Clinical trial NCT01693562
Conditions: Advanced Solid Tumors
Keywords: Advanced solid tumors
Sponsor: MedImmune LLC
Start date: 2012-09-05; Completion date: 2020-02-28
Enrollment: 1022 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a multicenter, open-label, first-time-in-human study with a standard 3+3 dose-escalation phase in participants with advanced solid tumors followed by an expansion phase in participants with advanced solid tumors. An exploration cohort has been added to determine the safety using every 4 weeks (Q4W) dosing.

Detailed description:
A dose-escalation and dose-expansion study of MEDI4736 (a monoclonal antibody that targets programmed cell death ligand-1 (PD-L1)) will evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity (IM), and antitumor activity of MEDI4736 in adult participants with solid tumors. A dose exploration cohort will look at the safety profile of Q4W dosing of MEDI4736.

Arms: arm 1: Participants will receive intravenous (IV) infusion of MEDI4736 (durvalumab) 0.1 mg/kg every 2 weeks (Q2W) in the dose-escalation phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. arm 2: Participants will receive IV infusion of MEDI4736 0.3 mg/kg Q2W in the dose-escalation phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. arm 3: Participants will receive IV infusion of MEDI4736 1 mg/kg Q2W in the dose-escalation phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. arm 4: Participants will receive IV infusion of MEDI4736 3 mg/kg Q2W in the dose-escalation phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. arm 5: Participants will receive IV infusion of MEDI4736 10 mg/kg Q2W in the dose-escalation phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. arm 6: Participants will receive IV infusion of MEDI4736 15 mg/kg every 3 weeks (Q3W) in the dose-escalation phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. arm 7: Participants will receive IV infusion of MEDI4736 20 mg/kg every 4 weeks (Q4W) in the dose-exploration phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. arm 8: Participants with squamous cell carcinoma of the head and neck (SCCHN) will receive IV infusion of MEDI4736 10 mg/kg Q2W in the dose-expansion phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. arm 9: Participants with non-SCCHN human papilloma virus positive (Non-SCCHN HPV+) will receive IV infusion of MEDI4736 10 mg/kg Q2W in the dose-expansion phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. arm 10: Participants with non-small-cell lung cancer (NSCLC) will receive IV infusion of MEDI4736 10 mg/kg Q2W in the dose-expansion phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. arm 11: Participants with hepatocellular carcinoma (HCC Total) will receive IV infusion of MEDI4736 10 mg/kg Q2W in the dose-expansion phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. arm 12: Participants with advance cutaneous melanoma (ACM) will receive IV infusion of MEDI4736 10 mg/kg Q2W in the dose-expansion phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. arm 13: Participants with uveal melanoma (UM) will receive IV infusion of MEDI4736 10 mg/kg Q2W in the dose-expansion phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. arm 14: Participants with gastroesophageal cancer (GEC) will receive IV infusion of MEDI4736 10 mg/kg Q2W in the dose-expansion phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. arm 15: Participants with triple-negative breast cancer (TNBC) will receive IV infusion of MEDI4736 10 mg/kg Q2W in the dose-expansion phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. arm 16: Participants with pancreatic adenocarcinoma (PAC) will receive IV infusion of MEDI4736 10 mg/kg Q2W in the dose-expansion phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. arm 17: Participants with urothelial carcinoma (UC) will receive IV infusion of MEDI4736 10 mg/kg Q2W in the dose-expansion phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. arm 18: Participants with glioblastoma multiforme (GBM) will receive IV infusion of MEDI4736 10 mg/kg Q2W in the dose- expansion phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. arm 19: Participants with ovarian cancer (OC) will receive IV infusion of MEDI4736 10 mg/kg Q2W in the dose-expansion phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. arm 20: Participants with soft- tissue sarcoma (STS) will receive IV infusion of MEDI4736 10 mg/kg Q2W in the dose-expansion phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. arm 21: Participants with small-cell lung cancer (SCLC) will receive IV infusion of MEDI4736 10 mg/kg Q2W in the dose-expansion phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. arm 22: Participants with microsatellite instability (MSI)-high cancer will receive IV infusion of MEDI4736 10 mg/kg Q2W in the dose-expansion phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. arm 23: Participants with nasopharyngeal carcinoma (NPC) will receive IV infusion of MEDI4736 10 mg/kg Q2W in the dose- expansion phase for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first.
Interventions: intervention 1: MEDI4736
Intervention descriptions: intervention 1: Participants will receive IV infusion of MEDI4736 for maximum of 12 months or until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first.

Protocol documents:
Prot_000.pdf: 
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A Phase 1/2 Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of MEDI4736 in Subjects With Advanced 
Solid Tumors
Sponsor Protocol Number: Protocol CD-ON-MEDI4736-1108
Application Number:
BB-IND 112249
EudraCT 2012-002206-52
Investigational Product:
MEDI4736
Sponsor:
MedImmune, LLC, a wholly-owned subsidiary of AstraZeneca
PLC, One MedImmune Way, Gaithersburg, Maryland, 20878, 
USA
Primary Medical Monitor:
 
Sponsor Medical Monitor:
 
Protocol History, Date
Original Protocol, 04Apr2012
Amendment 1, 11Jul2012
Amendment 2, 24Jul2012
Amendment 3, 12Jun2013
Amendment 4, 04Nov2013


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Administrative Change 1, 10Jan2014
Amendment 4.1, Germany, 08May2014
Amendment 5, 21May2014
Amendment 6, 18Jun2014
Administrative Change 2, 21Jul2014
Amendment 6, France, 30Jul2014
Amendment 6, United States, 11Sep2014
Administrative Change 3, 06Oct2014
Amendment 7, 17Nov2014
Amendment 8, 25Nov2015
Amendment 9, 04Feb2016


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TABLE OF CONTENTS
1
INTRODUCTION ....................................................................................................21
1.1
Disease Background........................................................................................21
1.2
Description of MEDI4736...............................................................................24
1.2.1Product Derivation ..................................................................................24
1.2.2Summary of Nonclinical Experience .......................................................24
1.2.3Summary of Clinical Experience .............................................................26
1.3
Research Hypothesis.......................................................................................30
1.4
Rationale for Study Conduct ...........................................................................30
1.5
Benefit-risk and Ethical Assessment................................................................31
2
STUDY OBJECTIVES.............................................................................................34
2.1
Primary Objective ...........................................................................................34
2.2
Secondary Objectives......................................................................................35
2.3
Exploratory Objectives....................................................................................35
3
STUDY DESIGN......................................................................................................35
3.1
Overview of Study Design ..............................................................................35
3.1.1Dose Escalation.......................................................................................39
3.1.2Dose Exploration.....................................................................................40
3.1.3Dose Expansion.......................................................................................40
3.2
Estimated Duration of Subject Participation....................................................43
3.3
Study-stopping Criteria ...................................................................................43
3.4
Rationale for Study Design and Doses.............................................................44
4
STUDY PROCEDURES...........................................................................................50
4.1
Subject Participation and Identification...........................................................50
4.2
Subject Selection and Withdrawal...................................................................50
4.2.1Inclusion Criteria.....................................................................................51
4.2.2Exclusion Criteria....................................................................................55
4.2.3Withdrawal Criteria.................................................................................57
4.2.4Replacement of Subjects .........................................................................58
4.3
Treatment Assignment ....................................................................................59
4.4
Blinding..........................................................................................................59
4.5
Study Medications ..........................................................................................59
4.5.1Investigational Products ..........................................................................59
4.5.1.1
Investigational Product Preparation........................................59
4.5.2Other Study Medications.........................................................................62
4.5.3Treatment Regimen.................................................................................62
4.5.3.1
Dose Escalation......................................................................62
4.5.3.2
Dose Exploration ...................................................................65


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4.5.3.3
Dose Expansion .....................................................................66
4.5.4Treatment Administration........................................................................67
4.5.5Monitoring of Dose Administration.........................................................68
4.5.6Dose Escalation.......................................................................................69
4.5.7Dose-limiting Toxicity ............................................................................70
4.5.8Dose Modification for Toxicity Management ..........................................71
4.5.9Treatment Compliance ............................................................................72
4.6
Concomitant Medications................................................................................72
4.6.1Permitted Concomitant Medications........................................................72
4.6.2Excluded Concomitant Medications ........................................................72
4.7
Subject Completion.........................................................................................73
4.8
End of the Study .............................................................................................73
5
STUDY PROCEDURES...........................................................................................73
5.1
Schedule of Study Procedures.........................................................................73
5.1.1Screening……….....................................................................................89
5.1.2Treatment Period.....................................................................................89
5.1.3End of Treatment.....................................................................................89
5.1.4Post-treatment Follow-up ........................................................................89
5.2
Description of Study Procedures .....................................................................89
5.2.1Medical History and Physical Examination, Electrocardiogram, 
Weight, and Vital Signs..........................................................89
5.2.2Clinical Laboratory Tests ........................................................................91
5.2.3Pharmacokinetic Evaluation and Methods ...............................................92
5.2.4Immunogenicity Evaluation and Methods................................................92
5.2.5Biomarker Evaluation and Methods.........................................................92
5.2.6Disease Evaluation and Methods .............................................................93
5.2.6.1
RECIST v 1.1.........................................................................95
5.2.6.2
Revised RANO Criteria..........................................................98
5.2.7Archival Tumor Samples and Tumor Biopsies.......................................100
5.2.7.1
Archival Tumor Samples......................................................100
5.2.7.2
Tumor Biopsies....................................................................101
5.2.8Patient-reported Outcomes Assessments................................................102
5.2.8.1
Pain Questionnaire ...............................................................102
5.2.8.2
EORTC QLQ-C30 and Cancer-specific Modules .................102
5.2.8.3
FACT-BL ............................................................................105
5.2.9Estimate of Volume of Blood to be Collected........................................106
6
ASSESSMENT OF SAFETY..................................................................................106
6.1
Safety Parameters..........................................................................................106


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6.1.1Adverse Events .....................................................................................106
6.1.2Serious Adverse Events.........................................................................107
6.1.3Other Events of Special Interest.............................................................108
6.1.3.1
Pneumonitis .........................................................................109
6.1.3.2
Hypersensitivity Reactions...................................................109
6.1.3.3
Hepatic Function Abnormalities (Hepatotoxicity).................109
6.2
Assessment of Safety Parameters ..................................................................110
6.2.1Assessment of Severity..........................................................................110
6.2.2Assessment of Relationship...................................................................111
6.2.2.1
Relationship to Investigational Product ................................111
6.2.2.2
Relationship to Protocol Procedures.....................................112
6.3
Recording of Safety Parameters ....................................................................112
6.3.1Recording of Adverse Events and Serious Adverse Events....................112
6.3.2Recording of Other Events of Special Interest .......................................113
6.4
Reporting Requirements for Safety Parameters .............................................113
6.4.1Study Reporting Period and Follow-up for Adverse Events ...................113
6.4.2Reporting of Serious Adverse Events ....................................................113
6.4.2.1
Study Reporting Period and Follow-up for Serious Adverse 
Events....................................................................113
6.4.2.2
Notifying the Sponsor of Serious Adverse Events ................114
6.4.2.3
Safety Reporting to Investigators, Institutional Review 
Boards or Independent Ethics Committees, and 
Regulatory Authorities...........................................115
6.4.3Other Events Requiring Immediate Reporting .......................................115
6.4.3.1
Overdose..............................................................................115
6.4.3.2
Hepatic Function Abnormality .............................................116
6.4.3.3
Pregnancy ............................................................................116
6.4.3.4
Events Meeting Study-stopping Criteria ...............................117
6.5
Safety Management During the Study...........................................................117
7
STATISTICAL CONSIDERATIONS.....................................................................118
7.1
General Considerations .................................................................................118
7.2
Analysis Populations.....................................................................................118
7.3
Endpoints......................................................................................................119
7.3.1Primary Endpoints.................................................................................119
7.3.2Secondary Endpoints.............................................................................121
7.3.2.1
Pharmacokinetics .................................................................121
7.3.2.2
Immunogenicity...................................................................122
7.3.2.3
Antitumor Activity...............................................................122
7.3.3Exploratory Endpoints...........................................................................123


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7.4
Subgroup Analysis ........................................................................................124
7.5
Interim Analysis............................................................................................124
7.6
Sample Size and Power Calculations.............................................................125
8
DIRECT ACCESS TO SOURCE DOCUMENTS...................................................130
9
QUALITY CONTROL AND QUALITY ASSURANCE ........................................130
9.1
Data Collection .............................................................................................130
9.2
Study Monitoring..........................................................................................131
9.3
Audit and Inspection of the Study .................................................................131
10
ETHICS..................................................................................................................132
10.1
Regulatory Considerations ............................................................................132
10.2
Institutional Review Board or Independent Ethics Committee.......................132
10.3
Informed Consent..........................................................................................133
10.4
Withdrawal of Consent for Continued Study Participation.............................134
11
DATA HANDLING AND RECORD KEEPING ....................................................135
12
FINANCING AND INSURANCE ..........................................................................135
13
PUBLICATION POLICY.......................................................................................135
14
REFERENCES .......................................................................................................136
15
SUMMARY OF PROTOCOL AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL ..................................................................147


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LIST OF IN-TEXT TABLES
Table 1. Number of Subjects Enrolled by Tumor Type in Dose-expansion Cohorts .............14
Table 2. Probability of Escalating for Different True Underlying Dose-limiting Toxicity Rate 
at a Given Dose Level.......................................................................18
Table 3. 
.....................................................19
Table 4. 
.....................................................19
Table 5. 
..................................................................................20
Table 1.2.3-1
 
...................................................................................29
Table 1.5-1
 
.......................................33
Table 3.1-1
Number of Subjects Enrolled by Tumor Type in Dose-expansion 
Cohorts.............................................................................................38
Table 3.1.3-1
NSCLC Dose-expansion Cohort PD-L1 Expression Requirements....41
Table 4.2.1-1
Highly Effective Methods of Contraception (< 1% Failure Rate) ......55
Table 4.5.1.1-1
Preparation of MEDI4736 Doses Less Than 1.0 mg/kg to Dose for 
Administration by Syringe ................................................................60
Table 5.1-1
Schedule of Study Procedures: Screening and Treatment Period .......75
Table 5.1-2
Q4W Schedule of Study Procedures: Screening and Treatment 
Period...............................................................................................83
Table 5.1-3
Schedule of Study Procedures: Follow-up for Subjects Who Have 
Completed MEDI4736 Treatment and Achieved Disease Control 
(Until Confirmed Progressive Disease) and Subjects Who Have 
Discontinued MEDI4736 Due to Toxicity in the Absence of 
Confirmed Progressive Disease.........................................................86
Table 5.2.6.1-1
Evaluation of Overall Response ........................................................97
Table 7.6-1
Probability of Escalation for Different True Underlying Dose-limiting 
Toxicity Rate at a Given Dose Level...............................................126
Table 7.6-2
..............................126
Table 7.6-3
..............................127
Table 7.6-4
Estimated ORR and 95% CI in Squamous NSCLC Subjects with 
Tumoral PD-L1 Expression ............................................................128
Table 7.6-5
...........................................................129
LIST OF IN-TEXT FIGURES
Figure 3.1-1
Study Flow Diagram.........................................................................37
Figure 4.5.3.1-1
Dosing Schema for MEDI4736 Q2W Dose-escalation Cohorts.........63
Figure 4.5.3.1-2
Dosing Schema for MEDI4736 Q3W Dose-escalation Cohorts.........65
Figure 4.5.3.2-1
Dosing Schema for MEDI4736 Q4W Dose-exploration Cohort ........66
Figure 4.5.3.3-1
Dosing Schema for MEDI4736 Q2W Dose-expansion Cohorts.........67


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LIST OF APPENDICES
Appendix 1
Signatures.......................................................................................170
Appendix 2
Pain Questionnaire..........................................................................172
Appendix 3
Patient-reported Outcome Questionnaire EORTC QLQ-C30...........173
Appendix 4
Patient-reported Outcome Questionnaire EORTC QLQ-BR23........175
Appendix 5
Patient-reported Outcome Questionnaire EORTC QLQ-LC13 ........177
Appendix 6
Patient-reported Outcome Questionnaire EORTC QLQ-STO22......178
Appendix 7
Patient-reported Outcome Questionnaire EORTC QLQ-PAN26 .....179
Appendix 8
Patient-reported Outcome Questionnaire EORTC QLQ-HCC18 .....181
Appendix 9
Patient-reported Outcome Questionnaire EORTC QLQ-H&N35.....182
Appendix 10
Patient-reported Outcome Questionnaire EORTC QLQ-BN20........185
Appendix 11
Patient-reported Outcome Questionnaire EORTC QLQ-OV28........186
Appendix 12
Patient-reported Outcome Questionnaire FACT-BL........................188
Appendix 13
Schedule of Study Procedures for Subjects in Retreatment of 
MEDI4736......................................................................................192
Appendix 14
Schedule of Study Procedures in Follow-up for Subjects Who Have 
Discontinued MEDI4736 Treatment Due to Confirmed Progressive 
Disease ...........................................................................................196
Appendix 15
.....................199


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List of Abbreviations
Abbreviation or 
Specialized Term
Definition
ADA
anti-drug antibody
ADCC
antibody-dependent cell-mediated cytotoxicity
AE
adverse event
AESI
adverse event of special interest
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
APC
antigen presenting cells 
AST
aspartate aminotransferase
BICR
blinded independent central review
BoR
best overall response
CD
cluster of differentiation
CI
confidence interval
Cmax
maximum observed concentration
CNS
central nervous system
CR
complete response
CRC
colorectal cancer
CRF
case report form
CT
computed tomography
CTC
circulating tumor cells
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte antigen 4
cynoPD-L1
cynomolgus monkey programmed death ligand 1
DC
disease control
DCR
disease control rate
DCR-24w
disease control rate at 24 weeks
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EGFR
epidermal growth factor receptor
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer quality-of-life 
questionnaire
EU
European Union
FACT-BL
Functional Assessment of Chronic Illness Therapy-bladder
FACT-G
Functional Assessment of Chronic Illness Therapy-general
FAS
full analysis set
Fc
fragment crystallizable


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Abbreviation or 
Specialized Term
Definition
FFPE
formalin fixed paraffin embedded
FLAIR
fluid attenuated inversion recovery
FTIH
first-time-in-human
GBM
glioblastoma multiforme
GCP
Good Clinical Practice 
GGT
gamma glutamyl transferase
GLP
Good Laboratory Practice
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
hPD-L1
human programmed death ligand 1
HPV
human papilloma virus
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IFN
interferon
IgG1
immunoglobulin G1
IgG1κ
immunoglobulin G1 kappa
IHC
immunohistochemistry 
IL
interleukin 
IM
immunogenicity
irAE
immune-related adverse event
IRB
Institutional Review Board
irRC
immune-related response criteria
IV
intravenous(ly)
IVRS
interactive voice response system
IWRS
interactive web response system
MAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
miRNA
micro ribonucleic acid
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MRSD
maximum recommended starting dose
MSI
microsatellite instability
MTD
maximum tolerated dose
NCI
National Cancer Institute
NK
natural killer
NOAEL
no-observed adverse-effect-level


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Abbreviation or 
Specialized Term
Definition
NSCLC
non-small cell lung cancer
OBD
optimal biological dose
OR
objective response
ORR
objective response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PD
progressive disease
PD-1
programmed death 1
PD-L1
programmed death ligand 1
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
PRO
patient-reported outcome
Q2W
every 2 weeks
Q3W
every 3 weeks
Q4W
every 4 weeks
RANO
Response Assessment in Neuro-oncology
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors 
RNA
ribonucleic acid
SAE
serious adverse event
SCCHN
squamous cell carcinoma of the head and neck
SCLC
small-cell lung cancer
SD
stable disease
SID
subject identification
sPD-L1
soluble programmed death ligand 1
SRT
Safety Review Team
SUSAR
suspected unexpected serious adverse reaction
TIL
tumor-infiltrating lymphocyte
TKI
tyrosine kinase inhibitor
TNBC
triple negative breast cancer
TNF-α
tumor necrosis factor alpha
UBC
urothelial bladder cancer
ULN
upper limit of normal
USA
United States of America
US FDA
United States Food and Drug Administration
WFI
water for injection
w/v
weight/volume


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Study Abstract
TITLE
A Phase 1/2 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MEDI4736 in Subjects With 
Advanced Solid Tumors
OBJECTIVES
Primary Objectives
Dose-escalation phase
The primary objective of the dose-escalation phase is to determine the maximum tolerated dose (MTD) or 
optimal biological dose (OBD), and the safety profile of MEDI4736 in subjects with advanced melanoma, 
renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and colorectal cancer (CRC) refractory to 
standard therapy or for which no standard therapy exists. 
Dose-exploration cohort
The primary objective of the dose-exploration cohort is to determine the safety profile of MEDI4736 using an 
every 4 weeks (Q4W) dosing schedule in subjects with advanced cutaneous melanoma, uveal melanoma, 
hepatocellular carcinoma (HCC), squamous cell carcinoma of the head and neck (SCCHN), NSCLC 
squamous histology, NSCLC non-squamous histology, gastroesophageal cancer, triple negative breast cancer 
(TNBC) and pancreatic adenocarcinoma.
Dose-expansion phase
The primary objectives of the dose-expansion phase are: 
1. To determine the safety profile of MEDI4736 in subjects with advanced cutaneous melanoma, uveal 
melanoma, HCC, SCCHN, NSCLC squamous histology, NSCLC non-squamous histology, 
gastroesophageal cancer, TNBC, pancreatic adenocarcinoma, urothelial bladder cancer (UBC), glioblastoma 
multiforme (GBM), ovarian cancer, soft tissue sarcoma, small-cell lung cancer (SCLC), microsatellite 
instability (MSI)-high cancers, human papilloma virus (HPV)-positive cancers, and nasopharyngeal 
carcinoma.
2. To evaluate the antitumor activity of MEDI4736 in subjects with non-squamous NSCLC who have received 
2 or more prior lines of therapy and subjects with squamous NSCLC who have received 1 prior lines of 
therapy and 2 or more prior lines of therapy as assessed by Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1 guidelines.
3. To evaluate the antitumor activity of MEDI4736 in subjects with programmed death ligand 1 (PD-L1)-
positive UBC as assessed by RECIST v1.1.
Secondary Objectives
1. To describe the pharmacokinetics (PK) of MEDI4736.
2. To determine the immunogenicity (IM) of MEDI4736.
3. To evaluate the antitumor activity of MEDI4736 (except for subgroups of UBC and NSCLC subjects where 
this is considered a primary objective) as assessed by RECIST v1.1.
4. To evaluate the antitumor activity of MEDI4736 in subjects with UBC, regardless of PD-L1 status as 
assessed by RECIST v1.1.
5. To evaluate the antitumor activity of MEDI4736 in subjects with PD-L1-negative UBC as assessed by 
RECIST v1.1.
6. To evaluate the antitumor activity of MEDI4736 as assessed by RECIST v1.1 in subjects with PD-L1-
positive UBC as compared to PD-L1-negative UBC.
Exploratory Objectives
 
 


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STUDY DESIGN 
This is a multicenter, open-label, first-time-in-human (FTIH) dose-escalation, dose-exploration, and 
dose-expansion study of MEDI4736 to evaluate the safety, tolerability, PK, IM, and antitumor activity of 
MEDI4637 in adult subjects with solid tumors. The dose-escalation phase will be conducted in subjects with 
advanced melanoma, RCC, NSCLC, or CRC followed by a dose -expansion phase in subjects with advanced 
cutaneous melanoma, uveal melanoma, HCC, SCCHN, NSCLC squamous histology, NSCLC non-squamous 
histology, gastroesophageal cancer, TNBC, pancreatic adenocarcinoma, UBC, GBM, ovarian cancer, soft 
tissue sarcoma, SCLC, MSI-high cancers, HPV -positive cancers, or nasopharyngeal carcinoma. In addition, a 
dose -exploration cohort will examine MEDI4736 at an alternative dosing schedule in subjects with advanced 
cutaneous melanoma, uveal melanoma, NSCLC, HCC, SCCHN, gastroesophageal cancer, TNBC, or 
pancreatic adenocarcinoma.
Dose Escalation
In the dose-escalation phase of the study, MEDI4736 will be administered every 2 weeks (Q2W), in sequential 
cohorts of 3-6 subjects each receiving one of 5 doses of MEDI4736 (0.1, 0.3, 1.0, 3.0,  or 10 mg/kg) via 
intravenous (IV) infusion. Dose escalation will be considered completed once an MTD or OBD is identified or 
the top dose of 10 mg/kg is reached. Provided the MTD is not exceeded at the 10 mg/kg dose level, additional 
cohorts of 3-6 subjects using doses above 10 mg/kg of MEDI4736 Q2W may be explored based on emerging 
PK or pharmacodynamic data suggesting maximal suppression of soluble programmed death ligand 1 (sPD-
L1) is not being maintained throughout the dosing interval or T-cell activation has not plateaued, respectively. 
Intermediate doses may be evaluated at the discretion of the sponsor based on available data. A total of 
20 subjects were enrolled in the Q2W dose-escalation phase including 4 subjects in each of the 0.1 and 
0.3 mg/kg cohorts, 3 subjects in each of the 1.0 and 3.0 mg/kg cohorts and 6 subjects in the 10 mg/kg cohort. 
The planned Q2W dose-escalation phase of the study is complete. 
Upon completion of dose escalation for the MEDI4736 Q2W dose-escalation arm, a separate dose-escalation 
arm of MEDI4736 administered every 3 weeks (Q3W) will be initiated. This arm will be conducted in parallel 
with the dose-expansion phase. The first cohort of 3-6 subjects will receive MEDI4736 Q3W at the highest 
dose level that has not exceeded the MTD or the OBD in the Q2W dose-escalation arm. MEDI4736 Q3W 
dose escalation may proceed with sequential cohorts of 3-6 subjects dependent upon acceptable safety, 
PK/pharmacodynamic, and clinical data. A total of 7 subjects have been enrolled in the 15 mg/kg Q3W 
dose-escalation arm and the planned Q3W dose-escalation phase of the study is complete.
Dose Exploration
Approximately 20 subjects with advanced cutaneous melanoma, uveal melanoma, NSCLC, HCC, SCCHN, 
gastroesophageal cancer, TNBC or pancreatic adenocarcinoma are being enrolled into the dose-exploration 
cohort at select sites in the United States. MEDI4736 will be administered Q4W, at a dose of 20 mg/kg 
MEDI4736 via IV infusion. 
Dose Expansion
The dose-expansion phase of the study will be conducted following completion of dose escalation for the 
MEDI4736 Q2W dose-escalation arm and in parallel with the MEDI4736 Q3W dose-escalation arm. The 
10 mg/kg dose administered Q2W was chosen to take into expansion. A minimum of 20 subjects each with 
advanced cutaneous melanoma, uveal melanoma, HCC, gastroesophageal cancer, TNBC, UBC, SCCHN, 
GBM, ovarian cancer, soft tissue sarcoma, SCLC, MSI-high cancers, and HPV-positive cancers will be 
enrolled (Table 1). In addition, a minimum of 10 subjects with pancreatic adenocarcinoma or nasopharyngeal 
carcinoma will be enrolled. Additional subjects, up to a total of 60 subjects in any of these dose-expansion 
cohorts may be enrolled if promising clinical activity is observed in that cohort. Approximately 110-140 
subjects with non-squamous histology NSCLC will be enrolled including approximately 10-30 subjects who 
are treatment naive, approximately 20-30 subjects who have received 1 prior line of therapy, and 
approximately 80 subjects who have received at least 2 prior lines of therapy. Approximately 170-190 subjects 
with squamous histology NSCLC will be enrolled including approximately 10-30 subjects who are treatment-
naive, approximately 80 subjects who have received 1 prior line of therapy, and approximately 80 subjects 
who have received at least 2 prior lines of therapy. 


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Table 1. Number of Subjects Enrolled by Tumor Type in Dose-expansion Cohorts
Tumor Type
Total Planned 
Enrollment
Subjects Enrolled 
as of 20Nov2015
Planned Enrollment Under 
Amendment 8 and Beyond
Advanced cutaneous melanoma
20
21
0
Uveal melanoma
20-60
24
Up to 36
HCC
20-60
41
Up to 19
SCCHN
20-60
63
0
Squamous NSCLC (Total)
     1L
     2L
     ≥ 3L
170-190
     10-30
     80
     80
151
29
51
70
Up to 39
Non-squamous NSCLC (Total)
     1L
     2L
     ≥ 3L
110-140
     10-30
     20-30
     80
143
30
34
79
0
Gastroesophageal
20-60
51
Up to 9
TNBC
20-60
40
Up to 20
Pancreatic adenocarcinoma
10-60
31
Up to 29
UBC (Total)
     Initial UBC subjects
     Amendment 8 and beyond
   PD-L1 positive
        PD-L1 negative
        Non-evaluable for PD-L1
20-192
20-60
132
≥ 70
50
12
60
60
0
0
0
0
Up to 132
0
Up to 132
≥ 70
50
12
GBM (Total)
     MGMT negative
20-60
≥ 10
20
Up to 40
Ovarian cancer (Total)
     Platinum sensitive
20-60
≥ 10
46
Up to 14
Soft tissue sarcoma
20-60
20
Up to 40
SCLC
20-60
21
Up to 39
MSI-high cancers
20-60
57
Up to 3
HPV-positive tumors (Total)
     Cervical cancer
20-60
≤ 10 a
22
10
Up to 38
Nasopharyngeal carcinoma
10-60
10
Up to 50
Total
692-1,322
821
Up to 508
GBM = glioblastoma multiforme; HCC = hepatocellular carcinoma; HPV = human papilloma virus; 
L = line; MGMT = O6-methylguanine-deoxyribonucleic acid methyltransferase promoter methylation; MSI 
= microsatellite instability; NSCLC = non-small cell lung cancer; PD-L1 = programmed death ligand 1; 
SCCHN = squamous cell carcinoma of the head and neck; SCLC = small-cell lung cancer; TNBC = triple 
negative breast cancer; UBC = urothelial bladder cancer.
a
A maximum of 10 cervical cancer subjects will be enrolled out of the initial 20 subjects in the 
HPV-positive tumors cohort. If the cohort is expanded beyond 20 subjects based on clinical activity, 
additional cervical cancer subjects may be enrolled.
An evaluation of a possible correlation between clinical activity of MEDI4736 and potential biomarkers (eg, 
PD-L1 expression on tumor or sPD-L1) will be ongoing throughout the study. Initially, tumoral PD-L1 


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expression will be assessed on screening samples after enrollment on an ongoing basis. After the first 
20-40 subjects in the HCC, gastroesophageal cancer, TNBC, UBC, GBM, ovarian cancer, soft tissue sarcoma, 
SCLC, HPV-positive cancers, pancreatic adenocarcinoma, and nasopharyngeal carcinoma dose-expansion 
cohorts are enrolled, additional subjects in the applicable cohorts may be required to have tumoral PD-L1 
expression as determined by prospective testing prior to enrollment. 
Under previous amendments of this protocol, a minimum of 5-10 subjects in the SCCHN dose expansion 
cohort were required to have tumoral PD-L1 expression. That requirement has been met and enrollment into 
the SCCHN cohort is complete. 
Under Amendment 7, all remaining subjects in the non-squamous NSCLC dose-expansion cohort were
required to have tumoral PD-L1 expression as determined by prospective testing prior to enrollment. In the 
squamous NSCLC dose-expansion cohort, a minimum of 10 subjects in the first-line therapy cohort, and a 
minimum of 35 subjects in each of the second-line therapy and third-line or greater therapy cohorts will be 
required to have tumoral PD-L1 expression as determined by prospective testing prior to enrollment.
Under Amendment 8 and beyond of this protocol, the UBC cohort will be expanded to evaluate the antitumor 
activity of MEDI4736 in subjects with PD-L1-positive UBC and validate the potential of PD-L1 expression 
(determined by immunohistochemistry [IHC]) to predict response to MEDI4736 treatment. Approximately 
132 additional UBC subjects will be enrolled in this cohort in order to include a minimum of 70 PD-L1-
positive subjects and 50 PD-L1-negative subjects, and approximately 12 subjects with non-evaluable PD-L1 
status.
 
 
 
 
To ensure that all of the additional UBC subjects contribute to the biomarker validation, subjects must have 
measurable disease at baseline by blinded independent central review (BICR). PD-L1 status will be 
determined by a central testing laboratory and will be derived from a fresh tumor biopsy taken during 
screening or an available tumor sample taken from ≤6 months prior to study entry. The tumor sample (fresh 
and/or recent [within 6 months prior to study entry]) used for PD-L1 analysis must be shipped to, and 
confirmed as received by, the Sponsor or central vendor prior to the first dose of MEDI4736. It is highly 
recommended that efforts are taken to ensure presence of tumor cells within the tumor sample prior to 
shipping for PD-L1 analysis. The tumor PD-L1 status will be determined by IHC with PD-L1-positive 
samples defined as ≥ 25% tumor cell or immune cell staining and PD-L1-negative samples defined as < 25% 
tumor cell and immune cell staining. In cases where subjects have more than one tumor sample from 
≤6 months prior to study entry available for testing, PD-L1 status will be derived from the most recent 
evaluable sample. PD-L1 status determined by IHC testing from tumor samples evaluated for screening into 
MedImmune Study D4190C00010 may be used if derived from a sample taken ≤ 6 months prior to study 
entry. Additional archival tumor tissue, from beyond 6 months prior to study entry is also required, if 
available.
All subjects will be evaluated regularly and their clinical status classified according to RECIST 
v1.1(Eisenhauer et al, 2009) with modification except for subjects with GBM who will have their clinical 
status classified according to the Response Assessment in Neuro-oncology (RANO) guidelines (Wen et al, 
2010). Modification of RECIST as described may discourage the early discontinuation of MEDI4736 and 
provide a more complete evaluation of its antitumor activity than would be seen with conventional response 
criteria. Nonetheless, the efficacy analysis will be conducted primarily based on RECIST v1.1. All subjects 
will be followed indefinitely for survival until the sponsor closes the study.


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SUBJECT POPULATION 
The subjects in this study will be adults 18 years of age or older. Subjects in the dose-escalation phase will 
have advanced melanoma, RCC, NSCLC, or CRC refractory to standard therapy or for which no standard 
therapy exists. Subjects in the dose-expansion phase will have advanced cutaneous melanoma, uveal 
melanoma, HCC, SCCHN, NSCLC squamous histology, NSCLC non-squamous histology, gastroesophageal 
cancer, TNBC, pancreatic adenocarcinoma, UBC, GBM, ovarian cancer, soft tissue sarcoma, SCLC, 
MSI-high cancers, HPV-positive cancer, or nasopharyngeal carcinoma. Subjects in the dose-exploration 
cohort will have advanced cutaneous melanoma, uveal melanoma, HCC, SCCHN, NSCLC squamous 
histology, NSCLC non-squamous histology, gastroesophageal cancer, TNBC or pancreatic adenocarcinoma. If 
approved first-line standard therapy is available, subjects must have failed, be intolerant to, be ineligible for, 
or have refused treatment. 
TREATMENT REGIMEN
Subjects will be treated in either a dose-escalation or a dose-expansion phase of the study or a dose-
exploration cohort. 
Dose Escalation
Subjects enrolled in the Q2W dose-escalation arm will receive one of 5 doses of MEDI4736 (0.1, 0.3, 1.0, 3.0, 
or 10 mg/kg) via IV infusion Q2W ± 3 days. Provided the MTD is not exceeded at the 10 mg/kg dose level, 
additional cohorts of 3-6 subjects using doses above 10 mg/kg of MEDI4736 Q2W may be initiated based on 
PK or pharmacodynamic data suggesting maximal suppression of sPD-L1 is not being maintained throughout 
the dosing interval or T-cell activation has not plateaued, respectively. Intermediate doses may be evaluated at 
the discretion of the sponsor based on available data. 
Upon the completion of dose escalation for the Q2W dose-escalation arm, a separate dose-escalation arm of 
MEDI4736 administered Q3W will be initiated. This Q3W dose-escalation arm will be carried out in parallel 
to the dose-expansion phase. The first cohort of subjects will receive MEDI4736 Q3W ± 3 days at the highest 
dose level that does not exceed the MTD or the OBD in the Q2W dose-escalation arm. Higher doses of 
MEDI4736 may be explored based upon acceptable safety, PK/pharmacodynamic, and clinical data. 
Treatment in the Q2W or Q3W dose-escalation arm will continue for 12 months or until confirmed 
progressive disease (PD), initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of 
consent, or other reasons to discontinue treatment occur. In the event of confirmed PD, subjects may continue 
to receive MEDI4736 in the absence of clinical deterioration and if investigators consider that subjects 
continue to receive benefit from treatment. Subjects who have achieved and maintained disease control (DC; 
ie, complete response [CR], partial response [PR], or stable disease [SD]) or clinical benefit through to the end 
of the 12-month treatment period will enter follow-up. Upon evidence of PD during follow-up, subjects will 
be re-administered MEDI4736 at the dose previously received or at 10 mg/kg, the dose chosen for the 
expansion phase via IV infusion Q2W or Q3W as appropriate. Subjects may continue MEDI4736 retreatment
for up to 12 months with the same treatment guidelines followed during the initial 12-month treatment period. 
Only one round of retreatment with MEDI4736 will be allowed. Subjects who have confirmed PD during the 
12-month initial treatment or retreatment period and cannot continue to receive MEDI4736 will enter follow-
up for 90-day safety assessments and survival follow-up.
Dose Exploration
MEDI4736 will be administered Q4W, at a dose of 20 mg/kg MEDI4736 via IV infusion. Treatment in the 
dose exploration cohort will continue on a Q4W schedule for 12 months or until confirmed PD, initiation of 
alternative cancer therapy, unacceptable toxicity, withdrawal of consent or other reasons to discontinue 
treatment occur. In the event of confirmed PD, subjects may continue to receive MEDI4736 in the absence of 
clinical deterioration and if investigators consider that subjects continue to receive benefit from treatment. 
Subjects who have achieved and maintained DC (ie, CR, PR, or SD) or clinical benefit through to the end of 
the 12-month treatment period will enter follow-up. Upon evidence of PD during follow-up, subjects will be 
re-administered MEDI4736 at 20 mg/kg via IV infusion Q4W. Subjects may continue MEDI4736 retreatment 
for up to 12 months with the same treatment guidelines followed during the initial 12-month treatment period. 
Only one round of retreatment with MEDI4736 will be allowed. Subjects who have confirmed PD during the 
12-month Q4W initial treatment or retreatment period and cannot continue to receive MEDI4736 will enter 
follow-up for 90-day safety assessments and survival follow-up.


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Dose Expansion
The dose-expansion phase of the study will be conducted following completion of dose escalation for the 
MEDI4736 Q2W dose-escalation arm and in parallel with the MEDI4736 Q3W dose-escalation arm. Subjects 
will receive MEDI4736 Q2W via IV infusion at the MTD/OBD or the highest dose evaluated during Q2W 
dose escalation if no MTD or OBD is determined.
Treatment in the dose-expansion phase will continue on a Q2W schedule for 12 months or until confirmed 
PD, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent or other reasons to 
discontinue treatment occur. In the event of confirmed PD, subjects may continue to receive MEDI4736 in the 
absence of clinical deterioration and if investigators consider that subjects continue to receive benefit from 
treatment. Subjects who have achieved and maintained DC (ie, CR, PR, or SD) or clinical benefit through to 
the end of the 12-month treatment period will enter follow-up. Upon evidence of PD during follow-up, 
subjects will be re-administered MEDI4736 at the dose previously received via IV infusion Q2W. Subjects 
may continue MEDI4736 retreatment for up to 12 months with the same treatment guidelines followed during 
the initial 12-month treatment period. Only one round of retreatment with MEDI4736 will be allowed. 
Subjects who have confirmed PD during the 12-month initial treatment or retreatment period and cannot 
continue to receive MEDI4736 will enter follow-up for 90-day safety assessments and survival follow-up. 
ASSESSMENT OF ENDPOINTS
MTD or OBD: Endpoints related to the primary objective of determining MTD or OBD include evaluation of 
dose-limiting toxicities (DLTs), overall safety, and parameters related to the OBD. The MTD evaluation will 
be based on data from subjects who completed the DLT evaluation period. The OBD will be determined based 
upon analysis of all available subject data, including safety, PK, pharmacodynamic, biomarker, and response 
data.
Safety: Endpoints include assessments of adverse events (AEs), serious adverse events (SAEs), laboratory 
evaluations, vital signs, electrocardiograms (ECGs; digital and central read at selected sites), and physical 
examinations. 
Pharmacokinetics: Individual MEDI4736 concentrations will be tabulated by dose cohort
Immunogenicity: The immunogenic potential of MEDI4736 will be assessed by summarizing the number and 
percentage of subjects who develop detectable anti-drug antibodies (ADAs). 
Antitumor activity: Assessments of antitumor activity will be based on the objective response rate (ORR), 
disease control rate (DCR), duration of response (DR), progression-free survival (PFS), and overall survival 
(OS). Response Evaluation Criteria in Solid Tumors v1.1 guidelines will be used to determine tumor response 
and to guide treatment decisions. The primary endpoint of antitumor activity in the NSCLC and UBC cohorts 
is objective response (OR), which is defined as a best overall response (BoR) of CR or PR according to 
RECIST v1.1 as determined by BICR. BoR is defined as the best response (in the order of CR, PR, SD, PD, 
and not evaluable) among all overall responses recorded from the start of treatment until objective 
documentation of PD (per RECIST v1.1 as assessed by BICR), or the last evaluable disease assessment in the 
absence of PD prior to initiation of subsequent anticancer therapy or discontinuation from the study, 
whichever occurs first. The best overall response of CR or PR must be confirmed. The ORR is defined as the 
proportion of subjects with OR. The 95% confidence interval (CI) of ORR will be estimated using the exact 
probability method. 
The ORR (based on RECIST v1.1 by BICR) along with its 95% CI will be provided for all NSCLC subjects in 
each line by histology and for the subpopulation in the ≥second-line squamous NSCLC subjects who have 
tumoral PD-L1 expression as determined by prospective testing prior to enrollment.
For UBC, the primary analysis of ORR based on RECIST v1.1 by BICR will be performed for all UBC 
subjects (second- or greater line of therapy) in the PD-L1-positive full analysis set (FAS) enrolled in the entire 
study. The FAS include all subjects who have been treated, have measurable disease at baseline per BICR, and 
have opportunity to be followed for at least 24 weeks. The primary endpoint for UBC cohort in PD-L1-
positive subgroup is considered to be met if the lower-limit of the exact 2-sided 95% CI for ORR excludes a 
historical response rate of 10% or less (Bellmunt et al, 2009). An analysis of ORR for all UBC subjects in the 
PD-L1-positive FAS enrolled under Amendment 8 and beyond will be conducted as a supportive analysis. 
If the primary endpoint for the PD-L1-positive subgroup of the UBC cohort is met, the ORR based on 
RECIST v1.1 by BICR along with its 95% CI will be also provided for all UBC subjects (second or greater 
line of  therapy) in the FAS (regardless of PD-L1 status) enrolled in the entire study. The primary endpoint 


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for UBC cohort in all-comers is considered to be met if the lower-limit of the exact 2-sided 95% CI for ORR 
excludes a historical response rate of 10% or less (Bellmunt et al, 2009). In addition, the ORR based on 
RECIST v1.1 by BICR along with its 95% CI will be provided for all UBC subjects (second- or greater line of 
therapy) in the PD-L1-negative FAS enrolled in the entire study and in the PD-L1-negative FAS enrolled 
under Amendment 8 and beyond. The primary analysis for UBC cohort will occur at least 24 weeks after the 
last PD-L1-positive UBC subject’s first dose of study treatment. The analyses of ORR per BICR described 
above for the UBC cohort will be repeated for the UBC subjects (second- or greater line of therapy) in the PD-
L1-positive FAS, the PD-L1-negative FAS, and the FAS (regardless of PD-L1 status) enrolled in the entire 
study. 
INTERIM ANALYSIS
For the UBC cohort, the first interim analysis will be conducted after approximately 30 PD-L1-positive UBC 
subjects are enrolled and followed for at least 12 weeks. The efficacy analysis will be based on investigator 
RECIST data.
The second interim analysis for the UBC cohort will be conducted after a minimum of 60 PD-L1-positive 
second- or greater line UBC subjects are enrolled in the entire study and followed for at least 16 weeks. The 
primary efficacy analysis population for this analysis will be based on the treated PD-L1-positive UBC 
subjects (second- or greater line) with measurable disease at baseline per BICR who have had an opportunity 
of being followed up for at least 16 weeks by the interim analysis. The analysis will be primarily based on 
RECIST v1.1 by BICR, and additional analysis based on investigator RECIST data will be conducted as 
supportive.
 
 
The enrollment will not be interrupted or 
terminated for efficacy based on the interim analysis.
SAMPLE SIZE AND POWER CALCULATIONS 
 
 
Dose-escalation phase: The number of subjects required will depend upon the toxicities observed as the study 
progresses. Up to approximately 50 evaluable subjects could be required if the separate Q3W dose escalation 
is implemented upon completion of dose escalation for the MEDI4736 Q2W dose-escalation arm. More 
subjects may be enrolled to investigate intermediate doses for MTD evaluation if DLTs are observed in either 
the 3.0 or 10 mg/kg dose cohort. In addition, more subjects may be enrolled if doses higher than 10 mg/kg 
Q2W are evaluated during dose escalation. Table 2 provides the probability of dose escalation to the next 
higher level for each underlying true DLT rate. For example, for a common toxicity that occurs in 10% of 
subjects, there is a greater than 90% probability of escalating to the next higher dose level. Conversely, for a 
toxicity that occurs at a rate of 60%, the probability of escalating to the next higher dose level is less than 
10%.
Table 2. Probability of Escalating for Different True Underlying Dose-limiting Toxicity Rate at a 
Given Dose Level
True underlying dose-
limiting toxicity rate
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of escalating dose
0.91
0.71
0.49
0.31
0.17
0.08
0.03
0.009
0.001
Dose-exploration cohort: Approximately 20 subjects will be enrolled in the dose-exploration cohort of the 
study to determine the safety of 20 mg/kg Q4W dose schedule. 
 
Dose-expansion phase: A minimum of approximately 692 subjects will be enrolled in the dose-expansion 
phase as described below. Additional subjects, described in each cohort below, may be enrolled if promising 
clinical activity is observed in any of these cohorts.
•
Advanced cutaneous melanoma, uveal melanoma, HCC, gastroesophageal cancer, TNBC, SCCHN, UBC
(initial cohort enrolled prior to Amendment 8), GBM, ovarian cancer, soft tissue sarcoma, SCLC, 


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MSI-high cancers, and HPV-positive cancers cohorts: A minimum of 20 subjects will be enrolled in each 
of these 13 disease cohorts. The sample size is chosen to obtain a preliminary assessment of antitumor 
activity in terms of DCR for each disease cohort. The DCR will be estimated by the proportion of subjects 
with CR, PR, or SD ≥ 12 weeks in each disease cohort and its 80% CI will be estimated by the exact 
probability method
 
Table 3. 
 
 
•
Pancreatic adenocarcinoma and nasopharyngeal carcinoma cohorts: A minimum of 10 subjects will be 
enrolled in each of these cohorts. The DCR will be estimated by the proportion of subjects with CR, PR, 
or SD ≥ 12 weeks in each cohort and its 80% CI will be estimated by the exact probability method
 
. Additional subjects, up to a total of 60 subjects in either of these 2 cohorts may be enrolled if 
promising clinical activity is observed in that cohort.
Table 4. 
 
control rate; PR = partial response; SD = stable disease.
•
NSCLC: Preliminary data from the dose-escalation phase of this study as well as data from other 
antibodies targeting the PD1/PD-L1 pathway suggest that subjects with NSCLC may benefit from 
treatment with an agent such as MEDI4736. As a result, a minimum of approximately 110 subjects in the 
non-squamous histology NSCLC cohort and 170 subjects in the squamous histology NSCLC cohort will 
be enrolled from among specific subpopulations of NSCLC as outlined below. 
◦
For the non-squamous NSCLC cohort, the enrollment will include approximately 10 subjects who are 
treatment-naïve, approximately 20 subjects who have received 1 prior line of therapy, and 
approximately 80 subjects who have received at least 2 prior lines of therapy. Additional subjects, up 
to 30 each for first-line and second-line therapy groups, may be enrolled. 
◦
For the squamous NSCLC cohort, the enrollment will include approximately 10 subjects who are 
treatment-naïve, approximately 80 subjects who have received 1 prior line of therapy, and 
approximately 80 subjects who have received at least 2 prior lines of therapy. Additional subjects, up 
to 30 for first-line therapy group, may be enrolled. 
◦
The minimum sample sizes of 10 and 20 subjects were chosen to provide a preliminary assessment of 
the ORR for MEDI4736 as first-line therapy for both squamous and non-squamous NSCLC and 
second-line therapy for non-squamous NSCLC, respectively, similar to the aforementioned cohorts in 
other tumor types. 
◦
The sample size of 80 subjects for MEDI4736 in ≥ third-line therapy in non-squamous NSCLC and 
as second-line therapy as well as ≥ third-line therapy for squamous NSCLC, respectively, was chosen 
to provide a formal statistical testing of the following hypothesis
H0: ORR ≤10% vs H1: ORR > 10%


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•
UBC: Under Amendment 7, approximately 60 UBC subjects were enrolled. Under Amendment 8 and 
beyond, approximately 132 additional UBC subjects with inoperable or metastatic disease (second- or 
greater line) will be enrolled, which includes a minimum total of 70 PD-L1-positive and 50 PD-L1-
negative subjects, and approximately 12 subjects with tumor samples non-evaluable for PD-L1, assuming 
a PD-L1-positive prevalence of 60% and approximately 10% of subjects with tumor samples not 
evaluable for PD-L1 (based on preliminary data from the initial UBC cohort of this study).
Of 192 UBC subjects enrolled in the study, it is expected that there will be approximately 100 PD-L1-positive 
subjects in the second- or greater line of treatment (approximately 30 enrolled under Amendment 7 and 
approximately 70 enrolled under Amendment 8 and beyond). As shown in Table 5, when the ORR is expected 
to be in the 17% to 33% range (Plimack et al, 2015; Rosenberg et al, 2015), a total of 100 subjects would 
provide a width of < 9% between the observed ORR and its lower limit of the exact 95% C
 
Table 5. 
 
