Clinical trial NCT02685826
Conditions: Multiple Myeloma
Keywords: Open-label Phase 1/2 Durvalumab MEDI4736 Lenalidomide (Len) Dexamethasone (dex) Multiple Myeloma Newly-Diagnosed (NDMM) Transplant Non-eligible (TNE) PD-L1 Durvalumab (DURVA)
Sponsor: Celgene
Start date: 2016-04-25; Completion date: 2022-09-06
Enrollment: 56 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, open-label, Phase 1/2 study to determine the recommended dose and regimen of durvalumab in combination with lenalidomide (LEN) with and without dexamethasone (dex) in adults with newly diagnosed multiple myeloma (NDMM).

The study will consist of a dose-finding phase as well as a parallel dose-expansion phase to determine the optimal regimen.

\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*

The study was placed on full clinical hold by the United States (US) Food and Drug Administration (FDA) on 05 Sep 2017. The decision by the FDA was based on data from non-Celgene-sponsored studies related to risks of anti-programmed cell death 1 (PD-1), pembrolizumab, in combination with immunomodulatory agents. As the result, the study was closed for further enrollment, and all subjects were discontinued from all study treatments (durvalumab, lenalidomide and dexamethasone). All subjects are being followed for second primary malignancies (SPMs), every 6 months for 5 years after the last subject has been enrolled as per protocol. After stopping data collection in the clinical database, any SPM events will continue to be recorded in the subject's source documents, and reported to Celgene Drug Safety.

Detailed description:
The dose-finding phase will determine recommended dose (RD) for durvalumab in combination with lenalidomide (LEN) with and without dexamethasone (dex) in a 28-day treatment cycle. Three treatment Cohorts (A, B, and C) will be enrolled in parallel:

* Cohort A: durvalumab + LEN + dex in high risk transplant non-eligible (TNE) newly diagnosed multiple myeloma (NDMM) participants;
* Cohort B: durvalumab + LEN + dex (dex for up to 12 cycles) in ≥ 65 years old TNE NDMM participants who are not high risk;
* Cohort C: durvalumab + LEN as maintenance in post-transplant high risk NDMM participants.

Based on experience with durvalumab for other indications, the initial dose of durvalumab will be 1500 mg for each treatment cohort. The dose of durvalumab might be de-escalated to 750 mg level.

The dose of LEN will be 25 mg (adjustable per the creatinine clearance \[CrCl\] value) on Days 1 to 21 of each 28-day treatment cycle for participants in Cohort A and B. The dose of LEN will be 10 mg on Days 1 to 21 of each 28-day treatment cycle for participants in Cohort C.

The dose of dex will be 40 mg/day (for participants ≤ 75 years old) or 20 mg/day (for participants \> 75 years old) on Days 1, 8, 15, and 22 of a 28-day cycle for Cohort A and Cohort B (for up to 12 cycles).

Initially, 6 participants will be enrolled into each cohort and each will receive 1500 mg durvalumab.

The dose-limiting toxicity (DLT) evaluation period will be the first treatment cycle.

* If ≤ 1 of the 6 initial participants experience a DLT within the first cycle, then the dose expansion phase may be initiated with durvalumab 1500 mg as the recommended dose (RD);
* If 2 or more of the 6 initial participants experience a DLT within the first cycle, then the maximum tolerated dose (MTD) has been exceeded and de-escalation to durvalumab 750 mg level after review of safety and pharmacokinetic/pharmacodynamic (PK/Pd) of the initial 6 participants by the Dose Review Team (DRT).

Any of the cohorts may be removed from the study based on emerging PK, Pd, efficacy or safety data.

Dose de-escalation will only occur after review of safety (DLT) and possibly PK/Pd data by the Dose Review Team ( DRT).

Note: In the US, two treatment arms (A and B) will be enrolled in parallel. Cohort C will enroll upon completion of at least 4 cycles of follow-up for safety assessment of Cohorts A and B.

Arms: arm 1: High risk, transplant non-eligible \[TNE\], newly diagnosed multiple myeloma (NDMM) participants who were administered

* Intravenous (IV) durvalumab at 1500 mg on Day 1 of each 28-day cycle
* Oral lenalidomide (LEN) 25 mg/day (adjust per the creatinine clearance \[CrCl\]) value on Days 1 to 21 of each 28-day treatment cycle
* Oral dexamethasone (dex) 40 mg/day (≤ 75 years old) or 20 mg/day (\> 75 years old) on Days 1, 8, 15, and 22 of each 28-day cycle arm 2: \>= 65 years old, transplant non-eligible \[TNE\], newly diagnosed multiple myeloma (NDMM) participants who were not high risk were administered

* Intravenous (IV) durvalumab at 1500 mg on Day 1 of each 28-day cycle
* Oral lenalidomide (LEN) 25 mg/day (adjust per the creatinine clearance \[CrCl\]) value on Days 1 to 21 of each 28-day treatment cycle
* Oral dexamethasone (dex) 40 mg/day (≤ 75 years old) or 20 mg/day (\> 75 years old) on Days 1, 8, 15, and 22 of each 28-day cycle, up to 12 cycles arm 3: High risk, post-transplant NDMM participants were administered the following as maintenance therapy:

* Intravenous (IV) durvalumab at 1500 mg on Day 1 of each 28-day cycle
* Oral lenalidomide (LEN) 10 mg/day on Days 1 to 21 of each 28-day treatment cycle
Interventions: intervention 1: Durvalumab intervention 2: Lenalidomide intervention 3: Dexamethasone
Intervention descriptions: intervention 1: single use vials administered via intravenous infusion intervention 2: capsules for oral administration intervention 3: tablets for oral administration

Protocol documents:
Prot_002.pdf: 
Official Title of Study: 
A PHASE 1/2 MULTICENTER, OPEN-LABEL STUDY TO DETERMINE THE RECOMMENDED DOSE 
AND REGIMEN OF DURVALUMAB (MEDI4736) IN COMBINATION WITH LENALIDOMIDE (LEN) 
WITH AND WITHOUT DEXAMETHASONE (DEX) IN SUBJECTS WITH NEWLY DIAGNOSED 
MULTIPLE MYELOMA (NDMM) 
 
NCT Number: NCT02685826 
 
Document Date (Date in which document was last revised): Dec 05, 2019 


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
1
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
TITLE PAGE
A PHASE 1/2 MULTICENTER, OPEN-LABEL STUDY TO 
DETERMINE THE RECOMMENDED DOSE AND 
REGIMEN OF DURVALUMAB (MEDI4736) IN 
COMBINATION WITH LENALIDOMIDE (LEN) WITH 
AND WITHOUT DEXAMETHASONE (DEX) IN 
SUBJECTS WITH NEWLY DIAGNOSED MULTIPLE 
MYELOMA (NDMM)
INVESTIGATIONAL PRODUCT (IP):
Lenalidomide, Dexamethasone and 
Durvalumab (MEDI4736)
PROTOCOL NUMBER:
MEDI4736-MM-002 
DATE FINAL:
24 Nov 2015
DATE AMENDMENT 1.0 FINAL:
27 Jun 2016
DATE AMENDMENT 2.0 FINAL:
06 Apr 2017
DATE AMENDMENT 3.0 FINAL:
05 Dec 2019
EudraCT NUMBER:
2015-004831-11
IND NUMBER:
127058
SPONSOR NAME/ ADDRESS:
Celgene International II Sàrl
Rue des Moulins 4
2108 Couvet, Switzerland
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or 
consultant for review by you, your staff, and ethics committee/institutional 
review board.  The information contained in this document is regarded as 
confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by 
law or regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.
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EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
2
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:  Global
Name:  
Title:  
 
Address: 86 Morris Avenue, Summit, NJ 07901 USA
Phone:  
Mobile:  
E-mail:  
Note: The back-up 24-hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls.
Back-up 24-hour Global Emergency Contact Call Center: 
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EDMS Doc. Number: 24328540 - 20680025
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Celgene Corporation
Confidential and Proprietary
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MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
CELGENE THERAPEUTIC AREA HEAD 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.  
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EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
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MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name:_______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from
Celgene representatives, the Declaration of Helsinki, International Council for
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.
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EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
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MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
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.
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
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EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
6
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
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
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EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
7
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
PROTOCOL SUMMARY
The study was placed on full clinical hold by the United States (US) Food and Drug 
Administration (FDA) on 05 Sep 2017. The decision by the FDA was based on data from non-
Celgene-sponsored studies related to risks of anti-programmed cell death 1 (PD-1), 
pembrolizumab, in combination with immunomodulatory agents. As the result, the study was 
closed for further enrollment, and all subjects were discontinued from all study treatments 
(durvalumab, lenalidomide and dexamethasone). All subjects are being followed for second 
primary malignancies (SPMs), every 6 months for 5 years after the last subject has been enrolled 
as per protocol. After stopping data collection in the clinical database, any SPM events will 
continue to be recorded in the subject’s source documents, and reported to Celgene Drug Safety.
Study Title
A Phase 1/2, multicenter, open-label study to determine the recommended dose and regimen of
durvalumab (MEDI4736) in combination with lenalidomide (LEN) with and without
dexamethasone (dex) in subjects with newly diagnosed multiple myeloma (NDMM).
Indication
Newly diagnosed multiple myeloma (NDMM).
Objectives
Primary Objective:

To determine the recommended dose of durvalumab in combination with LEN with 
and without dex in subjects with NDMM
Secondary Objectives:

To evaluate the safety and preliminary efficacy of durvalumab in combination with 
LEN with and without dex in subjects with NDMM

To evaluate the pharmacokinetics of durvalumab and LEN with and without dex in 
subjects with NDMM
Exploratory Objectives:

To evaluate additional efficacy of durvalumab in combination with LEN with and 
without dex in subjects with NDMM.
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EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
8
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Study Design
This is a multicenter, open-label, Phase 1/2 study to determine the recommended dose and 
regimen of durvalumab in combination with LEN with and without dex in subjects with NDMM. 
The study will consist of a dose-finding phase and a dose-expansion phase to determine the 
optimal regimen. See Figure 1 and Figure 2. 
Dose-finding Phase
The dose-finding phase will determine the recommend dose and regimen of durvalumab in 
combination with LEN with and without dex in a 28-day treatment cycle.
Three treatment arms (A, B and C) will be enrolled in parallel:
Treatment Cohort A (for high risk transplant non-eligible [TNE] NDMM subjects)

Intravenous (IV) durvalumab at 1500 mg on Day 1 of a 28-day cycle, 

Oral LEN 25 mg/day (adjust per the creatinine clearance [CrCl] value, see details in 
Section 7.2.1.2, and Table 4) on Days 1 to 21 of each 28-day treatment cycle, 

Oral dex 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) on Days 1, 8, 15, 
and 22 of each 28-day cycle.
Treatment Cohort B (for ≥65 years old TNE NDMM subjects who are not high risk)

Intravenous durvalumab at 1500 mg on Day 1 of a 28-day cycle, 

Oral LEN 25 mg/day (adjust per the CrCl value, see details in Section 7.2.1.2 and 
Table 4) on Days 1 to 21 of each 28-day treatment cycle, 

Oral dex 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) on Days 1, 8, 15, 
and 22 of each 28-day cycle (for up to 12 cycles),
Treatment Cohort C (for high risk post-transplant NDMM subjects as maintenance)

Intravenous durvalumab at 1500 mg on Day 1 of a 28-day cycle, 

Oral LEN 10 mg/day on Days 1 to 21 of each 28-day treatment cycle, 
All subjects on these 3 treatment Cohorts will continue study treatment until PD or unacceptable 
toxicity occurs.  
See detailed eligibility criteria on Section 4.2 and Section 4.3 for each cohort.
Based on experience with durvalumab in other indications (solid tumors and MDS), the initial 
dose of durvalumab will be at 1500 mg every treatment cycle for each cohort. In the event of 
dose limiting toxicities, the dose of durvalumab would be de-escalated to 750 mg level.
The Dose Review Team (DRT) are responsible for dosing decisions. The DRT members will 
consist of the following: Celgene medical monitor, Celgene lead safety physician, Celgene 
biostatistician, other Celgene functional area representatives as appropriate, and site investigator 
and/or designees.
Initially, 6 subjects will be enrolled into each cohort for dose-limiting toxicity (DLT) evaluation 
and will receive 1500 mg durvalumab. The DLT evaluation period will be the first treatment 
cycle.
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EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
9
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019

If ≤1 of the 6 initial subjects experience a DLT within the first cycle, then the dose-
expansion phase may be initiated with durvalumab 1500 mg as the recommended 
dose (RD); 

If 2 or more of the 6 initial subjects experience a DLT within the first cycle, then the 
maximum tolerated dose (MTD) has been exceeded and de-escalation to durvalumab
750 mg level after review of safety and PK/Pd of the initial 6 subjects by the DRT
Any of the cohorts may be removed from the study based on emerging PK, Pd, efficacy or safety 
data.
Dose de-escalation will only occur after review of safety data (DLT), and possibly PK/Pd data by 
the DRT. 
Dose-expansion Phase
All expansion decisions will be determined by the DRT after review of all safety, and if 
applicable PK/Pd, and/or biomarker, and/or preliminary efficacy data.
After all 6 subjects enrolled in the Dose-finding phase have completed the Cycle 1 treatment;
and all data are obtained and reviewed, additional eligible subjects (See detailed eligibility 
criteria on Section 4.2 and Section 4.3) for each respective cohort may be enrolled. The total of 
subjects for each Cohort can be expanded up to 40 (including 6 subjects enrolled in the dose-
finding phase and 34 in the expansion phase).
The expansion for each study cohort can be occurred independently.
Study Population
The study population is to include NDMM subjects who have measurable myeloma protein (M-
protein) by protein electrophoresis analyses (in serum [SPEP] and/or urine [UPEP]) per
International Myeloma Working Group (IMWG) criteria.
See Section 4.2 and Section 4.3 of the protocol for detailed eligibility criteria.
Length of Study
Screening period will be within 28 days prior to start of Cycle 1. Eligible subjects will be treated 
in 28-day cycles and may continue study treatment until PD or unacceptable toxicity occurs. All 
subjects will have an End of Treatment visit (EOT) within 7 days after discontinuation of all 
study treatment. Subjects are to return to the study site 28 + 3 days after the EOT visit and 90 
(+3) days after the last dose of durvalumab for safety follow-up visits. Occurrence of second 
primary malignancies (SPM) will continue to be monitored at the above required 90 day visit and 
then every 6 months up to 5 years after the last subject enrolled into the study. 
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 into different treatment cohorts based on the eligibility criteria.
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EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
10
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
For subjects in Cohort C, the study treatment is to be initiated at 100 days (±14 days) after 
transplant. 
The initial dose of durvalumab will be at 1500 mg on Day 1 of a 28-day treatment cycle for all 
treatment cohorts.
The dose of LEN will be 25 mg (adjustable per the CrCl value, see details in Section 7.2.1.2,
Table 4) on Days 1 to 21 of each 28-day treatment cycle for treatment Cohort A and Cohort B. 
The dose of LEN will be 10 mg on Days 1 to 21 of each 28-day treatment cycle for treatment 
Cohort C.
The dose of dex will be 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) on Days 1, 8, 
15, and 22 of a 28-day cycle for treatment Cohort A and Cohort B (for up to 12 cycles). 
Overview of Key Efficacy Assessments

Myeloma paraprotein

Serum immunoglobulins

Serum free light-chain

Corrected serum calcium

Response assessment (per IMWG Uniform Response Criteria)

Bone marrow aspiration/biopsy

Radiographic assessments of lytic bone lesions

Extramedullary plasmacytoma (EMP) assessments

Eastern Cooperative Oncology Group (ECOG) Performance Status

Cytogenetic findings in malignant myeloma clone

measured by ClonoSIGHT™ next 
generation sequencing (NGS) assay
Overview of Key Safety Assessments

Complete physical examination including vital signs

Clinical laboratory evaluations (hematology, serum chemistry, urinalysis, thyroid 
function tests)

Creatinine clearance 

Pregnancy testing / counseling

Electrocardiogram (ECG)

Concomitant medications and procedures

Immunogenicity of durvalumab

Adverse events, including adverse events of special interest (AESIs for example,
second primary malignancies)
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EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
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MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Pharmacokinetic

