Conditions: Squamous Cell Carcinoma of the Head and Neck
Keywords: programmed cell death ligand 1 (PD-L1), MEDI4736, Cytotoxic T-lymphocyte-associated antigen 4 {CTLA-4}, PFS, SCCHN
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 823
Healthy volunteers: no

Brief summary:
This is a randomized, open-label, multi-center, 3-arm, global Phase III study to determine the efficacy and safety of MEDI4736 + tremelimumab combination or MEDI4736 monotherapy versus SoC (EXTREME regimen) in the treatment of patients with SCCHN who have not received prior systemic chemotherapy for recurrent or metastatic disease.

Detailed description:
Patients will be randomized in a 2:1:1 ratio to MEDI4736 + tremelimumab combination therapy, MEDI4736 monotherapy, or SoC. Patients in all arms will continue therapy until progression. Tumor assessments will be performed on computed tomography scans or magnetic resonance imaging scans, preferably with intravenous (IV) contrast. Efficacy for all patients will be assessed by objective tumor assessments every 6 weeks for the first 24 weeks, then every 8 weeks thereafter until treatment discontinuation due to progression or toxicity. All patients will be followed every 3 months for survival after progression is confirmed.

Arms:
arm 1: MEDI4736 monotherapy. arm 2: MEDI4736+Tremelimumab combination therapy arm 3: Standard of Care treatment

Interventions: intervention 1: MEDI4736 intervention 2: Tremelimumab intervention 3: MEDI4736+Tremelimumab intervention 4: Cetuximab intervention 5: 5-fluorouracil (5FU) intervention 6: Cisplatin intervention 7: Carboplatin
Intervention descriptions: intervention 1: Anti-PD-L1 antibody intervention 2: Anti-CTLA-4 Antibody intervention 3: None intervention 4: Monoclonal Antibody intervention 5: Chemotherapy Agent intervention 6: Chemotherapy agent intervention 7: Chemotherapy Agent

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol
Drug Substance
MEDI4736 and 
Tremelimumab
Study Code
D419LC00001
Version 
12.0
Date
29 June 2020
A Phase III Randomized, Open-label, Multi-center, Global Study 
of MEDI4736 Alone or in Combination with Tremelimumab versus 
Standard of Care in the Treatment of First-line Recurrent or 
Metastatic Squamous Cell Head and Neck Cancer Patients
Sponsor:
AstraZeneca AB, 151 85 Södertälje, Sweden


Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
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VERSION HISTORY
Version 12.0, 29 June 2020
Changes to the protocol are summarized below.
Change of primary objective from MEDI4736 monotherapy versus Standard of 
Care (SoC) in patients who are at low risk of early mortality based on baseline 
laboratory values according to a model developed by AstraZeneca in terms of SoC, 
to MEDI4736 versus SoC in a biomarker-selected population (PD-L1 TC/IC high 
subgroup) in terms of overall survival (OS).
The primary objective of the study has been changed from MEDI4736 monotherapy 
versus SoC in patients who are at low risk of early mortality based on baseline 
laboratory values according to a specific prognostic model developed by AstraZeneca 
 to MEDI4736 versus SoC in a biomarker-selected 
subgroup (PD-L1 TC/IC high) in terms of OS. MEDI4736 monotherapy versus SoC in 
the population at low risk of early mortality will be included as a secondary objective in 
order to maximize the information generated on the utility of this model. The multiple 
testing procedure (MTP) has been updated accordingly to reflect this change. In line 
with the changes to the primary objective, the analysis of OS will be performed when 
approximately 147 death events have occurred in approximately 172 patients (85% 
maturity) across the MEDI4736 monotherapy and SoC treatment groups in the 
biomarker-selected population (PD-L1 TC/IC high subgroup).
All relevant sections throughout the protocol have been updated to reflect these changes. 
This includes the Synopsis, Section 1.2.5 (Study population rationale), Section 1.2.6 
(Rationale for endpoints), Section 2.1 (Primary objective), Section 2.2 (Secondary 
objectives), Section 2.3 (Safety objective), Section 8.2 (Sample size estimate), Section 
8.3 (Definitions of analysis sets), 8.4 (Outcome measures for analysis) and Section 8.5 
(Methods for statistical analysis).
This revision to the primary objective to focus on the PD-L1 high subgroup (TC/IC) is 
intended to address feedback from the US FDA regarding the use of the prognostic 
model to define a primary analysis population in KESTREL. The resulting changes are 
informed based on data external to the KESTREL study. Specifically, the phase 3 
KEYNOTE-048 study, which demonstrated that pembrolizumab monotherapy improved 
OS when compared with the EXTREME regimen in patients whose tumors had PD-L1 
expression ≥1 and ≥20 by Combined Positive Score (CPS) [hazard ratio (HR) 0.78 
(0.64–0.96), P=0.0086 and HR 0.61 (0.45– 0.83), P=0007, respectively] (Burtness et al., 
2019). The PD-L1 high cut-point (TC50/IC25) was previously defined (see KESTREL 
CSPv7.0). Additional data analysis from the Sponsor’s Phase 3 D4193C00002 
(EAGLE) study in second line squamous cell head and neck cancer (HNSCC) appear to 
further support the utility of PD-L1 to select patients with improved outcome when 
treated with MEDI4736.
 
 
When 
controlling for prognostic factors, the multivariate analysis of patients treated with 
MEDI4736 shows a tendency to better OS in the PD-L1 high (TC/IC) vs PD-L1 low 
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subgroup [HR=0.80 (95% CI 0.58–1.09)]. The primary objective will include the 
MEDI4736 monotherapy arm vs SoC (EXTREME), as the body of evidence described 
above supports that the primary utility of PD-L1 blockade in treatment of recurrent or 
metastatic HNSCC appears to be as in patients whose tumors express sufficient levels of 
PD-L1. 
Changes not related to the analysis of the primary objective include the following:
Synopsis, Section 8.5 (Methods for statistical analysis). These sections have been 
updated to include OS analysis in MEDI4736 + tremelimumab ctDNA TMB≥16 
mut/Mb as the fourth tier in the MTP based on ctDNA TMB results from the EAGLE 
study (Li et al 2020) and growing evidence of the value of this biomarker for identifying 
patients who may benefit from MEDI4736 + tremelimumab treatment.
Synopsis, Section 1.2.6 (Rationale for endpoints), Section 2.2 (Secondary 
objectives), Section 8.2 (Sample size estimate), Section 8.3 (Definition of analysis 
sets), Section 8.5 (Methods for statistical analysis). These sections have been updated 
to remove OS noninferiority analysis for MEDI4736 versus SoC in all randomized 
patients (all-comers) as a secondary objective and as the second level of the MTP. 
Synopsis, Section 2.3 (Safety objective), 8.3 (Definition of analysis sets), 8.5 
(Methods for statistical analysis). These sections have been updated to include the low 
risk of early mortality subgroup in the safety objectives. 
In addition to the changes listed above, minor administrative corrections have been 
made throughout the protocol and are not detailed here further.
Version 11.0, 04 October 2019
Changes to the protocol are summarized below.
Change of primary objective from MEDI4736 monotherapy versus SoC in all 
randomized patients (all-comers) in terms of OS to MEDI4736 monotherapy versus 
SoC in patients who are at low risk of early mortality based on baseline 
characteristics in terms of OS.
The primary objective of the study has been changed from MEDI4736 monotherapy 
versus SoC in all randomized patients (all-comers) to MEDI4736 monotherapy versus 
SoC in patients who are at low risk of early mortality based on baseline characteristics 
(hereafter referred to as “primary analysis population”) in terms of OS. The primary 
analysis population consists of patients identified by a model developed by AstraZeneca 
as having low risk of early mortality. The multiple testing procedure has been updated 
accordingly to reflect this change.  In line with the changes to the primary objective, the 
analysis of OS will be performed when approximately 254 death events have occurred in 
approximately 304 patients (84% maturity) across the MEDI4736 monotherapy and SoC 
treatment groups in the primary analysis population.
All relevant sections throughout the protocol have been updated to reflect these changes. 
This includes the Synopsis, Section 1.2 (Rationale for study design, doses and control 


Revised Clinical Study Protocol
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groups), Section 1.2.5 (Study population rationale), Section 1.2.6 (Rationale for 
endpoints), Section 2.1 (Primary objective), Section 2.2 (Secondary objectives), Section 
8.2 (Sample size estimate), Section 8.3 (Definitions of analysis sets) and Section 8.5 
(Methods for statistical analysis).
This change has been made based on emerging data that are external to the KESTREL 
study. Immune checkpoint inhibitors (ICIs) are profoundly changing the treatment of 
many types of cancer, including melanoma, non-small cell lung cancer (NSCLC), renal 
cell carcinoma (RCC), squamous cell carcinoma of the head and neck (SCCHN), 
urothelial carcinoma (UC), and Hodgkin’s lymphoma, and have been associated with 
long-lasting tumor responses. However, an early mortality (EM) phenomenon has been 
observed in many randomized clinical trials comparing ICIs with active comparator 
arms in advanced or metastatic cancer patients, even with overall benefit ultimately 
favoring ICI therapy (Champiat et al 2018). While the precise etiology of this 
phenomenon is not clearly established, it is characterized by what seems to be 
disproportionately higher mortality in the early treatment period favoring the active 
control arm, followed by subsequent benefit in overall survival (OS) favoring the ICI 
treatment arm. This is often reflected in the clinical data by the “crossing of the Kaplan-
Meier curves” suggesting a subpopulation of patients at a higher risk of EM whose 
advanced rate of tumor growth may require the cytotoxic tumor-debulking effect of 
chemotherapy. Accordingly, it is of great therapeutic interest to better predict the risk of 
early mortality for a given patient to better inform the appropriate treatment for their 
individual clinical state. To aid in this objective, AstraZeneca has developed and 
implemented a model that predicts a patient’s risk of early mortality to optimize the 
benefit:risk profile for treatment of patients with ICIs.
Changes not related to the analysis of the primary objective include the following: 
Synopsis, Section 1.2.6 (Rationale for endpoints), Section 2.2 (Secondary 
objectives), Section 8.2 (Sample size estimate), Section 8.3 (Definition of analysis 
sets), Section 8.5 (Methods for statistical analysis). These sections have been updated 
to include OS noninferiority analysis for MEDI4736 versus SoC in all randomized 
patients (all-comers) as a secondary objective and as the second level of the MTP. 
Synopsis, Section 1.2.6 (Rationale for endpoints), Section 2.2 (Secondary 
objectives), Section 8.2 (Sample size estimate), Section 8.3 (Definition of analysis 
sets) and Section 8.5 (Methods for statistical analysis). These sections have been 
updated to include OS analysis in the ctDNA Tumor Mutation Burden (TMB) subgroups 
for MEDI4736 versus SoC as the third level of the MTP and to specify the cutoff value 
for the ctDNA TMB high subgroup. 
In addition to the changes listed above, minor administrative corrections have been 
made throughout the protocol and are not detailed here further.
Version 10.0, 25 January 2019
Changes to the protocol are summarized below.


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Change of primary objective from MEDI4736 + tremelimumab combination 
therapy versus SoC in a biomarker-selected subgroup (PD-L1 TC/IC), to 
MEDI4736 monotherapy versus SoC in all randomized patients (all-comers) in 
terms of OS.
The primary objective of the study has been changed from MEDI4736 + tremelimumab 
combination therapy versus SoC in a biomarker-selected subgroup (PD-L1 TC/IC), to 
MEDI4736 monotherapy versus SoC in all randomized patients (all-comers) in terms of 
OS. The multiple testing procedure has been updated accordingly.  In line with the 
changes to the primary objective, the analysis of OS will be performed when 
approximately 336 death events have occurred in 380 patients (88% maturity) across the 
MEDI4736 monotherapy and SoC treatment groups in the all-comers population, and 
also when approximately 147 death events from the PD-L1 TC/IC subgroup have 
occurred in 172 patients (85% maturity) across the MEDI4736 monotherapy therapy and 
SoC treatment groups.  
All relevant sections throughout the protocol have been updated to reflect these changes.  
This includes the Synopsis, Section 1.2 (Rationale for study design, doses and control 
groups), Section 1.2.6 (Rationale for endpoints), Section 1.4 (Study design), Section 2.1 
(Primary objective), Section 2.2 (Secondary objectives), Section 8.1 (Statistical 
considerations), Section 8.2 (Sample size estimate), Section 8.5 (Methods for statistical 
analysis).
This change has been made based on emerging data in the field that are external to the 
KESTREL study, specifically recently announced results from a phase 3 study in 2nd
line recurrent/metastatic HNSCC patients (EAGLE). 
Changes not related to the analysis of the primary endpoints include the following: 
Synopsis, Section 1.2.5 (Study Population Rationale), Section 2.2 (Secondary 
objectives), Section 2.4 (Exploratory Objectives), Section 5.5.2.1 
 
, Section 8.3 (Definition of Analysis Sets). Section 8.5 (Methods for 
Statistical Analysis)
These sections have been updated to include ctDNA Tumor Mutational Burden (TMB) 
as a secondary analysis to investigate TMB as a marker of response to MEDI4736 
monotherapy and MEDI4736 + tremelimumab combination therapy. This analysis has 
been changed from an exploratory objective to a secondary objective. 
Section 2.4 (Exploratory objectives), Section 5.5.2.1 
 
Section 6.3.9 (Safety data to be collected following the final data cut-off of the 
study) and Section 7.2.2 (Duration of treatment (post final data cut-off)
These sections have been updated to clarify procedures following final data cut-off of 
the study.
Section 6.7.2 (Specific toxicity management and dose modification information –
MEDI4736 + tremelimumab combination therapy and MEDI4736 monotherapy)
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This section has been updated to clarify that the Toxicity Management Guidelines 
(TMGs) for durvalumab and tremelimumab will be provided to investigative sites as an 
Annex to the protocol document. 
In addition to the changes listed above, minor administrative corrections have been 
made throughout the protocol and are not detailed here further.
Version 9.0, 03 October 2018
Changes to the protocol are summarized below.
Change of Overall Survival in the all-comer population from primary objective to 
secondary objective 
OS in the all-comer population has been changed from a co-primary objective to a 
secondary objective of the study. OS in the PD-L1 TC/IC subgroup remains as the sole 
primary objective. The multiple testing procedure has been updated accordingly. In line 
with the changes to the primary objective, the requirement for OS analysis to be 
performed when 495 death events from the all-comers population have occurred in 570 
patients (87% maturity) has been removed. OS analysis will be performed when 
approximately 213 death events from the PD-L1 TC/IC subgroup population have 
occurred in 257 patients (83% maturity) across the MEDI4736 + tremelimumab 
combination therapy and SoC treatment groups and also when approximately 147 death 
events from the PD-L1 TC/IC subgroup population have occurred in 172 patients (85% 
maturity) across the MEDI4736 monotherapy therapy and SoC treatment groups.   
All relevant sections throughout the protocol have been updated to reflect these changes.  
This includes the Synopsis, Section 1.2.6 (Rationale for endpoints), Section 2.1 (Primary 
objective), Section 2.2 (Secondary objectives), Section 2.3 (Safety objective), Section 
8.2 (Sample size estimate), Section 8.3 (Definitions of analysis sets), Section 8.4 
(Outcome measures for analysis), Section 8.5 (Methods for statistical analysis), Section 
11 (References).
This change has been made based on emerging data in the field that are external to the 
KESTREL study. Specifically, recently announced interim analysis results from a phase 
3 study in 1st line recurrent/metastatic HNSCC patients (KEYNOTE-048) demonstrated 
that the PD-1 inhibitor Pembrolizumab monotherapy in patients with PD-L1 expression 
(Combined Positive Score (CPS) ≥ 20) resulted in significantly longer OS compared to 
the current standard of care for HNSCC in the first-line treatment setting. At the time of 
the interim analysis, the dual-primary endpoint of PFS for patients whose tumors 
expressed PD-L1 (CPS ≥ 20) had not been reached. In addition, recent analysis of 
mature HAWK (D4193C00001)/CONDOR (D4193C00003) data using the TC50/IC25 
algorithm confirmed that OS was signicantly improved in the PD-L1 (TC50/IC25) 
population. 
Changes not related to the analysis of the primary endpoints include the following: 


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Synopsis, Section 1.2.6 (Rationale for endpoints), Section 2.2 (Secondary 
objectives), Section 8.3 (Definition of analysis sets) and Section 8.5 (Methods for 
statistical analyses)
These sections have been updated to include DoR, BoR, TFST, TSST, APF6 and APF12 
as secondary objectives to assess the efficacy of MEDI4736 monotherapy compared to 
SoC. This change has been made to aid clinical interpretation of the MEDI4736 
monotherapy data following the update to the multiple testing procedure, and for 
consistency with the secondary efficacy objectives for the MEDI4737 + tremelimumab 
combination therapy.
Section 1.3.2.1 (MEDI4736), Section 4 (Study plan and timing of procedures), 
Section 6.7.1. (MEDI4736 + tremelimumab combination therapy and MEDI4736 
monotherapy adverse events of special interest), Section 6.7.2 (Specific toxicity 
management and dose modification information – MEDI4736 + tremelimumab 
combination therapy and MEDI4736 monotherapy)
These sections have been updated to inform Investigators that the Toxicity Management 
Guidelines (TMGs) for durvalumab and tremelimumab have been removed from the 
protocol (Table 8) and have become a standalone document. The most current version of 
these guidelines is to be maintained within the Site Master File. In addition, a version of 
the current TMG is available via https://tmg.azirae.com
Section 8.3.1 (PD-L1 TC/IC subgroup analysis)
This section has been updated to clarify the definition of PD-L1 high and PD-L1 low. 
Section 11 (References)
The following reference was removed in order to be consistent with changes made 
elsewhere in the protocol:  Burman et al 2009.
In addition to the changes listed above, minor administrative corrections have been 
made throughout the protocol and are not detailed here further.
Version 8.0, 13 Feb 2018  
Changes to the protocol are summarized below.
Change of Progression Free Survival from primary objective to secondary 
objective
PFS in the all-comer population has been changed from a primary objective to a 
secondary objective of the study.  Accordingly, the primary analysis of the secondary 
objective of PFS will now be conducted using investigator assessments and the 
sensitivity analysis will now be conducted by BICR.
All relevant sections throughout the protocol have been updated to reflect these changes. 
This includes the Synopsis, Section 1.2.6 (Rationale for endpoints), Section 1.4 (Study 
design), Section 2.1 (Primary objective), Section 2.2 (Secondary objectives), Section 8.2 
(Sample size), Section 8.4.1 (Calculation or derivation of efficacy variables) and Section 
8.5 (Methods for statistical analyses).  Table 12 (Summary of statistical assumptions) 


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has been updated.  Appropriate changes have been made throughout Section 8.5 
(Methods for statistical analysis), including revision of the multiple testing procedure 
(Figure 6) and removal of PFS analyses based on subgroups within the full analysis set.  
This change has been made based on emerging data in the field that are external to the 
KESTREL study.  Specifically, recently published data from 2 phase 3 trials in 2nd line 
R/M HNSCC patients demonstrated that despite showing improvements for PD-1 
inhibitors compared to standard of care in terms of OS, there was no such improvement 
for PD-1 for PFS (Ferris et al, N Engl J Med 2016, 375:1856-1867; Cohen et al, Annals 
of Oncology 2017, 28(suppl_5):v372-v394).  Numerically similar results were obtained 
in two phase 2 studies with durvalumab in a similar patient population (Zandberg et al, 
Annals of Oncology 2017, 28(suppl_5):v372-v394;  data on file).  Consequently, PFS is 
not considered to be a useful primary endpoint in this disease setting with such 
therapies. Investigator assessments are considered acceptable for secondary objectives 
and therefore the outcome measure for PFS has been changed from BICR to investigator 
assessments.   
Removal of interim analysis for Overall Survival 
The interim analysis for overall survival has been removed.  All relevant sections 
throughout the protocol have been updated to reflect this change. This includes the 
Synopsis, Section 8.2 (Sample size), Section 8.4.1 (Calculation or derivation of efficacy 
variables) and Section 8.5 (Methods for statistical analyses); and Section 8.5.8 (Interim 
analysis).   Table 12 (Summary of statistical assumptions) has been updated to reflect 
the statistical assumptions for the primary objectives following the removal of the 
interim analysis for OS.  This change has been made in order to allocate the full alpha 
on the final OS analysis, which is considered optimal when comparing against an active 
standard of care regimen. 
Increase in maturity level for the analysis of Overall Survival
The timing of the analysis of overall survival remains event driven.  In order to increase 
the maturity of overall survival events to ~85% in both the all-comers and the PD-L1 
TC/IC subgroup, the number of events required for the analysis has been increased 
(thereby increasing the power for the assumed average HR). All relevant sections 
throughout the protocol have been updated to reflect this change. This includes the 
Synopsis, Section 8.2 (Sample size), Section 8.4.1 (Calculation or derivation of efficacy 
variables) and Section 8.5 (Methods for statistical analyses). This change has been 
made in order to maximize the amount data available for the analysis of overall survival, 
which is considered optimal for immune checkpoint inhibitors which appear to be 
associated with long term clinical benefit.  
Changes not related to the analysis of the primary endpoints include the following:
Synopsis, Section 2.2 – Secondary objectives, Section 8.4.1.2 – RECIST-based 
secondary endpoints, and Section 8.5 – Methods for statistical analysis
These sections have been updated to reflect that investigator assessments, rather than 
BICR, will be used to derive the secondary objectives of ORR, DoR, BoR, APF6 and 
APF12.  In accordance with this change, the sensitivity analysis for PFS has been 


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updated to reflect that it is now based on BICR assessment rather than investigator 
assessment.  The change from BICR to investigator assessments was made to align with 
the outcome measure of the secondary objective of PFS.   
Synopsis, Section 2.2 – Secondary objectives, and Section 8.4.1.2 – RECIST-based 
secondary endpoints
These sections have been updated to include APF6, OS12 and OS18 as secondary 
objectives, as the proportion of patients alive, or alive and progression free, at these time 
points is considered to be a clinically meaningful objective.  
Section 1.3.2 – Identified and potential risks
The identified and potential risks associated with MEDI4736, tremelimumab, and 
MEDI4736 in combination with tremelimumab have been updated in order to align with 
the recently revised Investigator Brochures (MEDI4736 IB edition  12, 03 November 
2017; tremelimumab IB edition 8, 02 November 2017)
Section 3.10.3 – Survival status for withdrawn consent and lost to follow up 
patients
This section has been updated to clarify the reasons patients should be documented as 
“lost to follow-up” or “withdrawal of consent”, and that in order to support the primary 
endpoint of OS, the survival status of all patients should be re-checked and the case 
report forms updated if appropriate.  
Section 6.7.1 – MEDI4736 + tremelimumab combination therapy and MEDI4736 
monotherapy adverse events of special interest
This section has been updated to include the following as adverse events of special 
interest for MEDI4736 as monotherapy or in combination with tremelimumab:   
myocarditis, myositis/polymyositis, and other inflammatory responses that are rare but 
with a potential immune mediated aetiology.  In addition, the AESI of colitis was 
expanded to include diarrhea and intestinal perforation and the AESI of 
endocrinopathies was expanded to include hypopituitarism and type I diabetes mellitus.  
These changes were made in order to align with the recently revised Investigator 
Brochure (MEDI4736 IB edition 12, 03 November 2017).
Section 6.7.2 – Specific toxicity management and dose modification information –
MEDI4736 + tremelimumab combination therapy and MEDI473 monotherapy
This section has been updated to inform investigators that the most current version of
the Toxicity Management Guidelines (TMGs) is also available through the following 
link: https://tmg.azirae.com. In addition, clarification has been provided regarding the 
importance of thoroughly evaluating patients for potential alternate etiologies when 
assessing immune-mediated adverse events, and that in the absence of a clear alternative 
etiology, events should be considered potentially immune related.
Table 8 has been updated to include toxicity management guidelines for events of 
myocarditis, myositis/polymyositis, as well as for hepatitis-related events in patients 
with hepatocellular carcinoma; pediatric considerations are also included, although these 
are not relevant to the current study population.  In addition, the toxicity management 
guidelines have clarified that study drug/study regimen should be permanently 
discontinued for Grade 3 events with high likelihood for morbidity and/or mortality, 


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even if they are not currently noted in the guidelines.  It has also been clarified that 
permanent discontinuation of study drug is not required for Grade 4 events of 
hyperthyroidism, hypothyroidism, or Type 1 diabetes mellitus.  These changes have 
been made in order to align with the toxicity management guidelines across the 
durvalumab development program.
Section 7.2.2 – Duration of treatment
This section has been updated to clarify that patients who continue to receive benefit 
from their assigned treatment at the time of database closure may continue to receive 
treatment for as long as they are gaining clinical benefit, and that such patients are 
recommended to continue scheduled site visits and be monitored in order to manage 
AEs in accordance with the toxicity management guidelines.  In addition, any patient 
that may be proposed to move to a safety extension or roll-over study would be given a 
new Informed Consent Form.
Section 8.3.2 – PD-L1 TC/IC subgroup analysis set
This section has been updated to clarify that the assay used to define patients in the PD-
L1 TC/IC subgroup analysis set is the analytically validated VENTANA PD-L1 (SP263) 
assay.
Section 8.5.2.4 – Proportion of patients alive and progression free at 6 and 12 
months
This section has been updated to to clarify that proportion of patients alive and
progression free at 6 and 12 months will be summarized using the Kaplan-Meier curve.  
This change was made to be consistent with standard statistical methodology.
Section 8.5.2.7 – Proportion of OS 12, 18, and 24
This section has been updated to clarify that the proportion of patients alive at 12, 18 
and 24 months will be summarized using the Kaplan-Meier curve.  This change was 
made to be consistent with standard statistical methodology.
Section 11 – References
The following references were removed in order to be consistent with changes made 
elsewhere in the protocol:  Klein 2007, Lan and DeMets 1983, Pazdur 2008, Sun and 
Chen 2010, and Whitehead and Whitehead 1991.
In addition to the changes listed above, minor administrative corrections have been 
made throughout the protocol and are not detailed here further.
Version 7.0, 10 May 2017  
Changes to the protocol are summarized below.
Addition of Primary Objective for Overall Survival in a Biomarker Selected 
Subgroup 
A primary objective has been added for OS in a PD-L1 TC/IC-selected subgroup, 
defined as those patients having PD-L1 expression at any intensity in ≥ 50% of tumor 


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cells or ≥25 % of tumor-associated immune cells (PD-L1 TC/IC subgroup; TC≥50 
or IC≥25). In order to control the family wise error rate, the MTP has been adjusted.  
The wording to describe the primary endpoints has also been adjusted to avoid using the 
term “co-primary” (as this is more correctly applied only for situations where all the 
primary endpoints need to be significant, where-as we have used an MTP that enables a 
claim if only one is significant).  Furthermore, secondary objectives assessing the same 
endpoints for the all-comers have been added for the PD-L1 TC/IC-selected subgroup. 
The timing of the PFS analysis has been moved to coincide with the same time as the 
80% of death events interim analysis of OS, thereby removing the first interim analysis 
of OS from the protocol.
All relevant sections throughout the protocol have been updated to reflect these changes. 
This includes the Synopsis, Section 1.2.6 (Rationale for endpoints), Section 1.4 (Study 
design), Section 2.1 (Primary objective), Section 2.2 (Secondary objectives) and Section 
2.3 (Safety objective), which have been updated to reflect the PD-L1 TC/IC subgroup as 
an additional population for the OS primary objective and various secondary objectives; 
Section 8.2 (Sample size), where the statistical assumptions around the PD-L1 TC/IC-
selected subgroup have been added; and Sections 8.2, 8.5 (Methods for statistical 
analyses) and 8.5.8 (Interim analysis), where the timing of the PFS has been adjusted 
(thereby removing the first interim of OS) and the timing of the final OS analysis has 
been adjusted to allow for the required number of events in the PD-L1 TC/IC-selected 
subgroup. Section 8.3.2 has been adjusted to include the definition of the PD-L1 TC/IC-
selected subgroup. Table 12 (Summary of statistical assumptions) has been updated to 
include the assumptions regarding the PD-L1 TC/IC-selected subgroup, to remove the 
entries for the PD-L1 negative subgroup, and also to adjust the monotherapy versus 
SOC entries to reflect the same target hazard ratio as for the combination versus SOC 
comparisons. Appropriate changes have been made throughout Section 8.5 (Methods for 
statistical analysis). These include updating of the multiple testing procedure (Figure 6), 
detailing the new statistical analyses incorporating the PD-L1 TC/IC-selected subgroup 
(Section 8.5.1.2 Overall survival, Section 8.5.1.3 Subgroup analyses of PFS and OS, 
Section 8.5.2 Analysis of the secondary variables, Section 8.5.4 Safety data) and 
removal of the first interim analysis of OS (Section 8.5.8 Interim analysis). 
These changes have been made based on emerging data in the field that are external to 
the KESTREL study.  Specifically, recently published data in 2nd line R/M HNSCC 
patients suggest that PD-L1 expression on both tumor cells and tumor-associated 
immune cells may be associated with greater clinical benefit to immune checkpoint 
inhibitors (Chow et al 2016; Ferris et al, 2017).  PD-L1 expression on both tumor and 
tumor-associated immune cells was evaluated in patient samples from two phase 2 
studies, D4193C00001 (HAWK) and D4193C00003 (CONDOR).  These uncontrolled 
studies evaluated MEDI4736 alone or in combination with tremelimumab in 2nd line 
R/M SCCHN patients whose tumors expressed different levels of PD-L1 expression 
(HAWK: ≥25% PD-L1 tumor cell expression; CONDOR: <25% PD-L1 tumor cell 
expression).  Preliminary overall survival data from a pooled population of patients 
treated with MEDI4736 monotherapy across the HAWK and CONDOR studies was 
used to identify patients who appeared to be more likely to derive clinical benefit from 
MEDI473 treatment based on the level of PD-L1 expression in both tumor and tumor-
associated immune cells.  Based on this analysis, the biomarker-selected subgroup to be 


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evaluated for the primary objective of overall survival in the KESTREL study is defined 
as those patients whose tumors have PD-L1 expression of ≥50% in the tumor cells or 
≥25% in the tumor-associated immune cells [PD-L1 TC/IC subgroup; TC ≥50% or IC 
≥25%]. 
Other changes not related to the addition of the PD-L1 TC/IC-selected subgroup  
include the following:
Synopsis, Section 2.2 – Secondary objectives, Section 8.5 – Methods for statistical 
analysis (Table 16)
These sections have been updated to include the secondary objectives of Best objective 
response, Time to first subsequent therapy, and Time to second subsequent therapy, in 
order to be consistent with the existing secondary endpoints described in Section 8.4.1.4. 
Section 3.10.3 – Survival status for withdrawn consent and lost to follow up 
patients
This new section has been created to clarify that at the time of PFS and OS analyses, site 
personnel should attempt to obtain the survival status for all patients in the full analysis 
set and the safety analysis set who had previously withdrawn consent or were considered 
lost to follow-up using publicly available resources.
Section 5.1 – Efficacy assessments
This section has been updated to ensure consistency within the protocol and reflect that 
the baseline assessment should be performed no more than 28 days before 
randomization, rather than start of IP.
Section 7.1.1 – MEDI4736
This section has been updated to include instructions for preparation of MEDI4376 
doses for patients whose weight falls to <30 kg during the study.
Section 7.1.2 – Tremelimumab
This section has been updated to include instructions for preparation of tremelimumab 
doses for patients whose weight falls to <30 kg during the study.
Section 7.2.1 – Dose and treatment regimens
This section has been updated to clarify the appropriate dosing procedures to be 
followed if a patient’s weight falls below 30 kg during the study. 
Section 7.7 – Concomitant and other treatments
This section has been updated to clarify that the restriction on the use of monoclonal 
antibodies against PD-1, PD-L1 or CTLA-4 no longer applies to the 90 day period after 
the patient has discontinued IP.  This change is implemented in order to be consistent 
with the durvalumab program and to ensure that patients who are randomized to the 
SOC arm are not denied approved therapies in the 2nd line recurrent/metastatic setting 
which have previously demonstrated a survival benefit.
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These sections have been updated to indicate that the sensitivity analysis of PFS based
on RECIST 1.1 modified for confirmation of progression will be performed using site 
Investigator assessments, rather than BICR assessments.
Section 8.4.3.1 – EORTC QLQ-C30 
The population for the analysis of time to symptom deterioration has been updated to 
reflect those patients who have baseline scores of ≤90, in order to accommodate an 
increase of at least 10 points which is the minimum deterioration considered to be 
clinically meaningful.
The population for the analysis of time to QoL/function deterioration has been updated 
to reflect those patients who have baseline scores of ≥10 in order to accommodate a 
decrease of at least 10 points, which is the minimum deterioration considered to be 
clinically meaningful.
Section 8.4.4 – Calculation or derivation of pharmacokinetic variables
This section has been updated to reflect that PK parameters, such as peak and trough 
concentration of MEDI4736 and tremelimumab, will be derived from raw data 
measurements and that no formal non-compartmental PK analysis methods will be used 
as only sparse PK is being collected in this study. 
Section 8.5.7 – Pharmacokinetic/Pharmacodynamic relationships
This section has been removed because the PK/PD modeling is already covered in 
Section 8.4.4.1.
Appendix E – Guidelines for Evaluation of Objective Tumor Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid Tumors)
This section has been updated to ensure consistency with the protocol and reflect that 
the baseline assessment should be performed no more than 28 days before 
randomization, rather than start of IP.
In addition, minor administrative corrections have been made throughout the protocol 
and are not detailed here further.
Version 6.0, 31 August 2016  
Changes to the protocol are summarized below.
Synopsis, Section 8.2 – Sample Size Estimate
The sample size has been increased in order to power the co-primary endpoint of overall 
survival to 90%.  The revised sample size requires approximately 1016 patients to be 
screened in order to randomize 760 patients across the three treatment arms. The 
requirement for a minimum number of patients with PD-L1-negative disease has been 
removed because the primary endpoints are based on natural PD-L1 prevalence and the 
increased sample size ensures a sufficient number of PD-L1-negative patients will be 
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The section has also been updated to reflect a change in the alpha split between the PFS 
and OS co-primary endpoints, such that an alpha level of 0.01 will be used for PFS 
analysis and an alpha level of 0.04 will be used for OS analysis.  This change has been 
made to ensure both OS and PFS are powered to 90% while minimizing the number of 
patients exposed.  As a consequence, most of the alpha is spent on OS which is now 
considered to be the most important endpoint.   
The recruitment period has been updated to 13 months to reflect the current rate of 
enrolment into the trial, and the follow-up period and expected analysis timeframes have
been updated accordingly.  
The 18 month landmark OS analyses have been replaced with 24 month landmark OS 
analyses to be consistent with other trials.  
Synopsis, Section 8.2 – Sample size estimate, Section 8.5 – Methods for statistical 
analysis
The text has been updated to reflect that the primary PFS analysis will not require a 
minimum number of progression/death events in the PD-L1-negative population, as this 
secondary endpoint has been removed from the multiple testing procedure.
Section 1.3.2.1 – Potential Risks, MEDI4736  
This section has been updated based on recent data reviews to reflect the identified and 
potential risks associated with MEDI4736; this section is now consistent with available 
data.
Section 1.3.2.2 – Potential Risks, Tremelimumab  
This section has been updated based on recent data reviews to reflect the identified and 
potential risks associated with tremelimumab monotherapy; this section is now 
consistent with available data.
Section 1.4 – Study Design 
This section has been updated to clarify that the specified PD-L1 expression cut-off 
level will be used for the purpose of stratification; however, the cut-off level to be used 
for the subgroup analyses by PD-L1 status and for determining the PD-L1-negative 
subgroup in the MTP may be different and will be determined from emerging data 
outside of this trial.  This section has also been updated to reflect the revised sample size 
for both enrolled and randomized patients, as well as to remove the requirement for a 
minimum number of patients with PD-L1-negative disease accordingly.  Finally, Figure 
1 has been revised to reflect the increased sample size (n=760). 
Section 4 – Study Plan and Timing of Procedures  
This section has been modified to clarify when dosing may resume after a delay for 
either treatment-related toxicity or reasons other than treatment-related toxicity.  The 
timing of tumor efficacy (RECIST) assessments have been clarified in the text, 
consistent with the timings provided in Tables 2 and 3.   In addition, this section has 
been updated to include an explanation of how patients who remain on treatment at the 
time of final OS analysis will be followed, in order to provide clarity on data entry and 
SAE reporting processes when this occurs. 
 
 
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  Footnote ‘f’ in Table 2 has been updated to clarify 
that for patients on the MEDI4736+tremelimumab combination treatment arm, ADA 
samples collected at cycle 7 will be for MEDI4736 only. Footnote ‘g’ in Table 2 has 
been updated to clarify that pre-dose pharmacokinetic samples for both MEDI4736 and 
tremelimumab may be obtained within 60 minutes prior to the start of the tremelimumab 
infusion; this change has been made to simplify the procedures at the site on days of PK 
sample collection.  In addition,  footnotes have been added in Table 2 and 3 to clarify 
that the +/- 3 day window is relative to the day of dosing and that the PGIC patient-
reported outcome assessment will not be collected at screening or at cycle 1 as this 
questionnaire refers to a change from baseline status.  The tumor assessment schedule in 
Table 4 has been corrected to reflect that assessments will be performed every 6 weeks 
for the first 24 weeks relative to the date of randomization and every 8 weeks thereafter, 
until a patient has confirmed disease progression; this correction is made to align Table 
4 with the text in Section 5.1.
Section 5.1 – Efficacy Assessments 
The criteria for confirming radiographic progression have been clarified and aligned 
across the MEDI4736 program.  Specifically, the text now clarifies that new lesions 
identified at the previous scan timepoint are considered non-target lesions at the 
confirmatory scan timepoint.
Section 5.1.1 – Central reading of scans 
The list of guidelines available to sites for the central reading of scans has been updated.  
In addition, the text has been updated to reflect that results of either investigator 
assessments or of blinded central reviewer assessments will not be shared with the other 
party; this has been done for clarity around the central review process.  
Section 5.5.1 – Collection of exploratory biomarker data  
Section 5.5.2.1 – Collection of exploratory biomarker data, 
 
 
 
Section 6.7.2 – Management of IP-related toxicities; MEDI4736 + tremelimumab 
combination therapy and MEDI4736 monotherapy  
Table 8 has been updated to reflect the most current toxicity management guidelines for 
MEDI4736 +/- tremelimumab.  Specifically, references to “next scheduled treatment 
date” and “next scheduled dose”, and “once 5-7 days have passed” in regard to steroid 
completion, have been removed and instead the corresponding language has been 
updated to reflect that study drug/study regimen may be resumed if toxicity improves to 
Grade ≤1 (or baseline in some cases) after completion of steroid taper.  Importantly, the 
guidelines continue to be based on the maximum grade of each distinct toxicity 
observed.  In addition, it has been clarified in Table 8 that prednisone can be given 
orally (PO).
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Section 7.7 – Concomitant and other treatments  
The table of prohibited medications has been updated to indicate that short term use of 
immunosuppressive medications, including corticosteroids, for the acute management of 
non-IP-related emergencies (e.g., COPD, asthma, etc) is permitted.
Section 8.2 – Sample size estimate 
The text describing the PFS analyses being conducted under alpha control for both the 
MEDI4736 + tremelimumab combination therapy versus SoC in the PD-L1-negative 
population and the MEDI4736 monotherapy versus SoC in all-comers has been deleted 
because these comparisons have been removed from the multiple testing procedure.  The 
text describing the OS analysis for monotherapy MEDI4736 versus SoC in all-comers 
has been deleted because this comparison is not part of the initial levels of the MTP and 
this will instead be described in the statistical analysis plan.  The target hazard ratios, 
critical values, number of events, maturity, and power for the co-primary and secondary 
endpoints have been updated in Table 12 to reflect the values associated with an 
increased sample size.  
Section 8.3.2 – Definition of analysis sets; PD-L1-negative analysis set 
The definition of the PD-L1-negative analysis set has been updated to clarify that the 
cut-off level for PD-L1 status may be different from that used for stratification purposes, 
and that it will be determined from emerging data outside of this trial and included in the 
SAP prior to database lock.  
Section 8.3.4 – Definition of analysis sets; PK analysis set  
The definition of the PK analysis set has been updated to reflect that all patients who 
receive at least 1 dose of IP and for whom any post-dose data are available will be 
included.  
Section 8.5 – Methods for statistical analysis   
Table 16 has been updated to indicate that both stratified log-rank tests and Cox 
proportional method will be used for both PFS and OS endpoints, and that Duration of 
Response will be analyzed using descriptive statistics and Kaplan-Meier plot, in order to 
be consistent with changes in Section 8.5.1.    
The Multiple Testing Procedure has been updated to deprioritize the PFS analyses for 
the comparisons of MEDI4736 + tremelimumab combination therapy vs. SoC in the PD-
L1-negative population and the MEDI4736 monotherapy vs. SoC in the all-comer 
population, relative to the OS analyses.  In addition, it has been clarified that only the 
initial levels of the MTP are included in the protocol and that a full description of the 
detailed MTP, including the comparison of MEDI4736 monotherapy vs. SoC, is 
provided in the SAP. This section has also been updated to clarify that the comparisons 
of MEDI4736 + tremelimumab combination therapy vs. MEDI4736 monotherapy will 
not be included in the MTP and therefore will not be conducted under strict alpha 
control.
Section 8.5.1.1 – Analysis of the co-primary endpoints; Progression-free survival  


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The methods for PFS analysis have been updated to reflect that a stratified unadjusted 
Cox regression will be used to estimate the HR, along with a (1-α)% confidence interval, 
with the stratified log rank test being used to create the p-value only.  This approach is 
consistent with how such endpoints are normally analyzed.    
Section 8.5.1.2 – Analysis of the co-primary endpoints; Overall survival  
Description of a sensitivity analysis for OS, examining the censoring patterns to rule out 
attrition bias, has been moved into this section from elsewhere in the protocol, for 
clarity.
Section 8.5.1.3 – Analysis of the co-primary endpoints; subgroup analysis of PFS 
and OS   
The age at randomization subgroups have been further divided into 3 separate groups, in
order to be consistent with other phase 3 clinical trials (<65, ≥65 to <75, and ≥75).  The 
following subgroups have been added to this section based on potential prognostic 
implications:  ECOG performance status (0, 1) and Extent of Disease (only 
locoregionally recurrent, metastatic with or without locoregional recurrence).  Methods 
for subgroup analyses have been updated to reflect that a forest plot will be presented for 
the subgroup comparisons between MEDI4736 + tremelimumab combination therapy 
versus SoC in all-comers. 
Section 8.5.2.2 – Analysis of secondary variables; Duration of response  
The methods for analysis for duration of response have been updated to reflect that 
descriptive data will be provided rather than formal statistical analysis as the number of 
responders is expected to be small.
Section 8.5.3.1– Patient-reported outcomes; EORTC QLC-30 
The methods of analysis, and number of scales being analyzed for both time to symptom 
deterioration and time to HRQoL/function deterioration from the EORTC QLQ-C30, 
have been updated.  These revisions have been made to reduce the number of analyses 
and ensure the protocol is consistent with the statistical analysis plan.
Section 8.5.3.2 – Patient-reported outcomes; EORTC QLQ-H&N35
The methods of analysis, and the number of scales being analyzed for both time to 
symptom deterioration and symptom improvement from the EORTC QLQ-H&N35 have 
been updated.  These revisions have been made to reduce the number of analyses and 
ensure the protocol is consistent with the statistical analysis plan.
Section 8.5.9 – Interim analysis  
The expected amount of full death information and events to have occurred at the time 
of OS interim analyses, in both the all-comer and PD-L1-negative populations, have 
been updated to reflect the increased sample size. The 2-sided alpha level to be applied 
at the interim and final analyses have been updated as a result of the overall increase in 
alpha applied to the co-primary endpoint of OS.  This section has been modified in order 
to clarify that the final OS analysis is dependent only on a specific number of death 
events that would have occurred in the all-comer population across the MEDI4736 + 
tremelimumab combination therapy and the SoC treatment groups, rather than the all-
comer and PD-L1-negative populations.


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Appendix E – Guidelines for Evaluation of Objective Tumor Response Using 
RECIST1.1 Criteria
The following items have been added for clarity; 1) definition of the short axis, 2) 
statement that lymph nodes are collectively considered as a single organ, 3) A bilateral 
organ is considered a single organ for purposes of target lesions, 4) criteria for 
confirmation of progression have been updated to be consistent with main body of 
protocol, 5) details regarding which guidelines will be prepared for study sites, 6)  a list 
of guidelines available to sites for the central reading of scans has been updated, and 7) 
updated text to reflect that results of either investigator assessments or of BICR 
assessments will not be shared with the other party.
In addition, minor administrative corrections have been made throughout the protocol 
and are not detailed here further.
Version 5.0, 02 March 2016
Changes to the protocol are summarized below.
Protocol Synopsis: This section has been modified to clarify the patient population and 
eligibility criteria.  Additionally, this section has been updated to clarify that patients 
with progressive disease (PD) in target lesions that had previously shown an objective 
response are not eligible to continue immunotherapy treatment.  Text has also been 
added to clarify when radiographic documentation of PD is required.  This section has 
also been updated to reflect that patients must commence study drug within 5 working 
days of randomization.  The definitions of progression-free survival (PFS) and overall 
survival (OS) have been added.  Additionally, the text has been modified to reflect that 
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), according to 
Blinded Independent Central Review (BICR) assessments, will be used instead of 
Investigator assessments to derive the co-primary variable of progression-free survival 
(PFS) and the secondary variables of PFS, objective response rate (ORR), duration of 
response (DoR), and proportion of patients alive and progression free at 12 months 
(APF12).  Additionally, the timing and details pertaining to the two interim analyses for 
OS and for the final analysis of PFS and OS have been updated.  Non-inferiority 
analysis has been removed from this section.  The secondary objectives have been 
updated to add MEDI4736 monotherapy as a comparison to Standard of Care (SoC) in 
regard to the assessment of disease-related symptoms and health-related quality of life.  
Furthermore, in the outcome measures for secondary objectives, various items in the 
European Organisation for Research and Treatment of Cancer (EORTC) 30-item Core 
Quality of Life Questionnaire (QLQ-C30) and the 35-item Head and Neck Quality of 
Life Questionnaire (QLQ-H&N35) module have been prioritized.  Finally, specific 
instructions as to how the 440 PD-L1 negative patients will be distributed among the 
treatment arms have been removed. 
Section 1.1.3 (MEDI4736 [Durvalumab]): This section has been updated to included 
“durvalumab,” the generic name for MEDI4736.


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Section 1.1.6 (Rationale for Conducting this Study): This section has been modified to 
clarify the patient population and eligibility criteria.
Section 1.2 (Rationale for Study Design, Doses, and Control Groups): This section has 
been modified to clarify the patient population and eligibility criteria.  OS has also been 
added to the efficacy analysis in order to remain consistent with the rest of the protocol.
Section 1.2.5 (Study Population Rationale): This section has been modified to clarify the 
patient population and eligibility criteria.
Section 1.2.6 (Rationale for Endpoints): 
 
Section 1.4 (Study Design): This section (including Figure 1) has been modified to 
clarify the patient population and eligibility criteria.  Additionally, the requirement for 
human papilloma virus (HPV) testing to be done exclusively using the p16 
immunohistochemistry (IHC) assay has been updated to also allow testing according to 
local standards.  Furthermore, this section has been updated to clarify that patients with 
PD in target lesions that had previously shown an objective response are not eligible to 
continue immunotherapy treatment.  The text has also been modified to reflect that 
BICR assessments according to RECIST 1.1 will be used instead of Investigator 
assessments to derive the co-primary variable of PFS and the secondary variables of 
PFS, ORR, DoR, and APF12.  Furthermore, the sensitivity analyses of RECIST 1.1 
measurements per BICR has been removed from this section.  Figure 3 has been updated 
to reflect that soluble programmed cell death ligand 1 (sPD-L1) testing is no longer 
required.  Figure 3 has also been modified to clarify the timing of the baseline tumor 
assessment for patients restarting treatment.  Finally, specific instructions as to how the 
440 PD-L1 negative patients will be distributed among the treatment arms have been 
removed.
Section 2.1 (Primary Objective):  The text has been updated to reflect that BICR 
assessments according to RECIST 1.1 will be used instead of Investigator assessments 
to measure the co-primary objective of PFS.
Section 2.2 (Secondary Objectives): The text has been modified to reflect that BICR 
assessments according to RECIST 1.1 will be used instead of Investigator assessments 
to measure the secondary objectives of PFS, ORR, DoR, and APF12.  In the outcome 
measures for secondary objectives, various items in the EORTC QLQ-C30 and 
QLQ-H&N35 module have been prioritized.
Section 2.4 (Exploratory Objectives): 
 
 
Section 3.1 (Inclusion Criteria): This section has been modified to clarify the patient 
population and eligibility criteria.  Additionally, the requirement for HPV testing to be 
done exclusively using the p16 IHC assay has been removed.  The SI values for platelet 
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count and absolute neutrophil count have also been added to this section.  Finally, age-
specific requirements for evidence of post-menopausal status have also been updated.
Section 3.2 (Exclusion Criteria): This section has been modified to clarify the patient 
population and eligibility criteria.  The exclusion of patients who have received prior 
systemic therapy for recurrent or metastatic SCCHN has been removed as it duplicates 
the corresponding inclusion criterion.  The permissibility of steroid usage by patients in
the SoC arm has also been updated.  The exclusion criteria have also been modified to 
include patients with active tuberculosis, as well as those who have been involved in the 
planning/conduct of the study.
Section 3.3 (Patient Enrollment and Randomization): The requirement for HPV testing 
in patients with oral cavity tumors has been removed and it has been clarified that HPV 
results can be collected from historical medical records of any age. Additionally, the 
requirement for HPV testing to be done exclusively using the p16 IHC assay has been 
updated to also allow testing according to local standards.  A definition of pack-year has 
been added.  This section has also been updated to reflect that patients must commence 
study drug within 5 working days of randomization.
Section 3.9.1 (Procedures for Discontinuation of a Patient from Investigational Product 
[IP]): This section has been modified to clarify the procedures that take place when a 
patient discontinues the IP.
Section 4 (Study Plan and Timing of Procedures): Additional instructions pertaining to 
the timing of screening, randomization, dose delays, baseline, and laboratory procedures 
have been added to this section.  This section has also been updated to reflect that 
patients must commence study drug within 5 working days of randomization.  The 
timing of various laboratory assessments has been updated in Table 2.  Tables 2, 3, and 
4 have been modified to reflect that either reflex free triiodothyronine (T3) or free 
thyroxine (T4) will be measured (and not both) if thyroid-stimulating hormone (TSH) is 
abnormal.  Furthermore, the requirement to have urea and TSH results available prior to 
study drug infusion has been removed from Table 2. In addition, Table 3 has been 
updated to reflect that only TSH, and not free T3 and T4, should be measured in patients 
who do not complete treatment through Cycle 5.  In Tables 2 and 3, the requirement for 
HPV testing to be done exclusively using the p16 IHC assay and the requirement to have 
HPV testing completed within the 28 day screening window have been removed.  Tables 
2 and 3 have also been updated to reflect that sPD-L1 testing is no longer required.  
 
 Additionally, the window for Cycle 1 Day 1 in both 
Tables 2 and 3 has been changed to “not applicable,” and a window of ±3 days has been 
added for Cycles 7 until PD in Table 3.  Furthermore, text has been added to Tables 2 
and 3 to clarify when radiographic documentation of PD is required.  The frequency and 
timing of pharmacokinetic and ADA assessments has been modified in Tables 2 and 4.  
Tables 2, 3, and 4 have also been updated to decrease the frequency of electronic 
patient-reported outcome (ePRO) assessments.
Section 5.1 (Efficacy Assessments): Text related to the schedule of confirmation of 
objective tumor response has been deleted.  Additionally, text has been added to clarify 
when radiographic documentation of PD is required.  This section has also been 
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modified to clarify that RECIST 1.1 will be used to determine PFS, ORR, DoR, and 
APF12 using BICR assessments (as well as Investigator assessments for sensitivity 
analysis of PFS). 
Section 5.1.1 (Central Reading of Scans): This section has been updated to reflect that a 
full BICR will be performed for the PFS and ORR endpoints, rather than a sample BICR 
assessment.  The text has also been updated to clarify that the results of independent 
radiologic reviews will not be made available to Investigators, and the management of 
patients will be based upon Investigator assessments.
Section 5.2.1 (Laboratory Safety Assessments): The procedures involved in clinical 
laboratory safety tests have been updated (regarding pregnancy and TSH tests in 
particular).  Table 5 has been updated to include the schedule of bicarbonate and 
chloride testing as well as to remove uric acid from the clinical chemistry laboratory 
variables that will be measured during this study.  The hematology laboratory variables 
to be measured that are listed in Table 6 have also been updated.  Finally, the timing of 
urinalysis testing has been clarified in Table 7.
Section 5.2.4 (Vital Signs): This section has been modified to include separate 
procedures for the first infusion and subsequent infusions of MEDI4736 and/or 
tremelimumab.
Section 6.7 (Management of IP-related Toxicities): Specific guidelines related to 
toxicity management have been removed from this section.  Additionally, text has been 
added regarding guidelines in case of allergic reactions to dose administration.
Section 6.7.1 (MEDI4736 + Tremelimumab Combination Therapy and MEDI4736 
Monotherapy Adverse Events of Special Interest): Language related to the adverse 
events of special interest has been updated. 
Section 6.7.2 (MEDI4736 + Tremelimumab Combination Therapy and MEDI4736 
Monotherapy): The title of this subsection has been updated to reflect the content.  
Language related to immune-related adverse events has been removed from this section; 
specific guidelines related to toxicity management have been added to this section.  
Table 8 (Dosing modification and toxicity management guidelines for 
immune-mediated, infusion-related, and non-immune-mediated reactions) has been 
updated according to the current Toxicity Management Guidelines.
Section 6.8 (Study Governance and Oversight): This section has been updated to modify 
the timing of the Independent Data Monitoring Committee meetings.
Section 7.2.1 (Treatment Regimens): This section has been updated to clarify that 
patients with PD in target lesions that had previously shown an objective response are 
not eligible to continue treatment. Additionally, text has been added to clarify when 
radiographic documentation of PD is required.
Section 7.2.3 (Criteria for Retreatment for Patients in the MEDI4736 + Tremelimumab 
Arm): The timing of the baseline tumor assessment for patients restarting treatment has 
been clarified.


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Section 7.7 (Concomitant and Other Treatments): The first table in this section has been 
updated to clarify the usage of investigational anticancer therapy concurrent with those 
under investigation in this study as well as radiation and immunosuppressive steroids 
during the course of this study.
Section 8.2 (Sample Size Estimate): The timing and details pertaining to the 2 planned 
interim analyses have been updated.  Updates have been made to the text pertaining to 
sizing superiority analysis; non-inferiority analysis has been removed from this section.  
Text pertaining to the sizing for PFS of MEDI4736 monotherapy versus Standard of 
Care (SoC) has also been added.  Finally, specific instructions as to how the 440 PD-L1 
negative patients will be distributed among the treatment arms have been removed.
Section 8.3.2 (PD-L1-negative Analysis Set): This section has been modified to include 
a quantitative definition of PD-L1-negative status. 
Section 8.4.1.1 (RECIST 1.1-based Endpoints): This section has been updated to reflect 
that RECIST 1.1 will be used to determine PFS, ORR, DoR, and APF12 based on BICR 
assessments, rather than investigator assessments.  The sample BICR assessment has 
been removed. 
Section 8.4.1.2 (Co-primary Endpoint [PFS]): This section has been updated to clarify 
that the co-primary endpoint PFS will be assessed by RECIST 1.1 using BICR 
assessments, whereas a sensitivity analysis of PFS will be performed using Investigator 
assessments according to RECIST 1.1.  In addition, a sensitivity analysis of PFS based 
on RECIST 1.1 modified for confirmation of progression will be performed using 
BICR assessments.
Section 8.4.1.4 (Secondary Endpoints): This section has been updated to clarify that 
ORR by irRECIST 1.1 criteria using BICR assessments will not be reported as a 
secondary endpoint.   This section has also been modified to clarify that RECIST 1.1 
will determine ORR, DoR, APF12, and best objective response using BICR 
assessments.  Text has also been added regarding time from randomization to the second 
subsequent therapy or death.
Section 8.5 (Methods for Statistical Analyses): The number of patients with PD-L1-
negative tumors across the MEDI4736 + tremelimumab combination therapy and SoC 
treatment arms needed at the time of the PFS and OS analyses has been corrected.  The 
text has also been updated to clarify that PFS will be assessed by RECIST 1.1 using 
BICR assessments.  Table 16 has been updated to clarify that PFS, ORR, and DoR will 
be assessed by RECIST 1.1 using BICR assessments rather than investigator 
assessments; a sensitivity analysis of PFS will be performed using Investigator 
assessments according to RECIST 1.1 rather than a sample BICR assessment, and a 
sensitivity analysis of PFS will be performed using BICR assessments according to 
RECIST 1.1 modified for confirmation of progression.  Various patient-related 
outcome (PRO) endpoints have also been removed from Table 16.  The MTP has been 
simplified (both the text and Figure 6) and includes additional detail regarding the 
timing and assignment of alpha for two interim analyses of OS.  Additionally, 
non-inferiority analysis and the comparisons of the combination arm versus 
monotherapy arm for both PFS and OS have been removed from the multiple testing 


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procedure (MTP). Finally, subsections 8.5.1 through 8.5.4 have been combined to reflect 
analysis of the co-primary endpoints, and subsequent subsections of 8.5 have been re-
numbered accordingly.
Section 8.5.1.1 (Progression-free Survival): This section has been updated to clarify that 
the primary PFS analysis will be assessed by RECIST 1.1 using BICR assessments, that 
secondary analyses for PFS using BICR assessments will be performed for the 
comparisons of the combination versus SoC and the combination versus monotherapy in 
PD-L1-negative patients, and the comparison of monotherapy vs SOC in all comers.  
Section 8.5.1.2 (Overall Survival): The parameters for the analyses of OS have been 
clarified.
Section 8.5.1.3 (Subgroup Analysis of PFS and OS): This section has been updated to 
clarify that PFS will be assessed by RECIST 1.1 using BICR assessments.
Section 8.5.2.1 (Objective Response Rate): This section has been updated to clarify that 
ORR will be assessed by RECIST 1.1 using BICR assessments.  Details pertaining to 
the parameters and population to be studied in this analysis have also been clarified.
Section 8.5.2.2 (Duration of Response): This section has been updated to clarify that 
DoR will be assessed by RECIST 1.1 using BICR assessments.
Section 8.5.2.4 (Time from Randomization to PFS2): A definition of second progression 
has been added to this section.
Section 8.5.2.5 (Time from Randomization to First and Second Subsequent Therapy or 
Death): The text has been updated to reflect that time to the start of the first and the 
second therapy or death will be analyzed.
Section 8.5.3 (Patient-reported Outcomes): Details pertaining to the analysis of PRO 
endpoints have been added.
Section 8.5.9 (Interim Analysis): Text has been updated to reflect that there will be 
2 interim analyses for OS performed for superiority.  Details regarding the parameters 
for the interim analyses and potential outcomes have been added.  
Section 11 (List of References): References that are not cited in the protocol have been 
removed; newly cited references have been added.
Appendix E (Guidelines for Evaluation of Objective Tumor Response Using RECIST 
1.1 Criteria): This appendix has been updated to reflect changes to the criterion for 
non-measurable lesions.  Preferences for computed tomography and magnetic resonance 
imaging scans have been updated as well.  Additionally, text pertaining to the timing of 
the imaging for confirmation of response has been removed from this appendix.
Appendix F (Patient-Reported Outcomes): The PRO Common Terminology Criteria for 
Adverse Events questionnaire has been updated to remove certain symptoms and side 
effects from the questionnaire.


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Version 12.0
Date 29 June 2020
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Version 4.0, 1st December 2015 (D419LC00001CSP Amendment 3)
Changes to the protocol are summarized below.
Protocol Synopsis: Per Voluntary Harmonisation Procedure (VHP) review, an interim 
analysis for OS at the time of PFS analysis has been added.  The MTP has also been 
modified to include 1 interim analysis of OS.
Section 8.2 (Sample Size Estimate): Per VHP review, an interim analysis for OS at the 
time of PFS analysis has been added.  The MTP has also been modified to include 1 
interim analysis of OS.
Section 8.5 (Methods for Statistical Analyses): Per VHP review, an interim analysis for 
OS at the time of PFS analysis has been added.  The Multiple Testing Procedure has also 
been modified to include 1 interim analysis of OS, and Figure 6 has been updated to 
reflect this change.
Section 8.5.12 (Interim Analysis): Per VHP review, an interim analysis for OS at the 
time of PFS analysis has been added.  The MTP has also been modified to include 1 
interim analysis of OS.
Version 3.0, 9th November 2015 (D419LC00001CSP Amendment 2)
Changes to the protocol are summarized below.
Section 3.1 (Inclusion Criteria): In response to VHP review comments, the creatinine 
clearance requirement for patients who will be treated with cisplatin on the SoC arm has 
been revised to a minimum of 60 mL/min.  The age specific requirements for 
post-menopausal female patients have also been clarified with respect to pregnancy 
testing.
Section 3.2 (Exclusion Criteria): In response to VHP review comments, the time frame 
allowed for receipt of prior investigational anticancer therapy has been revised to be 28 
days or 5 half-lives, whichever is longer, prior to first study treatment.  Also in response 
to VHP review comments, contraception requirements have been modified such that 
female patients of childbearing potential must agree to use highly effective method of 
birth control and nonsterilized male patients who are sexually active with a partner of 
childbearing potential must agree to use condoms with spermicide.
Section 3.3 (Patient Enrollment and Randomization): The process for defining SoC at 
time of randomization has been clarified.
Section 3.8 (Restrictions): In response to VHP review comments, Table 1 has been 
updated to include only highly effective methods of contraception.
Section 4 (Study Plan and Timing of Procedures): In response to VHP review 
comments, the timing of scheduled pregnancy testing in Table 2 has been modified to 


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Version 12.0
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reflect that patients assigned to either the MEDI4736 + tremelimumab or MEDI4736 
monotherapy arms will undergo pregnancy testing at each study visit when IP is 
administered.
Section 5.2.1 (Laboratory Safety Assessments): In response to VHP review comments, 
the timing of scheduled pregnancy testing has been modified to reflect that patients 
assigned to either the MEDI4736 + tremelimumab or MEDI4736 monotherapy arms will 
undergo pregnancy testing at each study visit when IP is administered.
Version 2.0, 10th September 2015 (D419LC00001CSP Amendment 1)
Changes to the protocol are summarized below, 
Title Page: The title has been updated to reflect the 3-arm design of the trial in response 
to regulatory feedback.
Protocol Synopsis: The text has been modified to clarify the distribution of programmed 
cell death ligand 1 (PD-L1) negative patients across the treatment arms and to reflect 
that patients in any treatment arm, not only the immunomodulatory therapy (IMT) arms, 
will not be permitted to continue therapy if they develop PD in a target lesion after a 
clear response to therapy.  The definition of smoking history has also been clarified.  
Additional detail on the Ventana assay has also been added.  The SoC dosing regimen 
has been updated to correct minor inconsistencies within the text.  Also, the timing of 
confirmatory scans has been updated to be consistent across all treatment arms.  The 
contact information of the Co-International Coordinating Investigators has also been 
updated.  Finally, the title has been updated to reflect the 3-arm design of the trial in 
response to regulatory feedback.
Section 1.3.2.1 (MEDI4736): The potential risks of nephritis and pancreatitis for 
MEDI4736 have been updated to align with the most recent Investigator’s Brochure.
Section 1.4 (Study Design): This text in this section has been updated, along with Figure 
2, to clarify tumor biopsy collection procedures.  The text has also been modified to
clarify the distribution of PD-L1 negative patients across the treatment arms.  Figure 3 
has been updated to clarify that retreatment tumor assessments are relative to restarting 
study treatment.  Additionally, the text has been modified to reflect that patients in any 
treatment arm, not only the IMT arms, will not be permitted to continue therapy if they 
develop PD in a target lesion after a clear response to therapy.  The SoC dosing regimen 
has been updated to correct minor inconsistencies within the text.
Section 3.1 (Inclusion Criteria): This section has been modified to change the required 
PD-L1 tumor biopsy sample to a formalin-fixed and paraffin-embedded recently 
acquired tissue sample (preferred) or an archival tissue <3 years old and to clarify 
related tumor biopsy collection procedures.  Additionally, the text has been modified to 
reflect that patients in any treatment arm, not only the IMT arms, will not be permitted 
to continue therapy if they develop PD in a target lesion after a clear response to 
therapy.  Additional detail on the Ventana assay has also been added.  This section has 


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also been revised to clarify that SoC procedures prior to informed consent are not study 
procedures for this study.
Section 3.2 (Exclusion Criteria): An additional exclusion criterion that clarifies 
minimum patient weight needed for this study has been added.
Section 3.3 (Patient Enrollment and Randomization): This section has been updated to 
clarify tumor biopsy collection procedures.  The definition of smoking history has also 
been clarified.  This section has also been revised to clarify that patients should have no 
obvious exclusion parameters before a tumor sample is obtained.  The instances in 
which HPV status will be determined have also been clarified.  
Section 3.5 (Methods for Assigning Treatment Arms): The definition of smoking history 
has been clarified.  Additional detail on the Ventana assay has also been added.
Section 3.8 (Restrictions): The contraception restrictions have been updated to be in 
alignment across the MEDI4736 development program.
Section 4 (Study Plan and Timing of Procedures): In Table 2, TSH has been added to the 
assessments that must be available before commencing an infusion. Table 2 has also 
been updated to clarify that the first treatment period continues until PD and that SoC 
procedures prior to informed consent are not study procedures for this study.  In Table 3, 
the SoC dosing regimen has been updated to correct minor inconsistencies within the 
text. Table 3 has been further modified to include an assessment on Cycle 1, Day 1, 
Week 0 for the PRO measures in the SoC arm.  Furthermore, Tables 2 and 3 have been 
modified to change the required PD-L1 tumor biopsy sample to a formalin-fixed and 
paraffin-embedded recently acquired tissue sample (preferred) or an archival tissue <3 
years old and to clarify related tumor biopsy collection procedures.  Also, Tables 2 and 3 
have been updated to clarify which assessments performed 3 days prior to Day 1 do not 
need to be repeated at Day 1 and to clarify the timing of pregnancy testing in response to 
regulatory feedback.  Table 4 has been modified to clarify that pharmacokinetics should 
only be collected for the IMT arms at follow-up.
Section 4.1 (Enrollment/Screening Period): This section has been updated to clarify 
tumor biopsy collection procedures.
Section 5.1 (Efficacy Assessments): The timing of confirmatory scans has been updated 
to be consistent across all treatment arms.
Section 5.2.1 (Laboratory Safety Assessments): Table 5 has been modified to clarify that 
bicarbonate will not be evaluated at South Korean sites.
Section 5.5.1 (Collection of Patient Samples for Stratification by PD-L1): This section 
has been modified to change the required PD-L1 tumor biopsy sample to a formalin-
fixed and paraffin-embedded recently acquired tissue sample (preferred) or an archival 
tissue <3 years old and to clarify related tumor biopsy collection procedures.  Additional 
detail on the Ventana assay has also been added.


