A Phase 3 Randomized, Double-blind, Multicenter, Global Study of Monalizumab or Placebo in Combination With Cetuximab in Participants With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck Previously Treated With an Immune Checkpoint Inhibitor
Phase: PHASE3
Conditions: Squamous Cell Carcinoma of the Head and Neck
Sponsor: AstraZeneca

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
1 of 187
Clinical Study Protocol
Study Intervention
Monalizumab and cetuximab
Study Code
D7310C00001
Version
2.0
Date
07 July 2021
A Phase 3 Randomized, Double-blind, Multicenter, Global Study of 
Monalizumab or Placebo in Combination With Cetuximab in Participants
With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and 
Neck Previously Treated With an Immune Checkpoint Inhibitor
Sponsor Name: 
AstraZeneca AB
Legal Registered Address: 
151 85 Södertälje, Sweden
Regulatory Agency Identifier Number(s): IND number 145482
EudraCT number 2019-004770-25
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.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
2 of 187
Protocol Number: D7310C00001
Amendment Number: 1
Study Intervention: Monalizumab (IPH2201) and cetuximab
Study Phase: 3
Short Title: Study of Monalizumab Given With Cetuximab or Placebo Given with Cetuximab 
in Participants With Recurrent or Metastatic Head and Neck Cancer
Acronym: INTERLINK-1
Study Clinical Lead Name and Contact Information will be provided separately
International Co-ordinating Investigators: 
Abramson Cancer Center, Perelman Center for Advanced Medicine
West Pavilion, 2nd Floor, 3400 Civic Center Boulevard
Philadelphia, PA 19104 USA
Centre Léon Bérard
28, rue Laennec 
69373 Lyon Cedex 08 FRANCE
PPD
PPD

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
3 of 187
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 1
07 July 2021
Original Protocol
10 February 2020
Amendment 1 (07 July 2021)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the EU.
Overall Rationale for the Amendment
The protocol was updated to change the primary population of interest for the primary 
endpoint from the FAS to the HPV-unrelated Analysis Set (randomized participants who are 
either OPC HPV negative or non-OPC regardless of HPV status). To allow for the change in 
population assessed for the primary endpoint, the planned number of participants was
increased and the hierarchical testing procedure was updated. A futility analysis for OS was 
added as a new interim analysis for the HPV-unrelated Analysis Set . Guidance relating to the 
COVID-19 pandemic was added.
In addition, a number of non-substantial changes were made and errors were corrected.
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Protocol Amendment 
Summary of Changes 
Table
Section “Protocol Amendment Summary 
of Changes Table” was added.
To describe
changes in 
Amendment 1
Non-substantial
Section 1.1 Synopsis, 
Rationale
Text updated in line with changes to 
protocol body.
See below
See below
Section 1.1 Synopsis, 
Objectives and 
Endpoints
Text updated in line with changes to 
protocol body.
See below
See below
Section 1.1 Synopsis, 
Overall Design
Text updated in line with changes to 
protocol body. In addition, the number of 
sites was increased from 175 to 190.
See below
See below
Section 1.1 Synopsis, 
Number of Participants
Text updated in line with changes to 
protocol body.
See below
See below

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
4 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 1.1 Synopsis, 
Statistical Methods
Text updated in line with changes to 
protocol body.
See below
See below
Section 1.3 Schedule of 
Activities
Table 1
Added collection of PD-L1 results at 
screening, if available. Clarification added 
(Footnote “d”) that the most recent PD-L1 
results should be provided and if PD-L1 
results were not collected at screening, 
they will be collected retrospectively.
As part of the 
biomarker 
evaluation  
Non-substantial
Table 1
Added separate line for assessment of 
Coagulation parameters and footnote ‘j’ as 
mentioned in Section 8.2.4.
For clarification
Non-substantial
Table 1
Based on PK 
advice
Non-substantial
Table 1
Based on PK 
advice
Non-substantial
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
5 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Table 1 and Table 2
Order of T3 and T4 changed to T4 
followed by T3 in Table 1 and footnote “k” 
of Table 1 and in Table 2 and footnote “c” 
of Table 2; footnote “k” (Table 1)/footnote 
“c” (Table 2) changed from “Free T3 and 
free T4” to “Free T4 or/and free T3 (per 
local standard clinical practice)”.
To correct an 
error
Non-substantial
Section 2.2 Background
Updated to reflect most recent NCCN 
guidelines.
To present most 
recent 
guidelines
Non-substantial
Section 3 Objectives and 
Endpoints
Population used for analysis of the primary 
objective was changed from the FAS to the 
HPV-unrelated Analysis Set (randomized 
participants who are either OPC HPV 
negative or non-OPC regardless of HPV 
status).
Primary 
population was 
updated to 
reflect the 
updated primary 
population of 
interest 
(HPV-unrelated 
participants)
Substantial
The previous primary objective (to 
compare the effect of monalizumab and 
cetuximab (Arm A) relative to placebo and 
cetuximab (Arm B) by assessment of OS in 
all participants [ie, in the FAS]) was 
moved to a secondary objective.
The population was confirmed as all 
randomized patients.
To allow for the 
primary 
objective to be 
assessed in the 
HPV-unrelated 
Analysis Set
Substantial
For the secondary objective “To compare 
the effect of monalizumab and cetuximab 
(Arm A) relative to placebo and cetuximab 
(Arm B) by assessment of PFS, ORR, and 
DoR”, the populations to be analyzed were 
changed to “participants who are 
HPV-unrelated” and “all randomized 
participants”.
To clarify that 
the 
HPV-unrelated 
Analysis Set 
will also be used 
for this analysis
Substantial
Text added to the following objectives to 
clarify they will be analyzed in the 
HPV-unrelated population and in all
randomized participants:
“To assess disease-related symptoms, 
functioning, and HRQoL in participants 
treated with monalizumab and cetuximab 
(Arm A) compared to placebo and 
To clarify that 
these objectives 
will be analyzed 
in the 
HPV-unrelated 
Analysis Set 
and in all 
Substantial

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
6 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
cetuximab (Arm B) using the EORTC 
QLQ-C30 and the EORTC QLQ-H&N35 
questionnaires”
randomized 
participants
Section 4.1 Overall 
Design
To allow for the 
change in 
planned sample 
size given the 
primary 
population has 
been changed to 
HPV-unrelated 
population
Substantial
Now states that the IDMC will review data 
for both IAs (previously there was only 
one IA).
For clarity
Non-substantial
Text added to describe a cap on the number 
of OPC HPV-positive participants of 
approximately 20%.
To ensure 
sufficient 
sample size for 
HPV-unrelated 
participants
Substantial
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
7 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 4.1.1 Study 
Conduct Mitigation 
During Study 
Disruptions Due to 
Cases of Civil Crisis, 
Natural Disaster, or 
Public Health Crisis
New section to provide instructions in the 
case of civil crisis, natural disaster, or 
public health crisis.
In response to 
COVID-19 
pandemic, to 
reflect current 
AstraZeneca 
processes
Substantial
Section 4.2.1 Rationale 
for Study Design and 
Participant Population
Added clarification that unblinded 
pharmacists and ‘unblinded Study 
Monitors’ will be used in order to maintain 
the blind.
For clarification
Non-substantial
Text added to give rationale for testing in 
the HPV-unrelated population.
To align with 
the change to 
the primary 
population 
Non-substantial
Section 5.1 Inclusion 
Criterion 7
Added clarification that tumor tissue 
beyond the 3-month window and up to 
6 months old may be considered, provided 
that no intervening systemic regimen was 
ongoing at the time of sample collection. A 
reference to the Laboratory Manual was 
also added.
For clarification
Non-substantial
Section 5.2 Exclusion 
Criterion 13
Triplicate ECG timings replaced with a 
cross reference to Section 8.2.3.
For clarity
Non-substantial
Section 6.1.1 
Investigational 
Medicinal Products
Table 5
Updated to align 
with CSP 
template
Non-substantial
For clarification
Non-substantial
For clarification
Non-substantial
Clarified that cetuximab will be supplied 
by AstraZeneca, but if locally sourced the 
approved commercial product should be 
used.
For clarification
Non-substantial
Section 6.1.2 Dosing 
Instructions
Dosing regimen
For clarification
Non-substantial
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
8 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Now states that the total infusion duration 
for both interventions must not exceed 
8 hours.
Also states the iv line will be flushed 
according to local practices to ensure the 
full dose is administered, and the infusion 
time does not include the final flush time.
Section 6.2 
Preparation/Handling/ 
Storage/Accountability 
of Interventions
Clarified that IMP must be kept in original 
packaging.
For clarification
Non-substantial
Section 6.2.1.1 
Monalizumab
Removed the text stating that monalizumab 
should be protected from direct sunlight 
during preparation and handling.
Clarified that  the reconstitution and 
administration time of monalizumab must
not exceed values stated.
For clarification
Non-substantial
Non-substantial
Section 6.2.1.3 Placebo
Revised text to state an 
 
Clarified that the total infusion time must
not exceed 8 hours at room temperature.
For clarification
Non-substantial
6.3.1 Participant 
Enrollment and 
Randomization
Text added to describe a cap on the number 
of OPC HPV-positive participants of 
approximately 20%.
To ensure 
sufficient 
sample size for 
HPV-unrelated 
participants
Substantial
Amended to state all screening laboratory 
and imaging results must be obtained 
within 28 days of randomization (was 
“within 28 days of randomization/the first 
dose of study intervention”).
For consistency 
with tumor 
assessment 
timings in 
Non-substantial
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
9 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Inclusion 
Criterion 6
Amended to state a tumor tissue sample 
should be submitted to the central 
laboratory.
To ensure 
samples are 
submitted for 
analysis
Non-substantial
Section 6.5 Concomitant 
Therapy
Table 7
Text amended to state permitted vaccines 
are limited to non-live attenuated 
preparations. A reference to Appendix C 
was also added for details about 
vaccination against COVID-19.
To align with 
current 
AstraZeneca 
template
Non-substantial
Section 6.5.3 Rescue 
Medication
Removed the need to record the time of 
rescue medication administration.
Removed as this 
is not necessary
Non-substantial
Section 6.6 Dose 
Modification
Added reference for managing dose delays 
due to treatment-related toxicity.
To reflect 
current 
AstraZeneca 
processes
Non-substantial
Added reference to the new COVID-19 
Appendix C.
To reflect 
current 
AstraZeneca 
processes
Substantial
Replaced the term “IMP” with the 
specified study treatment.
For clarity
Non-substantial
Section 8.1.1 Imaging 
Tumor Assessments
Clarified that screening/baseline imaging 
should be performed no more than 28 days 
before randomization (not 28 days before 
start of study intervention).
For clarification
Non-substantial
Section 8.1.4.7 
Administration of 
Electronic PRO 
Questionnaires
Clarified that if technical or other device-
related issues prohibit completion of the 
questionnaires on the device, an 
appropriate backup option may be 
considered.
For clarification
Non-substantial
Clarified that relatives, friends, or clinic 
staff should not help participants decide on 
answers to the questionnaires.
For clarification
Non-substantial
Clarified that if a participant needs (rather 
than uses) visual aids for reading and they 
do not have them when attending clinic, 
they will be exempted from completing the 
ePROs at that visit.
For clarification
Non-substantial

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
10 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Clarified reasons for exemption from 
completing the ePROs, and added the need 
to contact AstraZeneca to determine if the 
participant is exempt.
For clarification
Non-substantial
Wording regarding language of the 
questionnaires updated; questions must not 
be translated from an available language in 
the device into the language the participant 
speaks.
For clarification
Non-substantial
Clarified (in relation to ePRO reporting) 
that Cycle 1 Day 1 is baseline.
For clarification
Non-substantial
Removed “REVPRDI” as the eCRF onto 
which completion status is to be recorded.
For clarification
Non-substantial
Text added to describe process regarding 
participant compliance.
For clarification
Non-substantial
Section 8.1.4.8 
WHO/ECOG PS
Numbering of WHO/ECOG classification 
corrected.
To correct an 
error
Non-substantial
Sentence added to state the ECOG status 
collected at screening must be reported in 
IRT and not re-assessed.
For clarification
Non-substantial
Section 8.2.2 Vital Signs
Added the approximate time window for 
collection of vital signs before cetuximab
dosing
For clarification
Non-substantial
Section 8.2.3 
Electrocardiograms
Resting ECG description changed to 
“semi-recumbent or supine”.
To correct an 
error
Non-substantial
Section 8.2.4 Clinical 
Safety Laboratory 
Assessments
Timing of sampling for coagulation 
parameters aligned with Table 8: “baseline 
on Day 1 (unless all screening laboratory 
hematology assessments are performed 
within 3 days prior to Day 1), and then as 
clinically indicated”
For clarification
Non-substantial
Table 8
Order of T3 and T4 changed to T4 
followed by T3 in Table 8; footnote “h” 
amended to “Free T4 or/and free T3 (per 
local standard clinical practice)…”.
To correct an 
error
Non-substantial
Table 8
Footnote c clarified that absolute 
neutrophil counts must be recorded at 
screening ie, they must not be recorded as 
percentages. 
For clarification
Non-substantial

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
11 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
The calculation of absolute counts from 
percentages was removed as this is not 
currently achievable.
Table 8
Coagulation was moved from the clinical 
chemistry column to the 
hematology/hemostasis column.
To correct an 
error
Non-substantial
Section 8.3 Adverse 
Events and Serious 
Adverse Events
Cross reference to new COVID-19 
Appendix C added.
To reflect 
current 
AstraZeneca 
processes
Substantial
Section 8.3.13.1 
Maternal Exposure
“Congenital abnormalities/abnormality” 
changed to “congenital 
anomalies/anomaly”.
This change is 
in line with 
regulatory 
requirements
Non-substantial
Section 8.3.13.2 Paternal 
Exposure
“Congenital abnormality” changed to 
“congenital anomaly”.
This change is 
in line with 
regulatory 
requirements
Non-substantial
Section 8.3.14 
Medication Error
Clarified that medication error information 
should be reported on the specific 
medication error eCRF.
Updated in line 
with new 
AstraZeneca 
requirements
Non-substantial
Section 8.3.15.2 
Cetuximab
Management of AEs with cetuximab text 
amended to refer to local label (details of 
actions to take have been removed).
To avoid 
possible 
mis-alignment 
with future 
changes to 
prescribing 
information
Substantial
Section 8.6.1 Collection 
of Mandatory Samples 
for Biomarker Analysis
Added clarification that tumor tissue 
beyond the 3-month window and up to 
6 months old may be considered, provided 
that no intervening systemic regimen was 
ongoing at the time of sample collection. A 
reference to the Laboratory Manual was 
also added.
For clarification
Non-substantial
Added clarification that fresh tumor biopsy 
should not be collected from lesions in 
proximity to structures that would make 
the collection procedure high risk. 
Per USA FDA 
request 
Non-substantial
Section 9.2 Sample Size 
Determination
Number of randomized participants 
increased from 600 to 624.
To align with 
the changes in 
Non-substantial

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
12 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 4 Study 
Design
Text amended to reflect change in 
population analyzed for the primary 
endpoint.
To reflect the 
change in the 
primary 
population
Substantial
Futility analysis for OS added for the 
HPV-unrelated Analysis Set.
Futility analysis 
was added for 
risk mitigation 
Substantial
Statistical methods for the primary 
endpoint were updated to reflect that 
analysis will be performed on 
HPV-unrelated participants.
To reflect the 
change in the 
primary 
population
Substantial
Text added to describe a cap on the number 
of OPC HPV-positive participants of 
approximately 20%.
To ensure 
sufficient 
sample size for 
HPV-unrelated 
participants
Substantial
Hypothesis text split to reflect hypotheses 
at each analysis (IA2 and final analysis).
For clarification
Substantial
Section 9.3 Populations 
for Analyses
Table 9
HPV-unrelated Analysis Set added to 
analysis of OS, PFS, ORR, DoR, PRO 
endpoints, demography and other baseline 
characteristics, and biomarkers.
To allow 
analysis for the 
updated primary 
population
Substantial
Table 9
Footnotes added to clarify definitions of 
ORR and PRO.
For clarification
Non-substantial
Section 9.3.1 
HPV-unrelated Analysis 
Set
New section added to describe new 
analysis set.
To allow 
analysis for the 
updated primary 
population
Substantial
Section 9.3.2 Full 
Analysis Set
Amended to state FAS will be used for 
summarizing baseline characteristics, all 
efficacy endpoints (including PROs) and 
biomarker analyses as secondary analyses.
The 
HPV-unrelated 
Analysis Set is 
the primary 
analysis set
Substantial
“Analysis for ORR will be based on 
participants in the FAS who had 
measurable disease at baseline. Analysis of
DoR will be based on participants in the 
It is more 
appropriate to 
include the 
description of 
the subset used 
for ORR and 
Non-substantial

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
13 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
FAS who achieved objective response” 
was removed.
DoR analyses in 
the sections for 
ORR and DoR
Section 9.3.3 Safety 
Analysis Set
Clarified that all participants who received 
any amount of study treatment (not at least 
1 dose) will be included in the Safety 
Analysis Set.
For clarification
Non-substantial
Section 9.4.1 General 
Considerations
Hypothesis text split to reflect hypotheses 
at each analysis (IA2 and final analysis).
For clarification
Substantial
Number of OS events and % maturity 
updated to reflect change in primary 
analysis population to HPV-unrelated 
Analysis Set.
To reflect the 
change in the 
primary 
population
Substantial
Text changed to reflect that the efficacy 
and PRO analyses will be performed on the 
HPV-unrelated population and repeated for 
the FAS as a secondary analysis.
Updated so that 
the PRO 
analysis is 
performed for 
both the primary 
and secondary 
populations
Substantial
Table 10
Added populations analyzed and amended 
stratification factors for each endpoint to 
reflect populations analyzed. Added OS in 
FAS as a secondary endpoint.
To reflect the 
change in the 
primary 
population
Substantial
Table 10
OS: KM plot of time to censoring removed 
from the sensitivity and supplemental 
analysis.
Removed as it is 
not considered 
necessary
Non-substantial
Table 10
OS: Cox proportional hazards models 
removed from the sensitivity and 
supplemental analysis.
For consistency 
with the SAP 
that has changed 
during 
development
Non-substantial
Section 9.4.1.1 Methods 
for Multiplicity Control
Text was added to more fully describe the 
hierarchical testing procedure.
For clarification
Non-substantial

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
14 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Number of OS events updated to reflect 
change in primary analysis population to 
HPV-unrelated Analysis Set; new figure 
added to describe multiplicity testing 
procedure.
To allow 
updated sample 
size justification 
with the change 
in the primary
population. To 
allow 
clarification in 
the multiple 
testing 
procedure of OS 
and PFS with 
the primary 
population 
(HPV-unrelated 
Analysis Set) 
and the 
secondary 
population 
(FAS)
Substantial
Statement that PFS will be formally tested 
only if OS is statistically positive replaced 
by statement that each statistical test will 
be performed only if the preceding test is 
positive.
To allow 
clarification in 
the multiple 
testing 
procedure of OS 
and PFS with 
the primary 
population 
(HPV-unrelated 
Analysis Set) 
and the
secondary 
population 
(FAS)
Substantial
Section 9.4.2.1 Primary 
Endpoint
Primary analysis 
Analysis set changed from FAS to 
HPV-unrelated Analysis Set.
As the population studied is now the 
HPV-unrelated Analysis Set, adjustment 
for HPV status was removed.
To allow 
analysis for the 
updated primary 
population and 
adjust the 
sensitivity 
analyses 
accordingly
Substantial
Sensitivity analysis
Added 
max-combo test 
as it is 
Non-substantial

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
15 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Details added regarding the stratified 
max-combo test that will be used as a 
sensitivity analysis.
Removal of KM plot for the time to 
censoring (attrition bias).
recommended 
by the 
Cross-Pharma 
Non-
proportional 
Hazard Working 
Group in the 
presence of non-
proportional 
hazards.
Removed KM 
plot of time to 
censoring as it is 
not as 
informational.
Cox proportional hazards models removed 
from the sensitivity and supplemental 
analysis.
For consistency 
with the SAP 
that has changed 
during 
development
Non-substantial
Analysis of OS in FAS
New section to describe analysis of OS in 
the FAS.
To describe 
analysis of 
secondary 
endpoint
Substantial
Subgroup analysis
Clarified that subgroup analyses will be 
performed on HPV-unrelated Analysis Set 
and FAS, where applicable.
To allow 
analysis for the 
updated primary 
population
Substantial
“Race” changed to “Race/ethnicity data” 
for clarification.
For clarification
Non-substantial
9.4.2.2.1 Progression-
free Survival
Analysis of PFS
Text amended to state PFS will be 
analyzed in the HPV-unrelated Analysis 
Set as well as the FAS.
To allow 
analysis in the 
primary 
population
Substantial
9.4.2.2.2 Objective 
Response Rate
Analysis of ORR
To allow 
analysis in the 
Substantial

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
16 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Text amended to state ORR will be 
analyzed in the HPV-unrelated Analysis 
Set as well as the FAS.
primary 
population
Section 9.4.2.2.4 Patient-
reported Outcome: 
EORTC QLQ-C30
Detailed information about PRO 
definitions were removed as the 
information will be included in the SAP. 
The number of analyses of PROs was 
reduced.
Information will 
be detailed in 
the SAP
Non-substantial
Text amended to state analyses will be 
performed on the HPV-unrelated Analysis 
Set as well as the FAS.
To allow 
analysis in the 
primary 
population
Substantial
Section 9.4.2.2.5 Patient-
reported Outcome: 
EORTC QLQ-H&N35
Detailed information about PRO 
definitions were removed as the 
information will be included in the SAP. 
Information will 
be detailed in 
the SAP
Non-substantial
Analysis methods
Text amended to state the analyses will be 
performed for the HPV-unrelated Analysis 
Set as well as the FAS.
The number of analyses of PROs was 
reduced.
To allow 
analysis in the 
primary 
population
Substantial
Section 9.4.2.3.1 Time 
from Randomization to 
Second Progression or 
Death
Removal of KM plot for the time to 
censoring (attrition bias).
Removed as it is 
not considered 
necessary
Non-substantial
Section 9.7 Impact of 
COVID-19 on Data
New section added to acknowledge 
possible impact of COVID-19 on the data: 
reference to SAP (where details will be 
supplied) included.
In response to 
COVID-19 
pandemic, to 
reflect current 
AstraZeneca 
processes
Substantial
Appendix B 2 
Definitions of Serious 
Adverse Event
“Congenital abnormality” changed to 
“congenital anomaly.
This change is 
in line with 
Non-substantial
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
17 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
regulatory 
requirements
Appendix C Changes 
Related to Mitigation of 
Study Disruptions Due 
to Cases of Civil Crisis, 
Natural Disaster, or 
Public Health Crisis, 
including COVID-19 
Outbreak 
New appendix added to describe study 
conduct details pertaining to COVID-19 
outbreak. 
All subsequent appendices renumbered.
In response to 
COVID-19 
pandemic, to 
reflect current 
AstraZeneca 
processes
Substantial
Appendix E 8 
Laboratory Tests (now 
Appendix F 8)
Table of Hy’s law laboratory tests: 
footnote “a” removed from HBV DNA as 
it is not applicable for HBV DNA; footnote 
“c” removed since the study is not 
expected to be conducted in China.
Amendment of 
error and 
clarification
Non-substantial
Throughout
The terms “Medical Monitor” and “Study 
Physician” were changed to “Study 
Clinical Lead”.
In line with 
latest 
AstraZeneca 
template
Non-substantial

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
18 of 187
TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3
TABLE OF CONTENTS .................................................................................................... 18
1
PROTOCOL SUMMARY ................................................................................ 23
1.1
Synopsis ........................................................................................................... 23
1.2
Schema............................................................................................................. 29
1.3
Schedule of Activities ....................................................................................... 29
2
INTRODUCTION............................................................................................ 44
2.1
Study Rationale ................................................................................................ 44
2.2
Background ...................................................................................................... 44
2.3
Benefit/Risk Assessment................................................................................... 46
2.3.1
Risk Assessment ............................................................................................... 46
2.3.2
Benefit Assessment........................................................................................... 48
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 49
3
OBJECTIVES AND ENDPOINTS................................................................... 50
4
STUDY DESIGN ............................................................................................. 52
4.1
Overall Design.................................................................................................. 52
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 54
4.2
Scientific Rationale for Study Design ............................................................... 54
4.2.1
Rationale for Study Design and Participant Population ..................................... 54
4.2.2
Rationale of Study Endpoints............................................................................ 55
4.3
Justification for Dose........................................................................................ 56
4.3.1
Rationale for Monalizumab Dose...................................................................... 56
4.3.2
Rationale for Cetuximab Dose .......................................................................... 58
4.4
End of Study Definition.................................................................................... 58
5
STUDY POPULATION.................................................................................... 58
5.1
Inclusion Criteria .............................................................................................. 58
5.2
Exclusion Criteria ............................................................................................. 61
5.3
Lifestyle Considerations ................................................................................... 64
5.4
Screen Failures ................................................................................................. 64
6
STUDY INTERVENTION ............................................................................... 65
6.1
Study Interventions Administered ..................................................................... 65
6.1.1
Investigational Medicinal Products ................................................................... 65
6.1.2
Dosing Instructions........................................................................................... 66
6.1.3
Duration of Treatment....................................................................................... 68
6.2
Preparation/Handling/Storage/Accountability of Interventions.......................... 68

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
19 of 187
6.2.1
Dose Preparation and Administration................................................................ 69
6.2.1.1
Monalizumab.................................................................................................... 69
6.2.1.2
Cetuximab ........................................................................................................ 70
6.2.1.3
Placebo............................................................................................................. 70
6.3
Measures to Minimize Bias: Randomization and Blinding ................................ 70
6.3.1
Participant Enrollment and Randomization ....................................................... 70
6.3.2
Procedures for Handling Incorrectly Enrolled or Randomized Participants........ 72
6.3.3
Methods for Assigning Treatment Arms............................................................ 72
6.3.4
Methods for Ensuring Blinding......................................................................... 73
6.4
Study Intervention Compliance......................................................................... 74
6.5
Concomitant Therapy........................................................................................ 75
6.5.1
Permitted Medication Prior to Study Intervention ............................................. 76
6.5.2
Drug-drug Interactions...................................................................................... 77
6.5.3
Rescue Medication............................................................................................ 77
6.6
Dose Modification ............................................................................................ 77
6.7
Intervention After the End of the Study............................................................. 78
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 79
7.1
Discontinuation of Study Intervention............................................................... 79
7.1.1
Procedures for Discontinuation of Study Intervention ....................................... 80
7.1.1.1
Tumor Assessment Post Discontinuation of Study Intervention......................... 80
7.1.1.2
7.1.1.3
Follow-up for Survival...................................................................................... 81
7.2
Participant Withdrawal From the Study............................................................. 81
7.3
Lost to Follow-up ............................................................................................. 82
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 83
8.1
Efficacy Assessments........................................................................................ 83
8.1.1
Imaging Tumor Assessments............................................................................. 83
8.1.2
8.1.3
Overall Survival................................................................................................ 84
8.1.4
Clinical Outcome Assessments.......................................................................... 84
8.1.4.1
EORTC QLQ-C30 ............................................................................................ 85
8.1.4.2
EORTC QLQ-H&N35 ...................................................................................... 85
8.1.4.3
8.1.4.4
8.1.4.5
8.1.4.6
8.1.4.7
Administration of Electronic PRO Questionnaires ............................................ 86
8.1.4.8
WHO/ECOG PS ............................................................................................... 88
8.2
Safety Assessments........................................................................................... 89
8.2.1
Physical Examinations...................................................................................... 89
8.2.2
Vital Signs ........................................................................................................ 89
8.2.3
Electrocardiograms........................................................................................... 90
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
20 of 187
8.2.4
Clinical Safety Laboratory Assessments............................................................ 91
8.3
Adverse Events and Serious Adverse Events..................................................... 92
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 92
8.3.2
Follow-up of AEs and SAEs ............................................................................. 93
8.3.3
Causality Collection.......................................................................................... 94
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 94
8.3.5
Adverse Events Based on Examinations and Tests ............................................ 94
8.3.6
Hy’s Law.......................................................................................................... 95
8.3.7
Disease Progression.......................................................................................... 95
8.3.8
New Cancers..................................................................................................... 95
8.3.9
Deaths .............................................................................................................. 95
8.3.10
Adverse Events of Special Interest.................................................................... 96
8.3.11
Safety Data to be Collected Following the Final DCO of the Study................... 97
8.3.12
Reporting of Serious Adverse Events................................................................ 97
8.3.13
Pregnancy......................................................................................................... 98
8.3.13.1
Maternal Exposure............................................................................................ 98
8.3.13.2
Paternal Exposure............................................................................................. 98
8.3.14
Medication Error............................................................................................... 99
8.3.15
Management of IMP-related Toxicities ............................................................. 99
8.3.15.1
Monalizumab.................................................................................................... 99
8.3.15.2
Cetuximab ...................................................................................................... 100
8.4
Overdose ........................................................................................................ 100
8.5
Human Biological Samples............................................................................. 101
8.5.1
Pharmacokinetics............................................................................................ 101
8.5.1.1
Determination of Drug Concentration ............................................................. 102
8.5.2
Immunogenicity Assessments ......................................................................... 102
8.6
Human Biological Sample Biomarkers ........................................................... 102
8.6.1
Collection of Mandatory Samples for Biomarker Analysis .............................. 102
8.6.2
Collection of Optional Biomarker Samples ..................................................... 103
8.6.3
Other Study-related Biomarker Research ........................................................ 103
8.7
8.8
Medical Resource Utilization and Health Economics ...................................... 104
8.9
Study Participant Feedback Questionnaire ...................................................... 104
9
STATISTICAL CONSIDERATIONS.............................................................. 104
9.1
Statistical Hypotheses..................................................................................... 104
9.2
Sample Size Determination............................................................................. 104
9.3
Populations for Analyses................................................................................. 106
9.3.1
HPV-unrelated Analysis Set ............................................................................ 106
9.3.2
Full Analysis Set............................................................................................. 107
9.3.3
Safety Analysis Set ......................................................................................... 107
9.3.4
Pharmacokinetic Analysis Set ......................................................................... 107
9.3.5
ADA Analysis Set........................................................................................... 107
9.4
Statistical Analyses ......................................................................................... 107
9.4.1
General Considerations................................................................................... 107
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
21 of 187
9.4.1.1
Methods for Multiplicity Control .................................................................... 110
9.4.2
Efficacy ...........................................................................................................111
9.4.2.1
Primary Endpoint.............................................................................................111
9.4.2.2
Secondary Endpoints ...................................................................................... 113
9.4.2.3
Exploratory Endpoints .................................................................................... 117
9.4.3
Safety ............................................................................................................. 118
9.4.3.1
Calculation or Derivation of Safety Variables.................................................. 118
9.4.3.2
Analysis of safety variables............................................................................. 120
9.4.4
Other Analyses................................................................................................ 120
9.4.4.1
Healthcare Resource Use ................................................................................ 120
9.4.4.2
Pharmacokinetic Data..................................................................................... 120
9.4.4.3
Immunogenicity Data...................................................................................... 120
9.4.4.4
Pharmacokinetic/Pharmacodynamic Relationships.......................................... 121
9.4.4.5
Biomarker Data .............................................................................................. 121
9.5
Interim Analyses............................................................................................. 121
9.6
Data Monitoring Committee ........................................................................... 122
9.7
Impact of COVID-19 on Data......................................................................... 122
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ...................................................................................... 122
11
REFERENCES............................................................................................... 182
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 29
Figure 2
Figure 3
Graphical Presentation of the Propose Multiple-Testing Procedure at IA2 
and FA................................................................................................... 111
LIST OF TABLES
Table 1
Schedule of Activities – Screening Period and Intervention Period .......... 30
Table 2
Schedule of Activities – Follow-up Period for Participants Who 
Discontinued Study Intervention Due to Disease Progression or Other 
Reason..................................................................................................... 40
Table 3
Preliminary Efficacy, Cohort 1 - Expansion Phase (Monalizumab + 
Cetuximab), All Subjects Treated (Study IPH2201-203).......................... 49
Table 4
Objectives and Endpoints......................................................................... 50
Table 5
Investigational Medicinal Products .......................................................... 65
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
22 of 187
Table 6
Prohibited Concomitant Medication/Therapy........................................... 75
Table 7
Permitted Concomitant Medication/Therapy............................................ 76
Table 8
Laboratory Safety Variables..................................................................... 91
Table 9
Summary of Outcome Variables and Analysis Populations .................... 106
Table 10
Pre-planned Statistical and Sensitivity Analyses to be Conducted for 
Efficacy and COA Endpoints................................................................. 108
Table 11
Summary of imaging modalities for tumor assessment........................... 149
Table 12
RECIST 1.1 Evaluation of TLs .............................................................. 157
Table 13
RECIST 1.1 Evaluation of NTLs ........................................................... 158
Table 14
RECIST 1.1 Overall Visit Response ...................................................... 159
Table 15
Highly Effective Methods of Contraception (< 1% Failure Rate) ........... 162
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 123
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 128
Appendix C
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis, including COVID-
19 Outbreak........................................................................................... 133
Appendix D
Handling of Human Biological Samples ................................................ 138
Appendix E
Appendix F
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 143
Appendix G
Guidelines for Evaluation of Objective Tumor Response Using RECIST 
1.1 Criteria (Response Evaluation Criteria in Solid Tumors).................. 149
Appendix H
Contraception Requirements.................................................................. 161
Appendix I
Patient-reported Outcomes..................................................................... 163
Appendix J
Study Participant Feedback Questionnaire ............................................. 174
Appendix K
Abbreviations ........................................................................................ 178
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
23 of 187
1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3 Randomized, Double-blind, Multicenter, Global Study of 
Monalizumab or Placebo in Combination With Cetuximab in Participants With Recurrent or 
Metastatic Squamous Cell Carcinoma of the Head and Neck Previously Treated With an 
Immune Checkpoint Inhibitor
Short Title: Study of Monalizumab Given With Cetuximab or Placebo Given with Cetuximab 
in Participants With Recurrent or Metastatic Head and Neck Cancer
Rationale: The aim of this study is to assess the efficacy and safety of monalizumab and 
cetuximab compared to placebo and cetuximab in participants with R/M SCCHN after 
receiving an ICI and platinum-based chemotherapy, regardless of the sequence of these 
therapies. Monalizumab is a first-in-class ICI that blocks the inhibitory CD94/NKG2A 
receptor resulting in the stimulation of NK cell and CD8+ T cell cytolytic activity.
Additionally, monalizumab enhances human NK-cell ADCC mediated by cetuximab. While 
monalizumab monotherapy has shown limited clinical activity, encouraging antitumor results 
have been observed following monalizumab and cetuximab combination therapy in patients 
with R/M SCCHN who have received prior platinum-based chemotherapy, including patients 
who have also received prior therapy with an ICI. This dual targeting could therefore provide 
greater antitumor activity than cetuximab alone. The combination of monalizumab and 
cetuximab could be a key option to improve clinical outcomes in patients with R/M SCCHN,
regardless of HPV status, after receiving an ICI.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
24 of 187
Objectives and Endpoints
Objective
Estimand a Description/Endpoint
Primary
To compare the effect of monalizumab and cetuximab 
(Arm A) relative to placebo and cetuximab (Arm B) 
by assessment of OS in HPV-unrelated participants
•
Population: The HPV-unrelated Analysis Set 
which will include all randomized participants
who are either OPC HPV negative or
non-OPC regardless of HPV status
•
Endpoint: OS, which is defined as time from 
randomization until the date of death due to 
any cause
•
Intercurrent events: If a participant is lost to 
follow-up or withdraws consent, OS will be 
censored based on the last recorded date on 
which the participant was known to be alive
•
Summary measure: p-value of treatment 
comparison using a stratified log rank test and 
hazard ratio of Arm A relative to Arm B with 
its confidence interval using a stratified Cox 
Proportional Hazards model
Secondary
To compare the effect of monalizumab and cetuximab 
(Arm A) relative to placebo and cetuximab (Arm B) 
by assessment of OS in all randomized participants
•
Population: The FAS which will include all 
randomized participants 
•
Endpoint: OS, which is defined as time from 
randomization until the date of death due to 
any cause
•
Intercurrent events: If a participant is lost to 
follow-up or withdraws consent, OS will be 
censored based on the last recorded date on 
which the participant was known to be alive
•
Summary measure: p-value of treatment 
comparison using a stratified log rank test and 
hazard ratio of Arm A relative to Arm B with 
its confidence interval using a stratified Cox 
Proportional Hazards model
To compare the effect of monalizumab and cetuximab 
(Arm A) relative to placebo and cetuximab (Arm B) 
by assessment of PFS, ORR, and DoR in participants 
who are HPV-unrelated and in all randomized 
participants
•
PFS is defined as time from randomization 
until disease progression, per RECIST 1.1 as
assessed by the investigator at local site or 
death due to any cause, whichever occurs first.
•
ORR is defined as the proportion of 
participants with measurable disease who have 
a confirmed CR or PR, as determined by the 
investigator at local site per RECIST 1.1.
•
DoR is defined as the time from the date of 
first documented response until date of 
documented disease progression or death in 
the absence of disease progression.
To assess disease-related symptoms, functioning, and 
HRQoL in participants treated with monalizumab and 
cetuximab (Arm A) compared to placebo and 
Symptoms, functioning, and global health 
status/QoL scale/item scores of the EORTC 
QLQ-C30 & EORTC QLQ-H&N35

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
25 of 187
Objective
Estimand a Description/Endpoint
cetuximab (Arm B) using the EORTC QLQ-C30 and 
the EORTC QLQ-H&N35 questionnaires in 
participants who are HPV-unrelated and in all 
randomized participants
•
Change from baseline scores across visits
•
Time to clinically meaningful deterioration in 
scores
To assess the PK of monalizumab
Concentration of monalizumab in blood and PK 
parameters (such as Cmax, Ctrough, as data allow; 
sparse sampling)
To investigate the immunogenicity of monalizumab 
Presence of ADAs for monalizumab (confirmatory 
results: positive or negative, titers)
To characterize the association between clinical 
outcome and protein expression in the tumor 
microenvironment in participants treated with 
monalizumab and cetuximab (Arm A) or placebo and 
cetuximab (Arm B) in participants who are 
HPV-unrelated and in all randomized participants
HLA-E and NKp46+ expression in pre-treatment 
and post-treatment tumor biopsies
Secondary safety
To assess the safety and tolerability of monalizumab 
and cetuximab (Arm A) compared to placebo and 
cetuximab (Arm B) in participants with R/M SCCHN 
previously treated with ICI
AEs, vital signs, clinical laboratory results, ECGs
a
Estimand is the target of estimation to address the scientific question of interest posed by the primary
objective. Attributes of an estimand include the population of interest, the variable (or endpoint) of 
interest, the specification of how intercurrent events are reflected in the scientific question of interest, 
and the population-level summary for the variable.
ADA = antidrug antibodies; AE = adverse event; Cmax = maximum serum concentration; CR = complete 
response; Ctrough = trough serum concentration; DoR = duration of response; ECG = electrocardiogram; 
EORTC = European Organisation for Research and Treatment of Cancer; FAS = full analysis set; 
HLA-E = human leukocyte antigen E; HPV = human papillomavirus; HRQoL = health-related quality of life; 
NK = natural killer; OPC = oropharyngeal cancer; ORR = objective response rate; OS = overall survival; 
PFS = progression-free survival; PK = pharmacokinetic(s); PR = partial response; QLQ-C30 = 30-item Core 
Quality of Life Questionnaire; QLQ-H&N35 = Quality of Life Questionnaire Head and Neck Module; 
RECIST 1.1 = Response Evaluation Criteria for Solid Tumors version 1.1; R/M = recurrent or metastatic; 
SCCHN = squamous cell carcinoma of the head and neck.
For exploratory objectives, see Section 3 of the protocol.
Overall Design
Study D7310C00001 is a Phase 3, randomized, double-blind, multicenter, global study 
assessing the safety and efficacy of monalizumab or placebo in combination with cetuximab 
in participants with R/M SCCHN not amenable to curative treatment previously treated with 
platinum-based chemotherapy and an ICI, regardless of the sequence of these therapies.
Approximately 190 sites globally will participate in this study.
Following a 28-day screening period, eligible participants will be randomized on Day 1 in a 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
26 of 187
2:1 ratio to one of the following treatment arms: (1) Arm A: monalizumab and cetuximab or 
(2) Arm B: placebo and cetuximab. Participants will be stratified by:
!
Human papillomavirus status: (i) OPC HPV positive or (ii) HPV-unrelated,
∀
The number of OPC HPV-positive participants will be closely monitored throughout 
the study and is planned to be capped at approximately 20% of the total sample size.
!
World Health Organization/ECOG PS (0 or 1), and 
!
Number of prior lines of therapy in the R/M setting (1 or 2)
∀
The number of participants in each stratum (1 or 2 prior lines of therapy in the R/M 
setting) will be closely monitored throughout the study. If a disproportionate number 
of participants are enrolled in a single stratum (eg, > 75% of the total sample size), 
the Sponsor may elect to close further recruitment into that stratum.
Participants will receive study intervention until disease progression, unacceptable toxicity, 
withdrawal of consent, or another discontinuation criterion is met. An IDMC will review 
safety data regularly and make recommendations regarding further study conduct. 
Disclosure Statement: This is a parallel group treatment study with 2 arms that is participant 
and investigator blinded.
Number of Participants:
Approximately 832 participants will be enrolled to achieve approximately 624 participants 
randomly assigned to study intervention while ensuring at least 498 participants who are either 
OPC HPV negative or non-OPC regardless of the HPV status (HPV-unrelated participants).
This includes approximately 416 participants randomized to Arm A (monalizumab and 
cetuximab) and 208 participants randomized to Arm B (placebo and cetuximab) in the overall 
population; while for the HPV-unrelated population, this includes approximately 
332 participants randomized to Arm A and 166 participants randomized to Arm B. 
Note: "Enrolled" means a participant's, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Potential participants who are screened for the purpose of determining eligibility for the study 
but are not randomly assigned in the study are considered “screen failures”. 
Intervention Groups and Duration:
Participants will be randomized in a 2:1 ratio to Arm A or Arm B. 
!
Arm A: monalizumab and cetuximab
Monalizumab 
 and cetuximab 400 mg/m2 iv initial dose followed by 
250 mg/m2 iv Q1W
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
27 of 187

Arm B: placebo and cetuximab
Placebo iv Q2W and cetuximab 400 mg/m2 iv initial dose followed by 250 mg/m2 iv
Q1W
Study intervention will continue until RECIST 1.1-defined radiological disease progression 
per investigator, unacceptable toxicity, withdrawal of consent, or another discontinuation 
criterion is met. Crossover between treatment arms will not be permitted. 
Follow-up of participants post discontinuation of study intervention
After discontinuation of study intervention, all participants will have safety assessment
follow-up for 3 months after their last dose of study intervention.
Participants who have discontinued study intervention in the absence of RECIST 1.1-defined 
radiological disease progression per investigator will continue with scheduled tumor 
assessments until RECIST 1.1-defined disease progression or death regardless of whether the 
participant started a subsequent anticancer therapy, unless they have withdrawn all consent to 
study-related assessments. 
Additionally, after study intervention discontinuation, all participants will be followed for 
survival status, subsequent anticancer therapy, and time to disease progression occurring 
during or after subsequent therapy (as determined per local standard clinical practice) until 
death, withdrawal of consent, or the end of the study.
Data Monitoring Committee: Yes
Statistical Methods
The primary objective of the study is to compare the effect of monalizumab and cetuximab 
(Arm A) relative to placebo and cetuximab (Arm B) in terms of OS in HPV-unrelated
participants. 
The primary endpoint OS is defined as the time from the date of randomization until death due 
to any cause. Secondary efficacy endpoints include PFS, ORR, DoR, and PROs.
The primary population is the HPV-unrelated Analysis Set which will include all randomized 
participants who are either OPC HPV negative or non-OPC regardless of the HPV status. The 
HPV status will be determined by HPV status in the eCRF and not the IVRS value. The 
HPV-unrelated Analysis Set and FAS (all randomized participants) will be used for 
summarizing baseline characteristics, all efficacy analyses, including PROs, and biomarker 
analyses. Treatment arms will be compared on the basis of randomized study intervention, 
regardless of the intervention actually received. Participants who were randomized but did not 
subsequently go on to receive study intervention are included in the analysis in the treatment 
arm to which they were randomized.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
28 of 187
The primary analysis of OS in the HPV-unrelated Analysis Set will be performed using a 
stratified log-rank test, adjusting for WHO/ECOG PS (0 or 1) and number of prior lines of 
therapy in the R/M setting (1 or 2). The HR and its CI will be estimated from a stratified Cox 
Proportional Hazards model. The analysis of OS in the FAS will be additionally stratified by 
HPV status (OPC HPV-positive or HPV-unrelated). These stratification factors will be 
determined based on the randomization.
There will be two planned IAs and one FA for the study.
Interim Analysis 1 (IA1): Futility in OS will be evaluated when approximately 99 OS events 
have occurred across Arm A and Arm B in HPV-unrelated participants (25% information 
fraction) in participants randomized at least 2 months before the DCO for the futility analysis 
(ie, with a minimum follow-up of 2 months).
Interim Analysis 2 (IA2): A hypothesis of monalizumab plus cetuximab (Arm A) prolongs OS 
compared to placebo plus cetuximab (Arm B) will be tested at IA2 when approximately 
278 OS events have occurred across Arm A and Arm B in HPV-unrelated participants 
(approximately 70% information fraction, 56% maturity).
Final Analysis (FA): A hypothesis of improved OS will be tested at the final analysis when
approximately 397 OS events have occurred across Arm A and Arm B in HPV-unrelated
participants (approximately 80% maturity).
If the true OS HR is 0.72, corresponding to an approximate 3-month improvement in median 
OS compared to Arm B of 7.7 months, approximately 397 OS events in HPV-unrelated
participants will provide approximately 86.5% power to demonstrate statistical significance at 
the 5% level (using a 2-sided test) for the FA. The 5% (2-sided) alpha for the OS analysis will 
be controlled at the IA2 and FA time points by using the Lan-DeMets (Lan and DeMets 1983)
spending function that approximates the O’Brien-Fleming approach, where the significance 
level applied depends upon the proportion of information (ie, information fraction) available 
at the time of IA2. For example, if the information fraction for OS at IA2 is 70% then the 
two-sided significance levels of 1.48% and 4.55% will be applied to IA2 and FA for OS, 
respectively. The smallest detectable treatment difference in HR, ie, critical value, that could 
be statistically significant at the FA is 0.81. With a planned recruitment period of 30 months, it 
is expected that a total of 498 HPV-unrelated participants are needed in order to achieve 
397 OS events with a follow-up period of approximately 12 months. The 278 OS events for 
the IA2 are expected to be reached approximately 30.5 months after the randomization of the 
first participant.
The number of OPC HPV-positive participants will be closely monitored throughout the study 
and is planned to be capped at approximately 20% of the total sample size. With the 
assumption that 20% of participants will be OPC HPV positive, approximately 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
29 of 187
624 randomized participants will be needed in the overall population. Under the same 
assumption of effect size in HR and median OS stated above, approximately 498 OS events 
are expected in all participants which will provide approximately 93.0% power to demonstrate 
statistical significance at the 5% level (using a 2-sided test) for the FA.
Strong control of the FWER at 5% level (2 sided) across the testing of OS and PFS endpoints 
will be achieved through a combined approach of alpha allocation to the OS analyses (IA2 and 
the FA) via alpha spending function as previously mentioned and a hierarchical testing 
procedure; that is, OS in FAS will be tested only if OS in HPV-unrelated analysis set met 
significance at IA2 or FA; PFS will be tested only if OS met statistical significance at IA2 or 
FA and PFS in FAS will be tested only if PFS in HPV-unrelated analysis set met statistical 
significance at IA2 or FA (Glimm et al 2010).
1.2
Schema
The general study design is summarized in Figure 1.
Figure 1
Study Design
a Prior platinum failure is defined as either: (i) disease progression during or after treatment with a platinum-
containing regimen for R/M disease or (ii) recurrence/progression during or within 6 months of the last dose of 
platinum as part of multimodal therapy for LA disease.
Eligible participants must not have received prior cetuximab, unless administered in the LA setting with 
radiotherapy and no disease progression for at least 6 months following the last cetuximab dose. 
b Study intervention regimens: monalizumab
; cetuximab, 400 mg/m2 iv
initial dose then 250 mg/m2 iv Q1W.
WHO/ECOG PS = World Health Organization/Eastern Cooperative Oncology Group performance status; iv = 
intravenous; HPV = human papillomavirus; LA = locally advanced; PD-(L)1 = programmed cell death-1 or 
programmed cell death ligand-1; 
;
R/M = recurrent/metastatic; 
SCCHN = squamous cell carcinoma of the head and neck.
1.3
Schedule of Activities
The SoA are presented in Table 1 for the screening and intervention periods and Table 2 for 
the follow-up period.
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
30 of 187
Table 1
Schedule of Activities – Screening Period and Intervention Period 
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
31 of 187
Table 1
Schedule of Activities – Screening Period and Intervention Period 
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
32 of 187
Table 1
Schedule of Activities – Screening Period and Intervention Period 
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
33 of 187
Table 1
Schedule of Activities – Screening Period and Intervention Period 
Procedure
Screening
Intervention period (1 cycle = 14 days)
For details 
see Section
C1
C2
C3
C4
C5
C6
C7+
C1
D1
C1
D8
C2
D1
C2
D8
C3
D1
C3
D8
C4
D1
C4
D8
C5
D1
C5
D8
C6
D1
C6
D8
C7
D1
C7
D8
Week
-4 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13+
14+
Day
-28 to -1
D1
D8
D15
D22
D29
D36
D43
D50
D57
D64
D71
D78
D85+
D92+
Window (days) a
NA
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
Biomarker sampling 
X
X
(opti
onal)
Tumor biopsy at 
time of progression 
(optional)
X
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
34 of 187
Table 1
Schedule of Activities – Screening Period and Intervention Period 
Procedure
Screening
Intervention period (1 cycle = 14 days)
For details 
see Section
C1
C2
C3
C4
C5
C6
C7+
C1
D1
C1
D8
C2
D1
C2
D8
C3
D1
C3
D8
C4
D1
C4
D8
C5
D1
C5
D8
C6
D1
C6
D8
C7
D1
C7
D8
Week
-4 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13+
14+
Day
-28 to -1
D1
D8
D15
D22
D29
D36
D43
D50
D57
D64
D71
D78
D85+
D92+
Window (days) a
NA
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
Pharmacokinetic measurements
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
35 of 187
Table 1
Schedule of Activities – Screening Period and Intervention Period 
Procedure
Screening
Intervention period (1 cycle = 14 days)
For details 
see Section
C1
C2
C3
C4
C5
C6
C7+
C1
D1
C1
D8
C2
D1
C2
D8
C3
D1
C3
D8
C4
D1
C4
D8
C5
D1
C5
D8
C6
D1
C6
D8
C7
D1
C7
D8
Week
-4 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13+
14+
Day
-28 to -1
D1
D8
D15
D22
D29
D36
D43
D50
D57
D64
D71
D78
D85+
D92+
Window (days) a
NA
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
Immunogenicity measurements
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
36 of 187
Table 1
Schedule of Activities – Screening Period and Intervention Period 
Procedure
Screening
Intervention period (1 cycle = 14 days)
For details 
see Section
C1
C2
C3
C4
C5
C6
C7+
C1
D1
C1
D8
C2
D1
C2
D8
C3
D1
C3
D8
C4
D1
C4
D8
C5
D1
C5
D8
C6
D1
C6
D8
C7
D1
C7
D8
Week
-4 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13+
14+
Day
-28 to -1
D1
D8
D15
D22
D29
D36
D43
D50
D57
D64
D71
D78
D85+
D92+
Window (days) a
NA
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
Efficacy measurements
Tumor imaging 
(RECIST 1.1)
X
Intravenous contrast-enhanced CT or MRI of the neck, chest, and abdomen (includes entire liver) Q8W (± 1 week) for the 
first 48 weeks after randomization and then Q12W (±1 week) thereafter (relative to randomization), until RECIST 1.1-
defined radiological disease progression; plus at least 1 additional follow-up scan. 
This schedule MUST be followed regardless of any delays in dosing.
8.1.1,  
Appendix G
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
37 of 187
Table 1
Schedule of Activities – Screening Period and Intervention Period 
Procedure
Screening
Intervention period (1 cycle = 14 days)
For details 
see Section
C1
C2
C3
C4
C5
C6
C7+
C1
D1
C1
D8
C2
D1
C2
D8
C3
D1
C3
D8
C4
D1
C4
D8
C5
D1
C5
D8
C6
D1
C6
D8
C7
D1
C7
D8
Week
-4 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13+
14+
Day
-28 to -1
D1
D8
D15
D22
D29
D36
D43
D50
D57
D64
D71
D78
D85+
D92+
Window (days) a
NA
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
PRO (e-device) and health economic measurements
Allocate ePRO 
device
X
8.1.4.7
ePRO device 
training
X
EORTC QLQ-C30
X
X
X
X 
then 
Q4W
8.1.4.1
EORTC QLQ-
H&N35
X
X
X
X 
then 
Q4W
8.1.4.2
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
38 of 187
Table 1
Schedule of Activities – Screening Period and Intervention Period 
Procedure
Screening
Intervention period (1 cycle = 14 days)
For details 
see Section
C1
C2
C3
C4
C5
C6
C7+
C1
D1
C1
D8
C2
D1
C2
D8
C3
D1
C3
D8
C4
D1
C4
D8
C5
D1
C5
D8
C6
D1
C6
D8
C7
D1
C7
D8
Week
-4 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13+
14+
Day
-28 to -1
D1
D8
D15
D22
D29
D36
D43
D50
D57
D64
D71
D78
D85+
D92+
Window (days) a
NA
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
Other assessment
Study intervention administration
a
Unless noted otherwise. 
The interval between monalizumab/placebo and cetuximab interventions should be at least 14 days for monalizumab/placebo and at least 7 days for cetuximab. If either 
intervention is delayed > 2 weeks then consult the Sponsor. See Section 6.6 for action in case of a dose delay.
b
May be obtained prior to 28-day screening window to permit tumor biopsy sample acquisition and analysis.
c
As clinically indicated.
d
The most recent PD-L1 results should be provided. If PD-L1 results were not collected at screening, they will be collected retrospectively.
e
For AEs/SAEs reported during screening, additional information such as medical history and concomitant medications may be needed.
f
Screening laboratory assessments must be obtained within 7 days prior to Day 1.
g
Pregnancy test may occur on Day 1, but results must be reviewed by the treating physician/investigator prior to dosing.
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
39 of 187
Table 1
Schedule of Activities – Screening Period and Intervention Period 
Procedure
Screening
Intervention period (1 cycle = 14 days)
For details 
see Section
C1
C2
C3
C4
C5
C6
C7+
C1
D1
C1
D8
C2
D1
C2
D8
C3
D1
C3
D8
C4
D1
C4
D8
C5
D1
C5
D8
C6
D1
C6
D8
C7
D1
C7
D8
Week
-4 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13+
14+
Day
-28 to -1
D1
D8
D15
D22
D29
D36
D43
D50
D57
D64
D71
D78
D85+
D92+
Window (days) a
NA
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
h
Results for urea and electrolytes, full blood count, and liver function tests must be available before commencing study intervention (samples must have been obtained 
within 3 days prior to initiating study intervention). 
During the intervention period, clinical chemistry and hematology assessments may be performed more frequently if clinically indicated.
i
If screening clinical chemistry and hematology assessments are performed within 3 days prior to Day 1, they do not need to be repeated on Day 1 if the participant’s 
condition has not changed. 
j
Coagulation parameters are to be assessed at baseline on Day 1 (unless all screening laboratory hematology assessments are performed within 3 days prior to Day 1), and 
then as clinically indicated.
k
If TSH is measured within 14 days prior to Day 1, it does not need to be repeated at Day 1. Free T4 or/and free T3 (per local standard clinical practice) will only be 
measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
l
No premedication is required prior to monalizumab administration. However, from Cycle 2, premedication with acetaminophen or an antihistamine might be prescribed, at 
the investigator’s discretion, if the participant experienced any Grade 1 to 3 infusion-related AE at the previous cycle.
m
Participants should be premedicated per US PI or local label (where available). Premedication may also be based on institutional guidance for management of infusion-
related reactions.
ADA = antidrug antibody; AE = adverse event; C = cycle; CT = computed tomography; 
 D = day; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; EORTC = European Organisation for Research and Treatment of Cancer; ePRO = electronic patient-reported outcome; 
 
HIV = human immunodeficiency virus; 
 
IHC = immunohistochemistry; IMP = investigational medicinal product; iv = intravenous; mos = months; MRI = magnetic resonance imaging; OPC = oropharyngeal cancer; 
PBMC = peripheral blood mononuclear cells; PD = progressive disease; PD-L1 = programmed cell death ligand-1; 
 
PK = pharmacokinetic; 
 
PS = performance status; Q4W = every 4 weeks; Q6W = every 6 weeks; Q8W = every 8 weeks; Q12W = every 12 weeks; QLQ-C30 = 30-item Core Quality of Life 
Questionnaire; QLQ-H&N35= Quality of Life Questionnaire Head and Neck Module; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; SAE = serious 
adverse event; 
; SPFQ = Study Participant Feedback Questionnaire; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-
stimulating hormone; US PI = United States Package Insert; W = week; WHO = World Health Organization; WOCBP = women of childbearing potential.
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
40 of 187
Table 2
Schedule of Activities – Follow-up Period for Participants Who Discontinued Study Intervention Due to 
Disease Progression or Other Reason
Procedure
End of 
treatment
Follow-up period
For details 
see Section
Month (post last dose IMP) 
1 
2
3
4
6
9
12+ 
Window
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
Clinical procedures
Full physical examination
X
8.2.1
WHO/ECOG PS a
X
X
X
8.1.4.8
Vital signs 
X
8.2.2
Weight
X
8.2.1
12-lead ECG (triplicate)
X
8.2.3
Concomitant medications
X
X
X
6.5
Subsequent anticancer therapy b
X
X
X
X
X
X
X 
then Q6M 
(± 2 weeks)
8.1.2
Safety measurements
Adverse events
X
X
X
8.3
Pregnancy test; serum or urine 
(WOCBP only)
X
X (as clinically indicated)
8.2.4
Clinical chemistry
X
X
X
Hematology
X
X
X
TSH (and reflex free T4 or/and free T3) c
X
X
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
41 of 187
Table 2
Schedule of Activities – Follow-up Period for Participants Who Discontinued Study Intervention Due to 
Disease Progression or Other Reason
Procedure
End of 
treatment
Follow-up period
For details 
see Section
Month (post last dose IMP) 
1 
2
3
4
6
9
12+ 
Window
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
Biomarker sampling
Tumor biopsy at time of progression 
(optional)
X
Pharmacokinetic measurements
Immunogenicity measurements
Efficacy measurements
Tumor imaging (RECIST 1.1)
Participants who discontinued study intervention due to reason other than disease progression or death (regardless 
of whether started subsequent anticancer therapy): intravenous contrast-enhanced CT or MRI of the neck, chest, 
and abdomen (includes entire liver) Q8W (± 1 week) for the first 48 weeks after randomization and then Q12W 
(±1 week) thereafter (relative to randomization), until RECIST 1.1-defined radiological disease progression; plus at 
least 1 additional follow-up scan..
8.1.1, 
Appendix G
Survival status: phone call for 
participants who refuse to return for 
evaluations and agree to be contacted d
X
X
X
X
X
X 
then
Q2M 
(± 2 weeks)
7.1.1.3
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
42 of 187
Table 2
Schedule of Activities – Follow-up Period for Participants Who Discontinued Study Intervention Due to 
Disease Progression or Other Reason
Procedure
End of 
treatment
Follow-up period
For details 
see Section
Month (post last dose IMP) 
1 
2
3
4
6
9
12+ 
Window
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
PRO (e-device) and health economic measurements
EORTC QLQ-C30
X
X
X
Every visit until RECIST 1.1-defined radiological disease 
progression (for participants who discontinued due to other 
reason) or start of subsequent anticancer therapy (whichever 
occurs first)
8.1.4.1
EORTC H&N35
X
X
X
8.1.4.2
Other assessment
SPFQ (optional)
X
8.9
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
43 of 187
Table 2
Schedule of Activities – Follow-up Period for Participants Who Discontinued Study Intervention Due to 
Disease Progression or Other Reason
Procedure
End of 
treatment
Follow-up period
For details 
see Section
Month (post last dose IMP) 
1 
2
3
4
6
9
12+ 
Window
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
a
WHO/ECOG PS should also be collected at other site visits, if appropriate site staff are available. In addition, WHO/ECOG performance status should be provided when 
subsequent anticancer therapy information is collected, where possible.
b
Details of any treatment for SCCHN (including surgery) post the last dose of study intervention must be recorded in the eCRF. At minimum, collect the start date and 
description of the subsequent anticancer therapy. 
c
Free T4 or/and free T3 (per local standard clinical practice) will only be measured if TSH is abnormal or if there is clinical suspicion of an adverse event related to the 
endocrine system.
d
Participants may be contacted in the week following data cutoffs to confirm survival status. Details of any treatment for SCCHN (including surgery) post the last dose of 
study intervention must be recorded in the eCRF.
ADA = antidrug antibody; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EORTC = European Organisation 
for Research and Treatment of Cancer;
iv = intravenous; MRI = magnetic resonance imaging;
 
 
 