Serum/plasma samples will be collected to assay concentrations of durvalumab and 
LEN
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical Methods
Up to 138 subjects are planned to be enrolled in the study: up to 36 total in the 3 cohorts for dose 
finding and up to 102 in the 3 cohorts for expansion. The actual number of subjects will depend 
on the number of dose level being tested. Data will be reviewed and analyzed on an ongoing 
basis to allow DRT for making the decisions.  Final analyses will be performed after the End of 
Trial has been reached. All analyses will use descriptive statistics.  No formal statistical 
comparison/testing will be performed.
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EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
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Celgene Corporation
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MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................7
1.
INTRODUCTION..................................................................................................19
1.1.
Disease Background ...............................................................................................19
1.2.
Compound Background ..........................................................................................19
1.2.1.
Durvalumab (MEDI4736).......................................................................................19
1.2.2.
Lenalidomide (LEN)...............................................................................................20
1.3.
Rationale ................................................................................................................20
1.3.1.
Study Rationale and Purpose ..................................................................................20
1.3.1.1.
Cancer and Immune Function .................................................................................20
1.3.1.2.
Immune-checkpoint Inhibition................................................................................21
1.3.2.
Rationale for the Study Design ...............................................................................22
1.3.3.
Rationale for Dose, Schedule, and Regimen Selection ............................................22
1.3.3.1.
Dose/Schedule........................................................................................................22
1.3.3.2.
Regimen .................................................................................................................23
1.3.4.
Rationale for Choice of Combination Compounds ..................................................23
1.3.5.
Rationale for Pharmacodynamics and Potential Predictive Biomarkers ...................25
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................27
2.1.
Study Objectives and Endpoints..............................................................................27
3.
OVERALL STUDY DESIGN ................................................................................30
3.1.
Study Design ..........................................................................................................30
3.1.1.1.
Dose Review Team (DRT) .....................................................................................31
3.1.1.2.
Dose-limiting Toxicity (DLT).................................................................................31
3.1.2.
Dose-expansion Phase ............................................................................................32
3.2.
Study Duration for Subjects....................................................................................35
3.2.1.
Screening Period.....................................................................................................35
3.2.2.
Treatment Period ....................................................................................................35
3.2.2.1.
End of Treatment Visit ...........................................................................................35
3.2.3.
Follow-up Period....................................................................................................35
3.3.
End of Trial ............................................................................................................36
4.
STUDY POPULATION.........................................................................................37
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4.1.
Number of Subjects ................................................................................................37
4.2.
Inclusion Criteria....................................................................................................37
4.3.
Exclusion Criteria...................................................................................................39
5.
TABLE OF EVENTS.............................................................................................42
6.
PROCEDURES......................................................................................................49
6.1.
Screening period.....................................................................................................49
6.2.
Treatment Period ....................................................................................................51
6.2.1.
End of Treatment....................................................................................................52
6.3.
Follow-up Period....................................................................................................53
6.3.1.
Safety Follow-up ....................................................................................................53
6.4.
Efficacy Assessment...............................................................................................54
6.4.1.
Laboratory Assessments for Efficacy Parameters....................................................54
6.4.2.
Bone Marrow Aspiration and/or Biopsy and Cytogenetics ......................................54
6.4.3.
Bone Lesion Assessment ........................................................................................55
6.4.4.
Extramedullary Plasmacytoma Assessments (EMPs) ..............................................55
6.4.5.
Assessment of Response.........................................................................................56
6.5.
Pharmacokinetics....................................................................................................56
6.5.1.
Pharmacokinetics of Lenalidomide .........................................................................56
6.5.2.
Pharmacokinetics of Durvalumab ...........................................................................56
6.5.3.
Immunogenicity Samples of Durvalumab ...............................................................57
57
58
7.
DESCRIPTION OF STUDY TREATMENTS........................................................59
7.1.
Description of Investigational Products...................................................................59
7.1.1.
Durvalumab (MEDI4736).......................................................................................59
7.1.2.
Lenalidomide (LEN)...............................................................................................60
7.1.3.
Dexamethasone (dex) .............................................................................................60
7.2.
Treatment Administration and Schedule .................................................................60
7.2.1.
Treatment Administration.......................................................................................60
7.2.1.1.
Durvalumab............................................................................................................60
7.2.1.2.
Lenalidomide..........................................................................................................61
7.2.1.3.
Dexamethasone ......................................................................................................61
7.2.2.
Treatment Schedule ................................................................................................62
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7.2.3.
Overdose ................................................................................................................63
7.2.4.
Dose Modifications and Interruptions .....................................................................63
7.2.4.1.
Dose Modification Instructions for Durvalumab .....................................................63
7.2.4.2.
Dose Modification Instructions for Lenalidomide ...................................................63
7.2.4.3.
Dose Modification Instructions for Dexamethasone................................................66
7.3.
Method of Treatment Assignment...........................................................................68
7.4.
Packaging and Labeling..........................................................................................68
7.5.
Investigational Product Accountability and Disposal ..............................................68
7.6.
Investigational Product Compliance........................................................................68
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................69
8.1.
Permitted Concomitant Medications and Procedures...............................................69
8.2.
Prohibited Concomitant Medications and Procedures..............................................69
8.3.
Required Concomitant Medications and Procedures................................................70
9.
STATISTICAL CONSIDERATIONS ....................................................................71
9.1.
Overview................................................................................................................71
9.2.
Study Population Definitions ..................................................................................71
9.3.
Sample Size and Power Considerations...................................................................71
9.4.
Background and Demographic Characteristics........................................................72
9.5.
Medical History......................................................................................................72
9.6.
Concomitant Medications and Procedures...............................................................72
9.7.
Subject Disposition.................................................................................................72
9.8.
Efficacy Analysis....................................................................................................73
9.8.1.
Response Using the IMWG Uniform Response Criteria..........................................73
9.8.2.
Response Improvement Rate Using the IMWG Uniform Response Criteria ............73
9.8.3.
Time to Response ...................................................................................................73
9.8.4.
Response Duration..................................................................................................73
9.8.5.
Progression Free Survival (PFS) .............................................................................74
9.8.6.
Overall Survival (OS).............................................................................................74
9.9.
Safety Analysis.......................................................................................................74
9.10.
Interim Analysis .....................................................................................................75
9.11.
Other Topics...........................................................................................................75
9.11.1.
Pharmacokinetic Analysis.......................................................................................75
75
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10.
ADVERSE EVENTS..............................................................................................76
10.1.
Monitoring, Recording, and Reporting of Adverse Events ......................................76
10.2.
Evaluation of Adverse Events.................................................................................76
10.2.1.
Seriousness.............................................................................................................76
10.2.2.
Severity/Intensity....................................................................................................78
10.2.3.
Causality ................................................................................................................78
10.2.4.
Duration .................................................................................................................79
10.2.5.
Action Taken..........................................................................................................79
10.2.6.
Outcome.................................................................................................................79
10.3.
Abnormal Laboratory Values..................................................................................79
10.4.
Pregnancy...............................................................................................................79
10.4.1.
Females of Childbearing Potential: .........................................................................80
10.4.2.
Male Subjects.........................................................................................................80
10.5.
Reporting of Serious Adverse Events......................................................................80
10.5.1.
Safety Queries ........................................................................................................81
10.6.
Expedited Reporting of Adverse Events..................................................................81
10.7.
Adverse Events of Special Interest..........................................................................82
10.7.1.
Second  PrimaryMalignancies (SPMs)....................................................................82
11.
DISCONTINUATIONS .........................................................................................83
11.1.
Treatment Discontinuation......................................................................................83
11.2.
Study Discontinuation ............................................................................................83
12.
EMERGENCY PROCEDURES.............................................................................84
12.1.
Emergency Contact.................................................................................................84
12.2.
Emergency Identification of Investigational Products .............................................84
13.
REGULATORY CONSIDERATIONS...................................................................85
13.1.
Good Clinical Practice............................................................................................85
13.2.
Investigator Responsibilities ...................................................................................85
13.3.
Subject Information and Informed Consent.............................................................86
13.4.
Confidentiality........................................................................................................86
13.5.
Protocol Amendments.............................................................................................86
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................86
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ................87
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13.8.
Termination of the Study ........................................................................................87
14.
DATA HANDLING AND RECORDKEEPING.....................................................88
14.1.
Data/Documents .....................................................................................................88
14.2.
Data Management...................................................................................................88
14.3.
Record Retention....................................................................................................88
15.
QUALITY CONTROL AND QUALITY ASSURANCE........................................90
15.1.
Study Monitoring and Source Data Verification......................................................90
15.2.
Audits and Inspections............................................................................................90
16.
PUBLICATIONS ...................................................................................................91
17.
REFERENCES.......................................................................................................92
18.
APPENDICES........................................................................................................98
Appendix A:
Table of Abbreviations ......................................................................................98
Appendix B:
International Myeloma Working Group Uniform Response Criteria.................101
Appendix C:
ECOG Performance Status...............................................................................103
Appendix D:
Durvalumab Treatment Modification and Toxicity Management 
Guidelines ............................................................................................................104
Appendix D-1:
Durvalumab Treatment Modification and Toxicity Management 
Guidelines for Immune-related Adverse Events ....................................................104
Appendix D-2:
Durvalumab Treatment Modification and Toxicity Management 
Guidelines for Infusion-related Reactions .............................................................120
Appendix D-3:
Durvalumab Treatment Modification and Toxicity Management 
Guidelines for Non-immune-mediated Reactions..................................................121
122
122
124
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LIST OF TABLES
Table 1:
Study Objectives.....................................................................................................27
Table 2:
Study Endpoints .....................................................................................................27
Table 3:
Table of Events.......................................................................................................42
Table 4:
Lenalidomide Dosing Guideline for Renal Insufficiency for Cohort A and 
Cohort B.................................................................................................................61
Table 5:
Planned Dose Level by Treatment Cohorts ............................................................62
Table 6:
Dose Modification Instructions for Lenalidomide for Hematologic Toxicity 
during a Cycle ........................................................................................................64
Table 7:
Dose Modification Instructions for Lenalidomide for Non-Hematologic 
Toxicity during a Cycle ..........................................................................................64
Table 8:
Lenalidomide Dose Reduction Steps (Daily Dosing) for Cohort A and 
Cohort B.................................................................................................................65
Table 9:
Lenalidomide Dose Reduction Steps (Every Other Day Dosing) for Cohort 
A and Cohort B.......................................................................................................66
Table 10:
Lenalidomide Dose Reduction Steps for Cohort C..................................................66
Table 11:
Dose Modifications for Dexamethasone-related Toxicities......................................66
Table 12:
Dexamethasone Dose Reduction Steps....................................................................67
Table 13:
Decision Operating Characteristics of ORR with 40 in the Expansion Dose 
for Cohort A and Cohort B .....................................................................................72
Table 14:
Decision Operating Characteristics of RIR with 40 in the Expansion Dose 
for Cohort C ...........................................................................................................73
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LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................33
Figure 2:
Study Scheme.........................................................................................................34
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1.
INTRODUCTION 
1.1.
Disease Background 
Multiple myeloma (MM) is a rare and incurable progressive neoplastic disease that accounts for 
12% of all hematological malignancies (Ferlay, 2015). It has been estimated that 24,050 new
cases and 11,090 deaths from MM occurred in the United States (US) in 2014 (Howlader, 2014), 
and that 114,000 new cases and 80,000 deaths from MM occurred globally in 2012 (Ferlay, 
2015).
Significant progress has been made in the treatment of MM with various combinations of 
melphalan, prednisone, dexamethasone, doxorubicin, cyclophosphamide, etoposide, cisplatin, 
immunomodulatory agents (thalidomide, lenalidomide and pomalidomide), and proteasome 
inhibitors (eg, bortezomib and carfilzomib) or with autologous stem cell transplant following 
high-dose chemotherapy (National Comprehensive Cancer Network [NCCN] Guidelines, 2015). 
Despite the progress in treatment options; such as newer IMiDs® and proteasome inhibitor 
classes of drugs, MM remains incurable using conventional treatments, with an overall 5-year 
relative survival of 45% (Howlader, 2014). New treatment options are therefore needed,
especially for the high risk newly diagnosed MM patients.
Multiple myeloma (MM) is more recently being recognized as a heterogeneous group of disease 
with variability in outcomes based on specific clinical and biologic predictors. With the recent 
increase in treatment armamentarium and the projected further increase in approved therapeutic 
agents in the coming years, the issue of having some mechanism to dissect this heterogeneity and 
rationally apply treatment is coming to the fore. Based on a number of robustly validated 
prognostic markers, MM patients can be broadly categorized into standard, intermediate and high 
risk for disease relapse, morbidity and mortality. The high-risk features include patient-specific 
factors such as old age, poor performance status and comorbidities; clinical features such as 
primary plasma cell leukemia and extramedullary disease; disease-specific biologic features such 
as deletion 17p, t (4;14) and high-risk gene expression profiling signatures (Chang, 2014; 
Usmani, 2015). In clinical practice, a better definition of MM subgroups is essential to provide 
more effective personalized therapies. Using combined the International Staging System (ISS) 
with chromosomal abnormalities (CA) and serum lactate dehydrogenase (LDH) to evaluate their 
prognostic value in newly diagnosed MM (NDMM) has improved prognostic power compared 
with the individual ISS, CA, and LDH parameters (Palumbo, 2015).
1.2.
Compound Background 
1.2.1.
Durvalumab (MEDI4736) 
Durvalumab (MEDI4736) is a human immunoglobulin (Ig) G1 kappa monoclonal antibody 
(mAb) targeted against human programmed cell death ligand 1 (PD-L1). Durvalumab is 
expressed in Chinese hamster ovary cells and has an overall molecular weight of approximately 
149 kDa. Durvalumab selectively binds to human PD-L1 (cluster of differentiation [CD274]) 
with high affinity and blocks its ability to bind to programmed cell death 1 (PD-1[CD279]) 
protein 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 
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reduces binding to the complement component C1q and the Fc gamma receptors responsible 
for mediating antibody-dependent cell-mediated cytotoxicity (ADCC) (Oganesyan, 2008).
Please refer to the durvalumab Investigator’s Brochure for detailed information concerning the 
available pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile 
of the investigational product (IP).
1.2.2.
Lenalidomide (LEN)
Lenalidomide (LEN) is a drug in the class of immunomodulatory drugs known as IMiDs®
compounds, which are structurally similar to thalidomide. Another IMiD® compound is 
pomalidomide. All three (thalidomide, lenalidomide, and pomalidomide) are approved for the 
treatment of MM, and are being evaluated for a number of other hematologic malignancies. The 
lenalidomide also has been approved for the treatment of relapsed mantle cell lymphoma (MCL) 
patients and myelodysplastic syndromes (MDS) associated with deletion 5q abnormality 
patients.
IMiDs® compounds may affect the immune system in several ways, such as inducing immune 
responses, enhancing activity of immune cells, altering and modulating the induction of pro- and 
anti-inflammatory cytokines, and inhibiting inflammation. IMiDs®are also anti-angiogenic. 
Although their precise mechanism of action is currently under investigation, these agents offer 
promise for their anticancer and anti-inflammatory activities.
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 investigational product (IP); as well as the current label of lenalidomide (Revlimid®
Prescribing Information, Revlimid Summary of Product Characteristics, Revlimid® Product 
Monograph).
1.3.
Rationale
1.3.1.
Study Rationale and Purpose
1.3.1.1.
Cancer and Immune Function
The importance of the immune system in cancer development and progression has been 
recognized during the past thirty years (Pardoll, 2015; Hanahan, 2011). Evidence for tumor 
immune surveillance, a process whereby the immune system recognizes and eliminates 
transformed and malignant cells, has been clearly shown in carcinogen-induced murine models 
of cancer (Shankaran, 2001; Dunn, 2005).  These data suggest that the immune system can seek 
and eliminates tumor cells, but also contribute to phenotypic and genotypic “shaping” of the 
tumor in a process called immunoediting (Dunn, 2004).  Similarly, the tumor and tumor 
microenvironment can disrupt and alter anti-tumor immune cells through a variety of 
mechanisms resulting in tumor growth. Once such mechanism is through coercing natural 
checkpoint pathways that control T cell activation and inhibition.  A seminal observation of 
inhibition of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) in murine models of cancer 
provided evidence that manipulation of checkpoint blockade could significantly impact tumor 
growth and survival (Leach, 1996).
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Another such checkpoint pathway involves Programmed cell death-1 (PD-1) and Programmed 
cell death ligand 1(PD-L1). PD-L1 is part of a complex system of receptors and ligands that are 
involved in controlling T-cell activation. PD-L1 acts at multiple sites in the body to help regulate 
normal immune responses and is utilized by tumors to help evade detection and elimination by 
the host immune system tumor response (Keir, 2008). In the lymph nodes, PD-L1 on antigen-
presenting cells binds to PD-1 or CD80 on activated T cells and delivers an inhibitory signal to 
the T cell (Keir, 2008; Park, 2010). This results in reduced T-cell activation and fewer activated 
T cells in circulation. In the tumor microenvironment, PD-L1 expressed on tumor cells binds to 
PD-1 and CD80 on activated T cells, thus providing an additional inhibitory signal and 
preventing T cells from killing target cancer cells and protecting the tumor from immune 
elimination (Hirano, 2005).  Additional mechanisms for PD-L1-mediated immune suppression 
have been described, including promoting regulatory T cell (Treg) skewing, effector T cell 
apoptosis, and inhibiting optimal antigen presentation (Chen, 2015).
PD-L1 is upregulated in a broad range of cancers with a high frequency, with up to 88% 
expression in some tumor types. In a number of these cancers, including lung (Mu, 2011), 
renal (Thompson, 2006; Thompson, 2005; Krambeck, 2007), pancreatic (Nomi, 2007; Loos, 
2008; Wang, 2010), ovarian cancer (Hamanishi, 2007), and hematologic 
malignancies (Andorsky, 2011; Brusa, 2013) tumor cell expression of PD-L1 is associated with 
reduced survival and an unfavorable prognosis.
1.3.1.2.
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. In human disease, engagement of 
TIL cell-surface receptors with these inhibitory ligands, such as CTLA-4, LAG-3, TIM-3, and 
PD-1, leads to a dysfunctional immune response, causes T-cell exhaustion, and facilitates tumor 
progression (Baitsch, 2012; Matsuzaki, 2010). 
The first successful demonstration of checkpoint blockade utilized a CTLA-4 antibody 
(Ipilimumab) in metastatic melanoma patients (Hodi, 2010).  Blockade of the PD-1, and PD-L1 
pathways have shown remarkable clinical activity not only in conventionally immune-responsive 
tumors such as melanoma (Robert, 2015; Hamid, 2013; Brahmer, 2012; Topalian, 2012) and 
renal cell carcinoma (Motzer, 2015) but also in non-small cell lung cancer (NSCLC) (Brahmer, 
2015; Garon, 2015), MSIhi colorectal cancer (Le Dung, 2015), and Hodgkins disease (Ansell, 
2015). The combination of PD-1 and CTLA-4 blockade is being evaluated across multiple solid 
and hematological disease indications and has proven effective in melanoma (Wolchok, 2013; 
Larkin, 2015).
Pembrolizumab and nivolumab are both PD-1 blocking antibodies and the first in the anti-PD-1 
pathway family of checkpoint inhibitors to gain approval from the US Food and Drug 
Administration (FDA). For metastatic melanoma, single agent pembrolizumab and nivolumab 
have been approved in the US, EU, Japan and other countries worldwide. The combination of 
nivolumab + ipilimumab has been approved in the US for metastatic melanoma. Pembrolizumab 
has been approved in the US and nivolumab in the US and EU for the treatment of advanced, 
previously treated squamous and non-squamous NSCLC. 
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1.3.2.
Rationale for the Study Design
Durvalumab has been studied primarily in subjects with solid tumors and a limited number of 
subjects with MDS but not on multiple myeloma subjects. While PK and safety of durvalumab as 
monotherapy and in combination have been characterized in more than 500 subjects, the 
paraprotein present in myeloma may alter the PK and Pd of durvalumab and higher doses may be 
required.   The durvalumab in combination with LEN+/- dex in the newly diagnosed multiple 
myeloma (NDMM) population has not been previously studied. While the starting dose of 1500 
mg is justified based on PK and Pd data and the expectation is that there will not be synergistic 
toxicity, dose de-escalation may be considered.  As dex may interfere with the immune mediated 
efficacy of durvalumab but has shown efficacy when added with LEN, this study aims to 
generate PK/Pd, safety and preliminary efficacy data with and without the use of dex.
1.3.3.
Rationale for Dose, Schedule, and Regimen Selection
1.3.3.1.
Dose/Schedule
1.3.3.1.1. Durvalumab (MEDI4736) 
The dose and schedule for durvalumab monotherapy (20 mg/kg every 4 weeks [Q4W]) was
selected based on 2 sets of data: (1) the safety analysis of doses (0.1, 0.3, 1.0, 3.0, and 10 mg/kg 
every 4 weeks [Q2W]) administered in Study CD-ON-MEDI4736-1108 (a Phase 1/2 study to 
evaluate the safety, tolerability, and PK of IV durvalumab given as monotherapy in subjects with 
advanced solid tumors; and (2) 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 sPD-L1 suppression data. Furthermore, the 10 
mg/kg Q2W dose was not associated with any dose-limiting toxicities (DLTs) in the dose 
escalation phase and was, therefore, selected for further evaluation in the dose-expansion phase 
of Study CD-ON-MEDI4736-1108. Safety information is presented for 19 patients exposed to 
1500 mg dose monotherapy (expressed as 20 mg/kg Q4W), in study CD-ON-MEDI4736-1108/ 
D4190C00001, and 4 patients exposed in study D4190C00002. There are over 100 patients 
treated at the 1500 mg (or the equivalent 20 mg/kg Q4W) dose in combination treatment studies.
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 every 3 
weeks [Q3W]; solid tumors) (Fairman, 2014). This population PK model adequately described 
monotherapy Pharmacokinetic 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). PK simulations indicate that a similar overall exposure as represented by area under 
the plasma concentration curves (AUCs) (4 weeks) is expected following both 10 mg/kg Q2W 
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and 20 mg/kg Q4W regimens. However, median 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 (WT) on PK of durvalumab
(coefficient of ≤ 0.5). The impact of body WT-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 WT of ~75 kg). A total of 1000 
patients were simulated using body WT distribution of 40–120 kg. Simulation results 
demonstrate that body WT-based and fixed dosing regimens yield similar median steady state 
PK concentrations with slightly less overall between-subject variability with fixed dosing 
regimen.  
Similar findings have been reported by others (Ng, 2006; Wang, 2009; Zhang, 2012; Narwal, 
2013). Wang and colleagues 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 
(Wang, 2009). In addition, they 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 pharmacokinetic/pharmacodynamics parameters (Zhang, 2012). 
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 WT of 75 
kg, a fixed dose of 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) is included in the 
current study.
1.3.3.1.2. Lenalidomide and Dexamethasone
The LEN and dex dose/schedule will be as per the current label for lenalidomide for NDMM 
(Revlimid® Prescribing Information, Revlimid Summary of Product Characteristics, Revlimid®
Product Monograph).
1.3.3.2.
Regimen
Durvalumab + LEN with and without dex
The synergistic anti-proliferative activity of IMiDs® and dex has been previously established in 
both in vitro and in vivo (Revlimid® Prescribing Information, Revlimid Summary of Product 
Characteristics, Revlimid® Product Monograph; Pomalyst® Prescribing Information; Imnovid™ 
Summary of Product Characteristics; Gandhi, 2010).  However, the immunostimulatory effect of 
IMiDs® may be inhibited by the anti-inflammatory action of dex (Gandhi, 2010).  In order to 
gain data on the impact of dex on the potential immunostimulatory synergy of durvalumab +LEN 
with dex will be tested in this study.  
1.3.4.
Rationale for Choice of Combination Compounds
Durvalumab (MEDI4736) is a human immunoglobulin G1 kappa monoclonal antibody targeted 
against PD-L1.  The proposed mechanism of action for durvalumab involves, immune system 
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activation leading to T-cell activation and proliferation, inhibition of human tumor growth via a 
T-cell-dependent mechanism, and immune mediated killing.
It has been observed that lenalidomide, an IMiD®, was capable of down-regulating the 
expression of PD-L1 on the malignant plasma cells from MM patients and that its in vitro 
application resulted in an enhancement of the myeloma-targeting activity of an anti-PD-1 
antibody (Benson, 2010).  Lenalidomide treatment not only results in a decrease in T-cell 
expression of PD-1 but also down-regulates expression of PD-L1 on malignant plasma cells from 
patients with MM.  When combined, lenalidomide and an anti-PD-L1 antibody demonstrated a 
synergistic antitumor effect by enhancing the T-cell mediated immune response to MM tumor 
cells (Görgün, 2015).  PD-L1 is highly expressed in BM-stroma cells (BMSC).  PD1/PD-L1-
blockade abrogates BMSC-induced MM growth, and combined blockade of PD-1/PD-L1 with 
lenalidomide further inhibits BMSC-induced tumor growth. These effects are associated with 
induction of intracellular expression of IFNγ and Granzyme-B in effector cells.  Lenalidomide 
with PD-1/PD-L1-blockade inhibits MDSC (myeloid-derived suppressor cells)-mediated 
immune suppression.  
Lenalidomide has shown efficacy in combination with dexamethasone for NDMM patients who 
are either 65 years of age or older or not candidates for stem cell transplant (Benboubker, 2014), 
and recently has been approved by both Food and Drug Administration (FDA) and European 
Medicines Agency (EMA) for this indication. Studies have been conducted in both the induction 
and maintenance transplant setting using lenalidomide.  
The LEN MM-020 Phase 3 is a pivotal study (FIRST Trial) with the largest data set in transplant 
non eligible (TNE) newly diagnosed multiple myeloma (NDMM) patients. 1623 patients were 
randomized to lenalidomide–dexamethasone in 28-day cycles until disease progression (535 
patients), to the same combination for 72 weeks (18 cycles; 541 patients), or to MPT for 72 
weeks (547 patients). The primary end point was progression-free survival with continuous 
lenalidomide–dexamethasone versus MPT. The median progression-free survival was 25.5 
months with continuous lenalidomide–dexamethasone, and 21.2 months with MPT (hazard ratio 
for the risk of progression or death, 0.72 for continuous lenalidomide–dexamethasone vs. MPT, 
P<0.001). Continuous lenalidomide–dexamethasone was superior to MPT for all secondary 
efficacy end points, Overall survival at 4 years was 59% with continuous lenalidomide–
dexamethasone, and 51% with MPT. 
Cytogenetic abnormalities in MM patients are prognostic importance and can be associated with 
poor outcomes. In the MM-020 study, a total of 762 of 1623 patients from the intent-to-treat 
population had validated cytogenetic profile, with 142 patient in the high-risk group (with 
t(4:14), or/and, t(14;16), or/and 17p13 deletions abnormality) and 620 patient in the non-high-
risk group. In the high-risk group, median duration of treatment was 10.0 months with 
lenalidomide–dexamethasone continuous, and 12.0 months with MPT. The lenalidomide–
dexamethasone continuous treatment resulted in a 24% reduced risk of death or progression 
compared with MPT and an even greater 32% reduced risk in patients without high-risk 
cytogenetics. In non–high-risk patients, median PFS was 31.1 months with lenalidomide–
dexamethasone continuous compared with 24.9 months with MPT, the OS was similar across 
treatment arms for high-risk patients. The ORRs in all cytogenetic risk groups favored 
lenalidomide–dexamethasone continuous vs MPT. In patients with high-risk cytogenetics, 
higher-quality responses were also observed with lenalidomide–dexamethasone continuous vs 
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MPT treatment; although OS and ORR benefits overall and in patients without high-risk 
cytogenetics were not as pronounced (Avet-Loiseau, 2015).
Three studies in the transplant setting noted prolonged time to disease progression when used in 
either the maintenance or induction therapy: Attal reported that the rate of complete or very good 
partial response was 84% for lenalidomide maintenance therapy and 76% for placebo (p = 0.009) 
(Attal, 2012); McCarthy reported that the median time to progression was 39 months among 
patients in the lenalidomide group and 21 months among patients in the placebo group (p < 
0.001) (McCarthy, 2012). The PFS was the primary end point for Palumbo’s study, and results 
showed median of 31 months of PFS for MPR-lenalidomide group compared with median of 14 
months for MPR only (hazard ratio, 0.49; p < 0.001) (Palumbo, 2012). 
Based on the current available information from the PD-L1 inhibition and lenalidomide, the 
combination of durvalumab + LEN + dex warrants further investigation in NDMM patients.  
1.3.5.
Rationale for Pharmacodynamics and Potential Predictive Biomarkers 
Durvalumab (MEDI4736) binds to human PD-L1 with high affinity and blocks its ability to bind 
PD-1, thus restoring 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 our understanding of the pharmacological effect of durvalumab
and contribute to decision making in the dose and schedule selection. In addition, a number of 
recent studies have reported a correlation between several molecular markers, including the 
expression level of PD-L1 in tumor and immune cells, neoantigen presentation and T-cell 
clonality, and the clinical activity of immune checkpoint inhibitors (Topalian, 2012; Herbst, 
2014). 
Experience of MEDI4736 in solid tumors showed that greater responses were observed in 
subjects with PD-L1-positive, and much lower rate of responses in subjects with PD-L1-negative 
tumors (Segal, 2014). More recent data indicates that a combination of elevated PD-L1 protein 
expression and elevated IFNgene expression in pretreatment tumor biopsies may predict the best 
response to durvalumab monotherapy (Higgs, 2015; Higgs, 2016). Thus, continued evaluation of
these biomarkers and a broad exploration of additional biomarkers related to immunological and 
disease factors are needed to aid the identification of potential predictive biomarkers for this 
therapy.
A key scientific objective of this clinical trial is to evaluate the dynamic changes in the 
microenvironment of the tumor. While understanding the immunologic characteristics at baseline 
may be both predictive and prognostic, it will be extremely critical to understand the changes in 
the local immune system following treatment with durvalumab and the combination agents.  
Biomarker analysis of durvalumab in non-small cell lung cancer patients demonstrated a 
statistically significant increase in CD8+ infiltrating lymphocytes from on-treatment tumor 
samples compared with pre-treatment biopsies. This data is consistent with the PD effects 
observed in tumor biopsies from patients treated with Atezolizumab (a PD-L1 inhibitor) and 
Pembrolizumab (a PD-1 inhibitor).  Notably, while pharmacodynamic response to durvalumab 
and MPDL3280A can also be observed in the periphery, peripheral markers have not been 
shown to be correlated with response.  For pembrolizumab, increase in CD8+ density at tumor or 
invasive margin after treatment is observed in responders while absent in progressors in 
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melanoma, indicating that the CD8+ TILs were activated and targeting the tumor (Tumeh, 
2014). Serial biopsy analyses for MPDL3280 showed that increases in PD-L1 protein expression 
and genes indicative of activated T cells (eg, granzyme, interferon [IFN]-gamma) were more 
frequently observed in patients who respond to the therapy compared with the nonresponders 
(Herbst, 2014).  
Evaluation of post-treatment tumor samples is critical for identifying pharmacodynamic changes 
that are induced by durvalumab. These biomarker data will facilitate better understanding of the 
mechanism of action for durvalumab alone or in combination with other agents to facilitate 
future clinical trial designs.  The data may also reveal new targets/additional immune system 
pathways to improve therapeutic outcomes. 
Recent research on the mechanism of action of lenalidomide, pomalidomide, and thalidomide 
suggest that in tumor cells and T cells, cereblon, a component of E3 ubiquitin ligase complexes, 
is a target for binding by these compounds. These studies showed that the loss of cereblon or its 
downstream substrates, such as Ikaros and Aiolos, decreases or eliminates the anti-tumor and 
immunomodulatory activity of lenalidomide and pomalidomide respectively (Ito, 2010; Zhu, 
2011; Lopez-Girona, 2012). In several retrospective analyses, high cereblon levels at baseline 
have been reported to be associated with better clinical outcomes in subjects treated with 
regimens containing lenalidomide, pomalidomide, or thalidomide. Thus, further investigation is 
warranted on whether there is any potential correlation of Cereblon levels to clinical outcomes 
by measuring baseline and on-treatment Cereblon levels in tumor and T cells. 
Since both durvalumab and LEN regulate immune cell activation and functions, we will also 
quantify subsets of immune cells and assess their functions from peripheral blood and bone 
marrow samples (at baseline and during treatment) to explore whether and how immune 
functions are modulated by the individual components and the combinations.
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2.
STUDY OBJECTIVES AND ENDPOINTS
2.1.
Study Objectives and Endpoints 
Table 1:
Study Objectives
Primary Objective
The primary objective of the study is to determine the recommended dose of durvalumab in combination 
with LEN +/- dex in subjects with NDMM.
Secondary Objective(s)
The secondary objectives are to 

Evaluate the safety and preliminary efficacy of durvalumab in combination with LEN +/- dex in 
subjects with NDMM

Evaluate the pharmacokinetics of durvalumab and LEN with and without dex in subjects with 
NDMM.
Exploratory Objective(s)
The exploratory objectives are to:

To evaluate additional efficacy of durvalumab in combination with LEN with and without dex in 
subjects with NDMM.
Table 2:
Study Endpoints
Endpoint
Name
Description
Primary 
Recommend Dose 
Review safety (including dose-limiting toxicities [DLTs]), and 
if applicable, PK/Pd, and/or biomarker, and/or preliminary 
efficacy data by Dose Review Team (DRT)
Secondary 
Safety 
Type, frequency, seriousness and severity of adverse events 
(AEs) (included second primary malignancies), and relationship 
of AEs to study treatment 
Secondary 
Overall Response Rate 
(ORR) (for Cohorts A 
and B)
Tumor response, including progressive disease, based on the 
investigator assessments according to the International 
Myeloma Working Group (IMWG) Uniform Response Criteria
(Rajkumar, 2011).
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Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Secondary
Response 
Improvement Rate 
(RIR) (for Cohort C)
Response improved from the assessment at the Cycle 1 Day 1 
(C1D1); 
(Pre-autologous stem cell transplantation [ASCT] diseases 
measurement will be used as baseline for response assessment)
Secondary 
Time to Response 
(TTR) (for Cohorts A 
and B)
Time from C1D1 to the first documentation of response 
Secondary 
Duration of response 
(DOR) (for Cohorts A 
and B)
Time from the first response (partial response [PR] or better) to 
the first documentation of disease progression or death, 
whichever is earlier, based on the investigator assessments 
according to the IMWG Uniform Response Criteria
Secondary
Pharmacokinetic
Typical serum/plasma PK parameters for durvalumab and 
lenalidomide, such as maximum observed concentration (Cmax), 
area under the concentration-time curve (AUC), time to 
maximum concentration (Tmax), terminal elimination half-life 
(t1/2), clearance (CL/F), and volume of distribution (Vz/F)
Secondary
Immunogenicity
Frequency of development of anti-drug antibodies and 
neutralization
Secondary
Progression-Free 
Survival (PFS)
Time from C1D1 to the first documentation of disease 
progression (based on the investigator assessments according to 
the IMWG Uniform Response Criteria) or death from any cause 
during study, whichever occurs earlier
Secondary
Overall Survival(OS)
Time from C1D1 to death due to any cause
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MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
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3.
OVERALL STUDY DESIGN
3.1.
Study Design
This is a multicenter, open-label, Phase 1/2 study to determine the recommended dose and 
regimen of durvalumab in combination with LEN with and without dex in subjects with NDMM. 
The study will consist of a dose-finding phase as well as a parallel dose-expansion phase to 
determine the optimal regimen. See Figure 1 and Figure 2 and Dose-finding Phase.
The dose-finding phase will determine recommended dose (RD) for durvalumab in combination 
with LEN with and without dex in a 28-day treatment cycle. Three treatment Cohorts (A, B, and 
C) will be enrolled in parallel:

Cohort A:  durvalumab + LEN +dex on high risk TNE NDMM subjects;

Cohort B: durvalumab + LEN +dex (for up to 12 cycles) on ≥65 years old TNE 
NDMM subjects who are not high risk;

Cohort C: durvalumab + LEN as maintenance on post-transplant high risk NDMM 
subjects;
In the US, two treatment arms (A and B) will be enrolled in parallel. Cohort C will enroll upon 
completion of at least 4 cycles of follow-up for safety assessment of Cohort A and B. 
 
 
 
On 05 Sep 2017, US FDA placed this study on full clinical hold. As a result, the study was 
closed for further enrollment, and all subjects were discontinued from all study treatments 
(durvalumab, lenalidomide and dexamethasone).
Based on experience with durvalumab for other indications, the initial dose of durvalumab will 
be 1500 mg for each treatment cohort. The dose of durvalumab might be de-escalated to 750 mg 
level.
The dose of LEN will be 25 mg (adjustable per the CrCl value, see details in Section 7.2.1.2,
Table 4) on Days 1 to 21 of each 28-day treatment cycle for subjects on Cohort A and B. The 
dose of LEN will be 10 mg on Days 1 to 21 of each 28-day treatment cycle for subjects on 
Cohort C.
The dose of dex will be 40 mg/day (for subjects ≤ 75 years old) or 20 mg/day (for subjects > 75 
years old) on Days 1, 8, 15, and 22 of a 28-day cycle for Cohort A and Cohort B (for up to 12 
cycles). 
Initially, 6 subjects will be enrolled into each cohort and each will receive 1500 mg durvalumab. 
The dose-limiting toxicity (DLT) evaluation period will be the first treatment cycle.

If ≤ 1 of the 6 initial subjects experience a DLT within the first cycle, then the dose-
expansion phase may be initiated with durvalumab 1500 mg as the recommended 
dose (RD); 
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Protocol MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
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MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019

If 2 or more of the 6 initial subjects experience a DLT within the first cycle, then the 
maximum tolerated dose (MTD) has been exceeded and de-escalation to durvalumab 
750 mg level after review of safety and PK/Pd of the initial 6 subjects by the DRT
Any of the cohorts may be removed from the study based on emerging PK, Pd, efficacy or safety 
data.
Dose de-escalation will only occur after review of safety (DLT) and possibly PK/Pd data by the 
DRT.
3.1.1.1.
Dose Review Team (DRT)
The DRT are responsible for dosing decisions. The DRT members will consist of the following:
Celgene medical monitor, Celgene lead safety physician, Celgene biostatistician, other Celgene 
functional area representatives as appropriate and site investigator and/or designees. 
Dosing decisions may include de-escalation to a lower dose; continuation, delay or termination 
of dosing, repetition of a dose level, or expansion of a treatment cohort. All available safety, and 
if applicable, PK/PD, biomarker, and preliminary efficacy data will be reviewed and can be 
considered in the DRT’s decisions.
Dose Review Meetings will be held to review all data, monitor safety, and make dosing and 
expansion decisions.
3.1.1.2.
Dose-limiting Toxicity (DLT)
Dose-limiting toxicities will be evaluated during the DLT evaluation period for the subjects in 
the dose-finding portion of the study. The DLT evaluation period will be defined as the first 
treatment cycle for each subject. Subjects are considered evaluable for assessment of DLT if 
they:

Receive 1 dose of durvalumab;
If the subjects did not complete the first cycle of study treatment due to the reason other than 
DLT will be replaced. 
Grading of DLTs will be according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) version 4.03 or higher.
The DLT is defined as the occurrence of any toxicity listed below:
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

Any other Grade 4 hematologic toxicity that does not resolve to patient’s pre-
treatment baseline level within 72 hours

Grade 4 anemia, unexplained by underlying disease
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EDMS Doc. Number: 24328540 - 20680025
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MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
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 reactions
While the rules for adjudicating DLTs in the context of dosing decisions are specified above, an 
AE not listed above may be defined as a DLT after consultation with the sponsor and 
investigators, based on the emerging safety profile.
3.1.2.
Dose-expansion Phase
All dose expansion decisions will be determined by the DRT after review of safety, and if 
applicable PK/Pd, biomarker and preliminary efficacy data. 
After all 6 subjects enrolled in the Dose-finding phase have completed the Cycle 1 treatment; 
and all data are obtained and reviewed, additional eligible subjects (see detailed eligibility 
criteria in Section 4.2 and Section 4.3) for each respective cohort may be enrolled. The total of 
subjects for each Cohort can be expanded up to 40 (including the subjects enrolled in the Dose-
finding Phase).
The expansion for each study cohort can occur independently.
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MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Figure 1:
Overall Study Design
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EDMS Doc. Number: 24328540 - 20680025
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Confidential and Proprietary
34
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Figure 2:
Study Scheme
LEN= lenalidomide; dex = dexamethasone; PD = progressive disease; EOT = end of treatment; IV = intravenous; 
TNE = transplant non-eligible;  
a LEN dose is adjusted per the creatinine clearance value, see details in Section 7.2.1.2 and Table 4.
b For Cohort B, the dex can be administered up to 12 cycles.
Cohort B 
TNE and ≥65 yrs old subjects
-IV DUR at 1500 mg on Day 1
-Oral LEN at 25 mg/day
a on Days 1 to 21 
-Oral dex
b at 40 mg/day (≤ 75 years old) or 20 
mg/day (> 75 years old) on Days 1, 8, 15, 22
Screening
Cohort C 
Post-transplant high risk subjects 
(maintenance)
-IV DUR at 1500 mg on Day 1
-Oral LEN at 10 mg/day on Days 1 to 21
Continue study treatment 
until disease progression 
(PD) or unacceptable 
toxicity or withdrawal of 
consent
Safety Follow-Up 
Eligible
NDMM 
subjects 
who meet 
inclusion/
exclusion 
criteria
End of Treatment 
(EOT)
-28 days post EOT
-90 days post last 
dose of DUR
-SPM will be 
monitored up to 5 
yrs after the last 
subject enrolled on 
study 
Cohort A 
TNE and high risk subjects 
-IV DUR at 1500 mg on Day 1
-Oral LEN at 25 mg/day
a on Days 1 to 21 
-Oral dex at 40 mg/day (≤ 75 years old) or 20 
mg/day (> 75 years old) on Days 1, 8, 15, 22
Treatment Phase (28-day cycle)
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EDMS Doc. Number: 24328540 - 20680025
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MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
3.2.
Study Duration for Subjects 
The study will consist of screening, treatment, and follow-up periods. Refer to Figure 2 for the 
study schema.
3.2.1.
Screening Period
Informed consent must be obtained prior to any study-specific procedures being performed. 
Subjects who meet all eligibility criteria and have completed all screening procedures may be 
enrolled into the study. Screening assessments must be completed within 28 days prior to the 
first dose of study treatment, depending on the specific assessment, as outlined in Table 3.
3.2.2.
Treatment Period
Eligible subjects will report to the study site to receive study treatment and protocol-specified 
procedures according to Table 3. The treatment period will consist of continuous 28-day cycles.
For the first 3 subjects of each cohort in the dose-finding portion, there will be at least a 24-hour 
observation period and 24 to 48 hours after that to communicate safety data (e.g., adverse event 
[AE], basic laboratory, and vital signs) to the sponsor before the dosing of the next subject 
occurs.
For subjects on Cohort C, the study treatment is to be initiated at 100 days (±14 days) after 
transplant. 
Dose modifications and interruptions are permitted as detailed in Section 7.2.4.
All subjects may continue to receive study treatment until disease progression or unacceptable 
toxicity occurs, or withdrawal of consent.
3.2.2.1.
End of Treatment Visit
Subjects are to return to the study site for the End of Treatment (EOT) Visit assessment within 7 
(± 3) days after discontinuation of all study treatment (Table 3).
3.2.3.
Follow-up Period
Subjects are to return to the study site 28 (+ 3) days after the EOT visit and 90 (+ 3) days after 
the last dose of durvalumab for safety follow-up visit procedures as outlined in Table 3. Adverse 
events and SAEs will be monitored until 90 days after last dose of durvalumab. Adverse events 
and SAEs that lead to study treatment discontinuation and/or study withdrawal should be 
followed until resolution, stabilization, or death. The occurrence of SPM will continue to be 
monitored at the above required 90 days visit and every 6 months up to 5 years after the last 
subject is enrolled into the study. Data entry into the clinical database will continue until 
15 Dec 2019. After this date, the occurrence of SPMs will continue to be monitored, and any 
events will continue to be recorded in the subject’s source documents and report to Celgene Drug 
Safety.
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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 the primary, secondary and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date.
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MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
4.
STUDY POPULATION
4.1.
Number of Subjects 
Up to 138 subjects with newly diagnosed MM will be enrolled in the United States, Canada, and 
Europe (including but not limited to France, Germany, Spain, Netherlands, and Italy).
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled into the study:
1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF) 
2. Subject must understand and voluntarily sign an ICF prior to any study-related 
assessments/procedures being conducted 
3. Subject is willing and able to adhere to the study visit schedule and other protocol 
requirements
4. Subject must have documented diagnosis with previously untreated (for cohort C, the 
induction and consolidation treatment along with the first ASCT are allowed), 
symptomatic MM as defined by the criteria below (Rajkumar, 2014; NCCN-MM, 2015):

MM diagnostic criteria (all 3 required);