 
 
 
 
  
The prevalence of PD-L1 status for UBC subjects will be monitored through the study. After a total of 
approximately 132 subjects are enrolled under Amendment 8 and beyond, the enrollment of only PD-L1-
positive subjects may continue to ensure a minimum total of 70 PD-L1-positive subjects are enrolled.
With 70 PD-L1-positive and 50 PD-L1-negative UBC subjects enrolled under Amendment 8 and beyond to 
validate the potential of PD-L1 expression to predict response to MEDI4736 treatment, 
 
The response rate for the PD-L1-negative group is assumed to be similar to that 
observed with chemotherapy in a second-line UBC population (Bellmunt et al, 2009).


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1
INTRODUCTION
1.1
Disease Background
Cancer continues to be a major global health burden. In the United States of America (USA), 
it is the second most common cause of death after heart disease, accounting for nearly one in 
every 4 deaths (American Cancer Society, 2011). The 5-year survival rate for all cancers 
diagnosed between 1999 and 2006 is 68%, which is 18% higher than the rate reported 
between 1975 and 1977, likely reflecting progress in diagnosing certain cancers earlier and 
improvements in treatment (American Cancer Society, 2011). Unfortunately, despite 
indisputable progress in the treatment of cancer, there continues to be an unmet medical need 
for more effective and less toxic therapies, especially for those patients with advanced 
disease that do not respond or have become resistant to existing therapies.
Recent advances in the treatment of advanced melanoma using ipilimumab (YERVOY™) 
have led to improvements in overall survival (OS) in both the first- and second-line setting 
(Robert et al, 2011; Hodi et al, 2010). Despite these improvements, there remains a need for 
new therapies as only a small proportion of melanoma patients attain durable responses and a 
survival benefit. In addition, treatment with anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) 
antibodies has been shown to result in significant immune-related toxicity that could lead to 
serious complications if not properly managed. The development of novel approaches to 
treatment may lead to improved outcomes in these populations.
The immune system is capable of identifying tumor-associated antigens and eliminating the 
cancerous cells expressing them. This process of tumor immune surveillance plays an 
important role in preventing and combating the growth of tumors. The process of immune 
surveillance is believed to result in a co-evolution of the tumor and immune response termed 
immunoediting, which is thought to follow 3 stages (Swann and Smyth, 2007). During the 
initial phase of elimination, the innate and adaptive immune systems detect and eliminate 
tumor cells. Elimination can result in complete clearance of tumor cells as is seen in rare 
cases of spontaneous regression of melanoma (Kalialis et al, 2009). However, if elimination 
is incomplete, the immune system and tumor may enter a state of equilibrium. During this 
second phase of immunoediting, the immune response selectively eliminates susceptible 
tumor cells and may prevent tumor progression. As the equilibrium phase persists, the tumor 
may evolve mechanisms to avoid or attenuate the immune response. The emergence of tumor 
cells with reduced immunogenicity (IM) or enhanced immunosuppressive mechanisms leads 
to the escape phase of immunoediting. During escape, many factors may contribute to the 
failure of the immune system to control tumor growth including expression of T-cell 


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inhibitory molecules, downregulation of tumor antigens, and presence of immunosuppressive 
regulatory T cells or immunosuppressive cytokines within the tumor microenvironment.
Enhancing the immune response may provide a means to regain control of tumors that have 
progressed to the escape phase during immunoediting. A number of mechanisms to stimulate 
the antitumor immune response have been successfully employed. Interleukin (IL)-2 and 
interferon (IFN) alpha have shown objective response rates (ORRs) of 12% to 23% in renal 
cell carcinoma (RCC), with durable complete responses (CRs) and partial responses (PRs) 
in some patients (Motzer et al, 2009; McDermott et al, 2005). High-dose IL-2 
has also led to survival benefit, but only in subjects with durable CRs (6%) in melanoma 
(Atkins et al, 1999). Recently sipuleucel-T, an immunotherapy consisting of activated 
autologous antigen-presenting cells, was granted United States Food and Drug 
Administration (US FDA) approval for treatment of metastatic hormone refractory prostate 
cancer (Madan and Gulley, 2011). Blockade of negative regulatory signals to T cells such as 
CTLA-4 and programmed death ligand 1 (PD-L1) has also shown promising clinical activity. 
Ipilimumab, which binds to CTLA-4 and prevents the interaction of CTLA-4 with cluster of 
differentiation 80 (CD80) and CD86, results in enhanced T-cell activation and proliferation 
(Lipson and Drake, 2011). Ipilimumab was granted US FDA approval in 2011 for the 
treatment of metastatic melanoma and is currently under investigation for several other 
malignancies.
PD-L1 (B7-H1, CD274) is part of a complex system of receptors and ligands that are 
involved in controlling T-cell activation. In normal tissue, PD-L1 is expressed on T cells, 
B cells, dendritic cells, macrophages, mesenchymal stem cells, bone marrow-derived mast 
cells, as well as various nonhematopoietic cells (Keir et al, 2008). Its normal function is to 
regulate the balance between T-cell activation and tolerance through interaction with its 
2 receptors, programmed death 1 (PD-1, CD279) and CD80 (B7-1). PD-L1 is also expressed 
by tumors and acts at multiple sites to help tumors evade detection and elimination by the 
host immune system. In the lymph nodes, PD-L1 on antigen presenting cells (APC) binding 
to PD-1 (CD279) or CD80 (B7-1) on activated T cells delivers an inhibitory signal to the 
T cell (Keir et al, 2008; Park J et al, 2010). Likewise, binding of CD80 on APCs to PD-L1 on 
T cells leads to inhibitory signaling in the T cell. These and bidirectional interactions 
between CD80 and PD-L1, expressed on both APCs and T cells, lead to further inhibition of 
T-cell activation. These interactions result in reduced T-cell activation and fewer activated 
T cells in the circulation. In the tumor microenvironment, PD-L1 expressed on tumor cells 
binds to PD-1 on activated T cells reaching the tumor. This delivers an inhibitory signal to 
those T cells, preventing them from killing target tumor cells, and protecting the tumor from 
immune elimination (Zou and Chen, 2008).


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PD-L1 is expressed in a broad range of cancers with a high frequency, up to 88% in 
some types of cancer. In a number of these cancers, including lung (Mu et al, 2011), 
renal (Thompson et al, 2005; Thompson et al, 2006; Krambeck et al, 2007), pancreatic
(Nomi et al, 2007; Loos et al, 2008; Wang et al, 2010), and ovarian (Hamanishi et al, 2007), 
the expression of PD-L1 is associated with reduced survival and unfavorable 
prognosis. In ovarian cancer, for example, the 5-year survival rate in patients with low 
levels of PD-L1 was 80.2%, compared to 52.6% in patients with high levels of PD-L1 
(Hamanishi et al, 2007). In lung cancer, only 20% of patients with tumors expressing 
PD-L1 survived for more than 3 years, compared to 49% of patients with tumors lacking 
PD-L1 (Mu et al, 2011). Based on these data, and on assessments of expression of PD-L1 on 
the surface of human tumors using proprietary immunohistochemistry methods for 
assessment, MEDI4736 has the potential to affect multiple types of solid tumors, including 
those with a high incidence rate and some less common types with limited treatment options 
and poor outcomes.
The levels of tumor-infiltrating lymphocytes (TILs), and more specifically cytotoxic T cells, 
have been correlated to improved prognosis in a number of cancers including colorectal, 
melanoma, and lung (Pages et al, 2010), suggesting that an antitumor immune response is 
beneficial to patients. It has been shown in vitro that an antibody that blocks the interaction 
between PD-L1 and its receptors can relieve PD-L1-dependent immunosuppressive effects 
and enhance the cytotoxic activity of antitumor T cells (Blank et al, 2006). Based on these 
findings, an anti-PD-L1 antibody could be used therapeutically to enhance antitumor immune 
responses in patients with cancer. Results of several preclinical studies using mouse 
tumor models support this hypothesis. In these studies, antibodies directed against PD-L1, 
or its receptor PD-1, showed antitumor activity (Hirano et al, 2005; Iwai et al, 2002; 
Okudaira et al, 2009; Zhang et al, 2008).
Blocking PD-L1 is a similar approach to that taken by ipilimumab, but has some potential 
advantages. Firstly, the expression of CTLA-4 and its ligands is restricted to the 
hematopoietic system; thus the site of action for molecules targeting CTLA-4 is solely the 
peripheral lymphoid organs. In contrast, PD-L1 is expressed not only on cells of the 
hematopoietic system but also on a range of tumor types. Targeting of PD-L1 could therefore 
have additional effects within the tumor microenvironment. Secondly CTLA-4 plays an early 
and critical role in controlling T-cell activation. This is reflected in the phenotype of CTLA-4 
knockout mice, which die at an age of between 3 and 4 weeks due to lymphoproliferative 
disease and tissue destruction. In contrast PD-L1, via binding to PD-1, acts later in the 
process of T-cell activation (Fife and Bluestone, 2008) and is considered more dispensable 
for the control of initial T-cell activation. This is reflected in the phenotype of PD-L1 


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knockout mice, which are viable and have normal T-cell numbers and activation levels, but 
which have increased T-cell activation in response to antigen and increased susceptibility in 
certain autoimmunity models (Dong et al, 2004; Latchman et al, 2004). Similarly, PD-1 
knockout mice show strain-specific phenotypes milder than those seen in CTLA-4 knockouts 
(Nishimura et al, 1998; Nishimura and Honjo, 2001). Based on these data, inhibition of 
PD-L1 would be expected to have reduced toxicity relative to inhibition of CTLA-4. In 
support of this, recent Phase 1 clinical studies testing the tolerability of agents targeting 
PD-1 have shown a more favorable toxicity profile than ipilimumab (Brahmer et al, 2010; 
Berger et al 2008; Wolchok et al, 2010).
1.2
Description of MEDI4736
MEDI4736 is briefly described below. Refer to the current Investigator’s Brochure for 
details.
1.2.1
Product Derivation
MEDI4736 is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody (MAb) 
directed against human PD-L1. MEDI4736 has an overall molecular weight of approximately 
149 kDa, including N-linked oligosaccharides. The antibody is composed of 2 identical 
heavy chains of approximately 49,670 Da each, and 2 identical light chains of approximately 
23,390 Da each. The fragment crystallizable (Fc) domain of MEDI4736 contains a triple 
mutation in the constant domain of the immunoglobulin G1 (IgG1) heavy chain that reduces 
binding to the complement component C1q and the Fcγ receptors responsible for mediating 
antibody-dependent cell-mediated cytotoxicity (ADCC) (Oganesyan et al, 2008). Subsequent 
to this triple mutation, the anticipated lack of MEDI4736-mediated ADCC and 
complement-dependent cytotoxicity were confirmed using cell-based functional assays. 
MEDI4736 is selective for recombinant PD-L1 and blocks the binding of recombinant PD-L1 
to the PD-1 and CD80 receptors.
1.2.2
Summary of Nonclinical Experience
 
 


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1.2.3
Summary of Clinical Experience
 
 
 
 
 
 
, 


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1.3
Research Hypothesis
The primary objectives of this Phase 1/2, first-time-in-human (FTIH), dose-escalation and 
dose-expansion study are to determine the maximum tolerated dose (MTD) or optimal 
biological dose (OBD), and safety profile of MEDI4736 in subjects with advanced solid 
malignancies and the antitumor activity of subjects with NSCLC and UBC. Secondary 
objectives include evaluation of the PK, IM, and antitumor activity of MEDI4736. The 
exploratory objectives are to evaluate biomarkers that may correlate with activity or 
prospectively identify patients likely to respond to MEDI4736 and to evaluate the effect of 
MEDI4736 on patient-reported outcomes (PROs).
The research hypothesis is that MEDI4736 will be adequately tolerated following 
administration in ascending doses to subjects with refractory solid tumors and that such 
administration may result in clinical benefit.
1.4
Rationale for Study Conduct
Currently available therapies for the advanced solid malignancies included in this study result 
in poor outcomes and there is a significant unmet medical need for additional treatment 
options in these patient populations. MEDI4736, an antibody that blocks the interaction 
between PD-L1 and its receptors, may relieve PD-L1-dependent immunosuppressive effects 
and enhance the cytotoxic activity of antitumor T cells. Given the preliminary clinical 
activity observed in all tumor types in the dose-expansion phase of this study, the recently 
available data from similar agents and the immunomodulatory mechanism of an anti-PD-L1 
MAb, MEDI4736 may offer benefit to patients with a broad range of cancers. Rationale for 
the selection of specific tumor types is provided in Section 3.4.
This study is intended to establish the MTD or OBD and the safety profile of MEDI4736, as 
well as the preliminary antitumor activity in subgroups of NSCLC and UBC. Other data to be 
evaluated include the PK, pharmacodynamics, IM, antitumor activity in additional tumor 
types, and potential biomarkers, which may correlate with response to MEDI4736 treatment. 
Specifically, the dose-expansion phase of this study will evaluate the antitumor activity of 


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MEDI4736 in several advanced solid malignancies where historical outcomes are poor and 
scientific rationale suggests that treatment with an anti-PD-L1 MAb may be beneficial. 
Potential biomarkers, including PD-L1 expression, will be evaluated on an ongoing basis. 
The results from this study will form the basis for decisions applied to ongoing and future 
studies.
1.5
Benefit-risk and Ethical Assessment
Subjects with advanced solid tumors refractory to standard treatment or for which no 
standard therapy exists represent a patient population with unmet medical needs. MEDI4736, 
a human MAb directed against hPD-L1, may offer benefit to this patient population. 
MEDI4736 has a high affinity for hPD-L1 and is able to completely block the interaction of 
recombinant hPD-L1 with both recombinant hPD-1 and recombinant human CD80 in a 
biochemical assay. In vitro, MEDI4736 enhances the proliferation and activation of primary 
human T cells cultured in the presence of recombinant PD-L1.
Nonclinical studies demonstrate that MEDI4736 inhibits tumor growth in mouse xenograft 
models. This activity is shown to be dependent upon the presence of human T cells, 
supporting the hypothesis that PD-L1 blockade can enhance antitumor immune response. No 
MEDI4736-associated risks have been reported in nonclinical safety studies in cynomolgus 
monkeys.
Promising evidence of clinical activity has been observed for molecules similar to 
MEDI4736, including other MAbs targeting the PD-1/PD-L1 pathway (Topalian et al, 2012; 
Hamid et al, 2013; Brahmer et al, 2012; Herbst et al, 2013). In these studies, encouraging 
response rates and durable responses have been observed across a range of tumor types. The 
experience to date with anti-PD-1/PD-L1 MAbs suggests that these agents can provide 
significant clinical activity with a manageable safety profile that is superior to that of the 
anti-CTLA-4 class.
 
 
 
 
 
 
 
 
 


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Clinically significant risks of interest with MEDI4736 and related molecules include 
immune-mediated reactions and their associated signs and symptoms, risks due to IM and 
other potential risks. Immune-mediated reactions/immune-related AEs (irAEs), also 
considered to be AEs of special interest (AESIs), are important risks of immune checkpoint 
inhibitors, and are being closely monitored in clinical studies with MEDI4736 monotherapy 
and combination therapy. 
Under previous versions of this protocol, inclusion criteria required that subjects have a 
creatinine clearance of ≥ 50 mL/min. Under Amendment 9, UBC subjects will be permitted 
to enroll with a creatinine clearance of ≥ 30 mL/min. In the UBC population, impaired renal 
function is common due to age, urinary tract obstruction, smoking-related vascular disease, 
or prior treatments including nephrectomy, cystectomy, and prior nephrotoxic chemotherapy 
(ie, commonly used platinum-based chemotherapy; Galsky et al, 2011). As such, lowering 
the creatinine clearance requirement for these subjects will allow for evaluation of 
MEDI4736 in a broader UBC patient population that may be more representative of a real 
world population. Given that MEDI4736 is an IgG1 MAb, and MAbs are not expected to be 
cleared through renal mechanisms, it is anticipated that exposure will not be significantly 
altered in subjects with impaired renal function. This is supported by population PK analysis 
of patients treated with MEDI4736, which demonstrated that creatinine clearance was not a 
significant covariate for drug clearance (Song et al, 2015). 
 
 
 
 
 
 
 
 


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In the overall study population, the most frequently reported MEDI4736-related renal AESIs
of all grades were acute kidney injury and blood creatinine increased (2 subjects each; 0.2%).
In the UBC population, MEDI4736-related renal AESIs were reported in 1 subject (Grade 3 
acute kidney injury; 1.6%).
Table 1.5-1
 
)
 
 
     
     
     
     
     
     
     
     
     
     
     
     
Given the available PK, clinical activity, and safety data observed in UBC subjects treated 
with MEDI4736 and the limited treatment options after failure of standard platinum-based 
regimens, allowing subjects with creatinine clearance ≥30 mL/min to be treated with 
MEDI4736 is justified. 
In order to mitigate potential risks to patients, this study has incorporated toxicity 
management guidelines developed for use across the broader MEDI4736 clinical 
development program. These guidelines are based on evidence and experience from ongoing 
studies of MEDI4736 and similar immune-modulating agents and are focused on frequent 


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monitoring for and early identification of potential immune-mediated events. Management 
principles include interruption of dosing and/or treatment with corticosteroids or more potent 
immunosuppressive agents as needed. In addition, the study has incorporated eligibility 
criteria to ensure patients that may be at risk would not be included (ie, by excluding those 
with prior autoimmune disease, inflammatory bowel disease, unresolved toxicities from prior 
therapies, or inadequate hematologic or organ function). 
2
STUDY OBJECTIVES
2.1
Primary Objective
Dose-escalation Phase
The primary objective of the dose-escalation phase is to determine the MTD or OBD, and the 
safety profile of MEDI4736 in subjects with advanced melanoma, RCC, NSCLC, and 
colorectal cancer (CRC) refractory to standard therapy or for which no standard therapy 
exists. 
Dose-exploration Cohort
The primary objective of the dose-exploration cohort is to determine the safety profile of 
MEDI4736 using an every 4 weeks (Q4W) dosing schedule in subjects with advanced 
cutaneous melanoma, uveal melanoma, HCC, SCCHN, NSCLC squamous histology, 
NSCLC non-squamous histology, gastroesophageal cancer, TNBC or pancreatic 
adenocarcinoma.
Dose-expansion Phase
The primary objectives of the dose-expansion phase are: 
1. To determine the safety profile of MEDI4736 in subjects with advanced cutaneous 
melanoma, uveal melanoma, HCC, SCCHN, NSCLC squamous histology, NSCLC 
non-squamous histology, gastroesophageal cancer, TNBC, pancreatic adenocarcinoma, 
UBC, GBM, ovarian cancer, soft tissue sarcoma, SCLC, MSI-high cancers, HPV-positive 
cancers, or nasopharyngeal carcinoma.
2. To evaluate the antitumor activity of MEDI4736 in subjects with non-squamous NSCLC 
who have received 2 or more prior lines of therapy and subjects with squamous NSCLC 
who have received 1 prior lines of therapy and 2 or more prior lines of therapy as 
assessed by RECIST v1.1. 
3. To evaluate the antitumor activity of MEDI4736 in subjects with PD-L1-positive UBC as 
assessed by RECIST v1.1.


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2.2
Secondary Objectives
The secondary objectives of this study are:
1. To describe the PK of MEDI4736.
2. To determine the immunogenicity of MEDI4736.
3. To evaluate the antitumor activity of MEDI4736 (except for subgroups of UBC and 
NSCLC subjects where this is considered a primary objective) as assessed by RECIST 
v1.1.
4. To evaluate the antitumor activity of MEDI4736 in subjects with UBC, regardless of 
PD-L1 status as assessed by RECIST v1.1.
5. To evaluate the antitumor activity of MEDI4736 in subjects with PD-L1-negative UBC
as assessed by RECIST v1.1.
6. To evaluate the antitumor activity of MEDI4736 as assessed by RECIST v1.1 in subjects 
with PD-L1-positive UBC as compared to PD-L1-negative UBC.
2.3
Exploratory Objectives
 
 
 
3
STUDY DESIGN
3.1
Overview of Study Design
This is a multicenter, open-label, FTIH dose-escalation, dose-exploration, and 
dose-expansion study of MEDI4736 to evaluate the safety, tolerability, PK, IM, and 
antitumor activity of MEDI4637 in adult subjects with solid tumors. A dose-escalation phase 
in subjects with advanced melanoma, RCC, NSCLC, or CRC using a Q2W (at doses up to 
10 mg/kg) schedule has completed enrollment without identification of an MTD. In addition, 
a dose-escalation cohort using a Q3W schedule at a dose of 15 mg/kg has fully enrolled 
without identification of an MTD. A dose-expansion phase using a dose and schedule of 
10 mg/kg Q2W is currently enrolling. A dose-exploration cohort using an alternative dose 
and schedule of 20 mg/kg Q4W is ongoing at select sites in the USA in parallel to the 
ongoing dose-expansion cohorts. 


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The dose-escalation phase will include subjects with advanced melanoma, RCC, NSCLC, or 
CRC followed by a dose-expansion phase in subjects with advanced cutaneous melanoma, 
uveal melanoma, HCC, SCCHN, NSCLC squamous histology, NSCLC non-squamous 
histology, gastroesophageal cancer, TNBC, pancreatic adenocarcinoma, UBC, GBM, ovarian 
cancer, soft tissue sarcoma, SCLC, MSI-high cancers, HPV-positive cancers, or 
nasopharyngeal carcinoma. In addition, a dose-exploration cohort will include subjects with 
advanced cutaneous melanoma, uveal melanoma, HCC, SCCHN, NSCLC squamous 
histology, NSCLC non-squamous histology, gastroesophageal cancer, TNBC or pancreatic 
adenocarcinoma. Therapeutic response criteria for these tumor types are defined in 
Section 4.2.1. 
Up to approximately 1,392 subjects could be required for the dose-escalation (n = 50), 
dose-exploration (n = 20), and dose-expansion (n = 692 – 1,322 based on emerging safety 
and clinical activity data) phases of the study. Subjects will be enrolled at approximately 
100 sites globally. A study flow diagram of the study design is shown in Figure 3.1-1.


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Figure 3.1-1
Study Flow Diagram
CRC = colorectal cancer; HCC = hepatocellular carcinoma; MTD = maximum tolerated dose; NSCLC = non-
small cell lung cancer; OBD = optimal biological dose; PK = pharmacokinetic; Q2W = every 2 weeks; Q3W = 
every 3 weeks; Q4W = every 4 weeks; RCC = renal cell carcinoma; SCCHN = squamous cell carcinoma of the 
head and neck; TNBC = triple negative breast cancer.
A minimum of approximately 750 subjects are to be enrolled in this study, including approximately 50 subjects 
in the dose-escalation phase, 20 subjects in the Q4W dose-exploration cohort, and 692 subjects in the dose-
expansion phase, with the possibility of enrolling more subjects in the expansion phase, if necessary, up to a 
maximum of 1,322 subjects based on the emerging safety and clinical activity profile (total study 
population = 1,392).
The Q3W MEDI4736 dose-escalation arm, the Q4W dose-exploration cohort, and the MEDI4736 dose-
expansion phase will be conducted in parallel. 
a
If 2 or more dose-limiting toxicities are observed in the first cohort, the starting dose may be de-escalated 
to 0.05 mg/kg given Q3W. Provided the MTD is not exceeded at the 10 mg/kg dose level, higher doses 
may be further explored based on clinical, safety, and PK/pharmacodynamic data. Intermediate doses may 
also be explored at the discretion of the sponsor based on available data.
b
The first cohort of 3-6 subjects will receive MEDI4736 at a dose equivalent to the highest dose level that 
has not exceeded the MTD or the OBD in the Q2W dose-escalation arm. Dose escalation may proceed with 
sequential cohorts of 3-6 subjects dependent upon acceptable safety, PK/pharmacodynamic, and clinical 
data.
MEDI4736 Dose-escalation Arm, Q2W Dosing a
(Melanoma, RCC, NSCLC, and CRC tumors)
Cohort 1 Q2W
0.1 mg/kg
(n = 4)
Cohort 2 Q2W
0.3 mg/kg
(n = 4)
Cohort 3 Q2W
1.0 mg/kg
(n = 3)
Cohort 4 Q2W
3.0 mg/kg
(n = 3)
Cohort 5 Q2W
10 mg/kg
(n = 6)
MEDI4736 Dose-escalation Arm, Q3W 
Dosing b
(Melanoma, RCC, NSCLC, and CRC 
tumors)
Q3W Cohort 15 mg/kg MEDI4736
(n= 7)
MTD/OBD Identified
MEDI4736 Dose-expansion Arms, Q2W Dosing
See Table 3.1-1 for tumor type details
MEDI4736 Dose-exploration Arm, 
Q4W Dosing 
(Melanoma, pancreatic, HCC, SCCHN, 
NSCLC, gastroesophageal, and TNBC 
tumors)
Q4W Cohort 20 mg/kg MEDI4736
(n = 20)


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Table 3.1-1
Number of Subjects Enrolled by Tumor Type in Dose-
expansion Cohorts
Tumor Type
Total 
Planned 
Enrollment
Subjects Enrolled 
as of 20Nov2015
Planned Enrollment Under 
Amendment 8 and Beyond
Advanced cutaneous melanoma
20
21
0
Uveal melanoma
20-60
24
Up to 36
HCC
20-60
41
Up to 19
SCCHN
20-60
63
0
Squamous NSCLC (Total)
     1L
     2L
     ≥ 3L
170-190
     10-30
     80
     80
151
29
51
70
Up to 39
Non-squamous NSCLC (Total)
     1L
     2L
     ≥ 3L
110-140
     10-30
     20-30
     80
143
30
34
79
0
Gastroesophageal
20-60
51
Up to 9
TNBC
20-60
40
Up to 20
Pancreatic adenocarcinoma
10-60
31
Up to 29
UBC (Total)
     Initial UBC subjects
     Amendment 8 and beyond
        PD-L1 positive
        PD-L1 negative
        Non-evaluable for PD-L1
20-192
20-60
132
≥ 70
50
12
60
60
0
0
0
0
Up to 132
0
Up to 132
≥ 70
50
12
GBM (Total)
     MGMT negative
20-60
     ≥ 10
20
Up to 40
Ovarian cancer (Total)
     Platinum sensitive
20-60
     ≥ 10
46
Up to 14
Soft tissue sarcoma
20-60
20
Up to 40
SCLC
20-60
21
Up to 39
MSI-high cancers
20-60
57
Up to 3
HPV-positive tumors (Total)
     Cervical cancer
20-60
     ≤ 10 a
22
10
Up to 38
Nasopharyngeal carcinoma
10-60
10
Up to 50
Total
692-1,322
821
Up to 508
GBM = glioblastoma multiforme; HCC = hepatocellular carcinoma; HPV = human papilloma virus; L = line; 
MGMT = O6-methylguanine-deoxyribonucleic acid methyltransferase promoter methylation; MSI = 
microsatellite instability; NSCLC = non-small cell lung cancer; PD-L1 = programmed death ligand 1; 
SCCHN = squamous cell carcinoma of the head and neck; SCLC = small-cell lung cancer; TNBC = triple 
negative breast cancer; UBC = urothelial bladder cancer.
a
A maximum of 10 cervical cancer subjects will be enrolled out of the initial 20 subjects in the HPV-
positive tumors cohort. If the cohort is expanded beyond 20 subjects based on clinical activity, additional 
cervical cancer subjects may be enrolled.


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3.1.1
Dose Escalation
MEDI4736 Dose-escalation Arm, Q2W Dosing
In the dose-escalation phase of the study, MEDI4736 will be administered Q2W, in 
sequential cohorts of 3-6 subjects each receiving one of 5 doses of MEDI4736 (0.1, 0.3, 1.0, 
3.0, or 10 mg/kg) via intravenous (IV) infusion. Dose escalation will be considered 
completed once an MTD or OBD is identified or the top dose of 10 mg/kg is reached. 
Provided the MTD is not exceeded at the 10 mg/kg dose level, additional cohorts of 3-6 
subjects using doses above 10 mg/kg of MEDI4736 Q2W may be explored based on 
emerging PK or pharmacodynamic data suggesting maximal suppression of sPD-L1 is not 
being maintained throughout the dosing interval or T-cell activation has not plateaued, 
respectively. The first cohort will enroll a minimum of 3 subjects, according to a standard 
3+3 design. Subjects in the first cohort will receive a dose of 0.1 mg/kg MED4736. The first 
IV infusion for subjects in this cohort will be 4 hours in duration; subsequent infusions for 
subjects in this cohort and all infusions for the remaining cohorts will be approximately 
60 minutes in duration. Subsequent cohorts will receive 0.3, 1.0, 3.0, or 10 mg/kg IV Q2W 
unless an MTD or OBD is identified before all dose-escalation cohorts are completed. 
Provided the MTD is not exceeded at the 10 mg/kg dose level, higher doses may be further 
explored based on clinical, safety, and PK/pharmacodynamic data generated from the study. 
Intermediate doses may be evaluated at the discretion of the sponsor based on available data. 
If ≥ 2 DLTs, as defined in Section 4.5.7, are observed in the first dose cohort, the starting 
dose will be de-escalated to half of the previous dose given (0.05 mg/kg) and will be 
administered Q3W. Refer to Section 4.5.6 for detailed dose-escalation procedures. A total of 
20 subjects have been enrolled in the Q2W dose-escalation phase of the study, including 
4 subjects in each of the 0.1 and 0.3 mg/kg cohorts, 3 subjects in each of the 1.0 and 3.0 
mg/kg cohorts and 6 subjects in the 10 mg/kg cohort. The planned Q2W dose-escalation 
phase of the study is complete.
MEDI4736 Dose-escalation Arm, Q3W Dosing 
Upon completion of dose escalation for the MEDI4736 Q2W dose-escalation arm, a separate 
dose-escalation arm of MEDI4736 administered Q3W will be initiated. This arm will be 
conducted in parallel with the dose-expansion phase (see below for description of dose 
expansion). The first cohort of 3-6 subjects will receive MEDI4736 via IV infusion Q3W at 
the highest dose level that has not exceeded the MTD or the OBD in the Q2W 
dose-escalation arm. MEDI4736 Q3W dose escalation may proceed with additional cohorts 
of 3-6 subjects dependent upon acceptable safety, PK/pharmacodynamic, and clinical data 


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according to the dose-escalation procedures described in Section 4.5.6. A total of 7 subjects 
have been enrolled in the 15 mg/kg Q3W dose-escalation arm and the planned Q3W dose-
escalation phase of the study is complete.
3.1.2
Dose Exploration 
A total of approximately 20 subjects with advanced cutaneous melanoma, uveal melanoma, 
pancreatic adenocarcinoma, NSCLC squamous histology, NSCLC non-squamous histology 
HCC, SCCHN, gastroesophageal cancer, or TNBC are being enrolled into the dose-
exploration cohort at select sites in the United States. MEDI4736 will be administered Q4W, 
at a dose of 20 mg/kg MEDI4736 via IV infusion. 
3.1.3
Dose Expansion
The dose-expansion phase of the study will be conducted following completion of dose 
escalation for the MEDI4736 Q2W dose-escalation arm and in parallel with the MEDI4736 
Q3W dose-escalation arm. The 10 mg/kg dose administered Q2W was chosen to take into 
expansion. 
A minimum of 20 subjects each with advanced cutaneous melanoma, uveal melanoma, HCC, 
SCCHN, gastroesophageal cancer, TNBC, UBC, GBM, ovarian cancer, soft tissue sarcoma, 
SCLC, MSI-high cancers, and HPV-positive cancers will be enrolled into tumor-specific 
expansion cohorts. In addition, a minimum of 10 subjects each with pancreatic 
adenocarcinoma or nasopharyngeal carcinoma will be enrolled. No more than 10 subjects 
with cervical cancer will be enrolled out of the 20 subjects in the HPV-positive cancers 
dose-expansion cohort. A minimum of 10 subjects without O6-methylguanine-deoxynucleic 
acid (DNA) methyltransferase promoter methylation will be enrolled in the GBM cohort. 
Similarly, a minimum of 10 subjects with platinum sensitivity will be enrolled in the ovarian 
cancer cohort. Additional subjects, up to a total of 60 subjects in any of these dose-expansion 
cohorts may be enrolled if promising clinical activity is observed in that cohort. If the 
HPV-positive cancers, MSI-high cancers, GBM, ovarian cancer, or soft tissue sarcoma 
cohorts are expanded beyond 20 subjects each, enrollment may be prioritized to tumor sub-
type(s) that showed promising clinical activity, at the sponsor’s discretion. Approximately 
110-140 subjects with non-squamous histology NSCLC will be enrolled including 
approximately 10-30 subjects who are treatment-naive, approximately 20-30 subjects who 
have received 1 prior line of therapy, and approximately 80 subjects who have received at 
least 2 prior lines of therapy. Approximately 170-190 subjects with squamous histology 
NSCLC will be enrolled including approximately 10-30 subjects who are treatment-naive, 


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approximately 80 subjects who have received 1 prior line of therapy, and approximately 
80 subjects who have received at least 2 prior lines of therapy. 
An evaluation of a possible correlation between clinical activity of MEDI4736 and potential 
biomarkers (eg, PD-L1 expression on tumor or sPD-L1) will be ongoing throughout the 
study. Initially, tumoral PD-L1 expression will be assessed on screening samples after 
enrollment on an ongoing basis. After the first 20-40 subjects in each of HCC, 
gastroesophageal cancer, TNBC, UBC, GBM, ovarian cancer, soft tissue sarcoma, SCLC, 
HPV-positive cancers, pancreatic adenocarcinoma, and nasopharyngeal carcinoma dose-
expansion cohorts are enrolled, additional subjects in the applicable cohorts may be required 
to have tumoral PD-L1 expression as determined by prospective testing prior to enrollment.  
Under previous amendments of this protocol, a minimum of 5-10 SCCHN subjects were 
required to have tumoral PD-L1 expression. That requirement has been met and enrollment 
into the SCCHN cohort is complete. Tumoral PD-L1 expression as determined by 
prospective testing prior to enrollment will be required for the squamous and non-squamous 
NSCLC cohorts as described below in Table 3.1.3-1.
Table 3.1.3-1
NSCLC Dose-expansion Cohort PD-L1 Expression 
Requirements
Cohort
Total Planned Enrollment 
(n)
Tumoral PD-L1 Requirement 
(Under Amendment 7)
Squamous NSCLC (Total)
     1L
     2L
     ≥ 3L
170-190
     10-30
     80
     80
Minimum of 80 PD-L1-positive
     Minimum of 10 PD-L1-positive
     Minimum of 35 PD-L1-positive
     Minimum of 35 PD-L1-positive
Non-squamous NSCLC (Total)
     1L
     2L
     ≥ 3L
110-140
     10-30
     20-30
     80
All remaining subjects PD-L1-postive
     All remaining subjects PD-L1-positive
     All remaining subjects PD-L1-positive
     All remaining subjects PD-L1-positive
L = line; NSCLC = non-small cell lung cancer; PD-L1 = programmed death ligand 1.
Under Amendment 8 and beyond of this protocol, the UBC cohort will be expanded to 
evaluate the antitumor activity of MEDI4736 in subjects with PD-L1-positive UBC and 
validate the potential of PD-L1 expression (determined by IHC) to predict response to 
MEDI4736 treatment. Approximately 132 additional UBC subjects will be enrolled in this 
cohort in order to include a minimum of 70 PD-L1-positive subjects and 50 PD-L1-negative 
subjects, and approximately 12 subjects with non-evaluable PD-L1 status. 
 
 
 


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In 
addition to validating the currently proposed PD-L1 selection criteria (≥ 25% PD-L1 staining 
on tumor or immune cells), inclusion of patients with PD-L1 staining above and below this 
cutoff will enable exploratory analyses potentially leading to a refinement of PD-L1 status 
definitions or to the qualification of alternative biomarkers for selection of UBC subjects
most likely to benefit from treatment with MEDI4736 in future clinical studies.
To ensure that all of the additional UBC subjects contribute to the biomarker validation, 
subjects must have measurable disease at baseline by blinded independent central review 
(BICR). PD-L1 status will be determined by a central testing laboratory and will be derived 
from a fresh tumor biopsy taken during screening or an available tumor sample taken from 
≤6 months prior to study entry. The tumor sample (fresh and/or recent within 6 months prior 
to study entry) used for PD-L1 analysis must be shipped to, and confirmed as received by, 
the Sponsor or central vendor prior to the first dose of MEDI4736. It is highly recommended 
that efforts are taken to ensure presence of tumor cells within the tumor sample prior to 
shipping for PD-L1 analysis. The tumor PD-L1 status will be determined by IHC with 
PD-L1-positive samples defined as ≥ 25% tumor cell or immune cell staining and PD-L1-
negative samples defined as < 25% tumor cell and immune cell staining. In cases where 
subjects have more than one tumor sample from ≤6 months prior to study entry available for 
testing, PD-L1 status will be derived from the most recent evaluable sample. PD-L1 status 
determined by IHC testing from tumor samples evaluated for screening into MedImmune 
Study D4190C00010 may be used if derived from a sample taken ≤ 6 months prior to study 
entry. Additional archival tumor tissue, from beyond 6 months prior to study entry is also 
required, if available.
As of 20Nov2015, 821 subjects have been treated in the dose-expansion phase of the study. 
Enrollment into dose-expansion cohorts may be discontinued at the discretion of the sponsor 
should emerging clinical or preclinical data suggest that continued treatment may not be 
beneficial to a given cohort.
All subjects will be evaluated regularly and their clinical status classified 
according to RECIST guidelines (v1.1; Eisenhauer et al, 2009) with modifications (see 
Section 5.2.6 for a description of disease evaluation) except for subjects with GBM who will 
have their clinical status classified according to the Response Assessment in Neuro-oncology 
(RANO) guidelines (Wen et al, 2010). Modification of RECIST as described may discourage 
early discontinuation of MEDI4736 and provide a more complete evaluation of its antitumor 
activity than would be seen with conventional response criteria. Nonetheless, the efficacy 


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analysis will be conducted primarily based on RECIST v1.1. All subjects will be followed 
indefinitely for survival until the sponsor closes the study or for the maximum duration per 
institutional standards. Adverse events and SAEs will be followed as per Section 6.4.
The endpoints to be measured in this study are described in Section 7.3.
3.2
Estimated Duration of Subject Participation
Subjects in the dose-escalation, dose-exploration, and dose-expansion phases will be treated 
for up to 12 months until confirmed progressive disease (PD), initiation of alternative cancer 
therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue 
treatment occur. In the event of PD, subjects may continue to receive MEDI4736 in the 
absence of clinical deterioration (see Section 5.2.6) and if investigators consider that subjects 
continue to receive benefit from treatment. Subjects who achieve and maintain disease 
control (DC; ie, CR, PR, or SD) or clinical benefit through to the end of the 12-month 
MEDI4736 treatment period will enter follow-up. Upon evidence of PD during follow-up, 
subjects will be re-administered MEDI4736 for up to another 12 months. Only one round of 
retreatment with MEDI4736 will be allowed. All subjects will be followed for survival and 
anticancer therapy indefinitely unless the sponsor decides to end the study.
3.3
Study-stopping Criteria
If the following occurs, administration of investigational product will be stopped and no 
additional subjects will be entered into the study:
•
Any safety finding assessed as related to investigational product that, in the opinion of 
the sponsor in consultation with a MedImmune safety review committee (or equivalent), 
contraindicates further dosing of study subjects.
If any such safety findings occur, further administration of the investigational product will be 
stopped and no further subjects will be entered into the study. Thereafter the regulatory 
authorities and Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) 
will be notified and a prompt cumulative review of safety data and the circumstances of the 
event in question will be conducted (see Section 6.5). The findings will be shared with the 
regulatory authorities and the IRBs/IECs. If it is deemed appropriate by the sponsor after 
review by a MedImmune safety review committee (or equivalent), justification for stopping 
the study will be sent to the regulatory authorities and the IRBs/IECs as required.


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Any subjects who have already received investigational product and are currently in the 
study at the time study-stopping criteria are met will continue to be followed by the 
investigator for safety (see Section 6.4.1).
Withdrawal criteria for individual subjects are provided in Section 4.2.3.
3.4
Rationale for Study Design and Doses
An open-label dose-escalation study with a dose-expansion arm is a common study design in 
early-phase oncology studies and is considered appropriate for a FTIH study.
The primary objective of the dose-escalation phase of this study is to determine the MTD or 
OBD of MEDI4736 in subjects with advanced melanoma, CRC, NSCLC, or RCC refractory 
to standard therapy or for which no standard therapy exists. This study population is 
appropriate for testing a FTIH compound with potential for significant toxicities. An unmet 
medical need exists for these patient populations given that they have exhausted alternative 
treatment options or available therapies. Moreover, subjects with less advanced disease still 
have options for life-prolonging therapy, and administration of an agent without proven 
benefit would be inappropriate.
The tumor types included in the dose-escalation phase are of interest for several reasons. 
There is a high unmet need for new treatment options in each of these diseases. 
Melanoma, NSCLC, and RCC are known to respond to immunotherapy (Hodi et al, 2010; 
Rosenblatt and McDermott, 2011; Topalian et al, 2012). Taken together with the proposed 
immunomodulatory mechanism of MEDI4736, there may be a greater chance of seeing 
antitumor activity in these malignancies.
The primary objective of the dose-expansion phase of this study is to determine the safety 
profile of MEDI4736 in subjects with advanced cutaneous melanoma, uveal melanoma, 
HCC, SCCHN, NSCLC squamous histology, NSCLC non-squamous histology, 
gastroesophageal cancer, TNBC, pancreatic adenocarcinoma, UBC, GBM, ovarian cancer, 
soft tissue sarcoma, SCLC, MSI-high cancers, HPV-positive cancers, and nasopharyngeal 
carcinoma. The dose-expansion phase will further evaluate the safety and preliminary 
antitumor activity of MEDI4736 at the MTD or OBD as assessed by RECIST v1.1 
guidelines. In addition, under Amendment 8 of this protocol, the UBC cohort will be 
expanded to evaluate the antitumor activity of MEDI4736 in subjects with PD-L1-positive 
UBC and validate the potential for PD-L1 expression to predict response to MEDI4736 
treatment.


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The malignancies included in the dose-expansion phase were based on the greatest unmet 
medical need, tumoral expression of PD-L1, and underlying biology in these tumor types. 
Although, these tumor types have approved first-line treatments, further therapeutic options 
are limited with second- and third-line treatments generally providing short OS. These tumor 
types present an opportunity for an anti-PD-L1 antibody to demonstrate benefit. 
Preliminary data from this study as well as emerging data from other antibodies targeting the 
PD-1/PD-L1 pathway suggest that subjects with multiple tumor types may benefit from 
treatment with an agent such as MEDI4736. Cancers that have historically shown 
responsiveness to immunotherapy may be likely to benefit from immune checkpoint 
blockade. Treatment of melanoma with immunotherapy is well established, with 
improvements in OS shown with anti-CTLA-4 (Hodi et al, 2010). Similarly, treatment of 
early stage bladder cancer with Bacillus Calmette-Guerin is well established and reduces the 
risk of recurrence (Sheley et al, 2000). While no longer considered to be a standard 
treatment, sarcoma was one of the first cancers to show response to immunotherapy with 
Coley’s toxins (McCarthy, 2006) and recent reports suggest sarcoma may be responsive to 
PD-L1 targeting antibodies (Sagiv-Barfi et al, 2014). In addition to this early clinical 
approach, unpublished data from syngeneic mouse models of sarcoma suggest that PD-1/ 
PD-L1 targeting antibodies may have activity in this disease. 
Cancers with viral and bacterial etiologies are known to express cell surface antigens which 
may be recognized by the immune system and immune checkpoint blockade may be 
advantageous in these diseases. Included in the expansion phase are cohorts designed to 
evaluate this hypothesis. The HPV -positive cancers cohort and nasopharyngeal carcinoma 
cohort will enroll subjects with HPV or Epstein bar virus associated cancers, respectively. 
Similarly, both SCCHN (HPV) and HCC (hepatitis B virus and hepatitis C virus [HCV]) 
have subpopulations with viral etiologies. Lastly, gastroesophageal cancer is associated with 
bacterial infection and may benefit from immunotherapy. For example, in a Phase 2 study in 
HCC, treatment with the anti-CTLA-4 antibody tremelimumab resulted in radiographic 
responses in 18% of subjects while demonstrating a decline in HCV load and an increase in 
anti-HCV immune response (Sangro et al, 2012). Tremelimumab has also demonstrated 
antitumor activity as monotherapy in gastroesophageal cancer and in combination with 
gemcitabine in pancreatic adenocarcinoma (Ralph et al, 2010; Aglietta et al, 2012).
Recent data suggest that NSCLC patients with a history of heavy smoking may be more 
prone to respond to an anti-PD-1/PD-L1 antibody.  Specifically, higher ORR following 
treatment with MPDL3280A were observed in NSCLC subjects with a history of smoking as 
compared to those without a history of smoking (Soria et al, 2013). One potential explanation 


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for this observation is that heavy smoking may lead to a greater frequency of mutations 
within the tumor and subsequently a greater diversity of tumor associated antigens that are 
recognizable by the immune system. Considering the preliminary data presented by 
Soria et al, it is reasonable to extend the exploration of this hypothesis into additional 
tumor types known to be associated with smoking (NSCLC, SCLC, SCCHN, and 
bladder cancer). These same tumor types, along with melanoma, cervical cancer, MSI-high 
cancers, and gastroesophageal cancer are also known to have a high mutational burden 
(Alexandrov et al, 2013).
Based on early antitumor activity signals in this study as well as from similar agents, the 
dose-expansion phase of the study will further explore the safety and clinical activity of 
MEDI4736 in specific subpopulations of NSCLC to support future studies planned in this 
tumor type. Specifically, the expansion phase will test the hypothesis that MEDI4736 will 
result in at least a 10% ORR in subjects with squamous NSCLC who have received 1 prior 
line of therapy and with squamous and non-squamous NSCLC who have received at least 
2 prior lines of therapy. In addition, the clinical activity of MEDI4736 will be explored in 
subjects who are treatment-naïve as a basis for potential future studies.
Tumor infiltrating lymphocytes are found in many tumors and are thought to be a marker of 
an immune response against the tumor. Cancers with high levels of infiltrating lymphocytes 
may benefit from checkpoint blockade. In TNBC and ovarian cancer, lymphocytic 
infiltration has been shown to be a strong prognostic factor (Loi et al, 2013; Sato et al, 2005; 
Leffers et al, 2009). Similarly, cancers with MSI are also known to harbor high 
levels of infiltrating lymphocytes targeting frame-shift peptides associated with MSI 
(Schwitalle et al, 2008). Ultimately, even in those patients with high levels of TILs, the 
underlying malignancy will usually recur and lead to death. This may suggest that although 
an immune response to the tumor has begun, there may be immune regulatory mechanisms 
hindering the antitumor response. These tumors may represent populations that could benefit 
from anti-PD-L1 therapy. 
Preclinical evidence suggests that anti-PD-1/PD-L1 therapy may be beneficial in GBM, 
particularly in combination with radiotherapy (Zeng et al, 2013). Clinical data also show that 
immune checkpoint blockade with an anti-CTLA-4 MAb is active in patients with brain 
metastases, suggesting that immune recognition of cancer within the central nervous system 
(CNS) is possible. (Queirolo et al, 2014). 
Current experience with immunotherapies suggests that only a subset of any given patient 
population is likely to benefit from treatment and that it might be beneficial to enrich the 


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patient population by selecting patients likely to respond to therapy. Independent data from 
multiple sources using different assays and scoring methods suggest that PD-L1 expression 
on tumor cells and/or tumor-infiltrating cells may be associated with greater clinical benefit 
in response to treatment with single agent anti-PD-1/PD-L1 agents: 
•
PD-L1 expression has been shown to correlate with clinical outcomes (ORR, 
progression-free survival [PFS], OS) in subjects with NSCLC treated with anti-
PD-1/PD-L1 antibodies including pembrolizumab, nivolumab, atezolizumab, or 
MEDI4736 (Garon et al, 2015; Borghaei et al, 2015; Vansteenkiste et al, 2015; 
Besse et al, 2015; Rizvi et al, 2015). 
•
Similarly, PD-L1 expression has been shown to correlate with ORR, PFS, and OS in 
subjects with UBC treated with atezolizumab (Rosenberg et al, 2015). 
 
-L1 expression may correlate with ORR in subjects treated with 
 
The totality of the emerging data suggest that PD-L1 expression may improve the probability 
and/or quality of response to single agent PD-1/PD-L1 pathway inhibitors, and therefore may 
have merit as an enrichment tool. The tumor types included in the expansion phase are 
thought to express PD-L1 over a broad range of frequencies and will allow for an exploration 
of the correlation between tumor expression of PD-L1 and the clinical activity of MEDI4736. 
Access to fresh tumor biopsies and archival tumor tissue in the dose-expansion phase will 
support exploration of potential biomarkers of response, including PD-L1, for MEDI4736. 
Based on currently available data from patients treated with MEDI4736 and similar 
molecules, clinical outcomes in UBC appear to correlate with PD-L1 expression. Data from 
the recently presented Phase 2 study of atezolizumab in previously treated UBC suggest that 
patients with tumors defined as IC 2/3 by the Ventana SP142 IHC assay (ie, ≥ 5% of immune 
cells staining positive for PD-L1) , achieved higher ORR (27%) and improved OS compared 
to those patients with tumors defined as IC 1 (≥ 1% but < 5% immune cell staining; 
ORR = 10%) or IC 0 (< 1% immune cell staining; ORR = 9%). In this study population, 
100 of 311 subjects (32%) were defined as IC 2/3, while 211 of 311 subjects (68%) were
defined as IC 0 or IC 1. The data available from Study 1108 also support the hypothesis that 
PD-L1 expression may be useful as a selection strategy to identify UBC patients most likely 
to benefit from treatment with MEDI4736. Based on initial prevalence data from the study, it 
is estimated that approximately 60% of UBC subjects may be classified as PD-L1-positive as 
defined by ≥25% staining in either tumor cells or immune cells. Validation of a PD-L1 
expression biomarker cutoff is warranted to allow for selection of UBC patients most likely 
to benefit from treatment with MEDI4736 alone and will inform ongoing registrational 
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The study will also allow for retreatment with MEDI4736 upon evidence of PD. 
Demonstration of any clinical benefit with reinduction in the absence of significant AEs 
would suggest that future studies should include a similar treatment option.
The secondary endpoint of antitumor activity will be assessed according to RECIST v1.1 
guidelines with modifications. Response to immunotherapy may differ 
from typical responses observed with cytotoxic chemotherapy including the following 
(Wolchok et al, 2009):
1. Response to immunotherapy may be delayed
2. Response to immunotherapy may occur after PD by conventional criteria
3. The appearance of new lesions may not represent PD with immunotherapy
4. Stable disease while on immunotherapy may be durable and represent clinical benefit
To account for these differences, the RECIST criteria will be modified so that PD must be 
confirmed at least 4 weeks after the initial assessment of PD in the absence of clinical 
deterioration. Treatment with MEDI4736 will continue between the initial assessment of 
progression and confirmation for progression. In addition, subjects may continue to receive 
MEDI4736 beyond confirmed PD in the absence of clinical deterioration (see Section 5.2.6) 
and if investigators consider that subjects continue to receive benefit from treatment. In the 
absence of clinical deterioration, RECIST criteria with such modifications may discourage 
the early discontinuation of MEDI4736 and provide a more complete evaluation of its 
antitumor activity than would be seen with conventional response criteria.
The starting dose of 0.1 mg/kg to be evaluated in this FTIH study was selected to provide a 
potentially pharmacologically active dose with transient PD-L1 suppression and was 
approximately 1/30 of the maximum recommended starting dose (MRSD). 
 
