be used to monitor minimal residual disease (MRD) 
in MCL and CLL as well as polymerase chain reaction techniques in FL.  Newer therapies 
including novel agents, have increased the partial response (PR) and complete response (CR)
rates dramatically in various histologies. Consequently, to adapt treatment intensity, extend 
duration of response, and prolong progression free survival, more sensitive clinical assessment 
methods are necessary to better define treatment outcomes at the molecular level.  The MRD 
assessments in MCL, CLL, and FL histologies in this study will be an additional tool for 
assessment of response and outcome.
Overall, 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 trial designs.  
The data may also reveal new targets/additional immune system pathways to improve therapeutic 
outcomes.
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2.
STUDY OBJECTIVES AND ENDPOINTS
Arm A is discontinued to the enrollment of new subjects. Subjects already enrolled and 
treated in Arm A who are receiving clinical benefit, based on the discretion of the 
investigator, may continue study treatment after being reconsented. 
Table 1:
Study Objectives
Primary Objectives
The primary objectives of the study are:
Dose finding part (Phase 1):

To assess the safety and tolerability of durvalumab when given in combination with 
lenalidomide and rituximab; ibrutinib; or bendamustine and rituximab to determine 
the recommended phase 2 dose (RP2D) of each combination in subjects with 
lymphoma or chronic lymphocytic leukemia (CLL)
Dose confirmation part (Phase 1):

To assess the safety of durvalumab as monotherapy and when given in combination 
with lenalidomide and rituximab; ibrutinib; or bendamustine and rituximab at the 
RP2D in subjects with lymphoma or CLL
Dose expansion part (Phase 2):

To evaluate the preliminary efficacy of durvalumab when given in combination with 
lenalidomide and rituximab; ibrutinib; or bendamustine and rituximab in subjects 
with lymphoma or CLL
Secondary Objectives
The secondary objectives are:
Dose finding and confirmation parts (Phase 1):

To make a preliminary assessment of antitumor activity of durvalumab as 
monotherapy and when given in combination with lenalidomide and rituximab;
ibrutinib; or bendamustine and rituximab in subjects with lymphoma or CLL
Dose expansion part (Phase 2):

To assess the safety of durvalumab when given in combination with lenalidomide and
rituximab; ibrutinib; or bendamustine and rituximab in subjects with lymphoma or 
CLL
All parts (Phase 1/2):

To characterize the pharmacokinetics (PK) of durvalumab as monotherapy and when 
given in combination

To characterize the PK of lenalidomide and ibrutinib when given in combination with 
durvalumab

To determine the pharmacodynamic (Pd) effects of durvalumab as monotherapy
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Table 1:
Study Objectives (Continued)
Exploratory Objectives
The exploratory objectives are:

To explore population PK analyses including the influence of intrinsic and extrinsic 
factors that may influence durvalumab exposures

To determine the immunogenicity of durvalumab as monotherapy and when given in 
combination

To explore the PK/Pd relationship, explore Pd mechanistic biomarkers for 
durvalumab and other combination agents in the study

To explore host immune and tumor molecular markers predictive of response to 
durvalumab and other agents when given in combination

To explore minimal residual disease (MRD) and its correlation with clinical outcome

To explore the abscopal effect (ie, immune-mediated tumor response outside the 
radiation field) of local involved field radiation therapy when given in combination 
with durvalumab
Analyses of well characterized biomarkers (eg, soluble PD-L1 [sPD-L1]) in Arm D) will be fully 
described in the statistical analysis plan and reported in the clinical study report, while analyses 
of non-characterized biomarkers will be exploratory and will not be reported in the clinical study 
report.
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Table 2:
Study Endpoints
Endpoint
Name
Description
Timeframe
Primary Endpoints:
Dose finding 
(Phase 1)
Safety
Non-tolerated dose (NTD), 
maximum-tolerated dose (MTD), and 
recommended Phase 2 dose (RP2D) 
determined based on the incidence of 
dose limiting toxicities (DLTs) that 
occur during the DLT evaluation 
period
DLT evaluation period: from 
the first dose of any
investigational product (IP) 
through the end of Cycle 1 
when given in combination 
with lenalidomide and 
rituximab; ibrutinib; or 
bendamustine and rituximab
Incidence of treatment-emergent 
adverse events using the NCI CTCAE 
criteria V4.03, including dose-
limiting toxicities (DLTs)
From the first dose of any IP
up to 90 days from the last 
dose of durvalumab or 
28 days from the last dose of 
any other IP, whichever 
occurs later 
Dose 
confirmation 
(Phase 1)
Safety
Incidence of treatment-emergent 
adverse events using the NCI CTCAE 
criteria V4.03
From the first dose of any IP 
up to 90 days from the last 
dose of durvalumab or 
28 days from the last dose of 
any other IP, whichever 
occurs later
Dose 
expansion
(Phase 2)
Preliminary 
efficacy:
Overall response rate (ORR) based on 
the tumor specific response criteria:
During durvalumab 
treatment (up to 13 cycles)
IWG Response 
Criteria for 
Malignant 
Lymphoma (the 
Lugano 
Classification) 
(Cheson 2014) 
and
ORR (lymphoma): Proportion of
subjects with best response of partial 
response (PR) and complete response 
(CR)
IWCLL 
Response 
Criteria for CLL 
(Hallek, 2008; 
Hallek, 2012; 
Hallek, 2013)
ORR (CLL): Proportion of subjects 
with best response of CR, CR with 
incomplete marrow recovery (CRi), 
nodular PR (nPR), PR, PR with 
lymphocytosis (PRL)
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Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
Secondary Endpoints:
Dose finding 
and 
confirmation 
(Phase 1)
Preliminary 
antitumor 
activity:
ORR based on the tumor specific 
response criteria:
During durvalumab 
treatment (up to 13 cycles)
IWG Response 
Criteria for 
Malignant 
Lymphoma (the 
Lugano 
Classification) 
(Cheson 2014)
ORR (lymphoma): Proportion of 
subjects with best response of PR or 
CR
IWCLL 
Response 
Criteria for CLL 
(Hallek, 2008; 
Hallek, 2012; 
Hallek, 2013)
ORR (CLL): Proportion of subjects 
with best response of CR, CRi, nPR, 
PR, or PRL
All parts 
(Phase 1/2)
Other efficacy 
parameters:
ORR based on the tumor specific 
response criteria:
During the study 
IWG Response 
Criteria for 
Malignant 
Lymphoma (the 
Lugano 
Classification) 
(Cheson 2014)
ORR (lymphoma): Proportion of 
subjects with best response of PR or 
CR
IWCLL 
Response 
Criteria for CLL 
(Hallek, 2008; 
Hallek, 2012; 
Hallek, 2013)
ORR (CLL): Proportion of subjects 
with best response of CR, CRi, nPR, 
PR, or PRL
Time to first 
response (TTR)
TTR (lymphoma): Time from first IP 
dose to the first documented response 
(PR or CR)
TTR (CLL): Time from first IP dose 
to the first documented response (CR,
CRi, nPR, PR, or PRL)
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Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
Duration of 
response (DoR)
DoR (lymphoma): Time from first 
CR or PR to progressive disease (PD) 
or death
DoR (CLL):
Time from first CR, CRi, nPR, PR, or 
PRL to PD or death
Progression-free 
survival (PFS)
PFS (lymphoma/ CLL):
Time from first IP dose to the first 
documented PD or death due to any 
cause, whichever occurs first
During the study treatment
Dose 
expansion 
(Phase 2)
Safety
Incidence of treatment-emergent 
adverse events using the NCI CTCAE 
criteria V4.03
From the first dose of any IP 
up to 90 days from the last 
dose of durvalumab or 
28 days from the last dose of 
any other IP, whichever 
occurs later
All parts 
(Phase 1/2)
PK
Serum/plasma samples will be 
collected to assay serum/plasma 
concentrations of durvalumab, 
lenalidomide and ibrutinib and to 
assess typical PK parameters such as 
maximum observed concentration 
(Cmax), area under the concentration-
time curve (AUC), time to maximum 
concentration (Tmax), terminal half-
life (t1/2), clearance (CL/F) and 
volume of distribution (Vz/F)
During Cycles 1 & 2 
Pd
Individual soluble PD-L1 (sPD-L1) in 
blood at baseline and at specified 
time points (monotherapy)
During the study treatment
Exploratory Endpoints:
All parts 
(Phase 1/2)
Population PK
Assessed by nonmixed effect 
modeling (NMEM) compartment 
analysis
During Cycles 1 & 2
All parts 
(Phase 1/2)
Immunogenicity
The number of subjects who develop 
anti-drug antibody (ADA) against 
durvalumab 
During durvalumab 
treatment
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Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
All parts 
(Phase 1/2)
Pd
Pharmacodynamic 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.
During the study treatment
Biomarker
Gene and/or protein expression of 
analytes including but not limited to 
PD-L1, PD-L2, PD-1, or cereblon, 
During the study treatment
Biomarker
The host immune activation status in 
peripheral blood and tumor at 
baseline and at specified time points 
during treatment
Biomarker
Baseline genetic/cytogenetic and 
other molecular biomarkers such as 
gene expression signatures related to 
disease or response
Biomarker
Measurements of minimal residual 
disease (MRD)
Abbreviations:  CLL = chronic lymphocytic leukemia; IWCLL = International Workshop on Chronic Lymphocytic 
Leukemia; IWG = International Working Group; NCI CTCAE = National Cancer Institute Common Terminology 
Criteria for Adverse Events; Pd = pharmacodynamic(s); PD-1 = programmed cell death 1; PD-L1 = programmed 
cell death ligand 1; PK = pharmacokinetic(s).
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3.
OVERALL STUDY DESIGN
This clinical 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
Study MEDI4736-NHL-001 is a multicenter, open-label, Phase 1/2 study assessing the safety, 
tolerability, PK, Pd, and preliminary efficacy of durvalumab as monotherapy and when given in 
combination in select subtypes of R/R lymphoma or R/R CLL.
The study will consist of 3 parts: dose finding (Phase 1), dose confirmation (Phase 1), and dose
expansion (Phase 2).  In this study, 4 treatment arms will be investigated:

Arm A: durvalumab and lenalidomide ± rituximab: discontinued to the enrollment 
of new subjects. Subjects already enrolled and treated who are receiving clinical 
benefit, based on the discretion of the investigator, may continue study 
treatment after being reconsented. 

Arm B: durvalumab and ibrutinib 

Arm C: durvalumab and rituximab ± bendamustine

Arm D: durvalumab (monotherapy)
The study will start with 3 dose finding cohorts (Arms A, B, and C) and one dose confirmation
cohort (Arm D) in parallel.
All treatment arms will be open for enrollment at study start except in the US, where Arm D will 
enroll depending on the availability of treatment slots and following the completion of 
assessment of responses from the combination therapy arms.
Subjects will be assigned to 1 of the 4 treatment arms based on the investigator’s choice led by
the subject’s eligibility status as per the inclusion/exclusion criteria described for each arm, prior 
antilymphoma/CLL therapy and response to prior therapy, medical history and also the 
availability of open treatment slots in a given cohort.
Please see Figure 2 for the overall study design and Table 3 for the selected histologies and 
planned number of subjects in each treatment arm and phase.
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If DLT ≤ 0/3 or 1/6
Confirm 
antitumor activity
Confirm 
RP2D 
If DLT ≥ 2/3 or 2/6
If DLT ≤ 0/3 or 1/6
If DLT ≥ 2/3 or 2/6
Confirm 
RP2D 
If DLT ≥ 2/3 or 2/6
Confirm 
antitumor activity
Figure 2:
Overall Study Design
ARM A   
R/R B-cell 
NHL
discontinued 
to the 
enrollment of 
new subjects
DL 1: Durvalumab + 
Lenalidomide 20 mg
DL 2: Durvalumab+ 
Lenalidomide 20 mg+ Rituximaba  
DL -1A: Durvalumab +    
Lenalidomide 10mg 
If DLT ≥ 2/3 or 2/6
ARM B    
R/R B-cell 
NHL/CLL
DL 1 c: Durvalumab
+ Ibrutinib 420 mg
If DLT ≤ 0/3 or 1/6
If DLT ≤ 0/3 or 1/6
DL 2: Durvalumab+ 
Ibrutinib 560 mg 
(NHL only)
DL -1: Durvalumab + 
Ibrutinib 280 mg
If DLT ≥ 2/3 or 2/6
DL 1: Durvalumab + 
Rituximab
DL 2 c: Durvalumab + 
Bendamustine 70 mg/m2 + 
Rituximab
ARM D 
Durvalumab 
monotherapy
DL 3: Durvalumab + 
Bendamustine 90 mg/m2+ 
Rituximab (NHL only)
No dose finding cohort
Confirm 
RP2D 
R/R CLL/SLL, MCL
R/R CLL/SLL, MCL
Confirm 
antitumor activity
R/R CLL/SLL, FL, 
DLBCL
R/R CLL/SLL, FL, 
DLBCL
R/R CLL/SLL, 
DLBCL, MCL, FL, 
HL
Abbreviations: CLL = chronic lymphocytic leukemia; DL = dose level; DLT = dose limiting toxicity; DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; HL = 
Hodgkin lymphoma; MCL = mantle cell lymphoma; NHL = non-Hodgkin lymphoma; RP2D = recommended phase 2 dose; R/R = relapsed/refractory; SLL = small lymphocytic
lymphoma; SRC = safety review committee; US = United States.
a Arm A DL 2 and -1B (discontinued to the enrollment of new subjects): Rituximab 375 mg/m2on Cycle 1 Days 2, 8, 15, 22 and then on Day 1 of every 28-day cycle from Cycles 2-.5.
b Arm A DL -2 and DL -3 (discontinued to the enrollment of new subjects): Rituximab 375 mg/m2on Cycle 1 Day 2 and then on Day 1 of every 28-day cycle from Cycles 2 through 8.
c Arm B DL 1 and Arm C DL 2: These dose levels will be the highest dose levels tested in subjects with CLL/SLL before opening CLL/SLL dose confirmation cohorts.
dArm A dose confirmation and dose expansion cohorts are discontinued and will not enroll new subjects. In addition, the add-on combination treatment with lenalidomide ± rituximab is
  no longer allowed.
Notes:  Durvalumab will be administered at a fixed dose of 1500 mg once every 4 weeks.  All treatment arms will be open for enrollment at study start. Arm D will not be open for 
enrollment at the study start in the US, where Arm D will enroll depending on treatment slot availability and following the completion of an assessment of responses from the 
combination therapy arms (ie, Arms A, B, and C).  Arm A is discontinued to the enrollment of new subjects. Only those subjects already enrolled and treated in Arm A who are 
receiving clinical benefit based on the discretion of the investigator, may continue study treatment after being reconsented.
DOSE EXPANSION
(Confirm efficacy in specific histology)
DOSE CONFIRMATION         
(Confirm RP2D and seek preliminary 
signal in specific histology)
Note for Arm D: At the time of disease
progression, the investigator may add study 
treatments previously investigated with durvalumab 
(eg, rituximab ± either lenalidomided or 
bendamustine; or ibrutinib) once a dose level for 
that combination therapy is deemed tolerable) or 
involved-field radiation to a single involved nodal 
site (ie, to evaluate for abscopal antitumor effect) 
for subjects who meet the criteria in Section 3.1.2
ARM C    
R/R B-cell 
NHL/CLL
DL -2: Durvalumab+ 
Lenalidomide 15mg+ 
Rituximab b
DL -1B: Durvalumab+ 
Lenalidomide 10 mg+ Rituximaba
DL -3: Durvalumab + 
Lenalidomide 10mg+ 
Rituximab b
If DLT ≤ 
0/3 or 1/6
Confirm 
RP2D 
R/R FL, DLBCLd
R/R FL, DLBCLd
DOSE FINDING
(Determine preliminary RP2D based on 3 + 3 design)
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EDMS Doc. Number: 24715418 - 20540270
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Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
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MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
In the dose finding part (Phase 1), a preliminary RP2D will be established for each durvalumab 
combination treatment using a 3 + 3 design (Storer, 1989).  For Arms A and C, prior to enrolling 
subjects to receive all 3 drugs, the doublet combinations (ie, Arm A: durvalumab and 
lenalidomide and Arm C: durvalumab and rituximab) will be evaluated.  Once the doublet 
combinations are deemed tolerable, the eventual triplet combination will be tested.  The 
durvalumab starting dose is fixed in each of these arms.  Three to 6 evaluable subjects will be 
evaluated in each dose finding cohort; therefore, approximately 15 to 60 (DLT evaluable)
subjects with B-cell NHL or CLL are anticipated to be enrolled in the dose finding part.  Subjects 
with CLL/SLL will not be eligible for Arm A.  The final number of subjects will depend on the 
number of dose levels tested and the number of DLTs observed within each cohort.  The 
durvalumab monotherapy arm will not have a dose finding cohort as the preliminary RP2D has 
been established, but it will need to be confirmed.
In Arms A, B, and C, an initial cohort of 3 subjects will be enrolled to a specific dose level to 
assess toxicities, before additional subjects are treated in that arm.  A dose level will be 
considered tolerable if 0 of 3 evaluable subjects experiences a DLT during the DLT evaluation 
period (ie, from the first IP dose through completion of Cycle 1 in Arms A, B, and C).  If 1 of 3
subjects experiences a DLT, up to 3 more subjects will be enrolled at that dose level.  A dose 
will be considered tolerable if ≤ 1 of 6 evaluable subjects experiences a DLT during the DLT 
evaluation period (defined in Section 7.2.2).  A dose will be considered to be a non tolerated 
dose (NTD) if ≥2 of 3 or 6 evaluable subjects at a dose level experience a DLT.  The maximum 
tolerated dose (MTD) is defined as the highest dose level below the NTD with 0 of 3 or ≤1 of 6 
evaluable subjects experiencing a DLT during DLT evaluation period.  Subjects will be 
considered evaluable for DLTs if they complete the DLT evaluation period or experience a DLT 
during the DLT evaluation period.  Non-evaluable subjects may be replaced with another subject 
at the same dose level.
After full enrollment and completion of the DLT evaluation period of each dose level, the 
number and type of DLTs and adverse events (AEs) occurring during the DLT evaluation period 
of that dose level will be assessed by the safety review committee (SRC), which includes the 
sponsor’s medical monitor, drug safety physician, and a subset of investigators who are 
participating in this clinical study.  If a dose level is considered tolerable by the SRC, the SRC 
may recommend to the sponsor that subsequent dose finding or dose confirmation cohorts may 
open for enrollment.
During the dose finding part, the decision to evaluate the subsequent dose level for a 
combination agent, an intermediate dose level, different dosing schedules not currently specified
(eg, rituximab dosing Q4W, rituximab dosing in mid-cycle, start of rituximab dosing after Cycle 
1, or changes in dose and schedule of other study drugs such as lenalidomide), the need to add 
additional subjects within any dose cohort, or to declare a dose level as tolerable will be 
assessed, recommended and documented by the SRC based on their review of clinical and 
laboratory safety data for a given dose cohort. 
The SRC will identify a preliminary RP2D for each treatment arm (except Arm D) based on an 
integrated assessment of the safety, available PK and Pd data, and preliminary efficacy 
information.
In the dose confirmation part (Phase 1), once the preliminary RP2D is established, each 
combination treatment arm will enroll approximately 10 subjects with each prespecified disease 
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Confidential and Proprietary
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histology (please see Table 3; 7 cohorts of 10 subjects) into Arms A, B, and C to confirm the 
tolerability and safety of the RP2D and identify the strongest antitumor signal in those 
histologies. The Arm D dose confirmation cohort will be open at study start and enroll a total of 
approximately 30 subjects into up to 5 cohorts.  In total, approximately 100 subjects are 
anticipated to enroll in the dose confirmation part. The Arm D dose confirmation cohort 
(durvalumab monotherapy) will start at the same time as the dose finding cohorts of the other 4 
arms.
In Arm D, at the time of disease progression, if subjects meet the criteria defined in Section
3.1.2, the investigator may add study treatments previously investigated with durvalumab within 
this protocol (eg, lenalidomide ± rituximab; rituximab ± bendamustine; rituximab; or ibrutinib) 
once a tolerable dose level is confirmed for that combination (in Arm D it will be permissible for 
the investigator to add rituximab alone if they consider that it is in the subject’s best interest), or 
the investigator may add local IFRT (please see Section 6.2 for further details).  Prior to addition 
of another therapy to durvalumab, the investigator must consult with the sponsor’s medical 
monitor.
If a promising antitumor signal is detected in any dose confirmation cohort, that cohort will 
expand and enroll approximately15 additional subjects to further assess the efficacy and to guide 
the future development of these investigational treatments in the dose expansion part 
(Phase 2).  In total, approximately 105 subjects are anticipated to enroll in the dose expansion 
part.
All subjects will be evaluated for efficacy on a regular basis as specified in the Section 6.4.  The 
efficacy assessments for CLL will be based on the modified International Workshop on Chronic 
Lymphocytic Leukemia (IWCLL) Response Criteria for CLL (Hallek, 2008; Hallek, 2012; 
Hallek, 2013) and for lymphoma based on the International Working Group (IWG) Response 
Criteria for Malignant Lymphoma (the Lugano Classification) (Cheson, 2014).
The SRC will continue to review safety data regularly throughout the study for all cohorts in a 
treatment arm for late toxicities (which are clearly not related to disease progression or 
concurrent illness) which may result in the need for dose reduction or discontinuation to make 
recommendations on dose modifications (eg, alternate schedule or dose levels not currently 
specified) as appropriate.  In addition, the SRC will review efficacy, PK or Pd data as available 
in order to make recommendations on, including, but not limited to, treatment cohort/study 
continuation and expansion in specific disease histology.  Each treatment arm may have a 
separate SRC as appropriate.
The study will also have a global scientific steering committee (GSSC) providing advice to the 
sponsor regarding study protocol design/amendments, study conduct and scientific integrity of 
the study as well as providing guidance to each SRC as appropriate.  The global scientific 
steering committee will serve in an advisory capacity to the sponsor. 
Operational details for the SRC and GSSC will be detailed in a separate charter document.
The sponsor will decide whether or not to open any dose confirmation or expansion cohort as 
well as decide whether or not to adjust the number of subjects enrolled into any planned cohort 
based on the recommendations of the SRC and/or GSSC and relevant emerging clinical or non-
clinical data. Please see Section 9.3.2 for the stopping rules defined for the dose confirmation 
cohorts for efficacy.
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EDMS Doc. Number: 24715418 - 20540270
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Protocol MEDI4736-NHL-001
Celgene International II Sarl
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Additional treatment arms and/or histologies may be added to the dose confirmation or 
expansion parts to explore the safety and efficacy as amendments to this protocol.
3.1.1.
Potential Pseudoprogression 
Atypical responses have been noted with the immune checkpoint inhibitors.  These atypical 
responses are characterized either by the early progression of existing lesions subsequently 
followed by response, or by the appearance of new lesions, with or without regression of existing 
tumor lesions (Cheson, 2016).  
For subjects in all cohorts and treatment arms, if a subject demonstrates early “tumor 
progression” (defined as occurring prior to or during Cycle 3 of durvalumab), the investigator is 
responsible for evaluating whether the subject is experiencing a possible pseudoprogression (ie, 
tumor flare which is local inflammatory reaction indicating early tumor response at sites of 
disease such as lymph nodes) which has been described in subjects with solid tumors being 
treated with durvalumab.
In situations where subjects are experiencing pseudoprogression as assessed by the investigator, 
subjects may continue the study treatment until a repeat scan, within 12 weeks after initial 
determination of pseudoprogression, confirms true tumor progression or clinical deterioration, 
whichever comes earlier.  Subjects must be considered likely to tolerate continued treatment and 
not at risk of serious complications in case of further tumor growth. Please refer to “Refinement 
of Lugano Classification lymphoma response criteria in the era of immunomodulatory therapy” 
for further guidance (Cheson, 2016).
In situations where subjects are experiencing documented true tumor progression as determined 
by the investigator, subjects should be discontinued from the study treatment.
3.1.2.
Criteria for Adding Combination Agent or Local Involved Field Radiation 
Therapy to Durvalumab Monotherapy at the time of Progression (Arm D)
For subjects in the durvalumab monotherapy arm (Arm D), at the time of disease progression, 
the investigator may add study treatments investigated with durvalumab in this protocol (ie, 
lenalidomide ± rituximab*; bendamustine ± rituximab; rituximab; or ibrutinib) once a dose level 
of a relevant combination therapy is deemed as tolerable by the SRC, or subjects can receive 
local involved field radiation therapy (IFRT) to a single involved nodal site (ie, to evaluate for a 
systemic abscopal antitumor effect).   
Subjects with CLL/SLL and RT will not be eligible to receive lenalidomide, and subjects with 
HL will not be eligible to receive ibrutinib.  Decisions about what additional treatment(s) will be 
added will be made in consultation with the sponsor’s medical monitor.
The add-on combination treatment with lenalidomide ± rituximab is no longer allowed.*
For adding a combination agent, a subject must meet the following criteria:
1. Has documented disease progression while on durvalumab monotherapy.
2. Has not received other anticancer/antilymphoma treatments for their disease following 
progression after durvalumab monotherapy.
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3. Does not meet any of the treatment discontinuation criteria in Section 11.1 (except for 
progressive disease [PD]).
4. Has an absence of rapidly progressing disease or threat to vital organs/critical anatomical 
sites (eg, spinal cord compression) requiring urgent alternative medical intervention.
5. Fulfills the laboratory eligibility values defined for specific study treatment (Section 4).
6. Has no prior exposure to new additional IP (ie, lenalidomide, ibrutinib or bendamustine).
7. Has resolution of any AEs from initial therapy (ie, durvalumab monotherapy) to ≤ Grade 
1 or baseline.
8. Fulfill other treatment specific eligibility criteria in Section 4 (ie, prior malignancy status, 
contraception, history or concurrent medical condition or concomitant medication status).
Subjects being considered for IFRT must have:
9. At least 1 measurable lesion (> 1.5 cm) outside of the involved field which will be 
irradiated.
Subjects who receive local IFRT as additional therapy will continue to follow the Arm D 
schedule (see Section 6.2).  
Subjects who receive a combination agent other than local IFRT will follow the visit schedules 
and assessments specific to each combination agent (eg, the Arm C visit schedule and 
assessments from Cycle 1 Day 1 will be followed by subjects who receive bendamustine and 
rituximab in addition to durvalumab) (see Section 6.2).  Pharmacokinetic samples for 
durvalumab will be collected following the addition of a combination agent.  No PK samples for 
lenalidomide or ibrutinib will be collected.  Those subjects will be treated according to the 
treatment schedules described for each arm in Section 7.2 based on the investigator’s medical 
judgment.
3.2.
Study Duration for Subjects 
The entire study is anticipated to last approximately 6 years. The anticipated study duration for a 
subject will be up to approximately 3 to 6 years depending on the assigned treatment arm and 
subject’s disease histology.  
The study will consist of 3 periods: Screening, Treatment and Follow-up.
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EDMS Doc. Number: 24715418 - 20540270
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Figure 3:
Overall Study Flow
3.2.1.
Screening Period
The Screening Period will begin once the subject signs the written informed consent form (ICF). 
All screening assessments must be completed within 28 days prior to Cycle 1 Day 1 (an 
Abbreviations:  ICF = informed consent form; IRT = interactive response technology; OS = overall survival; 
RP2D = recommended phase 2 dose; PFS = progression free survival; SPM = second primary malignancy
a See Section 7.2 for description of Treatment Administration and Schedule.
b All subjects who discontinue treatment and who maintain consent, will proceed directly to the Follow-up 
Period. This includes subjects who complete the full course of treatment, who discontinue treatment due to 
progression or toxicity, as well as those who discontinue before progression to pursue a new 
antilymphoma/CLL therapy. 
c During the Follow-up Period, efficacy assessments (imaging scans, physical exam, and laboratory tests) will 
continue at protocol specified time points until first disease progression, start of a new subsequent 
antilymphoma/CLL therapy, the end of the Efficacy Follow-Up Period, or withdrawal of consent, whichever 
occurs earlier. Please see Section 6.3.2.
d Subjects who have received lenalidomide (ie, subjects in Arm A or subjects in Arm D who have received 
lenalidomide as additional treatment at the time of progression) will be followed for SPMs for up to 5 years 
from the last subject’s first lenalidomide dose. 
Arm A is discontinued to the enrollment of new subjects.  Subjects already enrolled and treated in Arm A 
who are receiving clinical benefit, based on the discretion of the investigator, may continue study 
treatment after being reconsented. 
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EDMS Doc. Number: 24715418 - 20540270
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MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
exception may be biopsy samples).  During this period, the subjects will undergo assessments to 
determine their eligibility as described in Sections 4, 5, and 6. 
Subjects must undergo incisional/excisional/multiple core needle biopsies of their lymphoma in 
order to evaluate their tumor microenvironments as well as other biomarkers.  A formalin-fixed
biopsy specimen needs to be collected and submitted to the Central Laboratory during the 
Screening Period.
An archival lymph node/tumor formalin fixed paraffin embedded (FFPE) sample acquired by a 
surgical or core needle biopsy within 3 months prior to signing informed consent with no 
intervening treatment after the biopsy may be acceptable for enrollment of a subject with poorly
accessible tumor following discussion with the sponsor’s medical monitor.
In addition to the screening sample, it is strongly recommended to submit to the Central 
Laboratory any archival tumor biopsy samples collected prior to study entry (if available) for 
biomarker analysis.
Subjects who meet the eligibility criteria will be registered in the interactive response technology 
(IRT) for treatment assignment. 
3.2.2.
Treatment Period
The Treatment Period begins once the subject receives any IP (ie, durvalumab, lenalidomide, 
ibrutinib, bendamustine, or rituximab) (Cycle 1 Day 1).  Prior to the administration of first dose 
on Cycle 1 Day 1, the laboratory results must be reviewed by the investigator to reconfirm 
subject eligibility.  If the Central Laboratory results are not available for review yet, then the 
local laboratory results can be used to reconfirm subject eligibility.  Blood samples for 
laboratories related to safety events must always be collected and submitted to the Central 
Laboratory according to the schedule in Sections 5 and 6.  
Subjects will receive the study treatment (described in Section 7) until the completion of all
protocol-specified study treatment, disease progression, unacceptable toxicity, or discontinuation 
for any other reason.
Subjects will be assigned to 1 of the 4 treatment arms based on the investigator’s choice led by
the subject’s eligibility status as per the inclusion/exclusion criteria described for each arm, prior 
antilymphoma/CLL therapy and response to prior therapy, medical history and also the 
availability of open treatment slots in a given cohort.
Arm A is discontinued to the enrollment of new subjects. Subjects already enrolled and 
treated in Arm A who are receiving clinical benefit, based on the discretion of the 
investigator, may continue study treatment after being reconsented. In addition, the add-on 
combination treatment with lenalidomide ± rituximab is no longer allowed.*
During each 28-day treatment cycle, subjects will receive durvalumab (intravenous [IV]) 
infusion on Day 1 of Cycles 1 through 13 at a fixed dose of 1500 mg every 4 weeks in 
combination with: 

Arm A: Lenalidomide orally [PO]) once daily on Days 1 to 21 (inclusive) of each cycle 
for 12 months (Cycles 1 through 13) in indolent lymphoma histologies (eg, follicular 
lymphoma [FL] or marginal zone lymphoma [MZL]) or until disease progression in 
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
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aggressive lymphoma histologies (eg, diffuse large B-cell lymphoma [DLBCL]) ± 
rituximab (IV) infusion:

Rituximab Schedule 1 (dose levels 2 or -1B): on Days 2, 8, 15 and 22 of Cycle 1 
and on Day 1 of Cycles 2 through 5 or

Rituximab Schedule 2 (dose levels -2 and -3): on Day 2 of Cycle 1 and on Day 1
of Cycles 2 through 8 depending on the dose level assigned.

Arm B: Ibrutinib (PO) continuous, once daily until disease progression, unacceptable 
toxicity, starts new therapy, or discontinuation for any other reason, ie, subject withdraws 
consent or discontinues per investigator’s discretion.

Arm C: Rituximab (IV) infusion on Day 2 of Cycles 1 through 6 ± bendamustine (IV) 
infusion on Days 1 and 2 of Cycles 1 through 6.  Bendamustine may be stopped after 4 
cycles if the subject experiences a cumulative toxicity related to bendamustine and there 
is no clinical evidence of a favorable benefit to risk ratio for continuation of 
bendamustine treatment per the investigator’s medical judgment.  

Arm D: Durvalumab monotherapy arm.  At the time of disease progression, the 
investigator may add study treatments previously investigated with durvalumab in this 
protocol (ie, lenalidomide ± rituximab*; bendamustine ±  rituximab; rituximab; or 
ibrutinib) once a tolerable dose level is confirmed for that combination, or subjects can 
receive involved-field radiation to a single involved nodal site (ie, to evaluate for a 
systemic abscopal antitumor effect) if they meet the criteria defined in Section 3.1.2.  
Prior to addition of another therapy to durvalumab, the investigator must consult with the 
sponsor’s medical monitor.
Treatment arms and dose levels for each arm are described and tabulated in Section 7 and 9.3.
Subjects should return to the site as early as possible (within 7 days of last dose or decision for 
discontinuation) for the End of Treatment Visit assessments if a decision to permanently 
discontinue study treatment is made, or after completion of the last cycle of treatment. 
3.2.3.
Follow-up Period
The Follow-up Period will begin at study treatment completion or discontinuation.  
Safety Follow-up
All subjects will be followed for AEs (including second primary malignancies [SPMs]) and 
concomitant medications/ procedures for 90 days after the last dose of durvalumab or 28 days 
after the last dose of other IPs, whichever is the later date. 
Subjects who have received lenalidomide (ie, subjects in Arm A or subjects in Arm D who have 
received lenalidomide as additional treatment at the time of progression) will be followed for 
SPM for up to 5 years from the last subject’s first lenalidomide dose. 
Efficacy (Long-Term) Follow-up
The Efficacy Follow-up Period begins upon study treatment completion or discontinuation for 
each subject.  This includes subjects who complete the full course of treatment, who discontinue 
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treatment due to progression or toxicity, as well as those who discontinue before progression to 
pursue a new antilymphoma/CLL therapy. 
Subjects will be followed for first progression (if applicable), subsequent antilymphoma/CLL
therapy, and overall survival according to the schedule described in Section 6.3.  Therefore, 
efficacy assessments as defined in Section 6.3.2 will continue at the protocol-specified time 
points until first disease progression, withdrawal of consent, the start of a new 
antilymphoma/CLL therapy, or the end of the Efficacy Follow-up Period. In Arms A (indolent 
NHL: FL or MZL), C, and D, subjects will be followed for 24 months after their last durvalumab 
dose.  In Arms A (aggressive NHL) and B, subjects will be followed for 24 months after their 
last durvalumab dose or until their disease progression, whichever date occurs later.
Following completion or discontinuation of durvalumab treatment per protocol for all subjects 
and completion of the primary analysis (data cutoff date 06 Mar 2019), subjects are no longer 
required to be followed for disease progression, subsequent antilymphoma/CLL therapy, and 
overall survival. Follow-up procedures, efficacy assessments, central labs, imaging, and survival 
data will no longer be collected in the case report forms (CRFs). 
In Arm B, subjects receiving benefit from ibrutinib may continue to receive ibrutinib on-study 
per investigator’s medical judgement or discontinue study to receive ibrutinib commercially as 
standard of care treatment (off-study). Subjects who continue ibrutinib on-study will be treated 
per investigator’s medical judgement and standard of care at the investigative site. The 
investigator remains responsible to monitor safety, record AEs/SAEs in source documents, and 
report SAEs to Celgene Drug Safety as stipulated under the full protocol.  
3.3.
End of Trial
The End of Trial 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 prespecified in the protocol, 
whichever is the later date.
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
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4.
STUDY POPULATION
4.1.
Number of Subjects 
This study may enroll approximately 265 subjects globally in regions, including, but not limited 
to, the United States, Europe, and Japan.
The dose finding part will include the following:

Arm A: 6 to 30 subjects (this arm is discontinued to the enrollment of new 
subjects; subjects already enrolled and treated who are receiving clinical 
benefit, based on the discretion of the investigator, may continue study 
treatment after being reconsented)

Arm B: 6 to 12 subjects

Arm C: 3 to 18 subjects
The dose finding part may enroll approximately 15 to 60 (DLT evaluable) subjects; however, the 
final number of subjects necessary will depend on the number of dose levels studied and number 
of DLTs observed within each cohort.
The dose confirmation part may enroll approximately 20 subjects in Arm A (2 cohorts of 
10 subjects), 20 subjects in Arm B (2 cohorts of 10 subjects), 30 subjects in Arm C (3 cohorts of 
10 subjects), and 30 subjects in Arm D (5 cohorts of 5 to 10 subjects) for a total of approximately
100 subjects.
The dose expansion part may enroll approximately 30 subjects in Arm A (2 cohorts of 
15 subjects), 30 subjects in Arm B (2 cohorts of 15 subjects) and 45 subjects in Arm C (3 cohorts 
of 15 subjects) for a total of approximately 105 subjects.
Please see Table 3 for selected histologies and planned number of subjects in each treatment arm 
and study part, and Table 4 and Table 5 for eligible B-cell NHL or HL histologies.
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EDMS Doc. Number: 24715418 - 20540270
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Table 3:
Eligible Histologies per Treatment Arm and Part of the Study
Treatment Arm
Dose Finding (RP2D)
Dose Finding
Evaluation of the Safety of RP2D in Specific Histologyand Preliminary 
Signal Seeking
Dose Confirmation
ab
Preliminary Efficacy
Dose Expansionabe
Arm A
c
(Durvalumab + 
Lenalidomide ±
Rituximab)-
Discontinued to 
the enrollment 
of new subjects
R/R B-cell NHL
N = 6-30
R/R FL N = 10d
R/R DLBCL N = 10d
R/R FL N = 15d
R/R DLBCL N = 15d
Arm B
(Durvalumab + 
Ibrutinib)
R/R B-cell 
NHL/ CLL
N = 6-12
R/R CLL/SLL N = 10
R/R MCL N = 10
R/R CLL/SLL N = 15
R/R MCL N = 15
Arm C
(Durvalumab + 
Rituximab ± 
Bendamustine)
R/R B-cell 
NHL/ CLL
N = 3-18
R/R CLL/SLL N = 10
R/R FL N = 10
R/R DLBCL N = 10
R/R CLL/SLL N =15
R/R FL N = 15
R/R DLBCL N = 15
Arm D
(Durvalumab)
No dose finding
R/R CLL/SLL
R/R DLBCL
R/R FL 
R/R MCL
R/R HL
N = 30 (5-10 subjects in 
each histology)
Not planned
Abbreviations:  CLL = chronic lymphocytic leukemia; DLBCL = diffuse large B-cell lymphoma; FL = follicular 
lymphoma; HL = Hodgkin lymphoma; MCL = mantle cell lymphoma; NHL = non-Hodgkin lymphoma; N = 
number of subjects; R/R = relapsed/refractory; SLL = small lymphocytic lymphoma.
a Subjects with FL Grade 3b may be enrolled into DLBCL cohorts but are excluded from FL cohorts.
b Subjects with DLBCL not otherwise specified or T-cell/histiocyte rich large B-cell lymphoma will be eligible for 
the dose confirmation and expansion DLBCL cohorts.
c Arm A will exclude subjects with CLL/SLL.
d Arm A dose confirmation and dose expansion cohorts are discontinued and will not enroll new subjects.
e Celgene decided to not continue with the dose expansion part of the study.
Table 4:
Eligible B-cell Non-Hodgkin Lymphoma Histologies (Based on the 2008 
WHO Lymphoma Classification) for Phase 1 Dose Finding Cohorts
Eligible B-cell NHL Histologies
a
Follicular lymphoma (FL) 
Diffuse large B-cell lymphoma
(DLBCL), not otherwise specified
Mantle cell lymphoma (MCL)
Chronic lymphocytic leukemia 
(CLL)
Primary mediastinal (thymic) large 
B-cell lymphoma (PMBCL)
Nodal marginal zone 
lymphoma (nMZL)
Small lymphocytic lymphoma
(SLL)
ALK-positive large B-cell 
lymphoma (ALK-positive large 
BCL)
Splenic marginal zone 
lymphoma (sMZL)
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EDMS Doc. Number: 24715418 - 20540270
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Protocol MEDI4736-NHL-001
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Table 4:
Eligible B-cell Non-Hodgkin Lymphoma Histologies (Based on the 2008 
WHO Lymphoma Classification) for Phase 1 Dose Finding Cohorts
(Continued)
Eligible B-cell NHL Histologiesa
T-cell/histiocyte rich large B-
cell lymphoma (T-cell/
histiocyte-rich large BCL)
Transformed lymphomab
(TL)
Richter’s transformationb
(RT)
Abbreviations: ALK = anaplastic lymphoma kinase; WHO = World Health Organization.
a All histologies listed other than CLL/SLL and MZL are considered as fluorodeoxyglucose (FDG)-avid. 
b Transformed lymphoma and Richter’s transformation will be included but are not part of the 2008 WHO 
Lymphoma Classification.
Table 5:
Eligible Hodgkin Lymphoma Histologies (Based on the 2008 WHO 
Lymphoma Classification) for Arm D Dose Confirmation Cohort
aHodgkin Lymphoma Histologies
Classical Hodgkin lymphoma (cHL)
Nodular sclerosing cHL
Lymphocyte-rich cHL
Mixed cellularity cHL
Lymphocyte-depleted cHL
Abbreviations: WHO = World Health Organization
4.2.
Inclusion Criteria
Subjects with R/R lymphoma or CLL requiring therapeutic intervention must satisfy the 
following criteria to be enrolled in the study:
APPLY to ALL TREATMENT ARMS (Arm A is discontinued to the enrollment of new 
subjects)
1. Subject is ≥ 18 years of age and ≤ 80 years of age at the time of signing the informed 
consent form (ICF). 
Exception: At the discretion of the investigator, subjects > 80 years of age may be 
included if their Eastern Cooperative Oncology Group (ECOG) performance status is ≤ 1; 
each of their individual organ system scores must be ≤2 using the Modified Cumulative 
Illness Rating Scale (CIRS) for comorbidity (Salvi, 2008a; Salvi, 2008b; Appendix I)
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.
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Protocol MEDI4736-NHL-001
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4. Subject has histologically confirmed and documented eligible histologies as listed in 
Table 3, Table 4, or Table 5 as assessed by the investigator and local pathologist per the 
2008 WHO Lymphoma Classification (Swerdlow, 2008).
Eligible sub-histologies for the dose confirmation and/or expansion cohorts: 
a.
FL cohorts: FL grade 1, 2, and 3a
b. DLBCL (de novo) cohorts: DLBCL not otherwise specified, T-cell/histiocyte rich 
large B-cell lymphoma, and FL grade 3b
c.
MCL cohort: MCL
d. CLL/SLL cohorts: high risk CLL/SLL 
e.
HL cohort: cHL, nodular sclerosing cHL, lymphocyte-rich cHL, mixed cellularity 
cHL, lymphocyte-depleted cHL
5. Subject has been previously treated with at least one prior systemic chemotherapy, 
immunotherapy, or chemoimmunotherapy.
Note: Local involved field radiation therapy (IFRT) or antibiotic-based therapy is not 
deemed as systemic therapy for this study.
6. Subject with high-risk CLL/SLL is defined by the presence of at least one of the 
following factors:
a.
Complex karyotype;
b. del (17p) abnormality;
c.
Mutated TP53;
d. Ibrutinib or other BTK-inhibitor failure (defined as progression while on ibrutinib 
treatment [excluding isolated early lymphocytosis]; or an inadequate tumor 
response which is less than partial response [PR] [Hallek, 2008; Cheson, 2014]);
e.
Relapsed/progressive disease within 6 months of completing their last therapy
which may include investigational drug. 
7. Subject is willing and able to undergo biopsy:
a.
Subject with lymphoma is willing and able to undergo tumor/lymph node biopsy 
(incisional/excisional or multiple core needle)
o
During the Screening Period,
o
Any time during Cycle 2 (strongly recommended), and
o
At the time of disease progression from subjects who have achieved objective 
response (CR/PR) to study treatment.  
b. Subject with CLL is willing and able to undergo bone marrow biopsy during the 
Screening and Treatment Periods.
Material from a fine needle aspiration is not acceptable.
8. Subject who has documented active relapsed or refractory disease requiring therapeutic 
intervention.
9. Subject who has measurable disease: 
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EDMS Doc. Number: 24715418 - 20540270
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Protocol MEDI4736-NHL-001
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a.
For subject with lymphoma, bi-dimensionally measurable disease on cross-sectional 
imaging by computed tomography (CT) with at least one nodal or extranodal lesion 
≥2.0 cm in its longest dimension.
Note: A previously irradiated lesion is ineligible to be used as a measurable target
lesion.
b. For subject with CLL, in need of treatment as defined by IWCLL Guidelines for the 
Diagnosis and Treatment of CLL (Appendix H).
10. Subject who has performance status of 0, 1, or 2 on the ECOG scale.
11. Subject who has life expectancy of greater than 6 months.
12. Subject who fulfills the following laboratory requirements:
Table 6:
Eligible Laboratory Values
Laboratory Value/
Treatment Arms
Arm A
Arm B
Arm C
Arm D
ANC (cells/mm3)
≥ 1500
≥ 1000 
Subjects with ANC ≥ 500 (cells/mm3) may be allowed in the dose 
confirmation and expansion cohorts only if neutropenia is secondary 
to bone marrow involvement documented as ≥ 80% bone marrow 
infiltration of CLL cells or ≥ 50% bone marrow infiltration of lymphoma 
cells by pretreatment bone marrow biopsy following the discussion with 
the sponsor’s medical monitor.  These subjects should not have any 
evidence of active bacterial infection within 14 days of Cycle 1 Day 1 
(ie, off of oral and IV antibiotics for at least for 14 days).
These subjects will be excluded from the dose finding cohorts.
Platelets (cells/mm3)
≥ 75,000
Subjects with platelets ≥ 20,000 cells/mm3 may be allowed in the dose 
confirmation and expansion cohorts only if thrombocytopenia is 
secondary to bone marrow involvement documented as ≥ 80% bone 
marrow infiltration of CLL cells or ≥ 50% bone marrow infiltration of 
lymphoma cells by pretreatment bone marrow biopsy following the 
discussion with the sponsor’s medical monitor. 
These subjects should not have any evidence of active bleeding or 
clinically significant coagulopathy.
These subjects will be excluded from the dose finding cohorts.
AST/ALT (ULN)
≤ 2.5 × ULN
In the case of liver involvement by lymphoma, subjects with 
AST/ALT ≤ 5.0 × ULN may be allowed in the dose confirmation and 
expansion cohorts only following the discussion with the sponsor’s 
medical monitor.
These subjects will be excluded from the dose finding cohorts.
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
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Table 6:
Eligible Laboratory Values (Continued)
Laboratory Value/
Treatment Arms
Arm A
Arm B
Arm C
Arm D
Total Bilirubin (serum) 
(ULN)
≤ 1.5 × ULN  
In the case of Gilbert’s Syndrome, or documented liver or pancreatic 
involvement by lymphoma, subjects with total bilirubin ≤ 3.0 mg/dL may 
be allowed in the dose confirmation and expansion cohorts only 
following the discussion with the sponsor’s medical monitor.
These subjects will be excluded from the dose finding cohorts.
Creatinine Clearance 
(mL/min) based on 
Cockcroft-Gault formula
≥ 60
(eligible for 
all parts)
≥ 40
(ineligible 
for dose 
finding 
cohorts of 
Arm A)
≥ 40
PT/INR (ULN)
--
< 1.5 × ULN
--
--
PTT/aPTT (ULN)
--
< 1.5 × ULN
--
--
Abbreviations: ANC = absolute neutrophil count; aPTT = activated partial thromboplastin time; AST/ALT = 
aspartate transaminase / aspartate transaminase; CLL = chronic lymphocytic leukemia; INR = international 
normalized ratio; LLN = lower limit of normal; NHL = non-Hodgkin lymphoma; PTT = partial thromboplastin time; 
ULN = upper limit of normal.
13. Female subject of childbearing potential (FCBP1) who is sexually active with a male 
must: 
a.
Have 2 negative pregnancy tests as verified by the investigator prior to starting any IP 
therapy.  They must agree to ongoing pregnancy testing during the course of the 
study, and after the last dose of any IP. This applies even if the subject practices true 
abstinence2 from heterosexual contact.
b. Use effective methods (1 highly effective and 1 additional effective [barrier] method) 
of contraception from 28 days prior to starting durvalumab, and must agree to 
continue using such precautions while taking durvalumab (including dose 
interruptions) and for 90 days after the last dose of durvalumab.  Cessation of 
contraception after this point should be discussed with a responsible physician. 
                                               
1 A female subject 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).
2 True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable 
methods of contraception.
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
59
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
The following are examples of highly effective and additional effective methods of 
contraception:

Highly effective methods (defined as one that results in a low failure rate [ie, less 
than 1% per year] when used consistently and correctly): 
(i) Intrauterine device (IUD).  See Section 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]). 
(iii) Tubal ligation 
(iv) Partner’s vasectomy 