Monoclonal protein present in the serum and/or urine

Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary 
plasmacytoma*

Any one or more of the following myeloma defining events:
o
one or more of the following Myeloma-related organ dysfunction (at least one 
of the following);
[C] Calcium elevation (serum calcium >11.5 mg/dl )[> 2.65 mmol/L]
[R] Renal insufficiency (serum creatinine >2 mg/dl)[177 mol/L or more] 
or creatinine clearance < 40 ml/min
[A] Anemia (hemoglobin <10 g/dl or >2 g /dL below the lower limit of 
laboratory normal)
[B] Bone lesions (lytic or osteopenic) one or more bone lesions on skeletal 
radiography, CT, or PET-CT
o
one or more of the following biomarkers of malignancy:
Clonal bone marrow plasma cell percentage* ≥60%
Abnormal serum free light-chain ratio ≥100 (involved kappa) or < 0.01 
(involved lambda)
                                               
* Clonality should be established by showing κ/λ-light-chain restriction on flow cytometry, immunohistochemistry, 
or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy 
specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used.
Approved
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MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
>1 focal lesions detected by functional imaging including PET/CT and/or 
whole body magnetic resonance imaging (MRI)
AND have measurable disease by protein electrophoresis analyses as defined by the 
following:

IgG MM: Serum monoclonal paraprotein (M-protein) level 1.0 g/dl or urine M-
protein level 200 mg/24 hours

IgA MM: Serum M-protein level 0.5 g/dl or urine M-protein level 200 mg/24 
hours

IgM MM (IgM M-protein plus lytic bone disease documented by skeletal survey plain 
films): Serum M-protein level ≥ 1.0 g/dl or urine M-protein level ≥ 200 mg/24 hours

IgD MM: Serum M-protein level 0.05 g/dl or urine M-protein level 200 mg/24 
hours

Light chain MM: Serum M-protein level 1.0 g/dl or urine M-protein level 200 
mg/24 hours
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (see
Appendix C)
6. Females of childbearing potential (FCBP1) must:
a.
Have two negative pregnancy tests as verified by the investigator prior to starting 
study treatment. She must agree to ongoing pregnancy testing during the course of 
the study, and after end of study treatment. This applies even if the subject practices 
true abstinence2 from heterosexual contact.
b. She must either commit to true abstinence from heterosexual contact (which must be 
reviewed on a monthly basis and be source documented) or agree to use, and be able 
to comply with, effective contraception without interruption, 28 days prior to starting 
study treatment, during the study therapy (including dose interruptions), and for 90 
days after discontinuation of study treatment. 
c.
Refrain from egg cell and blood donation for 90 days after the final dose of 
durvalumab.
7. Male subjects must:
a.
Practice true abstinence2 (which must be reviewed on a monthly basis) or agree to use 
a condom during sexual contact with a pregnant female or a FCBP while participating 
in the study, during dose interruptions and for at least 90 days following study 
treatment discontinuation, even if he has undergone a successful vasectomy.
                                               
1 A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not 
undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea 
following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had 
menses at any time in the preceding 24 consecutive months)].
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, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception]. 
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MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
b. Refrain from sperm and blood donation for at least 90 days after the final dose of 
durvalumab
8. For Cohort A subject must be transplant non-eligible (TNE) and meet at least one of the 
following high risk factors:
a.
Cytogenetic abnormalities finding in malignant myeloma clone with t(4; 14); and / or 
del(17p); and / or 1q amplification; and / or t(14:16);or
b. ISS Stage III; or
c.
Serum LDH > 2 x ULN;
9. For Cohort B subject must be ≥65 years of age at the time of signing the informed 
consent form (ICF) and transplant non-eligible (TNE); excluding the subjects who meet 
the Cohort A criteria
10. For Cohort C subject must be after first autologous stem cell transplantation (ASCT) for 
NDMM and meet the following criteria:
a.
Have a post-transplant response as PR or better at the time of enrollment to this study;
b. Have one of the following high risk factors at the time of NDMM diagnosis;

Cytogenetic abnormalities finding in malignant myeloma clone with t(4; 14);  and 
/ or del(17p); and / or 1q amplification; and / or t(14; 16); or

ISS stage III; or

Serum LDH > 2 x ULN;
c.
MRD positive (defined as more than 1 malignant cell in 105 cells) measured by 
ClonoSIGHT™NGS assay of a BMA sample) at the time of enrollment to this study;
BMA sample collected at the time of multiple myeloma diagnosis, prior to induction 
therapy available for central MRD assessment by ClonoSIGHT™NGS assay
4.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Previous treatment with anti-myeloma therapy (does not include radiotherapy, 
bisphosphonates, or a single short course of steroid [ie, less than or equal to the 
equivalent of dexamethasone 40 mg/day for 4 days; such a short course of steroid 
treatment must not have been given within 14 days of Cycle 1 Day 1], for Cohort C, the 
induction and consolidation treatment along with the first ASCT are allowed)
2. Any of the following laboratory abnormalities:
a.
Absolute neutrophil count (ANC) < 1,000/µL
b. Untransfused platelet count < 75,000 cells/L 
c.
Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase
(SGOT/AST) or alanine aminotransferase (SGPT/ALT) > 2.5 × upper limit of normal 
(ULN)
d. Serum total bilirubin > 1.5 × ULN or > 3.0 mg/dL for subjects with documented 
Gilbert’s syndrome
Approved
5.0
v
Approved
2.0
v


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
40
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
e.
Corrected serum calcium >13.5 mg/dL (> 3.4 mmol/L)
3. Renal failure requiring hemodialysis or peritoneal dialysis
4. Any serious medical condition that places the subject at an unacceptable risk if he or she 
participates in this study. Examples of such a medical condition are, but are not limited 
to, subject with unstable cardiac disease as defined by: cardiac events such as myocardial 
infarction (MI) within the past 6 months, NYHA (New York Heart Association) heart 
failure class III-IV, uncontrolled atrial fibrillation or hypertension; subjects with 
conditions requiring chronic steroid or immunosuppressive treatment, such as rheumatoid 
arthritis, multiple sclerosis and lupus, that likely need additional steroid or 
immunosuppressive treatments in addition to the study treatment 
5. Peripheral neuropathy ≥ Grade 2
6. Primary AL (immunoglobulin light-chain) amyloidosis and myeloma complicated by 
amyloidosis
7. Prior history of malignancies, other than MM, unless the subject has been free of the 
disease for ≥ 5 years with the exception of the following non-invasive malignancies:
a.
Basal cell carcinoma of the skin
b. Squamous cell carcinoma of the skin
c.
Carcinoma in situ of the cervix
d. Carcinoma in situ of the breast
e.
Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, 
nodes, metastasis] clinical staging system) or prostate cancer that is curative
8. Subjects is positive for human immunodeficiency virus (HIV); chronic or active hepatitis
B or active hepatitis A, or C
9. Subject had prior exposure to immunotherapy, including, but not limited to, other anti-
CTLA-4, anti-PD-1, anti-PD-L1 monoclonal antibody or inhibitor, cell-based therapies, 
or cancer vaccines
10. Subjects has history of organ or allogeneic stem cell transplantation
11. Subjects who have had clinical evidence of central nervous system (CNS) or pulmonary 
leukostasis, disseminated intravascular coagulation, or CNS multiple myeloma, or plasma 
cell leukemia
12. Known or suspected hypersensitivity to the excipients contained in the formulation of 
durvalumab, lenalidomide, or dexamethasone
13. Major surgery (as defined by the investigator) within the 28 days prior to the first dose of 
study treatment
14. Received prior treatment (for any reason) with a monoclonal antibody within 5 half-lives 
of initiating study treatment
15. Use of any investigational agents within 28 days or 5 half-lives (whichever is longer) of 
initiating study treatment
Approved
5.0
v
Approved
2.0
v


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
41
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
16. Current or prior use of immunosuppressive medication within 14 days prior to the first 
dose of study treatment. The following are exceptions to this criterion: 
a.
Intranasal, inhaled, topical or local steroid injections (eg, intra-articular injection);
b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone 
or equivalent;
c.
Steroids as premedication for hypersensitivity reactions (eg, computed tomography 
[CT] scan premedication);
17. Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis, Crohn’s disease], diverticulitis with the 
exception of a prior episode that has resolved or diverticulosis, celiac disease, irritable 
bowel disease, or other serious gastrointestinal chronic conditions associated with 
diarrhea; systemic lupus erythematosus; Wegener’s syndrome [granulomatosis with 
polyangiitis]; myasthenia gravis; Graves’ disease; rheumatoid arthritis; hypophysitis, 
uveitis) within the past 3 years prior to the start of treatment. The following are 
exceptions to this criterion:
a.
Subjects with vitiligo or alopecia;
b. Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement; or
c.
Subjects with psoriasis not requiring systemic treatment;
18. History of primary immunodeficiency
19. Subject has incidence of gastrointestinal disease that may significantly alter the 
absorption of LEN 
20. Receipt of 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 30 
days after the last dose of durvalumab)
21. Unable or unwilling to undergo protocol required thromboembolism prophylaxis (for 
Cohort C, this will be only for the subjects who have a history of VTE)
22. Females who are pregnant, nursing or breastfeeding, or intend to become pregnant during 
the participation to the study
23. Any significant medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from participating in the study
24. Any condition including the presence of laboratory abnormalities, which places the 
subject at unacceptable risk if he/she were to participate in the study
25. Any condition that confounds the ability to interpret data from the study
Approved
5.0
v
Approved
2.0
v


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
42
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
5.
TABLE OF EVENTS
Table 3:
Table of Events
Screening 
Period
Treatment Period
Safety Follow-up Visits
Cycle 1
Cycle 2-4 
(±2 days for all 
visits)
≥ Cycle 5 
(±2 days 
for all 
visits)
EOT (≤7 
days from 
trt discon
decision)
28 days (+3) 
after EOT
90 days (+3) 
after last 
DUR dose
Events
-28 to -1
D1a
D8
D15
D22
D1
D15
D1
STUDY ENTRY AND GENERAL ASSESSMENTS
Informed consent
X
-
-
-
-
-
-
-
-
-
-
Inclusion/exclusion criteria
X
-
-
-
-
-
-
-
-
-
IRT registration
X
X
-
-
-
-
-
-
X
-
-
Complete medical history
X
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
Confirmation of Diagnosis /Stage
X
-
-
-
-
-
-
-
-
-
-
HIV and Hepatitis Screening 
Panel (A, B & C)
X
-
-
-
-
-
-
-
-
-
-
Cytogenetic data (done by central 
Lab)
X
-
-
-
-
-
-
-
-
-
-
Prior/ concomitant medication 
evaluation
X (-28 days 
from 
screening)
Continuous, until 90 days after last dose of durvalumab
Prior/ concomitant procedures 
evaluation
X (-28 days 
from 
screening)
Continuous, until 90 days after last dose of durvalumab
Approved
5.0
v
Approved
2.0
v


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
43
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Table 3:
Table of Events (Continued)
Screening
Period
Treatment Period
Safety Follow-up Visits
Cycle 1
Cycle 2-4 
(±2 days for all 
visits)
≥ Cycle 5 
(±2 days 
for all 
visits)
EOT (≤7 
days from 
trt discon 
decision)
28 days (+3) 
after EOT
90 days (+3) 
after last 
DUR dose
Events
-28 to -1
D1a
D8
D15
D22
D1
D15
D1
STUDY ENTRY AND GENERAL ASSESSMENTS
SAFETY ASSESSMENTS
Adverse event evaluation
Continuous starting after informed consent signature, until 90 days after last dose of durvalumab
Assessment of Second Primary 
Malignancy
Continuous starting after informed consent signature, up to 5 years after the last subject enrolled into the study
Physical examination 
X
X
-
-
-
X
-
X
X
-
-
Vital signs
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
Height
X
-
-
-
-
-
-
-
-
-
-
12-lead electrocardiogram (ECG)
X
Repeated only if clinically indicated
X
-
-
Clinical examination for 
peripheral neuropathy
X
-
-
-
-
-
-
-
-
-
-
Hematology laboratory (done by 
central laboratory)
X
X
X
X
X
X
X
X
X
X
X
Coagulation parameters (done by 
central laboratory)
X
X
-
X
-
X
-
X
X
-
X
Chemistry laboratory (done by 
central laboratory)
X
X
X
X
X
X
X
X
X
X
X
Thyroid function tests (done by 
central laboratory)i
X
X
X
X
X
C5 then 
every 2 
cycles
X
-
X
Approved
5.0
v
Approved
2.0
v


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
44
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Table 3:
Table of Events (Continued)
Screening 
Period
Treatment Period
Safety Follow-up Visits
Cycle 1
Cycle 2-4 
(±2 days for all 
visits)
≥ Cycle 5 
(±2 days 
for all 
visits)
EOT (≤7 
days from 
trt discon 
decision)
28 days (+3) 
after EOT
90 days (+3) 
after last 
DUR dose
Events
-28 to -1
D1a
D8
D15
D22
D1
D15
D1
STUDY ENTRY AND GENERAL ASSESSMENTS
Renal Function (CrCl using 
Cockcroft-Gault formula or 24 
hour urine collection method)
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
repeated during treatment if clinically indicated
X
-
-
Pregnancy test (minimum 
sensitivity 25 mIU/mL) for FCBP 
with regular or no menstrual 
cycles
-10 to -14 days and -24 hours prior to first dose 
weekly for 28 days after first dose, then, every 28 days
X
X
X
Pregnancy test (minimum 
sensitivity 25 mIU/mL) for FCBP 
with irregular menstrual cycles
-10 to -14 days and -24 hours prior to first dose 
weekly for 28 days after first dose, then, every 14 days
X
14 and 28 
days after last 
dose
X
Pregnancy counseling
X
X
-
-
-
X
-
X
X
X
X
Thromboembolism prophylaxis
for all subjects on LEN as part of 
treatmentb
-
Continuous during LEN treatment
-
-
EFFICACY AND OTHER ASSESSMENTS
ECOG Performance status
X
X
-
-
-
X
-
X
X
-
-
Assessment of response (IMWG 
Uniform Response Criteria)c
-
X
-
-
-
X
-
X
X
-
-
Approved
5.0
v
Approved
2.0
v


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
45
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Table 3:
Table of Events (Continued)
Screening 
Period
Treatment Period
Safety Follow-up Visits
Cycle 1
Cycle 2-4 
(±2 days for all 
visits)
≥ Cycle 5 
(±2 days 
for all 
visits)
EOT (≤7 
days from 
trt discon 
decision)
28 days (+3) 
after EOT
90 days (+3) 
after last 
DUR dose
Events
-28 to -1
D1a
D8
D15
D22
D1
D15
D1
Serum and urine electrophoresis
(done by central Lab)
X
X
-
-
-
X
-
X
X
-
-
STUDY ENTRY AND GENERAL ASSESSMENTS
Serum and urine immunofixation
(done by central laboratory)
X
X
-
-
-
X
-
X
X
-
-
Serum free light-chain assay
(done by central laboratory)
X
X
-
-
-
X
-
X
X
-
-
Quantitative serum 
immunoglobulin (done by central 
laboratory)
X
X
-
-
-
X
-
X
X
-
-
Beta-2 microglobulin (done by 
central laboratory)
X
X
-
-
-
X
-
X
X
-
-
Extramedullary plasmacytomas 
(EMP) clinical assessment
X
X
-
-
-
X
-
X
X
-
-
Minimal Residual Disease Assay 
(Bone Marrow Aspiration) for 
subjects on Cohort C (done by 
central laboratory)d
X
EMP radiological assessment 
(only required if history of or 
clinical indication of EMPs only 
assessable radiographically)
X
Day 1 starting at C3, then every 3 cycles thereafter
-
-
Approved
5.0
v
Approved
2.0
v


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
46
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Table 3:
Table of Events (Continued)
Screening 
Period
Treatment Period
Safety Follow-up Visits
Cycle 1
Cycle 2-4 
(±2 days for all 
visits)
≥ Cycle 5 
(±2 days 
for all 
visits)
EOT (≤7 
days from 
trt discon 
decision)
28 days (+3) 
after EOT
90 days (+3) 
after last 
DUR dose
Events
-28 to -1
D1a
D8
D15
D22
D1
D15
D1
STUDY ENTRY AND GENERAL ASSESSMENTS
Bone lesions assessment
X
(within 60 
days prior 
to first dose 
acceptable)
repeated during treatment if clinically indicated to confirm response or 
progression 
-
-
Pharmacokinetics
-
LEN PK sampling for all Cohorts 
C1D1:  pre-dose, 0.5, 1, 2, 4, and 8 hours post C1D1 LEN dose 
C1D15:  pre-dose, 0.5, 1, 2, 4, and 8 hours post C1D15 LEN dose
DUR PK sampling for all Cohorts:
-C1D1: pre-infusion (-60 to -5 minutes prior to dose), end of infusion (EOI), 
4 hours, 168 hours (C1D8), 336 hours (C1D15) and 504 hours (C1D22) after 
administration of DUR on C1D1
-C2D1: pre-infusion (-60 to -5 minutes prior to dose), end of infusion (EOI), 
4 hours, and 336 hours (C1D15) after administration of DUR on C2D1
-C4D1, C6D1, C10D1, and C14D1: pre-infusion (-60 to -5 minutes prior to 
dose)
-
-
Immunogenicity (ADA)
-
Pre-dose samples on C1D1, C2D1, C4D1, C6D1, C10D1 and C14D1.
-
-
Bone marrow aspirate and/or 
biopsy sampling for cytogenetics, 
% plasma cells, 
X
 
- BMA and BMB at time of CR confirmation for % plasma 
cells 
 
 
-
-
-
Approved
5.0
v
Approved
2.0
v


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
47
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Table 3:
Table of Events (Continued)
Screening 
Period
Treatment Period
Safety Follow-up Visits
Cycle 1
Cycle 2-4 
(±2 days for all 
visits)
≥ Cycle 5 
(±2 days 
for all 
visits)
EOT (≤7 
days from 
trt discon 
decision)
28 days (+3) 
after EOT
90 days (+3) 
after last 
DUR dose
Events
-28 to -1
D1a
D8
D15
D22
D1
D15
D1
STUDY ENTRY AND GENERAL ASSESSMENTS
 
 
 
 
 
 
 
 
 
 
STUDY TREATMENT (DUR, LEN, dex)f
COHORT A and Cohort B
DUR IV administrationg
-
X
-
-
-
X
-
X
-
-
-
Oral LEN 
-
Days 1-21/28 day cycle
-
-
-
Oral dex h
-
Days 1, 8, 15, 22 / 28-day cycle
-
-
-
COHORT C
DUR IV administrationg
-
X
-
-
-
X
-
X
-
-
-
Oral LEN
-
Days 1-21/28 day cycle
-
-
-
IP Accountability
-
X
-
-
-
X
-
X
X
-
-
Abbreviations:  
ADA = anti-drug antibody; AE = adverse event; AESI = adverse events of special interest; BMA = bone marrow aspirate; BMB = bone marrow biopsy; C = 
Cycle; CrCL = creatinine clearance; dex = dexamethasone; D= Day; DUR= durvalumab; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology 
Group;  EMP = extramedullary plasmacytomas; EOI = End of Infusion; EOT = End of Treatment; FCBP = female of child-bearing potential; h = hours; HIV = 
Approved
5.0
v
Approved
2.0
v


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
48
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
human immunodeficiency virus; IMWG = International Myeloma Working Group; IRT= integrated response technology; IV = intravenous; LEN = 
lenalidomide; min = minutes; NGS = next generation sequencing; PD = progressive disease;  PK = pharmacokinetics; PR = partial response;  trt discon = 
treatment  discontinuation
a On Cycle1 Day 1 (C1D1), safety laboratory assessments must be performed locally to confirm subject continues to meet the required safety laboratory values 
prior to initiating study treatment.  However, if screening assessments were performed within 72 hours of C1D1, safety laboratory and physical examinations 
need not be repeated at C1D1.
b For Cohort C, only applies to the subjects who have a history of VTE.
c Per IMWG Uniform Response Criteria all response categories and progressive disease require 2 consecutive assessments. For details of the procedures and 
timing, see Section 6.4.5.
dMinimal residual disease levels will be measured by ClonoSIGHT™ NGS assay.  Bone marrow aspirate samples will be collected at the screening, 
 
 (if not overlap with other BMA samples 
time points stated on section 6.4.2). Bone marrow aspirate samples collected at the time of multiple myeloma diagnosis must also be available for central 
analysis (ClonoSIGHT™ NGS assay) for subjects to be considered eligible for the study. The interval between BMA samplings should not be less than 6-
months. With the exception of the screening visit, if the subject underwent BMA sampling within 6-months of the required sampling date, sampling will be 
delayed until 6-months after the previous sample.
 
f All subjects may continue to receive study treatment until disease progression or unacceptable toxicity, or withdrawal of consent. 
g First and Second DURVA infusion:  Subjects will be monitored during and after DUR infusion. Vital signs will be measured prior to DUR administration (- 30 
minutes), every 15 minutes (± 5 minutes) during DUR administration, at the end of DUR infusion (± 5 minutes), and at 30 minutes (± 5 minutes) and 60 
minutes (± 5 minutes) after DUR infusion, followed by a 2-hour (± 15 minutes) period of observation. Subsequent DURVA infusions: vital signs will be 
measured prior to the start of the infusion. Subjects should be carefully monitored and blood pressure and other vital signs should be measured during and post 
infusion as per institution standard and as clinically indicated. Any clinically significant changes in vital signs should be entered onto an unscheduled vital 
signs CRF page. For the first 3 subjects of each cohort in the dose-finding portion, there will be at least a 24-hour observation period and 24 to 48 hours after 
that to communicate safety data (e.g., adverse event [AE], basic laboratory, and vital signs) to the sponsor before the dosing of the next subject occurs.
h For Cohort B, the dex can be administered for up to 12 cycles.
i From Cycle 5 onwards only thyroid stimulating hormone (TSH) will be assessed, if TSH is abnormal, then testing for free T4 and free T3 will be performed.
Approved
5.0
v
Approved
2.0
v


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
49
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
6.
PROCEDURES
Any questions regarding the protocol should be directed to the Celgene Medical Monitor or 
designee.
6.1.
Screening period
Screening evaluations will be performed for all subjects to determine study eligibility. These 
evaluations must be completed within 28 days of first dose unless noted otherwise below. 
Any questions regarding subject eligibility should be directed to the Celgene Medical Monitor or 
designee. Waivers to the protocol will not be granted during the conduct of this trial, under any 
circumstances.
Except for pregnancy tests and urinalysis, all safety-related laboratory assessments will be 
performed centrally; however, tests that may result in dose interruption and/or modification 
should also be performed locally to allow for treatment-related decisions during subject visits.  
All results from local laboratories used in treatment decisions or adverse event reporting must be 
entered as an unscheduled visit on the electronic case report form (eCRF).  
Screening laboratory values must demonstrate subject eligibility but may be repeated within the 
screening window, if necessary.
The following will be performed at screening as specified in Table 3, after informed consent has 
been obtained:

Interactive Response Technology (IRT) Registration 

Demographics (date of birth, sex, race, and ethnicity, if allowed by local regulations,
will be collected in the eCRF and/or IRT system)

Complete medical history (all relevant medical conditions diagnosed/occurring prior 
to screening should also be included)

Disease history (if available the date of initial diagnosis, staging at time of diagnosis, 
cytogenetics at diagnosis to be collected)

Prior and ongoing concomitant procedures (including all procedures occurring ≤ 28 
days before screening)

Prior and ongoing concomitant medication evaluation (including those taken ≤ 28 
days before screening)

Physical examination, including assessment for potential venous thromboembolism 
events (VTEs) (can be source documented only) 

Vital signs (including blood pressure, temperature, and heart rate)

Height 

Weight 

Clinical examination for peripheral neuropathy
Approved
5.0
v
Approved
2.0
v


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
50
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019

ECOG performance status (see Appendix C)

12-lead electrocardiogram (ECG)

Efficacy assessment/ tumor evaluation (see Section 6.4)

Cytogenetics (see Section 6.4.2)

MRD status measurement (for Cohort C subjects only, see Section 6.4.2)

Beta-2 microglobulin 

Hepatitis panel

HIV-1 antibody

Hematology panel including complete blood count (CBC) with differential, including 
red blood cell (RBC) count, hemoglobin, hematocrit, white blood cell (WBC) count 
(with differential), platelet count, mean corpuscular volume (MCV).

Coagulation parameters (prothrombin time/international normalize ratio, activated 
partial thromboplastin time, fibrinogen).

Chemistry panel including sodium, potassium, calcium, corrected serum calcium,
chloride, blood urea nitrogen (BUN), creatinine, glucose, albumin, total protein, 
alkaline phosphatase (ALP), bilirubin (total, direct and indirect), aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase 
(LDH), magnesium, bicarbonate, lipase, gamma glutamyl transferase (GGT), uric 
acid, triglycerides, cholesterol, amylase.  (NOTE:  Tests for AST, ALT, ALP, 
direct bilirubin, indirect bilirubin, and total bilirubin must be conducted and 
assessed concurrently)

Estimation of renal function will be assessed using the CrCl calculated based on the 
Cockcroft-Gault formula or the CrCl directly calculated from the 24 hour urine 
collection method.  Cockcroft-Gault formula: CrCl (mL/min) = (140 – age) (weight 
[kg]) / 72 (serum creatinine [mg/dl]); for females, the formula is multiplied by 0.85
(local laboratory)

Thyroid function tests (thyroid-stimulating hormone [TSH], Free tri-iodothyronine
(T3), and Free thyroxine (T4) levels 

Urinalysis (color, appearance, specific gravity, pH, protein, glucose, ketones, blood, 
bilirubin)

Pregnancy test is required for all female subjects of childbearing potential. Serum 
beta human chorionic gonadotropin (β-hCG) pregnancy test will be performed at 
Screening. Urine (or serum) pregnancy test will be performed to assess subject 
eligibility within 72 hours prior to the first administration of IP, if the initial serum 
pregnancy test did not already occur with 72 hours of dosing (negative results 
required for IP administration).

Counseling about pregnancy precautions and the potential risks of fetal exposure 
must be conducted. 
Approved
5.0
v
Approved
2.0
v


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
51
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019

Adverse event (including Adverse Events of Special Interest) evaluation begins when 
the subject signs the informed consent form.  See Section 10 for detailed definitions 
and reporting requirement for AEs. 

Bone marrow aspiration/biopsy (for cytogenetics, % plasma cells, 
)

6.2.
Treatment Period
The subject will begin treatment upon confirmation of eligibility. The subject must start 
treatment within 28 days of signing the ICF. For all subsequent visits, an administrative window 
of ± 2 days is permitted. On Cycle 1 Day 1, safety laboratory assessments must be performed 
locally to confirm subject continues to meet the required safety laboratory values prior to 
initiating study treatment.  However, if screening assessments were performed within 72 hours of 
Cycle 1 Day 1 (C1D1), safety laboratory and physical examinations need not be repeated at 
C1D1.
Treatment cycles are 28 days in duration, and will occur as described in Section 7.2.
The following evaluations will be performed at the frequency specified in the Table of Events, 
Table 3.  The evaluations should be performed prior to dosing on the visit day, unless otherwise 
specified.

Interactive Response Technology (IRT) Registration 

Subjects may be registered in the IRT up to 3 days prior to initiating study 
treatment on Cycle 1 Day 1 (C1D1)

Concomitant medications evaluation, and including thromboembolism prophylaxis

Concomitant procedures evaluation

Physical examination including assessment for potential venous thromboembolism 
events (VTEs) (can be source documented only)

Vital signs

Weight 

Hematology panel

Coagulation parameters

Chemistry panel

Estimation of renal function will be assessed using the creatinine clearance (CrCl)

Thyroid function tests

Cycles 1 – 4: TSH, free T4, free T3

Cycle 5 onward:  TSH, if TSH is abnormal, then reflex testing for free T4 and free 
T3 
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
12-lead electrocardiogram (ECG) (only if clinical indicated during the treatment 
period)

ECOG performance status (Day 1 of each treatment cycle)

Immunogenicity of durvalumab (Day 1 of each treatment cycle)

AE evaluation (including SPM)

Counseling about pregnancy precautions and the potential risks of fetal exposure 
must be conducted. (Day 1 of each treatment cycle)

Efficacy assessment (see Section 6.4)

Urinalysis (only if clinically indicated)

Urine (or serum) pregnancy test for FCBP (negative results required for study
treatment [durvalumab, LEN, or dex] administration)

Blood sampling for PK assessments (see Section 6.5)

 


Study treatment administered (durvalumab, LEN, or dex) and 
accountability/compliance
6.2.1.
End of Treatment
An end of treatment (EOT) evaluation will be performed for subjects who are withdrawn from 
treatment for any reason within 7 days (+/- 3) after the decision to permanently discontinue 
treatment has been made. 
The following evaluations will be performed as specified in the Table 3:

IRT registration

Physical examination including assessment for potential venous thromboembolism 
events (VTEs) (can be source documented only)

Vital signs

Weight

Concomitant medications evaluation

Concomitant procedures evaluation

Estimation of renal function will be assessed using the creatinine clearance (CrCl)

Thyroid function tests 

ECOG performance status 

12-lead ECG
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Celgene
Confidential and Proprietary
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MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019

AE evaluation (including SPM)

Hematology panel

Coagulation parameters 

Chemistry panel

Urinalysis 

Urine β-hCG (for FCBP) and pregnancy counseling

Efficacy assessment will be continued according to the schedule defined in the Table 
of Events, and does not need to be performed specifically for the EOT visit except as 
specified in Section 6.4.

 


Study treatment (durvalumab, LEN, or dex), and accountability/compliance
6.3.
Follow-up Period
6.3.1.
Safety Follow-up
All subjects will be followed for 90 days after the last dose of durvalumab for AE, including 
AESI, reporting, as well as SAEs made known to the investigator at any time thereafter that are 
suspected of being related to study IPs (durvalumab, LEN, or dex), as described in Section 10.1.
Subjects are to return to the study site 28 (+3) days after the EOT visit and 90 (+3) days after the 
last dose of durvalumab for safety follow-up visits procedures as specified Table 3.

Vital signs 

Weight

Concomitant medications evaluation (monitored until 90 days after the last dose of 
durvalumab

Concomitant procedures evaluation (monitored until 90 days after the last dose of 
durvalumab

Adverse event evaluation (monitored until 90 days after last dose of durvalumab; 
SPM will continue to be monitored after above required 90 days visit and every 6 
months up to 5 years after the last subject enrolled into the study). Data entry into the 
clinical database will continue until 15 Dec 2019. After this date, the occurrence of 
SPMs will continue to be monitored, and any events will continue to be recorded in 
the subject’s source documents and reported to Celgene Drug Safety

Hematology panel

Coagulation parameters (90 [+ 3] days after the last dose of durvalumab only)

Chemistry panel
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EDMS Doc. Number: 24328540 - 20680025
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Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
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MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019

Renal function (CrCl)

Thyroid function tests (90 [+ 3] days after the last dose of durvalumab only)

Urine β-hCG test (for females of childbearing potential)

Counseling about pregnancy precautions and the potential risks of fetal exposure for 
subjects receiving LEN

6.4.
Efficacy Assessment 
6.4.1.
Laboratory Assessments for Efficacy Parameters  
All laboratory assessments for efficacy will be performed centrally.
If screening assessments are performed within 72 hours of C1D1, efficacy laboratory 
assessments need not be repeated at C1D1.