 
 
 
The dose-escalation scheme of 0.1, 0.3, 1.0, 3.0, and 10 mg/kg MEDI4736 was designed to 
rapidly achieve dose levels at which clinical activity may be observed while maintaining an 
adequate safety margin. The range of doses selected was based on predicted PD-L1 
suppression and considerable safety margins in relation to the NOAEL.


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While both Q2W and Q3W dosing schedules are supported based on PK modeling data
derived from the nonclinical and clinical studies performed to date, the Q2W dosing schedule 
will be taken into the dose-expansion phase first.
 
 
This dosing regimen is expected to 
offer the opportunity to observe a clinical response in subjects with a variety of solid tumor 
malignancies.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4
STUDY PROCEDURES
4.1
Subject Participation and Identification
Study participation begins once written informed consent is obtained (see Section 10.3 for 
details). Once informed consent is obtained, a subject identification (SID) number will be 
assigned by a central system (eg, an interactive voice/web response system [IVRS/IWRS]), 
and the screening evaluations may begin to assess study eligibility (inclusion/exclusion) 
criteria. The SID number will be used to identify the subject during the screening process and 
throughout study participation, if applicable.
A master log of all consented subjects will be maintained at the site and will document all 
screening failures (ie, subjects who are consented but do not meet study eligibility criteria) 
including the reason(s) for screening failure (see Section 9.1 for details).
4.2
Subject Selection and Withdrawal
The subjects in this study will be adults 18 years of age or older. Subjects in the 
dose-escalation phase will have advanced melanoma, RCC, NSCLC, or CRC refractory to 
standard therapy or for which no standard therapy exists. Subjects in the dose-exploration 
cohort will be adults with advanced cutaneous melanoma, uveal melanoma, HCC, SCCHN, 
NSCLC squamous histology, NSCLC non-squamous histology, gastroesophageal cancer, 
TNBC, or pancreatic adenocarcinoma. Subjects in the dose-expansion phase of the study will 
be adults with advanced cutaneous melanoma, uveal melanoma, HCC, SCCHN, NSCLC 
squamous histology, NSCLC non-squamous histology, gastroesophageal cancer, TNBC, 
pancreatic adenocarcinoma, UBC, GBM, ovarian cancer, soft tissue sarcoma, SCLC, MSI-
high cancers, HPV-positive cancers, or nasopharyngeal carcinoma. If approved first-line 
standard therapy is available, subjects in the dose-expansion phase must have failed, be 
intolerant to, be ineligible for, or have refused treatment.
The investigator (physician) or qualified designee will discuss the study with a subject/the 
legal representative of a subject who is considered a potential candidate for the study and 
provide the subject/legal representative with the study-specific informed consent form(s) 
(ICF[s]) approved by the IRB/IEC. The investigator or designee will address any questions 
and/or concerns that the subject/legal representative may have and, if there is continued 
interest, will secure written informed consent for participation in the study. Written informed 
consent and any locally-required authorization (eg, Health Insurance Portability and 
Accountability Act [HIPAA] authorization in the USA, European Union [EU] Data Privacy 
Directive authorization in the EU), will be obtained prior to conducting any protocol-specific 


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procedures, including screening evaluations or medication washouts. See Section 10.3 for 
additional details concerning informed consent.
4.2.1
Inclusion Criteria
Subjects must meet all of the following criteria:
1. Written informed consent and any locally-required authorization (eg, HIPAA in the USA, 
EU Data Privacy Directive in the EU) obtained from the subject/legal representative prior 
to performing any protocol-related procedures, including screening evaluations
2. In the dose-escalation phase: histologically- or cytologically-confirmed advanced 
melanoma, RCC, NSCLC, or CRC that is refractory to standard therapy and for which no 
standard therapy exists
3. In the dose-expansion phase: histologically or cytologically confirmed advanced 
cutaneous melanoma, uveal melanoma, HCC, SCCHN, NSCLC squamous and non-
squamous histology, gastroesophageal cancer, TNBC, pancreatic adenocarcinoma, UBC, 
GBM, epithelial ovarian cancer, soft tissue sarcoma (excluding gastrointestinal stromal 
tumor), SCLC, MSI-high cancers, HPV-positive cancers, or nasopharyngeal carcinoma 
4. HCC subjects must be of Child-Pugh class A (not amenable to or refractory to 
locoregional therapy). Subjects with HCC associated with hepatitis B virus must be 
receiving adequate antiviral therapy
5. UBC cohort: Subjects must have histologically or cytologically confirmed inoperable or 
metastatic transitional cell (including transitional cell and mixed transitional cell/non-
transitional cell histologies) carcinoma of the urothelium (including the urinary bladder, 
ureter, urethra, and renal pelvis). 
a.
Subjects must have received and have progressed or are refractory to at least 1 but not 
more than 2 prior lines of systemic therapy for inoperable or metastatic disease, 
including a standard platinum-based regimen. Interval progression between 2 lines of 
therapy defines separate lines of therapy. Prior definitive chemoradiation for locally 
advanced disease, adjuvant treatment, or neoadjuvant treatment will be considered a 
prior line of therapy, provided that progression has occurred < 12 months from 
therapy [for chemoradiation and adjuvant treatment] or < 12 months from surgery [for 
neoadjuvant treatment].
6. Subjects with histologically or cytologically documented NSCLC must present with 
Stage IIIB/ Stage IV disease (according to version 7 of the International Association for 
the Study of Lung Cancer Staging Manual in Thoracic Oncology), or with recurrent or 
progressive disease following multimodal therapy (radiation therapy, surgical resection, 
or definitive chemoradiation therapy) for locally advanced disease
a.
For advanced stage NSCLC, maintenance therapy following platinum doublet-based 
chemotherapy is not considered as a separate regimen of therapy.
b. Prior platinum containing neoadjuvant chemotherapy for operable disease, adjuvant 
chemotherapy for completely resected disease or definitive chemoradiation therapy 
given for locally advanced disease is not considered a separate regimen of therapy.


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c.
For first-line therapy NSCLC cohorts: Subjects must not have received prior 
chemotherapy or systemic anti-neoplastic therapy (eg, tyrosine kinase inhibitor [TKI], 
MAb therapy) for advanced disease. Prior surgery and/or localized irradiation are 
permitted. 
d. For second-line therapy NSCLC cohorts: Subjects without known sensitizing 
epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase 
(ALK) rearrangements must have experienced disease progression or recurrence 
following one prior platinum based doublet chemotherapy for advanced disease. 
Subjects with sensitizing EGFR mutations or ALK rearrangements must have 
experienced disease progression or recurrence following either a TKI therapy or prior 
platinum based doublet chemotherapy for advanced disease.
e.
For third-line or greater therapy NSCLC cohorts: Subjects must have experienced 
disease progression or recurrence after both a platinum-doublet based chemotherapy 
regimen and at least 1 additional systemic therapy for advanced disease. For subjects 
with sensitizing EGFR mutations or ALK rearrangements, the additional therapy 
must include a TKI therapy. Additional therapies are defined as agents that are US 
FDA- or European Medicine Agency-approved for use after a prior regimen, given as 
monotherapy or in combination; or vinorelbine- or gemcitabine-containing regimens 
given as part of locally accepted standard-of-care, for subjects who are not candidates 
for docetaxel. 
f.
For subjects in the Q4W dose-exploration cohort, subjects are eligible if they meet 
any of the criteria for first-line, second-line, or third-line or greater therapy as 
described in 5c, 5d, or 5e above.
7. Subjects with SCCHN must have disease that is either metastatic or recurrent and deemed 
to be incurable by the investigator (subjects who refuse radical resection for recurrent 
disease are eligible). 
8. MSI-high cancers must have defective DNA mismatch repair by either: 
a.
High-frequency microsatellite instability with changes detected in 2 or more panels of 
microsatellite markers (BAT-25, BAT-26, NR-21, NR-24 and MONO-27); OR, 
b. Immunohistochemical analysis demonstrating absence of protein expression of any 1 
or more of the following proteins: MLH1, MSH2, MSH6, PMS2.
9. Subjects with HPV-positive cancers are eligible if they have a confirmed HPV-positive 
tumor by local laboratory. Subjects with HPV-positive SCCHN are only eligible for the 
SCCHN specific cohort. No more than 10 subjects with cervical cancer will initially be 
enrolled in this cohort
10. GBM cohort: Subjects with GBM must not have significant edema or shift from midline 
by intracranial imaging, or be symptomatic due to edema. A minimum of 10 subjects 
without O6-methylguanine-DNA methyltransferase promoter methylation will be enrolled 
in the GBM cohort
11. Epithelial ovarian cancer cohort: A minimum of 10 subjects with platinum sensitivity will 
be enrolled in the ovarian cancer cohort
12. If an approved first-line standard therapy is available, subjects must have failed, be 
intolerant to, be ineligible for, or have refused treatment


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13. Progressive disease as assessed by the investigator or treatment naïve at the time of study 
entry
14. Tumoral PD-L1 expression requirements are as follows:
a.
HCC, gastroesophageal cancer, TNBC, GBM, ovarian cancer, soft tissue sarcoma, 
SCLC, HPV-positive cancers, pancreatic adenocarcinoma, and nasopharyngeal 
carcinoma dose-expansion cohorts: after the first 20-40 subjects in each cohort are 
enrolled, additional subjects in the applicable cohorts may be required to have 
tumoral PD-L1 expression as determined by prospective testing prior to enrollment
b. Under previous versions of this protocol, a minimum of 5-10 SCCHN subjects were 
required to have tumoral PD-L1 expression. That requirement has been met, and 
enrollment into this cohort is complete
c.
NSCLC (squamous and non-squamous) dose-expansion cohorts:
▪
Non-squamous NSCLC: all remaining subjects to be enrolled will be required to 
have tumoral PD-L1 expression as determined by prospective testing prior to 
enrollment
▪
Squamous NSCLC: A minimum of 10 subjects in the first-line therapy cohort, 
and a minimum of 35 subjects in each of the second-line therapy and third-line or 
greater therapy cohorts will be required to have tumoral PD-L1 expression as 
determined by prospective testing prior to enrollment
d. UBC cohort:
▪
Subjects must consent to provide an archived tumor specimen from within 
6 months prior to study entry (ie, from subject signing consent to participate in the 
study) for PD-L1 IHC analysis. If not available, subjects must have at least 
1 lesion amenable to biopsy and consent to provide a pre-treatment fresh biopsy; 
tumor lesions planned for biopsy should not be lesions used as RECIST target 
lesions. Tumor tissue for PD-L1 analysis must be shipped to, and confirmed as 
received by, the Sponsor or designated central vendor prior to the first dose of 
investigational product. However, subjects may be dosed before PD-L1 results are 
known. It is highly recommended that efforts are taken to confirm presence of 
tumor cells within the tumor sample prior to shipping for PD-L1 analysis. In 
addition to the tumor tissue required for PD-L1 analysis, subjects in the UBC 
cohort must also provide additional older archival tissue regardless of age, if 
available.
15. Age ≥ 18 years at time of study entry
16. Females of childbearing potential who are sexually active with a nonsterilized male 
partner must use 2 methods of contraception, at least one of which must be highly 
effective, from screening, and must agree to continue using such precautions for 90 days 
after the final dose of MEDI4736; cessation of birth control after this point should be 
discussed with a responsible physician. Not engaging in sexual activity for the total 
duration of the drug treatment and the drug washout period is an acceptable practice; 
however, periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of birth control
a.
Females of childbearing potential are defined as those who are not surgically sterile 
(ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 


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postmenopausal (defined as 12 months with no menses without an alternative medical 
cause)
b. Subjects must use 2 acceptable methods of effective contraception, at least one of 
which is highly effective, as described in Table 4.2.1-1
c.
Female subjects should also refrain from breastfeeding throughout this period
17. Nonsterilized males who are sexually active with a female partner of childbearing 
potential must use a male condom with spermicide and another highly effective method 
of contraception (see Table 4.2.1-1) from Day 1 and for 90 days after receipt of the final 
dose of investigational product. Not engaging in sexual activity is an acceptable practice; 
however, occasional abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception.  Male subjects should refrain from sperm donation 
throughout this period
18. Eastern Cooperative Oncology Group (ECOG) status of 0 or 1
19. Adequate organ and marrow function as defined below (without growth factor or 
transfusion support within 28 days prior to first dose of investigational product):
a.
Hemoglobin ≥ 9 g/dL
b. Absolute neutrophil count ≥ 1,500/mm3
c.
Platelet count ≥ 100,000/mm3
d. AST and ALT ≤2.5 × institutional upper limit of normal (ULN); for subjects with 
HCC or liver metastases, AST or ALT ≤5 × ULN 
e.
Bilirubin ≤ 1.5 × ULN; for subjects with HCC or subjects with documented/suspected 
Gilbert’s disease, bilirubin ≤ 3 × ULN 
f.
Creatinine clearance ≥ 50 mL/min (or ≥ 30 mL/min for subjects with UBC) as 
determined by the Cockcroft-Gault equation (Cockcroft and Gault, 1976) or by 
24-hour urine collection for determination of creatinine clearance
20. Subjects must have at least 1 measurable lesion per RECIST v1.1 guidelines or per 
RANO guidelines (Wen et al, 2010) for subjects with GBM
a.
A previously irradiated lesion can be considered a target lesion if the lesion is well 
defined, measurable per RECIST v1.1, and there is objective evidence of interval 
increase in size
b. For subjects in the UBC cohort, measurable disease per RECIST v1.1 must be 
confirmed by BICR prior to enrollment
21. Available unstained archived tumor tissue sample in sufficient quantity to allow for 
pharmacodynamic analyses. Note: a biopsy must be performed for all subjects for which 
suitable archived tumor sample is not available (eg, recently diagnosed subjects or 
diagnosed with fine needle aspiration). In addition to the tumor tissue requirements 
specified in inclusion criterion 14d, subjects in the UBC cohort must also provide
additional older archival tissue regardless of age, if available. (See inclusion criterion 14d 
for tissue requirements for the UBC cohort.)
22. Life expectancy ≥ 16 weeks
23. At least 1 lesion amenable to biopsy (dose-expansion phase only, excluding GBM 
subjects) as described in Section 5.2.7.2. See inclusion criterion 14d for tissue 
requirements for the UBC cohort. 


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24. Willingness to provide consent for biopsy samples (dose-expansion phase only). Tumor 
biopsies will be required for all subjects as described in Section 5.2.7.2. Tumor lesions 
planned for biopsy should not be lesions used as RECIST target lesions. Note: biopsies 
are optional for subjects with GBM. If a biopsy is not performed for GBM subjects, an 
archival tissue sample will be required for study entry. Note: for subjects in the UBC 
cohort, this requirement does not apply if an archival tumor sample from within 6 months 
prior to study entry has been provided
25. In the dose-exploration cohort: histologically or cytologically confirmed advanced 
cutaneous melanoma, uveal melanoma, HCC, SCCHN, NSCLC squamous and non-
squamous histology, gastroesophageal cancer, TNBC, or pancreatic adenocarcinoma
Table 4.2.1-1
Highly Effective Methods of Contraception (< 1% Failure 
Rate)
Barrier/Intrauterine Methods
Hormonal Methods
•
Copper T intrauterine device
•
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®) a
Etonogestrel implants; eg, Implanon or Norplan
•
Intravaginal device; eg, ethinylestradiol and 
etonogestrel
•
Medroxyprogesterone injection: e.g. Depo-Provera 
•
Normal and low dose combined oral contraceptive pill
•
Norelgestromin/ethinylestradiol  transdermal system
•
Cerazette (desogestrel)
Note: A highly effective method of contraception is defined as one that results in a low failure rate (ie, less than 
1% per year) when used consistently and correctly. Note that some contraception methods are not considered 
highly effective (eg, male or female condom with or without spermicide; female cap, diaphragm, or sponge with 
or without spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal contraceptive 
pills where inhibition of ovulation is not the primary mode of action [excluding Cerazette/desogestrel which is 
considered highly effective]; and triphasic combined oral contraceptive pills).
a
This is also considered a hormonal method.
4.2.2
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
1. Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study or the follow-up period of an interventional study
2. Receipt of any immunotherapy, BRAF inhibitor (in cutaneous melanoma and uveal 
melanoma subjects), or investigational anticancer therapy within 4 weeks prior to the first 
dose of MEDI4736; in the case of MAbs (for investigational use or immunotherapy), 
6 weeks prior to the first dose of MEDI4736
3. Any prior Grade ≥ 3 irAE while receiving immunotherapy, including anti-CTLA-4 
treatment, or any unresolved irAE > Grade 1.
4. For all subjects, prior exposure to any anti-PD-1 or anti-PD-L1 antibody. For subjects in 
the UBC cohort, prior treatment with immunotherapy agents including, but not limited to, 
tumor necrosis factor receptor superfamily agonists or checkpoint inhibitors or natural 


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killer (NK) cell inhibitors including agents targeting KIR, PD-1, PD-L1, CTLA-4, OX40, 
CD27, CD137 (4-1BB), CD357 (GITR), and CD40. Prior treatment with Bacillus 
Calmette-Guerin therapy is permitted.
5. Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer 
treatment. Concurrent use of hormones for non-cancer-related conditions (eg, insulin for 
diabetes and hormone replacement therapy) is acceptable. 
Note: Local treatment of isolated lesions for palliative intent is acceptable (eg, by local 
surgery or radiotherapy)
6. Current or prior use of immunosuppressive medication within 28 days before the first 
dose of MEDI4736, with the exceptions of intranasal, topical, and inhaled corticosteroids 
or systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or 
equivalent (2 mg/day of dexamethasone or equivalent for subjects with GBM). Subjects 
with GBM must be on a stable dose of steroids for ≥7 days prior to study entry and prior 
to baseline imaging
7. Active or prior documented autoimmune disease within the past 2 years 
Note: Subjects with vitiligo, Grave’s disease, Hashimoto’s disease, or psoriasis not 
requiring systemic treatment (within the past 2 years) are not excluded
8. Active or prior documented inflammatory bowel disease (eg, Crohn’s disease, ulcerative 
colitis)
9. History of primary immunodeficiency
10. History of organ transplant that requires use of immunosuppressives
11. Known allergy or reaction to any component of the MEDI4736 formulation.
12. Untreated CNS metastatic disease, leptomeningeal disease, or cord compression. Note: 
Subjects previously treated for CNS metastases that are radiographically and 
neurologically stable for at least 42 days and do not require corticosteroids (of any dose) 
for symptomatic management for at least 14 days prior to the first dose of MEDI4736 are 
not excluded.
13. Other invasive malignancy within 2 years except for noninvasive malignancies such as 
cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductal carcinoma 
in situ of the breast that has/have been surgically cured. Cancer subjects with incidental 
histologic findings of prostate cancer that, in the opinion of the investigator, is not 
deemed to require active therapy (eg, incidental prostate cancer identified following 
cystoprostatectomy that is tumor/node/metastasis stage ≤ pT2N0) may be enrolled, 
pending discussion and approval with the study physician.
14. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to 
National Cancer Institute’s (NCI’s) Common Terminology Criteria for Adverse Events 
(CTCAE) (NCI CTCAE v4.03) Grade 0 or 1, or to levels dictated in the 
inclusion/exclusion criteria with the exception of alopecia. Subjects with irreversible 
toxicity that is not reasonably expected to be exacerbated by MEDI4736 may be included 
(eg, hearing loss) after consultation with the MedImmune medical monitor.
15. Major surgical procedure (as defined by the investigator) within 30 days prior to the first 
dose of MEDI4736 or still recovering from prior surgery
16. Females who are pregnant or lactating 


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17. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina 
pectoris, cardiac arrhythmia, severe active peptic ulcer disease or gastritis, or psychiatric 
illness/social situations that would limit compliance with study requirement or 
compromise the ability of the subject to give written informed consent 
18. Any condition that, in the opinion of the investigator, would interfere with evaluation of 
the investigational product or interpretation of subject safety or study results
19. Known history of tuberculosis
20. Subjects who are known to be human immunodeficiency virus (HIV) positive
21. Subjects who are known to be hepatitis B or C positive, except for subjects with HCC
22. Receipt of live attenuated vaccination within 30 days prior to study entry or within 
30 days of receiving MEDI4736
23. Subjects with pancreatic adenocarcinoma must not have more than 50% of the liver 
parenchyma replaced by tumor
24. Subjects with HCC must not have a history of bleeding from esophageal varices, unless 
the varices have been treated with no active bleeding within 30 days prior to the first dose 
of MEDI4736
25. Prior participation in clinical studies that include MEDI4736 alone or in combination, 
where the study has registrational intent and the analyses for the primary endpoint have
not yet been completed
4.2.3
Withdrawal Criteria
Permanent discontinuation of investigational product: An individual subject will not 
receive any further investigational product if any of the following occur in the subject in 
question:
1. Withdrawal of consent or lost to follow-up
2. Adverse event that, in the opinion of the investigator or the sponsor, contraindicates 
further dosing
3. Subject is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational therapy might constitute a 
safety risk
4. Pregnancy or intent to become pregnant
5. Any AE that meets criteria for discontinuation as defined in Appendix 15
6. Adverse event related to MEDI4736 that is Grade ≥ 3, with the exception of toxicities 
that do not meet criteria for discontinuation as defined in Appendix 15
7. Dose-limiting toxicity (See Section 4.5.7 for definition of DLT)
8. Grade ≥ 3 infusion reaction
9. Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal; eg, refusal to adhere to scheduled visits
10. Initiation of alternative anticancer therapy including another investigational agent


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11. Confirmation of PD and investigator determination that the subject is no longer 
benefiting from treatment with MEDI4736
Subjects who are permanently discontinued from further receipt of investigational product, 
regardless of the reason (withdrawal of consent, due to an AE, other), will be identified as 
having permanently discontinued treatment. Subjects who permanently discontinue treatment 
may either be considered to have completed the study or not to have completed the study 
(see Section 4.7).
Subjects who are permanently discontinued from receiving investigational product will be 
followed for safety per Section 6.4, including the collection of any protocol-specified blood 
specimens, unless consent is withdrawn or the subject is lost to follow-up or enrolled in 
another clinical study. All subjects will be followed for survival. Subjects who decline to 
return to the site for evaluations will be offered follow-up by phone every 3 months as an 
alternative.
Withdrawal of consent: If consent is withdrawn, the subject will not receive any further 
investigational product or further study observation. Note that the subject may be offered 
additional tests or tapering of treatment to withdraw safely.
Lost to follow-up: Subjects will be considered lost to follow-up only if no contact has been 
established by the time the study is completed (as defined in Section 4.8) such that there is 
insufficient information to determine the subject’s status at that time.
•
Note: Subjects who refuse continuing participation in the study, including phone contact, 
should be documented as “withdrawal of consent” rather than “lost to follow-up.” 
Investigators should document attempts to re-establish contact with missing subjects 
throughout the study period. If contact with a missing subject is re-established, the 
subject should not be considered lost to follow-up and any evaluations should resume 
according to the protocol.
4.2.4
Replacement of Subjects
Subjects in the dose-escalation cohorts are considered evaluable if they receive 2 doses of 
MEDI4736 or they discontinue MEDI4736 due to DLTs. Nonevaluable subjects in the 
dose-escalation cohorts will be replaced in the same dose cohort. Subjects enrolled in the 
dose-expansion or dose-exploration cohorts will not be replaced.


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4.3
Treatment Assignment
Each subject who meets the eligibility criteria will be assigned open-label investigational 
product. Investigational product (MEDI4736) must be administered within 1 business day 
after the investigational product is assigned. If there is a delay in the administration of 
investigational product such that it will not be administered within the specified timeframe, 
the study monitor must be notified immediately.
4.4
Blinding
This study is not blinded.
4.5
Study Medications
4.5.1
Investigational Products
MedImmune will provide the investigator(s) with adequate quantities of investigational 
product using designated distribution centers. MEDI4736 will be stored at 2-8°C (36-46°F) 
in a secure area with restricted access.
MEDI4736:
 
 
 
The investigator’s or site’s designated investigational product manager is required to 
maintain accurate investigational product accountability records. Upon completion of the 
study, copies of investigational product accountability records will be returned to 
MedImmune. All unused investigational product will be returned to a MedImmune-
authorized depot or disposed of upon authorization by MedImmune according to the 
investigational site policy.
4.5.1.1
Investigational Product Preparation
The dose of investigational product for administration must be prepared by the investigator’s 
or site’s designated investigational product manager using aseptic technique. Commercially 
available WFI and 0.9% (w/v) saline will be supplied by each site. Total in-use storage time 
from reconstitution of MEDI4736 to start of administration should not exceed 4 hours at 
room temperature or 24 hours at 2-8°C (36-46°F). If in-use storage time exceeds these limits, 
a new dose must be prepared from new vials. MEDI4736 does not contain preservatives and 
any unused portion must be discarded.


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Reconstitution of investigational product 
MEDI4736 requires reconstitution prior to use. The reconstitution should be performed with 
4.0 mL sterile WFI for each vial with the liquid added gently to the side of the vial to 
minimize product foaming. The vial should be gently rotated or swirled for 5 minutes or until 
dissolution is complete. The vial should not be shaken or vigorously agitated. Reconstituted 
MEDI4736 should stand undisturbed at room temperature for a minimum of 5 minutes or 
until the solution clarifies. The reconstituted solution should appear clear or slightly 
opalescent. A thin layer of bubbles on the liquid surface is considered normal.
Preparation of doses less than 1.0 mg/kg MEDI4736 for administration with a 
syringe
For IV doses less than 1.0 mg/kg, administration will be performed using a polypropylene 
syringe and IV administration set. Each dose will be administered as an admixture of 
MEDI4736 and 0.9% (w/v) saline prepared to a set volume. The delivery volume for each 
dose level is listed in Table 4.5.1.1-1. The preparation volume will include additional volume 
of admixture to allow for purging the lines of the administration set. 
Table 4.5.1.1-1
Preparation of MEDI4736 Doses Less Than 1.0 mg/kg to 
Dose for Administration by Syringe
Dose (mg/kg)
Delivery Volume (mL)
0.05
2
0.10 to 0.29
4
0.30 to 0.89
12
0.90 to 0.99
30
The dose preparation procedure is as follows:
1. Determine from Table 4.5.1.1-1 the correct delivery volume needed.
2. Calculate the amount of admixture to prepare using the formula below:
3. Preparation Volume (mL) = 
4. Delivery Volume (mL) + Hold-up Volume of Administration Set (mL)
5. Calculate the concentration of MEDI4736 in the admixture using the formula below:
6. Final Dose Concentration (mg/mL) =
7. Dose (mg/kg) × Subject Weight (kg) ÷ Delivery Volume (mL)
8. Determine the volume of reconstituted MEDI4736 (mL) to be prepared in 0.9% (w/v) 
saline required for the calculated concentration: 
9. Volume of MEDI4736 to be Diluted (mL) =


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10. Final Dose Concentration (mg/mL) × Preparation Volume (mL) ÷ Drug Product 
Concentration (nominal 50 mg/mL)
11. Determine the volume of 0.9% (w/v) saline (mL) used to dilute MEDI4736:
12. Volume of 0.9% (w/v) Saline (mL) =
13. Preparation Volume (mL) - Volume of MEDI4736 to be Diluted (mL)
The admixture should be prepared in a separate sterile container. Following preparation, the 
admixture must be mixed by gentle swirling or inversion. The admixture should then be 
inspected to ensure the solution is clear and then drawn up into the syringe. Intravenous lines 
are then purged and the specified delivery volume is administered, using a 0.2-μm in-line 
filter. Subjects in the first cohort will receive the initial infusion over approximately 4 hours. 
All remaining infusions for these subjects and other study subjects will be approximately 
60 minutes in duration. Disconnect the IV line when the correct volume has been delivered.
Example:
1. For a dose of 0.3 mg/kg, the Delivery Volume will be 12 mL.
2. The administration lines to be used have a hold-up volume of approximately 10 mL. The 
volume of admixture to prepare is 22 mL (12 mL + 10 mL)
3. The Final Dose Concentration of MEDI4736 for a subject weighing 100 kg and dosed at 
0.3 mg/kg will be 2.5 mg/mL. 
4. (0.3 mg/kg × 100 kg ÷ 12 mL)
5. The volume of reconstituted MEDI4736 required will be 1.1 mL.
6. (2.5 mg/mL × 22 mL ÷ 50 mg/mL)
7. The volume of 0.9% (w/v) saline required to dilute MEDI4736 will be 20.9 mL.
8. (22 mL - 1.1 mL)
After gentle mixing of the admixture in the syringe by gentle inversion the lines are purged 
and 12 mL is administered over the specified infusion time.
Preparation of MEDI4736 doses greater than or equal to 1.0 mg/kg and less
than or equal to 30 mg/kg for administration with an IV bag
No incompatibilities have been observed between MEDI4736 and polyethylene, polyolefin 
copolymers, or polyvinylchloride. Doses greater than or equal to 1.0 mg/kg will be 
administered using a 250 mL IV bag containing 0.9% (w/v) saline and delivered through an 
IV administration set. The volume of reconstituted MEDI4736 to add to the IV bag is 
calculated as follows:
Volume of MEDI4736 (mL) =


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Dose (mg/kg) × Subject Weight (kg) ÷ MEDI4736 Concentration (nominal 50 mg/mL)
Subject weight at baseline should be used for dosing calculations unless there is a ≥10% 
change in weight in which case the dosing day weight should be used. Dosing day weight can 
be used for dosing calculations instead of baseline weight per institutional standard. An 
additional volume of 0.9% (w/v) saline equal to the calculated volume of MEDI4736 to be 
added to the IV bag must be removed from the bag prior to addition of MEDI4736. The 
calculated volume of MEDI4736 is then added to the IV bag, and the bag is mixed by gentle 
inversion to ensure homogeneity of the dose in the bag. Following preparation of the dose, 
the entire contents of the IV bag should be administered as an IV infusion over 
approximately 60 minutes, using a 0.2-μm in-line filter. Flush the IV line with a volume of 
normal saline equal to the priming volume of the infusion set used after the contents of the 
IV bag are fully administered, or complete the infusion according to institutional policy to 
ensure the full dose is administered and document if the line was not flushed.
Example: For a subject weighing 80 kg and dosed at 10 mg/kg, 16 mL [10 mg/kg × 80 kg 
divided by 50 mg/mL] of MEDI4736 is to be diluted in a 250 mL IV bag containing 0.9% 
(w/v) saline. First, 16 mL of saline is removed from the IV bag, and then 16 mL of 
MEDI4736 is added to the bag. The bag is mixed by gentle inversion to ensure homogeneity 
of the dose in the bag and the diluted MEDI4736 is administered as described above.
4.5.2
Other Study Medications
No other study medications are specified for use in this clinical protocol.
4.5.3
Treatment Regimen
Subjects will be treated in a dose-escalation phase, dose-exploration cohort, or a dose-
expansion phase of the study.
4.5.3.1
Dose Escalation
MEDI4736 Q2W Dose-escalation Arm
Subjects enrolled in the Q2W dose-escalation arm will receive one of 5 doses of MEDI4736 
(0.1, 0.3, 1.0, 3.0, or 10 mg/kg) via IV infusion Q2W ± 3 days. Provided the MTD is not 
exceeded at the 10 mg/kg dose level, additional cohorts of 3-6 subjects using doses above 
10 mg/kg of MEDI4736 Q2W may be initiated based on PK or pharmacodynamic data 
suggesting maximal suppression of sPD-L1 is not being maintained throughout the dosing 
interval or T-cell activation has not plateaued, respectively. The rules for dose escalation 
described in Section 4.5.6 would apply in this setting. Intermediate doses may be evaluated at 


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the discretion of the sponsor based on available data. Dose modification for toxicities will be 
allowed as described in Appendix 15. 
Subjects will continue MEDI4736 Q2W treatment for 12 months or until confirmed PD, 
initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or other 
reasons to discontinue treatment occur (Figure 4.5.3.1-1). In the event of confirmed PD, 
subjects may continue to receive MEDI4736 in the absence of clinical deterioration (see 
Section 5.2.6) and if investigators consider that subjects continue to receive benefit from 
treatment.
Subjects who have achieved and maintained DC (ie, CR, PR, or SD) or clinical benefit 
through to the end of the 12-month Q2W treatment period will enter follow-up and be 
assessed according to the procedures outlined in Table 5.1-3. Upon evidence of PD during 
follow-up, subjects will be re-administered MEDI4736 at the dose previously received or at 
10 mg/kg, the dose chosen for the expansion phase via IV infusion Q2W (Appendix 13). 
Subjects may continue MEDI4736 Q2W retreatment for up to 12 months with the same 
treatment guidelines followed during the initial 12-month treatment period. Only one round 
of retreatment with MEDI4736 will be allowed. Subjects who have confirmed PD during the 
12-month Q2W initial treatment or retreatment period and cannot continue to receive 
MEDI4736 will enter follow-up for 90-day safety assessments and survival follow-up (see 
Appendix 14 for schedule of procedures).
Figure 4.5.3.1-1
Dosing Schema for MEDI4736 Q2W Dose-escalation 
Cohorts
Q2W = every 2 weeks.


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MEDI4736 Q3W Dose-escalation Arm 
Upon the completion of dose escalation for the Q2W dose-escalation arm, a separate 
dose-escalation arm of MEDI4736 administered Q3W will be initiated. This Q3W 
dose-escalation arm will be carried out in parallel to the dose-expansion phase. The first 
cohort of subjects will receive MEDI4736 Q3W ± 3 days at the highest dose level that does 
not exceed the MTD or the OBD in the Q2W dose-escalation arm. Higher doses of 
MEDI4736 may be explored based upon acceptable safety, PK/pharmacodynamic, and 
clinical data following the rules for dose escalation described in Section 4.5.6. 
Subjects will continue MEDI4736 Q3W treatment for 12 months or until confirmed PD, 
initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or other 
reasons to discontinue treatment occur (Figure 4.5.3.1-2). In the event of confirmed PD, 
subjects may continue to receive MEDI4736 in the absence of clinical deterioration (see 
Section 5.2.6) and if investigators consider that subjects continue to receive benefit from 
treatment.
Subjects who have achieved and maintained DC (ie, CR, PR, or SD) or clinical benefit 
through the end of the 12-month Q3W treatment period will enter follow-up and be assessed 
according to the procedures outlined in Table 5.1-3. Upon evidence of PD during follow-up, 
subjects will be re-administered MEDI4736 at the highest dose previously received via 
IV infusion Q3W (Appendix 13). Subjects may continue MEDI4736 Q3W retreatment for up 
to 12 months with the same treatment guidelines followed during the initial 12-month 
treatment period. Only one round of retreatment with MEDI4736 will be allowed. Subjects 
who have confirmed PD during the 12-month Q3W initial treatment or retreatment period 
and cannot continue to receive MEDI4736 will enter follow-up for 90-day safety assessments 
and survival follow-up (see Appendix 14 for schedule of procedures).


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Figure 4.5.3.1-2
Dosing Schema for MEDI4736 Q3W Dose-escalation 
Cohorts
Q3W = every 3 weeks.
4.5.3.2
Dose Exploration 
The dose-exploration cohort of the study will be conducted in parallel with the MEDI4736 
Q2W dose-expansion phase.
Subjects with advanced cutaneous melanoma, uveal melanoma, HCC, SCCHN, NSCLC 
squamous histology, NSCLC non-squamous histology, gastroesophageal cancer, TNBC or 
pancreatic adenocarcinoma, will receive MEDI4736 Q4W via IV infusion at 20 mg/kg.
Treatment in the dose-exploration cohort will continue on a Q4W schedule for 12 months or 
until confirmed PD, initiation of alternative cancer therapy, unacceptable toxicity, 
withdrawal of consent, or other reasons to discontinue treatment occur (Figure 4.5.3.2-1). In 
the event of confirmed PD, subjects may continue to receive MEDI4736 in the absence of 
clinical deterioration (see Section 5.2.6) and if investigators consider that subjects continue to 
receive benefit from treatment.
Subjects who have achieved and maintained DC (ie, CR, PR, or SD) or clinical benefit 
through the end of the 12-month Q4W treatment period will enter follow-up and be assessed 
according to the procedures outlined in Table 5.1-3. Upon evidence of PD during follow-up, 
these subjects will be re-administered MEDI4736 at 20 mg/kg via IV infusion Q4W 
(Table 5.1-2). Rebaseline will be required using the screening visit assessments with the 
exception of consent, collecting the pathology report, and collecting an archival tumor 
sample. In addition subject must not have met discontinuation criteria. Subjects may continue 
MEDI4736 Q4W retreatment for up to 12 months with the same treatment guidelines 
followed during the initial 12-month treatment period. Only one round of retreatment with 


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MEDI4736 will be allowed. Subjects who have confirmed PD during the 12-month Q4W 
initial treatment or retreatment period and cannot continue to receive MEDI4736 will enter 
follow-up for 90-day safety assessments and survival follow-up (see Appendix 14 for 
schedule of procedures).
Figure 4.5.3.2-1
Dosing Schema for MEDI4736 Q4W Dose-exploration 
Cohort
Q4W = every 4 weeks.
4.5.3.3
Dose Expansion
The dose-expansion phase of the study will be conducted following completion of the 
MEDI4736 Q2W dose-escalation arm and in parallel with the MEDI4736 Q3W 
dose-escalation arm and Q4W dose-exploration cohort.
Subjects with advanced cutaneous melanoma, uveal melanoma, HCC, SCCHN, NSCLC 
squamous histology, NSCLC non-squamous histology, gastroesophageal cancer, TNBC, 
pancreatic adenocarcinoma, UBC, GBM, ovarian cancer, soft tissue sarcoma, SCLC, MSI-
high cancers, HPV-positive cancers, or nasopharyngeal carcinoma will receive MEDI4736 
Q2W via IV infusion at the 10 mg/kg Q2W, the dose selected for the expansion phase of the 
study.
Treatment in the dose-expansion phase will continue on a Q2W schedule for 12 months or 
until confirmed PD, initiation of alternative cancer therapy, unacceptable toxicity, 


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withdrawal of consent, or other reasons to discontinue treatment occur (Figure 4.5.3.3-1). In 
the event of confirmed PD, subjects may continue to receive MEDI4736 in the absence of 
clinical deterioration (see Section 5.2.6) and if investigators consider that subjects continue to 
receive benefit from treatment. 
Subjects who have achieved and maintained DC (ie, CR, PR, or SD) or clinical benefit 
through the end of the 12-month Q2W treatment period will enter follow-up and be assessed 
according to the procedures outlined in Table 5.1-3. Upon evidence of PD during follow-up, 
these subjects will be re-administered MEDI4736 at the dose previously received via IV 
infusion Q2W (Appendix 13). Subjects may continue MEDI4736 Q2W retreatment for up to 
12 months with the same treatment guidelines followed during the initial 12-month treatment 
period. Only one round of retreatment with MEDI4736 will be allowed. Subjects who have 
confirmed PD during the 12-month Q2W initial treatment or retreatment period and cannot 
continue to receive MEDI4736 will enter follow-up for 90-day safety assessments and 
survival follow-up (see Appendix 14 for schedule of procedures).
Figure 4.5.3.3-1
Dosing Schema for MEDI4736 Q2W Dose-expansion 
Cohorts
Q2W = every 2 weeks.
4.5.4
Treatment Administration
The first day of dosing is considered Day 1. Subjects in the first dose-escalation cohort will 
receive the first dose of MEDI4736 as an IV infusion over 4 hours and subsequent doses as 
an IV infusion over approximately 60 minutes (± 5 minutes). In the remaining 
dose-escalation and expansion cohorts, MEDI4736 will be administered as an IV infusion 
over approximately 60 minutes (± 5 minutes). When a syringe is used for the infusion, the 
syringe should be disconnected when the correct volume has been infused. When an IV bag 


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is used for the infusion, the IV line will be flushed with a volume of normal saline equal to 
the priming volume of the infusion set used after the contents of the IV bag are fully 
administered (unless prohibited by institutional practice).
Since the compatibility of MEDI4736 with other IV medications and solutions, other than 
normal saline (0.9% [w/v] Sodium Chloride for Injection), is not known, the MEDI4736 
solution should not be infused through an IV line in which other solutions or medications are 
being administered. The date, start time, interruption, and completion time of MEDI4736 
administration must be recorded in the source documents.
4.5.5
Monitoring of Dose Administration 
Subjects will be monitored during and after the first infusion of MEDI4736 with assessment 
of vital signs within an hour prior to the start of the infusion, every 15 minutes (± 5 minutes) 
during the infusion, at the end of infusion (+ 5 minutes) and at 30 minutes (± 5 minutes) and 
60 minutes (± 5 minutes) postinfusion, followed by a 3-hour (± 15 minutes) period of 
observation. For subsequent doses (at dose levels of 10 mg/kg or less), the 3-hour 
observation period will not be required unless a subject experiences an infusion-related 
reaction or a higher dose level is being tested. The 3-hour observation period, however, will 
be required for the first 4 doses for any dose level > 10mg/kg (Q2W or Q3W) and for 
subjects in the 20 mg/kg Q4W dose-exploration cohort.
Acetaminophen and/or an antihistamine (eg, diphenhydramine) or equivalent medications per 
institutional standard may be administered prior to infusion at the discretion of the 
investigator for primary prophylaxis against infusion-related reactions. In the event of Grade 
≤2 infusion-related reaction, the infusion rate of MEDI4736 may be decreased by 50% or 
interrupted until resolution of the event (up to 4 hours) and re-initiated at 50% of the initial 
rate until completion of the infusion. In subjects experiencing Grade ≤2 infusion-related 
reaction, subsequent infusions may be administered at 50% of the initial rate. If a subject 
experiences an infusion-related reaction, acetaminophen and/or an antihistamine (eg, 
diphenhydramine) and/or corticosteroid or equivalent medications per institutional standard 
may be administered prior to subsequent infusions at the discretion of the investigator for 
secondary prophylaxis of infusion-related reactions. If the infusion-related reaction is Grade 
3 or higher in severity, treatment with MEDI4736 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


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site must have immediate access to emergency resuscitation teams and equipment in addition 
to the ability to admit subjects to an intensive care unit if necessary.
4.5.6
Dose Escalation
In the dose-escalation phase, the first dose of MEDI4736 will be administered to all subjects 
in the first cohort as a 0.1 mg/kg infusion given over 4 hours. Subsequent infusions (2nd and 
3rd doses, etc) for the first cohort will be given over approximately 60 minutes Q2W. The 
doses for subsequent cohorts will be 0.3, 1.0, 3.0, or 10 mg/kg, administered over 
approximately 60 minutes as an IV infusion Q2W unless an MTD or OBD is identified 
before all dose-escalation cohorts are completed. Higher doses may be further explored based 
on clinical, safety, and PK/pharmacodynamic data generated from the study. If 2 or more 
DLTs are observed in the first dose cohort, the dose will be de-escalated to half of the 
starting dose (0.05 mg/kg) and will be given Q3W.
Upon completion of dose escalation for the MEDI4736 Q2W dose-escalation arm, a separate 
Q3W dose-escalation arm will be initiated in parallel with the dose-expansion phase. The 
dose planned for the first Q3W escalation cohort is the dose that is the equivalent dosing rate 
(in average mg/kg/week) to the OBD or highest dose tested if an OBD was not identified. A 
lower dose may be used pending review of available data. For example, if dose escalation 
proceeds to 10 mg/kg Q2W, the planned starting dose in the Q3W dose escalation will be 
15 mg/kg Q3W.
If an MTD is reached prior to completing the Q2W dose escalation, the Q3W starting dose 
will be the equivalent dosing rate to the Q2W MTD. For example, if an MTD is identified at 
3.0 mg/kg Q2W, the starting dose in the Q3W dose escalation will be approximately 
4.5 mg/kg Q3W. The Q3W dose escalation will proceed based upon on available data. 
Additional MEDI4736 Q3W cohorts with 3-6 subjects each may be initiated based on 
acceptable clinical, safety, and PK/pharmacodynamic data following the rules for dose 
escalation described below. Because the DLT evaluation period for this study includes 
2 doses of MEDI4736, the timing of any toxicities observed during the Q2W escalation will 
be important in determining the maximum dose level to be evaluated in the Q3W escalation. 
If DLTs defining the Q2W MTD are observed prior to the second dose of MEDI4736, the 
Q3W dose escalation may not proceed past the Q2W MTD dose level. However, if the DLTs 
defining the Q2W MTD are observed after the second dose of MEDI4736, the Q3W dose 
escalation may proceed beyond the Q2W MTD.


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Rules for dose escalation are as follows:
1. The MTD will be determined based on the assessment of DLT (as defined in 
Section 4.5.7) during the DLT evaluation period, which is defined as the period from 
administration of the first dose of MEDI4736 until the planned administration of the third 
dose. Subjects are considered evaluable for assessment of DLT if they receive 2 full 
assigned doses of MEDI4736, or the subject experiences any DLT. Nonevaluable 
subjects will be replaced in the same dose cohort.
2. A minimum of 3 subjects will be enrolled in each dose cohort. 
3. The administration of MEDI4736 to the first and second subjects of each cohort will be 
separated by at least 24 hours.
4. Dose escalation to the next dose level is permitted only after the subject(s) enrolled in the 
current dose cohort have competed the DLT observation period and all safety data have 
been reviewed by a study-specific dose-escalation committee.
5. If 1 of the 3 subjects in any dose cohort experiences a DLT, that dose cohort will be 
expanded to a total of 6 subjects. If no more than 1 of 6 subjects in the cohort experiences 
a DLT, dose escalation may proceed.
6. If 2 or more subjects in a dose cohort experience a DLT during the DLT evaluation 
period, the MTD will be exceeded and no further subjects will be enrolled into that dose 
cohort. If this occurs, the preceding dose cohort will be evaluated for the MTD and a total 
of 6 subjects will be treated at the preceding dose. If no more than 1 of 6 subjects 
experiences a DLT at the preceding dose, then that dose level will be the MTD.
7. At the discretion of the sponsor, dose escalation may be stopped before an MTD is 
reached. In this case, the OBD may be chosen based on an assessment of PK, 
pharmacodynamic, biomarker, safety, and response data. An MTD does not have to be 
reached to expand a dose cohort if the available data demonstrate that a lower dose level 
may provide antitumor activity while minimizing potential risk.
8. Upon completion of the Q2W dose escalation, the cohort with either the highest dose 
level shown to be well tolerated or the OBD will be expanded to a total of 6 subjects (if 
not already done due to observation of a DLT).
9. A separate, Q3W dose escalation will be initiated following the completion of dose 
escalation for the Q2W dose-escalation arm and at the same time as the dose-expansion 
phase. Dose escalation will begin with the highest dose level that has not exceeded the 
MTD or the OBD in the Q2W dose-escalation arm and proceed as per the rules outlined 
above.
10. Upon completion of the Q3W dose escalation, the cohort with either the highest dose 
level that does not exceed the MTD or the OBD will be expanded to a total of 6 subjects 
(if not already done due to observation of a DLT).
4.5.7
Dose-limiting Toxicity
Dose-limiting toxicities will be evaluated during the dose-escalation phase. The period for 
evaluating DLTs will be from the time of first administration of MEDI4736 until the planned 
administration of the third dose of MEDI4736. Subjects who do not remain on the study up 


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to this time for reasons other than DLT will be replaced with another subject at the same dose 
level. Grading of DLTs will be according to the NCI CTCAE v4.03.
A DLT will be defined as any Grade 3 or higher treatment-related toxicity that occurs during 
the DLT evaluation period, including
•
Any Grade ≥ 3 colitis 
•
Any Grade ≥ 3 irAE including rash, pruritus, or diarrhea that does not downgrade to 
Grade ≤2 within 3 days after onset of the event despite maximal supportive care 
including systemic corticosteroids 
The definition excludes the following conditions: 
•
Grade 3 decrease in lymphocyte count or increase in GGT that downgrades to Grade ≤2 
within 7 days after onset of the event and resolves to Grade ≤ 1 or baseline within 
14 days
•
Grade 3 endocrinopathy that is managed with or without systemic corticosteroid therapy 
and/or hormone replacement therapy and the following criterion is met:
◦
The subject is asymptomatic
•
Grade 3 inflammatory reaction attributed to a local antitumor response (eg, inflammatory 
reaction at sites of metastatic disease, lymph nodes, etc) 
Immune-related AEs are defined as AEs of immune nature (ie, inflammatory) in the absence 
of a clear alternative etiology. In the absence of clinical abnormality, repeat laboratory 
testing will be conducted to confirm significant laboratory findings prior to designation as a 
DLT.
4.5.8
Dose Modification for Toxicity Management
Based on the mechanism of action of MEDI4736 leading to T-cell activation and 
proliferation, there is the possibility of observing irAEs during the conduct of this study. 
Potential irAEs may be similar to those seen with the use of ipilimumab and nivolumab, and 
may include immune-mediated enterocolitis, dermatitis, pneumonitis, hepatitis 
(hepatotoxicity), neurotoxicity, and endocrinopathies (Hodi et al, 2010; Brahmer et al, 2012; 
Topalian et al, 2012; Wolchok et al, 2013). Subjects should be monitored for signs and 
symptoms of irAEs in any organ. In the absence of an alternate etiology (eg, infection or 
PD), an immune-related etiology should be considered for signs or symptoms of colitis, 
pneumonitis, hepatitis/hepatotoxicity, neuropathy/neuromuscular toxicity, endocrinopathy, 
dermatitis, and nephritis.