PK = pharmacokinetic; 
 PS = performance status; Q2M = every 2 months; 
Q6M = every 6 months; QLQ-C30 = 30-item Core Quality of Life Questionnaire; QLQ-H&N35= Quality of Life Questionnaire Head and Neck Module; RECIST 
1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; SAE = serious adverse event; SCCHN = squamous cell carcinoma of the head and neck; SPFQ = Study 
Participant Feedback Questionnaire; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WHO = World Health Organization; wk = week; 
WOCBP = women of childbearing potential.
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
44 of 187
2
INTRODUCTION
Monalizumab is a first-in-class ICI targeting NKG2A. It is a non-depleting humanized IgG4 
mAb that binds with high affinity and specificity to, and blocks the inhibitory activity of the 
CD94/NKG2A receptor resulting in the stimulation of the cytolytic activity of CD94/NKG2A-
expressing NK cells and CD8+ T cells. Monalizumab is being developed for the treatment of 
various cancers, including solid tumors and hematologic malignancies either as monotherapy 
or in combination.
2.1
Study Rationale
The aim of the study is to assess the efficacy and safety of monalizumab and cetuximab, 
compared to placebo and cetuximab in participants with R/M SCCHN after receiving an ICI.
In addition to blocking the CD94/NKG2A receptor, monalizumab enhances human NK cell 
ADCC mediated by cetuximab. While monalizumab monotherapy has shown limited clinical 
activity, encouraging antitumor results have been observed following monalizumab and 
cetuximab combination therapy in patients with R/M SCCHN who have received prior 
platinum-based chemotherapy, including patients who have also received prior therapy with 
an ICI. This dual targeting could therefore provide greater antitumor activity than cetuximab 
alone. The combination of monalizumab and cetuximab could be a key option to improve 
clinical outcomes in patients with R/M SCCHN after receiving an ICI.
2.2
Background
Overall, outcomes in patients with R/M SCCHN remain poor and most patients will ultimately 
experience disease progression and eventually die of the disease. 
For 1L treatment of R/M SCCHN, the combination therapy of cetuximab plus platinum (either 
cisplatin or carboplatin) and 5-FU followed by cetuximab until progression or intolerance 
(EXTREME regimen) has been the standard of care in the European Union and the USA per 
the ESMO and NCCN guidelines, respectively (Gregoire et al 2010, NCCN 2021). In clinical 
practice, other single agents or doublet combinations, such as a taxane or cisplatin plus 
cetuximab, are also sometimes used as 1L treatment for R/M SCCHN when patients are not fit 
enough for the EXTREME regimen (Argiris et al 2017).
Squamous cell carcinoma of the head and neck tumors, like many other malignancies, create a 
highly immunosuppressive environment and are amenable to therapeutic intervention with 
immune-modulating agents (Curry et al 2014, Moy et al 2017). Recently, the PD-1 inhibitor 
pembrolizumab (KEYTRUDA®) received US FDA approval as: (i) a single agent for the
1L treatment of patients with metastatic or with unresectable, recurrent SCCHN whose tumors 
express PD-L1 (combined positive score ≥ 1, as determined by a US FDA-approved test) or 
(ii) in combination with platinum and 5-FU for the 1L treatment of patients with metastatic or 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
45 of 187
with unresectable, recurrent SCCHN (Keytruda  2021). The NCCN recommend 
pembrolizumab as a category 1 of evidence and consensus in the 1L R/M setting (NCCN 
2021).
Patients who progress or are intolerant to 1L therapy are typically treated with single-agent 
cetuximab, single-agent chemotherapy (eg, taxanes, methotrexate), or since recently with 
PD-1 inhibitors. Cetuximab was approved by the US FDA in 2006 and for a decade remained 
the only drug indicated for the treatment of patients with R/M SCCHN progressing after 
platinum-based therapy (Erbitux PI  2021). Cetuximab continues as one of the recommended 
treatment options in the NCCN guideline (NCCN 2021); the ESMO guideline notes that 
single-agent cetuximab has activity comparable to single-agent methotrexate with a favorable 
safety profile (Gregoire et al 2010). In 2016, the US FDA granted approval to pembrolizumab 
(under accelerated approval) and another PD-1 inhibitor nivolumab (OPDIVO®) in patients 
with R/M SCCHN with disease progression on or after platinum therapy (Keytruda  2021, 
Opdivo  2021).
Treatment for patients with R/M SCCHN who progress after receiving a PD-1 inhibitor, such 
as pembrolizumab/nivolumab monotherapy or pembrolizumab in combination with 
platinum-based chemotherapy, in the 1L or second-line setting is not clearly defined. A 
re-challenge with PD-(L)1 inhibitors is not currently recommended. As no treatment strategies 
in the immunotherapy-refractory disease setting are currently approved or uniformly adopted 
by the medical community, a suggested approach is to enroll a patient with R/M SCCHN into 
a clinical study assessing combination immunotherapy (Cohen et al 2019a). 
Human leukocyte antigen E, a nonclassical major histocompatibility complex class I 
molecule, is expressed on tumor cells in 78% to 86% of patients with SCCHN (Andre et al 
2018, Nasman et al 2013, Silva et al 2011). Human leukocyte antigen E is the ligand of the 
inhibitory CD94/NKG2A receptors that are found on NK cells and intratumoral CD8+ T cells 
in a variety of tumor types, including SCCHN (Braud et al 1998, Gooden et al 2011, Katou et 
al 2007, Lee et al 1998). The interaction of HLA-E with CD94/NKG2A receptor results in the 
inhibition of NK cell and cytotoxic T lymphocyte-dependent tumor lysis and may represent a 
significant immune-escape mechanism by tumor cells (Borrego et al 1998, Braud et al 1998, 
van Montfoort et al 2018). Monalizumab is a humanized mAb of the IgG4 subtype that 
specifically binds and blocks the function of CD94/NKG2A. 
Cetuximab is a chimeric monoclonal IgG1 antibody that is specifically directed against the 
EGFR. The EGFR is an important regulator of cell growth and differentiation. Upon ligand 
binding, EGFR homodimerizes or interacts with other HER members, ie, HER2 and HER3, to 
form heterodimers. This results in activation of downstream signaling cascades such as the 
RAS ERK pathway and PI3K/Akt pathway, thereby controlling many biological processes. 
These pathways play a pivotal role in multiple tumor types, including head and neck cancers, 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
46 of 187
and are frequently dysregulated via overexpression or autocrine stimulation. Targeting EGFR, 
eg, with an anti-EGFR mAb like cetuximab, is an important treatment modality for head and 
neck cancers. Several studies have suggested that ADCC activity is important for cetuximab 
clinical efficacy and is dependent on tumor cell surface EGFR expression (Kol et al 2017). 
It has been previously demonstrated in nonclinical studies that high expression of HLA-E and 
CD94/NKG2A on tumor cells and effector lymphocytes, respectively, impaired ADCC activity 
and reduced cetuximab clinical efficacy (Levy et al 2009). NKG2A blockade with 
monalizumab has been shown to increase cetuximab-dependent ADCC activity, which may 
translate into increased clinical benefit for the use of cetuximab. Additionally, nonclinical 
studies have shown increased cetuximab-dependent NK cell-mediated ADCC in SCCHN cell 
lines expressing HLA-E and EGFR when exposed to monalizumab (Andre et al 2018). As 
CD94/NKG2A inhibits the effector function of NK cells in the presence of HLA-E, it is 
expected that blocking of this inhibitory signaling pathway with monalizumab will increase 
cetuximab-dependent NK cell-mediated ADCC activity, which could subsequently lead to 
increased clinical benefit.
A detailed description of the chemistry, pharmacology, mechanism of action, efficacy, and 
safety of monalizumab and cetuximab is provided in the Monalizumab IB and cetuximab 
(ERBITUX®) current US PI or local label (where available).
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of
monalizumab and cetuximab may be found in the Monalizumab IB and current cetuximab
US PI or local label (where available).
2.3.1
Risk Assessment
Potential risks for monalizumab are related to hypersensitivity, including anaphylaxis, serious 
allergic reactions, and immune complex disease. Administration of any therapeutic 
immunoglobulin antibody/protein is associated with the potential to induce infusion-related 
and/or hypersensitivity reactions. Infusion-related reaction is an identified risk with 
monalizumab. Immune-mediated adverse events are considered important potential risks for
monalizumab. Activation of NK cells and subsets of T cells through blockade of inhibitory 
receptors may potentially lead to imAEs.
For cetuximab, skin reactions, hypomagnesemia, and infusion-related reactions are listed as 
very common (frequency of ≥ 10%) in the US PI or EU SmPC. Skin reaction is the most 
frequent side effect of cetuximab and may develop in more than 80% of patients.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
47 of 187
Current data suggest no change to the safety profile of either product when monalizumab is 
given in combination with cetuximab.
Monalizumab monotherapy
Study IND.221 (NCT0259301) is a completed Phase 1/2 externally-sponsored, open-label, 
dose-ranging, cohort-expansion, single-agent, multicenter study of monalizumab in adult 
participants with R/M gynecologic malignancies who had received prior platinum-based 
therapy. In the dose-ranging part, up to 18 participants (6/dose level) were to be randomized to 
receive monalizumab 1.0, 4.0, or 10 mg/kg iv Q2W. In the cohort-expansion part, up to 
40 participants were to receive monalizumab 10 mg/kg iv Q2W.
Study EORTC-1159 (NCT03088059/EudraCT 2017-000086-74) is an ongoing externally-
sponsored, biomarker-driven platform study in participants with R/M SCCHN who progressed 
after 1L platinum-based chemotherapy. In the closed immunotherapy cohort 1, participants 
were to receive monalizumab 10 mg/kg iv Q2W.
In Study IND.221, Grade 3 monalizumab-related AEs were reported for Study IND.221 in 
3/18 participants in the Phase 1b dose-ranging part: Grade 3 nausea, vomiting, dehydration 
(one participant each), and fatigue (2 participants); and in 2/40 participants in the 
cohort-expansion part: Grade 3 anorexia, nausea, dyspnea (one participant), and proctitis (one
participant). No treatment-related Grade 4 AEs were reported. In Study EORTC-1159, none of 
the participants in immunotherapy cohort 1 had a Grade 3 or 4 monalizumab-related AE. 
Monalizumab in combination with cetuximab
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
48 of 187
 
2.3.2 Benefit Assessment
While monalizumab monotherapy has shown limited clinical activity in participants with R/M 
SCCHN or gynecological malignancies (Tinker et al 2019a, 2019b), encouraging antitumor 
results have been observed following monalizumab and cetuximab combination therapy in 
participants with R/M SCCHN who have received prior platinum-based chemotherapy, 
including participants who have also received prior therapy with an ICI.  
The combination of monalizumab and cetuximab demonstrated preliminary efficacy in
participants with R/M SCCHN who had received prior platinum therapy (Cohen et al 2019c)
(Table 3). In Cohorts 1 and 2 of Study 203 (see Section 2.3.1), participants may have received 
up to 2 prior systemic therapies, including platinum-based chemotherapy. Additionally, 
subjects in Cohort 2 were to have received prior anti-PD-(L)1 therapy. As of the DCO date of 
30 April 2019, Cohort 1 completed enrollment of 40 participants with a median duration of 17 
months follow-up. Of these participants, 53% were considered resistant to platinum therapy
(ie, progressive disease on treatment or within 6 months after end of treatment), 53% had 
received more than one prior systemic regimen, and 43% had received prior PD-(L)1 inhibitor 
therapy (PD-[L]1 pretreated). The overall ORR per RECIST 1.1 was 27.5% 
(11/40 participants; 95% CI: 16%, 43%), with one CR. This represents an approximate
doubling of the ORR of cetuximab monotherapy reported as 13% in participants with R/M 
SCCHN participants who had progressed on 2 to 6 cycles of platinum therapy (Erbitux PI  
2021, Vermorken et al 2007). Median OS was 8.5 months. In PD-(L)1-pretreated participants, 
the ORR per RECIST 1.1 was 16.7% (3/18 participants with partial response [PR]; 95% CI: 
6%, 39%), with a median OS of 14.1 months. In participants who had not received prior 
therapy with a PD-(L)1 inhibitor (PD-[L]1 naive), the ORR was 36.4% (8/22 participants; 
95% CI: 20%, 57%), with one CR, and a median OS of 7.8 months. Preliminary data based on 
a recent data snapshot of 04 September 2019 from ongoing Cohort 2 in participants who had 
received prior platinum and prior PD-(L)1 therapy, showed an ORR of 24% (5/21 participants 
with PR; 95% CI: 11%, 45%). These results are consistent with the response rate seen in 
Cohort 1 PD-(L)1-pretreated participants.
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
49 of 187
Table 3
Preliminary Efficacy, Cohort 1 - Expansion Phase (Monalizumab + 
Cetuximab), All Subjects Treated (Study IPH2201-203)
Parameter
Total
(N = 40)
PD-(L)1 pre-treated
(N = 18)
PD-(L)1 naive
(N = 22)
ORR, % (95% CI)
27.5 (16, 43)
16.7 (6, 39)
36.4 (20, 57)
Complete response
1 (2.5)
0
1 (4.5)
Partial response
10 (25.0)
3 (16.7)
7 (31.8)
Median PFS
4.5 (3.5, 5.8)
5.1 (3.5, 8.8)
3.9 (3.5, 6.9)
Median OS
8.5 (7.5, 16.4)
14.1 (8.0, NR)
7.8 (6.9, 15.8)
Participants received monalizumab 10 mg/kg iv Q2W + cetuximab at the approved dosage of 400 mg/m2 iv
initial dose followed by subsequent weekly doses of 250 mg/m2 iv.
CI = confidence interval; NR = not reached; ORR = objective response rate; OS = overall survival; PD-(L)1 = 
programmed cell death-1 or programmed cell death ligand-1; PFS = progression-free survival; Q2W = every 2 
weeks; iv = intravenous.
Based on a data snapshot date of 30 April 2019.
With regards to cetuximab, single-agent cetuximab is active in the treatment of participants 
with R/M SCCHN who progressed on platinum therapy with an ORR of approximately 13% 
(Vermorken et al 2007), and is listed as a recommended treatment option for SCCHN patients 
in the R/M setting in the latest NCCN and ESMO guidelines (Gregoire et al 2010, NCCN 
2021) and SITC recommendations (Cohen et al 2019a). In the USA, the use of single-agent 
cetuximab is approved for R/M SCCHN progressing after platinum-based therapy (Erbitux PI  
2021).
2.3.3 Overall Benefit: Risk Conclusion
Taking into account the measures to minimize risk to participants in this study, the potential 
risks identified in association with monalizumab and cetuximab are justified by the anticipated 
benefits to participants with R/M SCCHN who have been previously treated with platinum-
based chemotherapy and an ICI.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
50 of 187
3
OBJECTIVES AND ENDPOINTS
Table 4
Objectives and Endpoints
Objective
Estimand a Description/Endpoint
Primary
To compare the effect of monalizumab and cetuximab 
(Arm A) relative to placebo and cetuximab (Arm B)
by assessment of OS in HPV-unrelated participants
•
Population: The HPV-unrelated Analysis Set 
which will include all randomized participants 
who are either OPC HPV negative or
non-OPC regardless of HPV status
•
Endpoint: OS, which is defined as time from 
randomization until the date of death due to 
any cause
•
Intercurrent events: If a participant is lost to 
follow-up or withdraws consent, OS will be 
censored based on the last recorded date on 
which the participant was known to be alive
•
Summary measure: p-value of treatment 
comparison using a stratified log rank test and 
hazard ratio of Arm A relative to Arm B with 
its confidence interval using a stratified Cox 
Proportional Hazards model
Secondary
To compare the effect of monalizumab and cetuximab 
(Arm A) relative to placebo and cetuximab (Arm B) 
by assessment of OS in all randomized participants
•
Population: The FAS which will include all 
randomized participants 
•
Endpoint: OS, which is defined as time from 
randomization until the date of death due to 
any cause
•
Intercurrent events: If a participant is lost to 
follow-up or withdraws consent, OS will be 
censored based on the last recorded date on 
which the participant was known to be alive
•
Summary measure: p-value of treatment 
comparison using a stratified log rank test and 
hazard ratio of Arm A relative to Arm B with 
its confidence interval using a stratified Cox 
Proportional Hazards model
To compare the effect of monalizumab and cetuximab 
(Arm A) relative to placebo and cetuximab (Arm B) 
by assessment of PFS, ORR, and DoR in participants 
who are HPV-unrelated and in all randomized
participants
•
PFS is defined as time from randomization 
until disease progression, per RECIST 1.1 as 
assessed by the investigator at local site or 
death due to any cause, whichever occurs first.
•
ORR is defined as the proportion of 
participants with measurable disease who have 
a confirmed CR or PR, as determined by the 
investigator at local site per RECIST 1.1.
•
DoR is defined as the time from the date of 
first documented response until date of 
documented disease progression or death in 
the absence of disease progression.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
51 of 187
Table 4
Objectives and Endpoints
Objective
Estimand a Description/Endpoint
To assess disease-related symptoms, functioning, and 
HRQoL in participants treated with monalizumab and 
cetuximab (Arm A) compared to placebo and 
cetuximab (Arm B) using the EORTC QLQ-C30 and 
the EORTC QLQ-H&N35 questionnaires in 
participants who are HPV-unrelated and in all
randomized participants
Symptoms, functioning, and global health 
status/QoL scale/item scores of the EORTC QLQ-
C30 & EORTC QLQ-H&N35
•
Change from baseline scores across visits
•
Time to clinically meaningful deterioration in 
scores
To assess the PK of monalizumab 
Concentration of monalizumab in blood and PK 
parameters (such as Cmax, Ctrough, as data allow; 
sparse sampling)
To investigate the immunogenicity of monalizumab 
Presence of ADAs for monalizumab (confirmatory 
results: positive or negative, titers)
To characterize the association between clinical 
outcome and protein expression in the tumor 
microenvironment in participants treated with 
monalizumab and cetuximab (Arm A) or placebo and 
cetuximab (Arm B) in participants who are 
HPV-unrelated and in all randomized participants
HLA-E and NKp46+ expression in pre-treatment 
and post-treatment tumor biopsies
Secondary safety
To assess the safety and tolerability of monalizumab 
and cetuximab (Arm A) compared to placebo and
cetuximab (Arm B) in participants with R/M SCCHN 
previously treated with ICI
AEs, vital signs, clinical laboratory results, ECGs
Exploratory
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
52 of 187
Table 4
Objectives and Endpoints
Objective
Estimand a Description/Endpoint
a
Estimand is the target of estimation to address the scientific question of interest posed by the primary 
objective. Attributes of an estimand include the population of interest, the variable (or endpoint) of 
interest, the specification of how intercurrent events are reflected in the scientific question of interest, 
and the population-level summary for the variable.
ADA = antidrug antibodies; AE = adverse event; Cmax = maximum serum concentration; CR = complete 
response; 
 Ctrough = trough serum concentration; DoR = duration of 
response; ECG = electrocardiogram; EORTC = European Organisation for Research and Treatment of 
Cancer; 
 FAS = full analysis set; HLA-E = human 
leukocyte antigen E; 
 HRQoL = health-
related quality of life; ICI = immune checkpoint inhibitor; NK = natural killer; OPC = oropharyngeal cancer; 
ORR = objective response rate; OS = overall survival; PFS = progression-free survival; 
 
 
 
 
 
PK = pharmacokinetic(s); PR = partial response; 
 
 QLQ-C30 = 30-item Core Quality of Life Questionnaire;
QLQ-H&N35 = Quality of Life Questionnaire Head and Neck Module; RECIST 1.1 = Response Evaluation 
Criteria for Solid Tumors version 1.1; R/M = recurrent or metastatic; SCCHN = squamous cell carcinoma of 
the head and neck; 
.
4
STUDY DESIGN
4.1
Overall Design
Study D7310C00001 is a Phase 3, randomized, double-blind, multicenter, global study 
assessing efficacy and safety of monalizumab and cetuximab compared to placebo and 
cetuximab in participants with R/M SCCHN previously treated with platinum-based 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
53 of 187
chemotherapy and an ICI, regardless of the sequence of these therapies. 
Approximately 624 eligible participants will be randomized in a 2:1 ratio to one of the 
following treatment arms. 
!
Arm A (n = 416): monalizumab and cetuximab
Monalizumab 
 and cetuximab 400 mg/m2 iv initial dose followed by
250 mg/m2 iv Q1W, as per label
!
Arm B (n = 208): placebo and cetuximab
Placebo iv Q2W and cetuximab 400 mg/m2 iv initial dose followed by 250 mg/m2 iv
Q1W, as per label
Participants will be stratified by the following (see Section 6.3.1 for more detail):
!
Human papillomavirus status (OPC HPV positive or HPV-unrelated),
∀
The number of OPC HPV-positive participants will be closely monitored throughout
the study and is planned to be capped at approximately 20% of the total sample size.
!
World Health Organization/ECOG PS (0 or 1), and
!
Number of prior lines of therapy in the R/M setting (1 or 2)
∀
The number of participants in each stratum (1 or 2 prior lines of therapy in the R/M
setting) will be closely monitored throughout the study. If a disproportionate number
of participants are enrolled in a single stratum (eg, > 75% of the total sample size),
the Sponsor may elect to close further recruitment into that stratum.
Participants will be treated until RECIS71.1-defined radiological disease progression per 
investigator, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion 
is met. Crossover between treatment arms will not be permitted. 
An IDMC will review safety data regularly and make recommendations regarding further 
study conduct(see Appendix A5). For both IAs, the IDMC will review unblinded interim data 
and inform the Sponsor whether the interim boundaries specified in Section 9.5are met.
After discontinuation of study intervention, all participants will have a 3-month safety 
follow-up (see Section 7.1.1).Participants who have discontinued study intervention in the 
absence of RECIST 1.1-defined radiological disease progression per investigator will continue 
with scheduled tumor assessments until RECIST1.1-defined disease progression or death. 
Additionally, all participants will be followed for survival status, subsequent anticancer 
therapy, and 
, withdrawal of consent, or the end of the study. 
An overview of the study design is presented inFigure 1.Details on the efficacy and safety 
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
54 of 187
endpoints are provided in Section 3.
Section 6.7 presents treatment options after the final DCO and database closure.
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis 
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster, or public health crisis (eg, 
during quarantines and resulting site closures, regional travel restrictions, and considerations if 
site personnel or study participants become infected with SARS-CoV-2 or similar pandemic 
infection) which would prevent the conduct of study-related activities at study sites, thereby 
compromising the study site staff or the participant’s ability to conduct the study. The 
investigator or designee should contact the study Sponsor to discuss whether the mitigation 
plans below should be implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain 
compliance with GCP, and minimize risks to study integrity.
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies) or local government, these changes may include the following options: 
!
Obtaining consent/re-consent for the mitigation procedures (note, in the case of verbal 
consent/re-consent, the ICF should be signed at the participant’s next contact with the 
study site).
!
Rescreening: additional rescreening for screen failure and to confirm eligibility to 
participate in the clinical study can be performed in previously screened participants. The 
investigator should confirm this with the designated Study Clinical Lead. 
!
Telemedicine or Remote visit (where applicable): remote contact with the participants
using telecommunications technology including phone calls and virtual or video visits. 
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix C.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Study Design and Participant Population
The primary aim of this study is to assess the efficacy of monalizumab and cetuximab 
compared to cetuximab and placebo in terms of OS. It is a double-blind, randomized study 
; unblinded Pharmacists and 
unblinded Study Monitors will be used in order to maintain the blind. 
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
55 of 187
Preliminary data show that the combination monalizumab and cetuximab is well tolerated 
(Cohen et al 2017, Cohen et al 2018a, Cohen et al 2018b) and has promising activity. As the 
estimated percentage of patients with cancer eligible for ICI (including but not limited to 
anti-PD-(L)1 antibodies) in the course of their disease is increasing, it is crucial to confirm the 
activity seen with monalizumab administered in combination with cetuximab in population of 
patients who have previously received ICI. 
Participants enrolled in this study will have R/M SCCHN arising in the oropharynx regardless 
of HPV status, hypopharynx, larynx (supraglottis, glottis, and subglottis) or oral cavity; must 
have progressed on or after previous systemic cancer therapy (up 2 prior systemic regimens in 
the R/M setting); are not amenable to further therapy having curative intent; and must have 
received prior treatment with platinum-based chemotherapy and a systemic PD-(L)1 inhibitor
in any setting, regardless of the sequence of these therapies (see inclusion criteria in 
Section 5.1).
Since HPV-positive OPC represents a biologically distinct disease (Taberna et al 2017), the 
study design proposed is considered the best approach to evaluate the contribution of 
monalizumab to cetuximab because the combination therapy will be compared directly to 
single-agent cetuximab in HPV-unrelated participants. Cetuximab is a valid treatment option 
for the study population per the revised NCCN and current ESMO guidelines (Gregoire et al 
2010, NCCN 2021) and SITC recommendations (Cohen et al 2019a). 
4.2.2
Rationale of Study Endpoints
Rationale for primary endpoint and other efficacy endpoints
The primary endpoint of the proposed study will be OS, defined as the time from the date of 
randomization until death due to any cause. Overall survival is considered the most reliable 
cancer endpoint supported by the US FDA and EMA guidelines (EMA 2017, FDA 2018a).
Rationale for other efficacy endpoints
The secondary efficacy endpoints will include PFS, ORR, DoR, and PRO measures. All 
tumor-related endpoints will be assessed by the investigator according to RECIST 1.1.
Target engagement of monalizumab will be assessed through HLA-E and NKp46+ expression 
in the TME and association with the participant’s radiologic response.
In addition to assessing OS and other clinical endpoints in oncology studies, it is important to 
assess the impact of the disease and its treatment on cancer symptoms, functioning, and 
HRQoL of the patient, to aid understanding of how clinical benefit relates to patient 
wellbeing, and for consideration in making risk-benefit evaluations. Moreover, PROs assist in 
the documentation of symptoms and specifically what symptoms and impacts are most 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
56 of 187
important to patients and how these relate to clinical outcomes. In this study, general cancer 
symptoms, functioning and HRQoL will be assessed with the EORTC QLQ-C30 while 
SCCHN-specific symptoms will be evaluated using the EORTC QLQ-H&N35. 
 
 The rationale for selecting the EORTC QLQ-C30 and 
QLQ-H&N35 and other PRO instruments is primarily because they have good coverage of the 
symptoms and impacts most important to SCCHN patients (Degboe et al 2018). These PRO 
questionnaires are also well established in oncology clinical studies for directly assessing 
patients’ experience of cancer as well as the treatment impact.
4.3
Justification for Dose
4.3.1
Rationale for Monalizumab Dose
Existing PK and pharmacodynamic data, modeling and simulation, and clinical data have been 
utilized to guide the regimen selection for the combination of monalizumab 
 plus 
cetuximab at 400 mg/m2 initial dose followed by 250 mg/m2 Q1W. See the Monalizumab IB 
for more detail on monalizumab PK, pharmacodynamics, immunogenicity, and clinical 
activity.
Available PK/pharmacodynamic data were analyzed from ongoing Phase 1/2 
Study D419NC00001 for monalizumab doses ranging from 
 to 
 or 
 
in combination with durvalumab 1500 mg Q4W. An approximate dose-proportional increase 
in PK exposure (Cmax and area under the serum drug concentration-time curve from time 0 to 
Day 28 post-dose) was observed with increasing doses of monalizumab (
 and 
). Full suppression of the target on NK cell in the periphery was observed over the 
dose range studied, consistent with engagement of monalizumab with NKG2a.
Pharmacokinetic data from the dose-escalation cohort in ongoing Phase 1b/2 Study 
IPH2201-203 (Study 203) of monalizumab 
to 
 in combination with 
cetuximab 400 mg/m2 initial dose followed by 250 mg/m2 Q1W showed an approximate 
dose-proportional increase in monalizumab Cmax over the dose range for the first dosing cycle. 
These data were consistent with the predicted monotherapy PK data (5th, 50th, and 95th 
percentiles) for a Q2W regimen.  
Antidrug antibody analyses of serum samples from treated participants in 
Study D419NC00001 and Study 203, showed a low ADA signal, close to the screening cut 
point, for all ADA-positive samples, suggesting either false positive result or low ADA 
concentration. PK profiles for participants with ADA-positive samples were not modified, 
indicating that ADA did not impact monalizumab exposure. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CC
I
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
57 of 187
Clinical data
A tolerable safety profile was observed for participants in Study 203 Cohorts 1 and 2 treated 
with monalizumab 
 or 
 respectively, plus cetuximab 400 mg/m2
initial dose followed by 250 mg/m2 Q1W. Promising clinical activity was observed in 
Cohort 1, with consistent preliminary results from ongoing Cohort 2. 
Based on these data, the combination of monalizumab 
plus cetuximab 
400 mg/m2 initial dose followed by 250 mg/m2 Q1W was selected for further development.
This dose is expected to achieve complete target saturation in the majority of participants and 
account for anticipated variability in PK, pharmacodynamics, and clinical activity in SCCHN 
populations.
Rationale for fixed-dose of monalizumab
Current ongoing studies with the combination of monalizumab and cetuximab administer 
monalizumab using either weight-based dosing (ie, monalizumab 
; Study 203 
Cohort 1) or 
dosing (ie, monalizumab
 Study 203 Cohort 2 and 
Study D419NC00001). 
Comparison of the observed monalizumab exposure between 
 and 
 showed 
similar preliminary PK exposure (Cmax and Ctrough) after the first monalizumab dose for the 
 dosage (monalizumab in combination with cetuximab, Study 203 Cohort 1) 
and the 
 dosage (monalizumab in combination with durvalumab, Study 
D419NC00001). The observed PK of monalizumab when administered in combination with 
cetuximab is within the range of monalizumab monotherapy PK.
A population PK model was developed for monalizumab using PK data from Study 203 and 
Study D419NC00001 in participants with solid tumors, including SCCHN, microsatellite-
stable colorectal cancer, ovarian cancer, endometrial cancer, non-small cell lung cancer, 
cervical cancer, or pancreatic cancer. At the time of analysis, a total of 95 evaluable 
participants treated with monalizumab 
 or 
 in combination with 
cetuximab (N = 30; Study 203) or monalizumab 
, or 
 or 
 
 in combination with durvalumab (N = 65; Study D419NC00001) were used for 
building the preliminary population PK model. To determine the impact of body weight-based 
(
) or 
 dosing (
) on monalizumab PK exposure, simulations 
were conducted (N = 500 participants/cohort with a body-weight distribution of 40 to 120 kg) 
and predicted steady state concentrations were compared. A 
 dose of 
 was selected 
to approximate 
 based on the median body weight of 75 kg. Simulation results 
demonstrated that body weight-based and 
-dosing regimens yield similar steady-state PK 
concentrations with similar overall between-participant variability. The predicted similarity of 
exposure following either of the dosing regimen is consistent with literature showing that an 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CC
I
CCI
CC
I
CCI
CCI
CC
I
CCI
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
58 of 187
exponent of the covariate model for body weight of approximately 0.5 is expected to yield 
similar median PK profiles without following either 
 or body weight-based dosing (Wang 
et al 2009). Therefore, based on an average body weight of 75 kg, a 
 dose of 
 
monalizumab is equivalent to 
 respectively.
The proposed Phase 3 study of monalizumab in combination with cetuximab, will use the 
 
dose of monalizumab 
 This dosing regimen is aligned with the standard flat 
dosing of monalizumab 
 being investigated in the multiple ongoing 
monalizumab clinical studies (see Monalizumab IB).
4.3.2
Rationale for Cetuximab Dose
The dose regimen for cetuximab in this study (400 mg/m2 initial dose followed by 250 mg/m2
Q1W starting on Day 8) is per the cetuximab US PI (Erbitux PI  2021). 
4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last scheduled procedure shown in the SoA (Section 1.3). Participants 
will be followed for survival status until death, withdrawal of consent, or the end of the study.
The end of the study is defined as the date of the last visit of the last participant in the study 
globally.
The study may be stopped if, in the judgment of the Sponsor, participants are placed at undue 
risk because of clinically significant findings.
See Section 6.7 for details on participant management following the final DCO as well as 
following study completion. 
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1
Participant must be ≥ 18 years of age at the time of signing the informed consent.
CC
I
CC
I
CCI
CCI
CC
I
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
59 of 187
Type of Participant and Disease Characteristics
2
Histologically or cytologically confirmed R/M SCCHN of the oral cavity, oropharynx, 
hypopharynx, or larynx who have progressed on or after previous systemic cancer therapy 
and are not amenable to curative therapy
3
Must have received prior treatment with a systemic PD-(L)1 inhibitor (in any setting)
4
Prior platinum failure as defined by either:

Disease progression during or after treatment with a platinum-containing regimen for
R/M disease or

Recurrence/progression within 6 months of the last dose of platinum as part of
multimodal therapy for LA disease
5
Received 1 or 2 prior systemic regimens for R/M SCCHN (see Section 6.3.1 for 
additional detail on prior lines of therapy)
6
At least one lesion that qualifies as a RECIST 1.1 TL at baseline (see Appendix G).
Tumor assessment by CT scan or MRI must be performed within 28 days prior to 
randomization.
7
Provide fresh or recently acquired tumor tissue (≤ 3 months prior to screening) for the 
purpose of biomarker testing. Tumor tissue collected when previous treatments were still 
ongoing is not acceptable.

Tumor tissue beyond the 3-month window and up to 6 months old may be considered 
with Sponsor consultation provided that no intervening systemic regimen was 
ongoing at the time of sample collection (see Laboratory Manual for more 
information).
8
For participants with OPC only: known HPV status prior to randomization (see 
Section 6.3.1)
9
WHO/ECOG PS of 0 or 1 at enrollment
10 Adequate organ function, defined as:
(a) Hemoglobin ≥ 9.0 g/dL
(b) Absolute neutrophil count ≥ 1500/mm3
(c) Platelets ≥ 75,000/mm3
(d) Total bilirubin ≤ 1.5 × institutional ULN. This will not apply to participants with 
confirmed Gilbert’s syndrome, who will be allowed in consultation with their 
physician.
(e) Aspartate aminotransferase and ALT ≤ 2.5 × institutional ULN; for participants with 
hepatic metastases, ALT and AST ≤ 5 × ULN
(f) Measured CrCL ≥30 mL/min or calculated CrCL ≥30 mL/min as determined by 
Cockcroft-Gault (using actual body weight)

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
60 of 187
o
Males:
CrCL(mL/min) = Weight (kg) × (140 - age)
72 × serum creatinine (mg/dL)
o
Females:
CrCL (mL/min) = Weight (kg) × (140 - age) × 0.85
72 × serum creatinine (mg/dL)
11 Minimum life expectancy of 12 weeks
Weight
12 Body weight > 30 kg
Sex
13 Male and/or female
Reproduction
14 Negative pregnancy test (“highly effective” urine or serum test) for female participants of 
childbearing potential.
15 Female participants must be one year post-menopausal, surgically sterile, or using an 
acceptable method of contraception (see Appendix H) for the duration of the study (from 
the time they sign consent) and for 4 months after the last dose of study intervention to 
prevent pregnancy. 
16 Male participants must be surgically sterile or using an acceptable method of 
contraception (see Appendix H) for the duration of the study (from the time they sign 
consent) and for 4 months after the last dose of study intervention to prevent pregnancy in 
a female partner. Male participants must not donate or bank sperm during the same time 
period.
Informed Consent
17 Capable of giving signed informed consent as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol
18 Provision of signed and dated, written ICF prior to any mandatory study specific 
procedures, sampling, and analyses 
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
61 of 187
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
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 
participants with squamous cell carcinoma of unknown primary or non-squamous 
histologies (eg, nasopharynx or salivary gland)
2
Prior cetuximab therapy (unless it was administered in curative LA setting with 
radiotherapy and no disease progression for at least 6 months following the last cetuximab 
dose)
3
Any unresolved toxicity NCI CTCAE ≥ Grade 2 from previous anticancer therapy with 
the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion 
criteria. 
∀
Participants with irreversible toxicity not reasonably expected to be exacerbated by 
treatment with monalizumab and cetuximab may be included only after consultation 
with the Study Clinical Lead.
4
Has carcinomatous meningitis and/or untreated central nervous system metastases 
identified either on the baseline brain imaging (see Appendix G) obtained during the 
screening period or identified prior to signing the ICF. Participants with a history of brain 
metastases or with suspected brain metastases at screening must have an MRI (preferred) 
or CT each preferably with iv contrast of the brain prior to study entry. Participants whose 
brain metastases have been treated may participate provided they show radiographic 
stability (defined as 2 brain images, both of which are obtained after treatment to the 
brain metastases. These imaging scans should both be obtained at least 4 weeks apart and 
show no evidence of intracranial progression). In addition, any neurologic symptoms that 
developed either as a result of the brain metastases or their treatment must have resolved 
or be stable either, without the use of steroids, or are stable on a steroid dose of 
≤10 mg/day of prednisone or its equivalent and anticonvulsants for at least 14 days prior 
to the start of treatment. Brain metastases will not be recorded as RECIST 1.1 TL at 
baseline.
5
Major surgical procedure (as defined by the investigator) within 28 days prior to the first 
dose of study intervention. Note: Local surgery of isolated lesions for palliative intent is 
acceptable.
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
62 of 187
6
History of allogeneic organ transplantation
7
History of allergic reactions or hypersensitivity attributed to compounds of similar 
chemical or biologic composition to cetuximab and monalizumab or any of their 
excipients
8
History of active primary immunodeficiency
9
Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or 
Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid 
arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:

Participants with vitiligo or alopecia

Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement 

Any chronic skin condition that does not require systemic therapy

Participants without active disease in the last 5 years may be included but only after 
consultation with the Study Clinical Lead

Participants with celiac disease controlled by diet alone
10 Active infection including tuberculosis (clinical evaluation that includes clinical history, 
physical examination and radiographic findings, and tuberculosis testing in line with local 
practice), hepatitis B (known positive HBV surface antigen [HBsAg] result), hepatitis C
(HCV), or human immunodeficiency virus (positive HIV 1/2 antibodies). Participants
with a past or resolved HBV infection (defined as the presence of hepatitis B core 
antibody [anti-HBc] and absence of HBsAg) are eligible. Participants positive for HCV 
antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
11 Uncontrolled intercurrent illness, including but not limited to: ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina 
pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease, serious chronic 
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations 
that would limit compliance with study requirement, substantially increase risk of 
incurring AEs or compromise the ability of the participant to give written informed 
consent
12 History of another primary malignancy except for:

Malignancy treated with curative intent and with no known active disease ≥ 5 years 
before the first dose of study treatment and of low potential risk for recurrence

Adequately treated non-melanoma skin cancer or lentigo maligna without evidence 
of disease

Adequately treated carcinoma in situ without evidence of disease

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
63 of 187

Participants with a history of prostate cancer (tumor/node/metastasis stage) of 
Stage ≤T2cN0M0 without biochemical recurrence or progression and who in the 
opinion of the investigator are not deemed to require active intervention
13 Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥500 ms 
calculated from 3 ECGs (see Section 8.2.3)
Prior/Concomitant Therapy
14 Any concurrent anticancer treatment. Concurrent use of hormonal therapy for 
non-cancer-related conditions (eg, hormone replacement therapy) is allowed.
15 Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine 
therapy, targeted therapy, biologic therapy, tumor embolization, mAbs, or investigational 
agents) or radiotherapy with curative intent (to more than 30% of the bone marrow or 
with a wide field of radiation) ≤28 days prior to the first dose of study intervention. If 
sufficient wash-out time has not occurred due to the schedule or PK properties of an 
anticancer agent, a longer wash-out period will be required, as agreed by the Sponsor and 
the investigator.
16 Current or prior use of immunosuppressive medication within 14 days before the first 
dose of study intervention. The following are exceptions to this criterion (see also 
Table 6):

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

Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)
17 Receipt of live attenuated vaccine within 30 days prior to the first dose of study 
intervention.
Note: Participants, if enrolled, should not receive live vaccine whilst receiving study 
intervention and up to 30 days after the last dose of study intervention.
Prior/Concurrent Clinical Study Experience
18 Participation in another clinical study with an investigational product administered in the 
last 28 days prior to randomization or concurrent enrollment in another clinical study, 
unless it is an observational (non-interventional) clinical study or during the follow-up 
period of an interventional study
19 Prior treatment with monalizumab 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
64 of 187
Other Exclusions
20 Involvement in the planning and/or conduct of the study (applies to both Sponsor staff 
and/or staff at the study site).
21 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions and requirements.
22 Previous study intervention assignment in the present study. 
23 For women only - currently pregnant (confirmed with positive pregnancy test) or breast-
feeding.
24 Genetics research study (optional): 
Exclusion criteria for participation in the optional (DNA) genetics research component of 
the study include:

Previous allogeneic bone marrow transplant

Transfusion of non-leukocyte-depleted blood or blood components within 120 days 
of genetic sample collection
5.3
Lifestyle Considerations
The following restrictions apply while the participant is receiving study intervention and for 
the specified times before and after:
1
Participants must follow the contraception requirements outlined in Appendix H.
2
Participants should not donate blood or blood components while participating in this 
study and through 4 months after the last dose of study intervention. 
3
Women must not breastfeed during the study, and for 4 months after the last dose of study 
intervention. 
Restrictions relating to concomitant medications are described in Section 6.5.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
do not fulfill the eligibility criteria, and therefore must not be randomized. These participants
should have the reason for study withdrawal recorded as “eligibility criteria not fulfilled” 
(ie, participant does not meet the required inclusion/exclusion criteria). This reason for study 
withdrawal is only valid for screen failures (ie, not randomized participants). 
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants to meet the Consolidated Standards of Reporting Trials publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAE. If a pre-screened 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
65 of 187
tissue and/or whole blood/serum/plasma sample has already been procured prior to screen 
failure, a biomarker evaluation will be conducted if feasible (consistent with the ICF).
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened a single time, but they may not be re-randomized. Rescreened participants should 
be assigned the same E-code as for the initial screening. Participants will reconfirm their 
consent to participate in the study by re-signing and dating their original ICF(s), next to their 
original signature and date, or according to local or site-specific procedures. All assessments 
must be repeated for rescreening unless they are within 28 days of randomization.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
6.1
Study Interventions Administered
6.1.1
Investigational Medicinal Products
Table 5
Investigational Medicinal Products
Intervention 
name
Monalizumab
Cetuximab
Placebo
Type 
Biologic
Biologic
Drug
Dose 
formulation
As sourced by 
AstraZeneca, cetuximab 
will be supplied as a 
liquid solution containing 
5 mg/mL cetuximab, 
sodium chloride, glycine, 
polysorbate 80, citric acid 
monohydrate, sodium 
hydroxide, and WFI.
If cetuximab is sourced 
locally it will be as the 
approved commercial 
product.
Unit dose 
strength(s)
500 mg (nominal) 
cetuximab per vial as 
sourced by AstraZeneca.
Cetuximab will be locally 
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
66 of 187
Table 5
Investigational Medicinal Products
Intervention 
name
Monalizumab
Cetuximab
Placebo
sourced as the approved 
commercial product.
Dosage level(s)
Initial dose: 400 mg/m2
Subsequent doses: 
250 mg/m2 Q1W 
Route of 
administration
iv infusion
Use
Experimental
Experimental/Active 
comparator
Placebo
IMP and NIMP
IMP
IMP
IMP
Sourcing
AstraZeneca
AstraZeneca source 
centrally or locally 
sourced where feasible
Sourced locally by 
site
Packaging and 
labelling
Each vial will be labelled 
in accordance with GMP 
Annex 13 and per country 
regulatory requirement.
Current/Forme
r name(s) or 
alias(es)
IPH2201
Erbitux®
Not applicable
 IMP = investigational medicinal product; NIMP 
= non-investigational medicinal product; 
 
.
6.1.2
Dosing Instructions
A physician must be present at the site or immediately available to respond to emergencies 
during all administrations of IMP. Fully functional resuscitation facilities should be available. 
As with any mAb, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis. See Section 6.6 and Section 8.3.15 for dose modification and management of 
IMP-related toxicities, respectively.
Section 6.2.1 describes dose preparation and administration. 
Permissible medications prior to administration of monalizumab or cetuximab are described in 
Section 6.5.1. No premedication is required prior to monalizumab administration, unless a 
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
67 of 187
participant has experienced an infusion-related AE in the previous cycle. For cetuximab, 
participants should be premedicated per US PI (antihistamine iv 30 to 60 minutes prior to the 
first infusion or subsequent infusions of cetuximab as deemed necessary) or local label (where 
available). Premedication may also be based on institutional guidance for management of 
infusion-related reactions.
Dosing regimen
The dosing regimen for Arm A and Arm B is presented in Figure 2 (see also SoA Table 1).
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
68 of 187
6.1.3
Duration of Treatment 
All study intervention will be administered beginning on Day 1. Participants in Arm A or 
Arm B will remain on study intervention until RECIST 1.1-defined radiological disease 
progression (refer to Appendix G) unless there is unacceptable toxicity, withdrawal of consent, 
or another discontinuation criterion is met. See Section 7.1 for information on discontinuation 
of study intervention for individual participants.
A follow-up scan is to be collected after the initial RECIST 1.1-defined disease progression, 
preferably at the next (and no later than the next) scheduled imaging visit, and no less than 
4 weeks after the prior assessment of disease progression (Eisenhauer et al 2009). This 
follow-up scan is evaluated using the Confirmation of Radiological Progression criteria 
outlined in Appendix G.
6.2
Preparation/Handling/Storage/Accountability of Interventions
1
The investigator or designee (eg, unblinded pharmacist) must confirm appropriate 
temperature conditions have been maintained during transit for all study intervention 
received and any discrepancies are to be reported and resolved before use of the study 
intervention.
2
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access limited to 
the investigator and authorized site staff.
3
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4
Further guidance and information for the final disposition of unused study interventions 
will be provided to the sites.
All IMPs should be stored in a secure and dry place. Vials of IMP for parenteral 
administration should be stored at 2 °C to 8 °C (36 °F to 46 °F; refrigerated) and must not be 
frozen. IMP must be kept in original packaging until use to prevent prolonged light exposure.
Placebo will be locally sourced by the study site and cetuximab will either be locally sourced 
by the study site or centrally supplied by the Sponsor. When centrally supplied, cetuximab 
will be labeled with local language translated text in accordance with regulatory guidelines.
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
69 of 187
6.2.1
Dose Preparation and Administration
6.2.1.1
Monalizumab
The dose of monalizumab for administration must be prepared by the investigator’s or site’s 
designated IMP manager using aseptic technique. 
 
Do not co-administer other drugs through the same infusion line.
The iv line will be flushed according to local practices to ensure the full dose is administered. 
Infusion time does not include the final flush time.
If either preparation time or infusion time exceeds the time limits, a new dose must be 
prepared from new vials. Monalizumab does not contain preservatives, and any unused 
portion must be discarded. 
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
70 of 187
6.2.1.2
Cetuximab
The dose of cetuximab for administration must be prepared by the investigator’s or site’s 
designated IMP manager using aseptic technique. See the Pharmacy Manual for guidance on 
cetuximab storage conditions, dose preparation, and dose administration. See Section 6.1.2 for 
the cetuximab dosing regimen.
6.2.1.3
Placebo
Do not co-administer other drugs through the same infusion line.
The iv line will be flushed according to local practices to ensure the full dose is administered.  
Infusion time does not include the final flush time.
If either preparation time or infusion time exceeds the time limits, a new placebo dose must be 
prepared.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Participant Enrollment and Randomization
Participants will be randomized in a 2:1 ratio to Arm A or Arm B. 
Randomization will be stratified by 
!
Human papillomavirus status (OPC HPV positive or HPV-unrelated),
∀
The number of OPC HPV-positive participants will be closely monitored throughout 
the study and is planned to be capped at approximately 20% of the total sample size.
!
World Health Organization/ECOG PS (0 or 1), and 
!
Number of prior lines of therapy in the R/M setting (1 or 2)
∀
The number of participants in each stratum (1 or 2 prior lines of therapy in the R/M 
setting) will be closely monitored throughout the study. If a disproportionate number 
of participants are enrolled in a single stratum (eg, > 75% of the total sample size), 
the Sponsor may elect to close further recruitment into that stratum.
All participants will be centrally assigned to randomized study intervention using an IRT.
Before the study is initiated, user guides, the log in information, and directions for the IRT 
will be provided to each site.
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
71 of 187
If participants withdraw from the study, then their randomization codes cannot be reused. 
Withdrawn participants will not be replaced. 
Investigators should keep a record (ie, the participant screening log) of participants who 
entered screening.
At screening/baseline (Days -28 to -1), the investigators or suitably trained delegate will:
!
Obtain signed informed consent before any study-specific procedures are performed. If 
laboratory or imaging procedures were performed for alternate reasons prior to signing 
consent, these can be used for screening purposes with consent of the participants. 
However, all screening laboratory and imaging results must have been obtained within 
28 days of randomization.
!
Have participants identified to the IRT per country regulations. A unique 7-digit 
enrollment number (E-code) will be obtained, through the IRT in the following format 
(ECCNNXXX: CC being the country code, NN being the center number, and XXX being 
the participant enrollment code at the center). This number is the participant’s unique 
identifier and is used to identify the participant on the eCRFs.
!
Obtain a tumor tissue sample for determination of HLA-E and NKp46 expression (see 
Section 8.6.1).
!
Determine participant eligibility (see Section 5.1 and Section 5.2).
!
Determine HPV status (positive or negative) for participants with OPC for purposes of 
stratification. HPV status will be assessed using local testing by IHC analysis with
CINtec® Histology p16 assay. Positive p16 IHC expression is defined as 70% or more of 
cytoplasmatic and nuclear staining of the tumor cells. Should the CINtec Histology assay 
not be available at a local institution, a tumor tissue sample should be submitted to the 
central laboratory for HPV assessment (details are provided in the Laboratory Manual).
!
Determine WHO/ECOG PS (0 or 1)
!
Determine the number of prior lines of therapy in the R/M setting (1 or 2) for 
stratification purposes.  
∀
For participants with LA disease previously treated with platinum 
(cisplatin/carboplatin) as part of multimodality therapy and progressed during or 
within 6 months after the last platinum dose, this will be considered as one line of 
therapy in the R/M setting.
!
. Participants who 
decide 
 to sign 
 the general study ICF, are eligible 
for study enrollment and all other study procedures.
At randomization, once the participant is confirmed to be eligible, the investigator or suitably 
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
72 of 187
trained delegate will:

Obtain a randomized treatment arm via the IRT. Randomization codes will be assigned 
strictly sequentially within each stratum and site/country/region as participant become 
eligible for randomization. The system will randomize the eligible participant to one of 
the 2 treatment arms.
If the participant is ineligible and not randomized, the IRT should be accessed to terminate the 
participant in the system.
Participants will begin treatment on Day 1. Every effort should be made to minimize the time 
between randomization and starting study intervention. It is strongly recommended that 
participants commence study intervention on the same day as randomization by IRT. If 
same-day treatment is not possible, then study intervention must occur within 2 days of 
randomization. Participants must not be randomized and treated unless all eligibility criteria 
have been met.
6.3.2
Procedures for Handling Incorrectly Enrolled or Randomized
Participants
Participants who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study intervention. There can be no exceptions to this rule. Participants 
who are enrolled but subsequently found not to meet all the eligibility criteria must not be 
randomized or started on study intervention and must be withdrawn from the study.
Where a participant does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on study treatment, the investigator should inform the Study Clinical Lead 
immediately, and a discussion should occur between the Study Clinical Lead and the 
investigator regarding whether to continue or discontinue the participant from study 
intervention. The Study Clinical Lead must ensure all decisions are appropriately documented 
and that the potential benefit/risk profile remains positive for the participant.
6.3.3
Methods for Assigning Treatment Arms
The actual treatment given to participants will be determined by the randomization scheme in 
the IRT. 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 randomization will be balanced within the IRT at the 
site/country/region/central level.
Randomization codes will be assigned strictly sequentially, within each stratum, as 
participants become eligible for randomization. The IRT will provide the kit identification 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
73 of 187
number for centrally supplied IMP to be allocated to the participant at the randomization visit 
and subsequent treatment visits.
6.3.4
Methods for Ensuring Blinding
The study will be conducted in a double-blind manner.
Monalizumab placebo 
 will 
be prepared by the unblinded pharmacist. The participant, the investigator, and study center 
staff will be blinded to treatment arm allocation and will remain blinded to each participant’s 
assigned study treatment throughout the course of the study. To maintain this blind, an 
otherwise uninvolved third party (ie, the unblinded pharmacist) will be unblinded to treatment 
allocation and will prepare monalizumab or placebo for a participant as specified by the 
randomization scheme and IRT (the unblinded pharmacist will be the only member of 
investigator site staff to know the randomization/treatment allocation details).
The IRT will provide to the investigator(s) or pharmacists the kit identification number to be 
allocated to the participant at the dispensing visit. Pharmacists will be given specific 
instructions for monalizumab/placebo preparation and will note if the double-blind conditions 
have been compromised or the blind has been broken. Lot numbers of monalizumab dispensed 
will be recorded by the pharmacist and monitored by an unblinded monitor. Other blinded 
study center staff and monitors will not be given access to lot number information. Blinded 
and unblinded access and notifications will be controlled using the IRT. 
Routines for this will be described in the IRT user manual that will be provided to each center.
The randomization code should not be broken except in medical emergencies when the 
appropriate management of the participant requires knowledge of the treatment 
randomization. The investigator documents and reports the action to the Sponsor, without 
revealing the treatment given to the participant to the Sponsor staff.
The Sponsor retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an IMP and that potentially require expedited reporting to 
regulatory authorities. Randomization codes will not be broken for the planned analyses of 
data until all decisions on the evaluability of the data from each individual participant have 
been made and documented.
No member of the extended study team at the Sponsor, at the investigational centers, or any 
blinded CRO handling data will have access to the randomization scheme until the time of the 
final analysis or any IA data where a decision is made to unblind the study. At such time, the 
Sponsor and any CRO handling data will have access to the randomization scheme. 
Exceptions are relevant persons within the Pharmaceutical Development Supply Chain at 
AstraZeneca or their designee, where the information is needed to package the study 
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
74 of 187
intervention; the drug safety departments at AstraZeneca; and the pharmacists required to 
dispense the study intervention at the study site. Investigators will be unblinded to treatment 
allocation only in cases of medical emergency. Additionally, at the request of the investigator, 
at progression of disease, the participant can be unblinded. 
The treatment codes and results will be kept strictly within AstraZeneca to safeguard the 
integrity of the blind and hence to minimize any possible bias in data handling. 
In the event that the treatment allocation for a participant becomes known to the investigator 
or other study staff involved in the management of study participants, or needs to be known to 
treat an individual participant for an AE, the Sponsor must be notified promptly by the 
investigator and, if possible, before unblinding. 
The IRT will be programmed with blind-breaking instructions. The blind may be broken if, in 
the opinion of the investigator, it is in the participant’s best interest for the investigator to 
know the study treatment assignment. The Sponsor must be notified before the blind is broken 
unless identification of the study intervention is required for a medical emergency in which 
the knowledge of the specific blinded study intervention will affect the immediate 
management of the participant’s condition (eg, antidote available). In this case, the Sponsor 
must be notified within 24 hours after breaking the blind. The date and reason that the blind 
was broken must be recorded in the source documentation and eCRF, as applicable. Study 
unblinding should occur after database lock, once all decisions on the evaluability of the data 
from each individual participant have been made and documented. 
6.4
Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date, and time if applicable, of dose 
administered in the clinic will be recorded in the source documents and recorded in the eCRF.
This information, plus drug accountability for all study interventions at every visit, will be 
used to assess compliance. The dose of study intervention and study participant identification 
will be confirmed at the time of dosing by a member of the study site staff other than the 
person administering the study intervention. Any change from the dosing schedule, dose 
delays/interruptions, and dose discontinuations should be recorded in the eCRF. Dose 
modifications for monalizumab/placebo and cetuximab are permitted per the guidelines 
described in Section 6.6.
Treatment compliance will be ensured by reconciliation of site drug accountability logs. 
The Investigator Product Storage Manager is responsible for managing the IMP from receipt 
by the study site until destruction of all unused IMP.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
75 of 187
6.5
Concomitant Therapy
Any concomitant treatment, procedure, or medication or vaccine including over-the-counter or 
prescription medicines, vitamins, and/or herbal supplements that the participant is receiving 
according to the schedule in the SoA (Section 1.3) must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
The Study Clinical Lead should be contacted if there are any questions regarding concomitant 
or prior therapy.
If any concomitant therapy is administered due to new or unresolved AE, it should be 
recorded.
Participants must be instructed not to take any medications, including over-the-counter 
products, without first consulting with the investigator.
Prohibited and permitted concomitant medications/therapies are described in Table 6 and 
Table 7, respectively. Refer also to the guidelines for management of IMP-related toxicities in 
Section 8.3.15. For cetuximab, refer to the local label (where available) with regard to 
warnings, precautions, and contraindications. 
Table 6
Prohibited Concomitant Medication/Therapy
Type of medication/treatment
Timeline/Instructions
Any investigational therapy other than 
those under investigation in this study
Until end of study treatment.
Any concurrent chemotherapy, 
radiotherapy, immunotherapy (including 
other monoclonal antibodies), or 
biologic or hormonal therapy for cancer 
treatment other than those under 
investigation in this study
Until end of study treatment. 
Concurrent use of hormones for non-cancer-related conditions 
(eg, insulin for diabetes and hormone replacement therapy) is 
acceptable. Local treatment of isolated lesions, excluding target 
lesions, for palliative intent is acceptable (eg, by local surgery or 
radiotherapy)

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
76 of 187
Table 6
Prohibited Concomitant Medication/Therapy
Type of medication/treatment
Timeline/Instructions
Immunosuppressive medications 
including, but not limited to, systemic 
corticosteroids at doses exceeding 
10 mg/day of prednisone or equivalent, 
methotrexate, azathioprine, and tumor 
necrosis factor-α blockers
Should not be given concomitantly or used for premedication prior 
to the infusions of IMP. The following are allowed exceptions:
•
Use of immunosuppressive medications for the management 
of IMP-related adverse events or infusion-related reactions
•
Short-term premedication for cetuximab where the local label
requires the use of steroids 
•
Short-term premedication for monalizumab/placebo 
following > Grade 2 infusion-related reaction at the previous 
cycle (see monalizumab TMG)
•
Use in participants with contrast allergies 
•
Use of inhaled, topical, and intranasal corticosteroids 
A temporary period of steroid use will be permitted if clinically 
indicated and considered to be essential for the management of 
non-immunotherapy-related events experienced by the participant 
(eg, chronic obstructive pulmonary disease, radiation, nausea, etc).
Live attenuated vaccines 
Within 30 days prior to the first dose of IMP, whilst receiving IMP 
and up to 30 days after the last dose of IMP.
Herbal and natural remedies which may 
have immune-modulating effects
Should not be given concomitantly unless agreed by the Sponsor
IMP = investigational medicinal product. 
Table 7
Permitted Concomitant Medication/Therapy
Type of medication/treatment
Timeline/Instructions
All necessary supportive care in the form of treatment or prophylaxis as 
clinically indicated eg, transfusion of blood products, antibiotics, 
anti-histamines, analgesics
Throughout the study 
Vaccines limited to non-live attenuated preparations (eg, influenza vaccine)
See Appendix C for vaccination against COVID-19
Throughout the study
COVID-19 = coronavirus disease 2019.
6.5.1
Permitted Medication Prior to Study Intervention
Monalizumab
No premedication is required prior to monalizumab administration. However, from Cycle 2, 
premedication with acetaminophen and/or an antihistamine drug might be prescribed, at the 
investigator’s discretion, if the participant experienced any Grade 1 to 3 infusion-related AE at 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
77 of 187
the previous cycle (see monalizumab TMG provided as a supplement to the CSP).
Cetuximab
Participants should be premedicated per US PI (antihistamine iv 30 to 60 minutes prior to the 
first infusion or subsequent infusions of cetuximab as deemed necessary) or local label (where 
available). Premedication may also be based on institutional guidance for management of 
infusion-related reactions.
6.5.2
Drug-drug Interactions
No formal drug-drug interaction studies have been conducted with monalizumab. 
Monalizumab and cetuximab are immunoglobulins and the primary elimination pathways are 
protein catabolism via reticuloendothelial system or target mediated disposition. Therefore, 
there are no anticipated drug-drug interactions between monalizumab and cetuximab based on 
the elimination pathway when monalizumab and cetuximab are administered in combination. 
Moreover, monalizumab and cetuximab are not expected to induce or inhibit the major drug 
metabolizing cytochrome P450 pathways. 
Based on available non-compartment analysis data, the observed PK of monalizumab when 
administered in combination with cetuximab is within the range of monalizumab monotherapy 
PK (see Monalizumab IB, Section 5.1 for further details).
6.5.3
Rescue Medication
Fully functional resuscitation facilities should be available at each site during infusion of the 
study interventions. Please see recommendations regarding rescue treatment (Section 6.1.2)
and management of IMP-related toxicities (Section 8.3.15). The date of rescue medication 
administration as well as the name and dosage regimen of the rescue medication must be 
recorded.
6.6
Dose Modification
It is important to keep the day on which monalizumab/placebo and cetuximab are 
administered as Day 1 of each 2-week cycle (except if one of the study interventions is 
permanently discontinued). If a participant does not meet monalizumab/placebo dosing 
criteria on Day 1 of any cycle, both monalizumab/placebo and cetuximab administration 
should be postponed for a week. If dosing criteria are not met after a week delay, suspension 
of study intervention will be extended for an additional week. In the absence of resolution 
after a 2-week delay, the investigator should contact the Sponsor for guidance on further 
dosing. If dosing delay is due to treatment-related toxicity, TMGs for monalizumab and local 
prescribing information for cetuximab should be followed (see Section 8.3.15).
For guidance on dose modification in relation to the novel coronavirus (COVID-19) outbreak, 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
78 of 187
see Appendix C.
Monalizumab/placebo
Dose delays are permitted for monalizumab/placebo (see management of 
monalizumab-related toxicities in Section 8.3.15.1). However, dose reduction is not permitted.
The duration between each monalizumab/placebo infusion should be at least 14 days (see
Table 1 for administration schedule, including acceptable window).
In the event that monalizumab/placebo is discontinued due to monalizumab/placebo-related 
toxicity, treatment with cetuximab may continue at the investigator’s discretion when toxicity 
resolves to ≤Grade 1. Note: If the investigator determines that a participant is ready to restart 
treatment prior to the toxicity resolving to ≤ Grade 1, the Sponsor should be consulted for an 
exception to this rule. 
Cetuximab
Cetuximab dose modification for the management of cetuximab-related toxicities should 
follow local standard clinical practice (see Section 8.3.15.2). For specific information, refer to 
the local label (where available) for cetuximab. 
The duration between each cetuximab infusion should be at least 7 days (see Table 1 for 
administration schedule, including acceptable window). If dosing of cetuximab is delayed on 
Day 1 of a cycle (ie, when monalizumab/placebo is also due to be given) then dosing of 
monalizumab/placebo should also be delayed (see above). If cetuximab is delayed due to 
toxicity on Day 8 of a cycle (ie, when single-dose cetuximab is due to be given), the dose of 
cetuximab will be omitted and the next cycle can continue as usual. 
In the event that cetuximab is discontinued due to cetuximab-related toxicity, treatment with 
monalizumab/placebo may continue at the investigator’s discretion when the 
cetuximab-related toxicity resolves to ≤Grade 2. Note: If the investigator determines that a 
participant is ready to restart treatment prior to the cetuximab-related toxicity resolving to 
≤Grade 2, the Sponsor should be consulted for an exception to this rule. 
6.7
Intervention After the End of the Study
As described in Section 4.4, the study will remain open until all participants have discontinued 
study intervention and completed their last expected visit/contact.
After the final DCO and database closure, the Sponsor will supply open-label IMP to 
participants who are receiving benefit from their assigned treatment, for as long as they and 
their physician considers they are gaining clinical benefit. See Section 8 for a description of 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
79 of 187
the assessments to be conducted for these participants. 
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, participants 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 visit assessments per its protocol. Any participant who would be proposed 
to move to such a study would be given a new ICF.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
Participants will be discontinued from study intervention in the following situations.  