Serum protein electrophoresis (sPEP) and urine protein electrophoresis (uPEP) test 
(performed on 24-hour urine collection) are required at screening, Day 1 of each 
cycle, and at End of Treatment. 

Serum and urine immunofixation (IFE) tests are required at screening, on Day 1 of 
each cycle, and at End of Treatment.

Quantitative serum immunoglobulin assessment includes IgG, IgA, IgM for all 
subjects, and IgE or IgD only for subjects with the respective MM sub-type (IgE or 
IgD) and is required at screening, on Day 1 of each cycle, and at End of Treatment.

Serum free light-chain assay is required at screening, on Day 1 of each cycle, and at 
End of Treatment.

Corrected serum calcium will be assessed as part of the serum chemistry labs 
performed at screening, Days 1 and 15 of every cycle, and at End of Treatment.

Beta-2 microglobulin test is required at screening, on Day 1 of each cycle, and at the 
End of Treatment.  
6.4.2.
Bone Marrow Aspiration and/or Biopsy and Cytogenetics
A bone marrow aspirate (BMA) and/or biopsy (BMB) is mandatory at the following time points:

Screening: BMA and BMB for the percentage plasma cells, and cytogenetics, 

During treatment:


 

BMA and BMB at the time of complete response (CR) confirmation for the 
percentage of plasma cells 
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Celgene
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

For all the subjects on the Cohort C, BMA will also be collected at the screening,
for MRD measurement by 
ClonoSIGHT™ NGS assay, if not overlap with the above samples collection time 
points (see footnote d on Table 3); BMA samples collected at the time of multiple 
myeloma diagnosis must also be available for central analysis (ClonoSIGHT™ 
NGS assay) for subjects to be considered eligible for the study 
The analysis of bone marrow for percentage of plasma cells will be performed locally.  The bone 
marrow aspirate/biopsy samples for cytogenetics and biomarkers will be submitted to a central 
laboratory.
6.4.3.
Bone Lesion Assessment 
Bone lesion assessment (skeletal survey) by x-ray, or CT scan (including PET/CT), or MRI will 
be performed at Screening and when clinically indicated. The same method (x-ray or CT scan or 
MRI) should be used throughout the study.  All films will be analyzed locally by the site 
investigator/radiologist. If a bone lesion assessment by x-ray or CT, or MRI scan was performed 
within 60 days prior to the start of Cycle 1, it may be used for the screening assessment. 
If assessment is done by x-ray, the following are the minimum plain radiological films required 
for the skeletal (bone) survey: 

Lateral skull 

Anteroposterior (AP) and lateral cervical spine 

AP and lateral thoracic spine 

AP and lateral lumbar spine 

Posteroanterior (PA) chest 

AP pelvis 

AP upper extremities, shoulder to elbow 

AP lower extremities hip to knee 
Other radiological films may be necessary to view symptomatic areas or known pre-existing 
lesions in skeletal regions not included in the films above.
6.4.4.
Extramedullary Plasmacytoma Assessments (EMPs)
Clinical assessment for EMPs will be performed at Screening, Day 1 of each cycle, and at End of 
Treatment.
Extramedullary plasmacytomas that are only assessable radiographically (by x-ray and/or 
conventional [spiral] CT/MRI scan) are required at Screening; at Cycle 3 Day 1 and every 3 
cycles thereafter (C6D1, C9D1, etc.) during treatment; at End of Treatment, and when clinically 
indicated to confirm a response (≥ partial response [PR]). The radiographic modality used at 
screening (eg, x-ray) will be repeated at each assessment time point throughout the study. All 
scans will be reviewed locally only.
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Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
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6.4.5.
Assessment of Response 
Starting from Cycle 2, response will be assessed by the investigators using the IMWG Uniform 
Response Criteria (Rajkumar, 2011) (Appendix B) at every cycle on Day 1 and at the End of 
Treatment visit. Investigator assessment of response will be based on the central laboratory data 
to ensure consistency across investigative sites.
For subjects on Cohort C, the response need be assessed as following: 
1) use the disease measure at the time of before ASCT as the baseline for response assessment; 
2) starting from Cycle 2, compare the response assessments with the response at the C1D1 to 
determine response improvement.
NOTE: Per IMWG Uniform Response Criteria all response categories and progressive disease 
require 2 consecutive assessments
6.5.
Pharmacokinetics 
Pharmacokinetic assessments are mandatory and will be performed for all subjects enrolled into 
the study. Details for sample collection, processing, storage, and shipment will be provided in the 
Laboratory Manual.
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 electronic case report form (eCRF) pages.
6.5.1.
Pharmacokinetics of Lenalidomide
Intense PK sampling will be performed for all subjects administered with LEN. The sampling 
time points will be as follows:

C1D1: predose (-60 to -5 minutes prior to dose), 0.5 hour (± 5 minutes), 1 hour (± 10 
minutes), 2 hours (± 10 minutes), 4 hours (± 10 minutes), and 8 hours (± 1 hour) after 
administration of lenalidomide

C1D15: predose (-60 to -5 minutes prior to dose), 0.5 hour (± 5 minutes), 1 hour (± 
10 minutes), 2 hours (± 10 minutes), 4 hours (± 10 minutes), and 8 hours (± 1 hour) 
after administration of lenalidomide
On both days, subjects will be asked NOT to take lenalidomide at home. Lenalidomide will be 
administered to these subjects at the study center after the collection of the predose PK blood 
sample.
6.5.2.
Pharmacokinetics of Durvalumab
Intense PK sampling will be performed for all subjects administered with durvalumab.  The 
sampling time points will be as follows:

C1D1: preinfusion (-60 to -5 minutes prior to dose), end of infusion (EOI) (-15 to 0 
minutes), 4 hours (± 1 hour), 168 hours (C1D8) (± 4 hour), 336 hours (C1D15) (± 4 
hour) and 504 hours (C1D22) (± 4 hour) after administration of durvalumab on C1D1
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EDMS Doc. Number: 24328540 - 20680025
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Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
57
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
C2D1: preinfusion (-60 to -5 minutes prior to dose), EOI ( -15 to 0 minutes), 4 hours 
(± 1 hour), and 336 hours (C2D15) (± 4 hour) after administration of durvalumab on 
C2D1

C4D1, C6D1, C10D1, and C14D1: preinfusion (-60 to -5 minutes prior to dose)
6.5.3.
Immunogenicity Samples of Durvalumab
Immunogenicity samples will be collected as follows:

Predose samples on C1D1, C2D1, C4D1, C6D1, C10D1 and C14D1. 
The samples will be stored and if warranted anti-drug antibodies (ADA) will be explored using 
these samples.
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number: 24328540 - 20680025
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Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
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MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
 
 
 
 
Approved
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EDMS Doc. Number: 24328540 - 20680025
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Confidential and Proprietary
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MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Products
The IP supply will be managed by Interactive Response Technology (IRT). All IP must be stored 
in accordance with the product label in a secured area to prevent unauthorized access.
United States and Canada:
Durvalumab (MEDI4736) and lenalidomide will be supplied by Celgene and labeled 
appropriately as investigational material. Labels will bear Celgene’s name and address, the 
protocol number, product name, dosage form and strength, medication identification/kit number, 
lot number, expiry date, dosing instructions, storage conditions, the quantity of IP contained, and 
required caution statements and/or regulatory statements as applicable.
Dexamethasone will not be supplied by Celgene; instead it will be obtained according to local 
clinical study agreement and in accordance with local guidelines. Additional information may be 
included on the label as needed or applicable.
Outside the United States and Canada:
Durvalumab (MEDI4736) and lenalidomide and dexamethasone will be supplied by Celgene and 
labeled appropriately as investigational material. Labels will bear Celgene’s name and address, 
the protocol number, EudraCT Number (if applicable), product name, dosage form and strength, 
medication identification/kit number, lot number, expiry date, dosing instructions, storage 
conditions, the quantity of IP contained, and required caution statements and/or regulatory 
statements as applicable.
Label(s) for IP supplied will contain information as required per local health authority.
7.1.1.
Durvalumab (MEDI4736) 
Durvalumab will be supplied by Celgene in single use vials in single count cartons. Each 10R 
vial will be supplied as a liquid solution containing 500 mg (nominal) of investigational product 
at a concentration of 50 mg/mL. Durvalumab should be stored in accordance with the product 
label. 
Site to supply the following:

IV infusion bags of normal saline (0.9% [w/v] sodium chloride injection, 250 mL 
size). Saline bags must be latex-free and can be made of polypropylene, polyethylene, 
polyolefin copolymers, or polyvinyl chloride. Infusion lines should contain a 0.2-μm 
in-line filter.  

Since the compatibility of durvalumab with other IV medications and solutions, other 
than normal saline, 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 preparation and storage please refer to the Pharmacy Manual. 
Approved
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7.1.2.
Lenalidomide (LEN)
Lenalidomide (LEN) will be supplied by Celgene in appropriate strengths for oral 
administration. Investigational product will be supplied in labeled blister cards. Lenalidomide 
should be stored in accordance with the product label. 
Please refer to the locally approved lenalidomide label for additional information on 
administration or storage information. 
7.1.3.
Dexamethasone (dex)
For sites outside the US and Canada, Celgene will provide commercial supplies of 
dexamethasone (dex) 2 mg and 4 mg tablets for oral administration. Dexamethasone should be 
stored in accordance with the product label.
For additional details and storage information please refer to the Pharmacy Manual.
7.2.
Treatment Administration and Schedule
The first day of study treatment dosing (durvalumab and LEN and/or dex) is considered Day 1 of 
a cycle.
7.2.1.
Treatment Administration
7.2.1.1.
Durvalumab
Durvalumab Product Dose Preparation/Administration
The IV infusion for subjects will be approximately 1 hour in duration.
For detailed information on durvalumab dose preparation and administration please refer 
to the Pharmacy Manual. 
Monitoring During/Post Durvalumab Infusion
First and Second DURVA infusion
Subjects will be monitored during and after infusion of durvalumab. Vital signs will be measured 
prior to durvalumab administration (± 30 minutes), every 15 minutes (± 5 minutes) during 
durvalumab administration, at the end of durvalumab infusion (± 5 minutes), and at 30 minutes 
(± 5 minutes) and 60 minutes (± 5 minutes) post infusion of durvalumab, followed by a 2-hour (± 
15 minutes) period of observation.
Subsequent DURVA infusions
For the subsequent DURVA infusion, vital signs will be measured prior to the start of the
infusion. Subjects should be carefully monitored and blood pressure and other vital signs should
be measured during and post infusion as per institution standard and as clinically indicated. Any
clinically significant changes in vital signs should be entered onto an unscheduled vital signs 
CRF page.
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 re-initiated at 
50% of the initial rate until completion of the infusion. In subjects experiencing Grade ≤ 2 
infusion-related reactions, subsequent infusions may be administered at 50% of the initial rate. 
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EDMS Doc. Number: 24328540 - 20680025
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Protocol MEDI4736-MM-002
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Confidential and Proprietary
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Acetaminophen 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, treatment with durvalumab will be discontinued. 
As with any antibody, allergic reactions to dose administration are possible. Therefore, 
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.
7.2.1.2.
Lenalidomide
Over 60% of a dose of lenalidomide is excreted in urine unmetabolized. Pharmacokinetic studies 
have revealed that the plasma area under the plasma concentration-time curve (AUC) of 
lenalidomide is inversely related to the CrCl (Chen, 2007). Therefore, the dose of lenalidomide 
must be adjusted for renal function on the first day of Cycle 1. The following are 
recommendations (see Table 4) for subjects enrolled into the study. The recommendations are 
applicable to renal function classified either by measured or Cockcroft-Gault estimated CrCl 
(Cockcroft, 1976; Luke, 1990) 
If the CrCl of subjects who had moderate or severe renal insufficiency at baseline (Day 1 of 
Cycle 1) improves during study treatment with the study treatment, then the dosing regimen of 
lenalidomide can be escalated to the level appropriate to the improved estimated CrCl (see
Table 4). Dose escalations are to be made at the start of the next cycle. Discuss with medical 
monitor if this occurs.
Table 4:
Lenalidomide Dosing Guideline for Renal Insufficiency for Cohort A and
Cohort B
Renal Function (CrCl)
Dosing
Normal to Mild RI (CrCl ≥ 50 mL/min)
25 mg once daily on Days 1 to 21 of each 28-day 
cycle
Moderate RI (30 ≤ CrCl < 50 mL/min)
10 mga once daily on Days 1 to 21 of each 28-day 
cycle
Severe RI (CrCl < 30 mL/ min)
15 mg once every other day from Day 1 to 21 of 
each 28-day cycle
CrCl = creatinine clearance; RI = renal insufficiency.
a This dose may be escalated to 15 mg after 2 Cycles at the discretion of the treating physician if the subject 
tolerates the 10 mg dose of lenalidomide without dose-limiting toxicity.
The lenalidomide starting dose for subjects on Cohort C is 10 mg on Days 1 to 21 of each 28-day 
cycle. 
7.2.1.3.
Dexamethasone
On Day 1 of Cycle 1, the starting dose of dexamethasone is 40 mg once daily on Days 1, 8, 15, 
and 22 of a 28-day treatment cycle for subjects who are 75 years of age on the date of 
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randomization. For subjects who are > 75 years of age on the date of randomization, the starting 
dose of dexamethasone is 20 mg once daily on Days 1, 8, 15, and 22 of a 28-day cycle.
7.2.2.
Treatment Schedule
Three treatment Cohorts (A, B, and C) will be enrolled in parallel in the dose-finding phase:

Cohort A:  durvalumab + LEN +dex on high risk TNE NDMM subjects

Cohort B:  durvalumab + LEN +dex (only up to 12 cycles) on ≥ 65 years old TNE 
NDMM subjects who are not high risk

Cohort C:  durvalumab + LEN on post-transplant high risk NDMM subjects as 
maintenance (the study treatment is to be initiated at 100 days [± 14 days] after 
transplant).
Initially, 6 subjects will be enrolled into each cohort, the detailed dosing schedule for each 
treatment Cohort is listed below in Table 5. See de-escalation rules in Section 3.1.
Table 5:
Planned Dose Level by Treatment Cohorts
Study IP
Treatment Cohort A
Treatment Cohort B
Treatment Cohort C
Starting 
dose level 
IV DUR 
1500 mg on Day 1 of a 28-
day cycle
1500 mg on Day 1 of a 
28-day cycle
1500 mg on Day 1 of a 
28-day cycle
Oral LEN
25 mg on Days 1 - 21 of a 
28-day cycle (adjustable 
per the CrCl value, see 
detail in Table 4
25 mg on Days 1 - 21 of a  
28-day cycle (adjustable 
per the CrCl value, see 
detail in Table 4  
10 mg on Days 1 - 21 of a 
28-day cycle  
Oral dex
40 mg/day (≤75 years old) 
or 20 mg/day (> 75 years 
old) on Days 1, 8, 15, and 
22 of a 28-day cycle  
40 mg/day (≤75 years 
old) or 20 mg/day (> 75 
years old) on Days 1, 8, 
15, and 22 of a 28-day 
cycle  (for up to 12 cycles)
Not applicable
De-
escalate  
dose level
IV DUR 
750 mg on Day 1 of a 28-
day cycle
750 mg on Day 1 of a 28-
day cycle
750 mg on Day 1 of a 28-
day cycle
Oral LEN
25 mg on Days 1 – 21 of a 
28-day cycle (adjustable 
per the CrCl value, see 
detail in Table 4  
25 mg on Days 1 – 21 of a 
28-day cycle (adjustable 
per the CrCl value, see 
detail in Table 4  
10 mg on Days 1 – 21 of a 
28-day cycle 
Oral dex 
40 mg/day (≤75 years old) 
or 20 mg/day (> 75 years 
old) on Days 1, 8, 15, and 
22 of a 28-day cycle  
40 mg/day (≤75 years 
old) or 20 mg/day (> 75 
years old) on Days 1, 8, 
15, and 22 of a 28-day 
cycle (for up to 12 cycles)
Not applicable
Abbreviations: CrCl = creatinine clearance; dex = dexamethasone; DUR= durvalumab; IV = Intravenous;  mg = 
milligrams; LEN = lenalidomide
Subjects who enrolled in the expansion phase will follow with the same study treatment schedule 
for the respective treatment cohort in the dose-finding phase (See Figure 1).
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7.2.3.
Overdose
Overdose, as defined for this protocol, refers to durvalumab, LEN, and dex dosing only. On a per 
dose basis, an overdose is defined as the following amount over the protocol-specified dose of 
durvalumab, LEN, or dex assigned to a given subject, regardless of any associated adverse 
events or sequelae.

For oral, any amount over the protocol-specified dose

For IV 10% over the protocol-specified dose
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency. On an infusion rate basis, an overdose is defined as any 
rate faster than the protocol-specified rate. Complete data about drug administration, including 
any overdose, regardless of whether the overdose was accidental or intentional, should be 
reported in the eCRF. See Section 10 for the reporting of AEs associated with overdose.
7.2.4.
Dose Modifications and Interruptions
Subjects will be evaluated for AEs at each visit with the NCI CTCAE version 4.03 or higher as a 
guide for the grading of severity.  
If the treatment has been interrupted and the next cycle is delayed beyond Day 28 of the prior 
cycle, then Day 1 of the next cycle will be defined as the first day that treatment is resumed.

If durvalumab dosing is withheld, then LEN and dex dosing must also be withheld. 

If durvalumab is permanently discontinued, then the subject must be permanently 
discontinued from all study treatments. (The subjects may continue to receive the 
LEN and/or dex until the ongoing cycle be completed.)

If LEN dosing is withheld or permanently discontinued, then durvalumab and dex 
dosing may be continued. 

If both LEN and durvalumab dosing are withheld, then dex must also be withheld.

If DEX dosing is withheld or permanently discontinued, then LEN and durvalumab
may be continued. 
7.2.4.1.
Dose Modification Instructions for Durvalumab
Refer to Appendix D for detailed instructions for durvalumab dose modifications and toxicity 
management 
7.2.4.2.
Dose Modification Instructions for Lenalidomide
Guidelines for lenalidomide dose interruptions and reductions are provided in Table 6, and 
Table 7 outlines the dose reduction steps for lenalidomide.  For the full prescribing information 
refer to the respective current Prescribing Information, Summary of Product Characteristics 
(SmPC), or equivalent document for the specific region/country for lenalidomide.
If local or central laboratory test results (CrCl) show a clinically significant worsening of renal 
function, the investigator should contact the medical monitor to discuss if dose reduction is 
necessary. Dose reduction for worsening CrCl at subsequent visit is not required by the protocol, 
Approved
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but if warranted after discussion with medical monitor, the site should use dosing Table 6, and 
Table 7 for the appropriate lenalidomide dose reduction. Dose reduction would be a 1 dose level 
(see Table 8, Table 9, and Table 10) reduction from the current dose level as outlined in those 
tables.
In addition, G-CSF (granulocyte colony stimulating factor) may be used to support the neutrophil 
count after the DLT assessment period has been completed (Cycle 1).
Instructions for dose interruptions and reductions for LEN-related hematologic toxicity occurring 
during a cycle are as follows:
Table 6:
Dose Modification Instructions for Lenalidomide for Hematologic Toxicity 
during a Cycle
Toxicity
Lenalidomide Dose Modification
Grade 4 neutropenia (ANC < 0.5 x 
109/L) 
or 
Febrile neutropenia (fever 38.5C 
and ANC < 1 x 109/L)
1) Stop lenalidomide dosing for the remainder of the cycle.
2) If the subject was not receiving G-CSF therapy, G-CSF 
therapy may be started at the discretion of the treating physician. 
On Day 1 of the next cycle, the dose of lenalidomide may be 
maintained if neutropenia was the only DLT and G-CSF 
treatments are continued. Otherwise, decrease by one dose level 
at start of next cycle (see Table 8, Table 9, and Table 10).
Grade 4 Thrombocytopenia 
(Platelets < 25 x109/L)
Stop lenalidomide dosing for remainder of cycle. Decrease by 
one dose level when dosing is resumed at next cycle (see 
Table 8, Table 9 and Table 10).
Other Grade 3 lenalidomide-related 
adverse events (excluding 
neutropenia, febrile neutropenia, and 
thrombocytopenia)
Stop lenalidomide dosing for remainder of cycle. Decrease by 
one dose level when dosing is resumed at next cycle (see 
Table 8, Table 9, and Table 10).
ANC = absolute neutrophil count; DLT = dose-limiting toxicity; G-CSF = granulocyte colony-stimulating factor.
Instructions for dose interruptions and reductions for lenalidomide-related non-hematologic 
toxicity occurring during a cycle are as follows:
Table 7:
Dose Modification Instructions for Lenalidomide for Non-Hematologic 
Toxicity during a Cycle
Toxicity
Lenalidomide Dose Modification
Rash = Grade 3
Stop dose for remainder of cycle. Decrease by one dose level 
when dosing is resumed at next cycle (rash must resolve to 
Grade 1).
Rash = Grade 4 or Blistering
Discontinue lenalidomide.
Constipation Grade 3
Stop dose for remainder of cycle. Initiate bowel regimen. 
Decrease by one dose level when dosing is resumed at next 
cycle (constipation must resolve to Grade 2). 
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Table 7:
Dose Modification Instructions for Lenalidomide for Non-Hematologic 
Toxicity during a Cycle (Continued)
Toxicity
Lenalidomide Dose Modification
Thrombosis/embolism Grade 3
If occurred during aspirin therapy or during a period of 
inadequate anticoagulation, initiate adequate anticoagulation 
treatment. Lenalidomide dosing may continue without 
interruption at the discretion of the treating physician. Dose 
level may be maintained at the discretion of the treating 
physician.
If occurred during adequate anticoagulation treatment 
(prophylactic dose of anticoagulation therapy with LMW 
heparin, heparin or Coumadin®), discontinue lenalidomide.
Hypo/hyperthyroidism Grade 2
Initiate appropriate medical therapy. Maintain dosing and 
dose level at discretion of treating physician.
Peripheral Neuropathy = Grade 3
Stop dose for remainder of cycle. Decrease by one dose level 
when dosing is resumed at next cycle (neuropathy must 
resolve to Grade 1).
Peripheral Neuropathy = Grade 4
Discontinue lenalidomide.
Other Grade 3 lenalidomide-related 
adverse events 
Stop dose for remainder of cycle. Decrease by one dose level 
when dosing is resumed at next cycle (adverse event must 
resolve to Grade 2).
d = dexamethasone; DLT = dose limiting toxicity; LMW = low molecular weight; 
To re-start lenalidomide treatment following a dose interruption at a new cycle, the neutrophil 
count must be ≥ 1000/μL, the platelet count must be ≥ 50,000/μL, and non-hematologic AEs 
must be resolved or improved as described in Table 7.
The following table describes the dose reduction steps for lenalidomide given once daily.
Table 8:
Lenalidomide Dose Reduction Steps (Daily Dosing) for Cohort A and Cohort
B
Dose Levels 
Lenalidomide on Days 1 to 21
of Every 28-Day Cycle
Starting Dose
25 mg/day on Days 1 to 21
Dose Level -1
20 mg/day on Days 1 to 21
Dose Level -2 
15 mg/day on Days 1 to 21
Dose Level -3
10 mg/day on Days 1 to 21
Dose Level -4
5 mg/day on Days 1 to 21
Dose Level -5
2.5 mg/day on Days 1 to 21
The following table describes the dose reduction steps for lenalidomide given once every other 
day.
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Table 9:
Lenalidomide Dose Reduction Steps (Every Other Day Dosing) for Cohort A 
and Cohort B
Dose Levels 
Lenalidomide from Day 1 to Day 21
of Each 28-Day Cycle
Starting Dose
15 mg once every other day from Day 1 to Day 21
Dose Level -1
10 mg once every other day from Day 1 to Day 21
Dose Level -2 
5 mg once every other day from Day 1 to Day 21
Dose Level -3
2.5 mg once every other day from Day 1 to Day 21
The following table describes the dose reduction steps for lenalidomide given to subjects on 
Cohort C.
Table 10:
Lenalidomide Dose Reduction Steps for Cohort C
Dose Levels 
Lenalidomide from Day 1 to Day 21
of Each 28-Day Cycle
Starting Dose
10 mg on Days 1 to 21
Dose Level -1
7.5 mg on Days 1 to 21
Dose Level -2 
5.0 mg on Days 1 to 21
Dose Level -3
2.5 mg on Days 1 to 21
If the dose of lenalidomide is reduced for a hematologic DLT, the dose of lenalidomide can be 
re-escalated up to the next higher dose level at the discretion of the treating physician if 
continued study treatment results in improved bone marrow function (no DLT for at least two 
consecutive cycles and an ANC ≥ 1,500/µL with a platelet count ≥ 100,000/µL at the beginning 
of a new cycle at the current dose level).
7.2.4.3.
Dose Modification Instructions for Dexamethasone
Guideline for dexamethasone dose interruptions and reductions are outlined in Table 11 and
Table 12.  For the full prescribing information refer to the respective current Prescribing 
Information, Summary of Product Characteristics (SmPC), or equivalent document for the 
specific region/country for dexamethasone.
Table 11:
Dose Modifications for Dexamethasone-related Toxicities
Toxicity
Dexamethasone Dose Modification
Dyspepsia = Grade 1-2
Maintain dose and treat with histamine (H2) blockers or 
equivalent.  Decrease by one dose level if symptoms persist.
Dyspepsia ≥ Grade 3
Interrupt dose until symptoms are controlled.  Add histamine 
(H2) blocker or equivalent and decrease one dose level when 
dosing is resumed.
Edema ≥ Grade 3
Use diuretics as needed and decrease dose by one dose level.
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Table 11:
Dose Modifications for Dexamethasone-related Toxicities (Continued)
Toxicity
Dexamethasone Dose Modification
Confusion or mood alteration ≥ Grade 2
Interrupt dose until symptoms resolve.  When dose is 
restarted, decrease dose by one dose level.
Muscle weakness (steroid myopathy) 
≥ Grade 2
Interrupt dose until muscle weakness ≤ Grade 1.  When dose is 
restarted, decrease dose by one dose level.
Hyperglycemia ≥ Grade 3
Decrease dose by one dose level.  Treat with insulin or oral 
hypoglycemic agents as needed.
Acute pancreatitis
Discontinue dexamethasone from treatment regimen.
Other ≥ Grade 3 dexamethasone-related 
adverse events
Stop dexamethasone dosing until the adverse event resolves to 
≤ Grade 2. Decrease by one dose level when dexamethasone 
dosing is resumed.
If recovery from toxicities is prolonged beyond 14 days, then the dose of dexamethasone will be 
decreased by 1 dose level when dose is restarted.
Table 12:
Dexamethasone Dose Reduction Steps 
Dose Level
≤ 75 years old
Dose
> 75 years old
Dose 
Starting Dose
40 mg
20 mg
Dose Level -1
20 mg
12 mg
Dose Level -2 
10 mg
8 mg
Dose Level -3 
8 mg
4 mg
Dose Level -4 
4 mg
NA
Dexamethasone-related dose-limiting toxicity must resolve as described in Table 11 in order to 
restart dexamethasone. If this condition is not met, a new cycle can be started, and 
dexamethasone will continue be interrupted, until adverse event resolution, then restarted 
dexamethasone in the ongoing cycle. If dex-related toxicity does not resolve as described in 
Table 11 within 14 days, then the dose of dex will be decreased by one dose level when dex 
treatment is resumed and the case should be discussed with the medical monitor (if a 
dexamethasone dose reduction is required for the new cycle due to dexamethasone-related 
toxicity that occurred during the previous cycle, an additional dex dose reduction step is not 
required for a delay of the start of a new cycle of > 14 days).
If a new cycle of LEN is initiated but dex is stopped, dex can only be restarted on a scheduled 
dosing day (Days 1, 8, 15, and 22).
Dexamethasone should be discontinued if a subject is unable to tolerate the lowest dose level. No 
dose re-escalation is permitted for dex.
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For subjects who experience a dexamethasone withdrawal toxicity, a dose tapering over a two 
day period to limit symptoms can be initiated at the discretion of the treating physician.
7.3.
Method of Treatment Assignment
Subjects will be assigned to either Cohort A, B, or C based on the eligibility criteria and current 
available slots. Slots will be assigned on a first come-first serve basis and will be valid for 48 
hours following assignment. Unconfirmed eligibility following 48 hours from slot assignment 
may result in forfeiture and subsequent reassignment of the slot. 
Celgene trial staff will review and verify specific eligibility criteria for all screened subjects prior 
to enrollment of subjects via the IRT.  
An IRT system will be used to track subject assignments to the treatment cohorts and dose 
levels.
7.4.
Packaging and Labeling
The label(s) for IP will include sponsor name, address and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, lot 
number, expiry date (where applicable), medication identification/kit number, dosing 
instructions, storage conditions, and required caution statements and/or regulatory statements as 
applicable. Additional information may be included on the label as applicable per local 
regulations.
7.5.
Investigational Product Accountability and Disposal 
Celgene (or designee) will review with the investigator and relevant site personnel, the process 
for IP return, disposal, and/or destruction including responsibilities for the site versus Celgene 
(or designee).
7.6.
Investigational Product Compliance
Accurate recording of all study IP administration (durvalumab, LEN, dex) will be made in the 
appropriate section of the subject’s eCRF and source documents. The investigator or designee is 
responsible for accounting for all study-specific IP (durvalumab, LEN, dex) either administered 
or in their custody during the course of the study.
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EDMS Doc. Number: 24328540 - 20680025
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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. 
See Appendix D for additional details on durvalumab toxicity management.
All concomitant medications, including blood and blood products, used from 28 days prior to 
first dose of study treatment until 90 days after the last dose of durvalumab must be reported on 
the eCRF. 
For information regarding other drugs that may interact with IP and affect its metabolism, 
pharmacokinetics, or excretion, please see the Investigators Brochure and/or local package insert.
8.1.
Permitted Concomitant Medications and Procedures
Subjects with myeloma-associated bone disease may receive bisphosphonate therapy prior to 
study entry, unless such therapy is contraindicated. The use of bisphosphonates is permitted 
throughout the study.
Platelet /red blood cell transfusions and hematopoietic growth factors are also permitted during 
the study. However, prophylactic use of platelet transfusions or hematopoietic growth factors to 
prevent a potential DLT should be avoided unless deemed medically necessary by the treating 
physician for subject safety.
Concurrent use of hormones for non-cancer related conditions (eg, insulin for diabetes and 
hormone replacement therapy) is acceptable.
8.2.
Prohibited Concomitant Medications and Procedures
The following medications are considered exclusionary during the study. The sponsor must be 
notified if a subject receives any of the following during the study:
1. For subjects in the Dose-finding Phase, the prophylactic use of hematopoietic growth 
factors or platelet/RBC transfusions will not be allowed during the first cycle (DLT 
evaluation period); 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. Subjects who fail absolute neutrophil count, or platelet
eligibility criteria at screening CANNOT be re-tested for the study after being treated 
with growth factors or platelet transfusion
2. Any investigational anticancer therapy
3. Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy),
immunotherapy, biologic or hormonal therapy for cancer treatment. 
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. Use of immunosuppressive medications 
for the management of investigational product-related AEs or in subjects with contrast 
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allergies is acceptable. In addition, use of inhaled, topical, intranasal corticosteroids or 
local steroid injections (eg, intra-articular injection) is permitted. Temporary use of 
corticosteroids for concurrent illnesses (eg, food allergies, CT scan contrast 
hypersensitivity, moderate to severe infusion-related reactions, etc) is acceptable upon 
discussion and agreement with the medical monitor
5. Live attenuated vaccines during the study through 30 days after the last dose of
durvalumab
6. Herbal and natural remedies are to be avoided
8.3.
Required Concomitant Medications and Procedures
All subjects in Cohort A and Cohort B are required to receive anti-thrombotic prophylaxis 
medication while receiving the LEN treatment on this study; for Cohort C, only subjects who 
have a history of VTE are required to receive anti-thrombotic prophylaxis medication.
Subjects unable or unwilling to undergo anti-thrombotic prophylactic treatment will not be 
eligible to participate in this study.
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9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
All analyses will use descriptive statistics. No formal statistical comparison/testing will be 
performed.
The analyses will be done by treatment cohort and dose level. Subjects treated with the 
recommended dose in the expansion portion will be combined with the corresponding dose level 
in the dose-determination portion as one single dose level for efficacy and safety analysis.  
9.2.
Study Population Definitions
The following 5 analysis populations will be used: 