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Version 12.0
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Section 5.5.2.2
Section 6.7.2 (Immune Related Adverse Events): An error in the definition of 
Pneumocystis carinii pneumonia has been corrected in Table 8.
Section 7.2.1 (Treatment Regimens): The SoC dosing regimen has been updated to 
correct minor inconsistencies within the text.  The timing of confirmatory scans has also 
been updated to be consistent across all treatment arms.
Section 8.2 (Sample Size Estimate): The text has been modified to clarify the 
distribution of PD-L1 negative patients across the treatment arms.  Additionally, hazard 
ratio values have been corrected for the MEDI4736 monotherapy versus SoC in all-
comers noninferiority analysis.
Section 8.3.2 (PD-L1-negative Analysis Set): Additional detail on the Ventana assay has 
been added.
Section 8.4.1.4 (Secondary Endpoints): A definition and description for the analysis of 
time from randomization to the first subsequent therapy or death has been added.
Section 8.5.5.5 (Time from Randomization to the First Subsequent Therapy or Death): A 
definition and description for the analysis of time from randomization to the first 
subsequent therapy or death has been added. 
Version 1.0, 6th July 2015
Initial creation
CCI


Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Edition Number 12.0
Date 29 June 2020
28(199)
This submission document contains confidential commercial information, disclosure of 
which is prohibited without providing advance notice to AstraZeneca and opportunity to 
object.
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The clinical study protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


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Study Code D419LC00001
Version 12.0
Date 29 June 2020
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PROTOCOL SYNOPSIS
A Phase III Randomized, Open-label, Multi-center, Global Study 
of MEDI4736 Alone or in Combination with Tremelimumab 
versus Standard of Care in the Treatment of First-line Recurrent 
or Metastatic Squamous Cell Head and Neck Cancer Patients
Co-International Coordinating Investigators
 
 
Study site(s) and number of patients planned
This study will enroll approximately 1016 patients with recurrent or metastatic (R/M) 
squamous cell carcinoma of the head and neck (SCCHN) who are not amenable to local 
curative therapy and who have not received prior systemic therapy for recurrent/metastatic 
disease.  Approximately 760 patients will be identified globally and will be randomized in 
a 2:1:1 ratio (380:190:190 patients) to receive MEDI4736 + tremelimumab combination 
therapy, MEDI4736 monotherapy, or Standard of Care (SoC). 
Study period
Phase of development
Estimated date of first patient enrolled
Q4 2015
III
Estimated date of last patient completed
Q1 2021
III
Q Quarter.
Study design
This is a randomized, open-label, multi-center, 3-arm, global Phase III study to determine 
the efficacy and safety of MEDI4736 +/- tremelimumab versus SoC (EXTREME regimen) 
in the treatment of patients with R/M SCCHN who are not amenable to local curative 
therapy with surgery or radiation and who have not received prior systemic therapy for 
recurrent/metastatic disease, unless it was given as part of multimodality treatment for 
locally advanced or locally recurrent disease.  Patients will undergo a screening assessment 
on their tumor tissue sample to determine PD-L1 expression status (defined by an 
analytically validated immunohistochemistry assay developed by VENTANA in which 
≥25% PD-L1 membrane expression in tumoral tissue is considered positive and <25% is 
considered negative for purposes of stratification; referred to hereafter as patients with PD-
L1-positive or –negative tumors, respectively).  Patients will be randomized in a 2:1:1 ratio 
to MEDI4736 + tremelimumab combination therapy, MEDI4736 monotherapy, or SoC in 
a stratified manner according to PD-L1 tumor expression status (as described above), 
PPD


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tumor location (oropharyngeal cancer [OPC] or non-OPC), and smoking history (>10 vs 
≤10 pack-years) to receive treatment with MEDI4736 + tremelimumab combination 
therapy, MEDI4736 monotherapy, or SoC therapy.  Patients with OPC will be further 
stratified by their human papilloma virus status (positive or negative).
Patients in all arms will continue therapy until progression.  Patients in all arms should 
continue receiving therapy in the setting of equivocal progressive disease (PD), at the 
Investigator’s discretion, until PD is confirmed.  Assessments in all arms should continue 
as per schedule until confirmation of PD.  Patients in all arms with confirmed PD by 
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) who, in the 
Investigator’s opinion, continue to receive benefit from their assigned treatment and who 
meet the criteria for treatment in the setting of PD may continue to receive their assigned 
treatment.  However, patients in the immunotherapy arms will not be permitted to continue 
immunotherapy if progression occurs after objective response (defined by RECIST 1.1) to 
immunotherapy treatment in the target lesions.  Patients who have discontinued treatment 
due to toxicity or symptomatic deterioration, clinical progression, or who have commenced 
subsequent anticancer therapy, will be followed up until confirmed disease progression 
and for survival.
Tumor assessments will be performed on computed tomography scans or magnetic 
resonance imaging scans, preferably with intravenous (IV) contrast.  Efficacy for all 
patients will be assessed by objective tumor assessments every 6 weeks for the first 
24 weeks, then every 8 weeks thereafter (relative to the date of randomization) until 
treatment discontinuation due to progression or toxicity.  All patients will be followed 
every 3 months for survival after progression is confirmed.  If an unscheduled assessment 
is performed, and the patient has not progressed, every attempt should be made to perform 
the subsequent assessments at their scheduled visits, but scans would not need to be 
repeated if obtained within 2 weeks of the scheduled assessment.  Patients with confirmed 
PD who discontinue treatment should have scans conducted according to local practice.
The primary objective of the study is:

To assess the efficacy of MEDI4736 monotherapy versus SoC (EXTREME) in a 
prespecified biomarker-selected subgroup of patients (PD-L1 TC/IC high 
subgroup) in terms of overall survival (OS)
The primary endpoint of the study is OS which will be assessed in a prespecified 
biomarker-selected subgroup of patients with tumors expressing PD-L1 in ≥50% of tumor 
cells (TC) or in ≥25% of tumor-associated immune cells (IC) (PD-L1 TC/IC high 
subgroup; TC≥50 or IC≥25) using the VENTANA PD-L1 SP263 assay.
Categorization of objective tumor response assessment at each post-screening imaging 
timepoint will be based on RECIST 1.1: complete response, partial response, stable disease 
(SD), and PD.  Investigator assessments according to RECIST 1.1 will be used to 
programmatically derive the secondary variables of progression-free survival (PFS), 
objective response rate (ORR), duration of response (DoR), best objective response (BoR), 
time to response (TTR) and proportion of patients alive and progression free at 6 (APF6) 
and 12 months (APF12). Additional secondary objectives will include proportion of 
patients alive at 12 (OS12), 18 (OS18) and 24 months after randomization (OS24), second 


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Version 12.0
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progression (PFS2), safety and tolerability, pharmacokinetics (PK), anti-drug antibody 
(ADA), and health-related quality of life.  Exploratory objectives will also be assessed.
Timepoint assessments showing PD for patients in the immunomodulatory therapy 
treatment arms should be confirmed preferably at the next scheduled imaging visit and no 
earlier than 4 weeks after the preceding assessment of PD in the absence of clinically 
significant deterioration.  Timepoint assessments showing PD for patients in the SoC arm 
should be confirmed preferably at the next scheduled imaging visit and no earlier than 4 
weeks after the preceding assessment of PD in the absence of clinically significant 
deterioration, if clinically feasible.  Treatment with MEDI4736 + tremelimumab 
combination therapy or MEDI4736 monotherapy will continue between the assessment of 
progression and its confirmation.  If progression is not confirmed, then the patient should 
continue receiving study treatment and participating in study assessments.  For patients 
randomized to the SoC arm in whom equivocal findings of progression are observed (eg, 
very small and uncertain new lesions, cystic changes, or necrosis in existing lesions), 
treatment should continue until the next scheduled assessment.  Patients with clinical 
evidence of progression who do not meet PD criteria by RECIST 1.1 should have 
radiographic documentation of PD.
Objectives
Primary Objectives:
Outcome Measure:
To assess the efficacy of MEDI4736 
monotherapy compared to SoC (EXTREME) 
in terms of OS  
OS in the PD-L1 TC/IC high subgroup
Secondary Objectives:
Outcome Measures:
To further assess the efficacy of MEDI4736 
monotherapy compared to SoC (EXTREME) 
in terms of OS, PFS, ORR, DoR, BoR, TTR, 
TFST, TSST, APF6, APF12, PFS2, OS12, 
OS18 and OS24 
OS in low risk of early mortality (EM) subgroup, 
ctDNA TMB high subgroup (≥16 mut/Mb) and all-
comers
OS12, OS18, OS24 in the PD-L1 TC/IC high 
subgroup, low risk of EM subgroup, ctDNA TMB
high subgroup (≥16 mut/Mb) and all-comers
PFS, ORR, APF6 and APF12 using site investigator 
assessments according to RECIST 1.1 in the PD-L1 
TC/IC high subgroup, low risk of EM subgroup, 
ctDNA TMB high subgroup (≥16 mut/Mb) and all-
comers 
DoR, BoR and TTR, using site investigator 
assessments according to RECIST 1.1 in the PD-L1 
TC/IC high subgroup and all-comers 
PFS2 using local standard clinical practice in the PD-
L1 TC/IC high subgroup and all-comers 
TFST and TSST in the PD-L1 TC/IC high subgroup 
and all-comers


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Secondary Objectives:
Outcome Measures:
To assess the efficacy of MEDI4736 + 
tremelimumab combination therapy compared 
to SoC (EXTREME) in terms of OS, PFS, 
ORR, DoR, BoR, TTR, TFST, TSST, APF6, 
APF12, PFS2, OS12, OS18 and OS24
OS, OS12, OS18, OS24 in the PD-L1 TC/IC high 
subgroup, low risk of EM subgroup, ctDNA TMB
high subgroup (≥16 mut/Mb) and all comers
PFS, ORR, APF6 and APF12 in the PD-L1 TC/IC 
high subgroup, low risk of EM subgroup, ctDNA 
TMB high subgroup (≥16 mut/Mb) and all-comers 
using site investigator assessments according to 
RECIST 1.1
DoR, BoR and TTR, using site investigator 
assessments according to RECIST 1.1 in the PD-L1 
TC/IC high subgroup and all-comers
PFS2 using local standard clinical practice in the PD-
L1 TC/IC high subgroup and all-comers 
TFST and TSST in the PD-L1 TC/IC high subgroup 
and all-comers
To assess the efficacy of MEDI4736 + 
tremelimumab combination therapy compared 
to MEDI4736 monotherapy in terms of PFS, 
ORR, and OS 
PFS and ORR using site investigator assessments 
according to RECIST 1.1 in the PD-L1 TC/IC high 
subgroup, low risk of EM subgroup, ctDNA TMB
high subgroup (≥16 mut/Mb) and all-comers 
OS in the PD-L1 TC/IC high subgroup, low risk of 
EM subgroup, ctDNA TMB high subgroup (≥16 
mut/Mb) and all-comers
To assess disease-related symptoms and 
health-related quality of life in patients treated 
with MEDI4736 + tremelimumab combination 
therapy and MEDI4736 monotherapy 
compared to SoC (EXTREME) using the 
European Organisation for Research and 
Treatment of Cancer (EORTC) 30-item Core 
Quality of Life Questionnaire (QLQ-C30) 
version 3 and the 35-item Head and Neck 
Quality of Life Questionnaire (QLQ-H&N35) 
module
EORTC QLcQ-C30: global health QoL, functioning 
(physical) and symptoms (fatigue) in the PD-L1 
TC/IC high subgroup and all-comers 
EORTC QLQ-H&N35: symptoms (pain, swallowing) 
in the PD-L1 TC/IC high subgroup and all-comers
Changes in World Health Organization/Eastern
Cooperative Oncology Group performance status in 
the PD-L1 TC/IC high subgroup all-comers
To assess the PK of MEDI4736 + 
tremelimumab combination therapy and 
MEDI4736 monotherapy
Concentration of MEDI4736 and tremelimumab in 
blood and PK parameters, such as peak concentration 
and trough (as data allow; sparse sampling) 
To investigate the immunogenicity of 
MEDI4736 and tremelimumab
Presence of ADAs for MEDI4736 and tremelimumab


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Safety Objective:
Outcome Measures:
To assess the safety and tolerability profile of 
MEDI4736 + tremelimumab combination 
therapy and MEDI4736 monotherapy 
compared to SoC (EXTREME) in the first-line 
setting for treatment of SCCHN
Adverse events, physical examinations, laboratory 
findings (including clinical chemistry, hematology, 
and urinalysis), vital signs (including blood pressure 
and pulse), and electrocardiograms in PD-L1 TC/IC 
high subgroup, low risk of EM subgroup and all-
comers.
Target patient population
Males and females aged 18 and over with histologically or cytologically confirmed 
PD-L1-positive or -negative, recurrent or metastatic SCCHN (oral cavity, oropharynx, 
hypopharynx, or larynx) and who are not amenable to local curative therapy with surgery 
or radiation and who have not received prior systemic therapy for recurrent/metastatic 
disease, unless it was given as part of multimodality treatment for locally advanced or 
locally recurrent disease.
Duration of treatment
Treatment with MEDI4736 + tremelimumab combination therapy, MEDI4736 
monotherapy, or SoC will commence within 5 working days of randomization and 
continue until confirmed progression, initiation of alternative cancer therapy, unacceptable 
toxicity, withdrawal of consent, or another discontinuation criterion is met at the 
Investigator’s discretion.  Patients in the SoC arm will be treated with SoC for a maximum 
of six 3-week cycles of cetuximab, a platinum, and 5-fluorouracil (5FU), with continuation 
of maintenance cetuximab in patients who have achieved SD or better until confirmed PD, 
initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or 
another discontinuation criterion is met.
A further description of treatment duration and retreatment options is provided in the 
Study Design section of this synopsis.
Patients in the MEDI4736 + tremelimumab combination therapy group may be eligible to 
receive retreatment with MEDI4736 + tremelimumab combination therapy if they meet 
certain criteria as stated in Section 3.1.
Investigational product, dosage, and mode of administration
MEDI4736 monotherapy: (1500 mg) will be administered via IV infusion every 4 weeks 
(q4w) until PD.
MEDI4736 + tremelimumab combination therapy: Tremelimumab (75 mg) will be 
administered via IV infusion q4w for a maximum of 4 doses, and MEDI4736 (1500 mg) 
will be administered via IV infusion q4w until PD.
SoC (EXTREME): Either cisplatin (at a dose of 100 mg/m2 of body surface area as an IV 
infusion) or carboplatin (at an area under the curve of 5 mg/mL/min as an IV infusion) on 
Day 1 of up to six 3-week cycles, and an infusion of 5FU (at a dose of 1000 mg/m2/day on 
Days 1 through 4) every 3 weeks, along with 400 mg/m2 of cetuximab on Cycle 1 Day 1 
and 250 mg/m2 weekly for up to 6 cycles and maintenance cetuximab at 250 mg/m2


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administered via IV infusion weekly thereafter in patients who achieve SD or better upon 
completion of chemotherapy until PD, toxicity, or withdrawal of consent.  
Statistical methods
The primary objective of this study is to assess the efficacy of MEDI4736 monotherapy 
treatment compared with SoC (EXTREME) in terms of OS in a prespecified biomarker-
selected subgroup of patients with tumors expressing PD-L1 in ≥50% of tumor cells or  
≥25% of tumor-associated immune cells (PD-L1 TC/IC high subgroup), who have not 
received prior systemic therapy for recurrent/metastatic disease, unless it was given as part 
of multimodality treatment for locally advanced or locally recurrent disease.
OS will be defined as the time from the date of randomization until death due to any cause.  
Secondary efficacy variables include

OS (assessed in the low risk of EM subgroup, ctDNA TMB high subgroup (≥16 
mut/Mb) and all-comers), PFS, ORR, APF6, APF12, OS12, OS18 and OS24 
(assessed in the  PD-L1 TC/IC high subgroup, low risk of EM subgroup, ctDNA 
TMB high subgroup (≥16 mut/Mb) and in all-comers), PFS2, DoR, BoR, TTR, 
TFST, TSST (assessed in the PD-L1 TC/IC high subgroup and all-comers) for 
MEDI4736 monotherapy versus SoC

OS, PFS, ORR, APF6, APF12, OS12, OS18 and OS24 (assessed in the  PD-L1 
TC/IC high subgroup, low risk of EM subgroup, ctDNA TMB high subgroup (≥16 
mut/Mb) and in all-comers), PFS2, DoR, BoR, TTR, TFST and TSST (assessed in 
the PD-L1 TC/IC high subgroup and all-comers) for MEDI4736 + tremelimumab 
combination therapy versus SoC

OS, PFS and ORR (assessed in the PD-L1 TC/IC high subgroup, low risk of EM 
subgroup, ctDNA TMB high subgroup (≥16 mut/Mb) and in all-comers) for 
MEDI4736 + tremelimumab versus MEDI4736 monotherapy. 
PFS (per RECIST 1.1 using site investigator assessment) will be defined as the time from 
the date of randomization until the date of objective disease progression or death (by any 
cause in the absence of progression) regardless of whether the patient discontinues therapy 
or receives another anticancer therapy prior to progression.  A sensitivity analysis of PFS 
will be performed based on data from blinded independent central review (BICR) 
assessments.
Efficacy data will be summarized and analyzed on an intent-to-treat (ITT) basis and the 
treatment groups will be compared on the basis of randomized treatment, regardless of the 
treatment actually received.  Patients who were randomized but did not subsequently go on 
to receive study treatment are included in the ITT population.
Approximately 760 patients will be randomized in a 2:1:1 ratio (380:190:190 patients) to 
receive MEDI4736 + tremelimumab combination therapy, MEDI4736 monotherapy, or 
SoC to assess OS (primary endpoint) in each treatment comparison.


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Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
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The primary analysis of OS will be performed when approximately 147 death events have 
occurred in approximately 172 patients (85% maturity) across the MEDI4736 
monotherapy and SoC treatment groups in the PD-L1 TC/IC high subgroup. All other 
endpoints will be analysed at this time.  No interim analyses will be performed for any 
efficacy endpoint.
The primary analysis of OS will test MEDI4736 monotherapy versus SoC in the PD-L1 
TC/IC high subgroup at a two-sided 5% level.  If superiority over SoC is found, a 
hierarchical multiple testing procedure will be employed to strongly control for the overall 
type I error at the 5% level (two-sided). Subsequent hypotheses in the hierarchy will be to 
test MEDI4736 monotherapy versus SoC   for the low risk of EM subgroupand ctDNA 
TMB high subgroup). Should these tests show  statistical significant evidence of 
superiority, MEDI4736 + tremelimumab combination therapy versus SoC will be tested in 
the ctDNA TMB high subgroup (≥16 mut/Mb), followed by MEDI4736 monotherapy 
versus SoC  for all-comers. The final hypothesis to be tested, should all previous tests 
show statistical significant evidence of superiority, will be to test MEDI4736 + 
tremelimumab combination therapy versus SoC for all-comers. All tests will be at the two-
sided 5% level and the procedure will stop at the first failure to find statistically significant 
evidence of superiority or if tests of all hypotheses show superiority over SoC.
If OS in the PD-L1 TC/IC high subgroup at 24 months was 30% with MEDI4736 
monotherapy and 12% with SoC (with a 10.1-month median OS), and assuming the true 
average OS HR is 0.59, the trial will have approximately 90% power to demonstrate 
statistical significance at the 5% level (using a 2-sided test) for the comparison of 
MEDI4736 monotherapy versus SoC in the PD-L1 TC/IC high subgroup, with the smallest 
treatment difference that could be statistically significant being an average HR of 0.72  
With a 17-month recruitment period and a minimum follow-up period of 23.6 months, it is 
anticipated that the analysis will be performed approximately 40.6 months after the first 
patient has been recruited.
The primary analysis of OS will use a stratified log-rank test (stratified for PD-L1 
expression tumor status [PD-L1 positive vs PD-L1 negative], tumor location [OPC vs non-
OPC, with a subsequent adjustment for HPV status in patients with OPC], and smoking 
history [>10 vs ≤10 pack-years] as entered in the IVRS system).  The effect of treatment 
will be estimated by the HR together with corresponding 95% confidence interval and p-
value.  
Safety data will be summarized descriptively.


Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
36(199)
TABLE OF CONTENTS
PAGE
TITLE PAGE...................................................................................... 1
VERSION HISTORY......................................................................... 2
PROTOCOL SYNOPSIS...................................................................29
TABLE OF CONTENTS...................................................................36
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.........43
1.
INTRODUCTION .............................................................................48
1.1
Background and rationale for conducting this study ...........................48
1.1.1
Squamous cell carcinoma of the head and neck ..................................48
1.1.2
Immunotherapies ...............................................................................49
1.1.3
MEDI4736 (Durvalumab) ..................................................................50
1.1.4
Tremelimumab...................................................................................50
1.1.5
MEDI4736 in combination with tremelimumab..................................51
1.1.6
Rationale for conducting this study ....................................................51
1.2
Rationale for study design, doses, and control groups.........................52
1.2.1
MEDI4736 monotherapy dose rationale .............................................53
1.2.2
MEDI4736 + tremelimumab combination therapy dose rationale .......54
1.2.3
Rationale for fixed dosing ..................................................................56
1.2.4
Standard of Care dose rationale..........................................................57
1.2.5
Study population rationale..................................................................57
1.2.6
Rationale for endpoints ......................................................................59
1.3
Benefit/risk and ethical assessment ....................................................60
1.3.1
Potential benefits................................................................................61
1.3.1.1
MEDI4736.........................................................................................61
1.3.1.2
Tremelimumab...................................................................................61
1.3.1.3
MEDI4736 + tremelimumab combination therapy..............................61
1.3.2
Identified and Potential risks..............................................................62
1.3.2.1
MEDI4736.........................................................................................62
1.3.2.2
Tremelimumab...................................................................................63
1.3.2.3
MEDI4736 + tremelimumab combination therapy..............................63
1.3.3
Overall benefit/risk and ethical assessment.........................................64
1.4
Study design ......................................................................................64
2.
STUDY OBJECTIVES......................................................................68
2.1
Primary objective...............................................................................68
2.2
Secondary objectives..........................................................................69
2.3
Safety objective..................................................................................70
2.4
Exploratory objectives .......................................................................71
3.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION,
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL....71


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Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
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3.1
Inclusion criteria ................................................................................72
3.2
Exclusion criteria ...............................................................................75
3.3
Patient enrollment and randomization ................................................77
3.4
Procedures for handling incorrectly enrolled patients .........................79
3.5
Methods for assigning treatment arms................................................79
3.6
Methods for ensuring blinding (not applicable) ..................................79
3.7
Methods for unblinding (not applicable).............................................79
3.8
Restrictions........................................................................................80
3.9
Discontinuation of investigational product .........................................81
3.9.1
Procedures for discontinuation of a patient from investigational 
product...............................................................................................81
3.10
Criteria for withdrawal of the patient from the study ..........................82
3.10.1
Screen failures ...................................................................................82
3.10.2
Withdrawal of the informed consent...................................................82
3.10.3
Survival status for withdrawn consent and lost to follow up patients ..83
3.11
Discontinuation of the study...............................................................83
4.
STUDY PLAN AND TIMING OF PROCEDURES...........................84
4.1
Enrollment/screening period ..............................................................95
4.2
Treatment period................................................................................95
4.3
Follow-up period................................................................................95
5.
STUDY ASSESSMENTS..................................................................95
5.1
Efficacy assessments..........................................................................96
5.1.1
Central reading of scans .....................................................................98
5.1.2
Survival assessments..........................................................................98
5.2
Safety assessments.............................................................................98
5.2.1
Laboratory safety assessments............................................................98
5.2.2
Physical examination .......................................................................101
5.2.3
Electrocardiograms ..........................................................................101
5.2.4
Vital signs........................................................................................102
5.2.5
Other safety assessments..................................................................103
5.3
Other assessments............................................................................103
5.3.1
Patient-reported outcomes................................................................103
5.3.1.1
EORTC QLQ-C30 ...........................................................................103
5.3.1.2
EORTC QLQ-H&N35 .....................................................................104
5.3.1.3
...................................................................................104
5.3.1.4
................................................................................................104
5.3.1.5
........................................................................................104
5.3.2
Administration of the patient-reported outcome questionnaires ........105
5.3.3
WHO/ECOG performance status......................................................106
5.4
Pharmacokinetics .............................................................................106
5.4.1
Collection of samples and determination of drug concentration........106
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Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
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5.4.2
Collection of samples to measure for the presence of anti-drug 
antibodies.........................................................................................106
5.4.3
Storage and destruction of pharmacokinetic/anti-drug antibody 
samples............................................................................................107
5.5
Biomarker analysis...........................................................................107
5.5.1
Collection of patient samples for stratification by PD-L1 .................107
5.5.2
Collection of exploratory biomarker data .........................................109
5.5.2.1
...................................................................109
5.5.2.2
.................................................................................110
5.5.3
Management of biomarker data........................................................110
5.5.4
Storage, re-use, and destruction of biological samples......................110
5.5.5
Labeling and shipment of biological samples ...................................111
5.5.6
Chain of custody of biological samples ............................................111
5.5.7
Withdrawal of informed consent for donated biological samples......111
5.6
Pharmacogenetics (not applicable) ...................................................111
5.7
Pharmacodynamics (not applicable) .................................................112
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT...........112
6.1
Definitions of serious adverse events................................................112
6.2
Recording of adverse events.............................................................112
6.2.1
Time period for collection of adverse events ....................................112
6.2.2
Follow-up of unresolved adverse events...........................................112
6.2.3
Variables..........................................................................................113
6.3
Definition of adverse events.............................................................114
6.3.1
Causality collection..........................................................................114
6.3.2
Relationship to protocol procedures .................................................114
6.3.3
Adverse events based on signs and symptoms..................................114
6.3.4
Adverse events based on examinations and tests ..............................115
6.3.5
Hy’s Law .........................................................................................115
6.3.6
Disease progression..........................................................................115
6.3.7
New cancers.....................................................................................115
6.3.8
Deaths..............................................................................................115
6.3.9
Safety data to be collected following the final data cut-off of the 
study................................................................................................116
6.4
Reporting of serious adverse events .................................................116
6.5
Overdose..........................................................................................117
6.6
Pregnancy ........................................................................................117
6.6.1
Maternal exposure............................................................................117
6.6.2
Paternal exposure.............................................................................118
6.7
Management of IP-related toxicities.................................................118
6.7.1
MEDI4736 + tremelimumab combination therapy and MEDI4736 
monotherapy adverse events of special interest.................................119
6.7.2
Specific toxicity management and dose modification information -
MEDI4736 + tremelimumab combination therapy and MEDI4736 
monotherapy....................................................................................120
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Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
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6.7.3
Management of toxicity attributable to agents in the Standard of Care 
arm ..................................................................................................121
6.8
Study governance and oversight.......................................................121
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .121
7.1
Identity of investigational product....................................................121
7.1.1
MEDI4736.......................................................................................122
7.1.2
Tremelimumab.................................................................................123
7.1.3
Standard of Care treatment...............................................................124
7.2
Dose and treatment regimens ...........................................................124
7.2.1
Treatment regimens..........................................................................124
7.2.2
Duration of treatment .......................................................................126
7.2.3
Criteria for Retreatment for Patients in the MEDI4736 + tremelimumab 
arm ..................................................................................................127
7.3
Labeling...........................................................................................128
7.4
Storage.............................................................................................128
7.5
Compliance......................................................................................128
7.6
Accountability..................................................................................128
7.7
Concomitant and other treatments ....................................................129
7.7.1
Other concomitant treatment ............................................................130
7.8
Post study access to study treatment.................................................130
8.
STATISTICAL ANALYSES BY ASTRAZENECA........................130
8.1
Statistical considerations ..................................................................130
8.2
Sample size estimate ........................................................................130
8.3
Definitions of analysis sets...............................................................132
8.3.1
  Full Analysis Set............................................................................132
8.3.2
   Safety Analysis Set .......................................................................132
8.3.3
PD-L1 TC/IC Analysis Set...............................................................132
8.3.4   PK Analysis Set.....................................................................................133
8.3.5   ctDNA TMB Analysis Set.....................................................................133
8.3.6  Low Risk of Early Mortality (EM) Analysis Set.....................................133
8.4
Outcome measures for analyses........................................................133
8.4.1
Calculation or derivation of efficacy variables..................................133
8.4.1.1
Primary and secondary endpoint (OS)..............................................133
8.4.1.2
RECIST 1.1-based endpoints ...........................................................133
8.4.1.3
Secondary  endpoints .......................................................................134
8.4.2
Calculation or derivation of safety variables.....................................137
8.4.2.1
Adverse events.................................................................................137
8.4.2.2
Safety assessments...........................................................................138
8.4.3
Calculation or derivation of patient-reported outcome variables .......138
8.4.3.1
EORTC QLQ-C30 ...........................................................................138
8.4.3.2
EORTC QLQ-H&N35 .....................................................................141
8.4.3.3
............142
8.4.4
Calculation or derivation of pharmacokinetic variables ....................142
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Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
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8.4.4.1
Population pharmacokinetics and exposure-response/safety analysis 142
8.4.4.2
Pharmacokinetic analysis .................................................................142
8.4.4.3
Immunogenicity analysis..................................................................142
8.5
Methods for statistical analyses........................................................143
8.5.1
Analysis of the primary endpoint......................................................147
8.5.1.1
Overall survival................................................................................147
8.5.1.2
Subgroup analysis of OS..................................................................148
8.5.2
Analysis of the secondary variable(s) ...............................................149
8.5.2.1
Progression-free survival..................................................................149
8.5.2.2
Objective response rate ....................................................................150
8.5.2.3
Duration of response ........................................................................150
8.5.2.4
Best objective response ....................................................................150
8.5.2.5
Time to response..............................................................................150
8.5.2.6
Proportion of patients alive and progression free at 6 and 12 months151
8.5.2.7
Time from randomization to PFS2 ...................................................151
8.5.2.8
Time from randomization to first and second subsequent therapy or 
death................................................................................................151
8.5.2.9
Proportion of OS12, OS18 and OS24...............................................151
8.5.3
Patient-reported outcomes................................................................151
8.5.3.1
EORTC QLQ-C30 ...........................................................................152
8.5.3.2
EORTC QLQ-H&N35 .....................................................................153
8.5.3.3
Exploratory patient-reported outcomes.............................................153
8.5.4
Safety data .......................................................................................153
8.5.5
Pharmacokinetic data .......................................................................154
8.5.6
Immunogenicity data........................................................................154
8.5.7
Biomarker data.................................................................................154
8.5.8
Interim analysis................................................................................154
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA.......154
9.1
Training of study site personnel .......................................................154
9.2
Monitoring of the study....................................................................155
9.2.1
Source data ......................................................................................155
9.2.2
Study agreements.............................................................................155
9.2.3
Archiving of study documents..........................................................155
9.3
Study timetable and end of study......................................................156
9.4
Data management by AstraZeneca ...................................................156
10.
ETHICAL AND REGULATORY REQUIREMENTS.....................157
10.1
Ethical conduct of the study .............................................................157
10.2
Patient data protection......................................................................157
10.3
Ethics and regulatory review ............................................................157
10.4
Informed consent .............................................................................158
10.5
Changes to the protocol and informed consent form.........................158
10.6
Audits and inspections .....................................................................159
11.
LIST OF REFERENCES .................................................................160


41(199)
Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
LIST OF TABLES
Table 1
Highly Effectivea methods of contraception ..........................81
Table 2
Schedule of assessments for the MEDI4736 + tremelimumab 
combination or MEDI4736 monotherapy arms and optional 
retreatment period for MEDI4736 + tremelimumab 
combination arm ...................................................................85
Table 3
Schedule of assessments for the Standard of Care treatment 
period....................................................................................89
Table 4
Schedule of assessments for patients who have discontinued
treatment with MEDI4736 + tremelimumab combination 
therapy, MEDI4736 monotherapy, or Standard of Care 
therapy..................................................................................92
Table 5
Clinical chemistry (serum or plasma) ..................................100
Table 6
Hematology ........................................................................100
Table 7
Urinalysisa...........................................................................101
Table 8
List of investigational products for this study ......................121
Table 9
MEDI4736 temperature and infusion time allowances.........123
Table 10
Tremelimumab temperature and infusion time allowances...124
Table 11
Summary of statistical assumptions.....................................131
Table 12
Summary of outcome variables and analysis populations.....132
Table 13
Mean change and visit response in health-related quality of 
life ......................................................................................139
Table 14
Visit response for HRQoL and disease-related symptoms....141
Table 15
Pre-planned statistical and sensitivity analysis to be 
conducted............................................................................144
Table16
Summary of methods of assessment ....................................180
Table 17
Evaluation of target lesions .................................................184
Table 18
Evaluation of non-target lesions ..........................................185
Table 19
Overall visit response..........................................................186
LIST OF FIGURES
Figure 1
Overall study design..............................................................66
Figure 2
Study flow chart - treatment periods......................................67


42(199)
Appendix A
Signatures ...........................................................................169
Appendix B
Additional Safety Information.............................................170
Appendix C
IATA 6.2 Guidance Document............................................173
Appendix D
Actions Required in Cases of Combined Increases in Liver 
Biochemistry and Evaluation of Hy’s Law ..........................174
Appendix E
Guidelines for Evaluation of Objective Tumor Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid 
Tumors) ..............................................................................179
Appendix F
Patient-Reported Outcomes.................................................189


Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
43(199)
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study
Protocol.
Abbreviation or 
special term
Explanation
5FU
5-Fluorouracil
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
APF6
Proportion of patients alive and progression free at 6 months
APF12
Proportion of patients alive and progression free at 12 months
AUC
Area under the curve
AUCss
Area under the serum drug concentration-time curve at steady state
ASCO
American Society for Clinical Oncology
BICR
Blinded Independent Central Review
BoR
Best objective response
BP
Blood pressure
BSC
Best supportive care
CD
Cluster of differentiation
CI
Confidence interval
Cmax,ss
Maximum serum concentration at steady state
CPS
Combined Positive Score
CR
Complete response
CRF
Case report form
CSA
Clinical study agreement
CSP
Clinical study protocol
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
ctDNA
Circulating tumor DNA
CTLA-4
Cytotoxic T–lymphocyte-associated antigen 4
Ctrough,ss
Trough concentration at steady state
DBL
Database Lock
DCO
Data Cut-Off


Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
44(199)
Abbreviation or 
special term
Explanation
DCR
Disease control rate
DLT
Dose-limiting toxicity
DoR
Duration of response
EBV
Epstein-Barr virus
EC
Ethics Committee, synonymous with Institutional Review Board (IRB)
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDoR
Expected duration of response
EGFR
Epidermal growth factor receptor
eCRF
Electronic case report form
EM
Early Mortality
EORTC
European Organisation for Research and Treatment of Cancer
ePRO
Electronic patient-reported outcome
EU
European Union
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
hCG
Human chorionic gonadotropin
HIV
Human immunodeficiency virus
HNSCC
Head and Neck Squamous Cell Carcinoma
HPV
Human papilloma virus
HR
Hazard ratio
HRQoL
Health-related quality of life
IB
Investigator’s Brochure
IC
Tumor-associated immune cells
ICF
Informed consent form
ICH
International Conference on Harmonisation
ICI
Immune Checkpoint Inhibitor
IDMC
Independent Data Monitoring Committee
IgE
Immunoglobulin E
IgG
Immunoglobulin G
IHC
Immunohistochemistry
CCI
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Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
45(199)
Abbreviation or 
special term
Explanation
IL
Interleukin
IMT
Immunomodulatory therapy
IP
Investigational product 
irAE
Immune-related adverse event
IRB
Institutional Review Board, synonymous with Ethics Committee (EC)
irRECIST 1.1
Immune-related response criteria updated with RECIST 1.1
ITT
Intent-to-Treat
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
mAb
Monoclonal antibody
Mb
Megabase
MDSC
Myeloid-derived suppressor cell
MedDRA
Medical Dictionary for Regulatory Activities
miRNA
Micro RNA
MMRM
MRI
Mixed effect model repeated measurement
Magnetic resonance imaging
mRNA
Messenger RNA
MTP
Multiple testing procedure
NCI
National Cancer Institute
NE
Not evaluable
NSCLC
Non-small cell lung cancer
OPC
Oropharyngeal cancer
ORR
Objective response rate
OS
Overall survival
OS12
Proportion of patients alive at 12 months after randomization
OS18
Proportion of patients alive at 18 months after randomization
OS24
Proportion of patients alive at 24 months after randomization
PCR
Polymerase chain reaction
PD
Progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
PFS
Progression-free survival
PFS2
Second progression
CCI
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Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
46(199)
Abbreviation or 
special term
Explanation
PK
Pharmacokinetic(s)
PR
Partial response
PRO
Patient-reported outcome
q2w
Every 2 weeks
q3w
Every 3 weeks
q4w
Every 4 weeks
q6w
Every 6 weeks
q8w
Every 8 weeks
QC
Quality check
QLQ-C30 v3
30-item core quality of life questionnaire, version 3
QLQ-H&N35
35-item head and neck quality of life questionnaire
QoL
Quality of life
QTcF
QT interval corrected for Fridericia’s formula
RCC
Renal cell carcinoma
RECIST 1.1
Response Evaluation Criteria in Solid Tumors version 1.1
RR
Response rate
SAE
Serious adverse event 
SAP
Statistical analysis plan
SAS
Safety Analysis Set
SCCHN
Squamous cell carcinoma of the head and neck
SD
Stable disease
SoC
Standard of Care
sPD-L1
Soluble programmed cell death ligand 1
T3
Triiodothyronine
T4
Thyroxine
TC
Tumor cells
TC/IC high subgroup
Patients with tumor expressing PD-L1 in TC≥50 or IC≥25
TFST
Time to the first subsequent therapy
TSST
Time to second subsequent therapy
Th1
Helper T cell 
TMB
Tumor Mutational Burden
TMG
Toxicity management guidelines
TTR
TSH
Time to response
Thyroid-stimulating hormone
CCI
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Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
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Abbreviation or 
special term
Explanation
UC
Urothelial cancer
ULN
Upper limit of normal
WBDC
Web Based Data Capture
WHO
World Health Organization
w/v
weight/volume


Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
Head and neck cancer is a collective term that encompasses the malignant tumors arising 
out of the oral cavity, pharynx, and larynx.  Worldwide, over half a million new head and 
neck cancer cases are diagnosed each year, accounting for approximately 5% of all 
incident cancers.  Over 90% of these head and neck cancers are squamous cell carcinoma 
subtype (squamous cell carcinoma of the head and neck [SCCHN]) with risk factors 
primarily attributed to prior alcohol or tobacco use or exposure to human papilloma virus 
(HPV).  HPV infection has been associated with oropharyngeal tumors specifically and is 
increasingly becoming the predominant risk factor for oropharyngeal SCCHN in the 
Western world.
The majority of patients who present with SCCHN will be diagnosed with either localized 
disease or locally advanced disease.  SCCHN diagnosed at a localized stage (Stage I/II) 
can be effectively treated with single-modality treatment (either surgery or radiation) and 
has a 5-year survival rate over 80%.  However, about 70% of SCCHN patients are 
diagnosed with locally advanced disease and 10% with metastatic disease, for which the 
survival rates are poor (Siegel et al 2014).  Patients with locally advanced disease typically 
receive multimodality treatment with curative intent, involving varied combinations of 
surgical resection, radiation therapy, and chemotherapy.  Five-year survival rates of up to 
30% to 40% have been seen with this treatment.  However, most of these patients 
eventually relapse with either locoregional recurrence, metastatic disease (20% to 30% of 
patients), or both (Vermorken and Specenier 2010).
For patients who relapse with no localized salvage surgical or radiation options or who 
develop or present with metastatic disease, there is no likelihood of cure.  Standard 
treatment options include a platinum doublet with either carboplatin or cisplatin along with 
a variety of chemotherapy agents, such as 5-fluorouracil (5FU) or taxanes.  In 2008, 
Vermorken et al established the superiority of the EXTREME regimen to these platinum 
doublets (Vermorken et al 2008).  The EXTREME regimen consists of triplet therapy with 
cetuximab, a recombinant human/mouse chimeric monoclonal antibody (mAb) to the 
epidermal growth factor receptor (EGFR), along with 5FU, and either carboplatin or 
cisplatin.  After completing six 3-week cycles of triplet therapy, patients with no evidence 
of progressive disease (PD) were able to continue single-agent cetuximab until progression 
of disease.  In a Phase III randomized study of cisplatin or carboplatin and 5FU compared 
to EXTREME, the EXTREME regimen was able to achieve an almost 3-month 
improvement in overall survival (OS) (10.1 months vs 7.4 months, hazard ratio 
[HR]=0.80; 0.64 to 0.99; p=0.04), a 2-month improvement in progression-free survival 
(PFS) (5.5 months vs 3.3 months; HR=0.54; p<0.001), and an increased response rate (RR) 
from 20% to 36% (p<0.001).  Based on these results, this regimen has become the standard 
first-line therapy for patients in the recurrent/metastatic setting.
While the toxicities of EXTREME were similar to the chemotherapy doublet, the rate and 
type of Grade 3 and 4 toxicities can make delivering these regimens especially challenging 
for the majority of head and neck cancer patients.  The most common Grade 3 or 4 adverse 
events (AEs) in the EXTREME arm were also common to chemotherapy and included 
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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
1.1.1
Squamous cell carcinoma of the head and neck


It is increasingly understood that cancers are recognized by the immune system, and, under 
some circumstances, the immune system may control or even eliminate tumors 
(Dunn et al 2004).  Studies in mouse models of transplantable tumors have demonstrated 
that manipulation of co-stimulatory or co-inhibitory signals can amplify T-cell responses 
against tumors (Peggs et al 2009).  This amplification may be accomplished by blocking 
co-inhibitory molecules, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) 
or programmed cell death 1 (PD-1), from binding with their ligands, B7 or B7-H1 
(programmed cell death ligand 1 [PD-L1]).  Biologically, SCCHN has attributes that 
suggest susceptibility to immune checkpoint blockade.  Multiple lines of evidence suggest 
that SCCHN tumors create a highly immunosuppressive environment and that the PD-
1/PD-L1 axis and inhibition of the activation of T cells play an important role, and may be 
amenable to therapeutic intervention with immune-modulating agents (Badoual et al 2010, 
Badoual et al 2013, Larkin et al 2015, Litwin et al 1998, Lyford-Pike et al 2013).  Virally 
driven tumors, including HPV-associated SCCHN, express viral antigens that may be 
recognized by the immune system.  In HPV-associated cancers, the E6 and E7 tumor-
specific antigens are known to be immunogenic, and studies have shown that HPV-specific 
T-cell responses form upon vaccination with these proteins (Kaufmann et al 2002).
Administering an immunotherapeutic agent to patients with HPV-positive SCCHN may
result in an anti-tumor immune response versus HPV tumor-specific antigens.  In patients
with HPV-negative SCCHN, the driving etiology is thought to be tobacco use.  Data
suggest that cancers associated with smoking such as non-small cell lung cancer (NSCLC),
small-cell lung cancer, and SCCHN may carry a high mutational burden (Alexandrov
et al 2013, Vogelstein et al 2013).  Tumors with high mutational burden produce
neoantigens, which may generate T-cell immunity.  This hypothesis may explain the
observation that patients with NSCLC with a history of heavy smoking may be more prone
to respond to anti-PD-1 or anti-PD-L1 therapy as compared to light or never smokers (Li et
al 2018; Norum et al 2018).  Specifically, higher objective response rates (ORRs)
following treatment with an anti-PD-L1 mAb were observed in patients with NSCLC with
a history of smoking as compared to those without a history of smoking (Champiat
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Study Code D419LC00001
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Date 29 June 2020
anemia (13%), neutropenia (22%), and thrombocytopenia (11%) with sepsis seen in 9 of 
222 patients in the EXTREME group.  Additionally, cetuximab-specific toxicities were 
observed, with Grade 3 skin reactions reported in 9% of patients and Grade 3 or 4 
infusion-related reactions reported in 3% of patients (Vermorken et al 2008).  While an 
80% dose intensity was noted with the regimen as a whole, in reality, this regimen can 
only be effectively delivered to younger, fitter patients with a 0 to 1 Eastern Cooperative 
Oncology Group (ECOG) performance status.  Unfortunately, the majority of patients 
diagnosed with head and neck cancer are older with a median age of 62 and have multiple 
comorbidities as a result of prior alcohol and tobacco use, including compromised cardiac 
and pulmonary function.  Furthermore, as a result of therapy for this disease, such as 
radiation and/or surgery along with the disease itself, many also have compromised 
nutritional status that further makes delivering aggressive therapy with a favorable 
outcome difficult.
This population is therefore in need of therapies that are not only more efficacious in 
offering a longer survival benefit or even cure but can also be delivered with less toxicity 
than traditional chemotherapy regimens such as EXTREME.
1.1.2
Immunotherapies


Tremelimumab is an immunomodulatory therapy (IMT) that is being developed by 
AstraZeneca for use in the treatment of cancer.  Tremelimumab is a human IgG2 mAb 
directed against CTLA-4, which is a critical regulatory signal for T-cell expansion and 
activation following an immune response and serves as a natural braking mechanism that
maintains T-cell homeostasis.  During T-cell activation, T cells upregulate CTLA-4, which 
binds to B7 ligands on antigen-presenting cells, sending an inhibitory signal that limits T-
cell activation.  Tremelimumab blocks the inhibitory signal resulting from CTLA-4 
binding to B7, leading to prolongation and enhancement of T-cell activation and 
expansion.  Thus, the mechanism of action of tremelimumab is indirect and is applied 
through enhancing T-cell–mediated immune response.
An extensive program of non-clinical and clinical studies has been conducted for 
tremelimumab both as monotherapy and combination therapy with conventional anticancer 
agents to support various cancer indications using different dose schedules.  As of the data 
cut-off date of 12 November 2014 (for all studies except D4190C00006 [hereafter referred 
to as Study 006], which has a cut-off date of 4 December 2014), 973 patients have 
received tremelimumab monotherapy (not including 497 patients who have been treated in 
the blinded Phase 2b study, D4880C00003) and 208 patients have received tremelimumab 
in combination with other agents.  Details on the safety profile of tremelimumab 
monotherapy are summarized in Section 1.3.2.2.  Refer to the current tremelimumab IB for 
a complete summary of non-clinical and clinical information; see Section 6.7 for guidance 
on management of tremelimumab-related toxicities.  
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Date 29 June 2020
et al 2014).  These data suggest that application of immune-modulating therapies in 
SCCHN may have a positive impact on clinical outcomes (Badoual et al 2010, Badoual 
et al 2013, Larkin et al 2015, Litwin et al 1998, Lyford-Pike et al 2013).  
1.1.3
MEDI4736 (Durvalumab)
MEDI4736 (durvalumab) is a human mAb of the immunoglobulin G (IgG) 1 kappa 
subclass that is being developed by AstraZeneca/MedImmune for use in the treatment of 
cancer (MedImmune is a wholly owned subsidiary of AstraZeneca; 
AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document.)  
The proposed mechanism of action for MEDI4736 is interference of the interaction of PD-
L1, which is expressed on cancer cells and a subset of leukocytes, with the PD-1 (cluster 
of differentiation [CD] 279) and B7-1 (CD80) molecules on antigen-presenting cells and T 
cells.  By binding to PD-L1 on tumor cells, the mechanism of action of MEDI4736 
includes stimulation of the patient’s anti-tumor immune response.
MEDI4736 has been given to humans as part of ongoing studies as a single drug or in 
combination with other drugs.  As of June 2014, 509 patients have been enrolled and 
treated in 10 ongoing clinical studies of MEDI4736 (5 employing MEDI4736 as 
monotherapy and 5 as combination therapy).  Details on the safety profile of MEDI4736 
monotherapy are summarized in Section 1.3.2.1.  Refer to the MEDI4736 Investigator’s 
Brochure (IB) for a complete summary of non-clinical and clinical information; see 
Section 6.7 for guidance on management of MEDI4736-related toxicities.
1.1.4
Tremelimumab


Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
Patients with recurrent or metastatic head and neck cancer are considered incurable.  Even 
with the established standard EXTREME regimen, consisting of cetuximab, a platinum, 
and 5FU, the expected survival is only 10 months with progression expected within 6 
months.  Hence, there is still a need for more efficacious therapies.  Furthermore, delivery 
of the EXTREME regimen can be challenging in a population of patients who are older 
and have multiple comorbidities.  Therefore, a regimen that is more efficacious and better 
tolerated would be of value.
SCCHN tumors, like many other malignancies, create a highly immunosuppressive 
environment and are amenable to therapeutic intervention with immune-modulating 
agents.  Clinical data from the Sponsor and competitor molecules indicate that anti–PD-
1/anti-PD-L1 agents can effectively achieve disease stabilization and durable responses 
when administered as monotherapy in pretreated patients.  Efficacious interventions to 
initiate and sustain an immune response will likely require a number of agents that harness 
different immune mechanisms to successfully mount an immune response.  Two specific 
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1.1.5
MEDI4736 in combination with tremelimumab
Targeting both PD-1 and CTLA-4 pathways may have additive or synergistic activity 
(Pardoll 2012), because the mechanisms of action of the CTLA-4 and PD-1 pathways are 
non-redundant and therefore ultimately lead to stimulation of an immune response.  
Support for this is seen in mouse syngeneic models of transplantable solid tumors, 
demonstrating superior anticancer activity of the combination therapy compared with 
monotherapy.  (Refer to the MEDI4736 IB for a full description of these results.)  
Furthermore, clinical data from the combination of CTLA-4 and PD-1 blockades in 
melanoma have resulted in higher 1-year survival and an ORR of 40% compared to either 
agent alone, with rapid, deep, and durable responses (Wolchok et al 2013).  Recent data 
also demonstrate that inhibiting both the PD-1 and CTLA-4 pathways is associated with 
enhanced clinical activity in patients with PD-L1-negative disease compared to PD-1 
inhibition alone, with median PFS of 11.2 months in patients with PD-L1-negative tumors 
who received ipilimumab and nivolumab compared to 2.8 months and 5.3 months for 
patients with PD-L1-negative tumors who received ipilimumab or nivolumab, respectively 
(Larkin et al 2015).  Therefore, AstraZeneca is investigating the use of MEDI4736 + 
tremelimumab combination therapy for the treatment of cancer.  
Study 006 is a Phase Ib dose-escalation study to establish safety, pharmacokinetic 
(PK)/pharmacodynamics, and preliminary antitumor activity of 
MEDI4736 + tremelimumab combination therapy in patients with advanced NSCLC.  
Preliminary efficacy, safety, and clinical data are summarized in Sections 1.3.1.3 and 
1.3.2.3 demonstrate that the combination can be safely combined, with evidence of clinical 
activity.  
The combination of MEDI4736 + tremelimumab is currently being evaluated in multiple 
ongoing Phase II and Phase III trials in patients with NSCLC and SCCHN 
(NCT02352948, NCT02453282, NCT02319044, and NCT02369874).  
Details on the safety profile of MEDI4736 + tremelimumab combination therapy is 
summarized in Section 1.3.2.3.
1.1.6
Rationale for conducting this study


Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
pathways, the PD-1–PD-L1 axis and the CTLA-4 pathway, have been successfully 
targeted by IMTs to obtain tumor reduction.
MEDI4736, an antibody that blocks the interaction between PD-L1 and its receptors, may 
relieve PD-L1-dependent immunosuppressive effects seen in SCCHN tumors and, 
therefore, enhance the cytotoxic activity of anti-tumor T-cells.  This hypothesis is 
supported by emerging clinical data from other mAbs targeting the PD-L1/PD-1 pathway, 
which provide early evidence of clinical activity and a manageable safety profile in 
multiple tumor types (Brahmer et al 2012, Topalian et al 2012).  Currently available data 
from the first-time-in-human, single-agent study (Study CD-ON-MEDI4736-1108; 
referred to hereafter as Study 1108) in patients with advanced solid tumors using 
MEDI4736 monotherapy indicates encouraging RRs and duration of response (DoR) with 
a manageable safety profile in patients with a variety of solid malignancies, including 
patients with SCCHN.  Preliminary data in the SCCHN expansion cohort demonstrated a 
confirmed ORR of 11% (7 out of 62 partial response [PR]) and a disease control rate 
(DCR) at 24 weeks of 15% (9 out of 62 patients) based on Response Evaluation Criteria in 
Solid Tumors version 1.1 (RECIST 1.1) (Segal et al 2015).  
The CTLA-4 and PD-1 pathways are non-redundant; therefore, while MEDI4736 
monotherapy has shown efficacy in pretreated SCCHN patients, the combination of 
MEDI4736 + tremelimumab may have synergistic activity that may further improve upon 
the RRs, clinical benefit, and PFS achieved with standard chemotherapy (Pardoll 2012).  
Phase II and Phase III studies of MEDI4736 monotherapy and the combination of 
MEDI4736 + tremelimumab in the second-line recurrent/metastatic population are being 
conducted to establish that this combination is active and safe.  Clinical data from 
competitor molecules utilizing the combination of CTLA-4 and PD-1 blockade in 
melanoma have demonstrated enhanced efficacy of this approach compared with either 
monotherapy agent (Postow et al 2015; Wolchok et al 2013).  
Based on the preliminary clinical efficacy and safety data observed in patients with solid 
tumors, including advanced SCCHN, from Study 1108 with MEDI4736 monotherapy and 
the data from Study 006 of the MEDI4736 + tremelimumab combination therapy in 
NSCLC, the Sponsor has a comprehensive program to develop MEDI4736 monotherapy 
and MEDI4736 + tremelimumab combination therapy for the treatment of SCCHN across 
multiple lines of therapy. The objective of earlier trials in this program was to determine 
the activity of MEDI4736 as monotherapy and also to establish the role of MEDI4736 in 
combination with tremelimumab in patients who had failed platinum-based therapy for 
recurrent/metastatic SCCHN. As part of this comprehensive development program, this 
Phase III study will determine the activity of MEDI4736 monotherapy compared to 
Standard of Care (SoC) in patients with PD-L1–positive and -negative R/M SCCHN who 
are not amenable to local curative therapy with surgery or radiation and who have not 
received prior systemic therapy for recurrent/metastatic disease, unless it was given as part 
of multimodality treatment for locally advanced or locally recurrent disease.
1.2
Rationale for study design, doses, and control groups
In this study, the efficacy of MEDI4736 with or without tremelimimab in terms of OS 
compared to SoC is being evaluated in SCCHN patients with R/M SCCHN who are not 
amenable to local curative therapy with surgery or radiation and who have received no 
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A dose of MEDI4736 1500 mg (corresponding to 20 mg/kg) every 4 weeks (q4w) is 
supported by in-vitro, non-clinical, clinical PK/pharmacodynamics, biomarkers, and 
activity data from Study 1108 in patients with advanced solid tumors and from a Phase I 
trial performed in Japanese patients with solid tumors (NCT01938612).
PK/Pharmacodynamic data
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses 
ranging from 0.1 to 10 mg/kg every 2 weeks (q2w) or 15 mg/kg every 3 weeks (q3w), 
MEDI4736 exhibited non-linear (dose-dependent) PK consistent with target-mediated drug 
disposition.  The PK approached linearity at ≥3 mg/kg q2w, suggesting near complete 
target saturation (membrane-bound and soluble programmed cell death ligand 1 [sPD-L1]), 
and further shows that the MEDI4736 dosing frequency can be adapted to a particular 
regimen given the linearity seen at doses higher than 3 mg/kg.  The expected half-life with 
doses ≥3 mg/kg q2w is approximately 21 days.  A dose-dependent suppression in 
peripheral sPD-L1 was observed over the dose range studied, consistent with engagement 
of MEDI4736 with PD-L1.  Dose-related changes in a variety of peripheral biomarkers 
have been observed over the dose range of 0.1 to 15 mg/kg.  A low level of 
immunogenicity has been observed.  No patients have experienced immune-complex 
disease following exposure to MEDI4736.  Of the 220 patients who received MEDI4736 
monotherapy and for whom PK/anti-drug antibody (ADA) data were available as of 
14 July 2014, five were ADA positive, with an impact on PK/pharmacodynamics reported 
in 1 patient at the 3 mg/kg dose.  
Data from Study 006 also show an approximately dose-proportional increase in PK 
exposure for MEDI4736 over the dose range of 3 to 20 mg/kg MEDI4736 q4w or q2w.  
(For further information on PK observations in Study 006, please refer to Section 1.2.2).  
A population PK model was developed using the data from Study 1108 (doses=0.1 to 
10 mg/kg q2w or 15 mg/kg q3w; Fairman et al 2014).  Multiple simulations indicate that a 
similar overall exposure is expected following both 10 mg/kg q2w and 20 mg/kg q4w 
regimens, as represented by area under the serum drug concentration-time curve at steady 
state (AUCss; 4 weeks).  Median maximum serum concentration at steady state (Cmax,ss) is 
expected to be higher with 20 mg/kg q4w (~1.5 fold) and median trough concentration at 
steady state (Ctrough,ss) is expected to be higher with 10 mg/kg q2w (~1.25 fold).  Clinical 
activity with the 20 mg/kg q4w dosing regimen is anticipated to be consistent with 
10 mg/kg q2w, with the proposed dose of 20 mg/kg q4w expected to (a) achieve complete 
target saturation in majority of patients; (b) account for anticipated variability in PK, 
pharmacodynamics, and clinical activity in diverse cancer populations; (c) maintain 
sufficient PK exposure in case of ADA impact; and (d) achieve PK exposure that yielded 
maximal antitumor activity in animal models.
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Date 29 June 2020
prior systemic therapy for recurrent/metastatic disease, unless it was given as part of 
multimodality treatment for locally advanced or locally recurrent disease.  The 
contribution of MEDI4736 monotherapy to the efficacy of combination treatment regimen 
and the efficacy of MEDI4736 + tremelimumab combination therapy compared to SoC 
will also be evaluated in a prospective, randomized fashion.
1.2.1
MEDI4736 monotherapy dose rationale


The MEDI4736 + tremelimumab combination therapy doses and regimen selected for this 
study are based on the goal of selecting an optimal combination dose of MEDI4736 and 
tremelimumab that would yield sustained target suppression (ie, sPD-L1), demonstrate 
promising efficacy, and have an acceptable safety profile.  
PK/Pharmacodynamics data
In order to reduce the dosing frequency of MEDI4736 to align with the q4w dosing of 
tremelimumab, while ensuring an acceptable PK/pharmacodynamics, safety, and efficacy 
profile, cohorts in Study 006 were narrowed to 15 and 20 mg/kg MEDI4736 q4w.  PK 
simulations from the MEDI4736 monotherapy data indicated that a similar AUCss (4 
weeks) was expected following both 10 mg/kg q2w and 20 mg/kg q4w MEDI4736.  The 
observed MEDI4736 PK data from the Study 006 were well in line with the predicted 
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Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
Clinical data
As of 8 April 2015, there is initial safety data for 16 patients receiving the 20 mg/kg q4w 
dosing regimen (12 patients from Study 1108 and 4 patients from the Japan Phase I trial).  
The toxicities observed with 20 mg/kg q4w are consistent with the 10 mg q2w regimen, 
and there were no dose-limiting toxicities (DLTs) observed.  Of the 12 patients in 
Study 1108, 42% of patients have experienced any grade AE, with 2 being Grade 3 and 
above (17%).  None of the Grade 3 and higher events was considered treatment-related.  
No patients on the Japan Phase I trial have experienced a Grade 3 or above AE.  At 
present, the data do not suggest that the safety profile of MEDI4736 will be different in the 
20 mg/kg q4w dosing regimen when compared to 10 mg/kg q2w regimen.  Data presented 
at the American Society for Clinical Oncology (ASCO) Meeting 2015, with a cut-off date 
of 7 April 2015, showed that MEDI4736 was well tolerated at a dose of 10 mg/kg q2w in 
the SCCHN subset of patients enrolled into Study 1108, with drug-related Grade ≥3 AEs 
reported in 10% of patients and no drug-related AEs leading to discontinuation or death.  
No drug-related colitis of any grade and no Grade ≥3 pneumonitis were reported 
(Segal et al 2015).
Efficacy data on the SCCHN patients in Study 1108, presented at ASCO 2015 (cut-off 
date: 7 April 2015), showed a DCR of 15% at 24 weeks (18% and 11% in patients with 
PD-L1-positive and -negative tumors, respectively) and ORR of 11% among 62 evaluable 
patients.  The ORR was higher (18%; 4 complete response [CR]/PR; n=22) in patients 
with PD-L1-positive tumors, defined as those with >25% of tumor cells with membrane 
staining for PD-L1, compared to patients with PD-L1-negative tumors (8%; 3 CR/PR; 
n=37) (Segal et al 2015).
Given the available clinical data (the similar AUCss [4 weeks], the modest differences in 
median Cmax,ss and Ctrough,ss, and the observation that both regimens maintain complete 
sPD-L1 suppression at trough), the 20 mg/kg (1500 mg) q4w and 10 mg/kg (750 mg) q2w 
regimens are expected to have similar efficacy and safety profiles, supporting further 
development with a dose of 1500 mg q4w.
While treatment has been continued for a maximum of 1 year in the majority of patients 
treated to date with MEDI4736, dosing will continue until confirmed PD in this study to 
ensure a balanced comparison to the SoC arm.
1.2.2
MEDI4736 + tremelimumab combination therapy dose rationale


Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
monotherapy PK data developed preclinically.  This demonstrates similar exposure of 
MEDI4736 20 mg/kg q4w and 10 mg/kg q2w, with no alterations in PK when MEDI4736 
and tremelimumab (doses ranging from 1 to 3 mg/kg) are dosed together.  While the 
median Cmax,ss is expected to be higher with 20 mg/kg q4w (approximately 1.5 fold) and 
median Ctrough,ss is expected to be higher with 10 mg/kg q2w (approximately 1.25 fold), 
this is not expected to impact the overall safety and efficacy profile, based on existing 
preclinical and clinical data.
Monotonic increases in pharmacodynamic activity were observed with increasing doses of 
tremelimumab relative to the activity observed in patients treated with MEDI4736 
monotherapy.  There was evidence of augmented pharmacodynamic activity relative to 
MEDI4736 monotherapy with combination doses containing 1 mg/kg tremelimumab, 
inclusive of both the 15 and 20 mg/kg MEDI4736 plus 1 mg/kg tremelimumab 
combinations.  
Clinical data
As of 15 April 2015, a total of 102 patients with advanced NSCLC have been treated in 
Study 006 (Antonia et al 2015).  Various dose combinations were explored, with doses of 
tremelimumab ranging from 1 to 10 mg/kg and doses of MEDI4736 ranging from 3 to 
20 mg/kg.  Seventy-four of these patients were in the q4w dosing schedule and 28 patients 
were in the q2w dosing schedule, with the goal of identifying the dose combination that 
best optimizes the risk:benefit profile in an acceptable range of PK and pharmacodynamic 
values.
Patients treated with doses of tremelimumab above 1 mg/kg had a higher rate of AEs, 
including discontinuations due to AEs, serious AEs (SAEs), and severe AEs.  The number 
of patients reporting any AE, Grade 3 AEs, SAEs, and treatment-related AEs was higher in 
the 10 mg/kg MEDI4736 + 3 mg/kg tremelimumab q2w cohort than the 10 mg/kg 
MEDI4736 + 1 mg/kg tremelimumab q2w cohort.  A similar pattern was noted in the q4w 
regimens, suggesting that, as the dose of tremelimumab is increased above 1 mg/kg, a 
higher rate of treatment-related events may be anticipated.  Further, the SAEs frequently 
attributed to IMT, pneumonitis and colitis, were more commonly seen in cohorts using 
either 3 mg/kg or 10 mg/kg of tremelimumab compared to the 1-mg/kg dose cohorts.  
Together, these data suggest that a combination using a tremelimumab dose of 1 mg/kg 
appeared to minimize the rate of toxicity when combined with MEDI4736.  As a result, all 
combination doses utilizing either the 3 or 10-mg/kg doses of tremelimumab were 
eliminated in the final dose selection.
In contrast, cohorts assessing higher doses of MEDI4736 with a constant dose of 
tremelimumab did not show an increase in the rate of AEs.  The data suggested that 
increasing doses of MEDI4736 may not impact the safety of the combination as much as 
the tremelimumab dose.  Further, safety data between the 10-mg/kg and 20-mg/kg cohorts 
were similar.
In Study 006, of all treatment cohorts in which clinical activity was observed, the cohort of 
18 patients treated in the 20 mg/kg MEDI4736 + 1 mg/kg tremelimumab group had the 
fewest AEs, Grade ≥3 AEs, SAEs, and treatment discontinuations due to AEs.  In this 
cohort, there was 1 treatment-related discontinuation due to sepsis, and no DLTs or 
treatment-related deaths were reported (Antonia et al 2015).  
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A population PK model was developed for MEDI4736 using monotherapy data from 
Study 1108 (Phase I study; N=292; doses=0.1 to 10 mg/kg q2w or 15 mg/kg q3w; solid 
tumors).  Population PK analysis indicated only a minor impact of body weight on the PK 
of MEDI4736 (coefficient of ≤0.5).  The impact of body weight-based (10 mg/kg q2w) 
and fixed dosing (750 mg q2w) of MEDI4736 was evaluated by comparing predicted 
steady-state PK concentrations (5th, median, and 95th percentiles) using the population PK 
model.  A fixed dose of 750 mg was selected to approximate 10 mg/kg (based on a median 
body weight of approximately 75 kg).  A total of 1000 patients were simulated using a 
body weight distribution of 40 to 120 kg.  Simulation results demonstrated that body 
weight-based and fixed dosing regimens yield similar median steady state PK 
concentrations, with slightly less overall between-patient variability with the fixed dosing 
regimen.  
Similarly, a population PK model was developed for tremelimumab using data from Phase 
I through III studies (N=654; doses=0.01 to 15 mg/kg q4w or every 90 days; metastatic 
melanoma; Wang et al 2014).  A population PK model indicated a minor impact of body 
weight on the PK of tremelimumab (coefficient of ≤0.5).  The body weight-based (1 mg/kg 
q4w) and fixed dosing (75 mg q4w; based on a median body weight of approximately 75 
kg) regimens were compared using predicted PK concentrations (5th, median, and 95th
percentiles) using a population PK model in a simulated population of 1000 patients with a 
body weight distribution of 40 to 120 kg.  Similar to MEDI4736, simulations indicated that 
both body weight-based and fixed dosing regimens of tremelimumab yield similar median 
steady-state PK concentrations, with slightly less overall between-patient variability with 
the fixed dosing regimen.
Similar findings have been reported by others (Narwal et al 2013, Ng et al 2006, 
Wang et al 2009, Zhang et al 2012).  Wang and colleagues investigated 12 mAbs and 
found that fixed and body weight-based dosing perform similarly, with fixed dosing being 
superior for 7 of 12 antibodies (Wang et al 2009).  In addition, they investigated 18 
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Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
Preliminary clinical activity of the MEDI4736 + tremelimumab combination did not 
appear to change with increasing doses of tremelimumab.  The 10-, 15-, and 20-mg/kg 
MEDI4736 q4w cohorts demonstrated objective responses at all doses of tremelimumab, 
and increasing doses of tremelimumab did not provide deeper or more rapid responses 
(Antonia et al 2015).
Efficacy data suggested that the 20 mg/kg MEDI4736 + 1 mg/kg tremelimumab dose 
cohort may demonstrate equivalent clinical activity to other dose combinations.  A total of 
8 of 18 patients in the 20 mg/kg MEDI4736 + 1 mg/kg tremelimumab cohort were 
evaluable for efficacy with at least 16 weeks of follow-up.  Of these, 50% (4 out of 
8 patients) had PR.  The DCR rate at 16 weeks was 50% (Antonia et al 2015).
All together, the data suggested that a 20 mg/kg (1500 mg) MEDI4736 + 1 mg/kg (75 mg) 
tremelimumab dose combination should be selected for further development.
While treatment has been continued for a maximum of 1 year in the majority of patients 
treated to date with MEDI4736 + tremelimumab combination therapy, dosing will 
continue until confirmed PD in this study to ensure a balanced comparison to the SoC arm.
1.2.3
Rationale for fixed dosing


This study will enroll patients with recurrent or metastatic SCCHN who are not amenable 
to local curative therapy with surgery or radiation and who have not received prior 
systemic therapy for recurrent/metastatic disease, unless it was given as part of 
multimodality treatment for locally advanced or locally recurrent disease.  Approximately 
70% of newly diagnosed SCCHN cancer patients will be diagnosed with locally advanced 
or local disease that is amenable to therapy with radiation, surgery, chemotherapy, or 
combination of the three.  However, for patients with recurrent disease that is not 
amenable to localized therapy or those who present with metastatic disease, no cure is 
currently available even with the current SoC regimen, EXTREME.  An unmet medical 
need exists for this patient population.
Current experience with single-agent studies utilizing PD-1 or PD-L1 inhibitors suggests 
that clinical responses may be restricted to a subset of any given patient population and 
that it might be beneficial to enrich the patient population by selecting patients likely to 
respond to therapy.  To date, no assay has been established or validated, and no single 
approach has proven accurate for patient enrichment.  However, independent data from 
multiple sources using different assays and scoring methods suggests that PD-L1 
expression on tumor cells and/or tumor-infiltrating cells may be associated with greater 
clinical benefit.  
Data from ongoing studies with MEDI4736 and other agents targeting the PD-1/PD-L1 
pathway suggest, as shown in a number of tumor types (eg, NSCLC, renal cell carcinoma, 
and melanoma), that treatment with monotherapy may be associated with a higher ORR in 
patients who are PD-L1-positive.
Data presented by AstraZeneca at the 2015 ASCO meeting (Segal et al 2015) demonstrate 
that treatment with MEDI4736 resulted in an ORR of 18% and 8% in patients with 
PD-L1-positive and -negative SCCHN tumors, respectively.  Therefore, it appears that the 
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therapeutic proteins and peptides and showed that fixed dosing performed better for 12 of 
18 in terms of reducing the between-patient variability in PK/pharmacodynamics 
parameters (Zhang et al 2012).  
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors.  Given the expectation of similar PK exposure and variability, 
AstraZeneca considered it feasible to switch to fixed dosing regimens.  Based on an 
average body weight of 75 kg, a fixed dose of 1.5 g q4w MEDI4736 (equivalent to 20 
mg/kg q4w) and 75 mg q4w tremelimumab (equivalent to 1 mg/kg q4w) is included in the 
current study.
1.2.4
Standard of Care dose rationale
Based on the significant 3-month survival benefit established by the EXTREME regimen 
by Vermorken et al, this regimen will serve as the control therapy for this study 
(Vermorken et al 2008).  As per the original publication, the Investigator will have the 
choice of using either carboplatin or cisplatin for the platinum component and any drug 
within the triplet regimen (cetuximab, a platinum, and 5FU) can be discontinued at any 
time due to toxicity at the discretion of the Principal Investigator.  
1.2.5
Study population rationale


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selection of patients based on PD-L1 expression levels within the tumor microenvironment 
may improve the probability and/or quality of responses to PD-1 pathway-targeting agents 
and, therefore, may have merit as a patient enrichment tool.  Competitors have presented 
similar data with this class of agents. Specifically, the phase 3 KEYNOTE-048 study, 
which demonstrated that pembrolizumab monotherapy improved OS when compared with 
the EXTREME regimen in patients whose tumors had PD-L1 expression ≥1 and ≥20 by 
Combined Positive Score (CPS) [hazard ratio (HR) 0.78 (0.64–0.96), P=0.0086 and HR 
0.61 (0.45– 0.83), P=0007, respectively] (Burtness et al., 2019). 
 