RECIST 1.1-defined radiological disease progression (refer to Section 6.1.3,
Section 8.1.1, and Appendix G)

Investigator determination that the participant is no longer benefiting from study 
intervention

An AE that, in the opinion of the investigator or the Sponsor, contraindicates further 
dosing

Any AE that meets criteria for discontinuation defined in the guidelines for management 
of IMP-related toxicities (see Section 8.3.15) or as defined in the local label (where 
available) for cetuximab

Participant decision. The participant is at any time free to discontinue study intervention, 
without prejudice to further treatment. A participant who discontinues study intervention 
is normally expected to continue to participate in the study (eg, for safety and survival 
follow-up) unless they specifically withdraw their consent to all further participation in 
any study procedures and assessments (see Section 7.3).

Severe non-compliance with the CSP as judged by the investigator or the Sponsor

For females of childbearing potential, pregnancy or intent to become pregnant

Initiation of subsequent anticancer therapy, including another investigational agent
Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study.
See the SoA (Section 1.3) for data to be collected at the time of study intervention 
discontinuation and follow-up for safety and other assessments.
If a participant discontinues treatment with one of the combination agents due to toxicity, they 
may continue with monalizumab/placebo or cetuximab in monotherapy within the study as 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
80 of 187
long as they are continuing to show clinical benefit, as judged by the investigator and in the 
absence of discontinuation criteria.
7.1.1
Procedures for Discontinuation of Study Intervention
The EOT visit should be performed and conducted one month after the participant 
permanently discontinues from study intervention. The assessments to be conducted at the 
EOT visit are specified in the SoA (Table 2). The reason for discontinuation should be 
documented in the source document and the appropriate section of the eCRF.
Participants who have permanently discontinued from further receipt of study intervention 
will need to be discontinued from the IRT.
The date of last intake of study intervention should be documented in the eCRF. 
Discontinuation of study intervention, for any reason, does not impact on the participant’s 
participation in the study. The participant should continue attending subsequent study visits 
and data collection should continue according to the study protocol. If the participant does not 
agree to continue in-person study visits, a modified follow-up must be arranged to ensure the 
collection of endpoints and safety information including new AEs, follow-up on any ongoing 
AEs and concomitant medications, and subsequent anticancer therapy. This could be a 
telephone contact with the participant at one month (+ 3 days) after study intervention is 
discontinued, a contact with a relative or treating physician, or information from medical 
records. The approach taken should be recorded in the medical records. A participant that 
agrees to modified follow-up is not considered to have withdrawn consent or to have 
withdrawn from the study.
The investigator should instruct the participant to contact the site before or at the time when 
study intervention is stopped. A participant that decides to discontinue study intervention will 
always be asked about the reason(s) and the presence of any AEs.
7.1.1.1
Tumor Assessment Post Discontinuation of Study Intervention
Participants who have discontinued study intervention prior to objective RECIST 1.1-defined 
radiological disease progression, regardless of whether they have commenced subsequent 
anticancer therapy will continue on their regular scan schedule (see SoA, Table 2) until 
RECIST 1.1-defined radiological disease progression or death, unless they have withdrawn all 
consent to study-related assessments.
7.1.1.2
 
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
81 of 187
7.1.1.3
Follow-up for Survival
Participants will be followed for survival status as indicated in the SoA (Table 2) until death, 
withdrawal of consent, or the end of the study. Survival information may be obtained via 
telephone contact with the participant or the participant’s family, or by contact with the 
participant’s current physician. Additional assessments to be performed at the time of survival 
follow-up are detailed in the SoA (Table 2).
Participants on treatment or in survival follow-up will be contacted following each DCO to 
provide complete survival data. These contacts should generally occur within 7 days after the 
DCO. 
7.2
Participant Withdrawal From the Study
!
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral,
compliance, or administrative reasons. This is expected to be uncommon.
!
A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records).
!
Upon withdrawal from the study, an EOT visit should be conducted, if possible. See SoA 
(Section 1.3) for data to be collected at the time of study withdrawal and follow-up and 
for any further evaluations that need to be completed.
∀
The participant will discontinue the study intervention and be withdrawn from the 
study at that time.
!
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
!
If a participant withdraws from the study, it should be confirmed if he/she is still agrees 
for samples to be used (see Section A 3). He/she may request destruction of any samples 
taken, and the investigator must document this in the site study records.  
!
The investigator must document the decision on use of existing samples in the site study 
records and inform the Global Study Team.
!
The Sponsor or its delegate will request investigators to collect information on 
participants’ vital status (dead or alive; date of death when applicable) during survival 
follow-up from publicly available sources, in accordance with local regulations. 
Knowledge of the vital status at study end in all participants is crucial for the integrity of 
the study.
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
82 of 187
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site by the time the study is 
completed (see Section 4.4), such that there is insufficient information to determine the 
participant’s status at that time.
Participants who decline to continue 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 participants throughout the study 
period. If contact with a missing participant is re-established, the participant should not be 
considered lost to follow-up and evaluations should resume according to the protocol.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
!
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.
!
Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant or next of kin by, eg, repeat telephone 
calls, certified letter to the participant’s last known mailing address, or local equivalent 
methods. These contact attempts should be documented in the participant’s medical 
record.
!
Efforts to reach the participant should continue until the end of the study. Should the 
participant be unreachable at the end of the study, he/she will be considered lost to 
follow-up with unknown vital status at the end of the study and censored at latest 
follow-up contact. 
In order to support key efficacy endpoints of OS, PFS, and 
, the survival status 
of all participants in the FAS and the SAF should be re-checked; this includes those 
participants who withdrew consent or are classified as “lost to follow-up.”
!
Lost to follow-up – Site personnel should check hospital records and a publicly available 
death registry (if available), as well as checking with the participants’ current physician, 
to obtain a current survival status. (The applicable eCRF modules will be updated.)
!
In the event that the participant has actively withdrawn consent to the processing of their 
personal data, the survival status of the participant 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.  
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
83 of 187
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA (see Section 1.3). Protocol
waivers or exemptions are not allowed. Assessments following final DCO and database 
closure until the end of the study are described in Section 8.3.11. 
!
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.
!
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
!
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
!
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
8.1
Efficacy Assessments
8.1.1
Imaging Tumor Assessments
This study will evaluate a primary endpoint of OS and secondary endpoints of PFS, ORR, and 
DoR for Arm A vs Arm B. 
 
With the exclusion of OS, efficacy will be derived (by the Sponsor) using investigator 
RECIST 1.1 assessments.
Tumor assessments use images from iv contrast-enhanced CT (preferred) of the neck 
(including the base of skull), chest, and abdomen (including the entire liver) collected during 
screening/baseline and at regular (follow-up) intervals during study intervention. Any other 
areas of disease involvement should be additionally imaged at screening based on known 
metastasis sites or by the signs and symptoms of individual participants. MRI with iv contrast 
is acceptable if CT is contraindicated. The imaging modality (CT/MRI) used for baseline 
tumor assessments should be kept the same consistently at each subsequent follow-up 
assessment throughout the study if possible. It is important to follow the tumor assessment 
schedule as closely as possible (refer to the SoA [Section 1.3]) relative to randomization. 
Screening/baseline imaging should be performed no more than 28 days before randomization 
and ideally should be performed as close as possible to randomization. Scanning/tumor 
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
84 of 187
assessments will continue throughout intervention until RECIST 1.1-defined radiological 
disease progression by investigator assessment (see Section 6.1.3). If an unscheduled 
assessment is performed (eg, to investigate clinical signs/symptoms of progression) and the 
participant has not progressed, every attempt should be made to perform the subsequent 
assessments at the next scheduled visit.  
Tumor assessment by RECIST 1.1 guidelines are provided in Appendix G.
8.1.2
8.1.3
Overall Survival 
Assessments for survival will be conducted according to the SoA (Table 2) following 
objective disease progression or treatment discontinuation. Survival information may be 
obtained via telephone contact with the participant, participant’s family, by contact with the 
participant’s current physician, or local death registries as described in Section 7.2.
8.1.4
Clinical Outcome Assessments
A COA is an assessment of a clinical outcome reported by a clinician, a patient, or a 
non-clinician observer, or through a performance-based assessment (FDA 2018b). A COA 
may be used in clinical studies to provide either direct or indirect evidence of treatment 
benefit. It is important to examine the impact of therapy on disease-related symptoms, 
physical function, and other HRQoL of the patient to aid understanding of how clinical benefit 
relates to patient well-being and for consideration in making benefit-risk evaluations. Patient-
reported outcome is one type of clinical outcome assessment and is a general term referring to 
all outcomes and symptoms that are directly reported by the patient. Moreover, PROs assist in 
the documentation of symptoms and specifically what symptoms and impacts are most 
important to patients and how these relate to clinical outcomes. Patient-reported outcomes
have become important in evaluating effectiveness of study treatments in clinical studies and 
will aid in understanding of the benefit-risk evaluation (Kluetz et al 2018). The following 
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
85 of 187
PROs will be administered in this study: EORTC QLQ-C30, EORTC QLQ-H&N35, 
 
. See 
questionnaires in Appendix I. Patient-reported outcomes will be administered according to the 
SoA during the treatment and follow-up periods (see Section 1.3). Patient-reported outcomes
will be translated into the language of the country being administere
 
.
8.1.4.1
EORTC QLQ-C30 
The EORTC QLQ-C30 was developed by the EORTC Quality of Life Group 1993 (see 
Appendix I 1). It consists of 30 items and measures symptoms, functioning, and global health 
status/QoL (Aaronson et al 1993) for all cancer types. Questions are grouped into 5 multi-item 
functional scales (physical, role, emotional, cognitive, and social); 3 multi-item symptom 
scales (fatigue, pain, and nausea/vomiting); a 2-item global QoL scale; 5 single items 
assessing additional symptoms commonly reported by cancer patients (dyspnea, loss of 
appetite, insomnia, constipation, and diarrhea), and one item on the financial impact of the
disease. The EORTC QLQ-C30 is a valid and reliable PRO instrument in this patient
population. 
8.1.4.2
EORTC QLQ-H&N35
The EORTC QLQ-H&N35 module is a 35-item self-administered questionnaire (see 
Appendix I 2). 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. 
8.1.4.3
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
86 of 187
8.1.4.4
8.1.4.5
8.1.4.6
8.1.4.7
Administration of Electronic PRO Questionnaires
Participants will complete the PRO assessments using an electronic tablet (ePRO) during 
clinic visits at the time points indicated in the SoA (see Section 1.3). It is important that the 
ePRO device is charged and set up for the participant prior to their arrival at the site for their 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
87 of 187
baseline PRO assessments (close to when the participant will be randomized), to ensure it is 
functioning properly and ready for use, in accordance with device training. The participant 
should be trained on the use of the device, including the importance of completing the PRO 
questionnaires throughout the study in accordance with the SoA.
The below instructions should be followed when collecting PRO data via an electronic device:
!
Patient-reported outcome questionnaires must be completed prior to treatment 
administration and ideally before any discussions of health status to avoid biasing the 
participant’s responses to the questions. As feasible, site staff should also ensure PRO 
questionnaires are completed prior to other study procedures, such as collection of 
laboratory samples, to further minimize bias.
!
When each instrument is due to be completed, the following order is observed; EORTC 
QLQ-C30 should be administered first followed by EORTC QLQ-H&N35, 
.
!
Patient-reported outcome questionnaires should be completed by the participant in a quiet 
and private location. 
!
The participant should be given sufficient time to complete the questionnaires at their 
own speed.
!
The research nurse or appointed site staff must explain to participants the value and 
relevance of ePRO participation so they are motivated to comply with questionnaire 
completion. Inform the participant that these questions are being asked to find out, 
directly from them, how they feel.
!
The research nurse or appointed site staff should stress that the information is not 
routinely shared with study staff. Therefore, if the participant has any medical problems, 
they should discuss them with the doctor or research nurse separately from the ePRO 
assessment.
!
The research nurse or appointed site staff must train the participant on how to use the 
ePRO device, using the materials and training provided by the ePRO vendor.
!
All PRO questionnaires are to be completed using the ePRO device. If technical or other 
device-related issues prohibit completion on the device, an appropriate backup option 
may be considered with prior approval from AstraZeneca.
!
The research nurse or appointed site staff must remind participants that there are no right 
or wrong answers, and avoid introducing bias by not clarifying items for the participant.
!
The participant should not receive help from relatives, friends, or clinic staff to decide on 
answers to the ePRO questionnaires. The responses are the participant’s alone.
!
On completion of the questionnaire at the site, it should be handed back to the designated 
responsible person, who should check that all questionnaires were completed.
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
88 of 187

If a participant needs visual aids (eg, spectacles or contact lenses) for reading and does 
not have them when he or she attends the clinic, the participant will be exempted from 
completing the ePROs at that clinic visit.

Site staff must not read the ePRO questionnaires on behalf of the participant. If the 
participant is unable to read the questionnaire (eg, is blind or illiterate, or not fluent in the 
available language), that participant is exempted from completing PRO questionnaires but 
may still participate in the study. If the participant cannot complete the ePRO 
questionnaires due to reasons other than being blind, illiterate, or fluent in language, the 
AstraZeneca study team must be contacted to determine if they can be exempted. 
Participants exempted in this regard should be flagged appropriately by the site staff in 
the source documents and in the REVPRDI eCRF.

Questions must not be translated from an available language in the device into the 
language the participant speaks.

It is vital that the ePRO reporting is initiated at Cycle 1 Day 1 dosing visit (baseline) as 
specified in the SoA to capture the effect of study treatment. The ePRO device must be 
charged and fully functional at the beginning of the baseline visit to ensure that the PROs 
can be completed at the start of the visit. 

Finally, the research nurse or appointed site staff will review the completion status of 
questionnaires during site visits and document the reason(s) why a participant could not 
complete assessments in the designated eCRF. 
The research nurse or appointed site staff must monitor compliance since 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 the site receives an email 
notification regarding the participant’s compliance, appropriate action should be taken 
(eg, discussion with participant to improve compliance, a check in call from the site to ask the 
participant if they have any difficulties in completing questionnaires on schedule, etc). 
A solution to enhance/resolve compliance should be discussed with the participant. 
Discussions and compliance review should be reflected in source documents.
8.1.4.8
WHO/ECOG PS
World Health Organization/ECOG PS will be assessed at the time points specified in the SoA 
(Section 1.3) 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 or 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

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
89 of 187
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
5
Dead
Any significant change from baseline or screening must be reported as an AE.
The ECOG status collected at screening must be reported in IRT and not re-assessed.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1
Physical Examinations
Physical examination, as well as assessment of height and weight, will be performed at time
points specified in the SoA (Section 1.3).

A full physical examination will include assessments of the head, eyes, ears, nose, and 
throat and the respiratory, cardiovascular, gastrointestinal, musculoskeletal, neurological, 
dermatological, hematologic/lymphatic, and endocrine systems. In addition, targeted 
physical examinations, eg, urogenital, are to be performed by the investigator based on 
clinical observations and symptomatology.

Targeted physical examinations are to be performed by the investigator on the basis of 
clinical observations and symptomatology.
Situations in which physical examination results should be reported as AEs are described in 
Section 8.3.5.
8.2.2
Vital Signs
Vital signs will be performed at time points specified in the SoA (Section 1.3).
Blood pressure and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available.
Vital signs will be measured after 5 minutes rest and will include temperature, systolic and 
diastolic blood pressure, and pulse and respiratory rate. 
First infusion 
On the first infusion day, participants will be monitored and vital signs collected/recorded in 
eCRF prior to, during, and after infusion of monalizumab/placebo as presented in the bulleted 
list below. 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
90 of 187
Blood pressure and pulse will be collected from participants before, during, and after each 
monalizumab/placebo infusion 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 infusion (halfway through infusion) 

At the end of the infusion (approximately 60 minutes ± 5 minutes)
If the monalizumab/placebo infusion takes longer than 60 minutes, then blood pressure and 
pulse measurements should follow the principles as described above or be taken more 
frequently if clinically indicated. A one-hour observation period is recommended after the first 
infusion of monalizumab/placebo. 
Vital signs will be collected in all participants before cetuximab dosing (approximately 
30 minutes before up to 0 minutes) and as clinically indicated during and after dosing, as per 
the local label and institutional standard. Any clinically significant changes in vital signs 
should be entered onto an unscheduled vital signs eCRF. 
Subsequent infusions 
Blood pressure, pulse, and other vital signs should be measured (approximately 30 minutes 
before up to 0 minutes), collected/recorded in the eCRF prior to the start of the infusions of 
monalizumab/placebo and cetuximab. Participants should be carefully monitored, and blood 
pressure and other vital signs should be measured during and post infusions as per institutional 
standard and as clinically indicated (and in line with the local label for cetuximab). Any 
clinically significant changes in vital signs should be entered onto an unscheduled vital signs 
eCRF.
Situations in which vital signs results should be reported as AEs are described in 
Section 8.3.5. For any AEs of infusion reactions, the vital signs values should be entered into 
eCRF.
8.2.3
Electrocardiograms
Triplicate 12-lead ECGs will be recorded at scheduled visits and as clinically indicated per the 
SoA (Section 1.3). An ECG will be obtained after the participant has been resting 
semi-recumbent or supine for at least 5 minutes and recorded while the participant remains in 
that position using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTcF intervals. 
Three individual ECG tracings should be obtained in succession, no more than 2 minutes 
apart. The full set of triplicates should be completed within 5 minutes. The machine-derived 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
91 of 187
QTc must be manually verified and interpreted by the investigator. All ECGs should be 
assessed by the investigator as to whether they are clinically significantly abnormal.
Situations in which ECG results should be reported as AEs are described in Section 8.3.5.
8.2.4
Clinical Safety Laboratory Assessments
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis 
will be taken at the visits indicated in the SoA (Section 1.3). Samples for determination of 
coagulation parameters are to be collected at baseline on Day 1 (unless all screening 
laboratory hematology assessments are performed within 3 days prior to Day 1), and then as 
clinically indicated. 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.
Clinical laboratory safety tests, including serum pregnancy tests, will be performed at a 
licensed clinical laboratory according to local standard procedures. Sample tubes and sample 
sizes may vary depending on laboratory method used and routine practice at the site.
Pregnancy tests may be performed at the site using a licensed test (urine or serum pregnancy 
test). Abnormal clinically significant laboratory results should be repeated as soon as possible 
(preferably within 24 to 48 hours). 
Table 8 presents the laboratory variables to be measured. Other safety tests to be performed at 
screening include assessments for hepatitis B surface antigen, hepatitis C antibodies, and HIV 
antibodies.
Table 8
Laboratory Safety Variables
Hematology/Hemostasis (whole blood)
Clinical chemistry (serum or plasma)
Hb
Creatinine a
Platelet count
Bilirubin, total b
Absolute neutrophil count c
ALP b
Absolute lymphocyte count c
AST b
Total WBC count
ALT b
Coagulation d
Albumin
aPTT, fibrinogen, and INR
Potassium
Calcium, total
Urinalysis e
Sodium
Bilirubin
Magnesium
Blood 
Phosphate
Protein/Albumin 
Amylase f
Glucose 
Lipase f
Color and appearance
Gamma-glutamyl transferase
Ketones
Glucose 
Specific gravity
Bicarbonate (where available)

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
92 of 187
Table 8
Laboratory Safety Variables
Hematology/Hemostasis (whole blood)
Clinical chemistry (serum or plasma)
pH
Chloride
LDH
Protein, total
TSH g
free T4 h
free T3 h
Urea or blood urea nitrogen, depending on local practice
a
Creatinine clearance will be calculated by the site using Cockcroft-Gault (using actual body weight).
b
Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently. If total 
bilirubin is ≥ 2 × ULN (and no evidence of Gilbert’s syndrome), then fractionate into direct and indirect bilirubin.
c
Can be recorded as absolute counts or as percentages, except at screening when absolute neutrophil count must be 
recorded. Total WBC count therefore has to be provided.
d
Coagulation parameters are to be assessed at baseline on Day 1 (unless all screening laboratory hematology 
assessments are performed within 3 days prior to Day 1), and then as clinically indicated.
e
Urinalysis should be done at baseline (screening) and then as clinically indicated. 
f
It is preferable that both amylase and lipase parameters are assessed. For sites where only one of these parameters is 
routinely measured, either lipase or amylase is acceptable.
g
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at Day 1.
h
Free T4 or/and free T3 (per local standard clinical practice) will only be measured if TSH is abnormal or if there is 
clinical suspicion of an AE related to the endocrine system.
ALP = alkaline phosphate; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = 
aspartate aminotransferase; INR = International Normalized Ratio; LDH = lactate dehydrogenase; T3 = triiodothyronine; 
T4 = thyroxine; TSH = thyroid stimulating hormone; ULN = upper limit of normal; WBC = white blood cell count.
In case a participant shows an AST or ALT ≥3 × ULN together with TBL ≥2 × ULN, please 
refer to Appendix F (Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law) for further instructions.
8.3
Adverse Events and Serious Adverse Events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section
The definitions of an AE or SAE can be found in Appendix B.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
For guidance in relation to the novel coronavirus (COVID-19) outbreak, see Appendix C.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events will be collected from time of signature of the ICF until 90 days after the last 
dose of study intervention (see SoA, Section 1.3). Collection and reporting of AEs and SAEs 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
93 of 187
after the final DCO is described in Section 8.3.11.
Serious adverse events will be recorded from the time of signing of ICF.
If the investigator becomes aware of an SAE with a suspected causal relationship to the IMP
that occurs after the end of the clinical study in a participant treated by him or her, the 
investigator shall, without undue delay, report the SAE to the Sponsor.
8.3.2
Follow-up of AEs and SAEs
Any AEs that are unresolved at the participant’s last AE assessment in the study are followed 
up by the investigator for as long as medically indicated, but without further recording in the 
eCRF. The Sponsor retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
Adverse event variables
The following variables will be collected for each AE;

Adverse event (verbatim)

The date when the AE started and stopped

Select the appropriate as required: 

The maximum CTCAE grade reported

Changes in CTCAE grade (report only the maximum CTCAE grade for a calendar 
day)

Whether the AE is serious or not

Investigator causality rating against the IMP(s) (yes or no)

Action taken with regard to IMP(s)

Administration of treatment for the AE 

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date investigator became aware of serious AE

Adverse event is serious due to

Date of hospitalization

Date of discharge

Probable cause of death

Date of death

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
94 of 187

Autopsy performed

Causality assessment in relation to Study procedure(s)

Causality assessment to other medication
The grading scales found in the NCI CTCAE, Version 5.0 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 can be downloaded from the Cancer 
Therapy Evaluation Program website (http://ctep.cancer.gov).
8.3.3 Causality Collection
The investigator should assess causal relationship between IMP 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 should also be assessed for other medication 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.
8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: ‘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.
8.3.5 Adverse Events Based on Examinations and Tests
The results from the CSP-mandated laboratory tests and vital signs will be summarized in the 
CSR. 
Deterioration as compared to baseline in protocol-mandated laboratory values, vital signs, and 
ECGs should therefore only be reported as an AE if it fulfills any of the SAE criteria, is the 
reason for discontinuation of treatment with the IMP, or is considered to be clinically relevant 
as judged by the investigator (this may include but is not limited to whether treatment or non-
planned visits were required or other action was taken with the study intervention, eg, dose 
adjustment or drug interruption).

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
95 of 187
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible, the reporting investigator
uses 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 AE(s).
Deterioration of a laboratory value, which 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 unless unequivocally 
related to the disease under study.
8.3.6 Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN may 
need to be reported as SAEs. Please refer to Appendix F for further instruction on cases of 
increases in liver biochemistry and evaluation of HL.
8.3.7 Disease Progression
Disease progression can be considered as a worsening of a participant’s condition attributable 
to the disease for which the IMP 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.
8.3.8
New Cancers
The development of a new cancer should be regarded as an AE and will generally meet at least 
one of the serious criteria. New primary cancers are those that are not the primary reason for 
the administration of study intervention and have been identified after the participant’s
inclusion in this study. They do not include metastases of the original cancer.
8.3.9
Deaths
All deaths that occur during the study intervention period, or within the protocol-defined 
follow-up period after the administration of the last dose of study intervention, must be 
reported as follows:

Death clearly resulting from disease progression should be documented in the eCRF in 
the Statement of Death page. It should not be reported as an SAE.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
96 of 187

Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported as an SAE within 24 hours. It should also be 
documented in the Statement of Death page in the eCRF. The report should contain a 
comment regarding the co-involvement of disease progression, if appropriate, and should 
assign the main and contributory causes of death.

Deaths with an unknown cause should always be reported as an SAE and documented in 
the Statement of Death page in the eCRF, but every effort should be made to determine a 
cause of death. 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 
Patient Safety or its representative within the usual time frames.
Deaths occurring after the protocol-defined follow-up period after the administration of the 
last dose of study intervention should be documented in the Statement of Death page. If the 
death occurred as a result of an event that started after the defined follow-up period and the 
event is considered to be due to a late-onset toxicity to study treatment, then it should also be 
reported as an SAE.
8.3.10
Adverse Events of Special Interest
Adverse events of special interest are events of scientific and medical interest specific to the 
further understanding of study intervention safety profile and require close monitoring and 
rapid communication by the investigators to the Sponsor. An AESI can be serious or 
non-serious. All AESIs will be recorded in the eCRF. Serious AESIs will be recorded and 
reported as per Section 8.3.12.
Adverse events of special interest for monalizumab include events with a potential immune-
mediated inflammatory mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants, and/or hormone replacement therapy. An 
imAE 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 imAE diagnosis. Appropriate efforts should be made to rule out neoplastic, 
infectious, metabolic, toxic, or other etiologic causes of the imAE. 
If the investigator has any questions in regard to an event being an imAE, the investigator 
should promptly contact the Study Clinical Lead.
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological etiology are also considered AESIs.
Further information on these risks (eg, presenting symptoms) can be found in the current 
version of the monalizumab IB. More specific guidelines for their evaluation and treatment 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
97 of 187
are described in detail in the monalizumab TMG (see Section 8.3.15). 
8.3.11
Safety Data to be Collected Following the Final DCO of the Study
For participants continuing to receive open-label IMP after the final DCO and database 
closure (see Section 6.7), it is recommended that the participant continue the scheduled site 
visits and investigators monitor the participant’s safety laboratory results prior to and 
periodically during treatment with IMP in order to manage AEs in accordance with toxicity-
management guidelines (see Section 8.3.15). All data post the final DCO and database closure 
will be recorded in the participant notes but, with the exception of SAEs, will not otherwise be 
reported for the purposes of this study.
All SAEs that occur in participants still receiving IMP (or within the 90 days following the 
last dose of IMP) post the final DCO and database closure must be reported as detailed in 
Section 8.3.12.
8.3.12
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the IMP, or to the 
study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate Sponsor representatives within one day ie, immediately but no later than 
24 hours of when they become aware of it.
The designated Sponsor representative works with the investigator to ensure that all the 
necessary information is provided to the Sponsor 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 where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform Sponsor
representatives of any follow-up information on a previously reported SAE within one 
calendar day ie, immediately but no later than 24 hours of when they become aware of it.
Once the investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated Sponsor representative.
If the EDC system is not available, then the investigator or other study site staff reports an
SAE to the appropriate Sponsor representative by telephone.
The Sponsor representative will advise the investigator/study site staff how to proceed. 
The reference documents for definition of expectedness/listedness are the IB for monalizumab

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
98 of 187
and the appropriate label for cetuximab. 
8.3.13
Pregnancy
All pregnancies and outcomes of pregnancy with conception dates following the first date of 
study intervention, including pregnancy in the partner of male participants, should be reported 
to AstraZeneca except if the pregnancy is discovered before the study participant has received 
any study intervention.
8.3.13.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, IMP should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IMP under study 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
anomalies/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 anomaly) should be followed up and documented even if the participant
was discontinued from the study.
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate Sponsor representatives within one day, ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is provided to the Sponsor Patient Safety data entry site within one or 5 calendar 
days for SAEs (see Section 8.3.12) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy.
8.3.13.2
Paternal Exposure 
Male participants should refrain from fathering a child or donating sperm during the study and 
for 4 months after the last dose of study intervention. 
Pregnancy of the participant’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 anomaly) occurring from the date of the first dose of study intervention
until 4 months after the last dose of study intervention should, if possible, be followed up and 
documented in the Pregnancy Report Form. Consent from the partner must be obtained before 
the Pregnancy Report Form is completed.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
99 of 187
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the investigator must obtain the consent of the participant’s partner. The local study team 
should adopt the Master Pregnant Partner Form in line with local procedures/requirements and 
submit it to the relevant Regulatory Authority/IRB/IEC prior to use.
8.3.14
Medication Error
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate Sponsor representatives within one day, ie, immediately but 
no later than 24 hours of when he or she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is completed on the specific medication error eCRF within one (initial 
fatal/life-threatening or follow up fatal/life-threatening) or 5 (other serious initial and follow 
up) calendar days if there is an SAE associated with the medication error (see Section 8.3.1) 
and within 30 days for all other medication errors.
The definition of a medication error can be found in Appendix B.
8.3.15
Management of IMP-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 IMP
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 IMP along with appropriate continuing 
supportive care. If medically appropriate, dose modifications are permitted. 

All dose modifications should be documented with clear reasoning and documentation of 
the approach taken.
See Section 6.6, and Sections 8.3.15.1 and Section 8.3.15.2 below for dose modification 
guidance. 
All toxicities will be graded according to NCI CTCAE, Version 5.0.
8.3.15.1
Monalizumab
The monalizumab TMGs provide information for the management of immune-mediated 
reactions, infusion-related reactions, and non-immune mediated reactions that may be 
observed with monalizumab, with specific instructions for dose modifications (omissions and 
discontinuations) and treatment interventions. The most current version of the TMGs is 
provided to the investigative site as a supplement to the CSP and is maintained within the Site 
Master File. 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
100 of 187
Participants should be thoroughly evaluated, and appropriate efforts should be made to rule 
out neoplastic, infectious, metabolic, toxic, or other etiologic causes of the suspected 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 
monalizumab should be permanently discontinued (see Section 7.1 and the monalizumab 
TMGs). Following the first dose of monalizumab, subsequent administration of monalizumab 
can be modified based on toxicities observed as described in the TMGs. 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 monalizumab regimen by the reporting investigator.
Dose reductions are not permitted. In case of doubt, the investigator should consult with the 
Study Clinical Lead.
8.3.15.2
Cetuximab
Please refer to the local label (where available) for the management of AEs with cetuximab.  
In case of infusion-related reactions to cetuximab, manage as per local label (where available)
for cetuximab and institutional guidance on management of infusion-related reactions. 
For management of AEs with cetuximab, refer to the local label.
8.4
Overdose
Use of monalizumab or cetuximab in doses exceeding those specified in the protocol is 
considered to be an overdose. There is currently no specific treatment in the event of overdose 
of monalizumab, and possible symptoms of overdose are not established. If an overdose of 
cetuximab occurs, please refer to the local label (where available). 

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module
If an overdose on an AstraZeneca IMP occurs in the course of the study, the investigator or 
other site personnel inform appropriate AstraZeneca representatives immediately, but no later 
than 24 hours of when he or she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is provided to the Sponsor Patient Safety data entry site within 1 or 5 calendar 
days for overdoses associated with an SAE (see Section 8.3.12) and within 30 days for all 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
101 of 187
other overdoses.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the study 
specific laboratory manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on Handling of Human Biological 
Sample see Appendix D.
Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed/repatriated. 

Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalization or 
6 months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
consented for future analyses. 

Pharmacokinetic samples may be disposed of or anonymized by pooling. Additional 
analyses may be conducted on the anonymized, pooled PK samples to further 
evaluate and validate the analytical method. Any results from such analyses may be 
reported separately from the CSR.

Remaining ADA sample aliquots will be retained at AstraZeneca or its designee for a 
maximum of 15 years following issue of the CSR. Additional use includes but is not 
limited to further characterization of any ADAs, confirmation and/or requalification of 
the assay, as well as additional assay development work. The results from future analysis 
will not be reported in the CSR.
8.5.1
Pharmacokinetics

Blood samples will be collected for measurement of serum concentrations of 
monalizumab and cetuximab as specified in the SoA. 

Samples may be collected at additional time points during the study if warranted and 
agreed upon between the investigator and the Sponsor, eg, for safety reasons. The timing 
of sampling may be altered during the course of the study based on newly available data 
(eg, to obtain data closer to the time of peak or trough matrix concentrations) to ensure 
appropriate monitoring. 

Serum samples will be used to analyze the PK of monalizumab and cetuximab. Samples 
collected for analyses of monalizumab and cetuximab serum concentration may also be 
used to evaluate safety or efficacy aspects related to concerns arising during or after the 
study.

Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory 
Manual.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
102 of 187
8.5.1.1
Determination of Drug Concentration
Samples for determination of drug concentration in serum will be assayed by bioanalytical test 
sites operated by or on behalf of the Sponsor, using an appropriately validated bioanalytical 
method. Full details of the analytical method used will be described in a separate bioanalytical 
report.
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel [until the study has been unblinded].
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report.
8.5.2
Immunogenicity Assessments
Blood samples for determination of ADA in serum will be assayed by bioanalytical test sites 
operated by or on behalf of the Sponsor, using an appropriately validated bioanalytical 
method. Full details of the methods used will be described in a separate report.
Antidrug antibody samples may also be further tested for characterization of the ADA 
response.
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
8.6
Human Biological Sample Biomarkers
8.6.1
Collection of Mandatory Samples for Biomarker Analysis
Samples for biomarker research are required and will be collected from all participants in this 
study as specified in the SoA (Section 1.3). Details for sample collection, processing, and 
testing are provided in the Laboratory Manual.
At screening, all participants will be asked to provide formalin-fixed paraffin-embedded
samples from archival or fresh tumor biopsy (acquired ≤3 months prior to screening). Tumor 
tissue beyond the 3-month window and up to 6 months old may be considered upon Sponsor 
consultation, provided that no intervening systemic regimen was ongoing at the time of 
sample collection (see the Laboratory Manual for more information). Archival tumor biopsies
older than 6 months (> 6 months) or collected when previous treatments were still ongoing are
not acceptable. Participants whose archival tumor tissue is unavailable or unsuitable for use 
will be asked to provide a fresh tumor biopsy. Fresh tumor biopsy should not be collected 
from lesions in proximity to cardiopulmonary, visceral, or vital neurovascular structures that 
could make the collection procedure high risk.
The screening tumor biopsy will be evaluated for the expression of HLA-E and NKp46 in the

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
103 of 187
TME by IHC. Associations between HLA-E Dnd NKp46 expression and the participant’s 
radiologicresponse (RECIST 1.1) will be assessed. 
 
 
8.6.2
Collection of Optional Biomarker Samples
Optional samples maybe collected for biomarker research aslisted in the SoA (Section 1.3).
All participantswill be asked to provide consent for collection of tumor biopsies once during 
treatment and at time of progression. 
 
 
8.6.3
Other Study-related Biomarker Research
8.7
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
104 of 187
 
8.8
Medical Resource Utilization and Health Economics
For economic evaluation for payer submissions, it is necessary to capture healthcare resource 
utilization related to the intervention and the underlying disease. Within this study, the 
following will be captured:
!
Treatment-related to AEs (including the method of delivery of the treatment) captured in 
AE/SAE assessment module
!
Treatment not related to the study obtained in Concomitant Medications eCRF
8.9
Study Participant Feedback Questionnaire
Participants will have the option to complete the anonymized SPFQ assessing their clinical 
study experience (see Appendix J; assessment schedule is presented in Section 1.3). 
Participants who do not wish to complete this questionnaire may still participate in the study. 
Individual participant-level responses will not be reviewed by investigators. Responses would 
be used by the Sponsor to understand where improvements can be made in the clinical study 
process. This questionnaire does not collect data about the participant’s disease, symptoms, 
treatment effect, or AEs and therefore would not be study data.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
The formal statistical analysis will be performed to test the following main hypotheses for 
monalizumab plus cetuximab (Arm A) or placebo plus cetuximab (Arm B): 
!
H0: No difference between Arm A and Arm B
!
H1: Difference between Arm A and Arm B
9.2
Sample Size Determination
Approximately 624 participants will be randomized 2:1 to monalizumab plus cetuximab 
(Arm A) or placebo plus cetuximab (Arm B). Randomization will be stratified by HPV status 
(OPC HPV positive or HPV-unrelated), WHO/ECOG PS (0 or 1), or number of prior lines of 
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
105 of 187
therapy in the R/M setting (1 or 2).
The study is powered to demonstrate superiority in the OS benefit of Arm A vs Arm B in 
HPV-unrelated participants with R/M SCCHN previously treated with an ICI.  
There will be two planned IAs and one FA for the study.
Interim Analysis 1 (IA1): Futility in OS will be evaluated when approximately 99 OS events 
have occurred across Arm A and Arm B in HPV-unrelated participants (25% information 
fraction) and randomized at least 2 months before the DCO for the futility analysis (ie, with a 
minimum follow-up of 2 months).
Interim Analysis 2 (IA 2): A hypothesis of  monalizumab plus cetuximab (Arm A) prolongs
OS compared to placebo plus cetuximab (Arm B) will be tested at IA2 when approximately 
278 OS events have occurred across Arm A and Arm B in HPV-unrelated participants 
(approximately 70% information fraction, 56% maturity).
Final Analysis (FA): A hypothesis of improved OS will be tested at the final analysis when
approximately 397 OS events have occurred across Arm A and Arm B in HPV-unrelated
participants (approximately 80% maturity).
If the true OS HR is 0.72, corresponding to an approximate 3-month improvement in median 
OS compared to Arm B of 7.7 months, approximately 397 OS events in HPV-unrelated
participants will provide approximately 86.5% power to demonstrate statistical significance at 
the 5% level (using a 2-sided test) for the FA. The 5% (2-sided) alpha for the OS analysis will 
be controlled at the IA2 and FA time points by using the Lan-DeMets (Lan and DeMets 1983)
spending function that approximates the O’Brien-Fleming approach, where the significance 
level applied depends upon the proportion of information (ie, information fraction) available 
at time of IA2. For example, if the information fraction for OS at IA2 is 70% then the 
two-sided significance levels of 1.48% and 4.55% will be applied to IA2 and FA for OS, 
respectively. The smallest detectable treatment difference in HR, ie, critical value, that could 
be statistically significant at the FA is 0.81. With a planned recruitment period of 30 months, it 
is expected that a total of 498 HPV-unrelated participants are needed in order to achieve 
397 OS events with a follow-up period of approximately 12 months. The 278 OS events for 
the IA2 are expected to be reached approximately 30.5 months after the randomization of the 
first participant.
The number of OPC HPV-positive participants will be closely monitored throughout the study 
and are planned to be capped at approximately 20%of the total sample size. With the 
assumption of 20% OPC HPV-positive participants in the overall participants, approximately 
624 randomized participants will be needed in overall population. Under the same assumption 
of effect size in HR and median OS stated above, approximately 498 OS events are expected 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
106 of 187
in all participants which will provide approximately 93.0% power to demonstrate statistical 
significance at the 5% level (using a 2-sided test) for the FA.
9.3
Populations for Analyses
Definitions of the analysis sets for each endpoint are provided in Table 9.
Table 9
Summary of Outcome Variables and Analysis Populations
Endpoint
Population
Efficacy data
OS
HPV-unrelated Analysis Set and Full Analysis Set
PFS
HPV-unrelated Analysis Set and Full Analysis Set
ORR a, DoR, and PRO b endpoints
HPV-unrelated Analysis Set and Full Analysis Set
Demography and other baseline characteristics
HPV-unrelated Analysis Set and Full Analysis Set
PK data
PK data
PK Analysis Set
Biomarker data
Biomarker data
HPV-unrelated Analysis Set and Full Analysis Set
Safety data
Exposure
Safety Analysis Set
AEs
Safety Analysis Set
Laboratory measurements
Safety Analysis Set
Vital signs and other safety
Safety Analysis Set
ADA data
ADA Analysis Set
a
ORR: measurable disease at baseline.
b
PRO: evaluable PRO measurements
ADA = antidrug antibody; AE = adverse event; DoR = duration of response; HPV = human papillomavirus; 
ORR = objective response rate; OS = overall survival; PFS = progression-free survival; 
PK = pharmacokinetic(s); PRO = patient-reported outcome.
9.3.1
HPV-unrelated Analysis Set
The primary population is the HPV-unrelated Analysis Set which will include all randomized 
participants who are either OPC HPV negative or non-OPC regardless of the HPV status. The 
HPV status will be determined by HPV status in the CRF and not the IVRS value. The 
HPV-unrelated Analysis Set will be used for summarizing baseline characteristics, all efficacy 
analyses, including PROs and biomarker analyses. Treatment arms will be compared on the 
basis of randomized study intervention, regardless of the intervention actually received. 
Participants who were randomized but did not subsequently go on to receive study 
intervention are included in the analysis in the treatment arm to which they were randomized.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
107 of 187
Analysis for ORR will be based on participants in the FAS who had measurable disease at 
baseline. Analysis of DoR will be based on participants in the FAS who achieved objective 
response.
9.3.2
Full Analysis Set
The FAS will include all randomized participants. The FAS will be used for summarizing 
baseline characteristics, all efficacy endpoints (including PROs) and biomarker analyses as 
secondary analyses. Treatment arms will be compared on the basis of randomized study 
intervention, regardless of the intervention actually received. Participants who were 
randomized but did not subsequently go on to receive study intervention are included in the 
analysis in the treatment arm to which they were randomized.
9.3.3
Safety Analysis Set
The SAF will consist of all participants who received any amount of study treatment. Safety 
data will not be formally analyzed but summarized descriptively using the SAF according to 
the intervention received; that is, erroneously-treated participants (eg, those randomized to 
Arm A but actually given Arm B intervention) will be summarized according to the study 
intervention they actually received.
9.3.4
Pharmacokinetic Analysis Set
All participants who receive at least one dose of 
 per the protocol 
for whom there is at least one reportable PK concentration and who do not violate or deviate 
from the protocol in ways that would significantly affect the PK analyses will be included in 
the PK Analysis Set. The population will be defined by the Study Clinical Lead, 
pharmacokineticist, and statistician prior to any PK analyses being performed.
9.3.5
ADA Analysis Set
The ADA Analysis Set will include all participants who have non-missing baseline ADA and 
at least one non-missing post-baseline ADA results. All major ADA analyses will be based on 
the ADA Analysis Set.
9.4
Statistical Analyses
Analyses will be performed by the Sponsor or its representatives. A comprehensive SAP will 
be developed and finalized before database lock and will describe the participant populations 
to be included in the analyses, and procedures for accounting for missing, unused, and 
spurious data. This section is a summary of the planned statistical analyses of the primary and 
secondary endpoints. Any deviations from this plan will be reported in the CSR.
9.4.1
General Considerations
A hypothesis of improved OS will be tested at IA2 when approximately 278 OS events have 
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
108 of 187
occurred across Arm A and Arm B in HPV-unrelated participants (approximately 56% 
maturity; IA2).
A hypothesis of improved OS will be tested at the final analysis when approximately 397 OS 
events have occurred across Arm A and Arm B in HPV-unrelated participants (approximately 
80% maturity; FA).
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 IMP, except for efficacy variables. For efficacy variables, baseline is defined 
as the last visit prior to randomization.
All data collected will be listed. Efficacy and PRO data will be summarized and analyzed 
based on the HPV-unrelated Analysis Set and will be repeated for FAS as a secondary 
analysis. PK data will be summarized and analyzed based on the PK Analysis Set. Safety data 
will be summarized on the SAF. Antidrug antibody data will be summarized on the ADA 
Analysis Set.
Results of all statistical analysis will be presented using a 95% CI and 2-sided p-value, unless 
otherwise stated.
The following table details which endpoints are to be subjected to formal statistical analysis, 
together with pre-planned sensitivity analyses, making it clear which analysis is regarded as 
primary for that endpoint.
Table 10
Pre-planned Statistical and Sensitivity Analyses to be Conducted for 
Efficacy and COA Endpoints
Endpoints analyzed
Notes
Overall survival (Primary) in 
HPV-unrelated Analysis Set
Primary confirmatory analysis
Stratified log-rank test adjusting for, WHO/ECOG PS and number of prior 
lines of therapy in the R/M setting for primary comparison of survival 
between randomized treatment arms
Sensitivity and supplemental analysis
Assessment of assumption of proportionality and stratified max combo test
Subgroup analysis using Cox model

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
109 of 187
Table 10
Pre-planned Statistical and Sensitivity Analyses to be Conducted for 
Efficacy and COA Endpoints
Endpoints analyzed
Notes
Overall survival (Secondary) in 
FAS
Secondary confirmatory analysis
Stratified log-rank test adjusting for HPV status, WHO/ECOG PS, number 
of prior lines of therapy in the R/M setting
Sensitivity and supplemental analysis
Subgroup analysis using Cox model
Progression-free survival 
(Secondary) in HPV-unrelated 
Analysis Set and FAS
PFS according to RECIST 1.1 based on investigator assessments will be 
analyzed as a secondary variable.  
Secondary confirmatory analysis 
For HPV-unrelated Analysis Set, stratified log-rank tests adjusting for
WHO/ECOG PS and number of prior lines of therapy in R/M setting, using 
PFS according to RECIST 1.1 based on investigator assessments
For FAS, stratified log-rank tests adjusting for HPV status, WHO/ECOG 
PS, number of prior lines of therapy in R/M setting, using PFS according to 
RECIST 1.1 based on investigator assessments
Sensitivity and supplemental analysis
Analysis using alternative censoring rules – attrition bias
Subgroup analysis using Cox proportional hazards model
Objective response rate 
(Secondary) in HPV-unrelated 
Analysis Set and FAS
For HPV-unrelated Analysis Set, logistic regression adjusted for 
WHO/ECOG PS, number or prior lines of therapy in the R/M setting, using 
tumor data according to RECIST 1.1 based on investigator assessment
For FAS, logistic regression adjusted HPV status, WHO/ECOG PS, 
number or prior linesof therapyin the R/M setting, using tumor data 
according to REC,ST1.1 based oninvestigator assessment
Duration of response (Secondary)
in HPV-unrelated Analysis Set 
and FAS
KM plots based on the tumor data using investigator assessment of 
RECIST 1.1. Median DoR calculated from the KM curve.
Each scale/item of EORTC 
QLQ-C30 and QLQ-H&N35 
(Secondary) in HPV-unrelated 
Analysis Set and FAS
Summary and descriptive statistics
Unadjusted change from baseline
Key symptoms, functions, global 
health status/QoL of EORTC 
QLQ-C30 and QLQ-H&N35 
(Secondary) in HPV-unrelated 
Analysis Set and FAS
MMRM analysis (overall and by each visit)
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
110 of 187
Table 10
Pre-planned Statistical and Sensitivity Analyses to be Conducted for 
Efficacy and COA Endpoints
Endpoints analyzed
Notes
Time to symptom, function, or 
HRQoL deterioration of key COA 
endpoints using EORTC 
QLQ-C30 and QLQ-H&N35 
(Secondary) in HPV-unrelated 
Analysis Set and FAS
Stratified log-rank test
COA = clinical outcome assessment; CR = complete response; DCR = disease control rate; DoR = duration of 
response; EORTC = European Organisation for Research and Treatment of Cancer; 
 
FAS = Full Analysis Set; HPV = human papillomavirus; 
HR = hazard ratio; HRQoL = health related quality of life; KM = Kaplan Meier; MMRM = mixed-effect model 
repeated measure; OS = overall survival; PFS = progression-free survival; 
 
 
 PR = partial response; 
 
PS = performance status; QLQ-C30 = 30-item Core Quality of Life Questionnaire; QLQ-H&N35 = 35-Item 
Head and Neck Cancer Quality of Life Questionnaire; QoL = quality of life; RECIST 1.1 = Response Evaluation 
Criteria in Solid Tumors, version 1.1; R/M = recurrent/metastatic; SAP = statistical analysis plan; SD = stable 
disease; WHO/ECOG = World Health Organization/Eastern Cooperative Oncology Group.
9.4.1.1
Methods for Multiplicity Control
Strong control of the FWER at 5% level (2 sided) across the testing of OS and PFS endpoints 
will be achieved through a combined approach of alpha allocation to the OS analyses (IA2 and 
the FA) via alpha spending function and a hierarchical testing procedure; that is, OS in FAS 
will be tested only if OS in HPV-unrelated analysis set met significance at IA2 or FA; PFS 
will be tested only if OS met statistical significance at IA2 or FA and PFS in FAS will be 
tested only if PFS in HPV-unrelated analysis set met statistical significance at IA2 or FA
(Glimm et al 2010) (Figure 3). The IA2 for OS will be conducted when approximately 278 of 
the 397 expected OS events (ie, 70% information fraction) have occurred in HPV-unrelated
participants. Using the Lan-DeMets spending function approximating O’Brien-Fleming 
boundaries, 2-sided significance levels of 0.0148 and 0.0455 will be applied to OS IA2 and 
FA, respectively (Lan and DeMets 1983). 
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
111 of 187
Figure 3
Graphical Presentation of the Propose Multiple-Testing Procedure at 
IA2 and FA
FA = final analysis; FAS = full analysis set; HPV = human papillomavirus; IA2 = interim analysis 2; 
OS = overall survival; PFS = progression-free survival.
Notes: At each analysis (IA2 and FA), PFS will be formally tested only if OS meets statistical significance.
Each statistical test will be performed only if the preceding test is statistically positive. At the 
time of OS IA2, the PFS data will be mature given its expected short median of 2.3 months in 
this population (Cohen et al 2019b, Ferris et al 2016, Rischin et al 2019) and it will be tested 
at 5% significance level. 
9.4.2
Efficacy 
9.4.2.1
Primary Endpoint
Derivation of primary endpoint
The primary endpoint OS is defined as the time from the date of randomization until date of 
death due to any cause. Any participant not known to have died at the time of analysis will be 
censored based on the last recorded date on which the participant was known to be alive.  
Note: Survival calls will be made following the date of DCO for the IAs or FA (these contacts 
should generally occur within 7 days of the DCO). If participants are confirmed to be alive or 
if the death date is post the DCO date, these participants will be censored at the date of DCO. 
Death dates may be found by checking publicly available death registries.
Primary analysis
Overall survival in the HPV-unrelated Analysis Set will be analyzed using a stratified log-rank 
test, adjusting for WHO/ECOG PS (0 or 1) and number of lines of prior therapy in the 
R/M setting (1 or 2). The HR and its CI will be estimated from a stratified Cox Proportional 
Hazards model. The effect in Arm A vs Arm B will be estimated by the HR together with its 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
112 of 187
corresponding CI and p-value (from stratified log-rank test). Kaplan-Meier plots will be 
presented by treatment arm. Summaries of the numbers and percentages of participants 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 arm.
Sensitivity analysis 
The assumption of proportionality will be assessed first by examining the 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, a stratified max-combo test will be used as a sensitivity 
analysis with the same stratification factors as the primary analysis. The max-combo test is 
based on an adaptive procedure, optimizing test statistics among log rank test (FH0,0) and the 
FH weighted log-rank test (Harrington and Fleming 1982) (FH0,1 and FH1 ,1) with alpha 
correction (Karrison 2016). It is a more robust and powerful test under NPH when compared 
to the log-rank test and is recommended by the Cross-Pharma Non-proportional Hazard 
Working Group in presence of NPH (Lin et al 2020). 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 will be investigated. In addition, the 
KM curve along with landmark analyses (eg, one-year OS rate) will also help in 
understanding the treatment benefit. 
Analysis of OS in FAS
Overall survival in the FAS will be analyzed similarly except that the stratified log-rank test 
will be adjusted for HPV status (OPC HPV positive or HPV-unrelated), WHO/ECOG PS (0 or 
1), and number of lines of prior therapy in the R/M setting (1 or 2).
Subgroup analysis
Subgroup analyses will be conducted comparing OS between Arm A vs Arm B in the 
following subgroups of the HPV-unrelated Analysis Set and FAS (but not limited to): 

Sex (male vs female)

Age at randomization (< 65 vs ≥ 65 years of age)

Human papillomavirus status (OPC HPV positive or HPV-unrelated) (applicable to FAS 
only)

WHO/ECOG PS (0 or 1) 

Number of prior lines of therapy in the R/M setting (1 or 2)

Race/ethnicity data (Asian vs non-Asian)

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
113 of 187
Other baseline variables may also be assessed if there is clinical justification or 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. Forest 
plots will be presented.
Additionally, for each subgroup, the HR (Arm A:Arm B) and 95% CI will be calculated from 
a Cox proportional hazards model with treatment as the only covariate. These will be 
presented on a forest plot including the HR and 95% CI from the overall population.  
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 and 
PFS.
9.4.2.2
Secondary Endpoints
The analysis of the secondary efficacy endpoints, PFS, ORR, and DoR, will be primarily 
based on the site investigator assessments using RECIST 1.1. 
All investigator RECIST 1.1 assessments, whether scheduled or unscheduled, will be included 
in the calculations. This is also regardless of whether a participant discontinues study 
intervention or receives another anticancer therapy.  
At each visit, participants 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 28 days prior to enrollment. If a 
participant has had a tumor assessment that cannot be evaluated, then the participant will be 
assigned a visit response of NE (unless there is evidence of progression in which case the 
response will be assigned as PD).
Please refer to Appendix G for the definitions of CR, PR, SD, and PD.
9.4.2.2.1
Progression-free Survival
Derivation of PFS
The secondary endpoint PFS will be defined as the time from randomization until progression, 
per RECIST 1.1 as assessed by the investigator at local site or death due to any cause, 
whichever occurs first, regardless of whether the participant withdraws from study 
intervention or receives another anticancer therapy prior to progression (ie, date of event or 
censoring – date of randomization + 1). Participants 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 participant progresses or dies after 2 or 
more consecutively missed visits, the participant will be censored at the time of the latest 
evaluable RECIST 1.1 assessment prior to the 2 missed visits. If the participant has no 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
114 of 187
evaluable visits or does 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 on 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 assessment/scan dates of the component that indicates
progression.