Safety population – includes all enrolled subjects who take at least one dose of study 
medication. All safety analyses will be based on this population

Dose-determining population - includes all subjects from the safety set who meet the 
minimum exposure criterion and have sufficient safety evaluations, or experience a 
DLT during the first treatment cycle 

Full analysis population - includes all subjects enrolled into this study

Efficacy evaluable population - includes all enrolled subjects who take at least one 
dose of study medication and who have measurable disease at baseline and at least 
one post-baseline response assessment

Pharmacokinetic population - includes all subjects who receive at least one dose of 
study medication and have evaluable PK profiles. If any subjects are found to be 
noncompliant with respect to dosing, have incomplete data, or encounter other 
circumstances that would affect the evaluation of the PK, a decision will be made on 
a case-by-case basis as to the inclusion of their PK data in the statistical analysis.
9.3.
Sample Size and Power Considerations
Up to 138 subjects are planned to be enrolled in the study: up to 36 total in the 3 cohorts for dose 
finding and up to 102 in the 3 cohorts for expansion. The actual number of subjects will depend 
on the number of dose level being tested.
Phase I expansion dose sample size estimation for Cohort A and Cohort B
Table 13 shows probability of observing an ORR ≥ 75% under different assumptions about the 
true ORR in this population. With a sample size of 40 subjects, this study has reasonable 
operating characteristics of observing an ORR ≥ 75% if the true ORR is 85% or higher.
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Table 13:
Decision Operating Characteristics of ORR with 40 in the Expansion Dose 
for Cohort A and Cohort B
True ORR
Probability of observing
an ORR ≥ 75% with 40 patients
(≥30 out of 40 patients)
60%
3.5%
65%
12.1%
70%
30.9%
75%
50.4%
80%
83.9%
85%
97.0%
90%
99.9%
Phase I expansion dose sample size estimation for Cohort C
Table 14 shows probability of observing a response improvement rate (RIR) ≥ 15% under 
different assumptions about the true RIR in this population. With a sample size of 40 subjects, 
this study has reasonable operating characteristics of observing an RIR ≥ 15% if the true RIR is 
25% or higher.
9.4.
Background and Demographic Characteristics
Age, height, weight, and other continuous baseline disease characteristics will be summarized 
using descriptive statistics, while gender, race, and other categorical variables will be provided 
using frequency tabulations. 
9.5.
Medical History
Medical history data will be summarized using frequency tabulations by MedDRA system organ 
class and preferred term.
9.6.
Concomitant Medications and Procedures
All concomitant medications and procedures documented during the study will be summarized 
using frequency tabulations. The Anatomical Therapeutic Chemical (ATC) coding scheme of the 
World Health Organization (WHO) will be used to group medications into relevant categories 
for these tabulations.
9.7.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent by cohort and dose 
level and follow-up phases. A summary of subjects enrolled by site will be provided. 
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Table 14:
Decision Operating Characteristics of RIR with 40 in the Expansion Dose for 
Cohort C
True ORR
Probability of observing 
a RIR ≥ 15% in Cohort C with 40 patients 
(≥6 out of 40 patients)
5%
1.4%
10%
20.6%
15%
56.7%
20%
83.9%
25%
95.7%
30%
99.1%
35%
99.9%
9.8.
Efficacy Analysis
9.8.1.
Response Using the IMWG Uniform Response Criteria
Tumor response, including progressive disease, will be assessed by the investigators.  
The overall response rate (ORR) will be calculated as the number of responders (at least a Partial 
Response [PR], divided by the number of subjects in the EE population. The ORR together with 
the proportions in each response category based on the IMWG Uniform Response Criteria (ie, 
Stringent Complete Response [sCR], Complete Response [CR], Very Good Partial Response 
[VGPR], Partial Response [PR], Stable Disease [SD], and Progressive Disease [PD]) will be 
examined. 
The best overall response categories (CR, VGPR, PR, SD, and progressive disease) will be 
tabulated by cohort and dose level. 
9.8.2.
Response Improvement Rate Using the IMWG Uniform Response Criteria
The Response improvement rate (RIR) analysis only be performed for subjects on Cohort C. The 
RIR defined response change from the assessment at the C1D1. The assessment by investigator 
using IMWG Uniform Response Criteria, will be tabulated by cohort and dose level.
9.8.3.
Time to Response
Time to response (for responders only, per IMWG Uniform Response Criteria) is calculated as 
the time from the first date of dosing of study medication to the first date of documented 
response (PR or better).
Time to response will be summarized using descriptive statistics by cohort and dose level for 
Cohorts A and B.
9.8.4.
Response Duration 
Duration of response (for responders only, per IMWG Uniform Response Criteria) is defined as 
time from the earliest date of documented response (PR or better) to the earliest date of disease 
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progression as determined by the investigator per IMWG Uniform Response Criteria or death 
during the study treatment, whichever occurred first. Duration of response will be summarized 
using Kaplan-Meier estimates by cohort and dose level as appropriate for Cohorts A and B; no 
statistical test will be performed.
Efficacy evaluable population will be used for all response related analyses.
9.8.5.
Progression Free Survival (PFS)
Progression free survival will be calculated as the time between enrollment and disease 
progression, as determined by the investigator using the IMWG Uniform Response Criteria, or 
death during study treatment, whichever occurred earlier. The PFS will be summarized using 
Kaplan-Meier estimates by cohort and dose level as appropriate; no statistical test will be 
performed. 
Full analysis population will be used for PFS analysis.
9.8.6.
Overall Survival (OS)
Overall survival is calculated as the time from enrollment 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 will be censored on the last-known-to-be-alive date. The OS will be 
summarized using Kaplan-Meier estimates by cohort and dose level as appropriate; no statistical 
test will be performed. 
Full analysis population will be used for OS analysis.
9.9.
Safety Analysis
All safety analyses will be conducted using the Safety population. All analyses will be presented 
by cohort and dose level. 
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) version 18 or higher. The severity of AEs will be graded according to the NCI 
CTCAE version 4.03 or higher.
Treatment-emergent adverse events (TEAEs) are defined as any AE occurring or worsening on 
or after the first treatment of the study IPs (durvalumab, LEN, dex) and within 90 days after the 
last dose of durvalumab. Treatment-emergent AEs, AEs leading to study IP discontinuation, AEs 
leading to dose reduction/interruption, AEs related to study IP, SAEs and AEs leading to death 
will be summarized by system organ class, and preferred term for each treatment group. A 
summary of AEs with NCI CTCAE Grade 3 or higher, as well as the most frequent preferred 
terms, will be provided. A summary of AEs by dosing cycle based on onset date will also be 
provided.
If a subject experiences the same preferred term multiple times, then the event will be counted 
only once and by greatest severity.
All deaths and reasons for death will be summarized. Death within 90 days after the last dose of 
durvalumab will be summarized separately. 
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Clinical laboratory values will be graded according to NCI CTC version 4.03 or higher for 
applicable tests. Baseline grade and worst grade during treatment for selected laboratory results 
will be summarized. Shift from baseline to the worst grade observed during the treatment for 
selected laboratory results will also be provided. For vital signs, shift from baseline to worst 
during the treatment in below, within, and above the normal ranges will be displayed in cross–
tabulations. Summary statistics (N, Mean, Standard Deviation, Median, Minimum, and 
Maximum) of observed and change from baseline values will be presented.
The overall ECG interpretation will be summarized by presenting the number and percentage of 
subjects with ‘Normal’, ‘Abnormal, not clinically significant’ and ‘Abnormal, clinically 
significant’ readings. Shift from baseline to worsen status during the treatment in the overall 
ECG interpretation will be displayed in cross–tabulations.
Graphical displays will be provided where useful to assist in the interpretation of results.
9.10.
Interim Analysis
There is no interim analysis for this study.
9.11.
Other Topics
9.11.1.
Pharmacokinetic Analysis
Noncompartmental PK parameters such as Tmax, Cmax, and AUC will be estimated from the 
plasma durvalumab and lenalidomide concentration-time profile. All concentration data and PK 
parameters will be summarized descriptively. The relationship between exposure and response 
(eg, toxicity and biomarkers) may be explored if appropriate.
 
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10.
ADVERSE EVENTS
10.1.
Monitoring, Recording, and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE. A diagnosis or syndrome should be recorded on 
the AE page of the eCRF rather than the individual signs or symptoms of the diagnosis or 
syndrome. 
Abuse, withdrawal, sensitivity, or toxicity to an IP 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 eCRF. (See Section 7.2.3 for the definition of overdose.) Any sequela of an accidental 
or intentional overdose of an IP should be reported as an AE on the AE eCRF. If the sequelae of 
an overdose is an SAE, then the sequelae must be reported on an SAE report form and on the AE 
eCRF. The overdose resulting in the SAE should be identified as the cause of the event on the 
SAE report form and eCRF 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, LEN, or 
dex overdose. Actual treatment should depend on the severity of the clinical situation and the 
judgment and experience of the treating physician.
All subjects will be monitored for AEs during the study. Assessments may include monitoring of 
any or all of the following parameters: the subject’s clinical symptoms, laboratory, pathological, 
radiological, or surgical findings, physical examination findings, or findings from other tests 
and/or procedures.
All AEs will be recorded by the investigator from the time the subject signs informed consent 
until 90 days after the last dose of durvalumab, as well as those SAEs made known to the 
investigator at any time thereafter that are suspected of being related to study IPs (durvalumab, 
LEN, dex). Adverse events and SAEs will be recorded on the AE page of the eCRF 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.
10.2.
Evaluation of Adverse Events
A qualified investigator will evaluate all adverse events 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);
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
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);

Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);

Is a congenital anomaly/birth defect;

Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Events not considered to be SAEs are hospitalizations for:

a standard procedure for protocol therapy administration.  However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE. 

routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.

the administration of blood or platelet transfusion as routine treatment of studied 
indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.

a procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling). However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable 
SAE.

hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.

a procedure that is planned (ie, planned prior to start of treatment on study); must be 
documented in the source document and the eCRF. Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.

an elective treatment of or an elective procedure for a pre-existing condition, 
unrelated to the studied indication, that has not worsened from baseline. 

emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the eCRF and the SAE Report Form 
must be completed.
For each SAE, the investigator will provide information on severity, start and stop dates, 
relationship the study IPs (durvalumab, LEN, dex), action taken regarding the study IPs 
(durvalumab, LEN, dex), and outcome.
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10.2.2.
Severity/Intensity
For both AEs and SAEs, the investigator must assess the severity/ intensity of the event. 
The severity/intensity of AEs will be graded based upon the subject’s symptoms according to the 
current active minor version of the Common Terminology Criteria for Adverse Events (CTCAE, 
Version 4.03 or higher); 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40
AEs that are not defined in the CTCAE should be evaluated for severity/intensity according to 
the following scale:

Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required

Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required

Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible

Grade 4 = Life-threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable

Grade 5 = Death – the event results in death
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.  
Seriousness, not severity, serves as a guide for defining regulatory obligations.
10.2.3.
Causality
The investigator must determine the relationship between the administration of the study IPs 
(durvalumab, LEN, dex) 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 study IPs 
(durvalumab, LEN, dex) 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 study 
IPs (durvalumab, LEN, dex) caused the adverse event.  
‘Reasonable possibility’ means there is evidence to suggest a 
causal relationship between the study IPs (durvalumab, LEN, 
dex) and the adverse event.
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Causality should be assessed and provided for every AE/SAE based on currently available 
information. Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional 
treatment 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 study IPs (durvalumab, LEN, dex) 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 study IPs (durvalumab, LEN, dex)
dose, or any other therapeutic intervention; or

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 eCRF. If the abnormality was not 
a part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. 
If possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets).
10.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject of childbearing 
potential or partner of childbearing potential of a male subject are immediately reportable events.
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The exposure of any pregnant female (eg, caregiver, pharmacist, study coordinator or monitor) to 
lenalidomide is also an immediately reportable event.
10.4.1.
Females of Childbearing Potential:
Pregnancies and suspected pregnancies (including elevated β-hCG or positive pregnancy test in a 
female subject of childbearing potential regardless of disease state) occurring while the subject is 
on study treatment, or within 90 days after last dose of durvalumab are considered immediately 
reportable events. Investigational product is to be discontinued immediately and the subject 
instructed to return any unused portion of the study IPs 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 monitor 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 the study IPs (durvalumab, LEN, or dex) should also be 
reported to Celgene Drug Safety by facsimile, or other appropriate method, within 24 hours of 
the investigator’s knowledge of the event using the SAE Report Form, or approved equivalent 
form.
10.4.2.
Male Subjects
If a female partner of a male subject taking study IPs (durvalumab, LEN, or dex) becomes 
pregnant, the male subject taking study IPs (durvalumab, LEN, or dex) should notify the 
investigator, and the pregnant female partner should be advised to call her 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 eCRF. 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 the study IPs) that occur during the 
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study (from the time the subject signs informed consent until 90 days after the last dose of 
durvalumab) or any SAE made known to the investigator at any time thereafter that are 
suspected of being related to the study IPs (durvalumab, LEN, dex). Serious adverse events 
occurring prior to treatment (after signing the ICF) will be captured.
The SAE report should provide a detailed description of the SAE and include a concise summary 
of hospital records and other relevant documents. If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
Safety as soon as these become available. Any follow-up data should be detailed in a subsequent 
SAE Report Form, or approved equivalent form, and sent to Celgene Drug Safety.
Where required by local legislation, the investigator is responsible for informing the Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event. The investigator must keep copies of all SAE 
information on file including correspondence with Celgene and the IRB/EC.
10.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail. The response time is expected to be no more than five (5) business 
days. Urgent queries (eg, missing causality assessment) may be handled by phone.
10.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to durvalumab and lenalidomide based on the Investigator 
Brochure (IB).
In the United States, 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, 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 dexamethasone based on the EU Summary 
of Product Characteristics (SmPC).
Celgene or its authorized representative shall notify the investigator of the following 
information:

Any AE suspected of being related to the use of study IPs (durvalumab, LEN, or dex)
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.
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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).
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.
10.7.
Adverse Events of Special Interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or non-serious. The 
rapid reporting of AESIs allows ongoing surveillance of these events in order to characterize and 
understand them in association with the use of this investigational product.
Further information on risks (eg, presenting symptoms) can be found in the current version of the 
Investigator Brochure including guidelines for their evaluation and treatment.
10.7.1.
Second PrimaryMalignancies (SPMs)
Second primary malignancies will be monitored as events of interest and must be reported as 
serious adverse events regardless of the treatment Cohort the subject is in (see Section 10.5).  
This includes any second primary malignancy, regardless of causal relationship to IPs (study 
drugs or control), occurring at any time for the duration of the study, from the time of signing the 
ICD for at least 5 years after the last subject is enrolled into the study.  Events of second primary 
malignancy are to be reported using the SAE report form and must be considered “Important 
Medical Events” if no other serious criteria apply; these events must also be documented in the 
appropriate page(s) of the eCRF (ie, AE and SPM eCRF) 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.). Data entry into the clinical database will continue until 15 Dec 2019. 
After this date the occurrence of SPMs will continue to be monitored, and any events will 
continue to be recorded in the subject’s source documents and reported to Celgene Drug Safety.
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11.
DISCONTINUATIONS
11.1.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the IP(s):

Progressive Disease

Adverse Event

Withdrawal by subject

Death

Lost to follow-up

Other (to be specified on the eCRF)
The reason for discontinuation of treatment should be recorded in the eCRF and in the source 
documents.
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor. However, prior to discontinuing 
a subject, the investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion.
11.2.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
study:

Completion of Study

Screen failure

Withdrawal by subject

Death

Lost to follow-up

Other (to be specified on the eCRF)
The reason for study discontinuation should be recorded in the eCRF and in the source 
documents.
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12.
EMERGENCY PROCEDURES
12.1.
Emergency Contact
In emergency situations, the investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page). This global 
Emergency Call Center is available 24 hours a day and 7 days a week. The representatives are 
responsible for obtaining your call-back information and contacting the on-call Celgene/contract 
research organization Medical Monitor, who will then contact you promptly.
Note: The back-up 24-hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls. 
12.2.
Emergency Identification of Investigational Products
This is an open-label study; therefore, IP will be identified on the package labeling. 
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13.
REGULATORY CONSIDERATIONS
13.1.
Good Clinical Practice
The study will be conducted in compliance with International Council for Harmonisation (ICH) 
Good Clinical Practices (GCPs).
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative, 
and investigator abide by Good Clinical Practice (GCP), as described in ICH Guideline E6 and in 
accordance with the general ethical principles outlined in the Declaration of Helsinki. The study 
will receive approval from an IRB/EC prior to commencement. The investigator will conduct all 
aspects of this study in accordance with applicable national, state, and local laws of the pertinent 
regulatory authorities.
13.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations. Celgene staff or an authorized representative will evaluate and approve all 
investigators who in turn will select their staff.
The investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of Celgene information. The investigator should maintain 
a list of Sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
The investigator is responsible for keeping a record of all subjects who sign an informed consent 
form (ICF) and are screened for entry into the study.  Subjects who fail screening must have the 
reason(s) recorded in the subject’s source documents.
The investigator, or a designated member of the investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification. The investigator must ensure timely and accurate completion of eCRFs 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.
Approved
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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.
The 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 AEs 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.
Approved
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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 IP 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.
14.2.
Data Management
Data will be collected via eCRF and entered into the clinical database per Celgene standard 
operation procedures (SOPs). This data will be electronically verified through use of 
programmed edit checks specified by the clinical team. Discrepancies in the data will be brought 
to the attention of the clinical team, and investigational site personnel, if necessary. Resolutions 
to these issues will be reflected in the database. An audit trail within the system will track all
changes made to the data.
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;

Record of any body fluids or tissue samples retained;

All other source documents (subject records, hospital records, laboratory records, 
etc); 
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
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, eCRFs, 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, eCRFs, 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 eCRFs 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 eCRFs 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 GCP guidelines and 
regulations.
The investigator is required to permit direct access to the facilities where the study took place, 
source documents, eCRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (eg, FDA, EMA, and Health Canada) 
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 13.4 all protocol- and amendment-related information, with the 
exception of the information provided by Celgene on public registry websites, is considered 
Celgene confidential information and is not to be used in any publications. Celgene protocol-
related information proposed for use in a publication must be submitted to Celgene for review 
and approval, and should not be utilized in a publication without express written approval from 
Celgene, or as described in the Clinical Trial Agreement.
Celgene will ensure Celgene-sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results. At a minimum, this applies to 
results from all Phase 3 clinical studies, and any other study results of significant medical 
importance. This also includes results relating to investigational medicines whose development 
programs have been discontinued.
Study results may also be presented at one or more medical congresses, and may be used for 
scientific exchange and teaching purposes. Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.
Eligibility for external authorship, as well as selection of first authorship, will be based on 
several considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable) and contribution to abstract, presentation and/or publication development.
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17.
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18.
APPENDICES
Appendix A: Table of Abbreviations
Abbreviation or 
Specialist Term
Explanation
ADA
Anti-drug antibody
ADL
Activity of daily life
AE
Adverse event
ALT
Alanine aminotransferase (SGPT)
AESI
Adverse event of special interest
ANC
Absolute neutrophil count
ASCT
Autologous stem cell transplantation
AST
Aspartate aminotransferase (SGOT)
AUC
Area under the plasma concentration-time curve
β-hCG
β-subunit of human chorionic gonadotropin
CBC
Complete blood count
CD
cluster of differentiation
Cmax
Maximum plasma concentration of drug
CR
Complete response
CrCl
Creatinine clearance
CRF
Case report form
CRP
Clinical Research Physician
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
Circulating tumor deoxyribonucleic acid
dex
Dexamethasone
DLT
Dose-limiting toxicity
DOR
Duration of response
DRT
Dose Review Team
DUR
Durvalumab (MEDI4736)
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EMP
Extramedullary plasmacytoma
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Abbreviation or 
Specialist Term
Explanation
EOT
End of treatment
Fc
Fragment crystallizable 
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIV
Human immunodeficiency virus
ICF
Informed consent form
ICH
International Council for Harmonisation
IND
Investigational New Drug
IP
Investigational Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ILD
Interstitial lung disease 
irAE
Immune-related adverse event
IV
Intravenous
LEN
lenalidomide
mAb
Monoclonal anti-body
MedDRA
Medical Dictionary for Regulatory Activities
MM
Multiple myeloma
MRD
Minimal residual disease
MRI
Magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NDMM
Newly diagnosed multiple myeloma
ORR
Overall response rate
OS
Overall survival
PD
Progressive disease
Pd
Pharmacodynamic(s)
PD-1
Programmed Cell Death 1
PD-L1
Programmed Cell Death Ligand 1
PD-L2
Programmed Cell Death Ligand 2
PFS
Progression-free survival
Approved
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EDMS Doc. Number: 24328540 - 20680025
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Abbreviation or 
Specialist Term
Explanation
PK
Pharmacokinetic(s)
PR
Partial response
Q4W, Q3W, Q2W
Every 4 weeks; every 3 weeks; every 2 weeks
RBC
Red blood cell count
RIR
Response improvement rate
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Steering committee
sCR
Stringent complete response
SD
Stable disease
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SOP
Standard operating procedure
SPM
Second primary malignancy
SUSAR
Suspected unexpected serious adverse reaction
t1/2
Terminal elimination half-life
TILs
Tumor-infiltrating lymphocytes 
TNE
Transplant non-eligible 
ULN
Upper limit of normal
US/USA
United States of America
VGPR
Very Good Partial Response 
Approved
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Approved
2.0
v


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
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101
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Appendix B: International Myeloma Working Group Uniform Response 
Criteria
Response Category
a
Response Criteria
Stringent Complete 
Response (sCR)
CR as defined below, plus
Normal free light-chain (FLC) ratio and
Absence of clonal plasma cells by immunohistochemistry or 2- to 4-color 
flow cytometry
Complete Response 
(CR)
Negative immunofixation of serum and urine and
Disappearance of any soft tissue plasmacytomas and
≤ 5% plasma cells in bone marrow
In patients in whom the only measurable disease is by serum FLC levels: 
CR in such patients indicates a normal FLC ratio of 0.26 to 1.65 in 
addition to CR criteria listed above. 
Very Good Partial 
Response (VGPR)
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or
90% or greater reduction in serum M-protein plus urine M-protein level 
<100 mg per 24 hours
In patients in whom the only measurable disease is by serum FLC levels: 
VGPR in such patients requires a > 90% decrease in the difference 
between involved and uninvolved FLC levels.
Partial Response (PR)
≥ 50% reduction of serum M-Protein and reduction in 24-hour urinary M-
protein by ≥ 90% or to < 200 mg per 24 hours
If the serum and urine M-protein are not measurable, a ≥ 50% decrease in 
the difference between involved and uninvolved FLC levels is required in 
place of the M-protein criteria.
If serum and urine M-protein are unmeasurable, and the serum free light 
assay is also unmeasurable, ≥ 50% reduction in plasma cells is required in 
place of M-protein, provided baseline bone marrow plasma cell 
percentage was ≥ 30%
In addition to the above, if present at baseline a ≥ 50% reduction in the 
size of soft tissue plasmacytomas is also required.
Stable Disease (SD)
Not meeting criteria for CR, VGPR, PR, or progressive disease
Approved
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Approved
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EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
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MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Response Category
a
Response Criteria
Progressive disease
Requires only one of the following:
Increase of 25% from lowest response value in any of the 
following:

Serum M-component (absolute increase must be ≥ 0.5 g/dL), 
and/or

Urine M-component (absolute increase must be ≥ 200 mg/24 h), 
and/or
Only in patients without measurable serum and urine M-protein levels: the 
difference between involved and uninvolved FLC levels (absolute 
increase must be ≥ 10 mg/dL)
Only in patients without measurable serum and urine M protein levels and 
without measurable disease by FLC levels, bone marrow plasma cell 
percentage (absolute percentage must be ≥ 10%)
Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas
Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL) 
that can be attributed solely to the plasma cell proliferative disorder
Additional Response Criteria
Molecular Complete 
Response
CR plus negative allele-specific oligonucleotide polymerase chain 
reaction (ASO-PCR), sensitivity 10-5
Immunophenotypic 
Complete Response 
Stringent CR plus
Absence of phenotypically aberrant plasma cells (clonal) in BM with a 
minimum of 1 million total BM cells analyzed by multiparametric flow 
cytometry (with > 4 colors)
Minimal Response (MR)
in patients with relapsed 
refractory myeloma 
adopted from the European 
Group for Blood and 
Marrow Transplantation 
(EBMT) criteria
≥ 25% but ≤ 49% reduction of serum M-protein and reduction in 24-hour 
urine M-protein by 50%-89%
In addition to the above criteria, if present at baseline, 25%-49% 
reduction in the size of soft tissue plasmacytomas is also required
No increase in size or number of lytic bone lesions (development of 
compression fracture does not exclude response)
a All response categories (CR, sCR, VGPR, PR, and PD) require 2 consecutive assessments made at any time before 
the institution of any new therapy; CR, sCR, VGPR, PR, and SD categories also require no known evidence of 
progressive or new bone lesions if radiographic studies were performed. VGPR and CR categories require serum 
and urine studies regardless of whether disease at baseline was measurable on serum, urine, both, or neither. 
Radiographic studies are not required to satisfy these response requirements. Bone marrow assessments need not 
be confirmed. For PD, serum M-component increases of more than or equal to 1 g/dL are sufficient to define 
relapse if the starting M-component is ≥ 5 g/dL.
Source:  Adapted from Rajkumar, 2011
Approved
5.0
v
Approved
2.0
v


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
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Confidential and Proprietary
103
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Appendix C: ECOG Performance Status 
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
Source: Oken, 1982
Eastern Cooperative Oncology Group, Robert Comis, MD, Group Chair.
Approved
5.0
v
Approved
2.0
v


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
104
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Appendix D: Durvalumab Treatment Modification and Toxicity Management Guidelines
Note: The toxicity management guidelines in Appendix D-1, D-2, and D-3 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.
Appendix D-1:
Durvalumab Treatment Modification and Toxicity Management Guidelines for Immune-related Adverse 
Events
Dose Modifications
Toxicity Management
Immune-related 
Adverse Events 
(Overall 
Management 
For toxicities 
not noted below)
Drug administration modifications of durvalumab will be made to 
manage potential immune-related AEs based on severity of 
treatment-emergent toxicities graded per NCI CTCAE v4.03.
In addition to the criteria for permanent discontinuation of 
durvalumab based on CTC grade/severity (table below) , 
permanently discontinue durvalumab 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 durvalumab

Recurrence of a previously experienced Grade 3 treatment-
related AE following resumption of dosing.
It is recommended that management of irAEs follow the guidelines 
presented in this table

Patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression, concomitant 
medications, infections, etc.)

In the absence of a clear alternative etiology, all events should 
be considered potentially immune related

Symptomatic and topical therapy should be considered for 
low-grade (Grade 1 or 2, unless otherwise specified) events 

For persistent (greater than 3 to 5 days) low-grade (Grade 2)  
or severe (Grade ≥3) events  promptly start prednisone 1-2
mg/kg/day PO or IV equivalent 

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 or IV equivalent])   until 
stabilization or improvement of symptoms, then resume 
corticosteroid tapering at a slower rate(> 28 days of taper)

More potent immunosuppressives such as TNF inhibitors (eg,
infliximab) – (also refer to the individual sections of the 
immune related adverse event for specific type of 
immunosuppressive) should be considered for events not 
responding to systemic steroids  

Discontinuation of durvalumab is not mandated for Grade 3 / 
Grade 4 inflammatory reactions attributed to local tumour 
response (eg, inflammatory reaction at sites of metastatic 
disease, lymph nodes etc.). Continuation of durvalumab in this 
Grade 1      No dose modification
Grade 2      Hold study drug/study regimen dose until Grade 2 
resolution to ≤Grade 1

If toxicity worsens then treat as Grade 3 or Grade 4
Study drug/study treatment can be resumed once event
stabilizes to Grade ≤ 1 after completion of steroid taper
Patients with endocrinopathies who may require 
prolonged or   continued steroid replacement can be 
retreated with durvalumab 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, and 3) doses 
of prednisone are at less than or equal to 10 mg/day or 
equivalent.
Approved
5.0
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Approved
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EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
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MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Dose Modifications
Toxicity Management
Grade 3   Depending on the individual toxicity, may permanently  
discontinue durvalumab. Please refer to guidelines 
below
situation should be based upon a benefit/risk analysis for that 
patient 
Grade 4    Permanently discontinue durvalumab
Note:  For Grade 3 and above asymptomatic amylase or lipase 
levels hold durvalumab and if complete work up shows no 
evidence of pancreatitis, may continue or resume durvalumab
Grade of the Event 
(NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Pneumonitis/ILD
Grade of 
Pneumonitis 
(CTCAE version 
4.03) 
General Guidance

Monitor patients for signs and symptoms of pneumonitis or 
ILD (new onset or worsening shortness of breath or cough).  
Patients should be evaluated with imaging and pulmonary 
function tests including other diagnostic procedures as 
described below

Initial work-up may include clinical evaluation, monitoring of 
oxygenation via pulse oximetry (resting and exertion), 
laboratory work-up and high-resolution CT scan 
Grade 1 
(Asymptomatic, 
clinical or diagnostic 
observations only, 
intervention not 
indicated)
No dose modification required. However, 
consider holding study drug/study 
regimen dosing as clinically appropriate 
and during diagnostic work-up for other 
etiologies
For Grade 1 (Radiographic Changes Only)

Monitor and closely follow up in 2-4 days for clinical 
symptoms, pulse oximetry (resting and exertion) and 
laboratory work-up and then as clinically indicated

Consider pulmonary and infectious disease consult
Grade 2 
(Symptomatic, 
medical intervention 
indicated, limiting 
instrumental ADL) 
Hold study drug/study regimen dose until 
Grade 2 resolution to ≤ Grade 1

If  toxicity worsens then treat as 
Grade 3 or Grade 4 

If toxicity improves to ≤ Grade 1, 
then the decision to reinitiate 
durvalumab will be based upon 
treating physician’s clinical 
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
Approved
5.0
v
Approved
2.0
v


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
106
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Grade of the Event 
(NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
judgment and after completion of 
steroid taper. 