Additional effective methods: 
(i) Male condom 
(ii) Diaphragm
(iii) Cervical cap
Implants and levonorgestrel-releasing intrauterine systems are associated with an 
increased risk of infection at the time of insertion and irregular vaginal bleeding. 
Prophylactic antibiotics should be considered particularly in subjects with neutropenia.
c.
Agree to abstain from breastfeeding during study participation and for at least 90 days 
after the last dose of durvalumab.
d. Refrain from egg cell donation while taking durvalumab and for at least 90 days after 
the last dose of durvalumab. 
14. Male subject who is sexually active with a female partner of childbearing potential must:
a.
Use male condom plus spermicide (even if he has undergone a successful vasectomy)
from starting dose of durvalumab (Cycle 1 Day 1) through 90 days after receipt of the 
last dose of durvalumab.  True abstinence is acceptable only when this is in line with 
the preferred and usual lifestyle of nonsterilized male subject.
b. Refrain from semen or sperm donation while taking durvalumab and for at least 90 
days after the last dose of durvalumab. 
Inclusion numbers 15-17 APPLY to ARM A only:
15. Female subject of childbearing potential must:
a.
Have 2 negative pregnancy tests as verified by the investigator prior to starting any IP 
therapy (ie, durvalumab, lenalidomide and rituximab).  They must agree to ongoing 
pregnancy testing during the course of the study, and after last dose of any IP.  This 
applies even if the subject practices true abstinence from heterosexual contact.
b. Either commit to true abstinence from heterosexual contact (which must be reviewed 
on a monthly basis) or agree to use, and be able to comply with, effective (1 highly 
effective and 1 additional effective method) contraception without interruption, 28 
days prior to starting any IP, during the IP therapy (including dose interruptions), and 
Approved
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EDMS Doc. Number: 24715418 - 20540270
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Protocol MEDI4736-NHL-001
Celgene International II Sarl
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60
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
for 12 months after the last dose of rituximab, 90 days after the last dose of 
durvalumab, or 28 days after the last dose of lenalidomide, whichever is longer. 
c.
Agree to abstain from breastfeeding during study participation and for at least 28 days 
after the last dose of lenalidomide or 12 months after the last dose of rituximab, 
whichever is longer.
d. Refrain from egg cell donation while taking durvalumab and for 90 days after the last 
dose of durvalumab.
16. Male subject must:
a.
Practice true abstinence or agree to use a condom during sexual contact with a 
pregnant female or an FCBP while participating in the study, during dose 
interruptions and for at least 28 days after the last dose of lenalidomide, or for at least 
90 days after the last dose of durvalumab, even if he has undergone a successful 
vasectomy, whichever is longer. 
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.
17. 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. 
c.
Agree not to share lenalidomide with another person.
d. Agree to be counseled about pregnancy precautions and risk of fetal exposure.
Inclusion numbers 18-19 APPLY to ARM B only:
18. Female subject of childbearing potential must:
a.
Have 2 negative pregnancy tests as verified by the investigator prior to starting any IP 
therapy (ie, durvalumab and ibrutinib).  They must agree to ongoing pregnancy 
testing during the course of the study, and after last dose of any IP.  This applies even 
if the subject practices true abstinence from heterosexual contact.
b. Either commit to true abstinence from heterosexual contact (which must be reviewed 
on a monthly basis) or agree to use, and be able to comply with, effective (1 highly 
effective and 1 additional effective method) contraception without interruption, 28 
days prior to starting IP therapy, during the IP therapy (including dose interruptions)
and for 90 days after the last dose of IP.
c.
Agree to abstain from breastfeeding during study participation and for at least 90 days 
after last dose of IP therapy.
d. Refrain from egg cell donation while taking durvalumab and for 90 days after the last 
dose of durvalumab.
19. Male subject must:
a.
Practice true abstinence or agree to use a condom during sexual contact with a 
pregnant female or an FCBP while participating in the study, during dose 
Approved
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EDMS Doc. Number: 24715418 - 20540270
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Protocol MEDI4736-NHL-001
Celgene International II Sarl
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interruptions and for at least 90 days following the last dose of IP, even if he has 
undergone a successful vasectomy, whichever is longer.
b. Agree to not donate semen or sperm during the IP therapy and for 28 days after the 
last dose of ibrutinib or 90 days after the last dose of durvalumab, whichever is 
longer.
Inclusion numbers 20-21 APPLY to ARM C only:
20. Female subject of childbearing potential must:
a.
Have 2 negative pregnancy tests as verified by the investigator prior to starting any IP 
therapy (ie, durvalumab, bendamustine and rituximab).  They must agree to ongoing 
pregnancy testing during the course of the study, and after last dose of any IP. This 
applies even if the subject practices true abstinence from heterosexual contact.
b. Either commit to true abstinence from heterosexual contact (which must be reviewed 
on a monthly basis) or agree to use, and be able to comply with, effective (1 highly 
effective and 1 additional effective method) contraception without interruption, 28 
days prior to starting IP therapy, during the IP therapy (including dose interruptions) 
and for 12 months after the last dose of rituximab or for 90 days after the last dose of 
the other IP (ie, bendamustine and/or durvalumab) dose, whichever is longer. 
c.
Agree to abstain from breastfeeding during study participation and for at least 12 
months after the last dose of rituximab.
d. Refrain from egg cell donation while taking durvalumab and for 90 days after the last 
dose of durvalumab.
21. Male subject must:
a.
Practice true abstinence or agree to use a condom during sexual contact with a 
pregnant female subject or an FCBP while participating in the study, during dose 
interruptions and for at least 90 days after the last dose of durvalumab or 6 months 
after the last dose of bendamustine, even if he has undergone a successful vasectomy, 
whichever is longer.
b. Agree to not donate semen or sperm during the IP therapy and for at least 90 days 
after the last dose of durvalumab or 6 months after the last dose of bendamustine, 
whichever is longer.
4.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
APPLY to ALL TREATMENT ARMS (Arm A is discontinued to the enrollment of new 
subjects)
1. Subject who has known or suspected central nervous system (CNS) or meningeal 
involvement by lymphoma.
2. Subject who has other lymphoma histologies which are not listed on Table 3, Table 4,
Table 5 (eg, human immunodeficiency virus [HIV]-associated lymphomas, CNS 
lymphoma, Waldenstrom’s macroglobulinemia).
a.
Subject has blastoid variants of MCL or MCL with blastoid transformation.
Approved
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EDMS Doc. Number: 24715418 - 20540270
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Protocol MEDI4736-NHL-001
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MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
b. Dose Confirmation and/or Expansion Parts only:
o
Transformed lymphoma or Richter’s transformation 
o
DLBCL histology other than: not otherwise specified or T-cell/histiocyte rich
3. Subject who has any histopathologic finding consistent with myelodysplastic syndrome
on bone marrow studies.
4. Subject who has any significant medical condition, laboratory abnormality, or psychiatric 
illness that would prevent the subject from participating in the study.
5. Subject who 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.
6. Subject who has any condition that confounds the ability to interpret data from the study.
7. Subject who has any uncontrolled inter-current illness including, but not limited to, 
ongoing or active infection, current pneumonitis, symptomatic congestive heart failure, 
uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung 
disease, or psychiatric illness/social situations that would limit compliance with study 
requirement, substantially increase risk of incurring AEs from durvalumab and/or other 
investigational treatment regimens, or compromise the ability of the subject to give 
written informed consent.
8. Subject who is concurrently enrolled in another clinical study, unless in a follow-up 
period or it is an observational study.
9. Subject who has any concurrent chemotherapy, immunotherapy, biologic, or hormonal 
therapy for cancer treatment. 
Note: Concurrent use of hormones for noncancer-related conditions (eg, insulin for 
diabetes and hormone replacement therapy) is acceptable. 
10. Subject who has received:
a.
Any systemic antilymphoma/leukemia therapy, or hematopoietic growth factors, 
blood or platelets transfusions within 14 days prior to the first dose of IP (ie, Cycle 1 
Day 1) and/or
b. Any radioimmunotherapy within 3 months prior to the first dose of IP (ie, Cycle 1 
Day 1).
Exception: The use of hematopoietic growth factors or blood product transfusional 
support for subjects with extensive marrow involvement by lymphoma or CLL may be 
allowed during the Screening Period after consultation with the sponsor’s medical 
monitor in the dose confirmation and expansion cohorts only (see Table 6).
11. Subject who has unresolved toxicities from prior anticancer therapy, defined as having 
not resolved to NCI CTCAE v4.03 ≤ Grade 1 with the exception of alopecia and 
laboratory values listed per the exclusion criteria. Subjects with irreversible toxicity that 
is not reasonably expected to be exacerbated by durvalumab or other investigational 
treatments may be included (eg, hearing loss) after consultation with the sponsor’s 
medical monitor.
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
63
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
12. Subject who received any prior mAb against PD-1 or PD-L1 and/or any prior:
a.
Arm A only: IMiDs (eg, lenalidomide, thalidomide);
b. Arm B only: ibrutinib or other BTK inhibitor;
c.
Arms C only: bendamustine (except dose level 1).
13. Subject who has history of organ transplant or allogeneic hematopoietic stem cell
transplantation.
14. Subject who has taken corticosteroids during the last week prior to the first dose of IP (ie, 
Cycle 1 Day 1), unless administered at a dose equivalent to ≤ 10 mg/day prednisone.
Exception: For subjects with bulky disease, systemic symptoms, compressive disease, or 
rapidly progressing adenopathies, pre-phase treatment with 1 mg/kg/day prednisone, or 
equivalent, for a maximum of 7 days is permitted prior to Cycle 1 Day 1, at the discretion 
of the investigator.  A washout period does not apply.  
15. Subject who 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 the last dose of durvalumab, whichever is longer).
16. Subject who has undergone major surgical procedure (as defined by the investigator) 
within 28 days prior to the first dose of the IP (ie, Cycle 1 Day 1) or still recovering from 
prior surgery.
17. Subject who has active documented autoimmune disease (including, but not limited to, 
inflammatory bowel disease, celiac disease, Wegener syndrome, hemolytic anemia, or 
immune thrombocytopenic purpura) prior to first dose of durvalumab.
Exception: Type 1 diabetes mellitus and hypothyroidism which are well controlled
18. Subject who has history of primary immunodeficiency or tuberculosis.
19. Subject who has known seropositivity for or active infection for human 
immunodeficiency virus (HIV) or hepatitis C virus (HCV).
20. Subject who is seropositive for or active viral infection with hepatitis B virus (HBV) 
a.
HBV surface antigen (HBsAg) positive
b. HBV surface antigen (HBsAg) negative, HBV core antibody (anti-HBc) positive, and 
detectable viral DNA
Note: 
A subject who is seropositive for anti-HBs because of prior exposure or vaccination (anti-
HBc and HBsAg negative) will be eligible. In this case, viral DNA does not need to be 
tested).
21. Female subject who is pregnant, breastfeeding, or intend to become pregnant during the 
participation in the study.
22. Subject who has other invasive malignancy within 2 years prior to signing the ICF except 
for noninvasive malignancies such as cervical carcinoma in situ, non-melanomatous 
carcinoma of the skin, ductal carcinoma in situ of the breast, or incidental histologic 
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
64
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical 
staging system) that has/have been surgically cured.
a.
Arm A only: Subject who has history of other malignancies, unless the subject has 
been free of the disease for ≥ 5 years prior to signing the ICF. 
Exceptions: History of previously treated basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin and related localized non-melanoma skin cancer, 
carcinoma in situ of the cervix, carcinoma in situ of breast, incidental histologic 
finding of prostate cancer (T1a or T1b using the TNM clinical staging system).
23. Subject who has known allergy or hypersensitivity to the active substance or any of the 
excipients, or to other humanized mAbs. 
Exclusion numbers 24-26 APPLY to ARM A only:
24. Subjects with CLL or SLL.
25. Subject who has peripheral neuropathy Grade 3 or 4.
26. Subject who is at risk for a thromboembolic event and is not willing to take prophylactic 
treatment.
Exclusion numbers 27-28 APPLY ARMS A and C only (if subject will receive rituximab):
27. Subject who does not have CD20 positive lymphoma or CLL.
28. Subject who has hypersensitivity to rituximab.
Exclusion numbers 29-32 APPLY to ARM B only:
29. Subject who has transfusion-dependent thrombocytopenia or a history of bleeding 
disorders or clinical conditions (eg, gastrointestinal bleeding or constitutional disorders) 
that may increase the risk of life-threatening bleeding when thrombocytopenic.
30. Subject who has history of stroke or intracranial hemorrhage within 6 months prior to 
signing the ICF.
31. Subject who receives the medications that are strong inhibitors or inducers of CYP3A 
(eg, itraconazole, ketoconazole, clarithromycin, ritonavir, phenytoin, pentobarbital, and 
rifampin) and cannot change.
32. Subject who has received concomitant anticoagulation with warfarin or other vitamin K 
antagonists within 7 days prior to signing the ICF and cannot change.  The use of other 
anticoagulants (eg, heparins) and antiplatelet agents is allowed per investigator’s 
discretion.  Investigator questions regarding this should be addressed to the sponsor’s 
medical monitor or the study country principal investigators.
Exclusion number 33 APPLIES to ARM C only (if subject will receive bendamustine):
33. Subject who should concurrently use allopurinol, eg, because of gout, and unwilling to 
switch to another equivalent medication. (Subjects with gout are advised to switch to 
another antigout medication, because of the risk of Stevens-Johnson syndrome observed 
in subjects using bendamustine and allopurinol).
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
65
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
5.
TABLE OF EVENTS
Table 7:
Table of Events – Arm A - Durvalumab and Lenalidomide ± Rituximab
(This arm is discontinued to enrollment of new subjects; the procedures apply to continuing subjects in the study.)
Events
Screeni
ng
Period
Treatment Period
Follow-up
C1
C2
C3
C4
C5
C6-13
C14/
EOT-D
≥ 
C15
EOT
a
D
-28 to -
1
D1
D2&D
3
D8, 
D15 & 
D22
D1
D15
D1
D15
D1
D15
D1
D1
D1
D1
Safety
D28/
D90
Efficacy
/SPM
b
Informed Consent 
X
IRT Registration 
X
X
X
X
X
X
X
X
X
X
X
Inclusion/Exclusion 
Criteria
X
Demographics
X
Medical History & 
Disease History
X
Prior Anticancer Therapy
X
Physical Examination & 
B Symptoms
X
X
X
X
X
X
X
X
X
X
X
X
(until 
PD)
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
Body Surface Area
X
X
Vital Sign Monitoring
c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG PS 
X
X
X
X
X
X
X
X
X
X
CIRS (only subjects > 80 
years)
X
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
66
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 7:
Table of Events – Arm A - Durvalumab and Lenalidomide ± Rituximab (Continued)
Events
Screening
Period
Treatment Period
Follow-up
C1
C2
C3
C4
C5
C6-13
C14/
EOT-
D
≥ 
C15
EOT
a
D
-28 to -1
D1
D2&D
3
D8, 
D15 & 
D22
D1
D15
D1
D15
D1
D15
D1
D1
D1
D1
Safety
D28
/D90
Efficacy 
/SPMb
12-lead ECG 
X
X
HBV Screening
X
CBC & Differential
X
X
X
(C1D3 
only)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(until 
PD)
Clinical Chemistry 
(including LDH)
X
X
X
(C1D3 
only)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(until 
PD)
GGT, Amylase, 
Lipase
X
X
X
X
X
X
X
X
X
X
X
X
Thyroid Function 
Tests
d
X
X
X
(C1D15 
only)
X
X
X
X
X
X
X
(C6, C8, 
C10, C12 
only) 
X
X
(D90 
only)
Calculated Creatinine 
Clearance (serum)
X
Coagulation
X
X
X
(C1D15 
only)
X
X
X
X
X
X
X
(D90 
only)
Quantitative
Immunoglobulins
X
X
Urinalysis
X
X
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
67
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 7:
Table of Events – Arm A - Durvalumab and Lenalidomide ± Rituximab (Continued)
Events
Screening
Period
Treatment Period
Follow-up
C1
C2
C3
C4
C5
C6-13
C14/
EOT-D
≥ C15
EOT a
D
-28 to -1
D1
D2&D
3
D8, 
D15 & 
D22
D1
D15
D1
D15
D1
D15
D1
D1
D1
D1
Safety 
D28
/D90
Efficacy 
/SPM b
Pregnancy Counseling
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test - for 
FCBP with Regular or 
No Menstrual Cycles
X
Once
-10 to -14 
days
X
Within
24 
hours 
of 
C1D1
X
X
X
X
X
X
X
X
X
28 days 
after 
last 
lenalid
omide 
dose & 
D90
Pregnancy Test- for 
FCBP with Irregular 
Menstrual Cycles
X
Once 
-10 to -14 
days
X
Within 
24 
hours 
of 
C1D1
X
X
X
X
X
X
X
Every cycle Days 1 and 15
X
Both 
14 &
28 days 
after 
last 
lenalid
omide 
dose & 
D90
Efficacy Response 
Assessment
X
X (C7 &
C10)
X
Every 6 cycles/months up to PD or start 
of a new antilymphoma therapy 
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
68
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 7:
Table of Events – Arm A - Durvalumab and Lenalidomide ± Rituximab (Continued)
Events
Screening
Period
Treatment Period
Follow-up
C1
C2
C3
C4
C5
C6-13
C14/
EOT-D
≥ C15
EOT a
D
-28 to -1
D1
D2&D3
D8, D15 
& D22
D1
D15
D1
D15
D1
D15
D1
D1
D1
D1
Safety 
D28
/D90
Efficacy 
/SPM b
CT Scans (Neck, 
Chest, Abdomen 
&Pelvis) (contrast-
enhanced unless 
contraindicated) 
(Lymphoma)
X
X
X
(C7 & 
C10)
X
Every 6 cycles/months up to PD or start 
of a new antilymphoma treatment
e
FDG-PET-CT 
(FDG-avid 
Lymphoma)
X 
(strongly 
recommen
ded)
To confirm CR by CT scan alone at any time during the study (within 14 days 
following demonstration of nodal CR by CT scan alone)
Bone Marrow Biopsy 
& Aspirate
(Lymphoma)
X
f
To confirm true CR (within 28 days of meeting the criteria for nodal CR by CT scan 
alone) except in subjects with no evidence of lymphomatous marrow involvement at 
baseline
g
MRD Assessment –
Whole Blood (in 
subjects with MCL 
and FL)h
X
Within 28 days of meeting the criteria for PET negative CR and then every 3 cycles 
while on treatment or every 6 months in follow-up until evidence of clinical PD
h
MRD Assessment –
Bone Marrow Aspirate
(in subjects with FL 
and MCL)h
Within 28 days of meeting the criteria for PET negative CR and then every 3 cycles 
while on treatment or every 6 months in follow-up (as available) h
PK- Blood Sampling 
for Durvalumab
i
X
X
X
X
X
X
X
(C6 & 
C10)
X
PK- Blood Sampling 
for Lenalidomide
j
X
X
(D2 only)
X
(D15 
only)
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
69
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 7:
Table of Events – Arm A - Durvalumab and Lenalidomide ± Rituximab (Continued)
Events
Screening
Period
Treatment Period
Follow-up
C1
C2
C3
C4
C5
C6-13
C14/
EOT-D
≥ C15
EOT a
D
-28 to -1
D1
D2&D3
D8, 
D15 & 
D22
D1
D15
D1
D15
D1
D15
D1
D1
D1
D1
Safety 
D28
/D90
Efficacy 
/SPMb
Immunogenicity 
(ADA)- Blood Sample
k
X
X
X
X (C6 
& C10)
X
Biomarker- Saliva 
(pharmacogenomics)
X
Biomarker- PBMC 
Isolation
X
X
X
X
Biomarker-Whole 
Blood for 
Immunophenotyping
X
X
X
(D8 & 
D15 
only)
X
X
Biomarker-Serum
X
X
X
Biomarker-Plasma 
(Cytokines/Soluble 
Factors)
X
X
X
X
X
X
X
Biomarker-Tumor 
Biopsy
l
(Lymphoma)
X
m
X
(recommend
ed)
At the time of disease progression (within 14 days) in subjects who achieved objective 
responses (CR/PR)
Biomarker- Bone 
Marrow Biopsy 
&Aspirate
n
(Lymphoma)
X
If available, bone marrow biopsy samples will be submitted to the Central Laboratory for biomarker analysis at any time performed (such as at 
the time of nodal CR by CT alone).
Durvalumab IV 
Infusion
X
X
X
X
X
X
Rituximab IV Infusion
Schedule 1 
(DL-1B & DL2)
X
(D2)
X
Weekly
X
X
X
X
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
70
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 7:
Table of Events – Arm A - Durvalumab and Lenalidomide ± Rituximab (Continued)
Events
Screening
Period
Treatment Period
Follow-up
C1
C2
C3
C4
C5
C6-13
C14/
EOT-D
≥ C15
EOT a
D
-28 to -1
D1
D2&
D3
D8, 
D15 & 
D22
D1
D15
D1
D15
D1
D15
D1
D1
D1
D1
Safety 
D28
/D90
Efficacy 
/SPMb
Rituximab IV Infusion 
Schedule 2
(DL-2 & DL-3)
X
(D2)
X
X
X
X
X
(C6, C7 
& C8)
Dispense Lenalidomide 
(PO) (in FL or MZL) 
X
X
X
X
X
X
Dispense Lenalidomide 
(PO) (in aggressive 
histologies)
X
X
X
X
X
X
X
X
Drug Accountability
X
X
X
X
X
X
X
X
X
X
Tumor Lysis 
Prophylaxis 
(Allopurinol or 
equivalent)-
recommended
X
X
X
Concomitant 
Medications/ 
Procedures
After signing informed consent through 90 days after the last dose of durvalumab or 28 days after the last dose of other study treatment(s), 
whichever occurs later.
Adverse Events (AE)
After signing informed consent through 90 days after the last dose of durvalumab or 28 days after the last dose of other study treatment(s), 
whichever occurs later.
Subsequent 
Antilymphoma/Antican
cer Treatment Status
After signing informed consent until the subject dies, withdraws consent from the study, or for up to:
-
24 months from the date of his/her last dose (in FL or MZL) or
-
24 months after his/her last durvalumab dose or disease progression, whichever date occurs later (in aggressive histologies).
Survival Status
Second Primary 
Malignancy (SPM) 
Assessment
After signing informed consent until the subject dies, withdraws consent from the study or for up to 5 years from the date of last subject’s first lenalidomide 
dose (including SPM follow-up 90 days after the last dose of durvalumab).
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
71
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Abbreviations:  ADA = anti-drug antibodies; BMB = bone marrow biopsy; C = cycle; CBC = complete blood count; CIRS = cumulative illness rating scale; 
CR = complete response; CT = computed tomography; D = day; DL = dose level; DLBCL = diffuse large B-cell lymphoma; ECG = electrocardiogram ; ECOG= 
Eastern Cooperative Oncology Group; EOT = end of treatment; EOT-D = end of durvalumab treatment; FCBP = female of childbearing potential; FDG = 
fluorodeoxyglucose; FDG-PET = fluorodeoxyglucose-positron emission tomography; FL = follicular lymphoma; fT3 = free triiodothronine; fT4 = free 
thyroxine; GGT = gamma glutamyl transferase; HBV = hepatitis B virus; HL = Hodgkin lymphoma; IRT = integrated response technology; IV = intravenous; 
LDH = lactic dehydrogenase; MCL = mantle cell lymphoma; MRD = minimal residual disease; MZL = marginal zone lymphoma; PBMC = peripheral blood
mononuclear cells; PD = progressive disease; PK = pharmacokinetics; PO = orally; PR = partial response; PS = performance status; SPM = second primary 
malignancy.
a For subjects with indolent lymphoma, the EOT for all study treatments and the EOT-D will be the same visit unless subjects discontinue durvalumab treatment 
(earlier than Cycle 13) due to toxicity.
b Efficacy Follow-up will be performed (a) up to 24 months from subject's last durvalumab dose (in FL or MZL) or (b) up to 24 months from subject's last 
durvalumab dose or disease progression, whichever occurs later (in aggressive histologies). Following completion or discontinuation of durvalumab treatment 
per protocol for all subjects and completion of the primary analysis (data cutoff date 06 Mar 2019), subjects are no longer required to be followed for disease 
progression, subsequent antilymphoma/CLL therapy, and overall survival. Follow-up procedures, efficacy assessments, central labs, imaging, and survival data 
will no longer be collected in the CRFs. 
c Subjects will have their blood pressure, pulse and body temperature measured before, during and after the infusion at the following times (based on a 60-minute 
infusion): 
-
At the beginning of the infusion (within an hour prior to start of durvalumab administration);
-
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 after the infusion (ie, 90, 120, 150, and 180 minutes from the start of the infusion) (± 5 
minutes) – for the first infusion only and then for subsequent infusions as clinically indicated.
-
If the infusion takes longer than 60 minutes, then blood pressure and pulse measurements should be collected every 30 minutes (± 5 minutes) and as 
described above or more frequently if clinically indicated.
d Thyroid stimulating hormone (TSH), fT4, and fT3. Cycle 6 onward:  TSH only, if TSH is abnormal, then reflex testing for fT4 and fT3. 
e Once a subject has experienced confirmed progression, or started a new antilymphoma therapy, no further scans, physicial examination, or laboratory 
assessments are required.
f Screening bone marrow biopsy is required in subjects with suspected bone marrow involvement by lymphoma per investigator's discretion. 
g If an FDG-PET-CT is performed and confirms FDG-negative CR, BMB and aspirate are not required for subjects with aggressive histologies (eg, DLBCL and 
HL).
h Please see Section Section 6.4.1.4 for MRD assessments.
i Please see Section Section 6.6.1 for PK sample collection time points for durvalumab.
j Please see Section Section 6.6.2 for PK sample collection time points for lenalidomide.
k Please see Section 6.7 for immunogenicity sample collection time points.
l In addition, it is strongly recommended to submit to the Central Laboratory any archival lymph node/tumor biopsy samples collected prior to study entry as 
well as any biopsy sample collected during the study for biomarker analysis.
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
72
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
m The only exception is that an archival diagnostic lymph node/tumor formalin-fixed paraffin-embedded (FFPE) biopsy acquired by a surgical or core needle 
biopsy within 3 months and with no intervening treatment prior to signing informed consent may be acceptable for enrollment in subjects with poorly 
accessible tumor following the discussion with the sponsor’s medical monitor.
n In addition, it is strongly recommended to submit to the Central Laboratory any archival bone marrow biopsy samples collected prior to study entry as well as 
any biopsy samples collected during the study for biomarker analysis.
Detailed information (including visit windows) for each assessment is provided in Section 6.
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
73
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 8:
Table of Events – Arm B - Durvalumab and Ibrutinib
Events
Screening
Period
Treatment Period
Follow-up
C1
C2
C3
C4
C5
C6-13
C14/
EOT-
D
≥ C15
EOT
D
-28 to -1
D1
D2&D
3
D8, 
D15 
& 
D22
D1
D15
D1
D15
D1
D15
D1
D1
D1
D1
Safety 
D28
/D90
Efficacy
a
Informed Consent 
X
IRT Registration 
X
X
X
X
X
X
X
X
X
X
Inclusion/Exclusion 
Criteria
X
Demographics
X
Medical History & 
Disease History
X
Prior Anticancer 
Therapy
X
Physical Examination
& B symptoms
X
X
X
X
X
X
X
X
X
X
X
X
(until 
PD)
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
Vital Sign Monitoring
b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
X
CIRS (only subjects > 
80 years)
X
12-lead ECG 
X
X
HBV Screening
X
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
74
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 8:
Table of Events – Arm B - Durvalumab and Ibrutinib (Continued)
Events
Screening
Period
Treatment Period
Follow-up
C1
C2
C3
C4
C5
C6-13
C14/
EOT-
D
≥ C15
EOT
D
-28 to -1
D1
D2&D
3
D8, 
D15 
& 
D22
D1
D15
D1
D15
D1
D15
D1
D1
D1
D1
Safety 
D28
/D90
Efficacya
CBC & Differential
X
X
X
(D3 
only)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(until 
PD)
Clinical Chemistry 
(including LDH)
X
X
X
(D3 
only)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(until 
PD)
GGT, Amylase, Lipase
X
X
X
X
X
X
X
X
X
X
X
X
Thyroid Function 
Tests
c
X
X
X
(D15 
only)
X
X
X
X
X
X
X
(C6, 
C8, 
C10, 
C12 
only)
X
X
(D90 
only)
Calculated Creatinine 
Clearance (serum)
X
Coagulation
X
X
X
(D15 
only)
X
X
X
X
X
X
X
(D90 
only)
Direct Antiglobulin-
Blood (CLL only)
d
X
Quantitative 
Immunoglobulins 
X
X
Urinalysis
X
X
Pregnancy Test for 
FCBP
X
X
X
X
X
X
X
X
X
X
X
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
75
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 8:
Table of Events – Arm B - Durvalumab and Ibrutinib (Continued)
Events
Screening
Period
Treatment Period
Follow-up
C1
C2
C3
C4
C5
C6-13
C14/
EOT-
D
≥ C15
EOT
D
-28 to -1
D1
D2&
D3
D8, 
D15 & 
D22
D1
D15
D1
D15
D1
D15
D1
D1
D1
D1
Safety 
D28
/D90
Efficacya
Efficacy Response 
Assessment
X
X (C7 
& C10)
X
Every 6 cycles/months up to PD or start 
of a new antilymphoma/CLL therapy
CT Scans (Neck, 
Chest, Abdomen 
&Pelvis) (contrast-
enhanced unless 
contraindicated) 
(Lymphoma)
X
X
X
(C7 & 
C10)
X
Every 6 cycles/months up to PD or start 
of a new antilymphoma/CLL therapy
e
FDG-PET-CT 
(FDG-avid 
Lymphoma)
X 
(strongly 
recommen
ded)
To confirm CR by CT scan alone at any time during the study (within 14 days 
following demonstration of nodal CR by CT scan alone)
Bone Marrow Biopsy 
& Aspirate
(Lymphoma)
X
f
To confirm true CR (within 28 days of meeting the criteria for nodal CR by CT scan 
alone) except in subjects with no evidence of lymphomatous marrow involvement at 
baseline
g
MRD Assessment-
Whole Blood (in 
subjects with MCL
and FL)
h
X
Within 28 days of meeting the criteria for PET negative CR and then every 3 cycles 
while on treatment or every 6 months in follow-up until evidence of clinical PDh
MRD Assessment-
Bone Marrow Aspirate
(in subjects with 
MCL and FL)h
Within 28 days of meeting the criteria for PET negative CR and then every 3 cycles 
while on treatment or every 6 months in follow-up (as available)h
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
76
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 8:
Table of Events – Arm B - Durvalumab and Ibrutinib (Continued)
Events
Screeni
ng
Period
Treatment Period
Follow-up
C1
C2
C3
C4
C5
C6-13
C14/
EOT-
D
≥ C15
EOT
D
-28 to -
1
D1
D2&D
3
D8,
D15 
& 
D22
D1
D15
D1
D15
D1
D15
D1
D1
D1
D1
Safety 
D28
/D90
Efficacya
CT Scans (Neck, Chest, 
Abdomen & Pelvis) 
(contrast-enhanced 
unless contraindicated)
(CLL)
i
X
X
j
(C7)
Bone Marrow Biopsy & 
Aspirate (CLL)
k
X
X 
(C7)
X
MRD Assessment –
Whole Blood (in 
subjects with CLL)
l
X
Within 14 days of meeting the criteria for suspected CR by clinical, CBC-based, 
and imaging assessments and then every 3 cycles while on treatment or every 6 
months in follow-up til evidence of clinical PDl
MRD Assessment –
Bone Marrow Aspirate 
(in subjects with CLL)l
Within 12 weeks of meeting the criteria for suspected CR by clinical, CBC-based, 
and imaging assessments and then every 3 cycles while on treatment or every 6 
months in follow-up til evidence of clinical PD (as available)l
PK- Blood Sampling for 
Durvalumab
m
X
X
X
X
X
X
X
C6 & 
C10)
X
PK- Blood Sampling for 
Ibrutinib
n
X
X
(D2 
only)
X
(D15 
only)
Immunogenicity (ADA)-
Blood Sample
o
X
X
X
X
(C6 & 
C10)
X
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
77
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 8:
Table of Events – Arm B - Durvalumab and Ibrutinib (Continued)
Events
Screening
Period
Treatment Period
Follow-up
C1
C2
C3
C4
C5
C6-13
C14/
EOT-
D
≥ C15
EOT
D
-28 to -1
D1
D2&D
3
D8, 
D15 
& 
D22
D1
D15
D1
D15
D1
D15
D1
D1
D1
D1
Safety 
D28
/D90
Efficacya
Biomarker- Saliva 
(pharmacogenomics)
X
Biomarker- PBMC 
Isolation
X
X
X
X
Biomarker-Whole 
Blood for 
Immunophenotyping
X
X
X
(D8 & 
D15 
only)
X
X
Biomarker-Serum
X
X
X
Biomarker-Plasma 
(Cytokines/Soluble 
Factors)
X
X
X
X
X
X
X
Biomarker-Tumor 
Biopsy
p
(Lymphoma)
X
q
X
(recommen
ded)
At the time of disease progression (within 14 days) in subjects who achieved objective 
responses (CR/PR)
Biomarker- Bone 
Marrow Biopsy 
&Aspirate
r
(Lymphoma)
X
If available, bone marrow biopsy samples will be submitted to the Central Laboratory for biomarker analysis at any time performed (such as 
at the time of nodal CR by CT alone).
Biomarker- Bone 
Marrow Biopsy 
&Aspirate (CLL)r
X
Bone marrow biopsy samples will be submitted to the Central Laboratory for biomarker analysis at any time performed.
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
78
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 8:
Table of Events – Arm B - Durvalumab and Ibrutinib (Continued)
Events
Screening
Period
Treatment Period
Follow-up
C1
C2
C3
C4
C5
C6-13
C14/
EOT-
D
≥ C15
EOT
D
-28 to -1
D1
D2&D
3
D8, 
D15 
& 
D22
D1
D15
D1
D15
D1
D15
D1
D1
D1
D1
Safety 
D28
/D90
Efficacya
Durvalumab IV 
Infusion
X
X
X
X
X
X
Dispense Ibrutinib 
(PO) 
X
X
X
X
X
X
X
Xs
Tumor Lysis Proph. 
(Allopurinol or 
equivalent) 
recommended
X
X
X
Concomitant 
Medications/ 
Procedures
After signing informed consent through 90 days after the last dose of durvalumab or 28 days after the last dose of other study treatment(s), whichever 
occurs later.
Adverse Events (AE)
After signing informed consent through 90 days after the last dose of durvalumab or 28 days after the last dose of other study treatment(s), whichever 
occurs later.
Subsequent 
Antilymphoma/Antica
ncer Treatment Status
After signing informed consent until the subject dies, withdraws consent from the study, or for up to
24 months after his/her last durvalumab dose or disease progression, whichever date occurs later.
Survival Status
Second Primary 
Malignancy (SPM) 
Assessment
After signing informed consent until the subject dies, withdraws consent from the study or for up to 90 days after the last dose of durvalumab or 28 days 
after the last dose of other study treatment(s), whichever occurs later.
Abbreviations:  ADA = anti-drug antibodies; BMB = bone marrow biopsy; C = cycle; CBC = complete blood count; CIRS = cumulative illness rating scale; 
CLL = chronic lymphocytic leukemia; CR = complete response; CT = computed tomography; D = day; DLBCL = diffuse large B-cell lymphoma; ECG = 
electrocardiogram; ECOG= Eastern Cooperative Oncology Group; EOT = end of treatment; EOT-D = end of durvalumab treatment; FC = flow cytometry;  
FCBP = female of childbearing potential; FDG = fluorodeoxyglucose; FDG-PET = fluorodeoxyglucose-positron emission tomography; FL = follicular 
lymphoma; fT3 = free triiodothronine; fT4 = free thyroxine; GGT = gamma glutamyl transferase; HBV = hepatitis B virus; IRT = integrated response 
technology; IV = intravenous; LDH = lactic dehydrogenase; MCL = mantle cell lymphoma; MRD = minimal residual disease; MZL = marginal zone lymphoma; 
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
79
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
PBMC = peripheral blood mononuclear cells; PD = progressive disease; PK = pharmacokinetics; PO = orally; PR = partial response; PS = performance status; 
SLL = small lymphocytic lymphoma; SPM = second primary malignancy; WBC = white blood cell.
a Efficacy Follow up will be performed up to 24 months from subject's last durvalumab dose or disease progression, whichever occurs later. Following 
completion or discontinuation of durvalumab treatment per protocol for all subjects and completion of the primary analysis (data cutoff date 06 Mar 2019), 
subjects are no longer required to be followed for disease progression, subsequent antilymphoma/CLL therapy, and overall survival. Follow-up procedures, 
efficacy assessments, central labs, imaging, and survival data will no longer be collected in the CRFs.  
b Subjects will have their blood pressure, and pulse, and body temperature measured before, during and after the infusion at the following times (based on a 60-
minute infusion):
-
At the beginning of the infusion (within an hour prior to start of durvalumab administration);
-
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 after the infusion (ie, 90, 120, 150, and 180 minutes from the start of the infusion) (± 5 
minutes) – for the first infusion only and then for subsequent infusions as clinically indicated.
-
If the infusion takes longer than 60 minutes, then blood pressure and pulse measurements should be collected every 30 minutes (± 5 minutes) and as 
described above or more frequently if clinically indicated.
c Thyroid stimulating hormone (TSH), fT4, and fT3. Cycle 6 onward:  TSH only, if TSH is abnormal, then reflex testing for fT4 and fT3. 
d Direct antiglobulin test will be performed at site's local laboratory.
e Once a subject has experienced confirmed progression, or started a new antilymphoma/CLL therapy, no further scans, physicial examination, or laboratory 
assessments are required.
f Screening bone marrow biopsy is required in subjects with suspected bone marrow involvement by lymphoma per investigator's discretion. 
g If an FDG-PET-CT is performed and confirms FDG-negative CR, BMB and aspirate are not required for subjects with aggressive histologies (eg, DLBCL and 
HL).
h Please see Section 6.4.1.4 for MRD assessments.
i In subjects with CLL, CT scan is highly recommended (unless its frequency exceeds local standards) to confirm suspected CR (by clinical and CBC-based) 
(within 8 weeks after clinical and CBC-based CR).
j In subjects with CLL, CT is required at Cycle 7 Day 1 (± 7 days) for only affected regions with abnormal findings at baseline.
k In subjects with CLL, BMB will be also performed to confirm suspected CR (by clinical, laboratory [including peripheral blood flow-negativity] and imaging) 
(within 12 weeks); and to evaluate cytopenia of uncertain cause (as clinically indicated).
l Please see Section 6.4.2.3 for further information about the MRD assessments in CLL.
m Please see Section 6.6.1 for PK sample collection time points for durvalumab.
n Please see Section 6.6.3 for PK sample collection time points for ibrutinib.
o Please see Section 6.7 for immunogenicity sample collection time points.
p In addition, it is strongly recommended to submit to the Central Laboratory any archival lymph node/tumor biopsy samples collected prior to study entry as 
well as any biopsy sample collected during the study for biomarker analysis. 
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
80
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
q The only exception is that an archival diagnostic lymph node/tumor formalin fixed paraffin embedded (FFPE) biopsy acquired by a surgical or core needle 
biopsy within 3 months and with no intervening treatment prior to signing informed may be acceptable for enrollment in subjects with poorly accessible tumor 
following the discussion with the sponsor’s medical monitor.
r In addition, it is strongly recommended to submit to the Central Laboratory any archival bone marrow biopsy samples collected prior to study entry as well as 
any biopsy samples collected during the study for biomarker analysis.
s For subjects remaining on ibrutinib treatment, study medication can be dispensed every 3 months with assessments done as per the investigator’s discretion. 
Detailed information (including visit windows) for each assessment is provided in Section 6.
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
81
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 9:
Table of Events – Arm C – Durvalumab and Rituximab ± Bendamustine
Events
Screening 
Period
Treatment Period
Follow-up
C1
C2-C6
C7-13
EOT-D/
EOT
D-28 to -1
D1
D2
D3
D 8, 15 
& 22
D1
D2
D15
D1
Safety
D28/D90
Efficacy
a
Informed Consent 
X
IRT Registration
X
X
X
X
X
X
X
Inclusion/Exclusion 
Criteria
X
Demographics
X
Medical History & Disease 
History
X
Prior Anticancer Therapy
X
Physical Examination & B 
symptoms
X
X
X
X
X
X
X
(until PD)
Height
X
Weight
X
X
X
X
X
Body Surface Area
X
X
Vital Sign Monitoring
b
X
X
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
CIRS (only subjects > 80 
years)
X
12-lead ECG
X
X
HBV Screening
X
CBC & Differential
X
X
X
X
X
X
X
X
X
X
(until PD)
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
82
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 9:
Table of Events – Arm C – Durvalumab and Rituximab ± Bendamustine (Continued)
Events
Screening 
Period
Treatment Period
Follow-up
C1
C2-C6
C7-13
EOT-D/
EOT
D-28 to -1
D1
D2
D3
D 8, 15 
& 22
D1
D2
D15
D1
Safety
D28/D90
Efficacya
Clinical Chemistry 
(including LDH)
X
X
X
X
X
X
X
X
X
X
(until PD)
GGT, Amylase, Lipase
X
X
X
X
X
X
X
Thyroid Function Tests
c
X
X
X 
(D15 
only)
X
(C2, C3, 
C4 & C6 
only)
X
(C2, C3, 
& C4 
only)
X(C8, 
C10, & 
C12 only) 
X
X
(D90 
only)
Calculated Creatinine 
Clearance (serum)
X
Coagulation
X
X
X 
(D15 
only)
X
X
X
X
(D90 
only)
Direct Antiglobulin- Blood 
(CLL only)
d
X
Quantitative 
Immunoglobulins 
X
X
Urinalysis
X
X
Pregnancy Test for FCBP
X
X
X
X
X
X
Efficacy Response 
Assessment
X
(C4)
X
(C7 & 
C10)
X
Every 6 cycles /months up 
to PD or start of a new 
antilymphoma/CLL therapy
CT Scans (Neck, Chest, 
Abdomen &Pelvis) 
(contrast-enhanced unless 
contraindicated) 
(Lymphoma)
X
X
(C4)
X
(C7 & 
C10)
X
Every 6 cycles/months up to 
PD or start of a new 
antilymphoma/CLL therapy
e
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
83
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 9:
Table of Events – Arm C – Durvalumab and Rituximab ± Bendamustine (Continued)
Events
Screening 
Period
Treatment Period
Follow-up
C1
C2-C6
C7-13
EOT-D/
EOT
D-28 to -1
D1
D2
D3
D 8, 15 
& 22
D1
D2
D15
D1
Safety
D28/D90
Efficacya
FDG-PET-CT
(FDG-avid Lymphoma)
X (strongly 
recommended)
To confirm CR by CT scan alone at any time during the study (within 14 days 
following demonstration of nodal CR by CT scan alone)
Bone Marrow Biopsy 
&Aspirate (Lymphoma)
Xf
To confirm true CR (within 28 days of meeting the criteria for nodal CR by CT 
scan alone) except in subjects with no evidence of lymphomatous marrow 
involvement at baselineg
MRD Assessment – Whole 
Blood (in subjects with 
MCL and FL)h
X
Within 28 days of meeting the criteria for PET negative CR and then every 3 
cycles while on treatment or every 6 months in follow-up until evidence of clinical 
PDh
MRD Assessment –Bone 
Marrow Aspirate (in 
subjects with MCL and 
FL)h
Within 28 days of meeting the criteria for PET negative CR and then every 3 
cycles while on treatment or every 6 months in follow-up (as available) h
CT Scans (Neck, Chest, 
Abdomen & Pelvis) 
(contrast-enhanced unless 
contraindicated)
i (CLL)
X
Xj
(C7)
Bone Marrow Biopsy & 
Aspiratek (CLL)
X
X (C7)
X
MRD Assessment – Whole 
Blood
(in subjects with CLL)l
X
Within 14 days of meeting the criteria for suspected CR (by clinical, CBC-based, 
and imaging assessments) and then every 3 cycles while on treatment or every 6 
months in follow-up until evidence of clinical PD
l
MRD Assessment – Bone 
Marrow Aspirate (in 
subjects with CLL)l
Within 12 weeks of meeting the criteria for suspected CR by clinical, CBC-based, 
and imaging assessments and then every 3 cycles while on treatment or every 6 
months in follow-up til evidence of clinical PD (as available)l
PK- Blood Sampling for 
Durvalumab
m
X
X
X
X
X
(C2, C4 & 
C6)
X
(C2)
X
(C10)
X
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
84
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 9:
Table of Events – Arm C – Durvalumab and Rituximab ± Bendamustine (Continued)
Events
Screening 
Period
Treatment Period
Follow-up
C1
C2-C6
C7-13
EOT-D/
EOT
D-28 to -1
D1
D2
D3
D 8, 15 
& 22
D1
D2
D15
D1
Safety
D28/D90
Efficacya
Immunogenicity (ADA)-
Blood Sample
n
X
X (C2, 
C4, & 
C6)
X
(C10)
X
Biomarker-Saliva 
(pharmacogenomics)
X
Biomarker- PBMC Isolation
X
X (C2 & 
C4)
X
Biomarker-Whole Blood for 
Immunophenotyping
X
X
X
(D8 & 
D15 
only)
X (C2)
X (C2)
Biomarker-Serum
X
X
X (C2)
Biomarker-Plasma 
(Cytokines / Soluble 
factors)
X
X
X (C2)
X (C2,
C3 & C4)
X 
Biomarker- Tumor Biopsy
o
(Lymphoma)
X
p
-Any time during C2 (recommended) and
- At the time of disease progression (within 14 days) in subjects who achieved 
objective responses (CR/PR)
Biomarker- Bone Marrow 
Biopsy &Aspirate
q
(Lymphoma)
X
If available, bone marrow biopsy samples will be submitted to the Central Laboratory for biomarker analysis at any time 
performed (such as at the time of nodal CR by CT alone).
Biomarker- Bone Marrow 
Biopsy & Aspirateq
(CLL)
X
Bone marrow biopsy samples will be submitted to the Central Laboratory for biomarker analysis at any time performed.
Durvalumab IV Infusion
X
X
X
Bendamustine IV Infusion
X
X
X
X
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
85
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 9:
Table of Events – Arm C – Durvalumab and Rituximab ± Bendamustine (Continued)
Events
Screening 
Period
Treatment Period
Follow-up
C1
C2-C6
C7-13
EOT-D/
EOT
D-28 to -1
D1
D2
D3
D 8, 15 
& 22
D1
D2
D15
D1
Safety
D28/D90
Efficacya
Rituximab IV Infusion
X
X
Drug accountability
X
X
X
X
X
Tumor Lysis Prophylaxis-
recommended
X
X
X
X
Concomitant Medications/ 
Procedures
After signing informed consent through 90 days after the last dose of durvalumab or 28 days after the last dose of other study 
treatment(s), whichever occurs later.
Adverse Events (AE)
After signing informed consent through 90 days after the last dose of durvalumab or 28 days after the last dose of other study 
treatment(s), whichever occurs later.
Subsequent 
Antilymphoma/Anticancer 
Treatment Status
After signing informed consent until the subject dies, withdraws consent from the study or for up to 24 months from the date of each subject’s last 
durvalumab dose.
Survival Status
Second Primary Malignancy 
Assessment (SPM)
After signing informed consent until the subject dies, withdraws consent from the study or for up to 90 days after the last dose of durvalumab or 
28 days after the last dose of other study treatment(s), whichever occurs later.
Abbreviations:  ADA = anti-drug antibodies; BMB = bone marrow biopsy; C = cycle; CBC = complete blood count; CIRS = cumulative illness rating scale; 
CLL = chronic lymphocytic leukemia; CR = complete response; CT = computed tomography; D = day; DLBCL = diffuse large B-cell lymphoma; ECG = 
electrocardiogram ; ECOG= Eastern Cooperative Oncology Group; EOT = end of treatment; EOT-D = end of durvalumab treatment; FC = flow cytometry; 
FCBP = female of childbearing potential; FDG = fluorodeoxyglucose; FDG-PET = fluorodeoxyglucose-positron emission tomography; FL = follicular 
lymphoma; fT3 = free triiodothronine; fT4 = free thyroxine; GGT = gamma glutamyl transferase; HBV = hepatitis B virus; IRT = Integrated response 
technology; IV = intravenous; HL = Hodgkin lymphoma; LDH = lactic dehydrogenase; MCL = mantle cell lymphoma; MRD = minimal residual disease; MZL = 
marginal zone lymphoma; PBMC = peripheral blood mononuclear cells; PD = progressive disease; PK = pharmacokinetics; PR = Partial Response; PS = 
performance status; SPM = second primary malignancy; WBC = white blood cell.
a Efficacy Follow-up will be performed up to 24 months from subject's last durvalumab dose. Following completion or discontinuation of durvalumab treatment 
per protocol for all subjects and completion of the primary analysis (data cutoff date 06 Mar 2019), subjects are no longer required to be followed for disease 
progression, subsequent antilymphoma/CLL therapy, and overall survival. Follow-up procedures, efficacy assessments, central labs, imaging, and survival data 
will no longer be collected in the CRFs. 
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
86
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
b Subjects will have their blood pressure, and pulse, and measured before, during and after the infusion at the following times (based on a 60-minute infusion):
-
At the beginning of the infusion (within an hour prior to start of durvalumab administration);
-
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 after the infusion (ie, 90, 120, 150, and 180 minutes from the start of the infusion) (± 5 
minutes) – for the first infusion only and then for subsequent infusions as clinically indicated.
-
If the infusion takes longer than 60 minutes, then blood pressure and pulse measurements should be collected every 30 minutes (± 5 minutes) and as 
described above or more frequently if clinically indicated.
c Thyroid stimulating hormone (TSH), fT4, and fT3.  Cycle 6 onward:  TSH only, if TSH is abnormal, then reflex testing for fT4 and fT3. 
d Direct antiglobulin test will be performed at site's local laboratory.
e Once a subject has experienced confirmed progression, or started a new antilymphoma/CLL therapy, no further scans, physicial examination, or laboratory 
assessments are required.
f Screening bone marrow biopsy is required in subjects with suspected bone marrow involvement by lymphoma per investigator's discretion. 
g If an FDG-PET-CT is performed and confirms FDG-negative CR, BMB and aspirate is not required for subjects with aggressive histologies (eg, DLBCL and 
HL).
h Please see Section 6.4.1.4 for MRD assessment
i In subjects with CLL, CT scan is highly recommended (unless its frequency exceeds local standards) to confirm suspected CR (by clinical and CBC-based) 
(within 8 weeks after clinical and CBC-based CR).
j In subjects with CLL, CT is required at Cycle 7 Day 1 (± 7 days) for only affected regions with abnormal findings at baseline.
k In subjects with CLL, BMB will be also performed to confirm suspected CR (by clinical, laboratory [including peripheral blood flow-negativity] and imaging) 
(within 12 weeks); and to evaluate cytopenia of uncertain cause (as clinically indicated).
l Please see Section 6.4.2.3 for MRD assessment in CLL.
m Please see Section 6.6.1 for PK sample collection time points for durvalumab. 
n Please see Section 6.7 for immunogenicity sample collection time points.
o In addition, it is strongly recommended to submit to the Central Laboratory any archival lymph node/tumor biopsy samples collected prior to study entry as 
well as any biopsy sample collected during the study for biomarker analysis.
p The only exception is that an archival diagnostic lymph node/tumor formalin fixed paraffin embedded (FFPE) biopsy acquired by a surgical or core needle 
biopsy within 3 months and with no intervening treatment prior to signing informed consent may be acceptable for enrollment in subjects with poorly 
accessible tumor following the discussion with the sponsor’s medical monitor.
q In addition, it is strongly recommended to submit to the Central Laboratory any archival bone marrow biopsy samples collected prior to study entry as well as 
any biopsy samples collected during the study for biomarker analysis.
Detailed information (including visit windows) for each assessment is provided in Section 6.
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
87
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 10:
Table of Events – Arm D – Durvalumab Monotherapy
Events
Screening 
Period
Treatment Period
Follow-up
C1
C2
C3
C4
C5
C6-13
(/C6-C19a)
EOT-D/ 
EOT
D
-28 to -1
D1
D2&D3
D8, 
D15 & 
D22
D1
D15
D1
D15
D1
D15
D1
D1
Safety
D28/ 
D90
Efficacyb
Informed Consent 
X
IRT Registration 
X
X
X
X
X
X
X
X
Inclusion/Exclusion 
Criteria
X
Demographics
X
Medical History & 
Disease History
X
Prior Anticancer 
Therapy
X
Physical 
Examination & B 
symptoms
X
X
X
X
X
X
X
X
X
X
(until PD)
Height
X
Weight
X
X
X
X
X
X
X
X
Vital Sign 
Monitoring
c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
CIRS (only subjects 
> 80 years)
X
12-lead ECG 
X
X
HBV Screening
X
CBC & Differential
X
X
X
(D3 
only)
X
X
X
X
X
X
X
X
X
X
X
X
(until PD)
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
88
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 10:
Table of Events – Arm D – Durvalumab Monotherapy (Continued)
Events
Screening 
Period
Treatment Period
Follow-up
C1
C2
C3
C4
C5
C6-13
(/C6-C19a)
EOT-D/ 
EOT
D
-28 to -1
D1
D2&D3
D8, 
D15 & 
D22
D1
D15
D1
D15
D1
D15
D1
D1
Safety
D28/ 
D90
Efficacyb
Clinical Chemistry 
(including LDH)
X
X
X
(D3 
only)
X
X
X
X
X
X
X
X
X
X
X
X
(until PD)
GGT, Amylase, Lipase
X
X
X
X
X
X
X
X
X
X
X
X
Thyroid Function Tests
d
X
X
X
(D15 
only)
X
X
X
X
X
X
X
(C6, C8, 
C10, C12/ 
if 
applicable:
C14, C16, 
C18 only)
X
X
(D90 
only)
Calculated Creatinine 
Clearance (serum) 
X
Coagulation
X
X
X 
(D15 
only)
X
X
X
X
X
X
X
(D90 
only)
Direct Antiglobulin-
Blood (CLL only)
e
X
Quantitative 
Immunoglobulins 
X
X
Urinalysis
X
X
Pregnancy Test for 
FCBP
X
X
X
X
X
X
X
X
X
Efficacy Response 
Assessment
X
X (C7 & 
C10)
Every 6 cycles/months up to PD
or start of a new 
antilymphoma/CLL therapy
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
89
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 10:
Table of Events – Arm D – Durvalumab Monotherapy (Continued)
Events
Screening 
Period
Treatment Period
Follow-up
C1
C2
C3
C4
C5
C6-13 (/C6-
C19 a)
EOT-
D/ 
EOT
D
-28 to -1
D1
D2&D3
D8, 
D15 & 
D22
D1
D15
D1
D15
D1
D15
D1
D1
Safety
D28/ D90
Efficacyb
CT Scans (Neck, Chest, 
Abdomen &Pelvis) 
(contrast-enhanced 
unless contraindicated) 
(Lymphoma)
X
X
X
(C7 & 10)
X
Every 6 cycles/months up 
to PD or start of a new 
antilymphoma/CLL
therapy 
f
FDG-PET-CT 
(FDG-avid 
Lymphoma)
X
(strongly 
recommended)
To confirm CR by CT scan alone at any time during the study (within 14 
days following demonstration of nodal CR by CT scan alone)
Bone Marrow Biopsy 
&Aspirate
(Lymphoma)
Xg
To confirm true CR (within 28 days of meeting the criteria for nodal CR 
by CT scan alone) except in subjects with no evidence of lymphomatous 
marrow involvement at baselineh
MRD Assessment –
Whole Blood (in 
subjects with MCL 
and FL)
i
X
Within 28 days of meeting the criteria for PET negative CR and then 
every 3 cycles while on treatment or every 6 months in follow-up until 
evidence of clinical PDi
MRD Assessment –
Bone Marrow Aspirate 
(in subjects with MCL 
and FL)i
Within 28 days of meeting the criteria for PET negative CR and then 
every 3 cycles while on treatment or every 6 months in follow-up (as 
available) i
CT Scans (Neck, Chest, 
Abdomen & Pelvis) 
(contrast-enhanced 
unless contraindicated)
(CLL)j
X
Xk
(C7)
Bone Marrow Biopsy 
& Aspirate (CLL)
l
X
X (C7)
X
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
90
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 10:
Table of Events – Arm D – Durvalumab Monotherapy (Continued)
Events
Screening 
Period
Treatment Period
Follow-up
C1
C2
C3
C4
C5
C6-13 
(/C6-C19a)
EOT-D/ 
EOT
D
-28 to -1
D1
D2&D3
D8, 
D15 & 
D22
D1
D15
D
1
D15
D1
D15
D1
D1
Safety
D28/ 
D90
Efficacyb
MRD Assessment –
Whole Blood (in 
subjects with CLL)
m
X
Within 14 days of meeting the criteria for suspected CR (by clinical, 
CBC-based, and imaging assessments) and then every 3 cycles while on 
treatment or every 6 months in follow-up until evidence of clinical PDm
MRD Assessment –
Bone Marrow Aspirate
(in subjects with 
CLL)m
Within 12 weeks of meeting the criteria for suspected CR by clinical, 
CBC-based, and imaging assessments and then every 3 cycles while on 
treatment or every 6 months in follow-up til evidence of clinical PD (as 
available)m
PK- Blood Sampling 
for Durvalumab
n
X
X
X
X
X
X
X
(C6 & 
C10)
X
Immunogenicity 
(ADA)- Blood    
Sampleo
X
X
X
X
(C6 &
C10)
X
Biomarker- Saliva 
(pharmacogenomics)
X
Biomarker- PBMC 
Isolation
X
X
X
X
Biomarker-Whole 
Blood for 
Immunophenotyping
X
X
X
(D8 & 
D15 
only)
X
X
Biomarker-Serum
X
X
X
Biomarker-Plasma 
(Cytokines / Soluble 
factors)
X
X
X
X
X
X
X
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
91
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 10:
Table of Events – Arm D – Durvalumab Monotherapy (Continued)
Events
Screening 
Period
Treatment Period
Follow-up
C1
C2
C3
C4
C5
C6-13 
(/C6-C19a)
EOT-D/ 
EOT
D
-28 to -1
D1
D2&D3
D8, 
D15 & 
D22
D1
D15
D1
D15
D1
D15
D1
D1
Safety
D28/ 
D90
Efficacyb
Biomarker-Tumor 
Biopsy(Lymphoma)
p
X
q
X
(recommended
)
At the time of disease progression (within 14 days) in subjects who achieved 
objective responses (CR/PR)
Biomarker- Bone 
Marrow Biopsy 
&Aspirate
(Lymphoma)
r
X
If available, bone marrow biopsy samples will be submitted to the Central Laboratory for biomarker analysis at any time performed 
(such as at the time of nodal CR by CT alone).
Biomarker- Bone 
Marrow Biopsy & 
Aspirate (CLL)r
X
Bone marrow biopsy samples will be submitted to the Central Laboratory for biomarker analysis at any time performed.
Durvalumab IV 
Infusion
X
X
X
X
X
X
Drug Accountability
X
X
X
X
X
X
X
Local IFRT (optional)
At the time of PD, subjects may receive local IFRT to a single involved nodal site based on the 
investigator’s discretion
s
Tumor Lysis 
Prophylaxis 
(Allopurinol or 
equivalent)
recommended
X
X
X
Concomitant 
Medications/ 
Procedures
After signing informed consent through 90 days after the last dose of durvalumab or 28 days after the last dose of other study treatment(s), whichever 
occurs later.
Adverse Events (AE)
After signing informed consent through 90 days after the last dose of durvalumab or 28 days after the last dose of other study treatment(s), whichever 
occurs later.
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
92
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 10:
Table of Events – Arm D – Durvalumab Monotherapy (Continued)
Events
Screening 
Period
Treatment Period
Follow-up
C1
C2
C3
C4
C5
C6-13
(/C6-C19a)
EOT-D/ 
EOT
D
-28 to -1
D1
D2&D3
D8, 
D15 & 
D22
D1
D15
D1
D15
D1
D15
D1
D1
Safety
D28/ 
D90
Efficacyb
Subsequent 
Antilymphoma/Anti-
cancer Treatment 
Status
After signing informed consent until the subject dies, withdraws consent from the study or for up to 24 months from the date of each subject’s last dose.
Survival Status
Second Primary 
Malignancy 
Assessment (SPM)
After signing informed consent until the subject dies, withdraws consent from the study or for up to 90 days after the last dose of durvalumab.
Abbreviations:  ADA = anti-drug antibodies; BMB = bone marrow biopsy; C = cycle; CBC = complete blood count; CIRS = cumulative illness rating scale; 
CLL = chronic lymphocytic leukemia; CR = complete response; CT = computed tomography; D = day; DLBCL = diffuse large B-cell lymphoma; ECG = 
electrocardiogram ; ECOG= Eastern Cooperative Oncology Group; EOT = end of treatment; EOT-D = end of durvalumab treatment; FCBP = female of 
childbearing potential; FDG = fluorodeoxyglucose; FDG-PET = fluorodeoxyglucose-positron emission tomography; FL = follicular lymphoma; GGT = gamma 
glutamyl transferase; HBV = hepatitis B virus; IFRT = involved field radiation therapy; IRT = Integrated response technology; LDH = lactic dehydrogenase; 
MCL = mantle cell lymphoma; MRD = minimal residual disease; IV = intravenous; PBMC = peripheral blood mononuclear cells; PD = progressive disease; PK 
= pharmacokinetics; PR = partial response; PS= performance status; SPM = second primary malignancy; WBC = white blood cell.
a Subjects who receive local IFRT, 2 Gy on each of 2 consecutive days to one tumor site, as an additional therapy to durvalumab will continue to follow the Arm 
D schedule.  Following IFRT, subjects will receive durvalumab for up to 6 cycles based on the investigator’s medical judgment. Please see Sections 3.1.2 and 
6.2 for further information.
b Efficacy Follow-up will be performed up to 24 months from subject's last durvalumab dose. Following completion or discontinuation of durvalumab treatment 
per protocol for all subjects and completion of the primary analysis (data cutoff date 06 Mar 2019), subjects are no longer required to be followed for disease 
progression, subsequent antilymphoma/CLL therapy, and overall survival. Follow-up procedures, efficacy assessments, central labs, imaging, and survival data 
will no longer be collected in the CRFs.
c Subjects will have their blood pressure, pulse and body temperature measured before, during and after the infusion at the following times (based on a 60-minute 
infusion):  
-
At the beginning of the infusion (within an hour prior to start of durvalumab administration);
-
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 after the infusion (ie, 90, 120, 150, and 180 minutes from the start of the infusion) (± 5 
minutes) – for the first infusion only and then for subsequent infusions as clinically indicated.
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
93
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
-
If the infusion takes longer than 60 minutes, then blood pressure and pulse measurements should be collected every 30 minutes (± 5 minutes) and as 
described above or more frequently if clinically indicated.
d Thyroid stimulating hormone (TSH), fT4, and fT3.  Cycle 6 onward:  TSH only, if TSH is abnormal, then reflex testing for fT4 and fT3.
e Direct antiglobulin test will be performed at site's local laboratory.
f Once a subject has experienced confirmed progression, or started a new antilymphoma/CLL therapy, no further scans, physical examination, or laboratory 
assessments are required.
g Screening bone marrow biopsy is required in subjects with suspected bone marrow involvement by lymphoma per investigator's discretion. 
h If an FDG-PET-CT is performed and confirms FDG-negative CR, BMB and aspirate is not required for subjects with aggressive histologies (eg, DLBCL and 
HL).
i Please see Section 6.4.1.4 for MRD assessments. 
j In subjects with CLL, CT scan is highly recommended (unless its frequency exceeds local standards) to confirm suspected CR (by clinical and CBC-based) 
(within 8 weeks after clinical and CBC-based CR).
k In subjects with CLL, CT is required at Cycle 7 Day 1 (± 7 days) for only affected regions with abnormal findings at baseline.
l In subjects with CLL, BMB will be also performed to confirm suspected CR (by clinical, laboratory [including peripheral blood flow-negativity] and imaging) 
(within 12 weeks); and to evaluate cytopenia of uncertain cause (as clinically indicated).
m Please see Section 6.4.2.3 for MRD assessments in CLL.
n Please see Section 6.6.1  for PK sample collection time points for durvalumab. 
o Please see Section 6.7 for immunogenicity sample collection time points.
p In addition, it is strongly recommended to submit to the Central Laboratory any archival lymph node/tumor biopsy samples collected prior to study entry as 
well as any biopsy sample collected during the study for biomarker analysis.
q The only exception is that an archival diagnostic lymph node/tumor formalin fixed paraffin embedded (FFPE) biopsy acquired by a surgical or core needle 
biopsy within 3 months and with no intervening treatment prior to signing informed consent may be acceptable for enrollment in subjects with poorly 
accessible tumor following the discussion with the sponsor’s medical monitor.
r In addition, it is strongly recommended to submit to the Central Laboratory any archival bone marrow biopsy samples collected prior to study entry as well as 
any biopsy samples collected during the study for biomarker analysis.
s Please see Sections Section 3.1.2, Section 6.2, and Section 7.1.6 for further information.  
Detailed information (including visit windows) for each assessment is provided in Section 6.
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
94
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
6.
PROCEDURES
Any questions regarding the protocol should be directed to the sponsor’s medical monitor or 
designee.
Arm A is discontinued to the enrollment of new subjects. Subjects already enrolled and 
treated in Arm A who are receiving clinical benefit, based on the discretion of the 
investigator, may continue study treatment after being reconsented. 
6.1.
Screening Period
Screening evaluations will be performed for all subjects to determine study eligibility after 
signing the informed consent form. These evaluations must be completed within 28 days of
administration of the first dose (Cycle 1 Day 1 [C1D1]) unless noted otherwise below. 
Inclusion/exclusion criteria must be reviewed and cleared prior to treatment assignment.  
Waivers to the protocol will not be granted during the conduct of this trial, under any 
circumstances.

