Conditions: Multiple Myeloma
Keywords: Multiple Myeloma Daratumumab Durvalumab Relapsed and Refractory Multiple Myeloma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 18
Healthy volunteers: no

Brief summary:
This is a single-arm, multicenter, Phase 2 study to evaluate the efficacy and safety of the combination regimen of daratumumab plus durvalumab (D2). The study will consist of 2 parts; Part 1 has a 2-stage design while Part 2 consists of an expansion phase. Subjects will receive intravenous (IV) DARA at 16 mg/kg on the same dosing schedule (weekly \[QW\], every 2 weeks \[Q2W\] or every 4 weeks \[Q4W\] of each 28-day cycle) received on their last prior therapy containing DARA. The dosing schedule for DARA may be adjusted during the course of the study as outlined in the protocol. Subjects will also receive IV DURVA at 1500 mg on Day 2 (Cycle 1) and on Day 1 (Cycles ≥ 2) of each 28-day treatment cycle.

Detailed description:
Indication:

This study will include subjects that have relapsed and refractory multiple myeloma (RRMM) after treatment with at least 3 prior antimyeloma therapies, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD®) or after development of double-refractoriness to a both a PI and an IMiD.

The most recent multiple myeloma (MM) treatment regimen should contain daratumumab (DARA) and subjects must have progressed on DARA while on this regimen. Stage 1 A cohort of 18 subjects will be enrolled to determine the preliminary efficacy of DARA plus DURVA. Once the 18 subjects have been enrolled, an interim analysis for futility purpose will be conducted to determine if the study can proceed to Stage 2.

Early Safety Monitoring Once 6 subjects have been enrolled and completed the first treatment cycle in Stage 1 of this study, the enrollment continuity would depend on the availability of safety data from the on-going Phase 2 study (MEDI4736-MM-003) of DARA and DURVA in previously DARA-naïve patients.

* If MEDI4736-MM-003 safety data are available and the tolerability profile of DARA plus DURVA has been determined to be adequate, then enrollment will continue as planned in Stage 1 without an early safety monitoring review of the data.
* If safety data are not available enrollment in this study will be paused for a review of the safety profile of DARA plus DURVA by a Dose Review Team (DRT), using the data from the first 6 patients.
* If ≥ 1 of the first 6 patients experiences a dose-limiting toxicity (DLT), the study will be halted for review and a change in the dosing regimen may be implemented.
* The DRT will consist of the Celgene Medical Monitor, Celgene lead Safety Physician, Celgene biostatistician, other Celgene functional area representatives, as appropriate, study specific consultants (MD/PhD), and site investigator and/or designees who have enrolled subjects to the study.
* All available safety and, if applicable, PK/(pharmacodynamic) Pd, biomarker, and preliminary efficacy data will be reviewed and can be considered in the DRT's decisions.
* A DRT meeting will be held to review all data and make decisions regarding continuity of the study.

Dose-limiting Toxicity

Dose-limiting toxicities (DLTs) may be evaluated during the DLT evaluation period for the initial 6 patients in Part 1 of the study. The DLT evaluation period will be defined as the first treatment cycle. Subjects are considered evaluable for assessment of DLT if they:

* Receive at least 1 dose of study treatments and experience a DLT OR
* Receive 1 dose of DURVA, 4 doses of DARA and complete the safety follow-up through the end of the DLT evaluation period.

Grading of DLTs will be according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03.

A DLT will be defined as below:

Hematologic DLT

1. Grade 4 neutropenia observed for greater than 5 days duration
2. Grade 3 neutropenia associated with fever (≥ 38.5 °C) of any duration.
3. Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding, or any requirement for platelets transfusion.
4. Any other Grade 4 hematologic toxicity that does not resolve to subject's pretreatment baseline level within 72 hours
5. Grade 4 anemia, unexplained by underlying disease. Non-hematologic DLT

a. Any nonhematological toxicity ≥ Grade 3 except for alopecia and nausea controlled by medical management b. Any treatment interruption greater than 2 weeks due to an AE. While the rules for adjudicating DLTs in the context of dose escalation 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.

Stage 2 If 3 or more subjects achieved a response (PR or better) out of the 18 subjects at the end of Stage 1, an additional 32 subjects will be enrolled to evaluate the safety and efficacy of DARA plus DURVA.

Part 2: Expansion Upon completion of Part 1, if at least 9 subjects achieve a response (PR or better) out of a total of 50 subjects and it is determined to further confirm the efficacy and safety of DARA plus DURVA, an additional 70 subjects may be enrolled.

An Independent Response Adjudication Committee (IRAC) will be set up for this trial to review study data. The IRAC will determine tumor response to therapy and to confirm the time of disease progression (PD) (if disease progressed) at scheduled or unscheduled visits for each subject.

The safety and efficacy of the study will be monitored by an independent Data Monitoring Committee (DMC) who are not involved in the trial conduct. The DMC will meet up and review study data at pre specified intervals throughout the trial.

In the event that the trial is halted for early safety monitoring, evaluation of the emerging safety data from the initial 6 patients enrolled in Part 1 will be performed by the Dose Review Team (DRT).

Safety data will be monitored by the Celgene Medical Monitor and Safety Physician on an ongoing basis throughout the study. Should a significant safety issue be identified, the DMC will be convened to make a recommendation as to the future conduct of the study.

The decision to discontinue a subject, which will not be delayed or refused by the Sponsor, remains the responsibility of the treating physician. However, prior to discontinuing a subject, the Investigator may contact the Medical Monitor and forward appropriate supporting documents for review and discussion.

The study will be conducted in compliance with the International Council on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements.

Arms:
arm 1: Subjects will also receive IV DURVA at 1500 mg on Day 2 (Cycle 1) and on Day 1 (Cycles ≥ 2) of each 28-day treatment cycle.

Subjects will receive intravenous (IV) DARA at 16 mg/kg on the same dosing schedule (weekly \[QW\], every 2 weeks \[Q2W\], or every 4 weeks \[Q4W\] of each 28-day treatment cycle) received during their last prior therapy containing DARA at the time of DARA progression

Interventions: intervention 1: DARATUMUMAB intervention 2: DURVALUMAB
Intervention descriptions: intervention 1: DARATUMUMAB intervention 2: DURVALUMAB

Protocol document:
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EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
1
MEDI4736-MM-005 Final: 03 Oct 2016
TITLE PAGE
MULTICENTER, SINGLE-ARM, PHASE 2 STUDY TO 
DETERMINE THE EFFICACY FOR THE 
COMBINATION OF DARATUMUMAB (DARA) PLUS 
DURVALUMAB (DURVA) (D2) IN SUBJECTS WITH 
RELAPSED AND REFRACTORY MULTIPLE 
MYELOMA (RRMM) WHO HAVE PROGRESSED ON 
DARA WHILE ON A DARA-CONTAINING REGIMEN 
AS THE MOST RECENT MULTIPLE MYELOMA 
THERAPY. “FUSION MM-005”
PROTOCOL NUMBER:
MEDI4736-MM-005
DATE FINAL:
03 Oct 2016
EudraCT NUMBER:
2016-003801-32
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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CELGENE PRO
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OPRIETARY INFORMATION
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ON 
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127058
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
2
MEDI4736-MM-005 Final: 03 Oct 2016
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information: US/Canada/Europe
Name:
Title:
Address: 86 Morris Avenue Summit, NJ 07052
Phone:
E-mail:
Note: The back-up 24-hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls.
Back-up 24-hour Global Emergency Contact Call Center: 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
3
MEDI4736-MM-005 Final: 03 Oct 2016
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.  
{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:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
4
MEDI4736-MM-005 Final: 03 Oct 2016
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 on 
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
5
MEDI4736-MM-005 Final: 03 Oct 2016
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:_______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
6
MEDI4736-MM-005 Final: 03 Oct 2016
PROTOCOL SUMMARY
Study Title
MEDI4736-MM-005 (FUSION MM-005):  A Multicenter, Single-arm, Phase 2 Study to 
Determine the Efficacy of the Combination of Daratumumab (DARA) Plus Durvalumab
(DURVA) (D2) in Subjects With Relapsed and Refractory Multiple Myeloma (RRMM) who 
have Progressed on DARA While on a DARA-containing Regimen as the Most Recent MM 
Therapy.
Indication
Relapsed and refractory multiple myeloma (RRMM) after treatment with at least 3 prior anti-
myeloma therapies, including a proteasome inhibitor (PI) and an immunomodulatory drug 
(IMiD®) or after development of double-refractoriness to a both a PI and an IMiD.
!
The most recent multiple myeloma (MM) treatment regimen should contain 
daratumumab (DARA) and subjects must have progressed on DARA while on this 
regimen.
!
Induction, bone marrow transplant with or without maintenance therapy is 
considered one regimen
!
Refractory is defined as disease that is nonresponsive on therapy, or progresses 
within 60 days of last therapy. Nonresponsive disease is defined as either failure to 
achieve minimal response or development of progressive disease while on therapy.
!
For subjects who received more than 1 regimen containing a PI their disease must be 
refractory to the most recent PI containing regimen.
!
For subjects who received more than 1 regimen containing a IMiD their disease must 
be refractory to the most recent IMiD containing regimen
Objectives
Primary: 
!
To determine the efficacy of DARA plus durvalumab (DURVA) in subjects with 
RRMM who have progressed on DARA while on a DARA-containing regimen as the
most recent MM treatment.
Secondary:
!
Determine the safety of DARA plus DURVA in subjects with RRMM who have 
progressed on DARA while on a DARA-containing regimen as the most recent MM 
treatment.
!
Further evaluate the efficacy of the combination of DARA plus DURVA in subjects 
with RRMM who have progressed on DARA while on a DARA-containing regimen
as the most recent MM treatment. Key efficacy measures include time-to-response
[TTR], duration of response [DOR], progression-free survival [PFS], and overall 
survival [OS].
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
7
MEDI4736-MM-005 Final: 03 Oct 2016
!
Evaluate the pharmacokinetics (PK) of DARA and DURVA in subjects with RRMM
who have progressed on DARA while on a DARA-containing regimen as the most 
recent MM treatment.
 
 
 
 
 
 
Study Design
This is a single-arm, multicenter, Phase 2 study to evaluate the efficacy and safety of the 
combination regimen of DARA plus DURVA (D2) in subjects with relapsed and refractory 
multiple myeloma after failure of prior therapies containing a PI, immunomodulatory drug and 
DARA. The study will be conducted in 2 parts: Part 1 and Part 2. Part 1 has a 2-stage design 
while Part 2 consists of an expansion phase. Subjects will receive intravenous (IV) DARA at 16 
mg/kg on the same dosing schedule (weekly [QW], every 2 weeks [Q2W], or every 4 weeks 
[Q4W] of each 28-day treatment cycle) received during their last prior therapy containing DARA
at the time of DARA progression.  Dosing schedules, for the administration of DARA, may be 
adjusted during the course of the study, as detailed in Section 7.2, provided that the subject has a 
response of stable disease (SD) or better. Subjects will also receive IV DURVA at 1500 mg on 
Day 2 (Cycle 1) and on Day 1 (Cycles ≥ 2) of each 28-day treatment cycle. 
Part 1:
Stage 1
A cohort of 18 subjects will be enrolled to determine the safety and preliminary efficacy of
DARA plus DURVA. Once 6 subjects have been enrolled in MEDI4736-MM-005 and 
completed the first treatment cycle in Stage 1 of this study, the enrollment continuity would 
depend on the availability of additional safety data from the ongoing Phase 2 study 
(MEDI4736-MM-003) of DARA and DURVA in previously DARA-naïve subjects.
!
If MEDI4736-MM-003 safety data are available and the tolerability profile of DARA 
plus DURVA is determined to be adequate, then enrollment will continue as planned 
in Stage 1 of MEDI4736-MM-005.
!
If safety data are not available in MEDI4736-MM-003, enrollment in MEDI4736-
MM-005 will be paused for a review of the safety profile of DARA plus DURVA by 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
8
MEDI4736-MM-005 Final: 03 Oct 2016
a Dose Review Team (DRT), using the data from the first 6 patients. See Section
3.1.1.1.1.
Once the 18 subjects have been enrolled in MEDI4736-MM-005 (end of Stage 1), an interim 
analysis for futility purpose will be conducted to determine if the study can proceed to Stage 
2.
Stage 2
If 3 or more subjects achieved a response (partial response [PR] or better) out of the 18 
subjects at the end of Stage 1, an additional 32 subjects will be enrolled to evaluate the safety 
and efficacy of DARA plus DURVA.
Part 2: 
Expansion
Upon completion of Part 1, if there are at least 9 subjects who achieved a response (PR or 
better) out of a total of 50 subjects and it is determined by the Sponsor to further confirm the 
efficacy and safety of DARA plus DURVA, an additional 70 subjects may be enrolled.
An Independent Response Adjudication Committee (IRAC) will be set up for this trial to 
perform an independent assessment of the efficacy data. The IRAC will determine tumor 
response to therapy and to confirm the time of disease progression (PD) (if disease progressed) at 
scheduled or unscheduled visits for each subject. 
The safety and efficacy of the study will be monitored by an independent Data Monitoring 
Committee (DMC) who are not involved in the trial conduct. The DMC will meet up and review 
study data at pre-specified intervals throughout the trial.  At time of the interim analysis, the 
DMC will assess the study data for futility. In addition to the DMC review, safety data will be 
monitored by the Celgene Medical Monitor and Safety Physician on an ongoing basis throughout 
the study. Should a significant safety issue be identified, the DMC will be convened to make a 
recommendation as to the future conduct of the study.
The study will be conducted globally and in compliance with the International Council on 
Harmonisation (ICH) Good Clinical Practices (GCPs).
Study Population
The study population will include subjects with multiple myeloma who have received at least 
3 prior lines of anti-myeloma regimens including a PI and an IMiD, or who are double-refractory 
to a PI and an IMiD. In addition, eligible subjects must have had progressive disease while on a 
DARA-containing regimen as the most recent MM therapy.
Approximately 120 subjects will be enrolled into this study.
!
Part 1, Stage 1: ~18 subjects
!
Part 1, Stage 2: ~32 subjects
!
Part 2, Expansion: ~70 subjects 
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!


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
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MEDI4736-MM-005 Final: 03 Oct 2016
Length of Study
The study will consist of the following consecutive phases: Screening, Treatment, and Follow-
up. The Screening Phase may not exceed a 28-day window prior to start of study treatment 
(Cycle 1 Day 1). Subjects may continue on study treatment until PD or unacceptable toxicity. All 
subjects will have an End of Treatment (EOT) visit 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 DURVA or DARA, whichever is later, for safety follow-up visits.
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.
Study Treatments
All subjects will receive: 
!
IV DARA at 16 mg/kg starting at the same dosing schedule as their immediate prior 
DARA regimen. (QW, Q2W, or Q4W of each 28-day cycle). The dosing schedule
may be adjusted during the course of the study as outlined in Section 7.2.  
!
IV DURVA at 1500 mg on Cycle 1 Day 2/28-day cycle then ≥Cycle 2 on Day 1/28-
day cycle
Overview of Key Efficacy Assessments
!
Myeloma paraprotein
!
Serum immunoglobulins
!
Serum free light chains
!
Corrected serum calcium
!
Percent of plasma cells in the bone marrow 
!
Radiographic assessments of lytic bone lesions
!
Extramedullary plasmacytoma (EMP) assessments
!
Response per the International Myeloma Working Group (IMWG) criteria
Overview of Key Safety Assessments
!
Complete physical examination including vital signs
!
Clinical laboratory evaluations
!
Pregnancy testing (FCBP only; see 
!
Electrocardiogram (ECG)
!
Concomitant medications and procedures
!
Adverse events (AEs) 
CCI
CELGENE PROPRIETARY INFORMATION
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Pre
Pre
!


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
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Overview of Key Pharmacokinetic Assessments
!
Serum samples will be collected to assay plasma concentrations of DURVA and 
DARA
 
 
 
 
 
 
Other
!
!
Eastern Cooperative Oncology Group (ECOG) Performance Status
Statistical Methods
The study will be conducted in 2 parts. 
In Part 1, a 2-stage design is used with 1 interim analysis for futility at the end of Stage 1. 
In Stage 1, 18 subjects will be enrolled and if at least 3 subjects out of 18 achieve a response (PR 
or better) by end of Cycle 3, the study will continue to Stage 2. If there are 2 or less subjects 
who achieved a response out of 18 subjects in Stage 1, the study will be terminated for futility 
and will not proceed to Stage 2. 
In Stage 2, an additional 32 subjects will be enrolled.
If it is determined at the end of Part 1 to further evaluate the efficacy and safety of the 
combination regimen of DARA plus DURVA, then up to an additional 70 subjects will be enrolled 
in Part 2. In total, approximately 120 subjects will be included in this study. 
The primary statistical analysis will be based on the full analysis set patient population, 
following the intent-to-treat (ITT) principle. For binary endpoints, the observed rate and 2-sided 
exact 95% confidence intervals (CIs) will be provided. For time-to-event type of endpoints, 
Kaplan-Meier method will be used. The Kaplan-Meier, as well as the median and its 95% CIs 
will be provided. Safety analysis will be based on all subjects who received at least 1 dose of
DARA plus DURVA.
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CELGENE PROPRIETARY INFO
orm
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provided.
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MATION
us DU
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MA
MA
RMA
ORM
OR


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
11
MEDI4736-MM-005 Final: 03 Oct 2016
TABLE OF CONTENTS
TITLE PAGE.................................................................................................................1
PROTOCOL SUMMARY .............................................................................................6
1.
INTRODUCTION..................................................................................... 18
1.1.
Disease Background .................................................................................. 18
1.2.
Compound Background ............................................................................. 18
1.2.1.
Durvalumab (MEDI4736).......................................................................... 18
1.2.2.
Daratumumab............................................................................................ 19
1.3.
Rationale ................................................................................................... 21
1.3.1.
Study Rationale and Purpose .....................................................................21
1.3.2.
Rationale for the Study Design .................................................................. 23
1.3.3.
Rationale for Dose, Schedule and Regimen Selection ................................ 24
1.3.3.1.
Durvalumab............................................................................................... 24
1.3.3.2.
Daratumumab............................................................................................ 24
1.3.3.3.
Potential for Synergistic Toxicities ............................................................ 25
2.
STUDY OBJECTIVES AND ENDPOINTS.............................................. 27
3.
OVERALL STUDY DESIGN ................................................................... 29
3.1.
Study Design ............................................................................................. 29
3.1.1.
Part 1: Selected 2-Stage.............................................................................29
3.1.1.1.
Stage 1....................................................................................................... 29
3.1.1.2.
Stage 2....................................................................................................... 30
3.1.1.3.
Part 2: Expansion....................................................................................... 30
3.2.
Study Duration for Subjects....................................................................... 33
3.3.
End of Trial ............................................................................................... 33
4.
STUDY POPULATION............................................................................ 34
4.1.
Number of Subjects ................................................................................... 34
4.2.
Inclusion Criteria....................................................................................... 34
4.3.
Exclusion Criteria...................................................................................... 36
5.
TABLE OF EVENTS................................................................................ 39
6.
PROCEDURES......................................................................................... 45
6.1.
Screening Period........................................................................................ 45
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9
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TAR


EDMS Doc. Number:
Durvalumab (MEDI4736)
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6.2.
Treatment Period ....................................................................................... 47
6.2.1.
End of Treatment....................................................................................... 48
6.3.
Follow-up Period....................................................................................... 49
6.3.1.
Safety Follow-up ....................................................................................... 49
6.4.
Efficacy Assessments ................................................................................ 50
6.4.1.
Laboratory Assessments for Efficacy Parameters....................................... 50
6.4.2.
Bone Marrow Aspiration and/or Biopsy..................................................... 51
6.4.3.
Bone Lesion Assessment ........................................................................... 51
6.4.4.
Extramedullary Plasmacytoma Assessments.............................................. 52
6.4.5.
Assessment of Response............................................................................ 52
6.4.5.1.
Investigator Assessment............................................................................. 52
6.4.5.2.
Independent Response Adjudication Committee Assessment ..................... 52
6.5.
Pharmacokinetics....................................................................................... 52
6.5.1.
Pharmacokinetics of Durvalumab .............................................................. 53
6.5.2.
Pharmacokinetics of Daratumumab............................................................ 53
6.8.
Blood Type, Rh and Indirect Antiglobulin Test (IAT)................................ 54
7.
DESCRIPTION OF STUDY TREATMENTS........................................... 56
7.1.
Description of Investigational Product(s)................................................... 56
7.1.1.
Durvalumab (MEDI4736).......................................................................... 56
7.1.2.
Daratumumab (Darzalex)........................................................................... 57
7.2.
Treatment Administration and Schedule .................................................... 57
7.2.1.
Treatment Administration.......................................................................... 57
7.2.1.1.
Durvalumab (MEDI4736).......................................................................... 57
7.2.1.2.
Daratumumab (Darzalex)........................................................................... 58
7.2.2.
Treatment Schedule ................................................................................... 60
7.2.2.1.
Daratumumab Plus Durvalumab Treatment Schedule ................................ 60
7.2.3.
Overdose ................................................................................................... 60
7.2.4.
Dose Modifications and Interruptions ........................................................ 60
7.2.4.1.
Dose Modification Instructions for Durvalumab ........................................ 61
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1
...... 52
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
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Confidential and Proprietary
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7.2.4.2.
Dose Modification Instructions for Daratumumab...................................... 61
7.3.
Treatment Assignment............................................................................... 62
7.4.
Packaging and Labeling............................................................................. 62
7.5.
Investigational Product Accountability and Disposal .................................62
7.6.
Investigational Product Compliance........................................................... 62
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................... 63
8.1.
Permitted Concomitant Medications and Procedures.................................. 63
8.2.
Prohibited Concomitant Medications and Procedures.................................63
8.3.
Required Concomitant Medications and Procedures................................... 64
9.
STATISTICAL CONSIDERATIONS ....................................................... 65
9.1.
Overview................................................................................................... 65
9.2.
Study Population Definitions ..................................................................... 65
9.2.1.
Full Analysis Set Population...................................................................... 65
9.2.2.
Efficacy Evaluable Population................................................................... 65
9.2.3.
Safety Population....................................................................................... 65
9.2.4.
Pharmacokinetic Population....................................................................... 65
9.3.
Sample Size and Power Considerations...................................................... 65
9.4.
Background and Demographic Characteristics........................................... 66
9.5.
Subject Disposition.................................................................................... 66
9.6.
Efficacy Analysis....................................................................................... 67
9.6.1.
Primary Efficacy Endpoint......................................................................... 67
9.6.2.
Secondary Efficacy Endpoints ................................................................... 67
9.7.
Safety Analysis.......................................................................................... 67
9.8.
Interim Analysis ........................................................................................ 68
9.9.
Other Topics.............................................................................................. 68
9.9.1.
Pharmacokinetic Analysis.......................................................................... 68
9.10.
Study Committees ..................................................................................... 69
9.10.1.
Data Monitoring Committee ...................................................................... 69
9.10.2.
Independent Review Adjudication Committee ........................................... 69
10.
ADVERSE EVENTS................................................................................. 70
10.1.
Monitoring, Recording and Reporting of Adverse Events .......................... 70
10.2.
Evaluation of Adverse Events.................................................................... 70
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GENE PROPRIETARY INFORMATION
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LGE