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 
methylprednisone at 2-4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(eg,infliximab at 5 mg/kg every 2 weeks). 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 PCP 
treatment (refer to current NCCN guidelines for treatment of  
cancer-related infections (Category 2B recommendation)
ab

Consider pulmonary and infectious disease consult

Consider as necessary discussing with study physician
Grade 3 or 4 
(Grade 3: Severe 
symptoms; limiting 
self-care ADL; 
oxygen indicated; 
Grade 4: life 
threatening 
respiratory 
compromise, urgent 
intervention 
indicated [e.g. 
tracheostomy or 
intubation]) 
Permanently discontinue study drug/ 
study regimen
For Grade 3 or 4 (severe or new symptoms, new/worsening hypoxia, 
life threatening 

Promptly initiate empiric IV methylprednisolone 1 to 4 
mg/kg/day or equivalent

Obtain pulmonary and infectious disease consult

Hospitalize the patient

Supportive Care (oxygen, etc.)

If no improvement within 3-5 days, additional workup should 
be considered and prompt treatment with additional 
immunosuppressive therapy such as TNF 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 

Once improving, gradually taper steroids over ≥28 days and 
consider prophylactic antibiotics, antifungals and in particular, 
anti PCP treatment (please refer to current NCCN guidelines 
for treatment of  cancer-related infections (Category 2B 
recommendation)a, b
Approved
5.0
v
Approved
2.0
v


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
107
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Grade of the Event 
(NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Diarrhea/ 
Enterocolitis
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)

Patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression, other 
medications, infections including testing for clostridium 
difficile toxin, etc.)

Steroids should be considered in the absence of clear 
alternative etiology, even for low grade events, in order to 
prevent potential progression to higher grade event

Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis
Grade 1 diarrhea  
(stool frequency of 
<4 over baseline per 
day) 
No dose modification
For Grade 1 diarrhea: 

Close monitoring for worsening symptoms

Consider symptomatic treatment including hydration, 
electrolyte replacement, dietary changes (eg, American 
Dietetic Association colitis diet), and loperamide. Use of 
probiotics as per treating physician’s clinical judgment
Grade 2 diarrhea 
(stool frequency of 4-
6 over baseline per 
day) 
Hold study drug/study regimen until 
resolution to ≤ Grade 1

If toxicity worsens then treat as 
Grade 3 or Grade 4
If toxicity improves to ≤ Grade 1 then 
study drug/study regimen can be resumed 
after completion of steroid taper   
For Grade 2 diarrhea: 

Consider symptomatic treatment including hydration, 
electrolyte replacement, dietary changes (e.g., 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 
Approved
5.0
v
Approved
2.0
v


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
108
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Grade of the Event 
(NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
perforation, and prompt treatment with IV methylprednisolone 
2-4 mg/kg/day started. 

If still no improvement within 3-5 days despite 2-4 mg/kg IV 
methylprednisolone, promptly start immunosuppressives such 
as (infliximab at 5 mg/kg once every 2 weeksa). Caution: 
Important to rule out bowel perforation and refer to infliximab 
label for general guidance before using infliximab  

Consult study physician if no resolution to ≤ Grade 1 in 3-4 
days

Once improving, gradually taper steroids over ≥28 days and 
consider prophylactic antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation])
Grade 3 or 4 diarrhea 
(Grade 3: stool 
frequency of ≥7 over 
baseline per day; 
Grade 4: life 
threatening 
consequences)
Permanently discontinue study 
drug/study regimen
For Grade 3 or 4 diarrhea:

Promptly initiate empiric IV methylprednisolone 2 to 4 
mg/kg/day or equivalent

Monitor stool frequency and volume and maintain hydration  

Urgent GI consult and imaging and/or colonoscopy as 
appropriate

If still no improvement within 3-5 days of IV 
methylprednisolone 2 to 4 mg/kg/day or equivalent, promptly 
start further immunosuppressives (e. g. infliximab at 5 mg/kg 
once every 2 weeks) 

Caution: Ensure GI consult to rule out bowel perforation and 
refer to infliximab label for general guidance before using 
infliximab 

Once improving, gradually taper steroids over ≥28 days and 
consider prophylactic antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN guidelines for 
treatment of  cancer-related infections [Category 2B 
recommendation])
Approved
5.0
v
Approved
2.0
v


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
109
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Grade of the Event 
(NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Hepatitis 
(Elevated LFTs)
Infliximab 
should not be 
used for 
management of 
Immune 
Related
Hepatitis
Grade of Liver 
Function Test 
Elevation (CTCAE 
version 4.03)
Any Grade

Monitor and evaluate liver function test: AST, ALT, ALP and 
total bilirubin 

Evaluate for alternative etiologies (eg, viral hepatitis, disease 
progression, concomitant medications) 
Grade 1 
(AST or ALT > to 3 
times ULN and/or 
TB > to 1.5 times 
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 to 
5 times ULN and/or 
TB >1.5-3.0 times 
ULN)
Hold study drug/study regimen dose until 
Grade 2 resolution to ≤ Grade 1

If toxicity worsens then treat as 
Grade 3 or Grade 4
If improves to ≤ Grade 1 or baseline then 
resume study drug/study 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, discuss with study 
physician.

If event is persistent (> 3-5 days) or worsens, promptly start 
prednisone 1-2 mg/kg/day PO or IV equivalent. 

If still no improvement within 3-5 days despite 1-2 mg/kg/day 
of prednisone PO or IV equivalent, consider additional workup 
and prompt treatment with IV methylprednisolone 2-4
mg/kg/day started.

If still no improvement within 3-5 days despite 2-4 mg/kg/day 
of IV methylprednisolone, promptly start immunosuppressives 
(mycophenolate mofetil)a . Discuss with study physician if 
mycophenolate mofetil is not available.  Infliximab should 
NOT be used

Once improving, gradually taper steroids over ≥28 days and 
consider prophylactic antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation])
Approved
5.0
v
Approved
2.0
v


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
110
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Grade of the Event 
(NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Grade 3
(AST or ALT >5-20 
times ULN and/or 
TB > 3.0-10 times 
ULN
For elevations in transaminases ≤ 8 × 
ULN, or elevations in bilirubin ≤ 5 × 
ULN 

Hold durvalumab dose until 
resolution to ≤ Grade 1 or baseline  

Resume study drug/study regimen
if elevations downgrade ≤ Grade 1 
or baseline within 14 days and 
after completion of steroid taper
Permanently discontinue durvalumab if 
the elevations do not downgrade to ≤ 
Grade 1 or baseline within 14 days 
For elevations in transaminases > 8 × 
ULN or elevations in bilirubin > 5 × 
ULN, discontinue durvalumab
Permanently discontinue durvalumab 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 P04) 
and in the absence of any alternative 
cause
c
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 
(mycophenolate mofetil)  Discuss with study physician if 
mycophenolate is not available. Infliximab should NOT be 
used

Hepatology consult, abdominal workup, and imaging as
appropriate.

Once improving, gradually taper steroids over ≥28 days and 
consider prophylactic antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation])
Grade 4 
(AST or ALT > 20 
times ULN and/or 
TB > 10 times ULN) 
Permanently discontinue study 
drug/study regimen
Approved
5.0
v
Approved
2.0
v


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
111
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Grade of the Event 
(NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Nephritis or 
Renal 
Dysfunction 
(Elevated Serum 
Creatinine) 
Grade of Elevated 
Serum Creatinine 
(CTCAE version 
4.03)
Any Grade 
General Guidance

Consult with Nephrologist

Monitor for signs and symptoms that may be related to 
changes in renal function (eg, routine urinalysis, elevated 
serum BUN and creatinine, decreased creatinine clearance, 
electrolyte imbalance, decrease in urine output, proteinuria, 
etc) 

Patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression, infections etc.)

Steroids should be considered in the absence of clear 
alternative etiology even for low grade events (Grade 2), in 
order to prevent potential progression to higher grade event
Grade 1 [Serum
Creatinine > 1-1.5X 
baseline; > ULN to 
1.5X ULN]
No dose modification
For Grade 1 elevated creatinine: 

Monitor serum creatinine weekly and any accompanying 
symptom

If creatinine returns to baseline, resume its regular 
monitoring per study protocol.

If it worsens, depending on the severity, treat as Grade 2 or 
Grade 3 or 4 

Consider symptomatic treatment including hydration, 
electrolyte replacement, diuretics, etc
Grade 2 [Serum 
Creatinine>1.5-3.0X 
baseline; >1.5X-
3.0XULN]
Hold durvalumab until resolution to ≤ 
Grade 1 or baseline

If toxicity worsens then treat as 
Grade 3 or Grade 4
If toxicity improves to ≤ Grade 1 or 
baseline then resume study drug/study 
regimen after completion of steroid taper 
For Grade 2 elevated creatinine: 

Consider symptomatic treatment including hydration, 
electrolyte replacement, diuretics, etc. 

Carefully monitor serum creatinine every 2-3 days and as 
clinically warranted

Consult Nephrologist and consider renal biopsy if clinically 
indicated

If event is persistent (> 3-5 days) or worsens, promptly start  
prednisone 1 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, additional 
Approved
5.0
v
Approved
2.0
v


EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
112
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Grade of the Event 
(NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
workup should be considered and prompt treatment with IV 
methylprednisolone at 2-4 mg/kg/day started. 

Once improving gradually taper steroids over ≥28 days and 
consider prophylactic antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]) 

When event returns to baseline, resume durvalumab and 
routine serum creatinine monitoring per study protocol
Grade 3 or 4 
(Grade 3:  Serum 
Creatinine > 3.0 X 
baseline; >3.0-6.0 X 
ULN
Grade 4: Serum 
Creatinine > 6.0 X 
ULN) 
Permanently discontinue study 
drug/study regimen

Carefully monitor serum creatinine on daily basis

Consult Nephrologist and consider renal biopsy if clinically 
indicated

Promptly start prednisone 1 to 2 mg/kg/day or IV equivalent 

If event is not responsive within 3-5 days or worsens despite 
prednisone at 1-2 mg/kg/day or IV equivalent, additional 
workup should be considered and prompt treatment with IV 
methylprednisolone 2-4 mg/kg/day started. 

Once improving, gradually taper steroids over ≥28 days and 
consider prophylactic antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation] 
Rash (excluding 
Bullous skin 
formations)
Grade of Skin Rash 
(Please refer to 
NCICTCAE 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 STUDY 
PHYSICIAN SHOULD BE CONTACTED AND DURVALUMAB
DISCONTINUED**
Grade 1 
No dose modification
For Grade 1:
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Grade of the Event 
(NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management

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 study drug/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 study 
drug/study regimen after 
completion of steroid taper
For Grade 2:

Obtain dermatology consult 

Consider symptomatic treatment including oral antipruritics 
(eg, diphenhydramine or hydroxyzine) and topical therapy (eg, 
urea cream)

Consider moderate-strength topical steroid 

If no improvement of rash/skin lesions occurs within 3-5 days 
or is worsening despite symptomatic treatment and/or use of 
moderate strength topical steroid, discuss with study physician 
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
Grade 3
Hold durvalumab until resolution to ≤ 
Grade 1 or baseline
If temporarily holding the study 
drug/study regimen does not provide 
improvement of the Grade 3 skin rash to 
≤ Grade 1 or baseline within 30 days, 
then permanently discontinue study 
drug/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, antifungals and anti PCP 
treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation])

Discuss with Study Physician
Grade 4
Permanently discontinue study 
drug/study regimen
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Protocol MEDI4736-MM-002
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Confidential and Proprietary
114
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Grade of the Event 
(NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Endocrinopathy 
(eg, 
hyperthyroidism, 
hypothyroidism, 
hypopituitarism, 
adrenal 
insufficiency, 
etc.)
Any Grade 
(Depending on the 
type of 
endocrinopathy, refer 
to NCI CTCAE 
version 4.03 for 
defining the CTC 
Grade/severity) 
General Guidance

Consult Endocrinologist

Monitor patients for signs and symptoms of endocrinopathies.  
Non-specific symptoms include headache, fatigue, behavior 
changes, changed mental status, vertigo, abdominal pain, 
unusual bowel habits, hypotension and weakness.

Patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression including brain 
metastases, infections, etc.)

Monitor and evaluate thyroid function tests: TSH, free T3 and 
free T4 and other relevant endocrine labs depending on 
suspected endocrinopathy. 

If a patient experiences an AE that is thought to be possibly of 
autoimmune nature (eg, thyroiditis, pancreatitis, hypophysitis, 
diabetes insipidus), the investigator should send a blood 
sample for appropriate autoimmune antibody testing 
Grade 1
(Depending on the 
type of 
endocrinopathy, refer 
to NCI CTCAE 
version 4.03 for 
defining the CTC 
Grade 1)
No dose modification
For Grade 1: (including those with asymptomatic TSH elevation)

Monitor patient with appropriate endocrine function tests

If TSH < 0.5X LLN, or TSH >2X ULN or consistently out of 
range in 2 subsequent measurements, include FT4 at 
subsequent cycles as clinically indicated and consider 
endocrinology consult
Grade 2 
(Depending on the 
type of 
endocrinopathy, refer 
to NCI CTCAE 
version 4.03 for 
defining the CTC 
Grade/severity 2)
For Grade 2 endocrinopathy other than 
hypothyroidism, hold durvalumab dose 
until subject is clinically stable

If toxicity worsens then treat as 
Grade 3 or Grade 4 
Study drug/study regimen can be 
resumed once event stabilizes and after 
completion of steroid taper
Patients with endocrinopathies who may 
require prolonged or continued steroid 
For Grade 2: (including those with symptomatic endocrinopathy)

Isolated hypothyroidism may be treated with replacement 
therapy without treatment interruption and without 
corticosteroids

Initiate hormone replacement as needed for management

Evaluate endocrine function, and as clinically indicated, 
consider pituitary scan

For patients with abnormal endocrine work up, except for 
those with isolated hypothyroidism, consider short-term, 
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Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
115
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Grade of the Event 
(NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
replacement can be retreated with study 
drug/study regimen on the following 
conditions: 1) the event stabilizes and is 
controlled, 2) the patient is clinically 
stable as per investigator or treating 
physician’s clinical judgement, and 3) 
doses of prednisone are at less than or 
equal to 10 mg/day or equivalent.
corticosteroids (eg, 1-2 mg/kg/day methylprednisolone or IV 
equivalent) and prompt initiation of treatment with relevant 
hormone replacement (eg, Levothyroxine, hydrocortisone, or 
sex hormones) 

Once improving, gradually taper steroids over ≥28 days and 
consider prophylactic antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation])

For patients with normal endocrine work up (lab or MRI 
scans), repeat labs/MRI as clinically indicated
Grade 3 or 4
(Depending on the 
type of 
endocrinopathy, refer 
to NCI CTCAE 
version 4.03 for 
defining the CTC 
grade/severity 3 or 4) 
For Grade 3 or 4 endocrinopathy other 
than hypothyroidism, hold durvalumab
dose until endocrinopathy symptom(s) 
are controlled
Study drug/study regimen can be 
resumed once event stabilizes and after 
completion of steroid taper   
For Grade 3 or 4:

Consult endocrinologist

Isolated hypothyroidism may be treated with replacement 
therapy without treatment interruption and without 
corticosteroids

Promptly initiate empiric IV methylprednisolone 1 to 2 
mg/kg/day or equivalent

Administer hormone replacement therapy as necessary.

For adrenal crisis, severe dehydration, hypotension, or shock:
immediately initiate intravenous corticosteroids with 
mineralocorticoid activity

Once improving, gradually taper immunosuppressive steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals and anti PCP treatment (please refer to current 
NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation])

Discuss with study physician
Immune 
mediated 
Neurotoxicity (to 
include but not 
Grade of 
Neurotoxicity 
Depending on the 
type of neurotoxicity, 
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Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
116
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Grade of the Event 
(NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
limited to limbic 
encephalitis. 
autonomic 
neuropathy, 
excluding 
Myasthenia 
Gravis and 
Guillain-Barre)
refer to NCI CTCAE 
version 4.03 for 
defining the CTC 
grade/severity
Any Grade 
General Guidance

Patients should be evaluated to rule out any alternative 
etiology (eg, disease progression, infections, metabolic 
syndromes and medications, etc.) 

Monitor patient for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness)

Consider appropriate diagnostic testing (eg, electromyogram 
and nerve conduction investigations)

Symptomatic treatment with neurological consult as 
appropriate
Grade 1
No dose modifications
See “Any Grade” recommendations above.
Grade 2

For acute motor neuropathies or 
neurotoxicity, hold durvalumab
dose until resolution to ≤ Grade 1

For sensory 
neuropathy/neuropathic pain, 
consider holding durvalumab dose 
until resolution to ≤ Grade 1.

If toxicity worsens then treat 
as Grade 3 or Grade 4 

Study drug/study regimen can 
be resumed once event and
after completion of steroid 
taper     

Discuss with the study physician 

Obtain Neurology Consult 

Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (eg, gabapentin, duloxetine, etc.)

Promptly start systemic steroids prednisone 1-2 mg/kg/day PO 
or IV equivalent 

If no improvement within 3-5 days despite 1-2 mg/kg/day 
prednisone PO or IV equivalent consider additional workup 
and promptly treat with additional immunosuppressive therapy 
(eg, IVIG)
Grade 3

Hold study drug/study regimen
dose until resolution to ≤ Grade 1

Permanently discontinue 
durvalumab if Grade 3 irAE does 
For Grade 3 or 4:

Discuss with study physician

Obtain Neurology Consult
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EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
117
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Grade of the Event 
(NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
not resolve to ≤ Grade 1 within 30 
days.

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 
immunosuppressants (eg, IVIG) 

Once stable, gradually taper steroids over ≥28 days
Grade 4

Permanently discontinue study 
drug/study regimen
Immune-
mediated 
peripheral 
neuromotor 
syndromes, such 
as Guillain-Barre 
and Myasthenia 
Gravis
General Guidance

The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain patients may 
unpredictably experience acute decompensations which can 
result in substantial morbidity or in the worst case, death. 
Special care should be taken for certain sentinel symptoms 
which may predict a more severe outcome, such as prominent 
dysphagia, rapidly progressive weakness, and signs of 
respiratory insufficiency or autonomic instability

Patients should be evaluated to rule out any alternative 
etiology (eg, disease progression, infections, metabolic 
syndromes and medications, etc.). It should be noted that the 
diagnosis of immune-mediated peripheral neuromotor 
syndromes can be particularly challenging in patients with 
underlying cancer, due to the multiple potential confounding 
effects of cancer (and its treatments) throughout the neuraxis. 
Given the importance of prompt and accurate diagnosis, it is 
essential to have a low threshold to obtain a neurological 
consult

Neurophysiologic diagnostic testing (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 

Important to consider that the use of steroids as the primary 
treatment of Guillain-Barre is not typically considered 
effective. Patients requiring treatment should be started with 
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EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
118
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Grade of the Event 
(NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
IVIG and followed by plasmapheresis if not responsive to 
IVIG
Grade 1
No dose modification

Discuss with the study physician

Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described above

Obtain a neurology consult unless the symptoms are very 
minor and stable
Grade 2
Hold study drug/study regimen dose until 
resolution to ≤ Grade 1
Permanently discontinue study 
drug/study regimen if it does not resolve 
to ≤ Grade 1 within 30 days or if there 
are signs of respiratory insufficiency or 
autonomic instability
Grade 2 

Discuss with the study physician 

Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described above

Obtain a Neurology Consult 

Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (eg, gabapentin, duloxetine, etc.)
MYASTHENIA GRAVIS

Steroids may be successfully used to treat Myasthenia 
Gravis. Important to consider that steroid therapy 
(especially with high doses) may result in transient 
worsening of myasthenia and should typically be 
administered in a monitored setting under supervision of 
a consulting neurologist.

Patients unable to tolerate steroids may be candidates for 
treatment with plasmapheresis or IVIG. Such decisions 
are best made in consultation with a neurologist, taking 
into account the unique needs of each patient.

If Myasthenia Gravis-like neurotoxicity present, consider 
starting acetylcholine esterase (AChE) inhibitor therapy 
in addition to steroids. Such therapy, if successful, can 
also serve to reinforce the diagnosis.
GUILLAIN-BARRE: 

Important to consider here that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 
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EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
119
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Grade of the Event 
(NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
considered effective. Patients requiring treatment should 
be started with IVIG and followed by plasmapheresis if 
not responsive to IVIG.
Grade 3
Hold durvalumab dose until resolution to 
≤ Grade 1
Permanently discontinue study 
drug/study regimen if Grade 3 irAE does 
not resolve to ≤ Grade 1 within 30 days 
or if there are signs of respiratory 
insufficiency or autonomic instability
For severe or life threatening (Grade 3 or 4) events: 

Discuss with study physician

Recommend hospitalization

Monitor symptoms and obtain neurological consult
MYASTHENIA GRAVIS

Steroids may be successfully used to treat Myasthenia 
Gravis.  It should typically be administered in a 
monitored setting under supervision of a consulting 
neurologist.

Patients unable to tolerate steroids may be candidates for 
treatment with plasmapharesis or IVIG.

If Myasthenia Gravis-like neurotoxicity present, consider 
starting acetylcholine esterase (AChE) inhibitor therapy 
in addition to steroids. Such therapy, if successful, can 
also serve to reinforce the diagnosis.
GUILLAIN-BARRE: 

Important to consider here that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 
considered effective. Patients requiring treatment should 
be started with IVIG and followed by plasmapheresis if 
not responsive to IVIG
Grade 4
Permanently discontinue study 
drug/study regimen
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EDMS Doc. Number: 24328540 - 20680025
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
120
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Appendix D-2:
Durvalumab Treatment Modification and Toxicity Management Guidelines for Infusion-related Reactions
Infusion-Related Reactions
Severity Grade
of the Event 
(NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Any Grade

Management per institutional standard at the discretion of investigator

Monitor patients for signs and symptoms of infusion-related reactions 
(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, etc.)
Grade 1
The infusion rate of study drug/study regimen may be 
decreased by 50% or temporarily interrupted until 
resolution of the event
For Grade 1 or Grade 2:

Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator 

Consider premedication per institutional standard prior to subsequent 
doses

Steroids should not be used for routine premedication of ≤Grade 2 
infusion reaction
Grade 2
The infusion rate of study drug/study 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
Grade 3/4
Permanently discontinue study drug/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)
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Durvalumab (MEDI4736)
Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
121
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
Appendix D-3:
Durvalumab Treatment Modification and Toxicity Management Guidelines for Non-immune-mediated 
Reactions
Non-immune Mediated Reactions
Any event greater than or equal to Grade 2, please discuss with Study Physician
Severity Grade of 
the Event 
(NCI CTCAE 
version 4.03)
Dose Modification
Toxicity Management
Any Grade
Note: dose modifications are not required for adverse events not deemed to be related to 
study treatment (ie, events due to underlying disease) or for laboratory abnormalities not 
deemed to be clinically significant.
Treat accordingly as per institutional 
standard 
1
No dose adjustment 
Treat accordingly as per institutional 
standard 
2
Hold study drug/study regimen until resolution to ≤Grade 1 or baseline
Treat accordingly as per institutional 
standard 
3
Hold study drug/study regimen until resolution to ≤Grade 1 or baseline
For AEs that downgrade to ≤Grade 2 within 7 days or resolve to ≤Grade 1 or baseline 
within 14 days, resume study drug/study regimen administration. Otherwise, discontinue 
study drug/study regimen
Treat accordingly as per institutional 
standard 
4
Discontinue study drug/study regimen (Note for Grade 4 labs, decision to discontinue 
would be based on accompanying clinical signs/symptoms and as per investigator’s 
clinical judgment and in consultation with the sponsor) 
Treat accordingly as per institutional 
standard 
Abbreviations:
AChE = acetylcholine esterase; ADA = American Dietetic Association; ADL = activity of daily life; AE = adverse event; ALP = alkaline phosphatase; ALT = 
alanine aminotransferase; AST = aspartate aminotransferase; CT = computed tomography; GI = gastrointestinal; FDA = Food and Drug Administration;
IDS=Infectious Disease Service; ILD = interstitial lung disease; IM = intramuscular; irAE = immune-related adverse event; IV = intravenous; IVIG = 
intravenous immunoglobulin G; MRI = magnetic resonance imaging; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse 
Events; NCCN = National Comprehensive Cancer Network; PCP = Pneumocystis pneumonia; PO = by mouth; TB = tuberculosis; TNF = tumor necrosis 
factor; TSH = thyroid stimulating hormone; ULN = upper limit of normal.
a ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD 
b FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation, NCI CTCAE version 4.03
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Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
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EDMS Doc. Number: 24328540 - 20680025
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Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
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EDMS Doc. Number: 24328540 - 20680025
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Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
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EDMS Doc. Number: 24328540 - 20680025
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Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
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EDMS Doc. Number: 24328540 - 20680025
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Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
126
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
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EDMS Doc. Number: 24328540 - 20680025
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Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
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EDMS Doc. Number: 24328540 - 20680025
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Protocol MEDI4736-MM-002
Celgene
Confidential and Proprietary
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EDMS Doc. Number: 24328540 - 20680025
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: Monday, 30 December 2019, 10:47 AM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
 ================================================
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EDMS Doc. Number: 24328540 - 21147783
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
3
MEDI4736-MM-002 Amendment 3.0 Final: 05 Dec 2019
1.
JUSTIFICATION FOR AMENDMENT
The primary purpose of this Protocol Amendment 3.0 is to close the clinical database and set an 
end date for second primary malignancies (SPMs) data collection in the clinical database. The 
SPMs will then be recorded in subject’s source documents and reported to Celgene Drug Safety. 
There are no subjects in active treatment in this study. All remaining subjects are in the Follow-
up Period (safety follow-up). For these subjects, the end date for data collection in the clinical 
database has been set for 15 Dec 2019. After this date, all subjects who have received 
lenalidomide, and are in safety follow-up, will continue to be followed for SPMs, as required by 
regulatory obligations. However, after this date, any reports of SPMs will be collected in the 
Celgene safety database and recorded in subject’s source documents. 
Title Page (updated)
1. Contact Information updated.
Protocol Summary
2. Addition of Clinical Hold on the study
Section 3.2.3 (updated)
3. Includes the end date for data entry in the clinical database. In addition, the SPMs will be 
recorded in subject’s source documents and reported to Celgene Drug Safety.
Section 6.3.1 (updated)
4. Includes the end date for data entry in the clinical database. In addition, the SPMs will be 
recorded in subject’s source documents and reported to Celgene Drug Safety.
Section 10.7.1 (updated)
5. Includes the end date for data entry in the clinical database. In addition, the SPMs will be 
recorded in subject’s source documents and reported to Celgene Drug Safety. 
The amendment also includes one other minor edition:
Editorial update, Section 10.6 - For the purpose of regulatory reporting, Celgene Drug Safety 
determine the expectedness of events (including events of disease progression) suspected of 
being related to durvalumab and lenalidomide based on the Investigator Brochure (IB), and 
dexamethasone based on the SmPC. Events of disease progression, including deaths due to 
disease progression for indications that are considered to be fatal, will not be assessed as 
expected adverse events.
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EDMS Doc. Number: 21849473 - 21147783
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
3
MEDI4736-MM-002 Amendment 2.0 Final: 06 Apr 2017
1.
JUSTIFICATION FOR AMENDMENT
Updates, clarifications, and corrections included in this amendment are summarized 
below:

Update to the Medical Monitor/ Emergency Contact Information

Update to disease background with more recent data/references. (Section 1.1)

Additional information related to programmed death-ligand 1 (PD-L1) expression on 
tumor and infiltrating immune cells in the tumor microenvironment. It is predicted 
that patients with higher levels of PD-L1 in either tumor cells or immune cells will 
have more activation of the programmed death-1 (PD-1) pathway in the T-cells and 
will be more responsive to anti-PD-L1 therapy (Herbst, 2014, Higgs, 2015; Higgs, 
2016). (Section 1.3.5)

 
 

Clarification of the definition of high risk cytogenetic factors in Inclusion Criteria
(Section 4.2). Updated definition of high risk cytogenetic factor in Inclusion Criteria 
8 and 10 from 1q rearrangement to 1q amplification.

Clarification to thyroid function tests for thyroid stimulating hormone (TSH)
assessment to be done from Cycle 5 onward (Table of Events and Section 6.2).

Update to the pharmacokinetic windows to allow greater logistical flexibility 
(Sections 6.5.1 and6.5.2, and Table of Events)

Update to name of International Council for Harmonisation (ICH): Site Principle 
Investigator Signature Page, Section 13.1, and Appendix A).

Removal of Aiolos/Ikaros protein biomarker testing from the protocol (Protocol 
Summary, Section 1.3.5, Section 6.6, Table 3).  The Aiolos/Ikaros test implemented 
at Covance is being removed across the entire Celgene MEDI4736 Program in 
immunomodulatory drug combination patients. Cereblon, Aiolos, and Ikaros will still 
be analyzed by RNA Seq analysis.

Update to soluble factor biomarker collection timepoints (Section 6.6, Table 3).  
Removal of C1D8, C1D22 and C2D15 collections to align with MedImmune and 
minimize patient collections.