Based on these 2 studies, durvalumab monotherapy 
results in better OS in the PD-L1 high subgroup (TC50/IC25) when compared to the PD-
L1 low population (HR=0.70; p=0.039). Median survival was 9.8 months versus 5.4 
months in the PD-L1 high and PD-L1 low subgroups respectively. Additional data analysis 
from the Sponsor’s Phase 3 D4193C00002 (EAGLE) study in second line HNSCC appear 
to further support the utility of PD-L1 to select patients with improved outcome when 
treated with durvalumab.
 
 
 When 
controlling for prognostic factors, the multivariate analysis of patients treated with 
durvalumab shows a tendency to better OS in the PD-L1 high (TC/IC) vs PD-L1 low 
subgroup [HR=0.80 (95% CI 0.58–1.09)].
Nevertheless, PD-L1-negative patients still appear to derive clinical benefit from 
PD-L1-directed therapies.  Segal et al noted DCRs (stable disease [SD] or better) at 24 
weeks of 18% and 11% in PD-L1-positive and -negative patients, respectively 
(Segal et al 2015).  For patients in the late line of disease with a median PFS of only 3 
months and OS of 6 months, maintaining at least SD is clinically beneficial.  These data 
demonstrate that clinical benefit can be achieved in both PD-L1-positive and -negative 
SCCHN patients.
MEDI4736 + tremelimumab combination therapy may further enhance RRs and clinical 
benefit rates in both PD-L1-negative and -positive patients and may be able to improve the 
probability and quality of response in PD-L1-negative patients compared to those who 
receive MEDI4736 alone.  As of 15 April 2015 from Study 006 investigating the clinical 
activity of combination of MEDI4736 + tremelimumab in NSCLC, data show that across a 
range of doses, the addition of tremelimumab to MEDI4736 results in an ORR of 27% in 
patients with PD-L1-negative NSCLC (Antonia et al 2015).  This compares favorably to 
the 5% ORR observed with MEDI4736 monotherapy in pretreated PD-L1-negative 
NSCLC patients (Rizvi et al 2015).  Increases in ORR may also be achieved in patients 
with PD-L1-positive disease, as an ORR of 27% was observed with MEDI4736 
monotherapy (Rizvi et al 2015), while an ORR of 33% was observed over the range of 
doses evaluated for the combination of MEDI4736 + tremelimumab (Antonia et al 2015).  
Acknowledging the limitations and necessary caveats associated with cross-trial 
comparisons, there appears to be an incremental benefit regardless of PD-L1 status in 
patients with NSCLC treated with the combination therapy; however, this benefit appears 
to be greater in the PD-L1-negative population.  Similar patterns are anticipated with 
SCCHN.  
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Based on this information, both PD-L1-negative and -positive SCCHN cancer patients 
with recurrent or metastatic disease who are not amenable to local curative therapy with 
surgery or radiation and who have not received prior systemic therapy for 
recurrent/metastatic disease may be enrolled in all arms of this study, as clinical benefit 
may be seen in both populations with monotherapy and combination immunotherapy.
Immune checkpoint inhibitors (ICIs) are profoundly changing the treatment of many types 
of cancer, including melanoma, NSCLC, renal cell carcinoma (RCC), SCCHN, urothelial 
carcinoma (UC), and Hodgkin’s lymphoma, and have been associated with long-lasting 
tumor responses. However, an early mortality (EM) phenomenon has been observed in 
many randomized clinical trials comparing ICIs with active comparator arms in advanced 
or metastatic cancer patients, even with overall benefit ultimately favoring ICI therapy 
(Champiat et al 2018). While the precise etiology of this phenomenon is not clearly 
established, it is characterized by what seems to be disproportionately higher mortality in 
the early treatment period favoring the active control arm, followed by subsequent benefit 
in OS favoring the ICI treatment arm. This is often reflected in the clinical data by the 
“crossing of the Kaplan-Meier curves” suggesting a subpopulation of patients at a higher 
risk of EM whose advanced rate of tumor growth may require the cytotoxic tumor-
debulking effect of chemotherapy. Accordingly, it is of great therapeutic interest to better 
predict the risk of early mortality for a given patient to better inform the appropriate 
treatment for their individual clinical state. To aid in this objective, AstraZeneca has 
developed and implemented a model that predicts a patient’s risk of early mortality to 
optimize the benefit:risk profile for treatment of patients with ICIs.Tumor mutational 
burden (TMB) has been associated with response in patients treated with PD-1 and CTLA-
4 inhibitors in several tumour types (Rizvi et al 2015b, Snyder et al 2014).  In a 
retrospective analysis of HNSCC patients treated with pembrolizumab, TMB was 
significantly associated with best overall response (BoR) (Siewert et al 2018).  Hanna et al 
(2018) also observed a significant difference in mutational load between responders and 
non-responders to anti-PD-1/PD-L1 agents (17.7 mut/Mb versus 7.1 mut/Mb).  
Furthermore, TMB was correlated with increased median overall survival.  In patients with 
TMB>10mut/Mb mOS was 20 months, compared to 6 months in patients with 
TMB<5mut/Mb, p=0.01).
There are numerous benefits of minimally invasive, blood-based biomarkers.  TMB assays 
using circulating tumour DNA (ctDNA) are under development.  Recently, in the 
MYSTIC study, high TMB measured in ctDNA was associated with improved OS in 
NSCLC patients treated with durvalumab and tremelimumab (Rizvi et al 2018).  There is 
no published data on the use of ctDNA TMB in HNSCC (Oliva et al 2018), however 
ctDNA is present in the blood in detectable quantities in patients with head and neck 
cancers (Bettegowda et al 2014).  In this study patient plasma samples will be analysed for 
ctDNA TMB using the Guardant OMNI panel. 
1.2.6
Rationale for endpoints
The primary aim of this study is to determine the efficacy of MEDI4736 monotherapy 
versus SoC (EXTREME) in a pre-specified PD-L1 TC/IC high subgroup in terms of OS.  
Testing for improvements in OS as a primary endpoint provides a non-biased assessment 
of direct clinical benefit to the patient (FDA Guidance 2011).


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Secondary efficacy endpoints include the following:

MEDI4736 monotherapy versus SoC: OS in the low risk of EM subgroup, ctDNA 
TMB high subgroup (≥16 mut/Mb) and all-comers. PFS, ORR, APF6, APF12, 
OS12, OS18 and OS24 assessed in the PD-L1 TC/IC high subgroup, low risk of 
EM subgroup, ctDNA TMB high subgroup (≥16 mut/Mb) and all-comers. PFS2, 
DoR, BoR, TTR, TFST and TSST in the PD-L1 TC/IC high subgroup and all-
comers.

MEDI4736 + tremelimumab combination therapy versus SoC: OS, PFS, ORR, 
APF6, APF12, OS12, OS18 and OS24 in the PD-L1 TC/IC high subgroup , low 
risk of EM subgroup, ctDNA TMB high subgroup (≥16 mut/Mb) and all-comers. 
PFS2, DoR, BoR, TTR, TFST and TSST in the PD-L1 TC/IC high subgroup and 
all-comers. 

MEDI4736 + tremelimumab versus MEDI4736 monotherapy: PFS, ORR and OS 
in the PD-L1 TC/IC high subgroup, low risk of EM subgroup, ctDNA TMB high 
subgroup (≥16 mut/Mb) and all-comers.
 
 
 
  IrRECIST 1.1 will take into account the unique kinetics of responses 
that have been observed and well characterized with this class of agents, including those 
observed in the ongoing Study 1108.
The secondary endpoints of health-related quality of life (HRQoL) assessments (the 
European Organisation for Research and Treatment of Cancer [EORTC] 30-item core 
quality of life questionnaire, version 3 [QLQ-C30 v3] and 35-item head and neck quality 
of life questionnaire [QLQ-H&N35]) will show the overall influence of the benefits and 
toxicity of the treatment from a patient’s perspective and will aid in the understanding of 
the benefit/risk evaluation.  These patient-reported outcome (PRO) questionnaires are 
well-established instruments that have been previously included in cancer clinical studies.  
The PK and immunogenicity of MEDI4736 + tremelimumab combination therapy are 
being examined to assess the PK and immunogenicity profiles of the combination of both 
agents and to determine the impact of each on PK, pharmacodynamics, and safety and 
efficacy parameters.  Biological samples will be used to explore potential biomarkers in 
tumor, plasma, and/or serum, which may influence the progression of cancer (and 
associated clinical characteristics) and/or response.  
1.3
Benefit/risk and ethical assessment
The following sections include summaries of the potential benefits and risks associated 
with MEDI4736 monotherapy, tremelimumab monotherapy, and MEDI4736 + 
tremelimumab combination therapy, respectively, prior to the overall benefit:risk 
assessment.
CCI


Patients are being enrolled in 10 ongoing clinical studies of MEDI4736 (5 employing 
MEDI4736 as monotherapy and 5 as combination therapy).  No studies have yet been 
completed.  Of the 414 patients treated with MEDI4736 (all dose levels) in all tumor types 
in Study 1108 as of 14 July 2014, a total of 169 patients were evaluable for response 
analysis, which included patients who had at least 24 weeks of follow-up as of 14 July 
2014 and had either at least 1 post-baseline tumor assessment or experienced clinical PD 
or death.  Nineteen patients (11.2%) had a best overall response of confirmed and 
unconfirmed CR/PR.  The DCR (CR + PR + SD ≥12 weeks) was 32% (54 of 169 patients).  
PD-L1 status (based on VENTANA/MedImmune assay) was known for 143 of 
169 evaluable patients, of whom 30 had PD-L1-positive tumors (defined by tumor staining 
≥25%).  A best overall response of CR/PR (confirmed and unconfirmed) was observed in 7 
of 30 (23.3%) patients with PD-L1-positive tumors and in 6 of 113 (5.3%) patients with 
PD-L1-negative tumors.
Recent data are available for patients with SCCHN in the expansion cohort of Study 1108 
(Segal et al 2015).  Sixty-two SCCHN patients were treated with MEDI4736 as 
monotherapy at 10 mg/kg q2w and evaluable for disease assessments as of the data cut-off 
date of 7 April 2015.  Tissue samples were retrospectively tested for PD-L1 expression 
using an immunohistochemistry (IHC) assay.  Of 62 SCCHN patients, an ORR of 11% 
was observed in the PD-L1-unselected population and in 18% and 8% of patients with 
PD-L1-positive (n=22) and PD-L1-negative disease (n=37), respectively, with DCR at 
24 weeks achieved in 18% and 11% of patients with PD-L1-positive and –negative 
disease, respectively.  DoRs ranged from 41 to 53 weeks in patients with PD-L1 positive 
disease and 16 to 54 weeks in patients with PD-L1-negative disease, with responses noted 
in both HPV-positive and -negative patients and in smokers and non-smokers.
1.3.1.2 Tremelimumab
In a single-arm, Phase II study (Study A3671008) of tremelimumab administered at 
15 mg/kg every 90 days to patients with refractory melanoma, a RR of 7% and a median 
OS of 10 months in the second-line setting (compared to approximately 6 months with best 
supportive care [BSC] reported from a retrospective analysis; Korn et al 2008) were 
observed (Kirkwood et al 2010).  In a randomized, open-label, first-line Phase III study of 
tremelimumab (administered at 15 mg/kg every 90 days) versus chemotherapy 
(dacarbazine or temozolomide) in advanced melanoma (Study A3671009), results of the 
final analysis showed a RR of 11% and median OS of 12.58 months in the first-line setting 
compared to 10.71 months with standard chemotherapy (Ribas et al 2013).  Additionally, 
in a Phase II maintenance study in patients with NSCLC (Study A3671015), PFS at 
3 months was 22.7% in the tremelimumab arm (15 mg/kg) compared with 11.9% in the 
BSC arm.
1.3.1.3 MEDI4736 + tremelimumab combination therapy
Preliminary efficacy data from Study 006 have demonstrated that this combination is 
clinically active and well tolerated.  As of 15 April 2015, 63 patients were evaluable for 
response across various MEDI4736 + tremelimumab combination therapy dose regimens.  
Of these, 27% (17 out of 63 patients) had a best response of PR and 41% (26 out of 
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1.3.1
1.3.1.1 MEDI4736


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63 patients) had disease control (CR, PR, SD >16 weeks).  In the MEDI4736 20 mg/kg 
plus tremelimumab 1 mg/kg q4w cohort, a total of 8 of 18 patients were evaluable for 
efficacy with at least 16 weeks of follow-up.  Of these, both the ORR and DCR at 16 
weeks were 50% (4 out of 8 patients) (Antonia et al 2015).  
A number of ongoing studies are assessing the activity of agents in patients with 
PD-L1-positive tumors.  There is also an unmet medical need in patients with PD-L1–
negative tumors that needs to be addressed.  Data, as of 15 April 2015 from Study 006,
show that with the addition of tremelimumab to MEDI4736, the ORR of 27% was 
achieved in patients with PD-L1-negative NSCLC.  As patients with PD-L1-positive 
disease also appear to achieve higher ORR with the combination (27% with MEDI4736 
monotherapy compared with 33% with MEDI4736 + tremelimumab combination therapy; 
Antonia et al 2015; Rizvi et al 2015), this study will enroll all patients with SCCHN, with 
an emphasis on those determined to be PD-L1 negative.
1.3.2
Identified and Potential risks
Overall risks
Monoclonal antibodies directed against immune checkpoint proteins, such as programmed 
cell death ligand 1 (PD-L1) as well as those directed against programmed cell death-1 
(PD-1) or cytotoxic T-lymphocyte antigen-4 (CTLA-4), aim to boost endogenous immune 
responses directed against tumor cells. By stimulating the immune system however, there 
is the potential for adverse effects on other tissues.
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues. These risks are 
generally events with a potential inflammatory or immune mediated mechanism and which 
may require more frequent monitoring and/or unique interventions such as 
immunosuppressants and/or endocrine therapy. These immune mediated effects can occur 
in nearly any organ system, and are most commonly seen as gastrointestinal AEs such as 
colitis and diarrhoea, pneumonitis/interstitial lung disease (ILD), hepatic AEs such as 
hepatitis and liver enzyme elevations, skin events such as rash and dermatitis and 
endocrinopathies including hypo- and hyper-thyroidism.
1.3.2.1 MEDI4736
Risks with MEDI4736 include, but are not limited to, diarrhea/colitis and intestinal 
perforation, pneumonitis/ILD, endocrinopathies (hypo- and hyper-thyroidism, type I 
diabetes mellitus, hypophysitis and adrenal insufficiency) hepatitis/increases in 
transaminases, nephritis/increases in creatinine, pancreatitis/increases in amylase and 
lipase, rash/pruritus/dermatitis, myocarditis, myositis/polymyositis, other rare or less 
frequent inflammatory events including neurotoxicities, infusion-related reactions, 
hypersensitivity reactions and infections/serious infections. 
For information on all identified and potential risks with durvalumab please always refer to 
the current version of the MEDI4736 IB.
In monotherapy clinical studies AEs (all grades) reported very commonly (≥ 10% of 
patients) are fatigue, nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, 
vomiting, back pain, pyrexia, asthenia, anemia, arthralgia, peripheral edema, headache, 


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rash, and pruritus. Approximately 9% of patients experienced an AE that resulted in 
permanent discontinuation of durvalumab and approximately 6% of patients experienced 
an SAE that was considered to be related to MEDI4736 by the study investigator.
The majority of treatment-related AEs were manageable with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of 
established treatment guidelines for immune-mediated toxicity (see the Dosing 
Modification and Toxicity Management Guidelines referenced in Section 6.7.2).
A detailed summary of MEDI4736 monotherapy AE data can be found in the current 
version of the MEDI4736 (Durvalumab) IB.
1.3.2.2 Tremelimumab
Risks with tremelimumab monotherapy include, but are not limited to, GI effects (colitis, 
diarrhoea, enterocolitis and intestinal perforation), endocrine disorders (hypo and 
hyperthyroidism, hypophysitis and adrenal insufficiency), skin effects (rash, and pruritus), 
elevations in lipase and amylase and clinical manifestations of pancreatitis, other 
gastrointestinal events e.g. ulcerative colitis, dehydration, nausea and vomiting; hepatic 
events including hepatitis, and liver enzyme elevations; pneumonitis and ILD; nervous 
system events including encephalitis, peripheral motor and sensory neuropathies, Guillain-
Barre and proximal muscle weakness; cytopenias including thrombocytopenia, anemia and 
neutropenia; infusion-related reactions, anaphylaxis, and allergic reactions; renal events 
including renal failure, acute kidney injury, nephritis, nephrotic syndrome, autoimmune 
nephritis and electrolyte abnormalities such as hypokalemia; autoimmune diseases 
including autoimmune arthritis, Sjogren's syndrome and giant cell temporal arteritis; 
hyperglycemia and diabetes mellitus; and pyrexia. 
Further information on these identified and potential risks can be found in the current 
version of the tremelimumab IB.
Using pooled data from monotherapy clinical studies AEs (all grades) reported very 
commonly (≥ 10% of patients)  were diarrhea, nausea, fatigue, pruritus, decreased appetite, 
rash,  vomiting, dyspnoea, constipation, cough, pyrexia, abdominal pain, decreased weight, 
headache, asthenia, and anaemia. Approximately 16% of patients experienced an AE that
resulted in permanent discontinuation of tremelimumab and approximately 45% of patients 
experienced an SAE.
A detailed summary of tremelimumab monotherapy AE data can be found in the current 
version of the tremelimumab IB. 
1.3.2.3 MEDI4736 + tremelimumab combination therapy
The safety of MEDI4736 + tremelimumab combination therapy was initially evaluated in 
the ongoing dose escalation and dose expansion Study 006, in patients with NSCLC, and is 
being studied in a number of other ongoing clinical trials, in a number of different 
indications, and has to date shown a manageable safety and tolerability profile.  
The types of risks with the combination of MEDI4736 + tremelimumab (based on an 
equivalent MEDI4736 dose of 20m/kg and a tremelimumab dose of 1mg/kg) are similar to 
those for MEDI4736 and tremelimumab monotherapy. Emerging data from study 006, 


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other studies evaluating the combination,  and from combinations of other agents in the 
same class indicate an increased frequency and/or severity of some of these immune-
mediated toxicities.
For information on all identified and potential risks with the MEDI4736+tremelimumab 
combination please always refer to the current version of the MEDI4736 IB.
In MEDI4736+tremelimumab combination studies at the dose of MEDI4736 20mg/kg and 
tremelimumab 1mg/kg AEs (all grades) reported very commonly (≥ 10% of patients) are 
fatigue, diarrhoea, nausea, dyspnea, decreased appetite, pruritus, vomiting, anaemia, 
constipation, cough, abdominal pain, pyrexia, back pain, arthralgia, hypothyroidism, 
asthenia, oedema peripheral, weight, decreased hyponatraemia and rash. 
Approximately 15% of patients experienced an AE that resulted in permanent 
discontinuation of study drug and approximately 15% of patients experienced an SAE that 
was considered to be related to MEDI4736 and tremelimumab by the study investigator.
A detailed summary of MEDI4736 + tremelimumab combination AE data can be found in 
the current version of the MEDI4736 IB.
1.3.3
Overall benefit/risk and ethical assessment
There remains a significant unmet medical need for additional treatment options for 
patients with recurrent or metastatic SCCHN who are not amenable to local curative 
therapy with surgery or radiation and who have not received prior systemic therapy in the 
metastatic setting.
The study design aims to minimize potential risks; intensive monitoring, including early 
safety assessment, is in place for those risks deemed to be most likely based on prior 
experience with the investigational products (IPs) (ie, MEDI4736 + tremelimumab 
combination therapy, MEDI4736 monotherapy, and SoC).
Based upon the available non-clinical and clinical safety data, the limited survival benefit 
provided by the currently available treatment options to patients, the limited life 
expectancy due to malignant disease, and the strength of the scientific hypotheses under 
evaluation, MEDI4736 monotherapy and in combination with tremelimumab proposed for 
evaluation in this study may have the potential to provide meaningful clinical benefit with 
a manageable safety and tolerability profile by generating durable clinical responses, 
thereby improving quality of life (QoL) and potentially extending survival.
Therefore, the investigation of the potential therapeutic efficacy of MEDI4736 
monotherapy  and MEDI4736 + tremelimumab combination in patients with PD-L1-
positive and -negative tumors is acceptable, and the overall benefit/risk assessment 
supports the proposed study design.
1.4
Study design
This is a randomized, open-label, multi-center, 3-arm, global Phase III study to determine 
the efficacy and safety of MEDI4736 +/- tremelimumab compared to SoC in the treatment 
of patients with recurrent or metastatic SCCHN who are not amenable to local curative 
therapy with surgery or radiation and who have not received prior systemic therapy for 


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recurrent/metastatic disease, unless it was given as part of multimodality treatment for 
locally advanced or locally recurrent disease.  A schematic diagram of the overall study 
design is shown in Figure 1, a flow chart of the study design treatment periods is presented 
in Figure 2, and a flow chart of the optional retreatment period for the MEDI4736 + 
tremelimumab combination therapy arm is presented in Figure 3.  
Patients will undergo an assessment on their tumor tissue sample to determine PD-L1 
status.  Patients with tumoral PD-L1 expression above or below a pre-specified cut-off 
level of ≥25%, as determined by an IHC assay (referred to hereafter as PD-L1–positive 
or -negative tumors, respectively), will be enrolled in the study.  If the patient has already 
been tested as a part of the screening process for any AstraZeneca study using the 
VENTANA assay, this test result can be used for the determination of eligibility.  The 
specified expression cut-off level of ≥25% in the tumor cells will be used for the purpose 
of stratification and therefore included in the stratified log rank tests for OS and PFS.  
HPV status will be assessed according to local standards or by the p16 IHC assay.  
Emerging data from 2nd line SCCHN studies suggests that PD-L1 expression on tumor 
tumor-infiltrating immune, as well as tumor cells, may be associated with greater clinical 
benefit with PD-1/PD-L1 inhibitors compared to tumor cell expression alone (Chow et al 
2016, Ferris et al 2017).  The D4193C00001 and D4193C00003 studies were used to 
identify a subgroup of patients that may be more likely to benefit from MEDI4736 +/-
tremelimumab treatment.  Based on this data, the pre-specified PD-L1 TC/IC high 
subgroup used in this study is defined as those patients whose tumors express PD-L1 on 
≥50% of tumor cells OR ≥25% of tumor-associated immune cells (TC≥50 or IC≥25) as 
assessed by the VENTANA  PD-L1 (SP263) Assay.  
Patients will be randomized in a 2:1:1 manner to either the MEDI4736 + tremelimumab 
combination arm, the MEDI4736 monotherapy arm, or the SoC arm.  Patients randomized 
to the MEDI4736 + tremelimumab combination arm will receive tremelimumab 75 mg 
intravenous (IV) q4w for 4 doses and MEDI4736 1500 mg IV q4w until PD, those in the 
MEDI4736 monotherapy arm will receive MEDI4736 1500 mg IV q4w monotherapy until 
PD, while patients in the SoC arm will receive up to six 3-week cycles consisting of a 
platinum [cisplatin 100 mg/m2 or carboplatin area under the curve (AUC) of 5 mg/mL/min 
IV]
V] on 
 1, 5FU 1000 mg/m2/day on Days 1 through 4, and weekly cetuximab.
Cetuximab will be administered at 400 mg/m2 on Day 1 of Cycle 1, and then 250 mg/m2
weekly for up to six 3-week cycles and 250 mg/m2 IV weekly for maintenance until
progression, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of
consent, or another discontinuation criterion is met (see Section 3.9).
Patients in all arms with confirmed PD by RECIST 1.1 who, in the Investigator’s opinion, 
continue to receive benefit from their assigned treatment and who meet the criteria for 
treatment in the setting of PD may continue to receive their assigned treatment (see 
Section 7.2.3).  Since the phenomenon of pseudoprogression in patients treated with 
immunotherapy is well documented and the limitations of RECIST 1.1 in identifying those 
who are achieving clinical benefit with immunotherapies are known, patients enrolled in 
the IMT arms will be permitted to continue therapy even in the presence of PD as per 
RECIST 1.1 (Weber et al 2012).  However, patients in the immunotherapy arms will not 
be permitted to continue immunotherapy if progression occurs after objective response 
(defined by RECIST 1.1) to immunotherapy treatment in the target lesions.  Patients in the 
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SoC arm may continue therapy in the setting of PD if they remain clinically stable, meet 
criteria for treatment in the setting of PD, and continue to receive some clinical benefit in 
the Investigator’s opinion.  
Patients in all arms with a symptomatic solitary lesion, a brain lesion, or a lesion of clinical 
importance (eg, impending fracture, etc) may be treated with radiation after approval from 
the Sponsor.  Non-irradiated lesions need to continue to be measurable by RECIST 1.1.  
The time interval between the last systemic treatment and radiation should be 10 days, and 
systemic treatment can be resumed 1 week post radiation.
Patients who have discontinued therapy due to disease progression will enter follow-up 
until death (see Table 4).  Patients who have discontinued treatment due to toxicity will be 
followed up until confirmed disease progression and for survival (see Table 4).
Tumor assessments will be performed on images from computed tomography (CT) or 
magnetic resonance imaging (MRI) scans, preferably with IV contrast, at the times 
specified in Table 2, Table 3, and Table 4.  RECIST 1.1 assessments using the investigator 
assessments will be used to derive the secondary variables of PFS, ORR, DoR, and 
proportion of patients alive and progression free at 6 and 12 months (APF6 and APF12).  
 
 See Section 5.1 and Appendix E for further information 
regarding RECIST 1.1 tumor assessments in this study.
This study will enroll approximately 1016 patients with PD-L1-positive and -negative 
disease at sites globally to obtain 760 patients who are likely to be evaluable for the 
primary endpoint.  
Figure 1
Overall study design
OS Overall survival; PD-L1 Programmed cell death ligand 1; PS Eastern Cooperative Oncology Group 
performance status; SCCHN Squamous cell cancer of the head and neck; SoC Standard of Care.
Target  Population

Patients with R/M 
SCCHN 

No prior systemic 
therapy  for R/M 
disease except if 
given as part of 
multimodality 
treatment for locally 
advanced  or locally 
recurrent disease

PS 0 to 1

Excludes 
nasopharyngeal 
cancer 

Excludes prior 
immunotherapy 
N = 760 patients
Primary
endpoint: 
OS
Randomization 
stratified for:

PD-L1 Status

Tumor location

Smoking history
MEDI4736 + Tremelimumab
N=380
Cetuximab + Platinum*
+5-Fluorouracil
(SoC - EXTREME)
N=190
  MEDI4736 monotherapy
N=190
* Platinum: carboplatin or cisplatin
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Figure 2
Study flow chart - treatment periods
a
Informed consent of study procedures and tumor sample acquisition may be obtained prior to the 
28-day screening window, if necessary, in order to permit tumor sample acquisition and analysis prior 
to randomization.  
b
Disease progression requires confirmation for patients receiving IMT.  Disease progression in patients 
in the SoC arm should be confirmed if clinically feasible (see Section 5.1 for more information).
c
Patients in the MEDI4736 + tremelimumab combination therapy arm who are eligible for retreatment 
will be treated according to Figure 3.
IMT Immunomodulatory therapy; PD Progressive disease; RECIST 1.1 Response Evaluation Criteria in 
Solid Tumors version 1.1.


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Figure 3
Study flow chart – optional retreatment for MEDI4736 + 
tremelimumab arm
a
With or without confirmation.
b
Before restarting MEDI4736 + tremelimumab combination therapy, the Investigator should ensure that 
the patient does not have any significant, unacceptable, or irreversible toxicities that indicate that 
continuing treatment will not further benefit the patient, and that the patient still meets all of the 
inclusion criteria and none of the exclusion criteria for this study including re-consenting to restart 
treatment.  To restart study treatment, the patient must not have received an intervening cancer therapy 
post study treatment discontinuation.  Patients should have a baseline tumor assessment within 28 days 
prior to restarting study treatment; all further scans should occur q8w until PD (relative to the date of 
restarting study treatment).
c
PK, ADA, and MDSC assessments do not need to be collected during retreatment.
ADA Anti-drug antibody; MDSC Myleoid-derived suppressor cell; PK Pharmacokinetics; q8w Every 8 
weeks; RECIST 1.1 Response Evaluation Criteria in Solid Tumors version 1.1.
2. STUDY OBJECTIVES
2.1
Primary objective
Primary Objectives:
Outcome Measure:
To assess the efficacy of MEDI4736 
monotherapy compared to SoC in terms of OS 
OS in the PD-L1 TC/IC high subgroup
OS Overall survival; SoC Standard of Care.


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2.2
Secondary objectives
Secondary Objectives:
Outcome Measures:
To further assess the efficacy of MEDI4736 
monotherapy compared to SoC (EXTREME) 
in terms of OS, PFS, ORR, DoR, BoR, TTR, 
TFST, TSST, APF6, APF12, PFS2, OS12, 
OS18 and OS24 
OS in low risk of early mortality (EM) subgroup, 
ctDNA TMB high subgroup (≥16 mut/Mb) and all-
comers
OS12, OS18, OS24 in the PD-L1 TC/IC high 
subgroup, low risk of EM subgroup, ctDNA TMB
high subgroup (≥16 mut/Mb) and all-comers
PFS, ORR, APF6 and APF12 using site investigator 
assessments according to RECIST 1.1 in the PD-L1 
TC/IC high subgroup, low risk of EM subgroup, 
ctDNA TMB high subgroup (≥16 mut/Mb) and all-
comers 
DoR, BoR and TTR, using site investigator 
assessments according to RECIST 1.1 in the PD-L1 
TC/IC high subgroup and all-comers 
PFS2 using local standard clinical practice in the PD-
L1 TC/IC high subgroup and all-comers 
TFST and TSST in thePD-L1 TC/IC high subgroup 
and all-comers
To assess the efficacy of MEDI4736 + 
tremelimumab combination therapy compared 
to SoC (EXTREME) in terms of OS, PFS, 
ORR, DoR, BoR, TTR, TFST, TSST, APF6, 
APF12, PFS2, OS12, OS18 and OS24
OS, OS12, OS18, OS24 in the PD-L1 TC/IC high 
subgroup, low risk of EM subgroup, ctDNA TMB
high subgroup (≥16 mut/Mb) and all comers
PFS, ORR, APF6 and APF12 in the PD-L1 TC/IC 
high subgroup, low risk of EM subgroup, ctDNA 
TMB high subgroup (≥16 mut/Mb) and all-comers 
using site investigator assessments according to 
RECIST 1.1
DoR, BoR and TTR, using site investigator 
assessments according to RECIST 1.1 in the PD-L1 
TC/IC high subgroup and all-comers
PFS2 using local standard clinical practice in the PD-
L1 TC/IC high subgroup and all-comers 
TFST and TSST in the PD-L1 TC/IC high subgroup 
and all-comers
To assess the efficacy of MEDI4736 + 
tremelimumab combination therapy compared 
to MEDI4736 monotherapy in terms of PFS, 
ORR, and OS 
PFS and ORR using site investigator assessments 
according to RECIST 1.1 in the PD-L1 TC/IC high 
subgroup, low risk of EM subgroup, ctDNA TMB
high subgroup (≥16 mut/Mb) and all-comers 
OS in the PD-L1 TC/IC high subgroup, low risk of 
EM subgroup, ctDNA TMB high subgroup (≥16 
mut/Mb) and all-comers


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Secondary Objectives:
Outcome Measures:
To assess disease-related symptoms and 
health-related quality of life in patients treated 
with MEDI4736 + tremelimumab combination 
therapy and MEDI4736 monotherapy 
compared to SoC (EXTREME) using the 
European Organisation for Research and 
Treatment of Cancer (EORTC) 30-item Core 
Quality of Life Questionnaire (QLQ-C30) 
version 3 and the 35-item Head and Neck 
Quality of Life Questionnaire (QLQ-H&N35) 
module
EORTC QLQ-C30: global health QoL, functioning 
(physical) and symptoms (fatigue) in the PD-L1 
TC/IC high subgroup and all-comers 
EORTC QLQ-H&N35: symptoms (pain, swallowing) 
in the PD-L1 TC/IC high subgroup and all-comers
Changes in World Health Organization/Eastern 
Cooperative Oncology Group performance status in 
the PD-L1 TC/IC high subgroup all-comers
To assess the PK of MEDI4736 + 
tremelimumab combination therapy and 
MEDI4736 monotherapy
Concentration of MEDI4736 and tremelimumab in 
blood and PK parameters, such as peak concentration 
and trough (as data allow; sparse sampling) 
To investigate the immunogenicity of 
MEDI4736 and tremelimumab
Presence of ADAs for MEDI4736 and tremelimumab
ADA Anti-drug antibody; APF6 Proportion of patients alive and progression free at 6 months; 
APF12 Proportion of patients alive and progression free at 12 months; BoR Best objective response; 
ctDNA Circulating tumor DNA; DNA Deoxyribonucleic acid; DoR Duration of response; ECOG Eastern 
Cooperative Oncology Group; EORTC European Organisation for Research and Treatment of Cancer; 
HRQoL Health-related quality of life; IC tumor-associated immune cells; ORR Objective response rate; 
OS Overall survival; OS12 Proportion of patients alive at 12 months after randomization; OS18 Proportion 
of patients alive at 18 months after randomization; OS24 Proportion of patients alive at 24 months after 
randomization; PD-L1 Programmed cell death ligand 1; PFS Progression-free survival; PFS2 Second 
progression; PK Pharmacokinetics; QLQ-C30 v3 30-item core quality of life questionnaire, version 3; QLQ-
H&N35 35-item head and neck quality of life questionnaire; QoL Quality of life; RECIST 1.1 Response 
Evaluation Criteria in Solid Tumors version 1.1; SCCHN Squamous cell carcinoma of the head and neck; 
SoC Standard of Care; TC tumor cells; TFST Time to first subsequent therapy; TMB Tumor mutation 
burden (The ctDNA TMB cutpoint of 16mut/Mb for MEDI4736+tremelimumab and MEDI4736 
monotherapy was derived from the EAGLE study (Li et al 2020) Li W, Wildsmith S, Ye J, Si H, Morsli N, 
He P et al. Plasma-based tumor mutational burden (bTMB) as predictor for survival in phase III EAGLE 
study: Durvalumab (D) +/- tremelimumab (T) versus chemotherapy (CT) in recurrent/metastatic head and 
neck squamous cell carcinoma (R/M HNSCC) after platinum failure. J Clin Oncol 2020;38:15_suppl, 6511-
6511.)).; TTR Time to response; TSST Time to second subsequent therapy; WHO World Health 
Organization.
2.3
Safety objective
Safety Objective:
Outcome Measures:
To assess the safety and tolerability profile of 
MEDI4736 + tremelimumab combination 
therapy and MEDI4736 monotherapy 
compared to SoC in the first-line setting for 
treatment of SCCHN
AEs, physical examinations, laboratory findings 
(including clinical chemistry, hematology, and 
urinalysis), vital signs (including BP and pulse), and 
ECGs in the PD-L1 TC/IC high subgroup, low risk of 
EM subgroup and all-comers
AE Adverse event; BP Blood pressure; ECG Electrocardiogram; IC tumor-associated immune cells;
SoC Standard of Care; TC tumor cells.


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2.4
Exploratory objectives
3. PATIENT SELECTION, ENROLLMENT, 
RANDOMIZATION, RESTRICTIONS, 
DISCONTINUATION, AND WITHDRAWAL 
Each patient should meet all of the inclusion criteria (Section 3.1) and none of the 
exclusion criteria (Section 3.2) for this study.  Under no circumstances will there be 
exceptions to this rule.
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3.1
Inclusion criteria
For inclusion in the study, patients should fulfill the following criteria:
SoC procedures obtained prior to informed consent for other purposes may be used for 
screening if the patient/legal representative consents to allow use of these procedures for 
screening purposes.
Patients must meet all of the following criteria:
1.
Age ≥18 years at the time of screening
2.
Written informed consent and any locally required authorization (eg, Health 
Insurance Portability and Accountability Act in the United States, European Union 
[EU] Data Privacy Directive in the EU) obtained from the patient/legal representative 
prior to performing any protocol-related procedures, including screening evaluations.  
(For patients aged <20 years and enrolling in Japan, a written informed consent 
should be obtained from the patient and his or her legally acceptable representative.)
3.
Histologically or cytologically confirmed recurrent or metastatic SCCHN (oral 
cavity, oropharynx, hypopharynx, or larynx) not amenable to local curative therapy 
with surgery or radiation therapy.
4.
No prior systemic therapy for recurrent/metastatic disease. Systemic therapy given 
as part of multimodality treatment for locally advanced or locally recurrent disease is 
allowed.
5.
Able and willing to give valid written consent to provide newly acquired tumor tissue 
(preferred) or archival tissue (<3 years old) for the purpose of establishing PD-L1 
status.  Tumor lesions used for newly acquired biopsies should not be the same 
lesions used as RECIST 1.1 target lesions, unless there are no other lesions suitable 
for biopsy.
6.
For patients with OPC only: known HPV status prior to randomization.
7.
Confirmed PD-L1–positive or –negative SCCHN by the VENTANA SP263 IHC 
assay 

On newly acquired tumor tissue (preferred) or archival tissue (<3 years old)

If the patient’s PD-L1 status has already been assessed using the analytically 
validated VENTANA assay as a part of the screening process for another 
AstraZeneca/MedImmune study, this test result can be used for the determination 
of eligibility.  

Note: A positive PD-L1 sample is measured using a defined cut-off based on 
≥25% of tumor cells with membrane staining of any intensity for PD-L1.  A 
negative PD-L1 sample is determined by 0% to 24% of tumor cells with 
membrane staining for PD-L1.
8.
World Health Organization (WHO)/ECOG performance status of 0 or 1 


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9.
At least 1 lesion, not previously irradiated, that can be accurately measured at 
baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have a 
short axis ≥15 mm) with CT or MRI and that is suitable for accurate repeated 
measurements as per RECIST 1.1 guidelines.  Lesions in a previously irradiated field 
can be used as measurable disease provided that there has been demonstrated 
progression in the lesion and the lesion measures at least 20 mm.
10.
Patients must have no prior exposure to immune-mediated therapy, including 
anti-CTLA-4, anti-PD-1, anti–PD-L1, or anti–programmed cell death ligand 2 
antibodies, excluding therapeutic anticancer vaccines.  Exposure to other 
investigational agents may be permitted after discussion with the Sponsor.
11.
Adequate organ and marrow function independent of transfusion for at least 7 days 
prior to screening and independent of growth factor support for at least 14 days prior 
to screening, defined as follows:

Hemoglobin ≥9 g/dL

Absolute neutrophil count ≥1500/mm3 (1.5 × 109/L)

Platelet count ≥100000/mm3 (100 × 109/L)

Serum bilirubin ≤1.5 × the upper limit of normal (ULN).  This will not apply to 
patients with confirmed Gilbert’s syndrome (persistent or recurrent 
hyperbilirubinemia [predominantly unconjugated bilirubin] in the absence of 
evidence of hemolysis or hepatic pathology), who will be allowed in consultation 
with their physician.

ALT and AST ≤2.5 × ULN; for patients with hepatic metastases, ALT and AST 
≤5 × ULN

Calculated creatinine clearance >40 mL/min as determined by Cockcroft-Gault 
(using actual body weight) (creatinine clearance of 60 mL/min is needed if 
cisplatin is used)
Males:
Creatinine Clearance =
Weight (kg) × (140 – Age)
(mL/min)
72 × serum creatinine (mg/dL)
Females:
Creatinine Clearance =
Weight (kg) × (140 – Age) × 0.85
(mL/min)
72 × serum creatinine (mg/dL)
12.
Evidence of post-menopausal status or negative urinary or serum pregnancy test for 
female pre-menopausal patients.  Women will be considered post-menopausal if they 
have been amenorrheic for 12 months without an alternative medical cause.  The 
following age-specific requirements apply: 


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Criteria for retreatment in the MEDI4736 + tremelimumab arm
Patients in the MEDI4736 + tremelimumab combination therapy arm are eligible to 
receive retreatment with the MEDI4736 + tremelimumab combination therapy provided 
progression occurred in the monotherapy portion of dosing and the patient meets all the 
criteria specified above for treatment beyond confirmed progression.  Patients who 
discontinue treatment in 1 treatment arm may not switch to treatment in a different group.
Additional details pertaining to retreatment are presented in Section 7.2.  Additional details 
pertaining to restrictions are presented in Section 3.8.
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
Women ≥50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments or if they have luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution.

Women <50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous
hormonal treatments and if they have luteinizing hormone and
follicle-stimulating hormone levels in the post-menopausal range for the
institution, or had radiation-induced oophorectomy with last menses >1 year ago,
or had chemotherapy-induced menopause with >1 year interval since last menses,
or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
Criteria for continuation of treatment in the setting of progressive disease
For all patients who are treated through progression at the Investigator’s discretion, the 
Investigator should ensure that patients still meet all of the inclusion criteria and none of 
the exclusion criteria for this study, and that patients meet the following specific criteria 
for treatment in the setting of PD:
1.
Written informed consent to continue treatment or retreatment in the setting of PD.
This consent document will specify that treatment beyond initial evidence of PD is
not the “standard-of-care” and that alternative treatment options, either locally
licensed treatments or other clinical trials, are available for this patient population.
2.
Absence of clinical symptoms or signs indicating clinically significant disease
progression
3.
No decline in WHO/ECOG performance status to >1
4.
Absence of rapid disease progression or threat to vital organs or critical anatomical
sites (eg, central nervous system metastasis, respiratory failure due to tumor
compression, or spinal cord compression) requiring urgent alternative medical
intervention
The IP should be discontinued if there is confirmed PD while receiving treatment
following a previous response (CR or PR) to the IP in the target lesions (ie, the
response and progression events both occurred in the target lesions while receiving
the IP during the treatment period).


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3.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Histologically or cytologically confirmed head and neck cancer of any other primary 
anatomic location in the head and neck not specified in the inclusion criteria 
including patients with SCCHN of unknown primary or non-squamous histologies 
(eg, nasopharynx or salivary gland)
2.
Tumor progression or recurrence within 6 months of last dose of platinum therapy 
given as part of multimodality treatment for locally advanced or locally recurrent 
disease.
3.
Receipt of any radiotherapy or hormonal therapy for cancer treatment within 30 days 
prior to first dose of study treatment.
4.
Receipt of last dose of an approved (marketed) anticancer therapy (chemotherapy, 
targeted therapy, biologic therapy, mAbs, etc) within 21 days prior to the first dose of 
study treatment.  If sufficient washout time has not occurred due to the schedule or 
PK properties of an agent, a longer washout period will be required, as agreed upon 
by AstraZeneca and the Investigator.
5.
Receipt of any investigational anticancer therapy within 28 days or 5 half-lives, 
whichever is longer, prior to the first dose of study treatment.
6.
Major surgical procedure (as defined by the Investigator) within 28 days prior to the 
first dose of IP.  Note: Local surgery of isolated lesions for palliative intent is 
acceptable.
7.
Any unresolved toxicity National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Event (CTCAE) Grade ≥2 from previous anticancer therapy 
with the exception of alopecia, vitiligo, lymphopenia, and the laboratory values 
defined in the inclusion criterion

Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis and 
may be included after consultation with the Study Physician.  

Patients with a toxicity not reasonably expected to be exacerbated by treatment 
with their assigned IP (eg, hearing loss, gastrostomy tube) may be included after 
consultation with the Study Physician.
8.
Current or prior use of immunosuppressive medication within 14 days before the first 
dose of their assigned IP.  The following are exceptions to this criterion unless 
otherwise indicated:

Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection)

Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or its equivalent


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
Steroids as pre-medication for hypersensitivity reactions (eg, CT scan 
pre-medication) and/or as anti-emetics for the SoC arm
9.
History of allogeneic organ transplantation
10.
Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis, Crohn’s disease], diverticulitis with the 
exception of a prior episode that has resolved or diverticulosis, celiac disease, or 
other serious gastrointestinal chronic conditions associated with diarrhea; systemic 
lupus erythematosus; Wegener syndrome [granulomatosis with polyangiitis]; 
myasthenia gravis; Graves’ disease; rheumatoid arthritis, hypophysitis, uveitis, etc) 
within the past 3 years prior to the start of treatment.  The following are exceptions to 
this criterion:

Patients with vitiligo or alopecia

Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement or psoriasis not requiring systemic treatment 
11.
Uncontrolled intercurrent illness, including, but not limited to ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, cardiac arrhythmia, interstitial lung disease, or psychiatric illness or 
social situations that would limit compliance with study requirements, substantially 
increase the risk of incurring AEs from IP, or compromise the ability of the patient to 
give written informed consent
12.
History of another primary malignancy within the last 5 years except for the 
following:

Non-invasive malignancies, such as cervical carcinoma in situ or non-
melanomatous carcinoma of the skin that has been surgically cured.  Other in situ 
carcinomas that have been adequately treated may be permitted after detailed 
discussion with the Sponsor.
13.
Patients with a history of brain metastases, spinal cord compression, or 
leptomeningeal carcinomatosis, or involvement of any other anatomic area that, in 
the opinion of the Investigator, may cause significant symptoms if an inflammatory 
reaction occurs
14.
Mean QT interval corrected for heart rate ≥470 ms calculated from 
3 electrocardiograms (ECGs) using Fridericia’s Correction 
15.
History of active primary immunodeficiency 
16.
Active tuberculosis
17.
Active infection including hepatitis B, hepatitis C, or human immunodeficiency virus 
(HIV)


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18.
Receipt of live, attenuated vaccine within 30 days prior to the first dose of IP.
Note: Patients, if enrolled, should not receive live vaccine during the study and up to
30 days after the last dose of IP.
19.
Female patients of childbearing potential who are pregnant or breast-feeding or who
are not willing to employ a highly effective method of birth control from screening to
90 days after the last dose of MEDI4736 monotherapy or 180 days after the last dose
of MEDI4736 + tremelimumab combination therapy and non-sterilized male patients
who are sexually active with a female partner of childbearing  potential who are not
willing to employ male condom plus spermicide from screening to 90 days after the
last dose of MEDI4736 monotherapy or 180 days after the last dose of MEDI4736 +
tremelimumab combination therapy.  For patients randomized to receive SoC
treatment, follow the local prescribing information relating to contraception, the time
limit for such precautions, and any additional restrictions for agents in the SoC
treatment regimen.
20.
Known allergy or hypersensitivity to IP or any IP excipient
21.
Any condition that, in the opinion of the Investigator, would interfere with evaluation
of the IP or interpretation of patient safety or study results
22.
For patients randomized to the SoC arm, any contraindication to a specific SoC agent
as specified by the accompanying package insert or Summary of Product
Characteristics
23.
Patient weight of <30 kg
24.
Involvement in the planning and/or conduct of the study (applies to both
AstraZeneca/MedImmune staff and/or staff at the study site)
Procedures for withdrawal of incorrectly enrolled patients are presented in Section 3.4.
3.3
Patient enrollment and randomization
Investigators should keep a record (ie, the patient screening log) of patients who entered 
screening (including assessment of PD-L1).  
At screening (Days -28 to -1), the Investigators or suitably trained delegate will:
1.
Obtain signed informed consent before any study-specific procedures are performed.
(Informed consent of study procedures may be obtained prior to the 28-day screening
window in order to permit tumor sample acquisition, which must be analyzed prior to
randomization.)
2.
Obtain a unique 7-digit enrollment number (E-code) through the Interactive Voice
Response System (IVRS)/Interactive Web Response System (IWRS) in the following
format (ECCNNXXX: CC being the country code, NN being the center number, and
XXX being the patient enrollment code at the center).  This number is the patient’s
unique identifier and is used to identify the patient on the electronic case report forms
(eCRFs).


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3.
For any patient who does not have obvious exclusion parameters, obtain tumor
sample and send for PD-L1 expression status evaluation.  (Obtaining the tumor
sample should be given the highest priority and, as such, the sample may be obtained
and sent for PD-L1 expression status evaluation prior to the 28-day screening
window in order to permit analysis prior to randomization.)  The PD-L1 result must
be available prior to randomization.
4.
Determine patient eligibility (see Sections 3.1 and 3.2).  Define HPV status if the
location of the tumor is oropharyngeal (oropharynx).  HPV results can be collected
from historical medical records of any age.  HPV status will be assessed using local
standards or using the p16 IHC assay.  If status is unknown and/or unavailable
locally, archival or newly acquired tissue specimen must be submitted for testing at a
reference laboratory.  See Laboratory Manual for detailed instructions in lieu of a
separate tumor sample.
At randomization, once the patient is confirmed to be eligible, the Investigator or suitably 
trained delegate will:
1.
Define the SoC (cetuximab, a platinum [carboplatin or cisplatin], and 5FU)
treatment (based on the most appropriate option for the patient) that the patient
would receive if randomized to SOC therapy.  This must be completed for all
patients.  The information will be recorded in the IVRS/IWRS.
2.
Record the patient’s PD-L1 status, tumor location (OPC or non-OPC), and smoking
history (>10 vs ≤10 pack-years [1 pack-year = 1 pack of 20 cigarettes per day for 1
year or equivalent]) as stratification factors in the IVRS.  Include the HPV status
(positive or negative) if the tumor is OPC.
3.
Obtain a unique randomization number via the IVRS/IWRS.  Numbers will start at
001 and will be assigned strictly sequentially by IVRS/IWRS as patients are eligible
for entry into the study.  The system will randomize the eligible patient to 1 of the
3 treatment arms.  (PD-L1 status results must be received from the central laboratory
by the IVRS/IWRS prior to randomization.)
If the patient is ineligible and not randomized, the IVRS/IWRS should be contacted to 
terminate the patient in the system.  
Every effort should be made to minimize the time between randomization and starting 
study drug.  Study drug must be administered within 5 working days of randomization 
(although it is recommended that patients commence study drug on the same day as 
randomization in the IVRS/IWRS if feasible).
Patients will begin treatment on Day 1.  Patients must not be treated unless all eligibility 
criteria have been met.
If a patient discontinues participation in the study, then his or her enrollment or patient 
identification number cannot be reused.  Withdrawn patients will not be replaced.


Revised Clinical Study Protocol
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Study Code D419LC00001
Version 12.0
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3.4
Procedures for handling incorrectly enrolled patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication.  There can be no exceptions to this rule.  Patients 
who are enrolled but found not to meet all the eligibility criteria must not be randomized or 
initiated on treatment and must be withdrawn from the study as a screen failure.
Where a patient does not meet all the eligibility criteria but is randomized in error or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca Study 
Physician immediately, and a discussion should occur between the AstraZeneca Study 
Physician and the Investigator regarding whether to continue or discontinue the patient 
from treatment.  The AstraZeneca Study Physician must ensure all decisions are 
appropriately documented.
3.5
Methods for assigning treatment arms
Patients must not be randomized unless all eligibility criteria have been met.
At baseline, patients who satisfy all the entry criteria will be centrally assigned to study 
drug by the IVRS/IWRS, according to the randomization scheme generated by the 
Biostatistics Group, AstraZeneca, or delegate.  
Patients enrolled in the study will be randomized (2:1:1) to treatment with MEDI4736 + 
tremelimumab combination therapy, MEDI4736 monotherapy, or SoC (cetuximab, a 
platinum [carboplatin or cisplatin based on Investigator’s choice], and 5FU).  Patients will 
be stratified by PD-L1 status (positive or negative, based on the analytically validated 
VENTANA/MedImmune assay), tumor location (OPC or non-OPC), and smoking history 
(>10 vs ≤10 pack-years).  Patients with OPC will be further stratified by HPV status.
The actual treatment given to patients will be determined by the randomization scheme in 
the IVRS/IWRS.  The randomization scheme will be produced by a computer software 
program that incorporates a standard procedure for generating randomization numbers.  
One randomization list will be produced for each of the randomization strata.  A blocked 
randomization will be generated, and all centers will use the same list in order to minimize 
any imbalance in the number of patients assigned to each treatment arm.
Patients will be identified to the Centralized Randomization Center per country 
regulations.  Randomization codes will be assigned strictly sequentially, within each 
stratum, as patients become eligible for randomization.  
If a patient discontinues participation in the study, then his/her enrollment/randomization 
code cannot be reused.  
3.6
Methods for ensuring blinding (not applicable)
Not applicable; this study is not blinded.
3.7
Methods for unblinding (not applicable)
Not applicable; this study is not blinded.


Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
80(199)
3.8
Restrictions
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after:
1.
Females of childbearing potential who are sexually active with a nonsterilized male
partner must use at least 1 highly effective method of contraception (see Table 1)
from screening and must agree to continue using such precautions for 90 days after
the last dose of MEDI4736 monotherapy or 180 days after the last dose of
MEDI4736 + tremelimumab combination therapy; cessation of birth control after this
point should be discussed with a responsible physician.  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.
Female patients should refrain from breastfeeding and egg cell donation throughout
this period.  It is strongly recommended for the male partner of a female patient to
also use a male condom plus spermicide throughout this period.

Females of childbearing potential are defined as those who are not surgically
sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete
hysterectomy) or post-menopausal (defined as 12 months with no menses without
an alternative medical cause).

Highly effective methods of contraception are described in Table 1. 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.
2.
Nonsterilized male patients who are sexually active with a female partner of
childbearing potential must use male condom and spermicide from screening and for
90 days after the last dose of MEDI4736 monotherapy or 180 days after the last dose
of MEDI4736 + tremelimumab combination therapy.  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 patients should refrain from sperm donation throughout the study period and
through 180 days after the last dose of MEDI4736 + tremelimumab combination
therapy.  It is strongly recommended for the female partner of a male patient to also
use an effective method of contraception throughout this period.
3.
SoC therapy: Follow the local prescribing information relating to contraception, the
time limit for such precautions, and any additional restrictions for agents in the SoC
treatment regimen.
4.
Patients should not donate blood while participating in this study and for 3 months
following the last dose of study treatment.
Restrictions relating to concomitant medications are described in Section 7.7.


Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
81(199)
Table 1
Highly Effectivea methods of contraception
Barrier/Intrauterine Methods
Hormonal Methods
• Copper T intrauterine device
• Levonorgesterel-releasing intrauterine system 
(eg, Mirena®)b
• Etonogestrel implants: eg, Implanon or Norplan
• Intravaginal device: eg, ethinylestradiol and 
etonogestrel
• Medroxyprogesterone injection: eg, Depo-Provera
• Normal and low dose combined oral contraceptive 
pill
• Norelgestromin/ethinylestradiol  transdermal 
system
• Cerazette (desogestrel)
a
Highly effective (ie, failure rate of <1% per year) 
b
This is also considered a hormonal method
3.9
Discontinuation of investigational product
An individual patient will not receive any further IP (MEDI4736 + tremelimumab 
combination therapy, MEDI4736 monotherapy, or SoC [cetuximab, a platinum, and 5FU]) 
if any of the following occur in the patient in question:

Withdrawal of consent from further treatment with IP.

An AE that, in the opinion of the Investigator or the Sponsor, contraindicates further 
dosing

Any AE that meets criteria for discontinuation as defined in Section 6

Pregnancy or intent to become pregnant

Non-compliance that, in the opinion of the Investigator or Sponsor, warrants 
discontinuation of study treatment (eg, refusal to adhere to scheduled visits)

Initiation of alternative anticancer therapy including another investigational agent 
unless specified in the protocol

Confirmed PD and Investigator determination that the patient is no longer benefiting 
from treatment with MEDI4736 + tremelimumab combination therapy, MEDI4736 
monotherapy, or SoC

Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per day (or 
equivalent) within 12 weeks after last dose of study drug/regimen due to a 
treatment-related toxicity

Treatment interval of ≥8 weeks of MEDI4736 + tremelimumab combination therapy 
or MEDI4736 monotherapy due to non-compliance.
3.9.1
Procedures for discontinuation of a patient from investigational 
product 
At any time, patients are free to discontinue the IP without prejudice to further treatment.  
A patient who decides to discontinue the IP will always be asked about the reason(s) for 
discontinuation and the presence of any AEs.  If possible, they will be seen and assessed 
by an Investigator.  AEs will be followed up (see Section 6).  The AstraZeneca Study 


Patients are free to withdraw from the study at any time (IP and assessments) without 
prejudice to further treatment.
Patients who withdraw consent for further participation in the study will not receive any 
further IP or further study observation, with the exception of follow-up for survival, which 
will continue until the end of the study unless the patient has expressly withdrawn his or 
her consent to survival follow-up.  Note that the patient may be offered additional tests or 
tapering of treatment to withdraw safely.
A patient who withdraws consent will always be asked about the reason(s) for withdrawal 
and the presence of any AE.  The Investigator will follow up AEs outside of the clinical 
study.  The patient will return ePRO devices, if applicable.  
If a patient withdraws from participation in the study, then his or her randomization or 
patient identification number cannot be reused.  Withdrawn patients will not be replaced.
Patients will be considered lost to follow-up only if no contact has been established by the 
time the study is completed (see Section 3.11), such that there is insufficient information to 
determine the patient’s status at that time.  Patients who refuse to continue participation in 
the study, including telephone contact, should be documented as “withdrawal of consent” 
rather than “lost to follow-up.”  Investigators should document attempts to re-establish 
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Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
Physician should be notified of any ongoing AE that may delay treatment or necessitate 
permanent discontinuation of treatment.
Patients who are permanently discontinued from further receipt of IP, regardless of the 
reason, will be identified as having permanently discontinued treatment.  Patients who are 
permanently discontinued from IP will enter follow-up and be asked to come in for every 
protocol-specified visit and follow all protocol procedures, including imaging and 
electronic patient-reported outcome (ePRO) questionnaires (see Table 4).  All patients will 
be followed up for survival until the end of the study.  Details of any treatment for SCCHN 
(including surgery or radiation) after the last dose of study treatment must be recorded in 
the eCRF, including the identity of subsequent anticancer therapies.  Patients who decline 
to return to the site for evaluations should be contacted by telephone every 3 months as an 
alternative.  
Patients who are permanently discontinued from receipt of IP should also be discontinued 
in the IVRS/IWRS.
3.10 Criteria for withdrawal of the patient from the study
3.10.1
Screen failures 
Screening failures are patients who do not fulfill the eligibility criteria for the study, and 
therefore must not be enrolled and randomized.  These patients should have the reason for 
study withdrawal recorded as “eligibility criteria not fulfilled” (ie, patient does not meet 
the required inclusion/exclusion criteria).  This reason for study withdrawal is only valid 
for screen failures (ie, not randomized patients).  Patients can be re-screened a single time, 
but they cannot be re-randomized.
3.10.2
Withdrawal of the informed consent


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Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
contact with missing patients throughout the study period.  If contact with a missing 
patient is re-established, the patient should not be considered lost to follow-up and any 
evaluations should resume according to the protocol.
3.10.3
Survival status for withdrawn consent and lost to follow up patients
Patients will be considered lost to follow-up only if no contact has been established by the 
time the study is completed (see Section 9.3), such that there is insufficient information to 
determine the patient’s status at that time.  Patients who refuse to continue participation in 
the study, including telephone contact, should be documented as “withdrawal of consent” 
rather than “lost to follow-up.”  Investigators should document attempts to re-establish 
contact with missing patients throughout the study period.  If contact with a missing 
patient is re-established, the patient should not be considered lost to follow-up and 
evaluations should resume according to the protocol.
In order to support the primary endpoint of OS, the survival status of all patients in the full 
analysis and the safety analysis sets should be re-checked, this includes those patients who 
withdrew consent or are classified as “lost to follow up.”    

Lost to Follow up – site personnel should check hospital records, the patients’ current
physician, and a publicly available death registry (if available) to obtain a current
survival status. (The applicable CRF modules will be updated.)

In the event that the patient has actively withdrawn consent to the processing of their
personal data, the survival status of the patient can be obtained by site personnel
from publicly available death registries (if available) where it is possible to do so
under applicable local laws to obtain a current survival status. (The applicable CRF
modules will be updated.)
3.11 Discontinuation of the study
The study may be stopped if, in the judgment of the AstraZeneca, study patients are placed 
at undue risk because of clinically significant findings that meet any of the following 
criteria:

Meet individual stopping criteria or are otherwise considered significant

Are assessed as causally related to study drug

Are not considered to be consistent with continuation of the study
In addition, the study may be stopped based on the findings of the interim safety analysis 
conducted by the Independent Data Monitoring Committee (IDMC) (see Section 6.8).
Regardless of the reason for termination, all data available for the patients at the time of 
discontinuation or follow-up must be recorded in the eCRFs.  All reasons for 
discontinuation of treatment must be documented
In terminating the study, AstraZeneca will ensure that adequate consideration is given to 
the protection of the patients’ interests.  If this study is discontinued, all other studies 
involving MEDI4736 or tremelimumab will remain open to enrollment and screening, if 
deemed appropriate by AstraZeneca.


Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
84(199)
4. STUDY PLAN AND TIMING OF PROCEDURES
The procedures for the screening and treatment periods in this study for the 
MEDI4736 + tremelimumab combination therapy and MEDI4736 monotherapy arms are 
presented in Table 2, for the SoC group is presented in Table 3, and the procedures for the 
follow-up period are presented in Table 4.
Imaging and standard procedures performed before signing the informed consent form
(ICF) may be used for screening purposes if the patient consents to the use of those results 
for screening purposes.  Screening procedures must be performed within 28 days of 
randomization.  Randomization must occur within 28 days of screening procedures and 
study drug dosing must occur within 5 working days of randomization.  Baseline 
procedures required for Cycle 1, Day 1 need not be repeated if they were performed within 
3 days prior to Cycle 1, Day 1.
All visits should be conducted based on the schedules provided in Table 2 through Table 4
below, unless otherwise indicated. 

For patients on the immunotherapy arms, if dosing must be delayed due to a
treatment-related toxicity, the toxicity management guidelines should be followed (as
referenced in Section 6.7.2).  If dosing must be delayed for reasons other than
treatment-related toxicity, dosing should occur as soon as clinically feasible.

For patients on the standard of care arm, dosing may be delayed for treatment-related
toxicity and subsequently resumed per the local standard clinical practice.  If dosing
must be delayed for reasons other than treatment-related toxicity, dosing should
occur as soon as clinically feasible.
Tumor efficacy (RECIST) assessments dates are not affected by dose delays and remain as 
originally scheduled, as they are based on the date of randomization (not the date of 
treatment).  All other scheduled assessments must be performed relative to the day of 
dosing (even if dosing is delayed); all laboratory procedures required for dosing should be 
performed within 3 days prior to dosing.
Following the OS analysis, patients still on randomized study treatment will continue to be 
supplied with study medication and will be managed at the discretion of the Investigator 
until discontinuation criteria are met.  The study database will be closed at this point and 
only serious adverse event (SAEs) will be reported.


Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
85(199)
Table 2
Schedule of assessments for the MEDI4736 + tremelimumab combination or MEDI4736 monotherapy 
arms and optional retreatment period for MEDI4736 + tremelimumab combination arm 
Screening
C1a
C2
C3
C4
C5
C6
C7
C8 until PD
Week
-4 to -1
0
4
8
12
16
20
24
28, 32, 36, 40, 44 (+4-wk 
intervals)
Day
-28 to -1
1
29
57
85
113
141
169
197, 225, 253, 281, 309 
(+28-day intervals)
Window (days)*
NA
NA
±3
±3
±3
±3
±3
±3
±3
Informed consent
Xb
Study procedures
Physical examination (full)
X
Medical history, past and current
X
Targeted physical examination (based on symptoms)
X
X
X
X
X
X
X
X
Vital signsc
X
X
X
X
X
X
X
X
X
ECGd
X
As clinically indicated
Concomitant medications
<--------------------------------------------------------------------------------------------------------------------
->
Demography, including baseline characteristics and 
tobacco use
X
HPV for oropharyngeal tumors onlye
Xb
Eligibility criteria
X
Pharmacokineticsf
MEDI4736 PK sample (serum)
Xh
Xg
Xg,h
Xg
Tremelimumab PK sample (serum; combination 
therapy arm only)
Xh
Xg
Xg,h
Laboratory assessments
Clinical chemistry
X
Xi
X
X
X
X
X
X
X
Hematology
X
Xi
X
X
X
X
X
X
X


Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
86(199)
Screening
C1a
C2
C3
C4
C5
C6
C7
C8 until PD
Week
-4 to -1
0
4
8
12
16
20
24
28, 32, 36, 40, 44 (+4-wk 
intervals)
Day
-28 to -1
1
29
57
85
113
141
169
197, 225, 253, 281, 309 
(+28-day intervals)
Window (days)*
NA
NA
±3
±3
±3
±3
±3
±3
±3
TSH (and reflex free T3 or free T4)j
X
Xi
X
X
X
X
X
X
X
Urinalysis
X
As clinically indicated
Hepatitis B surface antigen, Hepatitis C antibody, and 
HIV
X
Pregnancy testk
X
X
X
X
X
X
X
X
X
WHO/ECOG performance status
X
X
X
X
X
X
X
X
X
AE/SAE assessment
<--------------------------------------------------------------------------------------------------------------------
->
Drug accountability
X
X
X
X
X
X
X
X
IP administration
Monotherapy arm
MEDI4736l
X
X
X
X
X
X
X
X
Combination therapy arm
MEDI4736 (combination therapy)l,m
X
X
X
X
X
X
X
X
Tremelimumabl,m
X
X
X
X
Patient-reported outcome assessmentsn,f
EORTC QLQ-C30, 
X
X
q8w (±3 days) relative to the date of Cycle 1 Day 1
EORTC QLQ-H&N35, 
X
X
q4w (±3 days) relative to the date of Cycle 1 Day 1
Other laboratory assessments and assays
Immunogenicity assessment (ADA sampling 
[including ADA neutralizing antibodies] to identify 
ADA responses in patient circulation) for MEDI4736 
and tremelimumabf
X
X
X
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Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
87(199)
Screening
C1a
C2
C3
C4
C5
C6
C7
C8 until PD
Week
-4 to -1
0
4
8
12
16
20
24
28, 32, 36, 40, 44 (+4-wk 
intervals)
Day
-28 to -1
1
29
57
85
113
141
169
197, 225, 253, 281, 309 
(+28-day intervals)
Window (days)*
NA
NA
±3
±3
±3
±3
±3
±3
±3
Tumor biopsy or obtain archival tumor tissue <3 years 
old for PD-L1 statusp
Xb
Tumor evaluation (CT or MRI) (RECIST 1.1)q,r
X
First on-treatment scan at 6 weeks (+1 week) and then q6w (±1 week) for the first 
24 weeks relative to the date of randomization and then q8w (±1 week) thereafter
Health economics outcomes
*
Window for visits is relative to day of dosing, even if dosing is delayed, unless otherwise specified.
a
Cycle 1 Day 1 procedures do not need to be repeated if the same procedures were performed for screening purposes 3 days prior to Cycle 1 Day 1.
b
Informed consent of study procedures and tumor sample acquisition may be obtained prior to the 28-day screening window, if necessary, in order to permit tumor sample 
acquisition and analysis prior to randomization.  PD-L1 testing will be done from a newly acquired tumor biopsy (preferred) or archival tissue (<3 years old).  SoC 
procedures obtained prior to informed consent for other purposes may be used for screening if the patient/legal representative consents to allow use of these procedures 
for screening purposes.
c
Body weight is recorded along with vital signs. See Section 5.2.4 of the CSP for specific guidelines for measuring vital signs.
d
Any clinically significant abnormality detected requires a confirmatory ECG.
e
HPV status testing may be performed for oropharyngeal tumors only.  Local testing is acceptable and preferred.  If HPV status is unknown or unavailable locally, a newly 
acquired or archived tumor sample must be submitted for central testing at a reference laboratory as described in the Laboratory Manual.
f
For patients in the MEDI4736 + tremelimumab combination therapy arm:  ADA samples collected at cycle 7 will be for MEDI4736 only.   For patients in the MEDI4736 
+ tremelimumab combination therapy group who go on to retreatment, the same assessments should be done as in the first treatment period with the exception of the PK 
and ADA assessments, which do not need to be collected for retreatment.  All PRO questionnaires and health resource use should be completed q8w during retreatment.
g
Pre-dose (within 60 minutes prior to start of infusion).  For patients in the MEDI4736 + tremelimumab combination therapy arm:  pre-dose samples for both MEDI4736 
and tremelimumab can be taken within 60 minutes prior to the start of the tremelimumab infusion. 
h
Within 10 minutes of the end of infusion.
i
If screening assessments are performed within 3 days prior to Day 1 (first infusion day), they do not need to be repeated at Day 1.
j
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
k
For women of childbearing potential only.  A pregnancy test must be performed within 7 days before Cycle 1 Day 1.  A urine or serum pregnancy test is acceptable.
l
Results for electrolytes, full blood count, and liver function tests must be available before commencing an infusion (within 3 days).
m
During the combination portion of treatment, tremelimumab will be administered first; the MEDI4736 infusion will start approximately 1 hour (maximum 2 hours) after 
the end of the tremelimumab infusion.  If there are no clinically significant infusion reactions with the first cycle, then for all other cycles, MEDI4736 can be given 
immediately after the tremelimumab infusion has finished.
n
Patients will complete PROs using handheld devices at home.
o
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Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
88(199)
p
MEDI4736 + tremelimumab combination therapy only: The collection of tumor biopsies at the time of progression prior to retreatment is mandated; the Investigator must 
consult with the Study Physician if such sampling is not feasible.
q
RECIST 1.1 assessments will be performed using images from CT/MRI scans, preferably with IV contrast, of the neck (from base of skull) through the chest and 
abdomen (includes liver and adrenals).  Additional anatomy should be imaged based on signs and symptoms of individual patients at baseline and follow-up.  Baseline 
assessments should be performed no more than 28 days before the date of randomization and, ideally, should be performed as close as possible to the start of study 
treatment.  The scans for confirmation of progression should be performed preferably at the next scheduled visit and no less than 4 weeks after the initial assessment of 
PD (in the absence of clinically significant deterioration).  If an unscheduled assessment was performed and the patient has not progressed, every attempt should be made 
to perform the subsequent assessments at their next scheduled visit.  However, assessments do not need to be repeated if performed within 2 weeks of a scheduled scan.  
Patients with clinical evidence of progression who do not meet PD criteria by RECIST 1.1 should have radiographic documentation of PD.
r
Patients with confirmed PD in the MEDI4736 + tremelimumab combination therapy or MEDI4736 monotherapy arms who continue to receive clinical benefit may 
continue therapy at the discretion of the Investigator (following consultation with AstraZeneca) until a criterion in Section 3.9 is met.  Patients will have scans done at 6 
weeks post randomization and then every 6 weeks up to and including 24 weeks and then every 8 weeks thereafter.  For retreatment patients in the MEDI4736 + 
tremelimumab combination therapy arm, scans will be performed q8w post-initiation of therapy until PD.
s
 
t         
 
Note: All assessments on treatment days are to be performed prior to infusion, unless otherwise indicated.
ADA Anti-drug antibody; AE Adverse event; C Cycle; CSP Clinical study protocol; CT Computed tomography; 
 
ctDNA Circulating tumor DNA; ECG Electrocardiogram; ECOG Eastern Cooperative Oncology Group; EORTC European Organisation for Research and Treatment of 
Cancer; 
 HIV Human immunodeficiency virus; 
 HPV Human 
papilloma virus; IP Investigational product; IV Intravenous; MDSC Myleoid-derived suppressor cell; miRNA micro RNA; MRI Magnetic resonance imaging; 
mRNA Messenger RNA; NA Not applicable; PBMC Peripheral blood mononuclear cell; PCR Polymerase chain reaction; PD Progressive disease; PD-L1 Programmed cell 
death ligand 1; 
 PK Pharmacokinetics; 
 q4w Every 4 weeks; q6w Every 6 weeks; q8w Every 8 
weeks; QLQ-C30 30-Item core quality of life questionnaire; QLQ-H&N35 35-Item head and neck quality of life questionnaire; RECIST 1.1 Response Evaluation Criteria in 
Solid Tumors version 1.1; SAE Serious adverse event; SoC Standard of Care; TSH Thyroid-stimulating hormone; T3 Triiodothyronine; T4 Thyroxine; WHO World Health 
Organization.
CCI
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Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
89(199)
Table 3
Schedule of assessments for the Standard of Care treatment period
Screening
C1a
C2
C3
C4
C5
C6
Cycles 7 until PDb
Week
-4 to -1
0
3
6
9
12
15
q4w
Day
-28 to -1
1
22
43
64
85
106
Window (days)*
NA
NA
±3
±3
±3
±3
±3
±3
Informed consent
Xc
Study procedures
Physical exam (full)
X
Medical history, past and current
X
Targeted physical exam (based on 
symptoms)
X
X
X
X
X
X
q4w
Vital signsd
X
X
X
X
X
X
X
q4w
ECGe
X
As clinically indicated
Concomitant medications
<-------------------------------------------------------------------------------------------------------------------------------------------------------->
Demography, including baseline 
characteristics and tobacco use
X
HPV for oropharyngeal tumors 
onlyf
Xc
Eligibility criteria
X
Clinical chemistryg,h
X
X
X
X
X
X
X
q4w
Hematologyg,h
X
X
X
X
X
X
X
q4w
TSH (and reflex free T3 or free 
T4)j
X
Xi
Week 24
Urinalysis
X
Hepatitis B and C and HIV
X
Pregnancy testk
X
As clinically indicated
WHO/ECOG performance status
X
X
X
X
X
X
X
q4w
AE/SAE assessment 
<-------------------------------------------------------------------------------------------------------------------------------------------------------->


Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
90(199)
Screening
C1a
C2
C3
C4
C5
C6
Cycles 7 until PDb
Week
-4 to -1
0
3
6
9
12
15
q4w
Day
-28 to -1
1
22
43
64
85
106
Window (days)*
NA
NA
±3
±3
±3
±3
±3
±3
SoC administration
Cetuximabl,m
400 mg/m2 IV on Day 1 of Cycle 1, then 
250 mg/m2 IV weekly
Maintenance administration of 250 mg/m2 IV weekly
5FUl
1000 mg/m2/day IV on Days 1 through 4 for 
up to six 3-week cycles
Carboplatin or cisplatinl,n
Day 1 of up to six 3-week cycles
Patient-reported outcome assessmentso
EORTC QLQ-C30, 
X
X
q8w (±3 days) relative to the date of Cycle 1 Day 1
EORTC QLQ-H&N35, 
X
X
q4w (±3 days) relative to the date of Cycle 1 Day 1
Other laboratory assessments and assays
Tumor biopsy or obtain archival 
tumor tissue <3 years old for 
PD-L1 status 
Xc
Tumor evaluation (CT or MRI) 
(RECIST 1.1)q
X
First on-treatment scan at 6 weeks (+1 week) and then q6w (±1 week) for the first 24 weeks relative to the date of 
randomization and then q8w (±1 week) thereafter
*
Window for visits is relative to day of dosing, even if dosing is delayed, unless otherwise specified.
a
Cycle 1 Day 1 procedures do not need to be repeated if the same procedures were performed for screening purposes 3 days prior to Cycle 1 Day 1.
b
Patient visits will change from q3w to q4w after completion of chemotherapy.
c
Informed consent of study procedures and tumor sample acquisition may be obtained prior to the 28-day screening window, if necessary, in order to permit tumor sample 
acquisition and analysis prior to randomization.  PD-L1 testing will be done from a newly acquired tumor biopsy (preferred) or archival tissue (<3 years old).  
d
Pre-dose and as clinically indicated before every infusion or administration.
e
Any clinically significant abnormality detected requires a confirmatory ECG.
f
HPV status testing may be performed for oropharyngeal tumors only.  Local testing is acceptable and preferred.  If HPV status is unknown or unavailable locally, a newly 
acquired or archived tumor sample must be submitted for central testing at a reference laboratory as described in the Laboratory Manual.
g
To be collected q3w prior to the start of infusion and as clinically indicated.  Electrolytes should be monitored with cetuximab therapy as per institution guidelines.
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Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
91(199)
h
If screening assessments are performed within 3 days prior to Day 1 (first infusion day), they do not need to be repeated at Day 1.
i
If the patient does not complete treatment through Cycle 5, TSHshould be obtained after the patient’s last cycle.
j
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
k
For women of childbearing potential only.  A pregnancy test must be performed within 7 days before Cycle 1 Day 1.  A urine or serum pregnancy test is acceptable.
l
Patients will receive a maximum of six 3-week cycles of cetuximab, 5FU, and carboplatin or cisplatin.  Cetuximab will be administered on Cycle 1 Day 1 at 400 mg/m2
and then weekly at 250 mg/m2.  5FU will be administered on Day 1 through 4 and carboplatin or cisplatin will be administered on Day 1 of each 3-week cycle.  Patients 
with SD or better at the end of chemotherapy will then receive weekly cetuximab administration until PD, initiation of alternative cancer therapy, unacceptable toxicity, 
withdrawal of consent, or another discontinuation criterion is met.
m
Patients with SD at the end of these 6 cycles of chemotherapy should continue to receive cetuximab 250 mg/m2 weekly until PD, initiation of alternative cancer therapy, 
unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.
n
Patients will receive cisplatin 100 mg/m2 IV on Day 1 or carboplatin AUC of 5 mg/mL/min IV on Day 1 of up to six 3-week cycles.
o
Patients will complete PROs using handheld devices at home.
p
q
RECIST 1.1 assessments will be performed using images from CT/MRI scans, preferably with IV contrast, of the neck (from base of skull) through the chest and 
abdomen (includes liver and adrenals).  Additional anatomy should be imaged based on signs and symptoms of individual patients at baseline and follow-up.  Baseline 
assessments should be performed no more than 28 days before the date of randomization and, ideally, should be performed as close as possible to the start of study 
treatment.  The scans for confirmation of progression should be performed preferably at the next scheduled visit and no less than 4 weeks after the initial assessment of 
PD (in the absence of clinically significant deterioration).  If an unscheduled assessment was performed and the patient has not progressed, every attempt should be made 
to perform the subsequent assessments at their next scheduled visit.  However, assessments do not need to be repeated if performed within 2 weeks of a scheduled scan.  
Patients with clinical evidence of progression who do not meet PD criteria by RECIST 1.1 should have radiographic documentation of PD.
r
 
s        
Note: All assessments on treatment days are to be performed prior to infusion or administration, unless otherwise indicated.
5FU 5-Fluorouracil; AE Adverse event; AUC Area under the curve; C Cycle; CT Computed tomography; 
 
ctDNA Circulating tumor DNA; ECG Electrocardiogram; ECOG Eastern Cooperative Oncology Group; EORTC European Organisation for Research and Treatment of 
Cancer; 
 HIV Human immunodeficiency virus; 
 HPV Human 
papilloma virus; IV Intravenous; MDSC Myeloid-derived suppressor cells; miRNA micro RNA; MRI Magnetic resonance imaging; mRNA Messenger RNA; NA Not 
applicable; PBMC Peripheral blood mononuclear cell; PCR Polymerase chain reaction; PD Progressive disease; 
 
 q3w Every 3 weeks; q4w Every 4 weeks; q6w Every 6 weeks; q8w Every 8 weeks; QLQ-C30 30-Item core quality of life questionnaire; QLQ-
H&N35 35-Item head and neck quality of life questionnaire; RECIST 1.1 Response Evaluation Criteria in Solid Tumors version 1.1; SAE Serious adverse event; SD Stable 
disease; SoC Standard of Care; TSH Thyroid-stimulating hormone; T3 Triiodothyronine; T4 Thyroxine; WHO World Health Organization.
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Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
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Table 4
Schedule of assessments for patients who have discontinued treatment with MEDI4736 + tremelimumab 
combination therapy, MEDI4736 monotherapy, or Standard of Care therapy
Time since last dose of IP
Evaluation
Day (±3)
Months (±1 week)
12 months (±2 weeks)
30
2
3
6
9
Physical examination (full)
X
Vital signs (temperature, respiratory 
rate, BP, and pulse)
X
Weight
X
Pregnancy testa
X
As clinically indicated
AE/SAE assessment
X
X
X
Concomitant medications
X
X
X
WHO/ECOG performance status
At timepoints consistent with tumor assessments; at 30, 60, and 90 days following time since the last dose of IP; and then at initiation 
of subsequent anticancer therapyb
Subsequent anticancer therapyc and 
second progression assessmentd
<------------------------------------------------------------------------------------------------------------------------------------------------------->
Survival statusd
X
X
X
X (every 3 months)
Hematology
X
X
X
Clinical chemistry
X
X
X
TSH (and reflex free T3 or free T4)e
X
PK assessment for MEDI4736f
(MEDI4736 + tremelimumab
combination therapy and MEDI4736 
monotherapy arms only)
X
PK assessment for tremelimumabf
(MEDI4736 + tremelimumab
combination therapy arm only)
X


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Study Code D419LC00001
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Date 29 June 2020
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Time since last dose of IP
Evaluation
Day (±3)
Months (±1 week)
12 months (±2 weeks)
30
2
3
6
9
Immunogenicity assessment (ADA 
sampling [including ADA neutralizing 
antibodies] to identify ADA responses 
in patient circulation) for MEDI4736 
and tremelimumabf
(MEDI4736 + tremelimumab
combination therapy and MEDI4736 
monotherapy arms only)
X
If patients are not eligible for retreatment, all questionnaires and health resource use should be completed at Day 30, Month 2, and 
Month 3 from the date of confirmed PD and then stopped.
For patients in any group who discontinue their assigned IP for reasons other than disease progression (for example, due to 
toxicity or symptomatic deterioration), all questionnaires should be completed relative to the date of treatment on Cycle 1 Day1 
as follows: q8w until confirmed PD.
EORTC QLQ-C30g
EORTC QLQ-H&N35g
Tumor assessment (CT or MRI)
q6w (±1 week) for the first 24 weeks relative to the date of randomization and then q8w (±1 week) thereafter until confirmed disease 
progression
a
For women of childbearing potential only.  A urine or serum pregnancy test is acceptable.
b
WHO/ECOG performance status should also be collected at other site visits that the patient attends, if appropriate site staff are available to collect such 
information.  In addition, WHO/ECOG performance status should be provided when information on subsequent anticancer therapy is provided, where 
possible.
c
Details of any treatment for SCCHN (including surgery) post the last dose of study treatment must be recorded in the eCRF.
d
Patients may be contacted in the week following data cut-offs to confirm survival status.  Details of any treatment for SCCHN (including surgery) post 
the last dose of study treatment must be recorded in the eCRF.  Patients who discontinue treatment due to PD will be checked for survival status every 
3 months.  All patients will be followed for survival until the end of the study.  Patients who decline to return to the site for evaluations should be 
contacted by telephone every 3 months as an alternative.  Scans conducted on patients with confirmed PD in any treatment arm should be conducted 
according to local practice and are optional.
e
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
f
For patients with disease control (CR, PR, or SD) only.
g
Patients will complete PROs using handheld devices at home.
h
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Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
94(199)
i
 
ADA Anti-drug antibody; AE Adverse event; BP Blood pressure; CT Computed tomography; 
 
ECOG Eastern Cooperative Oncology Group; eCRF Electronic case report form; EORTC European Organisation for Research and Treatment of Cancer; 
 IP Investigational product; MRI Magnetic 
resonance imaging; PD Progressive disease; 
 q8w Every 8 weeks; QLQ-C30 30-
Item core quality of life questionnaire; QLQ-H&N35 35-Item head and neck quality of life questionnaire; SAE Serious adverse event; SCCHN Squamous 
cell carcinoma of the head and neck; TSH Thyroid-stimulating hormone; T3 Triiodothyronine; T4 Thyroxine; WHO World Health Organization.
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Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
A Web Based Data Capture (WBDC) system will be used for data collection and query 
handling.  The Investigator will ensure that data are recorded on the eCRFs as specified in 
this study protocol and in accordance with the instructions provided.
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded 
and the provision of answers to data queries according to the clinical study agreement 
(CSA).  The Investigator will sign the completed eCRFs.  A copy of the completed eCRFs 
will be archived at the study site.
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4.1
Enrollment/screening period
All screening and enrollment procedures will be performed according to the assessment 
schedule in Table 2 and Table 3.  
Written informed consent and any locally required privacy act document authorization 
must be obtained prior to performing any protocol-specific procedures, including 
screening/baseline evaluations.  All patients will be required to provide consent to supply a 
sample of their tumor (archival or recently obtained biopsy) for entry into this study.  This 
consent is included in the main patient informed consent form (ICF).
All screening/baseline procedures must be performed within 28 days before the first dose 
of treatment (Days -28 to -1).  Screening/baseline evaluations may be performed over 
more than 1 visit.  SoC procedures performed for other purposes prior to informed consent 
suitable for use as screening evaluations need not be repeated if the patient/legal 
representative consents to allow use of these procedures for screening purposes.  Informed 
consents of study procedures and tumor sample acquisition may be obtained prior to the 
28-day screening window in order to permit tumor sample acquisition; results of PD-L1
testing must be available prior to randomization.
4.2
Treatment period
All procedures to be conducted during the treatment period will be performed according to 
the assessment schedule (see Table 2 and Table 3).  
Whenever vital signs, ECGs, and blood draws are scheduled for the same nominal time, 
the assessments should occur in the following order: ECG, vital signs, and then blood 
draws.  The timing of the assessments should be such that it allows the blood draw (eg, PK 
blood sample) to occur at the exact nominal time.
4.3
Follow-up period
All procedures to be conducted will be performed according to the assessment schedule 
(see Table 4).  
Whenever vital signs, ECGs, and blood draws are scheduled for the same nominal time, 
the assessments should occur in the following order: ECG, vital signs, and then blood 
draws.  The timing of the assessments should be such that it allows the blood draw (eg, PK 
blood sample) to occur at the exact nominal time.
5. STUDY ASSESSMENTS


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Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
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5.1
Efficacy assessments
RECIST 1.1 criteria will be used to assess patient response to treatment by determining 
PFS, ORR, DoR, BoR, TTR, APF6 and APF12 using Investigator assessments (as well as 
BICR assessments for sensitivity analysis of PFS).  The RECIST 1.1 guidelines for 
measurable, non-measurable, target, and non-target lesions and the objective tumor 
response criteria (CR, PR, SD, or PD) are presented in Appendix E.  Second progression 
(PFS2) will be defined by local standard clinical practice.  OS, OS12, OS18 and OS24 will 
also be evaluated.
The methods of assessment of tumor burden used at baseline are CT and MRI scans, 
preferably with IV contrast, of the neck (including the base of skull) through chest and 
abdomen (includes liver and adrenals).  Any other areas of disease involvement should be 
additionally imaged based on the signs and symptoms of individual patients.
The baseline assessment should be performed no more than 28 days before randomization 
of MEDI4736 + tremelimumab combination therapy, MEDI4736 monotherapy, or SoC, 
and ideally as close as possible to the start of the IP.  Efficacy for all patients will be 
assessed by objective tumor assessments every 6 weeks (q6w) (±1 week) for the first 24 
weeks and then every 8 weeks (q8w) (±1 week) thereafter, relative to the date of 
randomization (see Table 2 and Table 3), until treatment discontinuation due to 
progression or toxicity.  If an unscheduled assessment is performed, and the patient has not 
progressed, every attempt should be made to perform the subsequent assessments at their 
scheduled visits.  Unscheduled scans do not need to be repeated if performed within 2 
weeks of a scheduled scan.  
For patients who discontinue therapy due to toxicity in the absence of progression, 
objective tumor assessments should be continued q6w for the first 24 weeks (relative to the 
date of randomization) then q8w until confirmed clinical disease progression.  
Disease progression for patients in the IMT treatment arms should be confirmed according 
to RECIST 1.1; timepoint assessments showing PD should be confirmed preferably at the 
next scheduled imaging visit and no earlier than 4 weeks after the preceding assessment of 
PD in the absence of clinically significant deterioration.  Disease progression in patients in 
the SoC arm should be confirmed by a scan obtained no earlier than 4 weeks after the 
initial assessment of PD and preferably at the next scheduled imaging visit, if clinically 
feasible.  Treatment in all arms will continue between the assessment of progression and 
its confirmation.  Patients with rapid tumor progression or with symptomatic progression 
that requires urgent medical intervention (eg, central nervous system metastasis, 
respiratory failure due to tumor compression, or spinal cord compression) will not be 
eligible to continue to receive study drug.
Radiographic progression would be considered confirmed if the following criteria are met:

≥20% increase in the sum diameters of target lesions compared with the nadir at
2 consecutive scan timepoints with an absolute increase of 5 mm, and/or

Significant progression (worsening) of non-target lesions at the confirmatory scan
timepoint compared with the first timepoint where progression of non-target lesions


Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
In the absence of clinically significant deterioration, the Investigator should continue study 
treatment until progression is confirmed.
If radiographic progression is not confirmed, then the patient should continue on study 
treatment and on treatment assessments.
If a patient discontinues treatment (and/or receives a subsequent cancer therapy) prior to 
progression, then the patient should still continue to be followed until confirmed objective 
disease progression.
Patients with clinical evidence of progression who do not meet PD criteria by RECIST 1.1 
should continue to be followed until there is radiographic documentation of PD.
Patients in all arms with a symptomatic solitary lesion, a brain lesion, or a lesion of clinical 
importance (eg, impending fracture, etc) may be treated with radiation after approval from 
the Sponsor.  Non-irradiated lesions need to continue to be measurable by RECIST 1.1.  
The time interval between the last systemic treatment and radiation should be 10 days, and 
systemic treatment can be resumed 1 week post radiation.
Categorization of objective tumor response assessment at each post-screening imaging 
timepoint will be based on the RECIST 1.1 criteria of response: CR, PR, SD, and PD.  
Target lesion progression will be calculated in comparison to when the tumor burden was 
at a minimum (ie, nadir; smallest sum of diameters previously recorded on study).  In the 
absence of progression, tumor response (CR or PR) and SD will be calculated in 
comparison to the baseline tumor measurements obtained before starting treatment.
If the Investigator is in doubt as to whether progression has occurred, particularly with 
response to non-target lesion or the appearance of a new lesion, it is advisable to continue 
treatment until the next scheduled assessment or sooner if clinically indicated and reassess 
the patient’s status.  If repeat scans confirm progression, then the date of the initial scan 
should be declared as the date of progression.
To achieve “unequivocal progression” on the basis of non-target disease, there must be an 
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.  A modest “increase” in the size of 1 or more non-target lesions 
is usually not sufficient to qualify for unequivocal progression status.
Following confirmed progression, patients should continue to be followed up for survival 
every 3 months as outlined in the study plan (see Table 4).  Patients with confirmed PD 
who discontinue MEDI4736 + tremelimumab combination therapy, MEDI4736 
monotherapy, or SoC should have scans conducted according to local practice; the scans 
may also be submitted for centralized collection and quality check (QC) and be held until 
the patient commences a new treatment (these scans are optional; see Table 4).
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was identified (Note: new lesions identified at the previous scan timepoint are 
considered non-target lesions at the confirmatory scan timepoint), and/or

Additional new unequivocal lesions at the confirmatory scan timepoint.


Blood and urine samples for determination of clinical chemistry, hematology, and 
urinalysis will be taken at the times indicated in the assessment schedules (see Table 2, 
Table 3, and Table 4).
Clinical laboratory safety tests will be performed in a licensed clinical laboratory 
according to local standard procedures.  Hematology, clinical chemistry, and urinalysis 
tests will be performed by the hospital’s local laboratory.  Urine pregnancy tests may be 
performed at the site using a licensed test.  Sample tubes and sample sizes may vary 
depending on the laboratory method used and routine practice at the site.  Clinically 
significant abnormal laboratory results should be repeated as soon as possible (preferably 
within 24 to 48 hours).
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.  The date, time of collection, and results (values, units, and reference ranges) 
will be recorded on the appropriate eCRF.
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Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
It is important to follow the assessment schedule as closely as possible.  Please refer to the 
study plans (Table 2, Table 3, and Table 4).
5.1.1
Central reading of scans
A BICR of radiological scans will be performed for a sensitivity analysis for the PFS 
endpoint.  
This sensitivity analysis will use all images, including unscheduled visit scans, collected 
prior to version 8 of the clinical study protocol (dated 13 Feb 2018), after which no further 
central collection of the scans will be done.  All images, including unscheduled visit scans, 
will be collected on an ongoing basis and quality checked and assessed centrally. 
Guidelines for image acquisition, anonymization, submission to the imaging CRO, and 
local storage will be provided in a separate document.  The results of Investigator 
assessments will not be communicated to the independent central reviewers, nor will the 
results of independent reviews be communicated to Investigators, and the management of 
patients will be based solely upon the results of the RECIST 1.1 assessment conducted by 
the Investigator.
5.1.2
Survival assessments
Assessments for survival must be made every 3 months following treatment 
discontinuation and/or upon disease progression.  Survival information may be obtained 
via telephone contact with the patient, patient’s family, or by contact with the patient’s 
current physician.  The details of first and subsequent therapies for cancer, after 
discontinuation of treatment, will be collected.  
In addition, patients on treatment or in survival follow-up will be contacted following the 
data cut-off for the primary analysis and all subsequent survival analyses to provide 
complete survival data.  These contacts should generally occur within 7 days of the data 
cut-off.
5.2
Safety assessments
5.2.1
Laboratory safety assessments


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Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
The laboratory variables to be measured are presented in Table 5 (clinical chemistry), 
Table 6 (hematology), and Table 7 (urinalysis).  
Note: For coagulation parameters, activated partial thromboplastin time and international 
normalized ratio are to be assessed at baseline and as clinically indicated.
Pregnancy tests on either urine (human chorionic gonadotropin [hCG]) or blood (serum 
β-hCG) samples will be performed for pre-menopausal women of childbearing potential at 
Screening and subsequent visits as specified in the assessment schedule (see Table 2, 
Table 3, and Table 4).  Tests will be performed by the hospital’s local laboratory unless 
otherwise specified.  If results are positive, the patient must not start or continue treatment.  
In the event of a suspected pregnancy during the study, the test should be repeated.
Other safety tests to be performed at screening include assessment for hepatitis B surface 
antigen, hepatitis C antibodies, HIV antibodies, and thyroid-stimulating hormone (TSH).  
Free triiodothyronine or free thyroxine will also be measured if the results of the TSH are 
abnormal or if there is clinical suspicion of an AE related to the endocrine system.


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Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
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Table 5
Clinical chemistry (serum or plasma)
Albumin
Glucose
Alkaline phosphatasea
Lactate dehydrogenase
ALTa
Lipase
Amylase
Magnesiumb,c
ASTa
Potassium
Bicarbonateb
Sodium
Calcium 
Total bilirubina
Chlorideb
Total protein
Creatinine clearanceb
Urea or blood urea nitrogen, depending on local practice
Creatinine
Gamma glutamyltransferaseb
a
Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed 
concurrently.  If total bilirubin is ≥2 × upper limit of normal (and evidence of Gilbert’s syndrome) then 
fractionate into direct and indirect bilirubin.
b
Bicarbonate (where available), chloride, creatinine clearance, gamma glutamyltransferase, and 
magnesium testing are to be performed at screening, on Day 1 (unless screening laboratory assessments 
are performed within 3 days prior to Day 1), and if clinically indicated.
c
For patients receiving cetuximab, magnesium monitoring and subsequent supplementation may occur 
more frequently as clinically indicated per site specific standards.
ALT Alanine aminotransferase; AST Aspartate aminotransferase
Table 6
Hematology
Eosinophils
Neutrophils
Hematocrit
Partial thromboplastin time
Hemoglobin
Platelet count
International normalized ratio
Red blood cell count
Lymphocytes
Total white cell count
Monocytes
Note: For coagulation parameters, activated partial thromboplastin time and international normalized ratio 
are to be assessed at baseline and as clinically indicated.


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Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
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Table 7
Urinalysisa
Bilirubin
Ketones
Blood
pH
Color and appearance
Protein
Glucose
Specific gravity
a
Urinalysis must be done at baseline and then as clinically indicated.
Note: Microscopy should be used as appropriate to investigate white blood cells and use the high power 
field for red blood cells.
If a patient shows an AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN, refer 
to Appendix D for further instructions.  These cases should be reported as SAEs if, after 
evaluation, they meet the criteria for a Hy’s Law case or if any of the individual liver test 
parameters fulfill any of the SAE criteria.  All patients with an elevated AST, ALT, or 
bilirubin value (the latter at ≥1.5 × ULN) at the time of the last dose of study treatment 
should have a further liver chemistry profile (AST, ALT, bilirubin, and alkaline 
phosphatase) performed 30 days (±3 days) after permanent discontinuation of study 
treatment.
Any clinically significant abnormal laboratory values should be repeated as clinically 
indicated and recorded on the eCRF.  Situations in which laboratory safety results should 
be reported as AEs are described in Section 6.3.4.
All patients with Grade 3 or 4 laboratory values at the time of completion or 
discontinuation from study treatment must have further tests performed until the laboratory 
values have returned to Grade 1 or 2, unless these values are not likely to improve because 
of the underlying disease.
5.2.2
Physical examination
Physical examinations will be performed according to the assessment schedules (see 
Table 2, Table 3, and Table 4) and will include clinically targeted assessments.  Height 
will be measured at screening only.  Situations in which physical examination results 
should be reported as AEs are described in Section 6.3.4.
5.2.3
Electrocardiograms
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout 
the study (see Table 2 and Table 3).  ECGs should be obtained after the patient has been in 
a supine position for 5 minutes and recorded while the patient remains in that position.  All 
ECGs must be obtained in triplicate.
At screening, a mean QT interval corrected for Fridericia’s formula (QTcF) will be 
calculated using 3 ECGs performed approximately 5 minutes apart.  The mean QTcF must 
be <470 ms for the patient to meet eligibility criteria.
In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 
2 additional 12-lead ECGs should be obtained over a brief period (eg, 30 minutes) on the 
same day or different day to confirm the finding.  


If the infusion takes longer than 60 minutes, then BP and pulse measurements should 
follow the principles as described above or be taken more frequently if clinically indicated.  
A 1-hour observation period is recommended after the first infusion of MEDI4736 + 
tremelimumab.  If no clinically significant infusion reactions are observed during or after 
the first cycle, subsequent infusion observation periods can be at the Investigator’s 
discretion (suggested 30 minutes after each MEDI4736 and tremelimumab infusion).
Subsequent infusions of MEDI4736 or tremelimumab:
For subsequent infusions, BP, pulse, and other vital signs should be measured prior to the 
start of the infusion.  Patients should be carefully monitored, and BP and other vital signs 
should be measured during and after infusion as per institution standard and as clinically 
indicated.  Any clinically significant changes in vital signs should be entered into the 
unscheduled vital signs case report form (CRF).
Infusions of SoC
Patients in the SoC group will be monitored pre-dose and as clinically indicated per the 
institutional standard before and after every administration.  
Situations in which vital signs results should be reported as AEs are described in 
Section 6.3.4.  For any AEs of infusion reactions, please enter the vital signs values into 
the CRF.
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Revised Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
Situations in which ECG results should be reported as AEs are described in Section 6.3.4.
5.2.4
Vital signs
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the assessment schedules (see Table 2, Table 3, and Table 4).  Body weight is 
also recorded along with vital signs.
First infusion of MEDI4736 or tremelimumab:
On the first infusion day, patients in the MEDI4736 + tremelimumab combination therapy 
group and the MEDI4736 monotherapy group will be monitored prior to, during, and after 
infusion of IP as presented in the bulleted list below.
Supine BP will be measured after the patient has rested for at least 5 minutes.  BP and 
pulse will be collected from patients in the MEDI4736 + tremelimumab combination 
therapy group and the MEDI4736 monotherapy group before, during, and after each 
infusion of IP at the following times (based on a 60-minute infusion):

Prior to the beginning of the infusion (measured once from approximately 30 minutes
before up to 0 minutes [ie, the beginning of the infusion])

Approximately 30 minutes during the infusion (halfway through infusion)

At the end of the infusion (approximately 60 ±5 minutes)


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PRO is an umbrella term referring to all outcomes and symptoms that are directly reported 
by the patient.  PROs have become a significant endpoint when evaluating effectiveness of 
treatments in clinical trials.  The following PROs will be administered in this study: 
EORTC QLQ-C30 (core questionnaire), QLQ-H&N35 (head and neck-specific 
questionnaire), 
 
 see Appendix F).
The PRO instruments will be completed by the patients at home using a handheld ePRO 
device.  All questionnaires should be completed according to the assessment schedules 
(see Table 2, Table 3 and Table 4).  If a patient does complete the questionnaires at a given 
visit, for example, at screening and at Cycle 1 Day 1, it is preferred that questionnaires be 
completed before any other study procedures (laboratory tests or imaging) are conducted.  
However, if questionnaires cannot be administered prior to study procedures for a given 
visit, all questionnaires must be completed prior to the patient receiving any results of 
laboratory tests or imaging or meeting with their study nurse or physician.  
It takes approximately 30 to 45 minutes for patients to complete all questionnaires; 
therefore, the burden to the patient is moderate.  For patients receiving retreatment after 
confirmed PD (MEDI4736 + tremelimumab combination therapy only), questionnaires
should be completed according to the assessment schedule in Table 2.
5.3.1.1 EORTC QLQ-C30
The EORTC QLQ-C30 is a 30-item self-administered questionnaire (see Appendix F).  
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/QoL 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 the 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 QoL have 7-point scales with ratings ranging from “Very poor” to “Excellent.”  For 
each of the 15 domains (9 multiple-item scales and 6 single item scales), final scores are 
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5.2.5
Other safety assessments
Pregnancy tests on either urine (hCG) or blood (serum β-hCG) samples will be performed 
for pre-menopausal women of childbearing potential at the times specified in the 
assessment schedule (see Table 2).  Tests will be performed by the hospital’s local 
laboratory.  If results are positive, the patient is ineligible and must be discontinued from 
the study.  In the event of a suspected pregnancy during the study, the test should be 
repeated.
Other safety tests to be performed at screening include assessment for hepatitis B surface 
antigen, hepatitis C antibodies, and HIV antibodies.
5.3
Other assessments
5.3.1
Patient-reported outcomes
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Version 12.0
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transformed such that they range from 0 to 100, where higher scores indicate greater 
functioning, greater QoL, or greater level of symptoms (Aaronson et al 1993).
5.3.1.2 EORTC QLQ-H&N35
The EORTC QLQ-H&N35 module is a 35-item self-administered questionnaire (see 
Appendix F).  There are 7 multiple item scales that assess pain in the mouth, problems 
with swallowing, senses, speech, social eating, social contact, and sexuality.  There are 11 
single-item measures assessing additional symptoms commonly reported by head and neck 
cancer patients, including problems with teeth, problems with mouth opening, dry mouth, 
sticky saliva, coughing, feeling ill, use of analgesics, use of nutritional supplements, use of 
a feeding tube, weight gain, and weight loss.  All but 5 questions have 4-point scales: “Not 
at all,” “A little,” “Quite a bit,” and “Very much.”  The 5 questions concerning use of 
analgesics, use of nutritional supplements, use of a feeding tube, weight gain, and weight 
loss have 2-point scales (“Yes” or “No”).  For each of the 18 domains (7 multiple-item 
scales and 11 single-item scales), final scores are transformed such that they range from 0 
to 100, where higher scores indicate greater level of symptoms (Singer et al 2013).
5.3.1.3
 
 
 
 
 
 
 
 
 
 
 
 
 
5.3.1.4
 
 
5.3.1.5
 
 
 
 
 
 
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5.3.2
Administration of the patient-reported outcome questionnaires
Patients will complete the PRO assessments by using a handheld ePRO device.
Each center must allocate the responsibility for the administration of the PRO devices to a 
specific individual (eg, a research nurse or study coordinator) and, if possible, assign a 
back-up person to cover if that individual is absent.  The PRO questionnaires must be 
completed per the schedule of assessments (see Table 2, Table 3, and Table 4).  Patients 
will be instructed to bring their handheld devices to every clinic visit.  In instances where 
the PRO assessments coincide with a clinic visit, the research nurse or study coordinator 
should verify that the questionnaire was completed before the visit.  If not, the patient 
should complete the questionnaire prior to any other study procedures and before 
discussion of disease progression to avoid biasing the patient’s responses to the questions.  
The following best practice guidelines should be followed when collecting PRO data via 
an electronic device:

The research nurse or appointed site staff must explain the value and relevance of
participation to patients and inform them that these questions are being asked in
order to find out from them directly how they feel.  This can help motivate patients to
comply with data collection.  The research nurse or appointed site staff should also
stress that the information is confidential.  Therefore, if the patient has any medical
problems, he/she should discuss them with the doctor or research nurse separately
from the ePRO assessment.

The research nurse or appointed site staff must train the patient on how to use the
ePRO device using the materials and training provided by the ePRO vendor, and also
provide guidance on whom to call if there are problems with the device.

The research nurse or appointed site staff must remind patients that there are no right
or wrong answers and avoid introducing bias by not clarifying items.  The patient
should not receive help from relatives, friends, or clinic staff to answer the PRO
questionnaires.
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The presence of ADA will be assessed in serum samples taken according to the assessment 
schedules (see Table 2 and Table 4).  
Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for 
both IPs (MEDI4736 and tremelimumab) using validated assays.  Tiered analysis will be 
performed to include screening, confirmatory, and titer assay components, and 
positive-negative cut points previously statistically determined from drug-naïve validation 
samples will be employed.  
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
The research nurse or appointed site staff must monitor compliance; minimizing
missing data is a key aspect of study success.  Compliance must be checked at each
study visit and should be checked more frequently to identify problems early.  If
compliance drops below 85%, a check-in call from the site to ask the patient if he/she
has any difficulties is highly recommended.
5.3.3
WHO/ECOG performance status
WHO/ECOG performance status will be assessed at the times specified in the assessment 
schedules (see Table 2, Table 3, and Table 4) based on the following:
0 = Fully active; able to carry out all usual activities without restrictions
1 = Restricted in strenuous activity but ambulatory and able to carry out light work 
or work of a sedentary nature, eg, light housework, office work
2 = Ambulatory and capable of self-care but unable to carry out any work activities.  
Up and about more than 50% of waking hours
3 = Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours
4 = Completely disabled; unable to carry out any self-care and totally confined to bed 
or chair
Any significant changes from baseline or screening must be reported as an AE.
5.4
Pharmacokinetics
5.4.1
Collection of samples and determination of drug concentration
Blood samples for determination of MEDI4736 and tremelimumab concentration in serum 
will be obtained according to the assessment schedules (see Table 2 and Table 4).  
Samples for determination of MEDI4736 and tremelimumab concentration in serum will 
be analyzed by a designated third party on behalf of AstraZeneca.  Samples will be 
collected, labeled, stored, and shipped as detailed in the Laboratory Manual.  Full details 
of the analytical method used will be described in a separate Bioanalytical Validation 
Report.
5.4.2
Collection of samples to measure for the presence of anti-drug 
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5.4.3
Storage and destruction of pharmacokinetic/anti-drug antibody 
samples
PK and ADA samples will be disposed of a maximum of 10 years after the IPs are 
approved for marketing.
PK and ADA samples may be disposed of or destroyed and anonymized by pooling.  
Additional analyses may be conducted on the anonymized, pooled PK samples to further 
evaluate and validate the analytical method.  Results from such analyses may be reported 
separately from the clinical study report (CSR).
Incurred sample reproducibility analysis, if any, will be performed alongside the 
bioanalysis of the test samples.  The results from the evaluation will not be reported in the 
CSR but separately in a Bioanalytical Validation Report.
 
 
5.5
Biomarker analysis
The patient’s consent to the use of donated biological samples is mandatory.  Tissue 
samples will be obtained from all screened patients.
Pretreatment tumor PD-L1 expression will be evaluated in all randomized patients.  Data 
will be compared between arms to determine if baseline PD-L1 status is prognostic and/or 
predictive of outcomes associated with MEDI4736 + tremelimumab combination therapy 
or MEDI4736 monotherapy versus SoC.  Baseline tumor requirements are briefly 
described in Section 5.5.1.
 
 
Details for collection, volumes, storage, and shipment of biologic samples are presented in 
a separate Laboratory Manual.
All samples collected for biomarker analyses will be stored at the study site, a reference 
laboratory, or at AstraZeneca facilities and may be used for subsequent research relevant 
to evaluating biological and/or clinical response to immunotherapy.
The results may be pooled with biomarker data from other MEDI4736 + tremelimumab 
combination therapy studies to evaluate biological responses across indications and to 
compare results in monotherapy versus combination settings.
5.5.1
Collection of patient samples for stratification by PD-L1
At screening, there is a mandatory provision of formalin-fixed and paraffin-embedded 
tissue to be used for determination of eligibility.  For the MEDI4736 + tremelimumab 
combination therapy arm only, there is a subsequent mandatory provision of tissue if 
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Study Code D419LC00001
Version 12.0
Date 29 June 2020
retreatment is planned unless, after discussion with Study Physician, biopsy is not 
clinically feasible:

MANDATORY: Provision of a newly acquired tumor sample (preferred) OR
archival tissue obtained within 3 years.  ONLY 1 sample (either newly acquired or
archival tissue) will be used to assess PD-L1 status for purposes of eligibility.  Where
multiple samples have been submitted for the same patient, results from the most
recent evaluable sample will inform patient status for eligibility.
Samples should be collected via a core needle of 18 gauge or larger or be collected as
an excisional tumor biopsy sample.  Where institutional practice, in this setting, uses
a smaller gauge needle, samples should be submitted in sufficient number to ensure
that availability of result can be achieved.
When tissue is newly obtained using an 18-gauge needle for the purpose of entry into
this study, 2 cores should be placed in formalin and processed to a single paraffin-
embedded block, as described in the Laboratory Manual.  When a smaller gauge
needle is used, the number of cores rises to 3 or 4.
The tumor specimen submitted to establish eligibility should be of sufficient quantity 
to allow for PD-L1 IHC analyses (see the Laboratory Manual).  Samples with limited
tumor content and fine needle aspirates are inadequate for defining tumor PD-L1
status.
Tumor lesions used for newly acquired biopsies should not be the same lesions used
as RECIST 1.1 target lesions, unless there are no other lesions suitable for biopsy.
In this instance, only core needle (not excisional/incisional) biopsy is recommended.
For patients with a single target lesion being used for a screening biopsy for PD-L1
testing, allow approximately 2 weeks before acquiring imaging scans for baseline
tumor assessment.


OPTIONAL: The collection of additional archived tumor tissue block (formalin-
fixed paraffin-embedded) is highly encouraged, where such samples exist in a
quantity sufficient to allow for analysis.  This specimen may be supplied at any time
during the study.  Tumor tissue block is preferred.  If a tissue block is unavailable,
unstained sections from the tissue block may be submitted.  Please consult the
Laboratory Manual for specific instructions and guidelines regarding sections.

OPTIONAL: The collection of additional biopsies (other than the mandatory tissue
biopsy required prior to retreatment for patients in the MEDI4736 + tremelimumab
combination therapy arm) is strongly encouraged.
Additional tumor biopsies collected as part of clinical care (eg, for mixed responses
or upon PD) can be submitted for further analysis.
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Study Code D419LC00001
Version 12.0
Date 29 June 2020
See the Laboratory Manual for further details of requirements including sample QC and 
shipping.
 
 
The analytically validated VENTANA PD-L1 SP263 IHC assay will be used to determine 
PD-L1 IHC status in this study for the purposes of stratification and for the analysis of the 
original diagnostic sample.  
To meet the requirement of FDA approval of a companion diagnostic, sections of the 
tumor will be retained at VENTANA for potential additional studies, as requested by the 
FDA, to support potential test approval.  
5.5.2
Collection of exploratory biomarker data
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5.5.2.2
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
5.5.3
Management of biomarker data
 
 
 
 
5.5.4
Storage, re-use, and destruction of biological samples
Samples will be stored for a maximum of 15 years from the end of study, after which they 
will be destroyed.  The results of this biomarker research may be reported in the CSR 
itself, as an addendum, or separately in a scientific report or publication.  The results of 
this biomarker research may be pooled with biomarker data from other studies involving 
MEDI4736 to generate hypotheses to be tested in future research.
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5.5.5
Labeling and shipment of biological samples
The Principal Investigator will ensure that samples are labeled and shipped in accordance 
with the Laboratory Manual and the Biological Substance, Category B, Regulations 
(materials containing or suspected to contain infectious substances that do not meet 
Category A criteria); see Appendix C “International Air Transportation Association 6.2 
Guidance Document.”
Any samples identified as Infectious Category A materials will not be shipped, and no 
further samples will be taken from the involved patients unless agreed upon with 
AstraZeneca and appropriate labeling, shipment, and containment provisions are approved.
5.5.6
Chain of custody of biological samples 
A full chain of custody will be maintained for all samples throughout their life cycle.
The Principal Investigator at each center will keep full traceability of collected biological 
samples from the patients while in storage at the center until shipment or disposal (where 
appropriate) and will keep documentation of receipt of arrival.
The sample receiver will keep full traceability of the samples while in storage and during 
use until used or disposed of or until further shipment and will keep documentation of 
receipt of arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, and auditing of external laboratory providers.
Samples retained for further use will be registered in the AstraZeneca Biobank system 
during the entire life cycle.
5.5.7
Withdrawal of informed consent for donated biological samples 
If a patient withdraws consent to the use of donated biological samples, the samples will 
be disposed of or destroyed and the action documented.  If samples have already been 
analyzed, AstraZeneca is not obliged to destroy the results of this research.
The Principal Investigator will:

Ensure that AstraZeneca is immediately notified of the patients’ withdrawal of
informed consent to the use of donated samples

Ensure that biological samples from that patient, if stored at the study site, are
immediately identified, disposed of or destroyed and the action documented

Ensure that the laboratory(ies) holding the samples is/are immediately informed
about the withdrawn consent and that samples are disposed of or destroyed, the
action is documented, and the signed document is returned to the study site

Ensure that the patient and AstraZeneca are informed about the sample disposal
5.6
Pharmacogenetics (not applicable)
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During the course of the study, all AEs and SAEs should be proactively followed up for 
each patient.  Every effort should be made to obtain a resolution for all events, even if the 
events continue after discontinuation or study completion.
Any AEs that are unresolved at the patient’s last visit in the study are followed up by 
the Investigator for as long as medically indicated, but without further recording in the 
eCRF.  AstraZeneca retains the right to request additional information for any patient 
with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
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5.7
Pharmacodynamics (not applicable)
Not applicable.
6. SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
6.1
Definitions of serious adverse events
An SAE is an AE occurring during any study phase (ie, screening, treatment, washout, or 
follow-up) that fulfills one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability or incapacity or substantial disruption of
the ability to conduct normal life functions

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardize the patient or may require medical
intervention to prevent one of the outcomes listed above
For further guidance on the definition of an SAE, see Appendix B.
6.2
Recording of adverse events
6.2.1
Time period for collection of adverse events 
AEs and SAEs will be collected from the time of signature of informed consent throughout 
the treatment period and including the follow-up period (up to 90 days after the last dose 
of IP or until initiation of another therapy).  AEs and SAEs collected prior to 
randomization will be reported as pre-randomization AEs and SAEs.  
6.2.2
Follow-up of unresolved adverse events


The grading scales found in the revised NCI CTCAE version 4.03 will be utilized for all 
events with an assigned CTCAE grading.  For those events without assigned CTCAE 
grades, the recommendation in the CTCAE criteria that converts mild, moderate, and 
severe events into CTCAE grades should be used.  A copy of the CTCAE version 4.03 can 
be downloaded from the Cancer Therapy Evaluation Program website
(http://ctep.cancer.gov).
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity, whereas seriousness is defined by the criteria in Section 6.1.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but it is not an SAE unless it meets the 
criteria shown in Section 6.1.  On the other hand, a stroke that results in only a limited 
degree of disability may be considered a mild stroke, but it would be an SAE if it satisfies 
the criteria shown in Section 6.1.
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6.2.3
Variables 
The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

The maximum CTCAE grade reported

Changes in CTCAE grade

Whether the AE is serious or not

Investigator causality rating against the IP (yes or no)

Action taken with regard to IP

Administration of treatment for the AE

Whether the AE caused the patient’s withdrawal from the study (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:

Date the AE met criteria for SAE

Date the Investigator became aware of the SAE

Seriousness criteria fulfilled

Date of hospitalization

Date of discharge

Probable cause of death

Date of death

Whether an autopsy was performed

Causality assessment in relation to study procedure(s)

Description of the AE


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Version 12.0
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All AEs spontaneously reported by the patient or reported in response to the open question 
from the study personnel: “Have you had any health problems since the previous visit/you 
were last asked?” or revealed by observation will be collected and recorded in the eCRF.  
When collecting AEs, the recording of diagnoses is preferred, when possible, to recording 
a list of signs and symptoms.  However, if a diagnosis is known and there are other signs 
or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately.
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6.3
Definition of adverse events
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition during or following exposure to a pharmaceutical product, 
whether or not the condition is considered to be causally related to the product.  An 
undesirable medical condition can be a symptom (eg, nausea or chest pain), sign 
(eg, tachycardia or enlarged liver), or the abnormal result of an investigation (eg, 
laboratory findings or ECG).  In clinical studies, an AE can include an undesirable medical 
condition occurring at any time, including run-in or washout periods, even if no study 
treatment has been administered.
The term ‘AE’ is used to include both serious and non-serious AEs.
6.3.1
Causality collection
The Investigator will assess the causal relationship between the IP and each AE and
answer “yes” or “no” to the question “Do you consider that there is a reasonable possibility 
that the event may have been caused by the investigational product?”
For SAEs, causal relationship will also be assessed for other medications and study 
procedures.  Note that, for SAEs that could be associated with any study procedure, the 
causal relationship is implied as “yes.”
A guide to the interpretation of the causality question is found in Appendix B.
6.3.2
Relationship to protocol procedures
The Investigator is also required to provide an assessment of the relationship of SAEs to 
protocol procedures on the SAE report form.  This includes both non-treatment–emergent 
(ie, SAEs that occur prior to the administration of IP) and treatment-emergent SAEs.  A 
protocol-related SAE may occur as a result of a procedure or intervention required during 
the study (eg, blood collection).  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 or intervention that was
described in the protocol for which there is no alternative etiology present in the
patient’s medical record.

Not protocol related: The event is related to an etiology other than the procedure or
intervention that was described in the protocol.  The alternative etiology must be
documented in the study patient’s medical record.
6.3.3
Adverse events based on signs and symptoms


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6.3.4
Adverse events based on examinations and tests
The results from protocol-mandated laboratory tests and vital signs measurements will be 
summarized in the CSR.  Deterioration as compared to baseline in protocol-mandated 
laboratory values and vital signs should therefore only be reported as AEs if they fulfill 
any of the SAE criteria or are the reason for discontinuation of treatment with the IP.
If deterioration in a laboratory value or vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory 
result or vital sign will be considered as additional information.  Whenever possible, the 
reporting Investigator should use the clinical rather than the laboratory term (eg, anemia 
versus low hemoglobin value).  In the absence of clinical signs or symptoms, clinically 
relevant deteriorations in non-mandated parameters should be reported as AEs.
Deterioration of a laboratory value that is unequivocally due to disease progression should 
not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical 
examination as compared with the baseline assessment will be reported as an AE.
6.3.5
Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 
× ULN may need to be reported as SAEs.  Please refer to Appendix D for further 
instruction on cases of increases in liver biochemistry and evaluation of Hy’s law.
6.3.6
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable 
to the disease for which the IP is being studied.  It may be an increase in the severity of the 
disease under study and/or increases in the symptoms of the disease. The development of 
new or progression of existing metastasis to the primary cancer under study should be 
considered as disease progression and not an AE.  Events, which are unequivocally due to 
disease progression should not be reported as an AE during the study.
6.3.7
New cancers
The development of a new cancer should be regarded as an SAE.  New primary cancers 
are those that are not the primary reason for the administration of the study treatment and 
have been identified after the patient’s inclusion in this study.
6.3.8
Deaths
All deaths that occur during the study, or within the protocol-defined follow-up period 
after the administration of the last dose of study treatment, must be reported as follows:

Death clearly resulting from disease progression should be reported to the Study
Physician at the next monitoring visit and should be documented in the eCRF.  It
should not be reported as an SAE.

Where death is not due (or not clearly due) to progression of the disease under study,
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Study Code D419LC00001
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All SAEs have to be reported, whether or not considered causally related to the IP or to 
any study procedure.  All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then the Investigator or other site personnel 
should inform the appropriate AstraZeneca representatives within 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that 
all the necessary information is provided to the AstraZeneca Patient Safety data entry site 
within 1 calendar day of initial receipt for fatal and life-threatening events and within 5 
calendar days of initial receipt for all other SAEs.
For fatal or life-threatening AEs in which important or relevant information is missing, 
active follow-up is undertaken immediately.  The Investigator or other site personnel will 
inform AstraZeneca representatives of any follow-up information on a previously reported 
SAE within 1 calendar day, ie, immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigator or other site personnel indicates that an AE is serious in the WBDC 
system, an automated e-mail alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site personnel 
will report an SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator or study site personnel how to 
proceed.
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24 hours.  The report should contain a comment regarding the co-involvement of PD, 
if appropriate, and should assign main and contributory causes of death.

Deaths with an unknown cause should always be reported as an SAE.  A
post-mortem may be helpful in the assessment of the cause of death, and if
performed, a copy of the post-mortem results should be forwarded to AstraZeneca
Drug Safety or its representative within the usual timeframes.
6.3.9
Safety data to be collected following the final data cut-off of the study
For patients continuing to receive IP treatment following the final data cut-off (DCO) and 
database closure, it is recommended that the patients continue the scheduled visits and 
investigators monitor the patient’s safety laboratory results prior to and periodically during 
treatment with IP in order to manage AEs in accordance with the MEDI4736 Toxicity 
Management Guidelines (Section 6.7.2). All data after the final DCO and database closure 
will be recorded in the patient notes but will not otherwise be reported for the purposes of 
this study, with the exception of SAEs, overdoses and pregnancies. 
All SAEs, overdoses and pregnancies that occur in patients still receiving IP treatment (or 
within 90 days following the last dose of MEDI4736 treatment) after the final DCO and 
database closure must be reported as detailed in Section 6.4 via paper SAE forms. 
6.4
Reporting of serious adverse events


If a patient becomes pregnant during the course of the study, the IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities or birth defects and spontaneous miscarriages should be reported and 
handled as SAEs.  Elective abortions without complications should not be handled as AEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and 
documented even if the patient was discontinued from the study.
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The reference document for the definition of expectedness or listedness is the IB for 
MEDI4736 and tremelimumab.
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study.  A medical emergency usually 
constitutes an SAE and is to be reported as such.
6.5
Overdose
Use of MEDI4736 + tremelimumab combination therapy or MEDI4736 monotherapy in 
doses in excess of those specified in the protocol are considered to be an overdose.  There 
is currently no specific treatment in the event of overdose of MEDI4736 or tremelimumab, 
and possible symptoms of overdose are not established.  
Please also refer to the local prescribing information for the SoC agents (eg, cisplatin or 
carboplatin prescribing information, 5FU prescribing information, cetuximab prescribing 
information).

An overdose with associated AEs will be recorded as the AE diagnosis or symptoms
in the relevant AE modules of the eCRF and in the Overdose eCRF module.

An overdose without associated symptoms will only be reported in the Overdose
eCRF module.
If an overdose of an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel will inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that 
all relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with an SAE, the standard reporting timelines apply, see Section 
6.4.  For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
6.6.1
Maternal exposure


All toxicities will be graded according to NCI CTCAE, version 4.03.
As with any antibody, allergic reactions to dose administration are possible.  Appropriate 
drugs and medical equipment to treat acute anaphylactic reactions must be immediately 
available, and study personnel must be trained to recognize and treat anaphylaxis.  The 
study site must have immediate access to emergency resuscitation teams and equipment in 
addition to the ability to admit patients to an intensive care unit if necessary.
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If any pregnancy occurs in the course of the study, then the Investigator or other site 
personnel should inform the appropriate AstraZeneca representatives within 1 day, ie, 
immediately but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that 
all relevant information is provided to the AstraZeneca Patient Safety data entry site within 
1 to 5 calendar days for SAEs (see Section 6.4) and within 30 days for all other 
pregnancies.
The same timelines apply when outcome information is available.
6.6.2
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and 
for 90 days following the last dose of MEDI4736 monotherapy or 180 days following the 
last dose of MEDI4736 + tremelimumab combination therapy.  Please follow the local 
prescribing information relating to contraception and the time limit for such precautions 
for the SoC agents.  
Pregnancy of the patient’s partner is not considered to be an AE.  However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality) should, if possible, be followed up and documented.
The outcome of any conception occurring from the date of the first dose until 90 days after 
the last dose of MEDI4736 monotherapy or 180 days following the last dose of 
MEDI4736 + tremelimumab combination therapy should be followed up and documented.  
Information on the pregnancy of a patient’s partner must be obtained directly from the 
patient’s partner.  Therefore, prior to obtaining information about the pregnancy, the 
Investigator must obtain the consent of the patient’s partner.
6.7
Management of IP-related toxicities
The following general guidance should be followed for management of toxicities.

Treat each of the toxicities with maximum supportive care (including holding the
agent suspected of causing the toxicity if required).

If the symptoms promptly resolve with supportive care, consideration should be
given to continuing the same dose of the assigned IP along with appropriate
continuing supportive care.  If medically appropriate, dose modifications are
permitted.

All dose modifications should be documented with clear reasoning and
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6.7.1
MEDI4736 + tremelimumab combination therapy and MEDI4736 
monotherapy adverse events of special interest
Adverse events of special interest (AESIs) are events of scientific and medical interest 
specific to the further understanding of the MEDI4736 and tremelimumab safety profile 
and require close monitoring and rapid communication by the Investigator to AstraZeneca.  
MEDI4736 and tremelimumab 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 these IPs.
AESIs for MEDI4736 +/- tremelimumab 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 immune-related 
adverse event (irAE) is defined as an AE that is associated with drug exposure and is 
consistent with an immune-mediated mechanism of action and where there is no clear 
alternate etiology.  Serologic, immunologic, and histologic (biopsy) data, as appropriate, 
should be used to support an irAE diagnosis.  Appropriate efforts should be made to rule 
out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the irAE. 
If the Investigator has any questions in regard to an AE being an irAE, the Investigator 
should promptly contact the Study Physician.
AESIs observed with MEDI4736 +/- tremelimumab include the following:

Diarrhea / Colitis and intestinal perforation

Pneumonitis / ILD

Hepatitis/transaminase increases 

Neuropathy/neuromuscular toxicity (eg, Guillain-Barré, and myasthenia gravis)

Endocrinopathy (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency, 
and hyper- and hypothyroidism and type I diabetes mellitus)

Rash / Dermatitis

Nephritis / Blood creatinine increases

Pancreatitis / serum lipase or amylase increases  

Myocarditis

Myositis / Polymyositis

Other inflammatory responses that are rare / less frequent with a potential immune-
mediated aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis 
and other events involving the eye, skin, haematological and rheumatological events.
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological aetiology are also considered AESIs.
Further information on these risks (eg, presenting symptoms) can be found in the current 
versions of the MEDI4736 and tremelimumab IBs.  More specific guidelines for their 


Comprehensive toxicity management guidelines (TMGs) have been developed to assist 
investigators with the recognition and management of toxicities associated with use of the 
immune-checkpoint inhibitors, durvalumab [MED4736] (PD-L1 inhibitor) and 
tremelimumab (CTLA-4 inhibitor). Given the similar underlying mechanism of toxicities 
observed with these two compounds, these TMGs are applicable to the management of 
patients receiving either drug as monotherapy or both drugs in combination. Additionally, 
these guidelines are applicable when either drug is used alone or both drugs are used in 
combination and, also other anti-cancer drugs (i.e., antineoplastic chemotherapy, targeted 
agents) are administered concurrently or sequentially as part of a protocol-specific 
treatment regimen. The TMGs provide information for the management of immune-
mediated reactions, infusion-related reactions, and non-immune mediated reactions that 
may be observed with checkpoint inhibitor monotherapy or combination checkpoint 
inhibitor regimens, with specific instructions for checkpoint inhibitor-specific dose 
modifications (including discontinuation) and treatment interventions. Investigators are 
advised however to use local practice guidelines and consult local references for the 
management of toxicities observed with other anti-cancer treatment.
The most current version of the TMGs is provided to the investigative site as an Annex to 
the Protocol document entitled “ Dosing Modification and Toxicity Management 
Guidelines for Immune-Mediated, Infusion-Related, and Non-Immune-Mediated 
Reactions MEDI4736 Monotherapy or Combination Therapy with Tremelimumab or 
Tremelimumab Monotherapy)” and is maintained within the Site Master File. In addition, 
a current version of the guidelines is also available through the following link: 
https://tmg.azirae.com. Please contact your clinical trial associate for information on how 
to gain access to this website.    
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an 
imAE diagnosis. In the absence of a clear alternative etiology, events should be considered 
potentially immune related.
In addition, there are certain circumstances in which MEDI4736 and tremelimumab should 
be permanently discontinued (see Section 3.9 of this protocol and the TMGs).
Following the first dose of IP, subsequent administration of MEDI4736 and tremelimumab 
can be modified based on toxicities observed as described in the Dosing Modification and 
Toxicity Management Guidelines.  These guidelines have been prepared by the Sponsor to 
assist the Investigator in the exercise of his/her clinical judgment in treating these types of 
toxicities.  These guidelines apply to AEs considered causally related to MEDI4736 
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evaluation and treatment are described in detail in the Dosing Modification and Toxicity 
Management Guidelines (as referenced in Section 6.7.2).  These guidelines have been 
prepared by the Sponsor to assist the Investigator in the exercise of his/her clinical 
judgment in treating these types of toxicities.  These guidelines apply to AEs considered 
causally related to the study drug/study regimen by the reporting Investigator.
6.7.2
Specific toxicity management and dose modification information -
MEDI4736 + tremelimumab combination therapy and MEDI4736 
monotherapy


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monotherapy and MEDI4736 + tremelimumab combination therapy by the reporting 
Investigator.
Dose reductions are not permitted.  In case of doubt, the Investigator should consult with 
the Study Physician.
6.7.3
Management of toxicity attributable to agents in the Standard of Care 
arm
IP-related toxicity management, including dose delays, reductions, and adjustments, for 
patients in the SoC group should be performed as indicated in the local prescribing 
information for the relevant agent.
6.8
Study governance and oversight
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the study protocol and letters to 
Investigators.
An IDMC comprised of independent experts will be convened and will meet 
approximately 3 months after the study has started or after the first 20 patients have been 
randomized, whichever occurs first, followed by 2 meetings for safety analysis 3 months 
apart, and subsequent meetings 6 months apart, to review safety assessments and make 
recommendations to continue, amend, or stop the study based on safety findings.
Full details of the IDMC procedures, processes, and interim analyses can be found in the 
IDMC Charter.
7. INVESTIGATIONAL PRODUCT AND OTHER 
TREATMENTS
7.1
Identity of investigational product
AstraZeneca will supply MEDI4736 and tremelimumab, while the SoC treatments 
(cetuximab, carboplatin or cisplatin, and 5FU) are expected to be supplied locally (see 
Table 8).
Table 8
List of investigational products for this study
Investigational product
Dosage form and strength
Manufacturer
MEDI4736
50 mg/mL, solution, IV
MedImmune
Tremelimumab
20 mg/mL, solution, IV
MedImmune
Standard of Care
Cetuximaba
IV (as sourced locally)
Various, depending upon the 
source
Carboplatina
IV (as sourced locally)
Various, depending upon the 
source


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Investigational product
Dosage form and strength
Manufacturer
Cisplatina
IV (as sourced locally)
Various, depending upon the 
source
5FUa
IV (as sourced locally)
Various, depending upon the 
source
a
Under certain circumstances when local sourcing is not feasible, a Standard of Care treatment may be 
supplied centrally through AstraZeneca.
5FU 5-Fluorouracil; IV Intravenous.
7.1.1
MEDI4736
MEDI4736 will be supplied by AstraZeneca as a 500-mg vial solution for infusion after 
dilution.  The solution contains 50 mg/mL MEDI4736, 26 mM 
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume 
(w/v) polysorbate 80; it has a pH of 6.0.  The nominal fill volume is 10 mL.  IP vials are 
stored at 2°C to 8°C (36°F to 46°F) and must not be frozen.
Preparation of MEDI4736 doses for administration with an IV bag
The dose of MEDI4736 for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique.  Total time from needle puncture of the 
MEDI4736 vial to the start of administration should not exceed:

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature
A dose of 1.5 g (for patients ≥30 kg in weight) will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final MEDI4736 concentration 
ranging from 1 to 20 mg/mL, and delivered through an IV administration set with a 0.2- or 
0.22-μm in-line filter.  Remove 30.0 mL of IV solution from the IV bag prior to addition 
of MEDI4736.  Next, 30.0 mL of MEDI4736 (ie, 1.5 g of MEDI4736) is added to the IV 
bag such that final concentration is within 1 to 20 mg/mL (IV bag volumes 100 to 1000 
mL).  Mix the bag by gently inverting to ensure homogeneity of the dose in the bag.
Weight-based dosing at 20 mg/kg (for patients whose weight falls to <30 kg during the 
study) will be administered using an IV bag containing 0.9% (w/v) saline or 5% (w/v) 
dextrose, with a final durvalumab (MEDI4736) concentration ranging from 1 to 20
mg/mL, and delivered through an IV administration set with a 0.2- or 0.22-μm in-line 
filter(w/v).  Mix the bag by gently inverting to ensure homogeneity of the dose in the bag.
Do not co-administer other drugs through the same infusion line.
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the 
total allowed time should not exceed 8 hours at room temperature.  Table 9 summarizes 
time allowances and temperatures.