Informed Consent must be obtained prior to beginning any 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 sponsor’s 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 antilymphoma/CLL therapy and PFS.

Withdraw consent for study treatment and Follow-up Period assessments, but 
allow data collection on subsequent antilymphoma/CLL therapy and OS.

Withdraw all consent.
If screening assessments are performed within 48 hours of Cycle 1 Day 1, safety laboratory and 
physical examinations including electrocardiogram (ECG), need not be repeated at Cycle 1 
Day 1.  The following will be performed or assessed at Screening (in all treatment arms) as 
specified in the Tables of Events Section 5, after informed consent has been obtained:

Interactive response technology (IRT) registration.

Demographics will include date of birth, sex, race, and ethnicity-if allowed by local 
regulations.

Complete medical history will be documented by a qualified clinician at the time of 
the Screening Visit.  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 findings will be 
recorded within the source document and the CRF.  Medical and medication history 
will be assessed in relation to the eligibility criteria as listed in Section 4.
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
95
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020

Disease history will include specific information regarding diagnosis, characteristics, 
and histology including grade. 

Prior anticancer therapies will include surgery, radiation, systemic, or stem cell 
transplant (only autologous stem cell transplant is allowed) for lymphoma or CLL.

Prior and concomitant medication evaluation will include those taken ≤28 days 
before screening, except for those taken for lymphoma or CLL.

Prior and concomitant procedures will include all procedures occurring ≤28 days 
before screening.

Physical examination including evaluation of lymph nodes, spleen and liver will be 
performed.   

B symptoms including fever greater than 38°C, drenching night sweats, and 
unintentional weight loss of > 10% of normal body weight over a period of 6 months 
or less.

Body weight and height (height at the Screening Visit only) will be measured.

Body surface area (BSA) will be calculated using the subject’s height and weight 
according to local pharmacy practice if the subject will receive rituximab or
bendamustine. 
It is up to pharmacist and investigator discretion whether BSA will be recalculated prior 
to preparing every cycle of rituximab or bendamustine, or whether the BSA calculated 
prior to the first dose (Cycle 1 Day 1) will be used throughout the study.  If BSA is to be 
recalculated, the same calculation method should be used throughout the study per 
subject.  

Vital signs will include blood pressure, pulse, and body temperature.

ECOG Performance Status (Oken, 1982) will be scored according to Table 11.
Table 11:
Performance Status by Eastern Cooperative Oncology Group Scale
Score
Description
0
Fully active, able to carry on all predisease 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.
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
96
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020

Modified Cumulative Illness Rating Scale (CIRS) is to be scored at the Screening 
Visit only for subjects who are > 80 years of age.  Each organ system is scored 
separately according to Appendix I and includes all of the following organ specific 
categories: cardiac, hypertension, vascular, respiratory, eye/ear/nose/throat/larynx, 
upper gastrointestinal, lower gastrointestinal, hepatic/biliary, renal, genitourinary, 
musculoskeletal, endocrine/metabolic, neurological, and psychiatric (Salvi, 2008a; 
Salvi, 2008b).  Lymphoma or CLL disease or related organ damage should not be 
assessed in this rating scale.  If there are 2 or more illnesses/impairments in one organ 
system, the illness/impairment with the highest severity will be evaluated.  Additional 
information for evaluating each organ system is provided in Appendix I.

12-lead electrocardiogram (ECG) will be recorded.
Screening safety laboratory tests (except for direct antiglobulin test in subjects with CLL) will 
be performed at the designated central laboratory; however, in urgent cases, local laboratory 
results may be used to guide clinical decisions and dose modifications, and, that data must be 
submitted to Celgene in the CRF, and whenever possible, a concurrent sample should be sent to 
the Central Laboratory.  Refer to the Laboratory Manual for sample handling, storage, and 
shipment instructions.  
Screening laboratory values must demonstrate subject eligibility, but may be repeated within the 
screening window, as necessary:  

Hepatitis B virus (HBV) testing 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).  If a subject is anti-HBc positive, the Central Laboratory will 
automatically perform a quantitative polymerase chain reaction test to measure viral 
DNA load. 

Complete blood count (CBC) with absolute differential will include hematocrit, 
hemoglobin, white blood cell count (WBC) with differential, and platelet count. 

Clinical chemistry and other laboratory tests will include albumin, alkaline 
phosphatase, alanine aminotransferase (ALT/SGPT), aspartate transaminase 
(AST/SGOT), bilirubin (total, direct, and indirect), calcium, chloride, creatinine, 
glucose, phosphorous, potassium, sodium, total protein, serum urea/blood urea 
nitrogen (BUN), and uric acid. 

Lactic dehydrogenase will be tested.

Gamma glutamyl transferase, amylase, and lipase will be tested.

Thyroid function tests will include thyroid stimulating hormone (TSH), free 
thyroxine (fT4), and free triiodothronine (fT3).

Calculated creatinine clearance (CrCl) will be estimated using the Cockcroft-Gault 
formula by the Central Laboratory:
CrCl (mL/min) = (140 – age) (weight [kg]) / 72 (serum creatinine [mg/dL]; for 
females, the formula is multiplied by 0.85 (Cockcroft, 1976).
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
Coagulation tests will include prothrombin time, international normalized ratio 
(INR) and partial thromboplastin time (PTT or activated PTT).

Direct antiglobulin test (also known as direct Coombs test) will be performed for 
subjects with CLL (Arms B, C, and D) at site’s local laboratory.

Quantitative immunoglobulins including IgG, IgA, and IgM will be measured.

Biomarker saliva and blood sample(s) will be collected as outlined in Section 6.8.  

Urinalysis (a urine dipstick may be used) will include color, appearance, specific 
gravity, pH, glucose, ketones, blood, bilirubin, and protein. A microscopic 
examination will be performed if urinalysis result is abnormal.

Pregnancy testing (Arms B, C, and D) is required for all females of childbearing 
potential (FCBP).  A urine (or serum) pregnancy tests (with a sensitivity of at least 25 
mIU/mL will be performed to assess subject eligibility at Screening and within 48 
hours prior to the first administration of IP in Arms B, C, and D. Negative results (2 
negative results: one performed during the Screening Visit and one performed within 
48 hours of Cycle 1 Day 1 prior to dosing) are required for IP administration.
Pregnancy testing for subjects receiving lenalidomide (applies to subjects in Arm 
A and subjects in Arm D who will receive subsequent lenalidomide treatment at 
the time of progression): FCBP must have 2 negative urine (or serum) pregnancy tests 
(with a sensitivity of at least 25 mIU/mL) prior to starting lenalidomide. The first 
pregnancy test must be performed within 10 to 14 days and the second pregnancy test 
must be performed within 24 hours prior to first lenalidomide dose. Negative results 
are required for IP administration.

Counseling about pregnancy precautions and the potential risks of fetal 
exposure (applies to all subjects in Arm A and subjects in Arm D who will receive 
additional lenalidomide treatment at the time of progression): must be conducted at 
Screening and before receiving any IP. 
Please consult the Lenalidomide Pregnancy Prevention Risk Management Plan 
(Appendix F) for details.

Biomarker biopsy sample (lymph node or tumor) collection is mandatory from all 
subjects with lymphoma during Screening and must be also submitted to the Central 
Laboratory for biomarker analysis defined in Section 6.8.  
The only exception is that an archival lymph node/tumor formalin-fixed paraffin-
embedded (FFPE) biopsy acquired by a surgical or core needle biopsy within 3 months 
and with no intervening treatment prior to signing informed consent may be acceptable 
for enrollment in subjects with poorly accessible tumor following the discussion with the 
sponsor’s medical monitor.
Subject eligibility will be based on the investigators’ and local pathologists’ assessment 
of the histopathology diagnosis.   

Bone marrow biopsy and aspirate collection during Screening is mandatory from 
subjects with CLL and per investigator’s discretion in subjects with suspected bone 
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marrow involvement by lymphoma.  The samples must be submitted to the Central 
Laboratory for biomarker analysis defined in Section 6.8.  

Computed tomography (CT) scans (neck, chest, and abdomen and pelvis) or 
integrated fluorodeoxyglucose-positron emission tomography with CT (FDG-PET-
CT) (whole body) should be performed during Screening. Please see Section 6.4 for 
further details. 

Adverse event/adverse events of special interest assessment (including SPMs)
begin when the subject signs the informed consent form.

Survival status will be assessed.

Subsequent antilymphoma/anticancer treatments status information will be 
collected.
6.2.
Treatment Period
Subjects will begin treatment following confirmation of eligibility. For all subsequent visits, an 
administrative window of ± 3 days for study Day 1 visits and ± 1 (except for otherwise noted) for 
scheduled interim study visits (eg, Day 18, 15, 22 visits) are allowed.
For subjects on ibrutinib, for all subsequent visits, clinic visits will be in accordance with 
standard of care per the investigator’s discretion. No data will be collected and eCRFs will not be 
completed.  The investigator remains responsible to monitor safety, record adverse events 
(AEs)/serious adverse events (SAEs)/second primary malignancies(SPMs) in source documents, 
and report SAEs and SPMs to Celgene Drug Safety.
Prior to the administration of first dose on Cycle 1 Day 1, the laboratory results must be 
reviewed by the investigator to reconfirm subject eligibility.  If the central safety laboratory 
results are not available for review yet, then the local safety laboratory results can be used to 
reconfirm subject eligibility.  Blood samples for safety laboratories must be always collected and 
submitted to the Central Laboratory according to the schedule in Sections 5 and below.
Subjects who receive lenalidomide should have at least a 7-day rest between two 21-day 
treatment periods and therefore this should be taken into consideration when applying the visit 
window of ± 3 days.
If assessments are performed within 48 hours of Day 1 of each cycle, safety laboratory and 
physical examinations need not be repeated on Day 1.  
Treatment cycles are 28 days in duration and will occur as described in Section 7.2.
Evaluations will be performed at the frequency specified in Section 5. The evaluations should be 
performed prior to dosing on the visit day, unless otherwise specified (such as PK or Pd).
Unscheduled assessments may be performed as clinically indicated (eg, more frequent 
monitoring of relevant blood tests, in case of adverse event, ECG, HBV testing, urinalysis, 
scans), and those visits should be also recorded in the subject’s source documents and CRF.
The following evaluations will be performed as specified in the Table of Events: 

Adverse event assessment/adverse events of special interest (including SPM).
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
Tumor lysis prophylaxis (TLS) is recommended.  Subjects will receive TLS 
prophylaxis or treatment (allopurinol or equivalent as per institutional guidelines) and 
be well hydrated (orally) during the first week of treatment administration in the first 
cycle, or as clinically indicated.  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.  
Please see Section 8.1.7 for further details.

Concomitant medications/procedures evaluation.

Physical examination including evaluation of lymph nodes, spleen and liver will be 
performed.  Documentation of any enlargement of the lymph nodes, spleen and/or 
liver should be recorded in the source document and CRF.

B symptoms including fever greater than 38°C, drenching night sweats, and 
unintentional weight loss of > 10% of normal body weight over a period of 6 months 
or less.

Body weight will be measured.

Body surface area (as required per the site’s local practice for rituximab or
bendamustine).

Vital signs will include blood pressure, pulse, and body temperature.
Subjects will have their blood pressure, pulse and body temperature measured before, during 
and after the infusion at the following times (based on a 60-minute infusion):

At the beginning of the infusion (within an hour prior to start of durvalumab 
administration)

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 after the infusion 
(ie, 90, 120, 150, and 180 minutes from the start of the infusion) (± 5 minutes) –
for the first infusion only and then for subsequent infusions as clinically 
indicated
If the infusion takes longer than 60 minutes, then blood pressure and pulse 
measurements should be collected every 30 minutes (± 5 minutes) and as 
described above or more frequently if clinically indicated.

ECOG Performance Status will be scored according to Table 11.
Safety laboratory tests will be performed at the designated central laboratory; however, in 
urgent cases, local laboratory results may be used to guide clinical decisions and dose 
modifications, and that data must be submitted to Celgene in the CRF, and whenever possible, a 
concurrent sample should be sent to the Central Laboratory.
Refer to the Laboratory Manual for sample handling, storage, and shipment instructions.  
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EDMS Doc. Number: 24715418 - 20540270
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Protocol MEDI4736-NHL-001
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
Complete blood count with absolute differential will include hematocrit, 
hemoglobin, WBC with differential, and platelet count. 

Clinical chemistry and other laboratory tests will include albumin, alkaline 
phosphatase, ALT/SGPT, AST/SGOT, bilirubin (total, direct, and indirect), calcium, 
chloride, creatinine, glucose, phosphorous, potassium, sodium, total protein, serum 
urea/ BUN and uric acid. 

Lactic dehydrogenase will be tested.

Gamma glutamyl transferase, amylase, and lipase will be tested.

Thyroid function tests will include:

Cycles 1 – 4: thyroid stimulating hormone (TSH), free thyroxine (fT4), and free 
triiodothronine (fT3) and

Cycle 6 onward:  TSH, if TSH is abnormal, then reflex testing for fT4 and fT3. 

Coagulation tests will include prothrombin time, international normalized ratio 
(INR) and partial thromboplastin time (PTT or activated PTT).

12-lead ECG will be performed on Cycle 14 Day 1 (as applicable) or at the End of 
Treatment for durvalumab (EOT-D).  

Urinalysis (a urine dipstick may be used) will include color, appearance, specific 
gravity, pH, glucose, ketones, blood, bilirubin, and protein.  A microscopic 
examination will be performed if urinalysis result is abnormal.  This will be 
performed on Cycle 14 Day 1 (as applicable) or at the End of Treatment for 
durvalumab (EOT-D).  

Quantitative immunoglobulins including IgG, IgA, and IgM will be measured on 
Cycle 14 Day 1 (as applicable) or at the End of Treatment for durvalumab (EOT-D).  

Pharmacokinetic, immunogenicity, and biomarker blood sample(s) and tumor 
samples will be collected as outlined in Sections 6.6, 6.7, and 6.8.

Biomarker biopsy sample (lymph node or tumor) collection is strongly 
recommended from all subjects with lymphoma anytime during Cycle 2 for 
biomarker analysis defined in Section 6.8.

Pregnancy test is required for all FCBP subjects. A urine (or serum) pregnancy test 
(with a sensitivity of at least 25 mIU/mL) will be performed within 48 hours prior to 
Day 1 dosing in each cycle (except lenalidomide). Negative results are required for 
IP administration.
Pregnancy testing for lenalidomide (applies to all subjects in Arm A and subjects 
in Arm D who will receive subsequent lenalidomide treatment at the time of 
progression): FCBP must have negative urine (or serum) pregnancy test (with a 
sensitivity of at least 25 mIU/mL) within 24 hours prior to lenalidomide dosing on 
Day 1 of each cycle.  Pregnancy testing will be done weekly in the first cycle. For 
FCBP with irregular menstrual cycles, pregnancy testing will also be performed on 
Day 15 of each cycle. Negative results are required for IP administration.  
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Protocol MEDI4736-NHL-001
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
Lenalidomide Counseling (applies to subjects in Arm A or subjects in Arm D who 
will receive additional lenalidomide treatment at the time of progression): must be
conducted while on treatment, at a minimum of every 28 days for all subjects. Please 
consult the Lenalidomide Pregnancy Prevention Risk Management Plan (Appendix F) 
for details.

Efficacy assessments for lymphoma and CLL (including contrast-enhanced CT 
scans, FDG-PET-CT, bone marrow biopsy and aspirate, and minimal residual disease 
[MRD] assessments for CLL, MCL, and FL) are described in detail in Section 6.4.

Interactive response technology registration.

Addition of combination agent or local IFRT to durvalumab monotherapy at the 
time of progression:
For subjects in the monotherapy arm, Arm D, at the time of disease progression, the 
investigator may add study treatments previously investigated once a dose level of a 
relevant combination therapy is deemed as tolerable by the dedicated SRC (ie, rituximab 
± either lenalidomide* or bendamustine; or monotherapy ibrutinib), or local IFRT with 
durvalumab, if subjects meet the criteria defined in Section 3.1.2.  
The add-on combination treatment with lenalidomide ± rituximab is no longer 
allowed.*
Subjects who receive a combination agent other than local IFRT will follow the visit 
schedules and assessments specific to each combination agent (eg, the Arm A visit 
schedule and assessments starting from Cycle 1 Day 1 will be followed by subjects who 
receive lenalidomide and rituximab in addition to durvalumab*).  Those subjects will be 
treated according to the treatment schedules described for each arm in Section 7.2 based 
on the investigator’s medical judgment.  Pharmacokinetic samples for durvalumab will be 
collected following the addition of a combination agent.  No PK samples for 
lenalidomide or ibrutinib will be collected. 
Subjects who receive local IFRT, 2 Gy on each of 2 consecutive days to one tumor site,
as additional therapy will continue to follow the Arm D schedule.  Following IFRT, 
subjects will receive durvalumab for up to an additional 6 cycles (eg, if a subject receives 
local IFRT following disease progression documented at the end of Cycle 13, he/she may 
receive 6 additional durvalumab doses, up to Cycle 19), or will complete the remaining 
scheduled durvalumab doses (ie, 13 cycles) based on the investigator’s medical 
judgment.  
The sponsor’s medical monitor should be contacted prior to adding a combination agent 
to durvalumab. 

Survival status will be assessed.

Subsequent antilymphoma/anticancer treatments status information will be 
collected.
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6.2.1.
End of Treatment
An end of all treatment (EOT) evaluation will be performed for subjects who are withdrawn 
from treatment for any reason as soon as possible after the decision to permanently discontinue 
treatment has been made.  
In Arm A (indolent lymphoma), Arm C, and Arm D, the EOT for all study treatments and the 
EOT-D will be the same visit unless subjects discontinue durvalumab treatment (earlier than 
Cycle 13) due to toxicity.  Please see Table 7, Table 8, Table 9, and Table 10.   
In Arm A (aggressive lymphoma) and Arm B, EOT visit for all study treatments will occur after 
EOT-D which is expected to be the same visit with Cycle 14 Day 1 as the combination treatment 
(ie, lenalidomide or ibrutinib) may continue beyond Cycle 13 (last scheduled durvalumab dose) 
until disease progression, unacceptable toxicity, starts new therapy, or discontinuation for any 
other reason, ie, subject withdraws consent or discontinues per investigator’s discretion.  A few 
assessments such as 12-lead ECG, quantitative immunoglobulins, urinalysis, the laboratory tests 
including gamma glutamyl transferase, amylase, lipase, TSH, fT4, and fT3, coagulation, and 
immunogenicity assessment will be performed at the EOT-D visit.  Please see Table 7 and
Table 8.
The following evaluations will be performed as specified in the Table of Events in Section 5:

Adverse event assessment/adverse events of special interest (including SPM).

Concomitant medications/procedures evaluation.

Physical examination including evaluation of lymph nodes, spleen and liver will be 
performed.  Documentation of any enlargement of the lymph nodes, spleen and/or 
liver should be recorded in the source document and CRF.

B symptoms including fever greater than 38°C, drenching night sweats, and 
unintentional weight loss of > 10% of normal body weight over a period of 6 months 
or less.

Body weight will be measured.

Vital signs will include blood pressure, pulse, and body temperature.

ECOG Performance Status will be scored according to Table 11.

12-lead electrocardiogram will be recorded (only at EOT-D).
Safety laboratory tests will be performed at the designated central laboratory; however, in 
urgent cases, local laboratory results may be used to guide clinical decisions and dose 
modifications, and, that data must be submitted to Celgene in the CRF, and whenever possible, a 
concurrent sample should be sent to the Central Laboratory.
Refer to the Laboratory Manual for sample handling, storage, and shipment instructions.  

Complete blood count with absolute differential will include hematocrit, 
hemoglobin, WBC with differential, and platelet count. 

Clinical chemistry and other laboratory tests will include albumin, alkaline 
phosphatase, ALT/SGPT, AST/SGOT, bilirubin (total, direct, and indirect), calcium, 
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chloride, creatinine, glucose, phosphorous, potassium, sodium, total protein, serum 
urea/ BUN and uric acid. 

Lactic Dehydrogenase will be tested.

Gamma glutamyl transferase, amylase, and lipase will be tested.

Thyroid function tests will include TSH, if TSH is abnormal, then reflex testing for 
fT4 and fT3 (only at EOT-D). 

Coagulation tests will include prothrombin time, international normalized ratio 
(INR) and partial thromboplastin time (PTT or activated PTT) (only at EOT-D).

Quantitative immunoglobulins including IgG, IgA and IgM will be measured (only 
at EOT-D).

Immunogenicity, and biomarker blood sample(s) and tumor samples will be 
collected as outlined in Sections 6.6, 6.7, and 6.8 (only at EOT-D).  

Urinalysis (a urine dipstick may be used) will include color, appearance, specific 
gravity, pH, glucose, ketones, blood, bilirubin, and protein. A microscopic 
examination will be performed if urinalysis result is abnormal.

Pregnancy testing is required for all FCBP subjects.  A urine (or serum) pregnancy 
test (with a sensitivity of at least 25 mIU/mL) will be performed at EOT and 28 days 
after the last dose of study treatment and 90 days after the last dose of durvalumab. 

Pregnancy testing for FCBP subjects with irregular menstrual cycles receiving 
lenalidomide (applies to all subjects in Arm A and subjects in Arm D who will 
receive subsequent lenalidomide treatment at the time of progression): A urine (or 
serum) pregnancy test (with a sensitivity of at least 25 mIU/mL) will be performed at 
EOT, 14 and 28 days after the last dose of lenalidomide.

Lenalidomide Counseling (applies to all subjects in Arm A and subjects in Arm D 
who will receive additional lenalidomide treatment at the time of progression): must 
be conducted. Please consult the Lenalidomide Pregnancy Prevention Risk 
Management Plan (Appendix F) for details.

Efficacy assessments for lymphoma and CLL (including contrast-enhanced CT 
scans, FDG-PET-CT, bone marrow biopsy and aspirate, and immunophenotyping of 
blood for circulating CLL cells by multiparameter flow cytometry) are described in 
detail in Section 6.4.

Interactive response technology registration (refer to the IRT Manual).

Survival status will be assessed.

Subsequent antilymphoma/anticancer treatments status information will be 
collected.
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6.3.
Follow-up Period 
6.3.1.
Safety Follow-up
All subjects will be followed for AEs (including SAEs and SPMs) and concomitant medications/
procedures for 90 days after the last dose of durvalumab or 28 days after the last dose of other 
study treatment(s), whichever occurs later.  Physical examination for lymphadenopathy and 
organomegaly, B symptoms, vital signs, CBC with differential, biochemistry including LDH test, 
thyroid function tests (TSH, if TSH is abnormal, then reflex testing for fT4 and fT3), 
coagulation, and pregnancy test will be performed according to the Table of Events in Section 5.
The subjects who have received lenalidomide (ie, Arm A or subjects or Arm D who have 
received lenalidomide at the time of progression) will be followed for SPM for up to five years 
from the last subject’s first lenalidomide dose.  Once the subjects complete the efficacy follow-
up described below, the SPM follow up may be via telephone and not require site visit.
6.3.2.
Efficacy (Long Term) Follow-Up
The Follow-up Period begins upon all study treatment discontinuation or completion as per 
protocol.  This includes subjects who complete the full course of treatment, who discontinue 
treatment due to progression or toxicity, as well as those who discontinue before progression to 
pursue a new antilymphoma/CLL therapy.  
Subjects will be followed for first progression, subsequent antilymphoma/CLL therapy, and 
overall survival.  Therefore, efficacy assessments will continue at the protocol specified time 
points until disease progression, withdrawal of ICF, subsequent antilymphoma/CLL treatment, or 
up to 24 months from subject’s last durvalumab dose. In addition, physical examination for 
lymphadenopathy and organomegaly, and CBC with differential and biochemistry including 
LDH test, will be repeated at the same time with the efficacy assessments according to the 
schedule described in Section 6.4.
Following the first documented progression, subjects will be followed for subsequent 
antilymphoma/CLL therapy and overall survival every 6 months until withdrawal of ICF, or up 
to 24 months from the subject’s last durvalumab dose. This follow-up may be via telephone and 
not require site visit.
Following completion or discontinuation of durvalumab treatment per protocol for all subjects 
and completion of the primary analysis (data cutoff date 06 Mar 2019), subjects are no longer 
required to be followed for disease progression, subsequent antilymphoma/CLL therapy, and 
overall survival. Follow-up procedures, efficacy assessments, central labs, imaging, and survival 
data will no longer be collected in the case report forms (CRFs).  
In Arm B, subjects receiving benefit from ibrutinib may continue to receive ibrutinib on-study 
per investigator’s medical judgement or discontinue study to receive ibrutinib commercially as 
standard of care treatment (off-study). Subjects who continue ibrutinib on-study will be treated 
per investigator’s medical judgement and in accordance with standard of care. 
6.4.
Efficacy Assessments
Efficacy response assessment for this study will be based on: 
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
Recommendations for Initial Evaluation, Staging, and Response Assessment of 
Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification (Cheson, 2014) 
(Appendix B) for subjects with lymphoma.

IWCLL Response Criteria for CLL (Hallek, 2008; Hallek, 2012; Hallek, 2013) 
(Appendix C) for subjects with CLL.
The following efficacy assessments will be performed at scheduled intervals throughout the 
study as described in the Table of Events in Section 5.
Scans previously acquired as standard of care within 28 days prior to Cycle 1 Day 1 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.
In this study, all tumor assessments will be performed by the investigator.  There is no Central 
Radiology.  However, tumor assessment data including images should be made available to the 
medical monitor or designee upon request.  Once a subject has experienced confirmed 
progression, no further scans are required.
6.4.1.
Efficacy Assessments in Lymphoma
For lymphoma, disease response to treatment is determined by the Lugano Classification 
including a careful review of imaging and laboratory studies and clinical findings. 
Integrated PET-CT is preferred for response assessment of FDG-avid lymphomas (eg, DLBCL, 
HL, FL, transformed large cell lymphoma, Richter’s transformation, PMBCL, T-cell/histiocyte 
rich large B-cell lymphoma, or ALK-positive large B-cell lymphoma), while dedicated CT scan 
alone is preferred for FDG-non-avid and variably FDG-avid histologies (eg, CLL/SLL, MZL).
6.4.1.1.
CT Scans of the Neck, Chest, Abdomen, and Pelvis (Lymphoma)
Contrast-enhanced CT scan alone is the primary modality for baseline staging and response 
assessment of FDG-non-avid and variably FDG-avid histologies.  Magnetic resonance imaging 
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.
The same imaging modality (eg, CT or MRI) and technique (eg, use of contract, slice thickness 
for scans) should be used throughout the study.  
The CT scan will be performed at:

Screening (within 28 days of Cycle 1 Day 1);

Cycles 4, 7, and 10 Day 1 (± 7 days);

End of durvalumab treatment (EOT-D)/Cycle 14 Day 1 (± 7 days); and

Every 6 cycles/months (± 7 days) thereafter.
Following completion of treatment or discontinuation treatment for any reason other than disease
progression, the CT scan assessment will continue until disease progression, subsequent 
antilymphoma/CLL treatment or withdrawal of consent in the Follow-up period (ie, up to 24 
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months from the subject’s last durvalumab dose) based on the schedule above. Unscheduled 
tests may be ordered at any time as clinically indicated.
Following completion of the primary analysis (data cutoff date 06 Mar 2019), CT scan 
assessments are no longer required to be collected in the CRFs. Subjects who continue to receive 
ibrutinib on-study will be treated per investigator’s medical judgement.
6.4.1.2.
FDG-PET-CT Scan (Whole Body) (Lymphoma)
Separate PET scans using 18F-fluorodeoxyglucose (18F-FDG) plus separate dedicated CT scans 
or integrated FDG-PET-CT are preferred for FDG-avid lymphomas (eg, DLBCL, HL, FL, 
transformed large cell lymphoma, Richter’s transformation, PMBCL, T-cell/histiocyte rich large 
B-cell lymphoma, or ALK-positive large B-cell lymphoma).  
FDG-PET-CT scans should be performed at: 

Screening (strongly recommended) (within 28 days of Cycle 1 Day 1) Any time 
during the study (within 14 days following demonstration of nodal CR by CT scan 
alone) to confirm CR by CT scan alone
Interim dedicated CT scans will be done at Cycles 4, 7, 10, or Cycle 14 Day 1/end of 
durvalumab treatment (EOT-D)/ (± 7 days) (please see Section 6.4.1.1).
FDG-PET-CT scans are optional at all other response assessment time points.
A positive 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 (please see Appendix B). 
A dedicated contrast-enhanced CT scan may be required in addition to the FDG-PET-CT 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.
6.4.1.3.
Bone Marrow Biopsy and Aspirate (Lymphoma)
Bone marrow biopsy (BMB) and aspirate to evaluate marrow disease (at site’s local pathology 
laboratory) and biomarker and/or MRD studies in FL and MCL (at designated analytical 
laboratories) will be performed at:

Screening (within 12 weeks of Cycle 1 Day 1) in subjects with suspected bone 
marrow involvement by lymphoma as per investigator’s discretion;

Any time necessary to confirm CR (within 28 days of meeting the criteria for nodal 
CR by CT (non-FDG-avid histologies) or FDG-PET-CT (in FDG-avid histologies)
scan alone except in subjects with no evidence of lymphomatous marrow 
involvement performed during screening.
Note: If an FDG-PET-CT is performed and confirms FDG-negative CR, no BMB and/or aspirate 
is required for subjects with aggressive lymphoma histologies (eg, DLBCL, HL).
If an archival specimen is not available or is not acceptable, a rebiopsy is required prior to Cycle 
1 Day 1. 
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6.4.1.4.
Minimal Residual Disease (MCL and FL)
Minimal residual disease will be assessed in subjects with MCL and FL by the designated central 
analytical laboratory.
The MRD in MCL will be monitored for clearing of CD19+, CD5+, and CD23- MCL cells by 
sensitive multiparameter flow cytometry.
The MRD in FL will be monitored for Bcl-2 by polymerase chain reaction (PCR) to see if there 
are any residual cells containing 14; 18 translocations.
From subjects with MCL or FL: 

Collect and submit a pretreatment blood sample for MRD on Cycle 1 Day 1

Confirm PET-negative CR and then:

In subjects with no evidence of lymphomatous marrow involvement documented 
at screening:

Collect and submit a blood sample and a bone marrow aspirate sample for 
MRD assessment (within 28 days of meeting the criteria for PET-negative 
CR)

Collect and submit repeat blood and bone marrow aspirate samples (as 
available) every 3 cycles while on treatment and every 6 months in the 
Follow-up Period until evidence of clinical disease progression during the 
study

In subjects with lymphomatous bone marrow involvement documented or no bone 
marrow biopsy performed at Screening:

Collect and submit bone marrow biopsy and aspirate samples to site’s local 
pathology laboratory to confirm no lymphomatous marrow involvement 
(within 28 days of meeting the criteria for PET-negative CR) (see Section 
6.4.1.3).  At the same time, collect and submit a blood and bone marrow 
aspirate sample for MRD assessment.

If CR is confirmed by no evidence of lymphomatous bone marrow 
involvement by site’s local pathology assessment, then collect and submit 
repeat blood and bone marrow samples (as available) every 3 cycles while on 
treatment and every 6 months in the Follow-up Period until evidence of 
clinical disease progression during the study

If CR based on imaging is not confirmed by BM examination, then no 
additional MRD samples will be collected.
6.4.2.
Efficacy Assessments in CLL
For CLL, disease response to treatment is determined based on the IWCLL Response Criteria 
including a careful review of laboratory and imaging studies as well as clinical findings. 
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6.4.2.1.
CT Scans of the Neck, Chest, Abdomen, and Pelvis (CLL)
Contrast-enhanced CT scans of the neck, chest, abdomen, and pelvis must be performed for all 
subjects with CLL.  Magnetic resonance imaging may be used only when CT with contrast is 
medically contraindicated or when the frequency of CT scans exceeds local standards. The same 
imaging modality should be used throughout the study.  Ultrasound is not an acceptable imaging 
modality for this study. 
The same imaging modality (eg, CT or MRI) and technique (eg, use of contract, slice thickness 
for scans) should be used throughout the study.  
The CT scans will be performed at:

Screening (within 28 days of Cycle 1 Day 1);

Cycle 7 Day 1 (± 7 days) is required for only affected regions with abnormal findings 
at baseline; and

Any time necessary to confirm suspected CR (by clinical [physical examination or 
symptoms] and CBC-based) (within 8 weeks after clinical and CBC-based CR)
(recommended unless its frequency exceeds local standards).
Additional CT scans are allowed as clinically indicated until disease progression, subsequent 
antilymphoma/CLL treatment, or withdrawal of consent in the Follow-up Period.  
Unscheduled tests may be ordered at any time as clinically indicated.
6.4.2.2.
Bone Marrow Biopsy and Aspirate (CLL)
Bone marrow biopsy (BMB) and aspirate to evaluate marrow disease (at site’s local laboratory)
and tumor microenvironment and/or MRD (at designated analytical laboratories) (biomarker 
analysis; please see Section 6.8) will be performed at:

Screening;

Cycles 7 Day 1 (± 7 days);

End of durvalumab treatment (EOT-D)/Cycle 14 Day 1 (± 7 days);

Any time necessary to confirm suspected CR (by clinical [physical examination or 
symptoms], CBC-based, and imaging assessments) (within 12 weeks); and

To evaluate cytopenia of uncertain cause (as clinically indicated).
6.4.2.3.
Minimal Residual Disease (Immunophenotyping of Blood for Circulating CLL 
Cells by Multiparameter Flow Cytometry) (CLL)
Minimal residual disease will be assessed in subjects with CLL by the designated central 
analytical laboratory.
From subjects with CLL (excluding SLL):

Collect and submit a pretreatment blood sample for MRD assessment on Cycle 1 
Day 1 
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
Collect and submit a blood sample for MRD assessment within 14 days of meeting 
the criteria for suspected CR by clinical, CBC-based, and imaging assessments

Collect and submit bone marrow biopsy and aspirate samples to site’s local pathology 
laboratory to confirm bone marrow recovery (within 12 weeks of meeting the criteria 
for suspected CR) (see Section 6.4.2.2). At the same time, collect and submit a blood 
and bone marrow aspirate sample for MRD assessment.

Collect and submit repeat blood and bone marrow aspirate samples (as available) 
every 3 cycles while on treatment and every 6 months in the Follow-up Period from 
subjects with CR/CRi until evidence of clinical disease progression during the study.
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; serum immunoglobulins; concomitant 
medications, therapies, and procedures; pregnancy testing (for FCBP only); and ECG.
Safety assessments will be performed during screening and will be repeated weekly in Cycle 1, 
bi-weekly in Cycles 2 through 4 in Arms A, B, D or Cycles 2 through 6 in Arm C, and once 
every 4 weeks thereafter for all arms. 
For subjects continuing on ibrutinib, clinic visits will be in accordance with standard of care per 
the investigator’s discretion.
The investigator remains responsible to monitor safety, record adverse events (AEs)/serious 
adverse events (SAEs)/second primary malignancies(SPMs) in source documents, and report 
SAEs and SPMs to Celgene Drug Safety.
Adverse event assessment begins when the subject signs the ICF.
Please see Section 10 for definition of AE and SAE.
6.6.
Pharmacokinetics
Pharmacokinetic assessments for durvalumab, lenalidomide and ibrutinib are mandatory and will 
be performed for all subjects enrolled into the study.
If PK samples collected from Phase 1 can achieve PK objective(s), no further PK sampling may 
be collected in the Phase 2 portion of the study.
On PK sampling days, dosing and sample collection information including dosing date, dosing 
time (24-hour clock), and actual PK blood sampling time (24-hour clock) should be accurately 
documented on the appropriate CRF pages.
6.6.1.
Pharmacokinetics of Durvalumab (All Arms)
Pharmacokinetic sampling will be performed for all subjects receiving durvalumab (including 
those subjects in Arm D who will receive additional combination treatment following disease 
progression).  The sampling time points will be as follows:
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Table 12:
Pharmacokinetic Sample Collection Timepoints (All Arms)
Cycle
Day
Time Point
1
1
Pre-durvalumab infusion (-4 hours to -5 minutes prior to durvalumab dose)
1
1
End of durvalumab infusion (EOI) (± 15 minutes)
1
1
4 hours post EOI (± 1 hour)
1
2
24 hours post EOI (± 8 hours)
1
3
48 hours post EOI (± 8 hours)
1
8
168 hours post EOI (± 24 hours)
1
15
336 hours post EOI (± 24 hours)
1
22
504 hours post EOI (± 24 hours)
2
1
Pre-durvalumab infusion (-4 hours to -5 minutes prior to durvalumab dose)
2
1
End of durvalumab infusion (EOI) (± 15 minutes)
2
1
4 hours post EOI (± 1 hour)
Table 12:
Pharmacokinetic Sample Collection Timepoints (All Arms) (Continued)
Cycle
Day
Time Point
2
15
336 hours post EOI (± 24 hours)
4
1
Pre-durvalumab infusion (-4 hours to -5 minutes prior to durvalumab dose)
6
1
Pre-durvalumab infusion (-4 hours to -5 minutes prior to durvalumab dose)
10
1
Pre-durvalumab infusion (-4 hours to -5 minutes prior to durvalumab dose)
14/EOT-D
1
Pre-durvalumab infusion (-4 hours to -5 minutes prior to durvalumab dose)
Abbreviation: EOI = end of infusion; EOT-D = end of treatment of durvalumab.
6.6.2.
Pharmacokinetics of Lenalidomide (Arm A Only)
PK sampling will be performed for all subjects enrolled in Arm A receiving lenalidomide
(excluding those subjects in Arm D who will receive lenalidomide as additional add-on 
combination treatment following disease progression).  The sampling time points will be as 
follows:
Table 13:
Pharmacokinetic Sample Collection Timepoints (Arm A Only)
Cycle
Day
Time Point
1
1
Pre-lenalidomide (-4 hours to -5 minutes prior to lenalidomide dose)
1
1
1 hour (± 10 minutes) post-lenalidomide dose
1
1
2 hours (± 10 minutes) post-lenalidomide dose
1
1
4 hours (± 10 minutes) post-lenalidomide dose
1
2
24 hours (± 2 hours) post-lenalidomide dose
1
15
Pre-lenalidomide 4 hours to -5 minutes prior to lenalidomide dose)
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1
15
1 hour (± 10 minutes) post-lenalidomide dose
1
15
2 hours (± 10 minutes) post-lenalidomide dose
1
15
4 hours (± 10 minutes) post-lenalidomide dose
6.6.3.
Pharmacokinetics of Ibrutinib (Arm B only)
PK sampling will be performed for all subjects enrolled in Arm B receiving ibrutinib (excluding 
those subjects in Arm D who will receive ibrutinib as additional add-on combination treatment 
following their infusion).  The sampling time points will be as follows:
Table 14:
Pharmacokinetic Sample Collection Timepoints (Arm B only)
Cycle
Day
Time point
1
1
Pre-ibrutinib (-4 hours to -5 minutes prior to ibrutinib dose)
1
1
1 hour (± 10 minutes) post-ibrutinib dose
1
1
2 hours (± 10 minutes) post-ibrutinib dose
Table 14:
Pharmacokinetic Sample Collection Timepoints (Arm B only) (Continued)
Cycle
Day
Time point
1
1
4 hours (± 10 minutes) post-ibrutinib dose
1
2
24 hours (±2 hours) post-ibrutinib dose
1
15
Pre-ibrutinib (-4 hours to -5 minutes prior to ibrutinib dose)
1
15
1 hour (± 10 minutes) post-ibrutinib dose
1
15
2 hours (± 10 minutes) post-ibrutinib dose
1
15
4 hours (± 10 minutes) post-ibrutinib dose
6.7.
Immunogenicity
Immunogenicity samples will be collected from all subjects receiving durvalumab (all 4 
treatment arms - including those subjects in Arm D who will receive additional add-on 
combination treatment following disease progression).
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 stored, and ADA will be explored using the stored samples.  The sampling time 
points will be as follows:
Table 15:
Immunogenicity Sample Collection Timepoints
Cycle
Day
Time Point
1
1
Pre-durvalumab infusion
2
1
Pre-durvalumab infusion
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Cycle
Day
Time Point
4
1
Pre-durvalumab infusion
6
1
Pre-durvalumab infusion
10
1
Pre-durvalumab infusion
14/EOT-D
1
Pre-durvalumab infusion
Abbreviations: EOT-D = end of treatment of durvalumab.
6.8.
Biomarkers, Pharmacodynamics, Pharmacogenomics 
Saliva, blood, bone marrow biopsy and aspirate (subjects with CLL and, if available, 
lymphoma), and tumor tissue biopsies will be collected and analyzed to evaluate protein, nucleic 
acid and cellular biomarkers that relate to durvalumab, combination treatment, and disease 
according to the schedule presented in Table 7, Table 8, Table 9, and Table 10.
6.8.1.
Tumor Tissue Biopsy for Biomarker Assessments (Lymphoma)
The collection of tumor tissue is mandatory in subjects with lymphoma.  The tumor biopsy will 
be collected either by tumor excision, incision, or multiple core needles (4 passages preferred)
and submitted to the Central Laboratory in order to evaluate tumor microenvironment as well as
to identify potential predictive/Pd biomarkers.
Table 16:
Tumor Tissue Biopsy Collection Timepoints for Biomarkers
Timepoints
Window
Requirement
Screening
a
Within 28 days of 
Cycle 1 Day 1
Mandatory
Any time during Cycle 2
-
Strongly recommended
At the time of PD in subject who
achieved objective responses (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)
Abbreviations: CR = complete response, PD = progressive disease, PR = partial response.
a An archival lymph node/tumor formalin fixed paraffin embedded (FFPE) biopsy sample acquired by a surgical or 
core needle biopsy within 3 months prior to signing informed consent and with no intervening treatment after the 
biopsy may be acceptable for enrollment of a subject with poorly accessible tumor following the discussion with 
the sponsor’s medical monitor. The discussion must take place prior to Screening (strongly recommended) 
or during Screening.
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.
Fine needle aspiration is not sufficient as a source of tumor biopsy material.  
Refer to the Laboratory Manual for sample collection and processing instructions.  
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6.8.2.
Bone Marrow Biopsy and Aspirate for Biomarker Assessments
Bone marrow biopsy and aspirate samples will be collected from subjects with CLL and from 
subjects with lymphoma (as available) to investigate tumor-immune microenvironment and other 
molecular markers associated with disease or response at the following time points below.  The 
samples will be analyzed at designated analytical laboratories for biomarkers.  
The assessments for bone marrow disease should be performed at site’s local pathology 
laboratories.
Table 17:
Bone Marrow Biopsy and Aspirate Collection Timepoints for Biomarkers -
CLL
Timepoints
Window
Requirement
Screening
Within 28 days of 
Cycle 1 Day 1
Mandatory
Cycle 7 Day 1
± 7 days
Mandatory
End of durvalumab treatment
(EOT-D)/Cycle 14 Day 1
± 7 days
Mandatory
Table 17:
Bone Marrow Biopsy and Aspirate Collection Timepoints for Biomarkers -
CLL (Continued)
Timepoints
Window
Requirement
To confirm suspected CR (by clinical, 
laboratory [including peripheral blood 
flow-negativity], and imaging 
assessments)
Within 12 weeks 
of suspected CR
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)
Abbreviations: CR = complete response, EOT-D = end of treatment – durvalumab
Table 18:
Bone Marrow Biopsy and Aspirate Collection Timepoints for Biomarkers -
Lymphoma
Timepoints
Window
Requirement
Screening
Within 12 weeks 
of Cycle 1 Day 1
If collected, submit to the Central 
Laboratory 
Nodal CR by CT or FDG-PET-CT alone
Within 4 weeks of 
nodal CR
If collected, submit to the Central 
Laboratory
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)
Abbreviations: CR = complete response; CT= computerized tomography; FDG= fluorodeoxyglucose; PET= 
positron emission tomography 
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In addition, it is strongly recommended to submit to the Central Laboratory any archival bone 
marrow biopsy samples collected prior to study entry or during the study at time points other 
than described above for biomarker analysis.
6.8.3.
Saliva and Blood Samples for Biomarker Assessments
A saliva sample for biomarkers will be collected at Screening.
Blood samples for biomarkers will be collected to analyze Pd/predictive/disease markers at the 
following time points:

Screening;

Cycle 1: Days 1, 8, and 15 (all predose, as applicable)

Cycle 2: Days 1 and 15 (all predose, as applicable)

Cycle 3: Day 15 (predose, as applicable) 

Cycle 4: Day 15 (predose, as applicable)

EOT-D/Cycle 14 Day 1 (predose, as applicable)
The type of samples which should be collected on each time point is listed in the Table of Events 
in Section 5.
Please refer to Sections 6.4.1.4 and 6.4.2.3 for the MRD monitoring in MCL, FL, and CLL.
Details for sample collection, processing, storage, and shipment will be provided in the 
Laboratory Manual.
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7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Product(s)
Investigational product supply will be managed by IRT. All IPs (except local IFRT) must be 
stored in accordance with the product label in a secured area to prevent unauthorized access.  
The IP (except local IFRT) will be labeled as per local regulations.  
7.1.1.
Durvalumab
Durvalumab (MEDI4736) will be supplied by Celgene in single use vials in single count cartons.
Each 10R 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.

Sites 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 -
0.22 μm in-line filter.  
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 be supplied as labeled blister cards. Lenalidomide should be stored 
in accordance to the product label. Lenalidomide should be stored in accordance to the product 
label. 
No new subjects are to be treated in combination with durvalumab plus lenalidomide with 
or without rituximab (Arm A). Subjects already enrolled and treated in Arm A who are 
receiving clinical benefit, based on the discretion of the investigator, may continue study 
treatment after being reconsented. 
For additional information on preparation and storage, please refer to the Pharmacy Manual. 
7.1.3.
Rituximab
Rituximab will be supplied outside the US by Celgene and labeled appropriately as 
investigational material for the study. For the US, rituximab will not be supplied by the sponsor; 
instead, it will be obtained according to local clinical study agreement and in accordance with 
local guidelines.  
Depending on local guidelines, this protocol allows the use of:
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
Rituximab IV standard infusion time

Rituximab IV biosimilars

Rituximab subcutaneous (1400 mg/11.7 mL fixed dose in FL or DLBCL;  and 1400 
mg/11.7 mL fixed dose at Cycle 1 followed by 1600 mg/13.4 mL fixed dose at Cycle 2 
onward  in CLL/SLL)
It is acceptable to use dose banding for rituximab or BSA capping at 2.0 mg/m2 as per local 
practice.
Please refer to the locally approved rituximab label or Pharmacy Manual for preparation, 
administration, or storage information. 
For additional information on preparation and storage, please refer to the Pharmacy Manual. 
7.1.4.
Ibrutinib
Ibrutinib will be supplied outside the US by Celgene and labeled appropriately as investigational 
material for the study.  For the US, ibrutinib will not be supplied by the sponsor; instead it will 
be obtained according to local clinical study agreement and in accordance with local guidelines.
Ibrutinib will be supplied as 140 mg capsules or 140 mg tablets.
For additional information on preparation and storage, please refer to the Pharmacy Manual. 
7.1.5.
Bendamustine
Bendamustine will be supplied outside the US by Celgene and labeled appropriately as 
investigational material for the study.  For the US, bendamustine will not be supplied for its 
approved indications by the sponsor; instead it will be obtained according to the local clinical 
study agreement and in accordance with local guidelines.
Bendamustine will be supplied in appropriate strengths in vial as injection solution and/or 
lyophilized powder for injection.
For additional information on preparation and storage, please refer to the Pharmacy Manual. 
7.1.6.
Local Involved Field Radiation Therapy
Local involved field radiation (IFRT) therapy may be added based on 2 Gy on each of 
2 consecutive days to one tumor site in subjects who have with at least 1 measurable lesion 
(> 1.5 cm and outside of the involved field that will be irradiated) at the time of disease 
progression in Arm D (durvalumab monotherapy). This therapy will be provided at the sites.
Following IFRT, the subject will receive monthly durvalumab doses for up to 6 cycles based on 
investigator’s medical judgment.
7.2.
Treatment Administration and Schedule
Subjects who are eligible will be assigned to one of the following arms (depending on the study 
part):

Arm A: durvalumab and lenalidomide ± rituximab (this arm is discontinued to the 
enrollment of new subjects; subjects already enrolled and treated who are 
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receiving clinical benefit, based on the discretion of the investigator, may 
continue study treatment after being reconsented)

Arm B: durvalumab and ibrutinib 

Arm C: durvalumab and rituximab ± bendamustine

Arm D: durvalumab (monotherapy)
7.2.1.
Dose Finding Cohorts (Phase 1)
The following dose finding cohorts are planned.
Table 19:
Planned Dose Finding Cohorts
Treatment Arm
Eligible Histologies
Arm A
a
(discontinued to the enrollment of new subjects)
R/R B-Cell NHL
Arm B
R/R B-cell NHL
R/R CLL
Arm C
R/R B-cell NHL
R/R CLL
Arm D
No dose finding cohort
Abbreviations: CLL = chronic lymphocytic leukemia; NHL = non-hodgkin lymphoma;
R/R = relapsed/refractory, SLL = small lymphocytic lymphoma.
a Arm A will exclude the subjects with CLL or SLL.
7.2.1.1.
Arm A: Durvalumab and Lenalidomide ± Rituximab (Discontinued to the 
Enrollment of New Subjects)
Subjects assigned to Arm A will receive: 

Durvalumab (IV) infusion on Day 1 of Cycles 1 through 13 (ie, 12 months);

Lenalidomide (PO) once daily on Days 1 to 21 (inclusive) of:

Cycles 1 through 13 in indolent NHL (ie, FL or MZL) or

All cycles of treatment period until disease progression, unacceptable toxicity, or 
discontinuation for any other reason in aggressive NHL (eg, DLBCL); and

Rituximab (IV) infusion:

Rituximab Schedule 1 (dose levels 2 and -1B): on Days 2, 8, 15 and 22 of Cycle 1 
and on Day 1 from Cycles 2 through 5

Rituximab Schedule 2 (dose levels -2 and -3): on Day 2 of Cycle 1 and on Day 1
from Cycles 2 through 8
All treatment cycles are 28 days.  Durvalumab infusion will be administered before any other IP
on the days which more than one investigational treatment should be given (eg, Day 1 of Cycles 
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1 through 13), and then lenalidomide administration and rituximab infusion are recommended to
follow, respectively.
Initial cohorts of 3 subjects will be treated at dose levels listed on Table 20.  If one DLT occurs 
in the first 3-subject cohort at a dose level during the DLT observation period (ie, from the time 
of the first IP dose through completion of Cycle 1), that cohort will enroll up to 6 subjects.  Even 
in the absence of a DLT, additional subjects may be evaluated within a dose cohort if 
recommended by the SRC to adequately evaluate the safety or treatment effects of durvalumab in 
combination with lenalidomide and/or rituximab (depending on dose level).
If dose level 1 is found to be the NTD, dose level -1A and dose level -1B may be explored at the 
discretion of the SRC. The SRC may decide to explore subsequent dose levels if dose level 2 is 
found to be NTD.  
The dose finding flow in Arm A is illustrated in Figure 4.
Table 20:
Dose Finding: Arm A Dose Levels (Discontinued to the Enrollment of New 
Subjects)
Dose Level
Durvalumab (IV)
Lenalidomide (PO)
Rituximab (IV)
(Schedule 1)
Rituximab (IV)
(Schedule 2)
-3
1500 mg
10 mg
-
375 mg/m2
-2
1500 mg
15 mg
-
375 mg/m2
-1B
1500 mg
10 mg 
375 mg/m2
-
-1A
1500 mg
10 mg 
-
-
1 (starting)
1500 mg
20 mg 
-
-
2
1500 mg
20 mg
375 mg/m2
-
Schedule
(28-day 
cycle)
Day 1 of Cycles 1-
13 
Once daily (QD) on 
Days 1-21 
-Up to 12 months in 
FL or MZL
-Up to disease 
progression in 
aggressive histologies
Weekly × 4 in 
Cycle 1 (Days 2, 8 
15, & 22) and Day 
1 of Cycles 2-5 
Day 2 of Cycle 1 
and Day 1 of 
Cycles 2- 8 
Abbreviations: IV = intravenous; PO = orally; QD = once daily.
7.2.1.1.1. Arm A: Durvalumab Administration (Discontinued to the Enrollment of New 
Subjects)
Durvalumab at a fixed dose of 1500 mg will be administered as an IV infusion (250 mL) over 
approximately one hour in duration on Day 1 of Cycles 1 through 13.
Durvalumab infusion will be administered before any other IP on Day 1.  Please refer to the 
Pharmacy Manual for dose preparation and administration guidance.
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7.2.1.1.1.1. Durvalumab Dose Administration 
Durvalumab must be administered at room temperature by controlled infusion via an infusion 
pump into a peripheral vein or central line. Please see the Pharmacy Manual for further details.
7.2.1.1.1.2. Monitoring of Dose Administration
Vitals signs will be monitored before, during and after infusion at the times specified in the 
Schedule of Assessment. Subjects are monitored (pulse rate, blood pressure, and body 
temperature) every 30 minutes during the infusion period (including times where infusion rate is 
slowed or temporarily stopped).
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of durvalumab may be 
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and reinitiated at 
50% of the initial rate until completion of the infusion. For subjects with a ≤Grade 2 
infusion-related reaction, subsequent infusions may be administered at 50% of the initial rate.
Acetaminophen/paracetamol and/or an antihistamine (eg, diphenhydramine) or equivalent 
medications per institutional standard may be administered at the discretion of the investigator.
If the infusion-related reaction is Grade 3 or higher in severity, durvalumab will be discontinued.  
The standard infusion time is one hour, however if there are interruptions during infusion, the 
total allowed time from infusion start to completion of infusion should not exceed 4 hours at 
room temperature, with maximum total time at room temperature not exceeding 4 hours 
(otherwise requires new infusion preparation).  
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, and 
study personnel must be trained to recognize and treat anaphylaxis. The study site must have 
immediate access to emergency resuscitation teams and equipment in addition to the ability to 
admit subjects to an intensive care unit if necessary.
7.2.1.1.2. Arm A: Lenalidomide Administration (Discontinued to the Enrollment of New 
Subjects)
Lenalidomide (PO) will be administered after the durvalumab infusions on the days (eg, Day 1 of 
Cycles 1 through 13) when more than one IP should be given.
Lenalidomide 10 mg, 15 mg, or 20 mg dose (depending on dose level in the dose finding part or 
renal function in the dose confirmation and expansion parts) should be taken orally once daily, at 
approximately the same time each day.  There is no requirement for taking lenalidomide with or 
without food, or with or without certain types of foods or liquids.
Lenalidomide doses will be taken from Days 1 through 21 of a 28-day cycle.  A 7-day rest period 
is required.  A rest period may be extended due to toxicity as needed.
Lenalidomide dose adjustment based on subject’s creatinine clearance in case of starting 
dose of lenalidomide 15 mg or 20 mg (the dose confirmation and expansion parts only):
Lenalidomide dosing will be based on subject’s creatinine clearance calculated using the 
Cockcroft-Gault formula using actual body weight.  This calculation will be performed by the 
Central Laboratory based on actual body weight.
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
Subjects who have a creatinine clearance ≥ 60 mL/min (≥1.0 mL/sec) will receive 
lenalidomide at a dose of 15 mg or 20 mg (depending on the dose level assigned) 
once daily on Days 1 through 21 of each 28-day cycle.  The subjects eligible for the 
dose finding part must have a creatinine clearance ≥ 60 mL/min (≥1.0 mL/sec).