Inclusion of circulating tumor deoxyribonucleic acid (ctDNA) biomarker testing
language (Protocol Summary, Section 6.6). Addition of language covering ctDNA 
testing on plasma samples currently being collected for soluble factor testing is being 
implemented.  MedImmune and others are investigating the use of this platform for 
less invasive monitoring of disease response and patient stratification assays. This 
platform could be utilized for a diagnostic assay for follow-on programs.
Approved
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EDMS Doc. Number: 21849473 - 21147783
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
4
MEDI4736-MM-002 Amendment 2.0 Final: 06 Apr 2017

Update to collect TCR Clonality and neoantigens PBMC sample at C2D15 timepoint
(Section 6.6).  This sample will be used to compare matched bone marrow and blood 
sampling at the same timepoint in TCR Clonality and neoantigen analyses.  If the 
PBMC sample shows equivalency to the bone marrow sample this could lead to less 
invasive sample collection. 

Update to soluble PD-L1 (sPD-L1) testing timepoints (Section 6.6).  The removal of 
all timepoints, except Screening and predose C1D1. mirrors what is being 
implemented across the entire Celgene MEDI4736 Program.

Update to References (Section 17)

Update to Durvalumab Treatment Modification and Toxicity Management Guidelines
(Appendices D-1, D-2 and D-3)

Corrections of minor spelling/grammatical errors.
References: 
Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, et al. Predictive 
correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;
515:563-80.
Higgs BW, Robbins PB, Blake-Haskins JA, Morehouse C, Streicher K, Zhu W, et al. High
tumoral IFNγ mRNA, PD-L1 protein and combined IFNγ mRNA/PD-L1 protein expression
associates with response to durvalumab (anti-PD-L1) monotherapy in NSCLC patients [abstract].
ECCO-ESMO – The 18th ECCO - 40th ESMO European Cancer Congress: Reinforcing
multidisciplinary. 2015 Sep 25-29; Vienna, Austria: Abstract 15LBA.
Higgs BW, Morehouse CA, Streicher KL, Rebelatto MC, Steele K, Jin X, et al. Baseline tumoral 
IFNγ mRNA and PD-L1 protein expression associated with overall survival in durvalumab-
treated NSCLC patients [poster]. Poster presented at the American Society of Clinical Oncology 
(ASCO) Annual Meeting. 2016 Jun 3–7; Chicago, IL; USA: Poster 3036.
Approved
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Approved
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v


EDMS Doc. Number: 21147480 - 21147783
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-MM-002
Celgene
Confidential and Proprietary
3
MEDI4736-MM-002 Amendment 1.0 Final:  27 Jun 2016
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
The monitoring of blood pressure and other vital signs during and post durvalumab infusion 
beyond Cycle 2 was modified to enable the study site to follow institutional standard practice 
or as clinically indicated at discretion of the treating physician. As reported in Durvalumab 
(MEDI4736) Investigator’s Brochure version 9.0 dated 22Jan2016, in clinical studies with 
durvalumab as a monotherapy, the incidence of reported potential infusion-related reaction 
was low. In particular for the serious case reports of investigator assessed infusion-related 
reaction, 10 of 1,265 subjects treated with durvalumab in 5 sponsored monotherapy studies 
(CD-ON-MEDI4736-1108, D4190C00002, D4190C00007, D4191C00003, and 
D4193C00001) reported 14 cases of infusion-related reactions, giving an overall frequency 
of 0.8% (10/1,265). These events/reactions respond to antihistamine, drug 
interruption/withdrawal, decrease in infusion rate and supportive treatment. In addition, in 
the current ongoing MEDI4736-MM-001 study (durvalumab ± pomalidomide ± 
dexamethasone in relapsed and refractory multiple myeloma), as of 09Jun2016, no 
significant infusion reactions have been reported for the 21 subjects treated with either 
durvalumab monotherapy, durvalumab + pomalidomide, or durvalumab + pomalidomide + 
dexamethasone. (Section 5 footnote g and Section 7.2.1.1)
Minor clarifications and corrections are summarized below:

Update to Table of Events to permit urinalysis to be performed by local laboratory 
(Section 5, Table of Events)

Update to Section 3.2.2 and Table of Events to clarify that for the first 3 subjects of 
each cohort in the dose-finding portion, there will be at least a 24-hour observation 
period.  The 24 hour observation period should be communicated to the sponsor 
within 24 to 48 hours.  The report should include safety data (e.g., adverse event 
[AE], basic laboratory, and vital signs] to the sponsor before the dosing of the next 
subject occurs. (Section 3.2.2, and Section 5 footnote g)

Update to Treatment Period from the time of Interactive Response Technology (IRT) 
to allow registration up to 3 days prior to initiating study treatment on Cycle 1 Day 1 
(C1D1) (Section 6.2)

Update from durvalumab given in combination with lenalidomide with “or” without 
dexmethasone, to with “and” without dexamethasone for grammatical clarity (Study 
Design, Section 1.3.3.2, and Section 3.1)

Correction of minor spelling/grammatical errors (Section 6.4.3 and Section 8.2)

Update from “Celgene Corporation” to “Celgene” for administrative reasons (Section
7.1.3)
Approved
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SAP_001.pdf: 
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Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
A PHASE 1/2 MULTICENTER, OPEN-LABEL STUDY TO DETERMINE THE 
RECOMMENDED DOSE AND REGIMEN OF DURVALUMAB (MEDI4736) IN 
COMBINATION WITH LENALIDOMIDE (LEN) WITH AND WITHOUT 
DEXAMETHASONE (DEX) IN SUBJECTS WITH NEWLY DIAGNOSED MULTIPLE 
MYELOMA (NDMM)
STUDY DRUG:
MEDI4736 (durvalumab)
PROTOCOL NUMBER:
MEDI4736-MM-002
DATE FINAL:
12th March 2018
Prepared by:
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.
PPD
CELGENE PROPR
The
Th
a
EN
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EL
EL
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ed by:
ed by:
RIETARY INFORMATION
RIE


Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
2
TABLE OF CONTENTS
SIGNATURE PAGE...................................................................................................................6
1.
LIST OF ABBREVIATIONS...................................................................................8
2.
INTRODUCTION..................................................................................................11
3.
STUDY OBJECTIVES...........................................................................................12
3.1.
Primary Objective...................................................................................................12
3.2.
Secondary Objectives .............................................................................................12
4.
INVESTIGATIONAL PLAN .................................................................................13
4.1.
Overall Study Design and Plan ...............................................................................13
4.2.
Study Endpoints .....................................................................................................15
4.3.
Stratification, Randomization, and Blinding............................................................16
4.4.
Sample Size Determination.....................................................................................17
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................19
5.1.
Reporting Conventions ...........................................................................................19
5.1.1.
Descriptive Statistics ..............................................................................................19
5.2.
Analysis Populations ..............................................................................................19
5.2.1.
Full Analysis Population.........................................................................................19
5.2.2.
Safety Population....................................................................................................20
5.2.3.
Efficacy Evaluable Population................................................................................20
5.2.4.
Dose-determining Population..................................................................................20
5.2.5.
Pharmacokinetic Population....................................................................................20
5.2.6.
Grouping of Dose Level..........................................................................................20
5.3.
Definitions..............................................................................................................20
5.3.1.
Date of First Administration of Study Treatment ....................................................20
5.3.2.
Date of Last Administration of Study Treatment.....................................................21
5.3.3.
Study Day...............................................................................................................21
5.3.4.
Baseline..................................................................................................................21
6.
SUBJECT DISPOSITION......................................................................................22
7.
PROTOCOL DEVIATIONS/ IMPORTANT PROTOCOL DEVIATIONS ............23
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................24
8.1.
Demographics.........................................................................................................24
CCI
CELGENE PROPRIETARY INFORMATION
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RMA


Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
3
8.2.
Baseline Characteristics..........................................................................................24
8.3.
Baseline Symptoms ................................................................................................24
8.4.
Medical History......................................................................................................25
8.5.
Prior Radiation and/or Antimyeloma Therapy.........................................................25
8.6.
Prior and Concomitant Medications........................................................................25
8.6.1.
Prior Medications ...................................................................................................25
8.6.2.
Concomitant Medications .......................................................................................25
8.7.
Concomitant Procedures.........................................................................................25
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................27
9.1.
Treatment Duration.................................................................................................27
9.2.
Cumulative Dose ....................................................................................................28
9.3.
Dose Exposure........................................................................................................28
9.4.
Average Daily Dose................................................................................................29
9.5.
Dose Intensity.........................................................................................................29
9.6.
Relative Dose Intensity...........................................................................................29
9.7.
Dose Modifications.................................................................................................30
10.
EFFICACY ANALYSIS ........................................................................................31
11.
SAFETY ANALYSIS ............................................................................................34
11.1.
Dose-limiting Toxicity............................................................................................34
11.2.
Adverse Events.......................................................................................................34
11.3.
Adverse Events of Special Interest..........................................................................36
11.4.
Clinical Laboratory Evaluations..............................................................................38
11.6.
Vital Sign Measurements........................................................................................38
11.7.
Electrocardiograms.................................................................................................39
11.8.
Eastern Cooperative Oncology Group Performance Status......................................39
11.9.
Pharmacokinetic Analysis.......................................................................................39
CCI
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GENE PROPRIETARY INFORMATION
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Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
4
13.
INTERIM ANALYSIS...........................................................................................41
14.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF THE 
PROTOCOL...........................................................................................................42
15.
REFERENCES.......................................................................................................43
16.
APPENDICES........................................................................................................44
16.1.
Handling of Dates...................................................................................................44
16.1.1.
Calculation Using Dates .........................................................................................44
16.1.2.
Calculation of Cycles..............................................................................................45
16.2.
Date Imputation Guideline......................................................................................45
16.2.1.
Impute Missing Adverse Events/Prior or Concomitant Medications........................45
16.2.1.
Adverse Events.......................................................................................................47
16.2.2.
Prior/Concomitant Medications/Procedures ............................................................47
16.2.3.
Impute Missing Disease Diagnosis Dates................................................................47
CCI
CELGENE PROPRIETARY INFORMATION
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Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
5
LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................8
Table 2:
Study Endpoints .....................................................................................................15
Table 3:
Decision Operating Characteristics of Overall Response Rate with 40 
Subjects in the Expansion Dose for Cohort A and Cohort B....................................17
Table 4:
Decision Operating Characteristics of Response Improvement Rate with 
40 Subjects in the Expansion Dose for Cohort C.....................................................18
Table 5:
Number of Days to be Covered by the Last Dose....................................................28
Table 6:
Lenalidomide Dosing Guideline for Renal Insufficiency for Cohort A and 
Cohort B.................................................................................................................29
Table 7:
Censoring Rules for PFS and DoR..........................................................................33
CELGENE PROPRIETARY INFORMATION
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Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
8
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
AE
Adverse event
AESI
Adverse event of special interest
AUC
Area under the curve
BMI
Body mass index
CI
Confidence interval
CL/F
Clearance
Cmax
Maximum plasma concentration of drug
CR
Complete response
CrCl
Creatinine clearance
CRO
Contract research organization
CRF
Case report form
CTCAE
Common terminology criteria for adverse events
Dex
Dexamethasone
DLT
Dose-limiting toxicity
DOR
Duration of response
DRT
Dose Review Team
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EE
Efficacy evaluable
EOT
End of treatment
FDA
Food and Drug Administration
HRQoL
Health-related quality of life
ICF
Informed consent form
IMWG
International Myeloma Working Group
IPD
Important protocol deviation
IRT
Interactive response technology
IV
Intravenous
CELGENE PROPRIETARY INFORMATION
e events
e events
am
operative O
operative O
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Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
9
KM
Kaplan-Meier
LEN
Lenalidomide
Max
Maximum 
MDS
Myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
MR
Minimal response
MRD
Minimal residual disease
MTD
Maximum tolerated dose
NCI
National Cancer Institute
NDMM
Newly diagnosed multiple myeloma
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
PE
Pulmonary embolism
PFS
Progression-free survival
PK
Pharmacokinetics
PR
Partial response
PT
Preferred Term
RD
Recommended dose 
RIR
Response improvement rate
SAP
Statistical analysis plan
SAS®
Statistical Analysis System
SD
Stable disease
SOC
System Organ Class
CELGENE PROPRIETARY INFORMATION
and 1
and 1
th ligand 2
h ligand 2
olism
sm
-free surviv
free surv
acokinetics
okinetics
artial respon
artial resp
Preferred
Preferred
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Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
10
SPM
Second primary malignancy 
STD
Standard deviation
t1/2
Terminal elimination half-life
TEAE
Treatment-emergent adverse event
Tmax
Time to maximum concentration
TTR
Time to response 
VAS
Visual analogue scale
VGPR
Very good partial response 
VTE
Venous thromboembolism
Vz/F
Volume of distribution
WHO
World Health Organization
CELGENE PROPRIETARY INFORMATION


Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol MEDI4736-MM-002
Celgene Corporation
Confidential and Proprietary
11
2.
INTRODUCTION
The statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s 
protocol MEDI4736-MM-002 “A Phase 1/2, multicenter, open-label study to determine the 
recommended dose (RD) and regimen of durvalumab (MEDI4736) in combination with 
lenalidomide (LEN) with and without dexamethasone (dex) in subjects with newly diagnosed 
multiple myeloma (NDMM).” The SAP contains definitions of analysis populations, derived 
variables and statistical methods for the analysis of efficacy and safety.
Throughout this SAP, the treatment arms will be referred to as Arms A, B and C. 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 for the final analysis. This SAP 
will be finalized and signed prior to the clinical database lock for the final analysis. All statistical 
analyses detailed in this SAP will be conducted using Statistical Analysis System (SAS)®
Version 9.1 or higher.
Due to the full clinical hold placed by the Food and Drug Administration (FDA), the study will 
prematurely terminate and data collected up to 15th December 2017 (ie date of the last follow-up 
data point required per protocol) will be included in the final analysis. An additional analysis 
focused on overall survival and second primary malignancies will be also performed up to 5 
years after the last subject is enrolled into the study, as required per protocol.
se of 
e o
his SAP 
is SAP 
All statist
All statisti
m (SAS)
m (SAS)®
(FDA), the
(FDA), the
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be also p
ed per proto
ed per pro


Durvalumab (MEDI4736)
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Celgene Corporation
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3.
STUDY OBJECTIVES
3.1.
Primary Objective
The primary objective of the study is to determine the RD of durvalumab in combination with 
LEN with and without dex in subjects with NDMM.
3.2.
Secondary Objectives
The secondary objectives are to
!
evaluate the safety and preliminary efficacy of durvalumab in combination with LEN 
with and without dex in subjects with NDMM.
!
evaluate the pharmacokinetic(s) (PK) of durvalumab and LEN with and without dex in 
subjects with NDMM.
 
 
 
 
 
CCI
CELGENE PROPRIETARY INFORMATION
h LEN
h LEN
d without de
without 
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OP
PRO
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Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol MEDI4736-MM-002
Celgene Corporation
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4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
This is a multicenter, open-label, Phase 1/2 study to determine the RD and regimen of 
durvalumab in combination with LEN with or without dex in subjects with NDMM. The study 
will consist of a Dose-finding Phase and a Dose-expansion Phase to determine the optimal 
regimen.
Dose-finding Phase
The Dose-finding Phase will determine the RD and regimen of durvalumab in combination with 
LEN with or without dex in a 28-day treatment cycle.
Three treatment cohorts (A, B and C) will be enrolled in parallel:
Treatment Cohort A (for high risk transplant non-eligible [TNE] NDMM subjects)
!
Intravenous (IV) durvalumab at 1500 mg on Day 1 of a 28-day cycle, 
!
Oral LEN 25 mg/day (adjust per the creatinine clearance [CrCl] value, see details in 
Section 7.2.1.2 and Table 4 of the protocol) on Days 1 to 21 of each 28-day treatment 
cycle, 
!
Oral dex 40 mg/day (O 75 years old) or 20 mg/day (> 75 years old) on Days 1, 8, 15, and 
22 of each 28-day cycle.
Treatment Cohort B (for Q 65 years old TNE NDMM subjects who are not high risk)
!
Intravenous durvalumab at 1500 mg on Day 1 of a 28-day cycle, 
!
Oral LEN 25 mg/day (adjust per the creatinine clearance [CrCl] value, see details in 
Section 7.2.1.2 and Table 4 of the protocol) on Days 1 to 21 of each 28-day treatment 
cycle, 
!
Oral dex 40 mg/day (O 75 years old) or 20 mg/day (> 75 years old) on Days 1, 8, 15, and
22 of each 28-day cycle (for up to 12 cycles).
Treatment Cohort C (for high risk post-transplant NDMM subjects as maintenance)
!
Intravenous durvalumab at 1500 mg on Day 1 of a 28-day cycle, 
!
Oral LEN 10 mg/day on Days 1 to 21 of each 28-day treatment cycle.
All subjects on these 3 treatment cohorts will continue study treatment until progressive disease 
(PD) or unacceptable toxicity occurs, or withdrawal of consent.
Based on experience with durvalumab in other indications (solid tumors and myelodysplastic 
syndrome [MDS]), the initial dose of durvalumab will be at 1500 mg every treatment cycle for 
each cohort. In the event of dose-limiting toxicities (DLTs), the dose of durvalumab would be 
de-escalated to a 750 mg dose level. 
The Dose Review Team (DRT) are responsible for dosing decisions. The DRT members will 
consist of the following: Celgene medical monitor, Celgene lead safety physician, Celgene 
CELGENE PROPRIETARY INFORMATION
tion with 
tion with
MM subjects
MM subjec
cycle,
cycle,
rCl] value, 
rCl] valu
21 of each
21 of each
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Durvalumab (MEDI4736)
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Celgene Corporation
Confidential and Proprietary
14
biostatistician, other Celgene functional area representatives as appropriate, and site investigator 
and/or designees. 
Initially, 6 subjects will be enrolled into each cohort for DLT evaluation and will receive 1500 
mg durvalumab. The DLT evaluation period will be the first treatment cycle.
!
If O 1 of the 6 initial subjects experience a DLT within the first cycle, then the Dose-
expansion Phase may be initiated with durvalumab 1500 mg as the RD; 
!
If 2 or more of the 6 initial subjects experienced a DLT within the first cycle, then the 
maximum tolerated dose (MTD) has been exceeded and de-escalation to the durvalumab 
750 mg dose level after review of safety and PK/Pd of the initial 6 subjects by the DRT.
Any of the cohorts may be removed from the study based on emerging PK, Pd, efficacy or safety 
data.
Dose de-escalation will only occur after review of safety data (DLT), and possibly PK/Pd data by 
the DRT.
Dose-expansion Phase 
All dose-expansion decisions will be determined by the DRT after review of all safety, and if 
applicable PK/Pd, and/or biomarker, and/or preliminary efficacy data.
After all 6 subjects enrolled in the Dose-finding Phase have completed the Cycle 1 treatment; 
and all data are obtained and reviewed, additional eligible subjects (see detailed eligibility 
criteria on Sections 4.2 and 4.3 of the protocol) for each respective cohort may be enrolled. The 
total of subjects for each cohort can be expanded up to 40 (including the 6 subjects enrolled in 
the Dose-finding Phase and 34 in the expansion phase).
The expansion for each study cohort can occur independently.
Study Population
The study population is to include NDMM subjects who have measurable myeloma protein 
(M-protein) by protein electrophoresis analyses (in serum [SPEP] and/or urine [UPEP]) per 
International Myeloma Working Group (IMWG) criteria. 
Length of Study
The screening period will be within 28 days prior to start of Cycle 1. Eligible subjects will be 
treated in 28-day cycles and may continue study treatment until PD or unacceptable toxicity 
occurs. All subjects will have an end of treatment visit (EOT) within 7 days after discontinuation 
of all study treatment. Subjects are to return to the study site 28 + 3 days after the EOT visit and 
90 (+ 3) days after the last dose of durvalumab for safety follow-up visits. Occurrence of second 
primary malignancies (SPM) will continue to be monitored at the above required 90-day visit 
and then every 6 months up to 5 years after the last subject enrolled into the study. 
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 pre-specified in the protocol, 
whichever is the later date.
mab
mab
 DRT.
DRT.
acy or safet
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review of a
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subject
ch respecti
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phase).
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will be wit
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days after th
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The End o
The End o
post-tre
ost-tre


Durvalumab (MEDI4736)
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Celgene Corporation
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Study Treatments
Subjects will be assigned into different treatment cohorts based on the eligibility criteria.
For subjects in Cohort C, the study treatment is to be initiated at 100 days (± 14 days) after 
transplant. 
The initial dose of durvalumab will be at 1500 mg on Day 1 of a 28-day treatment cycle for all 
treatment cohorts.
The dose of LEN will be 25 mg (adjustable per the CrCl value, see details in Section 7.2.1.2 of 
the protocol) on Days 1 to 21 of each 28-day treatment cycle for treatment Cohort A and 
Cohort B. 
The dose of LEN will be 10 mg on Days 1 to 21 of each 28-day treatment cycle for treatment 
Cohort C.
The dose of dex will be 40 mg/day (O 75 years old) or 20 mg/day (> 75 years old) on Days 1, 8, 
15, and 22 of a 28-day cycle for treatment Cohort A and Cohort B (for up to 12 cycles).
4.2.
Study Endpoints
Table 2:
Study Endpoints
Endpoint
Name
Description
Primary 
Recommend dose
Review safety (including DLTs), and if applicable, PK/Pd, 
and/or biomarker, and/or preliminary efficacy data by 
DRT
Secondary 
Safety 
Type, frequency, seriousness and severity of adverse 
events (AEs) (included SPMs), and relationship of AEs to 
study treatment
Overall Response Rate 
(ORR)
(for Cohorts A and B)
Proportion of subjects who achieved partial response (PR)
or better according to the IMWG Uniform Response 
Criteria (Rajkumar, 2011)
Response Improvement 
Rate (RIR) (for 
Cohort C)
Proportion of subjects who achieve a response 
improvement from baseline according to the IMWG
Uniform Response Criteria.
(Pre-autologous stem cell transplantation [ASCT] diseases 
measurement will be used as baseline for response 
assessment)
Time to Response (TTR) 
(for Cohorts A and B)
Time from the first date of dosing of study medication to 
the first date of documented response (PR or better).
Duration of Response 
(DoR) (for Cohorts A 
and B)
Time from the first response (PR or better) to the first 
documentation of disease progression or death, whichever 
is earlier, based on the investigator assessments according 
to the IMWG Uniform Response Criteria
CELGENE PROP
ate
and B)
and B)
Prop
Pro
OPRIETARY INFORMATION
f 
treatment
treatment
s old) on Da
old) on D
to 12 cycle
to 12 cycle
RY
y (including
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marker, and
marker, an
AR
pe, frequenc
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Ti
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GE
GE
C


Durvalumab (MEDI4736)
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Celgene Corporation
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Endpoint
Name
Description
Pharmacokinetics
Typical serum/plasma PK parameters for durvalumab and 
LEN, such as maximum observed concentration (Cmax), 
area under the concentration-time curve (AUC), time to 
maximum concentration (Tmax), terminal elimination half-
life (t1/2), clearance (CL/F), and volume of distribution 
(Vz/F)
 
Progression-free 
Survival (PFS)
Time from first dose to disease progression, as determined 
by the investigator using the IMWG Uniform Response 
Criteria, or death during study treatment, whichever 
occurred earlier
Overall Survival (OS)
Time from first dose to death due to any cause
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Table 2 of the protocol MEDI4736-MM-002. 
4.3.
Stratification, Randomization, and Blinding
Subjects will be assigned to either Cohort A, B, or C based on the eligibility criteria and current 
available slots. Slots will be assigned on a first come-first serve basis and will be valid for 
48 hours following assignment. Unconfirmed eligibility following 48 hours from slot assignment 
may result in forfeiture and subsequent reassignment of the slot.
CCI
CCI
CELGENE PROPRIETARY INFORMATION
AT
termined 
mined
Response
Response
hichever 
hichever 
AT
AT
any cause
any cause
OR
FO
Y I
TA
PR
OP
RO
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GE
GE
LGE
e: Table 2 of
e: Table 2 o
4.3.
4.3.
bje
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NE
GE
G


Durvalumab (MEDI4736)
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Celgene Corporation
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Celgene trial staff will review specific eligibility criteria for all screened subjects prior to 
enrollment of subjects via the interactive response technology (IRT).
An IRT will be used to track subject assignments to the treatment cohorts and dose levels.
4.4.
Sample Size Determination
Up to 138 subjects are planned to be enrolled in the study, of which up to 36 in the 3 cohorts for 
dose finding and up to 102 in the 3 cohorts for expansion. The actual number of subjects for the 
study will depend on the number of dose levels being tested.
Phase I expansion dose sample size estimation for Cohort A and Cohort B
Table 3 shows the probability of observing an ORR Q 75% under different assumptions about the 
true ORR in this population. With a sample size of 40 subjects, this study has reasonable 
operating characteristics of observing an ORR Q 75% if the true ORR is 85% or higher.
Table 3:
Decision Operating Characteristics of Overall Response Rate with 40 
Subjects in the Expansion Dose for Cohort A and Cohort B 
True ORR
Probability of observing an ORR ; 75% with 
40 subjects (; 30 out of 40 subjects)
60%
3.5%
65%
12.1%
70%
30.9%
75%
50.4%
80%
83.9%
85%
97.0%
90%
99.9%
ORR = overall response rate.
Table 4 shows probability of observing a RIR Q 15% under different assumptions about the true 
RIR in this population. With a sample size of 40 subjects, this study has reasonable operating 
characteristics of observing an RIR Q 15% if the true RIR is 25% or higher.
CELGENE PROPRIETARY INFORMATION
ons about th
ons about t
sonable
nable
or higher.
r higher.
e Rate with
Rate with
hort B
hort B
ng an ORR 
g an ORR
30 out of 40
30 out of 40
IN
3.5%
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With a sa
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ving an RI


Durvalumab (MEDI4736)
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Celgene Corporation
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Phase I expansion dose sample size estimation for Cohort C
Table 4:
Decision Operating Characteristics of Response Improvement Rate with 
40 Subjects in the Expansion Dose for Cohort C
True ORR
Probability of observing a RIR ; 15% with 
40 subjects (; 6 out of 40 subjects)
5%
1.4%
10%
20.6%
15%
56.7%
20%
83.9%
25%
95.7%
30%
99.1%
35%
99.9%
ORR = overall response rate; RIR = response improvement rate.
CELGENE PROPRIETARY INFORMATION
MA
MA
MA
RM
OR
FO
NF


Durvalumab (MEDI4736)
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Celgene Corporation
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5.
GENERAL STATISTICAL CONSIDERATIONS
5.1.
Reporting Conventions
Summary tables, listings, and any supportive SAS output will include a “footer” of explanatory 
notes that will indicate, at a minimum, the program name and the data extraction date (eg, the 
database lock date, run date).
The purpose of the data extraction date is to link the output to a final database, either active or 
archived, that is write-protected for replication and future reference. An output date will also 
appear on each output page and will indicate the date the output was generated by the analysis 
program. Individual source listings will display all the relative values supporting corresponding 
table and figure.
In addition:
!
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 (CIs) will be presented as 2-sided 80% CIs unless specified 
differently in specific analysis;
!
All listings will be sorted for presentation in order of cohort, dose level, 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; 
!
For handling of dates please refer to 16.1.
5.1.1.
Descriptive Statistics
By default, descriptive statistics for continuous variable include: n, mean, standard deviation 
(STD), Q1 and Q3, median, minimum (Min), and maximum (Max). Unless specified in the 
actual table shells, the mean, median, Q1 and Q3 should be displayed to the one more decimal 
place than the original data (derived analysis data). Standard deviation should be displayed to the 
two more decimal places than the original data (derived analysis data). The minimum and 
maximum should be displayed to the same number of decimal places as the original data.
5.2.
Analysis Populations
5.2.1.
Full Analysis Population
The Full Analysis Population (FAS) is defined as all subjects who are enrolled (subjects that sign 
the inform consent form and meet all eligibility criteria) in the study. Subjects will be analyzed 
according to the initial cohort actually assigned.
CELGENE PROPRIETARY INFORMATION
o 
alysis
ysis
esponding
sponding
und to 0.00
und to 0.00
ll be presen
l be prese
ded 80% CI
ded 80% CI
order of co
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have the an
have the a
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se refer to 
se refer to 
s
stics for con
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an, minimu
an, mini
mean, med
mean, med
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nal data (de
al places th
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ould be disp
ould be dis
Analy
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.2.1.
F
.2.1.
The Fu
The Fu
i


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5.2.2.
Safety Population
The Safety Population is defined as all enrolled subjects who receive at least 1 dose of the study 
medications. Subjects will be classified according to the initial durvalumab dose level received.
Drug exposure and all safety analyses (including AEs, labs and deaths) will be based on the 
Safety Population. Efficacy will also be analyzed based on the Safety Population. Subjects will 
be analyzed according to the initial cohort assigned.
5.2.3.
Efficacy Evaluable Population
The Efficacy Evaluable (EE) Population is defined as all enrolled subjects who receive at least 
1 dose of the study medications, and have at least 1 evaluable postbaseline response assessment. 
Efficacy endpoints including ORR, RIR, TTR, and DoR will be analyzed using the EE 
Population. Subjects will be analyzed according to the initial cohort assigned.
5.2.4.
Dose-determining Population
The Dose-determining Population consists of all subjects from the Safety Population who meet 
the minimum exposure criterion and have sufficient safety evaluations, or experience a DLT 
during the first treatment cycle. 
Dose-limiting toxicities will be evaluated during the DLT evaluation period for the subjects in 
the dose-finding portion of the study. The DLT evaluation period will be defined as the first 
treatment cycle for each subject. Subjects are considered evaluable for assessment of DLT if they 
receive 1 dose of durvalumab.
5.2.5.
Pharmacokinetic Population
The PK Population includes all subjects who receive at least 1 dose of study treatment and have 
at least 1 measurable PK assessment. If any subjects are found to be noncompliant with respect 
to dosing, have incomplete data, or encounter other circumstances that would affect the 
evaluation of the PK, a decision will be made on a case-by-case basis as to the inclusion of his 
PK data in the statistical analysis.
5.2.6.
Grouping of Dose Level
For all analyses by treatment cohort and dose level, subjects in the dose-finding portion will be 
combined with the corresponding dose level in the expansion phase as 1 single dose cohort. 
Subjects will be analyzed according to the initial dose level assigned.
5.3.
Definitions
5.3.1.
Date of First Administration of Study Treatment
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of any of the study drug (durvalumab, LEN, or dex) was administered.
For simplicity, the date of first administration of study treatment will also be referred as the start 
date of study treatment.
at least 
least 
ssessment.
ssessment.
e EE
EE
fety Popula
fety Popula
ions, or exp
ons, or ex
valuation p
aluation p
on period w
n period
red evaluab
red evaluab
who receiv
who rece
If any subj
If any s
r encounter
ncounter
n will be ma
will be ma
lysis.
ysis.
f Dose Lev
f Dose Le
y treatment 
treatment 
the corresp
the corresp
l be analyze
l be analyz
Defin
Defin
5.3.1.
.3.1.
The dat
he da


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5.3.2.
Date of Last Administration of Study Treatment
The date of last administration of study treatment is the last date when a nonzero dose of any of 
the study drugs (durvalumab, LEN, or dex) was administered.
5.3.3.
Study Day
The study day for safety assessments (eg, AE onset, laboratory abnormality occurrence, vital 
sign measurement, 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, response assessment, OS, PFS) will be 
calculated as the difference between the date of the event and the date of first dose plus 1. 
5.3.4.
Baseline
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 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. 
CELGENE PROPRIETARY INFORMATION
 1.1.
tudy drug i
tudy drug 
of these va
f these va
l be the ass
l be the a
on or prior
n or prior


Durvalumab (MEDI4736)
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6.
SUBJECT DISPOSITION
The total number of subjects with screen failure will be summarized and listed for all screened 
subjects. Enrollment by country and center will be presented for each treatment cohort for the 
FAS. 
A summary of subject disposition, cohort, and dose level for the FAS will be provided.
Reasons for discontinuing study treatment will be collected on the case report form (CRF) and 
will be summarized for all enrolled subjects with the following categories:
!
Completed
!
Death
!
Adverse event
!
Progressive disease
!
Subject withdrew consent
!
Lost to follow-up
!
Protocol violation
!
Other
Reasons for discontinuing/completing 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:
!
Completed
!
Death
!
Adverse event
!
Progressive disease
!
Subject withdrew consent
!
Lost to follow-up
!
Protocol violation
!
Other
CELGENE PROPRIETARY INFORMATION
more follo
more follo
and will b
and will
w consent
w consent
w-up
w-up
violation
iolation
erer


Durvalumab (MEDI4736)
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7.
PROTOCOL DEVIATIONS/ IMPORTANT PROTOCOL 
DEVIATIONS
Protocol deviations/ Important protocol deviations (PD/IPDs) will be reported and monitored 
throughout the study. PD/IPDs will be identified and assessed by the clinical research physician 
or designee following company standard operational procedure. Data of PD/IPDs will be 
finalized prior to database lock and summarized by cohort and dose level for the FAS. 
The following by-subject listing of subjects with demographic information will be provided:. 
!
Subject listing of discontinuation. 
!
Subject listing of screen failures.
!
Subject listing of PD/IPD.
!
Subject listing of being excluded from Safety, DLT, EE, or PK Population.
CELGENE PROPRIETARY INFORMATION
pulation.
ulation.