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All toxicities will be graded according to NCI CTCAE v4.03. 
Treatment modifications will not be required for AEs that are clearly not attributed to 
MEDI4736 (such as an accident) or for laboratory abnormalities that are not deemed to be 
clinically significant. Dose reductions are not permitted. Dose modification and management 
guidelines are provided in Appendix 15. Dosing may continue despite concurrent vitiligo of 
any AE grade.
4.5.9
Treatment Compliance
Investigational product is administered by study site personnel, who will monitor subject 
compliance.
4.6
Concomitant Medications
4.6.1
Permitted Concomitant Medications
Investigators may prescribe concomitant medications or treatments (eg, acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care 
except for those medications identified as “excluded” as listed in Section 4.6.2.
4.6.2
Excluded Concomitant Medications
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator.
The following medications are considered exclusionary during the study. The sponsor must 
be notified if a subject receives any of these during the study.
1. Any investigational anticancer therapy
2. Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic, or hormonal 
therapy for cancer treatment. Concurrent use of hormones for noncancer-related 
conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable. 
Note: Local treatment of isolated lesions for palliative intent is acceptable (eg, by local 
surgery or radiotherapy)
3. Immunosuppressive medications including, but not limited to systemic corticosteroids at 
doses beyond 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and 
tumor necrosis factor alpha (TNF-α) blockers. Use of immunosuppressive medications 
for the management of investigational product-related AEs and in subjects with contrast 
allergies is acceptable. In addition, use of inhaled, topical, and intranasal corticosteroids 
is permitted. Temporary courses of corticosteroids for treatment of underlying or 
concurrent illness or in the setting of palliative radiotherapy may be permitted upon 
discussion with the medical monitor. 


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4. Live attenuated vaccines within 30 days of MEDI4736 dosing
4.7
Subject Completion
An individual subject will be considered to have completed the study if the subject was 
followed up through the end of the study as defined in Section 4.8, regardless of the number 
of doses of investigational product that was received.
Subjects will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow-up (see Section 4.2.3).
4.8
End of the Study
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last subject in the study or the date the 
study is closed by the sponsor, whichever occurs first. All materials or supplies provided by 
the sponsor will be returned to the sponsor or designee upon study completion, as directed by 
the site monitor. The investigator will notify the IRB/IEC when the study has been 
completed.
5
STUDY PROCEDURES
5.1
Schedule of Study Procedures
All subjects who are assigned an SID number and receive any investigational product will be 
followed according to the protocol regardless of the number of doses received, unless consent 
is withdrawn. The investigator must notify the sponsor or designee of deviations from 
protocol visits or evaluations and these evaluations, if applicable, must be rescheduled or 
performed at the nearest possible time to the original schedule. Protocol deviations will be 
recorded on the source document with an explanation for the deviation and any study-
specific case report forms (CRFs) or logs designated for capturing protocol deviations, if 
applicable for the study. The investigator must comply with the applicable requirements 
related to the reporting of protocol deviations to the IRB/IEC.
Subjects/legal representatives will be instructed to call study personnel to report any 
abnormalities during the intervals between study visits and to come to the study site if 
medical evaluation is needed and the urgency of the situation permits. For emergency and 
other unscheduled visits to a medical facility other than the study site, medical records will 
be obtained by the investigator and made available to the sponsor or designee during 
monitoring visits.


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Schedules of study procedures for the screening and treatment period are presented in 
Table 5.1-1 for Q2W or Q3W dosing schedules and Table 5.1-2 for Q4W dosing schedule. 
Subjects in retreatment using the Q4W dosing schedule will follow the same schedule as 
initial treatment. A schedule of follow-up study procedures for subjects who have completed 
MEDI4736 treatment and achieved DC (until confirmed PD) and subjects who have 
discontinued MEDI4736 due to toxicity in the absence of PD is presented in Table 5.1-3. A 
schedule of retreatment for subject in dose-escalation and dose-expansion is presented in 
Appendix 13. A schedule of follow-up study procedures and description of each visit for 
subjects who have discontinued MEDI4736 treatment due to confirmed PD is presented in 
Appendix 14. A description of the study procedures is included in Section 5.2. The sponsor 
may stop the collection of an exploratory laboratory evaluation at any time based on 
available data.


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Table 5.1-1
Schedule of Study Procedures: Screening and Treatment Period
Evaluation
Screening
Day -28 to 
Day -1
Treatment Period (12 Months)
Dose 1
Dose 2 
(± 3 days)
Odd-
numbered 
Doses (after 
Dose 1; 
± 3 days)
Even-
numbered 
Doses 
(after 
Dose 2; 
± 3 days)
After 
6 Weeks 
(Day 43 
± 7 days)
After 12 
Weeks and 
16 Weeks 
(Days 85 and 
113) 
Then Every  
8 Weeks 
(± 7 days)
Days
Days
1
2 
(Dose-
escala-
tion 
only)
3 
(Dose-
escala-
tion 
only)
5 ± 1 
(Dose-
escala-
tion 
only)
10 
± 1
15 ± 1 
(for 
Q3W)
1
8 
± 1
Written informed 
consent/assignment
of SID number
X
Verify eligibility 
criteria
X
X
Pain questionnaire 
(dose-expansion 
phase only)
X
X
X (Doses 3 
and 5 only)
X
X
EORTC QLQ-C30 
and cancer-specific 
modules (dose-
expansion phase 
only)
X
X
X (Doses 3 
and 5 only)
X
X
FACT-BL (UBC 
subjects only)
X
X
X (Doses 3 
and 5 only)
X
X
Collect pathology 
report (if available)
X
Medical history
X
Smoking history
X
Hepatitis B and C; 
HIV
X
Serum βhCG
X


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Table 5.1-1
Schedule of Study Procedures: Screening and Treatment Period
Evaluation
Screening
Day -28 to 
Day -1
Treatment Period (12 Months)
Dose 1
Dose 2 
(± 3 days)
Odd-
numbered 
Doses (after 
Dose 1; 
± 3 days)
Even-
numbered 
Doses 
(after 
Dose 2; 
± 3 days)
After 
6 Weeks 
(Day 43 
± 7 days)
After 12 
Weeks and 
16 Weeks 
(Days 85 and 
113) 
Then Every  
8 Weeks 
(± 7 days)
Days
Days
1
2 
(Dose-
escala-
tion 
only)
3 
(Dose-
escala-
tion 
only)
5 ± 1 
(Dose-
escala-
tion 
only)
10 
± 1
15 ± 1 
(for 
Q3W)
1
8 
± 1
Urine hCG or serum 
βhCG
X
X
X
X
Kit assignment and 
MEDI4736 
administration
X
X
X
X
Protocol/Safety Evaluations
Physical 
examination
X
X
X
X
X
Vital signs a
X
X
X
X
X
Postinfusion 
observation a
X
X
X
X
Weight
X
X
X
X
X
Electrocardiogram, 
Q2W dose-
escalation arm b
X
X
X (every 4th dose)
Electrocardiogram, 
Q3W dose-
escalation arm b
X
X
X (every 3rd dose)
Electrocardiogram, 
Q2W dose-
expansion b,c
X
X
X (every 12 weeks
starting at Dose 3)


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Table 5.1-1
Schedule of Study Procedures: Screening and Treatment Period
Evaluation
Screening
Day -28 to 
Day -1
Treatment Period (12 Months)
Dose 1
Dose 2 
(± 3 days)
Odd-
numbered 
Doses (after 
Dose 1; 
± 3 days)
Even-
numbered 
Doses 
(after 
Dose 2; 
± 3 days)
After 
6 Weeks 
(Day 43 
± 7 days)
After 12 
Weeks and 
16 Weeks 
(Days 85 and 
113) 
Then Every  
8 Weeks 
(± 7 days)
Days
Days
1
2 
(Dose-
escala-
tion 
only)
3 
(Dose-
escala-
tion 
only)
5 ± 1 
(Dose-
escala-
tion 
only)
10 
± 1
15 ± 1 
(for 
Q3W)
1
8 
± 1
AE/SAE assessment
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
ECOG performance 
status
X
X
X
X
X
Laboratory Evaluations
Hepatitis B and C 
viral titers (only 
HCC subjects with 
hepatitis B or C)
X
X
Serum chemistry 
X
X
X
X
X
Thyroid function 
tests (TSH and free 
T3 and T4)
X
X
X
X
X
Hematology
X
Xd
X
X
X
X
X
Urinalysis
X
X
X
X
X
Coagulation 
parameters
X
X
X
X
Pharmacokinetic 
assessment, Q2W 
dose-escalation arm 
Xe
X
X
X
Xe
X
Xe


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Table 5.1-1
Schedule of Study Procedures: Screening and Treatment Period
Evaluation
Screening
Day -28 to 
Day -1
Treatment Period (12 Months)
Dose 1
Dose 2 
(± 3 days)
Odd-
numbered 
Doses (after 
Dose 1; 
± 3 days)
Even-
numbered 
Doses 
(after 
Dose 2; 
± 3 days)
After 
6 Weeks 
(Day 43 
± 7 days)
After 12 
Weeks and 
16 Weeks 
(Days 85 and 
113) 
Then Every  
8 Weeks 
(± 7 days)
Days
Days
1
2 
(Dose-
escala-
tion 
only)
3 
(Dose-
escala-
tion 
only)
5 ± 1 
(Dose-
escala-
tion 
only)
10 
± 1
15 ± 1 
(for 
Q3W)
1
8 
± 1
Pharmacokinetic 
assessment, Q3W 
dose-escalation arm 
Xe
X
X
X
X
Xe
X
Xe
Pharmacokinetic 
assessment, Q2W 
dose-expansion arm
Xe
Xe
X (every 12 weeks 
starting at Dose 3)
Pharmacokinetic 
assessment, Q2W 
UBC cohort
Xf
X
(Dose 3, 7, 
and 13 
[Day 29, 
85, and 
169])
Immunogenicity 
assessment dose-
escalation arms
X
X (Dose 3 
only)
X (begin 
after 
Dose 4)
Immunogenicity 
assessment dose-
expansion arms
X
X (every 12 weeks 
starting at Dose 3)
Immunogenicity 
assessment UBC 
cohort
X
X
(Dose 3, 7, and 13 
[Day 29, 85, and 169])


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Table 5.1-1
Schedule of Study Procedures: Screening and Treatment Period
Evaluation
Screening
Day -28 to 
Day -1
Treatment Period (12 Months)
Dose 1
Dose 2 
(± 3 days)
Odd-
numbered 
Doses (after 
Dose 1; 
± 3 days)
Even-
numbered 
Doses 
(after 
Dose 2; 
± 3 days)
After 
6 Weeks 
(Day 43 
± 7 days)
After 12 
Weeks and 
16 Weeks 
(Days 85 and 
113) 
Then Every  
8 Weeks 
(± 7 days)
Days
Days
1
2 
(Dose-
escala-
tion 
only)
3 
(Dose-
escala-
tion 
only)
5 ± 1 
(Dose-
escala-
tion 
only)
10 
± 1
15 ± 1 
(for 
Q3W)
1
8 
± 1
sPD-L1 
concentration  dose-
escalation arms
X
Xe
X
X
X
X
X
X
X
sPD-L1 
concentration dose-
expansion arms c
Xe
X 
X (every 12 weeks 
starting at Dose 3)
Flow cytometric 
analysis - absolute 
cell counts, immune 
cell subsets, 
activation markers 
dose-escalation arms
X
Xd
X
X
X
X
X
Flow cytometric 
analysis- absolute 
cell counts, immune 
cell subsets, 
activation markers 
dose-expansion 
arms c
X
X
X
X
X h
Circulating soluble 
factors dose-
escalation arms
X
X g
X
X
X
X g
X g
X g


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Table 5.1-1
Schedule of Study Procedures: Screening and Treatment Period
Evaluation
Screening
Day -28 to 
Day -1
Treatment Period (12 Months)
Dose 1
Dose 2 
(± 3 days)
Odd-
numbered 
Doses (after 
Dose 1; 
± 3 days)
Even-
numbered 
Doses 
(after 
Dose 2; 
± 3 days)
After 
6 Weeks 
(Day 43 
± 7 days)
After 12 
Weeks and 
16 Weeks 
(Days 85 and 
113) 
Then Every  
8 Weeks 
(± 7 days)
Days
Days
1
2 
(Dose-
escala-
tion 
only)
3 
(Dose-
escala-
tion 
only)
5 ± 1 
(Dose-
escala-
tion 
only)
10 
± 1
15 ± 1 
(for 
Q3W)
1
8 
± 1
Circulating soluble 
factors dose-
expansion arms 
X
X
X c
X c
X c
PBMC collection 
(immunodiversity, 
flow cytometry, or 
functional 
assessment) dose-
escalation arms
X
X
X
X
X
X
Anticancer/testis 
antigen antibodies 
dose-escalation arms
X
X
Anticancer/testis 
antigen antibodies 
dose-expansion 
arms c
X
X
Circulating tumor 
cells (dose 
escalation and 
TNBC for dose 
expansion)
X
X
X
miRNA/mRNA 
analysis dose-
escalation arms
X
X
X
X
X


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Table 5.1-1
Schedule of Study Procedures: Screening and Treatment Period
Evaluation
Screening
Day -28 to 
Day -1
Treatment Period (12 Months)
Dose 1
Dose 2 
(± 3 days)
Odd-
numbered 
Doses (after 
Dose 1; 
± 3 days)
Even-
numbered 
Doses 
(after 
Dose 2; 
± 3 days)
After 
6 Weeks 
(Day 43 
± 7 days)
After 12 
Weeks and 
16 Weeks 
(Days 85 and 
113) 
Then Every  
8 Weeks 
(± 7 days)
Days
Days
1
2 
(Dose-
escala-
tion 
only)
3 
(Dose-
escala-
tion 
only)
5 ± 1 
(Dose-
escala-
tion 
only)
10 
± 1
15 ± 1 
(for 
Q3W)
1
8 
± 1
miRNA/mRNA 
dose-expansion arms
X
X c
X c
X c
X c
Archival tumor 
tissue sample i
X
Confirm HPV status 
by central lab 
(HPV-positive 
cancers only)
X
Disease Evaluations
Disease assessment 
X j
X
X
Submission of 
baseline imaging for 
BICR (UBC cohort 
only)
X
Tumor biopsy 
(dose-expansion 
phase only) i
X
X c


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Template 14.1
Table 5.1-1
Schedule of Study Procedures: Screening and Treatment Period
Evaluation
Screening
Day -28 to 
Day -1
Treatment Period (12 Months)
Dose 1
Dose 2 
(± 3 days)
Odd-
numbered 
Doses (after 
Dose 1; 
± 3 days)
Even-
numbered 
Doses 
(after 
Dose 2; 
± 3 days)
After 
6 Weeks 
(Day 43 
± 7 days)
After 12 
Weeks and 
16 Weeks 
(Days 85 and 
113) 
Then Every  
8 Weeks 
(± 7 days)
Days
Days
1
2 
(Dose-
escala-
tion 
only)
3 
(Dose-
escala-
tion 
only)
5 ± 1 
(Dose-
escala-
tion 
only)
10 
± 1
15 ± 1 
(for 
Q3W)
1
8 
± 1
AE = adverse event; βhCG = beta human chorionic gonadotropin; BICR = blinded independent central review; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer quality-of-life questionnaire; FACT-BL = 
Functional Assessment of Chronic Illness Therapy-bladder; HCC = hepatocellular carcinoma; hCG = human chorionic gonadotropin; HIV = human 
immunodeficiency virus; HPV = human papilloma virus; IHC = immunohistochemistry; miRNA = micro ribonucleic acid; mRNA = messenger ribonucleic 
acid; PBMC = peripheral blood mononuclear cell; PD-L1 = programmed death ligand 1; Q2W = every 2 weeks; Q3W = every 3 weeks; SAE = serious 
adverse event; SID = subject identification; sPD-L1 = soluble programmed death ligand 1; TNBC = triple negative breast cancer; TSH = thyroid-stimulating 
hormone; UBC = urothelial bladder cancer.
Note: all samples are collected predose unless otherwise indicated.
a
Vital signs every 15 minutes (± 5 minutes) during MEDI4736 administration, at the end of infusion (+ 5 minutes), and at 30 and 60 minutes (± 5 minutes) 
post end of infusion, followed by a 3-hour (± 15 minutes) period of observation. For subsequent doses (at dose levels of 10 mg/kg or less), the 3-hour 
observation period will not be required unless a subject experiences an infusion-related reaction or a higher dose level is being tested.
b
ECGs will be collected during screening, on Dose 1, Day 1 (within an hour prior to start of infusion, within 30 minutes post-end of infusion, and 3 hours 
[± 15 minutes] post-end of infusion) and within an hour prior to start of infusion on remaining dosing days indicated.  Digital ECGs will be collected at 
selected sites. All other sites will perform ECGs per their institution’s standard.
c
Not required for subjects in the UBC cohort.
d
Predose (for both dose-escalation and dose-expansion subjects) and 3 hours (± 15 minutes) post end of infusion (for dose-escalation subjects only).
e
Predose and post dose (+ 5 minutes) post end of infusion. For Cohort 1 subjects only, an additional sample will be taken 2 hours after start of infusion.
f
End of infusion (+ 5 minutes).
g
Predose and 2 hours (± 15 minutes) post end of infusion.
h
Sample collected every other even dose (ie, every 8 weeks starting at Dose 4).
i
For subjects in the UBC cohort, either archival tumor tissue from within 6 months prior to study entry or a fresh biopsy is required for PD-L1 IHC testing. 
Additional older archival tissue regardless of age is also required, if available. 
j
Disease assessments performed as part of standard of care prior to subjects signing informed consent may be used for screening if obtained within 28 days 
before the first dose of investigational product.


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Table 5.1-2
Q4W Schedule of Study Procedures: Screening and Treatment Period
Procedure
Screening
Dose 1
Dose 2
Odd-numbered 
Doses (after 
Dose 1; ± 3 Days)
Even-numbered 
Doses (after 
Dose 2; ± 3 Days)
Weeks 6, 12, 
16, Then Every 
8 Weeks (± 
7 Days)
Day 1
Day 2
Day 15 ± 
1 Days
Day 1 
± 3 Days
Written informed 
consent/assignment 
of SID number
X
Verify eligibility 
criteria
X
Collect pathology 
report (if available)
X
Medical history
X
Smoking history
X
Hepatitis B and C; 
HIV
X
Serum βhCG
X
Urine hCG or serum 
βhCG
X
X
X
X
Physical 
examination 
(including weight)
X
X
X
X
X
X
Vital signs a
X
X
X
X
X
X
X
Electrocardiogram b
X
X
X (every other odd 
dose)
AE/SAE assessment
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X


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Template 14.1
Table 5.1-2
Q4W Schedule of Study Procedures: Screening and Treatment Period
Procedure
Screening
Dose 1
Dose 2
Odd-numbered 
Doses (after 
Dose 1; ± 3 Days)
Even-numbered 
Doses (after 
Dose 2; ± 3 Days)
Weeks 6, 12, 
16, Then Every 
8 Weeks (± 
7 Days)
Day 1
Day 2
Day 15 ± 
1 Days
Day 1 
± 3 Days
ECOG performance 
status
X
X
X
X
X
Hepatitis B and C 
viral titers (only 
HCC subjects with 
hepatitis B or C)
X
X
Serum chemistry 
X
X
X
X
X
X
Thyroid function 
tests (TSH and free 
T3 and T4)
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
Coagulation 
parameters
X
X
X
X
X
X
Pharmacokinetic 
assessment 
X c
X
X c
X d,e
X d,e
Immunogenicity
X
X
X
sPD-L1 
concentration
X
X c
X
X
X e
X e
Circulating soluble 
factors
X
X
X
X
X
Archival tumor 
tissue sample
X
Disease assessment 
X f
X
Tumor biopsy 
X
X (Week 6 ± 
7 Days only)


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Template 14.1
Table 5.1-2
Q4W Schedule of Study Procedures: Screening and Treatment Period
Procedure
Screening
Dose 1
Dose 2
Odd-numbered 
Doses (after 
Dose 1; ± 3 Days)
Even-numbered 
Doses (after 
Dose 2; ± 3 Days)
Weeks 6, 12, 
16, Then Every 
8 Weeks (± 
7 Days)
Day 1
Day 2
Day 15 ± 
1 Days
Day 1 
± 3 Days
Kit assignment and 
MEDI4736 
administration
X
X
X
X
Postinfusion 
observation
X
X
X
X
AE = adverse event; βhCG = beta human chorionic gonadotropin; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; HCC = 
hepatocellular carcinoma; hCG = human chorionic gonadotropin; HIV = human immunodeficiency virus; Q4W = every 4 weeks; SAE = serious adverse event; 
SID = subject identification; sPD-L1 = soluble programmed death ligand 1; TSH = thyroid-stimulating hormone.
Note: all samples are collected predose unless otherwise indicated.
a
Vital signs every 15 minutes (± 5 minutes) during MEDI4736 administration, at the end of infusion (+ 5 minutes), and at 30 and 60 minutes (± 5 minutes) 
post end of infusion, followed by a 3-hour (± 15 minutes) period of observation (for the first 4 doses only). For subsequent doses (starting at Dose 5), the 
3-hour observation period will not be required unless a subject experiences an infusion-related reaction or a higher dose level is being tested.
b
ECGs will be collected during screening, on Dose 1, Day 1 (within an hour prior to start of infusion, within 30 minutes post-end of infusion, and 3 hours 
[± 15 minutes] post-end of infusion) and within an hour prior to start of infusion on remaining dosing days indicated. ECGs will be performed per their 
institution’s standard.
c
Predose and post dose (+ 5 minutes) post end of infusion.
d
Predose and post dose (+ 5 minutes) post end of infusion for first 6 months (Doses 3-6). 
e
Sampling changes to even doses (ie every 8 weeks) only starting at Dose 6. Predose sampling only after Dose 6. 
f
Disease assessments performed as part of standard of care prior to subjects signing informed consent may be used for screening if obtained within 28 days 
before the first dose of investigational product.


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Template 14.1
Table 5.1-3
Schedule of Study Procedures: Follow-up for Subjects Who Have Completed MEDI4736 
Treatment and Achieved Disease Control (Until Confirmed Progressive Disease) and 
Subjects Who Have Discontinued MEDI4736 Due to Toxicity in the Absence of Confirmed 
Progressive Disease
Evaluation
End of 
Treatmenta
Time Since Last Dose of MEDI4736
Days
(± 3)
Months (± 1 week)
12 Months and 
Every 
3 Months 
(± 2 weeks)
14
30
2
3
4
6
8
10
Protocol/Safety Evaluations
Pain questionnaire (dose-expansion phase only)
X
X
X
X
X
X
X
X b
EORTC QLQ-C30 and cancer-specific modules (dose-expansion 
phase only)
X
X
X
X
X
X
X
X b
FACT-BL (UBC subjects only)
X
X
X
X
X
X
X
X b
Physical examination
X
X
Vital signs
X
X
Weight
X
X
Electrocardiogram c,d
X
X
AE/SAE assessment
X
X
X
X
X
Concomitant medications
X
X
X
ECOG performance status
X
X
Subsequent anticancer therapy
X
X
X
X
X
X
X
Survival status: phone contact with subjects who refuse to return for 
evaluations and agree to be contacted
X
X
X
X
X
X
X
Laboratory Evaluations
Hepatitis B and C viral titers (only HCC subjects with 
hepatitis B or C)
X
X
X
X
Hematology
X
X
Serum chemistry 
X
X
Thyroid function tests (TSH, and free T3 and T4)
X
X
Coagulation parameters
X
X
Urinalysis
X
X


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Template 14.1
Table 5.1-3
Schedule of Study Procedures: Follow-up for Subjects Who Have Completed MEDI4736 
Treatment and Achieved Disease Control (Until Confirmed Progressive Disease) and 
Subjects Who Have Discontinued MEDI4736 Due to Toxicity in the Absence of Confirmed 
Progressive Disease
Evaluation
End of 
Treatmenta
Time Since Last Dose of MEDI4736
Days
(± 3)
Months (± 1 week)
12 Months and 
Every 
3 Months 
(± 2 weeks)
14
30
2
3
4
6
8
10
Pharmacokinetic assessment
X d
X d
X
Immunogenicity assessment 
X d
X d
X
X d
sPD-L1 concentration d
X
X
X
Flow cytometric analysis - absolute cell counts, immune cell subsets, 
activation markers (Q2W and Q3W subjects only) d
X
X
X b
Circulating soluble factors d
X
X
X
X b
PBMC collection (immunodiversity, flow cytometry, or functional 
assessment; Q2W and Q3W subjects only) d
X
X
X b
Anticancer/testis antigen antibodies (Q2W and Q3W subjects only) d
X
X
X b
Circulating tumor cells (dose escalation and TNBC for dose 
expansion)
X
X
X
X b
miRNA/mRNA analysis (Q2W and Q3W subjects only) d
X
X
Disease Evaluation
Disease assessment 
X
X
X
X
X
X
X


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Template 14.1
Table 5.1-3
Schedule of Study Procedures: Follow-up for Subjects Who Have Completed MEDI4736 
Treatment and Achieved Disease Control (Until Confirmed Progressive Disease) and 
Subjects Who Have Discontinued MEDI4736 Due to Toxicity in the Absence of Confirmed 
Progressive Disease
Evaluation
End of 
Treatmenta
Time Since Last Dose of MEDI4736
Days
(± 3)
Months (± 1 week)
12 Months and 
Every 
3 Months 
(± 2 weeks)
14
30
2
3
4
6
8
10
AE = adverse event; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer 
quality-of-life questionnaire; ECG = electrocardiogram; FACT-BL = Functional Assessment of Chronic Illness Therapy-bladder; HCC = hepatocellular 
carcinoma; miRNA = micro ribonucleic acid; mRNA = messenger ribonucleic acid; PBMC = peripheral blood mononuclear cell; Q2W = every 2 weeks; Q3W 
= every 3 weeks; SAE = serious adverse event; sPD-L1= soluble programmed death ligand 1; TNBC = triple negative breast cancer; TSH = thyroid-
stimulating hormone; UBC = urothelial bladder cancer. 
a
End of treatment is defined as the last planned dosing visit within the 12-month treatment period. For subjects who discontinue treatment prior to 
12 months, end of treatment is considered the last visit where the decision is made to discontinue. All required procedures may be completed within 
± 7 days of the endo of treatment visit. Note: repeat disease assessment is not required if performed within 28 days prior to the end of treatment visit.
b
Stop evaluation at 12 months.
c
Digital ECGs will be collected at select sites. All other sites will perform ECGs per their institution’s standard.
d
Not required for subjects in the UBC cohort.


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5.1.1
Screening……….
All screening procedures must be performed within 28 days before the first dose of 
investigational product (Day -28 to Day -1), unless otherwise specified. The screening 
evaluations may be carried out over more than one visit. Written informed consent and any 
locally required privacy act document authorization must be obtained prior to performing any 
protocol-specific procedures, including screening evaluations. Disease assessments 
performed as part of standard of care prior to subjects signing informed consent may be used 
for screening if obtained within 28 days before the first dose of investigational product.
5.1.2
Treatment Period
Includes subjects who will be receiving the first infusion of MEDI4736 and subjects who are 
being retreated with MEDI4736 following evidence of PD in follow-up. If the subject has 
completed any safety laboratory tests or ECOG evaluation within 72 hours of Day 1, they 
will not need to be repeated.
5.1.3
End of Treatment
End of treatment is defined as the last planned dosing visit within the 12-month dosing 
period. For subjects who discontinue MEDI4736 prior to 12 months, end of treatment is 
considered the last visit where the decision is made to discontinue treatment. All required 
procedures may be completed within ± 7 days of the end of treatment visit. Repeat disease 
assessment is not required if performed within 28 days prior to the end of treatment visit.
5.1.4
Post-treatment Follow-up
Post-treatment follow-up assessments for subjects who have completed the MEDI4736 
12-month treatment and achieved DC (until confirmed PD) and subjects who have 
discontinued MEDI4736 due to toxicity in the absence of PD are shown in Table 5.1-3. 
Assessments for subjects who have discontinued MEDI4736 treatment due to confirmed PD 
are presented in Appendix 14.
5.2
Description of Study Procedures
5.2.1
Medical History and Physical Examination, Electrocardiogram, 
Weight, and Vital Signs
Findings from medical history (obtained at screening) and physical examination shall be 
given a baseline grade according to the procedure for AEs. Increases in severity of 
pre-existing conditions during the study will be considered AEs, with resolution occurring 
when the grade returns to the prestudy grade or below.


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Physical examinations will be performed on study days noted in Section 5.1, and will include 
assessments of the head, eyes, ears, nose, and throat, respiratory, cardiovascular, 
gastrointestinal, urogenital, musculoskeletal, neurological, psychiatric, dermatological,
hematologic/lymphatic, and endocrine systems; and height (at screening only).
Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) will be measured on 
study days noted in Section 5.1. On MEDI4736 treatment days, vital signs will be measured
within an hour prior to start of MEDI4736 administration, every 15 minutes (5 minutes) 
during MEDI4736 administration, at the end of infusion (+ 5 minutes), and at 30 minutes 
(± 5 minutes) and 60 minutes (± 5 minutes) postinfusion, followed by a 3-hour 
(± 15 minutes) period of observation. For subsequent doses (at dose levels of 10 mg/kg or 
less), the 3-hour observation period will not be required unless a subject experiences an 
infusion-related reaction or a higher dose level is being tested. The 3-hour observation 
period, however, will be required for the first 4 doses for any dose level > 10 mg/kg (Q2W or 
Q3W) and for subjects in the 20 mg/kg Q4W dose-exploration cohort.
All electrocardiograms (ECGs) recorded during the study will be obtained in triplicate (all 3 
within a 5-minute time period at least 1 minute apart). Approximately 150 subjects at select 
sites will have ECGs collected digitally for central analysis. All other sites will perform 
ECGs per their institution’s standards. All ECGs will be recorded at 25 mm/second. All 
12-lead ECGs should be recorded while the subject is in the supine position. A 12-lead ECG 
will be recorded for all subjects on study days noted in Section 5.1. The same method of 
assessment should be used throughout the study. Twelve-lead ECGs will be obtained after 
the subject has been resting in a supine position for at least 5 minutes in each case. On 
Dose 1, Day 1, ECGs will be recorded within an hour prior to start of infusion, within 
30 minutes post end of infusion, and 3 hours (± 15 minutes) post end of infusion. Further 
ECGs will be performed within an hour prior to start of infusion on remaining dosing days 
according to the schedule of study procedures (Section 5.1) and when clinically indicated, eg, 
in the event of a cardiac AE. As described in Section 5.1, ECGs are not required for subjects 
in the UBC cohort, unless clinically indicated.
Paper tracings will be used for local management, but a digital copy of ECGs at select sites 
will be held centrally by a central ECG provider, and the data from this review will be stored 
for analysis during or at the end of the study. The independent review will not replace the 
local review by the investigator or other medically–qualified designee. Clinical interpretation 
and management of subjects for all ECGs will be done locally.


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5.2.2
Clinical Laboratory Tests
Clinical laboratory safety tests including serum pregnancy tests will be performed in a 
licensed clinical laboratory. Urine pregnancy tests may be performed at the site using a 
licensed test (dipstick). Abnormal laboratory results should be repeated as soon as possible 
(preferably within 24 to 48 hours).
A Laboratory Manual will be provided to the sites that specifies the procedures for 
collection, processing, storage, and shipment of samples, as well as laboratory contact 
information, specific to this clinical research study.
The following clinical laboratory tests will be performed (see Section 5.1 for the schedule of 
tests):
Serum Chemistry
•
Calcium
•
GGT
•
Chloride
•
Lactic dehydrogenase 
•
Magnesium
•
Uric acid
•
Potassium
•
Creatinine
•
Sodium
•
Blood urea nitrogen
•
Bicarbonate
•
Glucose
•
AST
•
Albumin
•
ALT
•
Total protein
•
Alkaline phosphatase (ALP)
•
Triglycerides
•
Total bilirubin
•
Cholesterol
Note for serum chemistries: Tests for AST, ALT, ALP, and total bilirubin must be conducted concurrently 
and assessed concurrently
Hematology
•
White blood cell (WBC) count with differential
•
Platelet count
•
Red blood cell (RBC) count
•
Mean corpuscular volume
•
Hematocrit
•
Mean corpuscular hemoglobin concentration
•
Hemoglobin
Urinalysis
•
Color
•
Glucose
•
Appearance
•
Ketones
•
Specific gravity
•
Blood
•
pH
•
Bilirubin
•
Protein
•
Microscopy including WBC/high power field 
(HPF), RBC/HPF


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Pregnancy Test (females of childbearing potential only)
•
Urine hCG
•
Serum βhCG
Other Safety Tests
•
Coagulation tests: prothrombin time, partial thromboplastin time, fibrinogen
•
Hepatitis B surface antigen, hepatitis C antibody
•
HIV-1 antibody
•
Thyroid function tests: TSH, free T3 and free T4
•
Hepatitis B and C viral titers  (only HCC subjects with hepatitis B or C) 
5.2.3
Pharmacokinetic Evaluation and Methods
Measurement of MEDI4736 concentrations in serum will be performed using a validated 
immunoassay.
Details for collection, aliquoting, storage, and shipment of serum samples for PK evaluations 
are presented in a separate Laboratory Manual.
Blood samples for measurement of MEDI4736 concentrations in serum will be collected in 
samples taken according to the schedules presented in Section 5.1. 
5.2.4
Immunogenicity Evaluation and Methods
Presence of ADA will be assessed in samples taken according to the schedule presented in 
Section 5.1. Samples will be measured for the presence of ADA by MedImmune using a 
validated bridging immunoassay. Tiered analysis will be performed to include screening, 
confirmatory and titer assay components and positive-negative cut points will be employed 
that were statistically determined from drug naive validation samples. Samples will be 
collected for assessing the neutralization capacity in the future.
5.2.5
Biomarker Evaluation and Methods
Blood samples will be collected and analyzed to evaluate protein, nucleic acid, and 
cellular biomarkers that relate to MEDI4736 treatment according to the schedule presented in 
Section 5.1.
 
 
 


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Other biomarkers may be evaluated as determined by additional data. Details for sample 
collection, processing, storage, and shipment will be provided in the Laboratory Manual.
5.2.6
Disease Evaluation and Methods
Tumor assessments will be based on RECIST v1.1 guidelines (Eisenhauer et al, 2009) with 
modifications for all subjects, except those with GBM who will be evaluated based on 
RANO guidelines (Wen et al, 2010), and will be performed during screening and treatment 
according to the schedule presented in Section 5.1. Modification of RECIST as described 
may discourage the early discontinuation of MEDI4736 and provide a more complete 


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evaluation of its antitumor activity than would be seen with conventional response criteria. 
Nonetheless, the efficacy analysis will be conducted primarily based on RECIST v1.1. This 
assessment schedule also applies to those subjects who continue to receive MEDI4736 
beyond confirmed PD, and those subjects who re-enter treatment upon evidence of PD 
during follow-up. For those subjects who discontinue MEDI4736 as a result of confirmed 
PD, disease evaluation will be performed at the end of treatment visit if clinically appropriate 
(ie, in the absence of rapidly deteriorating clinical status). For those subjects who enter 
follow-up after discontinuing MEDI4736 as a result of toxicity or having achieved DC, 
disease evaluation will be performed at the end of treatment visit, every 2 months for 1 year, 
and every 3 months thereafter until the end of the study or confirmed PD. Additional disease 
assessments may be performed as clinically indicated.
All imaging assessments, including unscheduled visit scans, will be collected on an ongoing 
basis and sent to the sponsor or designee for storage. The centralized storage of imaging data 
is intended for BICR of disease assessments. At the discretion of the sponsor, a BICR of all 
scans used in the assessment of tumors by RECIST v1.1 and/or irRECIST will be conducted. 
Guidelines for imaging collection and storage will be provided in a separate charter. The 
management of subjects will be based solely upon the results of the assessment conducted by 
the investigator based on RECIST v1.1. Note: subjects who were assessed by immune-related 
response criteria (irRC) under older versions of this protocol will continue to be assessed by 
irRC.
The tumor assessment performed at 6 weeks after initiation of MEDI4736 will not be used to 
document antitumor efficacy or make decisions regarding subject participation in the study 
unless observed disease progression is accompanied by rapidly deteriorating clinical status. 
This is an exploratory disease assessment only and will be used to evaluate the kinetics of 
tumor response to MEDI4736. However, the investigator and/or subject may decide at any 
time that it is in the subject’s best interest to discontinue from the study.
Tumor assessments may include the following evaluations: physical examination (with 
photograph and measurement of skin lesions as applicable); computed tomography (CT) or 
magnetic resonance imaging (MRI) scan of the chest, abdomen, and pelvis; and CT or MRI 
scan of the brain. Computed tomography or MRI scan of the brain will be performed only at 
screening or if the subject is neurologically symptomatic. Subjects with GBM should use 
MRI with contrast for tumor assessments. The preferred method of disease assessment is CT 
with contrast except for subjects with GBM. If CT with contrast is contraindicated, CT 
without contrast is preferred over MRI. The same method is preferred for all subsequent 
tumor assessments.


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5.2.6.1
RECIST v 1.1
Physical examination
•
Lesions detected by physical examination will only be considered measurable if 
superficial, eg, skin nodules and palpable lymph nodes. Documentation by color 
photography including ruler is recommended for estimating the size of skin lesions.
CT scan with contrast of the chest, abdomen, and pelvis 
•
CT scans should be performed with contiguous cuts in slice thickness of 5 mm or less. 
Spiral CT should be performed using a 5-mm contiguous reconstruction algorithm.
MRI scans
•
MRI of the abdomen and pelvis is acceptable for measurement of lesions provided that 
the same anatomical plane is used for serial assessments. If possible, the same imaging 
device should be used for serial evaluations. In case of MRI, measurements will be 
preferably performed in the axial (transverse) plane on contrast-enhanced T1-weighted 
images. However, there are no specific sequence recommendations.
Measurability of Tumor Lesions 
Tumor lesions will be categorized as follows:
•
Measurable Lesions -  Must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size of: 
•
10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice 
thickness and a minimum of 10 mm). 
•
10 mm caliper measurement by clinical exam (when superficial).
•
Malignant lymph nodes are considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).
•
Nonmeasurable Lesions - Nonmeasurable lesions are defined as all other lesions (or 
sites of disease), including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm short axis). Lesions considered truly nonmeasurable 
include the following: leptomeningeal disease, ascites, pleural/pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
•
Target Lesions - All lesions up to a maximum of 5 lesions total (and a maximum of 
2 lesions per organ) representative of all involved organs should be identified as target 


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lesions. It may be the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.
•
Non-target Lesions - It is possible to record multiple nontarget lesions involving the 
same organ as a single item on the case record form (eg, “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”).
Response Criteria
Evaluation of Target Lesions
•
Complete Response - Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm (the 
sum may not be “0” if there are target nodes). 
•
Partial Response - At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters.
•
Progressive Disease - At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression.)
•
Stable Disease - Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum of diameters while on study.
Evaluation of Non-target Lesions
•
Complete Response - Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm short 
axis). 
•
Non-complete response/Non-progressive disease - Persistence of 1 or more 
non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.
•
Progressive Disease - Unequivocal progression of existing non-target lesions will be 
defined as the overall level of substantial worsening in non-target disease such that, even 
in presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. In the absence of measurable disease, 
change in non-measurable disease comparable in magnitude to the increase that would be 
required to declare PD for measurable disease. Examples include an increase in a pleural 
effusion from ‘trace’ to ‘large,’ an increase in lymphangitic disease from localized to 
widespread.


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Appearance of New Lesions
The appearance of new lesions is considered PD according to RECIST v 1.1 guidelines. 
Considering the unique response kinetics that have been observed with immunotherapy, new 
lesions may not represent true disease progression. In the absence of rapid clinical 
deterioration, subjects may continue to receive MEDI4736 if investigators consider that 
subjects continue to benefit from treatment (see Section 3.4 for a discussion of 
immunotherapy response kinetics). 
Evaluation of Overall Response with Modifications
Confirmation of CR and PR is required by a repeat assessment no less than 4 weeks from the 
date of first documentation. Progressive disease should be confirmed, preferably at the next 
scheduled disease assessment, and no less than 4 weeks from the first documentation of PD, 
in the absence of clinical deterioration. Treatment with MEDI4736 will continue between the 
initial assessment of PD and confirmation for PD. In addition, subjects may continue to 
receive MEDI4736 beyond confirmed PD in the absence of clinical deterioration and if 
investigators consider that subjects continue to receive benefit from treatment. In the absence 
of clinical deterioration, such modifications to the RECIST or RANO criteria may discourage 
the early discontinuation of MEDI4736 and provide a more complete evaluation of its 
antitumor activity than would be seen with conventional response criteria. Table 5.2.6.1-1
provides overall responses for all possible combinations of tumor responses in target and 
non-target lesions with or without the appearance of new lesions.
Table 5.2.6.1-1
Evaluation of Overall Response
Target Lesions
Non-target Lesions
New Lesions
Overall Response
Complete response
Complete response (or no non-
target lesion)
No
Complete response
No target lesion a
Complete response
No
Complete response
Complete response
Not evaluable b
No
Partial response
Complete response
Non-complete response /
non-progressive disease
No
Partial response
Partial response
Non-progressive disease and
not evaluable (or no non-target 
lesion) b
No
Partial response
Stable disease
Non-progressive disease and
not evaluable (or no non-target 
lesion) b
No
Stable disease
Not all evaluated
Non-progressive disease
No
Not evaluable
No target lesion a
Not all evaluated
No
Not evaluable


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Table 5.2.6.1-1
Evaluation of Overall Response
Target Lesions
Non-target Lesions
New Lesions
Overall Response
No target lesion a
Non-complete response /
non-progressive disease
No
Non-complete response /
non-progressive disease
Progressive disease
Any
Yes/No
Progressive disease
Any
Progressive disease
Yes/No
Progressive disease
Any
Any
Yes
Progressive disease
No target lesion a
Unequivocal progressive disease
Yes/No
Progressive disease
No target lesion a
Any
Yes
Progressive disease
a
Defined as no target lesion at baseline.
b
Not evaluable is defined as either when no or only a subset of lesion measurements are made at an 
assessment.
5.2.6.2
Revised RANO Criteria
All measurable and nonmeasurable lesions should be assessed using the same techniques as 
at baseline. Ideally, subjects should be imaged on the same MRI scanner, or at least with the 
same magnet strength, for the duration of the study to reduce difficulties in interpreting 
changes.
MRI Scans
Specific lesions must be evaluated serially, and comparative analysis of changes in the area 
of contrast enhancement, as well as the nonenhancing component, should be performed. The 
product of the maximal cross-sectional enhancing diameters will be used to determine the 
size of the contrast-enhancing lesions.
Minimum sequences required:
•
Pre-contrast T1, T2/ fluid attenuated inversion recovery (FLAIR)
•
Post-contrast T1, with two orthogonal planes (or a volume acquisition) recommended
•
Recommended slice thickness ≤ 5 mm with no gap
Measurability of Tumor Lesions 
Tumor lesions are categorized as follows:
•
Measurable disease is defined as bidimensionally contrast enhancing lesions with clearly 
defined margins by CT or MRI scan, with two perpendicular diameters of at least 10 mm, 
visible on two or more axial slices that are preferably, at most, 5 mm apart with 0-mm 
skip. 


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•
Nonmeasurable disease is defined as either unidimensionally measurable lesions, masses 
with margins not clearly defined, or lesions with maximal perpendicular diameters less 
than 10 mm. Subjects without measurable disease, such as those who undergo a gross 
total resection, cannot respond and can only achieve SD as their best radiographic 
outcome.
◦
There are two types of non-target lesions 
▪
Enhancing (T1 with contrast) 
▪
Non-enhancing (T2/FLAIR) 
◦
These are assessed subjectively. Some rules are recommended for objective 
assessment of progression eg, if a nonmeasurable enhancing lesion becomes 
measurable, AND either has absolute increase of > 5 mm OR > 25% in sum of 
products of diameter
Response Criteria
Evaluation of Target Lesions
•
Complete response - Requires all of the following: complete disappearance of all 
enhancing measurable and nonmeasurable disease sustained for at least 4 weeks; no new 
lesions; stable or improved non-enhancing (T2/FLAIR) lesions; patients must be off 
corticosteroids (or on physiologic replacement doses only); and stable or improved 
clinically. Note: Subjects with nonmeasurable disease only, cannot have a CR; the best 
response possible is SD.
•
Partial response - Requires all of the following: 50% decrease compared with baseline in 
the sum of products of perpendicular diameters of all measurable enhancing lesions 
sustained for at least 4 weeks; no progression of nonmeasurable disease; no new lesions; 
stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared with baseline scan; the corticosteroid dose at the time of the 
scan evaluation should be no greater than the dose at time of baseline scan; and stable or 
improved clinically. Note: Subjects with nonmeasurable disease only, cannot have a PR; 
the best response possible is SD.
•
Stable disease - Requires all of the following: does not qualify for CR, PR, or 
progression; stable nonenhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared with baseline scan. In the event that the corticosteroid dose was 
increased for new symptoms and signs without confirmation of disease progression on 
neuroimaging, and subsequent follow-up imaging shows that this increase in 
corticosteroids was required because of disease progression, the last scan considered to 
show SD will be the scan obtained when the corticosteroid dose was equivalent to the 
baseline dose.
•
Progression - Defined by any of the following: 25% increase in sum of the products of 
perpendicular diameters of enhancing lesions compared with the smallest tumor 
measurement obtained either at baseline (if no decrease) or best response, on stable or 
increasing doses of corticosteroids; significant increase in T2/FLAIR nonenhancing 


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lesion on stable or increasing doses of corticosteroids compared with baseline scan or 
best response after initiation of therapy not caused by comorbid events (eg, radiation 
therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or 
other treatment effects); any new lesion; clear clinical deterioration not attributable to 
other causes apart from the tumor (eg, seizures, medication adverse events, complications 
of therapy, cerebrovascular events, infection) or changes in corticosteroid dose; failure to 
return for evaluation as a result of death or deteriorating condition; or clear progression of 
nonmeasurable disease.
Evaluation of Enhancing Non-target Lesions
•
Complete response - All enhancing non-target lesions have disappeared completely
•
Incomplete response/SD - Enhancing lesions present; stable or decreased in size
•
Progressive disease - Unequivocal progression
•
Unable to assess - Unable to evaluate enhancing lesions because of technical factors
Evaluation of T2/FLAIR Lesion Response
•
Improved - Signal abnormality decreased
•
Unchanged - Unchanged compared to prior imaging
•
Worse - Unequivocal worsening/progression of signal abnormality
•
Unable to assess - Unable to evaluate non-enhancing lesions because of technical factors
5.2.7
Archival Tumor Samples and Tumor Biopsies
5.2.7.1
Archival Tumor Samples
Archival tumor samples are required for all subjects and adequate tissue for biomarker 
analysis must be deemed available during the screening period. This will be waived for 
subjects who have no archived sample because no previous biopsy has been performed 
(eg, recently diagnosed or diagnosed with fine needle aspiration); however a biopsy must be 
performed for all subjects for which suitable archived tumor sample is not available. Subjects 
in the UBC cohort must provide either a fresh tumor biopsy during screening or an archived 
tumor specimen from within 6 months prior to study entry (ie, from subject signing consent 
to participate in the study) for PD-L1 IHC analysis. In addition, UBC subjects must provide
additional archival tumor tissue regardless of age if available. Formalin fixed paraffin 
embedded (FFPE) tumor samples will be collected for IHC and additional correlative 
markers (eg, tumor mutation analysis, RNA analysis, and immunodiversity). If a tumor block 


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cannot be provided for this study, then only freshly prepared unstained sections should be 
provided as described in the Laboratory Manual.
5.2.7.2
Tumor Biopsies
Image-guided core needle tumor biopsy will be performed according to institutional practice 
during screening and again 6 weeks after initiation of MEDI4736 (if clinically appropriate, 
ie, repeat biopsy after 6 weeks does not pose unacceptable medical risk to a subject as 
determined by the investigator) for subjects in the dose-exploration cohort and 
dose-expansion phase of the study. For subjects in dose-expansion, tumor biopsies resulting 
in adequate tissue for analysis will be required during screening for 10 subjects each enrolled 
in the pancreatic adenocarcinoma and nasopharyngeal carcinoma cohorts; 20 subjects 
enrolled in the advanced cutaneous melanoma, uveal melanoma, HCC, gastroesophageal 
cancer, SCCHN, TNBC, UBC, ovarian cancer, soft tissue sarcoma, SCLC, MSI-high 
cancers, and HPV-positive cancers cohorts; and for all subjects enrolled in the NSCLC 
squamous histology and NSCLC non-squamous histology cohorts. If more than 10 subjects 
are enrolled in the pancreatic adenocarcinoma or nasopharyngeal carcinoma cohorts; more 
than 20 subjects are enrolled in the HCC, gastroesophageal cancer, SCCHN, TNBC, UBC, 
ovarian cancer, soft tissue sarcoma, SCLC, MSI-high cancers, or HPV-positive cancers 
cohorts, either a fresh biopsy during screening or archival tissue from less than 6 months 
prior to enrollment will be required. For all subjects in the UBC cohort enrolled under 
Amendment 8 and beyond, either a fresh biopsy during screening or archival tissue from less 
than 6 months prior to enrollment will be required for PD-L1 IHC analysis. Tumor biopsies 
at 6 weeks after initiation of MEDI4736 are strongly encouraged for all subjects with the 
exception of subjects in the UBC cohort. For subjects entering retreatment, tumor biopsies 
during rebaseline and at 6 weeks after initiation of retreatment are encouraged, if clinically 
feasible with the exception of subjects in the UBC cohort. Tumor lesions used for biopsy 
should not be lesions used as RECIST target lesions. Additional tumor biopsies are permitted 
as clinically indicated and if feasible (eg, for mixed responses or upon PD). If clinically 
practical, at each time point, subjects will undergo 4 core biopsies. The first and third core 
biopsies will be placed in formalin and processed for FFPE, while the second and fourth core 
biopsies (fourth biopsy, if available) will be immediately frozen in liquid nitrogen or 
equivalent method and then stored at -60°C or below.  In exceptional cases, excisional or 
punch biopsies are permitted and may be substituted for the required core biopsies if 
sufficiently large (4 mm or greater in diameter).
Tumor biopsies will be stored at MedImmune or an appropriate vendor selected by 
MedImmune. Core biopsies may be used for correlative studies such as IHC, tumor mutation 


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analysis, RNA analysis, proteomic analysis, and immunodiversity. Additional details for 
sample collection, processing, storage, and shipment will be provided in the Laboratory 
Manual.
5.2.8
Patient-reported Outcomes Assessments
The pain questionnaire, European Organisation for Research and Treatment of Cancer 
quality-of-life questionnaire (EORTC QLQ-C30), and cancer-specific modules are 
self-administered questionnaires and are to be completed by the subject without the 
assistance of the investigational site personnel. All questionnaires should be completed 
before any other study procedures are conducted at the visit. Patient-reported outcome 
questionnaires need to be administered at screening visit, Day 1 of Dose 1, 3, and 5, and at 
the same visit as the disease assessment by physical examination and CT scans, before 
other clinical procedures. If subjects get scans at an outside facility or missed a scheduled 
data collection, PRO questionnaires need to be administered at the next visit. It takes about 
15-20 minutes for subjects to complete all 3 questionnaires and the subjects are asked to only 
fill out questionnaires that have been validated to be relevant to their specific type of cancer; 
hence the burden to the subject is moderate. When the subject completes the questionnaires, 
study coordinators need to review the questionnaires for missing responses and then ask 
subject to date and sign at places specified in the questionnaires. Note: subjects who began 
treatment under older versions of this protocol prior to implementation of PRO assessments 
will not be required to complete the questionnaires. Subjects will not be required to complete 
questionnaires if unavailable in their native language. Subjects in the dose-exploration cohort 
are not required to complete PRO assessments.
5.2.8.1
Pain Questionnaire
A pain questionnaire (Appendix 2) containing one question is used: “On a scale ranging from 
0 (absent) to 10 (worst imaginable), please rate the severity of your pain in the last 24 hours.” 
5.2.8.2
EORTC QLQ-C30 and Cancer-specific Modules
The EORTC QLQ-C30 is a 30-item self-administered questionnaire (Appendix 3). There are 
9 multiple-item scales: 5 scales that assess aspects of functioning (physical, role, cognitive, 
emotional, and social); 3 symptom scales (fatigue, pain, and nausea and vomiting); and a 
global health status/quality of life scale. There are 5 single-item measures assessing 
additional symptoms commonly reported by cancer patients (dyspnea, loss of appetite, 
insomnia, constipation, and diarrhea) and a single item concerning perceived financial impact 
of the disease. All but 2 questions have 4-point scales: “Not at all,” “A little,” “Quite a bit,” 
and “Very much.” The 2 questions concerning global health status and quality of life have 


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7-point scales with ratings ranging from “Very poor” to “Excellent.” For each of the 
15 domains (9 multiple-item scales, 6 single-item scales), final scores are transformed such 
that they range from 0-100 whereas higher scores indicate greater functioning, greater quality 
of life, or greater level of symptom (Aaronson et al, 1993). 
Triple Negative Breast Cancer
For TNBC subjects, a disease-specific 23-item self-administered questionnaire for breast 
cancer was developed (EORTC QLQ-BR23; Appendix 4) to be used in conjunction with the 
EORTC QLQ-C30. It incorporates 4 functional scales (body image, sexual functioning, 
sexual enjoyment, and future perspective) and 4 symptom scales (arm symptoms, breast 
symptoms, systemic therapy side-effects, and upset by hair loss). Both questionnaires are 
widely used with cancer patients (Montazeri, 2008; Nagel et al, 2001; Svensson et al, 2010; 
Park et al, 2010).
The EORTC QLQ-BR23 contains 3 items that ask about sexual functioning. Although some 
subjects may view this as a highly personal issue area, for women with breast cancer 
sexuality can be greatly impacted. The developers of this standardized questionnaire included 
these items when the questionnaire was developed and require that they be retained. Subjects 
can skip these questions if they do not feel comfortable to answer. 
Lung Cancer
For NSCLC and SCLC subjects, a disease-specific 13-item self-administered questionnaire 
for lung cancer was developed (EORTC QLQ-LC13; Appendix 5) to be used in conjunction 
with the EORTC QLQ-C30 (Bergman et al, 1994). It comprises both multi-item and single-
item measures of lung cancer-associated symptoms (ie, coughing, hemoptysis, dyspnea, and 
pain) and side effects from conventional chemotherapy and radiotherapy (ie, hair loss, 
neuropathy, sore mouth, and dysphagia). 
Gastroesophageal Cancer
For gastroesophageal cancer subjects, a disease-specific 22-item self-
administered questionnaire for gastroesophageal cancer was developed 
(EORTC QLQ-STO22; Appendix 6) to be used in conjunction with the EORTC QLQ-C30 
(Blazeby, et al 2004). It comprises both multi-item and single-item measures of 
gastroesophageal cancer-associated symptoms (ie, dysphagia, pain, reflux, eating, anxiety) 
and side-effects from conventional chemotherapy and radiotherapy (ie, dry mouth, taste, 
body image, and hair loss). 