When censoring a participant for PFS, the participant will be censored at the latest of the
scan dates contributing to a particular overall visit assessment.
Analysis of PFS
The secondary endpoint PFS analysis will also be based on the programmatically derived 
RECIST 1.1 using the investigator tumor assessments. The analysis will be performed in both 
the HPV-unrelated Analysis Set and FAS using a stratified log-rank test, adjusting for HPV 
status (for FAS only), WHO/ECOG PS, and number of prior lines of therapy in the R/M 
setting. The effect of Arm A vs Arm B will be estimated by the HR together with its 
corresponding 95% CI and p-value.
Kaplan Meier plots of PFS will be presented by treatment arm. Summaries of the number and 
percentage of participants experiencing a PFS event and the type of event (RECIST 1.1 or 
death) will be provided along with median PFS for each treatment arm.
Sensitivity analysis of PFS
Sensitivity analyses will be performed to assess attrition bias by repeating the PFS analysis 
except that the actual PFS event times, rather than the censored times, of participants who 
progressed or died in the absence of progression immediately following 2 or more 
non-evaluable tumor assessments will be included. In addition, participants who take 
subsequent therapy prior to progression or death will be censored at their last evaluable 
assessment prior to taking the subsequent therapy. This analysis will be supported by a KM
plot of the time to censoring where the censoring indicator of the PFS analysis is reversed.
Further sensitivity analysis may be documented in the SAP. 
Subgroup analysis
Subgroup analyses will be conducted comparing PFS (per RECIST 1.1 using investigator 
assessments) between Arm A and Arm B in the subgroups, as specified in Section 9.4.2.1.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
115 of 187
9.4.2.2.2
Objective Response Rate
Derivation of ORR
ORR is defined as the proportion of participants with measurable disease who have a 
confirmed CR or PR, as determined by the investigator at local site per RECIST 1.1. Data 
obtained up until progression, or the last evaluable assessment in the absence of progression, 
will be included in the assessment of ORR. Participants who discontinue study intervention 
without progression, receive a subsequent therapy, and then respond will not be included as 
responders in the ORR.  
Analysis of ORR
Objective response rate will be based on the programmatically-derived RECIST using the 
investigator tumor data. ORR will be compared between Arm A and Arm B using a logistic 
regression model, adjusting for the same factors as the primary endpoint (HPV status [for FAS 
only], WHO/ECOG PS, number of prior lines of therapy in the R/M setting). The results of 
the analysis will be presented in terms of an odds ratio together with its associated profile 
likelihood 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 in the subset of 
participants in the HPV-unrelated Analysis Set who had measurable disease at baseline. This 
analysis will be repeated for the subset of participants in the FAS who had measurable disease 
at baseline.
Summaries will be produced that present the number and percentage of participants with a 
tumor response (CR/PR). Overall visit response data will be listed for all participants (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.
9.4.2.2.3 
Duration of Response
Derivation of DoR
The secondary endpoint DoR (per RECIST 1.1 using investigator assessment) 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 participant does not progress following a response, 
then their DoR will be censored at the PFS censoring time. Duration of response will not be 
defined for those participants who do not have documented response.
Analysis of DoR
Kaplan Meier plots of DoR based on the investigator assessment of RECIST 1.1 will be 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
116 of 187
presented. Median DoR will also be summarized and calculated from the KM curve. Only 
participants who have a confirmed response will be included in this summary table. Swimmer 
plots that clearly show the profile of each participant who responds will also be produced.
9.4.2.2.4
Patient-reported Outcome: EORTC QLQ-C30
Scoring
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 measure of health 
status scale in the EORTC QLQ-C30 according to the EORTC QLQ-C30 Scoring Manual.  
Higher scores on the global measure of health status and functional scales indicate better 
health status/function, but higher scores on symptom scales represent greater symptom 
severity. 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.  
Analysis methods
A main PRO instrument identified in the secondary objectives are global health status/QoL, 
physical functioning, fatigue, pain, and appetite loss subscales of the EORTC QLQ-C30.
The primary assessment of global health status/QoL, physical functioning, or symptom will 
focus on comparing the mean change from baseline between treatment arms. The analysis 
population will be a subset of the HPV-unrelated Analysis Set, including all participants in the 
HPV-unrelated Analysis Set with an evaluable baseline assessment and at least one evaluable 
post-baseline assessment. Change from baseline will be analyzed using a mixed-model 
repeated measurements analysis of all the post-baseline scores. The model will include 
treatment arm, visit, and treatment by visit interaction as explanatory variables, and the 
baseline score and baseline score by visit as covariates. Adjusted mean change from baseline 
estimates per treatment arm and corresponding 95% CIs will be presented, along with an 
overall estimate of the treatment difference, 95% CI, and p-value.
Additional analyses will include time to deterioration.
The analysis will be repeated for a subset of the FAS, including all randomized participants 
with an evaluable baseline assessment and at least one evaluable post-baseline assessment.
Details of all statistical analyses and appropriate sensitivity analyses will be described in full 
in the SAP. 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
117 of 187
9.4.2.2.5
Patient-reported Outcome: EORTC QLQ-H&N35
Scoring
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.
Analysis methods
Another main PRO instrument identified in the secondary objectives are from the 4-symptom 
scales/items in the QLQ-H&N35 (pain, swallowing, senses, and speech).
The primary assessment of symptoms will focus on comparing the mean change from baseline 
between treatment arms. The analysis population will be a subset of the HPV-unrelated
Analysis Set, including all participants in HPV-unrelated Analysis Set with an evaluable 
baseline assessment and at least one evaluable post-baseline assessment. Change from 
baseline will be analyzed using a mixed-model repeated measurements analysis of all the 
post-baseline scores. The model will include treatment arm, visit, and treatment by visit 
interaction as explanatory variables, and the baseline score and baseline score by visit as 
covariates. Adjusted mean change from baseline estimates per treatment arm and 
corresponding 95% CIs will be presented, along with an overall estimate of the treatment 
difference, 95% CI, and p-value.
Additional analyses will include time to deterioration. 
The analysis will be repeated for a subset of the FAS, including all randomized participants 
with an evaluable baseline assessment and at least one evaluable post-baseline assessment.
Details of all statistical analyses and appropriate sensitivity analyses will be described in full 
in the SAP. 
9.4.2.3
Exploratory Endpoints
9.4.2.3.1
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
118 of 187
9.4.2.3.2
9.4.2.3.3
9.4.2.3.4
9.4.3
Safety
9.4.3.1
Calculation or Derivation of Safety Variables
9.4.3.1.1
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 participants. Data from 
all cycles of treatment will be combined in the presentation of safety data. “On treatment” will 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
119 of 187
be defined as assessments between date of start dose and 90 days following discontinuation of 
IMP (ie, the last dose of monalizumab, cetuximab, or placebo). For AEs, on-treatment (or 
treatment-emergent) AEs will be defined as any AEs that started after dosing or prior to dosing 
and which worsen following exposure to the study treatment.
Adverse events observed up until 90 days following discontinuation of the IMP or until the 
initiation of the first subsequent therapy following discontinuation of treatment (whichever 
occurs first) will be used for the reporting of the AE summary tables. This will more 
accurately depict AEs attributable to study treatment only, as a number of AEs up to 90 days 
following discontinuation of the IMP are likely to be attributable to subsequent therapy. 
However, to assess the longer-term toxicity profile, AE summaries will also be produced 
containing AEs observed up until 90 days following discontinuation of the IMP (ie, without
taking subsequent therapy into account). Any events in this period that occur after a 
participant has received further therapy for cancer (following discontinuation of study 
treatment) will be flagged in the data listings.
The SAF will be used for reporting of safety data.
A separate data listing of AEs occurring > 90 days after discontinuation of IMP will be 
produced. These events will not be included in AE summaries.  
9.4.3.1.2
Other 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/RR1/3, where RR is in seconds
Corrected calcium product 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)] × 0.02)
The denominator used in laboratory summaries will only include evaluable participants, 
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 participants would have 
both a pre-dose and at least 1 post-dose value recorded.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
120 of 187
!
If a CTCAE criterion does not consider changes from baseline to be evaluable, the 
participant need only have 1 post-dose value recorded.
The denominator in vital signs data should include only those participants with recorded data.
9.4.3.2
Analysis of safety variables
All safety analyses will be performed on the SAF. Safety and tolerability data will be 
presented by treatment arm based on actual treatment received.
Data from all cycles of treatment will be combined in the presentation of safety data. Adverse 
events (both in terms of Medical Dictionary for Regulatory Activities preferred terms and 
CTCAE grade) will be listed individually by participant. The number of participants
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 produced.
Other safety data will be assessed in terms of physical examination, clinical chemistry, 
hematology, vital signs, WHO ECOG/PS, and ECGs. Exposure to monalizumab plus 
cetuximab combination therapy and cetuximab will be summarized. Time on study, dose 
delays/dose modifications of monalizumab and cetuximab will also be summarized. At the end 
of the study, appropriate summaries of all safety data will be produced, as defined in the SAP.
9.4.4
Other Analyses 
9.4.4.1
Healthcare Resource Use
The potential impact the disease and treatment have on healthcare resource use will be 
analyzed for the purposes of submissions to payers (eg, pricing and reimbursement 
agencies and health technology assessment bodies). Descriptive statistics (as appropriate, 
including means, median, counts and frequencies, standard deviation, interquartile range, 
skew, and range) will be provided for each treatment arm on the different types of hospital 
admissions, the length of stay for participants admitted to the hospital (eg, inpatient, 
emergency room, intensive care unit), as well as the participant’s primary sign or symptom. To 
support submissions to payers, additional analyses may be undertaken and will be outlined in 
a separate Payer Analysis Plan.
9.4.4.2
Pharmacokinetic Data
Monalizumab serum concentration data will be listed for each participant by monalizumab 
treatment and each dosing day; cetuximab serum concentration data will be listed for each 
participant with cetuximab treatment and each dosing day. Summary will be provided for PK 
Analysis Set.
9.4.4.3
Immunogenicity Data
Immunogenicity results will be listed by participant, and a summary will be provided by the 
number and percentage of participant who develop detectable 
 
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
121 of 187
and anti-cetuximab antibodies. The immunogenicity titer will be listed for samples confirmed 
positive for the presence of 
 and anti-cetuximab antibodies.  
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. A detailed plan 
will be written by the Sponsor Clinical Pharmacology group or designee.
9.4.4.4
Pharmacokinetic/Pharmacodynamic Relationships
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.
9.4.4.5
Biomarker Data
9.5
Interim Analyses 
Two IAs are planned as described below.
IA1: The first interim analysis will be performed when approximately 99 OS events have been 
observed in the HPV-unrelated participants (25% information fraction) in participants 
randomized at least 2 months before the DCO for the futility analysis (ie, with a minimum 
follow-up of 2 months). Based on enrollment assumptions, it is expected that this will occur 
approximately 19 months after randomization of the first participant. The objective of IA1 is 
to evaluate futility of the Arm A compared to Arm B in terms of OS in the HPV-unrelated
participants. 
OS will be analyzed using a stratified Cox Proportional Hazards model as described in 
Section 9.4.2.1 and HR with its CI will be reported. The futility criteria are determined as
observed HR at IA1 >
 which corresponds to 
 conditional power assuming future 
data is consistent with current IA trend. 
IA2: The second interim analysis will be performed when approximately 278 OS events have 
been observed in the study (56% maturity or 70% information fraction) in the HPV-unrelated 
population. Based on enrollment assumptions, it is expected that this will occur approximately 
30 months after randomization of the first participant.
The IA2 will evaluate the efficacy of Arm A compared to Arm B in terms of OS in the 
HPV-unrelated population (primary objective). 
CCI
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
122 of 187
The SAP will describe the planned IAs in greater detail.
9.6
Data Monitoring Committee
For details on the Independent Data Monitoring Committee, refer to Appendix A 5
9.7
Impact of COVID-19 on Data
Depending on the extent of any impact, summaries of data relating to participants diagnosed 
with COVID-19, and impact of COVID-19 on study conduct (in particular missed visits, 
delayed or discontinued study treatments, and other protocol deviations) may be generated. 
More detail will be provided in the SAP.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
123 of 187
Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines

Applicable ICH GCP Guidelines

Applicable laws and regulation

The protocol, protocol amendments, ICF, IB, and other relevant documents (eg,
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.

The Sponsor will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO but the accountability remains with the Sponsor.
Regulatory reporting requirements for SAEs

Prompt notification by the investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.

The Sponsor has a legal responsibility to notify both the local regulatory authority and
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.

For all studies except those utilizing medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review and then file it along with the [IB or state other documents] and will notify the
IRB/ IEC, if appropriate according to local requirements.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
124 of 187
A 2
Financial Disclosure
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.

Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants or their legally authorized representative will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act
requirements, where applicable, and the IRB/IEC or study center.

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.

If a participant declines to participate in a voluntary exploratory genetic research 
component of the study, there will be no penalty or loss of benefit to the participant and 
he/she will not be excluded from other aspects of the study.

If a participant’s partner becomes pregnant during or within 90 days after the last dose of 
study intervention, the partner is asked to sign the “Adult Study Informed Consent Form 
for Pregnant Partners of Study Patients” and provide information about the pregnancy 
accordingly. 
Participants who are rescreened will resign and date their original ICF(s), next to their original 
signature and date, or according to local or site-specific procedures.
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples. The investigator or authorized 
designee will explain to each participant the objectives of the analysis to be done on the 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
125 of 187
samples and any potential future use. Participants will be told that they are free to refuse to 
participate in any optional samples or the future use and may withdraw their consent at any 
time and for any reason during the retention period. 
A 4
Data Protection

Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.

The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the informed consent 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees Structure
The safety of all Sponsor clinical studies is closely monitored on an on-going basis by 
Sponsor representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the CSP and letters to investigators.
An IDMC comprised of independent experts will be convened and will meet approximately 
6 months after the study has started or after the first 60 participants have been randomized, 
whichever occurs first. The IDMC will review safety assessments and make recommendations 
to continue, amend, or stop the study based on safety findings. The committee will meet 
approximately every 6 months thereafter. For the IAs, the IDMC will review unblinded 
interim data and inform the Sponsor whether the interim boundaries specified in Section 9.5
are met. The IDMC will inform the Sponsor of its recommendation according to the IDMC 
Charter.  
Full details of the IDMC procedures, processes, and IAs can be found in the IDMC Charter. 
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the study results when they are available. 
The clinical study and/or summary of study results may also be available on other websites 
according to the regulations of the countries in which the study is conducted.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
126 of 187
A 7
Data Quality Assurance

All participant data relating to the study will be recorded on eCRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the relevant study plans.

The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

The Sponsor assumes accountability for actions delegated to other individuals (eg,
CROs).

Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor.
A 8
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.

Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
127 of 187
A 9
Study and Site Start and Closure
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant(s) in the study and should 
assure appropriate participant therapy and/or follow-up.
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.

The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
128 of 187
Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a patient or clinical study 
participant administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom (eg, nausea, chest pain), or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered.
B 2
Definitions of Serious Adverse Event
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
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. 

Is a congenital anomaly or birth defect

Is an important medical event that may jeopardize the participant or may require medical 
treatment to prevent one of the outcomes listed above.
AEs for malignant tumors reported during a study should generally be assessed as Serious 
AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be 
used. In certain situations, however, medical judgement on an individual event basis should be 
applied to clarify that the malignant tumor event should be assessed and reported as a 
Non-Serious AE. For example, if the tumor is included as medical history and progression 
occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumor, the AE may not fulfill the attributes for being assessed as Serious, although 
reporting of the progression of the malignant tumor as an AE is valid and should occur. Also, 
some types of malignant tumors, which do not spread remotely after a routine treatment that 
does not require hospitalization, may be assessed as Non-Serious; examples in adults include 
Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.
The above instruction applies only when the malignant tumor event in question is a new 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
129 of 187
malignant tumor (ie, it is not the tumor for which entry into the study is a criterion and that is 
being treated by the IMP under study and is not the development of new or progression of 
existing metastasis to the tumor under study). Malignant tumors that – as part of normal, if 
rare, progression – undergo transformation (eg, Richter's transformation of B cell chronic 
lymphocytic leukemia into diffuse large B cell lymphoma) should not be considered a new 
malignant tumor.
Life threatening
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
participant’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 participant was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study.
Important medical event or medical treatment
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 participant or may 
require medical treatment to prevent one 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 iv 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 anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalization

Development of drug dependency or drug abuse

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
130 of 187
Intensity rating scale
The grading scales found in the revised NCI CTCAE, Version 5.0 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 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 Appendix B 2. 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 not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2.
B 3
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.

Time Course. Exposure to suspect drug. Has the participant 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, other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? The Sponsor 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?

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
131 of 187

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 no available facts or arguments to suggest a 
causal relationship, 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.
B 4
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the participant 
or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error. 

Occurred

Was identified and intercepted before the participant received the drug

Did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed eg, kept in the fridge when it should be at room temperature 

Wrong participant received the medication (excluding IRT errors)

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
132 of 187

Wrong drug administered to participant (excluding IRT errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT - including those which lead to one of the above 
listed events that would otherwise have been a medication error 

Participant accidentally missed drug dose(s) eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
133 of 187
Appendix C
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis, including COVID-19 Outbreak
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
participants become infected with SARS-CoV-2 or similar pandemic infection) during which 
participants may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
agreement from the sponsor.
C 1
Reconsent of Study Participants During Study Interruptions
During study interruptions, it may not be possible for the participants to complete study visits 
and assessments on site and alternative means for carrying out the visits and assessments may 
be necessary, eg, remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Sections C 2 to C 4. Local and regional regulations and/or guidelines regarding 
reconsent of study participants should be checked and followed. Reconsent may be verbal if 
allowed by local and regional guidelines (note, in the case of verbal reconsent the ICF should 
be signed at the participant’s next contact with the study site). Visiting the study sites for the 
sole purpose of obtaining reconsent should be avoided. 
C 2
Rescreening of Participants to Reconfirm Study Eligibility 
Additional rescreening for screen failure due to study disruption can be performed in 
previously screened participants. The investigator should confirm this with the designated 
Study Clinical Lead.
In addition, during study disruption there may be a delay between confirming eligibility of a 
participants and either enrolment into the study or commencing of dosing with IMP. If this 
delay is outside the screening window specified in Section 6.3.1 the participant will need to be 
rescreened to reconfirm eligibility before commencing study procedures. This will provide 
another opportunity to re-screen a participant in addition to that detailed in Section 5.4. The 
procedures detailed in Section 6.3.1 must be undertaken to confirm eligibility using the same 
randomization number as for the participant.
C 3
Telemedicine Visit to Replace On-site Visit (Where Applicable)
In this appendix the term telemedicine visit refers to remote contact with the participants using 
telecommunications technology including phone calls, virtual or video visits, and mobile 
health devices.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
134 of 187
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the participants will allow AEs and concomitant medication to be reported and 
documented.
C 4
Data Capture During Telemedicine or Home/Remote Visits
Data collected during telemedicine or home/remote visits will be captured by the qualified 
HCP from the study site or TPV service in the source documents, or by the participant 
themselves.
C 5
COVID-19 Risk Assessment 
The safety of participants is of primary importance. Any potential risks of participating in the 
study, particularly with the added challenges due to COVID-19 outbreak, should be weighed 
against the anticipated benefit (see also Principle 2.2 of ICH GCP). Investigators are advised 
to use clinical judgment in determining infection prevention precautions for study participants.
The emergence of SARS-CoV-2 presents a potential safety risk for cancer patients. 
Participants enrolling in this study may require more frequent visits to the site for study 
treatment administration and for study assessments compared to participants receiving 
standard of care. Therefore, several risk mitigation factors have been implemented related to 
study conduct during the COVID-19 outbreak, for patient management in an event of 
COVID-19, and actions to be taken on study treatment (see Section C 8). With these measures 
in place, it is considered that the anticipated potential benefits for the participants enrolled in 
this study outweigh the potential risks. All implemented measures prioritize trial participant 
safety and data validity; in case these two conflict with each other, trial participant safety 
should always prevail (see also European Medicines Agency Guidance on the management of 
clinical trials during the COVID-19 [coronavirus] pandemic [EMA 2020]). 
Notably, participants with active COVID-19 infection confirmed by local laboratory testing
will not be eligible for study enrolment (see CSP Section 5.2, Exclusion Criterion 11). 
C 6
Potential Risks during COVID-19
Every effort should be made to follow the CSP. Section C 9 provides a dose modification and 
management plan for participants with confirmed or suspected COVID-19 who are being 
treated with IMP (monalizumab/placebo and cetuximab). The risk-benefit assessment should 
be carefully considered for each participant enrolling in the study based on the known safety 
risks related to COVID-19, individual needs, and local guidelines and restrictions. 
Investigators must continue to use their best clinical judgment in determining the most optimal 
care for participants and utmost diligence in determining their eligibility for study 
participation, continued study treatment, and overall assessment of benefit/risk of study 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
135 of 187
treatment or participation.
The sponsor must be promptly notified of a site’s inability to perform study activities due to 
COVID-19 outbreak in order to minimize any potential risks.
C 7
New Participant Enrolment
Study sites may continue to recruit new participants into the study provided the following 
activities to preserve study integrity can be met:

Upon discussion with the site monitor, the study site has confirmed the ability to enroll
and manage new participants effectively and in compliance with the protocol.

Data will continue to be entered into the eCRF and queries resolved in a timely manner. 
Per CSP Exclusion Criterion 11 (see CSP Section 5.2), participants with uncontrolled 
intercurrent illness, including but not limited to, ongoing or active infection are not eligible for 
the study participation and hence such participants (including those who have confirmed 
COVID-19) should not be included for study participation.
C 8
Study Treatment Administration
If an AE or SAE is associated with COVID-19, the investigator should determine whether the 
participants’ treatment with investigational product should continue, be interrupted, or be 
discontinued in accordance with the CSP.
Adverse events, SAEs, cycle delays and/or treatment suspensions associated with COVID-19 
along with logistical issues should be reported according to the eCRF Completion Guidelines. 
For dosing discontinuations, where applicable, the dosing discontinuation guidelines should 
be followed, and the End of Treatment Form(s) completed
C 9
Ongoing Participants
Participants receiving study intervention should continue to undergo safety assessments prior 
to dosing in accordance with the CSP. In case it is not feasible to perform safety assessments, 
study intervention should be interrupted until such assessments can be completed.
C 9.1
If a Participant has an Event Suspected to be COVID-19
Delay or omit study intervention as appropriate and test for COVID-19 per local health 
authority or institutional guidance. 

Signs and symptoms of COVID-19 include but are not limited to new onset of fever, 
new or worsening cough, shortness of breath, difficulty breathing and sometimes 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
136 of 187
abnormal chest imaging and may be similar to those of an imAE. Toxicity 
management guidelines for imAEs should be considered if the symptoms are 
consistent with an imAE.

In accordance with the CSP and the TMGs for imAEs, thorough evaluation should be 
performed to accurately identify the underlying pathology in case an AE is 
encountered for a participant. 

If COVID-19 is ruled out, study intervention may be resumed per the CSP and TMGs 
(if applicable).

If COVID-19 is confirmed or diagnosis still suspected after evaluation, manage 
COVID-19 per local guidance until full recovery. 
C 9.2
Participants with Confirmed COVID-19
Participants with confirmed COVID-19 (by local laboratory testing and/or combination of 
key symptoms) should have study intervention withheld and COVID-19 managed per local 
guidance.
In case of confirmed COVID-19 and a simultaneous imAE requiring treatment, investigators 
are advised to apply clinical judgement regarding the use of corticosteroids as per the 
monalizumab TMGs. This includes also the consideration of alternate immunosuppressive 
agents other than corticosteroids for imAE management, depending on the individual 
participant’s presentation (Curigliano et al 2020).
C 9.3
Restarting Study Intervention
Study intervention must not be resumed until recovery from COVID-19 (eg, confirmed by 
imaging, lab testing and/or absence of symptoms) and COVID-19-specific treatment has been 
completed per local guidance.
The Study Clinical Lead should be contacted if any additional guidance or clarification is 
needed.
C 9.4
Vaccination Against COVID-19
Protocol restrictions applying to live attenuated vaccines are relevant for live attenuated 
COVID-19 vaccines as well. Investigators should apply their discretion assessing the 
risk-benefit of other types of COVID-19 vaccines for participants in clinical trials. Ideally, 
administration of the vaccine should be done on a different day other than the day of study 
drug administration to differentiate any potential AEs seen from the vaccine and study drug. 
The administration of the vaccine and any potential AEs associated with the vaccine are to be 
documented on the concomitant medication and AE eCRFs, respectively.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
137 of 187
C 10
References
Curigliano et al 2020 
Curigliano G, Banerjee S, Cervantes A, Garassino M, Garrido P, Girard N et al. Managing 
cancer patients during the COVID-19 pandemic: an ESMO multidisciplinary expert 
consensus. Ann Oncol 2020;31(10):1320-35.
EMA 2020
EMA, Clinical Trials Facilitation and Coordination Group, European Commission. Guidance 
on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, 
Version 2, 27 March 2020. Available from: URL: 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf. Cited date: 17 December 2020.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
138 of 187
Appendix D
Handling of Human Biological Samples
D 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each center keeps full traceability of collected biological samples from the 
participants while in storage at the center until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during the 
remainder of the sample life cycle.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
D 2
Withdrawal of Informed Consent for Donated Biological Samples 
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples are already 
analyzed, AstraZeneca is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The investigator:

Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate.

Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented

Ensures that the participant and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organization(s) holding the samples is/are informed about the 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
139 of 187
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action documented and study site notified.
D 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B, or Exempt
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. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814. Infectious substances which cause disease only in animals must be assigned to 
UN 2900:
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, C, D, and E viruses. 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 - Substances that do not contain infectious substances or substances that are unlikely 
to cause disease in humans or animals are not subject to these regulations unless they meet the 
criteria for inclusion in another class.

Clinical study samples will fall into Category B or exempt under IATA regulations

Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).

Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
140 of 187
Appendix E
E 1
E 2
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
141 of 187
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
142 of 187
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
143 of 187
Appendix F
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
F 1
Introduction
This appendix describes the process to be followed in order to identify and appropriately 
report PHL cases and HL cases. It is not intended to be a comprehensive guide to the 
management of elevated liver biochemistries. 
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a participant meets 
potential PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible PHL events.
The investigator participates, together with the Sponsor clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than DILI caused by the IMP. 
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
F 2
Definitions
Potential Hy’s Law
Aspartate aminotransferase or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN at any point 
during the study following the start of study medication irrespective of an increase in ALP. 
Hy’s Law
Aspartate aminotransferase 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 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
144 of 187
elevations in transaminases and TBL must occur.
F 3
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 participant who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3 × ULN

AST ≥ 3 × ULN

TBL ≥ 2 × ULN
Local laboratories being used:
The investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
Determine whether the participant meets PHL criteria (see Section F 2 Definitions within this 
appendix for definition) by reviewing laboratory reports from all previous visits
Promptly enter the laboratory data into the laboratory eCRF
F 4
Follow-up
F 4.1
Potential Hy’s Law Criteria Not Met
If the participant does not meet PHL criteria the investigator will:

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the CSP.
F 4.2
Potential Hy’s Law Criteria Met
If the participant does meet PHL criteria the investigator will:

Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (See Section F 6)

Notify the Sponsor representative who will then inform the central study team 

Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
PHL; serious criteria ‘important medical event’ and causality assessment ‘yes/related’ 
according to CSP process for SAE reporting.

For participants that met PHL criteria prior to starting IMP, the investigator is not required 
to submit a PHL SAE unless there is a significant change # in the participant’s condition

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
145 of 187

The Study Clinical Lead contacts the investigator, to provide guidance, discuss and agree 
an approach for the study participants’ follow-up (including any further laboratory 
testing) and the continuous review of data

Subsequent to this contact the investigator will:

Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required.

Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Clinical Lead. 

Complete the three Liver eCRF Modules as information becomes available 
# A ‘significant’ change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST, or TBL) 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 Clinical Lead if there is any uncertainty.
F 5
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.
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Clinical Lead 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, to ensure timely analysis and reporting to health authorities within 15 calendar days from 
date PHL criteria was met. The Sponsor Global Clinical Lead or equivalent 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.
Where 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 eCRF

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
146 of 187

If the alternative explanation is an AE/SAE: update the previously submitted PHL SAE 
and AE eCRFs accordingly with the new information (reassessing event term; causality 
and seriousness criteria) following the Sponsor’s 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:

Send updated SAE (report term ‘Hy’s Law’) according to the Sponsor’s 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 15 calendar days 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:

Provides any further update to the previously submitted SAE of PHL, (report term now 
‘Hy’s Law case’) ensuring causality assessment is related to IMP and seriousness criteria 
is medically important, according to CSP process for SAE reporting.

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 still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
F 6
Actions Required When Potential Hy’s Law Criteria are Met 
Before and After Starting Study Treatment
This section is applicable to participants 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 participants’ condition# compared with 
the last visit where PHL criteria were met#

If there is no significant change no action is required

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
147 of 187

If there is a significant change, notify the Sponsor representative, who will inform the 
central Study Team, then follow the subsequent process described in Section F 4.2
F 7
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a participant 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. 
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 eg, chronic or progressing malignant disease, severe infection,
or liver disease or did the participant meet PHL criteria prior to starting study treatment 
and at their first on-study treatment visit as described in Section F 6?
If No: follow the process described in Section F 4.2 for reporting PHL as an SAE.
If Yes: Determine if there has been a significant change in the participant’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 Section F 4.2 for reporting 
PHL as an SAE
# A ‘significant’ change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST, or TBL) 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 Clinical Lead if there is any uncertainty.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
148 of 187
F 8
Laboratory Tests
These are recommended laboratory tests to be performed in cases of PHL. Any test results 
need to be recorded in the eCRF. 
Hy’s Law Laboratory Tests
Additional standard chemistry and coagulation 
tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HBV DNA
IgG anti-HCV
HCV RNA a
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-transferrin)
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-liver/kidney microsomal Ab (Anti-LKM)
Anti-smooth muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
a
HCV RNA is only tested when IgG anti-HCV is positive or inconclusive.
F 9
References
Aithal et al, 2011
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDA Guidance for Industry, July 2009
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from; https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
149 of 187
Appendix G
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 RECIST 1.1 guidelines (Eisenhauer et al 2009). 
Investigator assessments will use the RECIST 1.1 guidelines described in this appendix. 
Additional special guidance is provided for evaluation of scans collected after a RECIST 1.1-
defined radiological progression.
Imaging Modalities and Acquisition Specifications for RECIST 1.1
A summary of the imaging modalities that can be used for tumor assessment of TLs, NTLs, 
and NLs is provided in Table 11.
Table 11
Summary of imaging modalities for tumor assessment
Target lesions 
Non-target lesions
New lesions
CT
MRI
CT
MRI
Plain X-ray
Chest X-ray
CT
MRI
Plain X-ray
Chest X-ray
Bone scan (Scintigraphy)
FDG-PET/CT
CT = computed tomography; FDG-PET/CT = 18F-Fluoro-deoxyglucose positron emission tomography/CT; 
MRI = magnetic resonance imaging.
CT and MRI 
Computed tomography with iv contrast is the preferred imaging modality (although MRI with 
iv contrast is acceptable if CT is contraindicated) to generate reproducible anatomical images 
for tumor assessments (ie, for measurement of TLs, assessment of NTLs, and identification of 
NLs). It is essential that the same correct imaging modality, image acquisition parameters (eg, 
anatomic coverage, imaging sequences, etc), imaging facility, tumor assessor (eg, radiologist), 
and method of tumor assessment (eg, RECIST 1.1) are used consistently for each participant 
throughout the study. The use of the same scanner for serial scans is recommended, if 
possible. It is important to follow the image collection/tumor assessment schedule as closely 
as possible (refer to the SoA; Section 1.3), and this on-study imaging schedule MUST be 
followed regardless of any delays in dosing or missed imaging visits. If an unscheduled 
assessment is performed (eg, to investigate clinical signs/symptoms of progression) and the 
participant has not progressed, every attempt should be made to perform the subsequent scan 
acquisitions at the next scheduled imaging visit.
Due to its inherent rapid acquisition (seconds), CT is the imaging modality of choice. Body 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
150 of 187
scans should be performed with breath-hold scanning techniques, if possible. Therefore, CT of 
the chest is recommended over MRI due to significant motion artifacts (eg, heart, major blood 
vessels, breathing) associated with MRI. MRI has excellent contrast and spatial and temporal 
resolutions; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. The modality used at follow-up should be the same as 
was used at baseline, and the lesions should be measured/assessed on the same pulse 
sequence. In general, local oncology diagnostic imaging parameters are applied for scan 
acquisition. It is beyond the scope of this appendix to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases.
The most critical CT and MRI image acquisition parameters for optimal tumor evaluation are 
anatomic coverage, contrast administration, slice thickness, and reconstruction interval.
a.  Anatomic coverage: Optimal anatomic coverage for most solid tumors is the 
chest-abdomen (-pelvis). Coverage should encompass all areas of known predilection for 
metastases in the disease under evaluation and should additionally investigate areas that may 
be involved based on signs and symptoms of individual participants. Because a lesion later 
identified in a body part not scanned at baseline would be considered as a new lesion 
representing disease progression, careful consideration should be given to the extent of 
imaging coverage at baseline and at subsequent follow-up time points. This will enable better 
consistency not only of tumor measurements but also identification of new disease.
Required anatomical regions to be imaged for assessment of tumor burden (TLs and/or NTLs) 
at baseline and follow-up visits vary according to the study, and these time points are specified 
in the SoA (Section 1.3). Examples include the following:

Intravenous contrast-enhanced CT of chest-abdomen (including the entire liver and both 
adrenal glands) (-pelvis)

Non-contrast CT of chest and IV contrast-enhanced abdomen (including the entire liver 
and both adrenal glands) (-pelvis)

Intravenous contrast-enhanced CT or MRI of the head and neck

Intravenous contrast-enhanced MRI (preferred) or CT of the brain
For chest-abdomen (-pelvis) imaging, the following are scanning options in decreasing order 
of preference, with additional options (2 to 4) for consideration when participants have 
sensitivity to iv contrast or have compromised renal function:
1
Chest-abdomen (-pelvis) CT with iv CT contrast (most preferred)
2
Chest CT without iv contrast + abdomen (-pelvis) MRI with IV MRI contrast, if CT iv
contrast (iodine based) is medically contraindicated at any time during the study

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
151 of 187
3
Chest-abdomen (-pelvis) CT without iv contrast, if both iv CT and MRI contrast are 
medically contraindicated or the participant has compromised renal function
4
Chest-abdomen (-pelvis) MRI with iv MRI contrast, if CT cannot be performed at any 
time during the study
b.  Intravenous contrast administration: Optimal visualization and measurement of 
metastases in solid tumors require consistent administration (dose and rate) of iv contrast as 
well as timing of scanning. An adequate volume of a suitable contrast agent should be given 
so that the tumor lesions are demonstrated to best effect and a consistent method is used on 
subsequent examinations for any given patient. Oral contrast is recommended to help visualize 
and differentiate structures in the abdomen and pelvis.  
c.  Slice thickness and reconstruction interval: It is recommended that CT or MRI scans be 
acquired/reconstructed as contiguous (no gap) slices with ≤5-mm thickness throughout the 
entire anatomic region of interest for optimal lesion measurements. Exceptionally, particular 
institutions may perform medically acceptable scans at slice thicknesses > 5 mm. If this 
occurs, the minimum size of measurable lesions at baseline should be twice the slice thickness 
of the baseline scans.
For CT scans, all window settings should be included in the assessment, particularly in the 
thorax where lung and soft tissue windows should be considered. When measuring lesions, the 
TL should be measured on the same window setting for repeated examinations throughout the 
study.  
Chest X-ray
Chest X-ray assessment will not be used for the assessment of TLs. Chest X-ray can, however, 
be used to assess NTLs and to identify the presence of NLs. However, there is preference that 
a higher resolution modality, such as CT, be used to confirm the presence of NLs.
Plain X-ray 
Plain X-ray may be used as a method of assessment for bone NTLs and to identify the 
presence of new bone lesions.  
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 NTLs and followed by the same method per baseline 
assessment (CT, MRI, or X-ray).  
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 may be recorded in case positive hot-spots 
appear on a bone scan that were not present on a previous bone scan; however, a newly 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
152 of 187
observed equivocal hot-spot on a bone scan that cannot be verified with correlative imaging 
(CT, MRI, or X-ray) of the same anatomical region shall not be the only trigger for a PD 
assessment at that time point.  
FDG-PET/CT
1FDG-PET/CT scans may be used as a method for identifying new lesions for RECIST 1.1 
assessments according to the following algorithm: NLs will be recorded where there is 
positive FDG uptake1 not present on baseline or prior FDG-PET scan or in a location 
corresponding to a NL on a companion CT/MRI collected close in time to the FDG-PET scan. 
The PET portion of the PET/CT introduces additional data that may bias an investigator if it is 
not routinely or serially performed. Therefore, if there is no baseline or prior FDG-PET scan 
available for comparison, and no evidence of NLs on companion CT/MRI scans, then follow-
up CT/MRI assessments should continue as per the regular imaging schedule to verify the 
unequivocal presence of NLs.
At present, low-dose or attenuation correction CT portions of a combined FDG-PET/CT scan 
are of limited use in anatomically based efficacy assessments, and it is therefore suggested 
that they should not substitute for dedicated diagnostic contrast-enhanced CT scans for tumor 
measurements by RECIST 1.1. In exceptional situations, if a site can document that the CT 
performed, as part of a PET/CT examination, is of identical diagnostic quality (with iv 
contrast) to a dedicated diagnostic CT scan, then the CT portion of the PET/CT can be used 
for RECIST 1.1 tumor assessments. Caution that this is not recommended because the PET 
portion of the CT introduces additional (PET) data that may bias an investigator if it is not 
routinely or serially performed.
Ultrasound 
Ultrasound examination will not be used for RECIST 1.1 assessment of tumors as it is not a 
reproducible acquisition method (operator dependent), is subjective in interpretation, and may 
not provide an accurate assessment of the true tumor size. Tumors identified by ultrasound 
will need to be assessed by correlative CT or MRI anatomical scan.
1
A positive FDG-PET scan lesion should be reported only when an uptake (eg, SUV) greater than twice that of the surrounding tissue or liver is observed.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
153 of 187
Other Tumor Assessments
Clinical examination 
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will 
not be used for RECIST 1.1 assessments. Tumors identified by clinical examination will need 
to be assessed by correlative CT or MRI anatomical scans.
Endoscopy and laparoscopy 
Endoscopy and laparoscopy will not be used for tumor assessments as they are not validated 
in the context of tumor assessment.
Histology and cytology
Histology or tumor markers on tumor biopsy samples will not be used as part of the tumor 
response assessment as per RECIST 1.1.  
Results of cytological examination for the neoplastic origin of any effusion (eg, ascites, 
pericardial effusion, and pleural effusion) that appears or worsens during the study will not be 
used as part of the tumor response assessment as per RECIST 1.1.  
Furthermore, an overall assessment of CR (all other disease disappears/reverts to normal) 
would be changed to PR if an effusion remains present radiologically.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
154 of 187
Measurability of Tumor Lesions at Baseline
RECIST 1.1 measurable lesions at baseline
A tumor lesion that can be accurately measured at baseline as ≥10 mm in the longest diameter
nor non-nodal lesions or ≥15 mm in short axis2 diameter for lymph node lesions with iv
contrast-enhanced CT or MRI and that is suitable for accurate repeated measurements.
Non-measurable lesions at baseline

Truly non-measurable lesions include the following:

Bone lesions (see exception below for soft tissue component)

Leptomeningeal disease

Ascites, pleural effusion, or pericardial effusion

Inflammatory breast disease

Lymphangitic involvement of skin or lung

All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥10-mm to < 15-mm short axis diameter at baseline3)

Previously irradiated lesions 4
This study allows a previously irradiated lesion as a TL if there has been demonstrated 
progression in the lesion and it meets reproducible measurability and minimum size 
requirements and if this is the only lesion available. 

Brain metastasis
Special considerations regarding lesion measurability at baseline
                                               
2
The short axis is defined as the longest in-plane axis perpendicular to the long axis.
3
Lymph nodes with <10-mm short axis diameter are considered non-pathological and should not be recorded 
or followed as NTLs.
4
Localized post-radiation changes that affect lesion size may occur.  Therefore, lesions that have been 
previously irradiated are typically considered non-measurable and as NTL at baseline and followed up as 
part of the NTL assessment.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
155 of 187

Bone lesions

Bone scan, PET scan, or plain X-ray are not considered adequate imaging techniques 
to measure bone lesions; however, these techniques can be used to confirm the 
presence or disappearance of bone lesions.

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 lesions thought to represent 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 participant, these should be selected over cystic 
lesions as TLs.
RECIST 1.1 TL selection at baseline
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 TLs at baseline. Target lesions should be selected on the basis of their 
size (longest diameter for non-nodal lesions or short axis diameter 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 that can be measured reproducibly 
should be selected.
Lymph nodes, in any location (local/regional and distant), are collectively considered as a 
single organ, with a maximum of 2 lymph nodes as TLs. A bilateral organ (eg, adrenal glands), 
a segmented organ (eg, liver), or a multilobed organ (eg, lung) is each considered as a single 
organ.
The site and location of each TL should be documented, as well as the longest axis diameter 
for non-nodal lesions (or short axis diameter for lymph nodes). All measurements should be 
recorded in millimeters. At baseline, the sum of the diameters for all TLs will be calculated 
and reported as the baseline sum of diameters. At follow-up visits, the sum of diameters for all 
TLs will be calculated and reported as the follow-up sum of diameters.
Special cases for TL assessment at baseline

For TLs 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 
diameter.  

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
156 of 187

When lymph nodes are coalesced and no longer separable in a conglomerate mass, the 
maximal short-axis diameter of the coalesced mass should be recorded. Non-nodal lesions 
that coalesce should similarly be assessed by the long-axis diameter.

Tumor lesions selected for fresh screening biopsy should not be selected as TLs, unless 
imaging occurred at least approximately 2 weeks after biopsy, allowing time for healing.

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 diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as an NL.
RECIST 1.1 NTL selection at baseline
All other lesions, including non-measurable lesions and surplus measurable lesions, not 
recorded as TLs should be identified as NTLs at baseline. Measurements of these lesions are 
not required, but the presence or absence of each should be noted throughout follow-up.
Evaluation of Tumor Response and Progression
RECIST 1.1 TL assessment at follow-up
This section defines the criteria used to determine objective tumor visit response for 
RECIST 1.1-defined TLs. The imaging modality, location, and scan date of each TL identified 
previously at baseline should be documented at follow-up visits with the long axis diameter 
for non-nodal lesions or short axis diameter for lymph node lesions. All measurements should 
be recorded in whole millimeters. The sum of the diameters for all TLs at each follow-up visit 
will be compared to the baseline sum of diameters (for response or SD) or to the smallest prior 
(nadir) sum of diameters (for progression).
Special cases for TL assessment at follow-up:

If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as an NL.

If a TL splits into 2 or more parts, the sum of the diameters of those parts should be 
recorded.

If 2 or more TLs merge, then the sum of the diameters of the combined lesion should be 
recorded for 1 of the lesions and 0 mm recorded for the other lesion(s). If the merged TLs 
are non-nodal lesions, record the long axis diameter of the merged lesion. If pathologic 
lymph nodes coalesce and are no longer individually separable within a conglomerate 
mass, the maximal short axis diameter is recorded.

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.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
157 of 187

If a TL cannot be measured accurately due to it being too large, provide an estimate of the 
size of the lesion. The choice of “Too large to measure” in the case report form will 
trigger an overall visit response of PD. 

When a TL has had an unscheduled, non-protocol intervention, the following apply:

Target lesion intervention may include radiotherapy, embolization, excisional biopsy, 
surgery, etc. that is not a part of study treatment and might adversely affect the size 
of that TL.

If an intervention on a TL is ticked in the eCRF, the diameter of the lesion is still
recorded (0mm if no longer present) and is included in the sum of diameters. 

If a TL intervention is ticked, the intervention must be reported for all subsequent 
assessments of that TL. 

If a TL has an intervention, the only Overall Visit Responses allowed to be recorded 
by the investigator are NE or PD, with PD if the sum of diameters exceeds a 
20% increase and at least a 5 mm absolute increase in the visit sum of diameters 
compared to the previous minimum (nadir) sum of diameters. 

No visit with a recorded TL intervention can be used as the minimum (nadir) sum of 
diameters. 
Table 12
RECIST 1.1 Evaluation of TLs
CR
Disappearance of all TLs since baseline. Any pathological lymph nodes selected as TLs must 
have a reduction in short axis diameter to < 10 mm.
PR
At least a 30% decrease in the sum of the diameters of TL, taking as reference the baseline sum 
of diameters.
SD
Neither sufficient decrease in the sum of diameters to qualify for PR nor sufficient increase to 
qualify for PD.
PD
At least a 20% increase in the sum of diameters of TLs, taking as reference the smallest previous 
sum of diameters (nadir) - this includes the baseline sum if that is the smallest on study. In 
addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at 
least 5 mm from nadir.
NE
Only relevant if any of the TLs at follow-up were not assessed or NE (eg, missing anatomy) or 
had a lesion intervention at this visit. Note: If the sum of diameters meets the PD criteria, PD
overrides NE as a TL response.
NA
Only relevant if no TLs present at baseline.
CR = complete response; NA = not applicable; NE = not evaluable; PD = progression of disease; PR = partial 
response; SD = stable disease; TL = target lesion.
RECIST 1.1 NTL assessment at follow-up
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline. Measurements are not required for these lesions, but their status should be followed 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
158 of 187
at subsequent visits. At each visit, an overall assessment of the NTL response should be 
recorded by the investigator.
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 SD or PR in TLs, 
the overall tumor burden has increased sufficiently to merit unequivocal progression by NTLs.
A modest ‘increase’ in the size of one or more NTLs is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be 
extremely rare.
Table 13
RECIST 1.1 Evaluation of NTLs
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 NTLs.
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.
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 participants 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.
NA
Only relevant if no NTLs present at baseline
CR = complete response; NA = not applicable; NTL = non-target lesion; PD = progression of disease; TL = 
target lesion.
RECIST 1.1 NL identification at follow-up
Details, including the imaging modality, the date of scan, and the location of any NLs will also 
be recorded in the case report form. The presence of one or more NLs is assessed as 
progression. The finding of a NL 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 NL is equivocal, for example because of its small size, the treatment and 
tumor assessments should be continued until the previously (pre-existing) new lesion has been 
assessed as unequivocal at a follow-up visit, and then the progression date should be declared 
using the date of the initial scan when the NL first appeared.
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a NL and will indicate disease progression.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
159 of 187
RECIST 1.1 evaluation of overall visit response at follow-up
Derivation of overall visit response as a result of the combined assessment of TLs, NTLs, and 
NLs uses the algorithm shown in Table 14.
Table 14
RECIST 1.1 Overall Visit Response
Target lesions
Non-target lesions
New lesions
Overall visit response
CR
CR
No
CR
CR
NA
No
CR
NA
CR
No
CR
CR
Non CR/Non PD 
No
PR
CR
NE
No 
PR
PR
Non PD or NE or NA
No
PR
SD 
Non PD or NE or NA
No
SD
NA
Non-CR/Non-PD
No
SD (non-CR/non-PD)
NE
Non PD or NE
No
NE
NA
NE
No
NE
NA
NA
No
NED
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Note: An overall assessment of CR (all other disease disappears/reverts to normal) would be changed to PR if 
ascites remains present radiologically.
CR = complete response; NA = not applicable (only relevant if there were no non-target lesions at baseline), NE 
= not evaluable; NED = no evidence of diseases (only relevant if there were neither TLs nor NTLs at baseline); 
PD = progression of disease; PR = partial response; SD = stable disease; TL = target lesion.
The following overall visit responses are possible depending on the extent of tumor disease at 
baseline:

For participants with TLs (at baseline): CR, PR, SD, progression of disease (PD), or NE

For participants with NTLs only (at baseline): CR, Non-CR/Non-PD, PD, or NE

For participants with no disease at baseline: NED (available as an option in the eCRF), 
PD, or NE
Evaluation of scans subsequent to RECIST 1.1-defined progression
A follow-up scan is requested at least 4 weeks later and no longer than the next regularly 
scheduled imaging visit. The follow-up scans provide additional information to the 
investigator for participant management and further treatment decisions, and since the 
published RECIST 1.1 (Eisenhauer et al 2009) do not provide guidance on how to assess 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
160 of 187
scans acquired after RECIST 1.1-defined PD, supplemental instructions for investigators on 
how to evaluate these follow-up scans are provided below. A subsequent follow-up scan 
would be considered as having progressive disease if any of the following criteria are met:

Greater than or equal to 20% increase and at least a 5-mm increase in the sum of 
diameters of TLs compared with the nadir sum of diameters at 2 consecutive visits, and a 
further increase of ≥5 mm in the sum of diameters at the follow-up scan time point 
compared with the immediate prior time point

Significant progression (worsening) of NTLs at the follow-up scan time point compared 
with the immediate prior time point

Significant progression (worsening) of previous NLs (pre-existing NLs) at the follow-up 
scan time point compared with the immediate prior time point

Additional brand-new unequivocal lesions at the follow-up scan time point

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
161 of 187
Appendix H
Contraception Requirements
Contraception requirements for this study are as follows.
H 1
Female Participant of Child-bearing Potential
Please note, females of childbearing potential are defined as those who are post-menarche, not 
surgically sterile (ie, bilateral salpingectomy, bilateral oophorectomy, or complete 
hysterectomy) or post-menopausal.
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:

Women < 50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all hormonal replacement 
therapy and 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 hormonal replacement 
therapy, had radiation-induced menopause with last menses > 1 year ago, had 
chemotherapy-induced menopause with last menses > 1 year ago.
Female participants of childbearing potential who are not totally sexually abstinent 
(ie, refraining from heterosexual intercourse during the entire period of risk associated with 
study treatments) and intend to be sexually active with a nonsterilized male partner must use 
at least one highly effective method of contraception (Table 15) from the time of screening 
throughout the total duration of the drug treatment and for 4 months after the last dose of 
study intervention. Non-sterilized male partners of a female participant of childbearing 
potential must use a male condom plus spermicide (condom alone in countries where 
spermicides are not approved) throughout this period. Cessation of birth control after this 
point should be discussed with a responsible physician. Periodic abstinence (eg, calendar, 
symptothermal, post-ovulation methods), the rhythm method, the withdrawal method (coitus 
interruptus), and lactational amenorrhea method are not acceptable methods of contraception. 
Female participants should refrain from breastfeeding throughout this period.  
H 2
Male Participants With a Female Partner of Childbearing 
Potential
Non-sterilized male participants (including males sterilized by a method other than bilateral 
orchidectomy, eg, vasectomy) who are not abstinent and intend to be sexually active with a 
female partner of childbearing potential must use a male condom plus spermicide (condom 
alone in countries where spermicides are not approved) from the time of screening throughout 
the total duration of the drug treatment and for 4 months after the last dose of study 

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
162 of 187
intervention. Periodic abstinence (eg, calendar, symptothermal, post-ovulation methods), the 
rhythm method, the withdrawal method (coitus interruptus), and lactational amenorrhea 
method are not acceptable methods of contraception. Male participants should refrain from 
sperm donation throughout this period.
Vasectomized (ie, sterile) males are considered fertile and should still use a male condom plus 
spermicide as indicated above during the clinical study.
Even if the female partner is pregnant, male participants should still use a condom, as 
indicated above during the clinical study, if there is a concern about damaging the developing 
fetus from drug in ejaculate.
Female partners (of childbearing potential) of male participants must also use a highly 
effective method of contraception throughout this period (Table 15).
H 3
Highly Effective Methods of Contraception
Highly effective methods of contraception, defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly, are described in Table 15.
Note that some contraception methods are not considered highly effective (eg, male or female 
condom with or without spermicide; spermicide alone; female cap, diaphragm, or sponge with 
or without spermicide; non copper containing intrauterine device; progestogen-only oral 
hormonal contraceptive pills (also known as progesterone-only or “mini-pill”) where 
inhibition of ovulation is not the primary mode of action [excluding Cerazette®/desogestrel 
which is considered highly effective]; and triphasic combined oral contraceptive pills).
Table 15
Highly Effective Methods of Contraception (< 1% Failure Rate)
Barrier/intrauterine methods
Hormonal methods b
•
Copper T intrauterine device
•
Levonorgestrel-releasing intrauterine 
system (eg, Mirena®) a
•
Implants: Etonogestrel-releasing implants (eg, Implanon® 
or Norplant®)
•
Intravaginal devices: Ethinylestradiol/etonogestrel-
releasing intravaginal devices (eg, NuvaRing®) 
•
Injection: Medroxyprogesterone injection (eg, Depo-
Provera®)
•
Combined pill: Normal and low dose combined oral 
contraceptive pill
•
Patch: Norelgestromin/ethinylestradiol-releasing 
transdermal system (eg, Ortho Evra®)
•
Minipill: Progesterone based oral contraceptive pill using 
desogestrel: Cerazette® is currently the only highly 
effective progesterone-based pill
a
This is also considered a hormonal method.
b
The brand names in this table are examples only and availability will vary by country.

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
163 of 187
Appendix I
Patient-reported Outcomes
I 1
EORTC QLQ-C30
I 2
EORTC QLQ-H&N35
I 3
 
I 4
I 5
I 6
CCI
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
164 of 187
I 1
EORTC QLQ-C30

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
165 of 187

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
166 of 187
I 2
EORTC QLQ-H&N35

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
167 of 187

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
168 of 187
I 3
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
169 of 187
I 4
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
170 of 187
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
171 of 187
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
172 of 187
I 5
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
173 of 187
I 6
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
174 of 187
Appendix J
Study Participant Feedback Questionnaire

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
175 of 187

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
176 of 187

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
177 of 187

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
178 of 187
Appendix K
Abbreviations
Abbreviation or special 
term
Explanation
1L
first line
5-FU
5-fluorouracil
ADA
antidrug antibody
ADCC
antibody-dependent cell-mediated cytotoxicity
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BoR
best overall response
CI
confidence interval
Cmax
maximum serum concentration
COA
clinical outcome assessment
COVID-19
coronavirus disease 2019
CR
complete response
CrCL
creatinine clearance
CRO
Contract Research Organization
CSP
clinical study protocol
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
trough serum concentration
DCO
data cutoff
DILI
drug induced liver injury
DNA
deoxyribonucleic acid 
DoR
duration of response
ECG
electrocardiograms
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
Electronic Data Capture
EGFR
epidermal growth factor receptor
EMA
European Medicines Agency
EORTC
European Organisation for Research and Treatment of Cancer
EOT
end of treatment

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
179 of 187
Abbreviation or special 
term
Explanation
ePRO
electronic patient-reported outcome (questionnaire)
ESMO
European Society of Medical Oncology
EU SmPC
European Union Summary of Product Characteristics
EXTREME regimen
cetuximab + platinum (cisplatin or carboplatin) + 5-fluorouracil followed by 
cetuximab until progression or intolerance
FA
final analysis
FAS
Full Analysis Set
FDA
Food and Drug Administration
FDG
18F-Fluoro-deoxyglucose 
FH
Fleming-Harrington
FWER
familywise error rate
GCP
Good Clinical Practice
HBsAg
HBV surface antigen
HBV
hepatitis B
HCV
hepatitis C
HER
human epidermal growth factor receptor
HIV
human immunodeficiency virus
HL
Hy’s Law
HLA-E
human leukocyte antigen E
HPV
human papillomavirus
HPV-unrelated
randomized participants who are either OPC HPV negative or non-OPC
HR
hazard ratio
HRQoL
health-related quality of life
IA
interim analysis
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
ICI
immune checkpoint inhibitor
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IgG4
immunoglobulin G4
IHC
immunohistochemistry
CCI
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
180 of 187
Abbreviation or special 
term
Explanation
imAE
immune-mediated adverse event
IMP
investigational medicinal product
IRB
Institutional Review Board
IRT
Interactive Response Technology
iv
intravenous
IVRS
interactive voice response system
KM
Kaplan Meier
LA
locally advanced
mAb
monoclonal antibody
MRI
magnetic resonance imaging
NCCN
National Comprehensive Cancer Research
NCI
National Cancer Institute
NE
not evaluable
NED
no evidence of disease
NK
natural killer
NL
new lesion
NPH
non-proportional hazards
NTL
non-target lesion
OPC
oropharyngeal cancer
ORR
objective response rate
OS
overall survival
PBMC
peripheral blood mononuclear cells
PD
progressive disease
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand-1
PD-(L)1
programmed cell death-1 or programmed cell death ligand-1
PET
positron emission tomography
PFS
progression-free survival
 
PHL
potential Hy’s Law
PK
pharmacokinetic
PR
partial response
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
181 of 187
Abbreviation or special 
term
Explanation
PRO
patient-reported outcome
PS
performance status
Q1W
once weekly
Q2W
every 2 weeks
Q4W
every 4 weeks
QLQ-C30
30-item Core Quality-of-life Questionnaire
QLQ-H&N35
Quality of Life Questionnaire Head and Neck Module
QoL
quality of life
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, Version 1.1
REVPRDI
Review of PRO/Questionnaire/Diary
R/M
recurrent or metastatic
SAE
serious adverse event 
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome-coronavirus-2
SCCHN
squamous cell carcinoma of the head and neck
SD
stable disease
SITC
Society for Immunotherapy of Cancer
SoA
schedule of activities
SPFQ
Study Participant Feedback Questionnaire
TBL
total bilirubin
TL
target lesion
TME
tumor microenvironment
TMG
toxicity management guidelines
ULN
upper limit of normal
USA
United States of America
US FDA
United States Food and Drug Administration
US PI
United States Package Insert
WHO
World Health Organization
w/v
weight/volume

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
182 of 187
11
REFERENCES
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ et al. The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for 
use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365-76.
Andre P, Denis C, Soulas C, Bourbon-Caillet C, Lopez J, Arnoux T et al. Anti-NKG2A mAb 
Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK 
Cells. Cell. 2018;175(7):1731-43.e13.
Argiris A, Harrington KJ, Tahara M, Schulten J, Chomette P, Ferreira Castro A et al. 
Evidence-Based Treatment Options in Recurrent and/or Metastatic Squamous Cell Carcinoma 
of the Head and Neck. Front Oncol. 2017;772.
Borrego F, Ulbrecht M, Weiss EH, Coligan JE, Brooks AG. Recognition of human 
histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-
derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis. J 
Exp Med. 1998;187(5):813-8.
Braud VM, Allan DSJ, O'Callaghan CA, Söderström K, D'Andrea A, Ogg GS et al. HLA-E 
binds to natural killer cell receptors CD94/NKG2A, B and C. Nature. 1998;391(6669):795-9.
Cohen E, Bell R, Bifulco C, Burtness B, Gillison M, Harrington K et al. The Society for 
Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of 
squamous cell carcinoma of the head and neck (HNSCC). J Immunother Cancer. 
2019a;7(1):184.
Cohen E, Soulieres D, Le Tourneau C, Dinis J, Licitra L, Ahn M et al. Pembrolizumab versus 
methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous 
cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet. 
2019b;393(10167):156-67.
Cohen R, Salas S, Even C, Kotecki N, Jimeno A, Soulié A et al. Abstract 5666: Safety of the 
first-in-class anti-NKG2A monoclonal antibody monalizumab in combination with cetuximab: 
a phase Ib/II study in recurrent or metastatic squamous cell carcinoma of the head and neck 
(R/M SCCHN). Cancer Research. 2017;77(13 Supplement):5666.
Cohen R, Fayette J, Posner M, Lefebvre G, Bauman J, Salas S et al. Monalizumab in 
combination with cetuximab in recurrent or metastatic squamous cell carcinoma of the head 
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
183 of 187
and neck (R/M SCCHN): clinical and translational biomarker results. Abstract 051. Society 
for Immunotherapy of Cancer; Washington, DC. 2018a.
Cohen R, Fayette J, Posner M, Lefebvre G, Bauman J, Salas S et al. Phase II study of 
monalizumab, a first-in-class NKG2A monoclonal antibody, in combination with cetuximab in 
previously treated recurrent or metastatic squamous cell carcinoma of the head and neck (R/M 
SCCHN): Preliminary assessment of safety and efficacy. Abstract CT158. Cancer Research. 
2018b;78(13 Supplement):CT158-CT.
Cohen R, Lefebvre G, Posner M, Bauman J, Salas S, Even E et al. Monalizumab in 
combination with cetuximab in patients (pts) with recurrent or metastatic (R/M) head and neck 
cancer (SCCHN) previously treated or not with PD-(L)1 inhibitors (IO): 1-year survival data. 
Annals of Oncology. 2019c;30(suppl 5):v460.
Curry JM, Sprandio J, Cognetti D, Luginbuhl A, Bar-ad V, Pribitkin E et al. Tumor 
microenvironment in head and neck squamous cell carcinoma. Semin Oncol. 2014;41(2):217-
34.
Degboe A, Knight SL, Halling K, Trigg A, Al-Zubeidi T, Aldhouse N et al. Patients' 
experience of recurrent/metastatic head and neck squamous cell carcinoma and their 
perspective on the EORTC QLQ-C30 and QLQ-H&N35 questionnaires: a qualitative study. J 
Patient Rep Outcomes. 2018;2:33.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;45(2):228-47.
EMA. Guideline on the evaluation of anticancer medicinal products in man. 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-evaluation-
anticancer-medicinal-products-man-revision-5_en.pdf Published 2017. Accessed 22 
November 2019.
Erbitux (cetuximab) [package insert]. Princeton, NY: Bristol-Myers Squibb Company.; 2021.
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
184 of 187
Fayers P, Aaronson N, Bjordal K, Groenvold M, Curran D, Bottomley A. The EORTC QLQ-
C30 scoring manual (3rd edition). Published by: European Organisation for Research and 
Treament of Cancer, Brussels. 2001.
FDA. Guidance for industry: clinical trial endpoints for the approval of cancer drugs and 
biologics. https://www.fda.gov/media/71195/download. Published 2018a. Accessed 22 
November 2019.
FDA. FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) 
Resource [Internet]. Silver Spring (MD): Food and Drug Administration (US); 2016. Glossary. 
28 Jan 2016 [Updated 02 May 2018]. https://www.ncbi.nlm.nih.gov/books/NBK338448/Co-
published. Published 2018b. Accessed 05 November 2019.
Ferris RL, Blumenschein G, Jr., Fayette J, Guigay J, Colevas AD, Licitra L et al. Nivolumab 
for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 
2016;375(19):1856-67.
Gooden M, Lampen M, Jordanova ES, Leffers N, Trimbos JB, van der Burg SH et al. HLA-E 
expression by gynecological cancers restrains tumor-infiltrating CD8(+) T lymphocytes. Proc 
Natl Acad Sci U S A. 2011;108(26):10656-61.
Gregoire V, Lefebvre JL, Licitra L, Felip E. Squamous cell carcinoma of the head and neck: 
EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 
Ann Oncol. 2010;21 Suppl 5v184-6.
Harrington DP, Fleming TR. A class of rank test procedures for censored survival data. 
Biometrika. 1982;69(3):553-66.
CCI
CCI
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
185 of 187
Karrison TG. Versatile tests for comparing survival curves based on weighted log-rank 
statistics. Stata Journal. 2016;16(3):678-90.
Katou F, Ohtani H, Watanabe Y, Nakayama T, Yoshie O, Hashimoto K. Differing Phenotypes 
between Intraepithelial and Stromal Lymphocytes in Early-Stage Tongue Cancer. Cancer 
Research. 2007;67(23):11195.
Keytruda (pembrolizumab) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 
2021.
Kluetz PG, O'Connor DJ, Soltys K. Incorporating the patient experience into regulatory 
decision making in the USA, Europe, and Canada. Lancet Oncol. 2018;19(5):e267-e74.
Kol A, van Sccheltinga AT, Pool M, Gerdes C, de Vries E, de Jong S. ADCC Responses and 
blocking of EGFR-mediated Signaling and Cell Growth by Combining the Anti-EGFR 
Antibodies Imgatuzumab ad Cetuximab in NSCLC cells. Oncotarget. 2017;8(28):45432-46.
Lee N, Llano M, Carretero M, Ishitani A, Navarro F, Lopez-Botet M et al. HLA-E is a major 
ligand for the natural killer inhibitory receptor CD94/NKG2A. Proc Natl Acad Sci U S A. 
1998;95(9):5199-204.
Levy EM, Sycz G, Arriaga JM, Barrio MM, von Euw EM, Morales SB et al. Cetuximab-
mediated cellular cytotoxicity is inhibited by HLA-E membrane expression in colon cancer 
cells. Innate Immun. 2009;15(2):91-100.
Lin RS, Lin J, Roychoudhury S, Anderson KM, Hu T, Huang B et al. Alternative analysis 
methods for time to event endpoints under nonproportional hazards: a comparative analysis. 
Stat Biopharm Res. 2020;12(2):187-98.
Moy JD, Moskovitz JM, Ferris RL. Biological mechanisms of immune escape and 
implications for immunotherapy in head and neck squamous cell carcinoma. Eur J Cancer. 
2017;76152-66.
Nasman A, Andersson E, Nordfors C, Grun N, Johansson H, Munck-Wikland E et al. MHC 
class I expression in HPV positive and negative tonsillar squamous cell carcinoma in 
correlation to clinical outcome. Int J Cancer. 2013;132(1):72-81.
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
186 of 187
NCCN. Clinical practice guidelines in oncology: head and neck cancers. Version 3.2021 [cited 
Access Date]. Available from: https://www.nccn.org/guidelines/guidelines-
detail?category=1&id=1437.
Opdivo (nivolumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2021.
Rischin D, Harrington KJ, Greil R, Soulieres D, Tahara M, de Castro G et al. Protocol-
specified final analysis of the phase 3 KEYNOTE-048 trial of pembrolizumab (pembro) as 
first-line therapy for recurrent/metastatic head and neck squamous cell carcinoma (R/M 
HNSCC). Journal of Clinical Oncology. 2019;37(15_suppl):6000.
Silva TG, Crispim JC, Miranda FA, Hassumi MK, de Mello JM, Simoes RT et al. Expression 
of the nonclassical HLA-G and HLA-E molecules in laryngeal lesions as biomarkers of tumor 
invasiveness. Histol Histopathol. 2011;26(12):1487-97.
Taberna M, Mena M, Pavón MA, Alemany L, Gillison ML, Mesía R. Human papillomavirus-
related oropharyngeal cancer. Ann Oncol. 2017;28(10):2386-98.
Tinker AV, Hirte HW, Provencher DM, Butler MO, Ritter H, Tu D et al. Dose-ranging and 
cohort-expansion study of monalizumab (IPH2201) in advanced gynecologic malignancies:A 
trial of the Canadian Cancer Trials Group (CCTG):IND221. Clin Canc Res. 2019a;DOI: 
10.1158/078-0432.CCR-19-298.
Tinker AV, Hirte HW, Provencher DM, Butler MO, Ritter H, Tu D et al. Dose-ranging and 
cohort-expansion study of monalizumab(IPH2201) in advanced gynecologic malignancies:A 
trial of the Canadian Cancer Trials Group (CCTG):IND221. Clinical Cancer Research. 
2019b;clincanres.0298.2019.
van Montfoort N, Borst L, Korrer MJ, Sluijter M, Marijt KA, Santegoets SJ et al. NKG2A 
blockade potentiates CD8 T cell immunity induced by cancer vaccines. Cell. 
2018;175(7):1744-55.e15.
Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, Rolland F et al. Open-label, 
uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a 
single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head 
and neck who failed to respond to platinum-based therapy. J Clin Oncol. 2007;25(16):2171-7.
CCI
CCI

Clinical Study Protocol - 2.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
187 of 187
Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-based dosing 
of monoclonal antibodies in adult clinical trials. J Clin Pharmacol. 2009;49(9):1012-24.