Durvalumab (MEDI4736)
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8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Demographics and baseline characteristics will be summarized for the FAS. Individual subject 
listings will be provided to support the summary tables.
8.1.
Demographics
Age (years), height (cm), weight (kg), body mass index (BMI) (weight (kg) / height (m2)) at
baseline will be summarized descriptively. Age category (< 65 versus > 65 and < 75 versus 
Q 75 years), sex, race, and ethnicity will be summarized by frequency counts.
Age will be calculated as follows: age = Integer  [(Date of consent – Date of birth + 1) / 
365.25]. 
Subjects that have an International Staging System (ISS) Stage III, high-risk cytogenetic 
abnormalities (with t(4:14), or/and, t(14;16), or/and 17p13 deletions abnormality), or/and 1q 
amplification), or LDL (in U/L) > 2 Upper Limit of Normal (ULN) will be considered as high 
rick subjects. In addition to fulfilling the high-risk criteria, subjects in Cohort C would also have 
a post-transplant response of PR or better at the time of enrollment into this study and Minimal 
Residual Disease (MRD) positive (defined as more than 1 malignant cells in 10^5 cells) 
measured by ClonoSIGHTTM NGS assay of a BMA sample)..
8.2.
Baseline Characteristics
The number and percentage of subjects in each of the following categories will be presented.
1. Eastern Cooperative Oncology Group (ECOG) performance status at baseline;
2. Electrocardiogram (ECG) at baseline;
3. ISS stage and sub category at diagnosis;
4. Serum and Urine M-protein;
5. High-risk cytogenetic abnormalities at baseline for Cohort A, cytogenetic abnormalities 
at diagnosis for Cohort C.
Time from diagnosis to enrollment, vital signs (temperature, systolic blood pressure, diastolic 
blood pressure and pulse rate), serum and urine M-protein, light chain (kappa, lambda, 
kappa/lambda ratio), laboratory data at baseline will be summarized descriptively by cohort.
8.3.
Baseline Symptoms
The number and percentage of subjects presenting the following symptoms at baseline will be 
summarized descriptively along with the grade of the symptoms: motor neuropathy, sensory 
neuropathy, other neuropathy, neutropenia, thrombocytopenia, leukopenia, anemia, chronic 
kidney disease, hypercalcaemia, hypertension, arrhythmia, atrial fibrillation, diabetes mellitus 
and chronic obstructive pulmonary disease.
CELGENE PROPRIETARY INFORMATION
) / 
) / 
ogenetic
ogenetic
ality), or/an
ality), or/an
e considere
e considere
Cohort C w
Cohort C 
nto this stu
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iagnosis;
gnosis;
n;
bnormaliti
normaliti
ort C.
ort C.
enrollment
enrollmen
ulse rate), s
ulse rate),
o), laborato
o), laborato
Baseline S
Baseline 
mber and p
mber and p
marized de
marized de
europathy, 
europathy
kidney di
kidney di
d ch
d ch


Durvalumab (MEDI4736)
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8.4.
Medical History
Medical history will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA) Version 20.0, or higher. System organ class (SOC) and preferred term (PT) will be 
summarized by frequency and percentage. Tables will be provided for subjects in the FAS.
8.5.
Prior Radiation and/or Antimyeloma Therapy
Prior radiation therapies (all cohorts) and/or prior antimyeloma therapies (Cohort C only) will be 
summarized with frequency counts and percentages for the FAS. Prior radiation therapies will be 
summarized by type and location whereas prior antimyeloma therapies will be presented by 
World Health Organization (WHO) (March 2017 version, or higher) drug preferred name.  
For Cohort C, last prior antimyeloma therapies will be also presented by drug class and drug 
preferred name.
8.6.
Prior and Concomitant Medications
Medications initiated prior to the start of study treatment and continued after the start of study 
treatment will be counted as both prior and concomitant medications for the FAS.
8.6.1.
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.
The Anatomical Therapeutical Chemical (ATC) coding scheme of the WHO (March 2017
version, or higher) will be used to group medications into relevant categories.
All prior medications will be summarized by ATC level 1 and drug preferred name in frequency 
tabulations for the FAS.
8.6.2.
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 till the end of the last dose of study drug plus 90 days. 
The Anatomical Therapeutical Chemical (ATC) coding scheme of the WHO (March 2017
version, or higher) will be used to group medications into relevant categories.
All concomitant medications will be summarized by ATC level 1 and drug preferred name in 
frequency tabulations for the FAS. 
8.7.
Concomitant Procedures
The eCRF page records procedure, date, and indication. These procedures will be coded using 
MedDRA Version 20.0 or higher. A frequency summary of subjects by concomitant procedures 
summarized in frequency tabulations by SOC and PT by disease cohort for the FAS.
CELGENE PROPRIETARY INFORMATION
be
be
will be
ll be
by 
by 
ame. 
me. 
ss and drug
and drug
ued after th
ued after th
ons for the
ns for th
e started be
e started be
udy treatme
udy treatm
TC) coding
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medications
medication
rized by AT
rized by
dications
dications
s are defin
s are def
nd continue
d continu
drug till th
drug till th
al Therape
al Therap
higher) wil
higher) wil
comitant m
comitant m
uency tabu
uency tabu
8.7.
8.7.
e e


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Concomitant procedures will be identified as procedures or surgeries that occurred after or on the 
date of first dose of study drug and continued during the study treatment, or initiated on / after 
the date of the first dose of study drug till the end of the last dose of study drug plus 90 days.
CELGENE PROPRIETARY INFORMATION


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9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
9.1.
Treatment Duration
Treatment duration will be summarized by treatment arm and dose cohort for the Safety 
Population. 
The treatment duration (in weeks) for each individual study drug is defined as follows:
[(Treatment duration end date for individual study drug) – (1st dose of individual study drug)
+1]/7
Treatment duration end date is defined as Min [(last non-zero/non-missing dose date + days to be 
covered by the last dose), death date].
The treatment duration for the overall study (in weeks) is defined as follows:
[(Treatment duration end date for the overall study – first date when subject receives any 
dose of study drug + 1) / 7 (in weeks)
Treatment duration end date is defined as Min [(last non-zero/non-missing dose date of all study 
drugs + days to be covered by the last dose), death date].
In addition to treatment duration, the number of cycles received will also be summarized (Refer 
to 16.1.2 for the definition of cycle length).
The number of days to be covered by the last dose is defined in Table 5.
CELGENE PROPRIETARY INFORMATION
rug)
ug)
+ days to be
days to b
bject receiv
bject receiv
missing do
missing d
ived will al
ved will al
defined in 
defined 


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Table 5:
Number of Days to be Covered by the Last Dose 
Arm
Schedule
n = days to be covered by the actual last dose*
Cohort A
  durvalumab
CxD1
n=27
  LEN
CxD1 to CxD20
CxD21
n=0
n=7
  dex
CxD1
CxD8
CxD15
CxD22
n=6
n=6
n=6
n=6
Cohort B
  durvalumab
CxD1
n=27
  LEN
CxD1 to CxD20
CxD21
n=0
n=7
  dex
CxD1
CxD8
CxD15
CxD22
n=6
n=6
n=6
n=6
Cohort C
  durvalumab
CxD1
n=27
  LEN
CxD1 to CxD20
CxD21
n=0
n=7
  dex
N/A
* if schedule is not respected the number of days to be covered by the actual last dose will be adapted accordingly so 
that the last dose date + n corresponds to the study day 28 of the cycle.
9.2.
Cumulative Dose
Cumulative dose is defined as the sum of all doses taken across the treatment period in 
milligrams (mg). Cumulative dose will be calculated separately for each drug by treatment 
cohort and dose level.
Cumulative dose for (durvalumab/LEN/dex) = Sum of (administered dose of each cycle [mg])
9.3.
Dose Exposure
Dose exposure is defined as the total number of days on the study drug 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 treatment cohort and dose level.
CELGENE PROPRIETARY INFORMATION
T
AT
OR
O
n=0
n 0
n=7
n=7
NF
n=6
Y I
TA
ET
RI
PR
A
OP
RO
ber of days t
ber of days t
onds to the s
onds to the s
ve Dose
ve Dose
s defined a
 defined a
). Cumulat
). Cumulat
ose level.
ose level.
tive dose fo
ive dose f
3.
D
3.
D
Dose ex
Dose e
ase


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9.4.
Average Daily Dose
Average daily dose is defined as the cumulative dose divided by dose exposure (mg/day). 
Average dose will be calculated separately for each drug by treatment cohort and dose level.
9.5.
Dose Intensity
Dose intensity during the treatment is defined as the cumulative dose divided by treatment 
duration, ie, dose intensity (mg/day) = cumulative dose (mg) / treatment duration (day). Dose 
intensity will be calculated for each drug separately by treatment cohort and dose level.
9.6.
Relative Dose Intensity
Relative dose intensity is defined as the dose intensity divided by the planned dose intensity:
!
For durvalumab the planned dose intensity is (dose level) / per 28 days, with dose 
level of 750 or 1500 mg.
!
For LEN the planned dose intensity is (dose level)*21 / per 28 days, with an 
adjustable dose level based on renal function on the first day of cycle 1 and 10 mg 
for Cohort C.
!
For dex, the planned dose intensity is 40*4 = 160 mg / per 28 days for subjects 
O 75 years old, or 20*4 = 80 mg / per 28 days for subjects > 75 years old.
The dose of lenalidomide must be adjusted for renal function on the first day of Cycle on Days 1 
to 21 of each 28-day treatment cycle based on Table 6. 
Table 6:
Lenalidomide Dosing Guideline for Renal Insufficiency for Cohort A and 
Cohort B
Renal Function (CrCl)
Dosing
Normal to Mild RI (CrCl Q 50 mL/min)
25 mg once daily on Days 1 to 21 of each 28-day 
cycle
Moderate RI (30 O CrCl < 50 mL/min)
10 mga once daily on Days 1 to 21 of each 28-day 
cycle
Severe RI (CrCl < 30 mL/ min)
15 mg once every other day from Day 1 to 21 of 
each 28-day cycle
CrCl = creatinine clearance; RI = renal insufficiency.
a This dose may be escalated to 15 mg after 2 Cycles at the discretion of the treating physician if the subject 
tolerates the 10 mg dose of lenalidomide without dose-limiting toxicity.
In Cohorts A and B for LEN, if the CrCl Q 50 mL/min at the first day of Cycle 1, the planned 
dose intensity is (dose level)*21 / per 28 days, with dose level of 25 mg. 
In Cohorts A and B for LEN, if 30 O CrCl < 50 mL/min at the first day of Cycle 1, the planned 
dose intensity is (dose level)*21 / per 28 days, with dose level of 10 mg.
In Cohorts A and B for LEN, if CrCl < 30 mL / min at the first day of Cycle 1, the planned dose 
intensity is (dose level)*11 / per 28 days, with dose level of 15 mg. 
CELGENE 
mL/ min)
mL/ min)
E PROPRIETARY INFORMATION
se intensity
se intensit
8 days, with
8 days, wi
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r 28 days, 
st day of cy
t day of c
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se i


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9.7.
Dose Modifications
Dose reduction / interruption will be summarized separately for each drug, as applicable.
Durvalumab will be summarized according to dose delay / infusion interruption while 
lenalidomide and dexamethasone will be summarized according to dose reduction or 
interruption, as appropriate. The number of subjects who have at least 1 dose reduction /
interruption, number of dose reductions / interruptions per subject, reason for dose reduction /
interruption and time to first dose reduction / interruption will be summarized by drug, assigned 
cohort, and dose level.
CELGENE PROPRIETARY INFORMATION


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10.
EFFICACY ANALYSIS
Efficacy analyses pertaining to the response (eg, ORR, RIR, TTR and DoR) will be carried out 
on the EE Population. Supportive efficacy analyses for ORR and RIR will be also performed on 
the Safety Population.
Additional time-to-event analyses for PFS and OS will be based on the Safety and FAS 
Populations. All analyses will use descriptive statistics. Subjects treated with the recommended 
dose in the expansion portion will be combined with the corresponding dose level in the dose-
finding portion as one single dose level for efficacy and safety analysis. No formal statistical 
comparison / testing will be performed. 
Response Using the IMWG Uniform Response Criteria
Tumor response, including PD, will be assessed by the investigators.
The preliminary efficacy endpoint for Cohorts A and B is the ORR, calculated as the proportion 
of subjects achieving a PR or better as assessed by the investigators using the IMWG uniform 
response criteria. PR or better is defined as PR, very good partial response [VGPR], complete 
response [CR], or stringent complete response [sCR]. The ORR will be summarized together 
with the two-sided 80% exact confidence interval (CI).
The best overall clinical response categories (sCR, CR, VGPR, PR, Minimal Response [MR], 
stable disease [SD] and PD) will be also tabulated for Cohort A and B and dose level.
Response Improvement Rate Using the IMWG Uniform Response Criteria
The preliminary efficacy endpoint for Cohort C is the proportion of subjects achieving a RIR
from Cycle 1 Day 1 as assessed by the investigators using the IMWG Uniform Response 
Criteria. The RIR will be summarized together with the two-sided 80% exact CI.
Shift table from baseline will also be generated.
Time to Response (TTR)
Time to response (for responders only, per IMWG Uniform Response Criteria) is calculated as 
the time from the first date of dosing of study medication to the first date of documented 
response (PR or better). Subjects who do not achieve any defined response during the treatment 
period will be censored at the date of last adequate response assessment, disease progression, or 
death, whichever occurs first.
TTR will be summarized using descriptive statistics or listed by treatment cohort and dose level 
for Cohorts A and B using the EE Population.
Duration of Response (DoR)
Duration of response (for responders only, per IMWG Uniform Response Criteria) is defined as 
time from the earliest date of documented response (PR or better) to the earliest date of disease 
progression as determined by the investigator per IMWG Uniform Response Criteria or death 
during the study treatment by treatment cohort for Cohorts A and B, whichever occurs first. 
DoR will be summarized using descriptive statistics or listed by treatment cohort and dose level 
for Cohorts A and B using EE Population. Median duration of response and associated two-sided 
80% CI will be also estimated using the Kaplan-Meier (KM) method.
CELGENE PROPRIETARY INFORMATION
ed as the pr
d as the pr
the IMWG
the IMWG
nse [VGPR
nse [VGP
 be summa
be summa
R, PR, Min
R, PR, M
ort A and B
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iform Resp
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progressi
progressi
uring
uring


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Censoring rules are defined in Table 7.
 
 
 
Overall Survival (OS)
OS is calculated as the time from first dose to death due to any cause. Subjects who died will be 
considered as having events on the date of death. Subjects who are alive at the time of clinical 
data cut-off date will be censored at the earlier between last assessment at which the subject was 
known to be alive and cut-off date will be used. All subjects who were lost to follow-up prior to 
the clinical data cut-off date will also be censored at the time of last contact. Overall survival will 
be summarized using KM estimates by treatment cohort and dose level for the Safety Population
and the FAS.
Progression-free Survival (PFS)
Progression free survival will be calculated as the time between first dose and disease 
progression, as determined by the investigator using the IMWG Uniform Response Criteria, or 
death during study treatment, whichever occurs earlier. 
Median PFS along with the two-sided 80% CI will be summarized using KM estimates by 
treatment cohort and dose level for the Safety Population and FAS.
Censoring rules are defined in Table 7.
CCI
CELGENE PROPRIETARY INFORMATION
ill be
be
linical
nical
subject was
subject was
ow-up prior
w-up prio
erall surviv
erall sur
he Safety P
he Safety 
first dose an
st dose an
G Uniform 
G Unifo
ummarized
ummarize
ation and F
ation and


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Table 7:
Censoring Rules for PFS and DoR
Situation
Date of Progression or Censoring
Situation Outcome
Death within the first two 
scheduled assessments 
without disease progression
Date of death
Event
Progression 
If the first PD is a scheduled assessment then Date 
of first PD;
If the first PD is an unscheduled assessment and 
no previous assessment, then Date of PD;
If the first PD is an unscheduled assessment and 
has previous assessment, then Date of previous 
assessment (regardless of the response type) 
Event
Death between scheduled 
assessments 
Date of death
Event
No progression
Date of last adequate assessment with evidence of 
no progression
Censored
Death or progression after 
two or more missed 
scheduled assessments
Date of last adequate assessment with evidence of 
no progression
Censored
New antimyeloma /
nonprotocol treatment 
started prior to progression 
or death due to any reason 
Date of last adequate assessment with evidence of 
no progression before the start of new treatment
Censored
PD = progressive disease.
Source: United States Food and Drug Administration (US FDA) guidance for cancer trial endpoints for the approval 
of cancer drugs and biologics (FDA Guidance, 2007).
CELGENE PROPRIETARY INFORMATION
TI
Event
Ev
OR
NF
nce of 
ce of 
Cen
C
NF
NF
evidence o
evidence o
Y IN
sment with e
ment with e
e start of new
e start of n
AR
RIE
ion (US FDA
ion (US FDA
2007)
007).
OP


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11.
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. 
11.1.
Dose-limiting Toxicity
A DLT will be defined as below: 
Hematologic DLT
a.
Grade 4 neutropenia observed for greater than 5 days duration.
b. Grade 3 neutropenia associated with fever (Q 38.5°C / 101.3°F) of any duration.
c.
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding, or any 
requirement for platelets transfusion.
d. Any other Grade 4 hematologic toxicity that does not resolve to subject’s 
pre-treatment baseline level within 72 hours.
e.
Grade 4 anemia, unexplained by underlying disease.
Nonhematologic DLT
a.
Any nonhematologic toxicity Grade Q 3 except for alopecia and nausea controlled by 
medical management.
b. Any treatment interruption greater than 2 weeks due to AE.
While the rules for adjudicating DLTs in the context of dose decision are specified above, an AE 
not listed above may be defined as a DLT after consultation with the sponsor and investigators, 
based on the emerging safety profile.
Dose-limiting toxicity will be listed by treatment cohort and dose level using the Dose-
determining Population.
11.2.
Adverse Events
Adverse events will be analyzed in terms of treatment-emergent adverse events (TEAEs). All 
AEs will be coded using the MedDRA Version 20.0 or higher. The intensity of AEs will be 
graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 
4.03 or higher.
TEAEs include AEs between the earliest of the first dose date of either study drug and the 
maximum of the following 2 points below.
Maximum of: 
(a) 28 days after the last dose of LEN or dex
(b) 90 days after the last dose of durvalumab
A treatment-related TEAE is defined as a TEAE which is suspected to be related by the 
investigator to the study drug. 
CELGENE PROPRIETARY INFORMATION
tion.
tion.
or any 
or any 
bject’s
ect’s
opecia and
opecia and
s due to AE
due to A
f dose deci
f dose deci
sultation w
sultation w
ment cohor
ment cohor
ed in terms 
d in terms
e MedDRA
MedDR
Common T
Common
Es between
Es between
he followin
e follow
of:
of:
28 days aft
28 days aft
(b) 90 day
(b) 90 day
A treatm
A treatm
vest


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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.” 
The incidence of TEAEs will be summarized by MedDRA SOC and PT. The intensity of AEs 
will be graded 1 to 5 according to the 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). Tables 
summarizing the incidence of TEAEs will be generated, including but not limited to the 
following:
!
All TEAEs;
!
TEAEs by cycle;
!
All TEAEs with Grade Q 3; 
!
TEAEs with Grade 1 or 2; 
!
TEAEs by maximum Grade;
!
TEAEs reported as treatment-related; 
!
Treatment-related Grade 3 or higher TEAEs;
!
Serious TEAE;
!
Treatment-related serious TEAEs;
!
TEAEs with action of study drug permanently discontinued;
!
Treatment-related TEAEs with action of study drug permanently discontinued;
!
TEAEs with action of study drug dose delayed/reduced;
!
Treatment-related TEAEs with action of study drug dose delayed/reduced;
!
TEAEs with action of study drug dose/infusion interrupted;
!
Treatment-related TEAEs with action of study drug dose/infusion interrupted;
!
TEAEs with action of study drug dose/infusion delayed/reduced or interrupted;
!
Treatment-related TEAEs with action of study drug dose infusion delayed/reduced or 
interrupted;
!
TEAEs that led to death.
Listings for the corresponding summary tables will be presented separately. A listing for non-
treatment-emergent AEs will also be provided. 
All deaths and reasons for death will be summarized for the Safety Population. Deaths within 28 
and 90 days after the last dose of any drug component will be summarized separately. Death 
information will come from the death eCRF page
CELGENE PROPRIETARY INFORMATION
de
de
les
es 
;
ug permane
g perman
with action
ith action
study
study drug 
rug
y
TEAEs wi
TEAEs w
action of stu
ction of stu
-related TE
-related 
Es with act
Es with act
reatment-r
reatment-r
interrupte
interrupt
!
TEA
EA
istings for 
istings for
treatment
reatment
d


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11.3.
Adverse Events of Special Interest
The adverse events of special interest (AESIs) refer to a group of 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.
AESIs will be summarized separately for durvalumab and LEN. 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.
The following AESIs for durvalumab, as identified by MedImmune, will be summarized for 
regulatory purposes:
!
Diarrhea 
!
Colitis 
!
Intestinal perforations
!
Pneumonitis including ILD
!
Hepatitis/ Hepatic events
!
Hepatic laboratory parameters reported as AEs
!
Adrenal insufficiency
!
Type 1 diabetes mellitus
!
Hypophysitis
!
Thyroiditis
!
Hyperthyroid events
!
Thyroid laboratory parameters reported as AEs (increased thyroid activity))
!
Hypothyroid events
!
Thyroid laboratory parameters reported as AEs (decreased thyroid activity))
!
Rash / Dermatitis
!
Nephritis/ Renal events
!
Renal laboratory investigations reported as AEs
!
Pancreatitis
CELGENE PROPRIETARY INFORMATION
or 
tory parame
ory param
oid events
oid events
roid labora
roid labora
Rash / De
Rash / De
!
Nep
Nep
!


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!
Pancreatic laboratory investigations reported as AEs
!
Myocarditis
!
Myositis / Polymyositis
!
Myasthenia gravis
!
Guillain-Barré syndrome
!
Other rare/miscellaneous (other inflammatory responses that are rare / less frequent with 
a potential immune-mediated aetiology)
!
Infusion/hypersensitivity reactions
The following AESIs for LEN, based on risk definitions (search criteria) as outlined in the 
Revlimid risk management plan (RMP) approved at the time of data cut-off, will be summarized:
!
Hepatic disorders
!
Diarrhea
!
Constipation
!
Interstitial lung disease (interstitial pneumonitis)
!
Renal failure
!
Cutaneous reactions
!
Peripheral neuropathy
!
Hypersensitivity and angioedema
!
Neutropenia and infections
!
Teratogenicity
!
Thrombocytopenia and bleeding
!
Thromboembolic events
!
Tumor lysis syndrome
!
Cardiac failure
!
Cardiac arrhythmias
!
Ischemic heart disease (including myocardial infarction)
!
AML
!
B-cell malignancies
!
NMSC
!
Other hematologic malignancies
CELGENE PROPRIETARY INFORMATION
ent with
t with
s outlined i
outlined i
-off, will b
ff, wil
s)s)
ema
ema
ns
ns
nia and blee
nia and bl
bolic event
olic even
ysis syndro
ysis syndro
diac failure
diac failure
Cardiac ar
Cardiac ar
!
Ischem
Ischem
!
A
!


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!
Solid tumors
After review of the data, there may be other AESIs identified. In addition, the following 
summaries will be generated for TEAEs included in the above-mentioned AESIs:
!
All TEAEs of special interest;
!
TEAEs of special interest of Grade 3 or 4;
!
TEAEs of special interest by maximum Grade;
!
TEAEs of special interest by cycle (at first onset and any onset)
!
TEAEs of interest leading to study drug permanently discontinued;
!
TEAEs of interest leading to death
The list of AE PTs for each AESI can be based on the Standard MedDRA Query (SMQ) search 
and/or the clinical/medical considerations. 
SPMs, occurring at any time from the time of signing the informed consent up to and including 
the long-term follow-up period, will be summarized as events of interest. SPMs occurring before 
and after the first dose will be presented separately. SPMs are collected in the Serious Adverse 
Event for Second Primary Malignancies eCRF form.
Graphical displays will be provided where useful to assist in the interpretation of results.
Listings for the corresponding summary tables will be presented separately.
11.4.
Clinical Laboratory Evaluations
Clinical laboratory values from the central laboratories (hematology, chemistry) 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 assigned cohort, and dose level. Frequency distributions 
for shift from baseline to the worst grade during treatment period will be presented by treatment 
arm. 
Clinical laboratory values will be also summarized descriptively.
Listings of clinical laboratory data from central laboratory (hematology, chemistry, coagulation, 
thyroid function tests) with abnormal flags will be provided by subjects and tests. Listings will 
also be provided for the local laboratory data. 
 
11.6.
Vital Sign Measurements
For vital signs, with shifts from baseline to worst during treatment (below, within, and above the 
normal ranges) will be displayed in cross–tabulations for each treatment. Summary statistics of 
observed values and change from baseline values will be presented.
CCI
CELGENE PROPRIETARY INFORMATION
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11.6.
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LG
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11.7.
Electrocardiograms
The overall ECG interpretation will be summarized by presenting the number and percentage of 
subjects with ‘Normal’, ‘Abnormal, not clinically significant’, and ‘Abnormal, clinically 
significant’ by treatment. The shift from baseline to worst during treatment in the overall ECG 
interpretation will be displayed in cross–tabulations for each treatment.
11.8.
Eastern Cooperative Oncology Group Performance Status
Shift table from baseline to worst post-baseline in ECOG performance score will be displayed by 
cohort and dose level for the Safety Population.
11.9.
Pharmacokinetic Analysis
Pharmacokinetic analysis will be based on the PK Population. Typical serum / plasma PK 
parameters for durvalumab and LEN, such as maximum observed concentration (Cmax), area 
under the concentration-time curve (AUC), time to maximum concentration (Tmax), terminal 
elimination half-life (t1/2), clearance (CL/F), and volume of distribution (Vz/F) will be 
summarized descriptively by cohort and dose level using the PK Population.
 
CCI
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RM
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13.
INTERIM ANALYSIS
No formal interim analyses are planned. However, during the study, data will be analyzed and 
reviewed on an ongoing basis to allow for DRT to review and make decisions about dosing 
decisions
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14.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF 
THE PROTOCOL
PFS and OS will be derived from first dose date rather than from date of enrollment. This update 
is required to ensure consistency across time-to-event analyses.
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15.
REFERENCES
Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, 
FDA/CDER/CBER May 2007.
Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. Consensus 
recommendations for the uniform reporting of clinical trials: report of the International Myeloma 
Workshop Consensus Panel 1. Blood. 2011;117(18):4691-5.
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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 
16.2 (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 enrollment, 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. 
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, 
durvalumab) plus 1 day. The generalized calculation algorithm for relative day is the 
following: 
CELGENE PROPRIETARY INFORMATION
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!


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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 = 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
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.
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 31 Dec will be assigned to 
the missing fields.
!
If the year is after the year of first dosing, then 1 Jan will be assigned to the missing 
fields.
Missing day only 
CELGENE PROPRIETARY INFORMATION
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!
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.
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 or 
prior to the year of the first dosing date, then 31 Dec 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 after the year of the last dosing date, then 1 
Jan 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. 
CELGENE PROPRIETARY INFORMATION
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16.2.1.
Adverse Events
Partially missing AE start dates will be imputed in the ADaM dataset for AEs. If the AE end date 
is complete with no missing year, month, or day, and the partially missing start date imputed by 
the rules above is after the AE end date, then the start date will be imputed by the AE end date.
16.2.2.
Prior/Concomitant Medications/Procedures
Partially missing start/stop dates for prior/concomitant medications and partially missing start 
dates for prior/concomitant procedures will be imputed in the ADaM dataset for 
prior/concomitant medications/procedures. For prior/concomitant medications, if the stop date is 
complete with no missing year, month, or day, and the partially missing start date imputed by the 
rule below is after the stop date, then the start date will be imputed by the stop date.
Partially missing prior/concomitant medication/procedure start dates will be imputed by the 
earliest possible date given the non-missing field(s) of the date.
Partially missing prior/concomitant medication stop dates will be imputed by the latest possible 
date given the non-missing field(s) of the date.
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.
 
 
 
 
CCI
CELGENE PROPRIETARY INFORMATION
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Y INFORMATIO