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
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10.2.1.
Seriousness................................................................................................ 70
10.2.2.
Severity/Intensity....................................................................................... 72
10.2.3.
Causality ................................................................................................... 72
10.2.4.
Duration .................................................................................................... 73
10.2.5.
Action Taken............................................................................................. 73
10.2.6.
Outcome.................................................................................................... 73
10.3.
Abnormal Laboratory Values..................................................................... 73
10.4.
Pregnancy.................................................................................................. 73
10.4.1.
Females of Childbearing Potential: ............................................................ 74
10.4.2.
Male Subjects............................................................................................ 74
10.5.
Reporting of Serious Adverse Events......................................................... 74
10.5.1.
Safety Queries ........................................................................................... 75
10.6.
Expedited Reporting of Adverse Events..................................................... 75
10.7.
Adverse Events of Special Interest............................................................. 76
11.
DISCONTINUATIONS ............................................................................ 77
11.1.
Treatment Discontinuation......................................................................... 77
11.2.
Study Discontinuation ............................................................................... 77
12.
EMERGENCY PROCEDURES................................................................ 78
12.1.
Emergency Contact.................................................................................... 78
12.2.
Emergency Identification of Investigational Products ................................ 78
13.
REGULATORY CONSIDERATIONS...................................................... 79
13.1.
Good Clinical Practice............................................................................... 79
13.2.
Investigator Responsibilities ...................................................................... 79
13.3.
Subject Information and Informed Consent................................................ 80
13.4.
Confidentiality........................................................................................... 80
13.5.
Protocol Amendments................................................................................ 80
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................... 80
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ...81
13.8.
Termination of the Study ........................................................................... 81
14.
DATA HANDLING AND RECORDKEEPING........................................ 82
14.1.
Data/Documents........................................................................................ 82
14.2.
Data Management...................................................................................... 82
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CELGENE PROPRIETARY INFORMATION
3
...... 74
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3


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
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14.3.
Record Retention....................................................................................... 82
15.
QUALITY CONTROL AND QUALITY ASSURANCE........................... 84
15.1.
Study Monitoring and Source Data Verification......................................... 84
15.2.
Audits and Inspections............................................................................... 84
16.
PUBLICATIONS ...................................................................................... 85
17.
REFERENCES.......................................................................................... 86
18.
APPENDICES........................................................................................... 90
Appendix A:
Table of Abbreviations ......................................................................... 90
Appendix B:
International Myeloma Working Group Uniform Response Criteria......95
Appendix C:
ECOG Performance Status.................................................................... 97
Appendix D:
Staging Systems for Multiple Myeloma ................................................ 98
Appendix E:
Durvalumab Treatment Modification and Toxicity Management 
Guidelines .................................................................................................99
Appendix E-1:
Durvalumab Treatment Modification and Toxicity Management 
Guidelines for Immune-related Adverse Events ......................................... 99
Appendix E-2:
Durvalumab Treatment Modification and Toxicity Management 
Guidelines for Infusion-related Reactions ................................................ 117
Appendix E-3:
Durvalumab Treatment Modification and Toxicity Management 
Guidelines for Non-immune-mediated Reactions..................................... 118
Appendix F:
Guideline for Asthma Eligibility Criteria............................................. 119
CCI
0
...... 95
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..........
.......... 97
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te


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
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LIST OF TABLES
Table 1:
Study Objectives........................................................................................ 27
Table 2:
Study Endpoints ........................................................................................ 27
Table 3:
Dosing Schedules ...................................................................................... 31
Table 4:
Table of Events.......................................................................................... 39
Table 6:
Daratumumab Pre Infusion and Post Infusion Medications ........................ 59
Table 7:
Conversion Table for Glucocorticoid Dose ................................................ 59
Table 8:
Daratumumab-related Toxicity Management ............................................. 61
Table 9:
Estimated Overall Response Rate and 95% Confidence Interval Out of 120 
Subjects..................................................................................................... 66
Table 10:
Abbreviations and Specialist Terms........................................................... 90
Table 11:
Staging Systems for Multiple Myeloma ..................................................... 98
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59
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
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LIST OF FIGURES
Figure 1:
Mechanism of Action for Durvalumab....................................................... 19
Figure 2:
Mechanisms of Daratumumab Activity...................................................... 20
Figure 3:
Overall Study Design................................................................................. 32
Figure 4:
Study Schematic ........................................................................................ 33
CCI
CELGENE PROPRIETARY INFORMATION


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
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Confidential and Proprietary
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1.
INTRODUCTION 
1.1.
Disease Background 
Multiple myeloma (MM) is a rare and incurable progressive neoplastic disease that accounts for 
10% of all hematological malignancies. It has been estimated that 63,700 incident cases and 
79,410 deaths from MM occurred globally in 2013 (GBD, 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, carfilzomib, and ixazomab) or with autologous stem cell transplant 
following high-dose chemotherapy and more recently monoclonal antibodies (eg, daratumumab, 
elotuzumab) (National Comprehensive Cancer Network [NCCN]-MM Guidelines, 2016). The 
main considerations for choosing an appropriate treatment for relapsed and refractory multiple 
myeloma (RRMM) are: risk level, prior therapy, duration of response to prior therapy, residual 
toxicity, age, physical condition, and whether the patient is a candidate for stem cell 
transplantation (NCCN-MM Guidelines, 2016). 
Despite the progress in treatment options for MM, the disease follows a relapsing course in the 
majority of patients, regardless of treatment regimen or initial response to treatment. Multiple 
myeloma remains incurable using conventional treatments, with an overall 5-year relative 
survival rate of 48.5% (Howlader, 2016). New therapies are needed to treat RRMM patients.
1.2.
Compound Background 
1.2.1.
Durvalumab (MEDI4736)
Durvalumab (MEDI4736; DURVA) is a human immunoglobulin (Ig) G1 kappa monoclonal 
antibody (mAb) directed against human programmed death ligand-1 (PD-L1) protein. 
Durvalumab is expressed in Chinese hamster ovary cells and has an overall molecular weight of 
approximately 149 kDa. Durvalumab selectively binds human PD-L1 with high affinity and 
blocks its ability to bind to programmed cell death 1 (PD-1) protein and cluster of differentiation 
(CD)80. The fragment crystallizable (Fc) domain of DURVA contains a triple mutation in the 
constant domain of the IgG1 heavy chain that reduces binding to the complement component 
C1q and the Fc gamma receptors responsible for mediating antibody-dependent cell-mediated 
cytotoxicity (ADCC) (Oganesyan, 2008).
CCI
CELGENE PROPRIETARY INFORMATION
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Ogane


EDMS Doc. Number:
Durvalumab (MEDI4736)
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Figure 1:
Mechanism of Action for Durvalumab
Refer to the DURVA Investigator’s Brochure (IB) for detailed information concerning the 
available pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) 
profile of the investigational product (IP).
1.2.2.
Daratumumab
Daratumumab (DARA) is a human IgG1k monoclonal antibody that binds with high affinity to a 
unique epitope on CD38. It is a targeted immunotherapy that attacks tumor cells that overexpress 
CD38, a transmembrane glycoprotein, in a variety of hematological malignancies including 
multiple myeloma. Daratumumab was approved under the accelerated approval regulations in the 
United States (US) on 16 November 2015, and in the European Union (EU) on 24 May 2016, for 
the treatment of patients with multiple myeloma who have received at least three prior lines of 
therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are 
double-refractory to a PI and an immunomodulatory agent.
Daratumumab induces tumor cell death through diverse mechanisms of action, which include 
complement-dependent cytotoxicity (CDC), antibody dependent cell-mediated cytotoxicity
(ADCC), antibody-dependent cellular phagocytosis, and induction of apoptosis (de Weers, 2011; 
Lammerts van Bueren, 2014; Overdijk, 2015; Jansen 2012).  
CCI
CELGENE PROPRIETAR
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EDMS Doc. Number:
Durvalumab (MEDI4736)
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Figure 2:
Mechanisms of Daratumumab Activity
Krejcik, 2015
Daratumamab was shown as a single agent, in heavily pretreated patients with relapsed or
relapsed and refractory multiple myeloma, to have an overall response rate of 31% and a median 
overall survival of 20.1 months (Usmani, 2016). In addition, daratumamab in combination with 
bortezomib and dexamethasone (Vd) as well as Revlimid® and dexamethasone (Rd) have been 
shown to be effective.  The DARA plus Vd (DVd) combination was tested in the CASTOR trial, 
where 498 patients were randomized between Vd and DVd (Palumbo, 2016). A prespecified 
interim analysis showed that the rate of progression-free survival (PFS) was significantly higher 
in the DVd group than in the control group; the 12-month rate of PFS was 60.7% in the DVd
group versus 26.9% in Vd group. After a median follow-up period of 7.4 months, the median 
PFS was not reached in the DVd group and was 7.2 months in the Vd group (hazard ratio for 
progression or death with daratumumab versus control, 0.39; 95% confidence interval (CI), 0.28 
to 0.53; p<0.001). The rate of overall response (ORR) was higher in the DVd group than in the 
Vd group (82.9% versus. 63.2%, p<0.001), as were the rates of very good partial response
(VGPR) or better (59.2% versus. 29.1%, p<0.001) and complete response (CR) or better (19.2% 
versus. 9.0%, p = 0.001).  In the POLLUX trial (Dimopoulos, 2016), the DARA plus Rd (DRd) 
regimen was tested against Rd in a population of 569 patients with at least one prior therapy and 
maintaining sensitivity to Revlimid®. After a median follow-up of 13.5 months, DRd 
significantly improved patients’ median PFS, with the median PFS in the DRd group being not 
reached, compared with 18.4 months in the Rd arm (p<0.0001), translating to a 63% reduced risk 
of disease progression or death compared with Rd (hazard ratio = 0.37; 95% CI 0.27-0.52; 
CCI
CELGENE PROPRIETARY INFORMATION
nt, i
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aint
i t


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
21
MEDI4736-MM-005 Final: 03 Oct 2016
p<0.0001). Similarly, overall survival at 18 months was higher for daratumumab-treated patients: 
86 % for DRd and 76 % for Rd. Daratumumab led to a higher ORR, more than doubling the rate 
of CRs or better: ORR: 93% versus. 76% (p<0.0001), ≥ VGPR: 76% versus. 44% (p<0.0001)
and ≥ CR: 43% versus. 19% (p<0.0001).  The median duration of response was longer in the 
DRd group (not reached versus. 17.4 months) and the median time to response was shorter (1 
month versus. 1.3 months), 
Refer to the DARA IB for detailed information concerning the available pharmacology, 
toxicology, drug metabolism, clinical studies, and AE profile; as well as the current US label 
(Darzalex™Prescribing Information [PI], 2015) and Summary of Product Characteristics 
[SmPC] for the EU.
1.3.
Rationale
1.3.1.
Study Rationale and Purpose
The importance of the immune system in cancer development and progression has been 
recognized during the past decade (Hanahan, 2000). Failure of immune surveillance of pre-
neoplastic lesions and micro-metastases is a key step in cancer development. Chronically 
immunosuppressed individuals show higher rates of cancer. This observation led to the 
hypothesis that sporadic cancers among immune-competent individuals are likely to be 
minimally immunogenic, allowing for passive escape from immune surveillance. Recent data 
suggest that this may be an oversimplification. Some sporadic tumors are highly immunogenic, 
but actively suppress the local immune environment through production of immunosuppressive 
cytokines (Shields, 2010). As such, the local tumor environment is likely a highly dynamic 
environment where most tumors grow and metastasize through adaptive responses that modulate 
antitumor immunity. The complexity and redundancy of the immune system offers multiple 
targets that may be manipulated to maximize the body’s inherent immune response to a tumor. 
Immune response may be augmented by directly stimulating effector cells, indirectly stimulating 
effectors by augmenting antigen presentation activity or costimulation, or by suppressing 
immunosuppressive factors, cells, or messages (Monti, 2005).
DARA acts through multiple immune effector-mediated mechanisms, including CDC, ADCC, 
and antibody-dependent cellular phagocytosis.  In addition to direct targeting of CD38+ 
myeloma cells, recently published data suggests an immune stimulating/modulatory role of 
DARA. Increases in CD8+, CD4+ T cell ratios, antiviral responses, and T cell clonality were all 
observed after DARA treatment in a heavily pretreated, relapsed, and refractory patient 
population not expected to have strong immune responses (Krejcik, 2015). Improved clinical
responses were associated with changes in these parameters. In addition, DARA was shown to 
deplete regulatory T cells (Tregs) that express high levels of CD38. Reduction of these immune 
suppressive Tregs may promote expansion of cytotoxic CD8+ T cells which could have 
additional anti-tumor effects.  These data suggest an immune modulatory role of DARA that may 
contribute to its efficacy. (Krejcik, 2015).
The mechanism of resistance to DARA remains to be fully explained, but immune escape by 
upregulation of PD-L1 signaling through PD-1 is hypothesized to contribute to resistance. 
Adding durvalumab, while continuing daratumumab is hypothesized to potentially reverse this 
mechanism of resistance.
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contribute
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he m
he m


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
22
MEDI4736-MM-005 Final: 03 Oct 2016
Durvalumab (MEDI4736; DURVA) is a human IgG1 kappa mAb directed against human PD-L1
protein. Durvalumab selectively binds human PD-L1 with high affinity and blocks its ability to 
bind to PD-1 protein and cluster of differentiation (CD) 80. PD-1 is highly expressed on MM 
patient’s T cells and natural killer (NK) cells; and both plasmacytoid dendritic cells (pDCs) and 
MM cells express PD-L1. Dysfunctional T cells, NK cells, and functionally defective pDCs 
contribute to the immune suppression in MM (Chauhan, 2009; Ray, 2015). It has been shown 
that pDCs produce T cell and NK cell immune suppression in the MM bone marrow (BM) milieu 
by engaging immune checkpoints via the PD-L1/PD-1 signaling axis (Ray, 2015). Blockade of 
PD-L1/PD-1 using anti-PD-L1 antibody generates MM-specific CD8+ cytotoxic T lymphocyte 
activity, as well as enhances NK-cell-mediated MM cell cytolytic activity. 
As PD-L1-expressing pDCs are increased in MM bone marrow and localize with PD-L1-positive 
MM cells (Chauhan, 2009), PD-L1 expression may correlate with progression of disease, with 
highest levels in relapsed or relapsed/refractory MM. Indeed, a recent study showed that PD-L1 
expression positively correlates with increased proliferative potential of tumor cells and 
resistance to therapies in MM (Tamura, 2013). Combination treatment of anti-PD-L1 mAb, like
DURVA, with other anti-MM therapies that modulate MM-host immune responses, like DARA 
will potentially enhance both host anti-MM immunity and clinical response and warrant further 
exploration in the relapsed/refractory population being considered in this study.
The future of successful MM treatment lies in both the development of novel agents targeting the 
MM cells or the bone marrow microenvironment, and the development of rationally based 
combination therapies. As DARA use post approval, either alone, or in combination, increases, it 
is expected that patients who fail DARA-containing regimens will require new therapeutic 
options.
Targeted immunotherapy based on monoclonal antibodies against relevant tumor antigens has 
not only shown to be feasible, but also an effective approach in treating hematological 
malignancies. However, treatment options for heavily treated patients are limited, especially for 
those with disease that is double refractory to a PI and an immunomodulatory drug (IMiD®)
(Laubach, 2016). To date, targeting MM cells by a combination-therapy approach has 
demonstrated superior clinical response as compared with that of single agents (Cavo, 2011). In 
theory, combination treatment of anti-PD-L1 mAb, like DURVA, with other anti-MM therapies 
that modulate MM-host immune responses, like DARA, may enhance both host anti-MM 
immunity and clinical response and warrant further exploration in a relapsed/refractory 
population being considered in this study.  The importance of the PD-L1:PD-1 interaction has 
been recently further substantiated.  In a recent study, PD-L1–expressing myeloma cells treated 
with PD-1 molecules were shown to have induction of drug resistance through activation of the
Akt signaling pathway (Ishibashi, 2016). These results suggest that in the bone marrow
microenvironment, the interaction between PD-L1 on myeloma cells and PD-1 on tumor-specific 
CTLs not only inhibits CTL activity via the PD-1 signaling pathway but also induces drug 
resistance via PD-L1mediated reverse signals.
Current treatments may mitigate, but are unable to completely circumvent, the inherent genomic 
instability and clonal heterogeneity that leads to recurrent relapses and ultimately refractory MM.  
In addition, in the era of novel agents, where MM patients are surviving longer, physicians are 
encountering more resistant and atypical relapses. Salvaging such patients becomes particularly 
CCI
CELGENE PROPRIETARY INFORMATION
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
23
MEDI4736-MM-005 Final: 03 Oct 2016
challenging and their prognosis often remains dismal (Phipps, 2015).  There remains an unmet 
need for novel therapies that target different mechanisms of action. 
The principle of overcoming resistance to an agent through continuation of that agent alone or in 
conjunction with the addition of a second agent or combination has been explored more 
extensively in the area of solid tumors.  In lung cancer, discontinuation of epidermal growth 
factor receptor inhibitors (erlotinib and gefitinib) for radiographic progression resulted in 
increased rapidity of radiographic progression and onset of symptomatic progression that could 
be controlled by reinstitution of the same agents (Riely, 2007) with reduction in maximum 
standardized uptake value measurements. In melanoma, withdrawal of treatment after isolated 
progression of MAPK inhibitors in preparation for a new clinical trial sometimes led to rapid 
growth of remaining disease which had been controlled prior to that time point (Carlino, 2013).  
Multiple retrospective and prospective reports have described the clinical benefit potentially 
accruing from continuing particular agents in terms of PFS or overall survival (OS) in breast and 
colorectal cancers.  Specific examples include continuation of bevacizumab or cetuximab while 
switching to differing chemotherapy regimens in colon cancer (Masi, 2015; Ciardiello, 2016), 
and continuation of trastuzumab beyond progression in breast cancer (von Minckwitz, 2011; 
Jackish, 2014).  
Overcoming resistance and restoring a functional immune- surveillance system requires 
leveraging multiple, complementary mechanisms of action and agents that act in multiple phases 
of the cancer-immunity cycle. As such, combination immunotherapies that involve various 
phases of the cancer–immunity cycle may enhance the ability to prevent immune escape by 
targeting multiple mechanisms by which tumor cells avoid elimination by the immune system 
and with synergistic effects that may offer improved efficacy in broader patient populations 
(Morrissey, 2016). As CD38 expression is tied to response in patients with prior DARA 
treatment, and loss of CD38 correlates with development of resistance (Nijhof, 2016), it may be
the case that controlling disease after progression with DARA treatment may also require 
continuation of DARA to continue control of sensitive disease clones, with the addition of 
DURVA providing additional therapeutic benefit for control of remaining clones no longer 
expressing CD38.  
1.3.2.
Rationale for the Study Design
The study will be conducted in 2 parts: Part 1 and Part 2. 
Part 1 has a selected 2-stage design, where a limited number of subjects will be enrolled in Stage 
1 to ensure a sufficient efficacy signal is seen prior to enrolling additional subjects in Stage 2.
While durvalumab has been dosed to over 1,910 patients and is currently being evaluated in over 
30 Phase 3 clinical trials and daratumumab has received marketing approval, the combination of
these two agents has not yet been extensively studied. An ongoing Phase 2 clinical study,
MEDI4736-MM-003, is evaluating this two drug combination and is expected to provide
evidence of safety and tolerability prior to the initiation of this study. However, if these safety
data to clearly support the expected Phase 2 dose and schedule are not available prior to initiation
of this study, a safety run-in phase will be conducted prior to further enrollment of this study.
Once 6 subjects have been enrolled and completed the first treatment cycle in Stage 1 of this 
study, the enrollment continuity would depend on the availability of safety data from the ongoing 
CCI
CELGENE PROPRIETARY INFORMATION
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
24
MEDI4736-MM-005 Final: 03 Oct 2016
Phase 2 study (MEDI4736-MM-003) of DARA and DURVA in previously DARA-naïve 
patients. Details are provided in Section 3.1. 
If data are available and the safety profile of DARA plus DURVA has been evaluated as 
tolerable, enrollment in Part 1 Stage 1 will not be paused.
Part 2 will consist of an expansion phase and will be initiated once Part 1 has been completed 
and if a sufficient efficacy signal has been determined by the Sponsor at the end of Part 1, Stage 
2. 
1.3.3.
Rationale for Dose, Schedule and Regimen Selection
1.3.3.1.
Durvalumab
Nonclinical safety of DURVA was assessed in the pivotal Good Laboratory Practice (GLP) 13-
week intravenous (IV) repeat-dose toxicity study in sexually mature cynomolgus monkeys. 
Animals received an IV loading dose of 30, 60 or 200 mg/kg of DURVA on Day 1, followed by 
13 weekly IV doses of 15, 30 or 100 mg/kg, respectively. Animals were euthanized 3 days after 
the final dose, or after an 8-week treatment-free period. In the majority of animals exposure to 
DURVA and pharmacodynamics (as assessed by serum levels of free soluble PD-L1) were 
maintained throughout the dosing period. The IV administration of DURVA was not associated 
with any treatment-related effects on any of the endpoints studied (including clinical signs, 
bodyweights, ophthalmology, safety pharmacology endpoints (electrocardiograms [ECGs], 
respiratory rate, blood pressure and neurological examinations), peripheral blood leukocyte 
counts, clinical pathology parameters or gross and microscopic histopathology). The no observed 
adverse effect level (NOAEL) for DURVA in this study was therefore considered to be the 
200/100 mg/kg dose (area under the curve [AUC] = 34,900 μg·d/mL, maximum plasma 
concentration [Cmax] of drug = 7,470 μg/mL), the highest dose tested. 
Based on the data from the GLP 3-month toxicity study in cynomolgus monkeys and the 
resultant safety margins, the Sponsor believes that the safety of these doses is supported by the 
existing nonclinical safety data.
As per the latest IB (Version 9), with data cut off dates of 15 April 2015 to 18 September 2015, 
1,910 subjects have been treated across 30 ongoing DURVA studies, including 20 sponsored 
(6 monotherapy and 14 combination therapy) and 10 collaborative studies. Of the 1,910 
subjects, 1,279 received DURVA monotherapy, 468 received DURVA in combination with other 
agents, and 163 have been treated with blinded investigational product. No studies have been 
completed or terminated prematurely due to toxicity.
The maximally administered dose of DURVA to humans in clinical trials conducted to date has 
been 20 mg/kg, which is equivalent to the 1500 mg every 4 weeks (Q4W) starting dose proposed 
in study MEDI4736-MM-003.  Doses of DURVA up to 20 mg/kg as monotherapy did not define 
a non tolerated dose.
1.3.3.2.
Daratumumab
The DARA dose/schedule will be as per the current approved label in the US (Darzalex PI) and 
Summary of Product Characteristics [SmPC] for the EU.
CCI
CELGENE PROPRIETARY INFORMATION
ice (
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.3.3.2