6,*1$785(3$*(
7KLVLVDUHSUHVHQWDWLRQRIDQHOHFWURQLFUHFRUGWKDWZDVVLJQHG
HOHFWURQLFDOO\DQGWKLVSDJHLVWKHPDQLIHVWDWLRQRIWKHHOHFWURQLFVLJQDWXUH
'RFXPHQW1DPHGFFVSDPHQGPHQW
'RFXPHQW7LWOH
'&&OLQLFDO6WXG\3URWRFRO$PHQGPHQW
'RFXPHQW,'
9HUVLRQ/DEHO
&855(17/$7(67$33529('
6HUYHU'DWH
GG000\\\\++PPµ87&¶=
6LJQHGE\
0HDQLQJRI6LJQDWXUH
-XO87&
&RQWHQW$SSURYDO
-XO87&
&RQWHQW$SSURYDO
-XO87&
&RQWHQW$SSURYDO
-XO87&
&RQWHQW$SSURYDO
PPD
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
1 of 187
Clinical Study Protocol 
Study Intervention
Monalizumab and cetuximab
Study Code
D7310C00001
Version
3.0
Date
12 July 2022
A Phase 3 Randomized, Double-blind, Multicenter, Global Study of 
Monalizumab or Placebo in Combination With Cetuximab in Participants 
With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and 
Neck Previously Treated With an Immune Checkpoint Inhibitor
Sponsor Name: 
AstraZeneca AB
Legal Registered Address: 
151 85 Södertälje, Sweden
Regulatory Agency Identifier Number(s): IND number 145482
EudraCT number 2019-004770-25
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.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
2 of 187
Protocol Number: D7310C00001
Amendment Number: 1
Study Intervention: Monalizumab (IPH2201) and cetuximab
Study Phase: 3
Short Title: Study of Monalizumab Given With Cetuximab or Placebo Given with Cetuximab 
in Participants With Recurrent or Metastatic Head and Neck Cancer
Acronym: INTERLINK-1
Study Clinical Lead Name and Contact Information will be provided separately
International Co-ordinating Investigators: 
Abramson Cancer Center, Perelman Center for Advanced Medicine
West Pavilion, 2nd Floor, 3400 Civic Center Boulevard
Philadelphia, PA 19104 USA
Centre Léon Bérard
28, rue Laennec 
69373 Lyon Cedex 08 FRANCE
PPD
PPD

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
3 of 187
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 2
12 July 2022
Amendment 1
07 July 2021
Original Protocol
10 February 2020
Amendment 2 (12 July 2022)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the EU.
Overall Rationale for the Amendment
The protocol was updated to remove the exploratory objectives and the associated endpoints 
for assessment of cetuximab PK and ADA. The recent data from Study D419NC0001 and 
Study IPH2201-203 showed that there was no significant impact of co-administration of 
monalizumab on the PK exposure of monalizumab or cetuximab. In addition, cetuximab is an 
approved therapeutic across multiple tumour types in oncology, including head and neck 
cancer, with a well-established risk/benefit profile.
The observed Hazard Ratio at Interim Analysis 1 is revised from >0.85 to >0.874 and the 
corresponding conditional power from 29.4% to 20%.
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Protocol Amendment 
Summary of Changes 
Table
Section “Protocol Amendment Summary 
of Changes Table” was revised to add the 
Amendment 2.
To describe 
changes in 
Amendment 2
Non-substantial
Section 1.3 Schedule of 
Activities
Table 1
Removed ‘Cetuximab pre-dose serum 
sample for PK’, ‘Cetuximab post-dose 
serum sample for PK’ and ‘Cetuximab pre-
dose serum sample for ADA’.
To align with 
removal of 
exploratory 
objective of 
cetuximab PK 
and ADA 
assessment.
Substantial 
Table 2
Removed ‘Cetuximab serum sample for 
PK’ and ‘Cetuximab serum sample for 
ADA’.
To align with 
removal of 
exploratory 
objective of 
cetuximab PK 
and ADA 
assessment
Substantial
Section 3 Objectives and 
Endpoints
Table 4
Removed Exploratory objective and 
associated Estimand Description/Endpoints 
Removed 
because the 
recent data from 
Substantial

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
4 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
‘To assess the PK of cetuximab’ and ‘To 
investigate the immunogenicity of 
cetuximab’.
Study 
D419NC0001 
and Study 
IPH2201-203 
showed that 
there was no 
significant 
impact of co-
administration 
of monalizumab 
on the PK 
exposure of 
monalizumab or 
cetuximab
Section 6.1.2 Dosing 
Instructions
Dosing regimen
Text updated to read ‘Approximately 60 
minutes after the end of 
monalizumab/placebo dosing, participants 
will receive cetuximab.’
For clarity
Non-substantial
Section 6.2.1.1 
Monalizumab
Final monalizumab concentration revised 
from ‘3 to 20 mg/mL’ to ‘0.9 to 20mg/mL’
Added text ‘however the selected iv bag 
size must be ≤250mL.’
To provide 
clarity and 
restrict iv bag 
size to ≤250 
mL.
Non-substantial
Section 8.5.1 
Pharmacokinetics
Removed the sample requirement for 
pharmacokinetics for cetuximab.
To align with 
removal of 
exploratory 
objective of 
cetuximab PK 
assessment
Substantial
Section 9.3.4 
Pharmacokinetic 
Analysis Set
Removed cetuximab from the 
pharmacokinetic analysis set.
To align with 
removal of 
exploratory 
objective of 
cetuximab PK 
assessment
Substantial
Section 9.4.4.2 
Pharmacokinetic Data
Removed cetuximab serum concentration 
data requirement for PK analysis set.
To align with 
removal of 
exploratory 
objective of 
cetuximab PK 
assessment
Substantial
Section 9.4.4.3 
Immunogenicity Data
Removed requirement of anti-cetuximab 
antibodies from immunogenicity data
To align with 
removal of 
Substantial

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
5 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
exploratory 
objective of 
cetuximab ADA 
assessment
Section 9.5 Interim 
Analyses
Futility criteria revised to HR at IA1 from 
>0.85, corresponding to 29.4% conditional 
power, to >0.874 which corresponds to 
20% conditional power.
Modified to 
relax futility 
criteria based on 
strategic 
considerations
Substantial
Amendment 1 (07 July 2021)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the EU.
Overall Rationale for the Amendment
The protocol was updated to change the primary population of interest for the primary 
endpoint from the FAS to the HPV-unrelated Analysis Set (randomized participants who are 
either OPC HPV negative or non-OPC regardless of HPV status). To allow for the change in 
population assessed for the primary endpoint, the planned number of participants was 
increased and the hierarchical testing procedure was updated. A futility analysis for OS was 
added as a new interim analysis for the HPV-unrelated Analysis Set . Guidance relating to the 
COVID-19 pandemic was added.
In addition, a number of non-substantial changes were made and errors were corrected.
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Protocol Amendment 
Summary of Changes 
Table
Section “Protocol Amendment Summary 
of Changes Table” was added.
To describe 
changes in 
Amendment 1
Non-substantial
Section 1.1 Synopsis, 
Rationale
Text updated in line with changes to 
protocol body.
See below
See below
Section 1.1 Synopsis, 
Objectives and 
Endpoints
Text updated in line with changes to 
protocol body.
See below
See below
Section 1.1 Synopsis, 
Overall Design
Text updated in line with changes to 
protocol body. In addition, the number of 
sites was increased from 175 to 190.
See below
See below

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
6 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 1.1 Synopsis, 
Number of Participants
Text updated in line with changes to 
protocol body.
See below
See below
Section 1.1 Synopsis, 
Statistical Methods
Text updated in line with changes to 
protocol body.
See below
See below
Section 1.3 Schedule of 
Activities
Table 1
Added collection of PD-L1 results at 
screening, if available. Clarification added 
(Footnote “d”) that the most recent PD-L1 
results should be provided and if PD-L1 
results were not collected at screening, 
they will be collected retrospectively.
As part of the 
biomarker 
evaluation  
Non-substantial
Table 1
Added separate line for assessment of 
Coagulation parameters and footnote ‘j’ as 
mentioned in Section 8.2.4. 
For clarification
Non-substantial
Table 1
Based on PK 
advice
Non-substantial
Table 1
Based on PK 
advice
Non-substantial
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
7 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Table 1 and Table 2
Order of T3 and T4 changed to T4 
followed by T3 in Table 1 and footnote “k” 
of Table 1 and in Table 2 and footnote “c” 
of Table 2; footnote “k” (Table 1)/footnote 
“c” (Table 2) changed from “Free T3 and 
free T4” to “Free T4 or/and free T3 (per 
local standard clinical practice)”.
To correct an 
error
Non-substantial
Section 2.2 Background
Updated to reflect most recent NCCN 
guidelines.
To present most 
recent 
guidelines
Non-substantial
Section 3 Objectives and 
Endpoints
Population used for analysis of the primary 
objective was changed from the FAS to the 
HPV-unrelated Analysis Set (randomized 
participants who are either OPC HPV 
negative or non-OPC regardless of HPV 
status).
Primary 
population was 
updated to 
reflect the 
updated primary 
population of 
interest 
(HPV-unrelated 
participants)
Substantial
The previous primary objective (to 
compare the effect of monalizumab and 
cetuximab (Arm A) relative to placebo and 
cetuximab (Arm B) by assessment of OS in 
all participants [ie, in the FAS]) was 
moved to a secondary objective.
The population was confirmed as all 
randomized patients.
To allow for the 
primary 
objective to be 
assessed in the 
HPV-unrelated 
Analysis Set
Substantial
For the secondary objective “To compare 
the effect of monalizumab and cetuximab 
(Arm A) relative to placebo and cetuximab 
(Arm B) by assessment of PFS, ORR, and 
DoR”, the populations to be analyzed were 
changed to “participants who are 
HPV-unrelated” and “all randomized 
participants”.
To clarify that 
the 
HPV-unrelated 
Analysis Set 
will also be used 
for this analysis
Substantial
Text added to the following objectives to 
clarify they will be analyzed in the 
HPV-unrelated population and in all 
randomized participants:
“To assess disease-related symptoms, 
functioning, and HRQoL in participants 
treated with monalizumab and cetuximab 
(Arm A) compared to placebo and 
To clarify that 
these objectives 
will be analyzed 
in the 
HPV-unrelated 
Analysis Set 
and in all 
Substantial

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
8 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
cetuximab (Arm B) using the EORTC 
QLQ-C30 and the EORTC QLQ-H&N35 
questionnaires”
randomized 
participants
Section 4.1 Overall 
Design
To allow for the 
change in 
planned sample 
size given the 
primary 
population has 
been changed to 
HPV-unrelated 
population
Substantial
Now states that the IDMC will review data 
for both IAs (previously there was only 
one IA).
For clarity
Non-substantial
Text added to describe a cap on the number 
of OPC HPV-positive participants of 
approximately 20%.
To ensure 
sufficient 
sample size for 
HPV-unrelated 
participants
Substantial
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
9 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 4.1.1 Study 
Conduct Mitigation 
During Study 
Disruptions Due to 
Cases of Civil Crisis, 
Natural Disaster, or 
Public Health Crisis
New section to provide instructions in the 
case of civil crisis, natural disaster, or 
public health crisis.
In response to 
COVID-19 
pandemic, to 
reflect current 
AstraZeneca 
processes
Substantial
Section 4.2.1 Rationale 
for Study Design and 
Participant Population
Added clarification that unblinded 
pharmacists and ‘unblinded Study 
Monitors’ will be used in order to maintain 
the blind.
For clarification
Non-substantial
Text added to give rationale for testing in 
the HPV-unrelated population.
To align with 
the change to 
the primary 
population 
Non-substantial
Section 5.1 Inclusion 
Criterion 7
Added clarification that tumor tissue 
beyond the 3-month window and up to 
6 months old may be considered, provided 
that no intervening systemic regimen was 
ongoing at the time of sample collection. A 
reference to the Laboratory Manual was 
also added.
For clarification
Non-substantial
Section 5.2 Exclusion 
Criterion 13
Triplicate ECG timings replaced with a 
cross reference to Section 8.2.3.
For clarity
Non-substantial
Section 6.1.1 
Investigational 
Medicinal Products
Table 5
Updated to align 
with CSP 
template
Non-substantial
For clarification
Non-substantial
For clarification
Non-substantial
Clarified that cetuximab will be supplied 
by AstraZeneca, but if locally sourced the 
approved commercial product should be 
used.
For clarification
Non-substantial
Section 6.1.2 Dosing 
Instructions
Dosing regimen
For clarification
Non-substantial
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
10 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Now states that the total infusion duration 
for both interventions must not exceed 
8 hours.
Also states the iv line will be flushed 
according to local practices to ensure the 
full dose is administered, and the infusion 
time does not include the final flush time.
Section 6.2 
Preparation/Handling/ 
Storage/Accountability 
of Interventions
Clarified that IMP must be kept in original 
packaging.
For clarification
Non-substantial
Section 6.2.1.1 
Monalizumab
Removed the text stating that monalizumab 
should be protected from direct sunlight 
during preparation and handling.
Clarified that the reconstitution and 
administration time of monalizumab must
not exceed values stated.
For clarification
Non-substantial
Non-substantial
Section 6.2.1.3 Placebo
Revised text to state an
Clarified that the total infusion time must
not exceed 8 hours at room temperature.
For clarification
Non-substantial
6.3.1 Participant 
Enrollment and 
Randomization
Text added to describe a cap on the number 
of OPC HPV-positive participants of 
approximately 20%.
To ensure 
sufficient 
sample size for 
HPV-unrelated 
participants
Substantial
Amended to state all screening laboratory 
and imaging results must be obtained 
within 28 days of randomization (was 
“within 28 days of randomization/the first 
dose of study intervention”).
For consistency 
with tumor 
assessment 
timings in 
Non-substantial
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
11 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Inclusion 
Criterion 6
Amended to state a tumor tissue sample 
should be submitted to the central 
laboratory.
To ensure 
samples are 
submitted for 
analysis
Non-substantial
Section 6.5 Concomitant 
Therapy
Table 7
Text amended to state permitted vaccines 
are limited to non-live attenuated 
preparations. A reference to Appendix C 
was also added for details about 
vaccination against COVID-19.
To align with 
current 
AstraZeneca 
template
Non-substantial
Section 6.5.3 Rescue 
Medication
Removed the need to record the time of 
rescue medication administration.
Removed as this 
is not necessary
Non-substantial
Section 6.6 Dose 
Modification
Added reference for managing dose delays 
due to treatment-related toxicity.
To reflect 
current 
AstraZeneca 
processes
Non-substantial
Added reference to the new COVID-19 
Appendix C.
To reflect 
current 
AstraZeneca 
processes
Substantial
Replaced the term “IMP” with the 
specified study treatment.
For clarity
Non-substantial
Section 8.1.1 Imaging 
Tumor Assessments
Clarified that screening/baseline imaging 
should be performed no more than 28 days 
before randomization (not 28 days before 
start of study intervention).
For clarification
Non-substantial
Section 8.1.4.7 
Administration of 
Electronic PRO 
Questionnaires
Clarified that if technical or other device-
related issues prohibit completion of the 
questionnaires on the device, an 
appropriate backup option may be 
considered.
For clarification
Non-substantial
Clarified that relatives, friends, or clinic 
staff should not help participants decide on 
answers to the questionnaires.
For clarification
Non-substantial
Clarified that if a participant needs (rather 
than uses) visual aids for reading and they 
do not have them when attending clinic, 
they will be exempted from completing the 
ePROs at that visit.
For clarification
Non-substantial

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
12 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Clarified reasons for exemption from 
completing the ePROs, and added the need 
to contact AstraZeneca to determine if the 
participant is exempt.
For clarification
Non-substantial
Wording regarding language of the 
questionnaires updated; questions must not 
be translated from an available language in 
the device into the language the participant 
speaks.
For clarification
Non-substantial
Clarified (in relation to ePRO reporting) 
that Cycle 1 Day 1 is baseline.
For clarification
Non-substantial
Removed “REVPRDI” as the eCRF onto 
which completion status is to be recorded.
For clarification
Non-substantial
Text added to describe process regarding 
participant compliance.
For clarification
Non-substantial
Section 8.1.4.8 
WHO/ECOG PS
Numbering of WHO/ECOG classification 
corrected.
To correct an 
error
Non-substantial
Sentence added to state the ECOG status 
collected at screening must be reported in 
IRT and not re-assessed.
For clarification
Non-substantial
Section 8.2.2 Vital Signs
Added the approximate time window for 
collection of vital signs before cetuximab 
dosing
For clarification
Non-substantial
Section 8.2.3 
Electrocardiograms
Resting ECG description changed to 
“semi-recumbent or supine”.
To correct an 
error
Non-substantial
Section 8.2.4 Clinical 
Safety Laboratory 
Assessments
Timing of sampling for coagulation 
parameters aligned with Table 8: “baseline 
on Day 1 (unless all screening laboratory 
hematology assessments are performed 
within 3 days prior to Day 1), and then as 
clinically indicated”
For clarification
Non-substantial
Table 8
Order of T3 and T4 changed to T4 
followed by T3 in Table 8; footnote “h” 
amended to “Free T4 or/and free T3 (per 
local standard clinical practice)…”.
To correct an 
error
Non-substantial
Table 8
Footnote c clarified that absolute 
neutrophil counts must be recorded at 
screening ie, they must not be recorded as 
percentages. 
For clarification
Non-substantial

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
13 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
The calculation of absolute counts from 
percentages was removed as this is not 
currently achievable.
Table 8
Coagulation was moved from the clinical 
chemistry column to the 
hematology/hemostasis column.
To correct an 
error
Non-substantial
Section 8.3 Adverse 
Events and Serious 
Adverse Events
Cross reference to new COVID-19 
Appendix C added.
To reflect 
current 
AstraZeneca 
processes
Substantial
Section 8.3.13.1 
Maternal Exposure
“Congenital abnormalities/abnormality” 
changed to “congenital 
anomalies/anomaly”.
This change is 
in line with 
regulatory 
requirements
Non-substantial
Section 8.3.13.2 Paternal 
Exposure
“Congenital abnormality” changed to 
“congenital anomaly”.
This change is 
in line with 
regulatory 
requirements
Non-substantial
Section 8.3.14 
Medication Error
Clarified that medication error information 
should be reported on the specific 
medication error eCRF.
Updated in line 
with new 
AstraZeneca 
requirements
Non-substantial
Section 8.3.15.2 
Cetuximab
Management of AEs with cetuximab text 
amended to refer to local label (details of 
actions to take have been removed).
To avoid 
possible 
mis-alignment 
with future 
changes to 
prescribing 
information
Substantial
Section 8.6.1 Collection 
of Mandatory Samples 
for Biomarker Analysis
Added clarification that tumor tissue 
beyond the 3-month window and up to 
6 months old may be considered, provided 
that no intervening systemic regimen was 
ongoing at the time of sample collection. A 
reference to the Laboratory Manual was 
also added.
For clarification
Non-substantial
Added clarification that fresh tumor biopsy 
should not be collected from lesions in 
proximity to structures that would make 
the collection procedure high risk. 
Per USA FDA 
request 
Non-substantial
Section 9.2 Sample Size 
Determination
Number of randomized participants 
increased from 600 to 624.
To align with 
the changes in 
Non-substantial

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
14 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 4 Study 
Design
Text amended to reflect change in 
population analyzed for the primary 
endpoint.
To reflect the 
change in the 
primary 
population
Substantial
Futility analysis for OS added for the 
HPV-unrelated Analysis Set.
Futility analysis 
was added for 
risk mitigation 
Substantial
Statistical methods for the primary 
endpoint were updated to reflect that 
analysis will be performed on 
HPV-unrelated participants.
To reflect the 
change in the 
primary 
population
Substantial
Text added to describe a cap on the number 
of OPC HPV-positive participants of 
approximately 20%.
To ensure 
sufficient 
sample size for 
HPV-unrelated 
participants
Substantial
Hypothesis text split to reflect hypotheses 
at each analysis (IA2 and final analysis).
For clarification
Substantial
Section 9.3 Populations 
for Analyses
Table 9
HPV-unrelated Analysis Set added to 
analysis of OS, PFS, ORR, DoR, PRO 
endpoints, demography and other baseline 
characteristics, and biomarkers.
To allow 
analysis for the 
updated primary 
population
Substantial
Table 9
Footnotes added to clarify definitions of 
ORR and PRO.
For clarification
Non-substantial
Section 9.3.1 
HPV-unrelated Analysis 
Set
New section added to describe new 
analysis set.
To allow 
analysis for the 
updated primary 
population
Substantial
Section 9.3.2 Full 
Analysis Set
Amended to state FAS will be used for 
summarizing baseline characteristics, all 
efficacy endpoints (including PROs) and 
biomarker analyses as secondary analyses.
The 
HPV-unrelated 
Analysis Set is 
the primary 
analysis set
Substantial
“Analysis for ORR will be based on 
participants in the FAS who had 
measurable disease at baseline. Analysis of 
DoR will be based on participants in the 
It is more 
appropriate to 
include the 
description of 
the subset used 
for ORR and 
Non-substantial

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
15 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
FAS who achieved objective response” 
was removed.
DoR analyses in 
the sections for 
ORR and DoR
Section 9.3.3 Safety 
Analysis Set
Clarified that all participants who received 
any amount of study treatment (not at least 
1 dose) will be included in the Safety 
Analysis Set.
For clarification
Non-substantial
Section 9.4.1 General 
Considerations
Hypothesis text split to reflect hypotheses 
at each analysis (IA2 and final analysis).
For clarification
Substantial
Number of OS events and % maturity 
updated to reflect change in primary 
analysis population to HPV-unrelated 
Analysis Set.
To reflect the 
change in the 
primary 
population
Substantial
Text changed to reflect that the efficacy 
and PRO analyses will be performed on the 
HPV-unrelated population and repeated for 
the FAS as a secondary analysis.
Updated so that 
the PRO 
analysis is 
performed for 
both the primary 
and secondary 
populations
Substantial
Table 10
Added populations analyzed and amended 
stratification factors for each endpoint to 
reflect populations analyzed. Added OS in 
FAS as a secondary endpoint.
To reflect the 
change in the 
primary 
population
Substantial
Table 10
OS: KM plot of time to censoring removed 
from the sensitivity and supplemental 
analysis.
Removed as it is 
not considered 
necessary
Non-substantial
Table 10
OS: Cox proportional hazards models 
removed from the sensitivity and 
supplemental analysis.
For consistency 
with the SAP 
that has changed 
during 
development
Non-substantial
Section 9.4.1.1 Methods 
for Multiplicity Control
Text was added to more fully describe the 
hierarchical testing procedure.
For clarification
Non-substantial

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
16 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Number of OS events updated to reflect 
change in primary analysis population to 
HPV-unrelated Analysis Set; new figure 
added to describe multiplicity testing 
procedure.
To allow 
updated sample 
size justification 
with the change 
in the primary
population. To 
allow 
clarification in 
the multiple 
testing 
procedure of OS 
and PFS with 
the primary 
population 
(HPV-unrelated 
Analysis Set) 
and the 
secondary 
population 
(FAS)
Substantial
Statement that PFS will be formally tested 
only if OS is statistically positive replaced 
by statement that each statistical test will 
be performed only if the preceding test is 
positive.
To allow 
clarification in 
the multiple 
testing 
procedure of OS 
and PFS with 
the primary 
population 
(HPV-unrelated 
Analysis Set) 
and the 
secondary 
population 
(FAS)
Substantial
Section 9.4.2.1 Primary 
Endpoint
Primary analysis 
Analysis set changed from FAS to 
HPV-unrelated Analysis Set.
As the population studied is now the 
HPV-unrelated Analysis Set, adjustment 
for HPV status was removed.
To allow 
analysis for the 
updated primary 
population and 
adjust the 
sensitivity 
analyses 
accordingly
Substantial
Sensitivity analysis
Added 
max-combo test 
as it is 
Non-substantial

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
17 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Details added regarding the stratified 
max-combo test that will be used as a 
sensitivity analysis.
Removal of KM plot for the time to 
censoring (attrition bias).
recommended 
by the 
Cross-Pharma 
Non-
proportional 
Hazard Working 
Group in the 
presence of non-
proportional 
hazards.
Removed KM 
plot of time to 
censoring as it is 
not as 
informational.
Cox proportional hazards models removed 
from the sensitivity and supplemental 
analysis.
For consistency 
with the SAP 
that has changed 
during 
development
Non-substantial
Analysis of OS in FAS
New section to describe analysis of OS in 
the FAS.
To describe 
analysis of 
secondary 
endpoint
Substantial
Subgroup analysis
Clarified that subgroup analyses will be 
performed on HPV-unrelated Analysis Set 
and FAS, where applicable.
To allow 
analysis for the 
updated primary 
population
Substantial
“Race” changed to “Race/ethnicity data” 
for clarification.
For clarification
Non-substantial
9.4.2.2.1 Progression-
free Survival
Analysis of PFS
Text amended to state PFS will be 
analyzed in the HPV-unrelated Analysis 
Set as well as the FAS.
To allow 
analysis in the 
primary 
population
Substantial
9.4.2.2.2 Objective 
Response Rate
Analysis of ORR
To allow 
analysis in the 
Substantial

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
18 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Text amended to state ORR will be 
analyzed in the HPV-unrelated Analysis 
Set as well as the FAS.
primary 
population
Section 9.4.2.2.4 Patient-
reported Outcome: 
EORTC QLQ-C30
Detailed information about PRO 
definitions were removed as the 
information will be included in the SAP. 
The number of analyses of PROs was 
reduced.
Information will 
be detailed in 
the SAP
Non-substantial
Text amended to state analyses will be 
performed on the HPV-unrelated Analysis 
Set as well as the FAS.
To allow 
analysis in the 
primary 
population
Substantial
Section 9.4.2.2.5 Patient-
reported Outcome: 
EORTC QLQ-H&N35
Detailed information about PRO 
definitions were removed as the 
information will be included in the SAP. 
Information will 
be detailed in 
the SAP
Non-substantial
Analysis methods
Text amended to state the analyses will be 
performed for the HPV-unrelated Analysis 
Set as well as the FAS.
The number of analyses of PROs was 
reduced.
To allow 
analysis in the 
primary 
population
Substantial
Section 9.4.2.3.1 Time 
from Randomization to 
Second Progression or 
Death
Removal of KM plot for the time to 
censoring (attrition bias).
Removed as it is 
not considered 
necessary
Non-substantial
Section 9.7 Impact of 
COVID-19 on Data
New section added to acknowledge 
possible impact of COVID-19 on the data: 
reference to SAP (where details will be 
supplied) included.
In response to 
COVID-19 
pandemic, to 
reflect current 
AstraZeneca 
processes
Substantial
Appendix B 2 
Definitions of Serious 
Adverse Event
“Congenital abnormality” changed to 
“congenital anomaly.
This change is 
in line with 
Non-substantial
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
19 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
regulatory 
requirements
Appendix C Changes 
Related to Mitigation of 
Study Disruptions Due 
to Cases of Civil Crisis, 
Natural Disaster, or 
Public Health Crisis, 
including COVID-19 
Outbreak 
New appendix added to describe study 
conduct details pertaining to COVID-19 
outbreak. 
All subsequent appendices renumbered.
In response to 
COVID-19 
pandemic, to 
reflect current 
AstraZeneca 
processes
Substantial
Appendix E 8 
Laboratory Tests (now 
Appendix F 8)
Table of Hy’s law laboratory tests: 
footnote “a” removed from HBV DNA as 
it is not applicable for HBV DNA; footnote 
“c” removed since the study is not 
expected to be conducted in China.
Amendment of 
error and 
clarification
Non-substantial
Throughout
The terms “Medical Monitor” and “Study 
Physician” were changed to “Study 
Clinical Lead”.
In line with 
latest 
AstraZeneca 
template
Non-substantial

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
20 of 187
TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3
TABLE OF CONTENTS .................................................................................................... 20
1
PROTOCOL SUMMARY ................................................................................ 25
1.1
Synopsis ........................................................................................................... 25
1.2
Schema............................................................................................................. 31
1.3
Schedule of Activities ....................................................................................... 31
2
INTRODUCTION............................................................................................ 44
2.1
Study Rationale ................................................................................................ 44
2.2
Background ...................................................................................................... 44
2.3
Benefit/Risk Assessment................................................................................... 46
2.3.1
Risk Assessment ............................................................................................... 46
2.3.2
Benefit Assessment........................................................................................... 48
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 49
3
OBJECTIVES AND ENDPOINTS................................................................... 50
4
STUDY DESIGN ............................................................................................. 52
4.1
Overall Design.................................................................................................. 52
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 54
4.2
Scientific Rationale for Study Design ............................................................... 54
4.2.1
Rationale for Study Design and Participant Population ..................................... 54
4.2.2
Rationale of Study Endpoints............................................................................ 55
4.3
Justification for Dose........................................................................................ 56
4.3.1
Rationale for Monalizumab Dose...................................................................... 56
4.3.2
Rationale for Cetuximab Dose .......................................................................... 58
4.4
End of Study Definition.................................................................................... 58
5
STUDY POPULATION.................................................................................... 58
5.1
Inclusion Criteria .............................................................................................. 58
5.2
Exclusion Criteria ............................................................................................. 61
5.3
Lifestyle Considerations ................................................................................... 64
5.4
Screen Failures ................................................................................................. 64
6
STUDY INTERVENTION ............................................................................... 65
6.1
Study Interventions Administered ..................................................................... 65
6.1.1
Investigational Medicinal Products ................................................................... 65
6.1.2
Dosing Instructions........................................................................................... 66
6.1.3
Duration of Treatment....................................................................................... 68
6.2
Preparation/Handling/Storage/Accountability of Interventions.......................... 68

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
21 of 187
6.2.1
Dose Preparation and Administration................................................................ 68
6.2.1.1
Monalizumab.................................................................................................... 68
6.2.1.2
Cetuximab ........................................................................................................ 69
6.2.1.3
Placebo............................................................................................................. 70
6.3
Measures to Minimize Bias: Randomization and Blinding ................................ 70
6.3.1
Participant Enrollment and Randomization ....................................................... 70
6.3.2
Procedures for Handling Incorrectly Enrolled or Randomized Participants........ 72
6.3.3
Methods for Assigning Treatment Arms............................................................ 72
6.3.4
Methods for Ensuring Blinding......................................................................... 73
6.4
Study Intervention Compliance......................................................................... 74
6.5
Concomitant Therapy........................................................................................ 74
6.5.1
Permitted Medication Prior to Study Intervention ............................................. 76
6.5.2
Drug-drug Interactions...................................................................................... 77
6.5.3
Rescue Medication............................................................................................ 77
6.6
Dose Modification ............................................................................................ 77
6.7
Intervention After the End of the Study............................................................. 78
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 79
7.1
Discontinuation of Study Intervention............................................................... 79
7.1.1
Procedures for Discontinuation of Study Intervention ....................................... 80
7.1.1.1
Tumor Assessment Post Discontinuation of Study Intervention......................... 80
7.1.1.2
7.1.1.3
Follow-up for Survival...................................................................................... 81
7.2
Participant Withdrawal From the Study............................................................. 81
7.3
Lost to Follow-up ............................................................................................. 82
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 83
8.1
Efficacy Assessments........................................................................................ 83
8.1.1
Imaging Tumor Assessments............................................................................. 83
8.1.2
8.1.3
Overall Survival................................................................................................ 84
8.1.4
Clinical Outcome Assessments.......................................................................... 84
8.1.4.1
EORTC QLQ-C30 ............................................................................................ 85
8.1.4.2
EORTC QLQ-H&N35 ...................................................................................... 85
8.1.4.3
8.1.4.4
8.1.4.5
8.1.4.6
8.1.4.7
Administration of Electronic PRO Questionnaires ............................................ 86
8.1.4.8
WHO/ECOG PS ............................................................................................... 88
8.2
Safety Assessments........................................................................................... 89
8.2.1
Physical Examinations...................................................................................... 89
8.2.2
Vital Signs ........................................................................................................ 89
8.2.3
Electrocardiograms........................................................................................... 90
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
22 of 187
8.2.4
Clinical Safety Laboratory Assessments............................................................ 91
8.3
Adverse Events and Serious Adverse Events..................................................... 92
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 92
8.3.2
Follow-up of AEs and SAEs ............................................................................. 93
8.3.3
Causality Collection.......................................................................................... 94
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 94
8.3.5
Adverse Events Based on Examinations and Tests ............................................ 94
8.3.6
Hy’s Law.......................................................................................................... 95
8.3.7
Disease Progression.......................................................................................... 95
8.3.8
New Cancers..................................................................................................... 95
8.3.9
Deaths .............................................................................................................. 95
8.3.10
Adverse Events of Special Interest.................................................................... 96
8.3.11
Safety Data to be Collected Following the Final DCO of the Study................... 97
8.3.12
Reporting of Serious Adverse Events ................................................................ 97
8.3.13
Pregnancy......................................................................................................... 98
8.3.13.1
Maternal Exposure............................................................................................ 98
8.3.13.2
Paternal Exposure............................................................................................. 98
8.3.14
Medication Error............................................................................................... 99
8.3.15
Management of IMP-related Toxicities ............................................................. 99
8.3.15.1
Monalizumab.................................................................................................... 99
8.3.15.2
Cetuximab ...................................................................................................... 100
8.4
Overdose ........................................................................................................ 100
8.5
Human Biological Samples............................................................................. 101
8.5.1
Pharmacokinetics............................................................................................ 101
8.5.1.1
Determination of Drug Concentration ............................................................. 102
8.5.2
Immunogenicity Assessments ......................................................................... 102
8.6
Human Biological Sample Biomarkers ........................................................... 102
8.6.1
Collection of Mandatory Samples for Biomarker Analysis .............................. 102
8.6.2
Collection of Optional Biomarker Samples ..................................................... 103
8.6.3
Other Study-related Biomarker Research ........................................................ 103
8.7
8.8
Medical Resource Utilization and Health Economics ...................................... 104
8.9
Study Participant Feedback Questionnaire ...................................................... 104
9
STATISTICAL CONSIDERATIONS.............................................................. 104
9.1
Statistical Hypotheses..................................................................................... 104
9.2
Sample Size Determination............................................................................. 104
9.3
Populations for Analyses................................................................................. 106
9.3.1
HPV-unrelated Analysis Set ............................................................................ 106
9.3.2
Full Analysis Set............................................................................................. 107
9.3.3
Safety Analysis Set ......................................................................................... 107
9.3.4
Pharmacokinetic Analysis Set ......................................................................... 107
9.3.5
ADA Analysis Set........................................................................................... 107
9.4
Statistical Analyses ......................................................................................... 107
9.4.1
General Considerations................................................................................... 107
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
23 of 187
9.4.1.1
Methods for Multiplicity Control .................................................................... 110
9.4.2
Efficacy ...........................................................................................................111
9.4.2.1
Primary Endpoint.............................................................................................111
9.4.2.2
Secondary Endpoints ...................................................................................... 113
9.4.2.3
Exploratory Endpoints .................................................................................... 117
9.4.3
Safety ............................................................................................................. 118
9.4.3.1
Calculation or Derivation of Safety Variables.................................................. 118
9.4.3.2
Analysis of safety variables............................................................................. 120
9.4.4
Other Analyses................................................................................................ 120
9.4.4.1
Healthcare Resource Use ................................................................................ 120
9.4.4.2
Pharmacokinetic Data..................................................................................... 120
9.4.4.3
Immunogenicity Data...................................................................................... 120
9.4.4.4
Pharmacokinetic/Pharmacodynamic Relationships.......................................... 121
9.4.4.5
Biomarker Data .............................................................................................. 121
9.5
Interim Analyses............................................................................................. 121
9.6
Data Monitoring Committee ........................................................................... 122
9.7
Impact of COVID-19 on Data......................................................................... 122
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ...................................................................................... 122
11
REFERENCES............................................................................................... 182
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 31
Figure 2
Figure 3
Graphical Presentation of the Propose Multiple-Testing Procedure at IA2 
and FA................................................................................................... 111
LIST OF TABLES
Table 1
Schedule of Activities – Screening Period and Intervention Period .......... 32
Table 2
Schedule of Activities – Follow-up Period for Participants Who 
Discontinued Study Intervention Due to Disease Progression or Other 
Reason..................................................................................................... 40
Table 3
Preliminary Efficacy, Cohort 1 - Expansion Phase (Monalizumab + 
Cetuximab), All Subjects Treated (Study IPH2201-203).......................... 49
Table 4
Objectives and Endpoints......................................................................... 50
Table 5
Investigational Medicinal Products .......................................................... 65
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
24 of 187
Table 6
Prohibited Concomitant Medication/Therapy........................................... 75
Table 7
Permitted Concomitant Medication/Therapy............................................ 76
Table 8
Laboratory Safety Variables..................................................................... 91
Table 9
Summary of Outcome Variables and Analysis Populations .................... 106
Table 10
Pre-planned Statistical and Sensitivity Analyses to be Conducted for 
Efficacy and COA Endpoints................................................................. 108
Table 11
Summary of imaging modalities for tumor assessment........................... 149
Table 12
RECIST 1.1 Evaluation of TLs .............................................................. 157
Table 13
RECIST 1.1 Evaluation of NTLs ........................................................... 158
Table 14
RECIST 1.1 Overall Visit Response ...................................................... 159
Table 15
Highly Effective Methods of Contraception (< 1% Failure Rate) ........... 162
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 123
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 128
Appendix C
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis, including COVID-
19 Outbreak........................................................................................... 133
Appendix D
Handling of Human Biological Samples ................................................ 138
Appendix E
Appendix F
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 143
Appendix G
Guidelines for Evaluation of Objective Tumor Response Using RECIST 
1.1 Criteria (Response Evaluation Criteria in Solid Tumors).................. 149
Appendix H
Contraception Requirements.................................................................. 161
Appendix I
Patient-reported Outcomes..................................................................... 163
Appendix J
Study Participant Feedback Questionnaire ............................................. 174
Appendix K
Abbreviations ........................................................................................ 178
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
25 of 187
1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3 Randomized, Double-blind, Multicenter, Global Study of 
Monalizumab or Placebo in Combination With Cetuximab in Participants With Recurrent or 
Metastatic Squamous Cell Carcinoma of the Head and Neck Previously Treated With an 
Immune Checkpoint Inhibitor
Short Title: Study of Monalizumab Given With Cetuximab or Placebo Given with Cetuximab 
in Participants With Recurrent or Metastatic Head and Neck Cancer
Rationale: The aim of this study is to assess the efficacy and safety of monalizumab and 
cetuximab compared to placebo and cetuximab in participants with R/M SCCHN after 
receiving an ICI and platinum-based chemotherapy, regardless of the sequence of these 
therapies. Monalizumab is a first-in-class ICI that blocks the inhibitory CD94/NKG2A 
receptor resulting in the stimulation of NK cell and CD8+ T cell cytolytic activity. 
Additionally, monalizumab enhances human NK-cell ADCC mediated by cetuximab. While 
monalizumab monotherapy has shown limited clinical activity, encouraging antitumor results 
have been observed following monalizumab and cetuximab combination therapy in patients 
with R/M SCCHN who have received prior platinum-based chemotherapy, including patients 
who have also received prior therapy with an ICI. This dual targeting could therefore provide 
greater antitumor activity than cetuximab alone. The combination of monalizumab and 
cetuximab could be a key option to improve clinical outcomes in patients with R/M SCCHN, 
regardless of HPV status, after receiving an ICI. 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
26 of 187
Objectives and Endpoints
Objective
Estimand a Description/Endpoint
Primary
To compare the effect of monalizumab and cetuximab 
(Arm A) relative to placebo and cetuximab (Arm B) 
by assessment of OS in HPV-unrelated participants
•
Population: The HPV-unrelated Analysis Set 
which will include all randomized participants 
who are either OPC HPV negative or 
non-OPC regardless of HPV status
•
Endpoint: OS, which is defined as time from 
randomization until the date of death due to 
any cause
•
Intercurrent events: If a participant is lost to 
follow-up or withdraws consent, OS will be 
censored based on the last recorded date on 
which the participant was known to be alive
•
Summary measure: p-value of treatment 
comparison using a stratified log rank test and 
hazard ratio of Arm A relative to Arm B with 
its confidence interval using a stratified Cox 
Proportional Hazards model
Secondary
To compare the effect of monalizumab and cetuximab 
(Arm A) relative to placebo and cetuximab (Arm B) 
by assessment of OS in all randomized participants
•
Population: The FAS which will include all 
randomized participants 
•
Endpoint: OS, which is defined as time from 
randomization until the date of death due to 
any cause
•
Intercurrent events: If a participant is lost to 
follow-up or withdraws consent, OS will be 
censored based on the last recorded date on 
which the participant was known to be alive
•
Summary measure: p-value of treatment 
comparison using a stratified log rank test and 
hazard ratio of Arm A relative to Arm B with 
its confidence interval using a stratified Cox 
Proportional Hazards model
To compare the effect of monalizumab and cetuximab 
(Arm A) relative to placebo and cetuximab (Arm B) 
by assessment of PFS, ORR, and DoR in participants 
who are HPV-unrelated and in all randomized 
participants
•
PFS is defined as time from randomization 
until disease progression, per RECIST 1.1 as 
assessed by the investigator at local site or 
death due to any cause, whichever occurs first.
•
ORR is defined as the proportion of 
participants with measurable disease who have 
a confirmed CR or PR, as determined by the 
investigator at local site per RECIST 1.1.
•
DoR is defined as the time from the date of 
first documented response until date of 
documented disease progression or death in 
the absence of disease progression.
To assess disease-related symptoms, functioning, and 
HRQoL in participants treated with monalizumab and 
cetuximab (Arm A) compared to placebo and 
Symptoms, functioning, and global health 
status/QoL scale/item scores of the EORTC 
QLQ-C30 & EORTC QLQ-H&N35

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
27 of 187
Objective
Estimand a Description/Endpoint
cetuximab (Arm B) using the EORTC QLQ-C30 and 
the EORTC QLQ-H&N35 questionnaires in 
participants who are HPV-unrelated and in all 
randomized participants
•
Change from baseline scores across visits
•
Time to clinically meaningful deterioration in 
scores
To assess the PK of monalizumab
Concentration of monalizumab in blood and PK 
parameters (such as Cmax, Ctrough, as data allow; 
sparse sampling)
To investigate the immunogenicity of monalizumab 
Presence of ADAs for monalizumab (confirmatory 
results: positive or negative, titers)
To characterize the association between clinical 
outcome and protein expression in the tumor 
microenvironment in participants treated with 
monalizumab and cetuximab (Arm A) or placebo and 
cetuximab (Arm B) in participants who are 
HPV-unrelated and in all randomized participants
HLA-E and NKp46+ expression in pre-treatment 
and post-treatment tumor biopsies
Secondary safety
To assess the safety and tolerability of monalizumab 
and cetuximab (Arm A) compared to placebo and 
cetuximab (Arm B) in participants with R/M SCCHN 
previously treated with ICI
AEs, vital signs, clinical laboratory results, ECGs
a
Estimand is the target of estimation to address the scientific question of interest posed by the primary 
objective. Attributes of an estimand include the population of interest, the variable (or endpoint) of 
interest, the specification of how intercurrent events are reflected in the scientific question of interest, 
and the population-level summary for the variable.
ADA = antidrug antibodies; AE = adverse event; Cmax = maximum serum concentration; CR = complete 
response; Ctrough = trough serum concentration; DoR = duration of response; ECG = electrocardiogram; 
EORTC = European Organisation for Research and Treatment of Cancer; FAS = full analysis set; 
HLA-E = human leukocyte antigen E; HPV = human papillomavirus; HRQoL = health-related quality of life; 
NK = natural killer; OPC = oropharyngeal cancer; ORR = objective response rate; OS = overall survival; 
PFS = progression-free survival; PK = pharmacokinetic(s); PR = partial response; QLQ-C30 = 30-item Core 
Quality of Life Questionnaire; QLQ-H&N35 = Quality of Life Questionnaire Head and Neck Module; 
RECIST 1.1 = Response Evaluation Criteria for Solid Tumors version 1.1; R/M = recurrent or metastatic; 
SCCHN = squamous cell carcinoma of the head and neck.
For exploratory objectives, see Section 3 of the protocol.
Overall Design
Study D7310C00001 is a Phase 3, randomized, double-blind, multicenter, global study 
assessing the safety and efficacy of monalizumab or placebo in combination with cetuximab 
in participants with R/M SCCHN not amenable to curative treatment previously treated with 
platinum-based chemotherapy and an ICI, regardless of the sequence of these therapies. 
Approximately 190 sites globally will participate in this study.
Following a 28-day screening period, eligible participants will be randomized on Day 1 in a 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
28 of 187
2:1 ratio to one of the following treatment arms: (1) Arm A: monalizumab and cetuximab or 
(2) Arm B: placebo and cetuximab. Participants will be stratified by: 
!
Human papillomavirus status: (i) OPC HPV positive or (ii) HPV-unrelated, 
∀
The number of OPC HPV-positive participants will be closely monitored throughout 
the study and is planned to be capped at approximately 20% of the total sample size.
!
World Health Organization/ECOG PS (0 or 1), and 
!
Number of prior lines of therapy in the R/M setting (1 or 2)
∀
The number of participants in each stratum (1 or 2 prior lines of therapy in the R/M 
setting) will be closely monitored throughout the study. If a disproportionate number 
of participants are enrolled in a single stratum (eg, > 75% of the total sample size), 
the Sponsor may elect to close further recruitment into that stratum.
Participants will receive study intervention until disease progression, unacceptable toxicity, 
withdrawal of consent, or another discontinuation criterion is met. An IDMC will review 
safety data regularly and make recommendations regarding further study conduct. 
Disclosure Statement: This is a parallel group treatment study with 2 arms that is participant 
and investigator blinded.
Number of Participants:
Approximately 832 participants will be enrolled to achieve approximately 624 participants 
randomly assigned to study intervention while ensuring at least 498 participants who are either 
OPC HPV negative or non-OPC regardless of the HPV status (HPV-unrelated participants). 
This includes approximately 416 participants randomized to Arm A (monalizumab and 
cetuximab) and 208 participants randomized to Arm B (placebo and cetuximab) in the overall 
population; while for the HPV-unrelated population, this includes approximately 
332 participants randomized to Arm A and 166 participants randomized to Arm B. 
Note: "Enrolled" means a participant's, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Potential participants who are screened for the purpose of determining eligibility for the study 
but are not randomly assigned in the study are considered “screen failures”. 
Intervention Groups and Duration:
Participants will be randomized in a 2:1 ratio to Arm A or Arm B. 
!
Arm A: monalizumab and cetuximab
Monalizumab 
 and cetuximab 400 mg/m2 iv initial dose followed by 
250 mg/m2 iv Q1W
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
29 of 187

Arm B: placebo and cetuximab
Placebo iv Q2W and cetuximab 400 mg/m2 iv initial dose followed by 250 mg/m2 iv 
Q1W
Study intervention will continue until RECIST 1.1-defined radiological disease progression 
per investigator, unacceptable toxicity, withdrawal of consent, or another discontinuation 
criterion is met. Crossover between treatment arms will not be permitted. 
Follow-up of participants post discontinuation of study intervention
After discontinuation of study intervention, all participants will have safety assessment 
follow-up for 3 months after their last dose of study intervention.
Participants who have discontinued study intervention in the absence of RECIST 1.1-defined 
radiological disease progression per investigator will continue with scheduled tumor 
assessments until RECIST 1.1-defined disease progression or death regardless of whether the 
participant started a subsequent anticancer therapy, unless they have withdrawn all consent to 
study-related assessments. 
Additionally, after study intervention discontinuation, all participants will be followed for 
survival status, subsequent anticancer therapy, and time to disease progression occurring 
during or after subsequent therapy (as determined per local standard clinical practice) until 
death, withdrawal of consent, or the end of the study. 
Data Monitoring Committee: Yes
Statistical Methods
The primary objective of the study is to compare the effect of monalizumab and cetuximab 
(Arm A) relative to placebo and cetuximab (Arm B) in terms of OS in HPV-unrelated 
participants. 
The primary endpoint OS is defined as the time from the date of randomization until death due 
to any cause. Secondary efficacy endpoints include PFS, ORR, DoR, and PROs.
The primary population is the HPV-unrelated Analysis Set which will include all randomized 
participants who are either OPC HPV negative or non-OPC regardless of the HPV status. The 
HPV status will be determined by HPV status in the eCRF and not the IVRS value. The 
HPV-unrelated Analysis Set and FAS (all randomized participants) will be used for 
summarizing baseline characteristics, all efficacy analyses, including PROs, and biomarker 
analyses. Treatment arms will be compared on the basis of randomized study intervention, 
regardless of the intervention actually received. Participants who were randomized but did not 
subsequently go on to receive study intervention are included in the analysis in the treatment 
arm to which they were randomized.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
30 of 187
The primary analysis of OS in the HPV-unrelated Analysis Set will be performed using a 
stratified log-rank test, adjusting for WHO/ECOG PS (0 or 1) and number of prior lines of 
therapy in the R/M setting (1 or 2). The HR and its CI will be estimated from a stratified Cox 
Proportional Hazards model. The analysis of OS in the FAS will be additionally stratified by 
HPV status (OPC HPV-positive or HPV-unrelated). These stratification factors will be 
determined based on the randomization.
There will be two planned IAs and one FA for the study.
Interim Analysis 1 (IA1): Futility in OS will be evaluated when approximately 99 OS events 
have occurred across Arm A and Arm B in HPV-unrelated participants (25% information 
fraction) in participants randomized at least 2 months before the DCO for the futility analysis 
(ie, with a minimum follow-up of 2 months).
Interim Analysis 2 (IA2): A hypothesis of monalizumab plus cetuximab (Arm A) prolongs OS 
compared to placebo plus cetuximab (Arm B) will be tested at IA2 when approximately 
278 OS events have occurred across Arm A and Arm B in HPV-unrelated participants 
(approximately 70% information fraction, 56% maturity). 
Final Analysis (FA): A hypothesis of improved OS will be tested at the final analysis when 
approximately 397 OS events have occurred across Arm A and Arm B in HPV-unrelated 
participants (approximately 80% maturity). 
If the true OS HR is 0.72, corresponding to an approximate 3-month improvement in median 
OS compared to Arm B of 7.7 months, approximately 397 OS events in HPV-unrelated 
participants will provide approximately 86.5% power to demonstrate statistical significance at 
the 5% level (using a 2-sided test) for the FA. The 5% (2-sided) alpha for the OS analysis will 
be controlled at the IA2 and FA time points by using the Lan-DeMets (Lan and DeMets 1983)
spending function that approximates the O’Brien-Fleming approach, where the significance 
level applied depends upon the proportion of information (ie, information fraction) available 
at the time of IA2. For example, if the information fraction for OS at IA2 is 70% then the 
two-sided significance levels of 1.48% and 4.55% will be applied to IA2 and FA for OS, 
respectively. The smallest detectable treatment difference in HR, ie, critical value, that could 
be statistically significant at the FA is 0.81. With a planned recruitment period of 30 months, it 
is expected that a total of 498 HPV-unrelated participants are needed in order to achieve
397 OS events with a follow-up period of approximately 12 months. The 278 OS events for 
the IA2 are expected to be reached approximately 30.5 months after the randomization of the 
first participant.
The number of OPC HPV-positive participants will be closely monitored throughout the study 
and is planned to be capped at approximately 20% of the total sample size. With the 
assumption that 20% of participants will be OPC HPV positive, approximately 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
31 of 187
624 randomized participants will be needed in the overall population. Under the same 
assumption of effect size in HR and median OS stated above, approximately 498 OS events 
are expected in all participants which will provide approximately 93.0% power to demonstrate 
statistical significance at the 5% level (using a 2-sided test) for the FA.
Strong control of the FWER at 5% level (2 sided) across the testing of OS and PFS endpoints 
will be achieved through a combined approach of alpha allocation to the OS analyses (IA2 and 
the FA) via alpha spending function as previously mentioned and a hierarchical testing 
procedure; that is, OS in FAS will be tested only if OS in HPV-unrelated analysis set met 
significance at IA2 or FA; PFS will be tested only if OS met statistical significance at IA2 or 
FA and PFS in FAS will be tested only if PFS in HPV-unrelated analysis set met statistical 
significance at IA2 or FA (Glimm et al 2010).
1.2
Schema
The general study design is summarized in Figure 1.
Figure 1
Study Design
a Prior platinum failure is defined as either: (i) disease progression during or after treatment with a platinum-
containing regimen for R/M disease or (ii) recurrence/progression during or within 6 months of the last dose of 
platinum as part of multimodal therapy for LA disease.
Eligible participants must not have received prior cetuximab, unless administered in the LA setting with 
radiotherapy and no disease progression for at least 6 months following the last cetuximab dose. 
b Study intervention regimens: monalizumab 
; cetuximab, 400 mg/m2 iv 
initial dose then 250 mg/m2 iv Q1W.
WHO/ECOG PS = World Health Organization/Eastern Cooperative Oncology Group performance status; iv = 
intravenous; HPV = human papillomavirus; LA = locally advanced; PD-(L)1 = programmed cell death-1 or 
programmed cell death ligand-1; 
; 
; R/M = recurrent/metastatic; 
SCCHN = squamous cell carcinoma of the head and neck.
1.3
Schedule of Activities
The SoA are presented in Table 1 for the screening and intervention periods and Table 2 for 
the follow-up period.
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
32 of 187
Table 1
Schedule of Activities – Screening Period and Intervention Period 
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
33 of 187
Table 1
Schedule of Activities – Screening Period and Intervention Period 
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
34 of 187
Table 1
Schedule of Activities – Screening Period and Intervention Period 
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
35 of 187
Table 1
Schedule of Activities – Screening Period and Intervention Period 
Procedure
Screening
Intervention period (1 cycle = 14 days)
For details 
see Section
C1
C2
C3
C4
C5
C6
C7+
C1
D1
C1
D8
C2
D1
C2
D8
C3
D1
C3
D8
C4
D1
C4
D8
C5
D1
C5
D8
C6
D1
C6
D8
C7
D1
C7
D8
Week
-4 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13+
14+
Day
-28 to -1
D1
D8
D15
D22
D29
D36
D43
D50
D57
D64
D71
D78
D85+
D92+
Window (days) a
NA
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
Biomarker sampling 
X
X
(opti
onal)
Tumor biopsy at 
time of progression 
(optional)
X
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
36 of 187
Table 1
Schedule of Activities – Screening Period and Intervention Period 
Procedure
Screening
Intervention period (1 cycle = 14 days)
For details 
see Section
C1
C2
C3
C4
C5
C6
C7+
C1
D1
C1
D8
C2
D1
C2
D8
C3
D1
C3
D8
C4
D1
C4
D8
C5
D1
C5
D8
C6
D1
C6
D8
C7
D1
C7
D8
Week
-4 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13+
14+
Day
-28 to -1
D1
D8
D15
D22
D29
D36
D43
D50
D57
D64
D71
D78
D85+
D92+
Window (days) a
NA
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
Pharmacokinetic measurements
Immunogenicity measurements
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
37 of 187
Table 1
Schedule of Activities – Screening Period and Intervention Period 
Procedure
Screening
Intervention period (1 cycle = 14 days)
For details 
see Section
C1
C2
C3
C4
C5
C6
C7+
C1
D1
C1
D8
C2
D1
C2
D8
C3
D1
C3
D8
C4
D1
C4
D8
C5
D1
C5
D8
C6
D1
C6
D8
C7
D1
C7
D8
Week
-4 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13+
14+
Day
-28 to -1
D1
D8
D15
D22
D29
D36
D43
D50
D57
D64
D71
D78
D85+
D92+
Window (days) a
NA
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
Efficacy measurements
Tumor imaging 
(RECIST 1.1)
X
Intravenous contrast-enhanced CT or MRI of the neck, chest, and abdomen (includes entire liver) Q8W (± 1 week) for the 
first 48 weeks after randomization and then Q12W (±1 week) thereafter (relative to randomization), until RECIST 1.1-
defined radiological disease progression; plus at least 1 additional follow-up scan. 
This schedule MUST be followed regardless of any delays in dosing.
8.1.1,  
Appendix G
PRO (e-device) and health economic measurements
Allocate ePRO 
device
X
8.1.4.7
ePRO device 
training
X
EORTC QLQ-C30
X
X
X
X 
then 
Q4W
8.1.4.1
EORTC QLQ-
H&N35
X
X
X
X 
then 
Q4W
8.1.4.2
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
38 of 187
Table 1
Schedule of Activities – Screening Period and Intervention Period 
Procedure
Screening
Intervention period (1 cycle = 14 days)
For details 
see Section
C1
C2
C3
C4
C5
C6
C7+
C1
D1
C1
D8
C2
D1
C2
D8
C3
D1
C3
D8
C4
D1
C4
D8
C5
D1
C5
D8
C6
D1
C6
D8
C7
D1
C7
D8
Week
-4 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13+
14+
Day
-28 to -1
D1
D8
D15
D22
D29
D36
D43
D50
D57
D64
D71
D78
D85+
D92+
Window (days) a
NA
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
Other assessment
Study intervention administration
a
Unless noted otherwise. 
The interval between monalizumab/placebo and cetuximab interventions should be at least 14 days for monalizumab/placebo and at least 7 days for cetuximab. If either 
intervention is delayed > 2 weeks then consult the Sponsor. See Section 6.6 for action in case of a dose delay.
b
May be obtained prior to 28-day screening window to permit tumor biopsy sample acquisition and analysis.
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
39 of 187
Table 1
Schedule of Activities – Screening Period and Intervention Period 
Procedure
Screening
Intervention period (1 cycle = 14 days)
For details 
see Section
C1
C2
C3
C4
C5
C6
C7+
C1
D1
C1
D8
C2
D1
C2
D8
C3
D1
C3
D8
C4
D1
C4
D8
C5
D1
C5
D8
C6
D1
C6
D8
C7
D1
C7
D8
Week
-4 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13+
14+
Day
-28 to -1
D1
D8
D15
D22
D29
D36
D43
D50
D57
D64
D71
D78
D85+
D92+
Window (days) a
NA
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
c
As clinically indicated.
d
The most recent PD-L1 results should be provided. If PD-L1 results were not collected at screening, they will be collected retrospectively.
e
For AEs/SAEs reported during screening, additional information such as medical history and concomitant medications may be needed.
f
Screening laboratory assessments must be obtained within 7 days prior to Day 1.
g
Pregnancy test may occur on Day 1, but results must be reviewed by the treating physician/investigator prior to dosing.
h
Results for urea and electrolytes, full blood count, and liver function tests must be available before commencing study intervention (samples must have been obtained 
within 3 days prior to initiating study intervention). 
During the intervention period, clinical chemistry and hematology assessments may be performed more frequently if clinically indicated.
i
If screening clinical chemistry and hematology assessments are performed within 3 days prior to Day 1, they do not need to be repeated on Day 1 if the participant’s 
condition has not changed. 
j
Coagulation parameters are to be assessed at baseline on Day 1 (unless all screening laboratory hematology assessments are performed within 3 days prior to Day 1), and 
then as clinically indicated.
k
If TSH is measured within 14 days prior to Day 1, it does not need to be repeated at Day 1. Free T4 or/and free T3 (per local standard clinical practice) will only be 
measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
l
No premedication is required prior to monalizumab administration. However, from Cycle 2, premedication with acetaminophen or an antihistamine might be prescribed, at 
the investigator’s discretion, if the participant experienced any Grade 1 to 3 infusion-related AE at the previous cycle.
m
Participants should be premedicated per US PI or local label (where available). Premedication may also be based on institutional guidance for management of infusion-
related reactions.
ADA = antidrug antibody; AE = adverse event; C = cycle; CT = computed tomography; 
; D = day; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; EORTC = European Organisation for Research and Treatment of Cancer; ePRO = electronic patient-reported outcome; 
 
 5-level health state utility index; HIV = human immunodeficiency virus; 
; 
IHC = immunohistochemistry; IMP = investigational medicinal product; iv = intravenous; mos = months; MRI = magnetic resonance imaging; OPC = oropharyngeal cancer; 
PBMC = peripheral blood mononuclear cells; PD = progressive disease; PD-L1 = programmed cell death ligand-1; 
 