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Table 9
MEDI4736 temperature and infusion time allowances
Maximum time from needle puncture to start of 
administration
4 hours at room temperature, 24 hours at 2°C to 
8°C
Maximum time for IV bag infusion, including 
interruptions
8 hours at room temperature
In the event that either preparation time or infusion time exceeds the time limits outlined in 
the table, a new dose must be prepared from new vials.  MEDI4736 does not contain 
preservatives, and any unused portion must be discarded.
All details can be found in the Drug Handling Instructions.
7.1.2
Tremelimumab
Tremelimumab will be supplied by AstraZeneca as a 400-mg vial solution for infusion 
after dilution.  The solution contains 20 mg/mL tremelimumab, 20 mM histidine/histidine 
hydrochloride, 222 mM trehalose dihydrate, 0.27 mM disodium edetate dihydrate, and 
0.02% (w/v) polysorbate 80; it has a pH of 5.5.  The nominal fill volume is 20 mL.  IP 
vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen.
Preparation of tremelimumab doses for administration with an IV bag
The dose of tremelimumab for administration must be prepared by the Investigator’s or 
site’s designated IP manager using aseptic technique.  Total time from needle puncture of 
the tremelimumab vial to the start of administration should not exceed:

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature
A dose of 75 mg (for patients ≥30 kg in weight) will be administered using an IV bag 
containing 0.9% (w/v) saline, with a final tremelimumab concentration ranging from 0.1 to 
10 mg/mL, and delivered through an IV administration set with a 0.2- or 0.22-μm in-line 
filter.  Remove 3.8 mL of IV solution from the IV bag prior to addition of tremelimumab.  
Next, 3.8 mL of tremelimumab (ie, 75 mg of tremelimumab) is then added to the IV bag 
such that the final concentration is within 0.1 to 10 mg/mL (IV bag volumes of 50 to 
500 mL).  Mix the bag by gently inverting to ensure homogeneity of the dose in the bag.
Weight-based dosing at 1 mg/kg (for patients whose weight falls to < 30 kg during the 
study) will be administered using an IV bag containing 0.9% (w/v) saline, with a final 
tremelimumab concentration ranging from 0.10 to 10 mg/mL, and delivered through an IV 
administration set with a 0.2- or 0.22-μm in-line filter. 
Do not co-administer other drugs through the same infusion line.
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the 
total allowed time should not exceed 8 hours at room temperature.  Table 10 summarizes 
time allowances and temperatures.  


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Table 10
Tremelimumab temperature and infusion time allowances
Maximum time from needle puncture to start of 
administration
4 hours at room temperature, 24 hours at 2°C to 
8°C
Maximum time for IV bag infusion, including 
interruptions
8 hours at room temperature
In the event that either preparation time or infusion time exceeds the time limits outlined in 
the table, a new dose must be prepared from new vials.  Tremelimumab does not contain 
preservatives, and any unused portion must be discarded.
All details can be found in the Drug Handling Instructions.
7.1.3
Standard of Care treatment
Each SoC agent will be sourced as commercially available material/locally sourced, 
prescribed according to local regulations, and will be administered according to 
prescribing information or treatment guidance in general use by the Investigating site.  
Under certain circumstances when local sourcing is not feasible, a SoC agent will be 
supplied centrally by AstraZeneca.  This will be labeled with local language translated text 
in accordance with regulatory guidelines.
7.2
Dose and treatment regimens
7.2.1
Treatment regimens
MEDI4736 monotherapy: Patients enrolled on the MEDI4736 monotherapy arm of this 
study will receive 1500 mg MEDI4736 q4w via IV infusion beginning on Day 1 until PD 
(see Figure 4).  (N.B.  If a patient’s weight falls below 30 kg during the study, the patient 
should receive weight-based dosing equivalent to 20 mg/kg of MEDI4736 Q4W until the 
weight improves to ≥30 kg, at which point the patient should start receiving the fixed 
dosing of MEDI4736 (1500 mg Q4W.)
Figure 4
Dosing scheme - MEDI4736 monotherapy
Q4W Every 4 weeks.
MEDI4736 + tremelimumab combination therapy:


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Patients enrolled on the MEDI4736 + tremelimumab combination therapy arm of this 
study will receive 75 mg tremelimumab via IV infusion q4w for 4 doses beginning on Day 
1 and 1500 mg MEDI4736 via IV infusion q4w until PD (see Figure 5). (N.B.  If a 
patient’s weight falls to below 30 kg during the study, the patient should receive weight-
based dosing equivalent to 20 mg/kg MEDI4736 Q4W and 1 mg/kg tremelimumab Q4W
until the weight improves to ≥30 kg, at which point the patient should start receiving the 
fixed dosing of MEDI4736 (1500 mg) plus tremelimumab (75 mg) Q4W.)
During the first infusion of the combination regimen, tremelimumab will be administered 
first; the MEDI4736 infusion will start approximately 1 hour (maximum 2 hours) after the 
end of the tremelimumab infusion.  If there are no clinically significant infusion reactions 
with the first cycle, then for all other cycles, the MEDI4736 infusion can begin 
immediately after the tremelimumab infusion has finished.  
Figure 5
Dosing scheme - MEDI4736 + tremelimumab combination therapy
Q4W Every 4 weeks.
SoC (EXTREME): Patients in the SoC treatment arm will receive the EXTREME 
regimen consisting of a maximum of six 3-week cycles of cetuximab, a platinum, and 
5FU, with continuation of cetuximab.  Patients in this arm will receive either cisplatin (at a 
dose of 100 mg/m2 of body surface area on Day 1) or carboplatin (at an AUC of 5 
mg/mL/min on Day 1), at the discretion of the Investigator and an infusion of 5FU (at a 
dose of 1000 mg/m2/day on Days 1 through 4 of every 3-week cycle).  Cetuximab will be 
administered at an initial dose of 400 mg/m2 on Cycle 1 Day 1, followed by subsequent 
weekly doses of 250 mg/m2.  Weekly monotherapy with cetuximab should continue after 
the completion of up to 6 cycles of chemotherapy in patients who achieve SD or better.  
Any drug within the triplet regimen (cetuximab, a platinum, and 5FU) can be discontinued 
at any time due to toxicity at the discretion of the Principal Investigator.


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Patients will be treated with MEDI4736 + tremelimumab combination therapy, MEDI4736 
monotherapy, or SoC until confirmed PD (unless, in the Investigator’s opinion, the patient 
continues to receive benefit from the treatment and after discussion with the Sponsor), 
initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or 
another treatment discontinuation criterion is met (see Section 3.9).  Patients with PD in 
target lesions after objective response are not eligible to continue treatment.
Disease progression requires confirmation for patients receiving IMT.  All scans showing 
PD by RECIST 1.1 should be confirmed, preferably at the next scheduled visit and no 
earlier than 4 weeks after the preceding assessment of PD in the absence of clinical 
deterioration.  Disease progression in patients in the SoC arm should be confirmed by a 
scan obtained no earlier than 4 weeks after the initial assessment of PD and preferably at 
the next scheduled imaging visit, if clinically feasible.  Treatment in all arms will continue 
between the assessment of progression and its confirmation.  If progression is not 
confirmed, then the patient should continue receiving study treatment and participating in 
study assessments.  If progression is confirmed and the patient continues to receive some 
clinical benefit, treatment may be continued at the Investigator’s discretion.  Patients with 
clinical evidence of progression who do not meet PD criteria by RECIST 1.1 should have 
radiographic documentation of PD.
Patients who have discontinued treatment due to toxicity or symptomatic deterioration, or 
who have commenced subsequent anticancer therapy, will be followed up until confirmed 
disease progression and for survival (see Table 4).  Patients with confirmed progression in 
any arm cannot continue therapy if the progression occurs in a target lesion that has 
previously shown an objective response.
7.2.2
Duration of treatment
All treatment in all arms will be administered beginning on Day 1 until confirmed PD, 
unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met (at 
the Investigator’s discretion), as described below.  Patients in all arms with a symptomatic 
solitary lesion, a brain lesion, or a lesion of clinical importance (eg, impending fracture, 
etc) may be treated with radiation after approval from the Sponsor.  Non-irradiated lesions 
need to continue to be measurable by RECIST.  The time interval between the last 
systemic treatment and radiation should be 10 days, and systemic treatment can be 
resumed 1 week post radiation.
Treatment through progression is permitted in all arms if, in the Investigator’s opinion, the 
patient continues to receive benefit from the treatment.  Treatment through progression is 
at the Investigator’s discretion, and the Investigator should ensure that patients do not have 
any significant, unacceptable, or irreversible toxicities that indicate that continuing 
treatment will not further benefit the patient.  The Investigator should ensure that patients 
will meet all of the inclusion criteria and none of the exclusion criteria for this study and 
that these patients meet the following specific criteria for treatment in the setting of PD:

Written informed consent to continue treatment or retreatment in the setting of PD.
This consent document will specify that treatment beyond initial evidence of PD is
not the standard-of-care and that alternative treatment options, either locally licensed
treatments or other clinical trials, are available for this patient population.


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
Absence of clinical symptoms or signs indicating clinically significant disease
progression and no decline in WHO/ECOG performance status to >1.

Absence of rapid disease progression or threat to vital organs or critical anatomical
sites (eg, central nervous system metastasis, respiratory failure due to tumor
compression, or spinal cord compression) requiring urgent, alternative medical
intervention.
Patients who the Sponsor and Investigator determine may not continue treatment after 
confirmed PD will enter follow-up.  Patients who have discontinued treatment due to 
toxicity or symptomatic deterioration, or who have commenced subsequent anticancer 
therapy, will be followed for confirmed disease progression and survival.
Post final Data Cut Off (DCO)
Patients who continue to receive benefit from their assigned treatment at the final DCO 
and database closure may continue to receive their assigned treatment for as long as they 
and their physician feel they are gaining clinical benefit. For patients continuing to receive 
durvalumab treatment following the final DCO and database closure, it is recommended 
that the patients continue the scheduled site visits and investigators monitor the patient’s 
safety laboratory results prior to and periodically during treatment with durvalumab in 
order to manage AEs in accordance with the durvalumab toxicity management guidelines 
(as referenced in  Section 6.7.2).
In the event that a roll-over or safety extension study is available after final analysis, 
patients currently receiving treatment with durvalumab may be transitioned to such a 
study, and the current study would reach its end.  The roll-over or safety extension study 
would ensure treatment continuation with visits assessment per its protocol.  Any patient 
that would be proposed to move to such study would be given a new Informed Consent. 
7.2.3
Criteria for Retreatment for Patients in the MEDI4736 + 
tremelimumab arm
Patients who meet the criteria for retreatment may only receive retreatment once.  
Crossover within the study will not be permitted.  Patients meeting the retreatment criteria 
below will follow the same treatment guidelines followed during the initial treatment 
period, including the same dose and frequency of treatments, and a similar schedule of 
assessments (see Table 2).
Patients randomized to MEDI4736 monotherapy may not undergo retreatment.  
Patients randomized to MEDI4736 + tremelimumab combination therapy may undergo 
retreatment in the clinical scenario described below:
1.
Patients who complete the 4 dosing cycles of the MEDI4736 + tremelimumab
combination therapy portion of the regimen (with clinical benefit per Investigator’s
judgment) but subsequently have evidence of PD during the MEDI4736
monotherapy portion of the combination regimen, with or without confirmation
according to RECIST 1.1, may restart treatment with the entire combination regimen
(including monotherapy maintenance).


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For patients in the MEDI4736 + tremelimumab combination therapy arm, before a patient 
restarts treatment, the Investigator should ensure that the patient:
1.
Does not have any significant, unacceptable, or irreversible toxicities that indicate
continuing treatment will not further benefit the patient
2.
Still fulfills the eligibility criteria for this study, including re-consenting to restart
MEDI4736 + tremelimumab combination therapy
3.
Has not have received an intervening systemic anticancer therapy after their assigned
treatment discontinuation
4.
Has had a baseline tumor assessment within 28 days prior to restarting their assigned
treatment; all further scans should occur with the same frequency as during the initial
treatment (relative to the date of restarting treatment) until study treatment is stopped
5.
Undergoes a tumor biopsy as described in Section 5.5.1
During the retreatment period, patients in the MEDI4736 + tremelimumab combination 
therapy arm will resume 75mg of tremelimumab q4w for 4 doses and MEDI4736 dosing at 
1500 mg q4w until PD.
7.3
Labeling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfill GMP Annex 13 requirements for labelling.  
Label text will be translated into the local language.
Labels will be provided as either a single panel label or as multi-language booklet labels.
7.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions.  The 
IP label on the pack/bottle/carton specifies the appropriate storage.  Storage is also 
described in the IB.
7.5
Compliance
The administration of all study drugs (including IP) should be recorded in the appropriate 
sections of the eCRF.
Treatment compliance will be assured by reconciliation of site drug accountability logs.
7.6
Accountability
The study drug provided for this study will be used only as directed in the study protocol.  
The study personnel will account for all study drugs 
Drug accountability should be performed until the patient stops study treatment 
completely.  Study site personnel will account for all study drugs received at the site, for 
all unused study drugs, and for appropriate destruction of study drugs.  Certificates of 
delivery, destruction, and return should be signed.


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7.7
Concomitant and other treatments
The Investigator must be informed as soon as possible about any medication taken from 
the time of screening until the end of the clinical phase of the study (final study visit).  Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the eCRF.
Restricted, prohibited, and permitted concomitant medications are described in the 
following tables.  Refer to Section 6.7 for guidance on management of IP-related 
toxicities.
Prohibited medication/class of drug:
Usage:
Additional investigational anticancer therapy 
concurrent with those under investigation in 
this study
Should not be given whilst the patient is on IP 
treatment (including SoC) 
mAbs against CTLA-4, PD-1, or PD-L1
Should not be given whilst the patient is on IP 
treatment (including SoC).
Any concurrent chemotherapy, local therapy 
(except palliative therapy for non-target 
lesions, eg, radiotherapy, surgery, 
radiofrequency ablation), biologic therapy, or 
hormonal therapy for cancer treatment
Should not be given whilst the patient is on IP 
treatment (including SoC).  (Concurrent use of 
hormones for non-cancer-related conditions 
[eg, insulin for diabetes and hormone replacement 
therapy] is acceptable.  A symptomatic solitary 
lesion, a brain lesion, or a lesion of clinical 
importance (eg, impending fracture, etc) may be 
treated with radiation after approval from the 
Sponsor.)  
Immunosuppressive medications, including, 
but not limited to: systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or 
its equivalent, methotrexate, azathioprine, and 
TNF-α blockers  
Should not be given whilst the patient is on IP 
treatment (including SoC).  (Use of 
immunosuppressive medications for the management 
of IP-related AEs or in patients with contrast allergies 
is acceptable.  In addition, use of inhaled, topical, and 
intranasal corticosteroids is permitted.  Use of 
steroids as pre-medication for either hypersensitivity 
reactions (eg, CT scan pre-medication) or as 
anti-emetic prior to administration of SoC treatment 
is permitted.)  Short term use of immunosuppressive 
medications, including corticosteroids, for the acute 
management of non-IP-related emergencies (eg, 
COPD, asthma, etc) is permitted.
Live attenuated vaccines
Should not be given through 30 days after the last 
dose of IP (including SoC) during the study
AE Adverse event; CT Computed tomography; CTLA-4 Cytotoxic T-lymphocyte-associated antigen 4; 
IP Investigational product; mAb monoclonal antibody; PD-1 Programmed cell death 1; PD-L1 Programmed 
cell death ligand 1; SoC Standard of Care; TNF Tumor necrosis factor.


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Rescue/supportive medication/class of drug:
Usage:
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) 
deemed necessary by the Investigator to 
provide adequate prophylactic or supportive 
care, except for those medications identified as 
“prohibited” as listed above
To be administered as prescribed by the Investigator
BSC (including antibiotics, nutritional support, 
growth factor support, correction of metabolic 
disorders, optimal symptom control, and pain 
management [including palliative radiotherapy, 
etc])
Should be used when necessary for all patients
BSC Best supportive care.
7.7.1
Other concomitant treatment
Medications other than those described in Section 7.7 that are considered necessary for the 
patient’s safety and well-being may be given at the discretion of the Investigator and 
should be recorded in the appropriate sections of the eCRF.
7.8
Post study access to study treatment
After the efficacy analysis, AstraZeneca will continue to supply open-label drug to patients 
receiving MEDI4736 + tremelimumab combination therapy or MEDI4736 monotherapy 
up to clinical disease progression (Section 7.2).
8. STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
All statistical analyses will be performed by AstraZeneca or its representatives.  
A comprehensive statistical analysis plan (SAP) will be prepared and finalized within 3 
months of the first randomized patient and any subsequent amendments will be 
documented, with final amendments completed prior to reporting of the data.  The primary 
aim of the study is to compare the efficacy and safety of MEDI4736 monotherapy to SoC.
8.2
Sample size estimate
The study will enroll approximately 1016 patients in order to randomize 760 eligible 
patients in a 2:1:1 ratio (380:190:190 patients) to MEDI4736 + tremelimumab 
combination therapy, MEDI4736 monotherapy, or SoC. The study was originally sized to 
characterize the OS benefit of MEDI4736 + tremelimumab combination therapy versus 
SoC in the all-comers population.  The sizing assumes a 3-month delay in separation of the 
OS curves between each arm, hence the use of average HRs.
The primary analysis of OS will be performed when approximately 147 death events have 
occurred in approximately 172 patients (85% maturity) across the MEDI4736 
monotherapy and SoC treatment groups in the PD-L1 TC/IC high subgroup, assuming that 


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45% of the patients randomized are within this subgroup. No interim efficacy analyses will 
be performed in this study.
If OS at 24 months in the PD-L1 TC/IC high subgroup was 30% with MEDI4736 
monotherapy and 12% with SoC (with a 10.1-month median OS), and assuming the true 
average OS HR is 0.59, the trial will have approximately 90% power to demonstrate 
statistical significance at the 5% level (using a 2-sided test) for the comparison of 
MEDI4736 monotherapy versus SoC in the PD-L1 TC/IC high subgroup, with the smallest 
treatment difference that could be statistically significant being an average HR of 0.72.  
With a 17-month recruitment period and a minimum follow-up period of 23.6 months from 
“last patient in” assumed, it is anticipated that the analysis will be performed 
approximately 40.6 months after the first patient has been recruited.
Table 11 provides a summary of the statistical assumptions for the first two levels of the MTP.
Table 11
Summary of statistical assumptions
N ratio
Ove
rall 
HR
Landmarks at 
24 months
Events 
(maturity)
Power
Critical values
HR (landmarks)
Primary  
objective
OS: Mono 
versus SoC; 
PD-L1 TC/IC 
high subgroup
86:86
0.59
30% vs 12% 
147 (85%)
90%
0.72 (22%)
Secondary
objectives: 
OS: Mono 
versus SoC; 
low risk of EM 
subgroup
152:152
0.70
24% vs 12%
254 (84%)
81%
0.78 (19%)
Note: The sample size estimates in the PD-L1 TC/IC high subgroup comparisons assume that 45% of the 
patients randomized are within this subgroup; The sample size estimate in the low risk of EM 
subgroup assume that 80% of the patients randomized are within this subgroup.
EM Early mortality; HR Hazard ratio; IC tumor-associated immune cells; Mono MEDI4736 monotherapy; 
OS Overall survival; SoC Standard of Care (EXTREME); TC tumor cells.


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8.3
Definitions of analysis sets
Definitions of the analysis sets for each outcome variable are provided in Table 12.
Table 12
Summary of outcome variables and analysis populations
Outcome variable
Populations
Efficacy Data
OS, PFS, ORR, APF6, APF12, OS12, OS18, OS24, 
PD-L1 TC/IC analysis set, low risk of EM 
analysis set, ctDNA TMB analysis set and 
all-comers (FAS)
DoR, BoR, TTR, TFST, TSST, PFS2, PROs, and 
symptom endpoints
PD-L1 TC/IC analysis set and all-comers 
(FAS) 
Demography
PD-L1 TC/IC analysis set, and FAS (ITT 
population)
PK data
PK Analysis Set
Safety Data
Exposure
Safety Analysis Set
AEs
Safety Analysis Set
Laboratory measurements
Safety Analysis Set
Vital Signs
Safety Analysis Set
AE Adverse event; APF12 Proportion of patients alive and progression free at 12 months; BoR Best 
objective response; DoR Duration of response; EM Early mortality; FAS Full analysis set; IC tumor-
associated immune cells; ITT Intent-to-Treat; ORR Objective response rate; OS Overall survival; OS12 
Proportion of patients alive at 12 months; OS18 Proportion of patients alive at 18 months; OS24 Proportion
of patients alive at 24 months after randomization; PD-L1 Programmed cell death ligand 1; PFS Progression-
free survival; PFS2 Second progression; PK Pharmacokinetic; PRO Patient-reported outcome; TMB Tumor 
Mutation Burden (The ctDNA TMB cutpoint of 16mut/Mb for MEDI4736+tremelimumab and MEDI4736 
monotherapy was derived from the EAGLE study (Li et al 2020)).; TC tumor cells; TTR Time to response.
8.3.1
  Full Analysis Set
The full analysis set (FAS) will include all randomized patients (all-comers). Treatment 
groups will be compared on the basis of randomized study treatment, regardless of the 
treatment actually received.  Patients who were randomized but did not subsequently go on 
to receive study treatment are included in the analysis in the treatment group to which they 
were randomized.
8.3.2
   Safety Analysis Set
The Safety Analysis Set (SAS) will consist of all patients who received at least 1 dose of 
study treatment.  Safety data will not be formally analyzed but summarized using the SAS 
for the all-comers (FAS), the PD-L1 TC/IC high subgroup and the low risk of EM 
subgroup according to the treatment received, that is, erroneously treated patients (eg, 
those randomized to treatment A but actually given treatment B) will be summarized 
according to the treatment they actually received. 
8.3.3
PD-L1 TC/IC Analysis Set
The PD-L1 TC/IC analysis set will include the subset of patients in the FAS with PD-L1 
evaluable samples and available results as determined by the analytically validated 


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VENTANA PD-L1 (SP263) Assay. Subgroups are defined as PD-L1 high, low and 
unknown. 
PD-L1 high is defined as either ≥ 50% of the tumor cells (TC) or ≥ 25% of the immune 
cells (IC)  staining for PD-L1 at any intensity if >1% of the tumor area contains IC, or ≥ 
50% of TC or 100% of IC staining for PD-L1 at any intensity if 1% of the tumor area 
contains IC. PD-L1 low is defined as not meeting any of the criteria for PD-L1 high.
The scoring algorithm was derived from data from two phase 2 studies, D4193C00001 
(HAWK, DCO September 2016) and D4193C00003 (CONDOR, DCO March 2017). 
8.3.4   PK Analysis Set
All patients who receive at least 1 dose of IP per the protocol for whom any post-dose PK 
data are available.   
8.3.5   ctDNA TMB Analysis Set
The ctDNA TMB analysis set will include the subset of patients in the FAS with ctDNA 
TMB evaluable samples and available result. Subgroups are defined as ctDNA TMB high 
(≥16 mut/Mb), low (<16 mut/Mb). 
ctDNA TMB outputs will also incorporate the non-evaluable data set: Failed, Not Done, 
Not Provided, and No Call/not evaluable.   
8.3.6  Low Risk of Early Mortality (EM) Analysis Set
The low risk of EM analysis set consists of patients who are at low risk of early mortality 
 based on laboratory values according to a specific prognostic model 
. Further details will be provided in the SAP.
8.4
Outcome measures for analyses
8.4.1
Calculation or derivation of efficacy variables
8.4.1.1 Primary and secondary endpoint (OS)
OS is defined as the time from the date of randomization until death due to any cause.  
Any patient not known to have died at the time of analysis will be censored based on the 
last recorded date on which the patient was known to be alive.  
Note: Survival calls will be made following the date of data cut-off for the analysis (these 
contacts should generally occur within 7 days of the data cut-off).  If patients are 
confirmed to be alive or if the death date is post the data cut-off date, these patients will be
censored at the date of data cut-off.  Death dates may be found by checking publicly 
available death registries.
8.4.1.2      RECIST 1.1-based endpoints
The analysis of the other secondary endpoints, PFS, ORR, DoR, BoR, TTR, APF6 and 
APF12, will be based on the investigator assessments using RECIST 1.1.  In addition, 
PFS2 will be defined by local clinical practice.
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Investigator RECIST 1.1-based assessments
All RECIST 1.1 assessments, whether scheduled or unscheduled, will be included in the 
calculations.  This is also regardless of whether a patient discontinues study treatment or 
receives another anticancer therapy.  
At each visit, patients will be programmatically assigned a RECIST 1.1 visit response of 
CR, PR, SD, or PD depending on the status of their disease compared with baseline and 
previous assessments.  Baseline will be assessed within the 28 days prior to enrollment.  If 
a patient has had a tumor assessment that cannot be evaluated, then the patient will be 
assigned a visit response of not evaluable (NE; unless there is evidence of progression in 
which case the response will be assigned as PD).
Please refer to Appendix E for the definitions of CR, PR, SD, and PD.
BICR-based assessments
A BICR of radiological imaging data will be conducted according to RECIST 1.1 and used 
for a sensitivity analysis for the secondary objective of PFS.  All radiological scans for all 
patients (including those at unscheduled visits or outside visit windows) obtained prior to 
version 8 of the clinical study protocol (dated 13 Feb 2018) will be provided to the BICR.  
Prior radiotherapy will also be provided to the BICR to allow the selection of appropriate 
target lesions.
The imaging scans will be reviewed by 2 independent radiologists using RECIST 1.1 and 
will be adjudicated, if required.  For each patient, the BICR will define the overall visit 
response data (CR, PR, SD, PD, or NE) and the relevant scan dates for each time point (ie, 
for visits where response or progression is/is not identified).  If a patient has had a tumor 
assessment that cannot be evaluated, then the patient will be assigned a visit response of 
NE (unless there is evidence of progression, in which case the response will be assigned as 
PD).  Sensitivity analysis of PFS will be derived from the overall visit response date and 
the scan dates.
 
Further details of the BICR will be documented in the Imaging Charter.
8.4.1.3 Secondary  endpoints
Progresson Free Survival
PFS (per RECIST 1.1 as assessed by the investigator) will be defined as the time from the 
date of randomization until the date of objective disease progression or death (by any 
cause in the absence of progression) regardless of whether the patient discontinues therapy 
or receives another anticancer therapy prior to progression (ie, date of event or censoring –
date of randomization + 1).  Patients who have not progressed or died at the time of 
analysis will be censored at the time of the latest date of assessment from their last 
evaluable RECIST 1.1 assessment.  However, if the patient progresses or dies after 2 or 
more missed visits, the patient will be censored at the time of the latest evaluable RECIST 
1.1 assessment prior to the 2 missed visits.  If the patient has no evaluable visits or does 
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not have baseline data, they will be censored at Day 1 unless they die within 2 visits of 
baseline, then they will be treated as an event with date of death as the event date.
The PFS time will always be derived based on scan/assessment dates and not visit dates.
RECIST 1.1 assessments/scans contributing toward a particular visit may be performed on 
different dates.  The following rules will be applied:

For Investigator assessments, the date of progression will be determined based on the 
earliest of the RECIST 1.1 assessment/scan dates of the component that indicates 
progression.

For BICR assessments, date of progression will be determined based on the earliest 
of the dates of the component that triggered the progression on the first set of scans 
that indicates progression for the adjudicated reviewer selecting PD, or of either 
reviewer where both reviewers select PD as a timepoint response, and there is no 
adjudication for central review (BICR) data.

When censoring a patient for PFS, the patient will be censored at the latest of the 
dates contributing to a particular overall visit assessment.
Note: For target lesions, only the latest scan date is recorded out of all scans performed at 
that assessment for the target lesions, and similarly for non-target lesions, only the latest 
scan date is recorded out of all scans performed at that assessment for the non-target 
lesions.
A sensitivity analysis of PFS will be performed using BICR assessments according to 
RECIST 1.1.
 
 
 
 
 
 
 
 
Objective response rate
ORR (per RECIST 1.1 using investigator assessments) is defined as the number (%) of 
patients with at least 1 visit response of CR or PR.  Data obtained up until progression, or 
the last evaluable assessment in the absence of progression, will be included in the 
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assessment of ORR.  Patients who go off treatment without progression, receive a 
subsequent therapy, and then respond will not be included as responders in the ORR.  
Duration of response
DoR (per RECIST 1.1 using investigator assessments) will be defined as the time from the 
date of first documented response until the first date of documented progression or death in 
the absence of disease progression (ie, date of PFS event or censoring – date of first 
response + 1).  The end of response should coincide with the date of progression or death 
from any cause used for the RECIST 1.1 PFS endpoint.  
The time of the initial response will be defined as the latest of the dates contributing 
toward the first visit response of CR or PR.  If a patient does not progress following a 
response, then their DoR will be censored at the PFS censoring time.  DoR will not be 
defined for those patients who do not have documented response.
Time from randomization to second progression (PFS2)
PFS2 will be defined as the time from the date of randomization to the earliest of the 
progression event subsequent to that used for the PFS endpoint or death.  The date of 
second progression will be recorded by the Investigator in the eCRF and defined according 
to local standard clinical practice and may involve any of the following: objective 
radiological imaging, symptomatic progression, or death.  Second progression status will 
be reviewed (every 6 weeks for the first 48 weeks relative to the date of randomization and 
then every 8 weeks thereafter) following the progression event used for the primary 
variable PFS (the first progression) and status recorded.  Patients alive and for whom a 
second disease progression has not been observed should be censored at the last time 
known to be alive and without a second disease progression, that is, censored at the latest 
of the PFS or PFS2 assessment date if the patient has not had a second progression or 
death.
Time from randomization to the first subsequent therapy or death 
Time to the first subsequent therapy (TFST) or death will be defined as the time from the 
date of randomization to the earlier of either the start date of the first subsequent anticancer 
therapy after discontinuation of randomized treatment or the date of death (ie, the date of 
first subsequent cancer therapy, death, or censoring defined as the date of randomization + 
1 day).  Any patient not known to have received a first subsequent anticancer therapy will 
be censored at the last date that the patient was known not to have received a first 
subsequent anticancer therapy.  If a patient terminated the study before the first subsequent 
therapy for a reason other than death, the patient will be censored at the earliest of either 
the patient’s last known date to be alive or the study termination date.
Time from randomization to the second subsequent therapy or death
As a supportive summary to PFS2, time to second subsequent therapy (TSST) or death will 
be defined as the time from the date of randomization to the earlier of either the start date 
of the second subsequent anticancer therapy after discontinuation of first subsequent 
therapy, or the date of death.  Any patient not known to have had a second subsequent 
anticancer therapy will be censored at the last date when the patient was known not to have 
received a second subsequent anticancer therapy.  If a patient terminated the study for 


8.4.2.1 Adverse events
Safety and tolerability will be assessed in terms of AEs (including SAEs), deaths, 
laboratory data, vital signs, ECGs, and exposure.  These will be collected for all patients.  
Data from all cycles of treatment will be combined in the presentation of safety data.  “On 
treatment” will be defined as assessments between date of start dose and 90 days following 
discontinuation of IP (ie, the last dose of MEDI4736 + tremelimumab combination therapy 
or MEDI4736 monotherapy).  For AEs, on treatment (or treatment-emergent AEs) will be 
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reason other than death before second subsequent anticancer therapy, the patient will be 
censored at the earliest of the last known to be alive and termination dates.
Proportion of patients alive and progression free at  6 and 12 months
The APF6 and APF12 will be defined as the Kaplan-Meier estimate of PFS (per RECIST 
1.1 as assessed by the investigator) at 6 months and 12 months respectively.
Proportion of patients alive at 12, 18 and 24 months after randomization
The OS12, OS18 and OS24 will be defined as the Kaplan-Meier estimate of OS at 12, 18 
and 24 months respectively after randomization.  
Best objective response
Best objective response (BoR) is calculated based on the overall visit responses from each 
RECIST 1.1 assessment, as described in Appendix E.  It is the best response a patient has 
had during their time in the study up until RECIST 1.1 progression or the last evaluable 
assessment in the absence of RECIST 1.1 progression.
Categorization of BoR will be based on RECIST 1.1 (Appendix E) using the following 
response categories: CR, PR, SD, PD, and NE.
BoR will be determined programmatically based on RECIST 1.1 using all investigator 
assessments up until the first progression event.  For patients whose progression event is 
death, BoR will be calculated based upon all evaluable RECIST 1.1 assessments prior to 
death.
For patients who die with no evaluable RECIST 1.1 assessments, if the death occurs 
≤90 days (ie, 2 × (6 weeks ±3 days)) after randomization, then BoR will be assigned to the 
progression (PD) category.  For patients who die with no evaluable RECIST 1.1 
assessments, if the death occurs >90 days (ie, 2 × (6 weeks ±3 days)) after the date of 
randomization, then BoR will be assigned to the NE category.  
Progression events that have been censored due to them being >90 days after the last 
evaluable assessment will not contribute to the BoR derivation.
Time to response
Time to response (per RECIST 1.1 as assessed by the investigator) is defined as the time 
from the date of randomization until the date of documented response. The date of 
documented response should coincide with that used for the RECIST 1.1 DoR endpoint. 
8.4.2
Calculation or derivation of safety variables


PRO questionnaires will be assessed using the EORTC QLQ-C30 and EORTC 
QLQ-H&N35.  All items/questionnaires will be scored according to published scoring 
guidelines.  All PRO analyses will be based on the FAS.
8.4.3.1 EORTC QLQ-C30
The EORTC QLQ-C30 consists of 30 questions that can be combined to produce 
5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales 
(fatigue, pain, and nausea/vomiting), and a global measure of health status.  The EORTC 
QLQ-C30 will be scored according to the EORTC QLQ-C30 scoring manual (Fayers et al 
1999).  An outcome variable consisting of a score from 0 to 100 will be derived for each of 
the symptom scales, each of the functional scales, and the global health status scale in the 
EORTC QLQ-C30 according to the EORTC QLQ-C30 Scoring Manual.  Higher scores on 
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defined as any AEs that started after dosing or prior to dosing and which worsens 
following exposure to the treatment.
SAS will be used for reporting of safety data.
A separate data listing of AEs occurring more than 90 days after discontinuation of IP will 
be produced.  These events will not be included in AE summaries.  
8.4.2.2 Safety assessments
For the change from baseline summaries for vital signs, laboratory data, ECGs, and 
physical examinations, the baseline value will be the latest result obtained prior to the start 
of study treatment.  
QTcF will be derived during creation of the reporting database using the reported ECG 
values (RR and QT) using the following formula:
QTcF = QT/RR^ (1/3) where RR is in seconds
Corrected calcium product will be derived during creation of the reporting database using 
the following formulas:
Corrected calcium (mmol/L) = Total calcium (mmol/L) + ([40 – albumin (G/L)] × 0.02)
The denominator used in laboratory summaries will only include evaluable patients, ie, 
those who had sufficient data to have the possibility of an abnormality.
For example:

If a CTCAE criterion involves a change from baseline, evaluable patients would have
both a pre-dose and at least 1 post-dose value recorded.

If a CTCAE criterion does not consider changes from baseline to be evaluable, the
patient need only have 1 post-dose value recorded.
The denominator in vital signs data should include only those patients with recorded data.
8.4.3
Calculation or derivation of patient-reported outcome variables


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the global health status and functioning scales indicate better health status/function, but 
higher scores on symptom scales represent greater symptom severity.
The change from baseline in HRQoL will be assessed using the EORTC QLQ-C30 global 
QoL scale, which includes 2 items from the EORTC QLQ-C30: “How would you rate your 
overall health during the past week? (Item 29) and “How would you rate your overall QoL 
during the past week? (Item 30).” 
Definition of clinically meaningful changes
Changes in score compared with baseline will be evaluated.  A minimum clinically 
meaningful change is defined as an absolute change in the score from baseline of ≥10 for 
scales from the EORTC QLQ-C30 (Osoba et al 1998).  For example, a clinically 
meaningful improvement in physical function (as assessed by EORTC QLQ-C30) is 
defined as an increase in the score from baseline of ≥10, whereas a clinically meaningful 
deterioration is defined as a decrease in the score from baseline of ≥10.  At each post-
baseline assessment, the change in symptoms/functioning from baseline will be 
categorized as improvement, no change or deterioration as shown in Table 3.
Table 13
Mean change and visit response in health-related quality of life
Score
Change from baseline
Visit response
EORTC QLQ-C30 Global quality 
of life score
≥+10
Improvement
≥-10
Deterioration
Otherwise
No change
EORTC QLQ-C30 symptom scales
≥+10
Deterioration
≤-10
Improvement
Otherwise
No change
EORTC QLQ-C30 functional 
scales
≥+10
Improvement
≥-10
Deterioration
Otherwise
No change
EORTC European Organisation for Research and Treatment of Cancer; QLQ-C30 30-item core quality of 
life questionnaire.
For each subscale, if <50% of the subscale items are missing, then the subscale score will 
be divided by the number of non-missing items and multiplied by the total number of items 
on the subscales (Fayers et al 1999).  If at least 50% of the items are missing, then that 
subscale will be treated as missing.  Missing single items are treated as missing.  The 
reason for any missing questionnaire will be identified and recorded.  If there is evidence 
that the missing data are systematic, missing values will be handled to ensure that any 
possible bias is minimized.
Time to symptom deterioration
For each of the symptoms scales in the EORTC QLQ-C30, time to symptom deterioration 
will be defined as the time from randomization until the date of the first clinically 
meaningful symptom deterioration (an increase in the score from baseline of ≥10) or death 


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(by any cause) in the absence of a clinically meaningful symptom deterioration, regardless 
of whether the patient discontinues study treatment or receives another anticancer therapy 
prior to symptom deterioration.  Death will be included as an event only if the death occurs 
within 2 visits of the last PRO assessment where the symptom change could be evaluated.  
Patients whose symptoms (as measured by EORTC QLQ-C30) have not shown a clinically 
meaningful deterioration and who are alive at the time of the analysis will be censored at 
the time of their last PRO assessment where the symptom could be evaluated.  Also, if 
symptoms deteriorate after 2 or more missed PRO assessment visits or the patient dies 
after 2 or more missed PRO assessment visits, the patient will be censored at the time of 
the last PRO assessment where the symptom could be evaluated.  If a patient has no 
evaluable visits or does not have baseline data they will be censored at 0 days.  The 
population for the analysis of time to symptom deterioration will include a subset of the 
FAS who have baseline scores of ≤90.
Time to quality of life/function deterioration
For QoL, time to deterioration will be defined as the time from the date of randomization 
until the date of the first clinically meaningful deterioration (a decrease in the function 
scales or the global health status/QoL from baseline of ≥10) or death (by any cause) in the 
absence of a clinically meaningful deterioration, regardless of whether the patient 
discontinues study treatment or receives another anticancer therapy prior to QoL/function 
deterioration.  Death will be included as an event only if the death occurs within 2 visits of 
the last PRO assessment where the QoL/function change could be evaluated.  
Patients whose QoL (as measured by EORTC QLQ-C30) have not shown a clinically 
meaningful deterioration and who are alive at the time of the analysis will be censored at 
the time of their last PRO assessment where the QoL/function could be evaluated.  Also, if 
QoL deteriorates after 2 or more missed PRO assessment visits or the patient dies after 2 
or more missed PRO assessment visits, the patient will be censored at the time of the last 
PRO assessment where QoL/function could be evaluated.  If a patient has no evaluable 
visits or does not have baseline data they will be censored at 0 days.  The population for 
the analysis of time to QoL/function deterioration will include a subset of the FAS who 
have baseline scores of ≥10.
Symptom improvement rate
The symptom improvement rate will be defined as the number (%) of patients with 
2 consecutive assessments at least 14 days apart that show a clinically meaningful 
improvement (a decrease from baseline score ≥10 for EORTC QLQ-C30 symptom scales) 
in that symptom from baseline.  The denominator will consist of a subset of the FAS who 
have a baseline symptom score ≥10.
QoL/function improvement rate
The QoL/function improvement rate will be defined as the number (%) of patients with 
2 consecutive assessments at least 14 days apart that show a clinically meaningful 
improvement (an increase from baseline score ≥10 for EORTC QLQ-C30 functional scales 
and global health status/QoL) in that scale from baseline.  The denominator will consist of 
a subset of the FAS who have a baseline QoL/function score ≥10.


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Version 12.0
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8.4.3.2 EORTC QLQ-H&N35
The QLQ-H&N35 is a head and neck cancer-specific module from the EORTC comprising 
35 questions to assess head and neck cancer symptoms.  The head and neck cancer module 
includes 11 single items and 7 multi-item scales that assess pain, swallowing, senses (taste 
and smell), speech, social eating, social contact, and sexuality.  For all items and scales, 
high scores indicate increased symptomatology/more problems.  
The scoring approach for the QLQ-H&N35 is identical in principle to that for the symptom 
scales/single items of the EORTC QLQ-C30.  As the wording is reversed on the 
QLQ-H&N35, higher scores represent greater symptom severity.
Definition of clinically meaningful changes
Changes in score compared with baseline will be evaluated.  A minimum clinically 
meaningful change is defined as a change in the score from baseline of >10 for 
scales/items from QLQ-H&N35 (Bjordal et al 2000).  For example, a clinically meaningful 
deterioration or worsening in dry mouth (as assessed by QLQ-H&N35) is defined as an 
increase in the score from baseline of ≥10.  At each post-baseline assessment, the change 
in symptoms/functioning from baseline will be categorized as improved, no change, or 
deterioration, as shown in Table 14.
Table 14
Visit response for HRQoL and disease-related symptoms
Score
Change from baseline
Visit response
QLQ-H&N35 symptom scales and 
items
≥+10
Deterioration
≤-10
Improved
Otherwise
No change
HRQoL Health-related quality of life; QLQ-H&N35 35-item head and neck quality of life questionnaire.
Time to symptom deterioration
For each of the symptom scales/items in the QLQ-H&N35, time to symptom deterioration 
will be defined as the time from the date of the first dose until the date of the first clinically 
meaningful symptom deterioration (an increase in the score from baseline of ≥10) or death 
(by any cause) in the absence of a clinically meaningful symptom deterioration, regardless 
of whether the patient discontinues study treatment or receives another anticancer therapy 
prior to symptom deterioration.  Death will be included as an event only if the death occurs 
within 2 visits of the last PRO assessment where the symptom change could be evaluated.
Patients whose symptoms (as measured by the QLQ-H&N35) have not shown a clinically 
meaningful deterioration and who are alive at the time of the analysis will be censored at 
the time of their last PRO assessment where the symptom could be evaluated.  Also, if 
symptoms progress after 2 or more missed PRO assessment visits or the patient dies after 2 
or more missed PRO assessment visits, the patient will be censored at the time of the last 
PRO assessment where the symptom could be evaluated.  If a patient has no evaluable 
visits or does not have baseline data, they will be censored at 0 days.


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Symptom improvement rate
The symptom improvement rate will be defined as the number (%) of patients with 
2 consecutive assessments at least 14 days apart that show a clinically meaningful 
improvement (a decrease from baseline score >10 for QLQ-H&N35 scales/items) in that 
symptom from baseline.
8.4.3.3
 
 
 
 
 
 
 
 
8.4.4
Calculation or derivation of pharmacokinetic variables
8.4.4.1 Population pharmacokinetics and exposure-response/safety analysis
A population PK model may be developed using a non-linear mixed-effects modeling 
approach for MEDI4736 monotherapy and for MEDI4736 in combination with 
tremelimumab.  The impact of physiologically-relevant patient characteristics (covariates) 
and disease on PK of both agents may be evaluated.  The relationship between MEDI4736 
PK exposure or tremelimumab PK exposure and the effect on safety and efficacy end 
points may be evaluated.  The results of such analyses will be reported outside of the CSR.
8.4.4.2 Pharmacokinetic analysis
Pharmacokinetic data analyses of MEDI4736 and tremelimumab will be performed by the 
MedImmune Global Pharmacokinetics Pharmacodynamics (PK-PD) & Bioanalysis group 
or designee. No formal non-compartmental (NCA) PK analysis will be conducted due to 
the sparse PK sampling scheme for MEDI4736 and tremelimumab, which does not allow 
for meaningful determination of PK parameters.  MEDI4736 and tremelimumab 
concentration data and summary statistics will be tabulated by treatment arm and visit.  PK 
parameters, such as peak and trough concentration of MEDI4736 and tremelimumab, will 
be derived from raw data measurements as data allow. 
8.4.4.3 Immunogenicity analysis
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of patients who develop detectable ADAs against MEDI4736. The same 
analysis will be conducted for ADAs against tremelimumab.  The immunogenicity titer 
will be reported for samples confirmed positive for the presence of ADAs.  The effect of 
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immunogenicity on PK, pharmacodynamics, efficacy, and safety may be evaluated as data 
allow.
8.5
Methods for statistical analyses
The formal statistical analysis will be performed to test the main hypotheses: 

H0: No difference between MEDI4736 monotherapy and SoC

H1: Difference between MEDI4736 monotherapy and SoC
The primary objective is OS in the PD-L1 TC/IC high subgroup.  
The analysis of OS will be performed when approximately 147 death events have occurred 
in approximately 172 patients (85% maturity) across the MEDI4736 monotherapy and SoC 
treatment groups in the PD-L1 TC/IC high subgroup. All other endpoints will be analysed 
at this time.  No interim analyses will be performed for any efficacy endpoint.
Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
treatment arm.  Continuous variables will be summarized by the number of observations, 
mean, standard deviation, median, minimum, and maximum.  Categorical variables will be 
summarized by frequency counts and percentages for each category.  Unless otherwise 
stated, percentages will be calculated out of the population total for the corresponding 
treatment arm.  
Baseline will be the last assessment of the variable under consideration prior to the intake 
of the first dose of IP, except for efficacy variables.  For efficacy variables, baseline is 
defined as the last visit prior to randomization.
PK data will be summarized and analyzed based on the PK Analysis Set.  Safety data will 
be summarized on the safety analysis set.
Results of all statistical analyses will be presented using approximately-sized 95% CIs and 
2-sided p-values, unless otherwise stated.


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Table 15
Pre-planned statistical and sensitivity analysis to be conducted
Endpoints Analyzed
Notes
OS
Stratified log-rank  tests and Cox proportional method for:
Primary objectives
MEDI4736 monotherapy versus SoC in the PD-L1 TC/IC high subgroup 
(stratified by PD-L1 status, tumor location and smoking history)
Secondary objectives
-
MEDI4736 monotherapy versus SoC in the low risk of EM 
subgroup (stratified by PD-L1 status, tumor location and smoking 
history)
-
MEDI4736 monotherapy versus SoC in ctDNA TMB high 
subgroup (≥ 16mut/Mb)
-
MEDI4736 monotherapy versus SoC in all-comers population
-
MEDI4736 + tremelimumab combination therapy versus SoC in the 
PD-L1 TC/IC high subgroup (stratified by PD-L1 status, tumor 
location and smoking history)
-
MEDI4736 + tremelimumab combination therapy versus SoC in the 
low risk of EM subgroup (stratified by PD-L1 status, tumor 
location, and smoking history)
-
MEDI4736 + tremelimumab combination therapy versus SoC in 
ctDNA TMB high (≥16 mut/Mb) subgroup
-
MEDI4736 + tremelimumab combination therapy versus SoC in  
all-comers (stratified by PD-L1 status, tumor location, and smoking 
history)
-
MEDI4736 + tremelimumab combination therapy versus 
MEDI4736 monotherapy (PD-L1 TC/IC high subgroup, low risk of 
EM subgroup, ctDNA TMB high (≥16 mut/Mb) and all-comers); 
stratified by PD-L1 status, tumor location and smoking history)
Sensitivity Analyses:
Sensitivity analysis using the Max-combo test


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Endpoints Analyzed
Notes
PFS
Stratified log-rank tests and Cox proportional method for:
-
Secondary objectives using investigator assessments (RECIST 1.1): 
MEDI4736 monotherapy versus SoC (PD-L1 TC/IC high subgroup, 
low risk of EM subgroup, ctDNA TMB high (≥16 mut/Mb) 
subgroup and all-comers); stratified by PD-L1 status, tumor 
location and smoking history
-
MEDI4736 + tremelimumab combination therapy versus SoC (PD-
L1 TC/IC high subgroup, low risk of EM subgroup, ctDNA TMB 
high (≥16 mut/Mb) subgroup and all-comers); stratified by PD-L1 
status, tumor location and smoking history
-
MEDI4736 + tremelimumab combination therapy versus 
MEDI4736 monotherapy (PD-L1 TC/IC high subgroup, low risk of 
EM subgroup, ctDNA TMB high (≥16 mut/Mb) subgroup and all-
comers); stratified by PD-L1 status, tumor location and smoking 
history
Sensitivity analyses
-
Sensitivity analysis using BICR assessments (RECIST 1.1)
-
Sensitivity analysis based on RECIST 1.1 modified for 
confirmation of progression using site Investigator assessments 
Exploratory analyses
-
OS12, OS18 and OS24
OS rates using the Kaplan-Meier estimates at 12, 18 and 24 months for the 
PD-L1 TC/IC high subgroup, low risk of EM subgroup, ctDNA TMB high 
(≥16 mut/Mb) subgroup and all-comers
ORR
Logistic regression for:
Secondary objectives
-
Secondary analysis for the, PD-L1 TC/IC high subgroup, low risk 
of EM subgroup, ctDNA TMB high (≥16 mut/Mb) subgroup
and all-comers using investigator RECIST 1.1 assessments
Exploratory analyses
-
 
DoR
Descriptive statistics and Kaplan-Meier plot for the PD-L1 TC/IC high 
subgroup and all-comers
BoR
Descriptive statistics N (%) for the PD-L1 TC/IC high subgroup and all-
comers
TTR
Descriptive statistics N (%) for the PD-L1 TC/IC high subgroup and all-
comers
TFST
Stratified log-rank test for the PD-L1 TC/IC high subgroup and all-comers
TSST
Stratified log-rank test for the PD-L1 TC/IC high subgroup and all-comers
APF6 and APF12
PFS rates using the Kaplan-Meier estimates of PFS at 6 and 12 months for 
the low risk of EM subgroup, ctDNA TMB high (≥16 mut/Mb), PD-L1 
TC/IC high subgroup and all-comers
Time from randomization to 
second progression
Stratified log-rank test for the PD-L1 TC/IC high subgroup and all-comers
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Endpoints Analyzed
Notes
Time to symptom 
deterioration (EORTC QLQ-
C30 and EORTC 
QLQ-H&N35 endpoints)
Stratified log-rank test for the PD-L1 TC/IC high subgroup, and all-
comers
Improvement rate (EORTC 
QLQ-C30 and EORTC 
QLQ-H&N35 endpoints)
Logistic regression
For all-comers and the PD-L1 TC/IC high subgroup populations
Average change from 
baseline (EORTC QLQ-C30 
and EORTC QLQ-H&N35 
endpoints)
Mixed effect model repeated measurement (MMRM) analysis. Descriptive 
statistics including change from baseline for all-comers and the PD-L1 
TC/IC high subgroup populations. 
APF12 Proportion of patients alive and progression free at 12 months; BICR Blinded Independent Central 
Review; BoR Best objective response; ctDNA circulating tumor DNA;  DCR Disease control rate; 
DoR Duration of response; EM Early mortality; EORTC European Organisation for Research and Treatment 
of Cancer; HR Hazard ratio; IC tumor-associated immune cells; irRECIST 1.1 Immune-related response 
criteria updated for RECIST 1.1; ITT Intent-to-Treat; ORR Objective response rate; OS Overall survival; 
OS12 Proportion of patients alive at 12 months after randomization; OS18 Proportion of patients alive at 18 
months after randomization; OS24 Proportion of patients alive at 24 months after randomization; PD-
L1 Programmed death ligand 1; PFS Progression-free survival; QLQ-C30 30-item core quality of life 
questionnaire; QLQ-H&N35 35-item head and neck quality of life questionnaire; RECIST 1.1 Response 
Evaluation Criteria in Solid Tumors version 1.1; TC tumor cells; TFST Time to first subsequent therapy; 
TMB Tumor Mutation Burden; TTR Time to response; TSST Time to second subsequent therapy.
Multiple testing procedure (MTP)
In order to strongly control the type I error at 5% (2-sided), the MTP shown in Figure 6 
will be used across the primary endpoint (OS), treatment comparisons (MEDI4736 
monotherapy versus SoC and MEDI4736 + tremelimumab combination therapy versus 
SoC), and across the analysis populations (PD-L1 TC/IC high subgroup, low risk of EM 
subgroup, ctDNA TMB high (≥16 mut/Mb) subgroup, and all-comers). If the highest level 
hypothesis in the MTP is statistically significant then the next hypothesis in the hierarchy 
will then be tested, and so on through the hierarchy until a hypothesis is not-statistically 
significant. Implementation of this pre-defined ordered testing procedure will strongly 
control type I error at 5% (2-sided) among all key hypotheses.
Of note, the comparison of MEDI4736 + tremelimumab combination therapy versus 
MEDI4736 monotherapy and the comparison of MEDI4736 + tremelimumab combination 
therapy versus SoC (in the PD-L1 TC/IC high subgroup, and low risk of EM subgroup will 
not be included in the MTP, and therefore will not be conducted under strict alpha control.
The OS analysis will be performed when approximately 147 death events from the PD-L1 
TC/IC high subgroup have occurred in approximately 172 patients (85% maturity) across 
the MEDI4736 monotherapy and SoC treatment groups. All other endpoints will be 
analysed at this time.  No interim analyses will be performed for any efficacy endpoint.
Figure 6
Multiple testing procedure for controlling the overall type 1 error rate


Revised Clinical Study Protocol
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Study Code D419LC00001
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Date 29 June 2020
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Combo MEDI4736 + tremelimumab combination therapy; ctDNA circulating tumor DNA; EM Early 
mortality; IC tumor-associated immune cells; OS Overall survival; PD-L1 Programmed death ligand 1; SoC 
Standard of Care; TC tumor cells; TMB Tumor Mutation Burden 
8.5.1
Analysis of the primary endpoint 
8.5.1.1 Overall survival
The analysis of OS will be done using a stratified log-rank test stratified by PD-L1 status 
(positive versus negative), tumor location (OPC versus non-OPC, with a subsequent 
adjustment for HPV status in patients with OPC), and smoking history (>10 versus ≤10 
pack-years) as entered in the IVRS system. Refer to Figure 6 for the multiple testing 
procedure (MTP) with the primary objective at the first row of the testing sequence.


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Study Code D419LC00001
Version 12.0
Date 29 June 2020
The effect of treatment will be estimated by the HR together with its corresponding 95% 
CI and p-value, using a stratified Cox propotional hazards model.
Kaplan-Meier plots of OS will be presented by treatment arm.  Summaries of the number 
and percentage of patients who have died, those still in survival follow-up, those lost to 
follow-up, and those who have withdrawn consent will be provided along with the median 
OS for each treatment.
A sensitivity analysis for OS will examine the censoring patterns to rule out attrition bias, 
achieved by a Kaplan-Meier plot of time to censoring where the censoring indicator of OS 
is reversed.
Cox proportional hazards modeling will be employed to assess the effect of covariates on 
the HR estimate.  Details will be presented in the SAP.
Impact of switching (crossover outside of this study) to immunotherapies (or other 
potentially active investigational agents) on OS analyses
 
 
 
 
 
 
 
 
 
8.5.1.2 Subgroup analysis of OS
Subgroup analyses will be conducted comparing OS between MEDI4736 + tremelimumab 
combination therapy versus SoC, MEDI4736 monotherapy versus SoC and MEDI4736 + 
tremelimumab combination therapy versus MEDI4736 monotherapy in the PD-L1 TC/IC 
high subgroup, ctDNA TMB high subgroup (≥16 mut/Mb), low risk of EM subgroup and 
the FAS (all-comers): 

Sex (male, female)

Age at randomization (<65, ≥65-<75, ≥75 years of age)

PD-L1 TC≥25 status for stratification (positive, negative)

PD-L1 TC/IC expression (TC≥50 or IC≥25 (High), TC<50 and IC<25 (Low))


Tumor location/HPV (OPC/Positive, OPC/Negative, non-OPC/Any HPV)

Primary tumor site (oropharynx, oral cavity, hypopharynx, larynx)

Smoking history (>10, ≤10 pack-years)

Race (Asian, non-Asian)
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
ECOG Performance status (0, 1)

Extent of Disease (only locoregionally recurrent, metastatic with or without 
locoregional recurrence)
Treatment effect will be estimated by the HR together with its corresponding 95% CI 
using an unstratified Cox model with treatment as the only covariate.
Other baseline variables may also be assessed if there is clinical justification or if an 
imbalance is observed between the treatment arms.  The purpose of the subgroup analyses 
is to assess the consistency of treatment effect across expected prognostic and/or predictive 
factors. Only the HR estimate along with 95% CI will be presented.
No adjustment to the significance level for testing of the subgroup and sensitivity analyses 
will be made since all these analyses will be considered supportive of the analysis of OS.
A forest plot will be presented for the subgroups showing the comparison of MEDI4736 
+/- tremelimumab therapy versus SoC in the PD-L1 TC/IC subgroup, low risk of EM 
subgroup, all-comers and the ctDNA TMB (≥16 mut/Mb) subgroup. 
8.5.2
Analysis of the secondary variable(s)
8.5.2.1 Progression-free survival
The PFS analysis will be based on the programmatically derived RECIST 1.1 using the 
investigator assessments.  The analysis will be performed with the, PD-L1 TC/IC high 
subgroup, low risk of EM subgroup, ctDNA TMB high (≥16 mut/Mb) subgroup and all-
comers using a stratified log-rank test stratified by PD-L1 status (positive versus negative), 
tumor location (OPC versus non-OPC, with a subsequent adjustment for HPV status in 
patients with OPC), and smoking history (>10 versus ≤10 pack-years) as entered in the 
IVRS system.  
The effect of MEDI4736 monotherapy versus SoC treatment will be estimated by the HR 
together with its corresponding 95% CI and p-value. The stratification factors will be 
based on the values entered into IVRS at randomization even if it is subsequently 
discovered that these values were incorrect.
The hazard ratio (HR) of PFS, along with 95% confidence interval (using the same strata 
information as above) will be estimated using a stratified Cox model with treatment as the 
only covariate.
A PFS analysis will also be performed to compare MEDI4736 + tremelimumab 
combination therapy versus SoC as well as to compare MEDI4736 + tremelimumab
combination therapy versus MEDI4736 monotherapy for the  PD-L1 TC/IC high 
subgroup, low risk of EM subgroup, ctDNA TMB high (≥16 mut/Mb) subgroup, and all-
comers.  These analyses will be performed using the same methodology as described 
above. 
Kaplan-Meier plots of PFS will be presented by treatment arm in the low risk of EM 
subgroup, all-comers, PD-L1 TC/IC high subgroup and ctDNA TMB high (≥16 mut/Mb) 
subgroup  where appropriate.  


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Version 12.0
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A sensitivity analysis will be performed by analyzing the BICR assessments.  The 
stratified log-rank test will be repeated on these data.  The HR and CI will be presented.  
The methodology will be documented in the SAP.
 
 
8.5.2.2 Objective response rate
The ORR will be based on the programmatically derived RECIST 1.1 using investigator 
assessment data.  The ORR will be compared between MEDI4736 monotherapy versus 
SoC, MEDI4736 + tremelimumab versus SoC, and MEDI4736 + tremelimumab versus 
MEDI4736 monotherapy using logistic regression models adjusting for the same factors as 
the primary endpoint (PD-L1 status, tumor location, and smoking history).  The results of 
the analysis will be presented in terms of an odds ratio together with its associated profile 
likelihood 95% CI and p-value (based on twice the change in log-likelihood resulting from 
the addition of a treatment factor to the model).  This analysis will be performed on the 
PD-L1 TC/IC high subgroup, low risk of EM subgroup and all-comers. The ORR will 
again be compared between MEDI4736 +/- tremelimumab versus SoC using logistic 
regression models for the ctDNA TMB high (≥16 mut/Mb) subgroup.
 
Summaries will be produced that present the number and percentage of patients with a 
tumor response (CR/PR).  Overall visit response data will be listed and summarized over 
time for all patients (ie, the FAS).  For each treatment arm, BoR will be summarized by n 
(%) for each category (CR, PR, SD, PD, and NE).  No formal statistical analyses are 
planned for BoR.
8.5.2.3 Duration of response
Descriptive data will be provided for the DoR in responding patients, including the 
associated Kaplan-Meier curves (without any formal comparison of treatment arms or 
p-value attached).
8.5.2.4 Best objective response
BoR based on site investigator data (RECIST 1.1), for each treatment arm, BoR will be 
summarized by n (%) for each category (CR, PR, SD, PD and NE). No formal statistical 
analysis are planned for BoR.
8.5.2.5 Time to response
The TTR, based upon the site investigator assessment of RECIST 1.1, will be summarised 
(ie, number of patients [%] based upon the number of responders) by the scheduled 
assessment timepoint that the response was first observed.  Additionally, descriptive 
summary statistics (ie, minimum, maximum, median, Q1 and Q3) will also be presented. 
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8.5.2.6 Proportion of patients alive and progression free at 6 and 12 months
The APF6 and APF12 will be summarized (using the Kaplan-Meier estimate) and 
presented by treatment arm.  APF6 and APF12 will be compared between MEDI4736 
monotherapy versus SoC and MEDI4736 + tremelimumab combination therapy versus 
SoC, PD-L1 TC/IC high subgroup, low risk of EM subgroup, ctDNA TMB high (≥16 
mut/Mb) subgroup and all-comers by using the Kaplan-Meier estimate of PFS at 6 and 12 
months for each treatment.
8.5.2.7 Time from randomization to PFS2
PFS2 is defined as the time from the date of randomization to the earliest of the 
progression event subsequent to that used for the PFS endpoint.  PFS2 will be analyzed 
using a stratified log-rank tests, using the same methodology as described for the primary 
PFS endpoint.  The effect of MEDI4736 monotherapy versus SoC and MEDI4736 + 
tremelimumab combination therapy versus SoC for the PD-L1 TC/IC high subgroup and 
all-comers will be estimated by the HR together with its corresponding CI and p-value.  
Kaplan-Meier plots will be presented by treatment arm.  Summaries of the number and 
percentage of patients who have an event as well as who were censored will be provided 
along with the medians for each treatment.  
8.5.2.8 Time from randomization to first and second subsequent therapy or death 
For supportive purposes, the time to the start of the first and the second subsequent therapy 
or death will be analyzed for the PD-L1 TC/IC high subgroup and all-comers using the 
same methodology and model as that used for the analysis of PFS.  The HR for the 
treatment effect together with its 95% CI will be presented.  In addition, a Kaplan-Meier 
plot of the time to the start of the first and the second subsequent therapy will be presented 
by treatment arm, and the time between progression and start of the first and the second 
subsequent therapy will be assessed.  This interval will be summarized per treatment arm, 
but no formal comparisons will be made.  
In patients who received subsequent anticancer therapy, a summary table of the first and 
the second subsequent anticancer therapies by treatment arm will be provided, as well as 
response to the first and the second subsequent anticancer therapy by treatment arm (if 
available).
The number of patients prematurely censored will also be summarized.
8.5.2.9 Proportion of OS12, OS18 and OS24
OS12, OS18 and OS24 will be summarized (using the Kaplan-Meier estimate) and 
presented by treatment arm for the PD-L1 TC/IC high subgroup, low risk of EM subgroup, 
ctDNA TMB high (≥16 mut/Mb) and all-comers.
8.5.3
Patient-reported outcomes
The PRO endpoints that have been identified as secondary objectives are EORTC QLQ-
C30 time to HRQoL deterioration for global health status, time to symptom deterioration 
for functional physical domain, time to symptom deterioration for fatigue, and QLQ-
H&N35 time to symptom deterioration for these 2 symptoms; pain and swallowing.  These 
are not part of the main MTP, and as supportive endpoints will need a Bonferroni 


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Version 12.0
Date 29 June 2020
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adjustment to the significance level to aid interpretation.  Therefore, these 5 endpoints will 
be tested at a 1.0% significance level and 99% CIs will be produced.
The other time to symptom deterioration endpoints will be tested at a 5% significance level 
and 95% CIs will be produced.
8.5.3.1 EORTC QLQ-C30
Time to symptom deterioration in the PD-L1 TC/IC high subgroup and all-comers will be 
analyzed for each of the 3 symptom scales (fatigue, pain, and nausea/vomiting). Time to 
HRQoL/function deterioration in all-comers will be analyzed for the 5 function scales 
(physical, role, emotional, cognitive, and social) and global health status/QoL. These 
analyses will be done using a stratified log-rank test (at the 5% significance level), using 
the same methodology as described for the primary PFS endpoint.
The effect of MEDI4736 monotherapy versus SoC will be estimated by the HR together 
with its corresponding CI and p-value, using an unstratified Cox model with treatment as 
the only covariate.   Time to deterioration will be presented using a Kaplan-Meier plot for 
each of the 3 symptom scales (fatigue, pain, and nausea/vomiting), 5 functional scales 
(physical, role, emotional, cognitive, and social), and global health status/QoL by 
treatment arm.  Summaries of the number and percentage of patients who have an event as 
well as who were censored will be provided along with the medians for each treatment.
A summary of the symptom improvement rate for each of the 3 symptom scales (fatigue, 
pain and nausea/vomiting) will be produced.  Similarly, a summary of QoL/function 
improvement rate for each of the 5 function scales (physical, role, emotional, cognitive, 
and social) and global health status/QoL will be produced.  Symptom improvement rate 
and HRQoL/function improvement rate will be analyzed by comparing between treatment 
arms using a logistic regression model as described for the analysis of ORR.
Summaries of absolute and change from baseline values for each of the 3 symptom 
scales/items (fatigue, pain, and nausea/vomiting), 5 individual symptom items (dyspnea, 
insomnia, appetite loss, constipation, and diarrhea), 5 functional scales (physical, role, 
emotional, cognitive, and social) and the global health status\QoL score, and each 
functional domain will be reported by visit for each treatment arm.  Graphical 
presentations may also be produced as appropriate.  
Analysis of HRQoL or symptom will also be carried out by comparing mean change from 
baseline in the global health status/QoL, functions (physical, role, cognitive, social and 
emotional) scores (from the EORTC QLQ-C30 questionnaire).
Change from baseline will be derived using a MMRM analysis of all the post-baseline 
scores for each visit.  The model will include treatment, visit, and treatment by visit 
interaction as explanatory variables and the baseline score as a covariate. Adjusted mean 
estimates per treatment group and corresponding 95% CIs will be presented along with an 
overall estimate of the treatment difference, 95% CI and p-value. An overall adjusted mean 
estimate will be derived that will estimate the average treatment effect over visits giving 
each visit equal weight using least squares means. 