Subjects with moderate renal insufficiency (creatinine clearance ≥ 40 mL/min but      
< 60 mL/min; ≥ 0.5 mL/sec but < 1.0 mL/sec) will be eligible for the dose 
confirmation and expansion parts only. In this case, a lower starting dose of 
lenalidomide of 10 mg once daily will be given on Days 1 through 21 of a 28-day 
cycle. in Cycle 1 and in Cycle 2. If the subject remains free of IP-related Grade 3 or 
4 toxicities for at least 2 cycles, the dose may be increased to 15 mg once daily on 
Days 1 to 21 of a 28-day cycle at the discretion of the treating physician from Cycle 3 
onwards.
If subjects miss a dose of lenalidomide and it is within 12 hours of their normal dosing time, the 
subjects 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 ≥12-hour interval 
between 2 doses will not cause considerable drug accumulation.
7.2.1.1.3. Arm A: Rituximab Administration (Discontinued to the Enrollment of New 
Subjects)
Rituximab will be administered at 375 mg/m2 every week in Cycle 1 (Days 2, 8, 15, 22) and on 
Day 1 of every 28-day cycle from Cycles 2 through 5. 
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 up to the pharmacist’s and investigator’s discretion whether BSA will be recalculated prior 
to preparing every cycle of rituximab, or whether the BSA calculated prior to the first dose of 
rituximab will be used throughout the study.  If BSA is to be 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 the locally approved rituximab prescribing information.
7.2.1.2.
Arm B: Durvalumab and Ibrutinib 
Subjects assigned to Arm B will receive: 

Durvalumab (IV) infusion on Day 1 of Cycles 1 through 13 

Ibrutinib (PO) continuous once daily until disease progression, unacceptable toxicity, 
starts new therapy, or discontinuation for any other reason, ie, subject withdraws 
consent or discontinues per investigator’s discretion.
All treatment cycles are 28 days.  Durvalumab infusion will be administered before ibrutinib on 
the days which both IPs should be given.
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Initial cohorts of 3 subjects will be treated at dose levels listed in Table 21.  If one DLT occurs in 
the first 3-subject cohort at a dose level during the DLT observation period (ie, from the time of 
first IP dose through completion of Cycle 1), that cohort will enroll up to 6 subjects.  Even in the 
absence of a DLT, additional subjects may be evaluated within a dose cohort if recommended by 
the SRC to adequately evaluate the safety or treatment effects of durvalumab in combination 
with ibrutinib.  If dose level 1 is found to be the NTD, dose level -1 may be explored at the 
discretion of the SRC. Dose level 2 will enroll only the subjects with NHL.
The dose finding flow is illustrated Figure 5.
Table 21:
Dose Finding: Arm B Dose Levels
Dose Level
Durvalumab (IV)
Ibrutinib (PO)
-1
1500 mg
280 mg
1 (starting)
1500 mg
420 mg
2
1500 mg
560 mg (only in NHL)
Schedule
(28-day cycle)
Day 1 of Cycles 1-13 
Once daily on Days 1-28 (QD)
Abbreviations: IV = intravenous; PO = orally; QD = once daily.
7.2.1.2.1. Durvalumab Administration 
Please see Section 7.2.1.1.1.
7.2.1.2.2. Ibrutinib Administration 
Ibrutinib (PO) will be administered after the durvalumab infusion on the days (eg, Day 1 of 
Cycles 1 through 13) in which both investigational treatments should be given.  
Ibrutinib, depending on dose level, 280 mg (2 × 140 mg capsules/tablets), 420 mg (3 × 140 mg 
capsules/tablets; maximum allowed dose in CLL) or 560 mg (4 × 140 mg capsules/tablets; only 
in NHL) is administered orally once daily with 8 ounces (approximately 240 mL) of water.  The 
capsules should be swallowed intact and subjects should not attempt to open capsules or dissolve
them in water. Tablets should be swallowed intact and subjects should not attempt to crush or 
dissolve them in water.
If a dose is missed, it can be taken as soon as possible on the same day with a return to the 
normal schedule the following day.  The subject should not take extra capsules or tablets to make 
up the missed dose.
Ibrutinib dosing is continuous (without interruption) throughout the Treatment Period.  If Day 1 
durvalumab dosing is delayed for toxicity that does not require ibrutinib to be held for toxicity, 
ibrutinib dosing should continue.  If Day 1 (of any Cycle) durvalumab infusion is delayed due to 
scheduling delays, ibrutinib dosing should continue.
7.2.1.3.
Arm C: Durvalumab and Rituximab ± Bendamustine
Subjects assigned to Arm C will receive: 

Durvalumab (IV) infusion on Day 1 of Cycles 1 through 13  
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
Bendamustine (IV) infusion on Days 1 and 2 of Cycles 1 through 6  

Rituximab (IV) infusion on Day 2 Cycles 1 through 6

In NHL, rituximab dose is 375 mg/m2 in all cycles.

In CLL, rituximab dose is 375 mg/m2 (Cycle 1; first dose) and 500 mg/m2
(subsequent doses: Cycle 2 through 6).  
Bendamustine may be stopped after 4 cycles if the subject experiences a cumulative toxicity 
related to bendamustine and there is no clinical evidence of a favorable benefit to risk ratio for 
continuation of bendamustine treatment as per the investigator’s medical judgment.  If 
bendamustine is stopped earlier than 6 cycles, rituximab may be continued up to 6 cycles.
All treatment cycles are 28 days.  Durvalumab infusion will be administered before 
bendamustine on the days (eg, Day 1 of Cycles 1 through 6) which more than one investigational 
treatment should be given, and then bendamustine and rituximab administration are 
recommended to follow, respectively.
Initial cohorts of 3 subjects will be treated at dose levels listed on Table 22. If one DLT occurs 
in the first 3-subject cohort at a dose level during the DLT observation period (ie, from the time 
of first IP dose through completion of Cycle 1), that cohort will enroll up to 6 subjects.  Even in 
the absence of DLT, additional subjects may be evaluated within a dose cohort if recommended 
by the SRC to adequately evaluate the safety or treatment effects of durvalumab in combination 
with rituximab and/or bendamustine (depending on dose level).  If the dose level 2 is found to be 
the NTD, dose level -1 may be explored. 
The dose finding flow is illustrated in Figure 6.
Table 22:
Dose Finding: Arm C Dose Levels
Dose Level
Durvalumab (IV)
Rituximab (IV)
a
Bendamustine (IV)
1 (starting) 
1500 mg
375 mg/m2
-
2
b
1500 mg
375 mg/m2
70 mg/m2
3 
1500 mg
375 mg/m2
90 mg/m2(only in NHL)
Schedule
Day 1 of Cycles 1-13 
Day 2 of Cycles 1-6
Days 1 and 2 of Cycles 1-
6
Abbreviations:  IV= intravenous.
a In subjects with CLL, rituximab dose is 375 mg/m2 (first dose; Cycle 1) and 500 mg/m2 (subsequent doses; Cycle 
2 and on).
b In subjects with CLL, the maximum allowed dose of bendamustine will be 70 mg/m2.
7.2.1.3.1. Arm C: Durvalumab Administration
Please see Section 7.2.1.1.1.
7.2.1.3.2. Arm C: Bendamustine Administration
Bendamustine will be administered as a 30-minute IV infusion at a dose of 70 or 90 mg/m2 (only 
in NHL) (depending on dose level).  
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All dosage calculations for bendamustine will be based on the subject‘s body surface area
(BSA), using actual weight for calculations.  This will be determined during Screening or on the 
first day of IP administration of Cycle 1 and will be calculated using the subject’s height and 
weight according to local pharmacy practice. 
It is up to pharmacist’ and investigator’ discretion whether BSA will be recalculated prior to 
preparing every cycle of bendamustine, or whether the BSA calculated prior to the first dose of 
bendamustine will be used throughout the study.  If BSA is to be recalculated, the same 
calculation method should be used throughout the study per subject
The timing of bendamustine on Day 2 should be approximately the same time on Day 1.  The 
preparation and infusion of bendamustine will be according to the locally approved label.  
7.2.1.3.3. Arm C: Rituximab Administration
Rituximab will be administered at 375 mg/m2 to the subjects with NHL and at 375 mg/m2 (first 
dose) followed by 500 mg/m2 (subsequent doses) to the subjects with CLL on Day 2 of every 28-
day cycle from Cycles 1 through 6. 
All dosage calculations for rituximab will be based on the subject’s BSA, using actual weight for 
calculations.  This will be determined during Screening or on the first day of IP administration of 
Cycle 1 and will be calculated using the subject’s height and weight according to local pharmacy 
practice. 
It is up to pharmacist’ and investigator’ discretion whether BSA will be recalculated prior to 
preparing every cycle of rituximab, or whether the BSA calculated prior to the first dose of 
rituximab will be used throughout the study.  If BSA is to be recalculated, the same calculation 
method should be used throughout the study per subject.
Preparation, infusion rate, dose modification, premedication and guidance on pregnancy 
prevention should be performed according to the locally approved label or the Pharmacy Manual.
7.2.1.4.
Arm D: Durvalumab Monotherapy 
No dose finding cohort is planned.  Please see Section 7.2.8.1 for treatment schedule. 
7.2.2.
Definition of DLT Evaluation Period
Subjects enrolled in Arms A, B, and C will be observed for DLTs from the time of first IP dose 
through completion of Cycle 1.
7.2.3.
Definition of Dose Limiting Toxicity (DLT)
Dose limiting toxicities will be evaluated during the DLT evaluation period for the subjects in 
the dose finding cohorts.  The severity grading of adverse events will be determined according to 
National Cancer Institute CTCAE Version 4.03 (unless otherwise specified in Section 7.2.10.1).  
Dose limiting toxicities are described below:
A DLT will be defined as below:
Hematologic DLT

Grade 4 neutropenia observed for greater than 5 days duration
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
Grade 3 neutropenia associated with fever (≥ 38.5 °C) of any duration

Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding, or any 
requirement for platelets transfusion

Grade 4 anemia, unexplained by underlying disease

Any other grade 4 hematologic toxicity that does not resolve to subject’s pre-
treatment baseline level within 72 hours
Non-Hematologic DLT

Any non-hematological toxicity ≥ Grade 3 except for alopecia and nausea controlled 
by medical management

Any treatment interruption greater than 2 weeks due to adverse event
While the rules for adjudicating DLTs in the context of dose finding are specified above, an AE 
not listed above may be defined as a DLT after consultation with the sponsor and SRC based on 
the emerging safety profile.  
Should a subject experience a suspected DLT, the treating investigator should contact the 
sponsor’s medical monitor prior to declaring the event a DLT. All DLT cases will also be 
discussed with the SRC during regular calls with sites and their respective investigators aiming 
to review and share all safety related events including but not limited to DLTs.  Each study arm 
will have a dedicated SRC.
Please see Section 10 for further details on AE reporting.
7.2.4.
Definition of a Subject Evaluable for DLTs
Subjects enrolled during the dose finding part are considered evaluable for DLTs if they 
complete the DLT evaluation period specified for each cohort or experience a DLT during the 
DLT evaluation period. 
Non-evaluable subjects may be replaced with another subject at the same dose level. Additional 
subjects within any dose cohort may be enrolled at the discretion of the SRC.
7.2.5.
Definition of Non-Tolerated Dose (NTD)
A dose will be considered to be a non-tolerated dose (NTD) if ≥2 of 3 or 6 evaluable subjects in 
a dose level experience a DLT.  
7.2.6.
Definition of Maximum Tolerated Dose (MTD)
The MTD is defined as the highest dose level below the NTD with 0 of 3 or 1 of 6 (ie, < 1/3 of 
subjects) evaluable subjects experiencing DLTs during the DLT evaluation period.
7.2.6.1.
Determination of Preliminary RP2D
The SRC will identify a preliminary RP2D for each dose finding cohort based on an integrated 
assessment of the safety, PK, Pd, and preliminary efficacy (as available).  The RP2D selected 
will not exceed the MTD from the dose finding cohorts.
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7.2.6.2.
Evaluation of Alternate Treatment Schedules 
If the SRC determines that toxicity is due to duration or frequency of dosing of any 
investigational treatment regimen, intermittent dosing schedules not currently specified may be 
evaluated.  
7.2.7.
Safety Review Committee
Safety considerations, including but not limited to, decisions to open a new dose level cohort, 
additional subjects within any dose cohort, or declare a RP2D will be made by the safety review 
committee (SRC).  The SRC membership will be comprised of the sponsor’s medical monitor 
and drug safety physician, a subset of the investigators participating in the study who have 
sufficient prior experience in early phase studies in CLL or lymphoma. Other study team 
members (eg, study statistician) may also participate in SRC meetings as needed.
The safety review committee will be informed about any additional safety data available from 
other durvalumab studies that may affect their decisions and recommendations. 
The SRC will continue to review safety data regularly throughout the all phases of the study and 
make recommendations about study continuation and dose modifications for the IPs (eg, 
alternate schedule and dose levels not currently specified or split dose) as appropriate.
7.2.8.
Dose Confirmation Cohorts (Phase 1)
Once a preliminary RP2D in any dose finding cohort is determined, the relevant dose 
confirmation cohort may be open for enrollment. Arm D will start directly with the dose 
confirmation cohorts (no dose finding cohort).
Table 23:
Planned Dose Confirmation Cohorts
Treatment Arm
Eligible Histologiesab
Arm Ac
(discontinued to the enrollment of new subjects)
R/R FL N = 10d
R/R DLBCL N = 10d
Arm B
R/R CLL/SLL N = 10
R/R MCL N =10
Arm C
R/R CLL/SLL N = 10
R/R FL N = 10
R/R DLBCL N = 10
Arm D
R/R CLL/SLL
R/R DLBCL
R/R FL
R/R MCL
R/R HL
RT (5-10 subjects in each; N = 40)
Abbreviations: N = number of subject; R/R=relapsed/refractory.
a Subjects with FL Grade 3b may be enrolled into DLBCL cohorts will be excluded from FL cohorts.
b FL cohorts will enroll only subjects with FL Grade 1-3a.
c Arm A will exclude subjects with CLL or SLL.
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d  Arm A dose confirmation and dose expansion cohorts are discontinued and will not enroll new subjects.
7.2.8.1.
Arm D
Subjects assigned to Arm D will receive: 

Durvalumab (IV) infusion at a fixed dose of 1500 mg, on Day 1 of Cycles 1 through 
13.  All treatment cycles are 28 days.
The add-on combination treatment with lenalidomide ± rituximab is no longer allowed.*
For subjects in Arm D, at the time of disease progression, the investigator may add study 
treatments previously investigated once a tolerable dose level is confirmed for that combination 
(ie, rituximab ± either lenalidomide* or bendamustine; or monotherapy ibrutinib), or local IFRT 
with durvalumab, if subjects meet the criteria defined in Section 3.1.2.  
Subjects who receive a combination agent other than local IFRT will follow the visit schedules 
and assessments specific to each combination agent (eg, the Arm A visit schedule and 
assessments starting from Cycle 1 Day 1 will be followed by subjects who receive lenalidomide 
and rituximab in addition to durvalumab).  Those subjects will be treated according to the 
treatment schedules described for each arm in Section 7.2 based on the investigator’s medical 
judgment.  
Subjects who receive local IFRT, 2 Gy on each of 2 consecutive days to one tumor site, as 
additional therapy will continue to follow the Arm D schedule.  Following IFRT, subjects will 
receive durvalumab for up to an additional 6 cycles (eg, if a subject receives local IFRT 
following disease progression documented at the end of Cycle 13, he/she may receive 6 
additional durvalumab doses, up to Cycle 19), or will complete the remaining scheduled 
durvalumab doses (ie, 13 cycles) based on the investigator’s medical judgment.  
The sponsor’s medical monitor should be contacted prior to adding a combination agent to 
durvalumab. 
7.2.9.
Dose Expansion Cohorts (Phase 2)
The sponsor will decide on dose expansion based on the SRC recommendation and emerging and 
available clinical and non-clinical data.  The following cohorts are anticipated for expansion. 
Table 24:
Planned Dose Expansion Cohorts
Treatment Arm
Eligible Histologies
ab
Arm A
c
(discontinued to the enrollment of new subjects)
R/R FL N = 15d
R/R DLBCL N = 15d
Arm B
R/R CLL/SLL N = 15
R/R MCL N = 15
Arm C
R/R CLL/SLL N = 15
R/R FL N = 15
R/R DLBCL = 15
Arm D
Not planned
Abbreviations: N = number of subject; R/R = relapsed/refractory. 
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a Subjects with FL Grade 3b may be enrolled into DLBCL cohorts but will be excluded from FL cohorts.
b FL cohorts will enroll only subjects with FL Grade 1-3a.
c Arm A will exclude subjects with CLL or SLL.
d  Arm A dose confirmation and dose expansion cohorts are discontinued and will not enroll new subjects.
7.2.10.
Dose Modifications (Interruption/Reduction)
Dose modifications are permitted in any cycle for appropriate management of AEs. Dose 
reductions are allowed for lenalidomide, ibrutinib, and bendamustine.  No dose reductions are 
allowed for durvalumab or rituximab, but treatment may be interrupted or discontinued or 
infusion rate may be changed at the discretion of the investigator for severe infusion or allergic 
reactions, or other toxicities. 
Dose modifications must be recorded in the Dose Administration CRF.
7.2.10.1.
General Dose Modification Guidelines
Subjects will be evaluated for AEs at each visit with the NCI CTCAE version 4.03 used as a 
guide for the grading of severity, with the exception of:

Tumor lysis syndrome (Cairo, 2004) or

Laboratory abnormalities in CLL subjects as recommended by the IWCLL guidelines 
for the diagnosis and treatment of CLL (Hallek, 2008) as listed in Appendix E.
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 deemed 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 7.2.10.7.
Dose interruptions lasting beyond 28 days should be discussed with the sponsor’s medical 
monitor.
If the lowest dose of lenalidomide, ibrutinib, or bendamustine is not tolerated then it will be 
discontinued from the investigational treatment regimen. 
If any combination IP (ie, lenalidomide, ibrutinib, bendamustine, rituximab) is discontinued, 
subjects may continue on durvalumab with or without another combination IP; this will require 
discussion and agreement between the sponsor’s medical monitor and the investigator.
If durvalumab is discontinued, subjects will be discontinued from all study treatment.
7.2.10.2.
Dose Modification for Durvalumab
Based on the mechanism of action of durvalumab leading to T-cell activation and proliferation, 
there is the possibility of observing 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, 2013). Subjects should be monitored for signs and symptoms of 
imAEs. In the absence of an alternate etiology (eg, infection or disease progression), an 
immune-related etiology should be considered for signs or symptoms of enterocolitis, dermatitis, 
hepatitis, and endocrinopathy.  
Approved
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
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Confidential and Proprietary
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In addition to the dose modifications shown in, 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-related
3. Symptomatic and topical therapy should be considered for low-grade events
4. Systemic corticosteroids should be considered for a persistent low-grade event or for a 
severe event
5. More potent immunosuppressives 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 sponsor’s medical monitor. 
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. General guidelines regarding dose modification are provided in 
Section 7.2.10.1.
7.2.10.3.
Dose Modification for Lenalidomide (Discontinued to the Enrollment of New 
Subjects)
The dose of lenalidomide may be reduced successively by one level from the starting dose.  
There will be no more than one dose level reduction from one cycle to the next unless otherwise 
permitted after consultation with the sponsor’s medical monitor. No dose (re)escalation is 
permitted at any time unless as specified in Table 25 and Table 26.
In addition, if a subject continues to experience unacceptable toxicity at the lowest dose level 
allowed, lenalidomide will be discontinued permanently.  
Table 25:
Lenalidomide Dose Modification Levels for Subjects Initiating Treatment at 
20 mg Based on Pretreatment Creatinine Clearance ≥ 60 mL/min 
Dose
a
Once Daily on Days 1-21, Every 28-day Cycle
Level 1a (starting dose)
20 mg 
Level -1a  
15 mg 
Level -2a
10 mg 
Level -3a
b
5 mg 
a Once a subject's dose has been reduced, no dose re-escalation will be permitted.
b Subjects who cannot tolerate dose level -3a are to be discontinued from the Treatment Period of the study if the 
subject is receiving lenalidomide treatment only.
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
129
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 26:
Lenalidomide Dose Modification Levels for Subjects Initiating Treatment at 
10 mg Based on Pretreatment Creatinine Clearance ≥ 40 mL/min and < 60 
mL/min (Dose Confirmation and Expansion Parts Only)
Dose
a,b
Once Daily on Days 1-21, Every 28-day Cycle
Level 2b
c
15 mg 
Level 1b (starting dose)
10 mg 
Level -1b
5 mg 
Level -2b
d
2.5 mg 
a If the subject has not experienced any drug-related ≥ Grade 3 toxicity for at least 2 cycles, the dose may be 
increased to 15 mg once daily on Days 1 to 21 of each 28-day cycle at the discretion of the treating physician from 
cycle 3 and onwards.
b Once a subject's dose has been reduced, no dose re-escalation is permitted.
c Once the dose is escalated to 15 mg once daily for 21 days of every 28-day cycle, the dose may be reduced 
successively by 1 level, ie, to 10 mg.
d Subjects who cannot tolerate dose level -2b are to be discontinued from the Treatment period of the study if the 
subject is receiving on lenalidomide treatment only.
The new cycle of treatment may begin on the scheduled Day 1 of the next cycle if all of the 
following requalification criteria for lenalidomide are met:

A 7-day rest period has elapsed following the last dose of lenalidomide

The absolute neutrophil count (ANC) is ≥1000 cells/mm³ (1.0 × 109/L);

The platelet count is ≥ 50,000 cells/mm³ (50 × 109/L);

Study-drug-related allergic reaction or hypersensitivity not requiring discontinuation has 
resolved to ≤ Grade 1 severity;

Any other study-drug-related AE not requiring discontinuation has resolved to ≤ Grade 2 
severity.
If these requalification criteria are not met on Day 1 of a new cycle, the subject will be evaluated 
at least once every 7 days until the toxicity has resolved as described above. If a new cycle is 
delayed for more than 28 days, the sponsor’s medical monitor must be notified. The treatment 
can be resumed according to the investigators’ and the sponsor’s medical monitor’s clinical 
judgment.
The criteria above do not apply to laboratory abnormalities of subjects who are randomized with 
these laboratory abnormalities due to lymphoma infiltration of the bone marrow or documented 
liver involvement by lymphoma. In the absence of evidence of treatment-emergent toxicity, the 
new cycle of treatment may begin at the discretion of the investigator.
Doses that were missed, because of toxicity or any other reason, will not be rescheduled.
7.2.10.4.
Dose Modification for Rituximab
The dose of rituximab should not be reduced. The dose of rituximab may be interrupted and 
modified according to the clinical practice of the investigator’s institution (eg, dose splitting or 
Approved
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
130
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
dose banding), and in line with the approved prescribing information including administration, 
warnings, precautions, contraindications, and adverse reactions, as applicable. 
In case a dose of rituximab (in Arm A or C) is missed during the first cycle because of toxicity, it 
will not be rescheduled. In such situations, treatment with other combination drugs does not need 
to be interrupted.
In case of delay in the start of next cycle during (eg, Cycles 2 to 5 in Arm A and Cycles 2
through 6 in Arm C) due to toxicity, rituximab administration may be postponed until AE has 
resolved, at which point the next cycle is started.
If rituximab is discontinued due to toxicity, the subject may continue receiving the other agents 
per the specified schedule.  
7.2.10.5.
Dose Modification for Ibrutinib
The dose of ibrutinib may be reduced successively by one level from the starting dose.  There 
will be no more than one dose level reduction from one cycle to the next unless otherwise 
permitted after consultation with the sponsor’s medical monitor. At the investigator’s discretion, 
the dose of ibrutinib may be re-escalated after 2 cycles of a dose reduction in the absence of a 
recurrence of the toxicity that led to the reduction.
In addition, if a subject continues to experience unacceptable toxicity at the lowest dose level 
allowed, ibrutinib will be discontinued permanently.  If ibrutinib is discontinued due to toxicity, 
the subject may continue receiving durvalumab for up to 13 cycles.  If durvalumab is 
discontinued due to toxicity, the subject will be discontinued from all study treatment.
Subjects who continue to receive ibrutinib on-study will be treated per investigator’s medical 
judgement.
The dose reduction steps for ibrutinib are provided in Table 27 and Table 28:
Table 27:
Ibrutinib Dose Modification Levels - NHL
Dose
Once Daily Continuous
Level 1a (starting dose for NHL)
560 mg
Level -1a
420 mg
Level -2a
a
280 mg
Abbreviations: NHL = non-Hodgkin lymphoma.
a Subjects who cannot tolerate Dose Level -2a are to be discontinued from the Treatment Period of the study if the 
subject is receiving ibrutinib treatment only.
Table 28:
Ibrutinib Dose Modification Levels - CLL
Dose
Once Daily Continuous
Level 1b (starting dose for CLL)
420 mg
Level -1b
280 mg
Level -2b
a
140 mg
Abbreviations: CLL = chronic lymphocytic leukemia.
Approved
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
131
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
a Subjects who cannot tolerate Dose Level -2b are to be discontinued from the Treatment Period of the study if the 
subject is on ibrutinib treatment only.
7.2.10.6.
Dose Modification for Bendamustine
The dose of bendamustine may be reduced successively by one level from the starting dose.  At 
the investigator’s discretion, the dose of bendamustine may be cautiously re-escalated in 
subsequent cycles in subjects with CLL.
In addition, if a subject continues to experience unacceptable toxicity at the lowest dose level 
allowed, bendamustine will be discontinued permanently.  If bendamustine is discontinued due 
to toxicity, the subject may continue receiving durvalumab and/or rituximab for up to 13 cycles.  
If durvalumab is discontinued due to toxicity, the subject will be discontinued from all study 
treatment.
The dose reduction steps for bendamustine are provided in Table 29:
Table 29:
Bendamustine Dose Modification Levels 
Dose
Days 1 and 2 of Cycles 1 through 4 or 6
Level 1 (starting dose for NHL)
90 mg/m2
Level -1 (starting dose for CLL)
70 mg/m2
Level -2
50 mg/m2
7.2.10.7.
Dose Modification and Toxicity Management Guidelines
Dose modifications will not be required for AEs that are clearly not attributed to IPs or for 
laboratory abnormalities that are not deemed to be clinically significant (unless otherwise 
specified in Table 30, Table 31, and Table 32.  If an AE occurs, the investigator should assess 
whether the AE is related 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 Table 30, Table 31, and Table 32.
Arm A (durvalumab plus lenalidomide with or without rituximab) is discontinued to the 
enrollment of new subjects. Subjects already enrolled and treated in Arm A who are 
receiving clinical benefit, based on the discretion of the investigator, may continue study 
treatment after being reconsented.
It is important to note that these guidelines prepared by the sponsor are to assist the investigator 
in the exercise of his/her clinical judgment in treating these types of toxicities and should be 
applied to management of adverse events related to study treatment and not ANY adverse event.
In Arm B, subjects who continue to receive ibrutinib on-study will be treated per investigator’s 
medical judgement.
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
132
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 30:
General Dose Modification and Toxicity Management Guidelines for Immune-mediated Adverse Events
Immune-Mediated Reactions
Agent to be 
considered 
for dose 
modification
Dose Modifications
Toxicity Management
Immune-
Mediated 
Adverse 
Events 
(imAEs)
(Overall 
management 
of toxicities 
not described  
below)
Drug administration modifications of IP/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 
IP/regimen based on CTC AE grade/severity (table below), 
permanently discontinue IP/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 IP/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) follow the 
guidelines presented below:
-
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, subjects should 
be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression, 
concomitant medications, 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 (lasting more than 3 to 5 days) low-
grade (Grade 2) or severe (≥ Grade 3) events 
promptly start prednisone PO 1-2 mg/kg/day PO 
or IV equivalent
durvalumab 
lenalidomide
Grade 1: No dose modification 
Grade 2: Hold IP/study regimen dose until Grade 2 resolution to
≤ Grade 1 

If toxicity worsens, then treat as Grade 3 or Grade 4

IP/study regimen can be resumed once event stabilizes to 
≤ Grade 1 after completion of steroid taper
Approved
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
133
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 30:
General Dose Modification and Toxicity Management Guidelines for Immune-mediated Adverse Events 
(Continued)
Immune-Mediated Reactions
Agents to be 
considered for 
dose 
modification
Dose Modifications
Toxicity Management
Immune-
Mediated 
Adverse 
Events 
(imAEs) 
(continued)
Subjects with endocrinopathies who may require prolonged or 
continued steroid replacement can be retreated with IP/study 
regimen on the following conditions: 
1.
The event stabilizes and is controlled.
2.
The subject is clinically stable as per the investigator’s 
or treating physician’s clinical judgement.
3.
Doses of prednisone are at ≤ 10 mg/day or 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 study doctor, 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 2-4 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). 
durvalumab 
lenalidomide
Grade 3: Depending on the individual toxicity, may permanently 
discontinue IP/study regimen. Please refer to guidelines below.
Grade 4: Permanently discontinue IP/study regimen 
Note:  For Grade 3 asymptomatic amylase or lipase levels, hold 
IP/study regimen and if complete work up shows no evidence of 
pancreatitis, may continue or resume IP/study regimen.
Approved
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
134
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 30:
General Dose Modification and Toxicity Management Guidelines for Immune-mediated Adverse Events 
(Continued)
Immune-Mediated Reactions
Agents to be 
considered for 
dose 
modification
Dose Modifications
Toxicity Management
Immune-
Mediated 
Adverse 
Events 
(imAEs) 
(continued)
Note: IP/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 IP/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 
IP/study regimen for Grade 4 events (ie., hyperthyroidism, 
hypothyroidism, Type 1 diabetes mellitus). 
-
More potent immunosuppressives such as TNF 
inhibitors (eg, infliximab) - (also refer to 
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 jiroveci pneumonia (PJP, 
formerly known as Pneumocystis carinii 
pneumonia) prophylaxis, gastrointestinal 
protection, and glucose monitoring. 
-
Discontinuation of IP is not mandated for 
Grade 3 or Grade 4 inflammatory reactions 
attributed to local tumor response (eg, 
inflammatory reaction at sites of metastatic 
disease, lymph nodes, etc). Continuation of IP 
in this situation should be based upon a benefit-
risk analysis for that subject.
durvalumab 
lenalidomide
Abbreviations: AE = adverse event; CTCAE = Common Toxicity Criteria for Adverse Events; imAE = immune-mediated adverse event; IP = investigational 
product; IV = intravenous; NCI = National Cancer Institute; PO = orally; TNF = tumor necrosis factor. 
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
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Confidential and Proprietary
135
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Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Pneumonitis/
Interstitial 
Lung 
Disease 
(ILD)
Any Grade 
Grade of 
Pneumonitis 
(CTCAE version 
4.03)
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
durvalumab 
lenalidomide
Grade 1 
(Asymptomatic, 
clinical or 
diagnostic 
observations only, 
intervention not 
indicated)
No dose modification required. 
However, consider holding 
IP/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 IP/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 IP/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 1-2
mg/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 inhibitors (eg,
infliximab at 5 mg/kg every 2 weeks).
Approved
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
136
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Pneumonitis/
Interstitial 
Lung 
Disease 
(ILD) 
(continued)
Caution: 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-
Pneumocystis jiroveci pneumonia (PJP) treatment (refer to 
current NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]a
-
Consider pulmonary and infectious disease consult
-
Consider as necessary discussing with the sponsor’s 
medical monitor
durvalumab 
lenalidomide
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 IP/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 study physician
-
Hospitalize the subject
-
Supportive care (eg, oxygen)
-
If no improvement within 3-5 days, additional workup 
should be considered and prompt treatment with additional 
immunosuppressive therapy such as tumor necrosis factor 
inhibitors (eg, infliximab at 5 mg/kg every 2 weeks’ dose) 
started. Caution: rule out sepsis and refer to infliximab label 
for general guidance before using infliximab
Approved
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Approved
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
137
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered 
for dose 
modification
Pneumonitis/
Interstitial 
Lung 
Disease 
(ILD) 
(continued)
-
Once the subject is improving, gradually taper steroids over 
and consider prophylactic antibiotics, antifungal and in 
particular, anti-PJP treatment (please refer to current NCCN 
guidelines for treatment of cancer-related infections
[Category 2B recommendation]) a
durvalumab 
lenalidomide
Diarrhea/ 
Colitis
Any Grade 
Grade of diarrhea 
(CTCAE version 4.03)
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)
-
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; they can mask symptoms of 
perforation and peritonitis
Grade 1 diarrhea (Stool 
frequency of < 4 over 
baseline per day)
Grade 1 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
Approved
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
138
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Diarrhea/ 
Colitis 
(continued)
Grade 2 diarrhea 
(Stool frequency of 
4-6 over baseline 
per day) 
Grade 2 colitis 
(Abdominal pain; 
mucus or blood in 
stool)
Hold IP/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 IP/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
(infliximab at 5 mg/kg once every 2 weeksa). Caution: 
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, antifungal and anti 
PJP treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]) a
durvalumab 
lenalidomide
Approved
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Approved
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
139
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Diarrhea/ 
Colitis 
(continued)
Grade 3 diarrhea
(Stool frequency of 
≥ 7 over baseline 
per day)
Grade 3 colitis
(Severe abdominal 
pain, change in 
bowel habits, 
medical intervention 
indicated, peritoneal 
signs)
Permanently discontinue IP/study 
regimen if toxicity does not 
improve to Grade ≤1 within 
14 days; IP/study regimen can be 
resumed after completion of 
steroid taper.
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, antifungal, and anti 
PJP treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]) a
durvalumab 
lenalidomide
Grade 4 diarrhea 
(Life-threatening 
consequences)
Grade 4 colitis 
(Life-threatening 
consequences, 
urgent intervention 
indicated) 
Permanently discontinue IP/study 
regimen
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
140
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Hepatitis 
(Elevated 
LFTs)
Infliximab 
should not be 
used for 
management 
of Immune-
mediated 
Hepatitis
Any Grade
Grade of Liver 
Function Test Elevation 
(CTCAE version 4.03)
-
Monitor and evaluate liver function test (LFT): AST, ALT,
ALP and total bilirubin (TB)
-
Evaluate for alternative etiologies (eg, viral hepatitis, 
disease progression, concomitant medications)
durvalumab 
lenalidomide
Grade 1 
(AST or ALT >ULN 
and ≤3.0×ULN and/or 
TB > ULN and <1.5 × 
ULN)
No dose modification
If it worsens, treat as Grade 
2 event
For Grade 1 AST or ALT and/or TB elevation:       
-
Continue LFT monitoring per protocol
Grade 2 
(AST or ALT >3.0 
×ULN and ≤5.0×ULN 
and/or TB >1.5×ULN 
and <3.0 × ULN)
Hold IP/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 IP/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 the 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 work up 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 (ie, mycophenolate mofetil). a Discuss 
with the sponsor’s medical monitor if mycophenolate 
mofetil is not available. Infliximab should NOT be used.
PLEASE SEE 
section below to 
find guidance 
for 
management of 
“Hepatitis 
(elevated 
LFTS)” in 
hepatocellular 
carcinoma 
patients
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
141
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose
modification
Hepatitis 
(Elevated 
LFTs) 
(continued)
-
Once the subject is 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
durvalumab 
lenalidomide
Infliximab 
should not be 
used for 
management 
of Immune-
mediated 
Hepatitis
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 × ULN, or elevations in 
bilirubin ≤ 5 × ULN 

Hold IP/study regimen dose 
until resolution to ≤ Grade 
1 or baseline  

Resume IP/study regimen if 
elevations downgrade            
≤ Grade 1 or baseline 
within 14 days, and after 
completion of steroid taper

Permanently discontinue 
IP/study regimen if the 
elevations do not 
downgrade to ≤ Grade 1 or 
baseline within 14 days 
For Grade 3 or 4 AST or ALT and/or TB elevation:
-
Promptly initiate empiric IV methylprednisolone at 1 to 4 
mg/kg/day or equivalent 
-
If still no improvement within 3-5 days despite 1 to 4 
mg/kg/day methylprednisolone IV or equivalent, promptly 
start treatment with immunosuppressive therapy (ie, 
mycophenolate mofetil). Discuss with the sponsor’s 
medical monitor if mycophenolate is not available. 
Infliximab should NOT be used.
-
Perform hepatology consult, abdominal workup, and 
imaging as appropriate.
-
Once the subject is 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
PLEASE SEE 
section below to 
find guidance 
for 
management of 
“Hepatitis 
(elevated 
LFTS)” in 
hepatocellular 
carcinoma 
patients
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
142
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Hepatitis 
(Elevated 
LFTs) 
(continued)
Infliximab 
should not be 
used for
management 
of Immune-
mediated 
Hepatitis
For elevations in transaminases   
> 8 × ULN or elevations in 
bilirubin > 5 × ULN, discontinue 
IP/study regimen
Permanently discontinue IP/study 
regimen for any case meeting 
Hy’s law criteria (AST and/or 
ALT > 3x ULN + bilirubin > 2x 
ULN without initial findings of 
cholestasis (ie, elevated alkaline 
phosphatase) and in the absence 
of any alternative causeb
durvalumab 
lenalidomide
Grade 4 
(AST or ALT >20 
×ULN and/or TB 
>10×ULN)
Permanently discontinue IP/study 
regimen
PLEASE SEE 
section below to 
find guidance 
for 
management of 
“Hepatitis 
(elevated 
LFTS)” in 
hepatocellular 
carcinoma 
patients
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
143
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity 
Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Hepatitis 
(Elevated LFTs)
Infliximab 
should not be 
used for 
management of 
Immune-
mediated 
Hepatitis
See instructions at 
bottom of table 
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
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
−
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+ subjects: evaluate quantitative HBV viral load, 
quantitative HBsAg, or HBeAg
−
For HCV+ subjects: evaluate quantitative HCV viral load
−
Consider consulting hepatologist/Infectious disease 
specialist regarding change/implementation in/of antiviral 
medications for any subject 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
durvalumab 
lenalidomide
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
This section is 
only for 
management of 
“Hepatitis 
(elevated 
LFTs)” in 
hepatocellular 
carcinoma 
patients
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
144
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Hepatitis 
(Elevated 
LFTs) 
(continued)
Infliximab 
should not be 
used for 
management 
of Immune-
mediated 
Hepatitis
See instructions 
at bottom of table 
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 IP/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 
IP/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 consult hepatologist; consider abdominal 
ultrasound, including Doppler assessment of liver 
perfusion.
−
Consider, as necessary, discussing with study physician.
−
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 (ie, 
liver ultrasound), and consider starting immunosuppressives 
(ie, mycophenolate mofetil).a Discuss with study physician 
if mycophenolate mofetil is not available. Infliximab 
should NOT be used.
durvalumab 
lenalidomide
This section is 
only for 
management 
of “Hepatitis 
(elevated 
LFTs)” in 
hepatocellular 
carcinoma 
patients
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
145
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Hepatitis 
(Elevated LFTs) 
(continued)
Infliximab 
should not be 
used for 
management of 
Immune-
mediated 
Hepatitis
See instructions at 
bottom table
if transaminase 
rise is not isolated 
but (at any time) 
occurs in setting 
of either 
increasing 
bilirubin or signs 
of DILI/liver 
decompensation
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 IP/study regimen dose 
until resolution to Grade ≤1 
or baseline

Resume IP/study regimen if 
elevations downgrade to 
Grade ≤1 or baseline within 
14 days and after completion 
of steroid taper.

Permanently discontinue 
IP/study regimen if the 
elevations do not downgrade 
to Grade ≤1 or baseline 
within 14 days

Permanently discontinue 
IP/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 study physician.
−
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 study physician if 
mycophenolate is not available. Infliximab should NOT 
be used.
−
Once the subject is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines 
for treatment of cancer-related infections [Category 2B 
recommendation]).a
durvalumab 
lenalidomide
This section is 
only for 
management of 
“Hepatitis 
(elevated 
LFTs)” in 
hepatocellular 
carcinoma 
patients
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
146
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Hepatitis 
(Elevated LFTs) 
(continued)
Infliximab 
should not be 
used for 
management of 
Immune-
mediated 
Hepatitis
See instructions at 
bottom of table
if transaminase 
rise is not isolated 
but (at any time) 
occurs in setting 
of either 
increasing 
bilirubin or signs 
of DILI/liver 
decompensation
Grade 4
(Isolated AST 
or ALT 
>20×ULN, 
whether normal 
or elevated at 
baseline)
Permanently discontinue IP/study 
regimen.
For Grade 4:
Same as above 
(except would recommend obtaining liver biopsy early)
durvalumab 
lenalidomide
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 IP/study regimen
This section is 
only for 
management of 
“Hepatitis 
(elevated 
LFTs)” in 
hepatocellular 
carcinoma 
patients
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
147
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Nephritis or 
Renal 
Dysfunction 
(Elevated 
Serum 
Creatinine)
Any Grade
Grade of Elevated 
Serum Creatinine 
(CTCAE version 
4.03)
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) 
-
Subjects should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression, infections)
teroids 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
durvalumab 
lenalidomide
Grade 1 
(Serum Creatinine > 
1-1.5 × baseline; > 
ULN to 1.5 × ULN)
No dose modification
For Grade 1 elevated creatinine: 
-
Monitor serum creatinine weekly and any accompanying 
symptoms

If creatinine returns to baseline, resume its regular 
monitoring per study protocol.

If it worsens, depending on the severity, treat as Grade 
2, 3 or 4 
-
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics
Grade 2
(Serum Creatinine 
>1.5-3.0 × baseline;
>1.5-3.0 × ULN)
Hold IP/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 IP/study regimen 
after completion of steroid 
taper
For Grade 2 elevated creatinine: 
-
Consider symptomatic treatment including hydration, 
electrolyte replacement, and diuretics 
-
Carefully monitor serum creatinine every 2-3 days and as 
clinically warranted
-
Consult nephrologists and consider renal biopsy if clinically 
indicated
-
If event is persistent (> 3-5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent 
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
148
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Nephritis or 
Renal 
Dysfunction 
(Elevated 
Serum 
Creatinine) 
(continued)
-
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 the subject is improving, gradually taper steroids over 
≥ 28 days and consider prophylactic antibiotics, antifungals 
and anti PJP treatment (refer to current NCCN guidelines 
for treatment of cancer-related infections [Category 2B 
recommendation]) a
-
When event returns to baseline, resume IP/study regimen 
and routine serum creatinine monitoring per study protocol.
durvalumab 
lenalidomide
Grade 3
(Serum Creatinine 
> 3.0 × baseline; 
> 3.0-6.0 × ULN)
Grade 4
(Serum Creatinine > 
6.0 × ULN)
Permanently discontinue IP/study 
regimen
For Grade 3 or 4 elevated creatinine: 
-
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 the subject is improving, gradually taper steroids over 
≥ 28 days and consider prophylactic antibiotics, antifungals 
and anti PJP treatment (refer to current NCCN guidelines 
for treatment of cancer-related infections [Category 2B 
recommendation]) a
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
149
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Rash 
(excluding 
Bullous skin 
formations)
Any Grade
(refer to NCI
CTCAE version 
4.03 for definition 
of severity/grade 
depending on type 
of skin rash) 
General Guidance
-
Monitor for signs and symptoms of dermatitis (rash and 
pruritus) 
**IF THERE IS ANY BULLOUS FORMATION, THE 
SPONSOR’S MEDICAL MONITOR SHOULD BE 
CONTACTED AND IP/REGIMEN DISCONTINUED**
durvalumab 
lenalidomide
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
For persistent (> 1- 2 weeks)
Grade 2 events, hold scheduled
IP/study regimen until resolution
to ≤ Grade 1 or baseline 

If toxicity worsens, then treat 
as Grade 3 

If toxicity improves ≤ Grade 
1 or baseline, then resume 
IP/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, consider, as 
necessary, discussing with the sponsor’s medical monitor 
and promptly start systemic steroids prednisone 1-2 
mg/kg/day PO or IV equivalent  
-
Consider skin biopsy if persistent for > 1-2 weeks or recurs
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
150
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Rash 
(excluding 
Bullous skin 
formations)
(continued)
Grade 3
Hold IP/study regimen until 
resolution to ≤ Grade 1 or 
baseline

If temporarily holding the 
IP/study regimen does not 
provide improvement of the 
Grade 3 skin rash to ≤ Grade 
1 or baseline within 30 days, 
then permanently discontinue 
IP/study regimen 
For Grade 3 or 4:
-
Consult dermatology 
-
Promptly initiate empiric IV methylprednisolone 1 to 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, antifungal and anti 
PJP treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation])
-
Consider, as necessary, discussing with the sponsor’s 
medical monitor
durvalumab 
lenalidomide
Grade 4
Permanently discontinue IP/study
regimen 
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
151
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Endocrinopathy 
(eg, 
hyperthyroidism, 
hypothyroidism, 
Type 1 diabetes 
mellitus, 
hypophysitis, 
hypopituitarism, 
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 version 
4.03 for 
defining the 
CTC 
grade/severity)
General Guidance
-
Consider consulting an endocrinologist for endocrine 
events.
-
Consider, as necessary, discussing with study physician. 
-
Monitor subjects for signs and symptoms of 
endocrinopathies. Non-specific symptoms include 
headache, fatigue, behavior changes, changed mental status, 
vertigo, abdominal pain, unusual bowel habits, polydipsia, 
polyuria, hypotension and weakness.
-
Subjects should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression including brain 
metastases, infections)
-
Depending on the suspected endocrinopathy, monitor and 
evaluate thyroid function tests: TSH, fT3 and fT4 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 subject experiences an AE that is thought to be possibly 
of autoimmune nature (eg, thyroiditis, pancreatitis, 
hypophysitis, diabetes insipidus), the investigator should 
send a blood sample for appropriate autoimmune antibody 
testing
durvalumab 
lenalidomide
Grade 1
No dose modification
For Grade 1 (including those with asymptomatic TSH 
elevation):
-
Monitor subject with appropriate endocrine function tests
-
For suspected hypophysitis/hypopituitarism, consider
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
152
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Endocrinopathy 
(eg, 
hyperthyroidism, 
hypothyroidism, 
Type 1 diabetes 
mellitus, 
hypophysitis, 
hypopituitarism, 
adrenal 
insufficiency); 
exocrine event of 
amylase/lipase 
increased also 
included in this 
section
(continued)
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 fT4 at 
subsequent cycles as clinically indicated and consider 
consultation of an endocrinologist.
durvalumab 
lenalidomide
Grade 2 
For Grade 2 endocrinopathy other 
than hypothyroidism and Type 1
diabetes mellitus, hold IP/study 
regimen dose until subject is 
clinically stable

If toxicity worsens then treat 
as Grade 3 or Grade 4 

IP/study regimen can be 
resumed once event stabilizes 
to ≤ Grade 1 and after 
completion of steroid taper.
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 subjects 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, 1-2 mg/kg/day methylprednisone 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 IP/study regimen interruption, and without 
corticosteroids.
-
Isolated Type 1 diabetes mellitus (DM) may be treated with 
appropriate diabetic therapy, without IP/study regimen 
interruption, and without corticosteroids.
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
153
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Endocrinopathy 
(eg, 
hyperthyroidism, 
hypothyroidism, 
Type 1 diabetes 
mellitus, 
hypophysitis, 
hypopituitarism, 
adrenal 
insufficiency); 
exocrine event of 
amylase/lipase 
increased also 
included in this 
section
(continued)
Subjects with endocrinopathies 
who may require prolonged or 
continued steroid replacement 
(eg, adrenal insufficiency) can be
retreated with IP/study regimen 
on the following conditions: 
1.The event stabilizes and is 
controlled. 
2. The subject is clinically stable 
as per the investigator’s or 
treating physician’s clinical 
judgement.  
3. Doses of prednisone are at ≤ 10 
mg/day or equivalent.
-
Once subjects 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])
-
For subjects with normal endocrine work up (laboratory or 
MRI scans), repeat labs/MRI as clinically indicated.
durvalumab 
lenalidomide
Grade 3 or 4
For Grade 3 or 4 endocrinopathy 
other than hypothyroidism and 
Type 1 diabetes mellitus:

Hold IP/study regimen dose 
until endocrinopathy 
symptom(s) are controlled

IP/study regimen can be 
resumed once event stabilizes 
and after completion of 
steroid taper.
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 subjects 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 intravenous corticosteroids with 
mineralocorticoid activity.
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
154
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Endocrinopathy 
(eg, 
hyperthyroidism, 
hypothyroidism, 
Type 1 diabetes 
mellitus, 
hypophysitis, 
hypopituitarism, 
adrenal 
insufficiency); 
exocrine event of 
amylase/lipase 
increased also 
included in this 
section
(continued)
Patients with endocrinopathies 
who may require prolonged or 
continued steroid replacement 
(eg, adrenal insufficiency) can be 
retreated with IP/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 
≤10 mg/day or equivalent.
-
Isolated hypothyroidism may be treated with replacement 
therapy, without IP/study regimen interruption, and without 
corticosteroids.
-
Isolated Type 1 diabetes mellitus may be treated with 
appropriate diabetic therapy, without IP/study regimen 
interruption, and without corticosteroids.Once subjects 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
durvalumab 
lenalidomide
Immune 
mediated 
Neurotoxicity (to 
include but not 
limited to limbic 
encephalitis and 
autonomic 
neuropathy, 
excluding 
Myastenia 
Gravis and 
Guillain-Barre)
Any Grade 
(Depending on 
the type of 
neurotoxicity, 
refer to NCI 
CTCAE version 
4.03 for 
defining the 
CTC 
grade/severity)
General Guidance
-
Subjects should be evaluated to rule out any alternative 
etiology (eg, disease progression, infections, metabolic 
syndromes and medications) 
-
Monitor subject 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.
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
155
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Immune 
mediated 
Neurotoxicity (to 
include but not 
limited to limbic 
encephalitis and 
autonomic 
neuropathy, 
excluding 
Myastenia 
Gravis and 
Guillain-Barre)
(continued)
Grade 2

For acute motor neuropathies 
or neurotoxicity, hold 
IP/study regimen dose until 
resolution to ≤ Grade 1

For sensory 
neuropathy/neuropathic pain, 
consider holding IP/study 
regimen dose until resolution 
to ≤ Grade 1

If toxicity worsens then treat 
as Grade 3 or Grade 4 

IP/study regimen can be 
resumed once event improves 
to ≤ Grade 1 and after 
completion of steroid taper.
-
Consider, as necessary, disccusing 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, IV IG) 
durvalumab 
lenalidomide
Grade 3

Hold IP/study regimen dose 
until resolution to ≤ Grade 1

Permanently discontinue 
IP/study regimen if Grade 3 
imAE does not resolve to ≤ 
Grade 1 within 30 days.
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 to 2 
mg/kg/day or equivalent 
-
If 
no 
improvement 
within 
3-5 
days 
despite 
IV 
corticosteroids, consider additional workup and promptly 
treat with additional immunosuppressive therapy (eg, IV IG) 
-
Once stable, gradually taper steroids over ≥ 28 days 
Grade 4

Permanently discontinue 
IP/study regimen
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
156
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Immune-
mediated 
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). 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 
-
It is important to consider that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 
considered effective. Subjects requiring treatment should be 
started with IV IG and followed by plasmapheresis if not 
responsive to IV IG
durvalumab 
lenalidomide
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
157
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Immune-
mediated 
peripheral 
neuromotor 
syndromes,
such as 
Guillain-
Barre and 
Myasthenia 
Gravis
(continued)
Grade 1
No dose modification
-
Consider, as necessary, disccusing 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.
durvalumab 
lenalidomide
Grade 2

Hold IP/study regimen dose 
until resolution to ≤ Grade 1

Permanently discontinue 
IP/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)
MYASTHENIA GRAVIS
o
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.
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
158
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Immune-
mediated 
peripheral 
neuromotor 
syndromes,
such as 
Guillain-
Barre and 
Myasthenia 
Gravis
(continued)
o
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 
o
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: 
o
It is important to consider here that the use of 
steroids as the primary treatment of Guillain-Barre 
is not typically considered effective. 
o
Subjects requiring treatment should be started with 
IVIG and followed by plasmapheresis if not 
responsive to IVIG.
durvalumab 
lenalidomide
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
159
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Immune-
mediated 
peripheral 
neuromotor 
syndromes,
such as 
Guillain-
Barre and 
Myasthenia 
Gravis
(continued)
Grade 3

Hold IP/study regimen dose 
until resolution to ≤ Grade 
1Permanently discontinue 
IP/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 (severe or life threatening (Grade 3 or 4)
events): 
-
Consider, as necessary, discussing with the sponsor’s 
medical monitor
-
Recommend hospitalization
-
Monitor symptoms and obtain neurological consult
MYASTHENIA GRAVIS
o
Steroids may be successfully used to treat 
Myasthenia Gravis. It should typically be 
administered in a monitored setting under 
supervision of a consulting neurologist.
o
Subjects unable to tolerate steroids may be 
candidates for treatment with plasmapheresis or 
IVIG.
durvalumab 
lenalidomide
Grade 4

Permanently discontinue 
IP/study regimen
o
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: 
o
It is important to consider here that the use of 
steroids as the primary treatment of Guillain-Barre 
is not typically considered effective. 
o
Subjects requiring treatment should be started with 
IVIG and followed by plasmapheresis if not 
responsive to IV IG.
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
160
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
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 subjects with baseline 
cardiopulmonary disease and reduced cardiac function. 
−
Consider, as necessary, discussing with the study physician.
−
Monitor subjects 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.
−
Subjects should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression, other 
medications, or infections)
durvalumab 
lenalidomide
Grade 1
(asymptomatic 
with laboratory 
(eg, BNP) or 
cardiac imaging 
abnormalities)
No dose modifications required 
unless clinical suspicion is high, in 
which case hold IP/study regimen 
dose during diagnostic work-up for 
other etiologies. If IP/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.
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
161
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Myocarditis
(continued)
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 IP/study 
regimen dose until resolution 
to Grade 0. If toxicity rapidly 
improves to Grade 0, then the 
decision to reinitiate IP/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 
IP/study regimen.