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Pancreatic Adenocarcinoma
For pancreatic adenocarcinoma subjects, a disease-specific 26-item self-
administered questionnaire for pancreatic adenocarcinoma was developed (EORTC 
QLQ-PAN26; Appendix 7) to be used in conjunction with the EORTC QLQ-C30 
(Fitzsimmons and Johnson, 1998; Fitzsimmons et al, 2005). The module comprises 
26 questions assessing pain, dietary changes, jaundice, altered bowel habit, emotional 
problems related to pancreatic adenocarcinoma, and other symptoms such as cachexia, 
indigestion, flatulence, dry mouth, and taste changes. 
Head and Neck Cancer
For head and neck cancer, a disease-specific 35-item self-administered questionnaire for 
head and neck cancer was developed (EORTC QLQ-H&N35; Appendix 9) to be 
used in conjunction with the EORTC QLQ-C30 (Bjordal et al, 1994; Bjordal et al, 1999; 
Bjordal et al, 2000). It comprises both multi-item and single-item measures of head and neck 
cancer-associated symptoms (ie, pain, swallowing, senses, speech, social eating, social 
contact, sexuality) and side-effects from conventional chemotherapy and radiotherapy.
The EORTC QLQ-H&N35 contain items that ask about sexual functioning. Although some 
subjects may view this as a highly personal issue area, for those with head and neck cancer 
sexuality can be greatly impacted. The developers of this standardized questionnaire included 
these items when the questionnaire was developed and require that they be retained. Subjects 
can skip these questions if they do not feel comfortable to answer.
Hepatocellular Cancer
For HCC, a disease-specific 18-item self-administered questionnaire for HCC was developed 
(EORTC QLQ-HCC18; Appendix 8) to be used in conjunction with the EORTC QLQ-C30 
(Blazeby et al, 2004). It comprises multi-item scales assessing fatigue, body image, jaundice, 
nutrition, pain, and fever, with 2 single-items addressing sexual interest and abdominal 
swelling.
The EORTC QLQ-HCC18 contains items that ask about sexual functioning. Although some 
subjects may view this as a highly personal issue area, for those with head and neck cancer or 
HCC sexuality can be greatly impacted. The developers of this standardized questionnaire 
included these items when the questionnaire was developed and require that they be retained. 
Subjects can skip these questions if they do not feel comfortable to answer.


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Melanoma
With the exception for uveal melanoma, subjects are only required to complete the EORTC 
QLQ-C30 questionnaire. For uveal melanoma subjects, since most of the metastasis are in 
liver, the liver cancer module EORTC QLQ-HCC18 (Appendix 8), will be used to collect 
subject reported liver metastasis related symptoms in conjunction with the EORTC 
QLQ C30.
Glioblastoma Multiforme
For subjects with GBM, a disease-specific, 20-item self-administered questionnaire for brain 
cancer was developed (EORTC QLQ-BN20 [Osoba et al, 1996; Taphoorn et al, 2010; 
Maringwa et al, 2011]; Appendix 10) to be used in conjunction with the EORTC QLQ-C30. 
It includes 4 symptom scales (future uncertainty, visual disorder, motor dysfunction, and 
communication deficit) and 7 symptom items (headaches, seizures, drowsiness, hair loss, 
itching skin, weakness of both legs, and bladder control). The EORTC QLQ-C30 
and the EORTC QLQ-BN20 have been used in a number of brain cancer 
clinical trials (Taphoorn et al, 2005; Keime-Giubert et al, 2007; Grabenbauer et al, 2009; 
Chinot et al, 2011; Flechl et al, 2012).
Ovarian Cancer
For subjects with ovarian cancer, a disease-specific, 28-item self-administered questionnaire 
for women with ovarian cancer was developed (EORTC QLQ-OV28; Appendix 11) to be 
used in conjunction with the EORTC QLQ-C30.  It includes 7 items on 
abdominal/gastrointestinal symptoms, 3 items on peripheral neuropathy, 7 items on other 
chemotherapy side effects, 2 items on hormonal/menopausal symptoms, 2 items 
on body image, and 3 items on attitude toward disease and treatment (Cull et al, 2001; 
Greimela et al, 2003).
The EORTC QLQ-OV28 contains 4 items that ask about sexual functioning. Although some 
subjects may view this as a highly personal issue area, for women with ovarian cancer 
sexuality can be greatly impacted. The developers of this standardized questionnaire included 
these items when the questionnaire was developed and require that they be retained. Subjects 
can skip these questions if they do not feel comfortable answering them.
5.2.8.3
FACT-BL
For subjects with bladder cancer, a disease-specific, 39-item self-administered questionnaire 
for bladder cancer was developed (Functional Assessment of Chronic Illness Therapy-


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bladder [FACT-BL]; Appendix 12). Of the 39 questions, 27 come from the Functional 
Assessment of Chronic Illness Therapy-General (FACT-G) and 12 questions are specific to 
bladder cancer. All questions inquire about the subject’s health-related quality of life during 
the past week. The FACT-BL (version 4) covers the domains of physical well-being, 
social/family well-being, emotional well-being, functional well-being as well as urinary, 
bowel, and sexual function (Cella et al, 1993).
The FACT-BL contains 3 items that ask about sexual functioning; one of these items is for 
men only. Although some subjects may view this as a highly personal issue area, for people 
with bladder cancer sexuality can be greatly impacted. The developers of this standardized 
questionnaire included these items when the questionnaire was developed and require that 
they be retained. Subjects can skip these questions if they do not feel comfortable answering 
them.
5.2.9
Estimate of Volume of Blood to be Collected
Q2W or Q3W Dosing Schedule
A total of 45 mL will be required for all screening tests, which may be conducted over 1 or 
more days during screening. No more than 51 mL of blood will be drawn on any visit day 
after screening. Approximately 179 mL of blood will be collected at all visits related to the 
first dose. The total volume to be collected will depend on the number of doses administered 
and the length of follow-up. Subjects in the first cohort in the dose-escalation phase will have 
an additional 3.5-mL blood sample drawn for PK at 2 hours after the start of the first 
infusion. 
Q4W Dosing Schedule
Approximately 28 mL will be required for all screening tests. No more than 33 mL of blood 
will be drawn on any visit day after screening. Approximately 56 mL of blood will be 
collected at all visits related to the first dose. The total volume to be collected will depend on 
the number of doses administered and the length of follow-up.
6
ASSESSMENT OF SAFETY
6.1
Safety Parameters
6.1.1
Adverse Events
The International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice 
(GCP) E6(R1) defines an AE as:


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Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE includes but is not limited to any clinically significant worsening of a subject’s 
pre-existing condition. An abnormal laboratory finding (including ECG finding) that requires 
an action or intervention by the investigator, or a finding judged by the investigator to 
represent a change beyond the range of normal physiologic fluctuation, should be reported as 
an AE.
Adverse events may be treatment emergent (ie, occurring after initial receipt of 
investigational product) or nontreatment emergent. A nontreatment-emergent AE is any new 
sign or symptom, disease, or other untoward medical event that begins after written informed 
consent has been obtained but before the subject has received investigational product.
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition that did not 
worsen from baseline is not considered an AE (serious or nonserious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE.
6.1.2
Serious Adverse Events
An SAE is any AE that:
•
Results in death
•
Is immediately life-threatening
•
This term refers to an event in which the subject was at risk of death at the time of the 
event; it does not refer to an event that may have led to death.
•
Requires inpatient hospitalization or prolongation of existing hospitalization 
•
In general, hospitalization signifies that the subject has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in an outpatient setting. 
•
Results in persistent or significant disability/incapacity 
•
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.


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•
Is a congenital anomaly/birth defect in offspring of the subject
•
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above.
•
Medical or scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in this situation. Examples of medically important events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, or convulsions that do not result in hospitalizations; or development of drug 
dependency or drug abuse.
6.1.3
Other Events of Special Interest
Adverse events of special interest are events of scientific and medical interest specific to the 
further understanding of the MEDI4736 safety profile and require close monitoring and rapid 
communication by the investigator to the sponsor. MEDI4736 AESIs may be serious or non-
serious. The rapid reporting of these AESIs allows ongoing analysis of these events in order 
to characterize and understand them in association with the use of this investigational 
product.
Adverse events of special interest for MEDI4736 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 MEDI4736 monotherapy and combination therapy. An 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 study physician.
Adverse events of special interest observed with MEDI4736 include:
•
Colitis
•
Pneumonitis
•
ALT/AST increases / hepatitis / hepatotoxicity 
•
Neuropathy/neuromuscular toxicity (ie, events of encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis)


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•
Endocrinopathy (ie, events of hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism)
•
Dermatitis
•
Nephritis
•
Pancreatitis  (or labs suggestive of pancreatitis - increased serum lipase , increased serum 
amylase)
Further information on these risks (eg, presenting symptoms) can be found in Appendix 15.
6.1.3.1
Pneumonitis
Pneumonitis has been reported in association with use of anti-PD-L1/anti-PD-1 antibodies 
(Brahmer et al 2012). Initial work-up should include a high-resolution CT scan, ruling out 
infection, and pulse oximetry. Pulmonary consultation is recommended.
Further information on these risks (eg, presenting symptoms) can be found in the current 
version of the MEDI4736 Investigator’s Brochure. Guidelines for the management of 
subjects with immune-mediated events including pneumonitis are outlined in Appendix 15.
6.1.3.2
Hypersensitivity Reactions
Hypersensitivity reactions as well as infusion-related reactions have been reported with 
anti-PD-L1 and anti-PD-1 therapy (Brahmer et al 2012). As with the administration of any 
foreign protein and/or other biologic agents, reactions following the infusion of MAbs can be 
caused by various mechanisms, including acute anaphylactic (IgE-mediated) and 
anaphylactoid reactions against the MAb, and serum sickness. Acute allergic reactions may 
occur, may be severe, and may result in death. Acute allergic reactions may include 
hypotension, dyspnea, cyanosis, respiratory failure, urticaria, pruritus, angioedema, 
hypotonia, urticaria, arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, headache, 
hypertension, myalgia, vomiting and unresponsiveness.
Guidelines for management of subjects with hypersensitivity (including anaphylactic 
reaction) and infusion-related reactions are outlined in Appendix 15.
6.1.3.3
Hepatic Function Abnormalities (Hepatotoxicity)
Increased transaminases have been reported during treatment with anti-PD-L1 
(Brahmer et al 2012). Inflammatory hepatitis has been reported in 3% to 9% of subjects 
treated with anti-CTLA-4 MAbs (eg, ipilimumab). The clinical manifestations of 


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ipilimumab-treated patients included general weakness, fatigue, nausea and/or mild fever and 
increased liver function tests such as AST, ALT, alkaline phosphatase, and/or total bilirubin.
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 
3 × ULN and concurrent increase in bilirubin to greater than 2 × ULN (ie, Hy’s law cases). 
Concurrent findings are those that derive from a single blood draw or from separate blood 
draws taken within 8 days of each other. Follow-up investigations and inquiries will be 
initiated promptly by the investigational site to determine whether the findings are 
reproducible and/or whether there is objective evidence that clearly supports causation by a 
disease (eg, cholelithiasis and bile duct obstruction with distended gallbladder) or an agent 
other than the investigational product.
If the underlying diagnosis for the hepatic function abnormality is known (including 
progression of pre-existing disease such as primary or metastatic malignancy), the diagnosis 
should be recorded as an AE/SAE.
If the underlying diagnosis for the hepatic function abnormality remains unknown, the term 
“hepatic function abnormal” should be used to report the AE/SAE.
Hepatic function abnormality of unknown etiology, or which is considered attributable to 
investigational product, is required to be reported as “hepatic function abnormal” within 
24 hours of knowledge of the event to MedImmune Patient Safety using the SAE Report 
Form, even if the event is considered to be non-serious (see Section 6.4.2.2 for contact 
information). The investigator will review the data with the medical monitor. The 
investigator should then use clinical judgment to establish the cause based on local standard 
of care and follow the subject by conducting testing as clinically indicated.
6.2
Assessment of Safety Parameters
6.2.1
Assessment of Severity
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. Severity will be graded according to the NCI CTCAE v4.03. 
The determination of severity for all other events not listed in the CTCAE should be made by 
the investigator based upon medical judgment and the severity categories of Grade 1 to 5 as 
defined below.


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Grade 1 (mild)
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not 
generally interfere with usual activities of daily living.
Grade 2 (moderate)
An event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual 
activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject.
Grade 3 (severe)
An event that requires intensive therapeutic intervention. The 
event interrupts usual activities of daily living, or significantly 
affects the clinical status of the subject.
Grade 4 (life threatening)
An event, and/or its immediate sequelae, that is associated with 
an imminent risk of death or with physical or mental 
disabilities that affect or limit the ability of the subject to 
perform activities of daily living (eating, ambulation, toileting, 
etc).
Grade 5 (fatal)
Death (loss of life) as a result of an event.
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 6.1.2. A 
Grade 3 AE need not necessarily be considered an SAE. For example, a Grade 3 headache 
that persists for several hours may not meet the regulatory definition of an SAE and would be 
considered a nonserious event, whereas a Grade 2 seizure resulting in a hospital admission 
would be considered an SAE.
6.2.2
Assessment of Relationship
6.2.2.1
Relationship to Investigational Product
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
investigational product.
An event will be considered “not related” to use of the investigational product if any of the 
following tests are met:
•
An unreasonable temporal relationship between administration of the investigational 
product and the onset of the event (eg, the event occurred either before, or too long after, 
administration of the investigational product for it to be considered product-related)


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•
A causal relationship between the investigational product and the event is biologically 
implausible (eg, death as a passenger in an automobile accident)
•
A clearly more likely alternative explanation for the event is present (eg, typical adverse 
reaction to a concomitant drug and/or typical disease-related event)
Individual AE/SAE reports will be considered “related” to use of the investigational product 
if the “not related” criteria are not met.
“Related” implies that the event is considered to be “associated with the use of the drug” 
meaning that there is “a reasonable possibility” that the event may have been caused by the 
product under investigation (ie, there are facts, evidence, or arguments to suggest possible 
causation).
6.2.2.2
Relationship to Protocol Procedures
The investigator is also required to provide an assessment of relationship of SAEs to protocol 
procedures on the SAE Report Form. This includes nontreatment-emergent SAEs (ie, SAEs 
that occur prior to the administration of investigational product) as well as treatment-
emergent SAEs. A protocol-related SAE may occur as a result of a procedure or intervention 
required during the study (eg, blood collection, washout of an existing medication). The 
following guidelines should be used by investigators to assess the relationship of SAEs to the 
protocol:
Protocol related:
The event occurred due to a procedure/intervention that was described 
in the protocol for which there is no alternative etiology present in the 
subject’s medical record.
Not protocol related: The event is related to an etiology other than the procedure/ 
intervention that was described in the protocol (the alternative etiology 
must be documented in the study subject’s medical record).
6.3
Recording of Safety Parameters
6.3.1
Recording of Adverse Events and Serious Adverse Events
Adverse events will be recorded on the CRF using a recognized medical term or diagnosis 
that accurately reflects the event. Adverse events will be assessed by the investigator for 
severity, relationship to the investigational product, possible etiologies, and whether the 
event meets criteria of an SAE and therefore requires immediate notification to MedImmune 
Patient Safety. See Section 6.1.2 for the definition of SAEs, and Section 6.2.1 and 
Section 6.2.2 for guidelines for assessment of severity and relationship, respectively. If an 


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AE evolves into a condition that meets the regulatory definition of “serious,” it will be 
reported on the SAE Report Form.
6.3.2
Recording of Other Events of Special Interest 
Hepatic Function Abnormality
Events of hepatic function abnormality (as defined in Section 6.1.3.3) should be recorded 
according to the definitions of AE and SAE (Section 6.1.1 and Section 6.1.2, respectively):
•
If an event of hepatic function abnormality is considered to be related to a pre-existing 
condition and does not represent a worsening of this condition and/or is considered to be 
within the range of normal physiological fluctuation for the subject, the event does not 
meet the definition of an AE and does not need to be recorded as such.
•
If a definitive diagnosis for an underlying condition unrelated to the investigational 
product is established for an event of hepatic function abnormality, the diagnosis should 
be recorded as an AE/SAE per Section 6.3.1.
•
If no definitive diagnosis is determined for an event of hepatic function abnormality, the 
term “hepatic function abnormal” should be used to report the AE/SAE per Section 6.3.1.
6.4
Reporting Requirements for Safety Parameters
6.4.1
Study Reporting Period and Follow-up for Adverse Events
The reporting period for AEs is the period immediately following the time that written 
informed consent is obtained through 90 days after the last dose of MEDI4736 or until the 
initiation of alternative anticancer therapy.
New (nonserious) AEs that start after the reporting period has ended will not be collected. All 
AEs that start during the reporting period will be followed to resolution through the end of 
subject participation in the study.
6.4.2
Reporting of Serious Adverse Events 
6.4.2.1
Study Reporting Period and Follow-up for Serious Adverse Events
The reporting period for SAEs is the period immediately following the time that written 
informed consent is obtained through 90 days after the last dose of MEDI4736. After 
submitting an initial SAE report for a subject (to MedImmune Patient Safety), the 
investigator is required to follow the subject proactively and provide further information on 
the subject’s condition to MedImmune Patient Safety.


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At any time after completion of the study, if an investigator or qualified designee becomes 
aware of an SAE that is suspected by the investigator or qualified designee to be related to 
investigational product, the event must be reported to MedImmune Patient Safety.
The investigator is responsible for following all SAEs until resolution, until the subject 
returns to baseline status, or until the condition has stabilized with the expectation that it will 
remain chronic, even if this extends beyond study participation.
6.4.2.2
Notifying the Sponsor of Serious Adverse Events
Within 24 hours of identifying an SAE, regardless of the presumed relationship to the 
investigational product, the investigator or qualified designee must complete the SAE 
Report Form and fax it to MedImmune Patient Safety.
MedImmune contact information: 
Patient Safety 
MedImmune
One MedImmune Way
Gaithersburg, MD 20878
USA
Fax: +1 301-398-4205
The sponsor is responsible for reporting certain SAEs as expedited safety reports to 
applicable regulatory authorities, ethics committees, and participating investigators, in 
accordance with ICH Guidelines and/or local regulatory requirements (see Section 6.4.2.3). 
The sponsor may be required to report certain SAEs to regulatory authorities within 
7 calendar days of being notified about the event; therefore, it is important that investigators 
submit additional information requested by the sponsor as soon as it becomes available.
Investigators should provide all available information at the time of SAE Report Form 
completion. Investigators should not wait to collect additional information to fully document 
the event before notifying MedImmune Patient Safety of an SAE. When additional 
information becomes available, investigators should submit a follow-up SAE Report Form 
(separate from the initial report form) with the new information. Any follow-up information 
to an SAE also needs to be provided to MedImmune Patient Safety within 24 hours of 
learning of the new information.


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6.4.2.3
Safety Reporting to Investigators, Institutional Review Boards or 
Independent Ethics Committees, and Regulatory Authorities
The sponsor is responsible for reporting all applicable SAEs to regulatory authorities, 
investigators, and IRBs/IECs, as applicable, in accordance with national regulations in the 
countries where the study is conducted. The sponsor will also prepare an expedited report for 
other safety issues where these might materially alter the current benefit-risk assessment of 
an investigational product or that would be sufficient to consider changes in the 
administration of the investigational product or in the overall conduct of the study.
For all investigators located in the European Economic Area, the sponsor will be responsible 
for reporting suspected unexpected serious adverse reactions (SUSARs) and any other 
applicable SAEs to regulatory authorities including the European Medicines Agency, 
investigators, and IRBs/IECs, as applicable, in accordance with national regulations in the 
countries where the study is conducted. Suspected unexpected serious adverse reactions will 
be submitted within 7 days for fatal and life-threatening events and within 15 days for other 
serious events, unless otherwise required by national regulations.
For all other investigators, the sponsor will prepare an expedited report for all SAEs that are 
unexpected and potentially related to the investigational product, and copies will be 
distributed to all concerned regulatory authorities, investigator(s), and IRBs/IECs according 
to applicable laws and regulations. The investigational site also will forward a copy of all 
expedited reports to the site’s applicable IRB/IEC. Investigators must also submit safety 
information provided by the sponsor to the IRB/IEC as detailed in Section 10.1 and 
Section 10.2.
6.4.3
Other Events Requiring Immediate Reporting
6.4.3.1
Overdose
An overdose is defined as a subject receiving a dose of investigational product in excess of 
that specified in the Investigator’s Brochure, unless otherwise specified in this protocol.
Any overdose of a study subject with the investigational product, with or without associated 
AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to 
MedImmune Patient Safety using the Safety Fax Notification Form (see Section 6.4.2.2 for 
contact information). If the overdose results in an AE, the AE must also be recorded on the 
AE CRF (see Section 6.3.1). Overdose does not automatically make an AE serious, but if the 
consequences of the overdose are serious, for example death or hospitalization, the event is 
serious and must be reported as an SAE (see Section 6.3.1 and Section 6.4.2).


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6.4.3.2
Hepatic Function Abnormality
Hepatic function abnormality (as defined in Section 6.1.3) in a study subject, with or without 
associated clinical manifestations, is required to be reported as “hepatic function abnormal” 
within 24 hours of knowledge of the event to MedImmune Patient Safety using the Safety 
Fax Notification Form (see Section 6.4.2.2 for contact information), unless a definitive 
underlying diagnosis for the abnormality (eg, cholelithiasis and bile duct obstruction) that is 
unrelated to investigational product has been confirmed.
•
If the definitive underlying diagnosis for the abnormality has been established and is 
unrelated to investigational product, the decision to continue dosing of the study subject 
will be based on the clinical judgment of the investigator.
•
If no definitive underlying diagnosis for the abnormality is established, dosing of the 
study subject must be interrupted immediately. Follow-up investigations and inquiries 
must be initiated by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor. If the etiology of the event remains unconfirmed and/or is 
considered related to investigational product (see Section 6.2.2.1), a prompt cumulative 
review of safety data and the circumstances of the event in question will be conducted and 
assessed by the internal safety governance bodies (see Section 6.5) to determine whether 
continued dosing of current study subjects and/or study entry should be interrupted, whether 
the protocol will be modified, or whether the study will be discontinued permanently. 
Review and approval by the internal safety governance bodies is required for resumption of 
subject dosing or study entry in the event that the study is interrupted. Where applicable, 
regulatory authorities and IRBs/IECs will be notified of any actions taken with the study.
6.4.3.3
Pregnancy
Pregnancy in a female subject who has received investigational product is required to be 
reported within 24 hours of knowledge of the event to MedImmune Patient Safety using the 
Safety Fax Notification Form (see Section 6.4.2.2 for contact information).
Subjects who become pregnant during the study period must not receive additional doses of 
investigational product but will not be withdrawn from the study. After obtaining the 
subject’s consent, the pregnancy will be followed for outcome of the mother and child 
(including any premature terminations) and should be reported to MedImmune Patient Safety
after outcome. 


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Should the investigator become aware of a pregnancy in the partner of a male study subject 
who has received investigational product(s) this should be reported within 24 hours of 
knowledge of the event to MedImmune Patient Safety or designee using the Safety Fax 
Notification Form. The sponsor will endeavor to collect follow-up information on such 
pregnancies provided the partner of the study subject provides consent.
6.4.3.4
Events Meeting Study-stopping Criteria
Events that meet any of the study-stopping criteria (Section 3.3), with or without associated 
AEs or SAEs, are required to be reported within 24 hours of knowledge of the event to 
MedImmune Patient Safety using the Safety Fax Notification Form (see Section 6.4.2.2 for 
contact information). The occurrence of these events does not automatically make an AE 
serious, but if the consequences of the event are serious, for example death or hospitalization, 
the event is serious and must be reported as an SAE (see Section 6.3.1 and Section 6.4.2).
6.5
Safety Management During the Study
The MedImmune medical monitor has primary responsibility for the ongoing medical review 
of safety data throughout the study. This includes review of SAEs and timely review of AEs 
and “other events” reported during the study. MedImmune Patient Safety is responsible for 
the receipt, immediate review, investigation, and follow-up of SAEs and other immediately 
reportable events (eg, overdose and pregnancies) reported from the clinical study sites.
A study-specific Dose Escalation Committee will provide ongoing safety surveillance of the 
study, with regularly scheduled reviews of safety and other relevant data. This committee 
will be responsible for dose-escalation decisions and making recommendations regarding 
further conduct of the study. The Dose Escalation Committee includes the MedImmune 
medical monitor for the study, the MedImmune Patient Safety physician for the study, and 
the principal investigator from each actively enrolling study site. This committee will review 
data, including all AEs, laboratory parameters, PK and pharmacodynamic data, following the 
full enrollment of any dose-escalation cohort and completion of the DLT evaluation period. 
This committee will also review data at other time points in response to AEs assessed as 
medically relevant by the medical monitor. Dose-escalation decisions and outcomes of 
reviews of safety and other relevant data will be communicated to the internal safety 
governance bodies. The sponsor will notify sites when enrollment into each dose cohort has 
been completed and when enrollment into the next dose cohort is permitted.
The MedImmune Safety Review Team (SRT) provides safety surveillance, guidance, and 
oversight for all clinical development studies of MEDI4736 in which MedImmune has 


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sponsor accountabilities. The SRT reviews protocol-specific safety data at regularly 
scheduled meetings and ad hoc meetings, and provides oversight for individual study 
protocol safety committees, such as those specified for early-phase dose-escalation studies. 
Based on review of safety data, the SRT may recommend suspension of enrollment or 
subject dosing in clinical studies, request modification of study documents, or take other 
actions as deemed necessary.
7
STATISTICAL CONSIDERATIONS
7.1
General Considerations
Data will be provided in data listings sorted by treatment group and subject number. Tabular 
summaries will be presented by treatment group. Categorical data will be summarized by the 
number and percentage of subjects in each category. Continuous variables will be 
summarized by descriptive statistics, including mean, standard deviation, median, minimum, 
and maximum. Confidence intervals (CIs) will be two-sided, unless otherwise stated. Details 
of endpoint analyses will be described in the Statistical Analysis Plan.
7.2
Analysis Populations
The DLT Evaluable Population includes all subjects enrolled in the dose-escalation phase 
who receive at least 2 doses of MEDI4736 and complete the safety follow-up through the 
DLT evaluation period (defined as the time period from the first administration of 
MEDI4736 until the planned administration of the third dose of MEDI4736) or experience 
any DLT. The DLT Evaluable Population will be used for the MTD evaluation.
The As-treated Population includes all subjects who receive any treatment with MEDI4736. 
The As-treated Population will be used to evaluate baseline characteristics as well as all 
endpoints for the safety and efficacy profiles, unless otherwise specified.
The full analysis set (FAS) includes all subjects from the As-treated Population who have 
baseline disease assessment with measurable disease per BICR and at least 24 weeks 
follow-up at the time of the data cutoff (ie, dosed at least 24 weeks prior to the time of the 
data cutoff). This is the primary analysis population for the analysis of efficacy endpoints 
using the BICR data.
The PD-L1-positive FAS includes those PD-L1-positive subjects in the FAS as defined by an 
IHC assay developed by Ventana. The PD-L1-negative FAS includes those PD-L1-negative
subjects in the FAS as defined by an IHC assay developed by Ventana. The definition for a 


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subject whose PD-L1 status is PD-L1 positive or negative may be specific for each tumor 
type, as described below.
•
For NSCLC and SCCHN cohorts, positive for PD-L1 as defined by ≥ 25% tumor cell 
membrane for PD-L1 at any intensity. A subject’s PD-L1 status will be determined from 
a fresh tumor biopsy obtained during screening and/or available archival tumor samples. 
•
For the UBC cohort, positive for PD-L1 is defined as ≥ 25% tumor cell membrane or 
≥25% immune cell staining. A subject’s PD-L1 status will be derived from a fresh tumor 
biopsy taken during screening and/or available tumor samples taken from ≤6 months 
prior to study entry. In cases where multiple samples are available, a subject’s PD-L1 
status will be derived from the most recent tumor sample (prior to first dose of study 
treatment) with a quantifiable result. If all samples taken ≤6 months prior to the study 
entry are non-evaluable by IHC, PD-L1 status may be derived form an older archival 
sample.
7.3
Endpoints
7.3.1
Primary Endpoints
For the dose-escalation phase, the primary objective is to determine the MTD or OBD, and 
safety profile of MEDI4736 in subjects with advanced melanoma, RCC, NSCLC, and CRC 
refractory to standard therapy or for which no standard therapy exists.
Endpoints related to this objective include an evaluation of DLTs, overall safety, and 
parameters related to the MTD or OBD. The MTD evaluation will be based on the DLT 
Evaluable Population. The OBD will be determined based upon analysis of all available 
subject data, including safety, PK, pharmacodynamic, biomarker, and response data.
For the dose-expansion phase, the primary objectives are: 
•
To determine the safety profile of MEDI4736 in subjects with advanced cutaneous 
melanoma, uveal melanoma, HCC, SCCHN, NSCLC squamous histology, NSCLC 
non-squamous histology, gastroesophageal cancer, TNBC, pancreatic adenocarcinoma, 
UBC, GBM, ovarian cancer, soft tissue sarcoma, SCLC, MSI-high cancers, HPV-positive 
cancers, or nasopharyngeal carcinoma.
•
To evaluate the antitumor activity of MEDI4736 in subjects with non-squamous NSCLC 
who have received 2 or more prior lines of therapy and subjects with squamous NSCLC 
who have received 1 prior lines of therapy and 2 or more prior lines of therapy.
•
To evaluate the antitumor activity of MEDI4736 in subjects with PD-L1-positive UBC.
Endpoints for safety profile include assessments of AEs, SAEs, laboratory evaluations, vital 
signs, and physical examinations. The occurrence of AEs, abnormal laboratory values, and


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SAEs reported from the signing of an ICF through 90 days after the last dose of MEDI4736 
will be summarized and/or listed for all subjects who received at least one dose of 
MEDI4736 (As-treated Population). Any SAEs occurring after 90 days after the last dose of 
MEDI4736 that, in the opinion of the investigator, are related to study drug will also be 
reported and summarized and/or listed. Adverse events and SAEs will be graded according to 
the NCI CTCAE v4.03 and described by system organ class using the Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term, severity, and relationship to MEDI4736.
The primary endpoint of antitumor activity for the NSCLC and UBC cohorts is objective 
response (OR), which is defined as a best overall response (BoR) of CR or PR according to 
RECIST v1.1 as determined by BICR. BoR is defined as the best response (in the order of 
CR, PR, SD, PD, and not evaluable) among all overall responses recorded from the start of 
treatment until objective documentation of PD (per RECIST v1.1 as assessed by BICR), or 
the last evaluable disease assessment in the absence of PD prior to initiation of subsequent 
anticancer therapy or discontinuation from the study, whichever occurs first. The best overall 
response of CR or PR must be confirmed, which means a response of CR/PR is recorded at a
visit and confirmed by repeat imaging no less than 4 weeks after the visit when the response 
was first observed with no evidence of progression between the initial and CR/PR 
confirmation visits. The ORR is defined as the proportion of subjects with OR. The 95% CI 
of ORR will be estimated using the exact probability method. 
For NSCLC, the ORR (based on RECIST v1.1 by BICR) along with its 95% CI will be 
provided for all NSCLC subjects in each line by histology and for the subpopulation in the 
≥second-line squamous NSCLC subjects who have tumoral PD-L1 expression as determined 
by prospective testing prior to enrollment.
For UBC, the primary analysis of ORR based on RECIST v1.1 by BICR will be performed 
for all UBC subjects (second-or greater line of therapy) in the PD-L1-positive FAS enrolled 
in the entire study. The primary endpoint for UBC cohort in PD-L1-positive subgroup is 
considered to be met if the lower-limit of the exact 2-sided 95% CI for ORR excludes a 
historical response rate of 10% or less (Bellmunt et al, 2009). An analysis of ORR for all 
UBC subjects in the PD-L1-positive FAS enrolled under Amendment 8 and beyond will be 
conducted as a supportive analysis. 
If the primary endpoint for the PD-L1-positive subgroup of the UBC cohort is met, the ORR 
based on RECIST v1.1 by BICR along with its 95% CI will be also provided for all UBC 
subjects (second-or greater line of therapy) in the FAS (regardless of PD-L1 status) enrolled 
in the entire study. The primary endpoint for UBC cohort in all-comers is considered to be 


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met if the lower-limit of the exact 2-sided 95% CI for ORR excludes a historical response 
rate of 10% or less (Bellmunt et al, 2009). In addition, the ORR based on RECIST v1.1 by 
BICR along with its 95% CI will be provided for all UBC subjects (second- or greater line of 
therapy) in the PD-L1-negative FAS enrolled in the entire study and in the PD-L1-negative 
FAS enrolled under Amendment 8 and beyond. The primary analysis for UBC cohort will 
occur at least 24 weeks after the last PD-L1-positive UBC subject’s first dose of study 
treatment. The analyses of ORR per BICR described above for the UBC cohort will be 
repeated for the UBC subjects (second- or greater line of therapy) in the PD-L1-positive
FAS, the PD-L1-negative FAS and the FAS (regardless of PD-L1 status) enrolled in the 
entire study. 
In order to validate the potential of PD-L1 expression to predict response to MEDI4736 
treatment, the ORR per BICR for UBC subjects in the PD-L1-positive FAS and the PD-L1-
negative FAS enrolled under Amendment 8 and beyond will be compared using one-sided 
Fisher’s exact test with a significance level of 5%. The difference in the ORR along with the 
exact 2-sided 90% CI will be estimated based on Chan and Zhang’s method based on score 
statistics (Chan and Zhang, 1999). A multivariate logistic regression analysis may be 
conducted to assess the difference after adjusting for important baseline characteristics. An 
odds ratio with its associated profile likelihood 90% CI will be provided. 
Additional analysis of ORR as determined by the investigator according to RECIST v1.1 will 
be conducted in the same manner as those described for the BICR-assessed ORR. The 
investigator’s recorded measurements and assessments for target, non-target, and new lesions 
according to RECIST v1.1 will be used to derive the overall response and progression 
programmatically.
For the dose-exploration cohort, the primary objective is to determine the safety profile of 
MEDI4736 in subjects with advanced cutaneous melanoma, uveal melanoma, HCC, SCCHN, 
NSCLC squamous histology, NSCLC non-squamous histology, gastroesophageal cancer, 
TNBC and pancreatic adenocarcinoma using a Q4W dosing schedule. Endpoints for safety 
profile including assessments of AEs, SAEs, laboratory evaluations, vital signs, and physical 
examinations will be summarized in the same manner as those described above for 
dose-expansion phase.
7.3.2
Secondary Endpoints
7.3.2.1
Pharmacokinetics
Individual MEDI4736 concentrations will be tabulated by dose cohort along with descriptive 
statistics. Noncompartmental PK data analysis will be performed for data obtained from each 


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dose cohort with scheduled PK sample collection. If data allow, descriptive statistics of 
noncompartmental PK parameters (area under the curve, Cmax, systemic clearance, half-life) 
will be provided.
A population PK model will be developed using a non-linear mixed-effects modeling 
approach in subjects treated with MEDI4736. The impact of physiologically-relevant subject 
characteristics (covariates) and disease characteristics on PK will be evaluated. The 
relationship between MEDI4736 blood exposure and response or safety will be evaluated. 
Any such analysis will be described in a separate population PK/pharmacodynamic analysis 
plan and the results for this exploratory analysis will be reported separately from the main 
study report.
7.3.2.2
Immunogenicity
The immunogenic potential of MEDI4736 will be assessed by summarizing the number and 
percentage of subjects who develop detectable ADAs. The impact of ADAs on PK will be 
assessed if data allow. Samples will be collected for evaluating neutralizing capacity of 
ADAs in the future.
7.3.2.3
Antitumor Activity
Assessments of antitumor activity will be based on the ORR (except for subgroups of 
NSCLC and UBC cohorts where OR is considered the primary endpoint), DCR, 
duration of response (DR), progression-free survival (PFS), and OS. RECIST v1.1
(Eisenhauer et al, 2009) will be used to determine tumor response (see Section 5.2.6).
The ORR is defined in Section 7.3.1. The DCR is defined as the proportion of subjects with 
CR, PR, or SD (subjects achieving SD will be included in the DCR if they maintain SD for 
≥12 weeks). Disease control rate will be analyzed in a manner similar to ORR. The 95% CI 
of DCR will be estimated using the exact probability method. Duration of response will be 
defined as the duration from the first documentation of objective response to the first 
documented disease progression or death due to any cause, whichever occurs first. For 
subjects who are alive and progression-free at the time of data cutoff for analysis, DR will be 
censored at the last tumor assessment date. The DR will only be evaluated 
for the subgroup of subjects with an objective response using the Kaplan-Meier method 
(Kaplan and Meier, 1958).
Progression-free survival will be measured from the start of treatment with MEDI4736 until 
the documentation of disease progression or death due to any cause, whichever occurs first. 
For subjects who are alive and progression-free at the time of data cutoff for analysis, PFS 


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will be censored at the last tumor assessment date. Progression-free survival will be 
evaluated using the Kaplan-Meier method. Overall survival will be determined as the time 
from the start of treatment with MEDI4736 until death. For subjects who are alive at the time 
of data cutoff for analysis or lost to follow-up, OS will be censored on the last date when 
subjects are known to be alive. The OS will be evaluated using the Kaplan-Meier method 
(Kaplan and Meier, 1958).
Separate analyses of efficacy endpoints will be performed based on BICR assessment (if 
BICR data are available) and investigator assessment.
7.3.3
Exploratory Endpoints
Descriptive statistics will be the primary methods used for the exploratory analyses. 
Depending on the nature of the data, geometric mean and other appropriate statistical 
summaries might be used as well. It is hypothesized that MEDI4736 will induce measurable 
changes in the immune status of subjects. Among the variables to be examined in the 
exploratory analyses to assess these changes are:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8. Archived tumor samples may be evaluated by IHC for PD-L1 expression on tumor cells 
to evaluate any predictive or prognostic relationship with subject response to treatment. 
The expression level and localization of other immune-related or response-related 
markers by IHC may also include, but not be limited to, CTLA-4, CD3, CD4, CD8, 
CD45RO, FoxP3, granzyme B, OX40, PD-1, cleaved caspase 3 and Ki67 
9. Fresh (de novo) tumor biopsy samples (dose-expansion phase) may be examined for 
PD-L1 target expression and localization by IHC and possibly additional markers as 
above. These studies serve the purpose of evaluating target expression and modulation, 
and lymphocyte infiltration in response to treatment with MEDI4736. Correlation 
between target expression and modulation in tumor tissue and clinical activity will also 
be evaluated
10. Archived material (or biopsies if available), will be analyzed for the presence of key 
mutations which may include but are not limited to: K-ras, N-ras, B-raf, APC, B-catenin, 
ALK and C-met to evaluate their potential relevance and correlations with response to 
MEDI4736 treatment
 
 
7.4
Subgroup Analysis
In the dose-expansion phase, the antitumor activity by baseline PD-L1 expression (positive 
vs negative), line of therapy, ECOG performance status, and metastatic site at baseline, when 
practical and appropriate, will be assessed in each as well as across all disease cohorts.
In assessment of antitumor activity in the UBC population, subjects will be also be analyzed 
by baseline hemoglobin levels (≤ 10 g/dL vs > 10 g/dL), baseline creatinine clearance levels 
(< 60 mL/min vs ≥ 60 mL/min), PD-L1 subgroups defined based on tumor cell staining only, 
and PD-L1 subgroups defined based on immune cell staining only.
7.5
Interim Analysis
For the UBC cohort, the first interim analysis will be conducted after approximately 30 PD-
L1-positive UBC subjects are enrolled and followed for at least 12 weeks. The efficacy 
analysis will be based on investigator RECIST data.
The second interim analysis for the UBC cohort will be conducted after approximately a 
minimum of 60 PD-L1-positive second- or greater line UBC subjects are enrolled in the 
entire study and followed for at least 16 weeks. The primary efficacy analysis population for 
this analysis will be based on the treated PD-L1-positive UBC subjects (second- or greater 


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line) with measurable disease at baseline per BICR who have had an opportunity of being 
followed up for at least 16 weeks by the interim analysis. The analysis will be primarily 
based on RECIST v1.1 by BICR, and additional analysis based on investigator RECIST data 
will be conducted as supportive. 
The purpose of those interim analyses for the UBC cohort will be for early evaluation of 
efficacy and safety data for internal program decision and/or potential interactions with 
regulatory agencies on future development. Additional data cut-offs for the UBC cohort may 
also take place before the primary analysis of ORR to support interactions with the regulatory 
authorities. The enrollment will not be interrupted or terminated for efficacy based on the 
interim analysis.
7.6
Sample Size and Power Calculations
 
Dose-escalation Phase
The number of subjects required will depend upon the toxicities observed as the study 
progresses. Up to approximately 50 evaluable subjects (3+3 subjects per dose cohort) could 
be required during the dose-escalation phase if the separate Q3W escalation is implemented 
upon completion of dose escalation for the MEDI4736 Q2W dose-escalation arm. More 
subjects may be enrolled to investigate intermediate doses for MTD evaluation if DLTs are 
observed in either the 3.0 or 10 mg/kg dose cohort. In addition, more subjects may be 
enrolled if doses higher than 10 mg/kg Q2W are evaluated during dose escalation. 
Non-evaluable subjects will be replaced in the same dose cohort. Table 7.6-1 provides the 
probability of dose escalation to the next higher level for each underlying true DLT rate. For 
example, for a common toxicity that occurs in 10% of subjects, there is a greater than 90% 
probability of escalating to the next higher dose level. Conversely, for a toxicity that occurs 
with a rate of 60%, the probability of escalating to the next higher dose level is less than 
10%.


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Table 7.6-1
Probability of Escalation for Different True Underlying 
Dose-limiting Toxicity Rate at a Given Dose Level
True underlying DLT rate
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of escalating dose
0.91
0.71
0.49
0.31
0.17
0.08
0.03
0.009
0.001
DLT = dose-limiting toxicity.
Dose-exploration Phase
Approximately 20 subjects will be enrolled in the dose-exploration cohort of the study to 
determine the safety of 20 mg/kg Q4W dose schedule. 
 
 
 
Dose-expansion Phase
A minimum of approximately 692 subjects will be enrolled in the dose-expansion phase as 
follows. Additional subjects, described in each cohort below, may be enrolled if promising 
clinical activity is observed in any of these cohorts.
•
Advanced cutaneous melanoma, uveal melanoma, HCC, SCCHN, gastroesophageal 
cancer, TNBC, UBC (initial cohort enrolled prior to Amendment 8), GBM, ovarian 
cancer, soft tissue sarcoma, SCLC, MSI-high cancers, and HPV-positive cancers cohorts: 
A minimum of 20 subjects will be enrolled in each of these 13 disease cohorts. The 
sample size is chosen to obtain a preliminary assessment of antitumor activity in terms of 
DCR for each disease cohort. The DCR will be estimated by the proportion of subjects 
with CR, PR, or SD ≥ 12 weeks in each disease cohort and its 80% CI will be estimated 
by the exact probability method
 
 
Additional subjects, up to a total of 60 subjects 
in any of these dose-expansion cohorts may be enrolled if promising clinical activity is 
observed in that cohort. If the HPV-positive cancers, MSI-high cancers, GBM, ovarian, 
or soft tissue sarcoma cohorts are expanded beyond 20 subjects, enrollment may be 
prioritized to tumor sub-type(s) that showed promising clinical activity, at the sponsor’s 
discretion.
Table 7.6-2
 


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Table 7.6-2
 
 
•
Pancreatic adenocarcinoma and nasopharyngeal carcinoma cohorts: A minimum of 
10 subjects will be enrolled in each of these cohorts. The DCR will be estimated by the 
proportion of subjects with CR, PR, or SD ≥ 12 weeks in each cohort and its 80% CI will 
be estimated by the exact probability method (Table 7.6-3). Additional subjects, up to a 
total of 60 subjects in either of these 2 cohorts may be enrolled if promising clinical 
activity is observed in that cohort. 
Table 7.6-3
 
 
•
NSCLC: Preliminary data from the dose-escalation phase of this study as well as data 
from other antibodies targeting the PD-1/PD-L1 pathway suggest that subjects with 
NSCLC may benefit from treatment with an agent such as MEDI4736. As a result, a 
minimum of approximately 110 subjects in the non-squamous histology NSCLC cohort 
and 170 subjects in the squamous histology NSCLC cohort will be enrolled from among 
specific subpopulations of NSCLC as outlined below. 
◦
For the non-squamous NSCLC cohort, the enrollment will include approximately 
10 subjects who are treatment naïve, approximately 20 subjects who have received 
1 prior line of therapy, and approximately 80 subjects who have received at least 
2 prior lines of therapy. Additional subjects, up to a total of 30 each for the first-line 
and second-line therapy groups, may be enrolled.
◦
For the squamous NSCLC cohort, the enrollment will include approximately 
10 subjects who are treatment naïve, approximately 80 subjects who have received 
1 prior line of therapy, and approximately 80 subjects who have received at least 2 
prior lines of therapy. Additional subjects, up to a total of 30 for the first-line therapy 
group, may be enrolled.
◦
The minimum sample sizes of 10 and 20 subjects were chosen to provide a 
preliminary assessment of ORR for MEDI4736 as first-line therapy for both 
squamous and non-squamous NSCLC and second-line therapy for non-squamous 
NSCLC, respectively, similar to the aforementioned other cohorts in other tumor 
types. 