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8.5.3.2 EORTC QLQ-H&N35
Time to symptom deterioration in the PD-L1 TC/IC high subgroup and all-comers for each 
of the 4 symptom scales/items in the QLQ-H&N35 (pain, swallowing, senses and speech)
will be compared between treatment arms using a stratified log-rank test (at the 5% 
significance level) as described for the primary analysis of OS.
The effect of MEDI4736 monotherapy versus SoC will be estimated by the HR together 
with its corresponding CI and p-value, using an unstratified Cox model with treatment as 
the only covariate.
For each of the above 4 symptom scales/items in the QLQ-H&N35, time to deterioration in 
symptoms will be presented using a Kaplan-Meier plot.  Summaries of the number and 
percentage of patients experiencing a clinically meaningful deterioration or death, and the 
median time to deterioration, will also be provided for each treatment group.
A summary of the symptom improvement rate for each of the 4 symptom scales/items 
mentioned above will be produced.  The symptom improvement rate will be compared 
between treatment groups using a logistic regression model as described for ORR.  
Summaries of absolute and change from baseline values for each of the 7 symptom 
scales/items (pain, swallowing, senses, speech, social eating, social contact and sexuality)  
and 11 single-item measures (teeth, problems with mouth opening, dry mouth, sticky 
saliva, coughing, feeling ill, use of analgesics, use of nutritional supplements, use of a 
feeding tube, weight gain, and weight loss)  will be reported by visit for each treatment 
group.  Graphical presentations may also be produced as appropriate.   
The assessment of symptoms comparing mean change from baseline using the MMRM as 
described for EORTC QLQ-C30 will be repeated for pain, swallowing, senses, and speech 
of the EORTC QLQ-H&N35.  All assumptions and outputs as described for the EORTC 
QLQ-C30 are applicable and the same approach from EORTC QLQ-C30 will be applied.
8.5.3.3 Exploratory patient-reported outcomes
 
 
  
8.5.4
Safety data
Safety and tolerability data will be presented by treatment arm, for patients in the PD-L1 
TC/IC high subgroup, low risk of EM subgroup and all-comers, using the safety analysis 
set.    
Data from all cycles of treatment will be combined in the presentation of safety data.  AEs 
(both in terms of Medical Dictionary for Regulatory Activities [MedDRA] preferred terms 
and CTCAE grade) will be listed individually by patient.  The number of patients
experiencing each AE will be summarized by treatment arm and CTCAE grade.  
Additionally, data presentations of the rate of AEs per person-years at risk may be 
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produced.  Any safety summaries examining retreatment with MEDI4736 + tremelimumab 
will be produced separately.
Other safety data will be assessed in terms of physical examination, clinical chemistry, 
hematology, vital signs, and ECGs.  Exposure to MEDI4736 + tremelimumab combination 
therapy, MEDI4736 monotherapy, and SoC will be summarized.  Time on study, 
MEDI4736 + tremelimumab combination therapy, MEDI4736 monotherapy, and SoC 
dose delays and dose reductions in the SoC arm will also be summarized.  At the end of 
the study, appropriate summaries of all safety data will be produced, as defined in the 
SAP.
8.5.5
Pharmacokinetic data
PK concentration data of MEDI4736 and tremelimumab will be listed for each patient and 
each dosing day with a matching PK sample, and a summary will be provided for all 
evaluable patients.
8.5.6
Immunogenicity data
Immunogenicity results will be listed by patient, and a summary will be provided by the 
number and percentage of patients who develop detectable anti-MEDI4736 and 
anti-tremelimumab antibodies.  The immunogenicity titer and neutralizing ADA data will 
be listed for samples confirmed positive for the presence of anti-MEDI4736 and 
anti-tremelimumab antibodies.  
The effect of immunogenicity as well as the effect of its neutralizing properties on PK, 
pharmacodynamics, efficacy, and safety may be evaluated as data allow.  
8.5.7
Biomarker data
  
 
Subgroup analysis by HPV/EBV status may be performed, if data are available.
8.5.8
Interim analysis
Interim safety monitoring will be conducted by an IDMC.  Details of the plan and 
communication process will be provided in an IDMC Charter.
No interim analyses will be performed for any efficacy endpoint.
9. STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first patient is enrolled in the study, an AstraZeneca representative will review 
and discuss the requirements of the clinical study protocol (CSP) and related documents 
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with the investigational staff and train them in any study-specific procedures and 
IVRS/IWRS, WBDC, and any ePRO systems to be utilized.
The Principal Investigator will ensure that appropriate training relevant to the study is 
given to all of these staff and that any new information relevant to the performance of this 
study is forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing, and other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study 
site, including visits to

Provide information and support to the Investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the protocol, data are being 
accurately and timely recorded in the eCRFs, biological samples are handled in 
accordance with the Laboratory Manual, and study drug accountability checks are 
being performed

Perform source data verification (a comparison of the data in the eCRFs with the 
patient’s medical records at the hospital or practice and other records relevant to the 
study), including verification of informed consent of participating patients.  This will 
require direct access to all original records for each patient (eg, clinic charts).

Ensure that withdrawal of informed consent for the use of the patient’s biological 
samples is reported, biological samples are identified and disposed of or destroyed 
accordingly, and the action is documented and reported to the patient
The AstraZeneca representative will be available between visits if the Investigators or 
other staff at the centers need information and advice about the study conduct.
9.2.1
Source data
Refer to the CSA for location of source data.
9.2.2
Study agreements
The Principal Investigator at each center should comply with all the terms, conditions, and 
obligations of the CSA for this study.  In the event of any inconsistency between this CSP 
and the CSA, the terms of CSP shall prevail with respect to the conduct of the study and 
the treatment of patients.  In all other respects not relating to study conduct or treatment of 
patients, the terms of the CSA shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before 
any study-related procedures can take place or before any patients are enrolled.
9.2.3
Archiving of study documents
The Investigator will follow the principles outlined in the CSA.


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9.3
Study timetable and end of study
The end of the study is defined as the “last visit of the last patient undergoing the study.”  
The Investigator will be notified by the Sponsor when recruitment is complete.
The study is expected to start in Q4 2015 and end by Q3 2019.
The study may be terminated at individual centers if the study procedures are not being 
performed according to Good Clinical Practice (GCP) or if recruitment is slow.  
AstraZeneca may also terminate the entire study prematurely if concerns for safety arise 
within this study or in any other study involving MEDI4736.
9.4
Data management by AstraZeneca
Data management will be performed by a chosen vendor according to the Data 
Management Plan.  AEs and medical/surgical history will be classified according to the 
terminology of the latest version of MedDRA.  Medications will be classified according to 
the AstraZeneca Drug Dictionary.  Classification coding will be performed by the chosen 
vendor.
The data collected through third party sources will be obtained and reconciled against 
study data.
Data queries will be raised for inconsistent, impossible, or missing data.  All entries to the 
study database will be available in an audit trail.
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  The Data Management Plan will also clarify the roles 
and responsibilities of the various functions and personnel involved in the data 
management process.
When all data have been coded, validated, signed, and locked, a clean file will be declared.  
Any treatment-revealing data may be added thereafter, and the final database will be 
locked.
Serious adverse event reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site.  
Data management of genotype data
Any genotype data generated in this study will be stored in the AstraZeneca genotyping 
database or other appropriate secure system within AstraZeneca and/or a third party 
contracted to work with AstraZeneca to analyze samples.  The results from this genetic 
research may be reported in the CSR for the main study or in a separate report, as 
appropriate.
Some or all of the clinical datasets from the main study may be merged with the genetic 
data in a suitable secure environment separate from the clinical database.


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Data associated with human biological samples
Data associated with human biological samples will be transferred from laboratories 
internal or external to AstraZeneca.
10.ETHICAL AND REGULATORY REQUIREMENTS
10.1 Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in 
the Declaration of Helsinki and are consistent with International Conference on 
Harmonisation (ICH)/GCP, applicable regulatory requirements, and the AstraZeneca 
policy on Bioethics and Human Biological Samples.  
10.2 Patient data protection
The ICF will incorporate wording that complies with relevant data protection and privacy 
legislation.  In some cases, such wording will be in a separate accompanying document.
AstraZeneca will not provide individual genotype results to patients, their family members, 
their general physician, any insurance company, any employer, or any other third party, 
unless required to do so by law.
Precautions are taken to preserve confidentiality and prevent genetic data from being 
linked to the identity of the patient.  In exceptional circumstances, however, certain 
individuals might see both the genetic data and the personal identifiers of a patient.  For 
example, in the case of a medical emergency, an AstraZeneca Physician or an Investigator 
might know a patient’s identity and might also have access to his or her genetic data.  
Also, regulatory authorities may require access to the relevant files.  Even so, the patient’s 
medical information and the genetic files would remain physically separate.
10.3 Ethics and regulatory review
An Ethics Committee (EC)/Institutional Review Board (IRB) should approve the final 
study protocol, including the final version of the ICF and any other written information 
and/or materials to be provided to the patients.  The Investigator will ensure the 
distribution of these documents to the applicable EC/IRB and to the study site staff.
The opinion of the EC/IRB should be given in writing.  The Investigator should submit the 
written approval to AstraZeneca before enrollment of any patient into the study.  
The EC/IRB should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the protocol should be re-approved by the EC/IRB 
annually.


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Before enrollment of any patient into the study, the final study protocol, including the final 
version of the ICF, should be approved by the national regulatory authority or a 
notification to the national regulatory authority should be approved, according to local 
regulations.
AstraZeneca will handle the distribution of these documents to the national regulatory 
authorities.
AstraZeneca will provide regulatory authorities, ECs/IRBs, and Principal Investigators 
safety updates or reports according to local requirements.
Each Principal Investigator is responsible for providing the EC/IRB with reports of any 
serious and unexpected adverse drug reactions from any other study conducted with the IP.  
AstraZeneca will provide this information to the Principal Investigator so that he/she can 
meet these reporting requirements.
10.4 Informed consent
The Principal Investigator(s) at each center will:

Ensure that each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk, and benefit of the study

Ensure that each patient is notified that he or she is free to discontinue from the study 
at any time

Ensure that each patient is given the opportunity to ask questions and allowed time to 
consider the information provided

Ensure that each patient provides a signed and dated informed consent before 
conducting any procedure specifically for the study

Ensure that the original, signed ICF(s) is/are stored in the Investigator’s Study File

Ensure that a copy of the signed ICF is given to the patient

Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the ICF that is approved by an EC/IRB.
10.5 Changes to the protocol and informed consent form
For sites outside Japan
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and, where required, in a new version of the 
study protocol (revised CSP).
The amendment is to be approved by the relevant EC/IRB and, if applicable, the national 
regulatory authority, before implementation.  Local requirements are to be followed for 
revised protocols.


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AstraZeneca will distribute any subsequent amendments and new versions of the protocol 
to each Principal Investigator.  For distribution to EC/IRB, see Section 10.3.
If a protocol amendment requires a change to a center’s ICF, AstraZeneca and the center’s 
EC/IRB are to approve the revised ICF before the revised form is used.  
If required by local regulations, any administrative change will be communicated to or 
approved by each EC/IRB.
For sites in Japan only
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and AstraZeneca.  If it is necessary for the study protocol to be amended, the 
amendment should be submitted to the Head of the Study Site and be approved by its IRB.  
If applicable, AstraZeneca should submit a notification to the regulatory authority before it 
is implemented.  If a protocol amendment requires a change to a particular center’s ICF, 
then AstraZeneca and the center's IRB should be notified by the Principal Investigator.  
Approval of the revised ICF by AstraZeneca and IRB is required before the revised form is 
used.  If an administrative change is required, such a change should be notified to or 
approved by each IRB according to local requirements.
10.6 Audits and inspections
Authorized representatives of AstraZeneca, a regulatory authority, or an EC/IRB may 
perform audits or inspections at the center, including source data verification.  The purpose 
of an audit or inspection is to systematically and independently examine all study-related 
activities and documents, to determine whether these activities were conducted, and to 
determine if data were recorded, analyzed, and accurately reported according to the 
protocol, GCPs, ICH guidelines, and any applicable regulatory requirements.  The 
Investigator will contact AstraZeneca immediately if contacted by a regulatory agency 
about an inspection at the center.


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Study Code D419LC00001
Version 12.0
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Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
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Revised Clinical Study Protocol
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Study Code D419LC00001
Version 12.0
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Study Code D419LC00001
Version 12.0
Date 29 June 2020
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Clinical Study Protocol Appendix A
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
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Appendix A
Signatures
Electronically approved.


Clinical Study Protocol Appendix A
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
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Appendix B
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
“Life-threatening” means that the patient was at immediate risk of death from the adverse 
event (AE) as it occurred or it is suspected that use or continued use of the product would 
result in the patient’s death.  “Life-threatening” does not mean that had an AE occurred in a 
more severe form it might have caused death (eg, hepatitis that resolved without hepatic 
failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal edema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability, or incapacity but may jeopardize the patient or may require 
medical intervention to prevent 1 or more outcomes listed in the definition of serious.  These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalization

Development of drug dependency or drug abuse
A Guide to Interpreting the Causality Question
When making an assessment of causality, consider the following factors when deciding if 
there is a “reasonable possibility” that an AE may have been caused by the drug.


Clinical Study Protocol Appendix A
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
Time Course.  Exposure to suspect drug.  Has the patient actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of 
the suspect drug?

Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class?  Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?

No alternative cause.  The AE cannot be reasonably explained by another etiology such 
as the underlying disease, other drugs, or other host or environmental factors.

Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped?  AstraZeneca would not normally recommend or support a 
re-challenge.

Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a recognized feature of overdose of the drug?

Is there a known mechanism?
Causality of “related” is made if, following a review of the relevant data, there is evidence for 
a “reasonable possibility” of a causal relationship for the individual case.  The expression 
“reasonable possibility” of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as “not related.”
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
Creatinine Calculation
Cockcroft-Gault equation
Males:
Creatinine CL =
Weight (kg) × (140 - Age)
(mL/min)
72 × serum creatinine (mg/dL)


Clinical Study Protocol Appendix A
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
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Females:
Creatinine CL =
Weight (kg) × (140 - Age) 
× 0.85
(mL/min)
72 × serum creatinine (mg/dL)
MEDI4736 and Tremelimumab
There is no information to date on drug-drug interactions with MEDI4736 or tremelimumab 
either pre-clinically or in patients.  As MEDI4736 and tremelimumab are monoclonal 
antibodies and therefore proteins, they will be degraded to small peptides and amino acids and 
will be eliminated by renal and reticuloendothelial clearance.  It is therefore not expected that 
MEDI4736 or tremelimumab will induce or inhibit the major drug metabolizing cytochrome 
P450 pathways.  As a result, there are no expected pharmacokinetic drug-drug interactions.  
No formal drug-drug interaction studies have been conducted with tremelimumab.  However, 
in renal cell carcinoma studies, acute renal failure has been reported with the combination of 
tremelimumab and sunitinib.
The mechanism of action of MEDI4736 involves binding to PD-L1, and the mechanism of 
action of tremelimumab involves binding to CTLA-4; therefore, significant pharmacodynamic 
drug interactions with the commonly administered concomitant medications are not expected.  
Despite this, appropriate clinical monitoring in all of the planned clinical studies will be 
conducted to evaluate any potential drug-drug interactions. 


Clinical Study Protocol Appendix C
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Version 12.0
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Appendix C
IATA 6.2 Guidance Document
Labeling and Shipment of Biohazard Samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories.  For transport purposes the classification of infectious substances according to 
risk groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B, or 
Exempt.  There is no direct relationship between Risk Groups and categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus:

are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens

Clinical trial samples will fall into Category B or exempt under IATA regulations

Clinical trial samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable

Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to contain 
any risk of infection or contamination by using approved couriers and packaging / 
containment materials at all times.  The IATA 650 biological sample containment 
standards are encouraged wherever possible when road or rail transport is used. 


Clinical Study Protocol Appendix D
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
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Appendix D
Actions Required in Cases of Combined Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
Introduction
This appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries.  Specific guidance on the managing liver abnormalities can 
be found in Sections 5.2.1 and 6.7.2 of the protocol.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
Definitions
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥3 × Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥2 × ULN at any point during the study 
following the start of study medication  irrespective of an increase in Alkaline Phosphatase 
(ALP).
Hy’s Law (HL)
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.


Clinical Study Protocol Appendix D
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Study Code D419LC00001
Version 12.0
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Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥3 × ULN

AST ≥3 × ULN

TBL ≥2 × ULN
If a central laboratory is used
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative). 
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will:

Request a repeat of the test (new blood draw) by the central laboratory

Complete the appropriate unscheduled laboratory CRF module(s) with the original local 
laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:

Determine whether the patient meets PHL criteria (see Definitions of this appendix for 
definition) by reviewing laboratory reports from all previous visits (including both 
central and local laboratory results)
If a local laboratory is used
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Determine whether the patient meets PHL criteria (see Definitions of this Appendix for 
definition) by reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory CRF
Follow-up
Potential Hy’s Law criteria not met
If the patient does not meet PHL criteria the Investigator will:

Perform follow-up on subsequent laboratory results according to the guidance provided 
in the Clinical Study Protocol.


Clinical Study Protocol Appendix D
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Study Code D419LC00001
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Potential Hy’s Law criteria met
If the patient does meet PHL criteria the Investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will:

Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated 

Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Study Physician.  If a central laboratory is used, this includes deciding which 
the tests available in the Hy’s law lab kit should be used.

Complete the three Liver CRF Modules as information becomes available 

If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures
Review and Assessment of Potential Hy’s Law Cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP.  The AstraZeneca Medical Science Director and Global Safety Physician will also be 
involved in this review together with other subject matter experts as appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF

If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly 
and follow the AZ standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:


Clinical Study Protocol Appendix D
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
Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard processes. 

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:

Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above

Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met.  Update the SAE report according to the outcome of the 
review
Actions Required When Potential Hy’s Law Criteria are Met Before and After Starting 
Study Treatment
This section is applicable to patients with liver metastases who meet PHL criteria on study 
treatment having previously met PHL criteria at a study visit prior to starting study treatment.
At the first on study treatment occurrence of PHL criteria being met the Investigator will:

Determine if there has been a significant change in the patients’ condition# compared 
with the last visit where PHL criteria were met#

If there is no significant change no action is required

If there is a significant change notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described in 
Potential Hy’s Law criteria met of this Appendix
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST, or total bilirubin) in isolation or 
in combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this 
may be in consultation with the Study Physician if there is any uncertainty.
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a patient meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.  


Clinical Study Protocol Appendix D
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Study Code D419LC00001
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The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:

Was the alternative cause for the previous occurrence of PHL criteria being met found to 
be the disease under study e.g. chronic or progressing malignant disease, severe 
infection or liver disease, or did the patient meet PHL criteria prior to starting study 
treatment and at their first on study treatment visit as described in Actions Required 
When Potential Hy’s Law Criteria are Met Before and After Starting Study Treatment?
If No: follow the process described in Potential Hy’s Law criteria met of this appendix
If Yes:
Determine if there has been a significant change in the patient’s condition# compared with 
when PHL criteria were previously met

If there is no significant change no action is required

If there is a significant change follow the process described in Potential Hy’s Law 
criteria met of this appendix
#
A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this 
may be in consultation with the Study Physician if there is any uncertainty.
References
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf


Clinical Study Protocol Appendix E
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
179(199)
Appendix E
Guidelines for Evaluation of Objective Tumor Response 
Using RECIST 1.1 Criteria (Response Evaluation Criteria in 
Solid Tumors)
Introduction
This appendix details the implementation of Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 guidelines (Eisenhauer et al 2009) for the D419LC00001 study with regards to 
Investigator assessment of tumor burden including protocol-specific requirements for this 
study.
Definition of Measurable, Non-measurable, Target and Non-target Lesions
Only patients with measurable disease at baseline should be included in the study.  
Measurable disease is defined by the presence of at least 1 measurable (by RECIST 1.1) lesion 
which has not been previously irradiated.  A tumor lesion in a previously irradiated field can 
be assessed as measurable disease provided the lesion has been deemed to demonstrate 
progression.
Measurable:
A lesion, not previously irradiated per the protocol prior to enrollment, that can be accurately 
measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must 
have short axis ≥15 mm1) with computed tomography (CT) or magnetic resonance imaging 
(MRI) and that is suitable for accurate repeated measurements.  A tumor lesion in a previously 
irradiated field can be assessed as measurable disease provided the lesion has been deemed to 
demonstrate progression.
Non-measurable:

All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 mm to <15 mm short axis at baseline1).

Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, or abdominal masses/abdominal organomegaly identified 
by physical examination that is not measurable by CT or MRI.

Previously irradiated lesions that have not demonstrated progression2

Brain metastasis
1 Nodes with <10 mm short axis are considered non-pathological and should not be recorded or followed as 
non-target lesions (NTLs). The short axis is defined at the longest axis perpendicular to the long axis of the 
tumour. 
2 Localized post-radiation changes which affect lesion sizes may occur.  Therefore, lesions that have been 
previously irradiated and have not demonstrated progression will not be considered measurable and must be 
selected as NTL at baseline and followed up as part of the NTL assessment.


Clinical Study Protocol Appendix E
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
180(199)
Special cases:

Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability.  Blastic lesions are considered non-measurable.

Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present in 
the same patient, these should be selected as target lesions (TLs).
Target lesions:
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as TLs 
at baseline. Lymph nodes, in any location, are collectively considered as a single organ, with a 
maximum of 2 lymph nodes as TLs. A bilateral organ is considered as a single organ.
Non-target lesions:
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline.
Methods of Assessment
The same method of assessment and the same technique should be used to characterize 
each identified and recorded lesion at baseline and during follow-up visits.
A summary of the methods to be used for RECIST assessment is provided in Table 16, and 
those excluded from tumor assessments for this study are highlighted with the rationale 
provided.
Table16
Summary of methods of assessment
Target lesions 
Non-target lesions
New lesions
CT (preferred)
MRI
CT (preferred)
MRI
Clinical examination 
X-ray, Chest X-ray
CT (preferred)
MRI
Clinical examination 
X-ray, Chest X-ray
Ultrasound
Bone scan
FDG-PET
CT  Computed tomography; FDG-PET  18F-Fluoro-deoxyglucose positron emission tomography; MRI  Magnetic 
resonance imaging.
CT and MRI 
CT and MRI (both preferably with IV contrast) are generally considered to be the best 
currently available and reproducible methods to measure TL selected for response assessment 
and to assess NTL and identification of any new lesions.  


Clinical Study Protocol Appendix E
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
181(199)
In the D419LC00001 study, the methods of assessment of tumor burden used at baseline and 
follow-up visits are contrast-enhanced CT/MRI of the neck, chest, and abdomen (including 
liver and adrenal glands).  Any other areas of disease involvement should be additionally 
imaged based on the signs and symptoms of individual patients.  CT examination with 
intravenous contrast media administration is the preferred method.  MRI should be used where 
CT is not feasible or it is medically contra-indicated.  For brain lesion assessment, MRI is the 
preferred method.
Clinical examination 
In the D419LC00001 study, clinical examination will not be used for assessment of TL.  
Clinically detected lesions can be selected as TLs if they are assessed by CT or MRI scans.  
Clinical examination can be used to assess NTL and to identify the presence of new lesions.
X-ray
Plain X-ray 
In the D419LC00001 study plain X-ray may be used as a method of assessment for bone NTL 
and to identify the presence of new bone lesions.  
Ultrasound 
In the D419LC00001 study, ultrasound examination will not be used for assessment of TL and 
NTL as it is not a reproducible method, does not provide an accurate assessment of tumor size 
and it is subjective and operator dependent.  Ultrasound examination can, however, be used to 
identify the presence of new lesions.  If new clinical symptoms occur and an ultrasound is 
performed then new lesions should be confirmed by CT or MRI examination.
Endoscopy and laparoscopy 
In the D419LC00001 study, endoscopy and laparoscopy will not be used for tumor 
assessments as they are not validated in the context of tumor assessment.
Tumor markers 
In the D419LC00001 study, tumor markers will not be used for tumor response assessments as 
per RECIST 1.1.
Cytology and histology 
In the D419LC00001 study histology will not be used as part of the tumor response 
assessment as per RECIST 1.1.  
Isotopic bone scan 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or 
X-ray at baseline should be recorded as NTL and followed by the same method as per baseline 
assessment.  


Clinical Study Protocol Appendix E
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
182(199)
In the D419LC00001 study, isotopic bone scans may be used as a method of assessment to 
identify the presence of new bone lesions at follow-up visits.  New lesions will be recorded 
where a positive hot-spot that was not present on the baseline bone scan assessment is 
identified on a bone scan performed at any time during the study.  The Investigator should 
consider the positive hot-spot to be a significant new site of malignant disease and represent 
true disease progression in order to record the new lesion.  Confirmation by CT, MRI and 
X-ray is recommended where bone scan findings are equivocal.
FDG-PET scan
In the D419LC00001 study, 18F-Fluoro-deoxyglucose positron emission tomography 
(FDG-PET) scans may be used as a method for identifying new lesions, according with the 
following algorithm: New lesions will be recorded where there is positive 
18F-Fluoro-deoxyglucose uptake3 not present on baseline FDG-PET scan or in a location 
corresponding to a new lesion on CT/MRI at the same follow-up visit.  If there is no baseline 
FDG-PET scan available, and no evidence of new lesions on CT/MRI scans then follow-up 
CT/MRI assessments should be continued, scheduled as per protocol or clinical indicated, in 
order to confirm new lesions.
Tumor Response Evaluation 
Schedule of evaluation
RECIST 1.1 assessments will be performed using contrast-enhanced CT/MRI assessments of 
chest, abdomen, and pelvis.  Additional anatomy should be imaged based on signs and 
symptoms of individual patients at baseline and follow-up.  Baseline assessments should be 
performed no more than 28 days before randomization, and ideally should be performed as 
close as possible prior to the start of study treatment (see Table 2, Table 3, and Table 4 of the 
Clinical Study Protocol).  Follow-up assessments will be performed every 6 weeks ±1 week 
for the first 24 weeks relative to the date of randomization and then every 8 weeks ±1 week 
thereafter until confirmed objective disease progression as defined by RECIST 1.1 
(irrespective of the reason for stopping treatment or subsequent therapy).
Additional assessments will be performed post confirmed objective disease progression for 
patients remaining on assigned treatment, re-treatment, or until subsequent cancer therapy 
according to the clinical study protocol.
Any other sites at which new disease is suspected should also be adequately imaged at 
follow-up.
If an unscheduled assessment was performed and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits.  This 
schedule is to be followed in order to minimize any unintentional bias caused by some patients 
being assessed at a different frequency than other patients.
3 A positive FDG-PET scan lesion should be reported only when an uptake greater than twice that of the 
surrounding tissue is observed.


Clinical Study Protocol Appendix E
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
183(199)
Target lesions
Documentation of target lesions
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes collectively considered as a single organ), representative of all lesions involved 
should be identified as TL at baseline.  Target lesions should be selected on the basis of their 
size (longest diameter for non-nodal lesions or short axis for nodal lesions), but in addition 
should be those that lend themselves to reproducible repeated measurements.  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.
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes).  All measurements should be recorded in 
millimeters.  At baseline the sum of the diameters for all TL will be calculated and reported as 
the baseline sum of diameters.  At follow-up visits the sum of diameters for all TL will be 
calculated and reported as the follow-up sum of diameters.
Special cases:

For TL measurable in 2 or 3 dimensions, always report the longest diameter.  For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis.  

If the CT/MRI slice thickness used is >5 mm, the minimum size of measurable disease at 
baseline should be twice the slice thickness of the baseline scan.

If a lesion has completely disappeared, the longest diameter should be recorded as 0 mm.

If a TL splits into two or more parts, then record the sum of the diameters of those parts.  

If two or more TLs merge then the sum of the diameters of the combined lesion should 
be recorded for one of the lesions and 0 mm recorded for the other lesion(s).  

If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned.  If an accurate measure can be given, this should be 
recorded, even if it is below 5 mm.

If a TL cannot be measured accurately due to it being too large, provide an estimate of 
the size of the lesion.  Although a visit response of PD will be assigned in the vast 
majority of these cases, a case should be flagged and reviewed by the Study Physician in 
a blinded fashion if use of the estimated size in the calculation of TL would not give an 
overall visit response of PD.

When a TL has had any intervention eg, radiotherapy, embolization, surgery, during the 
study, the size of the TL should still be provided where possible and the intervention 
recorded in the RECIST case report form.


Clinical Study Protocol Appendix E
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
184(199)
Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumor visit 
response for TL (see Table 17).
Table 17
Evaluation of target lesions
Complete Response (CR)
Disappearance of all TLs since baseline.  Any pathological lymph 
nodes selected as TLs must have a reduction in short axis to 
<10 mm.
Partial Response (PR)
At least a 30% decrease in the sum of the diameters of TLs, taking 
as reference the baseline sum of diameters.
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD.
Progression of disease (PD)
At least a 20% increase in the sum of diameters of TLs and an 
absolute increase of at least 5 mm, taking as reference the smallest 
sum on study (this includes the baseline sum if that is the smallest 
on study).
Not Evaluable (NE)
Only relevant if any of the TLs were not assessed or not evaluable 
or had a lesion intervention at this visit.  Note: if the sum of 
diameters meets the progressive disease criteria, progressive 
disease overrides not evaluable as a TL response.
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; SD  Stable disease; 
TL  Target lesion.
Non-target lesions
Evaluation of non-target lesions
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline.  Measurements are not required for these lesions, but their status should be followed 
at subsequent visits.  At each visit an overall assessment of the NTL response should be 
recorded by the Investigator.  This section provides the definitions of the criteria used to 
determine and record overall response for NTL at the investigational site at each visit (see 
Table 18).


Clinical Study Protocol Appendix E
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
185(199)
Table 18
Evaluation of non-target lesions
Complete response (CR)
Disappearance of all NTLs since baseline.  All lymph nodes must 
be non-pathological in size (<10 mm short axis).
Non CR/Non PD
Persistence of one or more NTL with no evidence of progression.
Progression (PD)
Unequivocal progression of existing NTLs.  Unequivocal 
progression may be due to an important progression in one lesion 
only or in several lesions.  In all cases the progression MUST be 
clinically significant for the physician to consider changing (or 
stopping) therapy.
Not evaluable (NE)
Only relevant when one or some of the NTLs were not assessed 
and, in the Investigator’s opinion, they are not able to provide an 
evaluable overall NTL assessment at this visit.
Note: for patients without TLs at baseline, this is relevant if any of 
the NTLs were not assessed at this visit and the progression 
criteria have not been met.
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; NTL  Non-target 
lesion; TL  Target lesion.
To achieve “unequivocal progression” on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of stable disease or 
partial response in TLs, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest “increase” in the size of 1 or more NTLs is usually not 
sufficient to qualify for unequivocal progression status.
New lesions
Details of any new lesions will also be recorded with the date of assessment.  The presence of 
one or more new lesions is assessed as progression.  
A lesion identified at a follow up assessment in an anatomical location that was not scanned at
baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal: ie, not attributable to differences in 
scanning technique, change in imaging modality, or findings thought to represent something
other than tumor.
If a new lesion is equivocal, for example because of its small size, the treatment and tumor 
assessments should be continued until the new lesion has been confirmed.  If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan.


Clinical Study Protocol Appendix E
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
186(199)
Symptomatic deterioration
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for 
stopping study therapy.
Patients with “symptomatic deterioration” requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo tumor 
assessments where possible until objective disease progression is observed.
Evaluation of overall visit response
The overall visit response will be derived using the algorithm shown in Table 19.
Table 19
Overall visit response
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No or NE
CR
CR
NA
No or NE
CR
CR
Non CR/Non PD 
No or NE
PR
CR
NE
No or NE
PR
PR
Non PD or NE or NA
No or NE
PR
SD 
Non PD or NE or NA
No or NE
SD
NE
Non PD or NE or NA
No or NE
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR  Complete response, PR  Partial response, SD  Stable disease, PD  Progression of disease, NE  Not evaluable, 
NA  Not applicable (only relevant if there were no non-target lesions at baseline).


Clinical Study Protocol Appendix E
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
187(199)
Confirmation of Progression
Disease progression in the immunomodulatory therapy arms requires confirmation.  The 
confirmatory scan should occur preferably at the next scheduled visit and no earlier than 
4 weeks after the initial assessment of progression of disease (PD) in the absence of clinical 
deterioration.  Disease progression in patients in the Standard of Care arm should be 
confirmed by a scan obtained no earlier than 4 weeks after the initial assessment of PD and 
preferably at the next scheduled imaging visit, if clinically feasible.
Progression would be considered confirmed if the following criteria are met:

≥20% increase in the sum diameters of TLs compared with the nadir at 2 consecutive 
scan timepoints with an absolute increase of 5mm* and/or

significant progression (worsening) of NTLs at the confirmatory scan time-point 
compared with the first time point where progression of NTLs was identified (Note: new 
lesions identified at the previous scan timepoint are considered non-target lesions at the 
confirmatory scan timepoint), and/or

Additional new unequivocal lesions at the confirmatory scan time-point. 
* The assessment of progression requires a ≥20% increase in the sum diameters of target lesions at the first 
progression timepoint relative to the nadir.  The nadir is the smallest sum of diameters, and this may be at 
baseline or subsequent follow-up assessments.  The confirmatory scan confirms the persistence of the 
≥20% increase relative to the nadir.  The minimum absolute increase in the sum of diameters of target 
lesions is at least 5 mm at both assessments.
In the absence of significant clinical deterioration the Investigator should continue assigned 
treatment until progression is confirmed.  If progression is not confirmed, then the patient 
should continue on assigned treatment and on treatment assessments.  
If a patient discontinues treatment (and/or receives a subsequent cancer therapy) prior to 
progression, then the patient should still continue to be followed until confirmed objective 
disease progression.
Central Review
The imaging Contract Research Organization (iCRO) appointed by AstraZeneca to perform 
the collection, QC, and storage of images from the Investigator sites for this study will provide 
guidelines for image acquisition, image anonymization, image storage at the investigative site 
as source data, and image transfer to the iCRO.  The decision to perform a BICR by the iCRO 
is at the discretion of AstraZeneca.  If a BICR is performed, assessments will be performed by 
the central radiologists according to RECIST 1.1, and irRECIST 1.1 (Nishino et al 2013).  The 
management of patients will be based solely upon the local assessments conducted by the 
Investigator.
Further details of the Blinded Independent Central Review will be documented in the 
Independent Review Charter (also referred to as ‘Imaging Charter’).


Clinical Study Protocol Appendix E
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
188(199)
REFERENCES
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.  New response 
evaluation criteria in solid tumors: revised RECIST guideline (version 1.1).  Eur J Cancer 
2009;45(2):228-47.
Nishino et al 2013
Nishino M Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing a 
common language for tumor response to immunotherapy: Immune-related response criteria 
using unidimensional measurements. Clin Cancer Res, 2013;19(14):3936-43.


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
189(199)
Appendix F
Patient-Reported Outcomes


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
190(199)


Clinical Study Protocol Appendix F
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Study Code D419LC00001
Version 12.0
Date 29 June 2020
191(199)


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
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Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
193(199)
CCI


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
194(199)
CCI


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
195(199)
CCI


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
196(199)
CCI


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
197(199)
CCI


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
198(199)
CCI


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D419LC00001
Version 12.0
Date 29 June 2020
199(199)
CCI


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d419lc00001-csp-v12
Document Title:
D419LC00001 Clinical Study Protocol version 12
Document ID:
Doc ID-003967645
Version Label:
4.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
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30-Jun-2020 12:27 UTC
Content Approval
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Content Approval
30-Jun-2020 03:15 UTC
Content Approval
29-Jun-2020 22:56 UTC
Author Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
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PPD
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SAP_001.pdf: 
Statistical Analysis Plan
Drug Substance MEDI4736 and Tremelimumab
Study Code
D419LC00001
Edition Number 07
Date
16 DEC 2020
A Phase III Randomized, Open-Label, Multi-Center, Global Study of 
MEDI4736 Alone or in Combination with Tremelimumab versus Standard 
of Care (EXTREME) in the Treatment of First-line Recurrent or 
Metastatic Squamous Cell Head and neck Cancer patients


Statistical Analysis Plan 
Study Code D419LC00001
Edition Number 07
Date 19 March 2019
2
A Phase III Randomized, Open-Label, Multi-Center, Global Study of 
MEDI4736 Alone or in Combination with Tremelimumab versus Standard 
of Care (EXTREME) in the Treatment of First-line Recurrent or 
Metastatic Squamous Cell Head and neck Cancer patients
Study Statistician
Date
PPD


Statistical Analysis Plan 
Study Code D419LC00001
Edition Number 07
Date 19 March 2019
3
A Phase III Randomized, Open-Label, Multi-Center, Global Study of 
MEDI4736 Alone or in Combination with Tremelimumab versus Standard 
of Care (EXTREME) in the Treatment of First-line Recurrent or 
Metastatic Squamous Cell Head and neck Cancer patients
Global Product Statistician 
Date
PPD


Statistical Analysis Plan 
Study Code D419LC00001
Edition Number 07
Date 19 March 2019
4
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
SIGNATURE OF STUDY STATISTICIAN........................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ..................................3
TABLE OF CONTENTS.....................................................................................4
LIST OF ABBREVIATIONS ..............................................................................8
AMENDMENT HISTORY................................................................................ 12
1.
STUDY DETAILS............................................................................................. 16
1.1
Study objectives................................................................................................. 16
1.1.1
Primary Objective .............................................................................................. 16
1.1.2
Secondary Objectives......................................................................................... 17
1.1.3
Safety Objectives ............................................................................................... 19
1.1.4
Exploratory Objectives....................................................................................... 19
1.2
Study design ...................................................................................................... 20
1.3
Number of subjects ............................................................................................ 24
2.
ANALYSIS SETS ............................................................................................. 28
2.1
Definition of analysis sets .................................................................................. 28
2.1.1
Full analysis set (FAS)....................................................................................... 28
2.1.2
PD-L1 TC/IC analysis set................................................................................... 28
2.1.3
Safety analysis set.............................................................................................. 28
2.1.4
PK analysis set................................................................................................... 28
2.1.5
ctDNA TMB analysis set ................................................................................... 29
2.1.6
Low risk of early mortality (EM) analysis set..................................................... 29
2.1.7
ADA analysis set ............................................................................................... 29
2.2
Violations and deviations ................................................................................... 30
3.
PRIMARY AND SECONDARY VARIABLES................................................. 32
3.1
Derivation of RECIST Visit Responses.............................................................. 32
3.1.1
Blinded Independent Central Review (BICR) Assessment Using RECIST 
1.1...................................................................................................................... 34
3.1.2
Site Investigator Assessment Using RECIST 1.1................................................ 34
3.1.2.1
Target lesions (TLs)........................................................................................... 34
3.1.2.2
Non-target lesions (NTLs) and New lesions. ...................................................... 39
3.1.2.3
Site Investigator Assessment Using RECIST 1.1: Overall visit response ............ 40
3.1.3
Site Investigator Assessment Using RECIST 1.1 Modified for 
Confirmation of Progression .............................................................................. 41


Statistical Analysis Plan 
Study Code D419LC00001
Edition Number 07
Date 19 March 2019
5
3.2
Outcome Variables............................................................................................. 41
3.2.1
Primary endpoint (OS)....................................................................................... 41
3.2.1.1
Progression free survival (PFS).......................................................................... 41
3.2.2
Objective response rate ...................................................................................... 43
3.2.3
Duration of response .......................................................................................... 43
3.2.4
Time to response................................................................................................ 44
3.2.5
Proportion of patients alive and progression free at 6 and 12 months.................. 44
3.2.6
Proportion of patients alive at 12, 18 and 24 months........................................... 44
3.2.7
Time from randomization to the first subsequent therapy or death (TFST) ......... 44
3.2.8
Time from randomization to second subsequent therapy or death (TSST)........... 44
3.2.9
Time from randomization to second progression-free survival (PFS2)................ 44
3.2.10
Change in tumor size.......................................................................................... 45
3.2.11
Best objective response (BoR)............................................................................ 45
3.3
Safety................................................................................................................. 46
3.3.1
Adverse events (AEs)......................................................................................... 46
3.3.2
Treatment exposure............................................................................................ 48
3.3.3
Dose intensity .................................................................................................... 50
3.3.4
Laboratory data.................................................................................................. 50
3.3.5
ECGs ................................................................................................................. 51
3.3.6
Vital signs.......................................................................................................... 52
3.3.7
General considerations for safety assessments.................................................... 52
3.4
Patient reported outcome.................................................................................... 54
3.4.1
EORTC QLQ-C30 ............................................................................................. 54
3.4.2
EORTC QLQ-H&N35 ....................................................................................... 57
3.4.3
........................................................................ 58
3.4.4
..................................................................................................... 59
3.4.5
.................................................................................................................. 59
3.4.6
........................................................................................................... 59
3.5
Pharmacokinetics and Immunogenicity Variables .............................................. 60
3.5.1
Population of pharmacokinetics and exposure-response/safety analysis.............. 60
3.5.2
Pharmacokinetic analysis ................................................................................... 60
3.5.3
Immunogenicity analysis.................................................................................... 61
3.6
Biomarker variables ........................................................................................... 62
4.
ANALYSIS METHODS.................................................................................... 62
4.1
General principles.............................................................................................. 64
4.2
Analysis methods............................................................................................... 68
4.2.1
Analysis of primary variable (OS)...................................................................... 68
4.2.2
Subgroup analysis OS ........................................................................................ 71
4.2.3
Analysis of the secondary variable (PFS) ........................................................... 73
4.2.4
Objective response rate ...................................................................................... 74
4.2.4.1
Best Objective Response (BoR) ......................................................................... 74
4.2.5
Duration of response .......................................................................................... 74
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Statistical Analysis Plan 
Study Code D419LC00001
Edition Number 07
Date 19 March 2019
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4.2.6
Time to response................................................................................................ 74
4.2.7
Proportion of patients alive and progression free at 6 and 12 months
(APF12)............................................................................................................. 75
4.2.8
Time from randomization to PFS2 ..................................................................... 75
4.2.9
Time from randomization to first and second subsequent therapy or death ......... 75
4.2.10
Analysis of OS12, OS18 & OS24....................................................................... 75
4.2.11
Change in tumor size.......................................................................................... 75
4.2.12
Patient reported outcome.................................................................................... 76
4.2.12.1
EORTC QLQ-C30 ............................................................................................. 76
4.2.12.2
EORTC QLQ-H&N35 ....................................................................................... 78
4.2.12.3
.......................................................... 78
4.2.12.4
..................................................................................................... 79
4.2.12.5
.................................................................................................................. 79
4.2.13
Safety................................................................................................................. 79
4.2.13.1
Adverse Events .................................................................................................. 79
4.2.13.2
Laboratory assessments...................................................................................... 85
4.2.13.3
ECGs ................................................................................................................. 87
4.2.13.4
Vital signs.......................................................................................................... 87
4.2.14
WHO/ECOG performance status........................................................................ 87
4.2.15
PK Data ............................................................................................................. 88
4.2.16
Immunogenicity analysis.................................................................................... 88
4.2.17
Biomarker data................................................................................................... 88
4.2.18
Demographic, initial diagnosis and baseline characteristics data......................... 88
4.2.19
Treatment exposure............................................................................................ 90
4.2.20
Subsequent Therapy........................................................................................... 90
5.
INTERIM ANALYSES ..................................................................................... 90
6.
CHANGES OF ANALYSIS FROM PROTOCOL ............................................. 91
7.
REFERENCES .................................................................................................. 91
8.
APPENDIX ....................................................................................................... 96
8.1
Early risk of mortality prognostic model ............................................................ 96
LIST OF TABLES
Table 1
Primary Objectives................................................................................16
Table 2
Secondary Objectives............................................................................17
Table 3
Safety Objectives ..................................................................................19
Table 4
Exploratory Objectives..........................................................................19
Table 5
Summary of Statistical Assumptions and Calculations...........................27
Table 6
Summary of Outcome Variables and Analysis Populations....................29
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Statistical Analysis Plan 
Study Code D419LC00001
Edition Number 07
Date 19 March 2019
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Table 7
TL Visit Responses ...............................................................................35
Table 8
NTL Visit Responses ............................................................................39
Table 9
Overall Visit Responses ........................................................................40
Table 10
Change from BL and visit response for EORTC QLQ C30....................55
Table 11
Change from BL and visit response for EORTC QLQ H&N35..............58
Table 12
Pre-planned statistical and sensitivity analyses to be conducted.............66
Table 13
Changes of Analysis from Protocol .......................................................91
LIST OF FIGURES
Figure 1
Overall study design..............................................................................23
Figure 2
Study flow chart-treatment period .........................................................23
Figure 3
Study flow chart - optional retreatment for MEDI4736 + 
tremelimumab arm................................................................................24
Figure 4
Multiple testing procedure for controlling the type 1 error rate..............64


Statistical Analysis Plan 
Study Code D419LC00001
Edition Number 07
Date 19 March 2019
8
LIST OF ABBREVIATIONS
Abbreviation 
or special term
Explanation
ADA
Antidrug antibody
AE
Adverse event
AEPI
Adverse events of possible interest
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
ALQ
Above Limit of Quantification of PK assay
APF6
Proportion of patients alive and progression free at 6 months from randomization
APF12
Proportion of patients alive and progression free at 12 months from randomization
AST
Aspartate aminotransferase
Baseline
Refers to the last assessment prior to intake of the first dose of IP, except for 
Efficacy where baseline refers to the last visit prior to enrollment.
BICR
Blinded Independent Central Review
BLQ
Below Limit of Quantification of PK assay
BMI
Body Mass Index
BoR
Best objective response
CI
Confidence interval 
COVID-19
Coronavirus Disease 2019
CR
Complete response
CRA
Clinical Research Associate
CRF / eCRF 
Case Report Form (electronic)
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
ctDNA
Circulating tumor DNA
CTLA-4
Cytotoxic T–lymphocyte-associated antigen 4
CTM
Clinical team manager
CTMS
Clinical trial management system
DCO
Data cut-off
DCR
Disease control rate
DoR
Duration of response


Statistical Analysis Plan 
Study Code D419LC00001
Edition Number 07
Date 19 March 2019
9
Abbreviation 
or special term
Explanation
ECG
Electrocardiogram 
ECOG
Eastern Cooperative Oncology Group
EDoR
Expected Duration of Response
EM
Early mortality 
EORTC
European Organisation for Research and Treatment of Cancer
FAS
Full analysis set
HLT
High level term
HLGT
High level group term
HR
Hazard ratio
HRQoL
Health-related quality of life
IC
Tumor-associated immune cell
IDMC
Independent Data Monitoring Committee
ICR
Independent Central Reviewer
imAE
Immune-mediated Adverse Events
IMT
Immunomodulatory therapy
IP
Investigational product
irRECIST
Immune-related response criteria
ITT
Intent-to-treat
IV
Intravenous
KM
Kaplan-Meier
LLOQ
Lower Limit of Quantification of PK assay
MD
Medical doctor
MedDRA
Medical Dictionary for Regulatory Activities
MEDI4736
Immune-mediated therapy
mg
Milli-gram
MMA
Medical monitoring associate
MRI
Magnetic resonance imaging
MMRM
Mixed effect model repeat measurement
NA
Not applicable
NCI
National Cancer Institute
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Statistical Analysis Plan 
Study Code D419LC00001
Edition Number 07
Date 19 March 2019
10
Abbreviation 
or special term
Explanation
NE
Not evaluable
NED
No evidence of disease
NRR
No Reportable Result
NTL
Non-target lesions
ORR
Objective response rate
OS
Overall survival
OS24
Proportion of patients alive at 24 months from randomization
PD
Progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
PD-L1 –ve
Patients with PD-L1–negative tumor expression status
PD-L1 +ve
Patients with PD-L1–positive tumor expression status
PDx
Pharmacodynamic(s)
PFS
Progression free survival
PK
Pharmacokinetic(s)
PR
Partial response
PRO
Patient reported outcome
q12W
Every 12 weeks
q2W
Every 2 weeks
q4W
Every 4 weeks
QLQ-C30 v3
30-item core quality of life questionnaire, version 3
QLQ-H&N35
35-item head and neck quality of life questionnaire
QoL
Quality of life
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia's formula
RECIST 1.1
Response Evaluation Criteria In Solid Tumors version 1.1 
RPD
Relative Percent Difference
RR
Response rate
SAE
Serious adverse event
SAP
Statistical Analysis Plan
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Statistical Analysis Plan 
Study Code D419LC00001
Edition Number 07
Date 19 March 2019
11
Abbreviation 
or special term
Explanation
SCCHN
Squamous cell carcinoma of the head and neck
SD
Stable disease
SDV
Source data verify
SBP
Systolic blood pressure
TC
Tumor cell
TL
Target lesions
TMB
Tumor mutation burden
TFST
Time to first subsequent therapy
TTR
Time to Response
TSST
Time to second subsequent therapy
ULN
Upper limit of normal
WHO
World Health Organization


Statistical Analysis Plan 
Study Code D419LC00001
Edition Number 07
Date 19 March 2019
12
AMENDMENT HISTORY
Date
Brief description of change
May 2017
In line with the Clinical Study Protocol (CSP) Amendment 6

A primary objective has been added for OS in a PD-L1 TC/IC-selected 
subgroup. 

Furthermore, secondary objectives assessing the MEDI4736+Tremelimumab 
combination therapy versus standard of care in the PD-L1 TC/IC-selected 
subgroup have been included in addition to the all-comers. 

The timing of the PFS analysis has been moved to coincide with the same 
time as the 80% of death events interim analysis of OS, thereby removing the 
first interim analysis of OS from the protocol.

All relevant sections throughout the SAP have been updated to reflect these 
changes.

Sections 3.1, 3.1.3, 3.2.1 and all relevant sections have been updated to 
indicate that the sensitivity analysis of PFS based on RECIST 1.1 modified 
for confirmation of progression will be performed using site Investigator 
assessments, rather than BICR assessments.

Section 3.5.2 – Calculation or derivation of pharmacokinetic variables. This 
section has been updated to reflect that PK parameters, such as peak and 
trough concentration of MEDI4736 and tremelimumab, will be derived from 
raw data measurements and that no formal non-compartmental PK analysis 
methods will be used as only sparse PK is being collected in this study. 
In line with project wide developments 

Clarification that the progression date for BICR assessment will be based on 
progression scan dates (PROGSCDT) instead of the earliest scan dates

Clarification that the death summary table will now be broken into 3 separate 
tables

Stratification factors: Only the analysis for primary objectives will use IVRS 
based stratification factors; all other analyses, including subgroup analysis, 
baseline characteristics summaries, etc, as well as all other factors, will be 
based on the values recorded on the eCRF
Other Changes

Addition of BoR (best objective response)

Addition of BMI and BMI group at the patient characteristics summary

Added a text explaining how to impute missing dates

Addition of Mixed effect model repeated measurement (MMRM) analysis 
for EORTC QLQ-C30 and EORTC QLQ-H&N 35

Minor clarifications


Statistical Analysis Plan 
Study Code D419LC00001
Edition Number 07
Date 19 March 2019
13
January 2018
Brief description of change
In line with the Clinical Study Protocol (CSP) Amendment 7

Change of PFS from primary objective to secondary objective

Removal of interim analysis for overall survival (OS)

Addition of secondary objectives, APF6, OS12 and OS18

All analyses using tumor assessment data will use site investigator data as 
primary analysis instead BICR data, BICR will be used as either sensitivity 
 when applicable
In line with project wide developments 

Hazard ratio and confidence interval derived at landmarks as per Klein’s 
method were removed.

Clarifying the baseline definition for PRO variables

Summarizing AEs up to 90 days after last dose regardless of re-treatment
Other changes

Clarifying the approach to be used for deriving HR and its associated CI 
from Cox model

Providing details and clarifications for the derivation of exposure for the 
Combination and SOC arms

Additional minor clarifications such as attrition bias, two missed assessment 
for PFS, minimum duration needed for stable Disease, definition of potential 
Hy’s law and many others
July 2018
Brief description of change

The prior version of this SAP had only included the initial two levels of the 
MTP in the MTP figure.  Hence, the full MTP figure has now been included 
for accuracy.

The important protocol deviation list has been updated as PFS is no longer a 
primary endpoint. 

Text has now been added to detail how partial death dates will be handled.  

Minor text corrections and clarification have also been made.

The AESIs have been updated to be aligned with the CSP.

Text has now been added to detail how missing CRF stratification factors for 
sensitivity analysis of the primary objectives will be handled.

Text has been added to clarify the rules for handling BLQ data when a 
certain percentage of the serum concentrations are not quantifiable; and that 
ALQ results of the PK assay will be excluded from summary statistics 
calculations.
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Statistical Analysis Plan 
Study Code D419LC00001
Edition Number 07
Date 19 March 2019
14
March 2019
Brief description of change
In line with the Clinical Study Protocol (CSP) Amendment 8, CSP edition 9 and 
Amendment 9, CSP edition 10 includes changes as follows: 

The primary objective has changed from statistical testing for overall 
survival of MED4736 +tremelimumab combination therapy compared to 
SoC in the all-comer population to MED4736 monotherapy compared to 
SoC in the all-comer population

The MTP has been updated to reflect the change primary objective and 
prioritization of a secondary objective

The analysis of ctDNA TMB has been updated from 
 
secondary objective

All relevant sections throughout the SAP have been updated to reflect the 
two changes above

DoR, BoR, TFST, TSST, APF6 and APF12 have been included as secondary 
objectives to assess the efficacy of MEDI4736 monotherapy compared to 
SoC

The definition for PD-L1 high and PD-L1 low were clarified
Other changes

Clarifying that PRO analyses will include retreatment data

 

Minor administrative corrections 

Addition of ADA analysis set

Updating the derivation of the two missed visit rule for RECIST 1.1 
assessment

Addition of infection AEs to the safety outputs
June 2020
Brief description of change
In line with the CSP edition 12, the following changes have been made: 

Change of primary objective from MEDI4736 monotherapy versus SoC in 
all randomized patients (all-comers) to MEDI4736 monotherapy versus SoC 
in PD-L1 TC/IC high subgroup in terms of OS. All relevant sections 
throughout the SAP have been updated to reflect these changes.

The MTP has been updated to reflect the change in primary objective and 
prioritization of secondary objectives

The low risk of early mortality (EM) analysis set has been added and the 
secondary objectives have been updated to include this additional subgroup 
population
Other changes:
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Statistical Analysis Plan 
Study Code D419LC00001
Edition Number 07
Date 19 March 2019
15

All COVID-19 related non-important PDs and issues will now be 
summarized and listed

Addition of AEPIs and imAEs to the safety outputs

ECG and vital signs data will now be reported up to 90 days after date of last 
dose of study treatment or until initiation of subsequent therapy

A further sensitivity analysis for OS i.e. stratified max-combo test, has been 
included


In addition to the changes listed above, minor administrative corrections and 
clarifications have been made throughout the SAP and are not detailed here 
further
December 2020
Brief description of change

Further details have been added to the max-combo sensitivity analysis of OS, 
 

The MMRM analysis has been updated to include a baseline by visit 
interaction

An approach for handling duplicate PK data has been added
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Statistical Analysis Plan 
Study Code D419LC00001
Edition Number 07
Date 19 March 2019
16
1.
STUDY DETAILS
The target population for this study is male and female patients aged 18 and over with 
histologically or cytologically confirmed PD-L1-positive or -negative, recurrent or metastatic 
SCCHN (oral cavity, oropharynx, hypopharynx, or larynx) who are not amenable to local 
curative therapy with surgery or radiation and who have not received prior systemic therapy 
for recurrent/metastatic disease, unless it was given as part of multimodality treatment for 
locally advanced or locally recurrent disease.
Multiple lines of evidence suggest that SCCHN tumors create a highly immunosuppressive 
environment and that the PD-1/PD-L1 axis and inhibition of the activation of T cells play an 
important role and may be amenable to therapeutic intervention with immune-modulating 
agents (see CSP for detailed description).
MEDI4736, an antibody that blocks the interaction between PD-L1 and its receptors, may 
relieve PD-L1-dependent immunosuppressive effects and, therefore, enhance the cytotoxic 
activity of anti-tumor T-cells. This hypothesis is supported by emerging clinical data from 
other mAbs targeting the PD-L1/PD-1 pathway, which provide early evidence of clinical 
activity and a manageable safety profile in multiple tumor types (Brahmer et al 2012, Topalian 
et al 2012). Currently available data from the first-time-in-human, single-agent study 
(Study CD-ON-MEDI4736-1108; referred to hereafter as Study 1108) in patients with 
advanced solid tumors using MEDI4736 monotherapy indicates encouraging response rates 
(RRs) and duration of response (DoR) with a manageable safety profile in patients with a 
variety of solid malignancies, including patients with SCCHN.  Preliminary data in the 
SCCHN expansion cohort demonstrated a confirmed ORR of 11% (7 out of 62 partial 
response [PR]) and a disease control rate (DCR) at 24 weeks of 15% (9 out of 62 patients) 
based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) (Segal et al 
2015).
Combining immunotherapy agents has been shown to result in improved RR relative to those 
for monotherapy. The rationale for combining MEDI4736 and tremelimumab is that the 
mechanisms of CTLA-4 and PD-1 are non-redundant, suggesting that targeting both pathways 
may have additive or synergistic activity (Pardoll 2012), resulting in higher RRs in SCCHN. 
Evidence of clinical activity and manageable safety profile for this combination has been 
observed in Study D4190C00006. 
1.1
Study objectives
1.1.1
Primary Objective
Table 1
Primary Objectives
Primary Objective:
Outcome Measure:
To assess the efficacy of MEDI4736 monotherapy 
compared to SoC (EXTREME) in terms of OS  
OS in the PD-L1 TC/IC high subgroup
OS Overall survival; 


Statistical Analysis Plan 
Study Code D419LC00001
Edition Number 07
Date 19 March 2019
17
                    
1.1.2
Secondary Objectives
Table 2
Secondary Objectives
Secondary Objective:
Outcome Measures:
To further assess the efficacy of MEDI4736 
monotherapy compared to SoC (EXTREME) 
in terms of OS, PFS, ORR, DoR, BoR, TTR, 
TFST, TSST, APF6, APF12, PFS2, OS12, 
OS18 and OS24
OS in the low risk of early mortality (EM) subgroup, 
ctDNA TMB high subgroup (≥16 mut/Mb) and all-
comers 
OS12, OS18, OS24 in the PD-L1 TC/IC high 
subgroup, low risk of early mortality (EM) subgroup, 
ctDNA TMB high subgroup (≥16 mut/Mb) and all-
comers
PFS, ORR, APF6 and APF12 using site investigator 
assessments according to RECIST 1.1 in the PD-L1 
TC/IC high subgroup, low risk of early mortality 
(EM) subgroup, ctDNA TMB high subgroup (≥16 
mut/Mb) and all-comers
DoR, BoR and TTR using site investigator 
assessments according to RECIST 1.1 in the PD-L1 
TC/IC high subgroup and all-comers
PFS2 using local standard clinical practice in the PD-
L1 TC/IC high subgroup and all-comers
TFST and TSST in the PD-L1 TC/IC high subgroup 
and all-comers


Statistical Analysis Plan 
Study Code D419LC00001
Edition Number 07
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18
To assess the efficacy of MEDI4736 + 
tremelimumab combination therapy compared 
to SoC (EXTREME) in terms of OS, PFS, 
ORR, DoR, BoR, TTR, APF6, APF12, PFS2, 
TFST, TSST, OS12, OS18 and OS24
OS, OS12, OS18, OS24 in the PD-L1 TC/IC high 
subgroup, low risk of early mortality (EM) subgroup, 
ctDNA TMB high subgroup (≥16 mut/Mb) and all-
comers
PFS, ORR, APF6 and APF12 using site investigator 
assessments according to RECIST 1.1 in the PD-L1 
TC/IC high subgroup, low risk of early mortality 
(EM) subgroup, ctDNA TMB high subgroup (≥16 
mut/Mb) and all-comers
DoR, BoR and TTR using site investigator 
assessments according to RECIST 1.1 in the PD-L1 
TC/IC high subgroup and all-comers
PFS2 using local standard clinical practice in the PD-
L1 TC/IC subgroup and all-comers
TFST and TSST in the PD-L1 TC/IC high subgroup 
and all-comers
To assess the efficacy of MEDI4736 + 
tremelimumab combination therapy compared 
to MEDI4736 monotherapy in terms of PFS, 
ORR, and OS
PFS and ORR using site investigator assessments 
according to RECIST 1.1 in the PD-L1 TC/IC high 
subgroup, low risk of early mortality (EM) subgroup, 
ctDNA TMB high subgroup (≥16 mut/Mb) and all-
comers
OS in the PD-L1 TC/IC high subgroup, low risk of 
early mortality (EM) subgroup, ctDNA TMB high 
subgroup (≥16 mut/Mb) and all-comers
To assess disease-related symptoms and 
health-related quality of life in patients treated 
in patients treated with 
MEDI4736 + tremelimumab combination 
therapy and MEDI4736 monotherapy 
compared to SoC (EXTREME) using the 
EORTC QLQ-C30 v3 and the QLQ-H&N35 
module
EORTC QLQ-C30: global health QoL, functioning 
(physical) and symptoms (fatigue in the PD-L1 
TC/IC high subgroup and all-comers
EORTC QLQ-H&N35: symptoms (pain, swallowing) 
in the PD-L1 TC/IC high subgroup and all-comers
Changes in WHO/ECOG performance status in the 
PD-L1 TC/IC high subgroup and all-comers
To assess the PK of 
MEDI4736 + tremelimumab combination 
therapy and MEDI4736 monotherapy
Concentration of MEDI4736 and tremelimumab in 
blood and PK parameters, such as peak concentration 
and trough (as data allow; sparse sampling)
To investigate the immunogenicity of 
MEDI4736 and tremelimumab
Presence of ADAs for MEDI4736 and tremelimumab


Statistical Analysis Plan 
Study Code D419LC00001
Edition Number 07
Date 19 March 2019
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ADA Anti-drug antibody; APF6 Proportion of patients alive and progression free at 6 months; APF12 Proportion of patients alive and 
progression free at 12 months; DoR Duration of response; ECOG Eastern Cooperative Oncology Group; EM Early mortality; EORTC European 
Organisation for Research and Treatment of Cancer; HRQoL Health-related quality of life; ORR Objective response rate; OS Overall survival; 
OS12 Proportion of patients alive at 12 months after randomization; OS18 Proportion of patients alive at 18 months after randomization; 
OS24 Proportion of patients alive at 24 months after randomization; PFS Progression free survival; PFS2 Time from randomization to second 
PFS; TTR Time to response; TFST Time from randomization to first subsequent therapy or death; TSST Time from randomization to second  
subsequent therapy or death; IC Tumor associated immune cells; TC tumor cells; BoR Best objective response; QLQ-C30 v3 30-item core 
quality of life questionnaire, version 3; QLQH& N35 35-item head and neck quality of life questionnaire; QoL Quality of life; RECIST 1.1 
Response Evaluation Criteria in Solid Tumors version 1.1; SCCHN Squamous cell carcinoma of the head and neck; SoC Standard of Care; 
ctDNA Circulating tumor DNA; DNA Deoxyribonucleic acid; TMB Tumor mutation burden. The ctDNA TMB cut-point of 16 mut/MB for 
MEDI4736 + tremelimumab and MEDI4736 monotherapy was derived from the EAGLE study (Li et al, 2020).
1.1.3
Safety Objectives
Table 3
Safety Objectives
Safety Objective:
Outcome Measures:
To assess the safety and tolerability profile of 
MEDI4736 + tremelimumab combination 
therapy and MEDI4736 monotherapy 
compared to SoC (EXTREME) in the first-line 
setting for treatment of SCCHN
AEs, physical examinations, laboratory findings 
(including clinical chemistry, hematology, and 
urinalysis), vital signs (including blood pressure and 
pulse), and ECGs in the PD-L1 TC/IC high subgroup, 
low risk of EM subgroup and all-comers
AE Adverse Event; ECG Electrocardiogram; EM Early mortality; SoC Standard of Care; IC Tumor-associated immune cells; 
TC Tumor cells
1.1.4
Exploratory Objectives
Table 4
Exploratory Objectives
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Statistical Analysis Plan 
Study Code D419LC00001
Edition Number 07
Date 19 March 2019
20
1.2
Study design
This is a randomized, open-label, multi-center, 3-arm, global Phase III study to determine the  
efficacy and safety of MEDI4736 monotherapy compared to SoC in the treatment of patients 
with recurrent or metastatic SCCHN who are not amenable to local curative therapy with 
surgery or radiation and who have not received prior systemic therapy for recurrent/metastatic 
disease, unless it was given as part of multimodality treatment for locally advanced or locally 
recurrent disease. Note that MEDI4736 + tremelimumab combination therapy compared to 
SoC is a secondary objective.
A schematic diagram of overall study design is shown in Figure 1, a flow chart of the study 
design treatment periods is presented in 
Figure 2, and a flow chart of the optional retreatment period for the MEDI4736 + 
tremelimumab combination therapy arm is in Figure 3.
Patients will undergo an assessment on their tumor tissue sample to determine PD-L1 status. 
Patients with tumoral PD-L1 expression above or below a pre-specified cut-off level of ≥25%, 
as determined by an IHC assay (referred to hereafter as PD-L1–positive or -negative tumors, 
respectively), will be enrolled in the study. If the patient has already been tested as a part of 
the screening process for any AstraZeneca study using the VENTANA assay, this test result 
can be used for the determination of eligibility. The specified expression cut-off level of ≥25% 
in the tumor cells will be used for the purpose of stratification and therefore included in the 
stratified log rank tests for OS and PFS.
HPV status will be assessed in patients with oropharynx tumors according to local standards 
or by the p16 IHC assay.
Data presented by AstraZeneca at the 2015 ASCO meeting (Error! Reference source not 
found.) demonstrate that treatment with MEDI4736 resulted in an ORR of 18% and 8% in 
patients with PD-L1-positive and -negative SCCHN tumors, respectively.  Therefore, it 
appears that the selection of patients based on PD-L1 expression levels within the tumor 
microenvironment may improve the probability and/or quality of responses to PD-1 pathway-
targeting agents and, therefore, may have merit as a patient enrichment tool.  Competitors 
have presented similar data with this class of agents. Specifically, the phase 3 KEYNOTE-048 
study, which demonstrated that pembrolizumab monotherapy improved OS when compared 
with the EXTREME regimen in patients whose tumors had PD-L1 expression ≥1 and ≥20 by 
Combined Positive Score (CPS) [hazard ratio (HR) 0.78 (0.64–0.96), P=0.0086 and HR 0.61 
(0.45– 0.83), P=0007, respectively] (Burtness et al., 2019). 
 
 
 
 
 
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Statistical Analysis Plan 
Study Code D419LC00001
Edition Number 07
Date 19 March 2019
21

PD-L1 TC/IC high is defined as either ≥ 50% of the tumor cells (TC) or ≥ 25% of the 
immune cells (IC) staining for PD-L1 at any intensity if >1% of the tumor area contains 
IC, or ≥ 50% of TC or 100% of IC staining for PD-L1 at any intensity if 1% of the tumor 
area contains IC. 

PD-L1 low is defined as not meeting any of the criteria for PD-L1 high
Patients will be randomized in a 2:1:1 manner to either the MEDI4736 + tremelimumab 
combination arm, the MEDI4736 monotherapy arm, or the SoC arm respectively. Patients 
randomized to the MEDI4736 + tremelimumab combination arm will receive tremelimumab 
75 mg intravenous (IV) q4w for 4 doses and MEDI4736 1500 mg IV q4w until PD, those in 
the MEDI4736 monotherapy arm will receive MEDI4736 1500 mg IV q4w until PD, while 
patients in the SoC arm will receive up to six 3-week cycles consisting of a platinum [cisplatin 
100 mg/m2 or carboplatin area under the curve (AUC) of 5 mg/mL/min IV] on day 1 of each 
cycle, 5FU 1000 mg/m2/day on days 1-4 of each cycle, and cetuximab weekly; cetuximab will 
be administered at 400 mg/m2 on Day 1 of cycle 1, and then 250 mg/m2 weekly for up to six 3-
week cycles and 250 mg/m2 IV weekly for maintenance until disease progression, initiation of 
alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion is met (see Section 3.9 of CSP).
Patients in all arms with confirmed PD by RECIST 1.1 who, in the Investigator’s opinion, 
continue to receive benefit from their assigned treatment and who meet the criteria for 
treatment in the setting of PD may continue to receive their assigned treatment (see Section 
7.2.3 of CSP). Since the phenomenon of pseudoprogression in patients treated with 
immunotherapy is well documented and the limitations of RECIST 1.1 in identifying those 
who are achieving clinical benefit with immunotherapies are known, patients enrolled in the 
IMT arms will be permitted to continue therapy even in the presence of PD as per RECIST 1.1 
(Weber et al 2012). However, patients whose disease progresses in target lesions which had 
previously shown an objective response as defined by RECIST 1.1 will not be permitted to 
continue immunotherapy. Similarly, patients in the SoC arm may continue therapy in the 
setting of PD if they remain clinically stable, meet criteria for treatment in the setting of PD, 
and continue to receive some clinical benefit in the Investigator’s opinion.
Patients in all arms with a symptomatic solitary lesion, a brain lesion, or a lesion of clinical 
importance (e.g., impending fracture, etc) may be treated with radiation after approval from 
the Sponsor. Non-irradiated lesions need to continue to be measurable by RECIST 1.1. The 
time interval between the last systemic treatment and radiation should be 10 days, and 
systemic treatment can be resumed 1week post radiation.
Patients who have discontinued therapy due to disease progression will enter follow-up until 
death (see Table 4 CSP). Patients who have discontinued treatment due to toxicity or any 
reason other than disease progression will be followed up until confirmed disease progression 
and for survival (see Table 4 CSP).


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Tumor assessments will be performed on images from computed tomography (CT) or 
magnetic resonance imaging (MRI) scans, preferably with IV contrast, at the times specified 
in Table 2, Table 3, and Table 4 of CSP. RECIST 1.1 measurements as given by site 
investigator assessments will be used to derive the secondary variables PFS, ORR, DoR, BoR, 
TTR, and proportion of patients alive and progression free at 6 and 12 months (APF6 and 
APF12).
This study will enroll approximately 1016 patients with PD-L1-positive and -negative disease 
at sites globally to obtain 760 patients who are likely to be evaluable for the primary endpoint.
Below is a schematic diagram of the overall study design (Figure 1).  A flow chart for all 
treatment groups (MEDI4736 monotherapy, MEDI4736 + tremelimumab combination 
therapy, and SoC) is presented in Figure 2. A flow chart for patients on the MEDI4736 + 
tremelimumab combination therapy arm who enter the optional re-treatment phase is 
presented in Figure 3. 