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
25
MEDI4736-MM-005 Final: 03 Oct 2016
1.3.3.3.
Potential for Synergistic Toxicities
There are no completed studies of anti-CD38 combined with PD-1 or PD-L1 inhibitors. These 
molecular targets do not have known mechanistic synergies, although variation in the co-
expression of CD38/PD-1 has been studied as a marker of human immunodeficiency virus 
(HIV) infection, as a possible sign immune activation (Vollbrecht, 2010).  Related cases of 
pneumonia or interstitial lung disease (ILD) have been reported with DARA (11%) (Darzalex
PI), targeting CD38, and durvalumab (2%) (DURVA IB), targeting PD-L1. However, infections, 
and specifically pneumonias and ILDs, are well known clinical conditions in MM patients. With 
the exception of infusion-related reactions, the addition of DARA to standard MM treatment 
regimens did not seem to add toxicity to the safety profiles previously reported with these 
backbone regimens (Darzalex PI).  No other known synergistic toxicities are expected with 
DURVA and DARA.
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
CCI
CCI
PROPRIETARY INFORMATION
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
26
MEDI4736-MM-005 Final: 03 Oct 2016
 
 
CCI
CCI
CELGENE PROPRIETARY INFORMATION


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
27
MEDI4736-MM-005 Final: 03 Oct 2016
2.
STUDY OBJECTIVES AND ENDPOINTS
Table 1:
Study Objectives
Primary Objective
The primary objective of the study is to determine the efficacy of daratumumab (DARA) plus
durvalumab (DURVA) in subjects with relapsed and refractory multiple myeloma (RRMM) who have 
progressed on a current treatment regimen containing DARA.
Secondary Objective(s)
The secondary objectives are to:
!
Determine the safety of DARA plus DURVA in subjects with RRMM who have progressed 
while on a current treatment regimen containing DARA.
!
Evaluate additional measures of efficacy of DARA plus DURVA in subjects with RRMM who 
have progressed on a current treatment regimen containing DARA.
!
Evaluate the pharmacokinetics (PK) of DARA plus DURVA in subjects with RRMM who
have progressed on a current treatment regimen containing DARA.
 
 
 
 
 
Table 2:
Study Endpoints
Endpoint
Name
Description
Primary 
Overall response rate (ORR)
Tumor response (partial response [PR] or better), and the 
rate of progressive disease (PD) according to the
International Myeloma Working Group (IMWG) Uniform
Response Criteria (Rajkumar, 2011).
Secondary
Safety
Type, frequency, seriousness and severity of adverse
events (AEs), and relationship of AEs to study
treatment
Secondary
Time-to-response (TTR)
Time from treatment initiation to the first 
documentation of response (PR or greater)
CCI
CCI
CELGENE PROPRIETARY INFORMATION
AT
AT
AT
AT
e progressed
progresse
ects with RR
ects with R
bjects with R
bjects with 
RA.
RA.
MA
Y I
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PR
Endpoints
Endpoin
Na
Na
NE
Overall re
Overall re
EN
LG
econdary
econdary
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TAR
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RIE
OPR
ROP
RO


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
28
MEDI4736-MM-005 Final: 03 Oct 2016
Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Secondary 
Duration of response (DOR)
Time from the first documentation of response
(PR or greater) to the first documentation of PD or death, 
whichever is earlier, based on the investigator 
assessments according to the IMWG Uniform Response 
Criteria.
Progression-free survival 
(PFS)
Time from treatment initiation to the first documentation 
of PD or death from any cause during study, whichever
occurs earlier
Overall survival (OS)
Time from treatment initiation to death due to any cause
Secondary
Pharmacokinetic (PK)
parameters
Typical serum/plasma PK parameters for DURVA and 
DARA, 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)
 
 
 
 
 
 
 
  
 
 
CCI
CCI
CELGENE PROPRIETARY INFORMATION
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CEL


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
29
MEDI4736-MM-005 Final: 03 Oct 2016
3.
OVERALL STUDY DESIGN
3.1.
Study Design
This is a single-arm, multicenter, Phase 2 study to evaluate the efficacy and safety of the 
combination regimen of daratumumab plus durvalumab (D2). The study will consist of 2 parts; 
Part 1 has a 2-stage design while Part 2 consists of an expansion phase. Subjects will receive 
intravenous (IV) DARA at 16 mg/kg on the same dosing schedule (weekly [QW], every 2 weeks 
[Q2W]or every 4 weeks [Q4W] of each 28-day cycle) received on their last prior therapy 
containing DARA. The dosing schedule for DARA may be adjusted during the course of the 
study as outlined in Section 7.2.2.1. Subjects will also receive IV DURVA at 1500 mg on Day 2 
(Cycle 1) and on Day 1 (Cycles ≥ 2) of each 28-day treatment cycle. The dosing schedule is 
outlined in Table 3.
3.1.1.
Part 1: Selected 2-Stage 
3.1.1.1.
Stage 1
A cohort of 18 subjects will be enrolled to determine the preliminary efficacy of DARA plus 
DURVA. Once the 18 subjects have been enrolled, an interim analysis for futility purpose will 
be conducted to determine if the study can proceed to Stage 2.
3.1.1.1.1. Early Safety Monitoring
Once 6 subjects have been enrolled and completed the first treatment cycle in Stage 1 of this 
study, the enrollment continuity would depend on the availability of safety data from the on-
going Phase 2 study (MEDI4736-MM-003) of DARA and DURVA in previously DARA-naïve 
patients.
!
If MEDI4736-MM-003 safety data are available and the tolerability profile of DARA
plus DURVA has been determined to be adequate, then enrollment will continue as 
planned in Stage 1 without an early safety monitoring review of the data.
!
If safety data are not available enrollment in this study will be paused for a review of 
the safety profile of DARA plus DURVA by a Dose Review Team (DRT), using the 
data from the first 6 patients.
∃
If ≥ 1 of the first 6 patients experiences a dose-limiting toxicity (DLT) as outlined 
in Section 3.1.1.1.1.1, the study will be halted for review and a change in the 
dosing regimen may be implemented.
∃
The DRT will consist of the Celgene Medical Monitor, Celgene lead Safety 
Physician, Celgene biostatistician, other Celgene functional area representatives, 
as appropriate, and site investigator and/or designees who have enrolled subjects 
to the study.
∃
All available safety and, if applicable, PK/(
 and 
preliminary efficacy data will be reviewed and can be considered in the DRT’s 
decisions.
CCI
CCI
CELGENE PROPRIETARY INFORMATION
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
30
MEDI4736-MM-005 Final: 03 Oct 2016
∃
A DRT meeting will be held to review all data and make decisions regarding 
continuity of the study. 
3.1.1.1.1.1.
Dose-limiting Toxicity
Dose-limiting toxicities (DLTs) may be evaluated during the DLT evaluation period for the 
initial 6 patients in Part 1 of the study. The DLT evaluation period will be defined as the first 
treatment cycle. Subjects are considered evaluable for assessment of DLT if they:
!
Receive at least 1 dose of study treatments and experience a DLT 
OR
!
Receive 1 dose of DURVA, 4 doses of DARA and complete the safety follow-up 
through the end of the DLT evaluation period. 
Grading of DLTs will be according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) Version 4.03.
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 (≥ 38.5 °C) 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 
pretreatment baseline level within 72 hours
e.
Grade 4 anemia, unexplained by underlying disease.
Non-hematologic DLT
a.
Any nonhematological toxicity ≥ Grade 3 except for alopecia and nausea controlled 
by medical management
b. Any treatment interruption greater than 2 weeks due to an AE.
While the rules for adjudicating DLTs in the context of dose escalation 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.
3.1.1.2.
Stage 2
If 3 or more subjects achieved a response (PR or better) out of the 18 subjects at the end of Stage 
1, an additional 32 subjects will be enrolled to evaluate the safety and efficacy of DARA plus 
DURVA. 
3.1.1.3.
Part 2: Expansion
Upon completion of Part 1, if at least 9 subjects achieve a response (PR or better) out of a total of 
50 subjects and it is determined to further confirm the efficacy and safety of DARA plus 
DURVA, an additional 70 subjects may be enrolled. 
CCI
CELG
iti
GENE PROPRIETARY INFORMATION
low-up 
w-up 
Termino
erminololo
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ys duration
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VA. 
VA. 
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.1.1.3.
Upon c
Upon c


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
31
MEDI4736-MM-005 Final: 03 Oct 2016
An Independent Response Adjudication Committee (IRAC) will be set up for this trial to review 
study data. The IRAC will determine tumor response to therapy and to confirm the time of 
disease progression (PD) (if disease progressed) at scheduled or unscheduled visits for each 
subject. 
The safety and efficacy of the study will be monitored by an independent Data Monitoring 
Committee (DMC) who are not involved in the trial conduct. The DMC will meet up and review 
study data at pre specified intervals throughout the trial. 
In the event that the trial is halted for early safety monitoring, as outlined in Section 3.1.1.1.1, 
evaluation of the emerging safety data from the initial 6 patients enrolled in Part 1 will be 
performed by the Dose Review Team (DRT).  
Safety data will be monitored by the Celgene Medical Monitor and Safety Physician on an 
ongoing basis throughout the study. Should a significant safety issue be identified, the DMC will 
be convened to make a recommendation as to the future conduct of the study.
The decision to discontinue a subject, which will not be delayed or refused by the Sponsor, 
remains the responsibility of the treating physician. However, prior to discontinuing a subject, 
the Investigator may contact the Medical Monitor and forward appropriate supporting documents 
for review and discussion.
The study will be conducted in compliance with the International Council on Harmonisation 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good 
Clinical Practice (GCP) and applicable regulatory requirements.
Table 3:
Dosing Schedules
IV DURVA 
(Dose: 1500 mg)
IV DARA
(Dose: 16 mg/kg)
Cycle 1: Day 2 / 28-day cycle
Cycle ≥ 2: Day 1 / 28-day cycle
Subjects should start study treatment on the same 
dosing schedule as their last DARA-containing 
regimen (QW, Q2W, or Q4W)
The dosing schedule should be modified, during the 
course of the study, as shown below, provided that 
the subject has a response of stable disease (SD) or 
better:
QW frequency (Days 1, 8, 15, and 22/ 28-day 
cycle): Weeks 1 to 8 then Q2W Weeks 9 to 24
Q2W frequency (Days 1, 15/ 28-day cycle): Weeks 
1 to 16 then Q4W
Q4W frequency (Day 1/28-day cycle): Week 1
onwards until disease progression
DARA= daratumumab; DURVA=durvalumab; IV= intravenously; QW=weekly; Q2W=every 2 weeks; Q4W=every 
4 weeks.
CCI
CELGENE PROPRIETARY INFORMATION
n on an 
n on an 
d, the DMC
d, the DM
d by
d by the S
the S
y
p
discont
discontinui
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opririate sup
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rmaceut
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irements.
irements.
ET
RI
PR
CE
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DARA= d
DARA=
week
week


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
32
MEDI4736-MM-005 Final: 03 Oct 2016
Figure 3:
Overall Study Design
CCI
CELGENE PROPRIETARY INFORMATION


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
33
MEDI4736-MM-005 Final: 03 Oct 2016
Figure 4:
Study Schematic
3.2.
Study Duration for Subjects 
The study will consist of the following consecutive phases: Screening, Treatment, and Follow-
up. The Screening Phase may not exceed a 28-day window prior to start of study treatment 
(Cycle 1 Day 1). Subjects may continue on study treatment until PD or unacceptable toxicity. All 
subjects will have an End of Treatment (EOT) visit 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 DURVA or DARA for safety follow-up visits. 
3.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analysis, as pre specified in the protocol, 
whichever is the later date.
CCI
CELGENE PROPRIET
ts 
ts 
onsecut
onsecutive
i
eed a
eed a 28-
2
d
tinue on st
inue on st
eatment (E
eatment (E
e to return t
 to return t
se of DU
se of D R
Trial
Trial
al is defined
al is defined
nt f
nt fol
ol
f
ATION
lolow-u
-u
or primary
primary
ver i
ve
s the l
the l


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
34
MEDI4736-MM-005 Final: 03 Oct 2016
4.
STUDY POPULATION
4.1.
Number of Subjects 
Up to approximately 120 subjects with RRMM will be enrolled worldwide. 
!
Part 1, Stage 1: Up to 18 subjects
!
Part 1, Stage 2: Up to 32 subjects
!
Part 2, Expansion: Up to 70 subjects
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject received at least 3 prior anti-myeloma regimens including a PI and an 
immunomodulatory agent or is double-refractory to a PI and an immunomodulatory 
agent. 
!
Induction, bone marrow transplant with or without maintenance therapy is 
considered one regimen.
!
Refractory is defined as disease that is nonresponsive on therapy, or progresses 
within 60 days of last therapy. Nonresponsive disease is defined as either failure to 
achieve minimal response or development of progressive disease while on therapy.
!
For subjects who received more than 1 regimen containing a PI their disease must be 
refractory to the most recent PI containing regimen.
!
For subjects who received more than 1 regimen containing a immunomodulatory 
agent their disease must be refractory to the most recent immunomodulatory agent 
containing regimen.
2. All subjects must have failed DARA either as a single agent or in combination on last
MM therapy. Failure is defined as PD on DARA either as a single agent or in 
combination.
3. Subject has measurable disease defined as:
a.
M-protein (serum protein electrophoresis (sPEP) or urine protein electrophoresis 
(uPEP): sPEP ≥0.5 g/dL or uPEP ≥ 200 mg/24 hours) and/or 
b. Light chain MM without measurable disease in the serum or the urine: serum 
immunoglobulin free light chain ≥10 mg/dL and abnormal serum 
immunoglobulin kappa lambda free light chain ratio
4. Subject achieved a response (minimal response [MR] or better) to at least 1 prior 
treatment regimen.
5. Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status score 
of 2 or less.
6. Subject’s toxicities resulting from previous therapy (including peripheral neuropathy) 
have resolved or stabilized to ≤Grade 1.
CCI
CELGENE PROPRIETARY INFORMATION
and an
nd an 
unomodula
unomodu
enance the
nance the
sive
ive on ther
th
disease is de
ease is d
f progressiv
f progress
regimen co
regimen co
aining regim
aining regim
than 1 regi
than 1 regi
fractory to 
fractory to
ed DARA
DARA
defined as 
defined as 
urable dise
urable di
otein (seru
tein (seru
PEP): sPEP
PEP): sPEP
Li
Light chai
ght cha
immun
immun
imm
imm
. Subject 
Subject
treat
trea
5. S


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
35
MEDI4736-MM-005 Final: 03 Oct 2016
7. Subject is at least 18 years of age at the time of signing the informed consent form (ICF). 
8. Subject must understand and voluntarily sign an ICF prior to any study-related 
assessments/procedures being conducted. 
9. Subject is willing and able to adhere to the study visit schedule and other protocol 
requirements.
10. Females of childbearing potential (FCBP1) must:
a.
Have 2 negative pregnancy tests as verified by the investigator prior to starting 
study treatment. This applies even if the subject practices true abstinence from 
heterosexual contact.
i. Negative serum pregnancy test at screening 
ii. Negative serum or urine pregnancy test (investigator’s discretion) within 
72 hours prior to starting study treatment (Cycle 1, Day 1), and before
beginning each subsequent cycle of treatment, and after end of study 
treatment. 
1.
Note: Pregnancy testing does not need to be repeated prior to Cycle 1 if the 
serum pregnancy test for screening was performed within 72 hours of the first 
dose of study treatment.
b. Either practice true abstinence2 from heterosexual contact (which must be 
reviewed on a monthly basis and source documented) or agree to use, and be able 
to comply with, effective contraception without interruption (eg, oral, injectable, 
or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier 
contraceptive with spermicide; true abstinence; or vasectomized partner), 28 days 
prior to starting study treatment, during the study therapy (including dose 
interruptions), and for at least 90 days after discontinuation of study treatment. 
c.
Agree to abstain from breastfeeding during study participation and for at least 90 
days after the last dose of DARA or DURVA, whichever is later.
d. Refrain from egg cell donation for at least 90 days after the final dose of DURVA 
or DARA, whichever is later.
11. Male subjects must:
a.
Either 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 female 
of childbearing potential 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. 
b. Refrain from sperm donation for at least 90 days after the final dose of DURVA 
or DARA, whichever is later.
                                               
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.
CCI
CE
CELGENE PROPRIETARY INFORMATION
om
etion) with
etion) with
), and befo
), and befo
er end of st
er end of st
ated p
ted prio
rior to C
r to
o
med within 7
med within 
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thout interru
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tubal ligat
tubal ligati
bstinence; o
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uring the st
uring the s
0 days afte
days afte
feeding dur
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DARA or 
DARA or 
donation for
donation fo
er is later.
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ce true abs
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even if he h
even if he h
Refrain 
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or DA
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CE
1 A female
A female
underg
underg
l


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
36
MEDI4736-MM-005 Final: 03 Oct 2016
4.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Subject has had prior exposure to anti-CTLA-4, anti-PD-1, anti-PD-L1 mAbs, or cancer 
vaccines
2. Subject has received autologous stem cell transplantation (ASCT) within 12 weeks before 
the date of randomization.
3. History of organ or allogeneic stem cell transplantation
4. Subject received any of the following within the last 14 days of initiating study treatment:
a.
Plasmapheresis
b. Major surgery (as defined by the investigator)
c.
Radiation therapy other than local therapy for myeloma associated bone lesions
d. Use of any systemic anti-myeloma drug therapy (except for DARA either alone or in 
combination with other agents given with it)
5. Subject received prior treatment with a monoclonal antibody within 5 half-lives of 
initiating study treatment, other than DARA.
6. Subject is receiving concurrent chemotherapy or biologic or hormonal therapy for cancer 
treatment. Note: Concurrent use of hormones for noncancer-related conditions (eg, 
insulin for diabetes and hormone replacement therapy) is acceptable.
7. Subject has any of the following laboratory abnormalities:
a.
Absolute neutrophil count (ANC) < 1,000/μL
b. Platelet count: < 75,000/μL (it is not permissible to transfuse a subject to reach 
this level)
c.
Hemoglobin < 8 g/dL (< 4.9 mmol/L)(it is not permissible to transfuse a subject 
to reach this level)
d. Creatinine clearance (CrCl) < 45 mL/min (calculated using the Cockcroft-Gault 
formula or directly calculated from the 24-hour urine collection method)
e.
Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L)
f.
Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 
× upper limit of normal (ULN)
g. Serum total bilirubin > 1.5 × upper limit of normal (ULN) or > 3.0 mg/dL for 
subjects with documented Gilbert’s syndrome 
8. Subject has clinical evidence of central nervous system (CNS) or pulmonary leukostasis, 
disseminated intravascular coagulation, or CNS MM
9. Subject has known chronic obstructive pulmonary disease (COPD) with a forced 
expiratory volume in 1 second (FEV1) 50% of predicted normal. Note that forced 
expiratory testing (FEV1)is required for subjects suspected of having COPD and subjects 
must be excluded if FEV1 is < 50% of predicted normal. 
10. Subject has known moderate or severe persistent asthma within the past 2 years (see 
Appendix F) or uncontrolled asthma of any classification. Note that subjects who 
CCI
CELGENE PRO
t
ROPRIETARY INFORMATION
atm
atment:
ent:
one l
one lesi
esion
A eieith
ti er al
r 
wit
within 5 hal
hin 5 ha
gig c or horm
c or h
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) is 
bnormali
bnormal ti
) < 1,000/μ
 < 1,000/μ
is not perm
s not perm
4.9
4.9 mmo
mmol/
ce (CrC
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) <
ly calculat
ly calculat
um calcium
um calci
artate amin
artate a
r limit of no
limit of no
m total
total bili
bili
l
ubjects wi
ubjects with
th
ect has c
ect has clin
lin
sseminated
eminated
Subject h
Subject 
expira
expira
exp
exp