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◦
The sample size of 80 subjects for MEDI4736 as third or greater-line therapy in 
non-squamous NSCLC and as second-line therapy as well as third or greater-line 
therapy for squamous NSCLC, respectively, was chosen to provide a formal 
statistical testing of the following hypothesis
H0: ORR ≤10% vs H1: ORR > 10%
 
 
In order to have the estimation with reasonable precision for ORR in the NSCLC 
subpopulation with subjects who have tumoral PD-L1 expression, all remaining subjects in 
the non-squamous NSCLC dose-expansion cohort will be required to have tumoral PD-L1 
expression as determined by prospective testing prior to enrollment. In the squamous NSCLC 
dose-expansion cohort, a minimum of 80 subjects in the squamous NSCLC dose-expansion 
cohorts (a minimum of 10 subjects in the first-line therapy, a minimum of 35 subjects in each 
of the second-line therapy and third-line or greater therapy cohorts) will be required to have 
tumoral PD-L1 expression as determined by prospective testing prior to enrollment. 
Table 7.6-4 provides the estimated ORR and its 95% confidence interval (CI) in squamous 
NSCLC subjects based on the exact binomial distribution.
Table 7.6-4
Estimated ORR and 95% CI in Squamous NSCLC 
Subjects with Tumoral PD-L1 Expression
Category
N = 35 a
N = 70 b
N = 80 b
Number of 
CR/PR 
observed
7
9
11
18
21
25
20
24
28
Estimated 
ORR
20%
25.7%
31.4%
25.7%
30%
35.7%
25%
30%
35%
Lower 
limit of 
95% CI
8.4%
12.5%
16.9%
16.0%
19.6%
24.6%
16.0%
20.3%
24.7%
Upper 
limit of 
95% CI
36.9%
43.3%
49.3%
37.6%
42.1%
48.1%
35.9%
41.3%
46.5%
CI = confidence interval; CR = complete response; NSCLC = non-small cell lung cancer; ORR = objective 
response rate; PD-L1 = programmed death ligand 1; PR = partial response.
a
Subjects from either second-line therapy or third-line or greater therapy squamous NSCLC
b
Subjects from the second-line therapy and third-line or greater therapy squamous NSCLC cohorts pooled 
together


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•
UBC: Under Amendment 7, approximately 60 UBC subjects were enrolled. Under 
Amendment 8 and beyond, approximately 132 additional UBC subjects with inoperable 
or metastatic disease (second- or greater line) will be enrolled, which includes 
approximately 70 PD-L1-positive and 50 PD-L1-negative subjects, assuming a PD-L1-
positive prevalence of 60% and approximately 10% of subjects with tumor samples non-
evaluable for PD-L1 (based on preliminary data from the initial UBC cohort of this study; 
see Section 1.2.3). 
Of 192 UBC subjects enrolled in the study, it is expected that there will be approximately 
100 PD-L1-positive subjects in the second- or greater line of treatment (approximately 30 
enrolled under Amendment 7 and approximately 70 enrolled under Amendment 8 and 
beyond). 
when the ORR is expected to be in the 17% to 33% range 
(Plimack et al, 2015; Rosenberg et al, 2015), a total of 100 subjects would provide a width of 
< 9% between the observed ORR and its lower limit of the exact 95% CI
 
 
Table 7.6-5
 
 
 
 
 
  


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The prevalence of PD-L1 status for UBC subjects will be monitored through the study. After 
a total of approximately 132 subjects are enrolled under Amendment 8 and beyond, the 
enrollment of only PD-L1-positive subjects may continue to ensure a minimum total of 70 
PD-L1-positive subjects are enrolled.
With 70 PD-L1-positive and 50 PD-L1-negative UBC subjects enrolled under Amendment 8
and beyond to validate the potential of PD-L1 expression to predict response to MEDI4736 
treatment, 
The response 
rate for the PD-L1-negative group is assumed to be similar to that observed with 
chemotherapy in a second-line UBC population (Bellmunt et al, 2009).
8
DIRECT ACCESS TO SOURCE DOCUMENTS
The study will be monitored by the sponsor or designee on a regular basis throughout the 
study period. During monitoring visits, the investigator will provide direct access to all 
source documentation relevant to the subject’s participation in the study. Source 
documentation includes, but is not limited to, the subject’s clinic and/or office chart, hospital 
chart, ICFs, treatment notes, laboratory reports, pharmacy records, radiographs, recorded data 
from automated instruments, and any other records maintained to conduct and evaluate the 
clinical study. The investigator must also ensure that direct access to study documents be 
made available for study-related audits, IRB/IEC review, or regulatory inspection.
9
QUALITY CONTROL AND QUALITY ASSURANCE
9.1
Data Collection
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate and accurate case histories for the subjects treated under this protocol. 
Case histories include CRFs and supporting data including, but not limited to, signed and 
dated ICFs, progress notes, hospital charts, nurse’s notes, diary cards or other worksheets 
provided to subjects, laboratory reports, ECG strips, etc.
Subject demographics and key/essential disease baseline characteristics thought to affect 
outcome, ie, stratification variables and other prognostic factors, may be collected, as 
available, for all subjects who provide written informed consent. For subjects who provided 
informed consent and were not entered into the study, the reason the subject was not entered, 
ie, did not meet one or more inclusion criteria, met one or more exclusion criteria, or other 
(eg, lost to follow-up, consent withdrawn), may also be collected.


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9.2
Study Monitoring
The primary source document for this study will be the subject’s medical record. If separate 
research records are maintained by the investigator(s), both the medical record and the 
research records will be monitored/audited for the purposes of the study.
The investigator and institutions involved in the study will permit study-related monitoring 
and provide direct access to all study records and facilities. Adequate time and space for 
monitoring visits should be made by the investigator or other investigator site staff.
The monitor will visit study facilities at periodic intervals, in addition to maintaining 
necessary contact through telephone, e-mail, and letter, to ensure that the study is conducted 
and documented in accordance with the protocol, GCP, and applicable regulations. The 
monitor will assess subject enrollment and informed consent procedures; investigational 
product storage, dispensing, administration and accountability; compliance with protocol 
procedures; completeness and accuracy of data entered onto validated data collection 
instruments (paper CRF or electronic data screen) against original source documents; the 
continued acceptability of the facilities and qualifications of the site staff; and the occurrence 
of AEs/SAEs. All aspects of the study will be carefully monitored for compliance with the 
protocol, applicable regulatory requirements, GCP, and the site’s standard operating 
procedures.
The monitor will discuss the conduct and progress of the study with the investigator and 
other site staff. The investigator must cooperate with the monitor to ensure that corrective 
action is taken to resolve any problems noted in the course of the monitoring, and that the 
preventative measures are put into place to prevent recurrence of issues. In cases where 
compliance is not achieved, shipment(s) of investigational product to the investigator will be 
discontinued and study participation by that investigator will be terminated.
9.3
Audit and Inspection of the Study
During and after the study, the sponsor or its representative may conduct audits of any data 
and any facility participating in the study. The investigator and institutions involved in the 
study will permit such study-related audits and provide direct access to all study records and 
facilities. The investigator must maintain a comprehensive and centralized filing system of 
all study-related documentation that is suitable for inspection by the sponsor or its designated 
monitors, auditors, or regulatory agency representatives. The investigator agrees to 
participate in audits conducted at a convenient time in a reasonable manner.


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Government regulatory authorities may also perform inspections either during or after the 
study. In the event of an inspection by any regulatory authority, the investigator should 
promptly notify the sponsor. The investigator agrees to cooperate fully with inspections 
conducted by regulatory authorities and to allow representatives of the regulatory authority 
access to all study records. The investigator will forward to the sponsor a copy of any 
inspection records received.
10 ETHICS
10.1
Regulatory Considerations
The study will be conducted in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with the ICH guidelines on GCP, any applicable 
laws and requirements, and any conditions required by a regulatory authority and/or IRB/IEC 
that approves this study to be conducted in its territory. Good clinical practice is defined as a 
standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and 
reporting of clinical studies in a way that provides assurance that the data and reported results 
are credible and accurate, and that the rights, safety, and well-being of study subjects are 
protected.
Per GCP, the protocol will be reviewed and approved by the IRB or IEC of each participating 
center prior to study initiation. Serious adverse events regardless of causality will be reported 
to MedImmune Patient Safety or designee, and the investigator will keep the IRB/IEC 
informed as to the progress of the study.
The investigator will explain the nature of the study and will inform the subject/legal 
representative that participation is voluntary and that the subject can withdraw or be 
withdrawn from the study at any time. Written informed consent will be obtained from each 
subject/legal representative prior to the screening procedures to determine if study eligibility 
criteria are met. A copy of the signed ICF(s) will be given to every subject/legal 
representative, and the original(s) will be maintained with the subject’s records.
10.2
Institutional Review Board or Independent Ethics Committee
A list of IRB/IEC members or a Statement of GCP Compliance should be obtained by the 
investigator and provided to the sponsor.
Any documents that the IRB/IEC may need to fulfill its responsibilities, such as protocol 
amendments, and information concerning subject recruitment, payment, or compensation 
procedures, or information from the sponsor will be submitted to the IRB/IEC. The 


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IRB/IEC’s written unconditional approval of the study protocol, the ICF(s), and any other 
written materials to be provided to subjects will be in the possession of the investigator and 
the sponsor before the study is initiated. The IRB/IEC’s unconditional approval statement 
will be transmitted by the investigator to the sponsor prior to shipment of investigational 
product supplies to the site. This approval must refer to the study by exact protocol title and 
number, and should identify the documents reviewed and the date of review.
Protocol modifications or changes may not be initiated without prior written IRB/IEC 
approval except when necessary to eliminate immediate hazards to the subjects or when the 
change(s) involves only logistical or administrative aspects of the study. Such modifications 
will be submitted to the IRB/IEC and written verification that the modification was submitted 
should be obtained.
The IRB/IEC must be informed by the investigator of ICF changes or revisions of other 
documents originally submitted for review; serious and/or unexpected adverse experiences 
occurring during the study (as applicable according to local regulations); new information 
that may affect adversely the safety of the subjects or the conduct of the study; an annual 
update and/or request for re-approval; and when the study has been completed.
10.3
Informed Consent
Freely given informed consent will be obtained and documented for all subjects under this 
protocol (or a subject’s legal representative, if the subject is unable to provide informed 
consent) in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and are consistent with the ICH guidelines on GCP, any applicable laws and 
requirements, and any conditions required by a regulatory authority and/or IRB/IEC.
Information should be given in both oral and written form, and subjects or their legal 
representatives must be given ample opportunity to inquire about details of the study. Written 
informed consent will additionally be obtained for the conduct of certain protocol-specified 
procedures including consent for biopsy of tumor tissue in the dose-expansion phase of the 
study using separate ICFs. If the study will enroll subjects who are unable to give written 
informed consent, such as incapacitated subjects, informed consent will be obtained 
according to the site’s standard operating procedures.
The ICF(s) generated by the investigator must be approved by the IRB/IEC and be acceptable 
to the sponsor. Informed consent forms must be written so as to be understood by the 
prospective subject/legal representative. Informed consent will be documented by the use of 
a written ICF(s) approved by the IRB/IEC and signed and dated by the subject or the 


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subject’s legal representative, and by the person who conducted the informed consent 
discussion. The signature confirms the consent is based on information that has been 
understood. Each subject’s signed ICF(s) must be kept on file by the investigator for possible 
inspection by the sponsor or its designated monitors, auditors, or regulatory agency 
representatives. The subject or the subject’s legal representative should receive a copy of the 
signed and dated written ICF(s) and any other written information provided to the subject, 
and should receive copies of any signed and dated consent form updates and any 
amendments to the written information provided to subjects.
10.4
Withdrawal of Consent for Continued Study Participation
Data and Samples Obtained for the Main Study
Study data are protected by the use of a subject identification number, which is a number 
specific to the subject. The investigator is in control of the information that is needed to 
connect a study sample to a subject. A subject’s consent to the use of data does not have a 
specific expiration date, but the subject may withdraw consent at any time by notifying the 
investigator. If consent is withdrawn, any data collected prior to that time may still be given 
to and used by the sponsor but no new data or samples will be collected unless specifically 
required to monitor safety of the subject.
Samples Obtained for Genetic Research or Future Research
Samples obtained for genetic research or future research will be labeled with a sample 
identification number but will not be labeled with personal identifiers such as the subject’s 
name. A file linking this sample identification number with the SID number will be kept in a 
secure place at the sponsor with restricted access. If the subject withdraws consent for 
participating in the genetic research or future research, this link will allow the sponsor to 
locate the subject’s sample and destroy it. The coding of samples and results is to ensure that 
these research results are kept confidential by keeping the subject’s identity and these results 
separate.
If the subject consents to have his/her samples used for genetic research or future research, 
this additional research may not start immediately and may start at any time during the 
storage period. The subject’s sample(s) including any specimens of extracted DNA will be 
stored by the sponsor with similar samples from other subjects at a secure central laboratory. 
The subject’s samples will not be kept for more than 25 years after the end of the study in 
which they were collected. If the subject chooses not to allow his/her study samples to be 


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used for genetic research or future research, the samples will be destroyed by the sponsor 
once they are no longer required for the main study.
If consent is withdrawn after a sample has been taken but before the subject’s sample is sent 
to the sponsor for genetic research or future research, the investigator will arrange to have it 
destroyed. If consent is withdrawn after the subject’s sample(s) have been sent to the sponsor 
for genetic research or future research, the sponsor and the investigator will ensure that these 
sample(s) are destroyed unless the sample identification number has been removed and the 
subject can no longer be linked to any sample(s). However, if the subject’s sample(s) have 
already been used for research, the sponsor is not required to destroy results of this research. 
In this case only the remaining sample(s) will be destroyed.
11 DATA HANDLING AND RECORD KEEPING
To maintain confidentiality, all laboratory specimens, evaluation forms, reports, and other 
records transmitted outside the clinical site will be identified by a subject’s identification 
number or coded number and age. All study records, source medical records, and code sheets 
or logs linking a subject’s name to an SID number will be kept in a secure location. Study 
records such as CRFs may be maintained electronically and require the same security and 
confidentiality as paper. Clinical information will not be released without written permission 
of the subject/legal representative, except as specified in the ICF(s) (eg, necessary for 
monitoring by regulatory authorities or the sponsor of the clinical study). The investigator 
must also comply with all applicable privacy regulations (eg, HIPAA 1996, EU Data 
Protection Directive 95/46/EC).
Study documents (including subject records, copies of data submitted to the sponsor, study 
notebook, and pharmacy records) must be kept secured in accordance with the specific data 
retention periods that are described in the clinical study site agreement and based upon local 
requirements. Study documents must not be destroyed without prior written approval of the 
sponsor.
12 FINANCING AND INSURANCE
Financing and insurance are addressed in the individual site contracts.
13 PUBLICATION POLICY
Publication by the site of any data from this study must be carried out in accordance with the 
clinical study site agreement.


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15 SUMMARY OF PROTOCOL AMENDMENTS AND 
ADMINISTRATIVE CHANGES TO THE PROTOCOL
Protocol Amendment 1, 11Jul2012
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 1. Major changes to the protocol are summarized below.
Section 3.1 (Overview of Study Design): The section was updated to reflect that the first 
cohort will enroll a minimum of 3 subjects and that all subjects in this cohort will receive the 
initial dose as a 4-hour infusion. If 2 or more DLTs are observed in this cohort, the starting
dose will be de-escalated as previously described. The estimated number of subjects was 
changed to 110.
Section 4.5.1.1 (Investigational Product Preparation): The section was updated to reflect that 
the first cohort will enroll a minimum of 3 subjects and that all subjects in this cohort will 
receive the initial dose as a 4-hour infusion.
Section 4.5.5 (Monitoring of Dose Administration): The frequency of monitoring of vital 
signs during all infusions was changed to every 15 minutes (± 5 minutes). After the infusion, 
subject vital signs will be assessed at the end of infusion (± 5 minutes) and at 30 minutes 
(± 5 minutes) and 60 minutes (± 5 minutes) postinfusion, followed by a 3-hour period of 
observation.
The study site must have immediate access to emergency resuscitation teams and equipment 
in addition to the ability to admit subjects to an intensive care unit if necessary.
Section 4.5.6 (Dose Escalation): The rules for dose escalation were modified so that the 
definition of the DLT evaluation period is the time from the first dose of MEDI4736 until the 
administration of the third dose. Subjects are evaluable for assessment of DLTs if they 
receive 2 full assigned doses of MEDI4736. The section was also modified to reflect that all 
dose cohorts will include more than 1 subject.
Section 4.5.7 (Dose-limiting Toxicity): The period for evaluating DLTs is from the time of 
first administration of MEDI4736 until the administration of the third dose of MEDI4736.
The DLT definition was modified so that any Grade ≥3 colitis is a DLT, as is any Grade ≥3 
irAE of rash, pruritus, or diarrhea that does not downgrade to Grade ≤2 within 3 days after 
onset despite maximal supportive care including systemic corticosteroids. Previously stated 
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Section 5.1 (Schedule of Study Procedures): Tables 5.1-1 and 5.1-2 were modified to add the 
post-infusion observation to protocol/safety evaluations. 
Section 5.1.2 (Treatment Period), Section 5.1.3 (Maintenance Period for Subjects in the 
Expansion Phase Who Achieve Disease Control), and Section 5.2.1 (Medical History and 
Physical Examination, Electrocardiogram, Weight, and Vital Signs): The interval of vital 
signs monitoring during all infusions was changed to every 15 minutes (± 5 minutes). 
Postinfusion monitoring includes vital signs assessment at the end of infusion (± 5 minutes), 
at 30 minutes (± 5 minutes) and 60 minutes (± 5 minutes) postinfusion, followed by a 3-hour 
period of observation.
Section 7.2 (Analysis Populations): The definition of the DLT Evaluable Population was 
modified so that the DLT evaluation period is defined as the time period until the 
administration of the third dose of MEDI4736. 
Section 7.5 (Sample Size and Power Calculations): The sample size was modified to reflect a 
total of up to approximately 110 evaluable subjects and up to approximately 50 subjects in 
the dose-escalation phase.
Protocol Amendment 2, 24Jul2012
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 2. Major changes to the protocol are summarized below.
1. Section 5.1 (Schedule of Study Procedures): Table 5.1-1 was modified to schedule the 
first IM assessment during treatment on the day of the Dose 3 infusion. The IM 
assessment was added per FDA request in order to capture potential early onset of ADA.
2. Section 5.1.2.9 (Odd-numbered Doses [After Dose 1]): Per FDA request, an IM 
assessment was added before Dose 3 only. Remaining IM sample times are unchanged.
3. Section 5.2.3 (Pharmacokinetic Evaluation and Methods): The list of samples taken at the 
time of the second dose was corrected by adding Day 8.
4. Section 15 (Summary of Protocol Amendments and Administrative Changes to the 
Protocol), Amendment 1, was revised to clearly state that the postinfusion observation 
period of 3 hours follows the 60-minute vital sign assessment.
Protocol Amendment 3, 12Jun2013
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 3. The protocol was amended to reflect the following:


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•
The dose-expansion phase was broadened to include MEDI4736 treatment for the 
following tumor types: advanced cutaneous melanoma, uveal melanoma, HCC, SCCHN, 
NSCLC squamous and non-squamous histology, gastroesophageal cancer, TNBC, and 
pancreatic adenocarcinoma. Colorectal cancer was removed from the dose-expansion 
phase. These additional tumor types are included in the dose-expansion phase based on 
high unmet need and preclinical data suggesting that an anti-PD-L1 antibody may be 
beneficial in these populations.
•
Changed the duration of treatment from 6 months past the observation of DC plus an 
additional 6 months of maintenance (every 2 months) treatment to a treatment period of 
up to 12 months. The maintenance treatment period has been removed from this study 
and will be evaluated in future studies. The Q2W and Q3W treatment periods were 
extended to allow for continued treatment up to 12 months in the absence of maintenance 
treatment and to allow for consistent dosing across all subjects enrolled. In addition, 
language was added to permit continuation of treatment in subjects with confirmed PD 
but no signs of clinical deterioration if investigators consider that subjects continue to 
receive benefit from treatment. In the absence of rapid clinical deterioration, these 
changes may discourage the early discontinuation of MEDI4736 and provide a more 
complete evaluation of its antitumor activity.
•
Clarified that subjects in follow-up may be retreated with MEDI4736 at the highest dose 
previously received if evidence of PD is during follow-up, and that only one round of 
retreatment will be allowed.
•
Added assessments to evaluate PRO.
•
Revised objectives to support the dose-expansion phase and addition of PROs.
•
Antitumor activity will be assessed by RECIST guidelines (v1.1; Eisenhauer et al, 2009) 
with modifications instead of irRC. RECIST guidelines are the standard basis for disease 
assessments in solid tumors and will be familiar to investigators involved in the broader, 
revised dose-expansion phase of this study. In addition, clinical data to date with PD-1 
and PD-L1 targeting antibodies suggests that the majority of response patterns will be 
amenable to assessment with RECIST-based measurement.
•
B7-H1 was changed to PD-L1 throughout the protocol for consistency.
•
In addition, clarifications were added to certain sections to aid in operational 
implementation and minor copyedits were made.
Major changes to the protocol are summarized below: 
Title page: Updated to reflect the change in medical monitor.
List of Abbreviations: Updated to match the contents of this protocol amendment.
Study Abstract: Updated to be consistent with changes made to the body of the protocol 
amendment.


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Section 1.1 (Disease Background): Additional tumor types were mentioned for the 
dose-expansion phase, the life expectancy for each, and the treatment options.
Section 1.2.2 (Summary of Nonclinical Experience): New nonclinical data were added.
Section 1.2.3 (Summary of Clinical Experience): Available clinical safety, PK, 
pharmacodynamic, and ADA data from this study were added. Clinical experience from 
competitor data was added to discuss recent advancements and rationale for additional tumor 
types being added to the dose-expansion phase.
Section 1.3 (Research Hypothesis): Updated for consistency with change in exploratory 
objectives.
Section 1.4 (Rationale for Study Conduct): Included tumor types that were added to the 
dose-expansion phase.
Section 1.5 (Benefit-risk and Ethical Assessment): Updated to include competitor efficacy 
and safety data to support additional tumor types in the dose-expansion phase.
Section 2.1 (Primary Objective): A primary objective for the dose-expansion phase was 
added.
Section 2.3 (Exploratory Objectives): An exploratory objective for PROs was added for 
consistency with exploratory endpoint analysis.
Section 3.1 (Overview of Study Design): Updated to incorporate changes to dose-expansion 
phase and clarify presentation of study design; Figure 3.1-1 was revised for consistency with 
information in text and clarity of study design. The enrollment status for the MEDI4736 
Q2W dose-escalation arm was added.
Section 3.2 (Estimated Duration of Subject Participation): Changed the duration of treatment 
from 6 months past the observation of DC plus an additional 6 months of maintenance (every 
2 months) treatment to a period of up to 12 months. The maintenance treatment period has 
been removed from this study and will be evaluated in future studies. The Q2W and Q3W 
treatment periods were extended to allow for continued treatment up to 12 months in the 
absence of maintenance treatment and to allow for consistent dosing across all subjects 
enrolled. In addition, language was added to permit continuation of treatment in subjects with 
confirmed PD but no signs of clinical deterioration if investigators consider that subjects
continue to receive benefit from treatment. In the absence of rapid clinical deterioration, 
these changes may discourage the early discontinuation of MEDI4736 and provide a more 


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complete evaluation of its antitumor activity. Also, clarified that only one round of 
retreatment with MEDI4736 will be allowed.
Section 3.3 (Study-stopping Criteria): Changes were made to the criteria to align with new 
procedures and other protocols.
Section 3.4 (Rationale for Study Design and Doses): Included rationale to support the 
additional tumor types in the dose-expansion phase and the use of RECIST v1.1 guidelines 
with modification for disease assessment. 
Section 4.2 (Subject Selection and Withdrawal): Text was added to include all tumor types 
and therapeutic response criteria for the dose-expansion phase.
Section 4.2.1 (Inclusion Criteria): Incorporated additional inclusion criteria and revised 
existing criteria to support tumor types in the dose-expansion phase.
Section 4.2.2 (Exclusion Criteria): Incorporated additional exclusion criteria and revised 
existing criteria to support tumor types in the dose-expansion phase.
Section 4.2.3 (Withdrawal Criteria): Item 5 was added to align with study procedures and 
other protocols. Item 11 was expanded to require, in addition to confirmation of PD, an 
investigator determination that the subject is no longer benefiting from treatment with 
MEDI4736.
Section 4.5.1.1 (Investigational Product Preparation): Added statement that WFI will be 
supplied by each site, and clarified investigational product preparation to align with study 
procedures.  
Section 4.5.3 (Treatment Regimen): Section was expanded to provide more detailed 
description of the treatment regimens in the dose-escalation and dose-expansion phases, and 
include figures for clarity.
Section 4.5.4 (Treatment Administration): Revised text to align with study procedures.
Section 4.5.5 (Monitoring of Dose Administration): Window of ± 15 minutes was added to 
the postinfusion 3-hour period of observation for clarification of study procedure. Dose rate 
modification was clarified for subjects experiencing Grade ≤ 2 infusion-related reactions.
Section 4.5.6 (Dose Escalation): Clarified that the Q3W dose-escalation arm will be initiated 
in parallel with the dose-expansion phase. Criteria for exploring higher doses were also 
clarified.


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Section 4.5.7 (Dose-limiting Toxicity): Deleted hormone levels to be within normal limits as 
a criterion for managed Grade 3 endocrinopathy. 
Section 4.5.8 (Dose Modification for Toxicity Management): Added that dose modification 
will not be required for laboratory abnormalities that are not deemed to be clinically 
significant; Table 4.5.8-1 modified to include additional irAE terms and toxicity assessments. 
Section 4.6.1 (Permitted Concomitant Medications): Additional details were added for 
clarification.
Section 4.6.2 (Excluded Concomitant Medications): Additional details were added for 
clarification.
Section 5.1 (Schedule of Study Procedures), Section 5.1.1 (Screening), Section 5.1.2 
(Treatment Period), Section 5.1.3 (End of Treatment), Section 5.1.4 (Post Treatment 
Follow-up): 
•
Schedule of study procedures table for the maintenance period and section describing 
assessments during the maintenance period were removed for consistency with changes 
in treatment schedule;
•
Treatment periods were clarified;
•
PRO assessments were added for the dose-expansion phase;
•
Hepatitis B and C viral titers were added for HCC subjects with hepatitis B or C;
•
Every 8-week ECG assessments were deleted and scheduled to coincide with MEDI4736 
administration;
•
Assessment schedules were modified for alignment with changes to the dose-expansion 
cohorts and to accommodate subjects in retreatment. 
•
Table 5.1-2 was revised to only present a schedule of study procedures in follow-up for 
subjects who have completed the MEDI4736 12-month treatment and achieved DC and 
subjects who have discontinued MEDI4736 due to toxicity in the absence of PD. 
•
A new appendix was created (Appendix 9) to present a separate schedule of study 
procedures in follow-up for subjects who have discontinued MEDI4736 treatment due to 
confirmed PD.
Section 5.2.2 (Clinical Laboratory Tests): Added hepatitis B and C viral titers as an 
additional safety test for HCC subjects with hepatitis B or C.


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Section 5.2.3 (Pharmacokinetic Evaluation and Methods): Assessment schedule modified for 
alignment with changes to treatment schedule; assessment schedule for subjects being 
retreated with MEDI4736 after evidence of PD in follow-up was clarified.
Section 5.2.5 (Biomarker Evaluation and Methods): Added collection of CTC from TNBC 
subjects in the dose-expansion phase. Clarified that whole blood for RNA and/or 
miRNA/mRNA sample preparation will be collected from all subjects and tumor samples 
will be collected from dose-expansion subjects.
Section 5.2.6 (Disease Evaluation and Methods): Revised tumor assessments to be based on 
RECIST guidelines (v1.1; Eisenhauer et al, 2009) with modifications. The modification 
included is to require a repeat confirmatory scan upon documentation of disease progression, 
and is similar to the irRC.
Section 5.2.7.1 (Archival Tumor Samples): Clarified that archival tumor samples must be 
deemed available during the screening period, to permit assessment of tumoral PD-L1 
expression at screening if necessary to meet minimum requirement that 10 subjects with 
NSCLC and 10 subjects with TNBC have tumoral PD-L1 expression.
Section 5.2.7.2 (Tumor Biopsies): Clarification was added for the number of subjects 
required to have tumor biopsies in the dose-expansion phase. Biopsies using fine-needle 
aspirations were removed. Core biopsies are considered to be more valuable than fine-needle 
aspirations for the analyses included in this study.
Section 5.2.8 (Patient-reported Outcomes Assessments): New section was added to support 
addition of PRO endpoint.
Section 5.2.9 (Estimate of Volume of Blood to be Collected): Updated volume of blood to be 
collected to be consistent with study procedures.
Section 6.4.3.2 (Hepatic Function Abnormality): Included “(or equivalent)” after SMC since 
it may change in name.
Section 6.5 (Safety Management During the Study): The MedImmune safety management 
description was updated to reflect current practices.
Section 7.2 (Analysis Populations): Removed Efficacy Evaluable Population and changed 
title of Safety Population to As-treated Population. With the exception of MTD evaluation, 
all analyses, including safety and efficacy, will be conducted with the As-treated Population.


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Section 7.3.1 (Primary Endpoints): Identified the tumor types to be assessed under the 
primary objective for the dose-escalation phase and added a primary objective for the 
dose-expansion phase.
Section 7.3.2.3 (Antitumor Activity): Revised to align with change to RECIST guidelines 
with modification for tumor assessment instead of irRC. Modified the definition of duration 
of response to extend to death due to any cause, so that duration of response is now defined 
as the duration from the first documentation of objective response to the first documented 
disease progression or death due to any cause, whichever occurs first.
Section 7.3.3 (Exploratory Endpoints): Items 8 and 9, revised the assessments to be 
conducted on archived and fresh tumor samples. A PRO endpoint was added to support the 
exploratory objective.
Section 7.4 (Subgroup Analysis): New section added to describe the subgroup analysis for 
the dose-expansion cohorts.
Section 7.6 (Sample Size and Power Calculations): The sample size description for the 
dose-expansion was updated to reflect the changes in the number and size of cohorts.
Appendix 1: Updated to reflect changes in signatories.
Appendices 2 through 8: New appendices providing sample PRO questionnaires.
Appendix 9: New appendix presenting a schedule of study procedures in follow-up and a 
description of each visit for subjects who have discontinued MEDI4736 treatment due to 
confirmed PD. Assessments separated from follow-up assessments for subjects who 
completed MEDI4736 treatment and achieved DC and subjects who have discontinued 
MEDI4736 due to toxicity in the absence of PD for greater clarity.
Protocol Amendment 4, 04Nov2013
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 4. The protocol was amended to reflect the following:
•
The number of subjects to be enrolled in the NSCLC cohorts was increased.
•
The dose-expansion procedures were clarified and a number of sample timepoints were 
reduced.
•
A schedule of procedures for retreatment was added as an appendix for clarity.


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Major changes to the protocol are summarized below: 
List of Abbreviations: Updated to be consistent with the body of the protocol.
Study Abstract: Updated to reflect changes in the body of the protocol amendment.
Section 1.2.3 (Summary of Clinical Experience): Safety, efficacy, and PK data were updated.
Section 1.5 (Benefit-risk and Ethical Assessment): Section was updated to reflect current 
safety and efficacy data for the study.
Section 3 (Study Design): The study flow diagram was updated to reflect the revised number 
of subjects in each dose-expansion cohort.
Section 3.1.2 (Dose Expansion): A description of the NSCLC squamous and non-squamous 
cohorts was added to give details on the number of subjects with each line of therapy. A 
revision of the description of PD-L1 positive sample requirements for each cohort was also 
added.
Section 3.4 (Rationale for Study Design and Doses): A rationale for use of MEDI4736 in 
NSCLC was added.
Section 4.2.1 (Inclusion Criteria): Inclusion criterion #3c was added to define NSCLC 
requirements. Inclusion criterion #4 was modified to discuss the number of subjects and type 
of cancer that will be required to have PD-L1 tumor positivity in the study. Inclusion 
criterion #5 was added to define the number of subjects in each NSCLC cohort that is 
required to be tumoral PD-L1 positive for this study. Inclusion criterion #6 was added to 
define disease progression and what is required for the NSCLC previous lines of therapy. 
Inclusion criterion #13 was revised to give more details around archived tumor sample 
requirements. Inclusion criterion #15 was added and inclusion criterion #16 was revised to 
give more detail around biopsy requirements.
Section 4.5.5 (Monitoring of Dose Administration): Section was revised to remove the 
requirement for 3 hour observation period for subjects in dose-expansion since only one 
infusion-related reactions has been reported in the Q2W dose-escalation cohorts.
Section 5.1 (Schedule of Study Procedures): Tables 5.1-1 and 5.1-2 were modified to 
describe sampling during the dose-expansion phase and to reduce the number of laborartory 
evaluation required for subjects.


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Section 5.1.1 (Screening), Section 5.1.2 (Treatment Period), Section 5.1.3 (End of 
Treatment), and Section 5.1.4 (Post-treatment Follow-up): Sections were updated to reflect 
the changes to the schedule of study procedures.
Section 5.2.6 (Disease Evaluation and Methods): A sentence was added to clarify that scans 
would be stored for possible future central evaluation.
Section 5.2.7.1 (Archival Tumor Samples): The description of the archival tumor sample 
requirements was clarified.
Section 5.2.7.2 (Tumor Biopsies): The section was modified to clarify requirements for 
tumor biopsies and PD-L1 tumor positivity.
Section 5.2.8.2 (EORTC QLQ-C30 and Cancer-specific Modules): Several typographical 
errors were corrected.
Section 7.3.2.1 (Pharmacokinetics): A description of population analysis was added.
Section 7.6 (Sample Size and Power Calculations): The section was updated to reflect the 
changes in samples size for the NSCLC cohorts and the requirements for number of subjects 
per cohort that need to have tumoral PD-L1 positivity.
Appendix 2 (Pain Questionnaire): An example of the pain questionnaire was added for 
clarity.
Appendix 10 (Schedule of Study Procedures for Subjects in Retreatment of MEDI4736): A 
schedule of study procedures was added to clarify what procedures are required in 
retreatment.
Protocol Administrative Change 1, 10Jan2014
The purpose of this administration change is to correct inadvertent errors created during the 
last protocol amendment.
The following changes were made:
Cover Page – EudraCT number was added.
Section 3.1.2 (Dose Expansion) – Correct a typographical error.
Section 4.5.3.1 (Treatment Regimen) – Correct a typographical error.


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Section 4.5.3.2 (Dose Expansion) - Correct a typographical error.
Section 5.1 (Schedule of Study Procedures) – Align anticancer/testis antigen antibodies 
collection time points for dose-escalation and dose-expansion phases. Clarify that Visits for 
Dose 1 Days 3 and 5 are for dose-escalation subjects only.
Section 5.1.2.1 (Dose 1, Day 1) – Added note that PBMC collection is for dose-expansion 
phase only to match Table 5.1-1.
Section 5.1.2.3 (Dose 1, Day 3) – Clarify that miRNA/mRNA collection and AE/SAE 
assessments are only for subjects in the dose-escalation phase.
Section 5.1.2.4 (Dose 1, Day 5) – Added a note that Circulating soluble factor, hematology, 
and AE/SAE collections are only for subjects in the dose-escalation phase.
Section 5.1.2.9 (Odd-numbered Doses) – Immunogenicity assessment was clarified and add 
miRNA collection for dose-expansion subjects was added.
Section 5.1.2.10 (Even-numbered Doses) – Immunogenicity, PK, and sPD-L1 collections 
were clarified for dose-escalation and dose-expansion subjects to match Table 5.1-1.
Protocol Amendment 4.1, Germany, 08May2014
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 4. The protocol was amended to reflect the following:
•
Add EudraCT number to protocol
•
Add the dose-expansion rationale to the protocol.
Major changes to the protocol are summarized below: 
Cover page: The EudraCT number was added to the protocol.
Abstract and Section 3.1.2 (Dose Expansion): A statement was added that the 10 mg/kg Q2W 
is being taken into expansion.
Section 3.4 (Rationale for Study Design and Doses): A rationale for dose-expansion was 
added.
Table 4.5.8-1 (MEDI4736 Dose Modification Due to Toxicity): The column header was 
corrected.


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Protocol Amendment 5, 21May2014
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 5. The protocol was amended to reflect the following:
•
The title of the study was changed to a Phase 1/2 to support the NSCLC and SCCHN 
expansion cohorts. The dose-escalation phase was considered the Phase 1 part of the 
study and the dose-expansion phase is considered the Phase 2 portion of the study.
•
The number of subjects to be enrolled in the SCCHN expansion cohort is being increased 
based on preliminary efficacy and safety data in the first 60 subjects. The additional 
SCCHN subjects will be enrolled according to tumoral PD-L1 expression to allow for a 
correlation to clinical response. Additional clinical characteristics (prior therapies, HPV 
status, smoking history, etc.) and potential biomarkers will also be explored in relation to 
clinical benefit derived from MEDI4736 treatment in subjects with SCCHN.
•
The pancreatic adenocarcinoma and uveal melanoma expansion cohorts are being 
increased based on preliminary efficacy and safety in the first 20-30 subjects to allow for 
additional signal searching to identify a subset of patients that may benefit from 
MEDI4736 treatment (including any correlation between PD-L1 expression and clinical 
response). 
•
Eight new expansion cohorts were added based on the potential for efficacy of 
MEDI4736 in a broad range of tumor types. These additional cohorts were chosen based 
on 1) unmet medical need, 2) PD-L1 tumoral expression, 3) evidence of responsiveness 
to other immunotherapy treatments, 4) viral etiology and expression of virally-induced 
tumor associated antigens, 5) association of the cancer with TILs, 6) high levels of tumor 
antigens due to a high mutation burden or translocations, or 7) preclinical efficacy 
modeling.
•
Digital ECGs at select sites were added to provide robust ECG data for MEDI4736 and to 
support future pivotal studies.
•
Updated MEDI4736 clinical experience was added from monotherapy studies to provide 
clinical rationale (safety and preliminary efficacy) to support continuation of the study 
and addition of newly defined expansion cohorts.
•
Some study procedures were clarified and a number of sample timepoints were reduced 
to eliminate subject burden.
Major changes to the protocol are summarized below: 
Title Page: Replaced 
 
as back-up medical monitor. In addition, the EudraCT number was added to the 
protocol cover page.
List of Abbreviations: Updated to be consistent with the body of the protocol.


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Study Abstract: Updated to reflect changes in the body of the protocol amendment.
Section 1.1 (Disease Background): Out-dated data was removed.
Section 1.2.2 (Summary on Nonclinical Experience): Final interim audited data for a 
3-month GLP toxicity study were added.
Section 1.2.3 (Summary of Clinical Experience): Safety, efficacy, and PK data were updated 
for Study CD-ON-MEDI4736-1108 and safety data for Study D4190C00002 were added. In 
addition, data on other PD-1 and PD-L1 studies were updated.
Section 1.3 (Research Hypothesis): The co-primary objectives were added for completeness.
Section 1.4 (Rationale for Study Conduct):  The rationale of the study was updated to reflect 
the additional expansion cohorts and increased SCCHN expansion cohort.
Section 1.5 (Benefit-risk and Ethical Assessment): Section was updated to reflect current 
safety and efficacy data for the study.
Section 2.1 (Primary Objective): An additional primary objective for the dose-expansion 
phase was added for SCCHN.
Section 2.3 (Exploratory Objectives): A new exploratory objective of antitumor activity 
assessed by irRECIST was added.
Section 3 (Study Design): The study flow diagram was updated to reflect the revised number 
of subjects in each dose-expansion cohort. The description of dose expansion was revised to 
include the new tumor cohorts.
Section 3.4 (Rationale for Study Design and Doses): Rationale for use of MEDI4736 in 
bladder cancer, GBM, ovarian cancer, soft tissue sarcoma, SCLC, MSI-high cancers, 
HPV-positive cancers, and nasopharyngeal carcinoma were added. A rationale for dose-
expansion dose was added.
Section 4.2.1 (Inclusion Criteria): Inclusion criterion #3 was modified to add the new tumor 
types. Inclusion criterion #6 was added to further define the SCCHN population. Inclusion 
criterion #7 was added to define the MSI-high population. Inclusion criterion #8 was added 
to define the HPV-positive cancer population. Inclusion criterion #9 was added to limit the 
GBM subject population. Inclusion criterion #10 was added to define the ovarian population. 
Inclusion criterion #13 was modified to describe the requirement for each tumor type. 


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Inclusion criterion #19 was revised to add the RANO guidelines for GBM. The biopsy 
language in inclusion criteria #22 and #23 were modified to exclude GBM.
Section 4.2.2 (Exclusion Criteria): Exclusion criterion #6 was modified to describe the 
steroid dose and duration for GBM. Exclusion criterion #25 was added to describe edema in 
subjects with GBM.
Section 4.5.1.1 (Investigational Product Preparation): The language was modified to allow 
dose preparation up to 30 mg/kg and to allow dosing day weight to be used for dose 
calculation.
Section 4.5.3.2 (Dose Expansion): The new expansion cohorts were added.
Section 4.5.8 (Dose Modification for Toxicity Management):  Pneumonitis was added as 
potential irAE.
Table 4.5.8-1 (MEDI4736 Dose Modification Due to Toxicity): The column header was 
corrected.
Section 4.6.2 (Excluded Concomitant Medications): Temporary use of corticosteroids was 
added and may be permitted upon discussion with the medical monitor for underlying or 
concurrent illness.
Section 5.1 (Schedule of Study Procedures): Table 5.1-1 was modified to reduce procedures 
and visits during expansion and to add questionnaires and procedures for the new tumor 
types. Table 5.1-2 was modified to reduce procedures in follow-up. Footnotes were added to 
both tables to describe procedures and time requirements for clarification.
Section 5.1.1 (Screening): The detailed descriptions of procedures were removed to reduce 
redundancy and errors.
Section 5.1.2 (Treatment Period): The detailed descriptions of procedures were removed to 
reduce redundancy and errors.
Section 5.1.3 (End of Treatment): Section number revised. A definition of end of treatment 
was added for clarification. The detailed descriptions of procedures were removed to reduce 
redundancy and errors.
Section 5.1.4 (Post-treatment Follow-up): The detailed descriptions of procedures were 
removed to reduce redundancy and errors.


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Section 5.2.1 (Medical History and Physical Examination, Electrocardiogram, Weight, and 
Vital Signs): A description of ECG procedures was added and a description of digital ECG 
procedures was added.
Section 5.2.6 (Disease Evaluation and Methods): The RANO guidelines for GBM were 
added. 
Section 5.2.7.2 (Tumor Biopsies): The number of tumor biopsies by tumor type was revised 
and the new expansion cohort information was added.
Section 5.2.8.2 (EORTC QLQ-C30 and Cancer-specific Modules): Description of the GBM 
and ovarian cancer-specific modules were added.
Section 5.2.8.3 (FACT-BL): Section was added to describe the bladder cancer-specific 
module.
Section 6.1.3 (Other Events of Special Interest): Definition of AESI was added and 
descriptions of pneumonitis and hypersensitivity reactions were added.
Section 7.3.1 (Primary Endpoints): The description of the endpoint for SCCHN was added 
for completeness.
Section 7.6 (Sample Size and Power Calculations): Section was revised to reflect the 
increased sample sizes and the new expansion cohorts.
Section 14 (References): New references were added to support the text in the body of the 
protocol.
Appendix 10 (Patient-reported Outcome Questionnaire EORTC QLQ-BN20): Sample 
questionnaire added.
Appendix 11 (Patient-reported Outcome Questionnaire EORTC QLQ-OV28): Sample 
questionnaire added.
Appendix 12 (Patient-reported Outcome Questionnaire FACT-BL): Sample questionnaire 
added.
Appendix 13 (Schedule of Study Procedures for Subjects in Retreatment of MEDI4736): 
Table 13-1 was modified to reduce procedures in retreatment. Footnotes were added for 
clarification of timing and to add descriptions. 
Section 15.1 (Rebaseline) and Section 15.1.1 (Retreatment Period): The detailed descriptions 
of procedures were removed to reduce redundancy and errors.


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Appendix 14 (Schedule of Study Procedures in Follow-up for Subjects Who Have 
Discontinued MEDI4736 Treatment Due to Confirmed Progressive Disease): Flow 
cytometry at 2 months was removed from Table 15-2. The collection of the FACT-BL was 
added to Table 15-2. A description of digital ECGs was added to Table 15-2 as a footnote. 
The detailed descriptions of procedures were removed to reduce redundancy and errors.
Protocol Amendment 6, 18Jun2014
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 6. The protocol was amended to remove the expanded 2L SCCHN cohort after 
consultation with the US FDA.
Protocol Administrative Change 2, 21Jul2014
The purpose of this administrative change is to correct inadvertent errors created during the 
last protocol amendment.
The following changes were made: 
•
Section 5.1 (Schedule of Study Procedures), Table 5.1-1 – Removed footnote “c” for 
flow cytometry samples in dose-expansion cohorts and corrected footnote “c” to clarify 
that the 3-hour post end of infusion sample is for subjects in dose-escalation cohorts only.
•
Appendix 13 (Schedule of Study Procedures for Subjects in Retreatment of MEDI4736), 
Table 15-1 – Row added for ECGs for Q2W dose-expansion. Fixed footnote lettering to 
start at “a”; changed immunogenicity collection to every 12 weeks starting at Dose 3 to 
match PK sample; removed post-dose sample collections for sPD-L1from Dose 1 and 
every 12 weeks starting at Dose 3 for Q2W and every third dose for Q3W; removed post-
dose sample collection for PK from every 12 weeks starting at Dose 3 for Q2W and every 
third dose for Q3W; removed post-Dose 1 collection for flow cytometry; changed flow 
cytometry collection from odd doses to even doses after Dose 2; and fixed footnote 
lettering to match list throughout the table. Post-dose samples were removed from 
circulating soluble factors and the footnote deleted.
Protocol Amendment 6, France, 30Jul2014
The protocol was amended to state that French sites will not enroll subjects in the expanded 
NSCLC cohorts.
Protocol Amendment 6, United States, 11Sep2014
The purpose of this amendment was to add a 20-subject dose-exploration cohort to examine 
the safety of 20 mg/kg dosed Q4W.


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Major changes to the protocol are summarized below: 
Title Page: Added the 2 primary medical monitors from the CRO and removed the back-up 
medical monitor. Naimish Pandya was replaced with Dominic Lai as the sponsor’s medical 
monitor.
Study Abstract: Updated to reflect changes in the body of the protocol amendment.
Section 2.1 (Primary Objective): A primary objective for the dose-exploration cohort was 
added.
Section 3.1 (Overview of Study Design): The dose-exploration cohort was added and the 
sample size was revised to reflect the additional 20 subjects. Figure 3.1-1 was revised to add 
the dose-exploration cohort. 
Section 3.1.2 (Dose Exploration): Section was added to describe the dose-exploration cohort.
Section 3.4 (Rationale for Study Design and Doses): The rational for the Q4W dosing 
schedule for dose-exploration was added.
Section 4.2 (Subject Selection and Withdrawal): The dose-exploration cohort was added.
Section 4.2.1 (Inclusion Criteria): Inclusion criterion 5f was added to define the NSCLC 
subjects to be enrolled in the dose-exploration cohort. Inclusion criterion #24 was added to 
define the dose-exploration subjects.
Section 4.2.4 (Replacement of Subjects): Dose-exploration subjects will not be replaced.
Section 4.5.3.2 (Dose Exploration): Section added to describe the Q4W treatment for the 
dose-exploration subjects.
Section 4.5.5 (Monitoring of Dose Administration): The observation period for subjects in 
the dose-exploration cohort (Q4W) was added.
Section 5.1 (Schedule of Study Procedures): Table 5.1-2 was added to describe the schedule 
of study procedures for Q4W dosing. Reference to Table 5.1-2 for Q4W dosing was added.
Section 5.1.3 (End of Treatment): Sentence removed because it was left in error when the 
procedure descriptions were removed in Amendment 5.
Section 5.2.7.2 (Tumor Biopsies): A description of when tumor biopsies will be collected for 
dose-exploration was added for clarification.


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Section 5.2.8 (Patient-reported Outcomes Assessments): A statement was added the subjects 
in the dose-exploration cohort will not complete PROs.
Section 5.2.9 (Estimate of Volume of Blood to be Collected): A subsection was added to 
describe the blood volume for the dose-exploration cohort.
Section 7.3.1 (Primary Endpoints): The primary endpoints for the Q4W dosing schedule were 
added.
Section 7.6 (Sample Size and Power Calculations): Section updated to add dose-exploration 
cohort.
Appendix 13 (Schedule of Study Procedures for Subjects in Retreatment of MEDI4736): For 
Table 15-1, footnote “c” was added to PBMC collection for even numbered doses starting 
after Dose 2.
Appendix 14 (Schedule of Study Procedures in Follow-up for Subjects Who Have 
Discontinued MEDI4736 Treatment Due to Confirmed Progressive Disease): For Table 
15.1.1-1, Day 14 and Month 2 samples were removed for PK and sPD-L1.
Protocol Administrative Change 3, 06Oct2014
The purpose of this administrative change is to change the medical monitors and to correct 
inadvertent errors created during the last protocol amendment. 
The following changes were made:
Cover Page – The medical monitor section was updated to add the PRA medical monitors, to 
change the sponsor’s medical monitor from Naimish Pandya to Dominic Lai, and to remove 
the back-up medical monitor.
Section 5.1 (Schedule of Study Procedures) – A sentence was removed that was left in error. 
A sentence was added to point to the retreatment schedule. The location of the study 
procedures table for subject with progressive disease was corrected from Appendix 13 to 
Appendix 14. For Table 5.1-1, footnote “f” was added for PBMC samples in dose-expansion 
cohorts.
Section 5.1.3 (End of Treatment) – A sentence describing the end of treatment procedures 
that were removed in the last amendment was removed. The sentence referring to Appendix 
14 was moved to Section 5.1 (see above).
Section 5.1.4 (Post-treatment Follow-up) – Section was fixed to correct typographical error.