PK = pharmacokinetic; 
; 
PS = performance status; Q4W = every 4 weeks; Q6W = every 6 weeks; Q8W = every 8 weeks; Q12W = every 12 weeks; QLQ-C30 = 30-item Core Quality of Life 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
40 of 187
Table 1
Schedule of Activities – Screening Period and Intervention Period 
Procedure
Screening
Intervention period (1 cycle = 14 days)
For details 
see Section
C1
C2
C3
C4
C5
C6
C7+
C1
D1
C1
D8
C2
D1
C2
D8
C3
D1
C3
D8
C4
D1
C4
D8
C5
D1
C5
D8
C6
D1
C6
D8
C7
D1
C7
D8
Week
-4 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13+
14+
Day
-28 to -1
D1
D8
D15
D22
D29
D36
D43
D50
D57
D64
D71
D78
D85+
D92+
Window (days) a
NA
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
+2
±1
Questionnaire; QLQ-H&N35= Quality of Life Questionnaire Head and Neck Module; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; SAE = serious 
adverse event;
 SPFQ = Study Participant Feedback Questionnaire; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-
stimulating hormone; US PI = United States Package Insert; W = week; WHO = World Health Organization; WOCBP = women of childbearing potential.
Table 2
Schedule of Activities – Follow-up Period for Participants Who Discontinued Study Intervention Due to 
Disease Progression or Other Reason
Procedure
End of 
treatment
Follow-up period
For details 
see Section
Month (post last dose IMP) 
1 
2
3
4
6
9
12+ 
Window
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
Clinical procedures
Full physical examination
X
8.2.1
WHO/ECOG PS a
X
X
X
8.1.4.8
Vital signs 
X
8.2.2
Weight
X
8.2.1
12-lead ECG (triplicate)
X
8.2.3
Concomitant medications
X
X
X
6.5
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
41 of 187
Table 2
Schedule of Activities – Follow-up Period for Participants Who Discontinued Study Intervention Due to 
Disease Progression or Other Reason
Procedure
End of 
treatment
Follow-up period
For details 
see Section
Month (post last dose IMP) 
1 
2
3
4
6
9
12+ 
Window
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
Subsequent anticancer therapy b
X
X
X
X
X
X
X 
then Q6M 
(± 2 weeks)
8.1.2
Safety measurements
Adverse events
X
X
X
8.3
Pregnancy test; serum or urine 
(WOCBP only)
X
X (as clinically indicated)
8.2.4
Clinical chemistry
X
X
X
Hematology
X
X
X
TSH (and reflex free T4 or/and free T3) c
X
X
Biomarker sampling
Tumor biopsy at time of progression 
(optional)
X
Pharmacokinetic measurements
Immunogenicity measurements
CCI
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
42 of 187
Table 2
Schedule of Activities – Follow-up Period for Participants Who Discontinued Study Intervention Due to 
Disease Progression or Other Reason
Procedure
End of 
treatment
Follow-up period
For details 
see Section
Month (post last dose IMP) 
1 
2
3
4
6
9
12+ 
Window
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
Efficacy measurements
Tumor imagLng (RECIST 1.1)
Participants who discontinued study intervention due to reason other than disease progression or death (regardless 
of whether started subsequent anticancer therapy): intravenous contrast-enhanced CT or MRI of the neck, chest, 
and abdomen (includes entire liver) Q8W (± 1 week) for the first 48 weeks after randomization and then Q12W 
(±1 week) thereafter (relative to randomization), until RECIST 1.1-defined radiological disease progression; plus at 
least 1 additional follow-up scan..
8.1.1, 
Appendix G
Survival status: phone call for 
participants who refuse to return for 
evaluations and agree to be contacted d
X
X
X
X
X
X 
then
Q2M 
(± 2 weeks)
7.1.1.3
PRO (e-device) and health economic measurements
EORTC QLQ-C30
X
X
X
Every visit until RECIST 1.1-defined radiological disease 
progression (for participants who discontinued due to other 
reason) or start of subsequent anticancer therapy (whichever 
occurs first)
8.1.4.1
EORTC H&N35
X
X
X
8.1.4.2
Other assessment
SPFQ (optional)
X
8.9
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
43 of 187
Table 2
Schedule of Activities – Follow-up Period for Participants Who Discontinued Study Intervention Due to 
Disease Progression or Other Reason
Procedure
End of 
treatment
Follow-up period
For details 
see Section
Month (post last dose IMP) 
1 
2
3
4
6
9
12+ 
Window
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
± 1 week
a
WHO/ECOG PS should also be collected at other site visits, if appropriate site staff are available. In addition, WHO/ECOG performance status should be provided when 
subsequent anticancer therapy information is collected, where possible.
b
Details of any treatment for SCCHN (including surgery) post the last dose of study intervention must be recorded in the eCRF. At minimum, collect the start date and 
description of the subsequent anticancer therapy. 
c
Free T4 or/and free T3 (per local standard clinical practice) will only be measured if TSH is abnormal or if there is clinical suspicion of an adverse event related to the 
endocrine system.
d
Participants may be contacted in the week following data cutoffs to confirm survival status. Details of any treatment for SCCHN (including surgery) post the last dose of 
study intervention must be recorded in the eCRF.
ADA = antidrug antibody; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EORTC = European Organisation 
for Research and Treatment of Cancer;
; iv = intravenous; MRI = magnetic resonance imaging; 
 
; 
;
;
PK = pharmacokinetic; 
; PS = performance status; Q2M = every 2 months; 
Q6M = every 6 months; QLQ-C30 = 30-item Core Quality of Life Questionnaire; QLQ-H&N35= Quality of Life Questionnaire Head and Neck Module; RECIST 
1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; SAE = serious adverse event; SCCHN = squamous cell carcinoma of the head and neck; SPFQ = Study 
Participant Feedback Questionnaire; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WHO = World Health Organization; wk = week; 
WOCBP = women of childbearing potential.
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
44 of 187
2
INTRODUCTION
Monalizumab is a first-in-class ICI targeting NKG2A. It is a non-depleting humanized IgG4 
mAb that binds with high affinity and specificity to, and blocks the inhibitory activity of the 
CD94/NKG2A receptor resulting in the stimulation of the cytolytic activity of CD94/NKG2A-
expressing NK cells and CD8+ T cells. Monalizumab is being developed for the treatment of 
various cancers, including solid tumors and hematologic malignancies either as monotherapy 
or in combination.
2.1
Study Rationale
The aim of the study is to assess the efficacy and safety of monalizumab and cetuximab, 
compared to placebo and cetuximab in participants with R/M SCCHN after receiving an ICI.
In addition to blocking the CD94/NKG2A receptor, monalizumab enhances human NK cell 
ADCC mediated by cetuximab. While monalizumab monotherapy has shown limited clinical 
activity, encouraging antitumor results have been observed following monalizumab and 
cetuximab combination therapy in patients with R/M SCCHN who have received prior 
platinum-based chemotherapy, including patients who have also received prior therapy with 
an ICI. This dual targeting could therefore provide greater antitumor activity than cetuximab 
alone. The combination of monalizumab and cetuximab could be a key option to improve 
clinical outcomes in patients with R/M SCCHN after receiving an ICI.
2.2
Background
Overall, outcomes in patients with R/M SCCHN remain poor and most patients will ultimately 
experience disease progression and eventually die of the disease. 
For 1L treatment of R/M SCCHN, the combination therapy of cetuximab plus platinum (either 
cisplatin or carboplatin) and 5-FU followed by cetuximab until progression or intolerance 
(EXTREME regimen) has been the standard of care in the European Union and the USA per 
the ESMO and NCCN guidelines, respectively (Gregoire et al 2010, NCCN 2021). In clinical 
practice, other single agents or doublet combinations, such as a taxane or cisplatin plus 
cetuximab, are also sometimes used as 1L treatment for R/M SCCHN when patients are not fit 
enough for the EXTREME regimen (Argiris et al 2017).
Squamous cell carcinoma of the head and neck tumors, like many other malignancies, create a 
highly immunosuppressive environment and are amenable to therapeutic intervention with 
immune-modulating agents (Curry et al 2014, Moy et al 2017). Recently, the PD-1 inhibitor 
pembrolizumab (KEYTRUDA®) received US FDA approval as: (i) a single agent for the 
1L treatment of patients with metastatic or with unresectable, recurrent SCCHN whose tumors 
express PD-L1 (combined positive score ≥ 1, as determined by a US FDA-approved test) or 
(ii) in combination with platinum and 5-FU for the 1L treatment of patients with metastatic or 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
45 of 187
with unresectable, recurrent SCCHN (Keytruda  2021). The NCCN recommend 
pembrolizumab as a category 1 of evidence and consensus in the 1L R/M setting (NCCN 
2021).
Patients who progress or are intolerant to 1L therapy are typically treated with single-agent 
cetuximab, single-agent chemotherapy (eg, taxanes, methotrexate), or since recently with 
PD-1 inhibitors. Cetuximab was approved by the US FDA in 2006 and for a decade remained 
the only drug indicated for the treatment of patients with R/M SCCHN progressing after 
platinum-based therapy (Erbitux PI  2021). Cetuximab continues as one of the recommended 
treatment options in the NCCN guideline (NCCN 2021); the ESMO guideline notes that 
single-agent cetuximab has activity comparable to single-agent methotrexate with a favorable 
safety profile (Gregoire et al 2010). In 2016, the US FDA granted approval to pembrolizumab 
(under accelerated approval) and another PD-1 inhibitor nivolumab (OPDIVO®) in patients 
with R/M SCCHN with disease progression on or after platinum therapy (Keytruda  2021, 
Opdivo  2021).
Treatment for patients with R/M SCCHN who progress after receiving a PD-1 inhibitor, such 
as pembrolizumab/nivolumab monotherapy or pembrolizumab in combination with 
platinum-based chemotherapy, in the 1L or second-line setting is not clearly defined. A 
re-challenge with PD-(L)1 inhibitors is not currently recommended. As no treatment strategies 
in the immunotherapy-refractory disease setting are currently approved or uniformly adopted 
by the medical community, a suggested approach is to enroll a patient with R/M SCCHN into 
a clinical study assessing combination immunotherapy (Cohen et al 2019a). 
Human leukocyte antigen E, a nonclassical major histocompatibility complex class I 
molecule, is expressed on tumor cells in 78% to 86% of patients with SCCHN (Andre et al 
2018, Nasman et al 2013, Silva et al 2011). Human leukocyte antigen E is the ligand of the 
inhibitory CD94/NKG2A receptors that are found on NK cells and intratumoral CD8+ T cells 
in a variety of tumor types, including SCCHN (Braud et al 1998, Gooden et al 2011, Katou et 
al 2007, Lee et al 1998). The interaction of HLA-E with CD94/NKG2A receptor results in the 
inhibition of NK cell and cytotoxic T lymphocyte-dependent tumor lysis and may represent a 
significant immune-escape mechanism by tumor cells (Borrego et al 1998, Braud et al 1998, 
van Montfoort et al 2018). Monalizumab is a humanized mAb of the IgG4 subtype that 
specifically binds and blocks the function of CD94/NKG2A. 
Cetuximab is a chimeric monoclonal IgG1 antibody that is specifically directed against the 
EGFR. The EGFR is an important regulator of cell growth and differentiation. Upon ligand 
binding, EGFR homodimerizes or interacts with other HER members, ie, HER2 and HER3, to 
form heterodimers. This results in activation of downstream signaling cascades such as the 
RAS ERK pathway and PI3K/Akt pathway, thereby controlling many biological processes. 
These pathways play a pivotal role in multiple tumor types, including head and neck cancers, 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
46 of 187
and are frequently dysregulated via overexpression or autocrine stimulation. Targeting EGFR, 
eg, with an anti-EGFR mAb like cetuximab, is an important treatment modality for head and 
neck cancers. Several studies have suggested that ADCC activity is important for cetuximab 
clinical efficacy and is dependent on tumor cell surface EGFR expression (Kol et al 2017). 
It has been previously demonstrated in nonclinical studies that high expression of HLA-E and 
CD94/NKG2A on tumor cells and effector lymphocytes, respectively, impaired ADCC activity 
and reduced cetuximab clinical efficacy (Levy et al 2009). NKG2A blockade with 
monalizumab has been shown to increase cetuximab-dependent ADCC activity, which may 
translate into increased clinical benefit for the use of cetuximab. Additionally, nonclinical 
studies have shown increased cetuximab-dependent NK cell-mediated ADCC in SCCHN cell 
lines expressing HLA-E and EGFR when exposed to monalizumab (Andre et al 2018). As 
CD94/NKG2A inhibits the effector function of NK cells in the presence of HLA-E, it is 
expected that blocking of this inhibitory signaling pathway with monalizumab will increase 
cetuximab-dependent NK cell-mediated ADCC activity, which could subsequently lead to 
increased clinical benefit.
A detailed description of the chemistry, pharmacology, mechanism of action, efficacy, and 
safety of monalizumab and cetuximab is provided in the Monalizumab IB and cetuximab 
(ERBITUX®) current US PI or local label (where available).
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of 
monalizumab and cetuximab may be found in the Monalizumab IB and current cetuximab 
US PI or local label (where available).
2.3.1
Risk Assessment
Potential risks for monalizumab are related to hypersensitivity, including anaphylaxis, serious 
allergic reactions, and immune complex disease. Administration of any therapeutic 
immunoglobulin antibody/protein is associated with the potential to induce infusion-related 
and/or hypersensitivity reactions. Infusion-related reaction is an identified risk with 
monalizumab. Immune-mediated adverse events are considered important potential risks for 
monalizumab. Activation of NK cells and subsets of T cells through blockade of inhibitory 
receptors may potentially lead to imAEs. 
For cetuximab, skin reactions, hypomagnesemia, and infusion-related reactions are listed as 
very common (frequency of ≥ 10%) in the US PI or EU SmPC. Skin reaction is the most 
frequent side effect of cetuximab and may develop in more than 80% of patients.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
47 of 187
Current data suggest no change to the safety profile of either product when monalizumab is 
given in combination with cetuximab.
Monalizumab monotherapy
Study IND.221 (NCT0259301) is a completed Phase 1/2 externally-sponsored, open-label, 
dose-ranging, cohort-expansion, single-agent, multicenter study of monalizumab in adult 
participants with R/M gynecologic malignancies who had received prior platinum-based 
therapy. In the dose-ranging part, up to 18 participants (6/dose level) were to be randomized to 
receive monalizumab 1.0, 4.0, or 10 mg/kg iv Q2W. In the cohort-expansion part, up to 
40 participants were to receive monalizumab 10 mg/kg iv Q2W.
Study EORTC-1159 (NCT03088059/EudraCT 2017-000086-74) is an ongoing externally-
sponsored, biomarker-driven platform study in participants with R/M SCCHN who progressed 
after 1L platinum-based chemotherapy. In the closed immunotherapy cohort 1, participants 
were to receive monalizumab 10 mg/kg iv Q2W.
In Study IND.221, Grade 3 monalizumab-related AEs were reported for Study IND.221 in 
3/18 participants in the Phase 1b dose-ranging part: Grade 3 nausea, vomiting, dehydration 
(one participant each), and fatigue (2 participants); and in 2/40 participants in the 
cohort-expansion part: Grade 3 anorexia, nausea, dyspnea (one participant), and proctitis (one 
participant). No treatment-related Grade 4 AEs were reported. In Study EORTC-1159, none of 
the participants in immunotherapy cohort 1 had a Grade 3 or 4 monalizumab-related AE. 
Monalizumab in combination with cetuximab
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
48 of 187
 
2.3.2 Benefit Assessment
While monalizumab monotherapy has shown limited clinical activity in participants with R/M 
SCCHN or gynecological malignancies (Tinker et al 2019a, 2019b), encouraging antitumor 
results have been observed following monalizumab and cetuximab combination therapy in 
participants with R/M SCCHN who have received prior platinum-based chemotherapy, 
including participants who have also received prior therapy with an ICI.  
The combination of monalizumab and cetuximab demonstrated preliminary efficacy in 
participants with R/M SCCHN who had received prior platinum therapy (Cohen et al 2019c)
(Table 3). In Cohorts 1 and 2 of Study 203 (see Section 2.3.1), participants may have received
up to 2 prior systemic therapies, including platinum-based chemotherapy. Additionally, 
subjects in Cohort 2 were to have received prior anti-PD-(L)1 therapy. As of the DCO date of 
30 April 2019, Cohort 1 completed enrollment of 40 participants with a median duration of 17 
months follow-up. Of these participants, 53% were considered resistant to platinum therapy 
(ie, progressive disease on treatment or within 6 months after end of treatment), 53% had 
received more than one prior systemic regimen, and 43% had received prior PD-(L)1 inhibitor 
therapy (PD-[L]1 pretreated). The overall ORR per RECIST 1.1 was 27.5% 
(11/40 participants; 95% CI: 16%, 43%), with one CR. This represents an approximate 
doubling of the ORR of cetuximab monotherapy reported as 13% in participants with R/M 
SCCHN participants who had progressed on 2 to 6 cycles of platinum therapy (Erbitux PI  
2021, Vermorken et al 2007). Median OS was 8.5 months. In PD-(L)1-pretreated participants, 
the ORR per RECIST 1.1 was 16.7% (3/18 participants with partial response [PR]; 95% CI: 
6%, 39%), with a median OS of 14.1 months. In participants who had not received prior 
therapy with a PD-(L)1 inhibitor (PD-[L]1 naive), the ORR was 36.4% (8/22 participants; 
95% CI: 20%, 57%), with one CR, and a median OS of 7.8 months. Preliminary data based on 
a recent data snapshot of 04 September 2019 from ongoing Cohort 2 in participants who had 
received prior platinum and prior PD-(L)1 therapy, showed an ORR of 24% (5/21 participants 
with PR; 95% CI: 11%, 45%). These results are consistent with the response rate seen in 
Cohort 1 PD-(L)1-pretreated participants.
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
49 of 187
Table 3
Preliminary Efficacy, Cohort 1 - Expansion Phase (Monalizumab + 
Cetuximab), All Subjects Treated (Study IPH2201-203)
Parameter
Total
(N = 40)
PD-(L)1 pre-treated
(N = 18)
PD-(L)1 naive
(N = 22)
ORR, % (95% CI)
27.5 (16, 43)
16.7 (6, 39)
36.4 (20, 57)
Complete response
1 (2.5)
0
1 (4.5)
Partial response
10 (25.0)
3 (16.7)
7 (31.8)
Median PFS
4.5 (3.5, 5.8)
5.1 (3.5, 8.8)
3.9 (3.5, 6.9)
Median OS
8.5 (7.5, 16.4)
14.1 (8.0, NR)
7.8 (6.9, 15.8)
Participants received monalizumab 10 mg/kg iv Q2W + cetuximab at the approved dosage of 400 mg/m2 iv 
initial dose followed by subsequent weekly doses of 250 mg/m2 iv.
CI = confidence interval; NR = not reached; ORR = objective response rate; OS = overall survival; PD-(L)1 = 
programmed cell death-1 or programmed cell death ligand-1; PFS = progression-free survival; Q2W = every 2 
weeks; iv = intravenous.
Based on a data snapshot date of 30 April 2019.
With regards to cetuximab, single-agent cetuximab is active in the treatment of participants 
with R/M SCCHN who progressed on platinum therapy with an ORR of approximately 13% 
(Vermorken et al 2007), and is listed as a recommended treatment option for SCCHN patients 
in the R/M setting in the latest NCCN and ESMO guidelines (Gregoire et al 2010, NCCN 
2021) and SITC recommendations (Cohen et al 2019a). In the USA, the use of single-agent 
cetuximab is approved for R/M SCCHN progressing after platinum-based therapy (Erbitux PI  
2021). 
2.3.3 Overall Benefit: Risk Conclusion
Taking into account the measures to minimize risk to participants in this study, the potential 
risks identified in association with monalizumab and cetuximab are justified by the anticipated 
benefits to participants with R/M SCCHN who have been previously treated with platinum-
based chemotherapy and an ICI.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
50 of 187
3
OBJECTIVES AND ENDPOINTS
Table 4
Objectives and Endpoints
Objective
Estimand a Description/Endpoint
Primary
To compare the effect of monalizumab and cetuximab 
(Arm A) relative to placebo and cetuximab (Arm B) 
by assessment of OS in HPV-unrelated participants
•
Population: The HPV-unrelated Analysis Set 
which will include all randomized participants 
who are either OPC HPV negative or 
non-OPC regardless of HPV status
•
Endpoint: OS, which is defined as time from 
randomization until the date of death due to 
any cause
•
Intercurrent events: If a participant is lost to 
follow-up or withdraws consent, OS will be 
censored based on the last recorded date on 
which the participant was known to be alive
•
Summary measure: p-value of treatment 
comparison using a stratified log rank test and 
hazard ratio of Arm A relative to Arm B with 
its confidence interval using a stratified Cox 
Proportional Hazards model
Secondary
To compare the effect of monalizumab and cetuximab 
(Arm A) relative to placebo and cetuximab (Arm B) 
by assessment of OS in all randomized participants
•
Population: The FAS which will include all 
randomized participants 
•
Endpoint: OS, which is defined as time from 
randomization until the date of death due to 
any cause
•
Intercurrent events: If a participant is lost to 
follow-up or withdraws consent, OS will be 
censored based on the last recorded date on 
which the participant was known to be alive
•
Summary measure: p-value of treatment 
comparison using a stratified log rank test and 
hazard ratio of Arm A relative to Arm B with 
its confidence interval using a stratified Cox 
Proportional Hazards model
To compare the effect of monalizumab and cetuximab 
(Arm A) relative to placebo and cetuximab (Arm B) 
by assessment of PFS, ORR, and DoR in participants 
who are HPV-unrelated and in all randomized 
participants
•
PFS is defined as time from randomization 
until disease progression, per RECIST 1.1 as 
assessed by the investigator at local site or 
death due to any cause, whichever occurs first.
•
ORR is defined as the proportion of 
participants with measurable disease who have 
a confirmed CR or PR, as determined by the 
investigator at local site per RECIST 1.1.
•
DoR is defined as the time from the date of 
first documented response until date of 
documented disease progression or death in 
the absence of disease progression.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
51 of 187
Table 4
Objectives and Endpoints
Objective
Estimand a Description/Endpoint
To assess disease-related symptoms, functioning, and 
HRQoL in participants treated with monalizumab and 
cetuximab (Arm A) compared to placebo and 
cetuximab (Arm B) using the EORTC QLQ-C30 and 
the EORTC QLQ-H&N35 questionnaires in 
participants who are HPV-unrelated and in all 
randomized participants
Symptoms, functioning, and global health 
status/QoL scale/item scores of the EORTC QLQ-
C30 & EORTC QLQ-H&N35
•
Change from baseline scores across visits
•
Time to clinically meaningful deterioration in 
scores
To assess the PK of monalizumab 
Concentration of monalizumab in blood and PK 
parameters (such as Cmax, Ctrough, as data allow; 
sparse sampling)
To investigate the immunogenicity of monalizumab 
Presence of ADAs for monalizumab (confirmatory 
results: positive or negative, titers)
To characterize the association between clinical 
outcome and protein expression in the tumor 
microenvironment in participants treated with 
monalizumab and cetuximab (Arm A) or placebo and 
cetuximab (Arm B) in participants who are 
HPV-unrelated and in all randomized participants
HLA-E and NKp46+ expression in pre-treatment 
and post-treatment tumor biopsies
Secondary safety
To assess the safety and tolerability of monalizumab 
and cetuximab (Arm A) compared to placebo and 
cetuximab (Arm B) in participants with R/M SCCHN 
previously treated with ICI
AEs, vital signs, clinical laboratory results, ECGs
Exploratory
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
52 of 187
Table 4
Objectives and Endpoints
a
Estimand is the target of estimation to address the scientific question of interest posed by the primary 
objective. Attributes of an estimand include the population of interest, the variable (or endpoint) of 
interest, the specification of how intercurrent events are reflected in the scientific question of interest, 
and the population-level summary for the variable.
ADA = antidrug antibodies; AE = adverse event; Cmax = maximum serum concentration; CR = complete 
response; 
; Ctrough = trough serum concentration; DoR = duration of 
response; ECG = electrocardiogram; EORTC = European Organisation for Research and Treatment of 
Cancer; 
; FAS = full analysis set; HLA-E = human 
leukocyte antigen E; 
; 
; HRQoL = health-
related quality of life; ICI = immune checkpoint inhibitor; NK = natural killer; OPC = oropharyngeal cancer; 
ORR = objective response rate; OS = overall survival; PFS = progression-free survival; 
 
; 
 
; 
 
PK = pharmacokinetic(s); PR = partial response; 
 
; QLQ-C30 = 30-item Core Quality of Life Questionnaire;
QLQ-H&N35 = Quality of Life Questionnaire Head and Neck Module; RECIST 1.1 = Response Evaluation 
Criteria for Solid Tumors version 1.1; R/M = recurrent or metastatic; SCCHN = squamous cell carcinoma of 
the head and neck; 
.
4
STUDY DESIGN
4.1
Overall Design
Study D7310C00001 is a Phase 3, randomized, double-blind, multicenter, global study 
assessing efficacy and safety of monalizumab and cetuximab compared to placebo and 
cetuximab in participants with R/M SCCHN previously treated with platinum-based 
chemotherapy and an ICI, regardless of the sequence of these therapies. 
Approximately 624 eligible participants will be randomized in a 2:1 ratio to one of the 
following treatment arms. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
53 of 187
!
Arm A (n = 416): monalizumab and cetuximab
Monalizumab 
 and cetuximab 400 mg/m2 iv initial dose followed by 
250 mg/m2 iv Q1W, as per label
!
Arm B (n = 208): placebo and cetuximab
Placebo iv Q2W and cetuximab 400 mg/m2 iv initial dose followed by 250 mg/m2 iv 
Q1W, as per label
Participants will be stratified by the following (see Section 6.3.1 for more detail):
!
Human papillomavirus status (OPC HPV positive or HPV-unrelated),
∀
The number of OPC HPV-positive participants will be closely monitored throughout 
the study and is planned to be capped at approximately 20% of the total sample size.
!
World Health Organization/ECOG PS (0 or 1), and 
!
Number of prior lines of therapy in the R/M setting (1 or 2)
∀
The number of participants in each stratum (1 or 2 prior lines of therapy in the R/M 
setting) will be closely monitored throughout the study. If a disproportionate number 
of participants are enrolled in a single stratum (eg, > 75% of the total sample size), 
the Sponsor may elect to close further recruitment into that stratum. 
Participants will be treated until RECIST 1.1-defined radiological disease progression per 
investigator, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion 
is met. Crossover between treatment arms will not be permitted. 
An IDMC will review safety data regularly and make recommendations regarding further 
study conduct (see Appendix A 5). For both IAs, the IDMC will review unblinded interim data 
and inform the Sponsor whether the interim boundaries specified in Section 9.5 are met.
After discontinuation of study intervention, all participants will have a 3-month safety 
follow-up (see Section 7.1.1). Participants who have discontinued study intervention in the 
absence of RECIST 1.1-defined radiological disease progression per investigator will continue 
with scheduled tumor assessments until RECIST 1.1-defined disease progression or death. 
Additionally, all participants will be followed for survival status, subsequent anticancer 
therapy, and 
, withdrawal of consent, or the end of the study. 
An overview of the study design is presented in Figure 1. Details on the efficacy and safety 
endpoints are provided in Section 3.
Section 6.7 presents treatment options after the final DCO and database closure.  
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
54 of 187
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis 
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster, or public health crisis (eg, 
during quarantines and resulting site closures, regional travel restrictions, and considerations if 
site personnel or study participants become infected with SARS-CoV-2 or similar pandemic 
infection) which would prevent the conduct of study-related activities at study sites, thereby 
compromising the study site staff or the participant’s ability to conduct the study. The 
investigator or designee should contact the study Sponsor to discuss whether the mitigation 
plans below should be implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain 
compliance with GCP, and minimize risks to study integrity.
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies) or local government, these changes may include the following options: 
!
Obtaining consent/re-consent for the mitigation procedures (note, in the case of verbal 
consent/re-consent, the ICF should be signed at the participant’s next contact with the 
study site).
!
Rescreening: additional rescreening for screen failure and to confirm eligibility to 
participate in the clinical study can be performed in previously screened participants. The 
investigator should confirm this with the designated Study Clinical Lead. 
!
Telemedicine or Remote visit (where applicable): remote contact with the participants 
using telecommunications technology including phone calls and virtual or video visits. 
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix C.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Study Design and Participant Population
The primary aim of this study is to assess the efficacy of monalizumab and cetuximab 
compared to cetuximab and placebo in terms of OS. It is a double-blind, randomized study 
; unblinded Pharmacists and 
unblinded Study Monitors will be used in order to maintain the blind.  
Preliminary data show that the combination monalizumab and cetuximab is well tolerated 
(Cohen et al 2017, Cohen et al 2018a, Cohen et al 2018b) and has promising activity. As the 
estimated percentage of patients with cancer eligible for ICI (including but not limited to 
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
55 of 187
anti-PD-(L)1 antibodies) in the course of their disease is increasing, it is crucial to confirm the 
activity seen with monalizumab administered in combination with cetuximab in population of 
patients who have previously received ICI. 
Participants enrolled in this study will have R/M SCCHN arising in the oropharynx regardless 
of HPV status, hypopharynx, larynx (supraglottis, glottis, and subglottis) or oral cavity; must 
have progressed on or after previous systemic cancer therapy (up 2 prior systemic regimens in
the R/M setting); are not amenable to further therapy having curative intent; and must have 
received prior treatment with platinum-based chemotherapy and a systemic PD-(L)1 inhibitor 
in any setting, regardless of the sequence of these therapies (see inclusion criteria in 
Section 5.1).
Since HPV-positive OPC represents a biologically distinct disease (Taberna et al 2017), the 
study design proposed is considered the best approach to evaluate the contribution of 
monalizumab to cetuximab because the combination therapy will be compared directly to 
single-agent cetuximab in HPV-unrelated participants. Cetuximab is a valid treatment option 
for the study population per the revised NCCN and current ESMO guidelines (Gregoire et al 
2010, NCCN 2021) and SITC recommendations (Cohen et al 2019a).  
4.2.2
Rationale of Study Endpoints
Rationale for primary endpoint and other efficacy endpoints
The primary endpoint of the proposed study will be OS, defined as the time from the date of 
randomization until death due to any cause. Overall survival is considered the most reliable 
cancer endpoint supported by the US FDA and EMA guidelines (EMA 2017, FDA 2018a).
Rationale for other efficacy endpoints
The secondary efficacy endpoints will include PFS, ORR, DoR, and PRO measures. All 
tumor-related endpoints will be assessed by the investigator according to RECIST 1.1.
Target engagement of monalizumab will be assessed through HLA-E and NKp46+ expression 
in the TME and association with the participant’s radiologic response.
In addition to assessing OS and other clinical endpoints in oncology studies, it is important to 
assess the impact of the disease and its treatment on cancer symptoms, functioning, and 
HRQoL of the patient, to aid understanding of how clinical benefit relates to patient 
wellbeing, and for consideration in making risk-benefit evaluations. Moreover, PROs assist in 
the documentation of symptoms and specifically what symptoms and impacts are most 
important to patients and how these relate to clinical outcomes. In this study, general cancer 
symptoms, functioning and HRQoL will be assessed with the EORTC QLQ-C30 while 
SCCHN-specific symptoms will be evaluated using the EORTC QLQ-H&N35. 
 
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
56 of 187
 The rationale for selecting the EORTC QLQ-C30 and 
QLQ-H&N35 and other PRO instruments is primarily because they have good coverage of the 
symptoms and impacts most important to SCCHN patients (Degboe et al 2018). These PRO 
questionnaires are also well established in oncology clinical studies for directly assessing 
patients’ experience of cancer as well as the treatment impact.
4.3
Justification for Dose
4.3.1
Rationale for Monalizumab Dose
Existing PK and pharmacodynamic data, modeling and simulation, and clinical data have been 
utilized to guide the regimen selection for the combination of monalizumab 
 plus 
cetuximab at 400 mg/m2 initial dose followed by 250 mg/m2 Q1W. See the Monalizumab IB 
for more detail on monalizumab PK, pharmacodynamics, immunogenicity, and clinical 
activity.
Available PK/pharmacodynamic data were analyzed from ongoing Phase 1/2 
Study D419NC00001 for monalizumab doses ranging from 
 to 
 or 
 
in combination with durvalumab 1500 mg Q4W. An approximate dose-proportional increase 
in PK exposure (Cmax and area under the serum drug concentration-time curve from time 0 to 
Day 28 post-dose) was observed with increasing doses of monalizumab (
, and 
). Full suppression of the target on NK cell in the periphery was observed over the 
dose range studied, consistent with engagement of monalizumab with NKG2a.
Pharmacokinetic data from the dose-escalation cohort in ongoing Phase 1b/2 Study 
IPH2201-203 (Study 203) of monalizumab 
to 
 in combination with 
cetuximab 400 mg/m2 initial dose followed by 250 mg/m2 Q1W showed an approximate 
dose-proportional increase in monalizumab Cmax over the dose range for the first dosing cycle. 
These data were consistent with the predicted monotherapy PK data (5th, 50th, and 95th 
percentiles) for a Q2W regimen.  
Antidrug antibody analyses of serum samples from treated participants in 
Study D419NC00001 and Study 203, showed a low ADA signal, close to the screening cut 
point, for all ADA-positive samples, suggesting either false positive result or low ADA 
concentration. PK profiles for participants with ADA-positive samples were not modified, 
indicating that ADA did not impact monalizumab exposure. 
Clinical data
A tolerable safety profile was observed for participants in Study 203 Cohorts 1 and 2 treated 
with monalizumab 
 or 
 respectively, plus cetuximab 400 mg/m2
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CC
I
CCI
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
57 of 187
initial dose followed by 250 mg/m2 Q1W. Promising clinical activity was observed in 
Cohort 1, with consistent preliminary results from ongoing Cohort 2. 
Based on these data, the combination of monalizumab 
 plus cetuximab 
400 mg/m2 initial dose followed by 250 mg/m2 Q1W was selected for further development. 
This dose is expected to achieve complete target saturation in the majority of participants and 
account for anticipated variability in PK, pharmacodynamics, and clinical activity in SCCHN 
populations.
Rationale for fixed-dose of monalizumab
Current ongoing studies with the combination of monalizumab and cetuximab administer 
monalizumab using either weight-based dosing (ie, monalizumab 
; Study 203 
Cohort 1) or 
 dosing (ie, monalizumab 
; Study 203 Cohort 2 and 
Study D419NC00001). 
Comparison of the observed monalizumab exposure between 
 and 
 showed 
similar preliminary PK exposure (Cmax and Ctrough) after the first monalizumab dose for the 
 dosage (monalizumab in combination with cetuximab, Study 203 Cohort 1) 
and the 
 dosage (monalizumab in combination with durvalumab, Study 
D419NC00001). The observed PK of monalizumab when administered in combination with 
cetuximab is within the range of monalizumab monotherapy PK.
A population PK model was developed for monalizumab using PK data from Study 203 and 
Study D419NC00001 in participants with solid tumors, including SCCHN, microsatellite-
stable colorectal cancer, ovarian cancer, endometrial cancer, non-small cell lung cancer, 
cervical cancer, or pancreatic cancer. At the time of analysis, a total of 95 evaluable 
participants treated with monalizumab 
 or 
 in combination with 
cetuximab (N = 30; Study 203) or monalizumab 
, or
 or 
 
 in combination with durvalumab (N = 65; Study D419NC00001) were used for 
building the preliminary population PK model. To determine the impact of body weight-based 
(
) or 
 dosing (
) on monalizumab PK exposure, simulations 
were conducted (N = 500 participants/cohort with a body-weight distribution of 40 to 120 kg) 
and predicted steady state concentrations were compared. A 
 dose of 
 was selected 
to approximate 
 based on the median body weight of 75 kg. Simulation results 
demonstrated that body weight-based and 
-dosing regimens yield similar steady-state PK 
concentrations with similar overall between-participant variability. The predicted similarity of 
exposure following either of the dosing regimen is consistent with literature showing that an 
exponent of the covariate model for body weight of approximately 0.5 is expected to yield 
similar median PK profiles without following either 
 or body weight-based dosing (Wang 
et al 2009). Therefore, based on an average body weight of 75 kg, a 
 dose of 
 
monalizumab is equivalent to 
 respectively.
CCI
CCI
CC
I
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CC
I
CCI
CC
I
CCI
CCI
CC
I
CC
I
CC
I
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
58 of 187
The proposed Phase 3 study of monalizumab in combination with cetuximab, will use the 
 
dose of monalizumab 
 This dosing regimen is aligned with the standard 
 
dosing of monalizumab 
 being investigated in the multiple ongoing 
monalizumab clinical studies (see Monalizumab IB).
4.3.2
Rationale for Cetuximab Dose
The dose regimen for cetuximab in this study (400 mg/m2 initial dose followed by 250 mg/m2
Q1W starting on Day 8) is per the cetuximab US PI (Erbitux PI  2021). 
4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last scheduled procedure shown in the SoA (Section 1.3). Participants 
will be followed for survival status until death, withdrawal of consent, or the end of the study.
The end of the study is defined as the date of the last visit of the last participant in the study 
globally.
The study may be stopped if, in the judgment of the Sponsor, participants are placed at undue 
risk because of clinically significant findings.
See Section 6.7 for details on participant management following the final DCO as well as 
following study completion. 
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1
Participant must be ≥ 18 years of age at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2
Histologically or cytologically confirmed R/M SCCHN of the oral cavity, oropharynx, 
hypopharynx, or larynx who have progressed on or after previous systemic cancer therapy 
and are not amenable to curative therapy
3
Must have received prior treatment with a systemic PD-(L)1 inhibitor (in any setting)
4
Prior platinum failure as defined by either:
CC
I
CC
I
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
59 of 187

Disease progression during or after treatment with a platinum-containing regimen for 
R/M disease or

Recurrence/progression within 6 months of the last dose of platinum as part of 
multimodal therapy for LA disease
5
Received 1 or 2 prior systemic regimens for R/M SCCHN (see Section 6.3.1 for 
additional detail on prior lines of therapy)
6
At least one lesion that qualifies as a RECIST 1.1 TL at baseline (see Appendix G). 
Tumor assessment by CT scan or MRI must be performed within 28 days prior to 
randomization.
7
Provide fresh or recently acquired tumor tissue (≤ 3 months prior to screening) for the 
purpose of biomarker testing. Tumor tissue collected when previous treatments were still 
ongoing is not acceptable. 

Tumor tissue beyond the 3-month window and up to 6 months old may be considered 
with Sponsor consultation provided that no intervening systemic regimen was 
ongoing at the time of sample collection (see Laboratory Manual for more 
information). 
8
For participants with OPC only: known HPV status prior to randomization (see 
Section 6.3.1)
9
WHO/ECOG PS of 0 or 1 at enrollment
10 Adequate organ function, defined as:
(a) Hemoglobin ≥ 9.0 g/dL
(b) Absolute neutrophil count ≥ 1500/mm3
(c) Platelets ≥ 75,000/mm3
(d) Total bilirubin ≤ 1.5 × institutional ULN. This will not apply to participants with 
confirmed Gilbert’s syndrome, who will be allowed in consultation with their 
physician.
(e) Aspartate aminotransferase and ALT ≤ 2.5 × institutional ULN; for participants with 
hepatic metastases, ALT and AST ≤ 5 × ULN
(f) Measured CrCL ≥ 30 mL/min or calculated CrCL ≥ 30 mL/min as determined by 
Cockcroft-Gault (using actual body weight)
o
Males:
CrCL(mL/min) = Weight (kg) × (140 - age)
72 × serum creatinine (mg/dL)
o
Females:
CrCL (mL/min) = Weight (kg) × (140 - age) × 0.85
72 × serum creatinine (mg/dL)
11 Minimum life expectancy of 12 weeks

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
60 of 187
Weight
12 Body weight > 30 kg
Sex
13 Male and/or female
Reproduction
14 Negative pregnancy test (“highly effective” urine or serum test) for female participants of 
childbearing potential.
15 Female participants must be one year post-menopausal, surgically sterile, or using an 
acceptable method of contraception (see Appendix H) for the duration of the study (from 
the time they sign consent) and for 4 months after the last dose of study intervention to 
prevent pregnancy. 
16 Male participants must be surgically sterile or using an acceptable method of 
contraception (see Appendix H) for the duration of the study (from the time they sign 
consent) and for 4 months after the last dose of study intervention to prevent pregnancy in 
a female partner. Male participants must not donate or bank sperm during the same time 
period.
Informed Consent
17 Capable of giving signed informed consent as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol
18 Provision of signed and dated, written ICF prior to any mandatory study specific 
procedures, sampling, and analyses 
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
61 of 187
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
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 
participants with squamous cell carcinoma of unknown primary or non-squamous 
histologies (eg, nasopharynx or salivary gland)
2
Prior cetuximab therapy (unless it was administered in curative LA setting with 
radiotherapy and no disease progression for at least 6 months following the last cetuximab 
dose)
3
Any unresolved toxicity NCI CTCAE ≥ Grade 2 from previous anticancer therapy with 
the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion 
criteria. 

Participants with irreversible toxicity not reasonably expected to be exacerbated by 
treatment with monalizumab and cetuximab may be included only after consultation 
with the Study Clinical Lead.
4
Has carcinomatous meningitis and/or untreated central nervous system metastases 
identified either on the baseline brain imaging (see Appendix G) obtained during the 
screening period or identified prior to signing the ICF. Participants with a history of brain 
metastases or with suspected brain metastases at screening must have an MRI (preferred) 
or CT each preferably with iv contrast of the brain prior to study entry. Participants whose 
brain metastases have been treated may participate provided they show radiographic 
stability (defined as 2 brain images, both of which are obtained after treatment to the 
brain metastases. These imaging scans should both be obtained at least 4 weeks apart and 
show no evidence of intracranial progression). In addition, any neurologic symptoms that 
developed either as a result of the brain metastases or their treatment must have resolved 
or be stable either, without the use of steroids, or are stable on a steroid dose of 
≤10 mg/day of prednisone or its equivalent and anticonvulsants for at least 14 days prior 
to the start of treatment. Brain metastases will not be recorded as RECIST 1.1 TL at 
baseline.
5
Major surgical procedure (as defined by the investigator) within 28 days prior to the first 
dose of study intervention. Note: Local surgery of isolated lesions for palliative intent is 
acceptable.
6
History of allogeneic organ transplantation
7
History of allergic reactions or hypersensitivity attributed to compounds of similar 
chemical or biologic composition to cetuximab and monalizumab or any of their 
excipients

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
62 of 187
8
History of active primary immunodeficiency
9
Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or 
Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid 
arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:

Participants with vitiligo or alopecia

Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement 

Any chronic skin condition that does not require systemic therapy

Participants without active disease in the last 5 years may be included but only after 
consultation with the Study Clinical Lead

Participants with celiac disease controlled by diet alone
10 Active infection including tuberculosis (clinical evaluation that includes clinical history, 
physical examination and radiographic findings, and tuberculosis testing in line with local 
practice), hepatitis B (known positive HBV surface antigen [HBsAg] result), hepatitis C 
(HCV), or human immunodeficiency virus (positive HIV 1/2 antibodies). Participants 
with a past or resolved HBV infection (defined as the presence of hepatitis B core 
antibody [anti-HBc] and absence of HBsAg) are eligible. Participants positive for HCV 
antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
11 Uncontrolled intercurrent illness, including but not limited to: ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina 
pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease, serious chronic 
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations 
that would limit compliance with study requirement, substantially increase risk of 
incurring AEs or compromise the ability of the participant to give written informed 
consent
12 History of another primary malignancy except for:

Malignancy treated with curative intent and with no known active disease ≥ 5 years 
before the first dose of study treatment and of low potential risk for recurrence

Adequately treated non-melanoma skin cancer or lentigo maligna without evidence 
of disease

Adequately treated carcinoma in situ without evidence of disease

Participants with a history of prostate cancer (tumor/node/metastasis stage) of 
Stage ≤ T2cN0M0 without biochemical recurrence or progression and who in the 
opinion of the investigator are not deemed to require active intervention

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
63 of 187
13 Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥500 ms 
calculated from 3 ECGs (see Section 8.2.3)
Prior/Concomitant Therapy
14 Any concurrent anticancer treatment. Concurrent use of hormonal therapy for 
non-cancer-related conditions (eg, hormone replacement therapy) is allowed.
15 Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine 
therapy, targeted therapy, biologic therapy, tumor embolization, mAbs, or investigational 
agents) or radiotherapy with curative intent (to more than 30% of the bone marrow or 
with a wide field of radiation) ≤ 28 days prior to the first dose of study intervention. If 
sufficient wash-out time has not occurred due to the schedule or PK properties of an 
anticancer agent, a longer wash-out period will be required, as agreed by the Sponsor and 
the investigator.
16 Current or prior use of immunosuppressive medication within 14 days before the first 
dose of study intervention. The following are exceptions to this criterion (see also 
Table 6):

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

Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)
17 Receipt of live attenuated vaccine within 30 days prior to the first dose of study 
intervention.
Note: Participants, if enrolled, should not receive live vaccine whilst receiving study 
intervention and up to 30 days after the last dose of study intervention.
Prior/Concurrent Clinical Study Experience
18 Participation in another clinical study with an investigational product administered in the 
last 28 days prior to randomization or concurrent enrollment in another clinical study, 
unless it is an observational (non-interventional) clinical study or during the follow-up 
period of an interventional study
19 Prior treatment with monalizumab 
Other Exclusions
20 Involvement in the planning and/or conduct of the study (applies to both Sponsor staff 
and/or staff at the study site).

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
64 of 187
21 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions and requirements.
22 Previous study intervention assignment in the present study. 
23 For women only - currently pregnant (confirmed with positive pregnancy test) or breast-
feeding.
24 Genetics research study (optional): 
Exclusion criteria for participation in the optional (DNA) genetics research component of 
the study include:

Previous allogeneic bone marrow transplant

Transfusion of non-leukocyte-depleted blood or blood components within 120 days 
of genetic sample collection
5.3
Lifestyle Considerations
The following restrictions apply while the participant is receiving study intervention and for 
the specified times before and after:
1
Participants must follow the contraception requirements outlined in Appendix H.
2
Participants should not donate blood or blood components while participating in this 
study and through 4 months after the last dose of study intervention. 
3
Women must not breastfeed during the study, and for 4 months after the last dose of study 
intervention. 
Restrictions relating to concomitant medications are described in Section 6.5.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
do not fulfill the eligibility criteria, and therefore must not be randomized. These participants 
should have the reason for study withdrawal recorded as “eligibility criteria not fulfilled” 
(ie, participant does not meet the required inclusion/exclusion criteria). This reason for study 
withdrawal is only valid for screen failures (ie, not randomized participants). 
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants to meet the Consolidated Standards of Reporting Trials publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAE. If a pre-screened 
tissue and/or whole blood/serum/plasma sample has already been procured prior to screen 
failure, a biomarker evaluation will be conducted if feasible (consistent with the ICF). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
65 of 187
rescreened a single time, but they may not be re-randomized. Rescreened participants should 
be assigned the same E-code as for the initial screening. Participants will reconfirm their 
consent to participate in the study by re-signing and dating their original ICF(s), next to their 
original signature and date, or according to local or site-specific procedures. All assessments 
must be repeated for rescreening unless they are within 28 days of randomization.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
6.1
Study Interventions Administered
6.1.1
Investigational Medicinal Products
Table 5
Investigational Medicinal Products
Intervention 
name
Monalizumab
Cetuximab
Placebo
Type 
Biologic
Biologic
Drug
Dose 
formulation
As sourced by 
AstraZeneca, cetuximab 
will be supplied as a 
liquid solution containing 
5 mg/mL cetuximab, 
sodium chloride, glycine, 
polysorbate 80, citric acid 
monohydrate, sodium 
hydroxide, and WFI.
If cetuximab is sourced 
locally it will be as the 
approved commercial 
product.
Unit dose 
strength(s)
500 mg (nominal) 
cetuximab per vial as 
sourced by AstraZeneca.
Cetuximab will be locally 
sourced as the approved 
commercial product.
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
66 of 187
Table 5
Investigational Medicinal Products
Intervention 
name
Monalizumab
Cetuximab
Placebo
Dosage level(s)
Initial dose: 400 mg/m2
Subsequent doses: 
250 mg/m2 Q1W 
Route of 
administration
iv infusion
Use
Experimental
Experimental/Active 
comparator
Placebo
IMP and NIMP
IMP
IMP
IMP
Sourcing
AstraZeneca
AstraZeneca source 
centrally or locally 
sourced where feasible
Sourced locally by 
site
Packaging and 
labelling
Each vial will be labelled 
in accordance with GMP 
Annex 13 and per country 
regulatory requirement.
Current/Forme
r name(s) or 
alias(es)
IPH2201
Erbitux®
Not applicable
; IMP = investigational medicinal product; NIMP 
= non-investigational medicinal product; 
 
.
6.1.2
Dosing Instructions
A physician must be present at the site or immediately available to respond to emergencies 
during all administrations of IMP. Fully functional resuscitation facilities should be available. 
As with any mAb, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis. See Section 6.6 and Section 8.3.15 for dose modification and management of 
IMP-related toxicities, respectively.
Section 6.2.1 describes dose preparation and administration. 
Permissible medications prior to administration of monalizumab or cetuximab are described in 
Section 6.5.1. No premedication is required prior to monalizumab administration, unless a 
participant has experienced an infusion-related AE in the previous cycle. For cetuximab, 
participants should be premedicated per US PI (antihistamine iv 30 to 60 minutes prior to the 
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
67 of 187
first infusion or subsequent infusions of cetuximab as deemed necessary) or local label (where 
available). Premedication may also be based on institutional guidance for management of 
infusion-related reactions. 
Dosing regimen
The dosing regimen for Arm A and Arm B is presented in Figure 2 (see also SoA Table 1).
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
68 of 187
6.1.3
Duration of Treatment 
All study intervention will be administered beginning on Day 1. Participants in Arm A or 
Arm B will remain on study intervention until RECIST 1.1-defined radiological disease 
progression (refer to Appendix G) unless there is unacceptable toxicity, withdrawal of consent, 
or another discontinuation criterion is met. See Section 7.1 for information on discontinuation 
of study intervention for individual participants. 
A follow-up scan is to be collected after the initial RECIST 1.1-defined disease progression, 
preferably at the next (and no later than the next) scheduled imaging visit, and no less than 
4 weeks after the prior assessment of disease progression (Eisenhauer et al 2009). This 
follow-up scan is evaluated using the Confirmation of Radiological Progression criteria 
outlined in Appendix G.
6.2
Preparation/Handling/Storage/Accountability of Interventions
1
The investigator or designee (eg, unblinded pharmacist) must confirm appropriate 
temperature conditions have been maintained during transit for all study intervention 
received and any discrepancies are to be reported and resolved before use of the study 
intervention.
2
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access limited to 
the investigator and authorized site staff.
3
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4
Further guidance and information for the final disposition of unused study interventions 
will be provided to the sites.
All IMPs should be stored in a secure and dry place. Vials of IMP for parenteral 
administration should be stored at 2 °C to 8 °C (36 °F to 46 °F; refrigerated) and must not be
frozen. IMP must be kept in original packaging until use to prevent prolonged light exposure.
Placebo will be locally sourced by the study site and cetuximab will either be locally sourced 
by the study site or centrally supplied by the Sponsor. When centrally supplied, cetuximab 
will be labeled with local language translated text in accordance with regulatory guidelines.
6.2.1
Dose Preparation and Administration
6.2.1.1
Monalizumab
The dose of monalizumab for administration must be prepared by the investigator’s or site’s 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
69 of 187
designated IMP manager using aseptic technique. 
 
Do not co-administer other drugs through the same infusion line.
The iv line will be flushed according to local practices to ensure the full dose is administered. 
Infusion time does not include the final flush time.
If either preparation time or infusion time exceeds the time limits, a new dose must be 
prepared from new vials. Monalizumab does not contain preservatives, and any unused 
portion must be discarded. 
6.2.1.2
Cetuximab
The dose of cetuximab for administration must be prepared by the investigator’s or site’s 
designated IMP manager using aseptic technique. See the Pharmacy Manual for guidance on 
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
70 of 187
cetuximab storage conditions, dose preparation, and dose administration. See Section 6.1.2 for 
the cetuximab dosing regimen. 
6.2.1.3
Placebo
Do not co-administer other drugs through the same infusion line.
The iv line will be flushed according to local practices to ensure the full dose is administered.  
Infusion time does not include the final flush time.
If either preparation time or infusion time exceeds the time limits, a new placebo dose must be 
prepared.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Participant Enrollment and Randomization
Participants will be randomized in a 2:1 ratio to Arm A or Arm B. 
Randomization will be stratified by 
!
Human papillomavirus status (OPC HPV positive or HPV-unrelated),
∀
The number of OPC HPV-positive participants will be closely monitored throughout 
the study and is planned to be capped at approximately 20% of the total sample size.
!
World Health Organization/ECOG PS (0 or 1), and 
!
Number of prior lines of therapy in the R/M setting (1 or 2)
∀
The number of participants in each stratum (1 or 2 prior lines of therapy in the R/M 
setting) will be closely monitored throughout the study. If a disproportionate number 
of participants are enrolled in a single stratum (eg, > 75% of the total sample size), 
the Sponsor may elect to close further recruitment into that stratum.
All participants will be centrally assigned to randomized study intervention using an IRT. 
Before the study is initiated, user guides, the log in information, and directions for the IRT 
will be provided to each site.
If participants withdraw from the study, then their randomization codes cannot be reused. 
Withdrawn participants will not be replaced. 
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
71 of 187
Investigators should keep a record (ie, the participant screening log) of participants who 
entered screening.
At screening/baseline (Days -28 to -1), the investigators or suitably trained delegate will:
!
Obtain signed informed consent before any study-specific procedures are performed. If 
laboratory or imaging procedures were performed for alternate reasons prior to signing 
consent, these can be used for screening purposes with consent of the participants. 
However, all screening laboratory and imaging results must have been obtained within 
28 days of randomization.
!
Have participants identified to the IRT per country regulations. A unique 7-digit 
enrollment number (E-code) will be obtained, through the IRT in the following format 
(ECCNNXXX: CC being the country code, NN being the center number, and XXX being 
the participant enrollment code at the center). This number is the participant’s unique 
identifier and is used to identify the participant on the eCRFs.
!
Obtain a tumor tissue sample for determination of HLA-E and NKp46 expression (see 
Section 8.6.1).
!
Determine participant eligibility (see Section 5.1 and Section 5.2).
!
Determine HPV status (positive or negative) for participants with OPC for purposes of 
stratification. HPV status will be assessed using local testing by IHC analysis with 
CINtec® Histology p16 assay. Positive p16 IHC expression is defined as 70% or more of 
cytoplasmatic and nuclear staining of the tumor cells. Should the CINtec Histology assay 
not be available at a local institution, a tumor tissue sample should be submitted to the
central laboratory for HPV assessment (details are provided in the Laboratory Manual).
!
Determine WHO/ECOG PS (0 or 1)
!
Determine the number of prior lines of therapy in the R/M setting (1 or 2) for 
stratification purposes.  
∀
For participants with LA disease previously treated with platinum 
(cisplatin/carboplatin) as part of multimodality therapy and progressed during or 
within 6 months after the last platinum dose, this will be considered as one line of 
therapy in the R/M setting.
!
 Participants who 
decide 
to sign 
, 
 the general study ICF, are eligible 
for study enrollment and all other study procedures.
At randomization, once the participant is confirmed to be eligible, the investigator or suitably 
trained delegate will:
CCI
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
72 of 187

Obtain a randomized treatment arm via the IRT. Randomization codes will be assigned 
strictly sequentially within each stratum and site/country/region as participant become 
eligible for randomization. The system will randomize the eligible participant to one of 
the 2 treatment arms.
If the participant is ineligible and not randomized, the IRT should be accessed to terminate the 
participant in the system.
Participants will begin treatment on Day 1. Every effort should be made to minimize the time 
between randomization and starting study intervention. It is strongly recommended that 
participants commence study intervention on the same day as randomization by IRT. If 
same-day treatment is not possible, then study intervention must occur within 2 days of 
randomization. Participants must not be randomized and treated unless all eligibility criteria 
have been met.
6.3.2
Procedures for Handling Incorrectly Enrolled or Randomized 
Participants
Participants who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study intervention. There can be no exceptions to this rule. Participants 
who are enrolled but subsequently found not to meet all the eligibility criteria must not be 
randomized or started on study intervention and must be withdrawn from the study.
Where a participant does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on study treatment, the investigator should inform the Study Clinical Lead 
immediately, and a discussion should occur between the Study Clinical Lead and the 
investigator regarding whether to continue or discontinue the participant from study 
intervention. The Study Clinical Lead must ensure all decisions are appropriately documented 
and that the potential benefit/risk profile remains positive for the participant.
6.3.3
Methods for Assigning Treatment Arms
The actual treatment given to participants will be determined by the randomization scheme in 
the IRT. 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 randomization will be balanced within the IRT at the 
site/country/region/central level.
Randomization codes will be assigned strictly sequentially, within each stratum, as 
participants become eligible for randomization. The IRT will provide the kit identification 
number for centrally supplied IMP to be allocated to the participant at the randomization visit 
and subsequent treatment visits.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
73 of 187
6.3.4
Methods for Ensuring Blinding
The study will be conducted in a double-blind manner.
Monalizumab placebo 
 will 
be prepared by the unblinded pharmacist. The participant, the investigator, and study center 
staff will be blinded to treatment arm allocation and will remain blinded to each participant’s 
assigned study treatment throughout the course of the study. To maintain this blind, an 
otherwise uninvolved third party (ie, the unblinded pharmacist) will be unblinded to treatment 
allocation and will prepare monalizumab or placebo for a participant as specified by the 
randomization scheme and IRT (the unblinded pharmacist will be the only member of 
investigator site staff to know the randomization/treatment allocation details).
The IRT will provide to the investigator(s) or pharmacists the kit identification number to be 
allocated to the participant at the dispensing visit. Pharmacists will be given specific 
instructions for monalizumab/placebo preparation and will note if the double-blind conditions 
have been compromised or the blind has been broken. Lot numbers of monalizumab dispensed 
will be recorded by the pharmacist and monitored by an unblinded monitor. Other blinded 
study center staff and monitors will not be given access to lot number information. Blinded 
and unblinded access and notifications will be controlled using the IRT. 
Routines for this will be described in the IRT user manual that will be provided to each center.
The randomization code should not be broken except in medical emergencies when the 
appropriate management of the participant requires knowledge of the treatment 
randomization. The investigator documents and reports the action to the Sponsor, without 
revealing the treatment given to the participant to the Sponsor staff.
The Sponsor retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an IMP and that potentially require expedited reporting to 
regulatory authorities. Randomization codes will not be broken for the planned analyses of 
data until all decisions on the evaluability of the data from each individual participant have 
been made and documented.
No member of the extended study team at the Sponsor, at the investigational centers, or any 
blinded CRO handling data will have access to the randomization scheme until the time of the 
final analysis or any IA data where a decision is made to unblind the study. At such time, the 
Sponsor and any CRO handling data will have access to the randomization scheme. 
Exceptions are relevant persons within the Pharmaceutical Development Supply Chain at 
AstraZeneca or their designee, where the information is needed to package the study 
intervention; the drug safety departments at AstraZeneca; and the pharmacists required to 
dispense the study intervention at the study site. Investigators will be unblinded to treatment 
allocation only in cases of medical emergency. Additionally, at the request of the investigator, 
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
74 of 187
at progression of disease, the participant can be unblinded. 
The treatment codes and results will be kept strictly within AstraZeneca to safeguard the 
integrity of the blind and hence to minimize any possible bias in data handling. 
In the event that the treatment allocation for a participant becomes known to the investigator 
or other study staff involved in the management of study participants, or needs to be known to 
treat an individual participant for an AE, the Sponsor must be notified promptly by the 
investigator and, if possible, before unblinding. 
The IRT will be programmed with blind-breaking instructions. The blind may be broken if, in 
the opinion of the investigator, it is in the participant’s best interest for the investigator to 
know the study treatment assignment. The Sponsor must be notified before the blind is broken 
unless identification of the study intervention is required for a medical emergency in which 
the knowledge of the specific blinded study intervention will affect the immediate 
management of the participant’s condition (eg, antidote available). In this case, the Sponsor 
must be notified within 24 hours after breaking the blind. The date and reason that the blind 
was broken must be recorded in the source documentation and eCRF, as applicable. Study 
unblinding should occur after database lock, once all decisions on the evaluability of the data 
from each individual participant have been made and documented. 
6.4
Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date, and time if applicable, of dose 
administered in the clinic will be recorded in the source documents and recorded in the eCRF. 
This information, plus drug accountability for all study interventions at every visit, will be 
used to assess compliance. The dose of study intervention and study participant identification 
will be confirmed at the time of dosing by a member of the study site staff other than the 
person administering the study intervention. Any change from the dosing schedule, dose 
delays/interruptions, and dose discontinuations should be recorded in the eCRF. Dose 
modifications for monalizumab/placebo and cetuximab are permitted per the guidelines 
described in Section 6.6. 
Treatment compliance will be ensured by reconciliation of site drug accountability logs. 
The Investigator Product Storage Manager is responsible for managing the IMP from receipt 
by the study site until destruction of all unused IMP.
6.5
Concomitant Therapy
Any concomitant treatment, procedure, or medication or vaccine including over-the-counter or 
prescription medicines, vitamins, and/or herbal supplements that the participant is receiving 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
75 of 187
according to the schedule in the SoA (Section 1.3) must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
The Study Clinical Lead should be contacted if there are any questions regarding concomitant 
or prior therapy.
If any concomitant therapy is administered due to new or unresolved AE, it should be 
recorded.
Participants must be instructed not to take any medications, including over-the-counter 
products, without first consulting with the investigator.
Prohibited and permitted concomitant medications/therapies are described in Table 6 and 
Table 7, respectively. Refer also to the guidelines for management of IMP-related toxicities in 
Section 8.3.15. For cetuximab, refer to the local label (where available) with regard to 
warnings, precautions, and contraindications. 
Table 6
Prohibited Concomitant Medication/Therapy
Type of medication/treatment
Timeline/Instructions
Any investigational therapy other than 
those under investigation in this study
Until end of study treatment.
Any concurrent chemotherapy, 
radiotherapy, immunotherapy (including 
other monoclonal antibodies), or 
biologic or hormonal therapy for cancer 
treatment other than those under 
investigation in this study
Until end of study treatment. 
Concurrent use of hormones for non-cancer-related conditions 
(eg, insulin for diabetes and hormone replacement therapy) is 
acceptable. Local treatment of isolated lesions, excluding target 
lesions, for palliative intent is acceptable (eg, by local surgery or 
radiotherapy)

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
76 of 187
Table 6
Prohibited Concomitant Medication/Therapy
Type of medication/treatment
Timeline/Instructions
Immunosuppressive medications 
including, but not limited to, systemic 
corticosteroids at doses exceeding 
10 mg/day of prednisone or equivalent, 
methotrexate, azathioprine, and tumor 
necrosis factor-α blockers
Should not be given concomitantly or used for premedication prior 
to the infusions of IMP. The following are allowed exceptions:
•
Use of immunosuppressive medications for the management 
of IMP-related adverse events or infusion-related reactions
•
Short-term premedication for cetuximab where the local label 
requires the use of steroids 
•
Short-term premedication for monalizumab/placebo 
following > Grade 2 infusion-related reaction at the previous 
cycle (see monalizumab TMG)
•
Use in participants with contrast allergies 
•
Use of inhaled, topical, and intranasal corticosteroids 
A temporary period of steroid use will be permitted if clinically 
indicated and considered to be essential for the management of 
non-immunotherapy-related events experienced by the participant 
(eg, chronic obstructive pulmonary disease, radiation, nausea, etc).
Live attenuated vaccines 
Within 30 days prior to the first dose of IMP, whilst receiving IMP 
and up to 30 days after the last dose of IMP.
Herbal and natural remedies which may 
have immune-modulating effects
Should not be given concomitantly unless agreed by the Sponsor
IMP = investigational medicinal product. 
Table 7
Permitted Concomitant Medication/Therapy
Type of medication/treatment
Timeline/Instructions
All necessary supportive care in the form of treatment or prophylaxis as 
clinically indicated eg, transfusion of blood products, antibiotics, 
anti-histamines, analgesics
Throughout the study 
Vaccines limited to non-live attenuated preparations (eg, influenza vaccine)
See Appendix C for vaccination against COVID-19
Throughout the study
COVID-19 = coronavirus disease 2019.
6.5.1
Permitted Medication Prior to Study Intervention 
Monalizumab
No premedication is required prior to monalizumab administration. However, from Cycle 2, 
premedication with acetaminophen and/or an antihistamine drug might be prescribed, at the 
investigator’s discretion, if the participant experienced any Grade 1 to 3 infusion-related AE at 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
77 of 187
the previous cycle (see monalizumab TMG provided as a supplement to the CSP). 
Cetuximab
Participants should be premedicated per US PI (antihistamine iv 30 to 60 minutes prior to the 
first infusion or subsequent infusions of cetuximab as deemed necessary) or local label (where 
available). Premedication may also be based on institutional guidance for management of 
infusion-related reactions.
6.5.2
Drug-drug Interactions
No formal drug-drug interaction studies have been conducted with monalizumab. 
Monalizumab and cetuximab are immunoglobulins and the primary elimination pathways are 
protein catabolism via reticuloendothelial system or target mediated disposition. Therefore, 
there are no anticipated drug-drug interactions between monalizumab and cetuximab based on 
the elimination pathway when monalizumab and cetuximab are administered in combination. 
Moreover, monalizumab and cetuximab are not expected to induce or inhibit the major drug 
metabolizing cytochrome P450 pathways. 
Based on available non-compartment analysis data, the observed PK of monalizumab when 
administered in combination with cetuximab is within the range of monalizumab monotherapy 
PK (see Monalizumab IB, Section 5.1 for further details).
6.5.3
Rescue Medication
Fully functional resuscitation facilities should be available at each site during infusion of the 
study interventions. Please see recommendations regarding rescue treatment (Section 6.1.2) 
and management of IMP-related toxicities (Section 8.3.15). The date of rescue medication 
administration as well as the name and dosage regimen of the rescue medication must be 
recorded.
6.6
Dose Modification
It is important to keep the day on which monalizumab/placebo and cetuximab are 
administered as Day 1 of each 2-week cycle (except if one of the study interventions is 
permanently discontinued). If a participant does not meet monalizumab/placebo dosing 
criteria on Day 1 of any cycle, both monalizumab/placebo and cetuximab administration 
should be postponed for a week. If dosing criteria are not met after a week delay, suspension 
of study intervention will be extended for an additional week. In the absence of resolution 
after a 2-week delay, the investigator should contact the Sponsor for guidance on further 
dosing. If dosing delay is due to treatment-related toxicity, TMGs for monalizumab and local 
prescribing information for cetuximab should be followed (see Section 8.3.15).
For guidance on dose modification in relation to the novel coronavirus (COVID-19) outbreak, 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
78 of 187
see Appendix C.
Monalizumab/placebo
Dose delays are permitted for monalizumab/placebo (see management of 
monalizumab-related toxicities in Section 8.3.15.1). However, dose reduction is not permitted.
The duration between each monalizumab/placebo infusion should be at least 14 days (see 
Table 1 for administration schedule, including acceptable window). 
In the event that monalizumab/placebo is discontinued due to monalizumab/placebo-related 
toxicity, treatment with cetuximab may continue at the investigator’s discretion when toxicity 
resolves to ≤Grade 1. Note: If the investigator determines that a participant is ready to restart 
treatment prior to the toxicity resolving to ≤ Grade 1, the Sponsor should be consulted for an 
exception to this rule. 
Cetuximab
Cetuximab dose modification for the management of cetuximab-related toxicities should 
follow local standard clinical practice (see Section 8.3.15.2). For specific information, refer to 
the local label (where available) for cetuximab. 
The duration between each cetuximab infusion should be at least 7 days (see Table 1 for 
administration schedule, including acceptable window). If dosing of cetuximab is delayed on 
Day 1 of a cycle (ie, when monalizumab/placebo is also due to be given) then dosing of 
monalizumab/placebo should also be delayed (see above). If cetuximab is delayed due to 
toxicity on Day 8 of a cycle (ie, when single-dose cetuximab is due to be given), the dose of 
cetuximab will be omitted and the next cycle can continue as usual. 
In the event that cetuximab is discontinued due to cetuximab-related toxicity, treatment with 
monalizumab/placebo may continue at the investigator’s discretion when the 
cetuximab-related toxicity resolves to ≤Grade 2. Note: If the investigator determines that a 
participant is ready to restart treatment prior to the cetuximab-related toxicity resolving to 
≤Grade 2, the Sponsor should be consulted for an exception to this rule. 
6.7
Intervention After the End of the Study
As described in Section 4.4, the study will remain open until all participants have discontinued 
study intervention and completed their last expected visit/contact.
After the final DCO and database closure, the Sponsor will supply open-label IMP to 
participants who are receiving benefit from their assigned treatment, for as long as they and 
their physician considers they are gaining clinical benefit. See Section 8 for a description of 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
79 of 187
the assessments to be conducted for these participants. 
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, participants 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 visit assessments per its protocol. Any participant who would be proposed 
to move to such a study would be given a new ICF.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
Participants will be discontinued from study intervention in the following situations.  