If Grade 3-4, permanently 
discontinue IP/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 subject is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
or anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
durvalumab 
lenalidomide
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
162
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Myositis/Po
lymyositis 
(“Poly/myo
sitis”)
Any Grade

General Guidance
For Any Grade:
−
Monitor subjects for signs and symptoms of poly/myositis. 
Typically, muscle weakness/pain occurs in proximal 
muscles including upper arms, thighs, shoulders, hips, neck 
and back, but rarely affects the extremities including hands 
and fingers; also difficulty breathing and/or trouble 
swallowing can occur and progress rapidly. Increased 
general feelings of tiredness and fatigue may occur, and 
there can be new-onset falling, difficulty getting up from a 
fall, and trouble climbing stairs, standing up from a seated 
position, and/or reaching up.
−
If poly/myositis is suspected, a neurology consultation 
should be obtained early, with prompt guidance on 
diagnostic procedures. Myocarditis may co-occur with 
poly/myositis; refer to guidance under Myocarditis. Given 
breathing complications, refer to guidance under 
Pneumonitis/ILD. 
Given possibility of an existent (but previously unknown) 
autoimmune disorder, consider rheumatology consultation.
−
Consider, as necessary, discussing with the study physician.
−
Initial work-up should include clinical evaluation, creatine 
kinase, aldolase, LDH, BUN/creatinine, erythrocyte 
sedimentation rate or C-reactive protein level, urine 
myoglobin, and additional laboratory work-up as indicated, 
including a number of possible rheumatological/antibody 
tests (ie, 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
durvalumab 
lenalidomide
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
163
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Myositis/Po
lymyositis 
(“Poly/myo
sitis”)
(continued)
for evaluation of dysphagia or dysphonia.
-
Subjects should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression, other 
medications, or infections).
durvalumab 
lenalidomide
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 study physician.
Grade 2
(moderate pain 
associated with 
weakness; pain 
limiting 
instrumental 
activities of daily 
living [ADLs])

Hold IP/study regimen dose 
until resolution to Grade ≤1.

Permanently discontinue 
IP/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 study physician.
−
If clinical course is rapidly progressive (particularly if 
difficulty breathing and/or trouble swallowing), promptly 
start IV methylprednisolone 2 to 4 mg/kg/day systemic 
steroids along with receiving input from neurology 
consultant 
−
If clinical course is not rapidly progressive, start systemic 
steroids (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
Approved
7.0
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Approved
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
164
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 31:
Dose Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Myositis/Po
lymyositis 
(“Poly/myo
sitis”)
(continued)
-
(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 subject is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
or anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
durvalumab 
lenalidomide
Grade 3 or 4
(pain associated 
with severe 
weakness; limiting 
self-care ADLs)
For Grade 3:

Hold IP/study regimen dose 
until resolution to Grade ≤1.

Permanently discontinue 
IP/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 IP/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 study physician.
−
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 subject may require IV IG 
plasmapheresis.
−
Once the subject is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
or anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
Abbreviations: AChE = acetylcholine esterase; ACTH = adrenocorticotropic hormone; ADL = activities of daily living; AE = adverse event; ALP = alkaline 
phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BNP = brain natriuretic peptide; BUN = blood urea nitrogen; CT = computed 
Approved
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
165
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
tomography; CTC = common terminology criteria; CTCAE = common terminology criteria for adverse events; DILI = drug incuded liver injury; ECG = 
electrocardiogram; fT3 = free triiodothronine; fT4 = free thyroxine; GI = gastrointestinal; HBeAg = hepatitis B e-antigen; HBsAg = hepatitis B surface antigen;
HBV = hepatitis B virus; HCV = hepatitis C virus; IgG = Immunoglobulin; ILD = interstitial lung disease; IM = intramuscular; IP = investigational product; 
imAE = immune-mediated adverse event; IV = intravenous; IVIG = intravenous immune globulin; LDH = lactic dehydrogenase; LFT = liver function test; LLN 
= lower limit of normal; MRI = magnetic resonance imaging; NCCN = National Comprehensive Cancer Network; NCI = National Cancer Institute; PJP = 
Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); PO = orally; TB = total bilirubin; TSH = thyroid stimulating hormone; 
ULN = upper limit of normal.
a ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” (Postow, 2015). 
b FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury - Premarketing Clinical Evaluation NCI CTCAE version 4.03.
Approved
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Approved
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v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
166
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 32:
Dose Modification and Toxicity Management Guidelines for NON Immune-mediated Reactions
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Any Grade
Note: dose modifications are not required for adverse events not deemed to be related to IP/regimen (ie, events due to 
underlying disease) or for laboratory abnormalities not deemed to be clinically significant.
The following guidelines are not inclusive of all toxicities identified for each treatment. Please refer to the locally 
approved label of each treatment for additional guidelines as needed. 
Neutropenia
* unless 
secondary to 
lymphomato
us/CLL bone 
marrow 
involvement
Grade 3 
(ANC < 1000 
cells/mm³ 
[1x109/L])
durvalumab:

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. Otherwise, 
discontinue IP/study regimen
rituximab:

Follow your institutional standard or locally approved 
rituximab label as applicable
lenalidomide:

If sustained (≥ 7 days) Grade 3 or Grade 3 associated 
with fever (temperature ≥ 38.5°C), hold lenalidomide 
dose

If neutropenia resolves to ≤ Grade 2 (ANC ≥1000 
/mm3[ ≥1 × 109/L]), restart lenalidomide at next lower 
dose level
ibrutinib:

Hold ibrutinib if Grade 3 associated with infection or 
fever (temperature ≥ 38.5°C)

If neutropenia resolves to ≤ Grade 1 (ANC ≥1500 
/mm3 [≥1.5 × 109/L]) or baseline, restart the dose. If 
toxicity recurs, reduce dose by 140 mg. If toxicity 

Monitor CBC with differential at 
least weekly

Use of growth factors (G-CSF, GM-
CSF) is permitted as per ASCO or
ESMO Guidelines
bendamustine
lenalidomide
ibrutinib
rituximab
durvalumab
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
167
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 32:
Dose Modification and Toxicity Management Guidelines for NON Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Neutropenia
* unless 
secondary to 
lymphomatou
s/CLL bone 
marrow 
involvement
persists following 2 dose reductions, discontinue 
ibrutinib
bendamustine:

Delay bendamustine until neutropenia resolves to 
Grade 2 (ANC≥1000 /mm3[ ≥1 × 109/L])
In CLL only:

Reduce bendamustine dose to next lower dose level on 
Days 1 and 2 of subsequent cycles

May cautiously re-escalate bendamustine dose in 
subsequent cycles at the investigator’s discretion
bendamustine
lenalidomide
ibrutinib
rituximab
durvalumab
(continued)
Grade 4 
(ANC < 500 
cells/mm³ 
[0.5x109/L])
durvalumab:

Decision to discontinue would be based on 
accompanying clinical signs/symptoms and as per 
investigator’s clinical judgment and in consultation 
with the sponsor
rituximab:

Follow your institutional standard or locally approved 
rituximab label as applicable
lenalidomide:

Hold lenalidomide dose

If neutropenia resolves to ≤ Grade 2 (ANC ≥1000 
/mm3[ ≥1 × 109/L]), restart lenalidomide at next lower 
dose level
ibrutinib:

Hold ibrutinib if Grade 4 associated with infection or 
fever (temperature ≥ 38.5°C)

Monitor CBC with differential at 
least weekly

Use of growth factors (G-CSF, 
GM-CSF) is permitted as per 
ASCO or ESMO Guidelines
Approved
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Approved
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v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
168
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 32:
Dose Modification and Toxicity Management Guidelines for NON Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Neutropenia
* unless 
secondary to 
lymphomatou
s/CLL bone 
marrow 
involvement 
(continued)

If neutropenia resolves to ≤ Grade 1 (ANC ≥1500 
/mm3 [≥1.5 × 109/L]) or baseline, restart the dose. If 
toxicity recurs, reduce dose by 140 mg. If toxicity 
persists following 2 dose reductions, discontinue 
ibrutinib
bendamustine:

Delay bendamustine until neutropenia resolves to 
Grade 2 (ANC ≥1000 /mm3 [ ≥1 × 109/L]) 

Reduce bendamustine dose to next lower dose level on 
Days 1 and 2 of subsequent cycles

In CLL only: May cautiously re-escalate 
bendamustine dose in subsequent cycles at the 
investigator’s discretion
bendamustine
lenalidomide
ibrutinib
rituximab
durvalumab
Thrombocyto
penia
* unless 
secondary to 
lymphomatou
s/CLL bone 
marrow 
involvement
Grade 3
(Platelets 
<50,000 cells 
/mm³ [50 ×
09/L])
durvalumab:

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. Otherwise, 
discontinue IP/study regimen
rituximab:

Follow your institutional standard or locally approved 
rituximab label as applicable

Monitor CBC with differential at 
least weekly

Platelet transfusion is permitted as 
per ASCO Guidelines
bendamustine
lenalidomide
ibrutinib
rituximab
durvalumab
Approved
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Approved
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v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
169
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 32:
Dose Modification and Toxicity Management Guidelines for NON Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Thrombocyto
penia
* unless 
secondary to 
lymphomatou
s/CLL bone 
marrow 
involvement
(continued)
lenalidomide:

Hold lenalidomide dose

If thrombocytopenia resolves to ≤ Grade 2 (platelets 
≥50,000 cells /mm³ [50 ×109/L], restart lenalidomide at 
next lower dose 
ibrutinib:

No dose modification required
bendamustine:

Delay treatment until thrombocytopenia resolve to 
Grade 1 ≥75,000/mm3[ ≥75 × 109/L])

Reduce dose to next lower dose level on Days 1 and 2 
of subsequent cycles
In CLL only: May cautiously re-escalate dose in 
subsequent cycles at the investigator’s discretion
bendamustine
lenalidomide
ibrutinib
rituximab
durvalumab
Grade 4 
(Platelets 
<25,000 cells 
/mm³ [25 ×
109/L])
durvalumab:

Decision to discontinue would be based on 
accompanying clinical signs/symptoms and as per 
investigator’s clinical judgment and in consultation 
with the sponsor
rituximab:

Follow your institutional standard or locally approved 
rituximab label as applicable

Monitor CBC with differential at 
least weekly
Platelet transfusion is permitted as 
per ASCO Guidelines
Approved
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Approved
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v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
170
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 32:
Dose Modification and Toxicity Management Guidelines for NON Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Thrombocyto
penia
* unless 
secondary to 
lymphomatou
s/CLL bone 
marrow 
involvement
(continued)
lenalidomide:

Hold lenalidomide 

If thrombocytopenia resolves to ≤ Grade 2 (platelets 
≥50,000 cells /mm³ [50 × 109/L], restart lenalidomide 
at next lower dose 
ibrutinib:

Hold ibrutinib 

If thrombocytopenia resolves to ≤ Grade 1 (platelets 
≥75,000 cells /mm³ [75 × 109/L] or baseline, restart 
the dose. If toxicity recurs, reduce dose by 140 mg. If 
toxicity persists following 2 dose reductions, 
discontinue ibrutinib
bendamustine:

Delay treatment until thrombocytopenia resolves 
Grade 1 ≥75,000/mm3[ ≥75 × 109/L])
In CLL only:

Reduce dose to next lower dose level on Days 1 and 2 
of subsequent cycles

May cautiously re-escalate dose in subsequent cycles
bendamustine
lenalidomide
ibrutinib
rituximab
durvalumab
Stevens-
Johnson 
Syndrome or 
toxic 
epidermal 
necrosis
--
Discontinue all the agents
--
bendamustine
lenalidomide
ibrutinib
rituximab
durvalumab
Approved
7.0
v
Approved
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v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
171
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 32:
Dose Modification and Toxicity Management Guidelines for NON Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Thrombo-
embolic event
(Venous 
thrombosis/ 
Embolism)
Grade 3 or 4
rituximab:

Follow your institutional standard or locally approved 
rituximab label as applicable
lenalidomide:

Hold lenalidomide and start anticoagulation; restart 
lenalidomide at investigator’s discretion (maintain 
dose level)
ibrutinib:

Discontinue ibrutinib
bendamustine:

Delay bendamustine; start anticoagulation; restart at 
investigator’s discretion

Start anticoagulation treatment
lenalidomide
rituximab
bendamustine
ibrutinib
Hypothyroidi
sm
If the TSH is > 
ULN and subject 
is clinically 
euthyroid
lenalidomide:

No dose reduction or interruption

For other IPs, please see other non-hematologic AEs 
below

Repeat TSH on Day 1 of next cycle

Endocrinology evaluation is 
recommended and thyroid hormone 
replacement is allowed if clinically 
indicated
lenalidomide
(if not 
immune-
mediated)
If TSH is > ULN 
for more than 2 
cycles, or if 
subject has 
clinical 
symptoms of 
hypothyroidism
lenalidomide:

No dose reduction or interruption
Note: For other IPs, please see other non-hematologic AEs 
below
Approved
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Approved
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
172
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 32:
Dose Modification and Toxicity Management Guidelines for NON Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Hyperthyroidi
sm
If TSH < LLN 
and subject is 
clinically 
euthyroid
lenalidomide:

No dose reduction or interruption
Note: For other IPs, please see other non-hematologic 
AEs below

Repeat TSH at least every 3 months
(if not 
immune-
mediated)
If TSH <LLN at 
repeat evaluation 
and subject is 
clinically 
euthyroid 
lenalidomide:

No dose reduction or interruption
Note: For other IPs, please see other non-hematologic 
AEs below

Recommend endocrine evaluation
If TSH < LLN 
and subjects 
have symptoms 
of hyperthyroid 
(tremor, 
tachycardia, 
unintentional 
weight loss, or 
new onset night 
sweats)
lenalidomide:

Hold lenalidomide

If endocrine evaluation rules out hyperthyroidism, 
restart lenalidomide at the same dose 

If hyperthyroidism confirmed and alternative 
etiologies eliminated, restart lenalidomide at next 
lower dose
Note: For other IPs, please see other non-hematologic 
AEs below

Obtain endocrine evaluation and 
workup for alternative etiologies

Repeat TSH level on Day 1 of next 
cycle and contact the sponsor’s 
medical monitor
lenalidomide
Approved
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Approved
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
173
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 32:
Dose Modification and Toxicity Management Guidelines for NON Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Liver 
Function
(if not 
immune-
related)
ALT/ AST ≥ 
Grade 3 (> 5 ×
ULN) OR
Total bilirubin ≥ 
Grade 2 (> 1.5 
xULN)
lenalidomide:

Hold lenalidomide 

Restart lenalidomide if resolves to baseline within 14 
days 

If the resolution to baseline prolongs beyond 14 days 
and restart lenalidomide at next lower dose 

For other IPs, please see other non-hematologic AEs 
below

Follow weekly ALT/AST and total 
bilirubin until returns to baseline 

Repeat liver function test at least 
weekly to resolution
lenalidomide
Other AEs
Grade 2
durvalumab (not-immune mediated):

Hold durvalumab until resolution to ≤ Grade 1 or 
baseline
Treat accordingly as per 
local/institutional guidelines
---
rituximab/lenalidomide/ibrutinib:

No dose reduction or interruption 
bendamustine:

May continue bendamustine at the investigator’s 
discretion

Treat accordingly as per 
local/institutional guidelines
--
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
174
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 32:
Dose Modification and Toxicity Management Guidelines for NON Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be
considered for 
dose 
modification
Other AEs
(continued)
Grade 3 or 4
durvalumab:

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.. Otherwise, 
discontinue IP/study regimen

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)
rituximab:

Follow your institutional standard or locally approved 
rituximab label as applicable
lenalidomide:

Hold lenalidomide and restart at same when toxicity 
resolves to ≤ Grade 2 or next lower dose at the 
investigator’s discretion

Treat accordingly as per 
local/institutional guidelines
Approved
7.0
v
Approved
1.0
v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
175
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 32:
Dose Modification and Toxicity Management Guidelines for NON Immune-mediated Reactions (Continued)
AE
Toxicity Grade
Dose Modification
Toxicity Management
Agent to be 
considered for 
dose 
modification
Other AEs
(continued)
ibrutinib:

Hold ibrutinib 

If toxicity resolves to ≤ Grade 1 or baseline, restart the 
dose. If toxicity recurs, reduce dose by 140 mg. If 
toxicity persists following 2 dose reductions, 
discontinue ibrutinib
Bendamustine:

Delay treatment until resolves to ≤Grade 1

Reduce dose to next lower bendamustine dose. In 
CLL: May cautiously re-escalate dose in subsequent 
cycles
--
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; ASCO = American Society of Clinical Oncology;  AST 
= aspartate aminotransferase; CBC = complete blood count; CLL = chronic lymphocytic leukemia; ESMO = European Society of Medical Oncology; GCSF = 
granulocyte-colony stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; IP = investigational product; LLN = lower limit of 
normal; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; NSAID = non steroidal antiinflammatory drug; TSH = 
thyroid stimulating hormone; ULN = upper limit of normal.
Approved
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Approved
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v


EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
176
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
Table 33:
Dose Modification and Toxicity Management Guidelines for Infusion-related Reactions
Toxicity
Severity Grade of the 
Event (NCI CTCAE 
version 4.03
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)
Infusion-related 
Reactions
Grade 1

The infusion rate of IP/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/bendamustine

Steroids should not be used for routine 
premedication of ≤ Grade 2 infusion reactions 
Infusion-related 
Reactions
Grade 2

The infusion rate of study drug/regimen 
may be decreased 50% or temporarily 
interrupted until resolution of the event 

Subsequent infusions may be given at 50% 
of the initial infusion rate
Infusion-related 
Reactions
Grade 3/4

Permanently discontinue 
durvalumab/study 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)
Abbreviations:  IM = intramuscular; IP = investigational product; IV = intravenous; NCI CTCAE= National Cancer Institute Common Terminology Criteria for 
Adverse Events.
Approved
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
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Confidential and Proprietary
177
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
7.3.
Method of Treatment Assignment
Assignment of subjects to Arms A, B, C, and D, or each planned disease cohort within a 
treatment arm will be based on current open dose levels (DL) and available slots.  
Arm A is discontinued to the enrollment of new subjects. Only subjects currently enrolled and 
receiving clinical benefit, based on the discretion of the Investigator, can remain on treatment 
after being informed and reconsent.
An IRT will be used to track subject assignments to the treatment arms and dose levels.  
7.4.
Overdose
Overdose, as defined for this protocol, refers to durvalumab (IV), lenalidomide (PO), ibrutinib 
(PO), rituximab (IV), bendamustine (IV), or local IFRT (involved field radiation therapy).  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

Radiation therapy: any amount 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.  
7.5.
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.
7.6.
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.
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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 
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.   
7.7.
Investigational Product Compliance
For the oral medications of lenalidomide or ibrutinib, 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 bottles or blister cards, 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 a reconciliation of capsules/tablets will be done upon bottle or 
blister card return.   Subject compliance will be noted in the source records and on the 
appropriate CRFs based upon the interview and tablet/capsule count.
For the IV medications of durvalumab, rituximab, and bendamustine or local IFRT, the planned 
and administered dosage will be recorded in the source records and on the appropriate CRFs.
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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 trial treatments or disease progression. 
Supportive care, including, but not limited to antiemetic 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 any IP until 90 days after the last dose of durvalumab or 28 days after the last dose of 
other IPs, whichever occurs later, must be reported on the CRF. 
For information regarding other drugs that may interact with any IP and affect its metabolism, 
pharmacokinetics, or excretion, please see the IB and/or local package insert.
8.1.
Permitted/Recommended Concomitant Medications and Procedures
Investigators may prescribe concomitant medications or treatments deemed necessary to provide 
adequate supportive care except for those medications identified as “excluded” as listed in 
Section 8.2. 
Specifically, subjects should receive full supportive care during the study, including transfusions 
of blood and blood products, and treatment with antibiotics, antiemetics, antidiarrheals, and 
analgesics, and other care as deemed appropriate, and in accordance with their institutional 
guidelines.
8.1.1.
Growth Factors and Transfusions for Cytopenia (All Arms)
Growth factors (eg, G-CSF, GM-CSF, erythropoietin, etc) may be prescribed during the 
Treatment and Follow-up Periods at the investigator’s discretion and should be used in 
accordance with the American Society of Clinical Oncology’s (ASCO) guidelines or the 
European Society for Medical Oncology guidelines.  
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 platelet transfusions should not be administered during the Screening Period to 
increase a subject’s blood values in order to meet entry criteria.
In Phase 1, Dose Finding:  Erythropoietic and hematopoietic growth factors (eg, filgrastim 
and pegfilgrastim) as well as transfusional support (packed red blood cells and platelets) 
should not be given during the DLT observation period.  If they are administered this will be 
an indication of possible DLT.  However, it is permitted at the investigator’s discretion after a 
subject completes the first cycle or within the first cycle if a hematological DLT has already been 
declared for that subject.
8.1.2.
Infection Prophylaxis (All Arms)
Investigators may use their discretion in administering infection prophylaxis for subjects 
regarded to be at high risk (including, for example, but not limited to: acyclovir or similar drug 
for herpes zoster; trimethoprim/sulfamethoxazole for Pneumocystis jiroveci infection).  Monitor 
patients for fever, neutropenia and infections and appropriate antiinfective therapy should be 
instituted as indicated.  
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8.1.3.
Venous Thromboembolism Prophylaxis (Lenalidomide)
It is not known whether prophylactic anticoagulation or antiplatelet 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 
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.
8.1.4.
Nausea Prophylaxis (Bendamustine)
Premedication with an antiemetic prior to bendamustine infusion is recommended according to 
local practice.
8.1.5.
Infusion Reaction Prophylaxis (Rituximab, Bendamustine, 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.
Infusion reactions with bendamustine, which may include chills, fever, pruritus, and rash, are 
common. Rarely, anaphylactic and anaphylactoid reactions have occurred, particularly with the 
second or subsequent cycle(s).  
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 bendamustine or durvalumab.
8.1.6.
Early Antitumor Response (eg, Pseudoprogression, Flare Reaction) Treatment
(All Arms)
Early antitumor response (eg, pseudoprogression, flare reaction) is defined as a sudden and 
tender increase in the size of the disease bearing sites, including the lymph nodes, spleen and/or 
the liver often accompanied by low-grade fever, diffuse rash and in some cases increase in the 
peripheral blood lymphocyte counts.  Its treatment is up to the discretion of the investigator 
depending upon the severity and clinical situation. It is suggested that Grades 1 and 2 events be 
treated with nonsteroidal anti-inflammatory drugs (NSAIDs) (ie, ibuprofen 400 to 600 mg orally 
every 4 to 6 hours as needed), corticosteroids, and/or narcotic analgesics for pain management. 
In mild to moderate (Grades 1 and 2) cases, it is suggested that IP be continued along with 
symptomatic treatment as above.
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In more severe cases, IP should be interrupted, as indicated, and treatment with corticosteroids, 
NSAIDs, narcotic analgesics, and or antihistamines is suggested.  Refer to Section 7.2.10.7 for 
further instructions and dose modifications for Grades 3 and 4 events.
During the Treatment Period, emergency use of corticosteroids at any dose to treat the symptoms 
of this event is allowed at the investigator’s discretion.
8.1.7.
Tumor Lysis Syndrome Prophylaxis or Treatment (All Arms)
It is recommended that subjects receive tumor lysis syndrome (TLS) prophylaxis or treatment 
(allopurinol or equivalent as per institutional guidelines) and be well hydrated (orally) during the 
first week of treatment administration in the first cycle, or as clinically indicated.  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 assessed by the Cairo-Bishop Grading system (Appendix D) (not 
by NCI CTCAE) and the assessment includes both laboratory tumor lysis syndrome (LTLS) 
criteria and clinical TLS criteria.  If a subject develops LTLS (defined by the presence of 2 or 
more serum value abnormalities of uric acid, potassium, phosphorous, or calcium) or ≥ Grade 1 
TLS (defined by the presence of laboratory TLS and one or more of the following criteria: 
creatinine ≥ 1.5 × ULN, arrhythmia, or seizures), appropriate medical management should be 
initiated according to the local standard of care in each institution, along with vigorous IV 
hydration.  
Rasburicase for treatment of TLS is considered appropriate if it is approved by the local Health 
Authority.
8.1.8.
Progressive Multifocal Leukoencephalopathy (Rituximab)
John Cunningham (JC) virus infection resulting in progressive multifocal leukoencephalopathy 
(PML), which can be fatal, has been observed in subjects treated with rituximab. Subjects with 
new onset or changes to preexisting neurologic manifestations should be evaluated for PML. The 
symptoms of PML are unspecific and can vary depending on the affected region of the brain. 
Motor symptoms with corticospinal tract findings (eg, muscular weakness, paralysis, and sensory 
disturbances), sensory abnormalities, cerebellar symptoms, and visual field defects are common. 
Some signs/symptoms regarded as “cortical” (eg, aphasia or visual-spatial disorientation) may 
occur. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain 
MRI, and lumbar puncture (cerebrospinal fluid testing for JC viral DNA). Study treatment 
should be discontinued in subjects who develop PML. The subject should be referred to a 
neurologist for the evaluation and treatment of PML.
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 exclusionary or should be used with caution during 
the study. The sponsor must be notified if a subject receives any of these during the study.
1. Any investigational anticancer therapy;
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2. Any concurrent chemotherapy, radiation therapy (except IFRT in Arm D when the 
subject meets the criteria in Section 3.1.2), immunotherapy, biologic or hormonal therapy 
for cancer treatment;
3. Concurrent use of hormones for non-cancer-related conditions (eg, insulin for diabetes 
and hormone replacement therapy) is acceptable;
4. 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) blockers;
Notes: 
For subjects with bulky disease, systemic symptoms, compressive disease, or rapidly 
progressing adenopathies, pre-phase treatment with 1 mg/kg/day prednisone, or 
equivalent, for a maximum of 7 days is permitted prior to Cycle 1 Day 1, at the 
discretion of the investigator.  
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.
5. Live attenuated vaccines during the study through 120 days after the last dose of 
durvalumab and 12 months after last dose of rituximab or until recovery of B-cells, 
whichever occurs later;
6. Herbal and natural remedies are to be avoided.
7. Based 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.
8.2.1.
Prohibited Concomitant Medications for Arm B Only (Ibrutinib)
1. Concomitant anticoagulation with warfarin or other vitamin K antagonists is prohibited 
within 7 days prior to study entry, while on treatment with ibrutinib, and until 7 days after 
the last dose of ibrutinib. Alternative, anticoagulation can be given with caution.  
Investigators should consider the benefit-risk of withholding ibrutinib for at least 3 to 7 
days pre and postsurgery depending upon the type of surgery and the risk of bleeding;
2. Strong and moderate inhibitors of CYP3A should be avoided. For strong CYP3A 
inhibitors used for short-term, ibrutinib should be interrupted during the duration of the 
inhibitor use.  If a moderate inhibitor must be used, ibrutinib dose may be reduced.  
CYP3A inhibitors that are needed chronically are prohibited. In addition, grapefruit and 
Seville oranges should be avoided;  
3. Strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin and St. John’s Wort) 
should be avoided.
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Protocol MEDI4736-NHL-001
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8.2.2.
Prohibited Concomitant Medications for Arm C Only (Bendamustine)
1. Caution should be used, or alternative treatments considered if concomitant treatment 
with CYP1A2 inhibitors (eg, fluvoxamine, ciprofloxacin and other fluoroquinolones, 
amiodarone, ticlopidine, efavirenz, cimetidine) or inducers (eg, omeprazole, rifampin);
2. Caution should be used, or alternative treatments considered if concomitant treatment 
with allopurinol is needed as allopurinol may enhance the adverse effect (specifically, 
the risk of severe skin reactions) of bendamustine. 
8.3.
Required Concomitant Medications and Procedures
8.3.1.
Hepatitis B Virus Reactivation Prophylaxis
In subjects with prior HBV infection, HBV reactivation may occur during or after rituximab,
bendamustine or ibrutinib 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, bendamustine, ibrutinib or lenalidomide treatment. Such subjects should be 
monitored for clinical and laboratory signs (eg, elevation in liver enzymes) of hepatitis and/or 
HBV reactivation during and following rituximab, bendamustine, ibrutinib 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 1/2 study consists of a dose finding part (Phase 1), a dose confirmation part 
(Phase 1), and a dose expansion part (Phase 2). 
The primary objective of the dose finding part is to assess the safety and tolerability of 
durvalumab when given in combination with lenalidomide ± rituximab; ibrutinib; or 
bendamustine ± rituximab to determine the RP2D of each combination in subjects with 
lymphoma or CLL.
The primary objective of the dose confirmation part is to assess the safety and explore the 
preliminary efficacy of durvalumab as monotherapy and when given in combination with 
lenalidomide ± rituximab; ibrutinib; or bendamustine ± rituximab at the RP2D in subjects with 
lymphoma or CLL.
The primary objective of the dose expansion part is to further evaluate the preliminary efficacy 
of durvalumab when given in combination with lenalidomide ± rituximab; ibrutinib; or
bendamustine ± rituximab in subjects with lymphoma or CLL.
Arm A (durvalumab plus lenalidomide with or without rituximab) is discontinued to the 
enrollment of new subjects. Subjects already enrolled and treated in Arm A who are 
receiving clinical benefit, based on the discretion of the investigator, may continue study 
treatment after being reconsented.
On 05 Sep 2017, a Partial Clinical Hold was placed on 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-PD-1 antibody, pembrolizumab, in patients with multiple myeloma in 
combination with immunomodulatory agents. As a result, enrollment into Arm A (durvalumab 
plus lenalidomide with or without rituximab) was discontinued. Subjects already enrolled and 
treated in Arm A before the Partial Clinical Hold who were receiving clinical benefit, based on 
the discretion of the investigator, could continue study treatment if reconsented.
On 16 Sep 2017, following the Partial Clinical Hold, Celgene together with 
AstraZeneca/MedImmune confirmed the decision to close the enrollment of the study. The dose-
finding part of the study was completed for Arms B and C only. The dose-confirmation cohort of 
Arm A nor any of the dose expansion cohorts will open for enrollment.
9.2.
Study Population Definitions
The statistical analysis populations are defined as follows; the decision on 16 Sep 2017, 
following the Partial Clinical Hold alters the definition of population by not considering the dose 
expansion part.

Safety Population (for the dose finding part, the dose confirmation part, and the dose 
expansion part): All subjects who take at least one dose of IP. Reporting done on 
Safety Population will be done against actual treatment received.

DLT Evaluable Population (for the dose finding part):  In Arms A, B, and C, all 
subjects who take at least one dose of IP and completed the DLT evaluation through 
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the end of Cycle 1, or the subjects who take at least one dose of IP and have 
experienced at least one DLT prior to completion of Cycle 1. Reporting done on 
DLT Evaluable Population will be done against actual treatment received.

Efficacy Evaluable Population (for the dose confirmation part and the dose expansion 
part): All subjects who complete at least one cycle of their assigned treatment, have 
baseline and 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 non-missing biomarker assessment, excluding the disqualified 
assessments. Reporting done on Biomarker Evaluable Population will be done 
against actual treatment received.
9.3.
Sample Size and Power Considerations
On 05 Sep 2017, a Partial Clinical Hold was placed on 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-PD-1 antibody, pembrolizumab, in patients with multiple myeloma in 
combination with immunomodulatory agents. As a result, enrollment into Arm A (durvalumab 
plus lenalidomide with or without rituximab) was discontinued. Subjects already enrolled and 
treated in Arm A before the Partial Clinical Hold who were receiving clinical benefit, based on 
the discretion of the investigator, could continue study treatment if reconsented.
On 16 Sep 2017, following the Partial Clinical Hold, Celgene together with 
AstraZeneca/MedImmune confirmed the decision to close the enrollment of the study. The dose-
finding part of the study was completed for Arms B and C only. The dose-confirmation cohort of 
Arm A nor any of the dose expansion cohorts will open for enrollment
The original sample size for the dose finding part, the dose confirmation part, and the dose 
expansion part is described in the subsections below. There is a maximum of 60 (DLT evaluable)
subjects required for the dose finding part, a maximum of approximately 100 subjects for the 
dose confirmation part, and a maximum of approximately 105 subjects for the dose expansion 
part, thus, a total of approximately 265 subjects for the entire study.
9.3.1.
Dose Finding Part (Phase 1)
There are 3 treatment arms in the dose finding part, ie, Arm A (discontinued to the enrollment of 
new subjects), Arm B, and Arm C. The standard “3 + 3” dose escalation design will be used to 
identify MTD and RP2D for each treatment arm. The total sample size for the dose finding part 
ranges from 15 to 60 (DLT evaluable) subjects.  
Subjects will be considered evaluable for DLTs if they complete the DLT evaluation period or 
experience a DLT during the DLT evaluation period.  Non-evaluable subjects may be replaced 
with another subject at the same dose level.
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9.3.1.1.
Arm A (Discontinued to the Enrollment of New Subjects)
Subjects with R/R B-cell NHL will be enrolled into Arm A according to the chart below. There 
are 8 potential dose finding paths: 

DL1 DL2

DL1 DL2 DL-1B

DL1 DL2 DL-1BDL-2

DL1 DL2 DL-1BDL-2DL-3

DL1 DL-1A

DL1 DL-1A DL-1B

DL1 DL-1A DL-1BDL-2

DL1 DL-1A DL-1BDL-2DL-3
The sample size required for Arm A ranges from a minimum of 6 subjects (2 dose levels with 3 
subjects per dose level) to a maximum of 30 subjects (5 dose levels with 6 subjects per dose 
level).  
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DLT ≥ 2/3 or 2/6 
Figure 4:
Arm A Dose Finding Flow Chart
   
Abbreviations: D = durvalumab; DL = dose level; DLT = dose limiting toxicity; Len = lenalidomide; Ritux =
rituximab.
a DL 2 and -1B: Rituximab Schedule 1, rituximab every week in Cycle 1 (Days 2, 8, 15, 22) and on Day 1 of every 
28-day cycle from Cycles 2 through 5.
b DL -2 and DL -3: Rituximab Schedule 2, rituximabon Day 2 of Cycle 1 and on Day 1 of every 28-day cycle from 
Cycles 2 through 8.
9.3.1.2.
Arm B
Subjects with R/R B-cell NHL or CLL/SLL will be enrolled into Arm B according to the chart 
below. There are 2 potential dose finding paths: 

DL1 DL2 

DL1 DL-1
The sample size required for Arm B ranges from a minimum of 6 subjects (2 dose levels with 
3 subjects per dose level) to a maximum of 12 subjects (2 dose levels with 6 subjects per dose 
level). 
DL 2a:  
D + Len 20 mg
    + Ritux
DL 1:
D + Len 20 mg
DLT ≤ 0/3 or 1/6
DLT ≥2/3 or 2/6 
DL -1A: 
D + Len 10 mg
DLT ≤ 0/3 or 1/6
RP2D = DL 2 
      STOP
DLT ≥2/3 or 2/6 
RP2D = DL -1B 
DLT ≥2/3 or 2/6 
DL -1Ba: 
D + Len 10 mg
    + Ritux
DLT ≤ 0/3 or 1/6
RP2D = DL 1 or -1A
DLT ≥2/3 or 2/6 
DLT ≤ 0/3 or 1/6
DL -2b:
D + Len 15 mg
    + Ritux
DLT ≤ 0/3 or 1/6
RP2D = DL -2
DL -3b:
D + Len 10 mg
    + Ritux
DLT ≥2/3 or 2/6 
DLT ≤ 0/3 or 1/6
RP2D = DL -3
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Figure 5:
Arm B Dose Finding Flow Chart
A
Abbreviations: CLL/SLL = chronic lymphocytic leukemia/small lymphocytic lymphoma; D = durvalumab; DL = 
dose level; DLT = dose limiting toxicity; Ibr = ibrutinib; NHL = non-Hodgkin lymphoma.
a This dose level will be the highest dose level tested in subjects with CLL/SLL before opening CLL/SLL dose confirmation 
cohorts. 
9.3.1.3.
Arm C
Subjects with R/R B-cell NHL or CLL/SLL will be enrolled into Arm C according to the chart 
below. There are 2 potential dose finding paths: 
DL1 DL2 
DL1 DL2 DL3
The sample size required for Arm C ranges from a minimum of 3 subjects (1 dose levels with 3 
subjects per dose level) to a maximum of 18 subjects (3 dose levels with 6 subjects per dose 
level).  
DL 1a: 
D + Ibr 420 mg
DL 2: 
D + Ibr 560 mg 
(NHL only)
DLT ≤ 0/3 or 1/6
DLT ≥2/3 or 2/6 
      STOP
DLT ≥2/3 or 2/6 
RP2D = DL 1 (NHL) 
DLT ≤ 0/3 or 1/6
DL -1: 
D + Ibr 280 mg
RP2D = DL -1 
DLT ≥2/3 or 2/6 
DLT ≤ 0/3 or 1/6
RP2D = DL 1 (CLL/SLL) 
DLT ≤ 0/3 or 1/6
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Figure 6:
Arm C Dose Finding Flow Chart
Abbreviations: Bend = bendamustine; CLL/SLL = chronic lymphocytic leukemia/small lymphocytic lymphoma; D
= durvalumab; DL = dose level; DLT = dose limiting toxicity; NHL = non-Hodgkin lymphoma; Ritux = rituximab.
a This dose level will be the highest dose levels tested in subjects with CLL/SLL before opening CLL/SLL dose confirmation 
cohorts. 
9.3.2.
Dose Confirmation Part (Phase 1)
In the dose confirmation part, the planned sample size is based on clinical empirical and practical 
considerations traditionally used for Phase 1/2 studies.
For the dose confirmation, expected rate of overall response (CR/PR) was used in order to 
determine the stopping rules by targeting with 10 subjects a probability of less than 20% of 
observing a certain number of responses or fewer on the stopping rules (eg, for Arm C, histology 
R/R CLL/SLL, given expected ORR is 65%, the probability of observing 4 or less responses out 
of 10 subjects is equal to ~9.5%, and probability of observing 5 or less responses out of 10 
subjects is equal to ~24.9%).
Should the stopping rules described in Table 34 for the dose confirmation part be fulfilled, the 
SRC for that cohort and GSSC will be consulted to determine whether the clinical trial should 
completely stop further enrollment of subjects with a particular histology (ie, not advance to the 
dose expansion part), temporarily halt enrollment and await maturation of efficacy data to 
examine for example durability of responses, or enroll additional subjects either in the dose 
confirmation part or by formally advancing to the dose expansion part.  If there is no expected
activity and/or stopping rules are met for a certain dose level, other potential dose 
levels/schedules can be explored in the dose finding and confirmation parts based on the SRC
and/or GSSC recommendation.  The Sponsor may decide not to expand in any arm based on 
emerging internal or external data in relevant disease and therapeutic field or other reasons in 
consultation with the GSSC and/or SRC.
DL 3: 
D + Ritux
+ Bend 90 mg/m2
RP2D = DL3 (NHL)
DLT ≥2/3 or 2/6 
DLT ≤ 0/3 or 1/6
DLT ≤ 0/3 or 1/6
DL 1: 
D + Ritux
DL 2a: 
D +  Ritux
+ Bend 70 mg/m2
DLT ≥2/3 or 2/6 
STOP
RP2D = DL2 (NHL)
RP2D = DL2 (CLL/SLL)
RP2D = DL1
DLT ≤ 0/3 or 1/6 
DLT ≤ 0/3 or 1/6 
(NHL)
DLT ≥2/3 or 2/6 
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Table 34:
Dose Confirmation Part Stopping Rules for Efficacy
Treatment 
Arm
Subject Histology
Cohort
Stopping 
Rules
Justification
A
Discontinued 
to the 
enrollment of 
new subjects
R/R FL (N = 10)a
≤ 4 overall 
responses
Based on literature that the rituximab-
lenalidomide combination has ORR around 60%, 
the experimental arm has about 90% likelihood to 
continue the trial if its ORR is ≥ 65%.
R/R DLBCL (N = 10)a
≤ 2 overall 
responses
Based on literature that the rituximab-
lenalidomide combination has ORR around 25-
30%, the experimental arm has more than 80% 
likelihood to continue the trial if its ORR is ≥ 
40%.
B
R/R CLL/SLL
(N = 10)
≤ 5 overall 
responses
Based on literature that ibrutinib has ORR around 
70% in the patient population being studied, the 
experimental arm has about 90% likelihood to 
continue the trial if its ORR is ≥ 75%.
R/R MCL 
(N = 10)
≤ 5 overall 
responses
Based on literature that ibrutinib has ORR around 
65%, the experimental arm has about 90% 
likelihood to continue the trial if its ORR is ≥ 
75%.
C
R/R CLL/SLL
(N = 10)
≤ 4 overall 
responses
Based on literature that rituximab + 
bendamustine combination has ORR around 50% 
in the patient population being studied, the 
experimental arm has about 90% likelihood to 
continue the trial if its ORR is ≥ 65%.
R/R FL 
(N = 10)
≤ 2 CR
Based on literature that the standard care has CR 
rate around 40%, the experimental arm has about 
90% likelihood to continue the trial if it’s CR rate 
≥ 45%.
R/R DLBCL 
(N = 10)
≤ 2 overall 
responses
Based on literature that the standard care has 
ORR around 40%, the experimental arm has 
about 90% likelihood to continue the trial if its 
ORR is ≥ 45%.
D
R/R CLL/SLL
R/R DLBCL 
R/R FL 
R/R HL 
R/R MCL 
(5-10 subjects in each; 
total N = 30)
Information collection only
Abbreviations:  CLL = chronic lymphocytic leukemia; CR = complete response; FL = follicular lymphoma; DLBCL 
= diffuse large B-cell lymphoma; HL = Hodgkin lymphoma; MCL = mantle cell lymphoma; N = number of 
subjects; ORR = overall response rate; R/R = relapsed/refractory; SLL= small lymphocytic lymphoma.
a Arm A dose confirmation and dose expansion cohorts are discontinued and will not enroll new subjects.
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The total sample size for the dose confirmation part is estimated to be approximately 100 
subjects. The final number of subjects will depend on the number of subjects used to determine
RP2D in each arm/cohort in the dose finding part.
9.3.3.
Dose Expansion Part (Phase 2)
In the dose expansion part, the planned sample size is based on clinical empirical and practical 
considerations traditionally used for Phase 1/2 studies.
The total sample size for the dose expansion part is estimated to be approximately 105 subjects 
in Arms A, B, and C as described in the Table 24.  The final number of subjects will also depend 
on the number of arms/cohorts in which the RP2D can be confirmed from the dose confirmation 
part.
Table 35:
Dose Expansion Part Sample Size 
Treatment Arm
Subject Histology Cohort
A
Discontinued to the enrollment of new subjects
R/R FL (N = 15)a
R/R DLBCL (N = 15)a
B
R/R CLL (N = 15)
R/R MCL (N = 15)
C
R/R CLL (N = 15)
R/R FL (N = 15)
R/R DLBCL (N = 15)
Abbreviations:  CLL = chronic lymphocytic leukemia; CR = complete response; FL = follicular lymphoma; 
DLBCL= diffuse large B-cell lymphoma; MCL = mantle cell lymphoma; N = number of subjects; R/R = 
relapsed/refractory
a Arm A dose confirmation and dose expansion cohorts are discontinued and will not enroll new subjects.
For arm/cohort selected to continue in the dose expansion part, 15 additional subjects will be 
recruited. In order to make use of all available data, the data of 15 subjects in the dose expansion 
part and the data of 10 subjects in the dose confirmation part for a particular histology will be 
pooled together for treatment efficacy evaluation.  A total of approximately 25 subjects in a 
particular treatment arm and subject histology cohort will provide moderate estimate of the 
response rate with 95% confidence interval (CI) no wider than ± 20%, considered as moderate 
risk level for decision making and appropriate level of information in order to power potential 
future Phase 3 studies.
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.
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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
In the dose confirmation part (dose expansion part was not opened as originally planned), 
treatment efficacy will be evaluated by different histology cohorts for each treatment arm. For 
each subject in Arms A (indolent NHL: FL or MZL), C, D, treatment efficacy will be evaluated 
from his/her last durvalumab dose until 24 months; in Arms A (aggressive NHL) and B, 
treatment efficacy will be evaluated from his/her last durvalumab dose until 24 months after their 
last durvalumab dose or their disease progression, whichever date occurs later.
All efficacy evaluable subjects will be included for efficacy analysis.
Efficacy analysis will be performed for particular treatment arm and subject histology cohort by 
combining data from the dose confirmation part only as the dose expansion part was not opened.
For lymphoma subjects, response evaluation will be based on IWG Response Criteria for 
Malignant Lymphoma (the Lugano Classification) (Cheson 2014). The overall response rate 
(ORR) is defined as the percent of subjects with best response of CR or PR.  Duration of 
response (DoR) is defined for responders only as the time from the first response (CR or PR) to 
disease progression or death.
For CLL subjects, response evaluation will be based on IWCLL guidelines for diagnosis and 
treatment of CLL (Hallek, 2008), as modified by (Hallek, 2012) and (Hallek, 2013). The overall 
response rate (ORR) is defined as the percent of subjects with best response of CR, complete 
response with incomplete marrow recovery (CRi), nodular partial response (nPR), PR, or partial 
response with lymphocytosis (PRL). Duration of response (DoR) is defined for responders only 
as the time from the first response (CR, CRi, nPR, PR, or PRL) to disease progression or death.
The response rate based on the best response during durvalumab treatment as well as during the 
entire efficacy evaluation period will be summarized by subject histology cohort for each 
treatment arm.
For subjects with response but no progression, or death, duration of response will be censored at 
the last date that the subject was known to be progression free. Duration of response will be 
analyzed using the Kaplan-Meier method. Median DoR along with two-sided confidence interval 
will be provided for each treatment arm and subject histology cohort.
Progression-free survival (PFS) is calculated as the time from first IP dose to the first 
documented progression or death due to any cause during the entire efficacy evaluation period. 
For subjects with no progression or death, PFS will be censored at the last date that the subject 
was known to be progression free. Median PFS including 2-sided 95% CI will be provided for 
each histology cohort within the same treatment arm.
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EDMS Doc. Number: 24715418 - 20540270
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Overall survival (OS) is calculated as the time from first IP dose to the date of death due to any 
cause. For subjects who did not die, OS will be censored at the last date that the subject was 
known to be alive. OS will be analyzed similarly to PFS and DoR.
9.7.
Safety Analysis
Safety analysis will include all subjects in the Safety population.
Investigational product exposure will be summarized for each treatment arm and histology 
cohort including duration of investigational product, 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 histology 
cohort. 
Adverse events will be coded according to Medical Dictionary for Drug Regulatory Activities 
(MedDRA) and classified using the NCI CTCAE.  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 terms and adverse events of special interest (see Section 10.7) for a subject will be 
utilized for summaries of AEs by NCI CTCAE grade.
Subsets of AEs to be summarized include AESIs, SAEs, suspected treatment-related AEs, and 
AEs that resulted in withdrawal of investigational product. 
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.  
Laboratory data will be graded according to NCI CTCAE severity grade.  The frequencies of the 
worst severity grade observed during treatment will be displayed in cross-tabulations by baseline 
status for each treatment arm and histology cohort. 
For variables for which an NCI CTCAE scale 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 and histology cohort.
Change from baseline will be descriptively summarized at each post-baseline visit by treatment 
arm and histology cohort.
Laboratory shift tables will be produced by treatment arm.
9.8.
Interim Analysis
No formal interim analysis is planned for this study.
Following the decision to stop the follow-up data collection, no additional analyses will be 
performed after the primary analysis completion.
9.9.
Other Topics
The PK and biomarker analysis will be specified in separate analysis plan.
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EDMS Doc. Number: 24715418 - 20540270
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9.9.1.
Steering Committee
The conduct of this trial will be overseen by a global scientific steering committee (GSSC), 
presided over by the coordinating Principal Investigator(s) and if possible the lead investigators 
of each treatment arm from countries 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.
9.9.2.
Exploratory Analysis 
Possible relationships between molecular/cellular characteristics and safety and efficacy 
variables may be explored, as appropriate.
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EDMS Doc. Number: 24715418 - 20540270
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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 
preexisting 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 7.4 for the definition of 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, ibrutinib, rituximab, bendamustine, or local IFRT 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 from the last dose of durvalumab or 28 days from the last dose of any IP (ie, 
lenalidomide, ibrutinib, rituximab, bendamustine, or local IFRT), whichever occurs later, as well 
as those SAEs made known to the investigator at any time thereafter that are suspected of being 
related to study treatment.  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 primary analysis (data cutoff date 06 Mar 2019), AEs and SAEs are 
no longer required to be collected in the CRFs. 
For subjects still receiving ibrutinib on-study, investigators will continue to record all AEs/ SAEs 
in the subject’s source documents and report SAEs to Celgene Drug Safety, as well as those 
SAEs made known to the investigator at any time thereafter, that are suspected of being related 
to study treatment.  
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EDMS Doc. Number: 24715418 - 20540270
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10.2.
Evaluation of Adverse Events
A qualified investigator will evaluate all AEs as to: 
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; or

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.
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EDMS Doc. Number: 24715418 - 20540270
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
an elective treatment of or an elective procedure for a preexisting 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.
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 study treatment, action taken regarding the study treatment, 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 version of the NCI CTCAE Version 4.03 with the exception of TLS (Cairo, 
2004; Appendix D) and laboratory abnormalities as recommended by the IWCLL guidelines for 
the diagnosis and treatment of CLL (Hallek, 2008; Appendix E); 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40
Adverse events that are not defined in the NCI 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.
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10.2.3.
Causality
The investigator must determine the relationship between the administration of the IP(s) 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(s) caused the adverse event.  ‘Reasonable possibility’ means 
there is evidence to suggest a causal relationship between the 
IP(s) and the adverse event.
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
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
is judged to be of significant clinical importance, eg, 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.  
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 βhCG 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, ibrutinib, or bendamustine; 12 months 
after the last dose of rituximab; or 28 days after last dose of lenalidomide, whichever occurs 
later, are considered immediately reportable events. 
Investigational product is to be discontinued immediately and the subject instructed to return 
any unused portion of the IP (ie, lenalidomide or ibrutinib) 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 
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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.
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 from the last dose of durvalumab 
or 28 days from the last dose of any other study treatment [ie, lenalidomide, ibrutinib, rituximab, 
bendamustine, or local IFRT], whichever occurs later) or any SAE made known to the 
investigator at any time thereafter that are suspected of being related to IP or participation in the 
study (eg, a study-related procedure). In case of local regulations and/or requirements, any SAE 
made known to the investigator beyond the protocol-defined safety follow-up period above may 
be reported to Celgene Drug Safety even if not suspected of being related to IP or participation in 
the study (eg, a study-related procedure) 
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.  
Following completion of the primary analysis (data cutoff date 06 Mar 2019), AEs and SAEs are 
no longer required to be collected in the CRFs. 
For subjects still receiving ibrutinib on-study, investigators will continue to record all AEs/ SAEs 
in the subject’s source documents and report SAEs to Celgene Drug Safety, as well as those 
SAEs made known to the investigator at any time thereafter, that are suspected of being related 
to study treatment.    
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.
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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 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 Investigator’s
Brochure.
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 IPs (ie, rituximab, bendamustine, 
or ibrutinib) based on the EU Summary of Product Characteristics (SmPC). Any SAE that is 
suspected of being be related to local IFRT alone will not be assessed for expectedness or
reported in an expedited manner.
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 annual 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 
the understanding of durvalumab and may require close monitoring and rapid communication by 
the investigator to the sponsor. An AESI may be serious or nonserious The rapid reporting of 
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AESIs allows ongoing surveillance of these events in order to characterize and understand them 
in association with the use of durvalumab.
Adverse event of special interest for durvalumab include but are not limited to events with a 
potential inflammatory or immune-mediated mechanism and which may require more frequent 
monitoring and/or interventions such as steroids, immunosuppressants and/or hormone 
replacement therapy.  These AESIs are being closely monitored in clinical studies with 
durvalumab monotherapy and combination therapy. An immune-mediated adverse event (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 regards to an adverse event (AE) being an imAE, the 
investigator should promptly contact the sponsor’s medical monitor.
Further information on these AESI (eg, presenting symptoms) can be found in the current 
version of the Durvalumab Investigator’s Brochure. 
10.7.1.
Second Primary Malignancies (SPMs)
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 durvalumab;

28 days after last dose of other IPs; 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 primary analysis (data cutoff date 06 Mar 2019), SPMs will no 
longer be collected in the CRFs. For all subjects, investigators will continue to record SPMs in 
the subject’s source documents and report SPM events to Celgene Drug Safety. 
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
Any of the following events are considered sufficient reasons for discontinuing a subject from 
the IPs:

Adverse Event

Withdrawal by subject

Death

Lost to follow-up

Disease progression

Pregnancy

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 sponsor’s medical monitor and forward appropriate 
supporting documents for review and discussion.
11.2.
Study Discontinuation
Any of the following events are considered sufficient reasons for discontinuing a subject from 
the study:

Screen failure

Adverse event

Withdrawal by subject

Death

Lost to follow-up

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 Physicians 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 International Council for 
Harmonisation (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-s 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 re-
consented 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 primary analysis data cutoff date 06 Mar 
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 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 primary analysis data cutoff date 06 Mar 
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;

IP accountability records;
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
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, FDA, 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.
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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, contribution in essential correlative 
studies, participation in study steering committee (when applicable) and contribution to abstract, 
presentation and/or publication development.
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17.
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with nivolumab in relapsed or refractory Hodgkin's lymphoma.  N Engl J Med 2015;372(4):311-
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Armitage JO.  Treatment of non-Hodgkin’s lymphoma.  N Engl J Med 1993;328(14):1023-30.  
Baitsch L, Fuertes-Marraco SA, Legat A, Meyer C, Speiser DE. The three main stumbling 
blocks for anticancer T-cells. Trends Immunol 2012;33(7):364-72.
Bendeka® (bendamustine) [Package Insert].  North Wales, PA:  Teva Pharmaceuticals; 2016.  
Available from: http://bendeka.com/Pdf/PrescribingInformation.PDF.  Accessed February 08, 
2017.
Benson DM Jr, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B, et al.  The PD-
1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic 
target for CT-011, a novel monoclonal anti-PD-1 antibody.  Blood 2010;116(13):2286-94.
Blank C, Mackensen A.  Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an 
update on implications for chronic infections and tumor evasion.  Cancer Immunol Immunother 
2007;56(5):739-45.
Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al.  Phase I study of 
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18.
APPENDICES
Appendix A:  Table of Abbreviations
Abbreviation or 
Specialist Term
Explanation
ACTH
Adrenocorticotropic hormone
ADA
Anti drug antibodies
ADCC
Antibody-dependent cell-mediated cytotoxicity
ADL
Activities of daily living
AE
Adverse event
AESI
Adverse event of special interest
ALC
Absolute lymphocyte count
ALK
Anaplastic lymphoma kinase
ALT (SGPT)
Alanine transaminase (serum glutamate pyruvic transaminase)
ANC
Absolute neutrophil count
Anti-HBc
Antibody to the hepatitis B core antigen
Anti-HBs
Antibody to the hepatitis B surface antigen
Anti-PD-1
Anti-Programmed Cell Death 1
Anti-PD-L1
Anti-Programmed Cell Death Ligand 1
aPTT
Activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
AST (SGOT)
Aspartate aminotransferase (serum glutamic oxaloacetic transaminase)
AUC
Area under the curve
Β-hCG
Beta-human chorionic gonadotropin
BMB
Bone marrow biopsy
BMI
Body mass index
BNP
Brain natriuretic peptide
BPH
Benign prostate hypertrophy
BSA
Body surface area
BTK
Bruton’s tyrosine kinase
BUN
Blood urea nitrogen
CBC
Complete blood count
CD
Cluster of differentiation 
CHF
Congestive heart failure
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Abbreviation or 
Specialist Term
Explanation
cHL
Classical Hodgkin lymphoma
CI 
Confidence interval
CILS
Cumulative illness rating scale
CL
Clearance
c-LDL
Low density lipoprotein cholesterol
CLL
Chronic lymphocytic leukemia
Cmax
Maximum plasma concentration of drug
CNS
Central nervous system
COPD
Chronic obstructive pulmonary disease
CR
Complete response
CrCL
Creatinine clearance
CRF
Case report form
CRi
Complete response with incomplete marrow recovery 
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T-lymphocyte-associated antigen 4
CYP3A
Cytochrome P450, family 3, subfamily A
DILI
Drug induced liver injury
DL
Dose level
DLBCL
Diffuse large B-cell lymphoma
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
DOR
Duration of response
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders-IV
DVT
Deep venous thrombosis 
EC
Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EEA
European Economic Area
EGFR
Epidermal growth factor receptor 
EOI
End of infusion
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Abbreviation or 
Specialist Term
Explanation
EOT
End of (all) treatment
EOT-D
End of durvalumab treatment
Fc
Fragment crystallizable
FC
Flow cytometry
FCBP
Female (subject) of child bearing potential
FDA
Food and Drug Administration
FDG-PET
Fluorodeoxyglucose-positron emission tomography
FDG-PET-CT
Integrated FDG-PET with CT
FEV1
Forced expiratory volume in 1 second 
FFPE
Formalin fixed paraffin embedded
FISH
Fluorescence in situ hybridization
FL
Follicular lymphoma
fT3
Free triiodothronine
fT4
Free thyroxine
GCP
Good Clinical Practice
G-CSF
Granulocyte-colony-stimulating factor
GDS
Geriatric Depression Scale
GERD
Gastroesophageal reflux disease
GGT
Gamma glutamyl transferase
GI
Gastrointestinal
GM-CSF
Granulocyte-macrophage colony-stimulating factor
GSSC
Global scientific steering committee
HBeAg
Hepatitis B e antigen
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HBV-DNA
Hepatitis B virus deoxyribonucleic acid
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HL
Hodgkin lymphoma
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
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Abbreviation or 
Specialist Term
Explanation
IEC
Independent Ethics Committee
IFRT
Involved-field radiation therapy
IFNγ
Interferon γ
Ig
Immunoglobulin
IHC
Immunohistochemistry
ILD
Interstitial lung disease
IMiDs ®
Immunomodulatory agents
IND
Investigational new drug
INR
International normalized ratio 
iNHL
Indolent non-Hodgkin lymphoma
IP
Investigational product
imAE
Immune-mediated adverse events
IRB
Institutional review board
IRT
Integrated response technology
IUD
Intrauterine device
IV
Intravenous
IVIG
Intravenous immune globulin
IWCLL
International Workshop on Chronic Lymphocytic Leukemia
IWG
International Working Group
JC
John Cunningham
LDH
Lactic dehydrogenase
LLN
Lower limit of normal
LTLS
Laboratory tumor lysis syndrome
mAb
Monoclonal antibody
MCL
Mantle cell lymphoma
MDS
Myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MEDI4736
Durvalumab
MI
Myocardial infarction
MM
Multiple myeloma
MMSE
Comprehensive Geriatric Assessment
MRD
Minimum residual disease
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Abbreviation or 
Specialist Term
Explanation
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
MZL
Marginal zone lymphoma
N
Number of patients
NCI
National Cancer Institute
NHL
Non-Hodgkin lymphoma
NK
Natural killer
nPR
Nodular partial response
NSAID
Non steroidal anti-inflammatory drug
NSCLC
Non-small cell lung cancer
NTD
Non-tolerated dose
NYHA
New York Hearth Association
ORR
Overall response rate
OS
Overall survival
PAD
Peripheral arteries disease 
PBMC
Peripheral blood mononuclear cell
PCR
Polymerase chain reaction
Pd
Pharmacodynamics
PD
Progressive disease
PD-1
Programmed Cell Death 1
PD-L1
Programmed Cell Death Ligand 1
PD-L2
Programmed Cell Death Ligand 2
PFS
Progression-free survival
PK
Pharmacokinetics
PML
Progressive multifocal leukoencephalopathy
PO
Per oral
PR
Partial response
PRL
Partial response with lymphocytosis
PRN
Pro re nata; as needed
PTT
Partial thromboplastin time
Q2W
Once every 2 weeks
Q4W
Once every 4 weeks
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Abbreviation or 
Specialist Term
Explanation
QD
Once daily
QIG
Quantitative immunoglobulins
RP2D
Recommended Phase 2 dose
R/R
Relapsed or refractory
RT
Richter’s transformation
SAE
Serious adverse event
SLL
Small lymphocytic lymphoma
SmPC
Summary of product characteristics
SOP
Standard operating procedure
sPD-L1
Soluble PD-L1
SPM
Second primary malignancy
SRC
Safety Review Committee
SUSAR
Suspected unexpected serious adverse reaction
t1/2
Terminal elimination half-life
Th1
Type 1 T helper
TILs
Tumor-infiltrating lymphocytes
TLS
Tumor lysis syndrome
Tmax
Time to maximum concentration
TNF
Tumor necrosis factor
TNF-α
Tumor necrosis factor alpha
TNM
Tumor, nodes, metastasis
TSH
Thyroid stimulating hormone
TURP
Transurethral resection of the prostate
ULN
Upper limit of normal
US
United States
UTI
Urinary tract infection
Vz/F
Volume of distribution
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 B1:
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 
assessment
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
Abbreviations: 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 B2:
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
Nonmeasured 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
Nonmeasured 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 B2:
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
Nonmeasured 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 
slenic 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
Nonmeasured 
lesions
None
New or clear progression of preexisting 
nonmeasured lesions
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Table B2:
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
Abbreviations: 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 deescalation is investigated, it may be preferable to 
consider a score of 3 as inadequate responses (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. Nonmeasured 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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Appendix C:  Guidelines for the Diagnosis and Treatment Response of 
Chronic Lymphocytic Leukemia: International Workshop on Chronic 
Lymphocytic Leukemia
The guidelines for the diagnosis and treatment response of chronic lymphocytic leukemia are 
outlined in a report by the International Workshop on Chronic Lymphocytic Leukemia 
Hallek, 2008) with modifications (Hallek, 2012; Hallek, 2013).
Table C1:
Diagnostic Assessment of Chronic Lymphocytic Leukemia
Diagnostic Test
General Practice
Clinical Trial
History, Physical Examination
Always 
Always 
CBC and Differential Count 
Always 
Always 
Marrow Aspirate and Biopsy 
At cytopenia of uncertain cause 
At CR or cytopenia of uncertain 
cause 
Assessment for Minimal 
Residual Disease 
Not generally indicated 
Desirable 
Ultrasound of the Abdomen 
Possible, if previously abnormal 
Not generally indicated 
CT Scans of the Chest, Pelvis, 
and Abdomen 
Not generally indicated 
Recommended if previously 
abnormal and otherwise with a 
CR/PR 
Abbreviations:  CBC = complete blood counts; CR = complete response; CT = computerized tomography; PR = 
partial response.
Source: Hallek, 2008.
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Table C2:
Response Definition after Treatment for Chronic Lymphocytic Leukemia Patients
Parameter
Complete Response
Partial Response
Partial Response with 
Lymphocytosis
Progressive Disease
Lymphadenopathy 
None > 1.5 cm 
Decrease ≥ 50%, no increase 
or new 
Decrease ≥ 50%, no 
increase or new 
Increase ≥ 50% or new 
(>1.5 cm)
Hepatomegaly 
None 
Decrease ≥ 50% from 
baseline
Decrease ≥ 50% from 
baseline
Increase ≥ 50% or new
Group A
Splenomegaly 
None 
Decrease ≥ 50% from 
baseline
Decrease ≥ 50% from 
baseline
Increase ≥ 50% or new
Blood Lymphocytes 
< 4000/μL 
Decrease ≥ 50% from 
baseline
Persistent lymphocytosis 
due to mechanism of action 
of IP
Increase ≥ 50% over 
baseline
Marrow 
Normocellular, 
< 30% lymphocytes, no B-
lymphoid nodules
Hypocellular marrow defines CRi 
50% reduction in marrow 
infiltrate, or B-lymphoid 
nodules 
50% reduction in marrow 
infiltrate, or B-lymphoid 
nodules 
-
Group B
Platelet count
> 100,000/μL
> 100,000/μL or increase ≥
50% over baseline
> 100,000/μL or increase        
≥50% over baseline
Decrease of ≥ 50% from 
baseline secondary to CLL
Hemoglobin
> 11.0 g/dL
> 11.0 g/dL or increase ≥
50% over baseline
> 11.0 g/dL or increase ≥
50% over baseline
Decrease of > 2g/dL from 
baseline secondary to CLL
Neutrophils
> 1500/μL
> 1500/μL or increase ≥ 50% 
over baseline
> 1500/μL or increase        
≥ 50% over baseline
-
Complete Response (CR) = all of the criteria have to be met, and patients have to lack disease-related constitutional symptoms; 
CR with Incomplete Bone Recovery (CRi) = fulfills all criteria for a CR (including normal bone marrow biopsy and aspirate with no evidence of clonal infiltrate) 
except for persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to chronic lymphocytic leukemia (CLL) but likely related to drug toxicity; 
Nodular PR (nPR) = persistent bone marrow nodules (immunohistochemistry has to determine if primariliy of T cells or lymphocytes other than CLL cells or 
CLL cells) on bone marrow biopsy in subjects achieving a CR; If bone amrrow is hypocellular then a repeat determination should be performed after 4 weeks.
Partial Response (PR) and Partial Response with Lymphocytosis (PRL) = at least two of the criteria of Group A plus one of the criteria of Group B have to be 
met for a minimum duration of 2 months; Stable Disease (SD) = is the absence of Progressive Disease (PD) and failure to achieve at least PR;
PD = at least one of the above criteria of Group A or Group B has to be met.
Source: Hallek, 2008.
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Appendix D:  Cairo-Bishop Definitions of Tumor Lysis Syndrome
Table D1:  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 patient has or will receive 
adequate hydration (± alkalinization) and a hypouricaemic agent(s).
Table D2:  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 D3: Cairo-Bishop Grading System for TLS
Grade
LTLS
Creatinine
Cardiac Arrythmia
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
Abbreviations:  ADL= activities of daily living; LTLS = laboratory tumor lysis syndrome; TLS= tymor lysis
syndrome; ULN = upper limit of normal.  
  a Probably or definitely attributable to clinical TLS.
Source: Cairo, 2004
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Appendix E: Grading Scale for Hematologic Toxicity in Chronic 
Lymphocytic Leukemia Studies
Grade
a
Decrease in Platelets
b
or Hgb
c
(nadir) 
From Pretreatment Value (%)
Absolute Neutrophil Countd (mm3) 
(nadir)
0
No change to 10%
≥ 2,000
1
11% - 24%
≥ 1500 and < 2000
2
25% - 49%
≥ 1000 and < 1500
3
50% - 74%
≥ 500 and < 1000
4
≥ 75%
< 500
a Grades: 1, mild; 2, moderate; 3, severe; 4, life-threatening; 5, fatal.  Death occurring as a result of toxicity at any 
level of decrease from pretreatment will be recorded as Grade 5.
b Platelet counts must be below normal levels for Grades 1-4.  If, at any level of decrease the platelet count 
is < 20,000/mm3, this will be considered Grade 4 toxicity, unless a severe or life-threatening decrease in the initial 
platelet count (eg, 20,000/ mm3) was present pretreatment, in which case the subject is not evaluable for toxicity 
referable to platelet counts.
c Hemoglobin (Hgb) levels must be below normal levels for Grades 1-4.  Baseline and subsequent Hgb 
determinations must be performed before any given transfusions.  The use of erythropoietin is irrelevant for the 
grading of toxicity, but should be documented.
d If the absolute neutrophil count (ANC) reaches less than 1000/ mm3, it should be judged to be Grade 3 toxicity.  
Other decreases in white blood cell count, or in circulating granulocytes, are not to be considered, since a decrease 
in white blood cell count is a desired therapeutic end point.  A gradual decrease in granulocytes is not a reliable 
index in chronic lymphocytic leukemia for stepwise grading of toxicity.  The use of granulocyte-
colony-stimulating factor (G-CSF) is irrelevant for the grading toxicity, but should be documented.
Source: Hallek, 2008.
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Appendix F: Lenalidomide Pregnancy Prevention Risk Management Plan
The Pregnancy Prevention Risk Management Plan is a standalone document.
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Appendix G: Inhibitors or Inducers of CYP3A
Inhibitors and inducers of CYP3A are defined as follows. A comprehensive list of inhibitors can 
be found at the following website: http://medicine.iupui.edu/clinpharm/ddis/table.aspx. The 
general categorization into strong, moderate, and weak inhibitors according to the website is 
displayed below. Refer to Section 8.2 on instructions for concomitant use of CYP3A inhibitors 
or inducers with ibrutinib.
Inhibitors of CYP3A4/5
Inducers of CYP3A4/5
Strong inhibitors:
Carbamazepine
Indinavir
Efavirenz
Nelfinavir
Nevirapine
Ritonavir
Barbiturates
Clarithromycin
Glucocorticoids
Itraconazole
Modafinil
Ketoconazole
Oxcarbarzepine
Nefazodone
Phenobarbital
Saquinavir
Phenytoin
Telithromycin
Pioglitazone
Moderate inhibitors:
Rifabutin
Aprepitant
Rifampin
Erythromycin
St. John’s Wort
Diltiazem
Troglitazone
Fluconazole
Grapefruit Juice
Seville Orange Juice
Verapamil
Weak inhibitors:
Cimetidine
All Other Inhibitors:
Amiodarone
NOT Azithromycin
Chloramphenicol
Boceprevir
Delaviridine
Diethyl-Dithiocarbamate
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Inhibitors of CYP3A4/5
Inducers of CYP3A4/5
Fluvoxamine
Gestodene
iImatinib
Mibefradil
Mifepristone
Norfloxacin
Norfluoxetine
Star fruit
Telaprevir
Troleandomycin
Abbreviation: CYP = cytochrome P450.
Source: http://medicine.iupui.edu/clinpharm/ddis/table.aspx
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Appendix H: Criteria for Initiating Treatment in Subjects with CLL 
(Adopted and Modified from the IWCLL Guidelines for CLL Section 4)
Active disease should be clearly documented for protocol therapy. At least one of the following 
criteria should be met:
1. Evidence of progressive marrow failure as manifested by the development of, or 
worsening of, anemia and/or thrombocytopenia; 
2. Massive (ie, at least 6 cm below the left costal margin) or progressive or symptomatic 
splenomegaly;
3. Massive nodes (ie, at least 10 cm in longest diameter) or progressive or symptomatic 
lymphadenopathy;
4. Progressive lymphocytosis with an increase of more than 50% over a 2-month period or
lymphocyte doubling time (LDT) of less than 6 months. LDT can be obtained by linear 
regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks 
over an observation period of 2 to 3 months.  In patients with initial blood lymphocyte 
counts of less than 30 × 109/L (30 000/μL), LDT should not be used as a single parameter 
to define a treatment indication.  In addition, factors contributing to lymphocytosis or 
lymphadenopathy other than CLL (eg, infections) should be excluded.
5. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids 
or other standard therapy (see the IWCLL Guidelines for CLL section 10.2)
6. Constitutional symptoms, defined as any one or more of the following disease-related 
symptoms or signs:
a.
Unintentional weight loss of 10% or more within the previous 6 months;
b. Significant fatigue (ie, ECOG PS 2 or worse; inability to work or perform usual 
activities);
c.
Fevers higher than 100.5°F or 38.0°C for 2 or more weeks without other evidence of 
infection; or 
d. night sweats for more than 1 month without evidence of infection.
Hypogammaglobulinemia or monoclonal or oligoclonal paraproteinemia does not by itself 
constitute a basis for initiating therapy.  However, it is recommended to assess the change of
these protein abnormalities if patients are treated.  Patients with CLL may present with a 
markedly elevated leukocyte count; however, the symptoms associated with leukocyte 
aggregates that develop in patients with acute leukemia rarely occur in patients with CLL. 
Therefore, the absolute lymphocyte count should not be used as the sole indicator for treatment.
7. Patients who have resistant disease, a short time to progression after the first treatment, 
and/or leukemia cells with del(17p) often do not respond to standard chemotherapy and 
have a relatively short survival. Therefore, such patients should be offered investigative 
clinical protocols, including allogeneic hematopoietic stem cell transplantation.
Source: Hallek, 2008.
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Appendix I: Modified Cumulative Illness Rating Scale (CIRS)
RATING SUGGESTIONS (GENERAL PRINCIPLES)
Every single disease must be classified in the appropriate system. If there are several problems in 
the same system, only the most severe is rated. Example: For a patient suffering from a well-
controlled angina (Rated 2) and terminal heart failure (Rated 4), only the higher rated condition 
would be scored in the Cardiac system (eg, rating is 4).
The spread of a cancer may lead to rating the condition in more than one category. For example, 
a lung cancer with bone metastases treated with nonsteroidal anti-inflammatory drugs (NSAID) 
is Rated 4 in Respiratory and 2 in Musculoskeletal.
General rules for severity rating:
0 - No problem affecting that system or past problem without clinical relevance.
1 - Current mild problem or past significant problem.
2 - Moderate disability or morbidity and/or requires first line therapy.
3 - Severe problem and/or constant and significant disability and/or hard to control chronic 
problems (complex therapeutic regimen).
4 - Extremely severe problem and/or immediate treatment required and/or organ failure 
and/or severe functional impairment.
LEVEL 0
No problem or healed minor injuries; past childhood illnesses (chickenpox); minor surgery 
(carpal tunnel completely healed, caesarean); uncomplicated healed fractures; other past 
problems healed without sequel, residual or complication (pneumonia).
LEVEL 1
Any current medical problem that causes mild discomfort or disability, or has occasional 
exacerbations, having only minor impact on morbidity (asthma controlled with PRN [“as 
needed”] bronchodilators, occasional heartburn relieved with PRN antiacids). Medical problems 
that are not currently active but were significant problems in the past (passage of a kidney stone) 
or required major surgery (hysterectomy, cholecystectomy, appendectomy).
LEVEL 2
Medical conditions that require daily treatment or first line therapy (asthma controlled with 
inhaled steroids, gastro-esophageal reflux treated with daily medication, osteoarthritis requiring 
daily NSAID, etc.) and/or have moderate disability or morbidity.
LEVEL 3
Chronic conditions that are not controlled with first line therapy (asthma needing continuous 
corticosteroid therapy, symptomatic angina despite medical regimes, heart failure with symptoms 
or uncontrolled hypertension despite complex therapeutic regimen) and/or constant significant 
disability, but not severe disability.
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LEVEL 4
Any acute condition that requires immediate treatment or hospitalization (unstable angina, acute 
myocardial infarction, stroke, but also bladder outlet obstruction) and/or extremely severe 
problems; organ failure (end-stage renal disease needing dialysis, oxygen-dependent chronic 
obstructive pulmonary disease, terminal heart failure); severe sensory impairment (almost 
complete blindness or deafness, being wheelchair bound) and/or severely affected quality of life, 
severe impairment in function; delirium by medical (organic) conditions.
RATING MALIGNANCIES
Consistent scoring of severity ratings for various malignancies is a difficult problem. Each 
malignancy has its own rating system and prognostic indicators, the complexity of which would 
quickly exceed the aim of the intended simplicity and ease of use of CIRS.
The following general guidelines are intended to provide a reasonably accurate delineation of 
medical burden for cancer without excessive complexity.
Level 1: Cancer diagnosed in the remote past without evidence of recurrence or sequel in the past 
10 years or skin cancer excised in the past without major sequel (other than melanoma).
Level 2: No evidence of recurrence or sequel in the past 5 years.
Level 3: Required chemotherapy, radiation, hormonal therapy or surgical procedure for cancer in 
the past 5 years.
Level 4: Recurrent malignancy or metastasis (other than to lymph glands) or palliative treatment 
stage.
These ratings are to be made in the appropriate organ category for a given malignancy.
ORGAN-SPECIFIC CATEGORIES
The following organ specific categories will attempt to provide guidelines for consistent rating of 
comparable severity. Common conditions will be stressed with the focus on the “judgment 
strategy” that can be applied to other problems not listed. 
If there are several conditions in the same system, only the most severe is rated.
HEART
In this category only heart and coronary diseases have to be considered (not vascular): coronary 
arteries disease, heart failure, valvular heart diseases, heart disease secondary to hypertension, 
endocardities, miocardities, pericardities, arrhythmias (extrasystoles, bundle-branch blocks, atrial 
fibrillation, pacemaker placement), heart malignancies. Functional impact must be considered 
too, eg, New York Hearth Association (NYHA) II heart failure has different value between 
dependent and independent persons.
0 - No problems
1 - Remote MI (> 5 years ago); occasional [exertion] angina; asymptomatic valvular disease
2 - Congestive heart failure (CHF) compensated with medications (NYHA I-II); daily anti-
angina medications; left ventricular hypertrophy; atrial fibrillation, bundle branch block, 
daily anti-arrhythmic drugs (even for prophylaxis); pacemaker placement for 
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asymptomatic bradycardia (relieved by Holter electrocardiogram [ECG] monitoring); 
valvular disease requiring medical treatment
3 - Previous myocardial infarction (MI) (<5 years ago); abnormal stress test; status post 
(previous) percutaneous coronary angioplasty, coronary artery bypass graft surgery or 
other cardiac surgery (valve replacement); moderate CHF (NYHA II-III) or complex 
medical treatment; bifascicular block; pacemaker placement for cardiogenic syncope; 
pericardial effusion or pericarditis
4 - Acute coronary syndrome, unstable angina or acute MI; intractable CHF (NYHA III-IV 
acute or chronic); marked restriction to the normal activity of daily living secondary to 
cardiac status
HYPERTENSION
Consider only hypertension severity; organ damage (complications) should be considered into 
the respective categories.
0 - Normotension
1 - Borderline hypertension; hypertension compensated with salt restriction and weight loss, 
drug free (when drug therapy is indicated, but the patient does not take medications, the 
score is at least 2)
2 - Daily antihypertensive medications: hypertension controlled by 1 pill therapy (even fixed 
dose combinations)
3 - Hypertension requiring two or more pills for control
4 - Malignant hypertension, or hypertension not controlled by a complex therapeutic regimen
VASCULAR-HEMATOPOIETIC
Artery disease: carotid atherosclerosis, peripheral arteries disease (PAD), aneurysms (every site)
Venous disease: venous insufficiency, varices, deep venous thrombosis (DVT), pulmonary 
embolism, primary pulmonary hypertension
Hematopoietic disease: anemia, leucopenia, thrombocytopenia, hematological malignancy
Lymphopoietic disease: chronic lymphatic edema, lymphoma, spleen and thymus disease
Immunologic disease: systemic lupus erythematosus, systemic sclerosis (scleroderma), 
sarcoidosis, hypersensitivity
0 - No problem
1 - Venous insufficiency, varices, lymphedema; carotid stenosis <70%; hemoglobin 10-12 
g/dl (in females), 12-14 g/dl (in males); anemia of chronic “inflammatory” disease
2 - Previous DVT; one symptom of atherosclerosis disease (claudication, bruit, amaurosis 
fugax, absent pedal pulses) or daily medications (eg, anti-platelets drugs); PAD IIa-IIb by 
Fontaine; carotid stenosis > 70%; aortic aneurysm < 4 cm; hemoglobin 8-10 g/dl (in 
females), 10-12 g/dl (in males); anemia secondary to iron, B12 vitamin or folate 
deficiency, or to chronic renal failure; total white blood cell (WBC) 2000-4000/mmc; 
mild thrombocytopenia (50000-150000/mmc)
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3 - DVT or recent DVT (< 6 months ago); two or more symptoms of atherosclerosis (see 
above); PAD Fontaine III or recent/previous angioplasty (with or without stenting); 
hemoglobin < 8g/dl (in females), < 10 g/dl (in males); dyserythropoietic anemia; WBC <
2000/mmc; severe thrombocytopenia (< 50000/mmc)
4 - Pulmonary embolism (acute or recent/previous); atherosclerosis requiring surgical 
intervention (eg, aortic aneurysm > 4 cm, symptomatic carotid stenosis > 70%, PAD 
Fontaine IV or amputation for vascular causes, etc.); recent/previous vascular surgery; 
any hematological or vascular malignancy (including multiple myeloma)
In case of immunological disease, score should be assigned by considering blood abnormalities, 
stadium of organ damage and/or functional disability (2: symptoms controlled by daily 
medications; 3: symptoms not well controlled; 4: symptoms impossible to be controlled or short 
time poor prognosis)
RESPIRATORY
In this category, consider chronic obstructive pulmonary disease (COPD), asthma, emphysema, 
restrictive pulmonary interstitial lung diseases, malignancies of lung and pleura, pneumonia, and 
smoking status.
0 - No problem
1 - Recurrent episodes of acute bronchitis; currently treated asthma with PRN inhalers when 
required; cigarette smoker > 10 but < 20 pack years
2 - Instrumental diagnosis of COPD or pulmonary interstitial disease (x-ray, TC, spirometry); 
daily Prn inhalers (≤2 pharmacological classes); two or more episodes of pneumonia in 
the last 5 years; cigarette smoker < 20 but < 40 pack years
3 - Exertion dyspnea secondary to limited respiratory capacity, not well controlled by daily 
medications; required oral steroids for lung disease; daily PRN inhalers (3 
pharmacological classes); acute pneumonia treated as an outpatient
4 - Chronic supplementation of oxygen; respiratory failure requiring assisted ventilation, or 
previous (at least one episode); any lung or pleural neoplasm; acute pneumonia requiring 
hospitalization
Smoking is an important respiratory and cardiovascular risk, so it is considered as a disease, and 
it is rated according to lifetime pack years: 
Number of cigarette packs smoked per day × Number of years smoked in their lifetime
eg, 1 pack year = 20 cigarettes/day (1 pack) × 1 year
Ex-smokers should be rated too, but those who have been smoke free for the most recent 20 
years would merit a lower rating than currently smoking
Examples:
A. Patient smoking 20 cig/day (1 pack) for 25 years = 25 pack years – CIRS score: 2
B. Patient smoking 40 cig/day (2 packs) for 25 years = 50 pack years – CIRS score: 3
C. Ex-smoker of 20 cig/day (1 pack) for 25 years, he stopped 5 years ago – CIRS score: 2
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D. Ex smoker of 20 cig/day (1 pack) for 25 years, he stopped 20 years ago – CIRS score: 1
Classification of COPD could be more specific when instrumental data (objective evidence) are 
available: blood gases, forced expiratory volume in 1 second (FEV1), etc.
EYES, EARS, NOSE & THROAT, and LARYNX
To simplify the potential complexity of this category it was decided to score according to the 
severity of the disability created by sensory diseases (degree of limited autonomy and 
communication), and avoid rating each type of pathology. Sensory impairments should be rated 
after instrumental correction (corrective lenses, hearing aid, etc.).
Eyes: glaucoma, cataracts, macular degeneration (diabetic/hypertensive retinopathy), any other 
pathology
Ears: otitis, dizziness, any cause of hearing impairment
Nose & Throat: rhinitis, pharyngitis, nasal polyps, sinusitis, malignancies
Larynx: dysphonia, acute and chronic laryngitis, malignancies
0 - No problems
1 - Corrected vision with glasses; mild hearing loss; chronic sinusitis
2 - Difficulty in reading newspaper or drive although glasses; required hearing aid; chronic 
sinonasal complaints requiring medication; vertigo/dizziness requiring daily medications
3 - Severe low vision, partially blind (required an escort to venture out, unable to read 
newspaper); severe ear impairment (conversational heading still impaired with hearing 
aid); laryngeal dysphonia (not neurological dysarthria)
4 - Functional blindness/deafness: unable to read, recognize a familiar face, unable to 
conversational heading, even if “organically” he is not completely blind or deaf; 
laryngectomy (every cause, especially malignancies); required surgical intervention for 
vertigo; aphonia secondary to laryngeal impairment.
UPPER GASTROINTESTINAL SYSTEM
This category is comprehensive of the intestinal tract from esophagus to duodenum, and 
pancreatic trees: dysphagia, gastroesophageal reflux disease (GERD), hiatal hernia, esophageal 
diverticula, any type of gastritis (consider also H. Pylori eradication or not), gastric/duodenal 
ulcer, acute or chronic pancreatitis, malignancies (comprehensive of gastric lymphoma).
Pay attention that type 1 diabetes is rated under “metabolic.”
0 - No problem
1 - Hiatal hernia, GERD or gastritis requiring PRN medications; previous ulcer (> 5 years 
ago); previous Helicobacter pylori eradication therapy (> 5 years ago)
2 - Daily proton pump inhibitor/anti-acid medications; documented gastric or duodenal ulcer 
or Helicobacter pylori eradication therapy within 5 years
3 - Active gastric or duodenal ulcer; positive fecal occult blood test; any swallowing disorder 
or dysphagia; chronic pancreatitis requiring supplemental pancreatic enzymes for 
digestion; previous episode of acute pancreatitis
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4 - Any type of malignancies (see “Rating Malignancies”); previous gastric surgery because 
of cancer; history of perforated ulcer (gastric surgery not because of cancer, ulcorrhaphy); 
melena/heavy bleeding from upper gastrointestinal (GI) source; acute pancreatitis
LOWER GASTROINTESTINAL SYSTEM
Comprehensive of the rest of the GI system, from small bowel to anus: Whipple’s disease, 
diverticulosis, irritable bowel, malignancies. Constipation is rated, too, by type and frequency of 
laxatives required, or by history of impaction.
0 - No problems, previous appendectomy, previous hernia repair (without complications)
1 - Constipation managed with PRN medications; active hemorrhoids; intestinal hernia 
requiring surgery; previous hernia repair with complications (intestinal adherences, 
laparocele, etc.); irritable bowel syndrome (few symptoms)
2 - Constipation requiring daily bulk laxatives (psyllium, policarbophil, sterculia, guar gum, 
etc.), or stool softeners; diverticulosis (previous diverticulitis); inflammatory bowel 
disease in remission with medications (> 5 years ago)
3 - Bowel impaction/diverticulitis within the last year; daily use of stimulant (irritant) or 
osmotic laxatives (bysacodil, senna, glycerol, sodium docusate; lactulose, polyethylene 
glycol) or enemas; chronic bowel inflammation in remission with medications (<5 years 
ago)
4 - Diverticulitis flare up; active inflammatory disease; current impaction; 
hematochezia/active bleeding from lower GI source; bowel carcinoma
LIVER AND BILIARY TREES
Comprehensive of liver, gallbladder, biliary trees, portal system: acute and chronic hepatitis 
(viral, alcoholic, toxic, autoimmune, idiopathic), cirrhosis, portal hypertension, 
hemochromatosis, primary biliary cirrhosis, cholelithiasis, cholangitis, primary malignancies. As 
the hepato-biliary system is difficult to assess through the physical examination, therefore, 
laboratory results must be used.
0 - No problem
1 - History of hepatitis (actually normal values of transaminases); cholecystectomy
2 - Cholelithiasis; chronic hepatitis or previous hepatitis (<5 years ago) or any other liver 
disease (hemochromatosis, primary biliary cirrhosis) with mildly elevated transaminases 
(within 3-times normal values); heavy alcohol use within 5 years (should be rated in 
“psychiatric” category also)
3 - Chronic hepatitis or any other liver disease with marked elevation of transaminases (>3-
times normal values); elevated bilirubin
4 - Acute cholecystitis; any biliary obstruction; active hepatitis/liver cirrhosis; any liver or 
biliary tree carcinoma
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RENAL
This category is exclusive of kidney: kidney stones, acute/chronic renal failure, 
glomerulonephritis; nephrosic/nephritic syndrome; active/chronic pyelonephritis, diabetic or 
hypertensive nephropathy (albuminuria/proteinuria), renal carcinoma.
Bence-Jones proteinuria in multiple myeloma should not be considered.
0 - No problem exists
1 - Asymptomatic kidney stone; kidney stone passage within the last ten years; 
pyelonephritis within 5 years; kidney cysts without hematuria
2 - Serum creatinine > 1.5 but < 3 mg/dl without diuretic or antihypertensive medication 
(particularly angiotension converting enzyme-inhibitors or systemic renin-angiotension-
aldesterone blockers); kidney calculi requiring daily medications
3 - Serum creatinine > 3 mg/dl or > 1.5 mg/dl in conjunction with diuretics, antihypertensive, 
or bicarbonate therapy; active pyelonephritis; nephrosic syndrome; colic symptoms 
treated as an outpatient
4 - Required dialysis; renal carcinoma; colic symptoms requiring hospitalization
GENITOURINARY
Ureters, bladder, urethra.
Genitals, prostate, testicles, penis, seminal vesicles.
Uterus, ovaries. Mammary gland is rated under “metabolic.”
This category is comprehensive of all genitourinary tract impairments: ureteral or bladder stones, 
benign prostate hypertrophy (BPH), urinary tract infections (UTIs), prolapses, etc. Urinary 
incontinence and indwelling catheter should also be considered.
0 - No problem
1 - Stress incontinence; BPH without urinary symptoms; hysterectomy or ovariectomy 
(uterine fibroma, benign neoplasm)
2 - Pathological pap smear (or 2 consecutives abnormal); frequent UTIs (3 or more in the 
past year) in female or current UTIs; urinary incontinence (not stress) in females; BPH 
with urinary symptoms (frequency, urgency, hesitancy); status post transurethral resection 
of the prostate (TURP); any urinary diversion procedure; indwelling catheter; bladder 
calculi
3 - Prostatic cancer in situ (eg, incidentally found during TURP); vaginal bleeding; cervical 
carcinoma in situ; hematuria (any cause); urinary incontinence (not stress) in males; 
bladder polyps
4 - Acute urinary retention; current urosepsis; any genitourinary malignancies except as 
above
MUSCULOSKELETAL/INTEGUMENT
This is a very wide category, including: osteoarthritis, osteoporosis, any bone fracture; primary 
neoplasm (bone, muscle, connective tissue, skin), distinguishing melanoma from other localized 
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skin cancers; rheumatoid arthritis and polymyalgia rheumatica; muscular injuries (rotator cuff, 
long head of the biceps); pressure sores; any dermatological disease.
The scores of this category are strictly correlated to the disability they cause; for the evaluation 
of the level of disability, refer to basic activities of daily living and instrumental activities of 
daily living
NOTICE: Score the severity of each illness according to the level of disability caused by the 
same illness in this category, without considering the disability caused by other diseases. For 
example: A patient affected both by osteoarthritis and hemiplegia from a previous stroke has a 
high level of disabilityand must be scored 2 for disability by osteoarthritis (in this category) and 
4 for disability by stroke (in the neurological category); for a patient with both a deforming 
rheumatoid arthritis and a previous stroke without remaining outcomes, score 4 for disability 
from arthritis (in this category) and 2 for disability from stroke (in the neurological category).
0 - No problem exists
1 - Requires PRN medications for osteoarthritis (NSAID) or has mildly limited IADL from 
joint pathology; excised skin cancers (except melanoma); skin infections requiring 
antibiotics within a year
2 - Daily anti-osteoarthritis medications (NSAID) or use of assisitive devices or little 
limitation in ADL (previous arthroprosthesis or treated fracture with a low level of 
remaining disability); osteoporosis without vertebral fractures; daily medications for 
chronic skin diseases (even local, as psoriasis or pressure sores); non metastatic 
melanoma; daily medications for rheumatoid arthritis (except steroids) with a low level of 
disability
3 - Osteoarthritis with a moderate level of disability in ADL; requires chronic treatment with 
steroids for arthritic conditions or joints’ deformities or severely impaired; osteoporosis 
with vertebral compression fractures
4 - Wheelchair bound for osteomuscular disease; severe joint deformities or severely 
impaired usage; osteomyelitis; any bone or muscle or connective tissue neoplasm (see 
“Rating Malignancies”); metastatic melanoma.
Fractures and/or arthroprosthesis (both recent and old) have to be scored according to the level of 
disability they cause (considering outcomes also), in order to avoid confusion about possible 
classifications of different fractures or joints. The same for muscular diseases.
CENTRAL AND PERIPHERAL NERVOUS SYSTEM
This category includes the “somatic” pathologies of the central and peripheral nervous system: 
any kind of stroke, neurodegenerative diseases (Parkinson’s disease and parkinsonism, multiple 
sclerosis, amyotrophic lateral sclerosis, etc.), myelopathies, traumas with neurological outcomes, 
primary or secondary epilepsy, neuropathies (diabetic, alcoholic, any other etiology), primary 
tumors, chronic headaches (migraine), insomnia, etc. It must carefully estimate the severity and 
prognosis of the illness but also the functional impairment that the illness causes.
0 - No problem (or fewer convulsions in childhood)
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1 - Frequent headaches requiring PRN medications without impairment in Advanced ADL; 
previous transient ischemic attack (TIA) (one event); previous epilepsy, actually not 
treated, without crisis since more than 10 years ago.
2 - Chronic headache requiring daily medications (even for prophylaxis) or with regularly 
functional impairment in Advanced ADL (bed rest, job withdrawal, etc.); actual TIA or 
more than one previous TIA; previous stroke without significant residual; mild severity 
neurodegenerative diseases (see above), treated and well controlled; epilepsy controlled 
with drugs.
3 - Previous stroke with mild residual dysfunction (hemiparesis, dysarthria); any 
neurosurgical procedure; moderate severity neurodegenerative diseases (see above), not 
well controlled by medications; epilepsy in treatment but with periodic crisis.
4 - Acute stroke or previous stroke with severe residual dysfunction (hemiplegia, aphasia, 
severe vascular dementia) or more than one previous stroke (multi-infarct 
encephalopathy); severe neurodegenerative diseases (see above) causing disability in 
ADL; neurological coma.
Alzheimer’s disease and dementia should not be rated into this category (Psychiatric and 
behavioral diseases): Alzheimer’s disease should be listed only under psychiatric disorders; if 
dementia stems from vascular and/or mixed dementia and/or other neurological condition (eg,
Parkinson’s Disease), both “neurologic” and “psychiatric” categories should be endorsed at the 
appropriate level for severity, considering in this category the stroke and the multi-infarct 
encephalopathy responsible for the cognitive impairment (score 3 for stroke with remaining 
outcomes, score 4 for multi-infarct encephalopathy).
ENDOCRINE-METABOLIC SYSTEM AND BREAST (including systemic infections and 
poisonings)
Type 1 and type 2 diabetes (organ damage should be considered into the respective categories, 
like for hypertension), obesity and dyslipidemia (hypercholesterolemia) represent the core of this 
category; it includes also hypo- and hyper-thyroidism, hypo- and hyper-parathyroidism, adrenal 
pathologies (Cushing’ or Addison’ disease), hypogonadism, hypopituitarism, etc. Malignancies 
of these glands, both benignant (like thyroid nodules) and malignant (like thyroid or adrenal 
cancer, vipoma, etc.) are also included.
Even if it is an exocrine gland, breast was included in this category because the authors could not 
find a more appropriate one; thus, it includes breast cancer also.
Moreover, it includes: electrolyte disorders, sepsis, systemic infections (like tuberculosis, 
syphilis, AIDS) scored according to their severity and the functional impairment they cause (see 
general indications) and poisonings (chronic by metals or acute by pesticides or carbon 
monoxide).
0 - No problem
1 - Diabetes and/or dyslipidemia compensated with diet; mild obesity (Body mass index 
[BMI] 30 -35 kg/m2); hypothyroidism in replacement therapy (L-thyroxin); 
hyperthyroidism caused by Plummer’ adenoma surgically treated.
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2 - Diabetes compensated with oral hypoglycemic drugs or insulin (hemoglobin A1c < 7%); 
dyslipidemia well controlled by daily medications (low density lipoprotein cholesterol [c-
LDL] lower than the recommended target according to the individual global 
cardiovascular risk); moderate obesity (BMI 35-45 kg/m2); hyperthyroidism (Basedow, 
Plummer) in pharmacologic treatment; asymptomatic or surgically treated 
hyperparathyroidism; fibrocystic breast disease.
3 - Diabetes not well compensated by therapy (hemoglobin A1c 7-8.5%, presence of 
complications); dyslipidemia not well controlled (c-LDL higher than the recommended 
target according to the individual global cardiovascular risk; for instance, c-LDL> 100 
mg/dl in patients with previous myocardial infarction or stroke); severe obesity (BMI >
45 kg/m2); symptomatic hyperparathyroidism (for instance, hypercalcaemia); 
replacement therapy for adrenal failure; any electrolytes disorder requiring 
hospitalization.
4 - Uncontrolled diabetes (hemoglobin A1c > 8.5%) or one diabetic ketoacidosis or 
nonketotic hyperosmolar coma during the past year; genetic uncontrolled dyslipidemia; 
acute adrenal failure during hormonal replacement therapy; any neoplasm of thyroid, 
breast, adrenal gland (see “Rating Malignancies”).
NOTICE: When the patient is not treated with drug therapy for diabetes or dyslipidemia but he 
should be for the optimal control of the pathology (for instance, hemoglobin A1c > 7%, total 
cholesterol > 250 mg/dl), score the pathology according to the laboratory values, which really 
define its severity.
PSYCHIATRIC AND BEHAVIORAL DISEASES
This category includes both dementia and related behavioral disorders (psychosis, anxiety, 
depression, agitation) and all the pre-existing and/or not related to dementia psychiatric 
disorders. Since this is the only item analyzing patient’s mental status (all the others refer to 
physical status), it is very important to evaluate it considering carefully further information 
derived from the Comprehensive Geriatric Assessment (MMSE; Geriatric Depression Scale
[GDS], Neuro-Psychiatric Inventory if available).
0 - No psychiatric problem or history thereof
1 - Minor psychiatric condition or history thereof: previous (occasional) psychiatric treatment 
without hospitalization; major depressive event and/or use of antidepressants more than 
10 years ago without hospitalization; occasional use of minor tranquilizers (eg,
benzodiazepins; even if as hypnotherapy for insomnia); mild cognitive impairment 
(MMSE 25-28).
2 - A history of major depression (according to DSM-IV [Diagnostic and Statistical Manual 
of Mental Disorders-IV] criteria) within the last 10 years (treated or untreated); mild 
dementia (MMSE 20-25); previous admission to Psychiatric Department for any reason; 
history of substance abuse (more than ten years ago, including alcoholism).
3 - Current major depression (according to DSM-IV criteria) or more than two previous 
major depression episodes in the past 10 years; moderate dementia (MMSE 15-20); 
current and usual usage of daily anti-anxiety medications (even as hypnotherapy for 
Approved
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Approved
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EDMS Doc. Number: 24715418 - 20540270
Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
248
MEDI4736-NHL-001 Amendment #4 Final: 22 Apr 2020
insomnia); current or within the past ten years substance abuse or dependence (according 
to DSM-IV criteria); requires daily antipsychotic medication; previous attempt at suicide.
4 - Current mental illness requiring psychiatric hospitalization, institutionalization, or 
intensive outpatient management (psychiatric emergency, as attempt at suicide or severe 
depression with suicide purpose, acute psychosis or acute decompensation of chronic 
psychosis, severe substance abuse; severe agitation from dementia); severe dementia 
(MMSE < 15); delirium (acute confusion or altered mental status for medical (organic) 
reasons: in this case, codify also the medical cause in its own category with the 
appropriate level of severity).
It could be requested psychiatric consult for this category; dementia and depression, the most 
frequent diseases in the elderly, can be scored in details using the MMSE and GDS. The severity 
of any mental disorder (dementia, depression, anxiety, psychosis, substance abuse and all the 
others) has to be scored according to the level of functional impairment or disability they cause.
Source: Salvi, 2008b
Approved
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Approved
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EDMS Doc. Number: 24715418 - 20540270
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: Tuesday, 26 May 2020, 04:06 PM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
 ================================================
Approved
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Approved
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EDMS Doc. Number: 24715418 - 21902853
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
3
MEDI4736-NHL-001 Amendment #4 Final:  22 Apr 2020
1.
JUSTIFICATION FOR AMENDMENT
The purpose of Protocol Amendment #4 is twofold.
First, to address a formulation change for ibrutinib study treatment.  Currently supplied as 140 
mg capsules, this formulation is no longer commercially available.  The new formulation is a 140 
mg tablet with the same active ingredient.  The tablets were commercially approved as being 
equivalent to the original formulation.
The second purpose of this amendment is to allow subjects to be followed as per standard of care 
according to the investigator’s medical judgement.  
At the time of this Protocol Amendment #4, 10 subjects are receiving ibrutinib monotherapy. 
Significant changes included in this amendment are summarized below:

Subjects will move to a tablet formulation when the capsule formulation is no longer 
commercially available.
Commercially sourced 140 mg capsule formulation is being substituted on the markets by a 
140mg tablet formulation. 
Tablets will be supplied in a blister pack instead of a bottle.  Ibrutinib administration was 
updated to note the study treatment will be supplied as either capsules or tablets.
Revised Sections:  Section 7.1.4, Section 7.7, and Section 7.2.1.2.2

For subjects continuing on ibrutinib, scheduled clinic visits will be done according 
to standard of care per investigator’s discretion
Subjects on ibrutinib are routinely followed every three months as standard of care, not the 
current monthly schedule.  The schedule for investigational product (IP) dispensing and 
treatment visits will be done per the investigator’s medical judgement and standard of care at the 
investigative site. 
The investigator remains responsible to monitor safety, record adverse events (AEs)/serious 
adverse events (SAEs)/second primary malignancies(SPMs) in source documents, and report 
SAEs and SPMs to Celgene Drug Safety.
Revised Sections:  Protocol Summary, Section 3.2.3, Section 5/Table 8, Section 6.2, Section 
6.3.2, and Section 6.5. 
1.0
Approved
930197061
5.0
v
Approved
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EDMS Doc. Number: 24087454 - 21902853
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
3
MEDI4736-NHL-001 Amendment #3 Final: 12 Sep 2019
1.
JUSTIFICATION FOR AMENDMENT
The purpose of Protocol Amendment 3 is to close the study, discontinue the Follow-up Period,
and stop data collection in the clinical database.  
Following completion or discontinuation of durvalumab therapy per protocol for all subjects
(n=106), and completion of the primary analysis (data cutoff date 06 Mar 2019, defined as last 
durvalumab subject’s 90-day Safety Follow-up Visit), there are no further plans to evaluate long-
term efficacy, including overall survival for the remaining subjects on study.  Therefore, the 
Follow-up Period will be discontinued, and data collection will stop under this amendment. No 
additional statistical analysis on safety and efficacy will be performed. 
At the time of primary analysis data cutoff, 36 subjects were in follow-up. There were 13 
subjects on ibrutinib treatment (Arm B), and no subjects on treatment with lenalidomide or 
bendamustine. Subjects receiving benefit from ibrutinib may continue to receive ibrutinib on-
study per investigator’s medical judgement or discontinue study to receive ibrutinib 
commercially as standard of care treatment (off-study).
Subjects who received lenalidomide will continue to be followed for second primary 
malignancies (SPMs) as required by 
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 and all other study treatments, are no 
longer required to be followed for disease progression, subsequent antilymphoma/chronic 
lymphocytic leukemia (CLL) therapy, and overall survival. Follow-up procedures, efficacy 
assessments, central labs, imaging, and survival data can stop and will not be collected in the 
case report forms (CRFs). 
Revised Sections:  Protocol Summary, Section 3.2.3, Table 7, Table 8, Table 9, Table 10,
Section 6.3.2, and Section 6.4.1.1.

Subjects on ibrutinib therapy (Arm B) and discontinuation of follow-up data 
collection
In Arm B, ibrutinib continuous dosing is once daily until disease progression, unacceptable 
toxicity, starts new therapy, or discontinuation for any other reason, ie, subject withdraws 
consent or discontinues per investigator’s discretion. Subjects may discontinue study to receive 
ibrutinib commercially as standard of care treatment (off-study).
Subjects receiving benefit from ibrutinib may continue ibrutinib on-study based on investigator’s 
medical judgment. Follow-up efficacy assessments, central labs, imaging, and survival data will 
not be collected in the CRFs. The investigator remains responsible to monitor safety, record
adverse events (AEs)/serious adverse events (SAEs) in source documents, and report SAEs to 
Celgene Drug Safety as stipulated under the full protocol.   
Revised Sections:  Protocol Summary, Section 3.2.2, Section 3.2.3, Section 6.2.1, Section 6.3.2,
Section 6.4.1.1, Section 7.2.1.2, Section 10.1, and Section 10.5.
Approved
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v
Approved
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v


EDMS Doc. Number: 24087454 - 21902853
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
4
MEDI4736-NHL-001 Amendment #3 Final: 12 Sep 2019

Second Primary Malignancies (SPMs) data collection
Collection and monitoring of second primary malignancies will continue as events of interest and 
will be reported as SAEs regardless of treatment arm. 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 and reported as SAEs to Celgene Drug Safety. 
It is no longer required to collect SPMs in the clinical database, ie, AE and SPM CRFs.
Revised Sections: Protocol Summary and Section 10.7.1.
The amendment also includes several other minor clarifications: 

Editorial updates. – Protocol Summary, Table 3, Section 10.6 and Section 15.2.

Revised length of study from 8 years to 6 years. – Protocol Summary and Section 3.2.

Removed Canada and Health Canada. Protocol was not opened for enrollment in 
Canada. – Section 7.1.3, Section 7.1.4, Section 7.1.5, and Section 15.2.

Clarification on ibrutinib’s dose modifications and toxicity management will be per 
investigator’s medical judgement. – Section 7.2.10.5 and Section 7.2.10.7. 

Updated the originally planned statistical analyses due to the enrollment stop, 
discontinuation of dose expansion cohorts, and discontinuation of the Follow-up 
Period. – Section 9.1, Section 9.2, Section 9.3, and Section 9.6.

Specified that no additional analyses will be generated after the primary analysis data 
cutoff date (06 Mar 2019). Any data generated after this date will be maintained in 
the source documents and not required to be entered in the clinical database. –
Section 9.8, Section 14.1, and Section 14.2.
Approved
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Approved
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EDMS Doc. Number: 22417459 - 21902853
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
3
MEDI4736-NHL-001 Amendment #2 Final: 14 Dec 2017
1.
JUSTIFICATION FOR AMENDMENT
Protocol Amendment 2 is written to update the Toxicity Management Guidelines (TMGs) and to 
reflect that on 05 Sep 2017 the United States (US) Food and Drug Administration (FDA) placed a 
Partial Clinical Hold on this study. The decision by the FDA was based on risks identified in other 
trials for an anti-PD-1 antibody, pembrolizumab, in patients with multiple myeloma in 
combination with immunomodulatory agents.
Significant changes included in this amendment are summarized below:

Discontinuation of Arm A to the enrollment of new subjects
Arm A (durvalumab plus lenalidomide with or without rituximab) is discontinued to the 
enrollment of new subjects. Only those subjects already enrolled and treated who are receiving 
clinical benefit, based on the discretion of the investigator, can remain on treatment after being
informed and reconsented on the safety concerns with the combination of a programmed cell 
death-1 (PD-1) pathway inhibitor and an immunomodulatory agent. In addition, the add-on 
combination treatment with lenalidomide ± rituximab is no longer allowed. Other treatment arms 
in this study will continue unchanged. 
Changes to the protocol have been made in the Protocol Summary and Sections 2 through 7 and 
9 to reflect discontinuation of enrollment to Arm A.