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Section 5.2.1 (Medical History and Physical Examination, Electrocardiogram, Weight, and 
Vital Signs) – A typographical error in the abbreviation of ECG was corrected.
Appendix 13 (Schedule of Study Procedures for Subjects in Retreatment of MEDI4736), 
Table 15-1 – Footnote “c” was added for PBMC samples for even numbered doses after 
Dose 2.
Appendix 14 (Schedule of Study Procedures: Follow-up for Subjects Who 
Have Discontinued MEDI4736 Treatment Due to Confirmed Progressive Disease), 
Table 15.1.1-1 – Samples for Day 14 and 2 months post dose were removed or PK and 
sPD-L1.
Protocol Amendment 7, 17Nov2014
The purpose of this amendment was to change tumoral PD-L1 requirements for future 
subjects being enrolled. In addition, the toxicity management guidelines were updated to 
discuss inflammatory reactions attributed to local antitumor response. In addition, wording 
was removed to allow French sites to enroll in the expanded NSCLC cohorts.
Study Abstract: Updated to reflect changes in the body of the protocol amendment.
Section 1.2.3.1 (MEDI4736): Safety, efficacy, and PK data were updated for Study CD-ON-
MEDI4736-1108.
Section 1.5 (Benefit-risk and Ethical Assessment): Safety date for Study CD-ON-
MEDI4736-1108 was updated.
Section 3.1.3 (Dose Expansion): Table 3.1-1 was updated with recent data. Tumoral PD-L1 
status requirements were modified.
Section 4.2.1 (Inclusion Criteria): Tumoral PD-L1 requirements were changed in inclusion 
criterion #13.
Section 4.2.2 (Exclusion Criteria): Exclusion criterion #12 was modified to remove untreated 
CNS metastases.
Section 4.5.8 (Dose Modification for Toxicity Management): Guidelines were added to 
discuss inflammatory reactions attributed to local antitumor response. Guidelines for infusion 
related reactions were added for all grades to the table for clarity.
Section 5.2.7.2 (Tumor Biopsies): Tumoral PD-L1 status requirements were changed.


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Section 6.4.3.3 (Pregnancy): Reporting requirement for pregnancy in partners of male study 
subjects was added to align with global safety procedures. 
Section 7.3.1 (Primary Endpoint): The analysis for ORR by line of therapy and histology in 
the NSCLC subpopulations with subjects who have tumoral PD-L1 expression was added.
Section 7.6 (Sample Size and Power Calculations): Sample size justification for the 
requirements on tumoral PD-L1 expression for NSCLC subjects is provided.
Protocol Amendment 8, 25Nov2015
The purpose of this amendment was to expand the UBC cohort in the dose-expansion phase 
to evaluate the antitumor activity of MEDI4736 in subjects with PD-L1-positive UBC and 
validate the potential for PD-L1 expression to predict response to MEDI4736 treatment. In 
addition, the toxicity management guidelines were updated to reflect the current version 
(02Oct2015), and they were moved from the body of the protocol (Section 4.5.8) to 
Appendix 15. Key changes are listed below.
1. Title page: 
as the sponsor’s medical monitor.
2. Study Abstract: Updated to reflect changes in the body of the protocol amendment.
3. Section 1.2.3 (Summary of Clinical Experience): Updated to be consistent with the 
current MEDI4736 Investigator’s Brochure (version 8.0). In addition, data on the 
correlation between MEDI4736 clinical activity and PD-L1 expression were added to 
support expansion of the UBC cohort.
4. Section 1.4 (Rationale for Study Conduct): Updated to reflect the assessment of a 
correlation between PD-L1 expression and response to MEDI4736 treatment.
5. Section 1.5 (Benefit-risk and Ethical Assessment): Revised to reflect the updated data 
presented in Section 1.2.3 (Summary of Clinical Experience) and to be consistent with 
the updated emerging safety profile in the current MEDI4736 Investigator’s Brochure 
(version 8.0).
6. Section 2.1 (Primary Objective): Added a primary objective for the dose-expansion phase 
that will assess the antitumor activity of MEDI4736 in subjects with PD-L1-positive 
UBC.
7. Section 2.2 (Secondary Objectives): Updated this section to include secondary objectives 
for evaluation of the antitumor activity of MEDI4736 in UBC subjects by PD-L1-
negative status, comparing PD-L1-positive and PD-L1-negative status, and regardless of 
PD-L1 status.
8. Section 3.1 (Overview of Study Design): Updated to reflect expansion of the UBC cohort 
in the dose-expansion phase. In addition, updated the number of subjects (by tumor type) 
enrolled into the dose-expansion phase to show the most current enrollment status (based 
on data cutoff date of 20Nov2015).
9. Section 3.1.3 (Dose Expansion) and Section 3.4 (Rationale for Study Design and Doses): 
Updated to reflect expansion of the UBC cohort and rationale for the expansion (ie, 


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evaluation of the antitumor activity of MEDI4736 in subjects with PD-L1-positive UBC 
and validation of the potential of PD-L1 expression to predict response to treatment).
10. Section 4.2.1 (Inclusion Criteria): Revised the criteria to include the expanded UBC 
cohort. The following criteria were revised or added: 
◦
#5 (histology and prior treatment)
◦
#13d (tumor PD-L1 expression requirements)
◦
#19a, b (measureable lesions)
◦
#20 (archival tumor tissue)
◦
#22 (lesion amenable to biopsy)
◦
#23 (consent for biopsy samples)
11. Section 4.2.2 (Exclusion Criteria): Revised the criteria to include the expanded UBC 
cohort or other required updates. The following criteria were revised or added:
◦
#4 (prior exposure to immunotherapy)
◦
#13 (other invasive malignancy)
◦
#25 (prior participation in studies that include MEDI4736)
12. Section 4.5.8 (Dose Modification for Toxicity Management): Revised to be consistent 
with the updated emerging safety profile in the current MEDI4736 Investigator’s 
Brochure (version 8.0). In addition, dose modification and management guidelines for 
MEDI4736 were updated to be consistent with the 02Oct2015 version, and the guidelines 
tables were moved from this section to Appendix 15.
13. Section 5.1 (Schedule of Study Procedures): Updated schedule of study procedures tables 
to reflect expansion of the UBC cohort.
14. Section 5.2.6 (Disease Evaluation and Methods): Updated to indicate that a modified 
RECIST may be used to discourage early discontinuation of MEDI4736 and provide a 
more complete evaluation of antitumor activity than would be seen with conventional 
response criteria. In addition, disease assessment by BICR was added.
15. Section 5.2.7 (Archival Tumor Samples and Tumor Biopsies): Updated to include 
requirements for expanded UBC cohort.
16. Section 6.1.3 (Other Events of Special Interest): Added new AESI template language.
17. Section 6.5 (Safety Management During the Study): Replaced reference to “MedImmune 
SMC (or equivalent)” with “internal safety governance bodies”.
18. Section 7 (Statistical Considerations): Updated to reflect expansion of the UBC cohort for 
evaluation of the antitumor activity of MEDI4736 in subjects with PD-L1-positive UBC 
and validation of the potential correlation between PD-L1-positive expression and 
response to MEDI4736 treatment.
Protocol Amendment 9, 04Feb2016
The purpose of this amendment was to update eligibility criteria and PD-L1 testing 
requirements for the UBC cohort. In addition, clarifications were made to the analysis 
population for the UBC cohort. Key changes are listed below.


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1. Study Abstract: Updated to align with changes made to the protocol body.
2. Section 1.5 (Benefit-risk and Ethical Assessment): Updated with rationale to lower the 
creatinine clearance requirement for UBC subjects to ≥ 30 mL/min. 
3. Section 3.1 (Overview of Study Design): Updated subject enrollment numbers.
4. Section 3.1.3 (Dose Expansion): Changed to update the PD-L1 requirements for subjects 
in the UBC cohort such that subjects with a non-evaluable tumor sample will not be 
excluded. In addition, it was clarified that tumor samples to be used for PD-L1 testing 
must be shipped to, and confirmed as received by, the Sponsor or designated central 
vendor prior to dosing. It is estimated that approximately 10% of subjects will have 
tumors that are non-evaluable for PD-L1. As such, the sample size of the UBC cohort 
was increased by 10% from approximately 120 to approximately 132 subjects. Additional 
archival tumor tissue from beyond 6 months prior to study entry is also required, if 
available.
5. Section 4.2.1 (Inclusion Criteria): Updated as follows:
a.
Criterion 14.d was updated to reflect tumor tissue (fresh and/or recent within 6 
months prior to study entry) for PD-L1 analysis must be shipped to the Sponsor or 
designated central vendor prior to the first dose of investigational product. However, 
subjects may be dosed prior to known PD-L1 results. Subjects in the UBC cohort 
must also provide additional older archival tissue regardless of age, if available.
b. Criterion 19.f was updated to specify that UBC subjects with a creatinine clearance of 
≥ 30 mL/min will be eligible for study entry. 
c.
Criterion 21 was updated to indicate the additional tissue requirement for the UBC 
cohort, with reference to criterion 14d.
d. Criteria 16 and 17 and Table 4.2.1-1 were modified to align contraceptive 
requirements with other protocols and with new template language.
6. Section 4.2.2 (Exclusion Criteria): Criterion 13 was updated to clarify incidental 
histologic findings of prostate cancer would include findings that, in the opinion of the 
investigator, do not require active therapy (eg, following cystoprostatecomy that is 
tumor/node/metastasis stage ≤ pT2N0). Subjects with such findings may be enrolled 
pending discussion and approval with the study physician.
7. Section 4.4 (Blinding): Revised to remove formal blinding of PD-L1 status. However, 
existing procedures will be maintained to keep PD-L1 status for UBC subjects enrolled 
under Amendment 8 or above blinded from participating investigators/site staff, subjects, 
and contract research organization/Sponsor personnel who are involved in reviewing the 
clinical data. Detailed procedure to ensure the blinding will be specified under a separate 
study document.  
8. Table 5.1-1 (Schedule of Study Procedures: Screening and Treatment Period): Footnote i 
was modified to indicate that additional older archival tissue is required of UBC subjects 
if available. Footnote j was added to indicate that disease assessments performed as 
standard of care prior to signing of informed consent may be used for screening if 
obtained within 28 days prior to first dose of investigational product.
9. Table 5.1-2 (Q4W Schedule of Study Procedures: Screening and Treatment Period): 
Footnote f was added to indicate that disease assessments performed as standard of care 


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prior to signing of informed consent may be used for screening if obtained within 28 days 
prior to first dose of investigational product.
10. Section 5.1.1 (Screening): Revised to clarify that standard of care disease assessments
obtained within 28 days prior to first dose of investigational product may be used for 
screening, even if obtained prior to subjects signing informed consent. This change was 
made to avoid unnecessary repeated disease assessments. Footnote i was added to 
indicate that for subjects in the UBC cohort, additional archival tissue from > 6 months 
prior to study entry is also required, if available.
11. Section 5.2.7.1 (Archival Tumor Samples): For subjects in the UBC cohort who provide a 
fresh tumor biopsy or an archived tumor specimen from within 6 months prior to study 
entry (ie, from subject signing consent to participate in the study) for PD-L1 IHC analysis 
during screening for PD-L1 IHC testing, additional archival tumor tissue from > 6 
months prior to study entry is also required, if available.
12. Section 7.3.1 (Primary Endpoints) and Section 7.5 (Interim Analysis): Updated to reflect 
the change in PD-L1 requirements and clarify analysis population for the UBC cohort. 
13. Section 7.6 (Sample Size and Power Calculations): Updated to increase number of 
additional enrolled UBC subjects to take into account that PD-L1 status for some enrolled 
UBC subjects will be not evaluable due to change on PD-L1 requirements. Additional 
updates were made to be consistent with the updates in Section 7.3.1 (Primary 
Endpoints).


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Appendix 1
Signatures
Sponsor Signatures
A Phase 1/2 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MEDI4736 
in Subjects With Advanced Solid Tumors
I agree to the terms of this protocol and all amendments/administrative changes.
Signature and date: 
Electronic signature is appended _______
Clinical Development Therapeutic Area Head
One MedImmune Way, Gaithersburg MD, 20878, USA 
Telephone number: 


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Signature of Principal Investigator
A Phase 1/2 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MEDI4736 
in Subjects With Advanced Solid Tumors
I, the undersigned, have reviewed this protocol and all amendments, and I agree to conduct 
this protocol in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and are consistent with the International Conference on Harmonisation (ICH) 
guidelines on Good Clinical Practice (GCP), any applicable laws and requirements, and any 
conditions required by a regulatory authority and/or Institutional Review Board/Independent 
Ethics Committee (IRB/IEC).
I understand that the protocol may not be modified without written approval of the sponsor. 
All changes to the protocol must be submitted to the applicable regulatory authority and 
IRB/IEC, and must be approved by the IRB/IEC prior to implementation except when 
necessary to eliminate immediate hazards to the subjects or when the change(s), as deemed 
by the sponsor, involves only logistical or administrative changes. Documentation of 
IRB/IEC approval must be sent to the sponsor immediately upon receipt.
Signature and date: 
Name and title:  
Address including postal code: 
  
Telephone number: 
Site/Center Number (if available)
This document contains confidential information, which should not be copied, referred to, released, or published 
without written approval from MedImmune or AstraZeneca. Investigators are cautioned that the information in 
this protocol may be subject to change and revision.


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Appendix 2
Pain Questionnaire
Q1. On a scale ranging from 0 to 10, please rate the severity of your pain in the last 24 hours.
0
1
2
3
4
5
6
7
8
9
10
Absent
Worst 
imaginable


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Appendix 3
Patient-reported Outcome Questionnaire EORTC QLQ-
C30


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Appendix 4
Patient-reported Outcome Questionnaire EORTC QLQ-
BR23


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Appendix 5
Patient-reported Outcome Questionnaire EORTC QLQ-
LC13


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Appendix 6
Patient-reported Outcome Questionnaire EORTC QLQ-
STO22


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Appendix 7
Patient-reported Outcome Questionnaire EORTC QLQ-
PAN26


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Appendix 8
Patient-reported Outcome Questionnaire EORTC QLQ-
HCC18


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Appendix 9
Patient-reported Outcome Questionnaire EORTC QLQ-
H&N35


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Appendix 10
Patient-reported Outcome Questionnaire EORTC QLQ-
BN20


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Appendix 11
Patient-reported Outcome Questionnaire EORTC QLQ-
OV28


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Appendix 12
Patient-reported Outcome Questionnaire FACT-BL


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Appendix 13
Schedule of Study Procedures for Subjects in 
Retreatment of MEDI4736


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Table 1
Schedule of Study Procedures: Rebaseline and Retreatment Period
Evaluation
Rebaseline
Day -28 to 
Day -1
Treatment Period (12 Months)
Dose 1
Dose 2 
(± 3 
days)
Odd-
numbered 
Doses 
(after 
Dose 1; 
± 3 days)
Even-
numbered 
Doses 
(after 
Dose 2; 
± 3 days)
After 6 
Weeks 
(Day 43 
± 7 days)
After 12 Weeks and 16
Weeks (Days 85 and 
113) Then Every 8 
Weeks (± 7 days)
Days
Days
1
5 ± 1
10 ± 1
1
Verify discontinuation criteria 
not met
X
X
Medical history
X
Hepatitis B and C; HIV
X
Serum βhCG
X
Urine hCG or serum βhCG
X
X
X
X
Kit assignment and 
MEDI4736 administration
X
X
X
X
Protocol/Safety Evaluations
Physical examination
X
X
X
X
X
Vital signs a
X
X
X
X
X
Postinfusion observation
X
X
X
X
Weight
X
X
X
X
X
AE/SAE assessment
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
ECOG performance status
X
X
X
X
X
Laboratory Evaluations
Hepatitis B and C viral titers 
(only HCC subjects with 
hepatitis B or C)
X
X
Serum chemistry 
X
X
X
X
X


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Table 1
Schedule of Study Procedures: Rebaseline and Retreatment Period
Evaluation
Rebaseline
Day -28 to 
Day -1
Treatment Period (12 Months)
Dose 1
Dose 2 
(± 3 
days)
Odd-
numbered 
Doses 
(after 
Dose 1; 
± 3 days)
Even-
numbered 
Doses 
(after 
Dose 2; 
± 3 days)
After 6 
Weeks 
(Day 43 
± 7 days)
After 12 Weeks and 16
Weeks (Days 85 and 
113) Then Every 8 
Weeks (± 7 days)
Days
Days
1
5 ± 1
10 ± 1
1
Thyroid function tests (TSH 
and free T3 and T4)
X
X
X
X
X
Hematology
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
Coagulation parameters
X
X
X
X
Flow cytometric analysis -
absolute cell counts, immune 
cell subsets, activation markers
X
X 
X
X b
Circulating soluble factors c
X
X 
X 
X b
Disease Evaluations
Disease assessment 
X
X
X
Optional tumor biopsy (dose-
expansion phase only) c
X
X
AE = adverse event; βhCG = beta human chorionic gonadotropin; ECOG = Eastern Cooperative Oncology Group; HCC = hepatocellular carcinoma; hCG = 
human chorionic gonadotropin; HIV = human immunodeficiency virus; SAE = serious adverse event; TSH = thyroid-stimulating hormone; UBC = urothelial 
bladder cancer.  
a
Vital signs within an hour prior to the start of infusion, every 15 minutes (± 5 minutes) during MEDI4736 administration, at the end of infusion 
(+ 5 minutes), and at 30 and 60 minutes (± 5 minutes) postinfusion, followed by a 3-hour (± 15 minutes) period of observation. For subsequent doses (at 
dose levels of 10 mg/kg or less), the 3-hour observation period will not be required unless a subject experiences an infusion-related reaction or a higher 
dose level is being tested.
b
Sample collected at Dose 4 only.
c
Not required for subjects in the UBC cohort.


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Rebaseline
All rebaselining procedures must be performed within 28 days before the first retreatment 
dose of investigational product (Day -28 to Day 1), unless otherwise specified. The 
rebaseline evaluations may be carried out over more than one visit. If the subject has 
completed any safety laboratory tests or ECOG assessment within 72 hours of Day 1, they 
will not need to be repeated.
Retreatment Period
If the subject has completed any safety laboratory tests or ECOG assessment within 72 hours 
of Day 1, they will not need to be repeated.


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Appendix 14
Schedule of Study Procedures in Follow-up for 
Subjects Who Have Discontinued MEDI4736 Treatment 
Due to Confirmed Progressive Disease


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Table 1
Schedule of Study Procedures: Follow-up for Subjects Who Have Discontinued MEDI4736 
Treatment Due to Confirmed Progressive Disease
Evaluation
End of 
Treatment
Time Since Last Dose of MEDI4736
Days
(± 3)
Months (± 1 week)
12 Months and 
Every 
3 Months 
(± 2 weeks)
14
30
2
3
4
6
8
10
Protocol/Safety Evaluations
Pain questionnaire (dose-expansion phase only)
X
X
EORTC QLQ-C30 and cancer-specific modules (dose-expansion 
phase only)
X
X
FACT-BL (UBC subjects only)
X
X
Physical examination
X
X
Vital signs
X
X
Weight
X
X
Electrocardiogram a,b
X
X
AE/SAE assessment
X
X
X
X
X
Concomitant medications
X
X
X
ECOG performance status
X
X
Subsequent anticancer therapy
X
X
X
X
X
X
X
Survival status: phone contact with subjects who refuse to return for 
evaluations and agree to be contacted
X
X
X
X
X
X
X
Laboratory Evaluations
Hepatitis B and C viral titers (only HCC subjects with 
hepatitis B or C)
X
X
Hematology
X
X
Serum chemistry 
X
X
Thyroid function tests (TSH, and free T3 and T4)
X
X
Coagulation parameters
X
X
Urinalysis
X
X


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Table 1
Schedule of Study Procedures: Follow-up for Subjects Who Have Discontinued MEDI4736 
Treatment Due to Confirmed Progressive Disease
Evaluation
End of 
Treatment
Time Since Last Dose of MEDI4736
Days
(± 3)
Months (± 1 week)
12 Months and 
Every 
3 Months 
(± 2 weeks)
14
30
2
3
4
6
8
10
Pharmacokinetic assessment
X b
X b
X
Immunogenicity assessment 
X b
X b
X
sPD-L1 concentration b
X
X
Flow cytometric analysis - absolute cell counts, immune cell subsets, 
activation markersb
X
Circulating soluble factors b
X
X
PBMC collection (immunodiversity, flow cytometry, or functional 
assessment) b
X
Anticancer/testis antigen antibodies b
X
Circulating tumor cells (dose escalation and TNBC for dose 
expansion)
X
X
miRNA/mRNA analysis b
X
X
Disease Evaluation
Disease assessment
X
AE = adverse event; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 = European Organisation for Research and 
Treatment of Cancer quality-of-life questionnaire; FACT-BL = Functional Assessment of Chronic Illness Therapy-bladder; HCC = hepatocellular carcinoma; 
miRNA = micro ribonucleic acid; mRNA = messenger ribonucleic acid; PBMC = peripheral blood mononuclear cell; SAE = serious adverse event; sPD-L1= 
soluble programmed death ligand 1; TNBC = triple negative breast cancer; TSH = thyroid-stimulating hormone; UBC = urothelial bladder cancer. 
a
Digital ECGs will be collected at selected sites. All other sites will perform ECGs per their institution’s standard.
b
Not required for subjects in the UBC cohort.


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1 ASCO Educational Book 2015. Michael Pestow, MD. “Managing Immune Checkpoint Blocking Antibody Side Effects”.


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2 ASCO Educational Book 2015. Michael Pestow, MD. “Managing Immune Checkpoint Blocking Antibody Side Effects”.


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 Educational Book 2015. Michael Pestow, MD. “Managing Immune Checkpoint Blocking Antibody Side Effects”.


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4 FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation.


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testing 


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or 
autonomic instability


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 = acetylcholine esterase; AE = adverse event; ALP = alkaline phosphatase; ALT = alanine transaminase; ASCO = American Society of Clinical 
Oncology; AST = aspartate transaminase; BUN = blood urea nitrogen; CT = computed tomography; CTCAE = Common Terminology for Adverse Events; 
 
 


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SAP_001.pdf: 
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Statistical Analysis Plan
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Statistical Analysis Plan
Protocol Number: CD-ON-MEDI4736-1108
A Phase 1/2 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MEDI4736 
in Subjects With Advanced Solid Tumors


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Table of Contents
1
Introduction............................................................................................ 7
2
Study Overview ...................................................................................... 7
2.1
Study Objectives ................................................................................................ 7
2.1.1
Primary Study Objective(s)..................................................................... 7
2.1.2
Secondary Objectives.............................................................................. 8
2.1.3
Exploratory Objectives ........................................................................... 8
2.2
Study Design...................................................................................................... 8
2.3
Randomization and Blinding ............................................................................ 11
2.4
Sample Size Considerations.............................................................................. 12
2.4.1
MEDI4736 Dose-escalation .................................................................. 12
2.4.2
MEDI4736 Dose-exploration................................................................ 12
2.4.3
MEDI4736 Dose-expansion.................................................................. 13
2.4.3.1
NSCLC Cohorts ................................................................... 13
2.4.3.2
UC cohort............................................................................. 15
2.4.3.3
Cohorts Requiring a Minimum of 20 Subjects....................... 17
2.4.3.4
Cohorts Requiring a Minimum of 10 Subjects....................... 17
3
Statistical Methods ............................................................................... 18
3.1
General Considerations .................................................................................... 18
3.1.1
PD-L1 Expression Status ...................................................................... 19
3.2
Analysis Populations ........................................................................................ 20
3.3
Study Subjects.................................................................................................. 22
3.3.1
Subject Disposition and Completion Status........................................... 22
3.3.2
Demographics and Baseline Characteristics .......................................... 22
3.3.3
Study Drug Exposure............................................................................ 23
3.3.4
Concomitant Medications ..................................................................... 24
3.4
MTD/OBD Analysis......................................................................................... 24
3.5
Efficacy Analyses............................................................................................. 24
3.5.1
Primary Efficacy Endpoint and Analyses .............................................. 25


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3.5.2
Secondary Efficacy Endpoints and Analyses......................................... 27
3.5.3
Exploratory Efficacy Endpoints and Analyses....................................... 31
3.5.4
Subgroup Analysis................................................................................ 32
3.5.5
Handling of Dropouts and Missing Data ............................................... 34
3.6
Safety Analyses................................................................................................ 34
3.6.1
Adverse Events..................................................................................... 35
3.6.1.1
Adverse Events of Special Interest (AESI)............................ 37
3.6.1.2
AESIs During Which Systemic Steroids, Endocrine Therapy, or 
Other Immunosuppressants Were Administered.................... 38
3.6.1.3
Immune-mediated Adverse Events (imAE)........................... 39
3.6.1.4
Mortality .............................................................................. 41
3.6.1.5
Subgroup Analyses............................................................... 42
3.6.2
ECG ..................................................................................................... 43
3.6.3
Clinical Laboratory Parameters............................................................. 43
3.6.4
Vital Signs............................................................................................ 46
3.7
Pharmacokinetics of MEDI4736....................................................................... 46
3.7.1
......................................................................... 47
3.8
..................................................... 47
3.9
Assessment of Immunogenicity of MEDI4736 ................................................. 47
3.10
..................................................................... 48
4
Interim Analysis ................................................................................... 48
4.1
Interim Analyses for NSCLC Cohort................................................................ 48
4.2
Interim Analyses for UC cohort........................................................................ 49
4.2.1
Interim Analysis for PD-L1 Cutoff in UC ............................................. 49
4.2.2
Planned Interim Analysis for Efficacy................................................... 49
4.2.3
Additional Interim Analysis for Efficacy............................................... 51
4.2.4
Other Interim Analysis.......................................................................... 51
5
References............................................................................................. 52


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List of In-Text Tables
Table 2.2-1
Number of Subjects Enrolled by Tumor Type in Dose Expansion 
Cohorts ............................................................................................ 10
Table 2.4.1-1
Probability of Escalation for Different True Underlying Dose-limiting 
Toxicity Rate at a Given Dose Level ................................................ 12
Table 2.4.3-2
... 14
Table 2.4.3-3
…………………………………………16
Table 2.4.3-4
……………………..17
Table 2.4.3-5
……………………..18
Table 3-1
Summary of efficacy and safety variables and analysis populations.. 21
Table 3.5-1
Censoring Rule for Analysis of PFS………………..………………..28


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List of Abbreviations
Abbreviation or 
Specialized Term
Definition
ADA
Anti-drug antibody
AE
Adverse event
AESI
AEs of special interest
CI
Confidence interval
CR
Complete response
CRC
Colorectal cancer
CRF / eCRF
Case Report Form (electronic)
DC
Disease control
DCR
Disease control rate
DLT
Dose-limiting toxicity
DoR
Duration of response
DMPK
Drug Metabolism and Pharmacokinetics
ECG
Electrocardiography
ECOG
Eastern Cooperative Oncology Group
FTIH
First time in human
IC
Immune-cell
IM
Immunogenicity
imAE
Immune-mediated Adverse Event
IV
Intravenous
MedDRA
Medical Dictionary for Regulatory Activities
MTD
Maximum tolerated dose
NCI CTCAE
Common Terminology Criteria for Adverse Events (National Cancer 
Institute, Washington, DC)
NSCLC
Non-small cell lung cancer
OBD
Optimal biological dose
ORR
Overall response rate
OS
Overall survival
PD
Progressive disease


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Abbreviation or 
Specialized Term
Definition
PFS
Progression-free survival
PK-PD
Pharmacokinetics-Pharmacodynamics
PR
Partial response
PK
Pharmacokinetic(s)
Q2W
Every two weeks (Q = quoque, Latin)
Q3W
Every three weeks (Q = quoque, Latin)
Q4W
Every four weeks (Q = quoque, Latin)
RCC
Renal cell carcinoma
SAE
Serious adverse event
SAS
Statistical Analysis System (Cary, NC, USA)
SD
Stable disease
SPP
Statistical programming plan
TC 
Tumor-cell 
TEAE
Treatment-emergent adverse event
TSH
Thyroid-stimulating hormone 
UC
Urothelial carcinoma 


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1
Introduction
This document describes the statistical methodology and summaries for Study CD-ON-
MEDI4736-1108, and investigation of MEDI4736 in adult subjects with advanced solid 
tumors. As background information, an overview of the study design is provided. The main 
portion of this document details the statistical summaries relating to each study objective and 
describes the general conventions and definitions that will be used.
In addition, a set of table templates and specifications are planned to be created in a statistical 
programming plan (SPP) to complement this document.
2
Study Overview
2.1
Study Objectives
2.1.1 Primary Study Objective(s)
Dose-escalation Phase
The primary objective of the dose-escalation phase is to determine the MTD or OBD, and the 
safety profile of MEDI4736 in subjects with advanced melanoma, RCC, NSCLC, and CRC 
refractory to standard therapy or for which no standard therapy exists. 
Dose-expansion Phase
The primary objectives of the dose-expansion phase are: 

To evaluate the antitumor activity of MEDI4736 in subjects with non-squamous 
NSCLC who have received 2 or more prior lines of therapy and subjects with 
squamous NSCLC who have received 1 prior lines of therapy and 2 or more prior 
lines of therapy as assessed by RECIST version 1.1 guidelines. 

To evaluate the antitumor activity of MEDI4736 in subjects with PD-L1-high 
urothelial carcinoma (UC) as assessed by RECIST v1.1.

To determine the safety profile of MEDI4736 in subjects with advanced cutaneous 
melanoma, uveal melanoma, HCC, SCCHN, NSCLC squamous histology, NSCLC 
non squamous histology, gastroesophageal cancer, TNBC, pancreatic 
adenocarcinoma, urothelial carcinoma, glioblastoma multiforme (GBM), ovarian 
cancer, soft tissue sarcoma, small-cell lung cancer (SCLC), microsatellite instability 
(MSI) high cancers, human papilloma virus (HPV) positive cancers, or 
nasopharyngeal carcinoma.


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Dose-exploration Cohort
The primary objective of the dose-exploration cohort is to determine the safety profile of 
MEDI4736 using an every 4 weeks (Q4W) dosing schedule in subjects with advanced 
cutaneous melanoma, uveal melanoma, HCC, SCCHN, NSCLC squamous histology, NSCLC 
non-squamous histology, gastroesophageal cancer, TNBC or pancreatic adenocarcinoma.
2.1.2 Secondary Objectives

To describe the PK of MEDI4736

To determine the immunogenicity of MEDI4736

To evaluate the antitumor activity of MEDI4736 (except for subgroups of UC and 
NSCLC subjects where this is considered a primary objective) as assessed by RECIST 
v1.1.

To evaluate the antitumor activity of MEDI4736 in subjects with UC, regardless of 
PD-L1 status as assessed by RECIST v1.1.

To evaluate the antitumor activity of MEDI4736 in subjects with PD-L1-low/neg UC 
as assessed by RECIST v1.1.
To evaluate the antitumor activity of MEDI4736 as assessed by RECIST v1.1 in
subjects with PD-L1-high UC as compared to PD-L1-low/neg UC.
2.1.3 Exploratory Objectives
 
 
 
2.2
Study Design
Study CD-ON-MEDI4736-1108 is a multicenter, open-label, first-time-in-human (FTIH) 
dose-escalation, dose-exploration, and dose expansion study of MEDI4736 to evaluate the 
safety, tolerability, PK, IM, and antitumor activity of MEDI4637 in adult subjects with solid 
tumors. The dose-escalation phase will be conducted according to a standard 3+3 design at 


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doses from 0.1 to 10 mg/kg MEDI4736 Q2W and 15 mg/kg Q3W in subjects with advanced 
melanoma, renal cell carcinoma (RCC), NSCLC, or colorectal cancer (CRC) followed by a 
dose expansion phase in subjects with advanced cutaneous melanoma, uveal melanoma, 
HCC, SCCHN, NSCLC squamous histology, NSCLC non-squamous histology, 
gastroesophageal cancer, TNBC, pancreatic adenocarcinoma, urothelial carcinoma, GBM, 
ovarian cancer, soft tissue sarcoma, SCLC, MSI high cancers, human papilloma virus (HPV) 
positive cancers, or nasopharyngeal carcinoma; In addition, a dose exploration cohort will 
examine MEDI4736 at an alternative dosing schedule (20 mg/kg MEDI4736 Q4W) in 
subjects with advanced cutaneous melanoma, uveal melanoma, pancreatic adenocarcinoma, 
NSCLC, HCC, SCCHN, gastroesophageal cancer, TNBC or pancreatic adenocarcinoma. A 
study flow diagram of the study design is shown in Figure 2.2.1.
Figure 2.2.1
Study Flow Diagram
           
          
CRC = colorectal cancer; HCC = hepatocellular carcinoma; MTD = maximum tolerated dose; NSCLC = non-
small cell lung cancer; OBD = optimal biological dose; PK = pharmacokinetic; Q2W = every 2 weeks; Q3W = 
every 3 weeks; Q4W = every 4 weeks; RCC = renal cell carcinoma; SCCHN = squamous cell carcinoma of the 
head and neck; TNBC = triple negative breast cancer.
The Q3W MEDI4736 dose-escalation arm, the Q4W dose-exploration cohort, and the MEDI4736 dose-expansion 
phase will be conducted in parallel. 


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Table 2.2-1
Number of Subjects Enrolled by Tumor Type in Dose Expansion Cohorts
Tumor Type
Total Planned Enrollment
Advanced cutaneous melanoma
20
Uveal melanoma
20-60
HCC
20-60
SCCHN
20-60
Squamous NSCLC (Total)
     1L
     2L
     ≥ 3L
170-190
     10-30
     80
     80
Non-squamous NSCLC (Total)
     1L
     2L
     ≥ 3L
110-140
     10-30
     20-30
     80
Gastroesophageal
20-60
TNBC
20- 60
Pancreatic adenocarcinoma
10-60
UC (Total)
     Initial UC subjects
     Amendment 8 and beyond
        PD-L1 high
        PD-L1 low/neg
        Non-evaluable for PD-L1
20-192
20-60
132
≥ 70
50
12
GBM (Total)
     MGMT negative
20-60
     ≥ 10
Ovarian cancer (Total)
     Platinum sensitive
20-60
     ≥ 10
Soft tissue sarcoma
20-60
SCLC
20-60
MSI-high cancers
20-60
HPV + tumors (Total)
     Cervical cancer
20-60
     ≤ 10 a
Nasopharyngeal carcinoma
10-60
Total
692-1,322
In the Dose-expansion cohorts, an evaluation of a possible correlation between clinical 
activity of MEDI4736 and potential biomarkers (eg, PD-L1 expression on tumor or sPD-L1) 
for different disease types will be ongoing throughout the study. Initially, tumoral PD-L1 
expression will be assessed on screening samples after enrollment on an ongoing basis. After 
a cut-off determination for this assay, a minimum numbers of subjects with tumoral PD-L1 
expression above a pre-specified cut-off level (referred to hereafter as PD-L1 high) in the 


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applicable disease cohorts may be required by prospective testing prior to enrollment. After 
the first 20-40 subjects in each of HCC, gastroesophageal cancer, TNBC, UC, GBM, ovarian 
cancer, soft tissue sarcoma, SCLC, HPV-positive cancers, pancreatic adenocarcinoma, and 
nasopharyngeal carcinoma dose-expansion cohorts are enrolled, additional subjects in the 
applicable cohorts may be required to have tumoral PD-L1 expression as determined by 
prospective testing prior to enrollment. 
For UC cohort, an initial cohort of 63 subjects were enrolled prior to Amendment 8. Amongst 
these, the first 20 subjects were enrolled regardless of PD-L1 expression, and the remaining 
43 subjects were enrolled with a requirement of ≥ 5% tumor cells for PD-L1 expression
regardless of immune cell for PD-L1 expression in a pre-treatment tumor biopsy specimen. 
Under Amendment 8 and beyond of this protocol, the UC cohort will be expanded to evaluate 
the antitumor activity of MEDI4736 in subjects with PD-L1-high UC and validate the 
potential of PD-L1 expression (determined by IHC) to predict response to MEDI4736 
treatment. Approximately 132 additional UC subjects (regardless of PD-L1 status) will be 
enrolled in this cohort in order to include a minimum of 70 PD-L1-high subjects and 
50 subjects with PD-L1-low/no expression, and approximately 12 subjects with non-
evaluable PD-L1 status. 
 
 
2.3
Randomization and Blinding
This is an open-label and single-arm study. Randomization and blinding are not applicable to 
this study. However, for UC subjects enrolled under Amendment 8 or above, Investigators/ 
site staff, subjects and CRO/Sponsor personnel involved in reviewing the clinical data will be 
blinded to individual PD-L1 status. Investigators/site staff may be notified that a subject has 
an evaluable tumor sample or not, but the specific PD-L1 status (ie, PD-L1-high vs. PD-L1-
low/neg) will be blinded. Unblinding to individual PD-L1 status for those who were enrolled 
under Amendment 8 or above and included in the planned interim and primary/final analyses 
will occur after database lock for the respective analyses. 
In order to monitor the enrollment with respect to number of subjects with PD-L1-high and 
PD-L1-low/neg enrolled into the study, the aggregate PD-L1 status will be provided by a 
designated person who is not a member of the study team. Detailed procedure to ensure the 
blinding was specified under a separate study document.  


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Personnel at Ventana involved in testing PD-L1 status will be blinded to clinical data (except 
for information provided in the requisition form).
2.4
Sample Size Considerations
 
 
 
 
2.4.1 MEDI4736 Dose-escalation 
The number of subjects will depend upon the toxicities observed as the study progresses. Up 
to approximately 50 evaluable subjects (3+3 subjects per dose cohort) could be required 
during the dose-escalation phase if the separate Q3W escalation is implemented upon 
completion of dose escalation for the MEDI4736 Q2W dose-escalation arm. More subjects 
may be enrolled to investigate intermediate doses for MTD evaluation if DLTs are observed 
in either the 3.0 or 10 mg/kg dose cohort. In addition, more subjects may be enrolled if doses 
higher than 10 mg/kg Q2W are evaluated during dose escalation. Non-evaluable subjects will 
be replaced in the same dose cohort. Table 2.4.1-1 provides the probability of dose escalation 
to the next higher level for each underlying true DLT rate. For example, for a common 
toxicity that occurs in 10% of subjects, there is a greater than 90% probability of escalating to 
the next higher dose level. Conversely, for a toxicity that occurs with a rate of 60%, the 
probability of escalating to the next higher dose level is less than 10%.
Table 2.4.1-1
Probability of Escalation for Different True Underlying Dose-limiting Toxicity 
Rate at a Given Dose Level
True underlying DLT rate
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of escalating dose
0.91
0.71
0.49
0.31
0.17
0.08
0.03
0.009
0.001
DLT = dose-limiting toxicity.
2.4.2 MEDI4736 Dose-exploration 
Approximately 20 subjects will be enrolled in the dose-exploration cohort of the study to 
determine the safety of 20 mg/kg Q4W dose schedule. 
 


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2.4.3 MEDI4736 Dose-expansion 
A minimum of approximately 560 subjects will be enrolled in the dose-expansion. Additional 
subjects, described in each cohort below, may be enrolled if promising clinical activity is 
observed in any of these cohorts.
2.4.3.1 NSCLC Cohorts
Preliminary data from the dose-escalation phase of this study as well as data from other 
antibodies targeting the PD-1/PD-L1 pathway suggest that subjects with NSCLC may benefit 
from treatment with an agent such as MEDI4736. As a result, a minimum of approximately 
110 subjects in the non-squamous histology NSCLC cohort and 170 subjects in the squamous 
histology NSCLC cohort will be enrolled from among specific subpopulations of NSCLC as 
outlined below. 

For the non-squamous NSCLC cohort, the enrollment will include approximately 
10 subjects who are treatment naïve, approximately 20 subjects who have received 
1 prior line of therapy, and approximately 80 subjects who have received at least 2 
prior lines of therapy. Additional subjects, up to a total of 30 each for the first-line and 
second-line therapy groups, may be enrolled.

For the squamous NSCLC cohort, the enrollment will include approximately 
10 subjects who are treatment naïve, approximately 80 subjects who have received 
1 prior line of therapy, and approximately 80 subjects who have received at least 2 
prior lines of therapy. Additional subjects, up to a total of 30 for the first-line therapy 
group, may be enrolled.

The minimum sample sizes of 10 and 20 subjects were chosen to provide a 
preliminary assessment of ORR for MEDI4736 as first-line therapy for both 
squamous and non-squamous NSCLC and second-line therapy for non-squamous 
NSCLC, respectively, similar to the aforementioned other cohorts in other tumor 
types. 

The sample size of 80 subjects for MEDI4736 as third or greater-line therapy in 
non-squamous NSCLC and as second-line therapy as well as third or greater-line 


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therapy for squamous NSCLC, respectively, was chosen to provide a formal statistical 
testing of the following hypothesis
H0: ORR ≤10% vs H1: ORR > 10%
 
 
NSCLC Cohorts with Tumoral PD-L1 Expression Requirement
In order to have the estimation with reasonable precision for ORR in the NSCLC 
subpopulation including subjects who have tumoral PD-L1 expression, all remaining subjects 
as of protocol Amendment 7 in the non-squamous NSCLC dose-expansion cohort will be 
required to have tumoral PD-L1 expression as determined by prospective testing prior to 
enrollment. In the squamous NSCLC dose-expansion cohort, a minimum of 80 subjects will 
be required to have tumoral PD-L1 expression as determined by prospective testing prior to 
enrollment. Table 2.4.3-1 provides the detailed requirement of tumoral PD-L1 expression in 
NSCLC cohorts. 
 
Table 2.4.3-1
NSCLC Dose-expansion Cohort PD-L1 Expression Requirements
Cohort
Total Planned Enrollment (n)
Tumoral PD-L1 Requirement 
Squamous NSCLC (Total)
     1L
     2L
     ≥ 3L
170-190
     10-30
     80
     80
Minimum of 80 PD-L1+
     Minimum of 10 PD-L1+
     Minimum of 35 PD-L1+
     Minimum of 35 PD-L1+
Non-squamous NSCLC (Total)
     1L
     2L
     ≥ 3L
110-140
     10-30
     20-30
     80
All remaining subjects PD-L1+
     All remaining subjects PD-L1+
     All remaining subjects PD-L1+
     All remaining subjects PD-L1+
NSCLC = non-small cell lung cancer; PD-L1 = programmed cell death ligand 1.


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Table 2.4.3-2
 
 
2.4.3.2 UC cohort
Of 192 UC subjects enrolled in the study, it is expected that there will be approximately 100 
PD-L1-high subjects in the second- or greater line of treatment (approximately 30 enrolled
under Amendment 7 and approximately 70 enrolled under Amendment 8 and beyond). 
 
when the ORR is expected to be in the 17% to 33% range (Plimack et 
al, 2015; Rosenberg et al, 2015), a total of 100 subjects would provide a width of < 9% 
between the observed ORR and its lower limit of the exact 95% CI
 


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Table 2.4.3-3
 
 
 
 
  
The prevalence of PD-L1 status for UC subjects will be monitored through the study. After a 
total of approximately 132 subjects are enrolled under Amendment 8 and beyond, the 
enrollment of only PD-L1-high subjects may continue to ensure a minimum total of 70 PD-
L1-high subjects are enrolled.
With 70 PD-L1-high and 50 PD-L1-low/no expression UC subjects enrolled under 
Amendment 8 and beyond to validate the potential of PD-L1 expression to predict response 
to MEDI4736 treatment
 
. 


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The response rate for the PD-L1-low/neg group is assumed to be similar to that observed with 
chemotherapy in a second-line UC population (Bellmunt et al, 2009).
2.4.3.3 Cohorts Requiring a Minimum of 20 Subjects
Advanced cutaneous melanoma, uveal melanoma, HCC, SCCHN, gastroesophageal cancer, 
TNBC, GBM, ovarian cancer, soft tissue sarcoma, SCLC, MSI-high cancers, and 
HPV-positive cancers cohorts: A minimum of 20 subjects will be enrolled in each of these 
13 disease cohorts. The sample size is chosen to obtain a preliminary assessment of antitumor 
activity in terms of Disease Control Rate (DCR) for each disease cohort. The DCR will be 
estimated by the proportion of subjects with CR, PR, or SD ≥ 12 weeks in each disease 
cohort and its 80% CI will be estimated by the exact probability method 
 
 
 
Additional subjects, 
up to a total of 60 subjects in any of these dose-expansion cohorts may be enrolled if 
promising clinical activity is observed in that cohort. If the HPV-positive cancers, MSI-high 
cancers, GBM, ovarian, or soft tissue sarcoma cohorts are expanded beyond 20 subjects, 
enrolment may be prioritized to tumor sub-type(s) that showed promising clinical activity, at 
the sponsor’s discretion.
Table 2.4.3-4
%
 
2.4.3.4 Cohorts Requiring a Minimum of 10 Subjects
Pancreatic adenocarcinoma and nasopharyngeal carcinoma cohorts: A minimum of 
10 subjects will be enrolled in each of these cohorts. The DCR will be estimated by the 
proportion of subjects with CR, PR, or SD ≥ 12 weeks in each cohort and its 80% CI will be 
estimated by the exact probability method (Table 2.4.3-5). Additional subjects, up to a total 
of 60 subjects in either of these 2 cohorts may be enrolled if promising clinical activity is 
observed in that cohort. 


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Table 2.4.3-5
 
 
3
Statistical Methods
3.1
General Considerations
This study encompasses a variety of disease types, dose levels and dosing schedules in 3
phases (dose escalation, dose expansion and dose exploration). Therefore, final analyses for 
the clinical study report may be performed at a different time separately for each disease type. 
For each disease type, the data cut-off (DCO) for the primary analysis may take place at least 
24 weeks after the last subject is enrolled into each disease type, unless otherwise specified.
The final analysis for each disease type including all study endpoints may take place when 
overall survival for that disease type is considered mature or after the end of study. At the 
time of analysis, subject population data (i.e. demographic/baseline characteristics, 
disposition and treatment exposure) and safety data will also be summarized across all 
disease types as appropriate. In general, ccategorical data will be summarized by frequency 
distribution (number and percentage of subjects falling within each category). Continuous 
variables will be summarized by descriptive statistics.
Assessments of change from baseline to post-baseline or the ratio of post-baseline to baseline 
will include only those subjects with both baseline and post-baseline measurements. Unless 
otherwise specified, the baseline is defined as the last non-missing observation collected on 
or prior to the date of the first dose of study drug for treated subjects. The missing data for a 
parameter will not be imputed and the subjects with the missing data will be excluded from 
the summary of this parameter, unless otherwise specified. In general, all calculations will be 
performed prior to rounding.
The data analyses will be conducted using the SAS® System (SAS Institute, Inc., Cary, NC, 
USA) Version 9.3 or above in Unix (Sun OS) environment. All SAS® programs used to 
generate analytical results will be developed and validated 
.


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3.1.1 PD-L1 Expression Status 
PD-L1 expression status (high and low/neg) will be derived from percent of tumor cells 
and/or immune cells exhibiting cell surface staining for PD-L1 based on pre-specified 
threshold, assessed by IHC. In the case of multiple specimens (fresh biopsies and/or archival 
tissues) a subject’s PD-L1 status will be derived based on baseline PD-L1 expression, which 
is determined from the most recent tumor sample (prior to first dose of study treatment) with 
a quantifiable result.

For NSCLC and SCCHN cohorts, PD-L1 high subject is defined as a subject’s 
baseline PD-L1 expression with tumor-cell score [TC] ≥ 25%; PD-L1 low/neg subject 
is defined as a subject’s baseline PD-L1 expression with TC < 25%.

For the UC cohort, PD-L1 high subject is defined as a subject’s baseline PD-L1 
expression with TC ≥ 25% or immune-cell score [IC] ≥ 25%; PD-L1 low/neg subject 
is defined as a subject’s baseline PD-L1 expression with TC < 25% and IC< 25%. 
o
Note: when immune cell area represent ≤1% of the total tumour area, subjects
are defined as:

PD-L1 high when baseline PD-L1 expression with TC ≥ 25% or IC is 
100%. 

PD-L1 low/neg when baseline PD-L1 expression with TC < 25% and 
IC < 100%. 

For UC cohort, additional PD-L1 subgroups of interest based on baseline PD-L1 
expression are defined as the followings: 
o
TC high (TC ≥ 25%) vs TC low/neg (TC < 25%)
o
IC high (IC ≥ 25%) vs IC low/neg (IC < 25%)
o
Note: when immune cell area represent ≤1% of the total tumour area, 
subjects are defined as:

IC high when baseline PD-L1 expression with IC is 100%. 

IC low/neg when baseline PD-L1 expression with IC < 100%. 


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3.2
Analysis Populations
The Analysis Populations to be used for primary/final analyses are described below. The 
analysis population to be used for interim analyses are described in Section 4.
As-treated Population is defined as all subjects who receive any dose of MEDI4736.
Full analysis set (FAS) Population is defined as all subjects from the As-treated Population 
who had measurable disease at baseline per blinded central review (BICR) and had an 
opportunity to be followed for at least 24 weeks by the DCO date (i.e., received the first dose 
of MEDI4736 at least 24 weeks prior to the DCO date).

Measurable disease at baseline per BICR will be determined according to the BICR 
efficacy review (See details in BICR charter). Measurability will be determined by the 
reviewer selected by the adjudicator (if present). If no adjudication is required, then if 
either reviewer determines the subject to have measurable disease at baseline, the 
subject will be considered to be measurable. 
DLT Evaluable Population is defined as all subjects enrolled in the dose-escalation phase 
who receive at least two doses of MEDI4736 and complete the safety follow-up through the 
DLT evaluation period (defined as the time period until the administration of the third dose of 
MEDI4736) or experience any DLT. 
Re-treated Population is defined as all subjects who have entered follow-up and have been re-
treated with MEDI4736 after the initial 12 months treatment period.
The number and percent of subjects in each analysis population for evaluation will be 
summarized as described in Section 3.1. Unless stated otherwise, outcome variables will be 
summarized based on analysis populations given in Table 3-1.