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
37
MEDI4736-MM-005 Final: 03 Oct 2016
currently have controlled intermittent asthma or controlled mild persistent asthma are 
allowed to participate in the study.
11. Subject has plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome 
(polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), 
or amyloidosis
12. Subject has nonsecretory MM
13. Subject has known allergy or hypersensitivity to study drug formulations
14. Subject has active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis, Crohn’s disease], diverticulitis, celiac disease, 
irritable bowel disease, or other serious gastrointestinal chronic conditions associated 
with diarrhea; systemic lupus erythematosus; Wegener syndrome; myasthenia gravis; 
Graves’ disease; rheumatoid arthritis, hypophysitis, uveitis, etc) within the past 3 years 
prior to the start of treatment. The following are exceptions to this criterion: 
a.
Subjects with vitiligo or alopecia.
b. Subjects with hypothyroidism (eg, following Hashimoto’s disease) stable on 
hormone replacement.
c.
Psoriasis not requiring systemic treatment.
15. Subject has history of primary immunodeficiency
16. Subject is positive for human immunodeficiency virus (HIV-1), chronic or active 
hepatitis B or active hepatitis A or C.
17. Subject has received live, attenuated vaccine within 30 days prior to the first dose of 
DURVA (NOTE: Subjects, if enrolled, should not receive live vaccine during the study 
and through 30 days after the last dose of DURVA)
18. Subject is currently using or has used immunosuppressive medication within 14 days 
prior to the first study dose of study treatment. The following are exceptions to this 
criterion:
a.
Intranasal, topical, inhaled, 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, infusion-related 
reactions, computed tomography [CT] scan premedication).
19. Subject has any one of the following:
a.
Clinically significant abnormal ECG finding at screening
b. Congestive heart failure (New York Heart Association Class III or IV)
c.
Myocardial infarction within 12 months prior to starting study treatment
d. Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina 
pectoris
20. Subject has 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 noninvasive 
malignancies:
CCI
CELGENE PROPRIETARY INFORMATION
luding
ding
sease,
ease,
ociated 
ciated 
nia gravis;
nia gravis
the past 3 y
he past 3
iterion:
iterion
toto’s’s disease
diseas
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y virus (HI
cine within
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d, should no
d, should no
dose of 
ose of DUR
DU
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a.a.
Clin
Clin
b. C
c.c


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
38
MEDI4736-MM-005 Final: 03 Oct 2016
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
21. Subject is a female who is pregnant, nursing, or breastfeeding, or who intends to become 
pregnant during the participation in the study. 
22. Subject has any significant medical condition, laboratory abnormality, or psychiatric 
illness that would prevent the subject from participating in the study
23. Subject has any condition including the presence of laboratory abnormalities, which 
places the subject at unacceptable risk if he/she were to participate in the study
24. Subject has any condition that confounds the ability to interpret data from the study
CCI
CELGENE PROPRIETARY INFORMATION
c
, which
, which
study
study
from
from the stu
the st


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
39
MEDI4736-MM-005 Final: 03 Oct 2016
5.
TABLE OF EVENTS
Table 4:
Table of Events
Screening 
Period
Treatment Period
Follow-up Period
Events
-28 to -1
C 1-2
(±3 days)
C 3-6
(±3 days)
≥ C7 
(±3 
days)
EOT (≤7 days 
from trt 
discon 
decision)
28 
days 
(+3) 
after 
EOT
90 days (+3) 
after last 
DURVA/
DARA dose
D1a
D 2
D8
D 
15
D 22
D 1
D 15
D 1
Informed consent
X
-
-
-
-
-
-
-
-
-
-
-
Inclusion/exclusion criteria
X
-
-
-
-
-
-
-
-
-
-
-
IRT registration
X
X
-
-
-
-
-
-
-
X
-
-
Complete medical history
X
-
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
-
Prior disease history
X
-
-
-
-
-
-
-
-
-
-
-
Prior disease therapies
X
-
-
-
-
-
-
-
-
-
-
-
Forced expiratory volume test, 
(subjects with COPD)
X
-
-
-
-
-
-
-
-
-
-
-
Prior/concomitant medication 
evaluation
X (-28 days 
from the date 
when ICF was 
signed)
Continuous, until 90 days after last dose of DURVA or DARA, whichever is later
Blood Type, Rh, and IAT
-
X
-
-
-
-
-
-
-
-
-
-
Prior/concomitant procedures 
evaluation
X (-28 days 
from the date 
when ICF was 
signed)
Continuous, until 90 days after last dose of DURVA or DARA, whichever is later
AE evaluation
Continuous starting after informed consent signature, until 90 days after last dose of DURVA or DARA, whichever is later
Physical examination 
X
X
-
-
-
-
X
-
X
X
-
-
CCI
CELG
pri
prietet
GENE PROPRIETARY INFORMATION
e Corpora
e Corpora
ON
MA
7
(±3 
(±3
days)
days)
EO
EO
OR
FO
15
D 1
D 1
NF
IN
-
Y IN
IN
IN
Y IN
-
Y
RY
-
RY
RY
RY
R
-
A
-
ETA
E
-
IE
R E
-
-
-
-
RI
PR
-
PR
PR
PR
OPR
Continu
Continu
RO
X
-
X
E P
E P
E P
NE P
days
ays 
the date
he date
en ICF was 
n ICF was 
signed
signed)
NE
NE
NE
NE
Continu
Continu
GE
LG
EL
E


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
40
MEDI4736-MM-005 Final: 03 Oct 2016
Table 4:
Table of Events (Continued)
Screening 
Period
Treatment Period
Follow-up Period
Events
-28 to -1
C 1-2
(±3 days)
C 3-6
(±3 days)
≥ C7 (±3 
days)
EOT (≤7 days 
from trt 
discon 
decision)
28 
days 
(+3) 
after 
EOT
90 days 
(+3) after 
last 
DURVA/ 
DARA dose
D1a
D 2
D8
D 
15
D 22
D 1
D 15
D 1
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
-
-
-
-
-
-
-
-
-
-
-
Weight
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
C1
-
-
-
-
C6
-
-
X
-
-
Hepatitis and HIV-1 antibody
testing
X
-
-
-
-
-
-
-
-
-
-
-
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation parameters
X
X
-
-
X
-
X
-
X
X
-
-
Chemistry 
X
X
X
X
X
X
X
X
X
X
X
X
Thyroid Function Tests
(TSH and free T3/T4 at Screening and 
Cycles 1-4; TSH for Cycle 5 onwards; 
reflex testing for free T3/T4 only if 
TSH is abnormal)
X
X
-
-
-
-
X
-
X
X
-
X
Renal Function (CrCl) 
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
if clinically indicated
X
X
X
Pregnancy Testing (FCBP 
only)
Refer to Section 6.1
X
X
-
X
-
X
X
X
X
CCI
CELGE
pri
prietet
ENE
ENE PROPRIETARY INFORMATION
e Corpora
e Corpora
ON
Fo
Fo
TIO
AT
EOT (
EOT ≤7 day
≤7 day
from tr
from t
disc
di
de
MA
O
A
D 1
D 1
O
X
FO
N O
-
NF
IN
X
IN
IN
IN
Y IN
-
Y
RY
-
RY
RY
RY
RY
X
TA
E
-
ET
E
X
RIE
PR E
-
-
-
PR
PR
PR
ROPR
X
X
X
RO
PR
PR
PR
PR
X
E
NE


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
41
MEDI4736-MM-005 Final: 03 Oct 2016
Table 4:
Table of Events (Continued)
Screening 
Period
Treatment Period
Follow-up Period
Events
-28 to -1
C 1-2
(±3 days)
C 3-6
(±3 days)
≥ C7 
(±3 
days)
EOT (≤7 days 
from trt 
discon 
decision)
28 
days 
(+3) 
after 
EOT
90 days (+3) 
after last 
DURVA/ 
DARA dose
D1a
D 2
D8
D 
15
D 22
D 1
D 15
D 1
Antiviral prophylaxis
-
Initiate within 1 week of starting DARA and continue for 3 months following last dose of DARA.
EFFICACY AND OTHER ASSESSMENTS
ECOG Performance status
X
X
-
-
-
-
X
-
X
X
-
-
Assessment of response 
(IMWG Uniform Response 
Criteria)b
-
C2
-
-
-
-
X
-
X
X
-
-
Serum and urine protein 
electrophoresis
X
X
-
-
-
-
X
-
X
X
-
-
Serum and urine 
immunofixation
X
X
-
-
-
-
X
-
X
X
-
-
Serum free light chains assay
X
X
-
-
-
-
X
-
X
X
-
-
Quantitative serum 
immunoglobulin
X
X
-
-
-
-
X
-
X
X
-
-
EMP clinical assessment
X
X
-
-
-
-
X
-
X
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
X
-
Skeletal Survey for bone 
lesions
X
(within 60 days 
prior to first 
dose is 
acceptable)
Repeated during treatment if clinically indicated to confirm response or PD
-
CCI
pri
prietet
GENE PROPRIETARY INFORMATION
e Corpora
e Corpora
ON
Fol
Fo
TIO
AT
EOT (
EOT (≤7 day
≤7 day
from tr
from t
disc
di
de
MA
O
A
D 1
O
FO
e for 3 month
for 3 m
FO
FO
NF
-
IN
IN
IN
Y IN
-
Y
RY
X
TA
E
-
ET
R E
-
-
-
R
PR
-
-
-
-
OP
ROP
-
-
-
-
RO
PRO
Day
D
1 1
y
PR
PR
PR
NE
X
(within 60 day
(within 60 day
prior to fi
prior to 
dose
dose
acce
ac
EN
EL
EL
EL
EL
N


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
42
MEDI4736-MM-005 Final: 03 Oct 2016
Table 4:
Table of Events (Continued)
Screening 
Period
Treatment Period
Follow-up Period
Events
-28 to -1
C 1-2
(±3 days)
C 3-6
(±3 days)
≥ C7 
(±3 
days)
EOT (≤7 days 
from trt 
discon 
decision)
28 
days 
(+3) 
after 
EOT
90 days 
(+3) after 
last 
DURVA/ 
DARA dose
D1a
D 2
D8
D 
15
D 22
D 1
D 15
D 1
Bone marrow aspirate and/or 
biopsy sampling for 
cytogenetics, % plasma cells, 
X 
BMA and 
BMB 
cytogenetics, 
% plasma 
cells, 
- BMA and BMB at time of CR confirmation for % plasma cells 
 
β2-microglobulin
X
X
-
-
-
-
X
-
X
X
-
-
Pre- and post-DARA infusion 
medicationsc  (Refer to 
Section 7.2.1.2 )
-
X
-
X
X
X
X
X
X
-
-
-
DARA IV administration (QW, 
Q2W, or Q4W) Refer to 
Section 7.2.2
-
Xd
-
Xd
Xd
Xd
Xd
Xd
Xd
-
-
-
DURVA IV administration
-
C1D2
C2D1e
-
-
-
Xe
-
Xe
-
-
-
Study treatment (DURVA, 
DARA) 
accountability/compliance
-
X
X
X
X
X
X
X
X
X
-
-
Blood sample for DURVA PK 
(Refer to Section 6.5.1)
-
C2
C1
C1
C1
C1
C4,C6
-
C10, 
C14
-
-
-
Blood sample for DARA PK 
(Refer to Section 6.5.2) 
-
C1
-
C1
C1
C1
-
-
-
X
X
X
CCI
CCI
CCI
CCI
CCI
CCI
CELG
pri
prietet
LGENE PROPRIETARY 
X
AR
X
TA
E
Xd
RIE
OPR E
-
-
-
-
OP
PROP
X
X
X
PR
PR
PR
E PR
C2
C2
E
NE
-
EN
LG N
Y INFORMATION
e Corpora
e Corpora
ON
Fol
Fo
TIO
AT
EOT (
EOT (≤7 day
≤7 day
from tr
from t
disc
di
de
d
MA
O
A
D 1
O
FO
asma cells
asma cells
FO
FO
FO
NF
Y I
O
C


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
43
MEDI4736-MM-005 Final: 03 Oct 2016
Table 4:
Table of Events (Continued)
Screening 
Period
Treatment Period
Follow-up Period
Events
-28 to -1
C 1-2
(±3 days)
C 3-6
(±3 days)
≥ C7 
(±3 
days)
EOT (≤7 days 
from trt 
discon 
decision)
28 
days 
(+3) 
after 
EOT
90 days (+3) 
after last 
DURVA/ 
DARA dose
D1a
D 2
D8
D 
15
D 22
D 1
D 15
D 1
AE = adverse event; BMA = bone marrow aspirate; BMB = bone marrow biopsy; C = Cycle; COPD = chronic obstructive pulmonary disease; CR = complete response; CrCl = 
creatinine clearance; D= Day; DARA = daratumumab; DURVA= durvalumab; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF= electronic case 
report form; EMP = extramedullary plasmacytomas; EOT = End of Treatment; FCBP = female of childbearing potential; HIV = human immunodeficiency virus; IAT = indirect 
antiglobulin test; IMWG = International Myeloma Working Group; IRT= Interactive Response Technology; IV = intravenous; PD = disease progression; PK = pharmacokinetics; 
QW = weekly; Q2W = every 2 weeks; Q4W = every 4 weeks; TSH= thyroid stimulating hormone; trt discon = treatment discontinuation.
a On Cycle 1 Day 1 (C1D1), safety laboratory assessments must be performed locally (central confirmation is not required) 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 Per IMWG Uniform Response Criteria all response categories and progressive disease require 2 consecutive assessments.
c Pre infusion medications to be given before all daratumumab infusions (if necessary, oral pre infusion medications may be administered at the subject’s home on the day of the 
infusion, provided they are given within 3 hours prior to the infusion); post infusion medications to be given on the first and second days following all daratumumab infusions. 
d Every effort should be made to keep subjects on the planned dosing schedule (QW, Q2W, or Q4W) as detailed in Section 7.2.2. However, doses given within 3 days of the 
scheduled dose are permitted, as long as the interval between doses is at least 5 days. Blood pressure is to be measured at the following time points on C1D1 and C1D8: 
immediately before the start of the infusion; at approximately 30 minutes, 1 hour, 90 minutes, 2 hours, and 3 hours 30 minutes after the start of the infusion; at the end of the 
infusion; and 30 minutes and 1 hour (+/- 5 minutes) after the end of the infusion. For all other DARA infusions, blood pressure will be measured immediately before the infusion 
start and at the end of the infusion.
e First DURVA infusion:  blood pressure and pulse will be monitored, as follows (based on a 60-minute infusion): Prior to the beginning of the infusion (measured once from 
approximately 30 minutes before up to 0 minutes [ie, the beginning of the infusion]); approximately 30 minutes during the infusion (halfway through infusion); at the end of the 
infusion ( approximately 60 minutes ±5 minutes). If the infusion takes longer than 60 minutes, then blood pressure and pulse measurements should follow the principles as 
described above or be taken more frequently if clinically indicated.  For DURVA infusions on C2D1 onward, a +24 hour window is allowed and may be implemented per 
CCI
CCI
CE
pri
prietet
ELGENE PROPRIE
RIE
= Cycle;
= Cycle; COP
COP
CG = electroca
G = electroc
FCBP = fe
FCBP = fema
teractive R
active
es
R
roid stimulatin
oid stimulat
rformed local
rformed loc
ver, if screeni
ver, if screeni
ies and progre
es and progr
mab infusions
mab infus
to the infusio
to the infusio
e planned dos
planned do
erval between 
rval between 
at 
at approximate
approximat
 minutes)
minutes afte
aft
sure and puls
re and puls
up to 0 minut
up to 0 minut
inutes ±5 min
inutes ±5 m
more frequen
more frequen
NFORMATION
e Corpora
e Corpora
ON
AT
AT
AT
AT
s)
EOT (
EOT ≤
fr
M
FO
D 1
D 1
FO
FO
NFO
NF
N
IETARY INF


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
44
MEDI4736-MM-005 Final: 03 Oct 2016
investigator discretion.
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 eCRF page.
CCI
pri
prietet
TION
e Corpora
e Corpora
ON
ure an
ure and other v
d other v
hould be enter
ould be ente


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
45
MEDI4736-MM-005 Final: 03 Oct 2016
6.
PROCEDURES
Any questions regarding the protocol should be directed to the Celgene Medical Monitor or 
designee.
6.1.
Screening Period
The Screening Phase begins when the ICF is signed. Screening evaluations will be performed for 
all subjects to determine study eligibility. These evaluations must be completed within 28 days 
of first dosing unless noted otherwise below. 
Waivers to the protocol will not be granted during the conduct of this trial, under any 
circumstances.
Except for pregnancy tests, ECGs and urinalysis, all safety-related laboratory assessments will be 
performed centrally; however, tests that may result in dose interruption and/or modification may
also be performed locally to allow for treatment-related decisions during subject visits. All 
results from local laboratories used in treatment decisions or AE reporting must be entered as an 
unscheduled visit into the electronic case report form (eCRF).  
The following will be performed at screening as specified in Table 4 after informed consent has 
been obtained:
!
Interactive Response Technology (IRT) registration
∃
Note: Subject may be enrolled in the IRT up to 3 days prior to initiating study 
treatment on Cycle 1 Day 1 (C1D1)
!
Complete medical history (all relevant medical conditions diagnosed/occurring prior 
to screening should also be included)
!
Demographics (age, sex, race, and if allowed by local regulations, ethnicity, and date 
of birth, will be collected in the eCRF and/or IRT system)
!
Prior disease history (if available the date of initial diagnosis, staging at time of 
diagnosis [Appendix D], cytogenetics at diagnosis to be collected)
!
Prior disease therapies (including surgery, radiation, systemic or any other therapy for 
the subject’s disease)
!
Prior and concomitant medication evaluation (including those taken ≤ 28 days before 
the date that the ICF was signed, except for those taken for disease)
!
Prior and concomitant procedures evaluation (including all procedures occurring 
≤28 days before the date that the ICF was signed)
!
Adverse events 
!
Physical examination, including assessment for potential venous thromboembolism 
events (VTEs) (can be source documented only) 
!
Forced expiratory volume test (subjects with or suspected to have chronic obstructive 
pulmonary disease [COPD])
CCI
CELGENE PROPRIETARY INFORMATION
or 
or 
ays 
ys 
assessment
ssessmen
d/or modific
/or modifi
g subject vis
ubject
rting must 
rting must 
able
able 4 afa ter
f
istration
istration
e IRT up to
e IRT up to
D1)
D1)
evant med
evant med
ncluded)
cluded)
race, and i
race, and
ted in the e
ted in the 
ory
ory (if avail
(if avail
y
pendix D
ndix D], c
se th
therapi
erap e
ect’s disea
ect’s disea
or and conc
r and con
he date tha
e date tha
!
Pri
Prior an
r a
≤28
≤2
!


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
46
MEDI4736-MM-005 Final: 03 Oct 2016
!
Vital signs (including blood pressure, temperature, and heart rate)
!
Height and weight 
!
12-lead ECG (performed and reviewed locally)
!
Hepatitis panel
!
HIV-1 antibody test
!
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 
!
Coagulation parameters (prothrombin time/international normalized ratio, activated 
partial thromboplastin time, fibrinogen)
!
Chemistry panel including sodium, potassium, calcium, corrected serum calcium
(refer to Section 6.4.1), chloride, blood urea nitrogen (BUN), creatinine, glucose, 
albumin, total protein, alkaline phosphatase (ALP), bilirubin (total, direct, and 
indirect), AST, ALT, lactate dehydrogenase (LDH), magnesium, bicarbonate, lipase, 
gamma-glutamyl transferase (GGT), uric acid, triglycerides, cholesterol, and amylase.  
(NOTE: Tests for AST, ALT, ALP, direct bilirubin, indirect bilirubin, and total 
bilirubin must be conducted and assessed concurrently)
!
Thyroid function tests (thyroid-stimulating hormone [TSH], free T4, free T3)
!
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.
!
Urinalysis (color, appearance, specific gravity, pH, protein, glucose, ketones, blood, 
bilirubin)
!
Females of childbearing potential (FCBP) should have two negative medically 
supervised pregnancy tests assessed locally during screening. The subject may not 
receive any study treatment until the investigator has verified that the results of these 
pregnancy tests are negative.
o
The investigator will appraise a female subject as a FCBP according to the following 
definition (justification must be recorded in the eCRF and the source document):

FCBP is defined as a sexually mature woman who has not undergone a 
hysterectomy or bilateral oopherectomy or has not been naturally 
menopausal for at least 24 consecutive months (ie has had menses at any 
time in the preceeding 24 consecutive months). Amenorrhea following 
cancer therapy does not rule out childbearing potential.
o
Negative serum pregnancy test (minimum sensitivity of 25mIU/ml) at screening
o
Negative serum or urine pregnancy test (investigator’s discretion) within 72 hours 
prior to the start of study treatment (C1D1)
CCI
CELGENE PROPRIETARY INFORMATION
ng
ng
unt 
unt 
 activated
 activated
serum calc
serum calc
reatinine, g
eatinine, g
(total, dire
(total, d
nesium, bic
esium, bi
erides, chol
ides, chol
bin, indire
bin, ind
currently)
currently)
hormone [T
hormone [
essed using
ssed using
didirect
rect
i
ly 
ly ca
lt f
t form
orm
f
ula
ula
g/dl]); for f
g/dl]); for f
ce, specific
ce, specific
aring potent
ring potent
ancy
ancy tests
test
y
udy
ud treatm
trea
y
tests are ne
ests are ne
The investi
The investi
definitio
defini


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
47
MEDI4736-MM-005 Final: 03 Oct 2016

Note: Pregnancy testing does not need to be repeated prior to C1D1 if the screening 
assessment (serum pregnancy test) was performed within 72 hours of the first dose of 
study treatment

Note: Pregnancy testing is not required for non-FCBP subjects. 
!
Eastern Cooperative Oncology Group (ECOG) Performance Status (see Appendix C)
!
Efficacy assessments / tumor evaluations per the IMWG criteria (See Section 6.4). 
!
β2 microglobulin test
!
Bone marrow aspiration/biopsy (for cytogenetics, percent plasma cells, 
 
6.2.
Treatment Period
The subject will begin the treatment period upon confirmation of eligibility. The subject must 
start treatment within 28 days of signing the ICF. For all visits an administrative window of ± 3 
days is permitted. Safety laboratory testing at a local laboratory may be performed up to 3 days 
before the study treatment administration day. Results of these laboratory tests must be evaluated 
before each study treatment administration. 
Treatment cycles are 28 days in duration, the treatment and schedule will be as described in 
Section 7.2.
The following evaluations will be performed at the frequency specified in Table 4. The 
evaluations should be should be performed prior to dosing on the visit day, unless otherwise 
specified. 
!
Interactive Response Technology (IRT) registration
!
Concomitant medications evaluation
!
Concomitant procedures evaluation
!
Adverse event (continuously)
!
Physical examination, including assessment for potential VTEs (can be source 
documented only) 
!
Vital signs
!
Weight 
!
12-lead ECG (C1D1 and C6D1 immediately after DARA infusion)
!
Blood Type, Rh, and indirect antiglobulin test (IAT) should be done before the first 
dose of DARA. See Section 6.8 for additional details.
!
Hematology panel
!
Coagulation parameters 
!
Chemistry panel 
CCI
CCI
CELGENE PROPRIETARY INFORMATION
lity.y. The su
The
ministrative
ministrative
ay b
y e perfo
 perf
aboratory
abora
nd schedu
d sched
he frequenc
e frequen
or to dosin
or to dosin
olology
gy (IRT
(IRT
y
ns evaluat
evaluati
dures evalu
dures eva
(continuou
ontinuou
xaminat
xaminatioi n
nted
nted only
only)
alal signs
 signs
l
Weight 
Weight 
!
12-lea
l
!
B


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
48
MEDI4736-MM-005 Final: 03 Oct 2016
!
Thyroid function tests:
∃
Cycles 1 to 4: TSH, free T4, free T3
∃
Cycle 5 onward: TSH, if TSH is abnormal, then reflex testing for free T4 and free 
T3 
!
Renal function (CrCl) 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).
!
Urinalysis (only if clinically indicated)
!
Urine (or serum) pregnancy test for FCBP (negative results required for study 
treatment [DURVA and/or DARA] administration) within 72 hours prior to dosing on
D1 of every treatment cycle. The subject may not receive study treatment until the 
investigator has verified that the result of the pregnancy test is negative.
!
ECOG Performance Status 
!
Antiviral prophylaxis
!
Pre and post medication for DARA infusion (see Section 7.2.1.2)
!
Efficacy assessments (see Section 6.4)
!
β2 microglobulin test on Day 1 of each cycle
!
 