Updates to the Toxicity Management Guidelines (TMGs)
Update have been made to the general dose modification and TMGs (Tables 30, 31, and 32).
Other changes:

Addition of approved durvalumab indication for the treatment of locally advanced or 
metastatic urothelial carcinoma (Section 1.2.1)

Addition of rituximab intravenous biosimilars and rituximab subcutaneous usage for 
dose administration as they are becoming standard of care in some study sites
(Section 7.1.3)

Inclusion of risk of hepatitis B virus reactivation for ibrutinib as per ibrutinib 
summary of product characteristics (Section 8.3.1)

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: 21902969 - 21902853
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
3
MEDI4736-NHL-001 Amendment #1 Final: 04 May 2017
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:

Addition of 2 new dose levels (ie, dose levels -2 and -3) to the Arm A dose finding 
part
Initially, 4 potential dose levels were planned in Arm A.  The doublet combination of 
durvalumab and lenalidomide 20 mg (dose level 1) was studied and deemed tolerable by the 
dedicated Safety Review Committee (SRC) as 0 of 3 subjects dosed was reported with a dose 
limiting toxicity (DLT) during Cycle 1.  Thus, the triplet combination of durvalumab 1500 mg 
every 4 weeks (Q4W) and lenalidomide 20 mg plus rituximab (375 mg/m2 weekly × 4 in Cycle 1
and then Day 1 of Cycles 2 through 5) (dose level 2) followed.  This dose level was deemed not-
tolerated by the SRC as 3 of 3 subjects dosed were reported with at least 1 DLT during Cycle 1.  
Consequently, the next 3 subjects were assigned to the subsequent lower dose level which is the
same triplet combination with a reduced dose of lenalidomide 10 mg (dose level -1B).  This dose 
level is currently being evaluated for DLTs.  
In case dose level -1B is found to be not-tolerated by the SRC, new dose levels (ie, dose levels -2 
and -3) are planned with the triplet regimen described in this protocol amendment.  In dose 
levels -2 and -3, the combinations of durvalumab 1500 mg Q4W, lenalidomide 15 or 10 mg with
rituximab at a less dose-intense schedule (ie, 375 mg/m2 Q4W in Cycles 1 through 8) will be 
studied for tolerability.  
For these new 2 dose levels, up to 12 additional DLT evaluable subjects may need to be treated 
to confirm a preliminary recommended Phase 2 dose (RP2D).  
(Protocol Summary, Sections 3.1, 3.2.2, 4.1, 7.2.1.1, and 9.3.1.1, Figures 2 and 4, Tables 7 and
20)

Change to the allowed time windows for pretreatment archival lymph 
node/tumor biopsy and on treatment Cycle 2 biopsy samples, and removal of the 
requirement of a fresh frozen biopsy sample
Effective development of novel targeted therapies depends on the identification of correlative 
biomarkers in an attempt to identify patients who are most likely to benefit from these agents.  
Experience with the use of durvalumab in patients with solid tumors showed that higher response
rates were observed in subjects with programmed cell death ligand-1 (PD-L1)-positive tumors, 
compared with subjects with PD-L1 negative tumors in their pretreatment biopsy samples (Segal, 
2014).  Thus, further evaluation of these biomarkers and a broad exploration of additional 
biomarkers related to immunological and disease factors are needed to identify predictive 
biomarkers for durvalumab therapy in lymphoid malignancies.
As tumors may change their biologic profile over time and potentially in response to intervening 
treatments, an archival lymph node/tumor biopsy sample collected 18 months before study 
treatment start (as initially allowed) might not accurately reflect current molecular characteristic 
of tumor. To allow for an accurate assessment of tumor characteristics at baseline, an archival 
lymph node/tumor formalin fixed, paraffin embedded (FFPE) sample acquired by a surgical or 
core needle biopsy within 3 months prior to signing informed consent and with no intervening 
treatment after the biopsy is acceptable for enrollment of a subject with a poorly accessible 
tumor for biopsy following discussion with the sponsor’s medical monitor.  
Approved
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EDMS Doc. Number: 21902969 - 21902853
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
4
MEDI4736-NHL-001 Amendment #1 Final: 04 May 2017
Initially an on-treatment biopsy sample collection (strongly recommended) was planned at 
Cycle 2 Day 15 (± 3 days).  The collection of this biopsy sample will be allowed at any time 
during Cycle 2 for greater logistical flexibility. 
In addition, as the current technological advancements have made it possible to run the planned 
analyses on FFPE samples alone, a fresh frozen biopsy sample will not be necessary to submit 
for biomarker studies. 
(Sections 3.2.1, 4.2, 6.1, and 6.2)

Removal of Aiolos/Ikaros analysis (Arm A)
Aiolos and Ikaros are the downstream substrates of Cereblon which is the molecular target of 
lenalidomide and other immunomodulatory (IMiDs®) compounds.  The analyses in other 
durvalumab studies suggest that durvalumab has no effect on degradation of those substrates 
when given in combination with an IMiD compound. Thus, the planned blood collections and 
analyses (ie, pre- and 5 hours post dose at Cycle 1 Day 1, and Cycle 2 Day 1 and Day 15) for 
Aiolos and Ikaros in Arm A were removed.  
(Protocol Summary, Sections 1.3.6, 2, and 6.8.3 and Table 2)

Change to the secondary efficacy endpoints (Phase 1/2)
Time to first response has been added as an additional secondary endpoint for further 
characterization of disease response.  The timeframe for secondary overall response rate
endpoint has been changed from ‘during the study treatment’ to ‘during the study’ which will be 
inclusive of any study treatment related response documented during the treatment and follow-up 
periods of the study as objective responses to immune checkpoint inhibitors can take 
considerably longer to become apparent compared with conventional therapies and continued 
disease regression can be reported well after completion of the treatment.  
(Section 2 and Table 2)

Revision of inclusion criterion #6
Inclusion criterion #6 which defines subjects with high-risk chronic lymphocytic leukemia
(CLL)/small lymphocytic lymphoma (SLL), will be changed to allow the inclusion of subjects 
who failed therapy on any Bruton’s tyrosine kinase (BTK) inhibitor (not only ibrutinib).  As 
clinical trials with other BTK inhibitors (eg, acalabrutinib, tirabrutinib) are currently ongoing, 
there is an emerging patient population who fail on these newer or experimental BTK inhibitors, 
and who are considered to meet the criteria of high-risk CLL/SLL, too.   
(Section 4)
The amendment also includes several other updates, clarifications and corrections:

Addition of the informal study name “FUSION NHL 001” to the title page. The study 
name was added to allow easier conversational identification for potential subjects 
and health care professionals.  (Title Page and Protocol Summary) 

Addition of an exploratory objective and endpoint for assessment of abscopal effect 
(ie, immune-mediated tumor response outside the radiation field) with local IFRT 
when given in combination with durvalumab.  (Protocol Summary, Table 1)
Approved
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Approved
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EDMS Doc. Number: 21902969 - 21902853
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
5
MEDI4736-NHL-001 Amendment #1 Final: 04 May 2017

Revision of the name of the treatment arms to accommodate a case in which a doublet 
regimen may be a recommended regimen for Phase 2 instead of a planned triplet 
regimen based on the emerging data.  (Protocol Summary, Section 3.1 and 7.2, Table 
3)

Clarification that in the United States (US), treatment Arm D will enroll, pending 
availability of treatment slots, following the completion of response evaluation from 
the combination therapy arms (ie, Arms A, B, and C).  (Protocol Summary, Section 
3.1, and Figure 2)

Update of the number of subjects planned for:

Arm A dose finding part: revision from “6 to 18” to “6 to 30” DLT evaluable 
subjects with the addition of 2 new potential dose levels (N = 12) 

Arm C dose finding part: correction of the number of DLT evaluable subjects
from “6 to 18” to “3 to 18”

Overall dose finding part: revision from “18 to 48” to “15 to 60” DLT evaluable
subjects

Overall study: revision from approximately 253 to 265 subjects
(Protocol Summary, Sections 3.1, 4.1, and 9, Table 3)

Further description of the treatment assignment process as follows: “Subjects will be 
assigned to 1 of the 4 treatment arms based on the investigator’s choice led by the 
subject’s eligibility status as per the inclusion/exclusion criteria described for each 
arm, prior antilymphoma/CLL therapy and response to prior therapy, medical history 
and also the availability of open treatment slots in a given cohort.”  (Protocol 
Summary, Sections 3.1 and 3.2.2)

Update with new indications which have been approved for lenalidomide and 
ibrutinib in the US and/or Europe. (Sections 1.2.2 and 1.2.3)

Update with new indications which have been approved for the PD-1/PDL-1 blocking 
antibodies (ie, nivolumab, pembrolizumab, and atezolizumab) in the US, Europe, 
and/or Japan.  (Section 1.3.1)

Addition of Bendeka® as a reference product for bendamustine.  
(Sections 1.2.4 and 17)

Update of the entire section to clarify objectives of the translational development 
plan, including the addition of recent studies which suggest additional evidence of the 
value of pretreatment tumor characteristics and certain microenvironment changes in 
on-treatment tumor samples which may provide both prognostic correlative 
biomarkers and predictive correlative biomarkers for response (Rizvi, 2015; Higgs, 
2016).  Addition of specific sampling for biomarker assessments for each arm to 
Table of Events.   Addition of blood collection for biomarker peripheral blood 
mononuclear cell (PBMC) isolation at Cycle 2 Day 15 to allow comparison of 
biomarkers assessed in blood with on-treatment biopsies collected during Cycle 2.
(Sections 1.3.6, 6.4.1.4 and 6.4.2.3, and Tables 7, 8, 9 and 10).  
Approved
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EDMS Doc. Number: 21902969 - 21902853
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
6
MEDI4736-NHL-001 Amendment #1 Final: 04 May 2017

Clarification that monitoring of minimal residual disease (MRD) will be performed in 
mantle cell lymphoma (MCL) and CLL by multi-color flow cytometry techniques and
follicular lymphoma (FL) by polymerase chain reaction techniques.  Removal of the 
MRD monitoring by next generation sequencing (NGS) technique.  Split the MRD 
blood and bone marrow samples from the planned biomarker samples specified in 
Section 6.8. Addition of a whole blood sample at Cycle 1 Day 1 for baseline and 
repeat bone marrow aspirate samples (as available) along with peripheral blood for 
monitoring of the MRD.   Elaborated the timing for submission of a bone marrow 
aspirate sample and/ or blood sample for monitoring of MRD.  (Sections 1.3.6,
6.4.1.4, and 6.4.2.3, Tables 7, 8, 9 and 10)

Further elaboration of exploratory pharmacodynamic and biomarker endpoints.  
(Protocol Summary and Table 2)

Clarification that the MRD data will be reported in the clinical study report.  
(Table 1)

Clarification that the SRC dedicated to each treatment arm can review and make 
recommendations for assessment of different dosing schedules based on the emerging 
study data as necessary.  (Section 3.1)

Clarification on the characteristics of pseudoprogression which have been noted with 
immune checkpoint inhibitors and referenced the “Refinement of Lugano 
Classification lymphoma response criteria in the era of immunomodulatory therapy” 
for further guidance (Cheson, 2016).  Clarification that subjects may continue
receiving study treatment based on the investigator’s discretion in situations where 
the investigator cannot determine true tumor progression.  (Section 3.1.1)

Clarification that the safety laboratory results must be reviewed by the investigator 
prior to first dose on Cycle 1 Day 1 to reconfirm subject eligibility with additional 
guidance on use of central and/or local laboratory results for dosing decisions 
consistent with Section 6.   (Sections 3.2.2 and 6.2)

Addition that subjects who receive local IFRT will follow the Arm D visit schedule 
and assessments and subjects who receive combination agents will follow the visit 
schedules and assessments specific to each combination regimen to be consistent with 
Section 6.2.  (Section 3.1.2)

Clarification in the overall study flow figure that the efficacy assessments will 
continue during the Follow-up Period until start of a new subsequent 
antilymphoma/CLL therapy, end of the Efficacy Follow-Up Period, or withdrawal of 
informed consent form in addition to first disease progression, whichever occurs 
earlier.  (Section 3.2.3 and Figure 3)

Clarification that subjects with DLBCL not otherwise specified or T-cell/histiocyte 
rich B-cell lymphoma histologies will be eligible for the DLBCL cohorts planned for 
the dose confirmation and expansion parts.  (Table 3)

Addition of abbreviations for each lymphoma histology (eg, cHL for classical 
Hodgkin lymphoma).  (Tables 4 and 5) 
Approved
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Approved
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EDMS Doc. Number: 21902969 - 21902853
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
7
MEDI4736-NHL-001 Amendment #1 Final: 04 May 2017

Revision of inclusion criterion 4 to list eligible and the exclusion criterion 2 to specify 
ineligible histologies consistently with Table 3, Table 4, and Table 5 for the dose 
confirmation and expansion parts of the study. (Sections 4.2 and 4.3)

Clarification to inclusion criterion 9 that a previously irradiated lesion will not be 
qualified as a measurable target lesion.  (Section 4.2)

Addition to inclusion criterion 12 of further examples for highly effective hormonal 
contraceptives.  (Section 4.2)

Revision of the exclusion criterion 10 to exclude the subjects who have received 
radioimmunotherapy within 3 months prior to the first dose of the investigational 
product (IP) to allow recovery from possible therapy-associated bone marrow 
suppression secondary to this treatment.  (Section 4.3)

Clarification that prior exposure to bendamustine is not exclusionary for Arm C dose 
level 1 (exclusion criterion 12) as bendamustine will not be a part of the 
investigational combination treatment (ie, durvalumab and rituximab) in this dose 
level.  (Section 4.3)

Addition of an exception to exclusion criterion 14 to allow the use of pre-phase 
treatment with corticosteroids (1 mg/kg/day prednisone or equivalent) for a maximum 
of 7 days prior to Cycle 1 Day 1 for subjects with bulky disease, systemic symptoms, 
compressive disease, or rapidly progressing adenopathies. (Sections 4.3 and 8)

Clarification in exclusion criterion 17 that ‘well-controlled type 1 diabetes mellitus 
and hypothyroidism’ will not be exclusionary active autoimmune diseases. (Section 
4.3)

Clarification in exclusion criterion 20 that hepatitis B virus (HBV) deoxyribonucleic 
acid (DNA) testing will not be necessary in subjects who are seropositive for
antibody to the hepatitis B surface antigen (anti-HBs) only due to prior exposure or 
vaccination for consistency with Section 6.1.  (Section 4.3)

Removal of direct thrombin inhibitors (eg, dabigatran) from the exclusion criterion 32 
listing the anticoagulant agents which should not be used concomitantly with 
ibrutinib. (Section 4.3)

Clarification that the exclusion criteria 27 and 28 will apply only to subjects who will 
receive rituximab as a part of their study treatment and exclusion criteria 33 only to 
subjects who will receive bendamustine as a part of their study treatment.  (Section 
4.3)

Addition of lipase as a laboratory test to monitor for pancreatitis in addition to 
amylase for consistency with the dose toxicity and management guidelines.  
Clarification of B symptoms will be collected.  Revision of visit window from ± 2 
days to ± 3 days.  (Sections 6.1, 6.2, 6.2.1, and 6.3.1 and Tables 7, 8, 9, and 10)

Clarification that direct antiglobulin test for subjects with CLL will be performed at 
site’s local laboratories.  (Section 6.1 and Table 9)
Approved
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Approved
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EDMS Doc. Number: 21902969 - 21902853
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
8
MEDI4736-NHL-001 Amendment #1 Final: 04 May 2017

Clarification that total, direct, and indirect bilirubin will be performed during all 
relevant visits.  (Sections 6.1, 6.2, and 6.2.1)

Update of the allowed window for the vital signs which will be taken at pre-
durvalumab administration as “within an hour prior to start of durvalumab infusion.”  
(Sections 6.2 and Tables 7, 8, 9, and 10)

Clarification that the follow up for subsequent antilymphoma therapy and overall 
survival following disease progression may be via telephone and not require a site 
visit.  (Section 6.3.2)

Addition of the word “interim” to refer to the computed tomography (CT) scans at 
Cycle 4, 7, 10, or Cycle 14 Day 1/end of durvalumab treatment (EOT-D) referred to 
in Section 6.4.1.1 for the CT scan time points.  (Sections 6.4.1.1 and 6.4.1.2)

Removal of the fluorodeoxyglucose-positron emission tomography (FDG-PET) 
planned for Cycle 14 Day 1/end of durvalumab treatment (EOT-D).  (Section 6.4.1.2
and Tables 7, 8, 9, and 10)

Clarification of supporting efficacy assessments (ie, B symptoms, hematology and 
clinical chemistry laboratories) will be performed until documentation of disease 
progression.  (Section 6 and Tables 7, 8, 9, and 10)

Clarification that the same imaging modality (eg, CT or MRI) and technique (eg, use 
of contract, slice thickness for scans) should be used throughout the study.  (Section 
6.4.1.1 and 6.4.2.1.)

Clarification that bone marrow disease evaluation is performed at site’s local 
laboratory and MRD at designated analytical laboratories.  (Section 6.4.2.2.)

Update of the pharmacokinetic (PK) and immunogenicity sample collection time 
point windows to allow greater logistical flexibility.  Update of Table 12 with 4 
additional durvalumab PK blood draws at the corresponding time points with each 
immunogenicity sample planned.   (Sections 6.6 and 6.7, and Tables 7, 8, 9, 10, 12, 
13, 14, and 15)

Reorganization of Section 6.8 Biomarkers, Pharmacodynamics, Pharmacogenomics 
for a better read.  (Section 6.8.1, 6.8.2 and 6.8.3 and Tables 16, 17, and 18)

Revision of the specifications for required infusion supplies associated with 
durvalumab administration based on the Durvalumab Investigator’s Brochure.  
(Section 7.1.1)

Removal of the instructions for ibrutinib dosing in proximity to food intake based on 
the approved ibrutinib label.  (Section 7.2.1.2.2)

Dose banding and body surface area capping at 2.0 mg/m2 are allowed as per local 
practice.  (Section 7.1.3)

Update to the Dose Treatment Modification and Toxicity Management Guidelines. 
(Tables 30, 31, 32 and 33)
Approved
2.0
v
Approved
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v


EDMS Doc. Number: 21902969 - 21902853
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
9
MEDI4736-NHL-001 Amendment #1 Final: 04 May 2017

Removal of direct thrombin inhibitors from the prohibited concomitant medication 
with ibrutinib and added investigators should consider the benefit-risk of withholding 
ibrutinib for at least 3 to 7 days pre and postsurgery depending upon the type of 
surgery and the risk of bleeding based on the approved ibrutinib label. Update to the 
allowed timeframe for live attenuated vaccine post durvalumab or rituximab dose.
Addition of risk with intrauterine device.  (Section 8.2)

Added liver disease experts will be consulted and HBV DNA will be repeated in case
of any elevation in liver enzymes of subjects who are treated with rituximab, 
bendamustine or lenalidomide for monitoring and treatment management. (Section 
8.3.1)

Specified whether the reporting for each study population will be done against actual 
treatment received versus planned treatment.  Rephrased the biomarker endpoint for 
clarity. (Section 9)

Clarification that any serious adverse event (SAE) made known to the investigator at 
any time beyond the protocol-defined safety follow up period that are suspected of 
being related to participation in the study (eg, a study-related procedure) should also 
be reported to Celgene Drug Safety.  Addition based on the request received from 
German Central Ethics Committee that any SAE beyond the protocol-defined safety 
follow-up period may be reported to Celgene Drug Safety even if not suspected of 
being related to IP or participation in the study as required by local regulations.
(Section 10.5)

Correction of the reporting requirement for the expedited reporting of adverse events
in Japan from biannual to annual.  (Section 10.6)

Update of adverse event of special interest (AESI) section.  (Section 10.7)

Specification of “pregnancy” as a reason for treatment discontinuation.  (Section 11)

Update of the reference list with Bendeka®; Cheson, 2016; Higgs, 2016; and Rizvi, 
2015.  (Section 17)

Correction of typographical errors and updated tables and table footnotes to be
consistent with the revised text throughout the document.
Approved
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v
Approved
1.0
v

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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-NHL-001
Celgene 
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
A PHASE 1/2, OPEN-LABEL, MULTICENTER STUDY TO ASSESS THE SAFETY AND 
TOLERABILITY OF DURVALUMAB (ANTI-PD-L1 ANTIBODY) AS MONOTHERAPY 
AND IN COMBINATION THERAPY IN SUBJECTS WITH LYMPHOMA OR CHRONIC 
LYMPHOCYTIC LEUKEMIA
STUDY DRUG:
MEDI4736
PROTOCOL NUMBER:
MEDI4736-NHL-001
FINAL PROTOCOL DATE:
06 Nov 2015
PROTOCOL AMENDMENT No. 1 
DATE:
04 May 2017
PROTOCOL  AMENDMENT No 2 
DATE:
14 Dec 2017
Prepared by:
ICON Clinical Research
On behalf of
Celgene International II Sarl
Rue des Moulins 4
2108 Couvet
Switzerland
CONFIDENTIAL
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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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-NHL-001
Celgene 
Confidential and Proprietary
2
TABLE OF CONTENTS
LIST OF FIGURES ....................................................................................................................6
SIGNATURE PAGE...................................................................................................................7
1.
LIST OF ABBREVIATIONS...................................................................................8
2.
INTRODUCTION..................................................................................................12
3.
STUDY OBJECTIVES...........................................................................................13
3.1.
Primary Objective...................................................................................................13
3.2.
Secondary Objectives .............................................................................................13
4.
INVESTIGATIONAL PLAN .................................................................................15
4.1.
Overall Study Design and Plan ...............................................................................15
4.2.
Study Endpoints .....................................................................................................20
4.3.
Subject Allocation to Treatment Arms....................................................................23
4.4.
Sample Size Determination.....................................................................................23
4.4.1.
Dose-finding Part....................................................................................................23
4.4.2.
Dose-confirmation Part...........................................................................................24
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................27
5.1.
Reporting Conventions ...........................................................................................27
5.2.
Analysis Population................................................................................................28
5.2.1.
Safety Population....................................................................................................28
5.2.2.
Efficacy Evaluable Population................................................................................28
5.2.3.
Dose-limiting Toxicity Evaluable Population..........................................................28
5.2.4.
Pharmacokinetic Population....................................................................................28
5.3.
Definitions..............................................................................................................28
5.3.1.
Date of First Administration of Study Treatment ....................................................28
5.3.2.
Date of Last Administration of Study Treatment.....................................................28
5.3.3.
Study Day...............................................................................................................29
5.3.4.
Baseline..................................................................................................................29
5.3.5.
Dose-limiting Toxicity............................................................................................29
5.3.6.
Dose-limiting Toxicity Evaluation Period...............................................................29
5.3.7.
Nontolerated Dose..................................................................................................29
nit
nitioions
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Date of Fir
Date of Fir
Date o
Date o
3.3.
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Stu
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.3.4
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-NHL-001
Celgene 
Confidential and Proprietary
3
5.3.8.
Maximum Tolerated Dose ......................................................................................29
5.3.9.
Preliminary Recommended Phase 2 Dose...............................................................29
6.
SUBJECT DISPOSITION......................................................................................31
7.
PROTOCOL DEVIATIONS/VIOLATIONS ..........................................................32
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................33
8.1.
Demographic and Baseline Characteristics..............................................................33
8.2.
Disease Characteristics at Baseline .........................................................................33
8.3.
Medical History......................................................................................................33
8.4.
Prior Anticancer Therapies .....................................................................................33
8.5.
Prior and Concomitant Medications........................................................................34
8.5.1.
Prior Medications ...................................................................................................34
8.5.2.
Concomitant Medications .......................................................................................34
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................35
9.1.
Treatment Duration.................................................................................................35
9.2.
Cumulative Dose ....................................................................................................36
9.3.
Dose Exposure........................................................................................................37
9.4.
Average Daily Dose................................................................................................37
9.5.
Dose Intensity.........................................................................................................37
9.6.
Relative Dose Intensity...........................................................................................37
9.7.
Dose Modification..................................................................................................38
10.
EFFICACY ANALYSIS ........................................................................................39
10.1.
Response Rate ........................................................................................................39
10.2.
Time to Response ...................................................................................................39
10.3.
Duration of Response .............................................................................................39
10.4.
Progression-free Survival........................................................................................40
10.5.
Overall Survival .....................................................................................................40
11.
PHARMACOKINETIC ANALYSIS......................................................................43
12.
SAFETY ANALYSIS ............................................................................................44
12.1.
Dose-limiting Toxicity............................................................................................44
12.2.
Treatment-emergent Adverse Events ......................................................................45
12.3.
Adverse Events of Special Interest..........................................................................46
12.4.
Second Primary Malignancies.................................................................................48
3
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12.1.
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-NHL-001
Celgene 
Confidential and Proprietary
4
12.5.
Clinical Laboratory Evaluations..............................................................................49
12.7.
Vital Sign Measurements........................................................................................49
12.8.
Overall Electrocardiograms Interpretation...............................................................49
12.9.
Eastern Co-operative Oncology Group Performance Scores....................................50
13.
INTERIM ANALYSIS...........................................................................................51
14.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF THE 
PROTOCOL...........................................................................................................52
15.
REFERENCES.......................................................................................................53
16.
APPENDICES........................................................................................................54
16.1.
Handling of Dates...................................................................................................54
16.1.1.
Calculation Using Dates .........................................................................................55
16.1.2.
Calculation of Cycles..............................................................................................55
16.2.
Date Imputation Guideline......................................................................................56
16.2.1.
Impute Missing Adverse Events/Prior or Concomitant Medications........................56
16.2.2.
Medical History......................................................................................................57
16.2.3.
Impute Missing Disease Diagnosis Dates................................................................57
16.2.4.
Impute Missing Dates in Prior Systemic Therapies .................................................58
16.2.5.
Impute Missing Dates in Subsequent Cancer Therapy.............................................58
16.2.6.
Impute Missing Dates for Death .............................................................................59
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-NHL-001
Celgene 
Confidential and Proprietary
5
LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................8
Table 2: 
Study Endpoints .....................................................................................................20
Table 3:
Stopping Rules for the Dose-confirmation Part for Efficacy....................................25
Table 4:
Number of Days to be Covered by the Last Dose....................................................36
Table 5:
Actions Taken per Drug..........................................................................................38
Table 6: 
Event and Censoring Rules for PFS and DoR Based on FDA Guidelines................40
Table 7:
Event and Censoring Rules for PFS Based on EMA Guidelines..............................41
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38
...... 40
40
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...........41
4


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-NHL-001
Celgene 
Confidential and Proprietary
6
LIST OF FIGURES
Figure 1: 
Overall Study Design..............................................................................................17
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-NHL-001
Celgene 
Confidential and Proprietary
8
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
AE
Adverse event
AESI
Adverse event of special interest
ALT/SGPT
Alanine transaminase
aPTT
Activated partial thromboplastin time
AST/SGOT
Aspartate transaminase
ATC
Anatomical Therapeutical Chemical
AUC
Area under the curve
BSA
Body surface area
CI
Confidence interval
CL/F
Clearance
CLL
Chronic lymphocytic leukemia
Cmax
Maximum plasma concentration of drug
CR
Complete response
CRF
Case report form
CRi
Complete response with incomplete marrow recovery
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
CxDy
Cycle x Day y
DI
Dose intensity
DL
Dose level
DLBCL
Diffuse large B-cell lymphoma
DLT
Dose-limiting toxicity
DOR
Duration of response
ECG
Electrocardiogram
ECOG
Eastern Co-operative Oncology Group
EE 
Efficacy evaluable
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drug
with incomp
with inco
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of variatio
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x Day y
Dose intensi
ose intensi
Dose le
Dose
Di
Di
OR
OR
ECG
ECG


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-NHL-001
Celgene 
Confidential and Proprietary
9
Table 1:
Abbreviations and Specialist Terms (Continued)
EMA
European Medicines Agency
FDA
Food and Drug Administration
FL
Follicular lymphoma
fT3
Free triiodothyronine
fT4
Free thyroxine
GRT
Global range table
GSSC
Global Scientific Steering Committee
HL
Hodgkin lymphoma
ICF
Informed consent form
INR
International normalized ratio
IP
Investigational product
IWCLL
International Workshop on Chronic Lymphocytic Leukemia
IWG
International Working Group
IRT
Interactive response technology
IV
Intravenous
K
Terminal elimination rate constant
LEN
Lenalidomide
LLN
Lower limit of normal
LLOQ
Low limit of quantification
MCL
Mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MTD
Maximum-tolerated dose
MZL
Marginal zone lymphoma
NCI
National Cancer Institute
NHL
Non-Hodgkin’s lymphoma
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-NHL-001
Celgene 
Confidential and Proprietary
10
Table 1:
Abbreviations and Specialist Terms (Continued)
nPR
Nodular partial response
NTD
Non tolerated dose
ORR
Overall response rate
OS
Overall survival
Pd
Pharmacodynamics
PD
Progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
PD-L2
Programmed cell death ligand 2
PFS
Progression-free survival
PI
Principal investigator
PK
Pharmacokinetics
PR
Partial response
PRL
Partial response with lymphocytosis
PS
Performance status
PT
Preferred term
R/R
Relapsed/refractory
RDI
Relative dose intensity
RP2D
Recommended Phase 2 dose
SAP
Statistical analysis plan
SAS®
Statistical Analysis System
SD
Stable disease
SLL
Small lymphocytic lymphoma
SMQ
Standardized MedDRA query
SOC
System organ class
sPD-L1
Plasma concentration of soluble PD-L1 
SPM
Second primary malignancy 
SRC
Safety review committee
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PD-L1
L1


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-NHL-001
Celgene 
Confidential and Proprietary
11
Table 1:
Abbreviations and Specialist Terms (Continued)
t1/2
Terminal elimination half-life
TEAE
Treatment-emergent adverse event
Tmax
Time to maximum concentration
TSH
Thyroid-stimulating hormone
Vz/F
Volume of distribution
WHO
World Health Organization
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-NHL-001
Celgene 
Confidential and Proprietary
12
2.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s 
protocol MEDI4736-NHL-001 “A Phase 1/2, open label, multicenter study to assess the safety 
and tolerability of durvalumab (anti-PD-L1 antibody) as monotherapy and in combination 
therapy in subjects with lymphoma or chronic lymphocytic leukemia.”
This analysis plan is based on the final protocol version dated 06 Nov 2015, protocol amendment 
No. 1 dated 04 May 2017 and protocol amendment No 2 dated 14 Dec 2017. It contains 
definitions of analysis populations, derived variables, and statistical methods for the analysis of 
efficacy and safety outcomes.
These analyses include one primary analysis. No formal interim analysis is planned for this 
study. The purpose of the SAP is to ensure the credibility of the study findings by pre-specifying 
the statistical approaches to the analysis of study data prior to database lock and any data 
analysis for the final analysis. This SAP also provides a description of the strategy, rationale, and 
statistical techniques to be used to achieve the objectives of the dose-finding and 
dose-confirmation parts of the study. Dose-confirmation part enrollment can be adjusted 
according to the stopping rules described in Table 3.
This SAP will be finalized and signed prior to the clinical database lock for the primary analysis. 
All statistical analyses detailed in this SAP will be conducted using Statistical Analysis System 
(SAS®) Version 9.1 or higher.
On 05 Sep 2017, a Partial Clinical Hold was placed on 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-PD-1 antibody, pembrolizumab, in patients with multiple myeloma in
combination with immunomodulatory agents. Enrollment into Arm A (durvalumab plus 
lenalidomide with or without rituximab) was discontinued. Subjects already enrolled and treated 
in Arm A before the Partial Clinical Hold who were receiving clinical benefit, based on the 
discretion of the investigator, could continue study treatment if reconsented.
 
 
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-NHL-001
Celgene 
Confidential and Proprietary
13
3.
STUDY OBJECTIVES
On 05 Sep 2017, a Partial Clinical Hold was placed on this study by the US FDA. The decision 
by the FDA was based on risks identified in other trials for an anti-PD-1 antibody, 
pembrolizumab, in patients with multiple myeloma in combination with immunomodulatory 
agents. Enrollment into Arm A (durvalumab plus lenalidomide with or without rituximab) was 
discontinued. Subjects already enrolled and treated in Arm A before the Partial Clinical Hold 
who were receiving clinical benefit, based on the discretion of the investigator, could continue 
study treatment if reconsented.
The dose-finding study part was completed for Arms B and C only. The dose-confirmation 
cohort of Arm A nor any of the dose expansion cohorts will open for enrollment.
Therefore, dose-expansion objectives and analyses were removed from the SAP.
3.1.
Primary Objective
Dose-finding part:
!
To assess the safety and tolerability of durvalumab when given in combination with 
lenalidomide and rituximab; ibrutinib; or bendamustine and rituximab to determine the 
recommended Phase 2 dose (RP2D) of each combination in subjects with lymphoma or 
chronic lymphocytic leukemia (CLL).
Dose-confirmation part:
!
To assess the safety of durvalumab as monotherapy and when given in combination with 
lenalidomide and rituximab; ibrutinib; or bendamustine and rituximab at the RP2D in 
subjects with lymphoma or CLL.
3.2.
Secondary Objectives
Dose-finding and Confirmation parts:
!
To make a preliminary assessment of antitumor activity of durvalumab as monotherapy 
and when given in combination with lenalidomide and rituximab; ibrutinib; or 
bendamustine and rituximab in subjects with lymphoma or CLL.
All parts:
!
To characterize the pharmacokinetics (PK) of durvalumab as monotherapy and when 
given in combination.
!
To characterize the PK of lenalidomide and ibrutinib when given in combination with 
durvalumab.
!
To determine the pharmacodynamic (Pd) effects of durvalumab as monotherapy. 
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-NHL-001
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-NHL-001
Celgene 
Confidential and Proprietary
15
4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
This is a multicenter, open label, Phase 1/2 study assessing the safety, tolerability, PK, Pd, and 
preliminary efficacy of durvalumab as monotherapy and when given in combination in select 
subtypes of relapsed or refractory (R/R) lymphoma or R/R CLL. The study will consist of 
2 parts: dose-finding and dose-confirmation. Four treatment arms will be investigated:
!
Arm A: durvalumab and lenalidomide ± rituximab
On 05 Sep 2017, a Partial Clinical Hold was placed on this study by the US FDA. 
The decision by the FDA was based on risks identified in other trials for an anti-PD-1 
antibody, pembrolizumab, in patients with multiple myeloma in combination with 
immunomodulatory agents. Enrollment into Arm A (durvalumab plus lenalidomide 
with or without rituximab) was discontinued. Subjects already enrolled and treated in 
Arm A before the Partial Clinical Hold who were receiving clinical benefit, based on 
the discretion of the investigator, could continue study treatment if reconsented.
!
Arm B: durvalumab and ibrutinib 
!
Arm C: durvalumab and rituximab ± bendamustine
!
Arm D: durvalumab (monotherapy)
The study will start with 3 dose-finding cohorts (Arms A, B, and C) and 1 dose-confirmation 
cohort (Arm D).
All treatment arms will open for enrollment at study start (Note: US sites will not be enrolling 
patients into Arm D until full assessment of response from the combination therapy arms and 
initial data from Arm D from non-US sites has been submitted to the FDA. Subjects who meet 
the eligibility criteria for more than 1 treatment arm will be allocated to an open treatment arm 
by the sponsor based on site/principal investigator (PI) indicated preference.
The dose-finding part of the study was completed for Arms B and C only. The dose-confirmation 
cohort of Arm A nor any of the dose expansion cohorts will open for enrollment.
Dose-finding
Preliminary RP2D will be established for each durvalumab combination treatment using a 3 + 3 
design (Storer, 1989). Please refer to Figure 1 for the overall study design.
For Arms A and C, prior to enrolling subjects to receive all 3 drugs, the doublet combinations 
(ie. Arm A: durvalumab and lenalidomide and Arm C: durvalumab and rituximab) will be 
evaluated. Once the doublet combinations are deemed tolerable, the eventual triplet 
combinations will be tested. The durvalumab starting dose is fixed in each of these arms.
Initially 3 to 6 subjects will be evaluated in each dose-finding cohort; therefore, approximately 
15 to 60 (dose-limiting toxicity [DLT] evaluable) subjects with B-cell non-Hodgkin’s lymphoma 
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-NHL-001
Celgene 
Confidential and Proprietary
16
(NHL) or CLL are anticipated to be enrolled in the dose-finding part. Subjects with CLL/small 
lymphocytic lymphoma (SLL) will not be eligible for Arm A. The final number of subjects will 
depend on the number of dose levels tested and the number of DLTs observed within each 
cohort. The durvalumab monotherapy arm will not have a dose-finding cohort as the preliminary 
RP2D has been established, but it will need to be confirmed.
During the dose-finding part, the decision to evaluate the next higher dose level for a 
combination agent, an intermediate dose level, the need to add additional subjects within any 
dose cohort, or to declare a dose level as tolerable will be made by the safety review committee 
(SRC), based on their review of clinical and laboratory safety data for a given dose cohort. 
The SRC will identify a preliminary RP2D for each treatment arm (except Arm D) based on an 
integrated assessment of the safety, available PK and Pd data, and preliminary efficacy 
information.
Dose-confirmation 
Once the preliminary RP2D is established, each combination treatment arm will enroll 
approximately 10 subjects with each of the prespecified disease histologies into Arms A, B, and 
C, to confirm the tolerability, and safety of the RP2D, and to identify the strongest antitumor 
signal in those histologies. The Arm D dose-confirmation cohort will be open at study start and 
enroll a total of approximately 30 subjects into up to 5 cohorts based on histology. In total, 
approximately 100 subjects are anticipated to enroll in the dose-confirmation part. The Arm D 
dose-confirmation part (durvalumab monotherapy) will start at the same time as the dose-finding 
part of the other 3 arms. Stopping rules as indicated in Table 3 have been predefined for each 
Arm/histology to allow for decision on further enrollment and to proceed to expansion phase.
All subjects will be evaluated for efficacy on a regular basis. The efficacy assessments for CLL 
will be based on the modified International Workshop on Chronic Lymphocytic Leukemia 
(IWCLL) Response Criteria for CLL (Hallek, 2008; Hallek, 2012; Hallek, 2013) and for 
lymphoma based on the International Working Group (IWG) Response Criteria for Malignant 
Lymphoma (the Lugano Classification) (Cheson, 2014). The SRC will continue to review safety 
data regularly throughout the study for all cohorts in a treatment arm for late toxicities (which are 
clearly not related to disease progression or intercurrent illness) which may result in the need for 
dose reduction or discontinuation to make recommendations on dose modifications (eg. alternate 
schedule or dose levels) as appropriate. In addition, the SRC will review efficacy, PK or Pd data 
as available in order to make recommendations on, including, but not limited to, treatment 
cohort/study continuation and expansion in a specific disease histology. Each treatment arm has 
a dedicated SRC.
Based on the recommendations of the SRC and/or Global Scientific Steering Committee 
(GSSC), relevant emerging clinical or nonclinical data, the sponsor will decide whether or not to 
open any dose-confirmation as well as decide whether or not to adjust the number of subjects 
enrolled into any planned cohort.
Additional treatment arms and/or histologies may be added to the dose-confirmation part to 
explore the safety and efficacy as amendments to the protocol.
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Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Celgene International II Sarl
Confidential and Proprietary
17
If DLT ≤ 0/3 or 1/6
Confirm antitumor 
activity
Confirm 
RP2D 
If DLT ≥ 2/3 or 2/6
If DLT ≤ 0/3 or 1/6
If DLT ≥ 2/3 or 2/6
Confirm 
RP2D 
If DLT ≥ 2/3 or 2/6
Confirm antitumor 
activity
Confirm antitumor 
activity
Figure 1: 
Overall Study Design
ARM A   R/R 
B-cell NHL
discontinued 
to the 
enrollment of 
new subjects
DOSE FINDING
(Determine preliminary RP2D based on 3 + 3 design)
DL 1: Durvalumab+ 
Lenalidomide 20 mg
DL 2: Durvalumab+ Lenalidomide 
20 mg+ Rituximaba  
DL -1A: Durvalumab +        
Lenalidomide 10 mg 
If DLT ≥ 2/3 or 2/6
ARM B    
R/R B-cell 
NHL/CLL
DL 1 c: Durvalumab + 
Ibrutinib 420 mg
If DLT ≤ 0/3 or 1/6
If DLT ≤ 0/3 or 1/6
DL 2: Durvalumab+ 
Ibrutinib 560 mg 
(NHL only)
DL -1: Durvalumab + 
Ibrutinib 280 mg
If DLT ≥ 2/3 or 2/6
DL 1: Durvalumab + 
Rituximab
DL 2 c: Durvalumab + 
Bendamustine 70 mg/m2 + 
Rituximab
ARM D 
Durvalumab 
monotherapy
DL 3: Durvalumab + 
Bendamustine 90 mg/m2+ 
Rituximab (NHL only)
No dose finding cohort
Confirm 
RP2D 
R/R CLL/SLL, MCL
R/R CLL/SLL, MCL
R/R CLL/SLL, FL, DLBCL
R/R CLL/SLL, FL, 
DLBCL
R/R CLL/SLL, DLBCL, 
MCL, FL, HL
Abbreviations: CLL = chronic lymphocytic leukemia; DL = dose level; DLT = dose limiting toxicity; DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; HL = 
Hodgkin lymphoma; MCL = mantle cell lymphoma; NHL = non-Hodgkin lymphoma; RP2D = recommended phase 2 dose; R/R = relapsed/refractory; SLL = small lymphocytic 
lymphoma; SRC = safety review committee; US = United States.
a Arm A DL 2 and -1B (discontinued to the enrollment of new subjects): Rituximab 375 mg/m2 on Cycle 1 Days 2, 8, 15, 22 and then on Day 1 of every 28-day cycle from Cycles 2-5.
b Arm A DL -2 and  -3 (discontinued to the enrollment of new subjects): Rituximab 375 mg/m2 on Cycle 1 Day 2 and then on Day 1 of every 28-day cycle from Cycles 2 through 8.
c Arm B DL 1 and Arm C DL 2: These dose levels will be the highest dose levels tested in subjects with CLL/SLL before opening CLL/SLL dose confirmation cohorts.
d Arm A dose confirmation and dose expansion cohorts are discontinued and will not enroll new subjects. In addition, the add-on combination treatment with lenalidomide ± rituximab is 
no longer allowed.
Notes:  Durvalumab will be administered at a fixed dose of 1500 mg once every 4 weeks.  All treatment arms will be open for enrollment at study start. Arm D will not be open for 
enrollment at the study start in the US, where Arm D will enroll depending on treatment slot availability and following the completion of an assessment of responses from the combination 
therapy arms (ie, Arms A, B, and C).  
DOSE EXPANSION
(Confirm efficacy in specific histology)
DOSE CONFIRMATION          
(Confirm RP2D and seek preliminary 
signal in specific histology)
Note for Arm D: At the time of disease 
progression, the investigator may add study 
treatments previously investigated with durvalumab 
(eg, rituximab ± either lenalidomided or 
bendamustine; or ibrutinib) once a dose level for 
that combination therapy is deemed tolerable)
 
 
 
for subjects who meet the criteria in Section 
ARM C    R/R 
B-cell 
NHL/CLL
DL -2: Durvalumab+ 
Lenalidomide 15 mg+ 
Rituximabb
DL -1B: Durvalumab+ 
Lenalidomide 10 mg+ Rituximaba
DL -3: Durvalumab + 
Lenalidomide 10 mg+ 
Rituximabb
If DLT ≤ 
0/3 or 1/6
Confirm 
RP2D
R/R FL, DLBCLd
R/R FL, DLBCL d
Note for dose confirmation and dose expansion cohorts:
 
The dose finding study part was completed for Arms B and C only. The dose 
confirmation cohort of Arm A nor any of the dose expansion cohorts will open for 
enrollment.
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Durvalumab (MEDI4736)
Protocol MEDI4736-NHL-001
Confidential and Proprietary
18
Study Population
Eligible subjects must have previously received treatment with at least 1 systemic therapy and 
currently have R/R lymphoma or CLL requiring therapeutic intervention. Subjects with 
lymphoma must have at least 1 measurable lesion by computed tomography (CT) scan (≥ 2 cm in 
the longest dimension). Subjects with CLL must be in need of treatment as defined by modified 
IWCLL Guidelines for the Diagnosis and Treatment of CLL (Hallek, 2008) Appendix I of the 
study protocol. All subjects must have adequate liver, renal, and bone marrow function as 
defined in Section 4 of the protocol.
Length of Study
The entire study is anticipated to last approximately 6 years and will consist of 3 periods: 
Screening, Treatment, and Follow-up.
During the Screening Period, lasting up to 28 days from the time of signing informed consent to 
Cycle 1 Day 1 (an exception may be biopsy samples), subjects will undergo assessments to 
determine their eligibility.
Subjects who qualify for enrollment into the study will enter the Treatment Period, during which 
subjects will receive investigational product(s) (IP[s]) at a predetermined dose and schedule for 
up to 13 cycles (in Arm A [only subjects with indolent NHL], Arm C, and Arm D); disease 
progression (in Arm A [subjects with aggressive NHL] and Arm B); or discontinuation of 
treatment due to unacceptable toxicity or other reasons. Please refer to section 9 of the protocol
for further details.
Once subjects complete the Treatment Period, they will enter the Safety Follow-up Period. All 
subjects will be followed for adverse events (AEs) (including second primary malignancies 
[SPMs]) and concomitant medications/procedures for 90 days after the last dose of durvalumab 
or 28 days after the last dose of other IPs, whichever is the later date.
Subjects who have received lenalidomide (ie. subjects in Arm A or subjects in Arm D who have 
received lenalidomide as additional treatment at the time of progression) will be followed for 
SPMs for up to 5 years from the last subject’s first lenalidomide dose.
In the Efficacy Follow-up Period, subjects will be followed for first progression, subsequent 
antilymphoma/CLL therapy, and overall survival (OS). In Arms A (indolent NHL: follicular 
lymphoma [FL] or marginal zone lymphoma [MZL]), C, and D, subjects will be followed for 
24 months after their last durvalumab dose. In Arms A (aggressive NHL) and B, subjects will be 
followed for 24 months after their last durvalumab dose or their disease progression, whichever 
date occurs later.
The End of Trial 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 
 analysis, as prespecified in the protocol 
(whichever is the later date).
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Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol MEDI4736-NHL-001
Celgene
Confidential and Proprietary
19
Study Treatments
Subjects will be assigned to 1 of the 4 treatment arms based on the investigator’s choice led by 
the subject’s eligibility status as per the inclusion/exclusion criteria described for each arm, prior 
antilymphoma/CLL therapy and response to prior therapy, medical history and also the 
availability of open treatment slots in a given cohort.
During each 28-day treatment cycle, subjects will receive durvalumab (intravenous [IV]) 
infusion on Day 1 of Cycles 1 through 13 at a fixed dose of 1500 mg every 4 weeks in 
combination with:
Treatment Arm A
!
Lenalidomide orally (PO) once daily on Days 1 to 21 (inclusive) of each cycle for 
12 months (Cycles 1 through 13) in indolent lymphoma histologies (eg. FL or MZL) 
or until disease progression in aggressive lymphoma histologies (eg. diffuse large 
B-cell lymphoma [DLBCL]) ± rituximab (IV) infusion:
o
Rituximab Schedule 1 (dose levels 2 or -1B): on Days 2, 8, 15 and 22 of Cycle 
1 and on Day 1 of Cycles 2 through 5 or
o
Rituximab Schedule 2 (dose levels -2 and -3): on Day 2 of Cycle 1 and on 
Day 1 of Cycles 2 through 8 depending on the dose level assigned. Due to the 
study partial hold, the dose levels DL -2 and DL -3 will not be evaluated.  
Note: Arm A is discontinued to the enrollment of new subjects at DL -1B (no enrollment 
in DL -2 and -3).Only subjects already enrolled and treated in Arm A who are receiving 
clinical benefit, based on the discretion of the investigator, may continue study treatment 
after being reconsented. In addition, the add-on combination treatment with lenalidomide 
± rituximab is no longer allowed.
Treatment Arm B
!
Ibrutinib (PO) continuous, once daily until disease progression.
Treatment Arm C
!
Rituximab (IV) infusion on Day 2 of Cycles 1 through 6 ± bendamustine (IV) 
infusion on Days 1 and 2 of Cycles 1 through 6. Bendamustine may be stopped after 
4 cycles if the subject experiences a cumulative toxicity related to bendamustine, and 
there is no clinical evidence of a favorable benefit to risk ratio for continuation of 
bendamustine treatment per the investigator’s medical judgment. 
Treatment Arm D
!
Durvalumab monotherapy arm. At the time of disease progression, the investigator 
may add study treatments previously investigated with durvalumab in this protocol 
(ie. lenalidomide ± rituximab; bendamustine ± rituximab; rituximab; or ibrutinib) 
once a tolerable dose level is confirmed for that combination,
 
f they meet the criteria defined in Section 
3.1.2 of the study protocol. Prior to addition of another therapy to durvalumab, the 
investigator must consult with the sponsor’s medical monitor.
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Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol MEDI4736-NHL-001
Celgene
Confidential and Proprietary
20
4.2.
Study Endpoints
Table 2: 
Study Endpoints
Endpoint
Name
Description
Timeframe
Primary Endpoints:
Dose-finding 
Safety
Nontolerated dose (NTD), maximum-
tolerated dose (MTD), and
recommended Phase 2 dose (RP2D) 
determined based on the incidence of 
dose limiting toxicities (DLTs) that 
occur during the DLT evaluation 
period
DLT evaluation period: from 
the first dose of any 
investigational product (IP) 
through the end of Cycle 1 
when given in combination 
with lenalidomide and 
rituximab; ibrutinib; or 
bendamustine and rituximab 
Incidence of treatment-emergent 
adverse events (TEAEs) using the 
NCI CTCAE criteria V4.03, 
including dose-limiting toxicities 
(DLTs)
From the first dose of any IP 
up to 90 days from the last 
dose of durvalumab or 
28 days from the last dose of 
any other IP, whichever 
occurs later
Dose-
confirmation 
Safety
Incidence of treatment-emergent 
adverse events using the NCI CTCAE 
criteria V4.03
From the first dose of any IP 
up to 90 days from the last 
dose of durvalumab or 
28 days from the last dose of 
any other IP, whichever 
occurs later
Dose-finding 
and 
confirmation 
Preliminary 
antitumor 
activity:
IWG Response 
Criteria for 
Malignant 
Lymphoma (the 
Lugano 
Classification) 
(Cheson, 2014)
ORR based on the tumor specific 
response criteria:
ORR (lymphoma): Proportion of 
subjects with best response of PR or 
CR
During durvalumab 
treatment (up to 13 cycles)
Secondary Endpoints:
IWCLL 
Response 
Criteria for CLL 
(Hallek, 2008; 
Hallek, 2012; 
Hallek, 2013)
ORR (CLL): Proportion of subjects 
with best response of CR, CRi, nPR, 
PR, or PRL
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de and 
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Durvalumab (MEDI4736)
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Celgene
Confidential and Proprietary
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Table 2: 
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
All parts 
Other efficacy 
parameters:
ORR based on the tumor specific 
response criteria:
During the study treatment 
and the follow-up phase
IWG Response 
Criteria for 
Malignant 
Lymphoma (the 
Lugano 
Classification) 
(Cheson, 2014)
ORR (lymphoma): Proportion of 
subjects with best response of PR or 
CR
IWCLL 
Response 
Criteria for CLL 
(Hallek, 2008; 
Hallek, 2012; 
Hallek, 2013)
ORR (CLL): Proportion of subjects 
with best response of CR, CRi, nPR, 
PR, or PRL
Duration of 
response (DoR)
DoR (lymphoma): Time from first 
CR or PR to progressive disease (PD) 
or death
DoR (CLL): Time from first CR, 
CRi, nPR, PR, or PRL to PD or death
During the study treatment 
and the follow-up phase
Time to
response (TTR)
TTR (lymphoma): Time from first IP 
dose to first response (CR or PR)
TTR (CLL): Time from IP dose to 
first response (CR, CRi, nPR, PR, or 
PRL)
During the study treatment 
and the follow-up phase
Progression-free 
survival (PFS)
PFS (lymphoma/ CLL): Time from 
first IP dose to the first documented 
PD or death due to any cause, 
whichever occurs first
During the study treatment 
and the follow-up phase
All parts 
PK
Serum/plasma samples will be 
collected to assay serum/plasma 
concentrations of durvalumab, 
lenalidomide and ibrutinib and to 
assess typical PK parameters such as 
maximum observed concentration 
(Cmax), area under the concentration-
time curve (AUC), time to maximum 
concentration (Tmax), terminal half-
life (t1/2), clearance (CL/F) and 
volume of distribution (Vz/F)
During Cycles 1 & 2 
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Celgene
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Table 2: 
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
Pd
Individual soluble PD-L1 (sPD-L1), 
soluble factors levels in blood at 
baseline and at specified time points 
(monotherapy)
During the study treatment
Abbreviations: CLL = chronic lymphocytic leukemia; IP = investigational product; IWCLL = International 
Workshop on Chronic Lymphocytic Leukemia; IWG = International Working Group; NCI CTCAE = National 
Cancer Institute Common Terminology Criteria for Adverse Events; Pd = pharmacodynamic(s); 
 PD-L1 = programmed cell death ligand 1; 
 
; PK = pharmacokinetic(s).
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Durvalumab (MEDI4736)
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Celgene
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4.3.
Subject Allocation to Treatment Arms
The study will start with 3 dose-finding cohorts (Arms A, B, and C) and 1 dose-confirmation 
cohort (Arm D). All 4 treatment arms will be open for enrollment at study start.
An IRT will be used to track and make final subject assignments to the treatment arms and dose 
levels in all parts and arms of the study.  
The cohort availability will be tracked centrally with a Cohort Management Tool which will 
show the most current cohort status and be available for site’s view in the IRT website.
The treatment assignment in the dose-finding cohorts (ie. Arms A, B, and C) will be based on 
open dose levels, cohort availability, type of prior lymphoma/CLL therapy, and response to that 
therapy, and eligibility based on the inclusion/exclusion criteria.
The treatment assignment in the dose-confirmation and expansion cohorts will be based on 
cohort availability, type of prior lymphoma/CLL therapy, and response to that therapy, and 
eligibility based on the inclusion/exclusion criteria. For the planned number of patients with each 
histology in Arms A to D, refer to study protocol Table 3, Eligible Histologies per Treatment 
Arm and Part of the Study.
Investigators will be asked for their preference of treatment arm for each subject, and Sponsor 
will honor that request, whenever possible, according to cohort availability and study design. 
4.4.
Sample Size Determination
There is a maximum of 60 subjects required for the dose-finding part, a maximum of 
approximately 100 subjects for the dose-confirmation part, thus, a total of approximately 
160 subjects for the entire study.
 