Statistical Analysis Plan 
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Edition Number 07
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Figure 1
Overall study design
OS Overall survival; PD-L1 Programmed cell death ligand 1; PS Eastern Cooperative Oncology Group performance status; 
SCCHN Squamous cell cancer of the head and neck; SoC Standard of Care.
Figure 2
Study flow chart-treatment period
a
Informed consent of study procedures and tumor biopsy sample may be obtained prior to the 28-day screening window, if necessary, in 
order to permit tumor biopsy sample acquisition and analysis prior to randomization
b
Disease progression requires confirmation for patients receiving IMT.  Disease progression in patients in the SoC arm should be 
confirmed if clinically feasible (see Section 5.1 of the CSP for more information).
Target  Population

Patients with R/M 
SCCHN 

No prior systemic 
therapy  for R/M 
disease except if 
given as part of 
multimodality 
treatment for locally 
advanced  or locally 
recurrent disease

PS 0 to 1

Excludes 
nasopharyngeal 
cancer 

Excludes prior 
immunotherapy 
N = 760 patients
Primary
endpoint: 
OS
Randomization 
stratified for:

PD-L1 Status

Tumor location

Smoking history
MEDI4736 + Tremelimumab
N=380
Cetuximab + Platinum*
+5-Fluorouracil
(SoC - EXTREME)
N=190
 MEDI4736 monotherapy
N=190
* Platinum: carboplatin or cisplatin
d
e


Statistical Analysis Plan 
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c
Patients in the MEDI4736 + tremelimumab combination therapy arm who are eligible for retreatment will be treated according to 
Figure 3
d   
This refers to Table 3 in the CSP  
e   
This refers to Table 4 in the CSP  
IMT Immunomodulatory therapy; PD Progressive disease; RECIST 1.1 Response Evaluation Criteria in Solid Tumors version 1.1.
Figure 3
Study flow chart - optional retreatment for MEDI4736 + 
tremelimumab arm
a
With or Without confirmation
b
Before restarting MEDI4736 + tremelimumab combination therapy, the Investigator should ensure that the patient does not have any 
significant, unacceptable, or irreversible toxicities that indicate that continuing treatment will not further benefit the patient, and that 
the patient still meets all of the inclusion criteria and none of the exclusion criteria for this study including re-consenting to restart 
treatment.  To restart study treatment, the patient must not have received an intervening cancer therapy post study treatment 
discontinuation.  Patients should have a baseline tumor assessment within 28 days of restarting study treatment; all further scans 
should occur q8w until PD (relative to the date of restarting study treatment).
c
This refers to Table 2 in the CSP. PK, ADA, and MDSC assessments do not need to be collected during retreatment.
d   
This refers to Table 4 in the CSP  
ADA Anti-drug antibody; MDSC Myleoid-derived suppressor cell; PK Pharmacokinetics; q8w Every 8 weeks; RECIST 1.1 Response 
Evaluation Criteria in Solid Tumors version 1.1.
1.3
Number of subjects
The sample size for this study was selected to be consistent with the research hypothesis as 
described in Section 8.5 of the Clinical Study Protocol (CSP).
The study will enroll approximately 1016 patients in order to randomize 760 eligible patients 
in a 2:1:1 ratio (380:190:190 patients) to MEDI4736 + tremelimumab combination therapy, 
MEDI4736 monotherapy, or SoC respectively.  
The study was originally sized to characterize the OS benefit of MEDI4736 + tremelimumab 
combination therapy versus SoC in all-comers (i.e., regardless of PD-L1 tumor expression 
status) and in PD-L1 TC/IC subgroup population.  The sizing assumes a 3-month delay in 
separation of the OS curves between each arm, hence the use of average HRs.
d


Statistical Analysis Plan 
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With amendment 11 (CSP version 12) the primary objective was changed to characterize the 
OS benefit of MEDI4736 monotherapy versus SoC in the PD-L1 TC/IC high subgroup.  Due 
to this change the primary analysis of OS will be performed when approximately 147 death 
events have occurred in approximately 172 patients (85% maturity) across the MEDI4736 
monotherapy and SoC treatment groups in the PD-L1 TC/IC high subgroup population. The 
number of patients (172) assumes that 45% of patients randomized are within this subgroup. 
No interim efficacy analyses will be performed in this study.
If superiority over SoC is found, a hierarchical multiple testing procedure (MTP) will be 
employed to strongly control for the overall type I error at the 5% alpha level (two-sided), as 
shown in Section 4, Figure 4. 
MEDI4736 Monotherapy versus SoC in the PD-L1 TC/IC high subgroup (OS)
If OS at 24 months in the PD-L1 TC/IC high subgroup was 30% with MEDI4736 monotherapy and 
12% with SoC (with a 10.1-month median OS), and assuming the true average OS HR is 0.59; the trial 
will have approximately 90% power to demonstrate statistical significance at the 5% level (using a 2-
sided test) for the comparison of MEDI4736 monotherapy versus SoC in the PD-L1 TC/IC high 
subgroup, with approximately 147 events. With a 17-month recruitment period and a minimum follow-
up period of 23.6 months from “last patient in” assumed, it is anticipated that the analysis will be 
performed approximately 40.6 months after the first patient has been recruited. 
MEDI4736 Monotherapy versus SoC in the low risk of EM subgroup (OS)
Assuming approximately 80% of patients are in the low risk of EM subgroup and assuming 
the true average OS HR is 0.70, the trial will have approximately 81% power to demonstrate 
statistical significance at the 5% level (using a 2-sided test) for the comparison of MEDI4736 
monotherapy versus SoC in the low risk of EM subgroup, with approximately 254 events.  
MEDI4736 Monotherapy versus SoC in the ctDNA TMB high (≥16 mut/Mb) subgroup 
(OS)
Assuming approximately 16% of patients are in the ctDNA TMB high (≥16 mut/Mb) 
subgroup and assuming the true OS HR is 0.40, the trial will have approximately 82% power 
to demonstrate statistical significance at the 5% level (using a 2-sided test) for the comparison 
of MEDI4736 monotherapy versus SoC in the ctDNA TMB high (≥16 mut/Mb) subgroup, 
with approximately 48 events.  
MEDI4736 + tremelimumab combination therapy versus SoC in the ctDNA TMB high 
(≥16 mut/Mb) subgroup (OS)
Assuming the true OS HR is 0.40, the trial will have approximately 92% power to 
demonstrate statistical significance at the 5% level (using a 2-sided test) for the comparison of 
MEDI4736 + tremelimumab combination therapy versus SoC in the ctDNA TMB high (≥16 
mut/Mb) subgroup, with approximately 68 events.  


Statistical Analysis Plan 
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MEDI4736 monotherapy versus SoC in all-comers (OS)
If OS at 24 months in the all-comers population was 24% with MEDI4736 monotherapy and 
12% with SoC (with a 10.1-month median) and assuming the true average OS HR is 0.70, the 
trial will have approximately 91% power to demonstrate statistical significance at the 5% level 
(using a 2-sided test) for the comparison of MEDI4736 monotherapy versus SoC in all-
comers, with approximately 336 events. .  
MEDI4736 + tremelimumab combination therapy versus SoC-all comers (OS)
With approximately 570 patients randomized across the MEDI4736 + tremelimumab 
combination therapy and SoC treatment groups and a true average OS HR of 0.70, an 
estimated 495 death events (87% maturity) are expected to have occurred at 40.6 months from 
“first patient in,” providing 97% power to demonstrate statistical significance at the 5% level 
(using a 2-sided test), for the comparison of MEDI4736 + tremelimumab combination therapy 
versus SoC in all-comers.
Table 5 provides a summary of these statistical assumptions and calculations.


Statistical Analysis Plan 
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Table 5
Summary of Statistical Assumptions and Calculations
N ratio
Overall 
HR
Landmarks at 
24 months
Events 
(maturity)
Power
Critical 
values
HR 
(landmarks)
Primary 
Objectives
OS: Mono versus 
SoC; PD-L1 TC/IC 
high subgroup
86:86
0.59
30% vs 12%
147 (85%)
90%
0.72 (22%)
Secondary 
objectives: 
OS: Mono versus 
SoC; low risk of 
EM subgroup
152:152
0.70
24% vs 12%
254 (84%)
81%
0.78 (19%)
OS: Mono versus 
SoC; ctDNA TMB 
high (≥16 mut/Mb)
subgroup
30:30
0.40
43% vs 12%
48 (80%)
88%
0.56 (29%)
OS: Combo versus 
SoC; ctDNA TMB 
high (≥16 mut/Mb)
subgroup
60:30
0.40
43% vs 12%
68 (76%)
96%
0.62 (26%)
OS: Mono versus 
SoC; all-comers
190:190
0.70
24% vs 12%
336 (88%)
91%
0.81 (18%)
OS: Combo versus 
SoC; all-comers 
380:190
0.70
24% vs 12% 
495 (87%)
97%
0.83 (17%)
Note: The sample size estimates in the PD-L1 TC/IC high subgroup comparisons assume that 45% of the patients 
enrolled are within this subgroup. The sample size estimates in the low risk of EM subgroup assume that 
80% of the patients randomized are within this subgroup. The sample size estimates in the ctDNA TMB 
high (≥16 mut/Mb) subgroup assume that 16% of the patients randomized are within this subgroup. A 3-
month delayed effect is assumed for all hypotheses except for ctDNA TMB high. 
Combo MEDI4736 + tremelimumab combination therapy; HR Hazard ratio; IC tumor-associated immune cells; 
Mono MEDI4736 monotherapy; OS Overall survival; SoC Standard of Care; PD-L1 Programmed cell death 
ligand 1; PFS Progression-free survival; TC Tumor cells; TMB Tumor Mutational Burden.


Statistical Analysis Plan 
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2.
ANALYSIS SETS
2.1
Definition of analysis sets
Four analysis sets are defined for this study. Table 6 gives a summary of outcome variables 
and analysis populations.
2.1.1
Full analysis set (FAS)
The full analysis set (FAS) will include all randomized patients (all-comers) (i.e., the Intent-
to-Treat [ITT] population).  The FAS will be used for all efficacy analyses (including PROs).  
Treatment groups will be compared on the basis of randomized study treatment, regardless of 
the treatment actually received.  Patients who were randomized but did not subsequently go on 
to receive study treatment are included in the analysis in the treatment group to which they 
were randomized.
2.1.2
PD-L1 TC/IC analysis set 
The PD-L1 TC/IC analysis set will include the subset of patients in the FAS with PD-
L1evaluable samples and available results, as determined by the analytically validated 
VENTANA PD-L1 (SP263) Assay. Subgroups are defined as PD-LI TC/IC high, low or 
unknown.

PD-L1 TC/IC high defined as either ≥ 50% of the tumor cells (TC) or ≥ 25% of the 
immune cells (IC) staining for PD-L1 at any intensity if >1% of the tumor area 
contains IC, or ≥ 50% of TC or 100% of IC staining for PD-L1 at any intensity if 1% 
of the tumor area contains IC.  

PD-L1 TC/IC low is defined as not meeting any of the criteria for PD-L1 high.
The scoring algorithm was derived from data from two phase 2 studies, D4193C00001 
(HAWK, DCO September 2016) and D4193C00003 (CONDOR, DCO March 2017).  
2.1.3
Safety analysis set
All patients who received at least 1 dose of study treatment will be included in the safety 
analysis set.  The patients will be classified on the basis of the treatment actually received.  
When assessing safety and tolerability, summaries will be produced based on the safety 
analysis set.  Such summaries will be produced for all-comers and also for those in the PD-L1 
TC/IC high and low risk of EM subgroups separately.  
2.1.4
PK analysis set
All patients who received at least 1 dose of IP per the protocol for whom any post-dose PK 
data are available.


Statistical Analysis Plan 
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2.1.5
ctDNA TMB analysis set
The ctDNA TMB analysis set will include the subset of patients in the FAS with ctDNA TMB 
evaluable samples and available results. Subgroups are defined as ctDNA TMB high (≥16 
mut/Mb), low (<16 mut/Mb) and unknown. 
The “unknown” category includes the following ctDNA TMB outcomes: Failed, Not Done, 
Not Provided, and No Call/not evaluable.
2.1.6
Low risk of early mortality (EM) analysis set
The low risk of EM analysis set consists of patients identified as having low risk of early 
mortality based on laboratory values according to a specific prognostic model 
 
 
 
 
 
The detailed model specifications and description are documented in the SAP Appendix. 
2.1.7
ADA analysis set
Patients in the safety analysis set with non-missing baseline ADA result and at least 1 post-
baseline ADA result.
Table 6
Summary of Outcome Variables and Analysis Populations
Outcome variable
Population
Efficacy data
OS, PFS, ORR,  APF6 APF12, OS12, OS18, OS24
PD-L1 TC/IC analysis set, low risk of 
EM analysis set, ctDNA TMB 
analysis set and all-comers (FAS)
DoR, BoR, TTR, TFST, TSST, PFS2, PROs and symptom 
endpoints
PD-L1 TC/IC analysis set and all-
comers (FAS)
Study population and demography
PD-L1 TC/IC  analysis set and all-
comers (FAS)
PK data
PK analysis set
WHO/ECOG performance status
PD-L1 TC/IC  analysis set and all-
comers (FAS)
CCI


Statistical Analysis Plan 
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Outcome variable
Population
Safety Data
Exposure
Safety analysis set
AEs
Safety analysis set
Laboratory measurements
Safety analysis set
Vital signs
Safety analysis set
AE Adverse event; APF12 Proportion of patients alive and progression free at 12 months; DoR Duration of response; EM Early mortality; IC 
tumor-associated immune cell;  ITT Intent-to-Treat; ORR Objective response rate; OS Overall survival; OS12 Proportion of patients 
alive at 12 months; OS18 Proportion of patients alive at 18 months;  OS24 Proportion of patients alive at 24 months after 
randomization; PD-L1 Programmed cell death ligand 1; PFS Progression-free survival; PFS2 Second progression; 
PK Pharmacokinetic; PRO Patient-reported outcome; TC tumor cell; TTR Time to response; TFST Time to first subsequent therapy; 
TSST Time to second subsequent therapy; TMB Tumor Mutation Burden. The ctDNA TMB cut-point of 16 mut/MB for MEDI4736 + 
tremelimumab and MEDI4736 monotherapy was derived from the EAGLE study (Li et al 2020).
2.2
Violations and deviations
The important protocol deviations (PDs) specified below will be summarized and listed.  
None of the deviations listed below will lead to patients being excluded from the analysis sets 
described in Section 2.1. If the deviations are serious enough to have the potential to impact 
the primary analysis, sensitivity analyses may be performed. Eligibility criteria deviations are 
deviations from the protocol inclusion and exclusion criteria. Post-entry deviations are 
deviations from the protocol that occurred after the patient was randomized to the study.
The deviations below will be programmatically derived where feasible.
The following general categories will be considered important deviations and be listed and 
discussed in the Clinical Study Report (CSR) as appropriate for the study.

Patients who deviate from key entry criteria (Deviation 1). The key inclusion/exclusion 
criteria identified as the following: 
(Inclusion 3): Histologically or cytologically confirmed recurrent or metastatic 
SCCHN (oral cavity, oropharynx, hypopharynx, or larynx) not amenable to 
local curative therapy with surgery or radiation therapy
(Inclusion 4): No prior systemic therapy for recurrent/metastatic 
disease. Systemic therapy given as part of multimodality treatment for locally 
advanced or locally recurrent disease is allowed
(Inclusion 7): Confirmed PD-L1–positive or –negative SCCHN by the Ventana 
SP263 IHC assay

On newly acquired tumor tissue (preferred) or archival tissue (<3 years 
old)


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
If the patient’s PD-L1 status has already been assessed using the 
analytically validated Ventana assay as a part of the screening process 
for another AstraZeneca/MedImmune study, this test result can be used 
for the determination of eligibility

Note: A positive PD-L1 sample is measured using a defined cut-off 
based on ≥25% of tumor cells with membrane staining of any intensity 
for PD-L1.  A negative PD-L1 sample is determined by 0% to 24% of 
tumor cells with membrane staining for PD-L1
(Inclusion 8): World Health Organization (WHO)/ECOG performance status of 
0 or 1
(Exclusion 1): Histologically or cytologically confirmed head and neck cancer 
of any other primary anatomic location in the head and neck not specified in 
the inclusion criteria including patients with SCCHN of unknown primary or 
non-squamous histologies (e.g., nasopharynx or salivary gland)
(Exclusion 2): Tumor progression or recurrence within 6 months of last dose of 
platinum therapy given as part of multimodality treatment for locally advanced 
or locally recurrent disease
(Exclusion 13) Patients with a history of brain metastases, spinal cord 
compression, or leptomeningeal carcinomatosis, or involvement of any other 
anatomic area that, in the opinion of the Investigator, may cause significant 
symptoms if an inflammatory reaction occurs

Received prohibited concomitant medications (Deviation 2). Please refer to the CSP 
Section 7.7 for those medications that are detailed as being ‘excluded’ from permitted use 
during the study. This will be used as a guiding principle for the physician review of all 
medications prior to database lock. The output of important PDs due to use of prohibited 
concomitant medications will be based on Sponsor’s manual review. 
In addition to the programmatic determination of the deviations above, monitoring notes or 
summaries will be reviewed to determine any important post entry deviations that are not 
identifiable via programming, and to check that those identified via programming are correctly 
classified. The final classification will be made prior to database lock.  For example, details of 
disallowed concomitant medication use will be reviewed by a physician and may be 
determined as key.
In addition, all COVID-19 related non-important PDs and issues will be summarized and 
listed and included in the CSR. Treatment cycle and study visit delays resulting from COVID-
19 are captured in Veeva Clinical Vault (VCV) as protocol deviations with the PD code 
COVID19. These PDs will be extracted from VCV, reviewed by the study team and 
categorised accordingly for analysis and reporting prior to database lock.


Statistical Analysis Plan 
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3.
PRIMARY AND SECONDARY VARIABLES
3.1
Derivation of RECIST Visit Responses
The analyses of the RECIST 1.1 based secondary endpoints, PFS, ORR, DoR, TTR, BoR, 
APF6 and APF12, will be based on site investigator assessments using RECIST 1.1.  In 
addition, PFS2 will be defined by local clinical practice.
For all patients, the RECIST version 1.1 (see further Appendix E of the CSP) tumor response 
data will be used to determine each patient’s visit response.  It will also be used to determine 
if and when a patient has progressed and also their best objective response.  RECIST 1.1
assessments will be performed using CT/MRI assessments of the neck (from base of skull) 
though the chest and abdomen (including liver).  Additional anatomy should be imaged based 
on signs and symptoms of individual patients at baseline and follow-up.
The baseline assessments should be performed no more than 28 days before randomization 
and ideally should be performed as close as possible to the date of randomization (Tables 2 
and 3 of CSP). Follow-up assessments will be performed every 6 weeks for the first 24 weeks 
(relative to the date of randomization) and then every 8 weeks as indicated in the schedule of 
procedures until confirmed objective disease progression per RECIST 1.1.  The confirmatory 
scans should preferably be performed at the next scheduled visit (relative to the date of 
randomization) and no less than 4 weeks after the initial assessment of PD (in the absence of 
clinically significant deterioration). Confirmation of progression in patients in the SoC arm is 
preferable and should be done if clinically feasible. If an unscheduled assessment was 
performed and the patient has not progressed, every attempt should be made to perform the 
subsequent assessments at their scheduled visits (relative to the date of randomization).  All 
confirmatory scans should be recorded in the database.
Progression would be considered confirmed if the following criteria are met:

≥20% increase in the sum of diameters of target lesions (TL) compared with the nadir at 
2 consecutive visits with an absolute increase of 5 mm
The assessment of progression of ≥20% increase in the sum diameters of target lesions 
compared with the nadir is at the first progression time point relative to the nadir (the 
smallest sum of diameters and this may be at baseline or subsequent follow-up visit). The 
confirmed scan confirms the persistence of the ≥20% increase relative to the nadir.

And/or clinically significant progression (worsening) of non-target lesions (NTL) or new 
lesions at the confirmatory PD time point compared with the first time point where 
progression of non-target lesions or new lesions identified

And/or additional new unequivocal lesions at the confirmatory PD time point compared 
with the first time point new lesions were identified.
RECIST 1.1 will be regarded as primary in terms of the efficacy analyses and RECIST 1.1 
modified for confirmation of progression assessment is supportive (Section 3.1.3). 


Statistical Analysis Plan 
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In the absence of significant clinical deterioration, the investigator should continue study 
treatment until progression is confirmed.
If progression is not confirmed, then the patient should continue on study treatment and on 
treatment assessments. Treatment through PD in the Standard of Care group is at the 
Investigator’s discretion; however, a confirmatory scan is required for all patients in the 
Standard of Care group, if clinically feasible, even if a subsequent treatment is started.
If a patient discontinues treatment (and/or receives a subsequent cancer therapy) prior to 
progression, then the patient should still continue to be followed until confirmed objective 
disease progression.
Criteria for Retreatment for Patients in the MEDI4736 + tremelimumab arm
Patients who complete the 4 dosing cycles of the MEDI4736 + tremelimumab combination 
therapy portion of the regimen (with clinical benefit per Investigator’s judgment) but 
subsequently have evidence of PD during the MEDI4736 monotherapy portion of the 
combination regimen, with or without confirmation according to RECIST 1.1, may restart 
treatment with the entire combination regimen (including monotherapy maintenance).
For patients in the MEDI4736 + tremelimumab combination therapy arm, before a patient 
restarts treatment, the Investigator should ensure that the patient:
1.
Does not have any significant, unacceptable, or irreversible toxicities that indicate 
continuing treatment will not further benefit the patient
2.
Still fulfils the eligibility criteria for this study, including re-consenting to restart 
MEDI4736 + tremelimumab combination therapy
3.
Has not have received an intervening systemic anticancer therapy after their 
assigned treatment discontinuation  
4.
Has had a baseline tumor assessment within 28 days of restarting their assigned 
treatment; all further scans should occur every 8 weeks relative to the date of 
restarting treatment until study treatment is stopped
5.
Undergoes a tumor biopsy as described in Section 5.5.1 of the CSP
RECIST outcomes will be calculated using a computer program for both the BICR and site 
investigator data.  


Statistical Analysis Plan 
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3.1.1
Blinded Independent Central Review (BICR) Assessment Using RECIST 1.1
A BICR of radiological imaging data will be conducted according to RECIST 1.1 and used for 
a sensitivity analysis for the secondary objective of PFS.  This will use all radiological scans 
for all patients (including those at unscheduled visits or outside visit windows) obtained on or 
before Jan 8th, 2018 which was the data cut-off for the last BICR. (Cessation of the BICR at 
this data cut-off occurred due to PFS being changed to a secondary objective as documented 
in version 8 of the clinical study protocol so that the primary analysis will be conducted using 
investigator assessments instead of BICR).
Prior radiotherapy will also be provided to the BICR to allow the selection of appropriate 
target lesions.
The imaging scans will be reviewed by 2 independent radiologists using RECIST 1.1 and will 
be adjudicated, if required.  For each patient, the BICR will define the visit response data (CR, 
PR, SD, PD, or not evaluable [NE]) and the relevant scan dates for each timepoint (i.e., for 
visits where response or progression is/is not identified).  If a patient has had a tumor 
assessment that cannot be evaluated, then the patient will be assigned a visit response of NE 
(unless there is evidence of progression, in which case the response will be assigned as PD). 
Sensitivity analysis of PFS will be derived from the visit response data.
Further details of the BICR will be documented in the BICR Charter.
3.1.2
Site Investigator Assessment Using RECIST 1.1
All RECIST 1.1 assessments, whether scheduled or unscheduled, will be included in the 
calculations.  This is also regardless of whether a patient discontinues study treatment or 
receives another anticancer therapy. 
At each visit, patients will be programmatically assigned a RECIST 1.1 visit response of CR, 
PR, SD, or PD depending on the status of their disease compared with baseline and previous 
assessments.  Baseline will be assessed within the 28 days prior to randomization.  If a patient 
has had a tumor assessment that cannot be evaluated, then the patient will be assigned a visit 
response of NE (unless there is evidence of progression in which case the response will be
assigned as PD).
3.1.2.1
Target lesions (TLs)
Measurable disease is defined as having at least one measurable lesion, not previously 
irradiated, which is ≥ 10 mm in the longest diameter (except lymph nodes which must have 
short axis ≥ 15 mm) with CT or MRI and which is suitable for accurate repeated 
measurements.
A patient can have a maximum of 5 measurable lesions recorded at baseline with a maximum 
of 2 lesions per organ (representative of all lesions involved suitable for accurate repeated 
measurement) and these are referred to as target lesions (TLs).  If more than one baseline scan 
is recorded, then measurements from the one that is closest to the date of randomization will 


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be used to define the baseline sum of TLs.  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.
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at
baseline.  Measurements are not required for these lesions, but their status should be followed 
at subsequent visits.
Measurable disease (i.e.at least one TL) is one of the entry criteria for the study. However, if a 
patient with non-measurable disease is enrolled in the study, the evaluation of overall visit 
responses will be based on the overall NTL assessment and the absence/presence of new 
lesions (see Section 3.1.2.2 for further details).  If a patient does not have measurable disease 
at baseline then the TL visit response will be not applicable (NA).  
Table 7
TL Visit Responses
Visit Responses
Description
Complete Response (CR)
Disappearance of all target lesions since baseline.  Any 
pathological lymph nodes selected as target lesions must have 
a reduction in short axis to <10 mm.
Partial Response (PR)
At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters.
Progressive Disease (PD)
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.
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD
Not Evaluable (NE)
Only relevant in certain situations (i.e. if any of the target 
lesions were not assessed or not evaluable or had a lesion 
intervention at this visit; and scaling up could not be 
performed for lesions with interventions). Note: If the 
sum of diameters meets the progressive disease criteria, 
progressive disease overrides not evaluable as a target 
lesion response
Not Applicable (NA)
No target lesions are recorded at baseline
Rounding of TL data
For calculation of PD and PR for TLs, percentage changes from baseline and nadir (previous 
minimum) should be rounded to 1 decimal place before assigning a TL response.  For 
example, 19.95% should be rounded to 20.0% but 19.94% should be rounded to 19.9%


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Missing TL data 
For a visit to be evaluable, all TL measurements should be recorded.  However, a visit 
response of PD should still be assigned if any of the following occurred:

A new lesion is recorded.

An 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.
Note: the nadir can only be taken from assessments where all the TLs had a lesion diameter 
recorded.
Lymph nodes
For lymph nodes, if the size reduces to < 10 mm then these are considered non-pathological. 
However, a size will still be given and this size should still be used to determine the TL visit 
response as normal.  In the special case where all lymph nodes are < 10 mm and all other TLs 
are 0 mm then although the sum may be >0 mm the calculation of TL response should be 
over-written as a CR. 
TL visit responses subsequent to CR
A CR can only be followed by CR, PD or NE.  If a CR has occurred then the following rules 
at the subsequent visits must be applied:

Step 1:  If all lesions meet the CR criteria (i.e. 0 mm or < 10 mm for lymph nodes) then 
response will be set to CR irrespective of whether the criteria for PD of TL is also met (i.e. 
if a lymph node LD increases by 20% but remains < 10 mm). 

Step 2:  If some lesion measurements are missing but all other lesions meet the CR criteria 
(i.e. 0 mm or < 10 mm for lymph nodes) then response will be set to NE irrespective of 
whether when referencing the sum of TL diameters, the criteria for PD is also met. 

Step 3:  If not all lesions meet the CR criteria and the sum of lesions meets the criteria for 
PD then response will be set to PD

Step 4:  If after steps 1 – 3 a response can still not be determined the response will be set 
to remain as CR
TL too large to measure
If a TL becomes too big to measure this should be indicated in the database and a size (‘x’) 
above which it cannot be accurately measured should be recorded.  If using a value of x in the 
calculation of TL response would not give an overall visit response of PD, then this will be 


Statistical Analysis Plan 
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flagged and reviewed by the study team.  It is expected that a visit response of PD will remain 
in the vast majority of cases.  
TL too small to measure
If a TL becomes too small to measure a value of 5 mm will be entered into the database and 
used in TL calculations, unless the radiologist has indicated and entered a smaller value that 
can be reliably measured.  If a TL response of PD results then this will be reviewed by the 
study team.
Irradiated lesions/lesion intervention
Previously irradiated lesions (i.e. lesion irradiated prior to entry into the study) should be 
recorded as NTLs and should not form part of the TL assessment. Lesions in a previously 
irradiated field can be used as measurable disease provided that there has been demonstrated 
progression in the lesion.
Any TL (including lymph nodes), which has had intervention during the study (for example, 
radiotherapy / surgery / embolization), should be handled in the following way and once a 
lesion has had intervention then it should be treated as having intervention for the remainder 
of the study noting that an intervention will most likely shrink the size of tumors:

Step 1: the diameters of the TLs (including the lesions that have had intervention) will be 
summed and the calculation will be performed in the usual manner. If the visit response is 
PD this will remain as a valid response category. 

Step 2: If there was no evidence of progression after step 1, treat the lesion diameter (for 
those lesions with intervention) as missing and scale up as described below, as long as 
there remain 1/3 of the TLs with missing measurements.  If the scaling results in a visit 
response of PD then the patient would be assigned a TL response of PD.  

Step 3: If after both steps PD has not been assigned, then if appropriate, a scaled sum of 
diameters will be calculated (as long as 1/3 of the TLs with interventions), and PR or SD 
then assigned as the visit response.  Patients with intervention are evaluable for CR as long 
as all non-intervened lesions are 0 (or <10mm for lymph nodes) and the lesions that have 
been subject to intervention also has a value of 0 recorded. 
At subsequent visits the above steps will be repeated to determine the TL and overall visit 
response.  When calculating the previous minimum, lesions with intervention should be 
treated as missing and scaled up where appropriate (as per step 2 above).
Scaling (applicable only for irradiated lesions/lesion intervention)
If > 1/3 of target lesion measurements are treated as missing (because of intervention) then 
target lesion response will be NE, unless the sum of diameters of non-missing target lesion 
would result in PD (i.e. if using a value of 0 for missing lesions, the sum of diameters has still 
increased by 20% or more compared to nadir and the sum of target lesions has increased by 5 
mm from nadir).


Statistical Analysis Plan 
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If ≤ 1/3 of the target lesion measurements are treated as missing (because of intervention) then 
the results will be scaled up (based on the sizes at the nadir visit to give an estimated sum of 
diameters and this will be used in calculations; this is equivalent to comparing the visit sum of 
diameters of the non-missing lesions to the nadir sum of diameters excluding the lesions with 
missing measurements).
Example of scaling
Lesion
Longest diameter 
at nadir visit
Longest diameter 
at follow-up visit
1
7.2
7.1
2
6.7
6.4
3
4.3
4.0
4
8.6
8.5
5
2.5
Intervention
Sum
29.3
26
Lesion 5 has had an intervention at the follow-up visit. 
The sum of lesions 1-4 at the follow-up is 26 cm. The sum of the corresponding lesions at 
baseline visit is 26.8 cm.
Scale up as follows to give an estimated TL sum of 28.4cm:          
Lesions that split in two or more parts
If a TL splits in two, then the LDs of the split lesions should be summed and reported as the 
LD for the lesion that split. 
Lesions that merge
If two or more TLs merge, then the LD of the merged lesion should be recorded for one of the 
TL sizes and the other TL size should be recorded as 0 mm.
Change in method of assessment of TLs
CT and MRI are the only methods of assessment that can be used within the trial. If a change 
in method of assessment occurs between CT and MRI, this will be considered acceptable and 
no adjustment within the programming is needed.  
If a change in method involves clinical examination (e.g. CT changes to clinical examination 
or vice versa), any affected lesions should be treated as missing.    
cm
4.
28
3.
29
8.
26
26




Statistical Analysis Plan 
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3.1.2.2
Non-target lesions (NTLs) and New lesions.
At each visit an overall assessment of the NTL response should be recorded by the 
investigator. This section provides the definitions of the criteria used to determine and record 
overall response for NTL at the investigational site at each visit.
NTL response will be derived based on the investigator’s overall assessment of NTLs as 
follows:  
Table 8
NTL Visit Responses
Visit Responses
Description
Complete Response (CR)
Disappearance of all NTLs present at baseline with all 
lymph nodes non-pathological in size (<10 mm short 
axis).
Progressive Disease (PD)
Unequivocal progression of existing NTLs. Unequivocal 
progression may be due to an important progression in 
one lesion only or in several lesions. In all cases the 
progression MUST be clinically significant for the 
physician to consider changing (or stopping) therapy.
Non CR/Non PD
Persistence of one or more NTLs with no evidence of 
progression.
Not Evaluable (NE)
Only relevant when one or some of the NTLs were not 
assessed and, in the investigator's opinion, they are not 
able to provide an evaluable overall NTL assessment at 
this visit.
Note: For patients without TLs at baseline, this is relevant 
if any of the NTLs were not assessed at this visit and the 
progression criteria have not been met.
Not Applicable (NA)
Only relevant if there are no NTLs at baseline
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in the presence of SD or PR in 
TLs, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A 
modest ‘increase’ in the size of one or more NTLs is usually not sufficient to qualify for 
unequivocal progression status.
Details of any new lesions will also be recorded with the date of assessment. The presence of 
one or more new lesions is assessed as progression.
A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.


Statistical Analysis Plan 
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The finding of a new lesion should be unequivocal: i.e., not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumor.
If a new lesion is equivocal, for example because of its small size, the treatment and tumor 
assessments should be continued until the new lesion has been confirmed. If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan.
New lesions will be identified via a Yes/No tick box. The absence and presence of new lesions 
at each visit should be listed alongside the TL and NTL visit responses.
A new lesion indicates progression so the overall visit response will be PD irrespective of the 
TL and NTL response.
If the question ‘Any new lesions since baseline’ has not been answered with Yes or No and 
the new lesion details are blank this is not evidence that no new lesions are present and should 
be treated as NE in the derivation of overall visit response.
Symptomatic progression is not a descriptor for progression of NTLs: it is a reason for 
stopping study therapy and will not be included in any assessment of NTLs.
Patients with ‘symptomatic progression’ requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo tumor 
assessments where possible until objective disease progression is observed.
3.1.2.3
Site Investigator Assessment Using RECIST 1.1: Overall visit response
Table 9 defines how the previously defined TL and NTL visit responses will be combined 
with new lesion information to give an overall visit response.
Table 9
Overall Visit Responses
Target Lesions
Non-target lesions
New Lesions
Overall Response
CR
CR or NA
No (or NE)
CR
NA
CR
No (or NE)
CR
CR
Non CR/Non PD
No (or NE)
PR
CR
NE
No (or NE)
PR
PR
Non PD or NE or NA
No (or NE)
PR
SD
Non PD or NE or NA
No (or NE)
SD
NA
Non CR/Non PD
No (or NE)
SD 
NA
Non PD
NE
SD 
NE
Non PD or NE or NA
No (or NE)
NE
NA
NE
No (or NE)
NE


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Table 9
Overall Visit Responses
Target Lesions
Non-target lesions
New Lesions
Overall Response
PD
Any
Any
PD
Any
PD
Any
PD
Any
Any
Yes
PD
NA
NA
No
NED
CR Complete response, PR Partial response, SD Stable disease, PD Progression of disease, NE Not evaluable, 
NA Not applicable (only relevant if there were no TL/NTL at baseline), NED No evidence of disease.
3.1.3
Site Investigator Assessment Using RECIST 1.1 Modified for Confirmation of 
Progression
PFS as determined by RECIST 1.1 modified for confirmation of progression will be 
calculated using investigator assessments as detailed in Sections 3.1. This means that the visit 
response of PD must be confirmed by another visit response of PD at the next scheduled visit 
and no earlier than 4 weeks after the initial assessment of PD in the absence of clinical 
deterioration and if clinically feasible. Confirmation of progression needs to be 
programmatically derived.
3.2
Outcome Variables
All RECIST assessments, whether scheduled or unscheduled, will be included in the 
calculations.  This is also regardless of whether a patient discontinues investigational product 
or receives another anti-cancer therapy.  All efficacy and PRO data will be summarized and 
analysed using the full analysis set (FAS), refer to Table 6 for the analysis set for these 
variables.
3.2.1
Primary endpoint (OS)
OS is defined as the time from the date of randomization until death due to any cause (i.e., 
date of death or censoring – date of randomization + 1).  Any patient not known to have died 
at the time of analysis will be censored based on the last recorded date on which the patient 
was known to be alive (SUR_DAT, recorded within the SURVIVE module of the eCRF).
Note: Survival calls will be made following the date of data cut-off for the analysis (these 
contacts should generally occur within 7 days of the data cut-off).  If patients are confirmed to 
be alive or if the death date is post the data cut-off date, these patients will be censored at the 
date of data cut-off.  Death dates may be found by checking publicly available death registries 
(as applicable under local laws).
3.2.1.1
Progression free survival (PFS)
PFS (per RECIST 1.1 as assessed by investigator) will be defined as the time from the date of 
randomization until the date of objective disease progression or death (by any cause in the 


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absence of progression) regardless of whether the patient discontinues from therapy or 
receives another anticancer therapy prior to progression (i.e., date of event or censoring – date 
of randomization + 1).  Patients who have not progressed or died at the time of analysis will 
be censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 
assessment.  However, if the patient progresses or dies after 2 or more consecutive missed 
visits, the patient will be censored at the time of the latest evaluable RECIST 1.1 assessment 
prior to the 2 missed visits (Note: NE visit is not considered a missed visit). 
Given the scheduled visit assessment scheme (i.e., six-weekly for the first 24 weeks then 
eight-weekly thereafter) the definition of 2 missed visits will be as follows:

If the previous RECIST assessment is <= study day 35 (i.e. week 5) then two missing 
visits will equate to 13 weeks since the previous RECIST assessment, allowing for a late 
visit (i.e. 2 x 6 weeks + 1 week for a late assessment = 13 weeks).

If the previous RECIST assessment is >35 and < study day 120 (i.e. week 17) then two 
missing visits will equate to 14 weeks since the previous RECIST assessment, allowing 
for early and late visits (i.e. 2 x 6 weeks + 1 week for an early assessment + 1 week for a 
late assessment = 14 weeks).

If the two missed visits occur over the period when the scheduled frequency of RECIST 
assessments changes from six-weekly to eight-weekly this will equate to 16 weeks (i.e. 
take the average of 6 and 8 weeks which gives 7 weeks and then apply same rationale, 
hence 2 x 7 weeks + 1 week for an early assessment + 1 week for a late assessment = 16 
weeks). The time period for the previous RECIST assessment will be from study days 120 
to 161 (i.e. week 17 to week 23).

From week 23 (day 162) onwards (when the scheduling changes to eight-weekly 
assessments), two missing visits will equate to 18 weeks (i.e. 2 x 8 weeks + 1 week for an 
early assessment + 1 week for a late assessment = 18 weeks).
If the patient has no evaluable visits or does not have baseline data, they will be censored at 
Day 1 unless they die within 2 consecutive visits of baseline, then they will be treated as an 
event with date of death as the event date.
The PFS time will always be derived based on scan/assessment dates and not visit dates.
RECIST 1.1 assessments/scans contributing toward a particular visit may be performed on 
different dates.  The following rules will be applied:

For Investigator assessments, the date of progression will be determined based on the 
earliest of the RECIST 1.1 assessment/scan dates of the component that indicates 
progression.

For BICR assessments, date of progression will be determined from the progression date 
(PROGSCDT) provided by the BICR progression scan dates (PROGSCDT) dates.

When censoring a patient for PFS, the patient will be censored at the latest of the dates 
contributing to a particular overall visit assessment.


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Note: For target lesions, only the latest scan date is recorded out of all scans performed at that 
assessment for the target lesions, and similarly for non-target lesions, only the latest scan date 
is recorded out of all scans performed at that assessment for the non-target lesions.
PFS based on RECIST 1.1 modified for confirmation of progression may be performed for 
sensitivity analysis using the algorithm described above for the RECIST 1.1, but following a 
modification whereby any objective disease progression must be confirmed by the next 
scheduled scan.  The confirmatory scan must be no sooner than 4 weeks after the initial 
documented progression.  If disease progression is confirmed (or disease progression occurs 
and no further scans are recorded), then the date of progression will be when it was originally 
observed.  Patients with a single disease progression and no further tumor assessment scans 
will be treated as PD in the analysis.  In the absence of significant clinical deterioration, the 
investigational site is advised to continue the patient on their randomized MEDI4736 + 
tremelimumab combination therapy or MEDI4736 monotherapy until progression has been 
confirmed.  If progression is not confirmed, the patient should continue their randomized 
MEDI4736 + tremelimumab combination therapy or MEDI4736 monotherapy treatment and 
on-treatment assessments.  Treatment through PD in the SoC group is at the Investigator’s 
discretion; however, a confirmatory scan is required for all patients in the SoC group, if 
clinically feasible, even if a subsequent treatment is started.
3.2.2
Objective response rate
ORR (per RECIST 1.1 using investigator assessments) is defined as the number (%) of 
patients with at least 1 visit response of CR or PR.  Data obtained up until progression, or the 
last evaluable assessment in the absence of progression, will be included in the assessment of 
ORR.  Patients who discontinue study treatment without progression, receive a subsequent 
therapy, and then respond will not be included as responders in the ORR.  
Patients who continue study treatment through progression and subsequently respond with 
further treatment would not be included as responders in ORR assessment. Likewise, patients 
on the MEDI4736 + tremelimumab combination therapy arm who progress during the 
monotherapy portion of the regimen and subsequently respond with the optional retreatment 
regimen would not be included as responders in the ORR assessment.   
3.2.3
Duration of response
DoR (per RECIST 1.1 as assessed by investigator) will be defined as the time from the date of 
first documented response until the first date of documented progression or death in the 
absence of disease progression (i.e., date of PFS event or censoring – date of first response + 
1). The end of response should coincide with the date of progression or death from any cause 
used for the RECIST 1.1 PFS endpoint.  
The time of the initial response will be defined as the latest of the dates contributing towards 
the first visit response of CR or PR.   If a patient does not progress following a response, then 
their DoR will be censored at the PFS censoring time.  DoR will not be defined for those 
patients who do not have documented response.


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3.2.4
Time to response
Time to response (per RECIST 1.1 as assessed by the investigator) is defined as the time from 
the date of randomization until the date of documented response.  The date of documented 
response should coincide with that used for the RECIST 1.1 DoR endpoint.  
3.2.5
Proportion of patients alive and progression free at 6 and 12 months
The APF6 and APF12 will be defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 
as assessed by investigator) at 6 months and 12 months respectively.
3.2.6
Proportion of patients alive at 12, 18 and 24 months
The OS12, OS18 and OS24 will be defined as the Kaplan-Meier estimate of OS at 12, 18 and 
24 months respectively after randomization.
3.2.7
Time from randomization to the first subsequent therapy or death (TFST)
Time to the first subsequent therapy (TFST) or death will be defined as the time from the date 
of randomization to the earlier of either the start date of the first subsequent anticancer therapy 
after discontinuation of randomized treatment or the date of death (i.e., the date of first 
subsequent cancer therapy, death, or censoring defined as the date of randomization + 1 day).  
Any patient not known to have received a first subsequent anticancer therapy will be censored 
at the last date that the patient was known not to have received a first subsequent anticancer 
therapy.  If a patient terminated the study before the first subsequent therapy for a reason other 
than death, the patient will be censored at the earliest of either the patient’s last known date to 
be alive or the study termination date.
3.2.8
Time from randomization to second subsequent therapy or death (TSST)
As a supportive summary to PFS2, time to second subsequent therapy (TSST) or death will be 
defined as the time from the date of randomization to the earlier of either the start date of the 
second subsequent anticancer therapy after discontinuation of first subsequent therapy, or the 
date of death.  Any patient not known to have had a second subsequent anticancer therapy will 
be censored at the last date when the patient was known not to have received a second 
subsequent anticancer therapy.  If a patient terminated the study for reason other than death 
before second subsequent anticancer therapy, the patient will be censored at the earliest of the 
last known to be alive and termination dates.
3.2.9
Time from randomization to second progression-free survival (PFS2)
PFS2 will be defined as the time from the date of randomization to the earliest of the 
progression event subsequent to first subsequent therapy (TFST) or death.  Note the patient 
does not need to remain on their second treatment for the progression event to occur. The date 
of second progression will be recorded by the Investigator in the eCRF (PFS2 CRF) and 
defined according to local standard clinical practice and may involve any of the following: 
objective radiological imaging, symptomatic progression, or death.  Second progression status 
will be reviewed (every 6 weeks for the first 24 weeks relative to the date of randomization 
and then every 8 weeks thereafter) following the progression event used for the primary 


Statistical Analysis Plan 
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variable PFS (the first progression) and status recorded.  Patients alive and for whom a second 
disease progression has not been observed should be censored at the later of the date of 
assessment on the PFS2 form indicating no progression (PFSRESP=2) or at the date of the last 
evaluable RECIST assessment (or day 1 if no post-baseline RECIST data is available; date of 
withdrawal, date last known alive, DCO or, if a patient has not had a first subsequent therapy; 
the date last known not to have received a first subsequent therapy (TFST censoring date).
3.2.10
Change in tumor size
For supportive purposes percentage change from baseline in tumor size will be derived at each 
scheduled tumor assessment visit (hereafter referred to as week X for convenience). Best 
percentage change from baseline in tumor size will also be derived as the biggest decrease or, 
if no decrease, as the smallest increase in tumor size from baseline.
This is based on RECIST1.1 target lesion measurements taken at baseline and at the timepoint 
of interest. Tumor size is defined as the sum of the longest diameters of the target lesions for 
the site investigator data based upon RECIST assessments.  Target lesions are measurable 
tumor lesions.  The change in target lesion tumor size at week X will be obtained for each 
patient by taking the difference between the sum of the target lesions at week X and the sum 
of the target lesions at baseline. To obtain the percentage change in target lesion tumor size at 
week X the change in target lesion tumor size is divided by the sum of the target lesions at 
baseline and multiplied by 100 (i.e. (week X - baseline) / baseline * 100). More details on 
target lesions and measurements can be found in Section 3.1.
3.2.11
Best objective response (BoR)
Best objective response (BoR) is calculated based on the overall visit responses from each 
RECIST 1.1 assessment, as described in Appendix F.  It is the best response a patient has had 
during their time in the study up until RECIST 1.1 progression or the last evaluable 
assessment in the absence of RECIST 1.1 progression.
Categorization of BoR will be based on RECIST 1.1 (Appendix F) using the following 
response categories: CR, PR, SD, PD, and NE.
BoR will be determined programmatically based on RECIST 1.1 using all site investigator 
assessments up until the first progression event.  For patients whose progression event is 
death, BoR will be calculated based upon all evaluable RECIST 1.1 assessments prior to 
death.
For determination of a best response of CR/PR, at least one determination of CR/PR must be 
observed before progression disease (PD)
For determination of a best response of SD, at least one SD should be recorded at 5 weeks 
(i.e., 6 weeks minus 1 week), i.e. at least 35 days (to allow for an early assessment within the 
assessment window), after date of randomization (and not qualifying for CR or PR). 


Statistical Analysis Plan 
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For PD, patients who die with no evaluable RECIST 1.1 assessments, if the death occurs 
≤98 days (i.e., 2 × (6 weeks ±1week)) after randomization, then BoR will be assigned to the 
progression (PD) category.  For patients who die with no evaluable RECIST 1.1 assessments, 
if the death occurs >98 days (i.e., 2 × (6 weeks ±7 days)) after the date of randomization, then 
BoR will be assigned to the NE category.  
Progression events that have been censored due to them being >90 days because of 2 or more 
consecutive missed visits will not contribute to the BoR derivation.
3.3
Safety
Safety and tolerability will be assessed in terms of adverse events (AEs) (including serious 
adverse events [SAEs]), deaths, laboratory data, vital signs, electrocardiograms (ECGs) and 
exposure.  These will be collected for all patients. Data from all cycles of treatment will be 
combined in the presentation of safety data. ‘On treatment’ will be defined as assessments 
between date of start dose and 90 days following discontinuation of IP (i.e., the last dose of 
MEDI4736 monotherapy, MEDI4736 + tremelimumab combination therapy, or SoC) 
regardless of re-treatment period. For AEs, on treatment (or treatment-emergent AEs) will be 
defined as any AEs that started after dosing or prior to dosing and which worsens following 
exposure to the treatment. If an AE is not worse than the baseline (pre-dose) severity, then it 
will not be classified as TEAE.
Safety analysis set will be used for reporting of safety data.
3.3.1
Adverse events (AEs)
AEs and SAEs will be collected from the time of signature of informed consent throughout the 
treatment period and up to 90 days after the last dose of IP (MEDI4736 + tremelimumab, 
MEDI4736, or SoC) or until initiation of another therapy (excluding palliative radiation as 
anti-cancer therapy) regardless of whether the AE occurred during re-treatment with 
tremelimumab or not. Any AE occurring before treatment with IP will be included in the data 
listings but will not be included in the summary tables of AEs. 
The Medical Dictionary for Regulatory Activities (MedDRA) dictionary will be used to code 
the AEs. AEs will be graded according to the National Cancer Institute Common Terminology 
Criteria for AEs (CTCAE Version 4.03 or higher). 
AEs of special interest (AESIs)
Adverse events of special interest (AESIs) are events of scientific and medical interest specific 
to the further understanding of the MEDI4736 and tremelimumab safety profile and require 
close monitoring and rapid communication by the Investigator to the Sponsor. MEDI4736 and 
tremelimumab 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 these IPs.


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47
Currently, these AESI’s have been identified in the CSP as Diarrhea/Colitis and intestinal 
perforation, Pneumonitis/ILD, hepatitis/transaminase increases, Endocrinopathy (i.e. Events 
of hypophysitis/hypopituitarism, adrenal insufficiency, and hyper- and hypothyroidism and
type I diabetes mellitus), Neuropathy/neuromuscular toxicities (eg Guillain-Barre and 
myasthenia gravis), Rash/Dermatitis, Nephritis/blood creatinine increases, Pancreatitis/serum 
lipase or amylase increases, myocarditis, myositis/polymyositis and other inflammatory 
responses that are rare/less frequent with a potential immune-mediated aetiology including, 
but not limited to, pericarditis, sarcoidosis, uveitis and other events involving the eye, skin, 
haematological and rheumatological events. .
An AstraZeneca medically qualified expert, after consultation with the Global Patient Safety 
Physician, has reviewed the AEs of interest and identified which preferred terms contribute to 
each AESI. A further review will take place prior to database lock to ensure new terms not 
already included in the older MedDRA version are captured within the categories for the new 
higher MedDRA version. The list will be provided by AZ prior to database lock.
AEs of possible interest (AEPIs)
Adverse events of possible interest (AEPIs) are AEs that also have a potential inflammatory or 
immune-mediated pathophysiological basis resulting from the mechanism of action of 
durvalumab and/or tremelimumab but are more likely to have occurred due to other 
pathophysiological mechanisms and, thus, the likelihood the event is inflammatory or 
immune-mediated in nature is not high and/or is most often or usually explained by the other 
causes. These AEs not routinely arising from an inflammatory or immune-mediated 
mechanism of action – typically quite general clinical terms that usually present from a 
multitude of other causes –are classified as AEPIs.
A framework of questions was developed by the Sponsor to identify event terms that may 
have an inflammatory or immune-mediated mechanism of action but implicitly have a lower 
likelihood of that than other causes and, thus, should be included as an AEPI not an AESI 
term.
Immune-mediated Adverse Events (imAE)
Immune-mediated Adverse Events (imAE) will be identified from both AESIs and AEPIs 
based on programmatic rules that consider interventions involving systemic steroid therapy, 
immunosuppressant use, and/or endocrine therapy (which, in the case of AEPIs, occurs after 
first considering an Investigator’s causality assessment and/or an Investigator’s designation of 
an event as immune-mediated). Further details are provided in an imAE Charter v6. 
In addition, the Sponsor may perform medical review of those AESIs and classify them as 
imAEs or not imAEs via an independent manual adjudication process.
Infection Adverse Events
Infection is an identified risk for another anti-PDL1 drug atezolizumab and listed in the 
Warnings and Precautions of its US label.  Infection AEs will be presented in the CSR.


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3.3.2
Treatment exposure
Exposure will be defined separately for MEDI4736 monotherapy, MEDI4736 on the 
MEDI4736+ tremelimumab combination arm, tremelimumab on the 
MEDI4736+tremelimumab combination arm, and also separately for cetuximab, a platinum 
[carboplatin or cisplatin], and 5FU on the standard of care arm for the initial period of 
treatment and for the retreatment period as follows:
Total (or intended) exposure of MEDI4736 (monotherapy) 

Total (or intended) exposure is defined as the total treatment period from first dose 
date of study drug to earliest of “last dose date of study drug + 27 days” or death 
date or DCO.
Total (or intended) exposure of MEDI4736 (combination) 

Total (or intended) exposure is defined as the total treatment period from first dose 
date of study drug to the earliest of “last dose date of study drug + 27 days” or death 
date or DCO regardless of tremelimumab being re-started or not.
Total (or intended) exposure of tremelimumab (combination) 

Total (or intended) exposure is defined as the total treatment period from first dose 
date of study drug to the earliest of “last dose date of study drug + 27 days” or death 
date or DCO. This will include the sum of the duration in the 2 tremelimumab 
periods (i.e., initial period and re-treatment) but excluding the count of time 
between the 2 periods (for example, the duration would sum up to 6 months if they 
did 3 months in each case even if the 2 periods were separated by several months).
Actual exposure of MEDI4736/tremelimumab

Actual exposure is defined as above, but excluding total duration of dose delays. 
Actual treatment duration for tremelimumab will be derived similarly as was done 
by total exposure, that by combining the periods of tremelimumab and summing up 
the delays in each period.
Total (or intended) exposure for the SOC regimens (cetuximab, a platinum [carboplatin or 
cisplatin], and 5FU)

The total (or intended) exposure for the individual SOC regimens will be calculated 
according to the dose schedule required for each SOC regimen as follows: 
(a)
Cetuximab: Total (or intended) exposure is defined as the total treatment 
period from first dose date of study drug to the earliest of “last dose date 
of study drug + 6 days” or death date or DCO
(b)
Platinum and 5FU: Total (or intended) exposure is defined as the total 
treatment period from first dose date of study drug to the earliest of “last 
dose date of study drug + 20 days” or death date or DCO                  


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The total (or intended) exposure will also be summarised by combining the SOC treatments 
together. The following rules will be applied for SOC total

Total (or intended) exposure is defined as the total treatment period from first dose 
date of study drug to the earliest of “last dose date of YY SoC drug + xx days” or 
death date or DCO, xx depends on whether the patient was still receiving platinum 
or 5FU, or only on cetuximab:

if last dose of cetuximab is >14 days after last dose of platinum and 5FU, 
then YY=cetuximab and xx= 6 days

if last dose of cetuximab is < 14 days after last dose of platinum and 5FU, 
then YY=platinum and xx= 20 days  
Actual exposure will not be calculated for SOC.
Dose reductions are not permitted per the CSP for the immunotherapy agents (MEDI4736 or 
MEDI4736+tremelimumab). The actual exposure calculation makes no adjustment for any 
dose reductions that may have occurred. 
Exposure will also be measured by the number of cycles received. For the immunotherapy 
arms, a cycle corresponds to a 4-week treatment; for SOC, a cycle corresponds to a 3-week
treatment. If a cycle is prolonged due to toxicity, this should still be counted as one cycle. A 
cycle will be counted if treatment is started even if the full dose is not delivered. Each 
immunotherapy agent will be measured in terms of number of doses given.
Patients who permanently discontinue during a dose interruption
If a decision is made to permanently discontinue study treatment in-between cycles or during 
a cycle delay then the date of last administration of study medication recorded will be used for 
the calculation of exposure.
Calculation of duration of dose delays (for actual exposure):
MEDI4736 (monotherapy):

For all dosing dates:
Total duration of dose delays= Sum of (Date of the dose - Date of previous dose – 28 
days)
Thus, if no delays were encountered, the duration would sum up to 0, since infusions 
were done every four weeks.
MEDI4736 (given in combination):

Duration of dose delays= Sum of (Date of the dose - Date of previous dose – 28 days); 
this will include re-treatment period as was done for the exposure derivation
Tremelimumab (given in combination):


Statistical Analysis Plan 
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
Duration of dose delays= Sum of (Date of the dose - Date of previous dose – 28 days)
3.3.3
Dose intensity
Dose intensity will be derived for the initial treatment period and the re-treatment period for 
the immunotherapy agents. It will also be derived for each of the SOC agents (cetuximab, a 
platinum [carboplatin or cisplatin], and 5FU). Relative dose intensity (RDI) is the percentage 
of the actual dose delivered relative to the intended dose through to treatment discontinuation.
Relative dose intensity (RDI) will be defined as follows for MEDI4736, tremelimumab and all 
Standard of Care therapy:

RDI = 100% * d/D, where d is the actual cumulative dose delivered up to the actual last 
day of dosing and D is the intended cumulative dose up to the actual last day of dosing. D 
is the total dose that would be delivered, if there were no modification to dose or schedule.
For patients who started cisplatin and later switched to carboplatin, the last day of dosing for 
both the intended and actual dosing for cisplatin will be the last day prior to switching to 
carboplatin, and for carboplatin, day 1 will be the first day of dosing of carboplatin in these 
patients (e.g., if the first day of carboplatin was given on study day 22, then day1 for 
carboplatin=study day 22, etc). If patients switch from carboplatin to cisplatin in any way 
other than once from cisplatin to carboplatin, no RDI will be calculated for them.
In cases where the units for the recorded dose is different from the planned dose, the following 
conversion should be applied when feasible:
1. 100mg/m2 of body surface area: If the recorded dose is in mg instead of mg/m2, height and 
weight (use most current weight) will be used to derive body surface area using Du 
Bois formula)
2. AUC of 5 mg/mL/min: If the recorded dose unit is in mg instead of AUC then the 
following algorithm should be used to convert doses in mg to AUC
1.
 = 	
 ∗
(())
((mg/dL))# ∗($	%&ℎ(()&)/72), values for sex: 
Male=1, Female=0.85
2.
,-.&	(/01 = 1-.2345-(%6 738	 (9&)/( + 25)
3.
1-.2345-(%6738	 = ,-.&	(/01 ∗( + 25)
Note: For MEDI4736 monotherapy in the combination arm and tremelimumab, RDI would 
use the intended dose for the 2 periods (initial and re-treatment periods) combined.
3.3.4
Laboratory data
Laboratory data will be collected throughout the study, from screening to the follow-up visits 
as described in Tables 2, 3 and 4 of the CSP. Blood and urine samples for determination of 
hematology, clinical chemistry, and urinalysis will be collected as described in Section 5.2.1 


Statistical Analysis Plan 
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of the CSP.  For derivation of baseline and post baseline visit values considering visit window 
and how to handle multiple records, derivation rules as described in Section 3.3.7 below will 
be used.
Change from baseline in hematology and clinical chemistry variables will be calculated for 
each post-dose visit on treatment. CTCAE grades will be defined at each visit according to the 
CTCAE grade criteria using local or project ranges as required, after conversion of lab result 
to corresponding SI units. The following parameters have CTCAE grades defined for both 
high and low values: Potassium, Sodium, Magnesium, Glucose and Corrected calcium so high 
and low CTCAE grades will be calculated.
Corrected Calcium will be derived during creation of the reporting database using the 
following formula:
Corrected calcium (mmol/L) = Total calcium (mmol/L) + ([40 – Albumin (G/L)] x 0.02)
Absolute values will be compared to the project reference range and classified as low (below 
range), normal (within range or on limits of range) and high (above range).
The maximum or minimum on treatment value (depending on the direction of an adverse 
effect) will be defined for each laboratory parameter as the maximum (or minimum) post-dose 
value at any time.
Local reference ranges will be used for the primary interpretation of laboratory data. The 
denominator used in laboratory summaries of CTCAE grades will only include evaluable 
patients, in other words those who had sufficient data to have the possibility of an 
abnormality.
For example:

If a CTCAE criterion involves a change from baseline, evaluable patients would have both 
a pre-dose and at least 1 post-dose value recorded.

If a CTCAE criterion does not consider changes from baseline, to be evaluable the patient 
needs only to have 1 post dose-value recorded.
3.3.5
ECGs
ECG data obtained up until 90 days after date of last dose of study treatment, or until initiation 
of another therapy, will be used for reporting. For derivation of post baseline visit values 
considering visit window and to handle multiple records present in any visit window, 
derivation rules as described in Section 3.3.7 below will be used.
Investigator’s assessment of the ECG will be collected locally. 


Statistical Analysis Plan 
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3.3.6
Vital signs
Vital signs (blood pressure [BP], pulse, respiratory rate, and temperature) will be evaluated 
according to the assessment schedules (Tables 2, 3, and 4 from CSP).  
Vital signs data obtained up until 90 days after date of last dose of study treatment, or until 
initiation of another therapy, will be used for reporting. Change from baseline in vital signs 
variables will be calculated for each post-dose visit on treatment. For derivation of post 
baseline visit values considering visit window and to handle multiple records, derivation rules 
as described in Section 3.3.7 below will be used. 
The denominator in vital signs data should include only those patients with recorded data.
3.3.7
General considerations for safety assessments
Time windows will need defining for any presentations that summarize values by visit. (Note: 
this also applies to the PRO data, as well as safety analyses) The following conventions 
should also apply:

The time windows should be exhaustive so that data recorded at any time point has the 
potential to be summarized. Inclusion within the time window should be based on the 
actual date and not the intended date of the visit.

All unscheduled visit data should have the potential to be included in the summaries.

The window for the visits following baseline will be constructed in such a way that the 
upper limit of the interval falls half way between the two visits (the lower limit of the first 
post-baseline visit will be Day 0).  If an even number of days exists between two 
consecutive visits then the upper limit will be taken as the midpoint value minus 1 day.  

For summaries showing the maximum or minimum values, the maximum/minimum value 
recorded on treatment will be used (regardless of where it falls in an interval).

Listings should display all values contributing to a time point for a patient.

For visit based summaries:
o
If there is more than one value per patient within a time window then the 
closest value to the scheduled visit date should be summarized, or the earlier in 
the event the values are equidistant from the nominal visit date.  The listings 
should highlight the value for that patient that went into the summary table, 
wherever feasible. Note: in summaries of extreme values all post baseline 
values collected are used including those collected at unscheduled visits 
regardless of whether or not the value is closest to the scheduled visit date.  
o
To prevent very large tables or plots being produced that contain many cells 
with meaningless data, for each treatment group visit data should only be 


Statistical Analysis Plan 
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summarized if the number of observations is greater than the minimum of 20
and > 1/3 of patients dosed.

For summaries at a patient level, all values should be included, regardless of whether they 
appear in a corresponding visit based summary, when deriving a patient level statistic such 
as a maximum. 

Baseline will be defined as the last non-missing measurement prior to dosing with study 
treatment. For the re-treatment period then baseline is similarly defined as the last non-
missing measurement prior to the first dose on the re-treatment period. For laboratory data, 
any assessments made on day 1 will be considered pre-dose. Alternatively, if two visits are 
equally eligible to assess patient status at baseline (e.g., screening and baseline 
assessments both on the same date prior to first dose with no washout or other intervention 
in the screening period), the average can be taken as a baseline value. For non-numeric 
laboratory tests (i.e., some of the urinalysis parameters) where taking an average is not 
possible then the best value would be taken as baseline as this is the most conservative. In 
the scenario where there are two assessments on day 1, one with time recorded and the 
other without time recorded, the one with time recorded would be selected as baseline.
Where safety data are summarized over time, study day will be calculated in relation to 
date of first study treatment. 
Missing safety data will generally not be imputed. However, safety assessment values of the 
form of “< x” (i.e., below the lower limit of quantification) or > x (i.e., above the upper limit 
of quantification) will be imputed as “x” in the calculation of summary statistics but displayed 
as “< x” or “> x” in the listings. Furthermore:-

For missing diagnostic dates, if day and/or month are missing use 01 and/or Jan. If year is 
missing, put the complete date to missing.

For missing start AE dates, the following will be applied  
1.
Missing day- Impute the 1st of the month unless month is the same as month of the first 
dose of study drug then impute first dose date
2.
Missing day and month -Impute 1st January unless year is the same as first dose date 
then impute first dose date
3.
Completely missing-impute first dose date unless the end date suggests it could have 
started prior to this in which case impute the 1st January of the same year as the end 
date

For missing end AE dates, the following will be applied:
o
Missing day - Impute the last day of the month unless month is the same as month 
of the last dose of study drug then impute last dose date.


Statistical Analysis Plan 
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o
Missing day and month – impute 31st December unless year is the same as last 
dose date then impute last dose date.
1. If a patient is known to have died where only a partial death date is available then the date 
of death will be imputed as the latest of the last date known to be alive +1 from the 
database and the death date using the available information provided:-
a.
For Missing day only – using the 1st of the month 
b. For Missing day and month -using the 1st of January. 
3.4
Patient reported outcome
PROs will be assessed using the EORTC QLQ-C30, EORTC QLQ-H&N35, 
 
  All items/questionnaires will be 
scored according to published scoring guidelines. All PRO analyses will be based on the full 
analysis set (FAS).
3.4.1
EORTC QLQ-C30
The EORTC QLQ-C30 consists of 30 questions that can be combined to produce 5 functional 
scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and 
nausea/vomiting), and a global measure of health status.  The EORTC QLQ-C30 will be 
scored according to the EORTC QLQ-C30 scoring manual (Fayers et al 2001).  An outcome 
variable consisting of a score from 0 to 100 will be derived for each of the symptom scales, 
each of the functional scales, and the global health status scale in the EORTC QLQ-C30 
according to the EORTC QLQ-C30 Scoring Manual.  Higher scores on the global health status 
and functioning scales indicate better health status/function, but higher scores on symptom 
scales represent greater symptom severity.
The change from baseline in HRQoL will be assessed using the EORTC QLQ-C30 global 
QoL scale, which includes 2 items from the EORTC QLQ-C30: “How would you rate your 
overall health during the past week?” (Item 29), and “How would you rate your overall QoL 
during the past week?” (Item 30).
Definition of clinically meaningful changes
Changes in score compared with baseline will be evaluated.  A minimum clinically 
meaningful change is defined as an absolute change in the score from baseline of ≥10 for 
scales from the EORTC QLQ-C30 (Osoba et al 1998).  For example, a clinically meaningful 
improvement in physical function (as assessed by EORTC QLQ-C30) is defined as an 
increase in the score from baseline of ≥10, whereas a clinically meaningful deterioration is 
defined as a decrease in the score from baseline of ≥10.  At each post-baseline assessment, the 
change in symptoms/functioning from baseline will be categorized as improvement, 
no change or deterioration as shown in Table 10.
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Statistical Analysis Plan 
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Table 10
Change from BL and visit response for EORTC QLQ C30
Score
Change from baseline
Visit response
EORTC QLQ-C30 Global quality 
of life score
≥+10
Improvement
≤-10
Deterioration
Otherwise
No change
EORTC QLQ-C30 symptom 
scales/items
≥+10
Deterioration
≤-10
Improvement
Otherwise
No change
EORTC QLQ-C30 functional 
scales
≥+10
Improvement
≤-10
Deterioration
Otherwise
No change
EORTC European Organisation for Research and Treatment of Cancer; QLQ-C30 30-item core quality of life questionnaire.
For each subscale, if <50% of the subscale items are missing, then the subscale score will be 
divided by the number of non-missing items and multiplied by the total number of items on 
the subscales (Fayers et al 2001). If at least 50% of the items are missing, then that subscale 
will be treated as missing. Missing single items are treated as missing. The reason for any 
missing questionnaire will be identified and recorded. If there is evidence that the missing 
data are systematic, missing values will be handled to ensure that any possible bias is 
minimized.
Time to symptom deterioration
For each of the symptom scales in the EORTC QLQ-C30, time to symptom deterioration will 
be defined as the time from randomization until the date of the first clinically meaningful 
symptom deterioration (an increase in the score from baseline of ≥10) or death (by any cause) 
in the absence of a clinically meaningful symptom deterioration, regardless of whether the 
patient withdraws from study treatment or receives another anticancer therapy prior to 
symptom deterioration.  
Patients whose symptoms (as measured by EORTC QLQ-C30) have not shown a clinically 
meaningful deterioration and who are alive at the time of the analysis will be censored at the 
time of their last PRO assessment where the symptom could be evaluated.  Also, if symptoms 
deteriorate after two or more missed PRO assessment visits or the patient dies after two or 
more missed PRO assessment visits, the patient will be censored at the time of the last PRO 
assessment where the symptom could be evaluated (prior to the two missed assessment visits).  
If a patient has no evaluable visits or does not have baseline data they will be censored at 0 
days.  The population for the analysis of time to symptom deterioration will include a subset 
of the FAS who have baseline scores of ≤90.