!
Blood sampling for PK assessments (see Section 6.5)
!
!
Study treatment (DARA and DURVA) administration/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 after the decision to permanently discontinue treatment 
has been made. 
The following evaluations will be performed as specified in Table 4.
!
IRT registration
!
Concomitant medications evaluation (monitored until 90 days after last dose of 
DURVA or DARA, whichever is later)
!
Concomitant procedures evaluation (monitored until 90 days after last dose of 
DURVA or DARA, whichever is later)
!
Adverse event evaluation (monitored until 90 days after last dose of DURVA or 
DARA, whichever is later)
CCI
CCI
CCI
CELGENE PROP
RA and DU
RA and DU
ent
nt
EOT
EOT) evalu
val
son wi
on with
thinin
g evaluatio
g evaluatio
IRT regi
IRT reg
!
Con
Con
PRIE
ments (see 
ments (see
ETARY INFORMATION
the
he
study
study
pri
prior to dos
or to dos
atm
atment unt
t un
negat
egative.
ive.
Section
Section 7.2
7.
ycle
ycle
D
IET
OP


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
49
MEDI4736-MM-005 Final: 03 Oct 2016
!
Physical examination, including assessment for potential VTEs (can be source
documented only) 
!
Vital signs 
!
Weight
!
12-lead ECG
!
Hematology panel
!
Coagulation parameters 
!
Chemistry panel
!
Thyroid function tests (TSH, free T4, free T3)
!
Renal function (CrCl) 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.
!
Urinalysis
!
Urine (or serum) pregnancy test for FCBP
!
ECOG Performance Status
!
Antiviral prophylaxis
!
Efficacy assessments per the IMWG criteria will be performed according to the 
schedule defined in the Table of Events and do not need to be performed specifically 
for the EOT visit except as specified in Section 6.4.
!
β2 microglobulin test
!
!
Blood sampling for DARA PK assessments (see Section 6.5)
!
!
Study treatment (DARA and DURVA) 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 DURVA or DARA, whichever is 
later, for AEs, including adverse events of special interest (AESIs), reporting, as well as serious 
adverse events (SAEs) that had occurred within that time frame but were made known to the 
investigator at any time thereafter that are suspected of being related to study treatment 
(DURVA, DARA), as described in Section 10.1.
CCI
CCI
CCI
CELGENE PROPRIETARY INFORMATION
CrCl
CrCl didi
l
rect
re
i
Gault form
Gault form
mg/dl]); fo
mg/dl])
criteria
riteria will
wil
vents and d
vents and d
cified in
fied in Se
Se
r DARA
DARA PK
P
tm
tment (
ent (DA
D
ow
ow-up P
up P
Safety Fo
Safety Fo
bjbjects will 
ects will 
er,r, fofor AEs
r AEs
adverse eve
dverse ev
investig
nvestig
UR
ROP
E PR


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
50
MEDI4736-MM-005 Final: 03 Oct 2016
Subjects are to return to the study site 28 (+3) days after the EOT visit and 90 (+3) days after the 
last dose of DARA or DURVA, whichever is later, for safety follow-up visits procedures as 
specified in Table 4.
!
Concomitant medications evaluation (monitored until 90 days after last dose of 
DURVA or DARA, whichever is later)
!
Concomitant procedures evaluation (monitored until 90 days after last dose of 
DURVA or DARA, whichever is later)
!
Adverse event (including AESIs) evaluation (monitored until 90 days after last dose 
of DURVA or DARA, whichever is later)
!
Vital signs
!
Weight
!
Hematology panel
!
Chemistry panel
!
Thyroid function tests (TSH, free T4, free T3)
!
Renal function (CrCl) 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).
!
Urinalysis
!
Urine (or serum) pregnancy test for FCBP
!
Antiviral prophylaxis 
!
Blood sampling for DARA PK assessments (see Section 6.5)
!
6.4.
Efficacy Assessments
6.4.1.
Laboratory Assessments for Efficacy Parameters
All laboratory assessments for efficacy will be performed centrally.
If screening assessments are performed within 3 days of C1D1, efficacy laboratory assessments 
need not be repeated at C1D1:
!
Serum protein electrophoresis (sPEP) and urine protein electrophoresis (uPEP) tests 
(performed on 24-hour urine collection) are required at screening, on Day 1 of each 
cycle, and at the EOT Visit. 
!
Serum and urine immunofixation tests are required at screening, on Day 1 of each 
cycle, and at the EOT Visit.
CCI
CCI
CELGENE PRO
essment
ssments
ry Assessm
ry Assess
essments f
essments f
assessments
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repeated 
OPRIETARY INFORMATION
dose
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Serum
erum
(pe
(pe
RO


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
51
MEDI4736-MM-005 Final: 03 Oct 2016
!
Quantitative serum immunoglobulin assessment includes IgG, IgA, and IgM for all 
subjects, and IgE or IgD only for subjects with the respective MM subtype (IgE or 
IgD) and is required at screening, on Day 1 of each cycle, and at the EOT Visit.
!
Serum free light chains assay is required at screening, on Day 1 of each cycle, and at 
the EOT Visit.
!
Corrected serum calcium will be assessed as part of the safety serum chemistry 
assessments performed at screening, on Day 1 of each cycle, and at the EOT Visit.
6.4.2.
Bone Marrow Aspiration and/or Biopsy
A bone marrow aspirate (BMA) and biopsy (BMB) is mandatory at the following time points:
!
At screening, BMA and BMB for percent plasma cells, cytogenetics, 
 
!
During treatment:
∃
∃
BMA and BMB at the time of complete response (CR) confirmation for percent 
plasma cells 
∃
 
The analysis of bone marrow for percentage of plasma cells will be performed locally and at a 
central laboratory.
 
6.4.3.
Bone Lesion Assessment
Bone lesion assessment by x-ray (skeletal survey) or CT Scan will be performed at screening and 
when clinically indicated to confirm response or PD. The same method (x-ray or CT Scan) 
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 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 chest 
!
AP pelvis 
!
AP upper extremities, shoulder to elbow 
CCI
CCI
CCI
CCI
CCI
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CELGENE PROPRIE
eletal
eletal surve
sur
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study
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!
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NFORMATION
points:
points:
ORM
INF
ARY
ET


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
52
MEDI4736-MM-005 Final: 03 Oct 2016
!
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 
Clinical assessment for extramedullary plasmacytoma (EMP) assessments will be performed at 
screening, on Day 1 of every cycle, and at the EOT Visit. 
For EMPs that are only assessable radiographically (by x-ray and/or conventional [spiral] 
CT/magnetic resonance imaging [MRI] scan), scans are required at screening, at Cycle 3 Day 1, 
every 3 cycles thereafter (Cycle 6 Day 1, Cycle 9 Day 1, etc.) during treatment, at the EOT Visit, 
and when clinically indicated to confirm a response (≥ PR) or PD. 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. Celgene may request redacted copies of reports.
6.4.5.
Assessment of Response
6.4.5.1.
Investigator Assessment
Starting from Cycle 2, response will be assessed by the investigators using the International 
Myeloma Working Group (IMWG) Uniform Response Criteria (Rajkumar, 2011) (Appendix B)
at every cycle on Day 1 and at the EOT Visit. Response must be based on the central laboratory 
data to ensure consistency across investigative sites. All treatment discontinuation decisions due 
to disease progression will be made by treating physicians based on response as assessed using 
results from central laboratories by the IMWG criteria, except for new or increase in bone lesions 
or soft tissue plasmacytomas.
6.4.5.2.
Independent Response Adjudication Committee Assessment
An IRAC will be formed by a group of experts in the MM disease area to review efficacy data. 
For each subject, the IRAC will determine tumor response at scheduled or unscheduled visits, 
and the time of PD (if disease progressed). In addition, the IRAC will determine the best overall 
response of each subject up to time of the data cut off for interim and final analyses. 
The IRAC will adjudicate efficacy data incrementally according to IRAC Charter during the 
study.  The IRAC adjudicated response data will be used for efficacy analysis in all interim and 
final analyses.  Primary efficacy analyses will be conducted in tumor response data, including 
progressive disease (PD) that are assessed by the IRAC according to the IMWG Uniform 
Response Criteria (Appendix B).
NOTE: Per IMWG Uniform Response Criteria all response categories and progressive disease 
require 2 consecutive assessments except for radiographic or bone marrow assessments
6.5.
Pharmacokinetics
Serum samples will be collected to assay concentrations of DURVA and DARA. 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 eCRF pages.
CCI
CELGENE PROPRIETARY INFORMATION
Day
Day 1,1,
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6.5.
6.5
rum


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
53
MEDI4736-MM-005 Final: 03 Oct 2016
6.5.1.
Pharmacokinetics of Durvalumab
All subjects enrolled in Part 1 Stage 1 will participate in the DURVA PK sample collections at 
the following time points: 
!
C1D2: pre dose (-30 to -5 minutes prior to dose), end of infusion (EOI) (+5 minutes), 
!
C1D8: 144 hours post C1D2 dose (± 1 hour)
!
C1D15: 312 hours post C1D2 dose (± 1 hour),
!
C1D22: 480 hours post C1D2 dose (± 1 hour).
!
Additional DURVA PK samples to be collected 
 
 on C2D1, C4D1, C6D1, C10D1, and C14D1.
6.5.2.
Pharmacokinetics of Daratumumab
DARA PK sample collections will occur at the following time points for subjects enrolled in Part 
1 Stage 1: 
!
C1D1: predose (-30 to -5 minutes prior to dose), and EOI (+5 minutes)
!
C1D8: predose (-30 to -5 minutes prior to dose), and EOI (+5 minutes)
!
C1D15: predose (-30 to -5 minutes prior to dose), and EOI (+5 minutes)
!
C1D22: predose (-30 to -5 minutes prior to dose), and EOI (+5 minutes)
!
EOT
!
28 days after EOT, 
!
90 days after last DARA or DURVA dose
 
 
 
 
 
CCI
CCI
CCI
CELGENE PROPRIETARY INFORMATION
bjects enro
bjects enro
(+5 minut
+5 minut
EOI
EOI (+5 m
), and 
and EOI
EOI
dose), and 
dose), and E
RVA dose
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MA
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EN
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ELG
CEL
C


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
54
MEDI4736-MM-005 Final: 03 Oct 2016
6.8.
Blood Type, Rh and Indirect Antiglobulin Test (IAT)
Blood type, Rh, and IAT should be done before the first dose of DARA for the reasons detailed 
below. Subject RBC phenotyping (standard or extended) is an alternative option to the IAT test, 
if locally required. Either method must be completed prior to first DARA infusion.
DARA interferes with the indirect antiglobulin test (IAT), which is a routine pre-transfusion test 
performed to identify a patient’s antibodies to minor antigens so that suitable donor blood can be 
given for transfusion. DARA does not interfere with ABO/RhD typing. CD38 is expressed at 
very low levels on erythrocytes. DARA binds to the CD38 on erythrocytes, which results in a 
CCI
CCI
CELGE
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ARA
ION
GENE PROPRIETARY INFORMATIO


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
55
MEDI4736-MM-005 Final: 03 Oct 2016
positive IAT (Indirect Coombs Test).  This positive result masks the detection of antibodies to 
minor antigens and may prevent or delay blood banks from issuing donor blood for 
transfusion. This effect occurs during DARA treatment and for up to 6 months after treatment 
ends. Subjects will receive a patient identification wallet card for the study that includes the 
blood profile (ABO, Rh, and IAT or phenotyping) determined before the first infusion of DARA
along with information on the IAT interference for healthcare providers/blood banks. Subjects 
are to carry this card throughout the treatment period and for at least 6 months after treatment 
ends. Blood banks can eliminate the DARA interference with IAT by treating reagent RBCs 
with dithiothreitol (DTT) (Chapuy, 2015).
Possible methods for blood banks to provide safe RBCs for transfusion to subjects receiving 
DARA include:
a.
Providing ABO/RhD compatible, phenotypically (standard or extended phenotyping) 
or genotypically matched units
b. Providing ABO/RhD compatible, K-negative units after ruling out or identifying 
alloantibodies using dithiothreital-treated reagent RBCs
Uncrossmatched, ABO/RhD compatible RBC units should be administered if transfusion is 
needed emergently as per local blood bank practice.
Despite DARA binding to CD38 on erythrocytes, no indication of clinically significant 
hemolysis has been observed in DARA studies. For additional details, refer to the DARA IB.
CCI
CELGENE PROPRIETARY INFORMATION
ing
ng 
phenoty
phenotypip
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stered if tra
stered if tra
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n of clinica
clin
f
nal details,
al detail


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
56
MEDI4736-MM-005 Final: 03 Oct 2016
7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Product(s)
Investigational product supply will be managed by IRT. All IP must be stored in accordance with 
the product label in a secured area to prevent unauthorized access. 
United States:
Durvalumab (MEDI4736) will be supplied by Celgene and labeled appropriately as 
investigational material. Labels will bear Celgene’s name, telephone number 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 statement as applicable. 
Daratumumab (Darzalex) 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:
Durvalumab (MEDI4736), and Daratumumab (Darzalex) will be supplied by Celgene and 
labeled appropriately as investigational material. Labels will bear Celgene’s name, telephone 
number 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 statement as 
applicable. 
7.1.1.
Durvalumab (MEDI4736)
DURVA will be supplied by Celgene in single-use vials in single count cartons. Each 10 ml vial 
will be supplied as a vialed liquid solution containing 500 mg (nominal) of IP at a concentration 
of 50 mg/mL. DURVA should be stored in accordance with the product label. 
Sites are 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 DURVA with other IV medications and solutions, other 
than normal saline, is not known, the DURVA 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.
CCI
CELGENE PROPRIETARY INFORMATION
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
57
MEDI4736-MM-005 Final: 03 Oct 2016
7.1.2.
Daratumumab (Darzalex)
Daratumumab (Darzalex™) will be supplied by Celgene in single-use vials in single count 
cartons. Daratumumab is a colorless to pale yellow, preservative-free solution and will be 
supplied in 20 mL vials (20 m/mL) and/or 5 mL vials (20 mg/mL).
!
Since the compatibility of DARA with other IV medications and solutions, other than 
normal saline, is not known, the DARA 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. 
7.2.
Treatment Administration and Schedule
The first day of study treatment dosing (DARA and/or DURVA) is considered Day 1 of a cycle.
7.2.1.
Treatment Administration
On days when DARA and DURVA are dosed on the same day, the DARA infusion should be 
administered first, followed by the DURVA infusion. Simultaneous infusion of DARA and 
DURVA is prohibited. 
!
Since the compatibility of DARA or DURVA with other IV medications and solutions, 
other than normal saline, is not known, the DARA or DURVA solution should not be 
infused through an IV line in which other solutions or medications are being 
administered.
!
If DARA and DURVA will be infused through the same port, the port must be flushed 
with saline prior to attaching dedicated DARA IV line.
7.2.1.1.
Durvalumab (MEDI4736)
7.2.1.1.1. Durvalumab Product Dose Preparation/Administration
The IV infusion for subjects will be approximately 1 hour in duration.
For detailed information on DURVA dose preparation and administration please refer to the 
pharmacy manual. 
7.2.1.1.2. Monitoring During/After Durvalumab Infusion
7.2.1.1.2.1. First DURVA infusion
For the first DURVA infusion (C1D2), blood pressure and pulse will be monitored, as follows
(based on a 60-minute infusion):
!
Prior to the beginning of the infusion (measured once from approximately 30 minutes 
before up to 0 minutes [ie, the beginning of the infusion])
!
Approximately 30 minutes during the infusion (halfway through infusion) 
!
At the end of the infusion ( approximately 60 minutes ±5 minutes)
If the infusion takes longer than 60 minutes, then blood pressure and pulse measurements should 
follow the principles as described above or be taken more frequently if clinically indicated.
CCI
CELGENE PROPRIETARY INFORMATION
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
58
MEDI4736-MM-005 Final: 03 Oct 2016
7.2.1.1.2.2. Subsequent DURVA infusions
For the 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 
electronic case report form (eCRF) page. 
In the event of a ≤ Grade 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and reinitiated at 
50% of the initial rate until completion of the infusion. For patients with a ≤ Grade 2 
infusion-related reaction, subsequent infusions may be administered at 50% of the initial rate. 
Acetaminophen/paracetamol and/or an antihistamine (eg, diphenhydramine) or equivalent 
medications per institutional standard may be administered at the discretion of the 
investigator. If the infusion-related reaction is ≥ Grade 3 or higher in severity, study drug will be 
discontinued.
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, and 
study personnel must be trained to recognize and treat anaphylaxis. The study site must have 
immediate access to emergency resuscitation teams and equipment in addition to the ability to 
admit patients to an intensive care unit if necessary.
7.2.1.2.
Daratumumab (Darzalex)
Subjects should be carefully observed during DARA infusions. Refer to the full prescribing 
information for DARA (Darzalex PI).
Pre-infusion and post infusion medications for infusion reaction prophylaxis will be given as 
detailed in Table 6 for all subjects.
7.2.1.2.1. Infusion-related Reactions of Grade 1 or Grade 2
If the investigator assesses an adverse event to be related to the infusion, then the infusion should 
be paused. When the subject’s condition is stable, the infusion may be restarted at the 
investigator’s discretion. Upon restart, the infusion rate should be half of that employed before 
the interruption. Subsequently, the infusion rate may be increased at the investigator’s discretion.
If the subject experiences a Grade 2 or higher event of laryngeal edema, or a Grade 2 or higher 
event of bronchospasm that does not respond to systemic therapy and does not resolve within 
6 hours from onset, then the subject must be withdrawn from daratumumab treatment. 
7.2.1.2.2. Infusion-related Reactions of Grade 3 or Higher
For infusion-related adverse events that are Grade 4, the infusion should be stopped and the 
subject withdrawn from DARA treatment. 
For infusion-related adverse events that are Grade 3, the infusion must be stopped and the subject 
must be observed carefully until resolution of the adverse event or until the intensity of the event 
decreases to Grade 1, at which point the infusion may be restarted at the investigator’s discretion. 
Upon restart, the infusion rate should be half of that employed before the interruption. 
CCI
CELGENE PROPRIETARY INFORMATION
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
59
MEDI4736-MM-005 Final: 03 Oct 2016
Subsequently, the infusion rate may be increased at the investigator’s discretion. If the intensity 
of the adverse event returns to Grade 3 after restart of the infusion, then the procedure described 
in this section should be repeated, or the subject may be withdrawn from treatment. Should the 
intensity of the adverse event increase to Grade 3 for a third time, then the subject must be 
withdrawn from DARA treatment.
Table 6:
Daratumumab Pre Infusion and Post Infusion Medications
Time point
Medication
All Subjects
Pre infusion (~1 hr prior 
to every daratumumab 
(DARA)
administration)
Oral montelukast
(if approved and 
available)
per investigator discretion prior to first 
infusion
Intravenous (IV)
corticosteroid 
methylprednisolone 100 mg or equivalent dose 
of an intermediate-acting or long-acting 
corticosteroid ( Refer to Table 7 for conversion 
table). Following the second infusion, the dose 
of corticosteroid may be reduced 
(methylprednisolone 60 mg intravenously)
oral antipyretics 
acetaminophen 650 to 1000 mga
oral or IV antihistamine 
diphenhydramine 25 to 50 mg or equivalent
Post infusion 
Medication 
(1st and 2nd day after 
every DARA 
administration)
oral corticosteroidb
20 mg methylprednisolone or equivalent dose 
of a corticosteroid in accordance with local 
standards 
a If necessary, oral preinfusion medications may be administered at the subject’s home on the day of the infusion, 
provided they are given within 3 hours prior to the infusion
b For subjects with a history of obstructive pulmonary disorder, consider prescribing post infusion medications such 
as short and long-acting bronchodilators, and inhaled corticosteroids. Following the first four infusions, if the 
patient experiences no major infusion reactions, these additional inhaled post infusion medications may be 
discontinued.
Table 7:
Conversion Table for Glucocorticoid Dose
Generic Name
Oral or Intravenous Dose (mg)
Dexamethasone
0.75
Hydrocortisone
20
Methylprednisolone
4
Prednisolone
5
Prednisone
5
CCI
CELGENE PROPRIETARY INFORMATION
T
AT
quivalent do
quivalent d
ong
ong-acting
acting
ble
ble 7 for co
or co
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ond infusio
y be reduced
be redu
one 60 mg in
ne 60 mg in
RM
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650 to 10
IN
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dramine 2
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a corticoste
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the infusi
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and inhaled 
and inhaled
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on Table f
on Tabl
E
NE
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EN
prednisolon
prednisolon
G
dnisolone
dnisolone
LG
Prednison
Prednison
CE
C