 
4.4.1.
Dose-finding Part
There are 3 treatment arms in the dose-finding part, i.e. Arm A (discontinued to the enrollment 
of new subjects), Arm B, and Arm C. The standard “3 + 3” dose-escalation design will be used 
to identify the maximum tolerated dose (MTD) and RP2D for each treatment arm. The total 
sample size for the dose-finding part ranges from 15 to 60 subjects.  
Subjects will be considered evaluable for DLTs if they complete the DLT evaluation period or 
experience a DLT during the DLT evaluation period. Non-evaluable subjects may be replaced 
with another subject at the same dose level.
Arm A (Discontinued to the enrollment of new subjects)
Subjects with R/R B-cell NHL will be enrolled into Arm A. There are 8 potential dose-finding 
paths: 
!
DL1  DL2
!
DL1  DL2  DL-1B
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523


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!
DL1  DL2  DL-1B  DL-2
!
DL1  DL2  DL-1B  DL-2  DL-3
!
DL1  DL-1A
!
DL1  DL-1A  DL-1B
!
DL1  DL-1A  DL-1B  DL-2
!
DL1  DL-1A  DL-1B  DL-2  DL-3
The sample size required for Arm A ranges from a minimum of 6 subjects (2 dose levels with 
3 subjects per dose level) to a maximum of 30 subjects (5 dose levels with 6 subjects per dose 
level) as outlined in Figure 4 of the study protocol.
Arm B
Subjects with R/R B-cell NHL or CLL/SLL will be enrolled into Arm B. There are 2 potential 
dose-finding paths: 
!
DL1  DL2 or
!
DL1  DL-1
The sample size required for Arm B ranges from a minimum of 6 subjects (2 dose levels with 
3 subjects per dose level) to a maximum of 12 subjects (2 dose levels with 6 subjects per dose 
level) as outlined in Figure 5 of the study protocol.
Arm C
Subjects with R/R B-cell NHL or CLL/SLL will be enrolled into Arm C. There are 2 potential 
dose-finding paths: 
!
DL1  DL2; 
!
DL1  DL2  DL3
The sample size required for Arm C ranges from a minimum of 3 subjects (1 dose level with
3 subjects per dose level) to a maximum of 18 subjects (3 dose levels with 6 subjects per dose 
level) as outlined in Figure 6 of the study protocol.
4.4.2.
Dose-confirmation Part
In the dose-confirmation part, the planned sample size is based on clinical empirical and 
practical considerations traditionally used for Phase 1/2 studies.
For the dose confirmation, expected rate of overall response (CR/PR) was used in order to 
determine the stopping rule by targeting with 10 subjects a probability of less than 20% of 
observing response less or on the stopping rule (eg. for arm A, histology R/R, given expected 
ORR is 65%, probability of observing 4 or less responses out of 10 subjects is equal to ~9.5%, 
and probability of observing 5 or less responses out of 10 subjects is equal to ~24.9%).
Should the stopping rule described in Table 3 for the dose-confirmation part be fulfilled, the SRC 
for that cohort and GSSC will be consulted to determine whether the clinical trial should 
completely stop further enrollment of subjects with a particular histology (ie. not advance to the 
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dose-expansion part), temporarily halt enrollment and await maturation of efficacy data to 
examine for example durability of responses, or enroll additional subjects either in the 
dose-confirmation part or by formally advancing to the dose-expansion part. If there is no 
expected activity and/or stopping rules met for a certain dose level, other potential dose 
levels/schedules can be explored in the dose finding and confirmation parts based on the SRC 
and/or GSSC recommendation. The Sponsor may decide not to expand in any arm based on 
emerging internal or external data in relevant disease and therapeutic field or other reasons in 
consultation with the GSSC and/or SRC.
The total sample size for the dose-confirmation part is estimated to be approximately 
100 subjects. The final number of subjects will depend on the number of subjects used to 
determine RP2D that can be determined in each arm/cohort in the dose-finding part.
Table 3:
Stopping Rules for the Dose-confirmation Part for Efficacy
Treatment 
Arm
Subject Histology 
Cohort
Stopping 
Rule
Justification
A
Discontinued 
to the 
enrollment of 
new subjects
R/R FL (N = 10)
≤ 4 
overall 
responses
Based on literature that the rituximab-lenalidomide
combination has ORR around 60%, the 
experimental arm has about 90% likelihood to 
continue the trial if its ORR is ≥ 65%.  
R/R DLBCL (N = 10)
≤ 2 
overall 
responses
Based on literature that the rituximab-lenalidomide
combination has ORR around 25-30%, the 
experimental arm has more than 80% likelihood to 
continue the trial if its ORR is ≥40%.  
B
R/R CLL/SLL (N = 10)
≤ 5 
overall 
responses
Based on literature that ibrutinib has ORR around 
70% in the patient population being studied, the 
experimental arm has about 90% likelihood to 
continue the trial if its ORR is ≥ 75%.  
R/R MCL (N = 10)
≤ 5 
overall 
responses
Based on literature that ibrutinib has ORR around 
65%, the experimental arm has about 90% 
likelihood to continue the trial if its ORR is ≥75%.
C
R/R CLL/SLL (N = 10)
≤ 4 
overall 
responses
Based on literature that rituximab + bendamustine
combination has ORR around 50% in the patient 
population being studied, the experimental arm has 
about 90% likelihood to continue the trial if its ORR 
is ≥ 65%.  
R/R FL (N = 10)
≤ 2 CR
Based on literature that the standard care has CR 
rate around 40%, the experimental arm has about 
90% likelihood to continue the trial if it’s CR rate ≥ 
45%.  
R/R DLBCL (N = 10)
≤ 2 
overall 
responses
Based on literature that the standard care has ORR 
around 40%, the experimental arm has about 90% 
likelihood to continue the trial if its ORR is ≥ 45%.
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Celgene
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Table 3: 
Stopping Rules for the Dose-confirmation Part for Efficacy (Continued)
Treatment 
Arm
Subject Histology 
Cohort
Stopping 
Rule
Justification
D
R/R CLL/SLL 
R/R DLBCL 
R/R FL 
R/R HL 
R/R MCL 
(5-10 subjects in each; 
total N = 30)
Information collection only.
Abbreviations: CLL = chronic lymphocytic leukemia; CR = complete response; FL = follicular lymphoma; 
DLBCL = diffuse large B-cell lymphoma; HL = Hodgkin’s lymphoma; MCL = mantle cell lymphoma; 
N = number of subjects; ORR = overall response rate; R/R = relapsed/refractory; SLL = small lymphocytic 
lymphoma.
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5.
GENERAL STATISTICAL CONSIDERATIONS
5.1.
Reporting Conventions
!
Data from all study centers will be combined for analysis;
!
All statistical tests of the treatment effect will preserve a significance level of 0.050 
for 2-sided tests. Testing of interactions will be performed at the 0.100 significance 
level;
!
P-values will be rounded to 4 decimal places. P-values that round to 0.0000 will be 
presented as ‘<0.0001’ and p-values that round to 1.000 will be presented as 
‘>0.9999’;
!
Confidence intervals will be presented as 2-sided 95% CIs unless specified differently 
in specific analysis;
!
Summary statistics will consist of the number and percentage of subjects (or cycles, if 
appropriate) in each category for discrete variables, and the sample size, mean, 
median, standard deviation (SD), minimum, and maximum for continuous variables;
!
All mean and median values will be formatted to 1 more decimal place than the 
measured value. Standard deviation values will be formatted to 2 more decimal places 
than the measured value;
!
All percentages will be rounded to 1 decimal place. The number and percentage of 
responses will be presented in the form XX (XX.X%), where the percentage is in the 
parentheses;
!
All listings will be sorted for presentation in order of treatment arm, study center, 
subject, and date of procedure or event;
!
All analysis and summary tables will have the analysis population sample size (ie.
number of subjects);
!
The day of the first dose of any study drug will be defined as Day 1;
!
Baseline value will be defined as the last value on or before the first dose of study 
drug is administered; if multiple values are present for the same date, the average of 
these values will be used as the baseline (for character parameters like urinalysis
parameters, the worst value will be considered as baseline). For subjects who were 
not treated, the baseline will be the assessment value taken on the visit of Cycle 1 
Day 1 if available; otherwise, the value on or prior to enrollment date will be used.
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5.2.
Analysis Population
5.2.1.
Safety Population
The Safety Population (for all parts) is defined as all subjects who receive at least 1 dose of IP. 
Drug exposure and all safety analyses (including AEs, laboratory values, and deaths) will be 
based on the Safety Population. Subjects will be analyzed according to the actual treatment arm 
and dose level initially received.
5.2.2.
Efficacy Evaluable Population
Efficacy Evaluable (EE) Population (for the dose-finding, dose-confirmation, and
dose-expansion part) is defined as all subjects who complete at least 1 cycle of their assigned 
treatment, have baseline, and at least 1 post-baseline tumor response assessment. Subjects will be 
analyzed according to their initial treatment arm and dose level allocation.
5.2.3.
Dose-limiting Toxicity Evaluable Population
The DLT Evaluable Population (for the dose-finding part) is defined as all subjects in Arms A, 
B, and C, who take at least 1 dose of IP, and completed the DLT evaluation through the end of 
DLT evaluation period defined in the protocol, or the subjects who receive at least 1 dose of IP 
and have experienced at least 1 DLT prior to completion of the DLT evaluation period.
5.2.4.
Pharmacokinetic Population
The PK Population is defined as all subjects who receive at least 1 dose of IP and have at least 
1 measurable plasma concentration.
 
5.3.
Definitions
5.3.1.
Date of First Administration of Study Treatment
The date of first administration of study treatment is defined as the first date when a non-zero
dose of any of the study drugs (durvalumab, lenalidomide, ibrutinib, bendamustine, or rituximab) 
was administered. This date will be collected in the case report form (CRF).
For simplicity, the date of first administration of study treatment will also be referred as the start 
date of study treatment.
5.3.2.
Date of Last Administration of Study Treatment
The date of last administration of study treatment is defined as the last date when a non-zero
dose of any of the study drugs (durvalumab, lenalidomide, ibrutinib, bendamustine, or rituximab) 
was administered. This date will be collected in the CRF.
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First Adm
First Adm
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5.3.3.
Study Day
The study day for safety assessments (eg. AE onset, laboratory abnormality occurrence, vital 
sign measurement, and dose administration) will be calculated as the difference between the date 
of the assessment and the start date of study treatment plus 1. 
The study day for time-to-event assessments (eg. time to response [TTR], duration of response 
[DOR], OS, or progression-free survival [PFS]) will be calculated as the difference between the 
date of the event and the date of treatment assignment plus 1. 
The study day will be displayed in the data listings.
5.3.4.
Baseline
The last available assessment before or on the date of start of study treatment is taken as 
“baseline” assessment.
5.3.5.
Dose-limiting Toxicity 
Dose-limiting toxicities will be evaluated during the DLT evaluation period for the subjects in 
the dose-finding cohorts.
Subjects will be evaluated for AEs at each visit with the NCI CTCAE Version 4.03 used as a 
guide for the grading of severity, with the exception of:
!
Tumor lysis syndrome (Cairo, 2004) or
!
Laboratory abnormalities in CLL subjects as recommended by the IWCLL guidelines 
for the diagnosis and treatment of CLL (Hallek, 2008) as listed in Appendix E of the 
study protocol.
5.3.6.
Dose-limiting Toxicity Evaluation Period
Subjects enrolled in Arms A, B, and C will be observed for DLTs from the time of first IP dose
through completion of the DLT evaluation period defined in the protocol.
5.3.7.
Nontolerated Dose
A dose will be considered to be a nontolerated dose (NTD) if ≥ 2 of 3 or 6 evaluable subjects in a 
dose level experience a DLT.
5.3.8.
Maximum Tolerated Dose 
The MTD is defined as the highest dose level below the NTD with 0 of 3 or 1 of 6 (ie. < 1/3 of 
subjects) evaluable subjects experiencing DLTs during the DLT evaluation period.
5.3.9.
Preliminary Recommended Phase 2 Dose
The SRC will identify a preliminary RP2D for each dose-finding cohort based on an integrated 
assessment of the safety, PK, Pd, and preliminary efficacy information. The RP2D selected will 
not exceed the MTD from the dose-finding cohorts.
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The final number of subjects will depend on the number of dose levels and the number of DLTs 
observed within each cohort. The durvalumab monotherapy arm will not have a dose-finding 
cohort as the preliminary RP2D has been established, but it will need to be confirmed:
!
In Arms A, B, and C, an initial cohort of 3 subjects will be enrolled to a specific dose 
level to assess toxicities, before additional subjects are treated in that arm.  
!
A dose level will be considered tolerable if 0 of 3 evaluable subjects experiences a 
DLT during the DLT evaluation period.
!
If 1 of 3 subjects experiences a DLT, up to 3 more subjects will be enrolled at that 
dose level.  
!
A dose will be considered tolerable if ≤ 1 of 6 evaluable subjects experiences a DLT 
during the DLT evaluation period.  
!
A dose will be considered to be a nontolerated dose (NTD) if ≥ 2 of 3 or 6 evaluable 
subjects at a dose level experience a DLT.  
!
The MTD is defined as the highest dose level below the NTD with 0 of 3 or ≤ 1 of 
6 evaluable subjects experiencing a DLT during DLT evaluation period.  
!
Subjects will be considered evaluable for DLTs if they complete the DLT evaluation 
period or experience a DLT during the DLT evaluation period. Nonevaluable subjects 
may be replaced with another subject at the same dose level.
at t 
nces a DLT
nces a DLT
of 3 or 6 ev
of 3 or 6 ev
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6.
SUBJECT DISPOSITION
The total number of subjects who fail screening (“screen failures”) will be summarized with 
reason for screening failure.
A summary of subject disposition (subjects with ongoing assigned treatment, subjects completed 
with assigned treatment, subjects discontinued, along with primary reason for IP and study 
discontinuations) will be presented for the Safety Population and will be summarized using 
frequencies for Treatment and Follow-up Periods.
Reasons for discontinued study treatment will be summarized for all subjects with the 
following categories:
!
Death
!
Adverse event
!
Progressive disease
!
Lack of efficacy
!
Withdrawal by subject
!
Lost to follow-up
!
Protocol violation
!
Pregnancy
!
Other.
Reasons for discontinuing the study (ie, no more follow up visit and no longer participating the 
study) will be collected on the CRF, and will be summarized for all enrolled subjects with the 
following categories:
!
Death
!
Adverse event
!
Withdrawal by subject
!
Lost to follow-up
!
Other.
Listings will be provided for subjects enrolled but not treated with reasons, and for discontinued 
subjects with reason for treatment discontinuation.
The following by-subject listing of subjects will be provided:
!
Subject listing of discontinuation 
!
Subject listing of screen failures.
!
Subject listing of being excluded from Safety, DLT, EE, 
or PK 
Population.
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will be s
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by subjec
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will be prov
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7.
PROTOCOL DEVIATIONS/VIOLATIONS
The protocol deviations/violations will be identified and assessed by clinical research physician 
or designee following company standard operational procedure. The protocol 
deviations/violations will be summarized by dose cohort and arm for the Safety Population.
A protocol violation/deviation is defined as any departure from the approved protocol that:
!
Impacts the safety, rights, and/or welfare of the subject; 
!
Negatively impacts the quality or completeness of the data; or
!
Makes the informed consent document/form inaccurate. 
Protocol violations/deviations will be reported and monitored throughout the study. Data of 
protocol violations/deviations will be finalized prior to database lock. 
A by-subject listing of subjects with protocol violations in the Safety Population will be 
provided.
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pululatatioion wil


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8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
The demographics and baseline characteristics will be summarized for the Safety Population. 
Individual subject listings will be provided to support the summary tables.
Summaries using descriptive statistics for the demographics and baseline characteristics will be 
carried out by particular treatment arm, histology, and study part.
8.1.
Demographic and Baseline Characteristics
Age, height, weight, body surface area (BSA) based on Dubois’ method, absolute neutrophils, 
platelets, alanine transaminase (ALT/SGPT), aspartate transaminase (AST/SGOT), total 
bilirubin, creatinine clearance, international normalized ratio (INR), activated partial 
thromboplastin time (aPTT), amylase, lipase, thyroid-stimulating hormone (TSH), free 
triiodothyronine (fT3), and free thyroxine (fT4) will be summarized descriptively. 
Age group (< 65 or ≥65, < 75 or ≥ 75 years), sex, childbearing potential, race, ethnicity, Eastern 
Co-operative Oncology Group (ECOG) performance status, and baseline ECG will be 
summarized by frequency counts.
8.2.
Disease Characteristics at Baseline
Disease characteristics at baseline such as time from diagnosis, number of prior systemic 
regimens and time from end of last systemic regimen (see Section 16.2.4) will be summarized 
using descriptive statistics. 
Categorical/ordinal variables such as best response to first systemic regimen, best response to 
last systemic regimen, best response to any prior systemic regimen, prior autologous 
transplantation, best response to prior autologous transplantation, stage of disease at baseline 
(Ann Arbor), bone marrow involvement at baseline, presence of B-symptoms at baseline, and 
presence of bulky disease at baseline will be summarized with frequency counts and percentages.
Some other characteristics can be also summarized depending on the subject histology.
8.3.
Medical History
A summary of medical history will be presented by Medical Dictionary for Regulatory Activities 
(MedDRA, Version 18 or higher) system organ class (SOC) and preferred term (PT).
8.4.
Prior Anticancer Therapies
Whether subject had prior radiation therapy, prior cancer surgery, prior systemic anticancer 
therapy or prior stem cell transplantation will be summarized with frequency counts and 
percentages. In addition, prior exposure to anticancer therapies will also be summarized by 
regimen name with frequency counts and percentages.
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rophil
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total
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diagnosis, n
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8.5.
Prior and Concomitant Medications
8.5.1.
Prior Medications
Prior medications are defined as medications that were started before the start of the study 
treatment and either ended before the start of the study treatment or continued after study 
treatment. 
A summary showing the number and percentage of subjects who took at least one prior 
medication will be presented by the World Health Organization (WHO) anatomical therapeutic 
class (ATC) and preferred drug name for the Safety Population.
8.5.2.
Concomitant Medications
Concomitant medications are defined as medications that were either initiated before the first 
dose of study drug and continued during the study treatment, or initiated on/after the date of the 
first dose of study drug and on/before the date of treatment discontinuation (ie. until 90 days 
after the last dose of durvalumab or 28 days after the last dose of other IPs, whichever is the later 
date). 
A summary showing the number and percentage of subjects who took at least one concomitant 
medications will be presented by the WHO ATC and preferred drug name for the Safety 
Population. 
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ic
fore the fir
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9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
Study treatment and extent of exposure summaries will be provided based on the Safety 
Population. Descriptive statistics will be provided for treatment duration, number of cycles, 
cumulative dose, dose intensity (DI), and relative dose intensity (RDI) by treatment arm, 
histology, and dose level. 
9.1.
Treatment Duration
In this study the planned treatment duration of each drug is different, and therefore, the treatment 
duration of each drug will be summarized separately within the same treatment arm, histology, 
and dose level.
Treatment duration (weeks) for each drug (durvalumab, lenalidomide, ibrutinib, bendamustine, 
and rituximab) is defined as:
[(Treatment duration end date for individual study drug) – (date of Cycle 1 Day 1) + 1]/7
Treatment duration end date is defined as: Min [Max (last non-zero/non-missing dose date + 
days to be covered by the last dose), death date].
The number of days to be covered by the last dose is defined in Table 4.
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treatment 
atmen
histo
histolology
gy
ib, bendam
b, bendam
Cy
Cycle 1 Da
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o/non
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mis
d in
d in Table
Tabl


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Table 4:
Number of Days to be Covered by the Last Dose
Arm
Schedule
n = days to be covered by the actual last dose
Arm A
Durvalumab
CxD1
n = 27
Lenalidomide
CxD1 to CxD20
CxD21
n = 0
n = 7
Rituximab 
Dose level -1B, 2
C1D2
C1D8
C1D15
C1D22
CxD1
n = 5
n = 6
n = 6
n = 6
n = 27
Rituximab
Dose level -2, -3
C1D2
CxD1
n = 26
n = 27
Arm B
Durvalumab
CxD1
n = 27
Ibrutinib
CxD1 to CxD28
n = 0
Arm C
Durvalumab
CxD1
n = 27
Bendamustine
CxD1
CxD2
n = 0
n = 26
Rituximab
CxD2
n = 26
Arm D
Durvalumab
CxD1
n = 27
For other drugs, refer to above cases
Abbreviation: CxDy = Cycle x Day y.
9.2.
Cumulative Dose
The cumulative dose during treatment is defined as the sum of all doses taken across the 
treatment period for each study drug: durvalumab (in mg), lenalidomide (in mg), ibrutinib (in 
mg), rituximab (in mg/m2), or bendamustine (in mg/m2). Cumulative dose will be calculated 
separately for each drug by dose cohort, histology and treatment arm.
The number of subjects with overdoses will be also summarized separately for each drug by dose 
cohort, histology and treatment arm.
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9.3.
Dose Exposure 
Dose exposure is defined as the total number of days for each drug separately during the 
treatment phase (excluding the periods of dose break per protocol or dose interruptions). Dose 
exposure will be calculated separately for each drug by dose cohort, histology, and treatment 
arm.
9.4.
Average Daily Dose
Average daily dose of a particular drug is defined as the cumulative dose divided by dose 
exposure and expressed as mg/day or [mg/m2]/day. Average dose will be calculated separately 
for each drug by dose cohort, histology, and treatment arm.
9.5.
Dose Intensity
Dose intensity (DI) of a particular drug is defined as the cumulative dose per cycle and expressed 
as mg/cycle or [mg/m2]/cycle. It is calculated as cumulative dose divided by the number of 
cycles of the drug. The number of cycles of the drug is determined as the last cycle during which 
a subject received the drug regardless of the cycle being completed or discontinued.
Dose intensity will be calculated for each drug separately by dose cohort, histology, and 
treatment arm.  
Since in Arm A, dose level −1B and dose level 2, the rituximab dosing schedule is different for 
Cycle 1 and Cycles 2 to 5, its DI will be summarized for Cycle 1 and Cycles 2 through 5 
separately.
9.6.
Relative Dose Intensity
Relative dose intensity (RDI) is defined as the DI divided by the planned dose intensity* 100;
!
For durvalumab, the planned DI is 1500 mg/cycle. 
!
For lenalidomide (Arm A), the planned DI is (lenalidomide RP2D*21)/cycle. The 
lenalidomide RP2D level can be 10 or 20 mg.
!
For rituximab (Arm A), the planned DI is:
o
Dose level −1B and dose level 2:

[1500 mg/m2]/cycle for Cycle 1 with dose level calculated based on 
subject’s BSA.

[375 mg/m2]/cycle for Cycle 2 through 5 with dose level calculated based 
on subject’s BSA.
o
Dose level −2 and dose level −3: [375 mg/m2]/cycle for Cycle 1 through 8 with 
dose level calculated based on subject’s BSA.
!
For ibrutinib (Arm B), the planned DI is (ibrutinib RP2D*28)/cycle. The ibrutinib RP2D 
level can be 280, 420, or 560 mg.
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!
For rituximab (Arm C), the planned DI is:
o
For subjects with CLL/SLL:

[375 mg/m2]/cycle for Cycles 1 with dose level calculated based on 
subject’s BSA.

[500 mg/m2]/cycle for Cycles 2 through 6 with dose level calculated based 
on subject’s BSA.
o
For all other subjects: [375 mg/m2]/cycle for all cycles with dose level calculated 
based on subject’s BSA.
!
For bendamustine (Arm C), the planned DI is (bendamustine RP2D*2)/cycle for 
Cycles 1 through 6 with dose level calculated based on subject’s BSA. The bendamustine 
RP2D level can be 70 or 90 mg/m2.
Descriptive statistics of RDI will be presented for each drug separately, by dose cohort, 
histology, and treatment arm. RDI will not be displayed for dose finding part.
9.7.
Dose Modification
Dose delay/reduction/interruption will be summarized separately for each drug. Summaries 
include subjects who had at least 1 dose delay/reduction/interruption, reason for the dose 
delay/reduction/interruption, and time to first dose delay/reduction/interruption. 
Dose delay/reduction/interruption will be summarized for each drug separately, by dose cohort, 
histology, treatment arm and cycle.
There are 5 different actions which may be taken for each drug and captured in the CRF. All of 
these actions are not applicable to each drug (as summarized in the Table 5). The summary of 
actions taken will be customized for each drug (oral versus infusion).
Table 5:
Actions Taken per Drug
Dose delay
Dose 
reduction
Dose 
interruption
Infusion 
interruption 
(complete or 
incomplete)
Drug 
withdrawn
Durvalumab
X
n/a
n/a
X
X
Rituximab
X
n/a
n/a
X
X
Bendamustine
X
X
n/a
X
X
Ibrutinib
n/a
X
X
n/a
X
Lenalidomide
n/a
X
X
n/a
X
n/a = not applicable
&(/
alidomide
alidomide
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X
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n/a = not app
/a = not app


Durvalumab (MEDI4736)
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10.
EFFICACY ANALYSIS
All efficacy analyses will be carried out on the Safety or EE Populations. Efficacy analysis will 
be performed per arm, histology and study part by combining data from the dose-confirmation 
part. Efficacy analysis will also be performed separately for the dose-confirmation part and the 
dose-expansion part as well. 
Final analyses will be performed after the End of Trial has been reached. All analyses will use 
descriptive statistics. All confidence intervals will be provided at a level of 95% confidence 
interval. No formal statistical comparison/testing will be performed. 
For time-to-event endpoints (DoR and PFS) the detailed event and censoring criteria are listed in 
Table 6.
10.1.
Response Rate
Overall response rate using the Lugano Classification
For lymphoma subjects, response evaluation will be based on IWG response criteria for 
malignant lymphoma (the Lugano Classification) (Cheson, 2014). ORR is defined as the percent 
of subjects with best response of CR or PR.
Overall response rate using the IWCLL Guidelines
For chronic lymphocytic leukemia subjects, response evaluation will be based on IWCLL 
guidelines for diagnosis and treatment of CLL. The ORR is defined as the percent of subjects 
with best response of CR, complete response with incomplete marrow recovery (CRi), nodular 
partial response (nPR), PR or partial response with lymphocytosis (PRL).
The ORR during durvalumab treatment (only for Arms A, B and C) as well as during entire 
efficacy evaluation period will be summarized by subject histology cohort for each treatment 
arm for both responses criteria (Lugano classification and IWCLL).
10.2.
Time to Response
Time to response will be calculated as the time from first IP dose to the first response date (CR 
or PR for lymphoma subjects and CR, CRi, nPR, PR, or PRL for CLL subjects). TTR will be 
derived only for responder subjects.
TTR will be summarized using descriptive statistics (including only responder subjects) for each 
treatment arm.
10.3.
Duration of Response
Duration of response using the Lugano Classification
Duration of response is defined for responders only as the time from the first documented 
response (CR or PR) to disease progression or death (from any cause). For subjects with 
response but no progression, or death, DoR will be censored at the last date that the subject was 
known to be progression-free.
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OR
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he ORR is
with inco
with incom
nse with lym
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(only 
(only fo
for A
r
ummarized 
mmarize
Lugano clas
Lugano cla
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onse
e calculate
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a subjects a
subjects a
responder s
responder s
summarize
summarize
arm
rm.
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Du
Du
Duration
uration
urati
urati


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Duration of response using the IWCLL Guidelines
Duration of response is defined for responders only as the time from the first documented 
response (CR, CRi, nPR, PR, or PRL) to disease progression or death (from any cause). For 
subjects with response but no progression, or death, DoR will be censored at the last date that the 
subject was known to be progression-free.
Duration of response will be assessed using the Kaplan-Meier method to calculate the median 
duration of response including 2-sided 95% CI for each treatment arm and subject histology 
cohort.
10.4.
Progression-free Survival 
Progression-free survival will be calculated as the time from first IP dose to the first documented 
progression or death (from any cause) during the entire efficacy evaluation period. For subjects 
with no progression or death, PFS will be censored at the last assessment date the subject was 
known to be progression-free. Median PFS including 2-sided 95% CI will be provided for each 
histology cohort within the same treatment arm.
The primary analysis will be based on the FDA guidelines (see Table 6 for the event and 
censoring rules). A sensitivity analysis will be performed using the European Medicines Agency 
(EMA) guidelines (see Table 7 for the event and censoring rules).
10.5.
Overall Survival
Overall survival is calculated as the time from first IP dose to death due to any cause. Subjects 
who died will be considered as having events on the date of death. Subjects who were alive or 
lost to follow-up at the end of the study will be censored on the last-known-to-be-alive date. 
Overall survival will be analyzed similarly to PFS and DoR.
Table 6: 
Event and Censoring Rules for PFS and DoR Based on FDA Guidelines
Situation
Date Subject Has Event or is Censored 
Situation 
Outcome
Progression not after 2 or more 
missed scheduled assessments
during the treatment period
Date of PD
Event
Progression not after 1 or more 
missed scheduled assessments 
during the follow-up period
Date of PD
Event
Death not after 2 or more 
missed scheduled assessments 
during the treatment period
Date of death
Event
Death not after 1 or more 
missed scheduled assessments 
during the follow-up period
Date of death
Event
&(
Death 
Death not a
not a
missed s
missed 
ing
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IP dose to d
IP dose to
the date of
he date of
e censored 
censored 
to PFS and
o PFS an
Rules for P
ules for P
ate Subject 
ate Subject
23
35
3
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1 or more 
assessment
assessmen
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the treatm
*(
&(


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Table 6:
Event and Censoring Rules for PFS and DoR Based on FDA Guidelines 
(Continued)
Situation
Date Subject Has Event or is Censored 
Situation 
Outcome
Death or progression after 2 or 
more missed scheduled 
assessments during the 
treatment period
Date of last adequate assessment with evidence of no 
progression; if no adequate assessment exists then 
censored at date of first dose
Censored
Death or progression after 1 or 
more missed scheduled 
assessments during the follow-
up period
Date of last adequate assessment with evidence of no 
progression; if no adequate assessment exists then 
censored at date of first dose
Censored
New anti-lymphoma/non-
protocol treatment started prior 
to progression or death due to 
any reason. New anticancer 
therapy started prior to 
progression or death 
Date of last adequate assessment with evidence of no 
progression before anticancer therapy; if no adequate 
assessment exists then censored at date of first dose
Censored
No progression 
Date of last adequate assessment with evidence of no 
progression; if no adequate assessment exists then 
censored at date of first dose
Censored
Table 7:
Event and Censoring Rules for PFS Based on EMA Guidelines
Situation
Date Subject Has Event or is Censored 
Situation 
Outcome
Progression not after 2 or more 
missed scheduled assessments
during the treatment period
Date of PD 
Event
Progression not after 1 or more 
missed scheduled assessments 
during the follow-up period
Date of PD 
Event
Death not after 2 or more 
missed scheduled assessments 
during the treatment period
Date of death
Event
Death not after 1 or more 
missed scheduled assessments 
during the follow-up period
Date of death 
Event
t afterer 1 or 
1 or
d scheduled
d schedule
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PFS Bas
ect Has Eve
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23
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Date
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Celgene
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Table 7:
Event and Censoring Rules for PFS Based on EMA Guidelines (Continued)
Situation
Date Subject Has Event or is Censored 
Situation 
Outcome
Death or progression after 2 or 
more missed scheduled 
assessments during the 
treatment period
Date of documented progression or death
Event
Death or progression after 1 or 
more missed scheduled 
assessments during the follow-
up period
Date of documented progression or death
Event
New anti-lymphoma/non-
protocol treatment started prior 
to progression or death due to 
any reason. New anticancer 
therapy started prior to 
progression or death 
Date of documented progression or death
Event
No progression 
Date of last adequate assessment with evidence of no 
progression; if no adequate assessment exists then 
censored at date of first dose
Censored
 
 
 
 
 
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11.
PHARMACOKINETIC ANALYSIS
Serum samples will be collected to assay the serum concentrations of durvalumab as 
monotherapy and in combination with other drugs, the plasma concentrations of lenalidomide in 
combination with durvalumab, and the plasma concentrations of ibrutinib in combination with 
durvalumab.
Serum/plasma concentrations from durvalumab and/or combo-drugs will be listed and 
summarized by cycle, day, nominal time, and cohort using descriptive statistics (N, mean, 
standard deviation, coefficient of variation [CV%], geometric mean, geometric CV%, median, 
minimum, and maximum).
For concentration value below the low limit of quantification (LLOQ), a concentration value of 
zero will be included for the computation of arithmetic mean and a concentration value of 50% 
the LLOQ will be included for the computation of geometric mean.
Serum/plasma PK parameters (shown below but not limited to) will be calculated for 
durvalumab and/or combo-drugs using noncompartmental analysis:
!
AUC0-last: AUC from time 0 to the last measurable time point calculated using the 
log-linear trapezoidal method.
!
AUC0-inf: AUC from time 0 extrapolated to infinity, calculated as
AUC0-inf = AUC0-last + lqc/K, where lqc is the last quantifiable (measurable) 
concentration. 
!
Cmax: Maximum (peak) concentration.
!
Tmax: Time of maximum (peak) concentration.
!
K: Terminal elimination rate constant estimated by linear regression of log 
concentration vs. time; at least 3 data points are required to compute this parameter.
!
t1/2: Terminal elimination half-life computed as (log 2)/K.
!
CL/F: Apparent systemic clearance, calculated as Dose/AUC0-inf.
!
VZ/F: Apparent total volume of distribution, calculated as [CL/F/lz].
The log symbol above stands for natural log. PK parameters from durvalumab and/or 
combination IP will be listed and summarized by cycle, day, and cohort using descriptive 
statistics (N, mean, standard deviation, coefficient of variation [CV%], geometric mean, 
geometric CV%, median, minimum, and maximum).
Mean and individual plots of plasma concentrations will be presented in both original and 
semilogarithmic scales.
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dian,
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n value o
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alculated f
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12.
SAFETY ANALYSIS
The purpose of this section is to define the safety parameters for the study. All summaries of 
safety data will be conducted using the Safety Population. All analyses will be presented by 
treatment arm, histology, study part, and dose level.
12.1.
Dose-limiting Toxicity
Dose-limiting toxicities will be evaluated during the DLT evaluation period for the subjects in 
the dose-finding cohorts. The DLT evaluation period is starting from the first dose of any 
investigational product (IP) through the end of Cycle 1. The severity grading of adverse events 
will be determined according to National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.03 or higher unless otherwise specify in protocol 
Section 7.2.10.1 (Cairo, 2004 and IWCLL, 2008).
Hematologic DLT:
!
Grade 4 neutropenia observed for greater than 5 days duration;
!
Grade 3 neutropenia associated with fever (≥ 38.5 °C) of any duration;
!
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding, or any 
requirement for platelets transfusion;
!
Grade 4 anemia, unexplained by underlying disease;
!
Any other grade 4 hematologic toxicity that does not resolve to subject’s 
pre-treatment baseline level within 72 hours.
Nonhematologic DLT:
!
Any nonhematological toxicity ≥ Grade 3 except for alopecia and nausea controlled 
by medical management;
!
Any treatment interruption greater than 2 weeks due to adverse event.
While the rules for adjudicating DLTs in the context of dose-finding are specified above, an AE 
not listed above may be defined as a DLT after consultation with the sponsor and SRC based on 
the emerging safety profile.
Should a subject experience a suspected DLT, the treating investigator should contact the 
sponsor’s medical monitor prior to declaring the event a DLT. All DLT cases will also be 
discussed with the SRC during regular calls with sites and their respective investigators aiming 
to review, and share all safety related events including but not limited to DLTs. Each study arm 
will have a dedicated SRC.
The number of subjects who experienced DLTs will be summarized using DLT Evaluable 
Population. Dose-limiting toxicities will be also listed by dose cohort and arm using the Safety
Population.
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Durvalumab (MEDI4736)
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12.2.
Treatment-emergent Adverse Events
All safety analyses will be conducted using Safety Population. All analyses will be presented by 
treatment arm, histology, study part, and dose level. AEs will be coded according to the 
MedDRA Version 18 or higher.
Treatment-emergent adverse events (TEAEs) are defined as AEs occurring or worsening on or 
after the first treatment of the study treatment (durvalumab, lenalidomide, ibrutinib, 
bendamustine or rituximab) and within 90 days after last dose of durvalumab or 28 days after the 
last dose of other IPs, whichever is the later date, as well as those SAEs made known to the 
investigator at any time thereafter that are suspected of being related to study treatment.
The incidence of TEAEs will be summarized by MedDRA SOC and PT. The intensity of AEs 
will be graded according to the NCI CTCAE Version 4.03 or higher. For all other AEs not 
described in the CTCAE criteria, the intensity will be assessed by the investigator as mild (Grade
1), moderate (Grade 2), severe (Grade 3), life-threatening (Grade 4), or death (Grade 5).
A treatment-related TEAE is defined as TEAE which was considered to be related to the study 
drugs by the investigator.
If a subject experience the same AE more than once with different toxicity grade, then the event 
with the highest grade will be tabulated in “by grade” tables. If a subject experiences multiple 
AEs under the same PT (SOC), then the subject will be counted only once for that PT (SOC). In 
addition, AEs with a missing intensity will be presented in the summary table as an intensity 
category of “Missing.”
Tables summarizing the incidence of TEAEs will be generated per study phase within each arm
for each of the following:
!
All TEAEs;
!
TEAEs related to durvalumab or any other IP;
!
TEAE by CTCAE Grade 3 or 4;
!
TEAE by CTCAE Grade 1 or 2;
!
TEAE related to durvalumab or any other IP with Grade 3 or 4;
!
TEAEs with death outcome;
!
TEAEs with death outcome related to durvalumab or any other IP;
!
Serious TEAEs;
!
Serious TEAEs related to durvalumab or any other IP;
!
TEAEs leading to discontinuation of durvalumab or any other IP;
!
TEAEs leading to dose modifications of durvalumab or any other IP;
!
TEAEs by cycle of onset;
!
TEAEs related to durvalumab or any other IP by cycle onset;
!
Serious TEAEs by cycle of onset;
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Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol MEDI4736-NHL-001
Celgene
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!
TEAEs by maximum CTCAE grade;
!
TEAEs related to durvalumab or any other IP by maximum CTCAE grade;
!
Common (≥ 10%) TEAEs;
!
Common (≥ 10%) TEAEs related to durvalumab or any other IP.
To facilitate clinical study report writing, a summary table of TEAEs by PTs will also be 
provided.
Listings for the corresponding summary tables will be presented separately. A listing for non
TEAEs will also be provided.
All deaths and reasons for death will be summarized. Deaths occurring during the treatment 
period, within 28 days after the last dose of durvalumab and within 90 days after the last dose of 
durvalumab will be summarized separately.
12.3.
Adverse Events of Special Interest
The adverse events of special interest (AESI) refer to a group of terms/PTs from one or more 
SOCs relating to a defined medical condition or area of interest. Unless an AESI is defined by a 
single PT, the AESI generally refers to a group of PTs.
The AESI will be searched using the standardized MedDRA query (SMQ), sub-SMQ search 
criteria or a collection of selected ad-hoc PTs used to define and monitor the AESI. Adverse 
events of special interest will be summarized separately for durvalumab and lenalidomide. The 
AESI summary for each study treatment will be summarized by AESIs, which will be referred as 
AESI categories in tables and listings, and by PT.
Durvalumab AESI below will be summarized: 
!
Adrenal insufficiency
!
Colitis
!
Dermatitis
!
Diarrhoea
!
Guillain-Barre syndrome
!
Hepatic laboratory parameters reported as AEs
!
Hepatitis
!
Hypersensitivity/Anaphylactic reactions
!
Hyperthyroidism
!
Hypophysitis
!
Hypothyroidism
!
Infusion related reaction
!
Intestinal perforations
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Durvalumab (MEDI4736)
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!
Myasthenia gravis
!
Myocarditis
!
Myositis
!
Nephritis
!
Other rare/miscellaneous
!
Pancreatic laboratory investigations reported as AEs
!
Pancreatitis
!
Pneumonitis
!
Rash
!
Renal laboratory investigations reported as AEs
!
Thyroid laboratory parameters reported as AEs (decreased thyroid activity)
!
Thyroid laboratory parameters reported as AEs (increased thyroid activity)
!
Thyroiditis
!
Type 1 diabetes mellitus.
Lenalidomide AESI below will also be summarized for subjects in Arms A and D who received 
lenalidomide:
!
Cardiac arrhythmias
!
Cardiac failure
!
Infection
!
Invasive-AML
!
Invasive-B-cell malignancies
!
Invasive-Cumulative
!
Invasive-Other haematologic malignancies
!
Invasive-Solid tumors-Cumulative
!
Invasive-SPM hematologic malignancies
!
Invasive-SPM solid tumor-Renal and urinary
!
Invasive-SPM solid tumor-Reproductive
!
Invasive-SPM solid tumor-Respiratory
!
Invasive-SPM solid tumors-Breast
!
Invasive-SPM solid tumors-Endocrine
!
Invasive-SPM solid tumors-Gastrointestinal
!
Invasive-SPM solid tumors-Hepatobiliary
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!
Invasive-SPM solid tumors-Skin
!
Invasive-SPM solid tumors-Mesotheliomas
!
Invasive-SPM solid tumors-Miscellaneous
!
Invasive-SPM solid tumors-Nervous system
!
Invasive-SPM solid tumors-Ocular
!
Invasive-SPM solid tumors-Soft tissue
!
Invasive-SPM solid tumors-Skeletal
!
Ischaemic heart disease (including myocardial infarction)
!
Neutropenia
!
Non-invasive-SPM: Non-invasive skin cancers
!
Teratogenicity
!
Tumour flare reaction
!
Unspecified.
The final list of AESI for durvalumab and lenalidomide will be defined before database lock.
The incidence will be generated by preferred term for:
!
All TEAEs of interest;
!
TEAEs of interest by CTCAE Grade 3 or 4;
!
TEAEs of interest by cycle of onset;
!
TEAEs of interest related to durvalumab or any other IP;
!
TEAE of interest related to durvalumab or any other IP with Grade 3 or 4;
!
TEAEs of interest by maximum CTCAE grade.
12.4.
Second Primary Malignancies
Second primary malignancies will be collected at any time from the time of signing the informed 
consent form (ICF) until:
!
90 days after last dose of durvalumab;
!
28 days after last dose of other IPs; or
!
Up to 5 years from last subjects’ first lenalidomide dose for subjects in Arm A and 
subjects in Arm D who have received lenalidomide as additional treatment at the time 
of progression, whichever is the later date for an individual subject AESI.
The SPM events will be summarized by treatment arm, histology and study part. Summaries will 
present SPM as per categories, subcategories and preferred term.  Graphical displays will be 
provided where useful to assist in the interpretation of results. Listings for the corresponding 
summary tables will be presented separately.
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Durvalumab (MEDI4736)
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12.5.
Clinical Laboratory Evaluations
Descriptive statistics (N, mean, standard deviation, median, minimum and maximum) of 
observed and change from baseline values will be presented for hematology and biochemistry
laboratory tests.
Clinical laboratory values from the central laboratories will be graded according to NCI CTCAE
Version 4.03 or higher for applicable tests. The worst grade during the treatment period will be 
summarized by treatment arm. Frequency distributions for shift from baseline to the worst grade
during treatment period will be presented by treatment arm. Normal ranges will be used to 
determine the categories of High, Low, and Normal for all laboratory tests.
Listings of clinical laboratory data from central laboratory with abnormal flags will be provided 
by subjects and tests. Listings will also be provided for the local laboratory data. The local 
normal ranges data are derived based on global range table (GRT) file provided by Celgene.
 
12.7.
Vital Sign Measurements
For vital signs, the shift from baseline to worst during the treatment in below, within, and above 
the normal ranges will be displayed in cross–tabulations for each treatment. Normal ranges are 
defined as follows:
!
Systolic blood pressure (SBP)  Normal (100 – 140 mmHg, inclusive);
!
Diastolic blood pressure (DBP)  Normal (60 – 90 mmHg, inclusive);
!
Body temperature  Normal (35 – 38°C, inclusive);
!
Pulse  Normal (60 – 100 bpm, inclusive).
Summary statistics (N, mean, standard deviation, median, minimum, and maximum) of the worst 
values of each cycle and change from baseline values will be presented.
The worst value at each cycle will be defined as follow:
!
If all values during the cycle are within the normal range, the worst value will be the 
largest value;
!
If one value during the cycle is outside the normal range, the worst value will be the 
value outside the normal range;
!
If at least 2 values, during the cycle, are outside the normal range, the worst value 
will be the value having the largest absolute difference from the normal range bounds. 
In case of 2 values with same absolute difference, the largest value will be selected.
12.8.
Overall Electrocardiograms Interpretation
The overall ECG interpretation will be summarized by presenting the number and percentage of 
subjects with ‘Normal’, ‘Abnormal, not clinically significant’, and ‘Abnormal, clinically 
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50
significant’ by treatment at Baseline. The shift from baseline to worst during the treatment in the 
overall ECG interpretation will be displayed in cross–tabulations for each treatment.
12.9.
Eastern Co-operative Oncology Group Performance Scores
Shift table from baseline to worst post-baseline in ECOG performance score will be displayed by 
treatment arm and histology cohort for the Safety Population.
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13.
INTERIM ANALYSIS
No formal interim analyses are planned. However, the study will also have a GSSC providing 
advice to the sponsor regarding study protocol design/amendments, study conduct and scientific 
integrity of the study as well as providing guidance to each SRC as appropriate. The GSSC will 
serve in an advisory capacity to the sponsor.
Operational details for the SRC and GSSC will be detailed in a separate charter document.
The sponsor will decide whether or not to open any dose-confirmation or expansion cohort as 
well as decide whether or not to adjust the number of subjects enrolled into any planned cohort 
based on the recommendations of the SRC and/or GSSC and relevant emerging clinical or 
nonclinical data (the stopping rules for the dose-confirmation part are described in Table 3).
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Durvalumab (MEDI4736)
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14.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF 
THE PROTOCOL
 
The dose-finding study part was completed for Arms B and C only. The dose-confirmation 
cohort of Arm A nor any of the dose expansion cohorts will open for enrollment.


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15.
REFERENCES
Cairo MS, Bishop M.  Tumour lysis syndrome: new therapeutic strategies and classification. Br J 
Haematol 2004;127(1):3-11.
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations for initial evaluation, staging, and response assessment of Hodgkin and Non-
Hodgkin lymphoma: The Lugano Classification. J Clin Oncol 2014;32(27):3059-68.
(FDA) Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, FDA/CDER/CBER May 2007.
Guideline on the evaluation of anticancer medicinal products in man, EMA/CHMP/205/95/Rev.4 
13 December 2012.
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al.  
Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia:  a report from the 
International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer 
Institute -Working Group 1996 guidelines. Blood 2008;111(12):5446-56.
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al.  
Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia:  a report from the 
International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer 
Institute -Working Group 1996 guidelines. Blood 2008;111(12):5446-56.  E-letter:  Response 
assessment in chronic lymphocytic leukemia treated with novel agents causing an increase of 
peripheral blood lymphocytes. June 2012.
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al.  
Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia:  a report from the 
International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer 
Institute -Working Group 1996 guidelines. Blood 2008;111(12):5446-56.  E-letter:  Clarification 
of IWCLL criteria for a partial response to therapy. Nov 2013
Smith A, Howell D, Patmore R, Jack A, Roman E.  Incidence of haematological malignancy by 
sub-type: a report from the Hematological Malignancy Research Network. Br J Cancer
2011;105(11):1684-92. Storer BE. Design and analysis of phase I clinical trials. Biometrics 
1989:45(3):925-37.
nd d
205/95/Rev
205/95/Re
r H, et al. 
r H, et al.
mia:  a repor
mia:  a repor
he Nat
he Natioiona
n
6-56.
56.
ro G, Döhn
ro G, Döhn
ocy
ocytiti
y c leuke
c leuk
mia updating
ia updatin
;111(12):54
;111(12):5
with novel
with nov
-Cappi
Cappio F
o F
t of chronic
of chronic
mphocy
mphocytiti
y c
elines.
elines. Bloo
B
sponse to th
sponse to 
R, Jack 
R, Jack A,
A
e Hematolo
Hematolo
Storer BE.
Storer BE


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16.
APPENDICES
16.1.
Handling of Dates
Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (ie. the Date9. datetime format in SAS). Dates in the clinical database 
are classified into the categories of procedure dates, log dates, milestone dates, outcome dates, 
and special dates.
!
Procedure Dates are the dates on which given protocol-specified procedure are 
performed. They include the dates of laboratory testing, physical examinations, tumor 
scans, etc. They should be present whenever data for a protocol-specified procedure 
are present and should only be missing when a procedure are marked as NOT DONE 
in the database. Procedure dates will not be imputed.
!
Log Dates are dates recorded in CRF data logs. Specifically, they are the start and 
end dates for adverse events and concomitant medications/procedures. They should 
not be missing unless an event or medication is marked as ongoing in the database. 
Otherwise, incomplete log dates will be imputed according to the rules in Appendix 
17.2 (eg. for duration or cycle assignment, etc). However, in listings, log dates will be 
shown as recorded without imputation.
!
Milestone Dates are dates of protocol milestones such as randomization, study drug 
start date, study drug termination date, study closure date, etc. They should not be 
missing if the milestone occurs for a subject. They will not be imputed.
!
Outcome Dates are dates corresponding to study endpoints such as survival, 
progression, etc. In most cases they are derived either from a milestone (eg. the 
survival date is derived from the death date), or a procedure date (eg. the progression 
date is derived from the date of the tumor scan that was used to determine 
progression). They may be subject to endpoint-specific censoring rules if the outcome 
did not occur, but are not otherwise subject to imputation.
!
Special Dates cannot be classified in any of the above categories and they include the 
date of birth. They may be subject to variable-specific censoring and imputation rules. 
Dates recorded in comment fields will not be imputed or reported in any specific format. 
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Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol MEDI4736-NHL-001
Celgene
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55
16.1.1.
Calculation Using Dates
Calculations using dates (eg. subject’s age or relative day after the first dose of study drug) will 
adhere to the following conventions: 
!
Study days after the start day of study drug will be calculated as the difference 
between the date of interest and the first date of dosing of study drug (eg.
lenalidomide) plus 1 day. The generalized calculation algorithm for relative day is the 
following: 
o
If TARGET DATE >= DSTART then STUDY DAY = (TARGET DATE –
DSTART) + 1; 
o
Else use STUDY DAY = TARGET DATE – DSTART.
!
Note that Study Day 1 is the first day of treatment of study drug. Negative study days 
are reflective of observations obtained during the baseline/screening period. Note: 
Partial dates for the first study drug are not imputed in general. All effort should be 
made to avoid incomplete study drug start dates. 
!
Age (expressed in days) is calculated: AGE = DATE of CONSENT – DATE of 
BIRTH + 1. In practice, age will be transformed to years by dividing the difference 
by 365.25 days, then truncating. If date of birth is missing in the CRF then use the age 
recorded in the CRF.
!
Intervals that are presented in weeks will be transformed from days to weeks by using 
(without truncation) the following conversion formula:
WEEKS = DAYS/7
!
Intervals that are presented in months will be transformed from days to months by 
using (without truncation) the following conversion formula:
MONTHS = DAYS/30.4167
!
Intervals that are presented in years will be transformed from days to years by using 
(without truncation) the following conversion formula:
YEARS = DAYS/365.25
16.1.2.
Calculation of Cycles 
The start date of each treatment cycle will be calculated based on study drug exposure records 
for each subject. The start date of the first cycle will be the date when the subject receives any 
dose of study drug. 
Once the start dates, eg. S1, S2, S3… are calculated, the end date of each cycle is calculated as the 
day before the start date of the following cycle, ie. Ei = Si+1 -1. For the last cycle, the end date 
will be calculated as the start date plus prescribed cycle length, or the treatment discontinuation 
date, or the death date, whichever is earlier. If a date is on or after Si and before Si+1, the 
corresponding cycle number will be i.
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Durvalumab (MEDI4736)
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16.2.
Date Imputation Guideline
16.2.1.
Impute Missing Adverse Events/Prior or Concomitant Medications 
Incomplete Start Date:
Missing day and month
!
If the year is the same as the year of the first dosing date, then the day and month of 
the first doing date will be assigned to the missing fields.
!
If the year is prior to the year of first dosing date, then December 31 will be assigned 
to the missing fields.
!
If the year is after the year of first dosing, then January 1 will be assigned to the 
missing fields.
Missing day only 
!
If the month and year are the same as the year and month of first dosing date, then the 
first doing date will be assigned to the missing day.
!
If either the year of the partial date is before the year of the first dosing date or the 
years of the partial date and the first dosing date are the same but the month of partial 
date is before the month of the first dosing date, then the last day of the month will be 
assigned to the missing day.
!
If either the year of the partial date is after the year of the first dosing date or the 
years of the partial date and the first dose date are the same but the month of partial 
date is after the month of the first dosing date, then the first day of the month will be 
assigned to the missing day.
!
If the stop date is not missing, and the imputed start date is after the stop date, the 
start date will be imputed by the stop date. 
Missing day, month, and year
!
No imputation is needed, the corresponding AE will be included as TEAE. 
Incomplete Stop Date: If the imputed stop date is before the start date, then the imputed stop 
date will be equal to the start date.
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Missing day and month
!
If the year of the incomplete stop date is the same as the year of the last dosing date, 
then the day and month of the last dosing date will be assigned to the missing fields. 
!
If the year of the incomplete stop date is prior to the year of the last dosing date but is 
the same as the year of the first dosing date, then the first dosing date will be assigned 
to the missing date. 
!
If the year of the incomplete stop date is prior to the year of the last dosing date or 
prior to the year of the first dosing date, then December 31 will be assigned to the 
missing fields. 
!
If the year of the incomplete stop date is after the year of the last dosing date, then
January 1 will be assigned to the missing fields.
Missing day only 
!
If the month and year of the incomplete stop date are the same as the month and year 
of the last dosing date, then the day of the last dosing date will be assigned to the 
missing day. 
!
If either the year of the partial date is not equal to the year of the last dosing date or 
the years of the partial date and the last dosing date are the same but the month of 
partial date is not equal to the month of the last dosing date, then the last day of the 
month will be assigned to the missing day. 
16.2.2.
Medical History
Partially missing medical history start dates will be imputed in the ADaM dataset for medical 
history. The 16th of the month will be used to impute a partially missing start date that has only 
the day missing, and July 1st will be used to impute a partially missing start date that has both the 
month and day missing.
If the imputed start date is greater than the stop date:
!
If the imputed start date is before the first treatment day then start date will be 
assigned to stop date.
!
If the imputed start date is after the first treatment day then start date will be assigned 
to the first treatment day - 1.
16.2.3.
Impute Missing Disease Diagnosis Dates
For partial diagnosis dates, January will be assigned to the missing month; and the first day of 
the month will be assigned to the missing day.
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ater than th
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start da
stop date.
stop date.
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mputed sta
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month wil
onth wil


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16.2.4.
Impute Missing Dates in Prior Systemic Therapies
If day is missing, but month and year are non-missing: 
!
If start date has month strictly before month of end date, then impute day of end date 
to 1st of the month.
!
If start date has month equal to month of end date and day of start day is missing, 
then impute day of end date to 1st of the month.
!
If start date has month equal to month of end date and day of start day is non-missing, 
then impute day of the end date to the day of the start date.
If day and month are missing and year is non-missing: 
!
If start date has both day and month missing, then impute day to 1st of the month and 
month to January.
!
If start date has day missing but month non-missing, then impute day to 1st of the 
month and month to the same month as start date.
!
If start date has both day and month non-missing, then impute day and month to the 
same month to the day and month as the start date.
If day is non-missing, month is missing and year is non-missing: 
!
If start date has month missing, then impute month of the end date to January.
!
If start date has month non-missing, then impute month of the end date to month of 
the start date.
If year is missing:
!
No imputation.
16.2.5.
Impute Missing Dates in Subsequent Cancer Therapy
Patient will allow take other cancer therapy after discontinued from the study. The lymphoma 
therapy start/stop date will be collected. If the day of any date is missing, then the last day the 
nonmissing month will be assigned to the missing day; if day and month are both missing, then 
the December 31 of the nonmissing year will be assigned to the missing day.
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the month 
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te day
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y
mpute day
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ing: 
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month of th
onth of 
impute mo
impute m
in Subsequ
n Subseq
ncer therap
ncer therap
e co
e collected
llect
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e assign
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16.2.6.
Impute Missing Dates for Death
If death day is missing, but month and year are non-missing: 
!
If patient discontinued the additional treatment period and the reason for 
discontinuation is death:
∀
If month and year of the death date same as month and year of the discontinuation 
date then impute to date of additional treatment discontinuation date.
!
If patient discontinued the follow-up period and the reason for discontinuation is 
death:
∀
If month and year of the death date same as month and year of the discontinuation 
date then impute to date of follow-up discontinuation date.
!
If patient discontinued the assigned treatment period and the reason for 
discontinuation is death:
∀
If month and year of the death date same as month and year of the discontinuation 
date then impute to date of assigned treatment discontinuation date.
!
If patient does not discontinue the assigned treatment period then impute to the last 
date patient known alive.
If death month or year is missing:
!
No imputation.
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inuatioion
for 
for 
ear of the d
r of th
inuat
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n da
period then
eriod the