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Time to HRQoL/Function deterioration
For HRQoL, time to deterioration will be defined as the time from the date of randomization 
until the date of the first clinically meaningful deterioration (a decrease in the function scales 
or the global health status/QoL from baseline of ≥10) or death (by any cause) in the absence of 
a clinically meaningful deterioration, regardless of whether the patient withdraws from study 
treatment or receives another anticancer therapy prior to HRQoL/function deterioration.  
Patients whose HRQoL (as measured by EORTC QLQ-C30) have not shown a clinically 
meaningful deterioration and who are alive at the time of the analysis will be censored at the 
time of their last PRO assessment where the HRQoL/function could be evaluated.  Also, if 
HRQoL deteriorates after two or more missed PRO assessment visits or the patient dies after 2 
or more missed PRO assessment visits, the patient will be censored at the time of the last PRO 
assessment where HRQoL/function could be evaluated.  If a patient has no evaluable visits or 
does not have baseline data they will be censored at 0 days.  The population for the analysis of 
time to HRQoL/function deterioration will include a subset of the FAS who have baseline 
scores of ≥10.
Symptom improvement rate
The symptom improvement rate will be defined as the number (%) of patients with 
2 consecutive assessments at least 14 days apart that show a clinically meaningful 
improvement (a decrease from baseline score ≥10 for EORTC QLQ-C30 symptom scales) in 
that symptom from baseline.  The denominator will consist of a subset of the FAS who have a 
baseline symptom score ≥10.
HRQoL/function improvement rate
The HRQoL/function improvement rate will be defined as the number (%) of patients with 
2 consecutive assessments at least 14 days apart that show a clinically meaningful 
improvement (an increase from baseline score ≥10 for EORTC QLQ-C30 functional scales 
and global health status/QoL) in that scale from baseline.  The denominator will consist of a 
subset of the FAS who have a baseline HRQoL/function score ≤90.
PRO Compliance
Summary measures of overall compliance and compliance over time will be derived for the 
EORTC QLQ-C30. These will be based upon:

Received forms=number of EORTC QLQ-C30 forms 

Expected forms= number of patients still under HRQL follow-up at the specified 
assessment time excluding patients in countries with no available translation. For patients 
that have progressed, the latest of progression and safety follow-up will be used to assess 
whether the patient is still under HRQL follow-up at the specified assessment time. Date 
of study discontinuation will be mapped to the nearest visit date to define the number of 
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
Evaluable forms = subset of the expected EORTC QLQ-C30 forms with at least one 
subscale that can be determined. 

Compliance rate = Evaluable/Expected ×100

Evaluability rate = Evaluable/Received ×100
Thus the overall compliance rate is defined as number of patients with an evaluable baseline 
and at least one evaluable follow-up form (as defined above), divided by the number of 
patients expected to have completed at least a baseline EORTC QLQ-C30 form.
Compliance over time will be calculated separately for each visit, including baseline, as the 
number of patients with an evaluable baseline form and a form at the time point (as defined 
above), divided by number of patients still expected to complete forms at that visit. Similarly 
the evaluability rate over time will be calculated separately for each visit, including baseline, 
as the number of evaluable forms (per definition above), divided by the number of received 
forms.
3.4.2
EORTC QLQ-H&N35
The H&N35 is a head and neck cancer-specific module from the EORTC for head and neck 
cancer comprising 35 questions to assess head and neck cancer symptoms. The head and neck 
cancer module includes 11 single items and 7 multi-item scales that assess pain, swallowing, 
senses (taste and smell), speech, social eating, social contact, and sexuality. For all items and 
scales, high scores indicate increased symptomatology/more problems.
The scoring approach for the H&N35 is identical in principle to that for the symptom 
scales/single items of the EORTC QLQ-C30.  As the wording is reversed on the H&N35, 
higher scores represent greater symptom severity.
Definition of clinically meaningful changes
Changes in score compared with baseline will be evaluated.  The developers of the H&N35 
have suggested that a minimum clinically meaningful change is a change in the score from 
baseline of ≥10 for scales/items from the H&N35 module (Bjordal et al 2000).  For example, a 
clinically meaningful deterioration or worsening in dry mouth (as assessed by H&N35) is 
defined as an increase in the score from baseline of ≥10.  At each post-baseline assessment, 
the change in symptoms/functioning from baseline will be categorized as improved, no 
change, or deterioration, as shown in Table 11. 
 
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Table 11
Change from BL and visit response for EORTC QLQ H&N35
Score
Change from baseline
Visit response
H&N35 symptom scales and items
≥+10
Deterioration
≤-10
Improvement
Otherwise
No change
HRQoL Health-related quality of life; H&N35 35-item head and neck quality of life questionnaire.
Time to symptom deterioration
For each of the symptom scales/items in the H&N35, time to symptom deterioration will be 
defined as the time from randomization until the date of the first clinically meaningful 
symptom deterioration (an increase in the score from baseline of ≥10) or death (by any cause) 
in the absence of a clinically meaningful symptom deterioration, regardless of whether the 
patient withdraws from study treatment or receives another anticancer therapy prior to 
symptom deterioration.  Death will be included as an event only if the death occurs within 2 
visits of the last PRO assessment where the symptom change could be evaluated.
Patients whose symptoms (as measured by the H&N35) have not shown a clinically 
meaningful deterioration and who are alive at the time of the analysis will be censored at the 
time of their last PRO assessment where the symptom could be evaluated.  Also, if symptoms 
progress after 2 or more missed PRO assessment visits or the patient dies after 2 or more 
missed PRO assessment visits, the patient will be censored at the time of the last PRO 
assessment where the symptom could be evaluated.  If a patient has no evaluable visits or does 
not have baseline data, they will be censored at 0 days. The population for analysis of time to 
symptom deterioration will include a subset of the FAS population who has baseline scores 
≤90.
Symptom improvement rate
The symptom improvement rate will be defined as the number (%) of patients with 2 
consecutive assessments at least 14 days apart that show a clinically meaningful improvement 
(a decrease from baseline score ≥10 for H&N35 scales/items) in that symptom from baseline.
The denominator will consist of a subset of the FAS who have a baseline symptom score ≥10.
PRO Compliance
Summary measures of overall compliance and compliance over time will be derived for the 
EORTC QLQ-H&N35. These will be based upon the compliance derivation described for 
EORTC QLQ-C30
3.4.3
 
 
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3.4.4
 
 
 
 
 
 
3.4.5
 
 
 
 
3.4.6
 
 
 
 
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3.5
Pharmacokinetics and Immunogenicity Variables
Analyses to evaluate the pharmacokinetics of MEDI4736 monotherapy, and MEDI4736 + 
tremelimumab combination therapy and to investigate the immunogenicity of MEDI4736 and 
tremelimumab will be performed by a designated third party on behalf of AstraZeneca.
3.5.1
Population of pharmacokinetics and exposure-response/safety analysis
A population PK model may be developed using a non-linear mixed-effects modelling 
approach for MEDI4736 monotherapy and for MEDI4736 in combination with 
tremelimumab. The impact of physiologically-relevant patient characteristics (covariates) and 
disease on PK of both agents may be evaluated. The relationship between MEDI4736 PK 
exposure or tremelimumab PK exposure and the effect on safety and efficacy endpoints may 
be evaluated. The results of such an analyses, if conducted, will be reported outside of the
CSR.
3.5.2
Pharmacokinetic analysis
Pharmacokinetic data analyses of MEDI4736 and tremelimumab will be performed by the 
MedImmune Global Pharmacokinetics Pharmacodynamics (PK-PD) & Bioanalysis group or 
designee. No formal non-compartmental (NCA) PK analysis will be conducted due to the 
sparse PK sampling scheme for MEDI4736 and tremelimumab, which does not allow for 
meaningful determination of PK parameters.
MEDI4736 and tremelimumab concentration data and summary statistics will be tabulated by 
treatment arm and visit.  PK parameters, such as peak and trough concentration of MEDI4736 
and tremelimumab, will be derived from raw data measurements as data allow. 
For data below limit of quantification (BLQ) the following rules will apply:

If, at a given time point, 50% or less of the serum concentrations are not quantifiable 
(NQ), the geometric mean, CV%, geometric CV%, mean and SD will be calculated by 
substituting the limit of quantification (LOQ) for values which are NQ.

If more than 50%, but not all, of the concentrations are NQ, the geometric mean, 
CV%, geometric CV%, mean and SD will be reported as not calculable (NC).

If all the concentrations are NQ, the geometric mean and mean will be reported as NQ 
and the CV%, geometric CV% and SD as NC.
ALQ results of the PK assay will be excluded from summary statistics calculations.
If two results are obtained for one PK sample, the following rules will be applied:

If the results are ≤ +/- 30% of each other (by calculating the relative percent difference
(RPD)), then the mean of the two results will be reported


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
If the results are > +/- 30% of each other (RPD), then this will be reported as NRR (No 
Reportable Result)

If one result is BLQ and one > lower limit of quantification (LLOQ), this will be 
reported as NRR
The RPD will be calculated using the following formula: 
<7 (%) =
	8>5( 1 −	8>5( 2
A	-6 3B 	8>5(8 1 -6C 2 
 100
3.5.3
Immunogenicity analysis
Serum samples for ADA assessments will be conducted utilizing a tiered approach (screen, 
confirm, titer), and ADA data will be collected at scheduled visits shown in the CSP. ADA 
result from each sample will be reported as either positive or negative. If the sample is 
positive, the ADA titer will be reported as well. In addition, the presence of neutralizing 
antibody (nAb) will be tested for all ADA positive samples using a ligand-binding assay. The 
nAb results will be reported as positive or negative. A patient is defined as being ADA-
positive if a positive ADA result is available at any time, including baseline and all post-
baseline measurements; otherwise ADA negative.
The number and percentage of patients who develop detectable ADA to MEDI4736 or 
tremelimumab will be determined for each of the following categories for each treatment 
group. The denominator for percentage calculations is the number of ADA-evaluable patients 
in the treatment group. 

ADA positive at any visit, baseline and/or post-baseline. The percentage is known as ADA 
prevalence.

ADA positive post-baseline and positive at baseline

ADA positive post-baseline and not detected at baseline (treatment-induced ADA 
positive)

ADA not detected post-baseline and positive at baseline

Baseline ADA titer that was boosted by >=4-fold following drug administration 
(treatment-boosted ADA positive)

Treatment-emergent ADA positive, defined as the sum of treatment-induced ADA positive 
and treatment-boosted ADA positive. The percentage is known as ADA incidence.

Persistently positive ADA, defined as having at least 2 post-baseline ADA positive 
measurements with at least 16 weeks (112 days) between the first and last positive
measurements, or an ADA positive result at the last available assessment

Transiently positive ADA, defined as having at least one post-baseline ADA positive 
measurement and not fulfilling the conditions for persistently positive

nAb positive at baseline and/or post-baseline


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3.6
Biomarker variables
PD-L1 expression status used as stratification factor for randomization will be assessed for 
evaluable patients according to following criteria:

Positive: ≥ 25% tumor cell membrane positivity for PD-L1 at any intensity above 
background staining as noted on the corresponding negative control.

Negative: < 25% tumor cell membrane positivity for PD-L1 at any intensity above 
background staining as noted on the corresponding negative control.
4.
ANALYSIS METHODS
The main hypothesis to be tested is improved OS in PD-L1 TC/IC high subgroup population 
treated with MEDI4736 monotherapy and SoC.
The study will be considered positive (a success) if this hypothesis is statistically significant. 
A multiple testing procedure has been implemented to strongly control the type I error rate at 
5%  
Additional hypotheses will be tested using a multiple testing procedure, which is outlined in 
Figure 4.  The procedure will define the significance levels that should be applied to the 
interpretation of the nominal p-values.
The formal statistical analysis will be performed to test the main hypotheses: 

H0: No difference between MEDI4736 monotherapy and SoC

H1: Difference between MEDI4736 monotherapy and SoC
The primary objective is OS in the PD-L1 TC/IC high subgroup for MEDI4736 monotherapy 
versus SoC.  The study was originally sized to characterize the OS benefit of MEDI4736 + 
tremelimumab combination therapy versus SoC.  
With CSP version 12, the primary objective was changed to characterize the OS benefit of 
MEDI4736 monotherapy versus SoC in the PD-L1 TC/IC high subgroup, due to this change 
the analysis of OS will be performed when approximately 147 death events from the PD-L1 
TC/IC high subgroup population have occurred in approximately 172 patients (85% maturity) 
across the MEDI4736 monotherapy therapy and SoC treatment groups. All other endpoints 
will be analysed at this time.  No interim analyses will be performed for any efficacy endpoint
Multiple testing strategy
In order to strongly control the type I error at 5% 2-sided, a multiple testing procedure (MTP) 
will be used across the primary endpoint (OS), treatment regimens (MEDI4736 monotherapy, 
MEDI4736 + tremelimumab, and SoC), and across the analysis populations (PD-L1 TC/IC 


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high subgroup, low risk of EM subgroup, ctDNA TMB high (≥16 mut/Mb) subgroup and all-
comers).  If the highest-level hypothesis in the MTP is statistically significant, the next 
hypothesis in the hierarchy will then be tested as shown in Figure 4).
Hypotheses will be tested using a hierarchical multiple testing procedure to control for the 
overall type I error at the 0.05 level (two-sided).  With this approach, hypotheses will be tested 
in a predefined order (sequentially rejective manner at α=0.05) as outline in Figure 4. 
Hypotheses in the hierarchy will be to test MEDI4736 monotherapy versus SoC in the PD-L1 
TC/IC high subgroup population followed by MEDI4736 monotherapy versus SoC in the low 
risk of EM subgroup population, then MEDI4736 monotherapy versus SoC in the ctDNA 
TMB high (≥16 mut/Mb) subgroup, then MEDI4736 + tremelimumab combination therapy 
versus SoC in the ctDNA TMB high (≥16 mut/Mb) subgroup, then MEDI4736 monotherapy 
versus SoC in all-comers and finally MEDI4736 + tremelimumab combination therapy versus 
SoC in all-comers.  All tests will be at the two-sided 5% alpha level and the procedure will 
stop at the first failure to find statistically significant evidence of superiority or if tests of all 
hypotheses show statistically significant evidence of superiority over SoC. 
Note: the comparisons of MEDI4736 + tremelimumab combination therapy versus MEDI4736 
monotherapy and the comparison of MEDI4736 + tremelimumab combination therapy versus 
SoC (in the PD-L1 TC/IC high subgroup and low risk of EM subgroup) will not be included in 
the MTP, and therefore will not be conducted under strict alpha control.


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Figure 4
Multiple testing procedure for controlling the type 1 error rate
Combo MEDI4736 + tremelimumab combination therapy; EM Early mortality; IC tumor associated immune 
cell; Mono MEDI4736 monotherapy; OS Overall survival; PD-L1 Programmed death ligand 1; 
SoC Standard of Care; TC tumor cell; TMB Tumor Mutational Burden.
4.1
General principles
IVRS based stratification factors will be used for the analysis of primary objectives as well as 
the analyses for other secondary objectives namely; PFS, ORR, PFS2, TFST, TSST, Time to 


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deterioration of EORTC QLQ-C30 and EORTC QLQ-H&N35, improvement rate of EORTC 
QLQ-C30 and EORTC QLQ-H&N35. 
The subgroup analyses for the stratification factors as well as all other factors will be based on 
values recorded on the CRF. If there is >10% discordance in stratification factors as recorded 
in IVRS versus the Case Report Form (CRF), then a sensitivity analysis of the primary 
objectives, will be performed using CRF based stratification factors. For this sensitivity 
analysis if there are missing baseline covariate values, patients will be retained in the analysis 
by including the missing data as another stratification level.   
Other general principles that will be followed throughout the study include the following:

Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
treatment group.  Continuous variables will be summarized by the number of observations, 
mean, standard deviation, median, minimum, and maximum.  Categorical variables will be 
summarized by frequency counts and percentages for each category.  

Unless otherwise stated, percentages will be calculated out of the population total for the 
corresponding treatment arm.

For continuous data the mean and median will be rounded to 1 additional decimal place 
compared to the original data. The standard deviation will be rounded to 2 additional 
decimal places compared to the original data. Minimum and maximum will be displayed 
with the same accuracy as the original data. 

For categorical data, percentages will be rounded to 1 decimal place. 

Results of all statistical analysis will be presented using a 95% confidence interval (CI) 
and 2-sided p-value, unless otherwise stated.

All models will include 3 treatment groups and any pairwise comparisons will then be 
extracted.

SAS® version 9.4 or higher will be used for all analyses.

Palliative radiation will not be considered as a subsequent therapy.
Baseline will be the last assessment of the variable under consideration prior to the intake of 
the first dose of IP, except for efficacy variables.  For efficacy variables, baseline is defined as 
the last visit prior to randomization. For PRO variables, baseline will be defined as the latest 
evaluable assessment on or prior to date of first dose.
Outcomes variables will be summarized and analyzed based on the analysis populations 
detailed in Tables 6 and 12. All outputs will be summarized by treatment arm.    
In terms of retreatment, individual efficacy response data from the re-treatment phase will 
only be listed, however data from retreatment will be included in all PRO analyses. Any 


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derivations relative to baseline (e.g., day, RECIST derivations) in the retreatment period will 
be relative to the baseline scan prior to the retreatment period. 
Note that the AEs, SAEs and AESI/AEPI events will be reported regardless of whether the 
event occurred during re-treatment period or not. Additionally, if there are sufficient numbers 
of retreated patients to warrant separate summaries following combinations of summaries 
would also be produced:
The period for assessing safety data from the retreatment phase will start at the date of first 
dose in the retreatment phase

A small set of headline summaries of AE data from the retreatment phase only.
Table 12 details which efficacy endpoints are to be analyzed, together with pre-planned 
sensitivity analyses indicating which analysis is regarded as primary for that endpoint.  Formal 
statistical analysis will be done for only OS endpoint.  Nominal p-values will be provided for 
all other endpoint and sensitivity analyses. No adjustments for multiple testing of endpoints or 
subgroups will be made.
Table 12
Pre-planned statistical and sensitivity analyses to be conducted
Endpoints Analyzed
Notes
OS
Stratified log-rank tests and Cox proportional method for:
Primary objective
-
MEDI4736 monotherapy versus SoC in the PD-L1 TC/IC high 
subgroup (stratified by PD-L1 status, tumor location, and smoking 
history)
Secondary objectives
-
MEDI4736 monotherapy versus SoC in the low risk of EM subgroup, 
ctDNA TMB high (≥16 mut/Mb) subgroup and all-comers; (stratified 
by PD-L1 status, tumor location, and smoking history)
-
MEDI4736 + tremelimumab combination therapy versus SoC in the 
PD-L1 TC/IC high subgroup, low risk of EM subgroup, ctDNA TMB 
high (≥16 mut/Mb) subgroup and all-comers (stratified by PD-L1 
status, tumor location, and smoking history)
-
MEDI4736 + tremelimumab combination therapy versus MEDI4736 
monotherapy in the PD-L1 TC/IC high subgroup, low risk of EM 
subgroup, ctDNA TMB high (≥16 mut/Mb) subgroup and all-comers; 
(stratified by PD-L1 status, tumor location and smoking history)
Sensitivity analysis:
-
Sensitivity analysis using the stratified Max-combo test


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Endpoints Analyzed
Notes
PFS
Stratified log-rank tests and Cox proportional method for:
Secondary objectives using investigator assessments (RECIST 1.1): 
-
MEDI4736 monotherapy versus SoC for the PD-L1 TC/IC high 
subgroup; low risk of EM subgroup, ctDNA TMB high (≥16 mut/Mb) 
subgroup and all-comers; (stratified by PD-L1 status, tumor location 
and smoking history)
-
MEDI4736 + tremelimumab combination therapy versus SoC for PD-
L1 TC/IC high subgroup; low risk of EM subgroup, ctDNA TMB high 
(≥16 mut/Mb) subgroup and all-comers; (stratified by PD-L1 status, 
tumor location, and smoking history) 
-
MEDI4736 + tremelimumab combination therapy versus MEDI4736 
monotherapy for the PD-L1 TC/IC high subgroup; low risk of EM 
subgroup, ctDNA TMB high (≥16 mut/Mb) subgroup and all-comers;
(stratified by PD-L1 status, tumor location and smoking history)
Sensitivity Analyses:
-
Sensitivity analysis based on RECIST 1.1 modified for 
confirmation of progression using site investigator assessments 
-
Sensitivity analyses using BICR assessments (RECIST 1.1)
OS12, OS18 and OS24
Secondary analysis:
Kaplan-Meier estimates at 12, 18 and 24 months for:
-
MEDI4736 monotherapy therapy versus SoC for the PD-L1 TC/IC 
high subgroup; low risk of EM subgroup, ctDNA TMB high (≥16 
mut/Mb) subgroup and all-comers
-
MEDI4736 + tremelimumab combination therapy versus SoC for 
the PD-L1 TC/IC high subgroup; low risk of EM subgroup, ctDNA 
TMB high (≥16 mut/Mb) subgroup and all-comers
ORR
Logistic regression for:
Secondary objectives
-
MEDI4736 monotherapy therapy versus SoC for the PD-L1 TC/IC high 
subgroup; low risk of EM subgroup, ctDNA TMB high (≥16 mut/Mb) 
subgroup and all-comers using site investigator RECIST 1.1 
assessments
-
MEDI4736 + tremelimumab combination therapy versus SoC for the 
PD-L1 TC/IC high subgroup; low risk of EM subgroup, ctDNA TMB 
high (≥16 mut/Mb) subgroup and all-comers using site investigator 
RECIST 1.1 assessments
-
MEDI4736 + tremelimumab combination therapy versus MEDI4736 
monotherapy for the PD-L1 TC/IC high subgroup; low risk of EM 
subgroup, ctDNA TMB high (≥16 mut/Mb) subgroup and all-comers
using site investigator RECIST 1.1 assessments
BoR
Secondary objective
Descriptive statistic: N (%) using site Investigator data (RECIST 1.1) for all-
comers and the PD-L1 TC/IC high subgroup populations
DoR
Secondary objective
Descriptive statistics and Kaplan-Meier plot for all-comers and the PD-L1 
TC/IC high subgroup populations 


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Endpoints Analyzed
Notes
TTR
Secondary objective:
Kaplan-Meier plots and estimates using site investigator data (RECIST 1.1) 
for all-comers and the PD-L1 TC/IC high subgroup populations
APF6 and APF12
Secondary objective:
Kaplan-Meier estimate of PFS at 6 and 12 months for all-comers and the 
PD-L1 TC/IC high subgroup populations
PFS2
Secondary objective:
Stratified log-rank test for all-comers and the PD-L1 TC/IC high subgroup 
populations
TFST and TSST
Secondary objective:
Stratified log-rank test for all-comers and the PD-L1 TC/IC high subgroup 
populations
Time to deterioration EORTC 
QLQ-C30 and EORTC QLQ-
H&N35 endpoints)
Stratified log-rank test for all-comers and the PD-L1 TC/IC high subgroup 
populations
Improvement rate (EORTC 
QLQ-C30 and EORTC QLQ-
H&N35 endpoints)
Logistic regression
For all-comers and the PD-L1 TC/IC high subgroup populations
Average change from baseline 
(EORTC QLQ-C30 and 
EORTC QLQ-H&N35 
endpoints)
Mixed effect model repeated measurement (MMRM) analysis. 
Descriptive statistics including change from baseline
for all-comers and the PD-L1 TC/IC high subgroup populations
APF12 Proportion of patients alive and progression free at 12 months; BICR Blinded Independent Central 
Review; DoR Duration of response; EM Early mortality; EORTC European Organisation for Research and 
Treatment of Cancer; EQ-5D-5L EuroQol 5-Dimension, 5-Level health state utility index; HR Hazard ratio; 
ITT Intent-to-Treat; ORR Objective response rate; OS Overall survival; OS12 Proportion of patients alive 
at 12 months after randomization; OS18 Proportion of patients alive at 18 months after randomization; 
OS24 Proportion of patients alive at 24 months after randomization; ctDNA circulating tumor DNA; PD-
L1 Programmed death ligand 1; PFS Progression-free survival; QLQ-C30 30-item core quality of life 
questionnaire; QLQ-H&N35 35-item head and neck quality of life questionnaire; RECIST 1.1 Response 
Evaluation Criteria in Solid Tumors version 1.1; TTR Time to response, MMRM  Mixed effect model 
repeat measurement TMB Tumor Mutation Burden;
4.2
Analysis methods
4.2.1
Analysis of primary variable (OS)
The analysis of OS will be done using stratified log-rank test stratified by PD-L1 status 
(positive versus negative), tumor location (OPC versus non-OPC, with a subsequent 
adjustment for HPV status in patients with OPC), and smoking history (>10 versus ≤10 pack-
years) for generation of the p-value. 
The stratification factors will be based on the values entered into IVRS at randomization even 
if it is subsequently discovered that these values were incorrect. Sensitivity analysis using the 


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correct values will be performed if more than 10% of the subjects were incorrectly categorized 
in the wrong strata.
The effect of MEDI4736 monotherapy versus SoC treatment in the relevant analysis 
populations (Table 12) will be estimated by the HR together with its corresponding 95% CI. 
The hazard ratio (HR) of OS, along with its 95% confidence interval using the same strata 
information as above will be estimated using a stratified Cox proportional hazards model with 
treatment as the only covariate (with ties= Efron and any stratification variables included in 
the strata statement) and the CI calculated using a profile likelihood approach. 
Kaplan-Meier plots of OS will be presented by treatment arm.  Summaries of the number and 
percentage of patients who have died, those still in survival follow-up, those lost to follow-up, 
and those who have withdrawn consent will be provided along with the median OS for each 
treatment. 
An analysis of OS will again be performed to compare MEDI4736 + tremelimumab 
combination therapy versus SoC and MEDI4736 + tremelimumab combination therapy versus 
MEDI4736 monotherapy for the analysis populations described in Table 12.
Impact of switching treatment post study treatment discontinuation to immunotherapies 
(or other potentially active investigational agents) on OS analyses
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
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The following treatment comparisons will be performed, based on the primary analysis model:

PD-L1 TC/IC high subgroup – MEDI4736 monotherapy versus SoC

All-comers - MEDI4736 monotherapy versus SoC

All-comers – MEDI4736 + tremelimumab combination therapy versus SoC
Sensitivity Analysis for OS variable
A sensitivity analysis for OS will examine the censoring patterns to rule out attrition bias with 
regards to the primary treatment comparison. This analysis will be supported by Kaplan-Meier 
plot of time to censoring where the censoring indicator of OS is reversed.
In addition, to support OS analyses, duration of follow-up will be summarized using medians:

In censored patients who are alive at data cut-off only: Time from randomization to date of 
censoring (date last known to be alive) by treatment arm.

In all patients: Time from randomization to the date of death (i.e. overall survival) or to 
the date of censoring for censored patients regardless of treatment arm.
Effect of covariates on the HR estimate (Cox Proportional Hazards model)
As a sensitivity analysis, an unstratified Cox-proportional hazards modeling will be employed 
to assess the effect of covariates on the HR estimate for the primary analysis, i.e., the MODEL 
statement will include the treatment group variable and also the stratification factors (PD-L1 
Status, smoking status and tumor location) as main effects. Hazard ratio with associated 95% 
CI will be based the profile likelihood approach. 
This model will be done to ensure that any output from the Cox modeling is likely to be 
consistent with the results of the stratified log-rank test.
Moreover, another sensitivity analysis will be performed to evaluate the treatment effect, 
adjusted for pre-specified baseline prognostic factors. This analysis will be performed for the 
PD-L1 TC/IC high subgroup, low risk of EM subgroup, ctDNA TMB high (≥16 mut/Mb) 
subgroup and all-comers. For this analysis, a stratified Cox model adjusted for the following 
covariates will be used. The covariates are:

Sex at randomization (Male, Female)

Age at randomization (<65, ≥65<75, ≥75 years of age)

Race (Asian, non-Asian)

WHO/ECOG performance status (0, ≥1)

Primary Tumor location/HPV (OPC/Positive, OPC/Negative, non-OPC/Any HPV)


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
Extent of Disease (only locoregionally recurrent, metastatic with or without 
locoregional recurrence)
The Hazard ratio with two-sided 95% confidence interval will be based on profile likelihood 
approach.
The two models described above will include the effect regardless of whether the inclusion of 
effect significantly improves the fit of the model providing there is enough data to make them 
meaningful. 
Interactions between treatment and the stratification factors will also be tested to rule out any 
qualitative interaction using the approach of Gail and Simon 1985.
Assumptions of Proportionality
For OS, the assumption of proportionality will be assessed.  Proportional hazards will be 
checked first by examining plots of complementary log-log (event times) versus log (time) 
and, if these raise concerns, by fitting a time-dependent covariate to assess the extent to which 
this represents random variation. If a lack of proportionality is evident, the variation in 
treatment effect will be described by presenting piecewise HR calculated over distinct time 
periods. In such circumstances, the HR can still be meaningfully interpreted as an average HR 
over time unless there is extensive crossing of the survival curves. If lack of proportionality is 
found, this may be a result of treatment-by-covariate interactions, which may be investigated.
The Grambsch-Therneau non-proportionality test may also be used to check violation of the 
proportional hazards assumption (Grambsch and Therneau 1994). If a lack of proportionality 
is evident, the stratified max-combo test (Karrison 2016) will be conducted as a sensitivity 
analysis for OS to test for treatment differences in the case of non-proportional hazards. The
max-combo test is based on an adaptive procedure optimizing test statistics among the log-
rank test (FH0,0) and the Fleming-Harrington (FH) test (FH0,1; FH1,0) with alpha correction, 
and it is recommended by the Cross-Pharma Non-Proportional Hazards Working Group in the 
presence of non-proportional hazards (Lin et al 2020). This analysis will be produced by the 
Sponsor. 
4.2.2
Subgroup analysis OS
Subgroup analyses will be conducted comparing OS between MEDI4736 + tremelimumab
combination therapy versus SoC, MEDI4736 monotherapy versus SoC and MEDI4736+
tremelimumab combination therapy versus MEDI4736 monotherapy (in the PD-L1 TC/IC 
high subgroup, low risk of EM subgroup, ctDNA TMB high (≥16 mut/Mb) subgroup and all-
comers) for the following subgroups (but not limited to):

Sex (male, female)

Age at randomization (<65, ≥65<75, ≥75 years of age)


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
PD-L1 TC status for stratification (positive, negative)


PD-L1 TC/IC status (TC≥50 or IC≥25 (High), TC<50 and IC<25(Low))

ctDNA TMB (high (≥16 mut/Mb), low (<16 mut/Mb), unknown)

Tumor location/HPV (OPC/Positive, OPC/Negative, non-OPC/Any HPV), 

Primary tumor site (Oral cavity, Oropharynx, Larynx, Hypopharnyx)

Smoking history (>10, ≤10 pack-years)

Race (Asian, non-Asian)

ECOG Performance status (0,1)

Extent of Disease (only locoregionally recurrent, metastatic with or without 
locoregional recurrence)
For these subgroup analyses any patient with missing values will be excluded from that 
particular subgroup.
Treatment effect will be estimated by the HR together with its corresponding 95% CI using an 
unstratified Cox model with treatment as the only covariate. Hazard ratio with two-sided 95% 
confidence interval will be based on the profile likelihood approach
A forest plot will be presented for the subgroups showing the comparison of MEDI4736+
tremelimumab combination therapy versus SoC, MEDI4736 monotherapy versus SoC and  
MEDI4736+ tremelimumab combination therapy versus MEDI4736 monotherapy for the 
analysis populations described above.
The subgroup analyses for the stratification factors will be based on the values recorded on the 
eCRF as indicated above. Other baseline variables may also be assessed if there is clinical 
justification or if an imbalance is observed between the treatment arms.  The purpose of the 
subgroup analyses is to assess the consistency of treatment effect across expected prognostic 
and/or predictive factors. Only the HR estimate along with 95% CI will be presented.
No adjustment to the significance level for testing of the subgroup and sensitivity analyses 
will be made since all these analyses will be considered supportive of the analysis of OS.
If there are too few events available for a meaningful analysis of a particular subgroup 
comparison (it is not considered appropriate to present analyses where there are less than 20 
events within a subgroup category (i.e., when the events in the treatment comparison does not 
add up to 20) in a subgroup), the relationship between that subgroup and the primary endpoint 
(OS) will not be formally analyzed. In this case, only descriptive summaries will be provided.
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4.2.3
Analysis of the secondary variable (PFS)
The analysis of PFS will be based on the programmatically derived RECIST 1.1 using the site 
investigator assessments. The analysis will be performed using a stratified log-rank test 
stratified by PD-L1 status (positive versus negative), tumor location (OPC versus non-OPC, 
with a subsequent adjustment for HPV status in patients with OPC), and smoking history (>10 
versus ≤10 pack-years) for generation of the p-value. 
The stratification factors will be based on the values entered into IVRS at randomization even 
if it is subsequently discovered that these values were incorrect.
The effect of MEDI4736 monotherapy therapy versus SoC treatment in the relevant analysis 
populations (Table 12), will be estimated by the HR together with its corresponding 95% CI. 
The hazard ratio (HR) of PFS, along with its 95% confidence interval using the same strata 
information as above will be estimated using a stratified Cox proportional hazards model with 
treatment a as the only covariate (with ties= Efron and any stratification variables included in 
the strata statement) and the CI calculated using a profile likelihood approach 
PFS analysis will also be performed to compare MEDI4736 + tremelimumab combination 
therapy versus SoC as well as to compare MEDI4736 + tremelimumab combination therapy 
versus MEDI4736 monotherapy for the analysis populations detailed in Table 12. 
These analyses will be performed using the same methodology as for the primary objective 
described above.
Kaplan-Meier plots of PFS will be presented by treatment arm.  Summaries of the number and 
percentage of patients experiencing a PFS event and the type of event (RECIST 1.1 or death) 
will be provided along with median PFS for each treatment.
Sensitivity analyses for PFS variable:
A sensitivity analysis of PFS using the BICR tumor data will be performed. 
An sensitivity analysis of PFS using site investigator assessment based on RECIST 1.1 
modified for confirmation of progression will be performed.  The stratified log-rank test used 
for the secondary analysis of PFS will be repeated.
Furthermore, disagreements between the investigator and BICR assessment will also be 
summarised. Since the data cut-off for the last BICR is Jan 8th, 2018, this data cut-off will also 
be used for the investigator assessment in this table to allow for a fair comparison.
Subgroup analysis for PFS
Subgroup analyses will be conducted comparing PFS between MEDI4736 ± tremelimumab
combination therapy versus SoC. This subgroup analysis will be performed using the same 
subgroups and methodology from the OS subgroup analyses described in Section 4.2.2.  


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4.2.4
Objective response rate
The ORR will be based on the programmatically derived RECIST 1.1 using site investigator 
tumor data.  The ORR will be compared between MEDI4736 monotherapy versus SoC using 
logistic regression models adjusting for the same factors as the primary endpoint (PD-L1 
status, tumor location, and smoking history). The results of the analysis will be presented in 
terms of an odds ratio together with its associated profile likelihood 95% CI (e.g. using the 
option ‘LRCI’ in SAS procedure GENMOD) and p-value (based on twice the change in log-
likelihood resulting from the addition of a treatment factor to the model). 
A similar analysis will be performed for the comparison between MEDI4736 + tremelimumab 
combination versus SoC and between MEDI4736 + tremelimumab combination versus 
MEDI4736 monotherapy in for the analysis populations detailed in Table 12.  
Summaries will be produced that present the number and percentage of patients with a tumor 
response (CR/PR).  Overall visit response data will be listed and summarized over time for all 
patients (i.e., the FAS).  
Subgroup analysis for ORR
The analysis using logistic regression to compare ORR between MEDI4736 ± tremelimumab
combination therapy versus SoC will also be presented by subgroup. This subgroup analysis 
will be performed using the same subgroups from the OS subgroup analysis described in 
Section 4.2.2.
4.2.4.1
Best Objective Response (BoR)
BoR based on site investigator data (RECIST 1.1), for each treatment arm, BoR will be 
summarized by n (%) for each category (CR, PR, SD, PD, and NE).  No formal statistical 
analyses are planned for BoR.
4.2.5
Duration of response
Descriptive data will be provided for the DoR in responding patients (i.e. median duration of 
response and 95% CIs) by treatment arm, including the associated Kaplan-Meier curves 
(without any formal comparison of treatment arms or p-value attached). Swimmer plots will 
be produced. This depicts each patient’s nature and duration of response as a separate bar 
(horizontally) over time, ordered from the longest time in study to the shortest time in study. 
4.2.6
Time to response
The TTR, based upon the site investigator assessment of RECIST 1.1, will be summarised 
(i.e., number of patients [%] based upon the number of responders) by the scheduled 
assessment timepoint that the response was first observed.  Additionally, descriptive summary 
statistics (i.e., minimum, maximum, median, Q1 and Q3) will also be presented. 
As a sensitivity analysis, time to response will also be summarised based upon the site 
investigator tumor assessment data according to RECIST 1.1.


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This analysis will be performed on all-comers and the PD-L1 TC/IC subgroup population
4.2.7
Proportion of patients alive and progression free at 6 and 12 months (APF12)
The APF6 and APF12 will be summarized (using the Kaplan-Meier estimate) and presented 
by treatment arm.  
4.2.8
Time from randomization to PFS2
PFS2 will be analyzed using a stratified log-rank tests, using the same methodology as 
described for the PFS endpoint.  The effect of MEDI4736 + tremelimumab combination 
therapy versus SoC and the effect of MEDI4736 monotherapy versus SoC will be estimated 
by the HR together with its corresponding CI and p-value.  Kaplan-Meier plots will be 
presented by treatment arm.  Summaries of the number and percentage of patients who have 
an event as well as who were censored will be provided along with the medians for each 
treatment.  
4.2.9
Time from randomization to first and second subsequent therapy or death
For supportive purposes, the time to the start of first and the second subsequent therapy or 
death will be analyzed using the same methodology and model as that used for the analysis of 
PFS.  The HR for the treatment effect together with its 95% CI will be presented.  In addition, 
a Kaplan-Meier plot of the time to the start of first and the second subsequent therapy will be 
presented by treatment arm, and the time between progression and start of first and the second 
subsequent therapy will be assessed. This interval will be summarized per treatment arm, but
no formal comparisons will be made.  No multiplicity adjustment will be applied as this is 
viewed as a supportive endpoint.
In patients who received subsequent anticancer therapy, a summary table of first and the 
second subsequent anticancer therapies by treatment arm will be provided, as well as response 
to first and the second subsequent anticancer therapy by treatment arm (if available).
The number of patients prematurely censored will also be summarized.
4.2.10
Analysis of OS12, OS18 & OS24
OS12, OS18 and OS24 will be summarized (using the Kaplan-Meier estimate) and presented 
by treatment arm.  
4.2.11
Change in tumor size 
Tumor size will be presented graphically using waterfall plots, to present each subject’s best 
percentage change in tumor size as a separate bar, with the bars ordered from the largest 
increase to the largest decrease. Reference lines at the +20% and –30% change in tumor size 
levels will be added to the plots, which correspond with the definitions of progression and 
‘partial’ response respectively. Additional waterfall plots showing percentage change in tumor 
size at specific timepoints may be produced if it is felt that these are warranted to provide 
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Additionally, ‘spider’ plots will be produced. This depicts each patient’s percentage change in 
tumor size at each visit as a line over time.
The above outputs will be programmed for the site investigator data based upon RECIST 1.1 
assessments.
4.2.12
Patient reported outcome
The PRO endpoints that have been identified as secondary are EORTC QLQ-C30 time to
HRQoL deterioration for global health status, time to symptom deterioration for fatigue, time 
to symptom deterioration for functional deterioration for physical domain and QLQ-H&N35 
time to symptom deterioration for these 2 symptoms; pain and swallowing. These are not part 
of the main multiple testing procedures and as supportive endpoints will need a Bonferroni 
adjustment to the significance level to aid interpretation. Therefore, these 5 endpoints will be 
tested at a 1.0% significance level and 99% CIs will be produced for the comparison of 
MEDI4736 versus SoC.
The other time to symptom deterioration endpoints will be tested at a 5% significance level
and 95% CIs will be produced. Compliance rates summarizing questionnaire completion at 
each visit will be tabulated.
If missing data is substantial, multiple imputation approach and pattern-mixture model may be 
explored where appropriate.
4.2.12.1
EORTC QLQ-C30
Time to symptom deterioration will be analyzed for each of the 3 symptom scales (fatigue, 
pain, and nausea/vomiting).  Time to HRQoL/function deterioration will be analyzed for the 
5 function scales (physical, role, emotional, cognitive, and social) and global health 
status/QoL.  
This will be achieved by comparing treatment arms using a stratified log-rank test as 
described for the PFS and OS analysis.  The effect of MEDI4736 monotherapy versus SoC 
and MEDI4736 + tremelimumab combination therapy versus SoC treatment will be estimated 
by the HR together with its corresponding 95% CI using stratified Cox model with the same 
approach as described for PFS and OS analysis.
Time to deterioration will be presented using a Kaplan-Meier plot for each of the 3 symptom 
scales (fatigue, pain, and nausea/vomiting), 5 functional scales (physical, role, emotional, 
cognitive, and social), and global health status/QoL. 
A summary of the symptom improvement rate for each of the 3 symptom scales (fatigue, pain, 
and nausea/vomiting) items will be produced.  Similarly, a summary of HRQoL/function 
improvement rate for each of the 5 function scales (physical, role, emotional, cognitive, and 
social) and global health status/QoL will be produced.  Symptom improvement rate for each 
of the 3 symptom scales (fatigue, pain, and nausea/vomiting) and HRQoL/function 


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improvement rate for each of the 5 function scales (physical, role, emotional, cognitive, and 
social) and global health status/QoL will be analyzed by comparing between treatment arms 
using a logistic regression model as described for the analysis of ORR.  
Summaries of absolute and change from baseline values for each of the 3 symptom 
scales/items (fatigue, pain, and nausea/vomiting), 5 individual symptom items (dyspnea, 
insomnia, appetite loss, constipation, and diarrhea), 5 functional scales (physical, role, 
emotional, cognitive, and social), and the global health status\QoL score will be reported by 
visit for each treatment arm provided at least one treatment arm has 20 or more subjects with 
data at a given visit.  Graphical presentations may also be produced as appropriate.  
Analysis of HRQoL or symptom will also be carried out by comparing mean change from 
baseline in the global health status/QoL, functions (physical, role, cognitive, social and 
emotional) scores (from the EORTC QLQ-C30 questionnaire) between MEDI4736 + 
tremelimumab combination therapy versus SoC and MEDI4736 monotherapy compared versus 
SoC.  The analysis population for mean change in HRQoL or symptoms data will be the FAS 
(ITT) set and will include all randomised patients with an evaluable baseline assessment and 
at least one evaluable post baseline assessment. 
Change from baseline will be derived using a MMRM analysis of all the post-baseline scores 
for each visit.  The model will include treatment, visit, and treatment by visit interaction as 
explanatory variables and the baseline score and baseline score by visit interaction as 
covariates.  Adjusted mean estimates per treatment group and corresponding 95% CIs will be 
presented along with an overall estimate of the treatment difference, 95% CI and p-value. An 
overall adjusted mean estimate will be derived that will estimate the average treatment effect 
over visits giving each visit equal weight using least squares means. 
An unstructured matrix for the within-subject error variance-covariance will be used. If the 
model fit fails to converge, more parsimonious covariance structures will be considered to 
model the correlation between time-points from same patient. The following covariance 
structures will be tried in order until convergence is reached: Toeplitz with heterogeneity, 
autoregressive with heterogeneity, Toeplitz, autoregressive and compound symmetry. If either 
the autoregressive with heterogeneity or autoregressive structure is used, patient will be 
included as random effect.
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom 
(DDFM). Restricted maximum likelihood (REML) estimation will be used.
The analysis will be performed on all post-baseline visits up to the latest scheduled visit where 
20 or more (≥20) patients on each treatment arm have a score.
Summary measures of overall compliance and compliance over time will be derived for the 
EORTC QLQ-C30. These will be based upon the compliance derivation described in Section 
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4.2.12.2
EORTC QLQ-H&N35
Time to symptom deterioration for each of the 4 symptom scales/ items in the QLQ-H&N35 
(pain, swallowing, senses and speech) will be compared between treatment arms using a 
stratified log-rank test as described for the primary analysis of OS. The effect of MEDI4736 
monotherapy vs SoC and MEDI4736 + tremelimumab combination therapy versus SoC 
treatment will be estimated by the HR together with its corresponding 95% CI using stratified 
Cox model with the same approach as described for PFS and OS analysis.
For each of these 4 symptom scales/ items in the QLQ-H&N35 above, time to deterioration in 
symptoms will be presented using a Kaplan-Meier plot.  
A summary of the symptom improvement rate for each of the 4 symptom scales/items (pain, 
swallowing, senses and speech) will be produced.  The symptom improvement rate for each of 
the 4 symptom scales/items (pain, swallowing, senses and speech) will be compared between 
treatment groups using a logistic regression model as described for ORR.  
Summaries of absolute and change from baseline values for each of the 7 symptom scale/item 
(pain, swallowing, senses, speech, social eating, social contact and sexuality) and11 single-
item measures (teeth, problems with mouth opening, dry mouth, sticky saliva, coughing, 
feeling ill, use of analgesics, use of nutritional supplements, use of a feeding tube, weight 
gain, and weight loss) will be reported by visit for each treatment provided at least one 
treatment arm has 20 or more subjects with data at a given visit . Graphical presentations may 
also be produced as appropriate.  
The assessment of symptoms comparing mean change from baseline using the MMRM as 
described for EORTC QLQ-C30 will be repeated for pain, swallowing, senses, and speech of 
the EORTC QLQ-H&N35.  All assumptions and outputs as described for the EORTC QLQ-
C30 are applicable and the same approach from EORTC QLQ-C30 will be applied.
Summary measures of overall compliance and compliance over time will be derived for the 
EORTC QLQ-H&N35. These will be based upon the compliance derivation described for 
EORTC QLQ-C30
4.2.12.3
 
 
 
 
 
 
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4.2.12.4
4.2.12.5
 
4.2.13
Safety
Safety data will be summarized. No formal statistical analyses are planned for safety data. All 
safety and tolerability data will be presented for all-comers and also for those in the PD-L1 
TC/IC subgroup using the safety population. The following sections describe the planned 
safety summaries for AEs, vital signs, laboratory parameters, ECG and WHO/ECOG 
performance status. However, additional safety tables (not specified in this SAP) may need to 
be produced to aid interpretation of the safety data. This may include repeating the planned 
safety summaries for the low risk of EM subgroup. Any safety summaries examining 
retreatment with MEDI4736 + tremelimumab will be produced separately.
4.2.13.1
Adverse Events
All AEs, both in terms of current Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term and Common Toxicity Criteria for Adverse Events (CTCAE) grade, will be 
listed and summarized descriptively by count (n) and percentage (%). The current MedDRA 
dictionary will be used for coding. Any AE occurring before treatment with IP and which did 
not worsen during the course of the study will be included in the AE listings, but will not be 
included in the summary tables (unless otherwise stated). These will be referred to as ‘pre-
treatment’. However, any AE occurring before the administration of the first infusion on 
Study Day 1 that worsens after Study Day 1 will be regarded as treatment emergent and thus 
will be included in the summary tables. Note: If an AE is not worse than the baseline (pre-
dose) severity then it will not be classified as TEAE.
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AEs observed up until 90 days following discontinuation of IP or until the initiation of the 
first subsequent therapy (excluding palliative radiation as a subsequent therapy) following 
discontinuation of IP (whichever occurs first) regardless of whether the AE occurred during 
re-treatment with tremelimumab or not will be used for reporting of all of the AE summary 
tables. This will more accurately depict AEs attributable to IP only as opposed to presenting 
all AEs reported up to 90 days following discontinuation of IP. This is due to the fact that a 
number of AEs up to 90 days following discontinuation are likely to be attributable to 
subsequent therapy. However, to assess the longer term toxicity profile, a small selection of 
the AE summaries may be repeated containing AEs observed up until 90 days following 
discontinuation of IP (i.e. without taking subsequent therapy into account). A summary will 
also be produced containing all AEs (by system organ class and preferred term) observed from 
the initiation of the first subsequent therapy following discontinuation of IP until 90 days 
following discontinuation of IP treatment (i.e. summarizing those AEs experienced by patients 
taking subsequent therapy during the 90 days AE collection follow-up window post 
discontinuation of IP). Any data post 90 days last dose will be listed only apart from a 
separate summary that presents any events that occur prior to dosing or starting more than 90 
days after discontinuing IP. 
All reported AEs will be listed along with the date of onset, date of resolution (if AE is 
resolved) and investigator’s assessment of severity and relationship to study drug. Frequencies 
and percentages of patients reporting each preferred term will be presented (i.e. multiple 
events per patient will not be accounted for apart from any episode level summaries which 
may be produced). 
Summary information (the number and percent of patients by system organ class and preferred 
term) will be tabulated for:

All AEs 

All AEs causally related to study medication

AEs with CTCAE grade 3 or 4

AEs with CTCAE grade 3 or 4, causally related to study medication

AEs with outcome of death

AEs with outcome of death causally related to study medication

All SAEs

All SAEs causally related to study medication 

AEs leading to discontinuation of study medication

AEs leading to discontinuation of study medication, causally related to study medication


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
SAEs leading to discontinuation of study medication

SAEs leading to discontinuation of study medication, causally related to study medication

Immune mediated AEs based on pre-defined criteria presented in the immune mediated 
AE charter. 

Infusion reaction AEs 
An overall summary of the number and percentage of patients in each category will be 
presented.  In addition, a truncated AE table of most common AEs, showing all events that 
occur in at least 5% of patients in any treatment group will be summarized by preferred term, 
by decreasing frequency.  This cut-off may be modified after review of the data. When 
applying a cut-off (e.g., 5%), the raw percentage should be compared to the cut-off, no 
rounding should be applied first (i.e., an AE with frequency of 4.9% will not appear if a cut-
off is 5%).
Each AE event rate (per 100 patient years) will also be summarized by preferred term within 
each system organ class. For each preferred term, the event rate (defined as the number of 
patients with that AE divided by the total drug exposure of patients and then multiplied by 
365.25 x 100 to present in terms of 100 patient years) will be presented. For the MEDI4736 + 
tremelimumab arm, event rates will be based upon total combination duration including any 
tremelimumab re-treatment period (i.e. the very last dose date of study drug (MEDI4736 or 
tremelimumab) regardless of it being after tremelimumab re-started should be used as last 
dose in the calculation)
AEs will be assigned CTCAE grades (National Cancer Institute (NCI) CTCAE version 4.03) 
and summaries of the number and percentage of patients will be provided by maximum 
reported CTCAE grade, system organ class, preferred term. 
For each AE, time to first onset of the AE from the date of first dose will be presented in 
patients in the safety analysis.
A summary of 3 deaths tables 
1. All deaths (Full analysis set)
2. Deaths within 90 days of last dose (Safety analysis set)
3. Death within 90 days of last dose or prior to start of subsequent therapy (Safety 
analysis set)
will be provided with number and percentage of patients, categorized as:

Related to disease under investigation, 

AE with outcome = death,

Both related to disease under investigation and with AE outcome=death, 


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
Patients with unknown reason for death and

Other deaths. 
A corresponding listing will also be produced. 
Adverse events of special and possible interest 
Preferred terms used to identify adverse events of special interest (AESIs) and adverse events 
of possible interest (AEPIs) will be listed before database lock (DBL) and documented in the 
Study Master File. Grouped summary tables of certain MedDRA preferred terms will be 
produced and may also show the individual preferred terms which constitute each AESI/AEPI 
grouping.  For each ‘grouped’ term, the number (%) of patients experiencing any of the 
specified terms will be presented by maximum CTCAE grade. Additional summaries will 
include Time to Onset of first CTCAE grade 3 or 4. Time to onset of first AE for each 
grouped term and preferred term within it will also be produced. Groupings will be based on 
preferred terms provided by the medical team prior to DBL, and a listing of the preferred 
terms in each grouping will be provided.
Additional summaries of the above-mentioned grouped AE categories will include number 
(%) of patients who have:

At least one AESI/AEPI presented by outcome

At least one AESI/AEPI causally related to study medication (as determined by the 
reporting investigator)

At least one AESI/AEPI leading to discontinuation of IP
A summary of time to resolution to grade 1 or less and time to resolution to grade 2 or less 
will be provided. 
Additionally, there will be several summaries of AESIs/AEPIs requiring concomitant 
treatment, and particularly the relationship of AESIs/AEPIs to the use of immunosuppressive 
agents (i.e., depicting which AESI/AEPI triggered immunosuppressive use) and, separately, to 
the use of immunosuppressive agents at high doses (High dose is defined as >= 40mg of 
prednisone or equivalent per day). 
Immune-mediated Adverse events (imAEs)
The imAEs (as classified by the Sponsor) will be summarized in the similar manner as for the 
summaries for AESI/AEPI described above. The Sponsor will be responsible for producing 
these summaries.
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These AEs will be summarized by pooled terms and PTs in two ways: (1) using MedDRA 
HLGT/HLT pooled terms (2) Custom pooled terms. The list of terms will be provided in a 
separate excel file. The following summaries will be reported for both HLGT/HLT pooled 
terms and custom pooled terms and PTs:

Infection Adverse Events by pooled term and PT

Causally-related Infection AEs by pooled term and PT

Serious Infection AEs by pooled term and PT

Causally-related Serious Infection AEs by pooled term and PT

Infection AEs with maximum CTCAE grade by pooled term and PT

Infection AEs with outcome of death by pooled term and PT

Infection Adverse Events leading to treatment discontinuation by pooled term and PT

Infection Adverse Events leading to dose delay or interruption by pooled term and 
preferred term

Infection Adverse Events -List of preferred terms
Haemorrhages-related adverse events 
Treatment-emergent haemorrhage events will be identified using the Haemorrhage (excluding 
laboratory terms) Standardized Medical Dictionary for Regulatory Activities (MedDRA) 
Query (SMQ) from the current MedDRA version.
The following key summary tables and listings will be produced for the subset of patients who 
are reported to have a treatment-emergent adverse event within the Hemorrhage SMQ:

Haemorrhage SMQ patient disposition (all patients)

Haemorrhage SMQ Demographic characteristics (Safety Analysis Set)

Haemorrhage SMQ Disease characteristics at initial diagnosis or study entry (Safety 
Analysis Set)

Haemorrhage SMQ Extent of disease at study entry (Safety Analysis Set)

Haemorrhage SMQ Adverse events in any category - patient level (Safety analysis set)

Haemorrhage SMQ Adverse events and event rate by system organ class and preferred 
term (Safety analysis set)

Haemorrhage SMQ Time to onset of adverse event (days), arranged by system organ class 
and preferred term (Safety analysis set)

Haemorrhage SMQ Causally related adverse events by system organ class and preferred 
term (Safety analysis set)

Haemorrhage SMQ Adverse events by system organ class, preferred term, and maximum 
reported CTCAE grade (Safety analysis set)

Haemorrhage SMQ Adverse events of CTCAE grade 3 or 4 by system organ class and 
preferred term (Safety analysis set)

Haemorrhage SMQ Causally related adverse events of CTCAE grade 3 or 4 by system 
organ class and preferred term (Safety analysis set)

Haemorrhage SMQ All deaths (Safety Analysis Set)


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
Adverse events with outcome of death, by system organ class and preferred term (Safety 
analysis set)

Haemorrhage SMQ Adverse events with outcome of death, causally related to study 
treatment, by system organ class and preferred term (Safety analysis set)

Haemorrhage SMQ Serious adverse events by system organ class and preferred term 
(Safety analysis set)

Haemorrhage SMQ Serious adverse events, causally related to study treatment, by system 
organ class and preferred term (Safety analysis set)

Haemorrhage SMQ Adverse events, leading to discontinuation of study treatment, by 
system organ class and preferred term (Safety analysis set)

Haemorrhage SMQ Listing of Deaths (Safety Analysis Set)

Haemorrhage SMQ Serious adverse events - Listing of key information (Safety analysis 
set)

Haemorrhage SMQ Impact of concomitant medication with potential risk of bleeding on 
the occurrence of the most severe bleed within each patient (Safety analysis set)  

Haemorrhage SMQ Medical history of bleeding (Safety analysis set)
Summary of long-term tolerability:
To assess long term tolerability, provided that there are a sufficient number of patients with 
events to warrant it, prevalence plots, life table plots and cumulative incidence plots will be 
presented for each of the AESI grouped terms and any other events considered important after 
review of the safety data, provided there are ≥ 10 events, that is 10 events in at least one 
treatment group.
A prevalence plot provides information on the extent to which the events may be an ongoing 
burden to patients. The prevalence at time t after first dose of study treatment is calculated as 
the number of patients experiencing the event divided by the number of patients receiving 
study treatment or in safety follow-up at time t; generally, t is categorized by each day after 
dosing.  The prevalence will be plotted over time presented. Multiple occurrences of the same 
event are considered for each patient but a patient is only counted in the numerator whilst they 
are experiencing one of the occurrences of the event. These plots will only be produced for 
AESIs that have ≥10 events, that is 10 events in at least one treatment group.
For each AESI, median time to first onset of the AESI from the date of first dose will be 
presented in patients in the safety analysis.  Patients who did not experience the AESI will be 
censored at the end of their safety follow-up.  Summary tables of time to first onset for each 
AE will also be produced (e.g. 1-28 days, 29-56 days, 57-84 days, 85-112 days, >112 days).  
Median duration of the AE and AESI will be presented in patients who experienced each, as 
well as the median time to resolution to grade 1 or less and time to resolution to grade 2 or 
less.
A life table plot can be used to describe the time to onset of the event and specifically when 
patients are at most risk of first experiencing the event.  The hazard, or in other words, the 
probability of having an AE in a specified time period (e.g. 0-1 months, 1-3 months, 3-6 


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months, etc.) given that the patient reaches that time period without having an event is plotted 
for each time period.  These plots will only be produced for AESIs that have ≥10 events, that 
is 10 events in at least one treatment group.
A cumulative incidence plot of the raw cumulative incidence over time will be presented. The 
raw cumulative incidence is the actual probability that a patient will have experienced their 
first occurrence of the event by a given time point. These plots will only be produced for 
AESIs that have ≥10 events, that is 10 events in at least one treatment group.
4.2.13.2
Laboratory assessments
Data obtained up until the 90 days following discontinuation of IP or until the initiation of the 
first subsequent therapy following discontinuation of IP (whichever occurs first) will be used 
for reporting. This will more accurately depict laboratory toxicities attributable to IP only as a 
number of toxicities up to 90 days following discontinuation of IP are likely to be attributable 
to subsequent therapy. 
Data summaries and listings will be provided in International System (SI) of units.
All laboratory data will be listed. Flags will be applied to values falling outside - reference 
ranges (which will be explicitly noted on these listings where applicable), and to values for 
which CTCAE grading applies.
Scatter plots (shift plots) of baseline to maximum/minimum value (as appropriate) on 
treatment (i.e. on treatment is defined as data collected between the start of treatment and the 
relevant follow-up period following the last dose of IP) may be produced for certain 
parameters if warranted after data review.
Boxplots of absolute values by week, and boxplots of change from baseline by week, may be 
presented for certain parameters if warranted after data review up to Week 40.
Shift tables for laboratory values by worst common toxicity criteria (CTCAE) grade will be 
produced, and for specific parameters separate shift tables indicating hyper- and hypo-
directionality of change will be produced. The laboratory parameters for which CTCAE grade 
shift outputs will be produced are:

Hematology: Hemoglobin, Leukocytes, Lymphocytes, absolute count, Neutrophils, 
absolute count, Platelets

Clinical chemistry: ALT, AST, Alkaline Phosphatase  (ALP), Total bilirubin, Albumin, 
Magnesium – hypo and – hyper, Sodium – hypo and – hyper, Potassium – hypo and –
hyper, Corrected calcium – hypo and – hyper, Glucose – hypo and – hyper, GGT, 
Creatinine
For the parameters with no CTCAE grading that are listed in the CSP, shift tables from 
baseline to worst value on treatment will be provided. Additional summaries will include a 


Statistical Analysis Plan 
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shift table for urinalysis (Bilirubin, Blood, Glucose, Ketones, Protein) comparing baseline 
value to maximum on treatment value.
Hy's law
The following summaries will include the number (%) of patients who have:

Elevated ALT, AST, and Total bilirubin during the study
ALT
≥ 3x –≤ 5x ULN Upper Limit of Normal (ULN) during the study 
> 5x- ≤8x ULN 
> 8x -≤ 10x ULN  
>10x -≤20 ULN
and > 20x ULN
AST 
≥ 3x –≤5x ULN 
> 5x -≤8x ULN
> 8x -≤ 10x ULN
>10-≤ 20 ULN
and > 20x ULN 
Total bilirubin
≥2x -≤3x ULN,
>3x-≤5x ULN,
>5x ULN during the study
ALT or AST
≥3x - ≤5x ULN,
>5x - ≤8x ULN,


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>8x-≤10x ULN,
>10 -≤ 20 ULN
and >20x ULN during the study

ALT or AST ≥3x ULN and Total bilirubin ≥2x ULN during the study (Potential Hy’s law: 
The onset date of the ALT or AST elevation should be prior to or on the date of the Total 
bilirubin evaluation.)

Narratives will be provided in the CSR for patients who have ALT ≥ 3x ULN plus Total 
bilirubin ≥ 2x ULN or AST ≥ 3x ULN plus Total bilirubin ≥ 2x ULN at any visit.
Liver biochemistry test results over time for patients with elevated ALT (i.e. ≥ 3x ULN) or 
AST (i.e. ≥ 3x ULN), and elevated total bilirubin (i.e. ≥ 2x ULN) (at any time) will be plotted.  
Individual patient data where ALT or AST plus Total bilirubin are elevated at any time will be 
listed also.
Plots of ALT and AST vs. Total bilirubin will also be produced with reference lines at 3×ULN 
for ALT, AST, and 2×ULN for Total bilirubin. In each plot, Total bilirubin will be in the 
vertical axis.
Abnormal Thyroid function
Elevated TSH will be summarized per treatment group in terms of number (%) of patients 
with elevated TSH (higher than the upper normal range), low TSH (lower than lower normal 
range), elevated TSH post-dose and within normal range at baseline, low TSH post-dose and
within normal range at baseline.
4.2.13.3
ECGs
ECG data obtained up until the 90-day safety follow-up visit will be included in the summary 
tables.
Overall evaluation of ECG is collected at screening and as clinically indicated in terms of 
normal or abnormal, and the relevance of the abnormality is termed as “clinically significant” 
or “not clinically significant”. 
4.2.13.4
Vital signs
Boxplots for absolute values and change from baseline by week may be presented for certain 
vital signs parameters if warranted after data review, up to Week 40.
4.2.14
WHO/ECOG performance status
All WHO/ECOG performance status will be summarized over time.


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4.2.15
PK Data
MEDI4736/tremelimumab concentration data will be listed for each patient and each dosing 
day, and a summary provided for all patients in the PK analysis set. 
If the data are suitable, the relationship between PK exposure and efficacy/safety parameters 
may be investigated graphically or using an appropriate data modeling approach.
These outputs will be produced by a designated third party on behalf of AstraZeneca.
4.2.16
Immunogenicity analysis
A summary of the number and percentage of patients who develop detectable ADA to 
MEDI4736 or tremelimumab by ADA categories (Section 3.5.3) in MEDI4736 + 
tremelimumab combination therapy and MEDI4736 monotherapy arms will be presented. The 
denominator for percentage calculations will use the number of ADA-evaluable patients. 
Immunogenicity results will be listed for all patients in the Safety Analysis Set regardless of 
ADA-evaluable status. ADA titer and nAb data may be presented for samples confirmed 
positive for the presence of ADA to durvalumab and/or tremelimumab. AEs in ADA positive 
patients by ADA positive category (ADA-positive at any visit, treatment-emergent ADA-
positive, and nAb positive) may be listed.
The effect of immunogenicity as well as the effect of its neutralizing properties on PK, 
pharmacodynamics, efficacy, and safety will be evaluated, if the data allow.
4.2.17
Biomarker data
 
 
PD-L1 tumor cell expression (used for purposes of stratification) and PD-L1 tumor and tumor-
associated immune cell expression (used for purposes of identifying patients for the PD-L1 
TC/IC-selected subgroup) determined by IHC will be reported in the CSR. 
 
4.2.18
Demographic, initial diagnosis and baseline characteristics data
The following will be summarized for all patients in the FAS and PD-L1 TC/IC high subgroup 
analysis set (unless otherwise specified):

Patient disposition (including screening failures and reason for screening failure) 

Important protocol deviations specified in this SAP 

COVID-19 related non-important PDs

Inclusion in analysis populations 
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
Demographics (age, age group [< 65, ≥65<75, ≥ 75 years], sex, race and ethnicity) 

Patient characteristics at baseline (weight, weight group, BMI and BMI group)

Patient recruitment by country and centre

Previous disease-related treatment modalities

Disease characteristics at baseline (WHO/ECOG performance status, best response to 
previous therapy, overall disease classification)

Disease characteristics at initial diagnosis (primary tumor location, histology type, tumor 
grade, TNM classification, AJCC staging)

Extent of disease at baseline (recurrent or metastatic)

Disease related medical history

Time from most recent disease progression to randomization

Post-discontinuation cancer therapy

Smoking status (>10, ≤10 pack-years)

Nicotine use, categorized (current, former, never)

Alcohol use (current, former, never)

PD-L1 TC status for purposes of stratification (positive, negative) for all patients treated.

Human papilloma virus (HPV) status (positive or negative, for patients with 
oropharyngeal cancer only)

Stratification factors by IVRS and CRF

Discrepancy between local and central review

Concomitant medication during study treatment
Additional Demographic data will be summarized for the TMB high and low risk of EM
subgroups.
The following will also be listed for all patients in the FAS (unless otherwise specified) per 
ICH guidelines:

Important protocol deviations specified in this SAP 


Statistical Analysis Plan 
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
COVID-19 related non-important PDs

Subject excluded from analysis populations 

Demographics (age, age group [< 65, >=65-< 75, ≥ 75 years], sex, race and ethnicity) 
4.2.19
Treatment exposure
The following summaries related to MEDI4736, tremelimumab, and SoC will be produced for 
the safety analysis set:

Total exposure and a plot of exposure over time (See Section 3.3.2)

Actual exposure. (Actual exposure will not be provided for SoC patients)

Number of dose interruptions/delays and reasons for dose interruptions/delays (drug 
interruptions represent interruption of an infusion and therefore any interruptions recorded 
on dates when study treatment was not administered will not be counted, delays are 
defined as a dose delay that occurs between 2 administrations of study treatment)

RDI (entire intended treatment period).

Cumulative exposure over time (excludes 28-day window)
Summaries of exposure will also be presented for the subgroup of discontinued patients.
All treatment information data (study drug administration, MEDI4736, tremelimumab and 
SoC) will be listed for the safety analysis set.
4.2.20
Subsequent Therapy
Subsequent therapies received after discontinuation of IP will have summaries produced, 
together with number of regimens received.  Moreover, a descriptive summary will be 
produced for time to first and second subsequent therapy from randomization.
5.
INTERIM ANALYSES
Interim safety monitoring will be conducted by an IDMC. Details of the plan and 
communication process will be provided in an IDMC Charter.
No interim analyses will be performed for any efficacy endpoint.


Statistical Analysis Plan 
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6.
CHANGES OF ANALYSIS FROM PROTOCOL 
Table 13
Changes of Analysis from Protocol
SAP 
edition#
Section of SAP 
Affected (If 
applicable)
Change
Rationale
6
7.
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8.
APPENDIX
8.1
Early risk of mortality prognostic model
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