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
60
MEDI4736-MM-005 Final: 03 Oct 2016
7.2.2.
Treatment Schedule
7.2.2.1.
Daratumumab Plus Durvalumab Treatment Schedule
See Section 3.1 for dosing rules.
!
Intravenous DARA on the same dosing schedule received on last MM Dara-
containing regimen
∃
16 mg/kg starting at the same dosing schedule; QW, Q2W, or Q4W, as their last 
DARA-containing MM therapy. 
∃
Dosing schedule should be adjusted as shown below; provided that the patient has 
a response of stable disease (SD) or better:
!
QW frequency (Days 1, 8, 15 and 22/28-day cycle): Weeks 1 to 8 then Q2W 
Weeks 9 to 24
!
Q2W frequency(Days 1, 15 of a 28-day cycle): Weeks 1 to 16 then Q4W
!
Q4W frequency (Day 1 of each 28-day cycle):Week 1 onwards until disease 
progression
!
Intravenous DURVA:
∃
1500 mg on Day 2 of Cycle 1, then Day 1 of Cycle ≥ 2 of a 28-day cycle.  
NOTE: For all DURVA infusions after Cycle 1, a +1 day window is allowed 
(subject may either receive the DURVA infusion on same day as the DARA 
infusion or on the next day per the investigator’s discretion; concomitant 
administration of DARA and DURVA is prohibited).
7.2.3.
Overdose
Overdose, as defined for this protocol, refers to DURVA and DARA dosing only. On a per dose 
basis, an overdose is defined as the following amount over the protocol-specified dose of 
DURVA and DARA assigned to a given subject, regardless of any associated AEs or sequelae.
!
For IV, 10% over the protocol-specified dose
On a schedule or frequency basis, an overdose is defined as any amount 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 10.1 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 study treatment is 
resumed. 
CCI
CELGENE PROPRIETARY INFORMATION
atient has
ent has
o 8 th
then Q
en Q
1 to 16 the
1 to 16 the
k 1
k 1 onward
onward
of Cycle
Cycle
f
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RVA infusio
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DURVA is p
DURVA is p
col, ref
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f
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schedule or
chedule or
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the protoco
e, regardles
e, regardle
n the eCRF
the eCRF
4.4.
Dos
Dos
Subjects w
Subjects w
guiuide f
de f


EDMS Doc. Number:
Durvalumab (MEDI4736)
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!
If DURVA is permanently discontinued, then the subject must be permanently 
discontinued from all study treatments.
!
If DARA is withheld or permanently discontinued, then DURVA dosing may be 
continued.
7.2.4.1.
Dose Modification Instructions for Durvalumab
Refer to Appendix E for detailed instructions for DURVA dose modifications and toxicity
management.
7.2.4.2.
Dose Modification Instructions for Daratumumab
For dose modification instructions for DARA, refer to the full prescribing information (Darzalex
PI).
The criteria for a dose delay are:
!
Grade 4 hematologic toxicity, or Grade 3 or higher thrombocytopenia with bleeding; 
!
Febrile neutropenia of any grade;
!
Neutropenia with infection, of any grade;
!
Grade 3 or higher non-hematologic toxicities with the following exceptions: 
∃
Grade 3 nausea or Grade 3 vomiting that responds to antiemetic treatment, 
∃
Grade 3 diarrhea that responds to antidiarrheal treatment, 
∃
Grade 3 fatigue or asthenia that lasts for <7 days after the last administration of 
DARA.
DARA treatment should be resumed when the toxicity has resolved to %Grade 2. If DARA 
administration does not commence within the pre-specified window (Table 8) of the scheduled 
administration date, then the dose will be considered a missed dose. 
Administration may resume at the next planned dosing date. A missed dose will not be made up.
Table 8:
Daratumumab-related Toxicity Management
Cycles
Dosing 
Frequency
Dose Miss
Dosing Resumption
1 and 2
Weekly (QW)
>3 days
next planned QW dosing date
3 to 6
Biweekly 
(Q2W)
>7 days
next planned Q2W dosing date
7+
Every 4 weeks 
(Q4W)
>21 days
next planned Q4W dosing date
Any dose delay of more than 28 days due to toxicity will result in permanent discontinuation of 
DARA. Dose delays of more than 28 days for other reasons should be discussed with the 
Sponsor. 
CCI
CELGENE PROPRIETARY INFORMATION
on
on (Dar
Darzale
zale
ytopeni
topeni
y
a w
h th
the fo
e f llo
RY
t responds t
responds
tidiarrheal 
tidiarrheal
lasts for <
asts for <7
en the toxi
en the to
itithin the p
hin the
will be con
will be c
t the next p
t the next p
mab
ab-r-relat
Dosing 
Dosing
Frequenc
Frequenc
E
Weekly 
Weekly
EN
GE
Biw
Biw
(
GE
GE
GE
GE
ELG
CE


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
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62
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7.2.4.2.1. Interruption or Missed Doses
A dose delay of 3 days or more from the planned date of administration for any reason other than 
toxicities suspected to be related to DARA should be brought to the attention of the Sponsor at 
the earliest possible time. 
Subjects missing ≥3 consecutive planned doses of DARA for reasons other than toxicity should 
be withdrawn from treatment, unless, upon consultation with the Sponsor and the review of 
safety and efficacy, continuation is agreed upon.
7.3.
Treatment Assignment
Celgene trial staff will review specific eligibility criteria for all screened subjects prior to 
initiation of study treatment via the IRT.
An IRT will be used to track subject assignments to the treatment stages and/or parts.
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 investigational product return, disposal, and/or destruction including responsibilities for the 
site versus Celgene (or designee).
7.6.
Investigational Product Compliance
Accurate recording of all study treatment administration (DURVA and DARA) 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 treatment (DURVA and DARA) 
either administered or in their custody during the course of the study. 
CCI
CELGENE PROPRIETARY INFORMATION
toto
parts.
parts.
number, th
number, th
mount of IP
mount of I
on/kit numb
n/kit numb
ents and/or 
ents and/o
e label as a
e label as a
ntability 
ntability
vest
vestigator 
igator 
l, and/or de
l, and/or de
roduct Co
roduct C
dy
dy treatm
treat
y
en
the subject
e subject
for accoun
for accou
or in their c
r in their 


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
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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 anti-emetic medications, may be administered at the 
discretion of the investigator.  
See Appendix E for additional details on DURVA toxicity management.
All concomitant treatments, including blood and blood products, used from 28 days prior to first 
dose of study treatment until 90 days after last dose of DURVA or DARA, whichever is later,
must be reported on the eCRF. 
For information regarding other drugs that may interact with IP and affect its metabolism, PK, or 
excretion, please see the IBs and/or local package inserts.
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/RBC transfusions and hematopoietic growth factors are also permitted during the study.  
Concurrent use of hormones for noncancer-related conditions (eg, insulin for diabetes and 
hormone replacement therapy) is acceptable.
8.2.
Prohibited Concomitant Medications and Procedures
The following medications are prohibited (except for the outlined exceptions) during the study. 
The Sponsor must be notified if a subject receives any of these during the study.
1. Subjects who fail ANC, hemoglobin or platelet eligibility criteria at Screening should not 
be retested for the study after being treated with growth factors or platelet/RBC 
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. The following exceptions apply:
a.
Pre and post infusion medications as outlined in Table 6 and Table 7 for the 
management of infusion-related reactions.
b. Use of immunosuppressive medications in subjects with contrast allergies (eg, CT 
scan contrast hypersensitivity) is acceptable. 
c.
Use of inhaled, topical, or intranasal corticosteroids or local steroid injections (eg, 
intra-articular injection) is permitted. 
CCI
CELGENE PROPRIETARY INFORMATION
st
er,
lism, PK, o
lism, PK, 
onate therap
ate the
osphonates
sphonate
re also perm
re also p
ons (eg, in
ons (eg, in
cations an
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receives an
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er being
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anticance
chemother
chemothe
apy
py, bi
, biol
ologi
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suppressive
suppressiv
exceeding 
exceeding
mor necrosi
or necrosi
a.
P


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
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d. Temporary uses of corticosteroids for concurrent illnesses (eg, food allergies) are 
acceptable upon discussion and agreement with the Medical Monitor. 
5. Live attenuated vaccines during the study through 30 days after the last dose of DURVA. 
6. Herbal and natural remedies are to be avoided.
7. Egg cell and sperm donation
8.3.
Required Concomitant Medications and Procedures
!
Infusion reaction prophylaxis: Pre infusion and post infusion medications for 
infusion reaction prophylaxis will be given as detailed in Table 6.
!
Antiviral prophylaxis: All subjects must initiate antiviral prophylaxis to prevent 
herpes zoster reactivation within 1 week of starting DARA and continue for 3 months
following last dose of DARA.  
∃
Acceptable antiviral therapy includes acyclovir (eg, 400 mg given orally 3 times a 
day, or 800 mg given orally 2 times a day or per institutional standards), 
famciclovir (eg, 125 mg given orally, twice a day or per institutional standards), 
or valacyclovir (eg, 500 mg given orally, twice a day or per institutional 
standards), initiated within 1 week after the start of study drug.
CCI
CELGENE PROPRIETARY INFORMATION
o prevent 
o prevent 
nue for 3
nue for 3 m
g given ora
g given ora
ional
onal stand
stan
l
per inst
er institi ut
day or per i
y or per 
rt of 
rt of study
stud


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
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9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
This is a single-arm, multicenter, Phase 2 study to evaluate the efficacy and safety of the 
combination regimen of DARA plus DURVA in subjects with RRMM who have progressed 
while on last MM treatment (DARA-containing regimen)
This section defines the subject populations for the statistical data analyses, the justifications of 
sample size, and the methodologies that will be used for the efficacy and safety analyses. All 
statistical analyses specified in the protocol will be conducted using SAS Version 9.2 or higher 
unless otherwise specified. 
9.2.
Study Population Definitions
For the purpose of statistical analyses and data presentation, the study populations are defined as 
follows:
9.2.1.
Full Analysis Set Population
The full analysis set population (FAS) will include all enrolled subjects. The primary efficacy 
analyses will be performed on the FAS population. 
9.2.2.
Efficacy Evaluable Population
The supportive efficacy analyses will be performed on the efficacy evaluable (EE) population, 
which will include all enrolled subjects who take at least one dose of D2 and who have 
measureable disease at baseline and at least one post-baseline efficacy measurement. 
9.2.3.
Safety Population
The safety population will include all subjects who take at least one dose of D2. All safety 
analyses will be based on this population.  
9.2.4.
Pharmacokinetic Population
The PK population will include all subjects who received at least one dose of study treatment and 
who have at least one measureable plasma concentration. For subjects who are determined to be 
noncompliant with respect to administration of IP, or for subjects with incomplete data, a 
decision as to their inclusion in the population will be made on a case-by-case basis prior to the 
analysis. 
9.3.
Sample Size and Power Considerations
The study consists of 2 parts. In Part 1, a two-stage design with one interim analysis for futility 
at the end of Stage 1 is used. PASS software, Version 13.03 has been used to calculate the 
sample sizes. Setting the Type I error rate at 0.05, a total sample size of 50 subjects provides a 
power of at least 80% to reject the null hypothesis of ORR less than 10% with a target response 
rate of 25%. In Stage 1, 18 subjects will be enrolled and if there are at least 3 subjects out of 18 
who achieved a response (PR or above) by end of cycle 3, the study will continue to Stage 2. If 
there are 2 or less subjects who achieved a response out of 18 subjects in Stage 1, the study will 
CCI
CELGENE PROPRIETARY INFORMATION
igher 
igher 
ioi ns
n are de
re de
ubjects. Th
jects. Th
on the effic
on the eff
at least one
at least on
e post
e post-base
base
l subjects
l subject w
ulat
ulatioi n.  
c Populatio
c Populati
include all 
include a
measureab
measure
 respect to 
respect to 
eir inclusio
eir inclusio
Sa
Samp
mp
e study
study con
con
y
at the end o
t the end 
ample 
ample


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
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be terminated for futility and will not proceed to Stage 2. In Stage 2, an additional 32 subjects 
will be enrolled. If there are at least 9 subjects who achieved a response out of a total of 50 
subjects from Stages 1 and Stage 2, the null hypothesis will be rejected. If it is determined at the 
end of Part 1 to further evaluate the efficacy and safety of the combination regimen of DARA 
plus DURVA, then up to an additional 70 subjects will be enrolled in Part 2. This will bring the 
total number of subjects treated during the study up to approximately 120. The additional 
subjects will add to the certainty about the efficacy and safety of this combination therapy.  
Table 9 shows the exact 95% CIs around the response rates observed based on different 
scenarios. For example, if the observed ORR is 25%, the lower limit of the 95% CI will be 
17.5%. If the observed ORR is 30%, the lower limit of the 95% CI will be 22.0%.  
Table 9:
Estimated Overall Response Rate and 95% Confidence Interval Out of 120 
Subjects
Number of Responders in 120 Subjects
ORR
95% Confidence Interval
30
25.0  %
17.5, 33.7
31
25.8 %
18.3, 34.6
32
26.7 %
19.0, 35.5
33
27.5 %
19.7, 36.4
34
28.3 %
20.5, 37.3
35
29.2 %
21.2, 38.2
36
30.0 %
22.0, 39.0
37
30.8 %
22.7, 39.9
38
31.7 %
23.5, 40.8
39
32.5 %
24.2, 41.7
40
33.3 %
25.0, 42.5
ORR=overall response rate
9.4.
Background and Demographic Characteristics
Subjects’ age, height, weight, and baseline characteristics will be summarized using descriptive 
statistics, while gender, race and other categorical variables will be provided using frequency 
tabulations. Medical history data will be summarized using frequency tabulations by system 
organ class (SOC) and preferred term (PT). 
9.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent.  A summary of 
subjects enrolled by site will be provided. Protocol deviations will be summarized using 
frequency tabulations.
CCI
CELGENE PROPRIETARY INFORMATION
ut of 120 
t of 120 
nfidence In
nfidence 
OR
17.5,
17.5, 3
FO
18
1
NF
IN
Y
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AR
29.2 %
9.2 %
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5.
Su
S
Subject d
Subject d
ason


EDMS Doc. Number:
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9.6.
Efficacy Analysis
Primary efficacy analyses will be performed on the FAS population. Supportive efficacy 
analyses will also be performed using the EE population. 
9.6.1.
Primary Efficacy Endpoint
The primary efficacy endpoint will be based on the tumor response, including PD, as assessed by 
an IRAC using the IMWG Uniform Response Criteria. 
The overall response rate (ORR) will be calculated as the number of responders (PR or better), 
divided by the number of subjects in the FAS population. The ORR together with the proportions 
in each category based on the IMWG criteria (ie, stringent complete response [sCR], complete 
response [CR], very good partial response [VGPR], partial response [PR], stable disease [SD], 
and disease progression [PD] will be tabulated, together with the 2-sided exact 95% CI. 
This efficacy analysis will be conducted after the 18 subjects from Stage 1 have completed at 
least 3 cycles of treatment, Stage 2 of the Part 1 study and at the end of Part 2 of the study if the 
decision has been made to expand the study. 
9.6.2.
Secondary Efficacy Endpoints
Time-to-response (for responders only, per IMWG Uniform Response Criteria) is calculated as 
the time from treatment initiation of study treatment to the first date of documented response (PR 
or better). Time to response will be summarized using descriptive statistics.
Duration of response (for responders only, per IMWG criteria) is defined as time from the 
earliest date of documented response (PR or better) to the first documentation of PD or death, 
whichever is earlier. Duration of response will be analyzed using the Kaplan-Meier (KM) 
method. Median duration of response along with the two-sided CI will be provided. 
Progression-free survival is defined as time from treatment initiation to the first date of 
documented PD or death from any cause during the study, whichever occurs earlier. Subjects 
who do not have a PFS event will be censored on the last adequate assessment date. PFS will be 
summarized using the KM method. 
Overall survival is defined as time from treatment initiation to death due to any cause. Subjects 
who are alive or lost to follow-up will be censored on the last-known-alive date. The OS will be 
analyzed using the KM method. Median OS and the corresponding 95% CI will be provided. 
9.7.
Safety Analysis
All subjects in the safety population who receive at least 1 dose of DARA plus DURVA, will be 
included in the safety analyses. Adverse events, vital sign measurements, physical exam 
findings, clinical laboratory data, ECG interpretations, pregnancy tests for FCBP, concomitant 
medications and procedures will be tabulated and summarized. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Adverse event listings will include the verbatim term and the MedDRA preferred 
tem. Adverse events will be graded according to the CTCAE Version 4.03 criteria. 
CCI
CELGENE PROPRIETARY INFORMATION
r), 
r), 
portions 
ortions 
om
omplete
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vers
d


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
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The frequency of AEs will be tabulated by MedDRA SOC and PT. In the by-subjects analysis, a 
subject having the same event more than once will be counted only once. Adverse events leading 
to discontinuation from treatment, leading to dose reduction/interruption/delay, classified as 
CTCAE Grade 3 or higher, DARA, DURVA-related events, and serious AEs will be tabulated 
and listed separately. By-subject listings of all AEs, serious AEs, and their attributes will be 
provided. 
Primary cause of death recorded on the eCRF death form will be coded according to MedDRA 
and summarized by SOC and PT. By-subject listing of death will also be provided. 
Clinical laboratory results will be summarized descriptively and will include a display of change 
from baseline. Laboratory values outside of the normal ranges will be identified. Laboratory data 
will be graded according to CTCAE Version 4.03 criteria for select analytes unless otherwise 
specified. The frequencies of the worst severity grade observed during treatment will be 
displayed in cross-tabulations by screening status. 
9.8.
Interim Analysis
This study will be conducted in 2 parts. Part 1 and Part 2. Part 1 consists of one pre-planned 
interim analysis for futility purposes at the completion of Stage 1.
9.9.
Other Topics
9.9.1.
Pharmacokinetic Analysis
Noncompartmental PK parameters such as time to maximum concentration (Tmax), maximum 
observed concentration (Cmax), area under the curve (AUC), terminal elimination half-life (t1/2 ), 
clearance (CL/F), and volume of distribution (Vz/F) will be estimated from the plasma 
concentration-time profile. All concentration data and PK parameters will be summarized 
descriptively. 
 
 
 
 
 
 
 
CCI
CCI
CELGENE PROPRIETARY INFORMATION
hange
hange
atory
atory data
dat
y
therwise
therwise
will be
ill be
ists of
sts of one
one
maximum 
maximum
urve (AUC)
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(Vz/F) wil
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CEL
EL


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
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9.10.
Study Committees
9.10.1.
Data Monitoring Committee 
An external and independent DMC with multidisciplinary representation will be established to 
monitor the safety data regularly.
The DMC will review the safety and the efficacy data at the end of Stage 1. If the study is to 
proceed to Stage 2, the DMC will also review the safety and efficacy data at the end of Stage 2. 
The DMC chairman may convene formal DMC meetings if there are any unusual safety/efficacy 
concerns. The Sponsor can also request a DMC review of the safety data if unexpected safety 
concerns arise during the conduct of the trial. The DMC responsibilities, authorities, and 
procedures will be detailed in the DMC charter.  
9.10.2.
Independent Review Adjudication Committee
An IRAC will be set up for this trial to  assess the response data for each subject using the 
IMWG Uniform Response Criteria. The IRAC will determine the tumor response to therapy and 
to confirm the time of disease progression (PD) (if disease progressed) at scheduled or 
unscheduled visits for each subject. 
CCI
C
C
I
shed to
shed to
he study
he study i
y s
the end of 
the end o
y unusual sa
unusu
data if unex
ata if unex
ilit
li ies, auth
es, aut
ee
ponse
onse data
data f
determine 
determine
(if di
(if disease 
sease 


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
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Confidential and Proprietary
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10.
ADVERSE EVENTS
10.1.
Monitoring, Recording and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a 
preexisting condition) should be considered an AE. A diagnosis or syndrome should be recorded 
on the AE page of the case report form (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 CRF. If the sequela of an 
overdose is an SAE, then the sequela must be reported on an SAE report form and on the AE 
CRF. The overdose resulting in the SAE should be identified as the cause of the event on the 
SAE report form and CRF but should not be reported as an SAE itself.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary. There is no known specific antidote for DURVA, or DARA, 
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 DURVA or DARA, whichever is later, as well as those SAEs 
made known to the Investigator at any time thereafter that are suspected of being related to study 
IPs (DARA, DURVA). Adverse events and SAEs will be recorded on the AE page of the CRF 
and in the subject’s source documents. All SAEs must be reported to Celgene Drug Safety within 
24 hours of the Investigator’s knowledge of the event by facsimile, or other appropriate method, 
using the SAE Report Form, or approved equivalent form. 
10.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all AEs as to: 
10.2.1.
Seriousness
An SAE is any AE occurring at any dose that:
!
Results in death;
!
Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE);
CCI
CELGENE PROPRIETARY INFORMATION
orded 
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oms of 
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reported on
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Report Form
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0.2.1.
0.2.1.
S
An SAE
An SA


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
71
MEDI4736-MM-005 Final: 03 Oct 2016
!
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);
!
Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);
!
Is a congenital anomaly/birth defect;
!
Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Events not considered to be SAEs are hospitalizations for:
!
a standard procedure for protocol therapy administration.  However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE. 
!
routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.
!
the administration of blood or platelet transfusion as routine treatment of studied 
indication. However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.
!
a procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling). However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable 
SAE.
!
hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.
!
a procedure that is planned (ie, planned prior to start of treatment on study); must be 
documented in the source document and the CRF. Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.
!
an elective treatment of or an elective procedure for a pre-existing condition, 
unrelated to the studied indication, that has not worsened from baseline. 
!
emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the CRF and the SAE Report Form 
must be completed.
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to the IP, action taken regarding the IP, and outcome.
CCI
CELGENE PROPRIETARY INFORMATION
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
72
MEDI4736-MM-005 Final: 03 Oct 2016
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
Adverse events 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 IPs (DARA, 
DURVA) and the occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
A causal relationship of the AE to IPs (DARA, DURVA)
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 IPs 
(DARA, DURVA) caused the AE. ‘Reasonable possibility’ means 
there is evidence to suggest a causal relationship between the IP and 
the adverse event.
CCI
CELGENE PROPRIETARY INFORMATION
edical
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Suspecte