RECIST 1.1-defined radiological disease progression (refer to Section 6.1.3, 
Section 8.1.1, and Appendix G)

Investigator determination that the participant is no longer benefiting from study 
intervention

An AE that, in the opinion of the investigator or the Sponsor, contraindicates further 
dosing

Any AE that meets criteria for discontinuation defined in the guidelines for management 
of IMP-related toxicities (see Section 8.3.15) or as defined in the local label (where 
available) for cetuximab

Participant decision. The participant is at any time free to discontinue study intervention, 
without prejudice to further treatment. A participant who discontinues study intervention 
is normally expected to continue to participate in the study (eg, for safety and survival 
follow-up) unless they specifically withdraw their consent to all further participation in 
any study procedures and assessments (see Section 7.3).

Severe non-compliance with the CSP as judged by the investigator or the Sponsor

For females of childbearing potential, pregnancy or intent to become pregnant

Initiation of subsequent anticancer therapy, including another investigational agent
Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study.
See the SoA (Section 1.3) for data to be collected at the time of study intervention 
discontinuation and follow-up for safety and other assessments.
If a participant discontinues treatment with one of the combination agents due to toxicity, they 
may continue with monalizumab/placebo or cetuximab in monotherapy within the study as 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
80 of 187
long as they are continuing to show clinical benefit, as judged by the investigator and in the 
absence of discontinuation criteria.
7.1.1
Procedures for Discontinuation of Study Intervention
The EOT visit should be performed and conducted one month after the participant 
permanently discontinues from study intervention. The assessments to be conducted at the 
EOT visit are specified in the SoA (Table 2). The reason for discontinuation should be 
documented in the source document and the appropriate section of the eCRF.
Participants who have permanently discontinued from further receipt of study intervention 
will need to be discontinued from the IRT.
The date of last intake of study intervention should be documented in the eCRF. 
Discontinuation of study intervention, for any reason, does not impact on the participant’s 
participation in the study. The participant should continue attending subsequent study visits 
and data collection should continue according to the study protocol. If the participant does not 
agree to continue in-person study visits, a modified follow-up must be arranged to ensure the 
collection of endpoints and safety information including new AEs, follow-up on any ongoing 
AEs and concomitant medications, and subsequent anticancer therapy. This could be a 
telephone contact with the participant at one month (+ 3 days) after study intervention is 
discontinued, a contact with a relative or treating physician, or information from medical 
records. The approach taken should be recorded in the medical records. A participant that 
agrees to modified follow-up is not considered to have withdrawn consent or to have 
withdrawn from the study.
The investigator should instruct the participant to contact the site before or at the time when 
study intervention is stopped. A participant that decides to discontinue study intervention will 
always be asked about the reason(s) and the presence of any AEs.
7.1.1.1
Tumor Assessment Post Discontinuation of Study Intervention
Participants who have discontinued study intervention prior to objective RECIST 1.1-defined 
radiological disease progression, regardless of whether they have commenced subsequent 
anticancer therapy will continue on their regular scan schedule (see SoA, Table 2) until 
RECIST 1.1-defined radiological disease progression or death, unless they have withdrawn all 
consent to study-related assessments.
7.1.1.2
 
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
81 of 187
7.1.1.3
Follow-up for Survival
Participants will be followed for survival status as indicated in the SoA (Table 2) until death, 
withdrawal of consent, or the end of the study. Survival information may be obtained via 
telephone contact with the participant or the participant’s family, or by contact with the 
participant’s current physician. Additional assessments to be performed at the time of survival 
follow-up are detailed in the SoA (Table 2).
Participants on treatment or in survival follow-up will be contacted following each DCO to 
provide complete survival data. These contacts should generally occur within 7 days after the 
DCO. 
7.2
Participant Withdrawal From the Study
!
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon.
!
A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records).
!
Upon withdrawal from the study, an EOT visit should be conducted, if possible. See SoA 
(Section 1.3) for data to be collected at the time of study withdrawal and follow-up and 
for any further evaluations that need to be completed.
∀
The participant will discontinue the study intervention and be withdrawn from the 
study at that time.
!
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
!
If a participant withdraws from the study, it should be confirmed if he/she is still agrees 
for samples to be used (see Section A 3). He/she may request destruction of any samples 
taken, and the investigator must document this in the site study records.  
!
The investigator must document the decision on use of existing samples in the site study 
records and inform the Global Study Team.
!
The Sponsor or its delegate will request investigators to collect information on 
participants’ vital status (dead or alive; date of death when applicable) during survival 
follow-up from publicly available sources, in accordance with local regulations. 
Knowledge of the vital status at study end in all participants is crucial for the integrity of 
the study.
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
82 of 187
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site by the time the study is 
completed (see Section 4.4), such that there is insufficient information to determine the 
participant’s status at that time.
Participants who decline to continue 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 participants throughout the study 
period. If contact with a missing participant is re-established, the participant should not be 
considered lost to follow-up and evaluations should resume according to the protocol.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
!
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.
!
Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant or next of kin by, eg, repeat telephone 
calls, certified letter to the participant’s last known mailing address, or local equivalent 
methods. These contact attempts should be documented in the participant’s medical 
record.
!
Efforts to reach the participant should continue until the end of the study. Should the 
participant be unreachable at the end of the study, he/she will be considered lost to 
follow-up with unknown vital status at the end of the study and censored at latest 
follow-up contact. 
In order to support key efficacy endpoints of OS, PFS, and 
, the survival status 
of all participants in the FAS and the SAF should be re-checked; this includes those 
participants who withdrew consent or are classified as “lost to follow-up.”
!
Lost to follow-up – Site personnel should check hospital records and a publicly available 
death registry (if available), as well as checking with the participants’ current physician, 
to obtain a current survival status. (The applicable eCRF modules will be updated.)
!
In the event that the participant has actively withdrawn consent to the processing of their 
personal data, the survival status of the participant 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.  
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
83 of 187
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA (see Section 1.3). Protocol
waivers or exemptions are not allowed. Assessments following final DCO and database 
closure until the end of the study are described in Section 8.3.11. 
!
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.
!
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
!
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
!
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
8.1
Efficacy Assessments
8.1.1
Imaging Tumor Assessments
This study will evaluate a primary endpoint of OS and secondary endpoints of PFS, ORR, and 
DoR for Arm A vs Arm B. 
. 
With the exclusion of OS, efficacy will be derived (by the Sponsor) using investigator 
RECIST 1.1 assessments.
Tumor assessments use images from iv contrast-enhanced CT (preferred) of the neck 
(including the base of skull), chest, and abdomen (including the entire liver) collected during 
screening/baseline and at regular (follow-up) intervals during study intervention. Any other 
areas of disease involvement should be additionally imaged at screening based on known 
metastasis sites or by the signs and symptoms of individual participants. MRI with iv contrast 
is acceptable if CT is contraindicated. The imaging modality (CT/MRI) used for baseline 
tumor assessments should be kept the same consistently at each subsequent follow-up 
assessment throughout the study if possible. It is important to follow the tumor assessment 
schedule as closely as possible (refer to the SoA [Section 1.3]) relative to randomization. 
Screening/baseline imaging should be performed no more than 28 days before randomization 
and ideally should be performed as close as possible to randomization. Scanning/tumor 
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
84 of 187
assessments will continue throughout intervention until RECIST 1.1-defined radiological 
disease progression by investigator assessment (see Section 6.1.3). If an unscheduled 
assessment is performed (eg, to investigate clinical signs/symptoms of progression) and the 
participant has not progressed, every attempt should be made to perform the subsequent 
assessments at the next scheduled visit.  
Tumor assessment by RECIST 1.1 guidelines are provided in Appendix G.
8.1.2
 
8.1.3
Overall Survival 
Assessments for survival will be conducted according to the SoA (Table 2) following 
objective disease progression or treatment discontinuation. Survival information may be 
obtained via telephone contact with the participant, participant’s family, by contact with the 
participant’s current physician, or local death registries as described in Section 7.2.
8.1.4
Clinical Outcome Assessments
A COA is an assessment of a clinical outcome reported by a clinician, a patient, or a 
non-clinician observer, or through a performance-based assessment (FDA 2018b). A COA 
may be used in clinical studies to provide either direct or indirect evidence of treatment 
benefit. It is important to examine the impact of therapy on disease-related symptoms, 
physical function, and other HRQoL of the patient to aid understanding of how clinical benefit 
relates to patient well-being and for consideration in making benefit-risk evaluations. Patient-
reported outcome is one type of clinical outcome assessment and is a general term referring to 
all outcomes and symptoms that are directly reported by the patient. Moreover, PROs assist in 
the documentation of symptoms and specifically what symptoms and impacts are most 
important to patients and how these relate to clinical outcomes. Patient-reported outcomes 
have become important in evaluating effectiveness of study treatments in clinical studies and 
will aid in understanding of the benefit-risk evaluation (Kluetz et al 2018). The following 
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
85 of 187
PROs will be administered in this study: EORTC QLQ-C30, EORTC QLQ-H&N35, 
 
See 
questionnaires in Appendix I. Patient-reported outcomes will be administered according to the 
SoA during the treatment and follow-up periods (see Section 1.3). Patient-reported outcomes 
will be translated into the language of the country being administered,
 
8.1.4.1
EORTC QLQ-C30 
The EORTC QLQ-C30 was developed by the EORTC Quality of Life Group 1993 (see 
Appendix I 1). It consists of 30 items and measures symptoms, functioning, and global health 
status/QoL (Aaronson et al 1993) for all cancer types. Questions are grouped into 5 multi-item 
functional scales (physical, role, emotional, cognitive, and social); 3 multi-item symptom 
scales (fatigue, pain, and nausea/vomiting); a 2-item global QoL scale; 5 single items 
assessing additional symptoms commonly reported by cancer patients (dyspnea, loss of 
appetite, insomnia, constipation, and diarrhea), and one item on the financial impact of the 
disease. The EORTC QLQ-C30 is a valid and reliable PRO instrument in this patient 
population. 
8.1.4.2
EORTC QLQ-H&N35
The EORTC QLQ-H&N35 module is a 35-item self-administered questionnaire (see 
Appendix I 2). 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. 
8.1.4.3
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
86 of 187
8.1.4.4
8.1.4.5
8.1.4.6
8.1.4.7
Administration of Electronic PRO Questionnaires
Participants will complete the PRO assessments using an electronic tablet (ePRO) during 
clinic visits at the time points indicated in the SoA (see Section 1.3). It is important that the 
ePRO device is charged and set up for the participant prior to their arrival at the site for their 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
87 of 187
baseline PRO assessments (close to when the participant will be randomized), to ensure it is 
functioning properly and ready for use, in accordance with device training. The participant 
should be trained on the use of the device, including the importance of completing the PRO 
questionnaires throughout the study in accordance with the SoA.
The below instructions should be followed when collecting PRO data via an electronic device:
!
Patient-reported outcome questionnaires must be completed prior to treatment 
administration and ideally before any discussions of health status to avoid biasing the 
participant’s responses to the questions. As feasible, site staff should also ensure PRO 
questionnaires are completed prior to other study procedures, such as collection of 
laboratory samples, to further minimize bias.
!
When each instrument is due to be completed, the following order is observed; EORTC 
QLQ-C30 should be administered first followed by EORTC QLQ-H&N35, 
!
Patient-reported outcome questionnaires should be completed by the participant in a quiet 
and private location. 
!
The participant should be given sufficient time to complete the questionnaires at their 
own speed.
!
The research nurse or appointed site staff must explain to participants the value and 
relevance of ePRO participation so they are motivated to comply with questionnaire 
completion. Inform the participant that these questions are being asked to find out, 
directly from them, how they feel.
!
The research nurse or appointed site staff should stress that the information is not 
routinely shared with study staff. Therefore, if the participant has any medical problems, 
they should discuss them with the doctor or research nurse separately from the ePRO 
assessment.
!
The research nurse or appointed site staff must train the participant on how to use the 
ePRO device, using the materials and training provided by the ePRO vendor.
!
All PRO questionnaires are to be completed using the ePRO device. If technical or other 
device-related issues prohibit completion on the device, an appropriate backup option 
may be considered with prior approval from AstraZeneca. 
!
The research nurse or appointed site staff must remind participants that there are no right 
or wrong answers, and avoid introducing bias by not clarifying items for the participant.
!
The participant should not receive help from relatives, friends, or clinic staff to decide on 
answers to the ePRO questionnaires. The responses are the participant’s alone.
!
On completion of the questionnaire at the site, it should be handed back to the designated 
responsible person, who should check that all questionnaires were completed.
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
88 of 187

If a participant needs visual aids (eg, spectacles or contact lenses) for reading and does 
not have them when he or she attends the clinic, the participant will be exempted from 
completing the ePROs at that clinic visit.

Site staff must not read the ePRO questionnaires on behalf of the participant. If the 
participant is unable to read the questionnaire (eg, is blind or illiterate, or not fluent in the 
available language), that participant is exempted from completing PRO questionnaires but 
may still participate in the study. If the participant cannot complete the ePRO 
questionnaires due to reasons other than being blind, illiterate, or fluent in language, the 
AstraZeneca study team must be contacted to determine if they can be exempted. 
Participants exempted in this regard should be flagged appropriately by the site staff in 
the source documents and in the REVPRDI eCRF.

Questions must not be translated from an available language in the device into the 
language the participant speaks.

It is vital that the ePRO reporting is initiated at Cycle 1 Day 1 dosing visit (baseline) as 
specified in the SoA to capture the effect of study treatment. The ePRO device must be 
charged and fully functional at the beginning of the baseline visit to ensure that the PROs 
can be completed at the start of the visit. 

Finally, the research nurse or appointed site staff will review the completion status of 
questionnaires during site visits and document the reason(s) why a participant could not 
complete assessments in the designated eCRF. 
The research nurse or appointed site staff must monitor compliance since 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 the site receives an email 
notification regarding the participant’s compliance, appropriate action should be taken 
(eg, discussion with participant to improve compliance, a check in call from the site to ask the 
participant if they have any difficulties in completing questionnaires on schedule, etc). 
A solution to enhance/resolve compliance should be discussed with the participant. 
Discussions and compliance review should be reflected in source documents. 
8.1.4.8
WHO/ECOG PS
World Health Organization/ECOG PS will be assessed at the time points specified in the SoA 
(Section 1.3) 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 or 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

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
89 of 187
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
5
Dead
Any significant change from baseline or screening must be reported as an AE. 
The ECOG status collected at screening must be reported in IRT and not re-assessed.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1
Physical Examinations
Physical examination, as well as assessment of height and weight, will be performed at time 
points specified in the SoA (Section 1.3).

A full physical examination will include assessments of the head, eyes, ears, nose, and 
throat and the respiratory, cardiovascular, gastrointestinal, musculoskeletal, neurological, 
dermatological, hematologic/lymphatic, and endocrine systems. In addition, targeted 
physical examinations, eg, urogenital, are to be performed by the investigator based on 
clinical observations and symptomatology.

Targeted physical examinations are to be performed by the investigator on the basis of 
clinical observations and symptomatology.
Situations in which physical examination results should be reported as AEs are described in 
Section 8.3.5.
8.2.2
Vital Signs
Vital signs will be performed at time points specified in the SoA (Section 1.3). 
Blood pressure and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available.
Vital signs will be measured after 5 minutes rest and will include temperature, systolic and 
diastolic blood pressure, and pulse and respiratory rate. 
First infusion 
On the first infusion day, participants will be monitored and vital signs collected/recorded in 
eCRF prior to, during, and after infusion of monalizumab/placebo as presented in the bulleted 
list below. 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
90 of 187
Blood pressure and pulse will be collected from participants before, during, and after each 
monalizumab/placebo infusion 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 infusion (halfway through infusion) 

At the end of the infusion (approximately 60 minutes ± 5 minutes)
If the monalizumab/placebo infusion takes longer than 60 minutes, then blood pressure and 
pulse measurements should follow the principles as described above or be taken more 
frequently if clinically indicated. A one-hour observation period is recommended after the first 
infusion of monalizumab/placebo. 
Vital signs will be collected in all participants before cetuximab dosing (approximately 
30 minutes before up to 0 minutes) and as clinically indicated during and after dosing, as per 
the local label and institutional standard. Any clinically significant changes in vital signs 
should be entered onto an unscheduled vital signs eCRF. 
Subsequent infusions 
Blood pressure, pulse, and other vital signs should be measured (approximately 30 minutes 
before up to 0 minutes), collected/recorded in the eCRF prior to the start of the infusions of 
monalizumab/placebo and cetuximab. Participants should be carefully monitored, and blood 
pressure and other vital signs should be measured during and post infusions as per institutional 
standard and as clinically indicated (and in line with the local label for cetuximab). Any 
clinically significant changes in vital signs should be entered onto an unscheduled vital signs 
eCRF.
Situations in which vital signs results should be reported as AEs are described in 
Section 8.3.5. For any AEs of infusion reactions, the vital signs values should be entered into 
eCRF.
8.2.3
Electrocardiograms
Triplicate 12-lead ECGs will be recorded at scheduled visits and as clinically indicated per the 
SoA (Section 1.3). An ECG will be obtained after the participant has been resting 
semi-recumbent or supine for at least 5 minutes and recorded while the participant remains in 
that position using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTcF intervals. 
Three individual ECG tracings should be obtained in succession, no more than 2 minutes 
apart. The full set of triplicates should be completed within 5 minutes. The machine-derived 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
91 of 187
QTc must be manually verified and interpreted by the investigator. All ECGs should be 
assessed by the investigator as to whether they are clinically significantly abnormal.
Situations in which ECG results should be reported as AEs are described in Section 8.3.5.
8.2.4
Clinical Safety Laboratory Assessments
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis 
will be taken at the visits indicated in the SoA (Section 1.3). Samples for determination of 
coagulation parameters are to be collected at baseline on Day 1 (unless all screening 
laboratory hematology assessments are performed within 3 days prior to Day 1), and then as 
clinically indicated. 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.
Clinical laboratory safety tests, including serum pregnancy tests, will be performed at a 
licensed clinical laboratory according to local standard procedures. Sample tubes and sample 
sizes may vary depending on laboratory method used and routine practice at the site. 
Pregnancy tests may be performed at the site using a licensed test (urine or serum pregnancy 
test). Abnormal clinically significant laboratory results should be repeated as soon as possible 
(preferably within 24 to 48 hours). 
Table 8 presents the laboratory variables to be measured. Other safety tests to be performed at 
screening include assessments for hepatitis B surface antigen, hepatitis C antibodies, and HIV 
antibodies.
Table 8
Laboratory Safety Variables
Hematology/Hemostasis (whole blood)
Clinical chemistry (serum or plasma)
Hb
Creatinine a
Platelet count
Bilirubin, total b
Absolute neutrophil count c
ALP b
Absolute lymphocyte count c
AST b
Total WBC count
ALT b
Coagulation d
Albumin
aPTT, fibrinogen, and INR
Potassium
Calcium, total
Urinalysis e
Sodium
Bilirubin
Magnesium
Blood 
Phosphate
Protein/Albumin 
Amylase f
Glucose 
Lipase f
Color and appearance
Gamma-glutamyl transferase
Ketones
Glucose 
Specific gravity
Bicarbonate (where available)

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
92 of 187
Table 8
Laboratory Safety Variables
Hematology/Hemostasis (whole blood)
Clinical chemistry (serum or plasma)
pH
Chloride
LDH
Protein, total
TSH g
free T4 h
free T3 h
Urea or blood urea nitrogen, depending on local practice
a
Creatinine clearance will be calculated by the site using Cockcroft-Gault (using actual body weight).
b
Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently. If total 
bilirubin is ≥ 2 × ULN (and no evidence of Gilbert’s syndrome), then fractionate into direct and indirect bilirubin.
c
Can be recorded as absolute counts or as percentages, except at screening when absolute neutrophil count must be 
recorded. Total WBC count therefore has to be provided.
d
Coagulation parameters are to be assessed at baseline on Day 1 (unless all screening laboratory hematology 
assessments are performed within 3 days prior to Day 1), and then as clinically indicated.
e
Urinalysis should be done at baseline (screening) and then as clinically indicated. 
f
It is preferable that both amylase and lipase parameters are assessed. For sites where only one of these parameters is 
routinely measured, either lipase or amylase is acceptable.
g
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at Day 1.
h
Free T4 or/and free T3 (per local standard clinical practice) will only be measured if TSH is abnormal or if there is 
clinical suspicion of an AE related to the endocrine system.
ALP = alkaline phosphate; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = 
aspartate aminotransferase; INR = International Normalized Ratio; LDH = lactate dehydrogenase; T3 = triiodothyronine; 
T4 = thyroxine; TSH = thyroid stimulating hormone; ULN = upper limit of normal; WBC = white blood cell count.
In case a participant shows an AST or ALT ≥ 3 × ULN together with TBL ≥2 × ULN, please 
refer to Appendix F (Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law) for further instructions. 
8.3
Adverse Events and Serious Adverse Events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section
The definitions of an AE or SAE can be found in Appendix B.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
For guidance in relation to the novel coronavirus (COVID-19) outbreak, see Appendix C.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events will be collected from time of signature of the ICF until 90 days after the last 
dose of study intervention (see SoA, Section 1.3). Collection and reporting of AEs and SAEs 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
93 of 187
after the final DCO is described in Section 8.3.11.
Serious adverse events will be recorded from the time of signing of ICF.
If the investigator becomes aware of an SAE with a suspected causal relationship to the IMP 
that occurs after the end of the clinical study in a participant treated by him or her, the 
investigator shall, without undue delay, report the SAE to the Sponsor.
8.3.2
Follow-up of AEs and SAEs
Any AEs that are unresolved at the participant’s last AE assessment in the study are followed 
up by the investigator for as long as medically indicated, but without further recording in the 
eCRF. The Sponsor retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
Adverse event variables
The following variables will be collected for each AE;

Adverse event (verbatim)

The date when the AE started and stopped

Select the appropriate as required: 

The maximum CTCAE grade reported

Changes in CTCAE grade (report only the maximum CTCAE grade for a calendar 
day)

Whether the AE is serious or not

Investigator causality rating against the IMP(s) (yes or no)

Action taken with regard to IMP(s)

Administration of treatment for the AE 

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date investigator became aware of serious AE

Adverse event is serious due to

Date of hospitalization

Date of discharge

Probable cause of death

Date of death

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
94 of 187

Autopsy performed

Causality assessment in relation to Study procedure(s)

Causality assessment to other medication
The grading scales found in the NCI CTCAE, Version 5.0 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 can be downloaded from the Cancer 
Therapy Evaluation Program website (http://ctep.cancer.gov).
8.3.3 Causality Collection
The investigator should assess causal relationship between IMP 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 should also be assessed for other medication 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.
8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: ‘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.
8.3.5 Adverse Events Based on Examinations and Tests
The results from the CSP-mandated laboratory tests and vital signs will be summarized in the 
CSR. 
Deterioration as compared to baseline in protocol-mandated laboratory values, vital signs, and 
ECGs should therefore only be reported as an AE if it fulfills any of the SAE criteria, is the 
reason for discontinuation of treatment with the IMP, or is considered to be clinically relevant 
as judged by the investigator (this may include but is not limited to whether treatment or non-
planned visits were required or other action was taken with the study intervention, eg, dose 
adjustment or drug interruption).

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
95 of 187
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible, the reporting investigator 
uses 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 AE(s).
Deterioration of a laboratory value, which 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 unless unequivocally 
related to the disease under study.
8.3.6 Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN may 
need to be reported as SAEs. Please refer to Appendix F for further instruction on cases of 
increases in liver biochemistry and evaluation of HL.
8.3.7 Disease Progression
Disease progression can be considered as a worsening of a participant’s condition attributable 
to the disease for which the IMP 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.
8.3.8
New Cancers
The development of a new cancer should be regarded as an AE and will generally meet at least 
one of the serious criteria. New primary cancers are those that are not the primary reason for 
the administration of study intervention and have been identified after the participant’s 
inclusion in this study. They do not include metastases of the original cancer.
8.3.9
Deaths
All deaths that occur during the study intervention period, or within the protocol-defined 
follow-up period after the administration of the last dose of study intervention, must be 
reported as follows:

Death clearly resulting from disease progression should be documented in the eCRF in 
the Statement of Death page. It should not be reported as an SAE.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
96 of 187

Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported as an SAE within 24 hours. It should also be 
documented in the Statement of Death page in the eCRF. The report should contain a 
comment regarding the co-involvement of disease progression, if appropriate, and should 
assign the main and contributory causes of death.

Deaths with an unknown cause should always be reported as an SAE and documented in 
the Statement of Death page in the eCRF, but every effort should be made to determine a 
cause of death. 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 
Patient Safety or its representative within the usual time frames.
Deaths occurring after the protocol-defined follow-up period after the administration of the 
last dose of study intervention should be documented in the Statement of Death page. If the 
death occurred as a result of an event that started after the defined follow-up period and the 
event is considered to be due to a late-onset toxicity to study treatment, then it should also be 
reported as an SAE.
8.3.10
Adverse Events of Special Interest
Adverse events of special interest are events of scientific and medical interest specific to the 
further understanding of study intervention safety profile and require close monitoring and 
rapid communication by the investigators to the Sponsor. An AESI can be serious or 
non-serious. All AESIs will be recorded in the eCRF. Serious AESIs will be recorded and 
reported as per Section 8.3.12.
Adverse events of special interest for monalizumab include events with a potential immune-
mediated inflammatory mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants, and/or hormone replacement therapy. An 
imAE 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 imAE diagnosis. Appropriate efforts should be made to rule out neoplastic, 
infectious, metabolic, toxic, or other etiologic causes of the imAE. 
If the investigator has any questions in regard to an event being an imAE, the investigator 
should promptly contact the Study Clinical Lead.
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological etiology are also considered AESIs.
Further information on these risks (eg, presenting symptoms) can be found in the current 
version of the monalizumab IB. More specific guidelines for their evaluation and treatment 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
97 of 187
are described in detail in the monalizumab TMG (see Section 8.3.15). 
8.3.11
Safety Data to be Collected Following the Final DCO of the Study
For participants continuing to receive open-label IMP after the final DCO and database 
closure (see Section 6.7), it is recommended that the participant continue the scheduled site 
visits and investigators monitor the participant’s safety laboratory results prior to and 
periodically during treatment with IMP in order to manage AEs in accordance with toxicity-
management guidelines (see Section 8.3.15). All data post the final DCO and database closure
will be recorded in the participant notes but, with the exception of SAEs, will not otherwise be 
reported for the purposes of this study.
All SAEs that occur in participants still receiving IMP (or within the 90 days following the 
last dose of IMP) post the final DCO and database closure must be reported as detailed in 
Section 8.3.12.
8.3.12
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the IMP, or to the 
study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate Sponsor representatives within one day ie, immediately but no later than 
24 hours of when they become aware of it.
The designated Sponsor representative works with the investigator to ensure that all the 
necessary information is provided to the Sponsor 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 where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform Sponsor 
representatives of any follow-up information on a previously reported SAE within one 
calendar day ie, immediately but no later than 24 hours of when they become aware of it.
Once the investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated Sponsor representative.
If the EDC system is not available, then the investigator or other study site staff reports an 
SAE to the appropriate Sponsor representative by telephone.
The Sponsor representative will advise the investigator/study site staff how to proceed. 
The reference documents for definition of expectedness/listedness are the IB for monalizumab 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
98 of 187
and the appropriate label for cetuximab. 
8.3.13
Pregnancy
All pregnancies and outcomes of pregnancy with conception dates following the first date of 
study intervention, including pregnancy in the partner of male participants, should be reported 
to AstraZeneca except if the pregnancy is discovered before the study participant has received 
any study intervention. 
8.3.13.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, IMP should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IMP under study 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
anomalies/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 anomaly) should be followed up and documented even if the participant 
was discontinued from the study.
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate Sponsor representatives within one day, ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is provided to the Sponsor Patient Safety data entry site within one or 5 calendar 
days for SAEs (see Section 8.3.12) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy.
8.3.13.2
Paternal Exposure 
Male participants should refrain from fathering a child or donating sperm during the study and 
for 4 months after the last dose of study intervention. 
Pregnancy of the participant’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 anomaly) occurring from the date of the first dose of study intervention 
until 4 months after the last dose of study intervention should, if possible, be followed up and 
documented in the Pregnancy Report Form. Consent from the partner must be obtained before 
the Pregnancy Report Form is completed.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
99 of 187
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the investigator must obtain the consent of the participant’s partner. The local study team 
should adopt the Master Pregnant Partner Form in line with local procedures/requirements and 
submit it to the relevant Regulatory Authority/IRB/IEC prior to use.
8.3.14
Medication Error
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate Sponsor representatives within one day, ie, immediately but 
no later than 24 hours of when he or she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is completed on the specific medication error eCRF within one (initial 
fatal/life-threatening or follow up fatal/life-threatening) or 5 (other serious initial and follow 
up) calendar days if there is an SAE associated with the medication error (see Section 8.3.1) 
and within 30 days for all other medication errors.
The definition of a medication error can be found in Appendix B. 
8.3.15
Management of IMP-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 IMP 
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 IMP along with appropriate continuing 
supportive care. If medically appropriate, dose modifications are permitted. 

All dose modifications should be documented with clear reasoning and documentation of 
the approach taken.
See Section 6.6, and Sections 8.3.15.1 and Section 8.3.15.2 below for dose modification 
guidance. 
All toxicities will be graded according to NCI CTCAE, Version 5.0.
8.3.15.1
Monalizumab
The monalizumab TMGs provide information for the management of immune-mediated 
reactions, infusion-related reactions, and non-immune mediated reactions that may be 
observed with monalizumab, with specific instructions for dose modifications (omissions and 
discontinuations) and treatment interventions. The most current version of the TMGs is 
provided to the investigative site as a supplement to the CSP and is maintained within the Site 
Master File. 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
100 of 187
Participants should be thoroughly evaluated, and appropriate efforts should be made to rule 
out neoplastic, infectious, metabolic, toxic, or other etiologic causes of the suspected 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 
monalizumab should be permanently discontinued (see Section 7.1 and the monalizumab 
TMGs). Following the first dose of monalizumab, subsequent administration of monalizumab 
can be modified based on toxicities observed as described in the TMGs. 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 monalizumab regimen by the reporting investigator.
Dose reductions are not permitted. In case of doubt, the investigator should consult with the 
Study Clinical Lead.
8.3.15.2
Cetuximab
Please refer to the local label (where available) for the management of AEs with cetuximab.  
In case of infusion-related reactions to cetuximab, manage as per local label (where available) 
for cetuximab and institutional guidance on management of infusion-related reactions. 
For management of AEs with cetuximab, refer to the local label. 
8.4
Overdose
Use of monalizumab or cetuximab in doses exceeding those specified in the protocol is 
considered to be an overdose. There is currently no specific treatment in the event of overdose 
of monalizumab, and possible symptoms of overdose are not established. If an overdose of 
cetuximab occurs, please refer to the local label (where available). 

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module
If an overdose on an AstraZeneca IMP occurs in the course of the study, the investigator or 
other site personnel inform appropriate AstraZeneca representatives immediately, but no later 
than 24 hours of when he or she becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all relevant 
information is provided to the Sponsor Patient Safety data entry site within 1 or 5 calendar 
days for overdoses associated with an SAE (see Section 8.3.12) and within 30 days for all 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
101 of 187
other overdoses.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the study 
specific laboratory manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on Handling of Human Biological 
Sample see Appendix D.
Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed/repatriated. 

Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalization or 
6 months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
consented for future analyses. 

Pharmacokinetic samples may be disposed of or anonymized by pooling. Additional 
analyses may be conducted on the anonymized, pooled PK samples to further 
evaluate and validate the analytical method. Any results from such analyses may be 
reported separately from the CSR.

Remaining ADA sample aliquots will be retained at AstraZeneca or its designee for a 
maximum of 15 years following issue of the CSR. Additional use includes but is not 
limited to further characterization of any ADAs, confirmation and/or requalification of 
the assay, as well as additional assay development work. The results from future analysis 
will not be reported in the CSR.
8.5.1
Pharmacokinetics

Blood samples will be collected for measurement of serum concentrations of 
monalizumab as specified in the SoA. 

Samples may be collected at additional time points during the study if warranted and 
agreed upon between the investigator and the Sponsor, eg, for safety reasons. The timing 
of sampling may be altered during the course of the study based on newly available data 
(eg, to obtain data closer to the time of peak or trough matrix concentrations) to ensure 
appropriate monitoring. 

Serum samples will be used to analyze the PK of monalizumab. Samples collected for 
analyses of monalizumab serum concentration may also be used to evaluate safety or 
efficacy aspects related to concerns arising during or after the study.

Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory 
Manual.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
102 of 187
8.5.1.1
Determination of Drug Concentration
Samples for determination of drug concentration in serum will be assayed by bioanalytical test 
sites operated by or on behalf of the Sponsor, using an appropriately validated bioanalytical 
method. Full details of the analytical method used will be described in a separate bioanalytical 
report.
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel [until the study has been unblinded].
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report.
8.5.2
Immunogenicity Assessments
Blood samples for determination of ADA in serum will be assayed by bioanalytical test sites 
operated by or on behalf of the Sponsor, using an appropriately validated bioanalytical 
method. Full details of the methods used will be described in a separate report.
Antidrug antibody samples may also be further tested for characterization of the ADA 
response.
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
8.6
Human Biological Sample Biomarkers
8.6.1
Collection of Mandatory Samples for Biomarker Analysis
Samples for biomarker research are required and will be collected from all participants in this 
study as specified in the SoA (Section 1.3). Details for sample collection, processing, and 
testing are provided in the Laboratory Manual.
At screening, all participants will be asked to provide formalin-fixed paraffin-embedded 
samples from archival or fresh tumor biopsy (acquired ≤ 3 months prior to screening). Tumor 
tissue beyond the 3-month window and up to 6 months old may be considered upon Sponsor 
consultation, provided that no intervening systemic regimen was ongoing at the time of 
sample collection (see the Laboratory Manual for more information). Archival tumor biopsies 
older than 6 months (> 6 months) or collected when previous treatments were still ongoing are 
not acceptable. Participants whose archival tumor tissue is unavailable or unsuitable for use 
will be asked to provide a fresh tumor biopsy. Fresh tumor biopsy should not be collected 
from lesions in proximity to cardiopulmonary, visceral, or vital neurovascular structures that 
could make the collection procedure high risk.
The screening tumor biopsy will be evaluated for the expression of HLA-E and NKp46 in the

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
103 of 187
TME by IHC. Associations between HLA-E and NKp46 expression and the participant’s 
radiologic response (RECIST 1.1) will be assessed. 
 
 
8.6.2
Collection of Optional Biomarker Samples
Optional samples may be collected for biomarker research as listed in the SoA (Section 1.3).
All participants will be asked to provide consent for collection of tumor biopsies once during 
treatment and at time of progression.
 
8.6.3
Other Study-related Biomarker Research
8.7
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
104 of 187
 
 
8.8
Medical Resource Utilization and Health Economics
For economic evaluation for payer submissions, it is necessary to capture healthcare resource 
utilization related to the intervention and the underlying disease. Within this study, the 
following will be captured:
!
!
Treatment-related to AEs (including the method of delivery of the treatment) captured in 
AE/SAE assessment module
!
Treatment not related to the study obtained in Concomitant Medications eCRF
8.9
Study Participant Feedback Questionnaire
Participants will have the option to complete the anonymized SPFQ assessing their clinical 
study experience (see Appendix J; assessment schedule is presented in Section 1.3). 
Participants who do not wish to complete this questionnaire may still participate in the study. 
Individual participant-level responses will not be reviewed by investigators. Responses would 
be used by the Sponsor to understand where improvements can be made in the clinical study 
process. This questionnaire does not collect data about the participant’s disease, symptoms, 
treatment effect, or AEs and therefore would not be study data.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
The formal statistical analysis will be performed to test the following main hypotheses for 
monalizumab plus cetuximab (Arm A) or placebo plus cetuximab (Arm B): 
!
H0: No difference between Arm A and Arm B
!
H1: Difference between Arm A and Arm B
9.2
Sample Size Determination
Approximately 624 participants will be randomized 2:1 to monalizumab plus cetuximab 
(Arm A) or placebo plus cetuximab (Arm B). Randomization will be stratified by HPV status 
(OPC HPV positive or HPV-unrelated), WHO/ECOG PS (0 or 1), or number of prior lines of 
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
105 of 187
therapy in the R/M setting (1 or 2). 
The study is powered to demonstrate superiority in the OS benefit of Arm A vs Arm B in 
HPV-unrelated participants with R/M SCCHN previously treated with an ICI.  
There will be two planned IAs and one FA for the study.
Interim Analysis 1 (IA1): Futility in OS will be evaluated when approximately 99 OS events 
have occurred across Arm A and Arm B in HPV-unrelated participants (25% information 
fraction) and randomized at least 2 months before the DCO for the futility analysis (ie, with a 
minimum follow-up of 2 months).
Interim Analysis 2 (IA 2): A hypothesis of  monalizumab plus cetuximab (Arm A) prolongs 
OS compared to placebo plus cetuximab (Arm B) will be tested at IA2 when approximately 
278 OS events have occurred across Arm A and Arm B in HPV-unrelated participants 
(approximately 70% information fraction, 56% maturity).
Final Analysis (FA): A hypothesis of improved OS will be tested at the final analysis when 
approximately 397 OS events have occurred across Arm A and Arm B in HPV-unrelated
participants (approximately 80% maturity). 
If the true OS HR is 0.72, corresponding to an approximate 3-month improvement in median 
OS compared to Arm B of 7.7 months, approximately 397 OS events in HPV-unrelated 
participants will provide approximately 86.5% power to demonstrate statistical significance at 
the 5% level (using a 2-sided test) for the FA. The 5% (2-sided) alpha for the OS analysis will 
be controlled at the IA2 and FA time points by using the Lan-DeMets (Lan and DeMets 1983)
spending function that approximates the O’Brien-Fleming approach, where the significance 
level applied depends upon the proportion of information (ie, information fraction) available 
at time of IA2. For example, if the information fraction for OS at IA2 is 70% then the 
two-sided significance levels of 1.48% and 4.55% will be applied to IA2 and FA for OS, 
respectively. The smallest detectable treatment difference in HR, ie, critical value, that could 
be statistically significant at the FA is 0.81. With a planned recruitment period of 30 months, it 
is expected that a total of 498 HPV-unrelated participants are needed in order to achieve 
397 OS events with a follow-up period of approximately 12 months. The 278 OS events for 
the IA2 are expected to be reached approximately 30.5 months after the randomization of the 
first participant.
The number of OPC HPV-positive participants will be closely monitored throughout the study 
and are planned to be capped at approximately 20%of the total sample size. With the 
assumption of 20% OPC HPV-positive participants in the overall participants, approximately 
624 randomized participants will be needed in overall population. Under the same assumption 
of effect size in HR and median OS stated above, approximately 498 OS events are expected 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
106 of 187
in all participants which will provide approximately 93.0% power to demonstrate statistical 
significance at the 5% level (using a 2-sided test) for the FA.
9.3
Populations for Analyses
Definitions of the analysis sets for each endpoint are provided in Table 9.
Table 9
Summary of Outcome Variables and Analysis Populations
Endpoint
Population
Efficacy data
OS
HPV-unrelated Analysis Set and Full Analysis Set
PFS
HPV-unrelated Analysis Set and Full Analysis Set
ORR a, DoR, and PRO b endpoints
HPV-unrelated Analysis Set and Full Analysis Set
Demography and other baseline characteristics
HPV-unrelated Analysis Set and Full Analysis Set
PK data
PK data
PK Analysis Set
Biomarker data
Biomarker data
HPV-unrelated Analysis Set and Full Analysis Set
Safety data
Exposure
Safety Analysis Set
AEs
Safety Analysis Set
Laboratory measurements
Safety Analysis Set
Vital signs and other safety
Safety Analysis Set
ADA data
ADA Analysis Set
a
ORR: measurable disease at baseline.
b
PRO: evaluable PRO measurements
ADA = antidrug antibody; AE = adverse event; DoR = duration of response; HPV = human papillomavirus; 
ORR = objective response rate; OS = overall survival; PFS = progression-free survival; 
PK = pharmacokinetic(s); PRO = patient-reported outcome.
9.3.1
HPV-unrelated Analysis Set
The primary population is the HPV-unrelated Analysis Set which will include all randomized 
participants who are either OPC HPV negative or non-OPC regardless of the HPV status. The 
HPV status will be determined by HPV status in the CRF and not the IVRS value. The 
HPV-unrelated Analysis Set will be used for summarizing baseline characteristics, all efficacy 
analyses, including PROs and biomarker analyses. Treatment arms will be compared on the 
basis of randomized study intervention, regardless of the intervention actually received. 
Participants who were randomized but did not subsequently go on to receive study 
intervention are included in the analysis in the treatment arm to which they were randomized.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
107 of 187
Analysis for ORR will be based on participants in the FAS who had measurable disease at 
baseline. Analysis of DoR will be based on participants in the FAS who achieved objective 
response.
9.3.2
Full Analysis Set
The FAS will include all randomized participants. The FAS will be used for summarizing 
baseline characteristics, all efficacy endpoints (including PROs) and biomarker analyses as 
secondary analyses. Treatment arms will be compared on the basis of randomized study 
intervention, regardless of the intervention actually received. Participants who were 
randomized but did not subsequently go on to receive study intervention are included in the 
analysis in the treatment arm to which they were randomized.
9.3.3
Safety Analysis Set
The SAF will consist of all participants who received any amount of study treatment. Safety 
data will not be formally analyzed but summarized descriptively using the SAF according to 
the intervention received; that is, erroneously-treated participants (eg, those randomized to 
Arm A but actually given Arm B intervention) will be summarized according to the study 
intervention they actually received.
9.3.4
Pharmacokinetic Analysis Set
All participants who receive at least one dose of 
 per the protocol for whom there 
is at least one reportable PK concentration and who do not violate or deviate from the protocol 
in ways that would significantly affect the PK analyses will be included in the PK Analysis 
Set. The population will be defined by the Study Clinical Lead, pharmacokineticist, and 
statistician prior to any PK analyses being performed.
9.3.5
ADA Analysis Set
The ADA Analysis Set will include all participants who have non-missing baseline ADA and 
at least one non-missing post-baseline ADA results. All major ADA analyses will be based on 
the ADA Analysis Set.
9.4
Statistical Analyses
Analyses will be performed by the Sponsor or its representatives. A comprehensive SAP will 
be developed and finalized before database lock and will describe the participant populations 
to be included in the analyses, and procedures for accounting for missing, unused, and 
spurious data. This section is a summary of the planned statistical analyses of the primary and 
secondary endpoints. Any deviations from this plan will be reported in the CSR.
9.4.1
General Considerations
A hypothesis of improved OS will be tested at IA2 when approximately 278 OS events have 
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
108 of 187
occurred across Arm A and Arm B in HPV-unrelated participants (approximately 56% 
maturity; IA2).
A hypothesis of improved OS will be tested at the final analysis when approximately 397 OS 
events have occurred across Arm A and Arm B in HPV-unrelated participants (approximately 
80% maturity; FA).
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 IMP, except for efficacy variables. For efficacy variables, baseline is defined 
as the last visit prior to randomization.
All data collected will be listed. Efficacy and PRO data will be summarized and analyzed 
based on the HPV-unrelated Analysis Set and will be repeated for FAS as a secondary 
analysis. PK data will be summarized and analyzed based on the PK Analysis Set. Safety data 
will be summarized on the SAF. Antidrug antibody data will be summarized on the ADA 
Analysis Set.
Results of all statistical analysis will be presented using a 95% CI and 2-sided p-value, unless 
otherwise stated.
The following table details which endpoints are to be subjected to formal statistical analysis, 
together with pre-planned sensitivity analyses, making it clear which analysis is regarded as 
primary for that endpoint.
Table 10
Pre-planned Statistical and Sensitivity Analyses to be Conducted for 
Efficacy and COA Endpoints
Endpoints analyzed
Notes
Overall survival (Primary) in 
HPV-unrelated Analysis Set
Primary confirmatory analysis
Stratified log-rank test adjusting for, WHO/ECOG PS and number of prior 
lines of therapy in the R/M setting for primary comparison of survival 
between randomized treatment arms
Sensitivity and supplemental analysis
Assessment of assumption of proportionality and stratified max combo test
Subgroup analysis using Cox model

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
109 of 187
Table 10
Pre-planned Statistical and Sensitivity Analyses to be Conducted for 
Efficacy and COA Endpoints
Endpoints analyzed
Notes
Overall survival (Secondary) in 
FAS
Secondary confirmatory analysis
Stratified log-rank test adjusting for HPV status, WHO/ECOG PS, number 
of prior lines of therapy in the R/M setting
Sensitivity and supplemental analysis
Subgroup analysis using Cox model
Progression-free survival 
(Secondary) in HPV-unrelated 
Analysis Set and FAS
PFS according to RECIST 1.1 based on investigator assessments will be 
analyzed as a secondary variable.  
Secondary confirmatory analysis 
For HPV-unrelated Analysis Set, stratified log-rank tests adjusting for 
WHO/ECOG PS and number of prior lines of therapy in R/M setting, using 
PFS according to RECIST 1.1 based on investigator assessments 
For FAS, stratified log-rank tests adjusting for HPV status, WHO/ECOG 
PS, number of prior lines of therapy in R/M setting, using PFS according to 
RECIST 1.1 based on investigator assessments
Sensitivity and supplemental analysis
Analysis using alternative censoring rules – attrition bias
Subgroup analysis using Cox proportional hazards model
Objective response rate 
(Secondary) in HPV-unrelated 
Analysis Set and FAS
For HPV-unrelated Analysis Set, logistic regression adjusted for 
WHO/ECOG PS, number or prior lines of therapy in the R/M setting, using 
tumor data according to RECIST 1.1 based on investigator assessment
For FAS, logistic regression adjusted HPV status, WHO/ECOG PS, 
number or prior lines of therapy in the R/M setting, using tumor data 
according to RECIST 1.1 based on investigator assessment
Duration of response (Secondary) 
in HPV-unrelated Analysis Set 
and FAS
KM plots based on the tumor data using investigator assessment of 
RECIST 1.1. Median DoR calculated from the KM curve.
Each scale/item of EORTC 
QLQ-C30 and QLQ-H&N35 
(Secondary) in HPV-unrelated 
Analysis Set and FAS
Summary and descriptive statistics
Unadjusted change from baseline
Key symptoms, functions, global 
health status/QoL of EORTC 
QLQ-C30 and QLQ-H&N35 
(Secondary) in HPV-unrelated 
Analysis Set and FAS
MMRM analysis (overall and by each visit)
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
110 of 187
Table 10
Pre-planned Statistical and Sensitivity Analyses to be Conducted for 
Efficacy and COA Endpoints
Endpoints analyzed
Notes
Time to symptom, function, or 
HRQoL deterioration of key COA 
endpoints using EORTC 
QLQ-C30 and QLQ-H&N35 
(Secondary) in HPV-unrelated 
Analysis Set and FAS
Stratified log-rank test
COA = clinical outcome assessment; CR = complete response; DCR = disease control rate; DoR = duration of 
response; EORTC = European Organisation for Research and Treatment of Cancer; 
 
; FAS = Full Analysis Set; HPV = human papillomavirus; 
HR = hazard ratio; HRQoL = health related quality of life; KM = Kaplan Meier; MMRM = mixed-effect model 
repeated measure; OS = overall survival; PFS = progression-free survival; 
 
; 
; PR = partial response; 
; 
PS = performance status; QLQ-C30 = 30-item Core Quality of Life Questionnaire; QLQ-H&N35 = 35-Item 
Head and Neck Cancer Quality of Life Questionnaire; QoL = quality of life; RECIST 1.1 = Response Evaluation 
Criteria in Solid Tumors, version 1.1; R/M = recurrent/metastatic; SAP = statistical analysis plan; SD = stable 
disease; WHO/ECOG = World Health Organization/Eastern Cooperative Oncology Group.
9.4.1.1
Methods for Multiplicity Control
Strong control of the FWER at 5% level (2 sided) across the testing of OS and PFS endpoints 
will be achieved through a combined approach of alpha allocation to the OS analyses (IA2 and 
the FA) via alpha spending function and a hierarchical testing procedure; that is, OS in FAS 
will be tested only if OS in HPV-unrelated analysis set met significance at IA2 or FA; PFS 
will be tested only if OS met statistical significance at IA2 or FA and PFS in FAS will be 
tested only if PFS in HPV-unrelated analysis set met statistical significance at IA2 or FA 
(Glimm et al 2010) (Figure 3). The IA2 for OS will be conducted when approximately 278 of 
the 397 expected OS events (ie, 70% information fraction) have occurred in HPV-unrelated 
participants. Using the Lan-DeMets spending function approximating O’Brien-Fleming 
boundaries, 2-sided significance levels of 0.0148 and 0.0455 will be applied to OS IA2 and 
FA, respectively (Lan and DeMets 1983). 
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
111 of 187
Figure 3
Graphical Presentation of the Propose Multiple-Testing Procedure at 
IA2 and FA
FA = final analysis; FAS = full analysis set; HPV = human papillomavirus; IA2 = interim analysis 2; 
OS = overall survival; PFS = progression-free survival.
Notes: At each analysis (IA2 and FA), PFS will be formally tested only if OS meets statistical significance.
Each statistical test will be performed only if the preceding test is statistically positive. At the 
time of OS IA2, the PFS data will be mature given its expected short median of 2.3 months in 
this population (Cohen et al 2019b, Ferris et al 2016, Rischin et al 2019) and it will be tested 
at 5% significance level. 
9.4.2
Efficacy 
9.4.2.1
Primary Endpoint
Derivation of primary endpoint
The primary endpoint OS is defined as the time from the date of randomization until date of 
death due to any cause. Any participant not known to have died at the time of analysis will be 
censored based on the last recorded date on which the participant was known to be alive.  
Note: Survival calls will be made following the date of DCO for the IAs or FA (these contacts 
should generally occur within 7 days of the DCO). If participants are confirmed to be alive or 
if the death date is post the DCO date, these participants will be censored at the date of DCO. 
Death dates may be found by checking publicly available death registries.
Primary analysis
Overall survival in the HPV-unrelated Analysis Set will be analyzed using a stratified log-rank 
test, adjusting for WHO/ECOG PS (0 or 1) and number of lines of prior therapy in the 
R/M setting (1 or 2). The HR and its CI will be estimated from a stratified Cox Proportional 
Hazards model. The effect in Arm A vs Arm B will be estimated by the HR together with its 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
112 of 187
corresponding CI and p-value (from stratified log-rank test). Kaplan-Meier plots will be 
presented by treatment arm. Summaries of the numbers and percentages of participants 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 arm.
Sensitivity analysis 
The assumption of proportionality will be assessed first by examining the 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, a stratified max-combo test will be used as a sensitivity 
analysis with the same stratification factors as the primary analysis. The max-combo test is 
based on an adaptive procedure, optimizing test statistics among log rank test (FH0,0) and the 
FH weighted log-rank test (Harrington and Fleming 1982) (FH0,1 and FH1 ,1) with alpha 
correction (Karrison 2016). It is a more robust and powerful test under NPH when compared 
to the log-rank test and is recommended by the Cross-Pharma Non-proportional Hazard 
Working Group in presence of NPH (Lin et al 2020). 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 will be investigated. In addition, the 
KM curve along with landmark analyses (eg, one-year OS rate) will also help in 
understanding the treatment benefit. 
Analysis of OS in FAS
Overall survival in the FAS will be analyzed similarly except that the stratified log-rank test 
will be adjusted for HPV status (OPC HPV positive or HPV-unrelated), WHO/ECOG PS (0 or 
1), and number of lines of prior therapy in the R/M setting (1 or 2).
Subgroup analysis
Subgroup analyses will be conducted comparing OS between Arm A vs Arm B in the 
following subgroups of the HPV-unrelated Analysis Set and FAS (but not limited to): 

Sex (male vs female)

Age at randomization (< 65 vs ≥ 65 years of age)

Human papillomavirus status (OPC HPV positive or HPV-unrelated) (applicable to FAS 
only)

WHO/ECOG PS (0 or 1) 

Number of prior lines of therapy in the R/M setting (1 or 2)

Race/ethnicity data (Asian vs non-Asian)

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
113 of 187
Other baseline variables may also be assessed if there is clinical justification or 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. Forest 
plots will be presented.
Additionally, for each subgroup, the HR (Arm A:Arm B) and 95% CI will be calculated from 
a Cox proportional hazards model with treatment as the only covariate. These will be 
presented on a forest plot including the HR and 95% CI from the overall population.  
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 and 
PFS.
9.4.2.2
Secondary Endpoints
The analysis of the secondary efficacy endpoints, PFS, ORR, and DoR, will be primarily 
based on the site investigator assessments using RECIST 1.1. 
All investigator RECIST 1.1 assessments, whether scheduled or unscheduled, will be included 
in the calculations. This is also regardless of whether a participant discontinues study 
intervention or receives another anticancer therapy.  
At each visit, participants 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 28 days prior to enrollment. If a 
participant has had a tumor assessment that cannot be evaluated, then the participant will be 
assigned a visit response of NE (unless there is evidence of progression in which case the 
response will be assigned as PD).
Please refer to Appendix G for the definitions of CR, PR, SD, and PD.
9.4.2.2.1
Progression-free Survival
Derivation of PFS
The secondary endpoint PFS will be defined as the time from randomization until progression, 
per RECIST 1.1 as assessed by the investigator at local site or death due to any cause, 
whichever occurs first, regardless of whether the participant withdraws from study 
intervention or receives another anticancer therapy prior to progression (ie, date of event or 
censoring – date of randomization + 1). Participants 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 participant progresses or dies after 2 or 
more consecutively missed visits, the participant will be censored at the time of the latest 
evaluable RECIST 1.1 assessment prior to the 2 missed visits. If the participant has no 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
114 of 187
evaluable visits or does 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 on 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 assessment/scan dates of the component that indicates 
progression.