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Table 3-1
Summary of efficacy and safety variables and analysis populations
Outcome variable
Populations
Efficacy Data
ORR, DCR, BoR, DoR, DSD (using BICR dara)
FAS (primary population)/ As-treated 
Population (supportive population)
ORR DCR, BoR, DoR, DSD (using investigator 
data)
As-treated Population
PFS, OS, 
As-treated Population
Safety Data 
DLT
DLT Evaluable Population
Demography and baseline characteristics
As-treated Population/FAS
Subject  disposition 
As-treated Population/FAS
Prior and Concomitant Medications
As-treated Population
Exposure
As-treated Population
Adverse events
As-treated Population
Laboratory measurements
As-treated Population
Vital Signs
As-treated Population
ECG
As-treated Population
BoR Best objective response; DCR Disease control rate; DoR Duration of response; DSD Duration of stable 
disease; ORR Objective response rate; OS Overall survival; PFS Progression-free survival
All analyses will be based on the treatment that the subject actually received. Efficacy data 
and/or safety data will be summarized for the initial treatment period and re-treatment period 
separately, unless otherwise specified. For safety summary, initial treatment period is defined 
from the time of first dose to the time of being re-treated or till 90 days (+7 days to allow visit 
window) after the last dose of the initial treatment period, whichever comes first. Re-
treatment period is defined from the time of first dose of being re-treated till 90 days (+7 days 
to allow visit window) after the last dose of the re-treatment period.  Efficacy data and/or 
safety data during the re-treatment period may be summarized for Re-treatment population if 
data warranted, in which case a small set of summaries of efficacy and safety data from the 


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re-treatment period only, and summaries of safety data from the initial treatment period and 
the re-treatment period aggregated will be produced.
To avoid biasing the central reviewers, the baseline scans prior to re-treatment will not be 
identified (see further in the BICR charter) thus there is no intention to differentiate between 
efficacy data from the re-treatment period based upon BICR and those from the initial 
treatment period.
3.3
Study Subjects
3.3.1 Subject Disposition and Completion Status
The number and percentage of subjects screened, screed failed, reasons for screening failures, 
treated, completed treatment, and not completed treatment due to any of the following 
reasons: AE; Death; Lost to follow-up; Investigator discretion; Subject non-compliant with 
treatment; Initiation of alternative therapy; Withdrawal of consent; Disease progression; 
Protocol violation; Subject request; and Other will be summarized.
Subject status at the end of study will be summarized in terms of the number and percent of 
subjects who are classified as the following: completed protocol-defined end of study, lost to 
follow-up, withdrawal of consent, death, or other.
3.3.2 Demographics and Baseline Characteristics
The following demographics and baseline characteristicswill be listed and/or summarised:

Demographic: demographic information related to sex, age, race, ethnicity, weight, 
and height will be presented. 

Disease characteristics at baseline: A summary of disease characteristics at baseline 
may include, but not be limited to disease stage, time from initial diagnosis to study 
entry. 

Baseline tumor characteristics will be summarized, including number and sites of both 
target lesions and non-target lesions.

Prior cancer treatment: The summary may include, but not be limited to the number of 
prior systemic regimen for SCCHN or line of prior therapy for NSCLC and UC 
cohorts, type of treatment (i.e. surgery, radiotherapy, chemotherapy, biologic).
Smoking History and other smoking related variables (for cigarette users, extent of 
use will be expressed as pack years).


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
ECOG: ECOG performance status will be summarized using frequency distribution.
Summary of disease specific baseline characteristics will also be included but not limited to:

NSCLC: histology, exposure to prior TKI therapy, exposure to prior platinum-base 
therapy, mutation status for non-squamous NSCLC (EGFR, ALK, and KRAS).

SCCHN: HPV status, anatomical location, previous therapy with platinum-based 
regimen, previous therapy with cetuximab

Cutaneous melanoma: BRAF mutation , NRAS mutation

MSI-high cancer: MSI-H types, Method of determining DNA mismatch repair

GBM: MGMT status, IDH1/IDH2 mutation

Nasopharyngeal carcinoma: EBV status

Ovarian cancer: mutations status, BRCA1 mutation, BRCA2 mutation，platinum 
sensitive

HPV positive cancer: HPV positive cancer types

UC: site of primary tumor, histology, hemoglobin at baseline (<10 g/dL), baseline 
creatinine clearance (<60 mL/min), previous therapy with platinum-based regimen 
(cisplatin-based, carboplatin-based, other platinum combination), time from last prior 
systemic therapy (<=3 months), prior BCG administrated and extent of disease at 
study entry (liver, lymph node only, and visceral metastasis derived based on baseline 
tumor scan). 
o
Visceral metastasis included liver, lung, bone, or any non-lymph node or soft 
tissue metastasis.
3.3.3 Study Drug Exposure
Study drug exposure will be derived separately for initial treatment and re-treatment periods. 
Summary of study treatment exposure for initial treatment period will include descriptive 
statistics of the following: treatment duration, number of MEDI4736 doses and total 
MEDI4736 dose received during the study, dose intensity and relative dose intensity of 
MEDI4736. The treatment duration in 8 weeks interval (<=8 weeks, 8-16 weeks, etc) and 
relative dose intensity (<=60%, 60%-80%, >80%-90%, >90%-100% and >100%) will also be 
summarized using frequency distribution. 
The dose intensity (mg/kg/dose interval) for MEDI4736 is defined as total actual dose (in 
mg/kg) that a subject received per dose interval. Relative dose intensity is defined as the dose 


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intensity divided by the planned dose per dose interval. The details of the dose intensity 
calculation will be provided in the SPP.
Dosing modification of MEDI4736 will be summarized for the initial treatment and re-
treatment periods for the following categories: the number of subjects with dose 
delays/omissions, the reasons for dose delay/omissions (AEs, scheduling conflict, and other), 
the number of subjects for whom the entire dose was not administered as scheduled (infusion 
interruption), and the reasons the entire dose was not administered as scheduled (AEs and 
other).
3.3.4 Concomitant Medications
Prior and concomitant medications will be summarized by the second highest ATC class and 
preferred term. Within each level of summarization (ATC class and preferred term), a 
subject will be counted once if he/she takes one or more medications.
Prior medications are defined as those with a start date prior to the date of first dose of study 
medication. Concomitant medications include those medications:

with a start date greater than or equal to the date of first dose of study medication, or 

with a start date prior to the date of first dose of study medication and a stop date 
either after the date of first dose of study medication or marked as “continuing”, or
3.4
MTD/OBD Analysis
The number of DLTs during the Dose Escalation Phase will be presented by dose levels and 
overall. The MTD level (which can be different for Q2W and Q3W) may be indicated in the 
summary.
3.5
Efficacy Analyses
Efficacy analyses will be performed separately for each disease type on subjects who have 
received MEDI4736 10 mg/kg Q2W in either the dose escalation or expansion phases. 
Efficacy data from 10 mg/kg Q2W in either the Dose Escalation Phase or Dose Expansion 
Phase will be combined for analyses. 
For NSCLC cohorts (squamous and non-squamous), efficacy analyses will also be performed 
separately for each cohort by line of therapy (1st line, 2nd line, 3rd line or above, and 2nd line or 
above) with a further breakdown by PD-L1 status (PD-L1 high and PD-L1 low/no 
expression). Analyses will be repeated for all NSCLC subjects regardless of histology. 


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For the SCCHN cohort, efficacy analyses will be performed separately for HPV positive, 
HPV negative and overall (regardless of HPV status), with a further breakdown by PD-L1 
status (PD-L1 high and PD-L1 low/no expression).
For the UC cohort, efficacy analyses will be performed for 2L+ UC subjects regardless of 
PD-L1 expression, with a further breakdown by the PD-L1 subgroups including TC high vs 
low/neg, IC high vs low/neg , and PD-L1 high (either TC or IC high) vs PD-L1 low/neg (both 
TC and IC low/neg). See Section 3.1.1. 
PFS/OS analysis will not be presented if there are not a sufficient number of events (at least 
10) in each subgroup.  
3.5.1 Primary Efficacy Endpoint and Analyses
Primary Efficacy Endpoint
The primary efficacy endpoint for the NSCLC cohort and the UC cohort in this study is 
objective response, which is defined as a best overall response (BoR) of confirmed CR or PR
based on RECIST v1.1 by BICR. 
BoR is calculated based on the overall visit responses from each assessment including 
unscheduled visits.  It is the best response a subject has had from the start of treatment until 
objective documentation of PD (per RECIST v1.1 as assessed by BICR), or subject 
withdrawn from the study, or subject started new anticancer therapy, whichever occurs first.
Categorization of BoR will be based on RECIST v1.1 using the following response 
categories/orders: CR , PR, SD, PD, and NE. Overall visit responses along with the date of 
response will be provided by the BICR (i.e. the reviewers will provide the overall visit 
response according to RECIST 1.1 and no programmatic derivation of visit response is 
necessary).
A BoR of CR or PR must be confirmed. A CR/PR requires confirmation no less than 4 weeks 
(28 days) after the first response criterion was met and with no evidence of progression 
between the initial and CR/PR confirmation visit.  A confirmed CR is defined as two CRs
that were separated by at least 28 days with no evidence of progression in-between. A 
confirmed PR is defined as two PRs or an un-confirmed PR and an un-confirmed CR that 
were separated by at least 28 days with no evidence of progression in-between.


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For determination of a BoR of SD, the SD should be recorded at least 6 weeks +/- 7 days, i.e. 
at least 35 days (to allow for the assessment window), after the date of the first dose. For a 
subject without measurable lesions at baseline, overall visit response “Non-CR/non-PD 
which is preferred over “stable disease” will be provided by the ICR (See further details in 
the ICR charter). For the determination of BoR, an overall visit response with “Non-CR/non-
PD” is considered as SD. 
Subjects who responded with an unconfirmed CR/PR at the time of data cutoff will be reported 
as unconfirmed CR/PR under the SD category provided the minimum criteria for SD duration 
(35 days) are met, otherwise this will be reported under the NE category.
Analysis of Primary Endpoint
Objective response rate is defined as the proportion of subjects with OR. The primary 
endpoint of OR based on RECIST v1.1 by BICR will be analyzed by estimating the ORR and 
its 2-sided 95% CI with the exact probability method.
An objective response will be considered as an ongoing response if the subject who had
documented OR is still alive and progression-free (per RECIST v1.1 as assessed by BICR) at
the time of data cutoff. The number and percentage of subjects with ongoing response will be 
provided. The percentage is calculated based on number of subjects with OR. Additional 
details related to analysis of ORR for UC cohort are described below. 
Analysis of ORR for UC cohort 
The primary analysis of ORR based on RECIST v1.1 by BICR will be performed for all 2L+ 
PD-L1 high UC subjects in the FAS enrolled in the entire study. The primary endpoint for 
UC cohort in PD-L1-high subgroup is considered to be met if the lower-limit of the exact 2-
sided 95% CI for ORR excludes a historical response rate of 10% (Bellmunt et al, 2009). An 
analysis of ORR for all 2L+ PD-L1 high UC subjects in the FAS enrolled under Amendment 
8 and beyond will be conducted as a supportive analysis. The primary analysis for UC cohort 
will occur at least 24 weeks after the last PD-L1-high UC subject’s first dose of study 
treatment.
If the primary endpoint for the PD-L1-high subgroup of the UC cohort is met, the ORR based 
on RECIST v1.1 by BICR along with its 95% CI will be also provided for all 2L+ UC 
subjects in the FAS (regardless of PD-L1 status) enrolled in the entire study. The primary 


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endpoint for UC cohort in all-comers is considered to be met if the lower-limit of the exact 2-
sided 95% CI for ORR excludes a historical response rate of 10% (Bellmunt et al, 2009). 
Additional analysis of ORR as determined by the investigator according to RECIST v1.1 will 
be conducted for As-treated Population with opportunity to be followed for at least 24 weeks, 
in the same manner as those described for the BICR-assessed ORR. The investigator’s 
recorded measurements and assessments for target, non-target, and new lesions according to 
RECIST v1.1 will be used to derive the overall response and progression programmatically.
Concordance/Discordance of BoR programmatically derived per RECIST 1.1 based on 
investigator disease responses and the disease response per BICR will be summarized in a 
frequency table. The agreement rate for subjects with objective responses and with objective 
responses will be also provided. 
3.5.2 Secondary Efficacy Endpoints and Analyses
The secondary efficacy endpoints include objective response (except for subgroups of 
NSCLC and UC cohorts where OR is considered the primary endpoint), duration of response
(DoR), disease control (DC), time to response (TTR), duration of stable disease (DSD), 
progression-free survival (PFS), overall survival (OS), and change in target lesion size. All 
endpoints except Overall Survival (OS) are based on RECIST 1.1 as assessed by the BICR (if 
available) and investigator. The site investigator disease response assessment will be a 
programmatically-derived from the investigator’s recorded measurements and assessments 
for target, non-target, and new lesions according to RECIST v1.1.  
Duration of Response
Duration of Response (DoR) is defined as the time from the date of first documented response 
(CR or PR) until the first date of documented PD (per RECIST v1.1), or death due to any cause, 
whichever occurs first. For subjects who are alive and progression-free at the time of data cut-
off for analysis, DoR will be censored at the PFS censoring time. The PFS censoring rule 
specified in Table 3.5-1 will be applied. 
The DoR will only be evaluated for subjects who have a documented confirmed response (CR 
or PR) based on RECIST v1.1 and is calculated as following:
DoR (months) = (Date of PD/Death or censoring – Date of first response + 1) / (365.25 / 12)


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If the visit when the initial CR or PR is observed spans multiple dates, the latest date will be 
used for calculation of response duration.
The median DoR and its 95% CI will be estimated using the Kaplan-Meier method.
Disease Control 
The Disease Control (DC) is defined as a best overall response of confirmed CR, confirmed 
PR or SD (per RECIST v1.1). Disease control at 12 and 24 weeks is defined as a best overall 
response of confirmed CR, confirmed PR or having SD with duration of SD for a minimum 
duration of 12 weeks (-7 days, i.e., 77 days), and 24 weeks (-7 days, i.e., 161 days), following 
the start of study treatment, respectively. A window of 1 week is applied since not all subjects 
adhere to the scheduled tumor measurement date. 
The secondary endpoint of DC will be analyzed by estimating the Disease Control Rate 
(DCR), defined as the proportion of subjects with DC and its 2-sided 95% CIs using an exact 
probability method.
Progression-free survival
Progression-free survival (PFS) is defined as the time from the date of the first dose of study 
treatment(s) until the first date of documented PD (per RECIST v1.1) or death due to any 
cause, whichever occurs first, regardless of whether the subject withdraws from treatment or 
receives another anti-cancer therapy prior to progression.
For subjects who are alive and progression-free at the time of data cutoff for analysis, PFS
will be censored at the time of the date of last evaluable disease assessment.  If the subject
progresses or dies after ≥2 consecutively missed disease assessments, PFS will be censored 
at the time of the latest evaluable disease assessment prior to the missed assessments.
PFS (months) = (Date of PD/Death or censoring – Date of first dose + 1) / (365.25 / 12).
The details of censoring rule are listed in Table 3.5-1:
Table 3.5-1 Censoring Rule for Analysis of PFS
Situation
Date of PD /  Death or Censoring
Primary 
Outcome
No disease assessment at 
baseline or post-baseline visits
Date of first dose
Censored
Alive and progression-free
Date of last evaluable disease 
assessment
Censored


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Situation
Date of PD /  Death or Censoring
Primary 
Outcome
Documented Progressive 
Disease (PD)
Date of earliest sign of PD
Progressed
Death before first progressive 
disease assessment
Date of death  
Progressed
Death between adequate 
assessment visits
Date of death  
Progressed
PD or death immediately after 
≥2 consecutively missed or NE
disease assessments
Date of last evaluable progression-
free disease assessment prior to 
missed or NE assessments
Censored
In this study, progression or death after ≥2 consecutive missed disease assessment visits is 
defined (according to disease assessment schedules specified in the protocol) as below: 

≥ 126 days (two disease assessment visits [16 weeks] plus 2 weeks window to allow 
for a late assessment) since the last post-baseline evaluable disease assessment, if 
progression or death occurs prior to end of treatment.   

≥ 136 days (two disease assessment visits [4 months] plus 2 weeks visit window to 
allow for a late assessment) since the last post-baseline evaluable disease assessment, 
if progression or death occurs after end of treatment but within 12 months since last 
dose of study treatment. 

≥ 211 days (two disease assessment visits [6 months] plus 4 weeks visit window to 
allow for a late assessment) since the last post-baseline evaluable disease assessment, 
if progression or death occurs after 12 months since last dose of study treatment. 
The date of PD (per RECIST v1.1) for DoR, DSD and PFS endpoints will be derived as the 
date of one of the following criteria in case of multiple radiographic assessments performed 
at different times for the same visit assessment. The earliest date will be chosen: 

Earliest assessment date for target lesions (in the same visit) if the sum of longest 
diameters (SLD) meets the criteria for PD;

Earliest assessment date for any non-target lesion with a status of unequivocal 
progression (in the same visit) if PD is documented based on the non-target lesion 
response;

Earliest of new tumor lesion dates (in the same visit).


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The date of PD (per RECIST v1.1) for DoR, Duration of stable disease and PFS endpoints 
based on the BICR will be derived as the following: 

For adjudicated subjects, the date of PD is obtained from the date of PD assessed by 
the reviewer that the adjudicator agreed with. 

For non-adjudicated subjects, the date of PD is derived as the earliest of the PD dates 
from reviewers.
Median PFS with its 95% CI and the proportion of subject with progression free at time points 
of interest, such as 6 months (PFS-6m), 9 months (PFS-9m) and 12 months (PFS-12m) with its 
95% CI, will be evaluated using the Kaplan-Meier method.
Duration of Stable Disease
Duration of stable disease (DSD) is defined as the time from the first dose of study 
treatment(s) until the first date of documented PD (per RECIST v1.1), or death due to any 
cause, whichever occurs first. For subjects who are alive and progression-free at the time of 
data cut-off for analysis, duration of SD will be censored at the PFS censoring time. The PFS 
censoring rule specified in Table 3.5-1 will be applied. The DSD will only be evaluated for 
subjects with a BoR of SD based on RECIST v1.1. Duration of SD is defined as follows:
DSD (months) = (Date of PD/Death or censoring – Date of first dose + 1) / (365.25 / 12)
The median DSD and its 95% CI will be estimated using the Kaplan-Meier method.
Time to Response 
Time to response (TTR) is defined as the time from the first dose of study treatment until the 
first documentation of disease response and will be evaluated only in subjects who have 
confirmed CR or PR based on RECIST v1.1. TTR is defined as follows:
TTR (months) = (Date of first CR or PR – Date of the first dose of study treatment + 1) / 
(365.25/12)
The median TTR and its 95% CI will be assessed using Kaplan-Meier method.
Overall Survival
Overall survival (OS) will be measured from the start of study treatment(s) until death due to 
any cause. For any subject who is not known to have died at the time of data cutoff for
analysis, OS will be censored at the last recorded date on which the subject was known to be 


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alive. If subjects are confirmed to be alive or if the death date is post the data cutoff date, 
these subjects will be censored at the date of data cutoff.
Overall survival (months) = (Date of death or censoring – Date of MED4736 start + 1) / 
(365.25 / 12).
OS will be summarized using Kaplan-Meier estimates (median time, 95%CI for median time
and 6-month, 9-months and 1-year OS rates with 95% CIs).
Percent Change in Target Lesion Sizes
Best percentage change from baseline of the sum of the longest diameters (SLD) of target
lesions per RECIST 1.1 will be derived as the biggest decrease or the smallest increase from 
baseline on the SLD among all post-baseline disease assessment including unscheduled 
assessments. The best percentage change by subject will be presented in a ‘Waterfall’ plot, to 
show each subject’s best percentage as a separate bar, with the bars ordered from the largest 
increase to the largest decrease. Additionally, the percent change from baseline of the SLD 
for the BICR data per RECIST 1.1 at each post-baseline disease assessment will be presented 
by subject.  
For the BICR data, SLD of target lesions (per RECIST v1.1) from the reviewer selected by 
the adjudicator will be used when adjudication for overall visit response has occurred, but in 
the case where no adjudication was required the SLDs of target lesions (per RECIST v1.1) 
from the reviewer who reviewed the baseline scan first will be used for the derivation.
3.5.3 Exploratory Efficacy Endpoints and Analyses
 
 
 
 
 
 
 
 


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3.5.4 Subgroup Analysis
In order to assess the consistency of treatment benefit, the exploratory analyses of ORR 
(based on both BICR determination and investigator determination according to RECIST 1.1) 
will be performed for some applicable cohorts.
For NSCLC cohorts, the analyses of ORR will be performed for all PD-L1 high 2L+ 
squamous NSCLC subjects and all PD-L1 high 2L+ NSCLC subjects (regardless of 
histology) by the following subgroups:

Age (<65, ≥ 65 yrs)

Sex (Female, Male)

Race (White, Others)

Region (North America, Europe, Asia)

ECOG performance status (0, 1)

Smoking status (Never, Former, Current)
For SCCHN cohorts, the analyses of ORR  will be performed for all SCCHN subjects by the 
following subgroups, with a further breakdown by PD-L1 status (PD-L1 high vs PD-L1 
low/no expression):

Age (<65, ≥ 65 yrs)

Sex (Female, Male)

Race (White, Others)

Region (North America, Europe, Asia)

ECOG performance status (0, 1)

Smoking status (Never, Former, Current)

HPV status (positive, negative)


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For UC cohorts, the analyses of ORR will be performed for all 2L+ UC subjects by the 
following subgroups, with a further breakdown by the PD-L1 subgroups including TC high 
vs low/neg, IC high vs low/neg, and PD-L1 high (either TC or IC high) vs PD-L1 low/neg
(both TC and IC low/neg).
The subgroup will be (but not limited) as follows.

Age (<65, ≥ 65 yrs)

Sex (Female, Male)

Race (White, other)

Region (North America, Europe, Asia)

ECOG performance status (0, 1)

Smoking status (Never, Former, Current)

Site of primary tumor 

Liver metastatic at baseline (Yes, No)

Lymph node only disease at baseline (Yes, No) Visceral metastatic at baseline (Yes, 
No)

Baseline creatinine clearance (<60 mL/min, >=60 mL/min)

Baseline hemoglobin (<10 g/dL, >=10 g/dL)

Prior therapy with platinum-based regimen (Cisplatin-based, Carboplatin-based)

Time from last prior systemic therapy (<=3 months, >3 months)

Prior BCG (Yes, No)

Bellmunt risk factor including hemoglobin < 10 g/dL, ECOG ≥ 1, and the presence of 
liver metastasis (0, 1, 2, 3)


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3.5.5 Handling of Dropouts and Missing Data
For a description of the handling of censored data for efficacy endpoints such as PFS, DoR, 
DSD and OS, see Sections 3.5.2.
Missing Target lesion measurement data 
For the disease response derivation in target lesion (TL) data, if a lesion size is missing due to 
the lesion being too small to be measured, the missing value is defaulted to 5 mm. If a lesion 
size is missing due to technical difficulty of the measurement (i.e., poor quality of scan, 
blurring lesion etc.), the measurement for that lesion will not be imputed and the target lesion 
visit response is not evaluable (NE).  Overall visit response will also be NE. However, a visit 
response of PD should still be assigned if any of the following occurred:

A new lesion is recorded

A non-target lesion (NTL) visit response of PD is recorded

The sum of TLs is sufficiently increased to result in a 20% increase, and an absolute 
increase of ≥5mm, from nadir even assuming the non-recorded TLs have disappeared
3.6
Safety Analyses
Safety data including AEs, SAEs, laboratory parameters, ECGs, vital signs and ECOG 
performance status, will be summarized by disease type and overall across disease type on 
subjects who have received MEDI4736 10 mg/kg Q2W unless otherwise specified. Safety 
data from subjects receiving 10 mg/kg Q2W in the dose escalation phase and dose expansion 
phase will be combined for analyses. Selected AE/SAE summaries by dose levels across all 
disease types will be provided to assess dose response. 
For NSCLC cohorts (squamous and non-squamous), the SCCHN cohort and UC cohort, 
safety analyses will be performed by PD-L1 status (PD-L1 high and PD-L1 low/neg) and 
overall for all subjects in respective cohorts who received MEDI4736 at doses of 10 mg/kg 
Q2W. For NSCLC, safety summaries will be provided for all NSCLC subjects regardless of 
histology. For the UC cohort, safety summaries will be provided for all UC subjects 
regardless of line of therapy. 
Repeated or unscheduled tests will not be summarized for each scheduled visit, but will be 
included for summaries of “Worst-case” on treatment values and shift-table analyses. “Worst-
case” on treatment (i.e. maximum or minimum on-treatment value depending on the direction 


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of an adverse effect) is defined as the nadir and/or zenith including any scheduled and 
unscheduled post-baseline assessments that occur through the final safety follow up visit. The 
final safety follow up visit (last record on study) is defined as the last visit with non-missing 
data that occurred up till 30 days (+7 days to allow visit window) following the last dose of 
MEDI4736 for ECGs, vital signs, ECOG, laboratory parameters except hematology; up till 
90 days (+7 days to allow visit window) following last dose of MEDI4736 or till the 
initiation of the subsequent anticancer therapy (excluding palliative radiotherapy given as 
monotherapy), whichever occurs first for hematology laboratory parameter. 
If the number of subjects with available data is less than 1/3 of the total number of subjects in 
the As-treated Population for overall summary (across disease types) or for one disease type 
at one scheduled time of evaluation, no summary statistics will be presented at that time point
for overall summary or for that disease type, unless otherwise indicated.
3.6.1 Adverse Events
Adverse events will be coded using Medical Dictionary for Regulatory Activities and assigned 
grades based on NCI CTCAE v4.03.
Summaries of adverse events will include only "treatment-emergent" events. Treatment-
emergent adverse event (TEAE) will be defined for the initial treatment period and the re-
treatment period separately. TEAEs are defined as any adverse events that first occur on or 
after the date of initial receipt of MEDI4736 and with an onset date no more than 90 days after 
the last dose of MEDI4736 at each treatment period.  Any AEs that are considered as non-
treatment emergent will be presented in the listings only.  
The AE reporting period for this study is the period through 90 days after the last dose of 
MEDI4736 or until the initiation of alternative anticancer therapy per protocol, therefore, the 
primary set of AE summaries will be based on the TEAEs observed up until 90 days after the 
last dose of MEDI4736 or until the initiation of the subsequent anticancer therapy (excluding 
palliative radiotherapy given as monotherapy) following discontinuation of MEDI4736 will be 
used for the AE summary tables. Selected AE summaries (i.e. SAE, AESI, and AE resulting in 
death) will also be produced containing AEs observed up until 90 days after the last dose of 
MEDI4736 (without taking subsequent therapy into account) as the secondary set of AE 
summaries. Any adverse events in the period that occur after a subject has received subsequent 
anticancer therapy (following discontinuation of MEDI4736) will be flagged in the data 
listings.


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Subjects will be counted only once for each preferred term, once for each system organ class, 
and by the worst CTCAE grade, regardless of how many events the subject experienced. The 
TEAE summaries for the primary set (i.e. AEs until 90 days following discontinuation of study 
treatment or until the initiation of the first subsequent therapy excluding palliative radiotherapy 
given as monotherapy, whichever occurs first) to be provided are listed below.

All  TEAE 

TEAE with CTCAE grade 3 or higher

TEAE by Highest Severity 

Treatment related TEAE

Treatment related TEAE with CTCAE grade 3 or higher

Treatment related TEAE by Highest Severity 

Serious  TEAE

Serious TEAE by Highest Severity 

Serious TEAE by Serious AE Criteria 

Treatment related Serious  TEAE

TEAE Resulting in Permanent Discontinuation of MEDI4736

Treatment related TEAE Resulting in Permanent Discontinuation of MEDI4736

TEAE Resulting in Dose Delay 

Treatment related TEAE Resulting in Dose Delay 

TEAE and Treatment related Resulting in Death
An overall summary of the number and percentage of subjects in each category as described 
above will be provided.  Another overview of TEAE in each category with excluding disease 
progression of specific cancer types will also be provided.   


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In addition, the TEAE summaries listed below will be produced for the secondary set (i.e. 
AEs until 90 days following discontinuation of study treatment).

Serious TEAE

Treatment related Serious  TEAE

TEAE and Treatment related Resulting in Death
3.6.1.1 Adverse Events of Special Interest (AESI)
Some clinical concepts (including some selected individual preferred terms) have been 
considered “AEs of special interest” (AESI) to the MEDI4736 program. Some AESI’s have 
been described in protocol section 5.3. These AESIs will be identified based on sponsor-
defined ad-hoc queries (AHQ). A listing of the preferred terms in each grouping will be 
provided prior to data base lock. The AESI grouping have been identified as the following:
Adrenal insufficiency, Diarrhoea, Colitis, Select hepatic events, Infusion related/
Hypersensitivity/Anaphylactic reactions, Pneumonitis, Hyperthyroidism, Hypophysitis, 
Hypothyroidism, Dermatitis, Rash, Select pancreatic events, Select renal events, Other rare 
events of a potential immune-mediated nature. 
AESI summaries by grouped term and preferred term for the primary set (i.e. AESIs until 90 
days following discontinuation of study treatment or until the initiation of the first subsequent 
therapy excluding palliative radiotherapy given as monotherapy, whichever occurs first) to be 
provided are listed below.

All  AESI (Any Grade and CTCAE grade 3 or higher)

AESI by Highest Severity 

Treatment related AESI (Any Grade and CTCAE grade 3 or higher)

Treatment related AESI by Highest Severity 

Serious AESI 

AESI Resulting in Permanent Discontinuation of MEDI4736

AESI Resulting in Dose Delay 

AESI and Treatment related AESI Resulting in Death


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
AESI ongoing at death

AESI ongoing at DCO

AESI by outcome
In addition, the AESI summaries listed below will be produced for the secondary set (i.e. 
AESIs until 90 days following discontinuation of study treatment).

All  AESI

AESI by Highest Severity 

Treatment related AESI

Treatment related AESI by Highest Severity 
3.6.1.2 AESIs During Which Systemic Steroids, Endocrine Therapy, or Other
Immunosuppressants Were Administered
AESIs during which systemic steroids, endocrine therapy, or other immunosuppressants were
administered will be programmatically identified by searching for dates of initiation of these 
agents and comparing to the onset dates and resolution dates of AESIs for individual subjects. 
Specifically, an AESI during which systemic steroids, or other immunosuppressants were 
administered is defined as AESI for which there was concomitant administration of systemic 
steroids, or other immunosuppressants, within 30 days of onset of the AESI, but prior to its 
resolution. Similarly, an AESI (hyperthyroidism, hypophysitis, or hypothyroidism) during 
which endocrine therapy were administered is defined as AESI for which there was 
concomitant administration of endocrine therapy within 30 days of onset of the AESI, but 
prior to its resolution. 
The concomitant medications administered to subjects will be identified by searching the 
clinical database for select ATC codes to identify systemic steroids, endocrine therapy and 
other immunosuppressants. See a list of select ATC codes in the imAE Charter.  
Summaries of AESIs during which systemic steroids, endocrine therapy, or other 
immunosuppressants were administered for the primary set (i.e. AESIs until 90 days 
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therapy excluding palliative radiotherapy given as monotherapy, whichever occurs first)  to 
be provided are listed below.

AESI and treatment related AESI during which systemic steroid were administered
(Any grade, >=Grade 3 and by Highest Severity)

AESI and treatment related AESI during which high-dose systemic steroid were 
administered (Any grade, >=Grade 3 and by Highest Severity)
o
High-dose systemic steroid is defined as dose greater than or equal to 
40 mg prednisone or equivalent per day

AESI and treatment related AESI during which other immunosuppressives were 
administered (Any grade, >=Grade 3 and by Highest Severity)

AESI and treatment related AESI during which systemic steroid or other 
immunosuppressives were administered (Any grade, >=Grade 3 and by Highest 
Severity)

AESI and treatment related AESI (Hyperthyroidism, Hypophysitis, and 
Hypothyroidism only) during which endocrine therapy were administered (Any 
grade, >=Grade 3 and by Highest Severity)
3.6.1.3 Immune-mediated Adverse Events (imAE)
To fully characterize the AESI (excluding AESI group Infusion related/ Hypersensitivity/
Anaphylactic reactions) during which systemic steroids, endocrine therapy, or other 
immunosuppressants were administered (See Section 3.6.1.2), the Sponsor will perform 
medical review of those AESIs and classify them as immune- mediated AEs (imAEs) or not 
imAEs. See further details in the imAE Charter. 
Immune-mediated AEs will be defined as any AESIs that (1) required the use of systemic 
steroids, endocrine therapy, or other immunosuppressants within 30 days of onset of the 
AESI and prior to resolution, (2) is consistent with an immune mediated mechanism of 
action, and (3) for which, there is no clear alternate etiology. 
Since the clinical database for this study does not specifically link the start of medication 
with an adverse event, imAEs will therefore be derived by first programmatically identifying 
AESIs, for which there was concomitant administration of systemic steroids, endocrine 


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therapy, or other immunosuppressants, within 30 days of onset of the AESI, but prior to its 
resolution. A further clinical evaluation of all such events will be made to ensure there was 
no clear alternate etiology before classifying them as imAEs for the purpose of analysis and 
reporting. Note that for this study, adverse event that changes grade is reported as a new 
adverse event record with new onset date in the clinical database.  
The imAEs will be summarized in the same manner as for the summaries for AESI described 
above in Section 3.6.1.1 and Section 3.6.1.2 for the primary set (i.e. imAEs until 90 days 
following discontinuation of study treatment or until the initiation of the first subsequent 
therapy excluding palliative radiotherapy given as monotherapy, whichever occurs first). 
In addition, the following analyses of imAE will be provided by imAE group. See further 
details in the imAE Charter with respect to derivation rules associated with time to first onset 
and resolution of imAE. 

Time to first onset of imAE (Descriptive statistics with median and range for time to 
first onset of AE, and frequency for number of subjects with time to first onset of AE 
within 1-28 days, 29-56 days, 57-84 days, 85-112 days, >112 days will be provided.)

Time to first onset of CTCAE grade 3 or higher imAE

Time to resolution of imAE (Time to resolution will be calculated from first onset to 
complete resolution, and will be summarized using the Kaplan-Meier method. Median 
and range will be presented.)

Time to resolution of Grade >=3 imAE (Time to resolution will be calculated from 
first onset of Grade >=3 event to complete resolution, and will be summarized using 
the Kaplan-Meier method. Median and range will be presented.)

Time to resolution of Grade >=2 imAE (Time to resolution will be calculated from 
first onset of Grade >=2 event to complete resolution, and will be summarized using 
the Kaplan-Meier method. Median and range will be presented.)

Time to resolution/improvement of Grade >=3 imAE (Time to resolution/
improvement will be calculated from first onset of Grade >=3 event to resolution or 
the event improved to Grade 2 or lower, and will be summarized using the Kaplan-
Meier method. Median and range will be presented.)
In addition, the following analyses regarding systemic steroid use for imAE will be provided
by imAE group. See further details in the imAE Charter with respect to derivation rules 


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associated with duration and time to systemic steroid use for imAE. The following analysis 
except for duration of steroid use will be produced by imAE group for both all systemic 
steroids and high dose systemic steroids. 

Starting steroid dose

Time to first steroid dose

Highest dose steroid given 

Time to highest steroid dose

Duration of initial steroid use (first use of steroid per subject per imAE group, 
regardless of initial dose)

Duration of initial high dose steroid use (first use of a steroid where the starting dose
meets high dose definition per subject per imAE group)
3.6.1.4 Mortality
Deaths occurring while subjects were on study treatment, in the safety follow-up period, or 
after completion of the safety follow-up period will be summarized as below:

Total number of deaths (including deaths ≤90 days after last dose of study medication 
and deaths occurring ≥90 days after the last dose of study drug)

Total number of deaths related only to disease under investigation, as determined by 
investigator (including deaths ≤90 days after last dose of study medication and deaths 
occurring ≥90 days after the last dose of study drug)

Number of deaths ≤90 days after last dose of study medication

Total number of deaths related only to TEAE and onset date prior to initiation of 
subsequent anti-cancer therapy (excluding palliative radiotherapy given as 
monotherapy)

Total number of deaths related only TEAE and onset date post initiation of 
subsequent anti-cancer therapy (excluding palliative radiotherapy given as 
monotherapy) but ≤90 days after last dose of study medication

Total number of subjects where death was reported to be related to the disease under 
investigation (as determined by the investigator) and TEAE (onset date prior to 
initiation of subsequent anti-cancer therapy excluding palliative radiotherapy given as 
monotherapy) 


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
Total number of subjects where death was reported to be related to the disease under 
investigation (as determined by the investigator) and TEAE (onset date after initiation 
of subsequent anti-cancer therapy excluding palliative radiotherapy given as 
monotherapy)

Subjects with unknown reason for death and other deaths (not falling in the above 
categories)
Note that if a Grade 5 AE considered as “disease progression” is the only AE/SAE with 
outcome of death reported, and the investigator assessed causality as not related to study drug 
for a subject, then this subject will be listed under the “Death related to disease under 
investigation ONLY”, instead of under the corresponding AE/TEAE categories.
3.6.1.5 Subgroup Analyses
The following safety endpoints are selected for subgroup analyses across all disease types. 

All  TEAE 

TEAE with CTCAE grade 3 or higher

Serious  TEAE

TEAE Resulting in Permanent Discontinuation of MEDI4736

TEAE Resulting in Death 

All AESI 
The subgroup will be (but not limited) as follows.

Age (<65, ≥ 65 yrs)

Sex (Female, Male)

Race (White, Black/African-American, Asian, other)

Region (North America, Europe, Asia)

ECOG performance status (0, 1)

Smoking status (Never, Former, Current)

Baseline creatinine clearance (<60 mL/min, >=60 mL/min)


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
Baseline hemoglobin (<10 g/dL, >=10 g/dL)
3.6.2 ECG
Electrocardiogram (ECG) parameters (PR, RR, QRS, QT, QTcB, and QTcF) from central 
read (if available) and local read will be summarized separately using descriptive statistics for 
actual values and changes from baseline by scheduled time of evaluation including end of 
treatment visit and 30 days safety follow-up visit as well as for the maximum post-baseline
values. A single value will be used for the measurement of an interval from triplicate ECGs.  
This value is the average of the three measurements from the individual ECGs. If triplicate 
ECGs are not performed, the value from a single ECG will be used for summary. The QTcF 
will be considered as the primary correction method to assess subject cardiac safety. Since 
RR from local read is not captured on the eCRFs, no QTcB or QTcFs for local read will be 
derived, and QTcB or QTcF captured on the eCRFs from local read will be used for 
summary.  
The number and percentage of subjects having the following notable ECG interval values on 
treatment will be summarized.

Maximum QTcF and QTcB intervals 450 milliseconds, > 480 milliseconds, > 500 
milliseconds 

Maximum uncorrected QT intervals 500 milliseconds

Maximum changes from baseline in QTcF and QTcB 30, >60 and 90 milliseconds 
For the outlier analysis on the ECG intervals, only the subject with “new” cases (as compared 
to baseline) will be included for summary. “New” means the category of the QTc 
abnormality was not present at baseline and became present for at least one post-baseline 
ECG assessment. For example, a subject is classified as new QTc > 450 msec if that subject 
had a baseline QTc <=450 msec and had a maximum post-baseline QTc interval > 450 msec. 
Percentages are calculated based on the number of subjects who had a baseline and at least 
one post-baseline assessment.
3.6.3 Clinical Laboratory Parameters
Laboratory tests will be grouped according to hematology, serum chemistry, urinalysis, 
coagulation, and thyroid function tests (TSH, free T3, and free T4).


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For all continuous laboratory assessments, absolute value and change from baseline will be 
summarized for each scheduled assessment, and “worst-case” on treatment using descriptive 
statistics.
Analyses of Laboratory Parameters with NCI CTCAE Grade
Laboratory abnormalities with toxicity grades according to the NCI CTCAE 4.03 will be 
derived according to laboratory values. Shift tables from baseline to worst toxicity grade on 
treatment will be presented. Separate summaries indicating hyper- and hypo- directionality of 
change will be produced, where appropriate. In addition, the number and percentage of 
subjects experiencing at least 1-Grade shift, at least 2-Grade shift, and any shift to a worst
post-baseline toxicity Grade of 3 to 4 from baseline will be summarized. For each lab test
condition, percentages are calculated based on the number of treated subjects who have a 
baseline and at least one post-baseline assessment. In the shift table analysis, for a given 
subject, if the CTCAE grade is missing for all post baseline assessments for one laboratory 
test, the subject will be counted only once for that laboratory test under the “Missing” 
CTCAE grade category. If a subject has both missing and non-missing CTCAE grades for 
one laboratory test, the missing CTCAE grade of that laboratory test will be treated as the 
lowest grade. 
Laboratory abnormalities with toxicity grades according to the NCI CTCAE 4.03 will be 
derived for the following parameters:

Hematology: Anemia (Hemoglobin hypo), White Blood Cell, Neutrophils, Platelets,
Lymphocytes

Serum chemistry: Alanine Amino Transferase (ALT), Aspartate Amino Transferase 
(AST), Alkaline Phosphatase (ALP), Total bilirubin, Creatinine (without taking 
baseline into account when deriving CTCTAE grade), Albumin, Cholesterol,
Magnesium hypo and hyper, Sodium hypo and hyper, Potassium hypo and hyper, 
Corrected calcium hypo and hyper, Glucose hypo and hyper, Bicarbonate 
Analyses of Laboratory Parameters without NCI CTCAE Grade
For selected parameters including thyroid function tests (TSH, free T3, and free T4) with no 
CTCAE grading shift tables from baseline to “Worst-case” on treatment value will be 
provided. “Worst-case” on treatment value will be categorized as low (L), normal (N), or 
high (H) using laboratory reference range (on both directions). 


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Additional summaries will include a shift table for urinalysis (Bilirubin, Blood, Glucose, 
Ketones, Protein) comparing the baseline value to the maximum on-treatment value.
Liver Function Parameters
Subjects with elevated post-baseline ALT, AST or Total Bilirubin that fall into the following 
categories will be identified. Number and percentage of these subjects will be tabulated.
Liver Function Parameters
Category
ALT

>=3 × – <=5 × ULN

>5 × – <=8 × ULN

>8 × – <=10 × ULN

>10 × – <=20 × ULN

>20 × ULN
AST

>=3 × – <=5 × ULN

>5 × – <=8 × ULN

>8 × – <=10 × ULN,

>10 × – <=20 × ULN

>20 × ULN
Total bilirubin

>=2 × – <=3 × ULN

>3 × – <=5 × ULN

>5 × ULN 
ALT or AST

>=3 × – <=5 × ULN

>5 × – <=8 × ULN

>8 × – <=10 × ULN,

>10 × – <=20 × ULN   

>20 × ULN
Potential Hy’s law

(AST >= 3 × ULN or ALT >= 3 × ULN) 
anda Total Bilirubin >= 2×ULN
ULN: upper limit of normal range. 
a: Total Bilirubin >= 2×ULN is defined as at least one case of post-dose TBL >= 2 x ULN occurred after the first 
incidence date of ALT >= 3 x ULN or AST>= 3 x ULN post treatment


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Individual subject data where elevated ALT or AST plus total bilirubin fall into the “Potential 
Hy’s law” will be listed.
Assessment of Nephrotoxicity 
Creatinine clearance rate (CCr) will be calculated using serum creatinine and the Cockcroft-
Gault formula (Cockcroft and Gault 1976) to estimate glomerular filtration rate (GFR). Shift 
tables from baseline to “Worst-case” on treatment CCr value will be provided. Baseline and 
“Worst-case” on treatment CCr value will be categorized for the following categories:

Normal: ≥ 90 mL/min

Mild Impairment: ≥ 60 − < 90 mL/min

Moderate Impairment: ≥ 30 − < 60 mL/min 

Severe Impairment: ≥ 15 − < 30 mL/min 

Kidney Failure: < 15 mL/min 
3.6.4 Vital Signs
Descriptive statistics of baseline value, post-baseline value and change from baseline value 
for heart rate, blood pressure, temperature, and respiratory rate will be provided for each 
scheduled time point including end of treatment visit and 30 days safety follow-up visit as 
well as for the maximum and minimum post-baseline on treatment values.
3.7
Pharmacokinetics of MEDI4736
Only subjects who receive at least 1 dose of MEDI4736, and provide at least 1 post-treatment 
sample, will be evaluated. 
Individual MEDI4736 concentrations will be tabulated with descriptive statistics. The PK of 
MEDI4736 will be assessed using parameters including Cmax, trough concentration (Cmin), 
time to Cmax and AUC after the first dose. MEDI4736 steady-state PK parameters including 
peak concentration at steady state (Cmax,ss), trough concentration at steady state (Cmin,ss), and 
time to Cmax will be estimated. Accumulation to steady state will be assessed as the ratio of 


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Cmax,ss:Cmax and Cmin,ss:Cmin. All PK parameters will be estimated by non-compartmental 
analysis. Descriptive statistics of non-compartmental PK parameters will be provided.
Pharmacokinetic data analyses will be performed by the MedImmune MedImmune Clinical 
Pharmacology, Pharmacometrics, and DMPK group or designee. 
3.7.1
 
 
 
 
 
 
 
 
 
 
 
 
3.8
 
 
 
 
.
3.9
Assessment of Immunogenicity of MEDI4736
Only subjects who receive at least one dose of MEDI4736 and provide the baseline and at 
least 1 post-treatment sample, will be evaluated. 


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Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of subjects who develop detectable anti-MEDI4736 antibodies. The 
immunogenicity titer will be reported for samples confirmed positive for the presence of 
anti-MEDI4736 antibodies. The impact of ADAs on PK will also be assessed if data allow. 
Samples confirmed positive for ADAs may also be evaluated for neutralizing antibody 
activity.
Analyses to assess the immunogenic potential of MEDI4736 will be performed by the 
MedImmune Clinical Pharmacology, Pharmacometrics, and DMPK group or designee.
3.10
 
4
Interim Analysis
Interim analyses for disease types other than NSCLC and UC cohorts including efficacy 
(based on the site investigator-assessed tumor data) and key safety analyses may be  
performed prior to the final analysis for the clinical study report 
 
 
4.1
Interim Analyses for NSCLC Cohort 
For the NSCLC cohorts, the PD-L1 expression status cutoff determination analysis based on 
percent of tumor cells exhibiting cell surface staining assessed by immumohistochemistry 
(IHC) was made from a subset of NSCLC subjects with clinical outcome data and PD-L1 
status available as of 29 April 2014.
 
 
No efficacy 
analysis using BICR data was performed and no data were available from BICR for those 
interim analyses.  


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4.2
Interim Analyses for UC cohort 
4.2.1
Interim Analysis for PD-L1 Cutoff in UC 
Following review of PD-L1 expression and response data (assessed by investigator per 
RECIST v1.1) in the initial 20 UC subjects enrolled and followed for a minimum of 12 
weeks, a cutoff of 25% for either IC or TC in a baseline sample was chosen for response 
analysis because the presence of PD-L1 in >=25% of immune cells or >= 25% of tumor cells 
both appeared to enrich for response. 
 
 
 
4.2.2
Planned Interim Analysis for Efficacy
An interim analysis of efficacy will be conducted after approximately 103 UC subjects 
treated with MEDI4736 had an opportunity to be followed for at least 13 weeks (at least two 
RECIST follow-up scans plus 1 week visit window). 
The primary analysis of ORR (exact 95% confidence interval) at the time of the interim 
analysis will be based on RECIST v1.1 by BICR for all treated UC subjects with an 
opportunity to be followed for at least 13 weeks (as primary efficacy population). Supportive 
analysis using BICR-assessed ORR will be performed for all treated UC subjects with an 
opportunity to be followed for at least 24 weeks (as supportive efficacy population). Similar 
analyses using BICR-assessed ORR will be also performed for all treated 2L+ post-platinum 
UC subjects, which is defined as subjects with locally advanced or metastatic UC who either 
have disease progression during or following platinum-containing chemotherapy, or have 
disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-
containing chemotherapy. 
In order to assess the potential effect of the patterns of PD-L1 expression on antitumor 
activity of MEDI4736 in UC subjects, efficacy data will also be analyzed by pre-specified 
subgroups based on PD-L1 expression (See Section 3.1.1). Analysis of secondary endpoints 
as outlined in Section 3.5.2 will also be performed. For endpoints dependent on disease 
assessments, the analysis of those endpoints will also be repeated based on the investigator 
assessments of tumor data. 


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The Analysis Populations to be used for the interim analyses are described below.

As-treated Population is defined as all subjects who received any dose of MEDI4736. 
To avoid the underestimation of the safety due to an insufficient follow-up period, the 
As-treated Population will be restricted to subjects dosed at least 30 days prior to the 
DCO date for interim analysis. This is the analysis population for the interim analysis 
of all safety data.

Primary Efficacy Population is defined as all UC subjects in the As-treated Population 
who had an opportunity to be followed for at least 13 weeks by the DCO date for
interim analysis (i.e., received the first dose of MEDI4736 at least 13 weeks prior to 
the DCO date).This is the primary analysis population for the interim analysis of all 
efficacy data. 

Supportive Efficacy Population is defined as all UC subjects in the As-treated 
Population who had an opportunity to be followed for at least 24 weeks by the DCO 
date for interim analysis (i.e., received the first dose of MEDI4736 at least 24 weeks 
prior to the DCO date). This is the supportive analysis population for the interim 
analysis of all efficacy data. 
An updated efficacy analysis will be conducted on the primary efficacy population from the 
first planned interim analysis (i.e., approximately 103 subjects, as described above). This 
analysis will be done based on a DCO date, which will be approximately 90 days after the 
DCO date for the first interim analysis. Key efficacy information, including ORR and 
duration of response will be updated at this time.
There are no plans to stop the trial based on either of these analyses and no formal statistical 
adjustments are planned. However, results from these analyses may be shared with the 
regulatory agencies for discussions on future development and registration opportunities of 
MEDI4736 in UC subjects.
Safety analyses at the planned interim analyses will be based on all UC subjects who received
any dose of MEDI4736 and had opportunity to be followed for at least 30 days (i.e. subjects 
dosed at least 30 days prior to the DCO date).  The safety analyses will be conducted as 
described in Section 3.6.  


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4.2.3
Additional Interim Analysis for Efficacy
An additional efficacy analysis will be conducted for UC subjects in the As-treated 
Population from the first planned interim analysis (i.e., approximately 191 subjects) as 
described in Section 4.2.2. This additional efficacy analysis will be done in the same manner 
as described above for the planned interim analysis. The DCO date used for this analysis will 
be same DCO date used for updated efficacy analysis, as described in Section 4.2.2. 
There are no plans to stop the trial based on either of these analyses and no formal statistical 
adjustments are planned. However, results from these analyses may be shared with the 
regulatory agencies for discussions on future development and registration opportunities of 
MEDI4736 in UC subjects.
4.2.4
Other Interim Analysis
An interim analysis for the Breakthrough Therapy Designation (BTD) request was conducted 
after approximately 30 PD-L1-high UC subjects were enrolled and followed for at least 12 
weeks. A total of 61 UC subjects treated as of 20 November 2015 were included for safety 
analysis. Of the 61 treated UC subjects, 42 were considered response evaluable. The efficacy 
data (based on investigator RECIST data) and adverse event data was analyzed by PD-L1 
status and overall. 
 
 
 
Additional interim analyses may take place to support interactions with the regulatory 
authorities. The enrollment will not be interrupted or terminated for efficacy based on those 
interim analyses.


MedImmune
MEDI4736
Protocol CD-ON-MEDI4736-1108
Statistical Analysis Plan
12JAN2017; Version 6.0
CONFIDENTIAL AND PROPRIETARY
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