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
73
MEDI4736-MM-005 Final: 03 Oct 2016
Causality should be assessed and provided for every AE/SAE based on currently available 
information. Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP 
that has not been manufactured or provided by Celgene, please provide the name of the 
manufacturer when reporting the event.
10.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
10.2.5.
Action Taken
The Investigator will report the action taken with IPs (DARA, DURVA) as a result of an AE or 
SAE, as applicable (eg, discontinuation, interruption, or dose reduction of IPs, 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; or
!
requires treatment, modification/ interruption of IPs (DARA, DURVA) 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 an SAE.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the CRF. If the abnormality was not a 
part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. If 
possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets).
10.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject of childbearing 
potential or partner of childbearing potential of a male subject are immediately reportable events. 
CCI
CELGENE PROPRIETARY INFORMATION
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abnorm
bnormalal


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
74
MEDI4736-MM-005 Final: 03 Oct 2016
10.4.1.
Females of Childbearing Potential:
Pregnancies and suspected pregnancies (including elevated β-subunit human chorionic 
gonadotropin [β-hCG]) or positive pregnancy test in a female subject of childbearing potential 
regardless of disease state) occurring while the subject is on study treatment, or within 90 days 
after last dose of DURVA / DARA, whichever occurs later are considered immediately reportable 
events. Investigational product is to be discontinued immediately and the subject instructed to 
return any unused portion the Investigator. The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported to Celgene Drug Safety immediately by email, phone or 
facsimile, or other appropriate method, using the Pregnancy Initial Report Form, or approved 
equivalent form. 
The female subject should be referred to an obstetrician-gynecologist, preferably one 
experienced in reproductive toxicity for further evaluation and counseling.
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the Investigator 
should report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the SAE Report 
Form, or approved equivalent form.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IPs (DARA, DURVA) 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 IPs (DARA, DURVA) becomes pregnant, the male 
subject taking IPs (DARA, DURVA) should notify the Investigator, and the pregnant female 
partner should be advised to call their healthcare provider immediately.
10.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the CRF. All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event by facsimile, 
or other appropriate method (eg, via email), using the SAE Report Form, or approved equivalent 
form. This instruction pertains to initial SAE reports as well as any follow-up reports.
The Investigator is required to ensure that the data on these forms are accurate and consistent. 
This requirement applies to all SAEs (regardless of relationship to IPs [DARA, DURVA]) that 
occur during the study (from the time the subject signs informed consent until 90 days after the 
last dose of DURVA or DARA, whichever is later) or any SAEs made known to the Investigator 
at any time thereafter that are suspected of being related to IPs (DARA, DURVA). Serious
adverse events occurring prior to treatment (after signing the ICF) will be captured.
CCI
CELGENE PROPRIETARY INFORMATION
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
75
MEDI4736-MM-005 Final: 03 Oct 2016
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 DURVA and DARA based on their respective IBs.
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 IPs for human use (ENTR/CT3) and also in accordance with country-specific 
requirements. 
Events of disease progression for the disease under study (including deaths due to disease 
progression for indications that are considered to be fatal) will be assessed as expected AEs and 
will not be reported as expedited safety reports to regulatory authorities.
Celgene or its authorized representative shall notify the Investigator of the following 
information: 
!
Any AE suspected of being related to the use of IPs (DARA, DURVA) in this study 
or in other studies that is both serious and unexpected (ie, suspected unexpected 
serious adverse reaction [SUSAR]);
!
Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
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).
CCI
CELGENE PROPRIETARY INFORMATION
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
76
MEDI4736-MM-005 Final: 03 Oct 2016
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 DURVA(MEDI4736) 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 durvalumab.
AESIs for durvalumab include but are not limited to events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants and/or hormone replacement therapy. These 
AESIs are being closely monitored in clinical studies with durvalumab monotherapy and 
combination therapy. An immune-related adverse event (irAE) is defined as an AE that is 
associated with drug exposure and is consistent with an immune-mediated mechanism of action 
and where there is no clear alternate etiology. Serologic, immunologic, and histologic (biopsy) 
data, as appropriate, should be used to support an irAE diagnosis. Appropriate efforts should be 
made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the irAE.
If the Investigator has any questions in regards to an AE being an irAE, the Investigator should 
promptly contact the Medical Monitor.
Further information on these AESIs (eg, presenting symptoms) can be found in the current 
version of the DURVA IB (Section 5.5.2 Summary of Risks). 
CCI
CELGENE PROPRIETARY INFORMATION
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
77
MEDI4736-MM-005 Final: 03 Oct 2016
11.
DISCONTINUATIONS
11.1.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product(s):
!
Adverse event
!
Withdrawal by subject
!
Pregnancy
!
Death
!
Lost to follow-up
!
Other (to be specified on the CRF)
The reason for discontinuation of treatment should be recorded in the CRF and in the source 
documents.
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor.  However, prior to discontinuing 
a subject, the Investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion.
11.2.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
study:
!
Screen failure
!
Adverse event
!
Withdrawal by subject
!
Pregnancy
!
Death
!
Lost to follow-up
!
Other (to be specified on the CRF)
The reason for study discontinuation should be recorded in the CRF and in the source 
documents.
CCI
CELGENE PROPRIETARY INFORMATION
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
78
MEDI4736-MM-005 Final: 03 Oct 2016
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, IPs will be identified on the package labeling.
CCI
CELGENE PROPRIETARY INFORMATION
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
79
MEDI4736-MM-005 Final: 03 Oct 2016
13.
REGULATORY CONSIDERATIONS
13.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative,
and Investigator abide by Good Clinical Practice (GCP), as described in International Council on 
Harmonisation (ICH) Guideline E6 and in accordance with the general ethical principles outlined 
in the Declaration of Helsinki. The study will receive approval from an IRB/EC prior to 
commencement. The Investigator will conduct all aspects of this study in accordance with 
applicable national, state, and local laws of the pertinent regulatory authorities.
13.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations.  Celgene staff or an authorized representative will evaluate and approve all 
Investigators who in turn will select their staff.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of Celgene information. The Investigator should maintain 
a list of Sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an informed consent 
form (ICF) and are screened for entry into the study.  Subjects who fail screening must have the 
reason(s) recorded in the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The Investigator must ensure timely and accurate completion of CRFs and queries.
The information contained in the protocol and amendments (with the exception of the 
information provided by Celgene on public registry websites) is considered Celgene confidential 
information.  Only information that is previously disclosed by Celgene on a public registry 
website may be freely disclosed by the Investigator or its institution, or as outlined in the Clinical 
Trial Agreement.  Celgene protocol, amendment and IB information is not to be made publicly 
available (for example on the Investigator’s or their institution’s website) without express written 
approval from Celgene.  Information proposed for posting on the Investigator’s or their 
institution’s website must be submitted to Celgene for review and approval, providing at least 5 
business days for review.
At the time results of this study are made available to the public, Celgene will provide 
Investigators with a summary of the results that is written for the lay person. The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.
CCI
CELGENE PROPRIETARY INFORMATION
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
80
MEDI4736-MM-005 Final: 03 Oct 2016
13.3.
Subject Information and Informed Consent
The Investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date.  The original ICF signed and dated by the study subject and by the person 
consenting the study subject prior to the study subject’s entry into the study, must be maintained 
in the Investigator’s study files and a copy given to the study subject.  In addition, if a protocol is 
amended and it impacts on the content of the informed consent, the ICF must be revised.  Study 
subjects participating in the study when the amended protocol is implemented must be re-
consented with the revised version of the ICF.  The revised ICF signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the Investigator’s 
study files and a copy given to the study subject.
13.4.
Confidentiality
Celgene affirms the subject's right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Celgene requires 
the Investigator to permit Celgene's representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual.
13.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene Clinical Research 
Physician/Medical Monitor.  Amendments will be submitted to the IRB/EC for written approval.  
Written approval must be obtained before implementation of the amended version occurs.  The 
written signed approval from the IRB/EC should specifically reference the Investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/IEC approval but will be submitted to the IRB/IEC 
for information purposes.
13.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF, and any other appropriate documents will 
be submitted to the IRB/EC with a cover letter or a form listing the documents submitted, their 
dates of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is 
sought. If applicable, the documents will also be submitted to the authorities in accordance with 
local legal requirements.
IP can only be supplied to an Investigator by Celgene or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
CCI
CELGENE PROPRIETARY INFORMATION
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
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Confidential and Proprietary
81
MEDI4736-MM-005 Final: 03 Oct 2016
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.
CCI
CELGENE PROPRIETARY INFORMATION
otocol
ocol
aluated to
aluated to
also be rev
also be rev
and, if app
and, if app
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!


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
82
MEDI4736-MM-005 Final: 03 Oct 2016
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 CRF and entered into the clinical database per Celgene SOPs. This 
data will be electronically verified through use of programmed edit checks specified by the 
clinical team.  Discrepancies in the data will be brought to the attention of the clinical team, and 
investigational site personnel, if necessary.  Resolutions to these issues will be reflected in the 
database.  An audit trail within the system will track all changes made to the data.
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.); 
!
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
CCI
CELGENE PROPRIETARY INFORMATION
ene S
ne SOPs. T
OPs.
specified by
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
83
MEDI4736-MM-005 Final: 03 Oct 2016
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. The 
Investigator or institution should take measures to prevent accidental or premature destruction of 
these documents.
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CELGENE PROPRIETARY INFORMATION
of 
of 


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15.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative
for compliance with applicable government regulations with respect to current GCP and SOPs.
15.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study.  All aspects of the study are reviewed with the Investigator and the staff at a study 
initiation visit and/or at an Investigators’ Meeting.  Prior to enrolling subjects into the study, a 
Celgene representative will review the protocol, CRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the Investigator.  Monitoring will 
include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone.  During monitoring visits, the facilities, 
investigational product storage area, CRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Celgene representative in accordance with the 
Study Monitoring Plan.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the CRFs against the appropriate source documentation.  Any resulting 
discrepancies will be reviewed with the Investigator and/or his/her staff.  Any necessary 
corrections will be made directly to the CRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified.  Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
15.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, CRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (eg, FDA, EMA, 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.
CCI
CELGENE PROPRIETARY INFORMATION
a
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
85
MEDI4736-MM-005 Final: 03 Oct 2016
16.
PUBLICATIONS
As described in Section 13.2, all protocol- and amendment-related information, with the 
exception of the information provided by Celgene on public registry websites, is considered 
Celgene confidential information and is not to be used in any publications.  Celgene protocol-
related information proposed for use in a publication must be submitted to Celgene for review 
and approval, and should not be utilized in a publication without express written approval from 
Celgene, or as described in the Clinical Trial Agreement.  
Celgene will ensure Celgene-sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results.  At a minimum, this applies to 
results from all Phase 3 clinical studies, and any other study results of significant medical 
importance.  This also includes results relating to investigational medicines whose development 
programs have been discontinued.
Study results may also be presented at one or more medical congresses, and may be used for 
scientific exchange and teaching purposes.  Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.  
Eligibility for external authorship, as well as selection of first authorship, will be based on 
several considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable) and contribution to abstract, presentation and/or publication development.
CCI
CELGENE PROPRIETARY INFORMATION
es to
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tion and/o


EDMS Doc. Number:
Durvalumab (MEDI4736)
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17.
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05-27. 
27. 
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tem
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u
Hanahan D
Hanahan 
rbs
b


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
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MEDI4736-MM-005 Final: 03 Oct 2016
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
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Confidential and Proprietary
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d 2016;
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
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von Minckwitz G, Schwedler K, Schmidt M, Barinoff J, Mundhenke C, Cufer T, et al. 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
90
MEDI4736-MM-005 Final: 03 Oct 2016
18.
APPENDICES
Appendix A: Table of Abbreviations
Table 10:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
ADCC
Antibody-dependent cell-mediated cytotoxicity
ADL
Activity of daily life
AE
Adverse event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase 
ANC
Absolute neutrophil count
ASCT
Autologous stem cell transplantation
AST
Aspartate aminotransferase 
AUC
Area under the curve
BM
Bone marrow
β-hCG
β-subunit of human chorionic gonadotropin
BMA
Bone marrow aspirate
BMB
Bone marrow biopsy
BUN
Blood urea nitrogen
C
Cycle
CBC
Complete blood count
CD 
Cluster of differentiation
CDC
Complement-dependent cytotoxicity
CIs
Confidence intervals
CIPs
Complementary-inhibitory proteins
CL/F
Clearance
Cmax
Maximum observed concentration 
CNS
Central nervous system
COPD
Chronic obstructive pulmonary disease
CR
Complete response
CrCl
Creatinine clearance
CT
Computed tomography
CCI
CELGENE PROPRIETARY INFORMATION
T
AT
AT
AT
AT
AT
MA
RM
OR
FO
NF
IN
Y
RY
AR
ionic gonad
onic gonad
TA
te
ET
opsy
opsy
RI
nitrogen
nitrogen
PR
OP
mplete bloo
mplete blo
RO
Cluster of 
Cluster of
PR
E
Comp
Co
E P
NE
C
NE
NE
NE
EN
GE
LG
NS
NS
EL
COPD
COPD
CE
C


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Table 10:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
CTCAE
Common Terminology Criteria for Adverse Events
D
Day
D2
Daratumumab plus durvalumab
DARA
Daratumumab
DURVA
Durvalumab
DLT
Dose-limiting toxicity
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DOR
Duration of response
DRT
Dose Review Team
EC
Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EE
Efficacy evaluable
EEA
European Economic Area
EMP
Extramedullary plasmacytoma
EOI
End of infusion
EOT
End of Treatment
EU
European Union
FAS
Full analysis set
Fc
Fragment crystallizable
FCBP
Females of childbearing potential
FDA
Food and Drug Administration
FEV
Forced expiratory volume
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HIV
Human immunodeficiency virus
IAT
Indirect antiglobulin test
IB
Investigator’s Brochure
CCI
IV
IV
CE
GLP
GLP
CELGENE P
Full ana
ll an
PROPRIETARY INFORMATION
T
AT
AT
AT
AT
MA
RM
OR
FO
NF
IN
Y
Group
roup
AR
TA
ET
ic Area
ic Area
IE
ry plasmacyt
y plasmac
R
usion
usion
OP
f f Trereatmen
atmen
O
European Un
European 
R
P
E
Frag
Fra
E
NE
NE
NE
NE
EN
G
LG
CE
C


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Table 10:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
ICF
Informed consent form
ICH
International Council on Harmonisation
IFNγ
Interferon gamma
Ig
Immunoglobulin
ILD
Interstitial lung disease
IMWG
International Myeloma Working Group
IMiD
Immunomodulatory drug
IND
Investigational New Drug
IP
Investigational product
IRAC
Independent Response Adjudication Committee
irAE
Immune related adverse events
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent to treat
IV
Intravenous
KM
Kaplan-Meier
mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MM
Multiple myeloma
MR
Minimal response
MRI
Magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NK
Natural killer cells
NOAEL
No observed adverse effect level
ORR
Overall response rate
OS
Overall survival
PD
Disease progression
CCI
CCI
CC
I
CELGENE PROPRIETARY INFORMATION
T
AT
AT
AT
AT
MA
RM
OR
FO
tee
ee
NF
IN
Y
gy
AR
TA
ET
IE
ntibody
ntibody
R
Dictionary fo
ictionary
OP
iple myelom
ple myelom
O
Minima
Minimal resp
l r
R
Magneti
agne
P
E
NE
NE
NE
NE
EN
G
AEL
AEL
LG
ORR
ORR
CE
S
C
E 


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Table 10:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
PD-1
Programmed cell death-1
PD-L1
Programmed death-ligand 1
PFS
Progression-free survival
PI
Proteasome inhibitor
PI
Prescribing Information
PK
Pharmacokinetics
PR
Partial response
PT
Preferred term
QW
Weekly
Q2W
Every 2 weeks
Q4W
Every 4 weeks
RBC
Red blood cell 
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
RRMM
Relapsed and refractory multiple myeloma
SAE
Serious adverse event
sCR
Stringent complete response
SD
Stable disease
SmPC
Summary of Product Characteristics
SOC
System organ class
SOP
Standard operating procedure
sPD-L1
Soluble programmed death-ligand 1
sPEP
Serum protein electrophoresis
SUSAR
Suspected unexpected serious adverse reaction
t1/2
Terminal elimination half-life
Tmax
Time to maximum concentration
TCR
T-cell receptor
TSH
Thyroid stimulating hormone
Tregs
Regulatory t-cells
TTR
Time-to-response
CCI
CELGENE PROPRIETARY INFORMATION
T
AT
AT
AT
AT
MA
RM
OR
FO
NF
IN
Y
Solid Tum
Solid Tu
AR
TA
y multiple m
y multiple m
ET
ent
ent
IE
plete respon
plete resp
R
ease
ease
OP
mary of Prod
mary of Pro
O
System orga
System or
R
Standard
nda
P
E
Solu
Sol
E
NE
NE
NE
NE
EN
G
LG
TCR
TCR
CE
SH
SH
C


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Table 10:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
ULN
Upper limit of normal
uPEP
Urine protein electrophoresis
USA
United States of America
VGPR
Very good partial response
VTE
Venous thromboembolism
Vz/F
Volume of distribution
WBC
White blood cell 
CCI
CELGENE PROPRIETARY INFORMATION
T
AT
AT
AT
AT
MA
RM
OR


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Appendix B: International Myeloma Working Group Uniform Response 
Criteria
Response Category
a
Response Criteria
Stringent Complete 
Response (sCR)
Complete response (CR) as defined below, plus
Normal serum 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 
chain assay is also unmeasurable, a ≥ 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 (PD)
CCI
CELGENE PROPR
tion of serum
ion of ser
≥90% or t
90% o
erum and u
erum and
difference b
difference b
place of the 
place of th
If serum 
f ser
chain 
chain
req
req
PRIETARY INFORMATION
or 
AT
s by serum 
s by ser
tio of 0.26 to
io of 0.26 
MA
by immunof
by immunof
m M
m M-protein
-protein
e only measu
only meas
nts requires 
nts requires
and uninvo
and uninvo
Y IN
PR
E
Disease (SD
Disease (S
G
ELG


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Appendix B: International Myeloma Working Group Uniform Response 
Criteria (Continued)
Response Categorya
Response Criteria
Progressive disease (PD)
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 bone marrow 
(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.
CCI
CELGENE PROPRIETARY INFORMATION
),),
0 mg/24 h),
0 mg/24 h)
M-protein le
protein le
evels (absolu
evels (absol
nd urine M p
nd urine M p
, bone marro
bone mar
e ≥ 10%)
≥ 1
esions or so
esions or s
isting bone 
isting bone
emia (corre
emia (corr
lely to the p
lely to the 
AT
E
ive allele
ve allele-sp
SO-PCR), s
PCR), s
RI
nt CR 
nt C
plus
lus
sence of phe
ence of phe
BM
BM) with a
with
multipara
multipara
OP
E
MR)
MR)
psed 
psed 
ma
the Europea
he Europea
Blood and 
lood and 
Transplanta
nsplant
MT) criteri
MT) criteria
≥ 25%
≥ 2
ur
ur
E P
EL
E
All response c
response c
the instituti
the institut
progress
progre
nd u
d


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Appendix C: ECOG Performance Status
Eastern Cooperative Oncology Group (ECOG) Performance Status
Grade
ECOG Performance Status
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 self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
Eastern Cooperative Oncology Group, Robert Comis, MD, Group Chair.
CCI
CELGENE PROPRIETARY INFORMATION
a
AT
es. Up 
 Up
AT
AT
AT
% of waking
of waking
RM
ned to bed o
ned to bed o
O
NF
IN


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Appendix D: Staging Systems for Multiple Myeloma
Table 11:
Staging Systems for Multiple Myeloma 
Stage
Durie-Salmon Criteria
a
International Staging
System (ISS) Criteria
b
I
All of the following:
Hemoglobin value > 10 g/dL
Serum calcium value normal or <  12 mg/dL
Bone x-ray, normal bone structure (scale 0), or 
solitary bone plasmacytoma only
Low M-component production rates
IgG value < 5 g/dL; 
IgA value < 3 g/dL
Urine light chain M-component on
electrophoresis < 4 g/24h
Serum beta-2 microglobulin < 3.5 
mg/L
Serum albumin ≥ 3.5 g/dL
II
Neither Stage I nor Stage II
Neither Stage I nor Stage II
III
One or more of the following:
Hemoglobin value < 8.5 g/dL
Serum calcium value normal or > 12 mg/dL
Advanced lytic bone lesions (scale 3)
High M-component production rates
IgG value > 7 g/dL; 
IgA value > 5 g/dL
Urine light chain M-component on
electrophoresis > 12 g/24h
Serum beta-2 microglobulin ≥ 5.5 
mg/L
Subclassification Criteria
A  Normal renal function (serum creatinine value < 2.0 
mg/dL)
B  Abnormal renal function (serum creatinine value ≥ 2.0 
mg/dL)
Not applicable
a Durie, 1975.
b Greipp, 2005.
CCI
CELGENE PROPRIETA
ponent on
ponent on
g/24h
g/24h
TARY INFORMATION
AT
either Stage 
ither 
Y I
Serum bet
Serum bet
mg/L
mg/L
RY
TA
serum creati
um creati
unction (seru
nction (ser
RO
EN
5.


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Appendix E: Durvalumab Treatment Modification and Toxicity Management Guidelines
Note: The toxicity management guidelines in Appendix E-1, E-2, and E-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 E-1:
Durvalumab Treatment Modification and Toxicity Management Guidelines for Immune-related Adverse 
Events
Immune-Mediated Reactions
Dose Modifications
Toxicity Management
Immune-related 
Adverse Events 
(Overall 
Management For 
toxicities not 
noted below)
Drug administration modifications of study drug/study regimen will 
be made to manage potential 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 study 
drug/regimen based on CTC grade/severity (table below),
permanently discontinue study drug/study regimen for the following 
conditions: 
!
Inability to reduce corticosteroid to a dose of ≤10 mg of 
prednisone per day (or equivalent) within 12 weeks after last 
dose of study drug/regimen
!
Recurrence of a previously experienced Grade 3 treatment-
related AE following resumption of dosing.
It is recommended that management of irAEs follow the 
guidelines presented in this table
-
Patients should be thoroughly evaluated to rule out any 
alternative etiology (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 PO 1-2mg/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 2-4mg/kg/day PO 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 
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 at the 
next scheduled dose once event stabilizes to 
Grade ≤1 after completion of steroid taper
Patients with endocrinopathies who may require 
prolonged or continued steroid replacement 
CCI
CEL
pri
prietet
ELGENE PROPRIETARY INFORMATION
e Corpora
e Corpora
ON
o assist the
assist th
be applied
be applied
for Immun
for Immu
FO
Tox
To
NF
wing 
wing 
10 mg of 
10 mg of 
2 weeks
2 week afte
afte
ced Grade 3 
ced Grad
 of dosing.
f dosing
ommended th
ommended
elines presen
elines presen
-
Pati
Pa
a
IN
TA
tion
ion
RO
drug/study
ug/stud re
y
toto ≤ Grade 
rad
toxicity 
toxicity wo
w
Grade 4
Grade 4
Study 
Study drug/
drug/
next 
next
Gr
Pa
Pa
EL


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Immune-Mediated Reactions
Dose Modifications
Toxicity Management
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.
steroids.  
-
Discontinuation of study drug 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 study drug in this situation should be 
based upon a benefit/risk analysis for that patient 
Grade 3
Depending on the individual toxicity, may 
permanently discontinue study drug/study 
regimen. Please refer to guidelines below
Grade 4
Permanently discontinue study drug/study 
regimen 
Note:  For Grade 3 and above asymptomatic amylase or lipase levels 
hold study drug/regimen and if complete work up shows no evidence 
of pancreatitis, may continue or resume study drug/regimen
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
CCI
CELG
pri
prietet
LGE
nly, 
nly, 
not 
ot
)
GENE PROPRIETARY INFORMATION
e Corpora
e Corpora
ON
O
ment
ent
TIO
dy drug is not
y drug is n
flammatory 
flammatory
onse (
onse (eg,
eg, inf
inf
atic disease, 
atic disease, 
n of study dr
of study d
on a benefit/
on a benefit
AT
A
ls
dence
denc
A
TA
ET
ose modifica
ose modifica
onsider holdi
nsider holdi
dosing as c
dosing as c
diagnos
diagno
E P
LGE


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Immune-Mediated Reactions
Dose Modifications
Toxicity Management
Grade 2 
(Symptomatic, 
medical 
intervention 
indicated, limiting 
instrumental ADL) 
Hold study drug/study regimen dose until 
Grade 2 resolution to ≤ Grade 1
•
If toxicity worsens then treat as Grade 3 or 
Grade 4 
•
If toxicity improves to ≤Grade 1 then the 
decision to reinitiate study drug/regimen 
will be based upon treating physician’s 
clinical judgment and after completion of 
steroid taper.
For Grade 2 (Mild to Moderate New Symptoms)
-
Monitor symptoms daily and consider hospitalization
-
Promptly start systemic steroids (eg, prednisone 1-
2mg/kg/day PO or IV equivalent)
-
Reimaging as clinically indicated
-
If no improvement within 3-5 days, additional workup 
should be considered and prompt treatment with IV 
methylprednisolone 2-4mg/kg/day started 
-
If still no improvement within 3-5 days despite IV 
methylprednisone at 2-4/g/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)
a, b
-
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 
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 
CCI
CEL
pri
prietet
ELGE
mise, urgent 
mise, urgent 
ventio
vention n
o
ELGENE PROPRIETARY INFORMATION
e Corpora
e Corpora
ON
O
ment
ent
TIO
w Symptoms
w Symptom
ily and 
ly and consi
con
emic steroids
emic steroid
or IV equiva
IV equiva
as clinically i
clinically
provement w
provement w
d be conside
be con
ethy
ethylpredn
lpredniso
is
If still no i
till no 
methy
m
lp
imm
im
(
AT
TA
disco
discontinue s
ntinue 
RO
GE


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Immune-Mediated Reactions
Dose Modifications
Toxicity Management
indicated [eg, 
tracheostomy or 
intubation]) 
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
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 
Hold study drug/study regimen until resolution 
to ≤ Grade 1
For Grade 2 diarrhea: 
-
Consider symptomatic treatment including hydration, 
CCI
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ELGENE PROPRIETARY INFORMATION
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diarrhea 
diarrhea 
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frequency o
LG
E G


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
103
MEDI4736-MM-005 Final: 03 Oct 2016
Immune-Mediated Reactions
Dose Modifications
Toxicity Management
4-6 over baseline 
per day) 
•
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 
electrolyte replacement, dietary changes (eg, American 
Dietetic Association colitis diet), and loperamide 
and/or budesonide 
-
Promptly start prednisone 1 to 2  mg/kg/day PO or IV 
equivalent 
-
If event is not responsive within 3-5 days or worsens 
despite prednisone at 1-2 mg/kg/day PO or IV 
equivalent, GI consult should be obtained for 
consideration of further workup such as imaging and/or 
colonoscopy to confirm colitis and rule out perforation, 
and prompt treatment with IV methylprednisolone 2-
4mg/kg/day started. 
-
If still no improvement within 3-5 days despite 2-
4mg/kg IV methylprednisolone, promptly start 
immunosuppressives such as (infliximab at 5 mg/kg 
once every 2 weeks3). 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])
3
ASCO Educational Book 2015 Michael Postow MD “Managing Immune Checkpoint Blocking Antibody Side Effects.
CCI
CE
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prietet
ELGENE PROPRIETARY INFORMAT
etary change
etary change
itis diet), and
s diet), 
ednisone 1 to
ednisone 1 to
not responsiv
not responsiv
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and prom
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AT
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ELG
ook 2015 Mi
ok 2015 Mi


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
104
MEDI4736-MM-005 Final: 03 Oct 2016
Immune-Mediated Reactions
Dose Modifications
Toxicity Management
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 4mg/kg/day or equivalent, 
promptly start further immunosuppressives (eg, 
infliximab at 5 mg/kg once every 2 weeks).  
-
Caution: Ensure GI consult to rule out bowel 
perforation and refer to infliximab label for general 
guidance before using infliximab. 
-
Once improving, gradually taper steroids over ≥28 days
and consider prophylactic antibiotics, antifungals and 
anti PCP treatment (please refer to current NCCN 
guidelines for treatment of cancer-related infections 
[Category 2B recommendation])
Hepatitis 
(Elevated LFTs)
Infliximab 
should not be 
used for 
management of 
Immune Related
Hepatitis
Grade of 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 
CCI
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prietet
E PROPRIETARY INFORMAT
ric IV methy
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valent
valent
frequency and
frequency an
GI consult an
GI consult an
priate
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still no impr
still no impr
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promptl
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-
Ca
C
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t worsens, tr
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GE
GE
GE
GE


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
105
MEDI4736-MM-005 Final: 03 Oct 2016
Immune-Mediated Reactions
Dose Modifications
Toxicity Management
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 toxicity improves to ≤Grade 1 or 
baseline resume study drug/study regimen 
after completion of steroid taper 
For Grade 2 AST or ALT and or TB elevation : 
-
Regular and frequent checking of LFTs (eg, every 1-2 
days) until elevations of these are improving or 
resolved.  
-
If no resolution to ≤ Grade 1 in 1-2 days, discuss with 
study physician.
-
If event is persistent (> 3-5 days) or worsens, promptly 
start prednisone 1-2mg/kg/day PO or IV equivalent. 
-
If still no improvement within 3-5 days despite 1-
2mg/kg/day of prednisone PO or IV equivalent, 
consider additional workup and prompt treatment with 
IV methylprednisolone 2-4mg/kg/day started.
-
If still no improvement within 3-5 days despite 2-
4mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives (mycophenolate mofetil)4.
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])
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 study drug/study regimen dose until 
resolution to ≤ Grade 1 or baseline 
-Resume study drug/study regimen if 
elevations downgrade ≤ Grade 1 or 
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,
4
ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects”, by Michael Postow MD.
CCI
CELGENE PROPRIETARY INFORMATION
e Corpora
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ON
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O
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B elevation
checking of L
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If still no 
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levations in
elevations 
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Hold s
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ook 2015
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“M


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
106
MEDI4736-MM-005 Final: 03 Oct 2016
Immune-Mediated Reactions
Dose Modifications
Toxicity Management
baseline within 14 days and after 
completion with steroid taper.
Permanently discontinue study drug/study 
regimen if the elevations do not downgrade to 
≤ Grade 1 or baseline within 14 days 
For elevations in transaminases > 8 × ULN or 
elevations in bilirubin > 5 × ULN, 
discontinue study drug/study regimen 
Permanently discontinue study drug/study 
regimen for any case meeting Hy’s law 
criteria (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 causeiv
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 
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
CCI
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prietet
LGE
LGENE PROPRIETARY INFORMAT
with immunos
with immuno
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henolate is n
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Once impro
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al Guidance
l Guidanc
PR
GE


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
107
MEDI4736-MM-005 Final: 03 Oct 2016
Immune-Mediated Reactions
Dose Modifications
Toxicity Management
Grade 1 [Serum 
Creatinine > 1-1.5
X baseline; > ULN 
to 1.5 X ULN]
No dose modification
For Grade 1 elevated creatinine: 
-
Monitor serum creatinine weekly and any 
accompanying symptom
!
If creatinine returns to baseline, resume its 
regular monitoring per study protocol.
!
If it worsens, depending on the severity, treat 
as Grade 2 or Grade 3 or 4 
-
Consider symptomatic treatment including hydration, 
electrolyte replacement, diuretics, etc.
Grade 2 [Serum 
Creatinine>1.5-3.0
X baseline; >1.5 X-
3.0 X ULN]
Hold study drug/study regimen until resolution 
to ≤ Grade 1 or baseline
•
If toxicity worsens then treat as Grade 3 or 
Grade 4
•
If toxicity improves to ≤Grade 1 or
baseline then resume study drug/study 
regimen after completion of steroid taper.  
For Grade 2 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 workup should be considered and 
prompt treatment with IV methylprednisolone at 2-
4mg/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 study 
drug/study regimen and routine serum creatinine 
monitoring per study protocol.
CCI
CELGENE PROPRIETA
pri
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tudy 
tudy
eroid taper
eroid taper
LGE
TARY INFORMATION
e Corpora
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ON
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ine weekly a
ine weekly 
ptom
ptom
tinine returns
nine returns
ular monitori
lar monito
If it worsens
If it worsens
as Grade 2
as Gr
onsider symp
nsider symp
electroly
ectrolyte re
te r
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AT
Grade 2 elev
de 2 elev
-
Con
Co
e
-
Y IN
TA


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
108
MEDI4736-MM-005 Final: 03 Oct 2016
Immune-Mediated Reactions
Dose Modifications
Toxicity Management
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 PO or IV 
equivalent 
-
If event is not responsive within 3-5 days or worsens 
despite prednisone at 1-2 mg/kg/day PO or IV 
equivalent, additional workup should be considered and 
prompt treatment with IV methylprednisolone 2-
4mg/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 
NCI CTCAE 
version 4.03 for 
definition of 
severity/grade 
depending on type 
of skin rash)
General Guidance
Monitor for signs and symptoms of dermatitis (rash and 
pruritus) 
**IF THERE IS ANY BULLOUS FORMATION, THE 
STUDY PHYSICIAN SHOULD BE CONTACTED AND 
STUDY DRUG DISCONTINUED**
Grade 1 
No dose modification
For Grade 1:
-
Consider symptomatic treatment including oral 
antipruritics (eg, diphenhydramine or hydroxyzine) and 
topical therapy (eg, urea cream)
Grade 2
For persistent (> 1- 2 weeks) Grade 2 events, 
hold scheduled study drug/study regimen 
For Grade 2 :
-
Obtain dermatology consult 
CCI
CEL
pri
prietet
ELGENE PROPRIETARY INFORMATION
e Corpora
e Corpora
ON
O
ment
ent
TIO
creatinin
reatinine on
on
and consider 
and conside
prednisone 1 
ednisone 1 
is not respon
s not respon
te prednison
e predn
quivalent, ad
quivalent, ad
prompt tre
mpt tr
4mg/kg
4mg/kg
-
Onc
On
AT
TA
RIE
ose modifica
ose modific
E P
GE
G
ELG


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
109
MEDI4736-MM-005 Final: 03 Oct 2016
Immune-Mediated Reactions
Dose Modifications
Toxicity Management
until resolution to ≤ Grade 1 or baseline 
!
If toxicity worsens then treat as Grade 
3 
!
If toxicity improves to ≤Grade 1 or 
baseline then resume study drug/study 
regimen after completion of steroid 
taper.  
-
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 study drug/study regimen 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 
CCI
CELGENE P
pri
prietet
E PROPRIETARY INFORMATION
e Corpora
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ON
O
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TIO
tment includ
tment includ
hydramine o
dramin
rea cream)
ea cream)
e-strength to
strength to
ment of rash
ment of ra
s worsening d
s worsening 
se of modera
se of modera
study physic
udy ph
eroids predni
eroids predni
Consider sk
nsider 
recurs
r
AT
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or 
or 
rmanently
rmanently
regimen
regimen
For Grade 3 
For Grade 3
-
Y
TA
dy drug/stud
dy drug/stud
RI
E P


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
110
MEDI4736-MM-005 Final: 03 Oct 2016
Immune-Mediated Reactions
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 < 0.5 X 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.
CCI
pri
prietet
PROPRIETARY INFORMAT
gns and symp
gns and sym
Non
on-specific s
specific 
, behavior ch
, behavior ch
abdominal p
abdominal p
n and weakne
and weakn
should be th
should be th
native etiolog
tive eti
ain metastase
ain metastas
Monitor an
onitor a
T3 and fr
d f
depen
de
ATION
e Corpora
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ON
O
ment
ent
TIO
-
If
AT
TA
ET
P


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
111
MEDI4736-MM-005 Final: 03 Oct 2016
Immune-Mediated Reactions
Dose Modifications
Toxicity Management
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 study drug/study 
regimen 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 
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.
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, corticosteroids (eg, 1-2mg/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.
CCI
CELGENE 
pri
prietet
E PROPRIETA
able
able
an’s
an’s
f f 
qual to 10
ual to 10
E
TARY INFORMAT
symptomatic
symptomat
idism may b
idism may b
erapy withou
rapy withou
icosteroids
costeroids
hormone repl
hormone rep
agement
ement
valuate endo
valuate endo
indicated
icated
-
For pat
F
ATION
e Corpora
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ON
O
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ent
TIO
for 
for
AT
TA


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
112
MEDI4736-MM-005 Final: 03 Oct 2016
Immune-Mediated Reactions
Dose Modifications
Toxicity Management
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 study drug/study 
regimen dose until endocrinopathy symptom(s) 
are controlled
Study drug/study regimen can be resumed once 
event stabilizes and after completion of steroid 
taper 
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 
limited to limbic 
encephalitis.
autonomic 
neuropathy,
excluding
Myasthenia 
Gravis and 
Guillain-Barre)  
Grade of 
Neurotoxicity 
Depending on the 
type of 
neurotoxicity, 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.) 
CCI
CE
pri
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ELGENE PROPRIETARY INFORMAT
istst
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EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
113
MEDI4736-MM-005 Final: 03 Oct 2016
Immune-Mediated Reactions
Dose Modifications
Toxicity Management
-
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 study 
drug/study regimen dose 
until resolution to ≤ 
Grade 1
!
For sensory 
neuropathy/neuropathic 
pain, consider holding 
study drug/study regimen 
dose until resolution to ≤ 
Grade 1.
o If toxicity worsens 
then treat as Grade 3 
or Grade 4 
!
Study drug/study regimen
can be resumed once 
event improves to ≤
Grade 1 stabilizes 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 1-2mg/kg/day PO or IV 
equivalent 
-
If no improvement within 3-5 days despite 1-2mg/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
For Grade 3 or 4:
-
Discuss with study physician
CCI
CE
pri
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ELGENE PROPRI
en
toto ≤ ≤
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ty worse
treat as Grad
eat as Grad
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Grade 4 
udy 
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EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
114
MEDI4736-MM-005 Final: 03 Oct 2016
Immune-Mediated Reactions
Dose Modifications
Toxicity Management
!
Permanently discontinue 
Study drug/study regimen 
if Grade 3 irAE does not 
resolve to ≤ Grade 1 
within 30 days.
-
Obtain Neurology Consult
-
Consider hospitalization
-
Promptly initiate empiric IV methylprednisolone 1 to 2 mg/kg/day 
or equivalent
-
If no improvement within 3-5 days despite IV corticosteroids, 
consider additional workup and promptly treat with additional 
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 IVIG and 
followed by plasmapheresis if not responsive to IVIG
CCI
CEL
pri
prietet
ELGENE PROPRI
ELGE
RIETARY INFORMATION
e Corpora
e Corpora
ON
O
ment
ent
TIO
thylpredniso
thylpredniso
n 3-5 days de
5 days d
rkup and pro
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ts (eg,
eg, IVIG
IVIG)
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dually tape
AT
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ence acu
rbidity or in 
rbidity or in
for certain se
for certain se
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outcome
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inst
-
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N
RI


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
115
MEDI4736-MM-005 Final: 03 Oct 2016
Immune-Mediated Reactions
Dose Modifications
Toxicity Management
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
o
Steroids may be successfully used to treat Myasthenia 
Gravis. Important to consider that steroid therapy 
(especially with high doses) may result in transient 
worsening of myasthenia and should typically be 
administered in a monitored setting under supervision of a 
consulting neurologist.
o
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.
o
If Myasthenia Gravis-like neurotoxicity present, consider 
starting acetylcholine esterase (AChE) inhibitor therapy in 
addition to steroids. Such therapy, if successful, can also 
serve to reinforce the diagnosis.
!
GUILLAIN-BARRE: 
o
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.
CCI
pri
prietet
ELGE
CE GENE PROPRIETARY INFO
study physic
udy phy
e taken to m
e taken to m
ecompensatio
ecompensa
ORMATION
e Corpora
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cribed above
cribed above
unless the sym
less the sy
AT
a Neurology
a Neurology
sory neuropa
sory neurop
appropriate m
propriate m
!
MYA
MYA
o
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GE
RI


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
116
MEDI4736-MM-005 Final: 03 Oct 2016
Immune-Mediated Reactions
Dose Modifications
Toxicity Management
Grade 3
Hold study drug/study regimen 
dose until resolution to ≤ Grade 
1
Permanently discontinue Study 
drug/study regimen if Grade 3 
irAE does not resolve to ≤ 
Grade 1 within 30 days or if 
there are signs of respiratory 
insufficiency or autonomic 
instability
For severe or life threatening (Grade 3 or 4) events: 
-
Discuss with study physician
-
Recommend hospitalization
-
Monitor symptoms and obtain neurological consult
!
MYASTHENIA GRAVIS
o
Steroids may be successfully used to treat Myasthenia 
Gravis.  It should typically be administered in a monitored 
setting under supervision of a consulting neurologist.
o
Patients unable to tolerate steroids may be candidates for 
treatment with plasmapheresis or IVIG.
o
If Myasthenia Gravis-like neurotoxicity present, consider 
starting acetylcholine esterase (AChE) inhibitor therapy in 
addition to steroids. Such therapy, if successful, can also 
serve to reinforce the diagnosis.
!
GUILLAIN-BARRE: 
! 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 
a ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD.
b NCI CTCAE version 4.03.
FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation.
CCI
CELGENE PR
pri
prietet
ROPRIETARY INFORMAT
nts:
nts:
in neurologic
neurologi
VIS
VIS
y be success
y be success
It should typi
should
g under super
under supe
tients unable
tients unab
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t Blocking A
Blocking A
y: Drug Indu
: Drug Ind


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
117
MEDI4736-MM-005 Final: 03 Oct 2016
Appendix E-2:
Durvalumab Treatment Modification and Toxicity Management Guidelines for Infusion-related Reactions
Infusion-Related Reactions
Severity 
Grade
Dose Modifications
Toxicity Management
Any Grade
General Guidance
-
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 reactions.
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)
CCI
CELGENE PRO
pri
prietet
ROPRIETARY INFORMATION
e Corpora
e Corpora
ON
ted Reacti
ted Reac
AT
nagement
nagement
MA
l standard at 
standard 
s and sympto
s and sympt
ing chills, flu
ng chills, flu
d pressure, dy
d pressure, 
laxis (
axis (eg
eg, gen
ge
tachycardia, 
achycardia
OR
de 2:
de 2:
minophen an
minophen an
titutional stan
itutional stan
Consider pre
Consider pr
doses
doses
-
Stero
ero
inf
in
Y I
PR
en
For 
F
PR
PR
PR
ROPR


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
118
MEDI4736-MM-005 Final: 03 Oct 2016
Appendix E-3:
Durvalumab Treatment Modification and Toxicity Management Guidelines for Non-immune-mediated 
Reactions
Non-immune Mediated Reactions
(Note:  As applicable, for early phase studies, the following sentence may be added: “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 
AChE = acetylcholine esterase; ADA = American Dietetic Association; ADL= activity of daily life; AE = adverse event; ALP = alkaline phosphatase; ALT = 
alanine aminotransferase; AST = aspartate aminotransferase; BUN= blood urea nitrogen; CT = computed tomography; CTC= common terminology criteria; GI = 
gastrointestinal; FT4= free T4; ILD = interstitial lung disease; IM = intramuscular; irAE = immune-related adverse event; IV = intravenous; LFT= liver function 
tests; LLN= lower level normal; MRI=magnetic resonance imaging; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse 
Events; PO = by mouth; TB= total bilirubin; TNF = tumor necrosis factor; TSH = thyroid stimulating hormone; ULN = upper limit of normal.
CCI
CELGENE 
pri
prietet
E PROPR
for Grade 4 l
for Grade 
signs/sympto
signs/sympto
RIETARY INFORMATION
e Corpora
e Corpora
ON
-mediated
mediate
ase discuss wi
e discuss wi
AT
T
MA
FO
toto
es not 
not 
Tre
Tre
FO
FO
FO
IN
ne
ne
RY
or baseline
or baselin
solve to
solve 
≤G
ministration. O
nistration. 
TA
th the
h the Spons
Spon
R
RO
sociation;
sociation; A
e; BUN= blo
BUN= b
sease; IM = 
sease; IM =
nance imagin
nance im
= tumor necr
= tumor nec


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
119
MEDI4736-MM-005 Final: 03 Oct 2016
Appendix F: Guideline for Asthma Eligibility Criteria
CCI
CELGENE PROPRIETARY INFORMATION


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MM-005
Celgene Corporation
Confidential and Proprietary
120
MEDI4736-MM-005 Final: 03 Oct 2016
Appendix F: Guideline for Asthma Eligibility Criteria (Continued)
CCI


EDMS Doc. Number:
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.
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