When censoring a participant for PFS, the participant will be censored at the latest of the 
scan dates contributing to a particular overall visit assessment.
Analysis of PFS
The secondary endpoint PFS analysis will also be based on the programmatically derived 
RECIST 1.1 using the investigator tumor assessments. The analysis will be performed in both 
the HPV-unrelated Analysis Set and FAS using a stratified log-rank test, adjusting for HPV 
status (for FAS only), WHO/ECOG PS, and number of prior lines of therapy in the R/M 
setting. The effect of Arm A vs Arm B will be estimated by the HR together with its 
corresponding 95% CI and p-value.
Kaplan Meier plots of PFS will be presented by treatment arm. Summaries of the number and 
percentage of participants experiencing a PFS event and the type of event (RECIST 1.1 or 
death) will be provided along with median PFS for each treatment arm.
Sensitivity analysis of PFS
Sensitivity analyses will be performed to assess attrition bias by repeating the PFS analysis 
except that the actual PFS event times, rather than the censored times, of participants who 
progressed or died in the absence of progression immediately following 2 or more 
non-evaluable tumor assessments will be included. In addition, participants who take 
subsequent therapy prior to progression or death will be censored at their last evaluable 
assessment prior to taking the subsequent therapy. This analysis will be supported by a KM 
plot of the time to censoring where the censoring indicator of the PFS analysis is reversed.
Further sensitivity analysis may be documented in the SAP. 
Subgroup analysis
Subgroup analyses will be conducted comparing PFS (per RECIST 1.1 using investigator 
assessments) between Arm A and Arm B in the subgroups, as specified in Section 9.4.2.1.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
115 of 187
9.4.2.2.2
Objective Response Rate
Derivation of ORR
ORR is defined as the proportion of participants with measurable disease who have a 
confirmed CR or PR, as determined by the investigator at local site per RECIST 1.1. Data 
obtained up until progression, or the last evaluable assessment in the absence of progression, 
will be included in the assessment of ORR. Participants who discontinue study intervention 
without progression, receive a subsequent therapy, and then respond will not be included as 
responders in the ORR.  
Analysis of ORR
Objective response rate will be based on the programmatically-derived RECIST using the 
investigator tumor data. ORR will be compared between Arm A and Arm B using a logistic 
regression model, adjusting for the same factors as the primary endpoint (HPV status [for FAS 
only], WHO/ECOG PS, number of prior lines of therapy in the R/M setting). The results of 
the analysis will be presented in terms of an odds ratio together with its associated profile 
likelihood 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 in the subset of 
participants in the HPV-unrelated Analysis Set who had measurable disease at baseline. This 
analysis will be repeated for the subset of participants in the FAS who had measurable disease 
at baseline.
Summaries will be produced that present the number and percentage of participants with a 
tumor response (CR/PR). Overall visit response data will be listed for all participants (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.
9.4.2.2.3 
Duration of Response
Derivation of DoR
The secondary endpoint DoR (per RECIST 1.1 using investigator assessment) 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 participant does not progress following a response, 
then their DoR will be censored at the PFS censoring time. Duration of response will not be 
defined for those participants who do not have documented response.
Analysis of DoR
Kaplan Meier plots of DoR based on the investigator assessment of RECIST 1.1 will be 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
116 of 187
presented. Median DoR will also be summarized and calculated from the KM curve. Only 
participants who have a confirmed response will be included in this summary table. Swimmer 
plots that clearly show the profile of each participant who responds will also be produced.
9.4.2.2.4
Patient-reported Outcome: EORTC QLQ-C30
Scoring
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 measure of health 
status scale in the EORTC QLQ-C30 according to the EORTC QLQ-C30 Scoring Manual.  
Higher scores on the global measure of health status and functional scales indicate better 
health status/function, but higher scores on symptom scales represent greater symptom 
severity. 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.  
Analysis methods
A main PRO instrument identified in the secondary objectives are global health status/QoL, 
physical functioning, fatigue, pain, and appetite loss subscales of the EORTC QLQ-C30.
The primary assessment of global health status/QoL, physical functioning, or symptom will 
focus on comparing the mean change from baseline between treatment arms. The analysis 
population will be a subset of the HPV-unrelated Analysis Set, including all participants in the 
HPV-unrelated Analysis Set with an evaluable baseline assessment and at least one evaluable 
post-baseline assessment. Change from baseline will be analyzed using a mixed-model 
repeated measurements analysis of all the post-baseline scores. The model will include 
treatment arm, visit, and treatment by visit interaction as explanatory variables, and the 
baseline score and baseline score by visit as covariates. Adjusted mean change from baseline 
estimates per treatment arm and corresponding 95% CIs will be presented, along with an 
overall estimate of the treatment difference, 95% CI, and p-value.
Additional analyses will include time to deterioration. 
The analysis will be repeated for a subset of the FAS, including all randomized participants 
with an evaluable baseline assessment and at least one evaluable post-baseline assessment.
Details of all statistical analyses and appropriate sensitivity analyses will be described in full 
in the SAP. 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
117 of 187
9.4.2.2.5
Patient-reported Outcome: EORTC QLQ-H&N35
Scoring
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.
Analysis methods
Another main PRO instrument identified in the secondary objectives are from the 4-symptom 
scales/items in the QLQ-H&N35 (pain, swallowing, senses, and speech).
The primary assessment of symptoms will focus on comparing the mean change from baseline 
between treatment arms. The analysis population will be a subset of the HPV-unrelated
Analysis Set, including all participants in HPV-unrelated Analysis Set with an evaluable 
baseline assessment and at least one evaluable post-baseline assessment. Change from 
baseline will be analyzed using a mixed-model repeated measurements analysis of all the 
post-baseline scores. The model will include treatment arm, visit, and treatment by visit 
interaction as explanatory variables, and the baseline score and baseline score by visit as 
covariates. Adjusted mean change from baseline estimates per treatment arm and 
corresponding 95% CIs will be presented, along with an overall estimate of the treatment 
difference, 95% CI, and p-value.
Additional analyses will include time to deterioration. 
The analysis will be repeated for a subset of the FAS, including all randomized participants 
with an evaluable baseline assessment and at least one evaluable post-baseline assessment.
Details of all statistical analyses and appropriate sensitivity analyses will be described in full 
in the SAP. 
9.4.2.3
Exploratory Endpoints
9.4.2.3.1
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
118 of 187
9.4.2.3.2
9.4.2.3.3
9.4.2.3.4
9.4.3
Safety
9.4.3.1
Calculation or Derivation of Safety Variables
9.4.3.1.1
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 participants. Data from 
all cycles of treatment will be combined in the presentation of safety data. “On treatment” will 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
119 of 187
be defined as assessments between date of start dose and 90 days following discontinuation of 
IMP (ie, the last dose of monalizumab, cetuximab, or placebo). For AEs, on-treatment (or 
treatment-emergent) AEs will be defined as any AEs that started after dosing or prior to dosing 
and which worsen following exposure to the study treatment.
Adverse events observed up until 90 days following discontinuation of the IMP or until the 
initiation of the first subsequent therapy following discontinuation of treatment (whichever 
occurs first) will be used for the reporting of the AE summary tables. This will more 
accurately depict AEs attributable to study treatment only, as a number of AEs up to 90 days 
following discontinuation of the IMP are likely to be attributable to subsequent therapy. 
However, to assess the longer-term toxicity profile, AE summaries will also be produced 
containing AEs observed up until 90 days following discontinuation of the IMP (ie, without 
taking subsequent therapy into account). Any events in this period that occur after a 
participant has received further therapy for cancer (following discontinuation of study 
treatment) will be flagged in the data listings.
The SAF will be used for reporting of safety data.
A separate data listing of AEs occurring > 90 days after discontinuation of IMP will be 
produced. These events will not be included in AE summaries.  
9.4.3.1.2
Other 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/RR1/3, where RR is in seconds
Corrected calcium product 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)] × 0.02)
The denominator used in laboratory summaries will only include evaluable participants, 
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 participants would have 
both a pre-dose and at least 1 post-dose value recorded.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
120 of 187
!
If a CTCAE criterion does not consider changes from baseline to be evaluable, the 
participant need only have 1 post-dose value recorded.
The denominator in vital signs data should include only those participants with recorded data.
9.4.3.2
Analysis of safety variables
All safety analyses will be performed on the SAF. Safety and tolerability data will be 
presented by treatment arm based on actual treatment received.
Data from all cycles of treatment will be combined in the presentation of safety data. Adverse 
events (both in terms of Medical Dictionary for Regulatory Activities preferred terms and 
CTCAE grade) will be listed individually by participant. The number of participants 
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 produced.
Other safety data will be assessed in terms of physical examination, clinical chemistry, 
hematology, vital signs, WHO ECOG/PS, and ECGs. Exposure to monalizumab plus 
cetuximab combination therapy and cetuximab will be summarized. Time on study, dose 
delays/dose modifications of monalizumab and cetuximab will also be summarized. At the end 
of the study, appropriate summaries of all safety data will be produced, as defined in the SAP.
9.4.4
Other Analyses 
9.4.4.1
Healthcare Resource Use
The potential impact the disease and treatment have on healthcare resource use will be 
analyzed for the purposes of submissions to payers (eg, pricing and reimbursement 
agencies and health technology assessment bodies). Descriptive statistics (as appropriate, 
including means, median, counts and frequencies, standard deviation, interquartile range, 
skew, and range) will be provided for each treatment arm on the different types of hospital 
admissions, the length of stay for participants admitted to the hospital (eg, inpatient, 
emergency room, intensive care unit), as well as the participant’s primary sign or symptom. To 
support submissions to payers, additional analyses may be undertaken and will be outlined in 
a separate Payer Analysis Plan.
9.4.4.2
Pharmacokinetic Data
Monalizumab serum concentration data will be listed for each participant with monalizumab 
treatment and each dosing day. Summary will be provided for PK Analysis Set.
9.4.4.3
Immunogenicity Data
Immunogenicity results will be listed by participant, and a summary will be provided by the 
number and percentage of participant who develop detectable 
 
The immunogenicity titer will be listed for samples confirmed positive for the presence of 
  
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
121 of 187
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. A detailed plan 
will be written by the Sponsor Clinical Pharmacology group or designee.
9.4.4.4
Pharmacokinetic/Pharmacodynamic Relationships
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.
9.4.4.5
Biomarker Data
9.5
Interim Analyses 
Two IAs are planned as described below.
IA1: The first interim analysis will be performed when approximately 99 OS events have been 
observed in the HPV-unrelated participants (25% information fraction) in participants 
randomized at least 2 months before the DCO for the futility analysis (ie, with a minimum 
follow-up of 2 months). Based on enrollment assumptions, it is expected that this will occur 
approximately 19 months after randomization of the first participant. The objective of IA1 is 
to evaluate futility of the Arm A compared to Arm B in terms of OS in the HPV-unrelated 
participants. 
OS will be analyzed using a stratified Cox Proportional Hazards model as described in 
Section 9.4.2.1 and HR with its CI will be reported. The futility criteria are determined as 
observed HR at IA1 >
 which corresponds to 
 conditional power assuming future 
data is consistent with current IA trend. 
IA2: The second interim analysis will be performed when approximately 278 OS events have 
been observed in the study (56% maturity or 70% information fraction) in the HPV-unrelated 
population. Based on enrollment assumptions, it is expected that this will occur approximately 
30 months after randomization of the first participant.
The IA2 will evaluate the efficacy of Arm A compared to Arm B in terms of OS in the 
HPV-unrelated population (primary objective). 
The SAP will describe the planned IAs in greater detail.
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
122 of 187
9.6
Data Monitoring Committee
For details on the Independent Data Monitoring Committee, refer to Appendix A 5
9.7
Impact of COVID-19 on Data
Depending on the extent of any impact, summaries of data relating to participants diagnosed 
with COVID-19, and impact of COVID-19 on study conduct (in particular missed visits, 
delayed or discontinued study treatments, and other protocol deviations) may be generated. 
More detail will be provided in the SAP.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
123 of 187
Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines

Applicable ICH GCP Guidelines

Applicable laws and regulation

The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.

The Sponsor will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO but the accountability remains with the Sponsor.
Regulatory reporting requirements for SAEs

Prompt notification by the investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.

The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.

For all studies except those utilizing medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review and then file it along with the [IB or state other documents] and will notify the 
IRB/ IEC, if appropriate according to local requirements.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
124 of 187
A 2
Financial Disclosure
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.

Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants or their legally authorized representative will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center.

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.

If a participant declines to participate in a voluntary exploratory genetic research 
component of the study, there will be no penalty or loss of benefit to the participant and 
he/she will not be excluded from other aspects of the study.

If a participant’s partner becomes pregnant during or within 90 days after the last dose of 
study intervention, the partner is asked to sign the “Adult Study Informed Consent Form 
for Pregnant Partners of Study Patients” and provide information about the pregnancy 
accordingly. 
Participants who are rescreened will resign and date their original ICF(s), next to their original 
signature and date, or according to local or site-specific procedures.
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples. The investigator or authorized 
designee will explain to each participant the objectives of the analysis to be done on the 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
125 of 187
samples and any potential future use. Participants will be told that they are free to refuse to 
participate in any optional samples or the future use and may withdraw their consent at any 
time and for any reason during the retention period. 
A 4
Data Protection

Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.

The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the informed consent 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees Structure
The safety of all Sponsor clinical studies is closely monitored on an on-going basis by 
Sponsor representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the CSP and letters to investigators.
An IDMC comprised of independent experts will be convened and will meet approximately 
6 months after the study has started or after the first 60 participants have been randomized, 
whichever occurs first. The IDMC will review safety assessments and make recommendations 
to continue, amend, or stop the study based on safety findings. The committee will meet 
approximately every 6 months thereafter. For the IAs, the IDMC will review unblinded 
interim data and inform the Sponsor whether the interim boundaries specified in Section 9.5
are met. The IDMC will inform the Sponsor of its recommendation according to the IDMC 
Charter.  
Full details of the IDMC procedures, processes, and IAs can be found in the IDMC Charter. 
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the study results when they are available. 
The clinical study and/or summary of study results may also be available on other websites 
according to the regulations of the countries in which the study is conducted.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
126 of 187
A 7
Data Quality Assurance

All participant data relating to the study will be recorded on eCRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the relevant study plans.

The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

The Sponsor assumes accountability for actions delegated to other individuals (eg, 
CROs).

Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor.
A 8
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.

Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
127 of 187
A 9
Study and Site Start and Closure
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant(s) in the study and should 
assure appropriate participant therapy and/or follow-up.
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.

The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
128 of 187
Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a patient or clinical study 
participant administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom (eg, nausea, chest pain), or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered.
B 2
Definitions of Serious Adverse Event
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
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. 

Is a congenital anomaly or birth defect

Is an important medical event that may jeopardize the participant or may require medical 
treatment to prevent one of the outcomes listed above.
AEs for malignant tumors reported during a study should generally be assessed as Serious 
AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be 
used. In certain situations, however, medical judgement on an individual event basis should be 
applied to clarify that the malignant tumor event should be assessed and reported as a 
Non-Serious AE. For example, if the tumor is included as medical history and progression 
occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumor, the AE may not fulfill the attributes for being assessed as Serious, although 
reporting of the progression of the malignant tumor as an AE is valid and should occur. Also, 
some types of malignant tumors, which do not spread remotely after a routine treatment that 
does not require hospitalization, may be assessed as Non-Serious; examples in adults include 
Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.
The above instruction applies only when the malignant tumor event in question is a new 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
129 of 187
malignant tumor (ie, it is not the tumor for which entry into the study is a criterion and that is 
being treated by the IMP under study and is not the development of new or progression of 
existing metastasis to the tumor under study). Malignant tumors that – as part of normal, if 
rare, progression – undergo transformation (eg, Richter's transformation of B cell chronic 
lymphocytic leukemia into diffuse large B cell lymphoma) should not be considered a new 
malignant tumor.
Life threatening
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
participant’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 participant was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study.
Important medical event or medical treatment
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 participant or may 
require medical treatment to prevent one 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 iv 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 anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalization

Development of drug dependency or drug abuse

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
130 of 187
Intensity rating scale
The grading scales found in the revised NCI CTCAE, Version 5.0 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 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 Appendix B 2. 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 not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2.
B 3
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.

Time Course. Exposure to suspect drug. Has the participant 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, other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? The Sponsor 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?

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
131 of 187

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 no available facts or arguments to suggest a 
causal relationship, 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.
B 4
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the participant 
or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error. 

Occurred

Was identified and intercepted before the participant received the drug

Did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed eg, kept in the fridge when it should be at room temperature 

Wrong participant received the medication (excluding IRT errors)

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
132 of 187

Wrong drug administered to participant (excluding IRT errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT - including those which lead to one of the above 
listed events that would otherwise have been a medication error 

Participant accidentally missed drug dose(s) eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
133 of 187
Appendix C
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis, including COVID-19 Outbreak
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
participants become infected with SARS-CoV-2 or similar pandemic infection) during which 
participants may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
agreement from the sponsor.
C 1
Reconsent of Study Participants During Study Interruptions
During study interruptions, it may not be possible for the participants to complete study visits 
and assessments on site and alternative means for carrying out the visits and assessments may 
be necessary, eg, remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Sections C 2 to C 4. Local and regional regulations and/or guidelines regarding 
reconsent of study participants should be checked and followed. Reconsent may be verbal if 
allowed by local and regional guidelines (note, in the case of verbal reconsent the ICF should 
be signed at the participant’s next contact with the study site). Visiting the study sites for the 
sole purpose of obtaining reconsent should be avoided. 
C 2
Rescreening of Participants to Reconfirm Study Eligibility 
Additional rescreening for screen failure due to study disruption can be performed in 
previously screened participants. The investigator should confirm this with the designated 
Study Clinical Lead.
In addition, during study disruption there may be a delay between confirming eligibility of a 
participants and either enrolment into the study or commencing of dosing with IMP. If this 
delay is outside the screening window specified in Section 6.3.1 the participant will need to be 
rescreened to reconfirm eligibility before commencing study procedures. This will provide 
another opportunity to re-screen a participant in addition to that detailed in Section 5.4. The 
procedures detailed in Section 6.3.1 must be undertaken to confirm eligibility using the same 
randomization number as for the participant.
C 3
Telemedicine Visit to Replace On-site Visit (Where Applicable)
In this appendix the term telemedicine visit refers to remote contact with the participants using 
telecommunications technology including phone calls, virtual or video visits, and mobile 
health devices.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
134 of 187
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the participants will allow AEs and concomitant medication to be reported and 
documented.
C 4
Data Capture During Telemedicine or Home/Remote Visits
Data collected during telemedicine or home/remote visits will be captured by the qualified 
HCP from the study site or TPV service in the source documents, or by the participant 
themselves.
C 5
COVID-19 Risk Assessment 
The safety of participants is of primary importance. Any potential risks of participating in the 
study, particularly with the added challenges due to COVID-19 outbreak, should be weighed 
against the anticipated benefit (see also Principle 2.2 of ICH GCP). Investigators are advised 
to use clinical judgment in determining infection prevention precautions for study participants.
The emergence of SARS-CoV-2 presents a potential safety risk for cancer patients. 
Participants enrolling in this study may require more frequent visits to the site for study 
treatment administration and for study assessments compared to participants receiving 
standard of care. Therefore, several risk mitigation factors have been implemented related to 
study conduct during the COVID-19 outbreak, for patient management in an event of 
COVID-19, and actions to be taken on study treatment (see Section C 8). With these measures 
in place, it is considered that the anticipated potential benefits for the participants enrolled in 
this study outweigh the potential risks. All implemented measures prioritize trial participant 
safety and data validity; in case these two conflict with each other, trial participant safety 
should always prevail (see also European Medicines Agency Guidance on the management of 
clinical trials during the COVID-19 [coronavirus] pandemic [EMA 2020]). 
Notably, participants with active COVID-19 infection confirmed by local laboratory testing
will not be eligible for study enrolment (see CSP Section 5.2, Exclusion Criterion 11). 
C 6
Potential Risks during COVID-19
Every effort should be made to follow the CSP. Section C 9 provides a dose modification and 
management plan for participants with confirmed or suspected COVID-19 who are being 
treated with IMP (monalizumab/placebo and cetuximab). The risk-benefit assessment should 
be carefully considered for each participant enrolling in the study based on the known safety 
risks related to COVID-19, individual needs, and local guidelines and restrictions. 
Investigators must continue to use their best clinical judgment in determining the most optimal 
care for participants and utmost diligence in determining their eligibility for study 
participation, continued study treatment, and overall assessment of benefit/risk of study 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
135 of 187
treatment or participation.
The sponsor must be promptly notified of a site’s inability to perform study activities due to
COVID-19 outbreak in order to minimize any potential risks.
C 7
New Participant Enrolment
Study sites may continue to recruit new participants into the study provided the following 
activities to preserve study integrity can be met:

Upon discussion with the site monitor, the study site has confirmed the ability to enroll 
and manage new participants effectively and in compliance with the protocol.

Data will continue to be entered into the eCRF and queries resolved in a timely manner. 
Per CSP Exclusion Criterion 11 (see CSP Section 5.2), participants with uncontrolled 
intercurrent illness, including but not limited to, ongoing or active infection are not eligible for 
the study participation and hence such participants (including those who have confirmed 
COVID-19) should not be included for study participation.
C 8
Study Treatment Administration
If an AE or SAE is associated with COVID-19, the investigator should determine whether the 
participants’ treatment with investigational product should continue, be interrupted, or be 
discontinued in accordance with the CSP.
Adverse events, SAEs, cycle delays and/or treatment suspensions associated with COVID-19 
along with logistical issues should be reported according to the eCRF Completion Guidelines. 
For dosing discontinuations, where applicable, the dosing discontinuation guidelines should 
be followed, and the End of Treatment Form(s) completed
C 9
Ongoing Participants
Participants receiving study intervention should continue to undergo safety assessments prior 
to dosing in accordance with the CSP. In case it is not feasible to perform safety assessments, 
study intervention should be interrupted until such assessments can be completed.
C 9.1
If a Participant has an Event Suspected to be COVID-19
Delay or omit study intervention as appropriate and test for COVID-19 per local health 
authority or institutional guidance. 

Signs and symptoms of COVID-19 include but are not limited to new onset of fever, 
new or worsening cough, shortness of breath, difficulty breathing and sometimes 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
136 of 187
abnormal chest imaging and may be similar to those of an imAE. Toxicity 
management guidelines for imAEs should be considered if the symptoms are 
consistent with an imAE.

In accordance with the CSP and the TMGs for imAEs, thorough evaluation should be 
performed to accurately identify the underlying pathology in case an AE is 
encountered for a participant. 

If COVID-19 is ruled out, study intervention may be resumed per the CSP and TMGs 
(if applicable).

If COVID-19 is confirmed or diagnosis still suspected after evaluation, manage 
COVID-19 per local guidance until full recovery. 
C 9.2
Participants with Confirmed COVID-19
Participants with confirmed COVID-19 (by local laboratory testing and/or combination of 
key symptoms) should have study intervention withheld and COVID-19 managed per local 
guidance.
In case of confirmed COVID-19 and a simultaneous imAE requiring treatment, investigators 
are advised to apply clinical judgement regarding the use of corticosteroids as per the 
monalizumab TMGs. This includes also the consideration of alternate immunosuppressive 
agents other than corticosteroids for imAE management, depending on the individual 
participant’s presentation (Curigliano et al 2020).
C 9.3
Restarting Study Intervention
Study intervention must not be resumed until recovery from COVID-19 (eg, confirmed by 
imaging, lab testing and/or absence of symptoms) and COVID-19-specific treatment has been 
completed per local guidance.
The Study Clinical Lead should be contacted if any additional guidance or clarification is 
needed.
C 9.4
Vaccination Against COVID-19
Protocol restrictions applying to live attenuated vaccines are relevant for live attenuated 
COVID-19 vaccines as well. Investigators should apply their discretion assessing the 
risk-benefit of other types of COVID-19 vaccines for participants in clinical trials. Ideally, 
administration of the vaccine should be done on a different day other than the day of study 
drug administration to differentiate any potential AEs seen from the vaccine and study drug. 
The administration of the vaccine and any potential AEs associated with the vaccine are to be 
documented on the concomitant medication and AE eCRFs, respectively.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
137 of 187
C 10
References
Curigliano et al 2020 
Curigliano G, Banerjee S, Cervantes A, Garassino M, Garrido P, Girard N et al. Managing 
cancer patients during the COVID-19 pandemic: an ESMO multidisciplinary expert 
consensus. Ann Oncol 2020;31(10):1320-35.
EMA 2020
EMA, Clinical Trials Facilitation and Coordination Group, European Commission. Guidance 
on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic,
Version 2, 27 March 2020. Available from: URL: 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf. Cited date: 17 December 2020.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
138 of 187
Appendix D
Handling of Human Biological Samples
D 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each center keeps full traceability of collected biological samples from the 
participants while in storage at the center until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during the 
remainder of the sample life cycle.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
D 2
Withdrawal of Informed Consent for Donated Biological Samples 
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples are already 
analyzed, AstraZeneca is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The investigator:

Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate.

Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented

Ensures that the participant and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organization(s) holding the samples is/are informed about the 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
139 of 187
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action documented and study site notified.
D 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B, or Exempt
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. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814. Infectious substances which cause disease only in animals must be assigned to 
UN 2900:
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, C, D, and E viruses. 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 - Substances that do not contain infectious substances or substances that are unlikely 
to cause disease in humans or animals are not subject to these regulations unless they meet the 
criteria for inclusion in another class.

Clinical study samples will fall into Category B or exempt under IATA regulations

Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).

Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
140 of 187
Appendix E
E 1
E 2
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
141 of 187
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
142 of 187
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
143 of 187
Appendix F
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
F 1
Introduction
This appendix describes the process to be followed in order to identify and appropriately 
report PHL cases and HL cases. It is not intended to be a comprehensive guide to the 
management of elevated liver biochemistries. 
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a participant meets 
potential PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible PHL events.
The investigator participates, together with the Sponsor clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than DILI caused by the IMP. 
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
F 2
Definitions
Potential Hy’s Law
Aspartate aminotransferase or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN at any point 
during the study following the start of study medication irrespective of an increase in ALP. 
Hy’s Law
Aspartate aminotransferase 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 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
144 of 187
elevations in transaminases and TBL must occur.
F 3
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 participant who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3 × ULN

AST ≥ 3 × ULN

TBL ≥ 2 × ULN
Local laboratories being used:
The investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
Determine whether the participant meets PHL criteria (see Section F 2 Definitions within this 
appendix for definition) by reviewing laboratory reports from all previous visits
Promptly enter the laboratory data into the laboratory eCRF
F 4
Follow-up
F 4.1
Potential Hy’s Law Criteria Not Met
If the participant does not meet PHL criteria the investigator will:

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the CSP.
F 4.2
Potential Hy’s Law Criteria Met
If the participant does meet PHL criteria the investigator will:

Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (See Section F 6)

Notify the Sponsor representative who will then inform the central study team 

Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
PHL; serious criteria ‘important medical event’ and causality assessment ‘yes/related’ 
according to CSP process for SAE reporting.

For participants that met PHL criteria prior to starting IMP, the investigator is not required 
to submit a PHL SAE unless there is a significant change # in the participant’s condition

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
145 of 187

The Study Clinical Lead contacts the investigator, to provide guidance, discuss and agree 
an approach for the study participants’ follow-up (including any further laboratory 
testing) and the continuous review of data

Subsequent to this contact the investigator will:

Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required.

Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Clinical Lead. 

Complete the three Liver eCRF Modules as information becomes available 
# A ‘significant’ change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST, or TBL) 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 Clinical Lead if there is any uncertainty.
F 5
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.
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Clinical Lead 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, to ensure timely analysis and reporting to health authorities within 15 calendar days from 
date PHL criteria was met. The Sponsor Global Clinical Lead or equivalent 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.
Where 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 eCRF

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
146 of 187

If the alternative explanation is an AE/SAE: update the previously submitted PHL SAE 
and AE eCRFs accordingly with the new information (reassessing event term; causality 
and seriousness criteria) following the Sponsor’s 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:

Send updated SAE (report term ‘Hy’s Law’) according to the Sponsor’s 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 15 calendar days 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:

Provides any further update to the previously submitted SAE of PHL, (report term now 
‘Hy’s Law case’) ensuring causality assessment is related to IMP and seriousness criteria 
is medically important, according to CSP process for SAE reporting.

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 still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
F 6
Actions Required When Potential Hy’s Law Criteria are Met 
Before and After Starting Study Treatment
This section is applicable to participants 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 participants’ condition# compared with 
the last visit where PHL criteria were met#

If there is no significant change no action is required

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
147 of 187

If there is a significant change, notify the Sponsor representative, who will inform the 
central Study Team, then follow the subsequent process described in Section F 4.2
F 7
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a participant 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. 
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 eg, chronic or progressing malignant disease, severe infection, 
or liver disease or did the participant meet PHL criteria prior to starting study treatment 
and at their first on-study treatment visit as described in Section F 6?
If No: follow the process described in Section F 4.2 for reporting PHL as an SAE.
If Yes: Determine if there has been a significant change in the participant’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 Section F 4.2 for reporting 
PHL as an SAE
# A ‘significant’ change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST, or TBL) 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 Clinical Lead if there is any uncertainty.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
148 of 187
F 8
Laboratory Tests
These are recommended laboratory tests to be performed in cases of PHL. Any test results 
need to be recorded in the eCRF. 
Hy’s Law Laboratory Tests
Additional standard chemistry and coagulation 
tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HBV DNA
IgG anti-HCV
HCV RNA a
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-transferrin)
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-liver/kidney microsomal Ab (Anti-LKM)
Anti-smooth muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
a
HCV RNA is only tested when IgG anti-HCV is positive or inconclusive.
F 9
References
Aithal et al, 2011
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDA Guidance for Industry, July 2009
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from; https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
149 of 187
Appendix G
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 RECIST 1.1 guidelines (Eisenhauer et al 2009). 
Investigator assessments will use the RECIST 1.1 guidelines described in this appendix. 
Additional special guidance is provided for evaluation of scans collected after a RECIST 1.1-
defined radiological progression.
Imaging Modalities and Acquisition Specifications for RECIST 1.1
A summary of the imaging modalities that can be used for tumor assessment of TLs, NTLs, 
and NLs is provided in Table 11.
Table 11
Summary of imaging modalities for tumor assessment
Target lesions 
Non-target lesions
New lesions
CT
MRI
CT
MRI
Plain X-ray
Chest X-ray
CT
MRI
Plain X-ray
Chest X-ray
Bone scan (Scintigraphy)
FDG-PET/CT
CT = computed tomography; FDG-PET/CT = 18F-Fluoro-deoxyglucose positron emission tomography/CT; 
MRI = magnetic resonance imaging.
CT and MRI 
Computed tomography with iv contrast is the preferred imaging modality (although MRI with 
iv contrast is acceptable if CT is contraindicated) to generate reproducible anatomical images 
for tumor assessments (ie, for measurement of TLs, assessment of NTLs, and identification of 
NLs). It is essential that the same correct imaging modality, image acquisition parameters (eg, 
anatomic coverage, imaging sequences, etc), imaging facility, tumor assessor (eg, radiologist), 
and method of tumor assessment (eg, RECIST 1.1) are used consistently for each participant 
throughout the study. The use of the same scanner for serial scans is recommended, if 
possible. It is important to follow the image collection/tumor assessment schedule as closely 
as possible (refer to the SoA; Section 1.3), and this on-study imaging schedule MUST be 
followed regardless of any delays in dosing or missed imaging visits. If an unscheduled 
assessment is performed (eg, to investigate clinical signs/symptoms of progression) and the 
participant has not progressed, every attempt should be made to perform the subsequent scan 
acquisitions at the next scheduled imaging visit.
Due to its inherent rapid acquisition (seconds), CT is the imaging modality of choice. Body 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
150 of 187
scans should be performed with breath-hold scanning techniques, if possible. Therefore, CT of 
the chest is recommended over MRI due to significant motion artifacts (eg, heart, major blood 
vessels, breathing) associated with MRI. MRI has excellent contrast and spatial and temporal 
resolutions; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. The modality used at follow-up should be the same as 
was used at baseline, and the lesions should be measured/assessed on the same pulse 
sequence. In general, local oncology diagnostic imaging parameters are applied for scan 
acquisition. It is beyond the scope of this appendix to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases.
The most critical CT and MRI image acquisition parameters for optimal tumor evaluation are 
anatomic coverage, contrast administration, slice thickness, and reconstruction interval.
a.  Anatomic coverage: Optimal anatomic coverage for most solid tumors is the 
chest-abdomen (-pelvis). Coverage should encompass all areas of known predilection for 
metastases in the disease under evaluation and should additionally investigate areas that may 
be involved based on signs and symptoms of individual participants. Because a lesion later 
identified in a body part not scanned at baseline would be considered as a new lesion 
representing disease progression, careful consideration should be given to the extent of 
imaging coverage at baseline and at subsequent follow-up time points. This will enable better 
consistency not only of tumor measurements but also identification of new disease.
Required anatomical regions to be imaged for assessment of tumor burden (TLs and/or NTLs) 
at baseline and follow-up visits vary according to the study, and these time points are specified 
in the SoA (Section 1.3). Examples include the following:

Intravenous contrast-enhanced CT of chest-abdomen (including the entire liver and both 
adrenal glands) (-pelvis)

Non-contrast CT of chest and IV contrast-enhanced abdomen (including the entire liver 
and both adrenal glands) (-pelvis)

Intravenous contrast-enhanced CT or MRI of the head and neck

Intravenous contrast-enhanced MRI (preferred) or CT of the brain
For chest-abdomen (-pelvis) imaging, the following are scanning options in decreasing order 
of preference, with additional options (2 to 4) for consideration when participants have 
sensitivity to iv contrast or have compromised renal function:
1
Chest-abdomen (-pelvis) CT with iv CT contrast (most preferred)
2
Chest CT without iv contrast + abdomen (-pelvis) MRI with IV MRI contrast, if CT iv 
contrast (iodine based) is medically contraindicated at any time during the study

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
151 of 187
3
Chest-abdomen (-pelvis) CT without iv contrast, if both iv CT and MRI contrast are 
medically contraindicated or the participant has compromised renal function
4
Chest-abdomen (-pelvis) MRI with iv MRI contrast, if CT cannot be performed at any 
time during the study
b.  Intravenous contrast administration: Optimal visualization and measurement of
metastases in solid tumors require consistent administration (dose and rate) of iv contrast as 
well as timing of scanning. An adequate volume of a suitable contrast agent should be given 
so that the tumor lesions are demonstrated to best effect and a consistent method is used on 
subsequent examinations for any given patient. Oral contrast is recommended to help visualize 
and differentiate structures in the abdomen and pelvis.  
c.  Slice thickness and reconstruction interval: It is recommended that CT or MRI scans be 
acquired/reconstructed as contiguous (no gap) slices with ≤ 5-mm thickness throughout the 
entire anatomic region of interest for optimal lesion measurements. Exceptionally, particular 
institutions may perform medically acceptable scans at slice thicknesses > 5 mm. If this 
occurs, the minimum size of measurable lesions at baseline should be twice the slice thickness 
of the baseline scans.
For CT scans, all window settings should be included in the assessment, particularly in the 
thorax where lung and soft tissue windows should be considered. When measuring lesions, the 
TL should be measured on the same window setting for repeated examinations throughout the 
study.  
Chest X-ray
Chest X-ray assessment will not be used for the assessment of TLs. Chest X-ray can, however, 
be used to assess NTLs and to identify the presence of NLs. However, there is preference that 
a higher resolution modality, such as CT, be used to confirm the presence of NLs.
Plain X-ray 
Plain X-ray may be used as a method of assessment for bone NTLs and to identify the 
presence of new bone lesions.  
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 NTLs and followed by the same method per baseline 
assessment (CT, MRI, or X-ray).  
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 may be recorded in case positive hot-spots 
appear on a bone scan that were not present on a previous bone scan; however, a newly 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
152 of 187
observed equivocal hot-spot on a bone scan that cannot be verified with correlative imaging 
(CT, MRI, or X-ray) of the same anatomical region shall not be the only trigger for a PD 
assessment at that time point.  
FDG-PET/CT
1FDG-PET/CT scans may be used as a method for identifying new lesions for RECIST 1.1 
assessments according to the following algorithm: NLs will be recorded where there is 
positive FDG uptake1 not present on baseline or prior FDG-PET scan or in a location 
corresponding to a NL on a companion CT/MRI collected close in time to the FDG-PET scan. 
The PET portion of the PET/CT introduces additional data that may bias an investigator if it is 
not routinely or serially performed. Therefore, if there is no baseline or prior FDG-PET scan 
available for comparison, and no evidence of NLs on companion CT/MRI scans, then follow-
up CT/MRI assessments should continue as per the regular imaging schedule to verify the 
unequivocal presence of NLs.
At present, low-dose or attenuation correction CT portions of a combined FDG-PET/CT scan 
are of limited use in anatomically based efficacy assessments, and it is therefore suggested 
that they should not substitute for dedicated diagnostic contrast-enhanced CT scans for tumor 
measurements by RECIST 1.1. In exceptional situations, if a site can document that the CT 
performed, as part of a PET/CT examination, is of identical diagnostic quality (with iv 
contrast) to a dedicated diagnostic CT scan, then the CT portion of the PET/CT can be used 
for RECIST 1.1 tumor assessments. Caution that this is not recommended because the PET 
portion of the CT introduces additional (PET) data that may bias an investigator if it is not 
routinely or serially performed.
Ultrasound 
Ultrasound examination will not be used for RECIST 1.1 assessment of tumors as it is not a 
reproducible acquisition method (operator dependent), is subjective in interpretation, and may 
not provide an accurate assessment of the true tumor size. Tumors identified by ultrasound 
will need to be assessed by correlative CT or MRI anatomical scan.
                                               
1
A positive FDG-PET scan lesion should be reported only when an uptake (eg, SUV) greater than twice that of the surrounding tissue or liver is observed.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
153 of 187
Other Tumor Assessments
Clinical examination 
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will 
not be used for RECIST 1.1 assessments. Tumors identified by clinical examination will need 
to be assessed by correlative CT or MRI anatomical scans.
Endoscopy and laparoscopy 
Endoscopy and laparoscopy will not be used for tumor assessments as they are not validated 
in the context of tumor assessment.
Histology and cytology
Histology or tumor markers on tumor biopsy samples will not be used as part of the tumor 
response assessment as per RECIST 1.1.  
Results of cytological examination for the neoplastic origin of any effusion (eg, ascites, 
pericardial effusion, and pleural effusion) that appears or worsens during the study will not be 
used as part of the tumor response assessment as per RECIST 1.1.  
Furthermore, an overall assessment of CR (all other disease disappears/reverts to normal) 
would be changed to PR if an effusion remains present radiologically.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
154 of 187
Measurability of Tumor Lesions at Baseline
RECIST 1.1 measurable lesions at baseline
A tumor lesion that can be accurately measured at baseline as ≥ 10 mm in the longest diameter 
nor non-nodal lesions or ≥ 15 mm in short axis2 diameter for lymph node lesions with iv 
contrast-enhanced CT or MRI and that is suitable for accurate repeated measurements.
Non-measurable lesions at baseline

Truly non-measurable lesions include the following:

Bone lesions (see exception below for soft tissue component)

Leptomeningeal disease

Ascites, pleural effusion, or pericardial effusion

Inflammatory breast disease

Lymphangitic involvement of skin or lung

All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10-mm to < 15-mm short axis diameter at baseline3)

Previously irradiated lesions 4
This study allows a previously irradiated lesion as a TL if there has been demonstrated 
progression in the lesion and it meets reproducible measurability and minimum size 
requirements and if this is the only lesion available. 

Brain metastasis
Special considerations regarding lesion measurability at baseline
                                               
2
The short axis is defined as the longest in-plane axis perpendicular to the long axis.
3
Lymph nodes with <10-mm short axis diameter are considered non-pathological and should not be recorded 
or followed as NTLs.
4
Localized post-radiation changes that affect lesion size may occur.  Therefore, lesions that have been 
previously irradiated are typically considered non-measurable and as NTL at baseline and followed up as 
part of the NTL assessment.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
155 of 187

Bone lesions

Bone scan, PET scan, or plain X-ray are not considered adequate imaging techniques 
to measure bone lesions; however, these techniques can be used to confirm the 
presence or disappearance of bone lesions.

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 lesions thought to represent 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 participant, these should be selected over cystic 
lesions as TLs.
RECIST 1.1 TL selection at baseline
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 TLs at baseline. Target lesions should be selected on the basis of their 
size (longest diameter for non-nodal lesions or short axis diameter 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 that can be measured reproducibly 
should be selected.
Lymph nodes, in any location (local/regional and distant), are collectively considered as a 
single organ, with a maximum of 2 lymph nodes as TLs. A bilateral organ (eg, adrenal glands), 
a segmented organ (eg, liver), or a multilobed organ (eg, lung) is each considered as a single 
organ.
The site and location of each TL should be documented, as well as the longest axis diameter 
for non-nodal lesions (or short axis diameter for lymph nodes). All measurements should be 
recorded in millimeters. At baseline, the sum of the diameters for all TLs will be calculated 
and reported as the baseline sum of diameters. At follow-up visits, the sum of diameters for all 
TLs will be calculated and reported as the follow-up sum of diameters.
Special cases for TL assessment at baseline

For TLs 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 
diameter.  

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
156 of 187

When lymph nodes are coalesced and no longer separable in a conglomerate mass, the 
maximal short-axis diameter of the coalesced mass should be recorded. Non-nodal lesions 
that coalesce should similarly be assessed by the long-axis diameter.

Tumor lesions selected for fresh screening biopsy should not be selected as TLs, unless 
imaging occurred at least approximately 2 weeks after biopsy, allowing time for healing.

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 diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as an NL.
RECIST 1.1 NTL selection at baseline
All other lesions, including non-measurable lesions and surplus measurable lesions, not 
recorded as TLs should be identified as NTLs at baseline. Measurements of these lesions are 
not required, but the presence or absence of each should be noted throughout follow-up.
Evaluation of Tumor Response and Progression
RECIST 1.1 TL assessment at follow-up
This section defines the criteria used to determine objective tumor visit response for 
RECIST 1.1-defined TLs. The imaging modality, location, and scan date of each TL identified 
previously at baseline should be documented at follow-up visits with the long axis diameter 
for non-nodal lesions or short axis diameter for lymph node lesions. All measurements should 
be recorded in whole millimeters. The sum of the diameters for all TLs at each follow-up visit 
will be compared to the baseline sum of diameters (for response or SD) or to the smallest prior 
(nadir) sum of diameters (for progression).
Special cases for TL assessment at follow-up:

If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as an NL.

If a TL splits into 2 or more parts, the sum of the diameters of those parts should be 
recorded.

If 2 or more TLs merge, then the sum of the diameters of the combined lesion should be 
recorded for 1 of the lesions and 0 mm recorded for the other lesion(s). If the merged TLs 
are non-nodal lesions, record the long axis diameter of the merged lesion. If pathologic 
lymph nodes coalesce and are no longer individually separable within a conglomerate 
mass, the maximal short axis diameter is recorded.

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.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
157 of 187

If a TL cannot be measured accurately due to it being too large, provide an estimate of the 
size of the lesion. The choice of “Too large to measure” in the case report form will 
trigger an overall visit response of PD. 

When a TL has had an unscheduled, non-protocol intervention, the following apply:

Target lesion intervention may include radiotherapy, embolization, excisional biopsy, 
surgery, etc. that is not a part of study treatment and might adversely affect the size 
of that TL.

If an intervention on a TL is ticked in the eCRF, the diameter of the lesion is still 
recorded (0mm if no longer present) and is included in the sum of diameters. 

If a TL intervention is ticked, the intervention must be reported for all subsequent 
assessments of that TL. 

If a TL has an intervention, the only Overall Visit Responses allowed to be recorded 
by the investigator are NE or PD, with PD if the sum of diameters exceeds a 
20% increase and at least a 5 mm absolute increase in the visit sum of diameters 
compared to the previous minimum (nadir) sum of diameters. 

No visit with a recorded TL intervention can be used as the minimum (nadir) sum of 
diameters. 
Table 12
RECIST 1.1 Evaluation of TLs
CR
Disappearance of all TLs since baseline. Any pathological lymph nodes selected as TLs must 
have a reduction in short axis diameter to < 10 mm.
PR
At least a 30% decrease in the sum of the diameters of TL, taking as reference the baseline sum 
of diameters.
SD
Neither sufficient decrease in the sum of diameters to qualify for PR nor sufficient increase to 
qualify for PD.
PD
At least a 20% increase in the sum of diameters of TLs, taking as reference the smallest previous 
sum of diameters (nadir) - this includes the baseline sum if that is the smallest on study. In 
addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at 
least 5 mm from nadir.
NE
Only relevant if any of the TLs at follow-up were not assessed or NE (eg, missing anatomy) or 
had a lesion intervention at this visit. Note: If the sum of diameters meets the PD criteria, PD 
overrides NE as a TL response.
NA
Only relevant if no TLs present at baseline.
CR = complete response; NA = not applicable; NE = not evaluable; PD = progression of disease; PR = partial 
response; SD = stable disease; TL = target lesion.
RECIST 1.1 NTL assessment at follow-up
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline. Measurements are not required for these lesions, but their status should be followed 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
158 of 187
at subsequent visits. At each visit, an overall assessment of the NTL response should be 
recorded by the investigator.
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 SD or PR in TLs, 
the overall tumor burden has increased sufficiently to merit unequivocal progression by NTLs. 
A modest ‘increase’ in the size of one or more NTLs is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be 
extremely rare.
Table 13
RECIST 1.1 Evaluation of NTLs
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 NTLs.
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.
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 participants 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.
NA
Only relevant if no NTLs present at baseline
CR = complete response; NA = not applicable; NTL = non-target lesion; PD = progression of disease; TL = 
target lesion.
RECIST 1.1 NL identification at follow-up
Details, including the imaging modality, the date of scan, and the location of any NLs will also 
be recorded in the case report form. The presence of one or more NLs is assessed as 
progression. The finding of a NL 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 NL is equivocal, for example because of its small size, the treatment and 
tumor assessments should be continued until the previously (pre-existing) new lesion has been 
assessed as unequivocal at a follow-up visit, and then the progression date should be declared 
using the date of the initial scan when the NL first appeared.
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a NL and will indicate disease progression.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
159 of 187
RECIST 1.1 evaluation of overall visit response at follow-up
Derivation of overall visit response as a result of the combined assessment of TLs, NTLs, and 
NLs uses the algorithm shown in Table 14.
Table 14
RECIST 1.1 Overall Visit Response
Target lesions
Non-target lesions
New lesions
Overall visit response
CR
CR
No
CR
CR
NA
No
CR
NA
CR
No
CR
CR
Non CR/Non PD 
No
PR
CR
NE
No 
PR
PR
Non PD or NE or NA
No
PR
SD 
Non PD or NE or NA
No
SD
NA
Non-CR/Non-PD
No
SD (non-CR/non-PD)
NE
Non PD or NE
No
NE
NA
NE
No
NE
NA
NA
No
NED
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Note: An overall assessment of CR (all other disease disappears/reverts to normal) would be changed to PR if 
ascites remains present radiologically.
CR = complete response; NA = not applicable (only relevant if there were no non-target lesions at baseline), NE 
= not evaluable; NED = no evidence of diseases (only relevant if there were neither TLs nor NTLs at baseline); 
PD = progression of disease; PR = partial response; SD = stable disease; TL = target lesion.
The following overall visit responses are possible depending on the extent of tumor disease at 
baseline:

For participants with TLs (at baseline): CR, PR, SD, progression of disease (PD), or NE

For participants with NTLs only (at baseline): CR, Non-CR/Non-PD, PD, or NE

For participants with no disease at baseline: NED (available as an option in the eCRF), 
PD, or NE
Evaluation of scans subsequent to RECIST 1.1-defined progression
A follow-up scan is requested at least 4 weeks later and no longer than the next regularly 
scheduled imaging visit. The follow-up scans provide additional information to the
investigator for participant management and further treatment decisions, and since the 
published RECIST 1.1 (Eisenhauer et al 2009) do not provide guidance on how to assess 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
160 of 187
scans acquired after RECIST 1.1-defined PD, supplemental instructions for investigators on 
how to evaluate these follow-up scans are provided below. A subsequent follow-up scan 
would be considered as having progressive disease if any of the following criteria are met:

Greater than or equal to 20% increase and at least a 5-mm increase in the sum of 
diameters of TLs compared with the nadir sum of diameters at 2 consecutive visits, and a 
further increase of ≥ 5 mm in the sum of diameters at the follow-up scan time point 
compared with the immediate prior time point

Significant progression (worsening) of NTLs at the follow-up scan time point compared 
with the immediate prior time point

Significant progression (worsening) of previous NLs (pre-existing NLs) at the follow-up 
scan time point compared with the immediate prior time point

Additional brand-new unequivocal lesions at the follow-up scan time point

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
161 of 187
Appendix H
Contraception Requirements
Contraception requirements for this study are as follows.
H 1
Female Participant of Child-bearing Potential
Please note, females of childbearing potential are defined as those who are post-menarche, not 
surgically sterile (ie, bilateral salpingectomy, bilateral oophorectomy, or complete 
hysterectomy) or post-menopausal.
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:

Women < 50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all hormonal replacement 
therapy and 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 hormonal replacement 
therapy, had radiation-induced menopause with last menses > 1 year ago, had 
chemotherapy-induced menopause with last menses > 1 year ago.
Female participants of childbearing potential who are not totally sexually abstinent 
(ie, refraining from heterosexual intercourse during the entire period of risk associated with 
study treatments) and intend to be sexually active with a nonsterilized male partner must use 
at least one highly effective method of contraception (Table 15) from the time of screening 
throughout the total duration of the drug treatment and for 4 months after the last dose of 
study intervention. Non-sterilized male partners of a female participant of childbearing 
potential must use a male condom plus spermicide (condom alone in countries where 
spermicides are not approved) throughout this period. Cessation of birth control after this 
point should be discussed with a responsible physician. Periodic abstinence (eg, calendar, 
symptothermal, post-ovulation methods), the rhythm method, the withdrawal method (coitus 
interruptus), and lactational amenorrhea method are not acceptable methods of contraception. 
Female participants should refrain from breastfeeding throughout this period.  
H 2
Male Participants With a Female Partner of Childbearing 
Potential
Non-sterilized male participants (including males sterilized by a method other than bilateral 
orchidectomy, eg, vasectomy) who are not abstinent and intend to be sexually active with a 
female partner of childbearing potential must use a male condom plus spermicide (condom 
alone in countries where spermicides are not approved) from the time of screening throughout 
the total duration of the drug treatment and for 4 months after the last dose of study 

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
162 of 187
intervention. Periodic abstinence (eg, calendar, symptothermal, post-ovulation methods), the 
rhythm method, the withdrawal method (coitus interruptus), and lactational amenorrhea 
method are not acceptable methods of contraception. Male participants should refrain from 
sperm donation throughout this period.
Vasectomized (ie, sterile) males are considered fertile and should still use a male condom plus 
spermicide as indicated above during the clinical study.
Even if the female partner is pregnant, male participants should still use a condom, as 
indicated above during the clinical study, if there is a concern about damaging the developing 
fetus from drug in ejaculate.
Female partners (of childbearing potential) of male participants must also use a highly 
effective method of contraception throughout this period (Table 15).
H 3
Highly Effective Methods of Contraception
Highly effective methods of contraception, defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly, are described in Table 15.
Note that some contraception methods are not considered highly effective (eg, male or female 
condom with or without spermicide; spermicide alone; female cap, diaphragm, or sponge with 
or without spermicide; non copper containing intrauterine device; progestogen-only oral 
hormonal contraceptive pills (also known as progesterone-only or “mini-pill”) where 
inhibition of ovulation is not the primary mode of action [excluding Cerazette®/desogestrel 
which is considered highly effective]; and triphasic combined oral contraceptive pills).
Table 15
Highly Effective Methods of Contraception (< 1% Failure Rate)
Barrier/intrauterine methods
Hormonal methods b
•
Copper T intrauterine device
•
Levonorgestrel-releasing intrauterine 
system (eg, Mirena®) a
•
Implants: Etonogestrel-releasing implants (eg, Implanon® 
or Norplant®)
•
Intravaginal devices: Ethinylestradiol/etonogestrel-
releasing intravaginal devices (eg, NuvaRing®) 
•
Injection: Medroxyprogesterone injection (eg, Depo-
Provera®)
•
Combined pill: Normal and low dose combined oral 
contraceptive pill
•
Patch: Norelgestromin/ethinylestradiol-releasing 
transdermal system (eg, Ortho Evra®)
•
Minipill: Progesterone based oral contraceptive pill using 
desogestrel: Cerazette® is currently the only highly 
effective progesterone-based pill
a
This is also considered a hormonal method.
b
The brand names in this table are examples only and availability will vary by country.

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
163 of 187
Appendix I
Patient-reported Outcomes
I 1
EORTC QLQ-C30
I 2
EORTC QLQ-H&N35
I 3
 
I 4
I 5
I 6
CCI
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
164 of 187
I 1
EORTC QLQ-C30

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
165 of 187

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
166 of 187
I 2
EORTC QLQ-H&N35

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
167 of 187

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
168 of 187
I 3
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
169 of 187
I 4
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
170 of 187
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
171 of 187
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
172 of 187
I 5
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
173 of 187
I 6
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
174 of 187
Appendix J
Study Participant Feedback Questionnaire

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
175 of 187

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
176 of 187

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
177 of 187

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
178 of 187
Appendix K
Abbreviations
Abbreviation or special 
term
Explanation
1L
first line
5-FU
5-fluorouracil
ADA
antidrug antibody
ADCC
antibody-dependent cell-mediated cytotoxicity
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BoR
best overall response
CI
confidence interval
Cmax
maximum serum concentration
COA
clinical outcome assessment
COVID-19
coronavirus disease 2019
CR
complete response
CrCL
creatinine clearance
CRO
Contract Research Organization
CSP
clinical study protocol
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
trough serum concentration
DCO
data cutoff
DILI
drug induced liver injury
DNA
deoxyribonucleic acid 
DoR
duration of response
ECG
electrocardiograms
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
Electronic Data Capture
EGFR
epidermal growth factor receptor
EMA
European Medicines Agency
EORTC
European Organisation for Research and Treatment of Cancer
EOT
end of treatment

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
179 of 187
Abbreviation or special 
term
Explanation
ePRO
electronic patient-reported outcome (questionnaire)
ESMO
European Society of Medical Oncology
EU SmPC
European Union Summary of Product Characteristics
EXTREME regimen
cetuximab + platinum (cisplatin or carboplatin) + 5-fluorouracil followed by 
cetuximab until progression or intolerance
FA
final analysis
FAS
Full Analysis Set
FDA
Food and Drug Administration
FDG
18F-Fluoro-deoxyglucose 
FH
Fleming-Harrington
FWER
familywise error rate
GCP
Good Clinical Practice
HBsAg
HBV surface antigen
HBV
hepatitis B
HCV
hepatitis C
HER
human epidermal growth factor receptor
HIV
human immunodeficiency virus
HL
Hy’s Law
HLA-E
human leukocyte antigen E
HPV
human papillomavirus
HPV-unrelated
randomized participants who are either OPC HPV negative or non-OPC
HR
hazard ratio
HRQoL
health-related quality of life
IA
interim analysis
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
ICI
immune checkpoint inhibitor
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IgG4
immunoglobulin G4
IHC
immunohistochemistry
CCI
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
180 of 187
Abbreviation or special 
term
Explanation
imAE
immune-mediated adverse event
IMP
investigational medicinal product
IRB
Institutional Review Board
IRT
Interactive Response Technology
iv
intravenous
IVRS
interactive voice response system
KM
Kaplan Meier
LA
locally advanced
mAb
monoclonal antibody
MRI
magnetic resonance imaging
NCCN
National Comprehensive Cancer Research
NCI
National Cancer Institute
NE
not evaluable
NED
no evidence of disease
NK
natural killer
NL
new lesion
NPH
non-proportional hazards
NTL
non-target lesion
OPC
oropharyngeal cancer
ORR
objective response rate
OS
overall survival
PBMC
peripheral blood mononuclear cells
PD
progressive disease
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand-1
PD-(L)1
programmed cell death-1 or programmed cell death ligand-1
PET
positron emission tomography
PFS
progression-free survival
 
PHL
potential Hy’s Law
PK
pharmacokinetic
PR
partial response
CCI
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
181 of 187
Abbreviation or special 
term
Explanation
PRO
patient-reported outcome
PS
performance status
Q1W
once weekly
Q2W
every 2 weeks
Q4W
every 4 weeks
QLQ-C30
30-item Core Quality-of-life Questionnaire
QLQ-H&N35
Quality of Life Questionnaire Head and Neck Module
QoL
quality of life
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, Version 1.1
REVPRDI
Review of PRO/Questionnaire/Diary
R/M
recurrent or metastatic
SAE
serious adverse event 
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome-coronavirus-2
SCCHN
squamous cell carcinoma of the head and neck
SD
stable disease
SITC
Society for Immunotherapy of Cancer
SoA
schedule of activities
SPFQ
Study Participant Feedback Questionnaire
TBL
total bilirubin
TL
target lesion
TME
tumor microenvironment
TMG
toxicity management guidelines
ULN
upper limit of normal
USA
United States of America
US FDA
United States Food and Drug Administration
US PI
United States Package Insert
WHO
World Health Organization
w/v
weight/volume

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
182 of 187
11
REFERENCES
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ et al. The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for 
use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365-76.
Andre P, Denis C, Soulas C, Bourbon-Caillet C, Lopez J, Arnoux T et al. Anti-NKG2A mAb 
Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK 
Cells. Cell. 2018;175(7):1731-43.e13.
Argiris A, Harrington KJ, Tahara M, Schulten J, Chomette P, Ferreira Castro A et al. 
Evidence-Based Treatment Options in Recurrent and/or Metastatic Squamous Cell Carcinoma 
of the Head and Neck. Front Oncol. 2017;772.
Borrego F, Ulbrecht M, Weiss EH, Coligan JE, Brooks AG. Recognition of human 
histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-
derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis. J 
Exp Med. 1998;187(5):813-8.
Braud VM, Allan DSJ, O'Callaghan CA, Söderström K, D'Andrea A, Ogg GS et al. HLA-E 
binds to natural killer cell receptors CD94/NKG2A, B and C. Nature. 1998;391(6669):795-9.
Cohen E, Bell R, Bifulco C, Burtness B, Gillison M, Harrington K et al. The Society for 
Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of 
squamous cell carcinoma of the head and neck (HNSCC). J Immunother Cancer. 
2019a;7(1):184.
Cohen E, Soulieres D, Le Tourneau C, Dinis J, Licitra L, Ahn M et al. Pembrolizumab versus 
methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous 
cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet. 
2019b;393(10167):156-67.
Cohen R, Salas S, Even C, Kotecki N, Jimeno A, Soulié A et al. Abstract 5666: Safety of the 
first-in-class anti-NKG2A monoclonal antibody monalizumab in combination with cetuximab: 
a phase Ib/II study in recurrent or metastatic squamous cell carcinoma of the head and neck 
(R/M SCCHN). Cancer Research. 2017;77(13 Supplement):5666.
Cohen R, Fayette J, Posner M, Lefebvre G, Bauman J, Salas S et al. Monalizumab in 
combination with cetuximab in recurrent or metastatic squamous cell carcinoma of the head 
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
183 of 187
and neck (R/M SCCHN): clinical and translational biomarker results. Abstract 051. Society 
for Immunotherapy of Cancer; Washington, DC. 2018a.
Cohen R, Fayette J, Posner M, Lefebvre G, Bauman J, Salas S et al. Phase II study of 
monalizumab, a first-in-class NKG2A monoclonal antibody, in combination with cetuximab in 
previously treated recurrent or metastatic squamous cell carcinoma of the head and neck (R/M 
SCCHN): Preliminary assessment of safety and efficacy. Abstract CT158. Cancer Research. 
2018b;78(13 Supplement):CT158-CT.
Cohen R, Lefebvre G, Posner M, Bauman J, Salas S, Even E et al. Monalizumab in 
combination with cetuximab in patients (pts) with recurrent or metastatic (R/M) head and neck 
cancer (SCCHN) previously treated or not with PD-(L)1 inhibitors (IO): 1-year survival data. 
Annals of Oncology. 2019c;30(suppl 5):v460.
Curry JM, Sprandio J, Cognetti D, Luginbuhl A, Bar-ad V, Pribitkin E et al. Tumor 
microenvironment in head and neck squamous cell carcinoma. Semin Oncol. 2014;41(2):217-
34.
Degboe A, Knight SL, Halling K, Trigg A, Al-Zubeidi T, Aldhouse N et al. Patients' 
experience of recurrent/metastatic head and neck squamous cell carcinoma and their 
perspective on the EORTC QLQ-C30 and QLQ-H&N35 questionnaires: a qualitative study. J 
Patient Rep Outcomes. 2018;2:33.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;45(2):228-47.
EMA. Guideline on the evaluation of anticancer medicinal products in man. 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-evaluation-
anticancer-medicinal-products-man-revision-5_en.pdf Published 2017. Accessed 22 
November 2019.
Erbitux (cetuximab) [package insert]. Princeton, NY: Bristol-Myers Squibb Company.; 2021.
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
184 of 187
Fayers P, Aaronson N, Bjordal K, Groenvold M, Curran D, Bottomley A. The EORTC QLQ-
C30 scoring manual (3rd edition). Published by: European Organisation for Research and 
Treament of Cancer, Brussels. 2001.
FDA. Guidance for industry: clinical trial endpoints for the approval of cancer drugs and 
biologics. https://www.fda.gov/media/71195/download. Published 2018a. Accessed 22 
November 2019.
FDA. FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) 
Resource [Internet]. Silver Spring (MD): Food and Drug Administration (US); 2016. Glossary. 
28 Jan 2016 [Updated 02 May 2018]. https://www.ncbi.nlm.nih.gov/books/NBK338448/Co-
published. Published 2018b. Accessed 05 November 2019.
Ferris RL, Blumenschein G, Jr., Fayette J, Guigay J, Colevas AD, Licitra L et al. Nivolumab 
for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 
2016;375(19):1856-67.
Gooden M, Lampen M, Jordanova ES, Leffers N, Trimbos JB, van der Burg SH et al. HLA-E 
expression by gynecological cancers restrains tumor-infiltrating CD8(+) T lymphocytes. Proc 
Natl Acad Sci U S A. 2011;108(26):10656-61.
Gregoire V, Lefebvre JL, Licitra L, Felip E. Squamous cell carcinoma of the head and neck: 
EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 
Ann Oncol. 2010;21 Suppl 5v184-6.
Harrington DP, Fleming TR. A class of rank test procedures for censored survival data. 
Biometrika. 1982;69(3):553-66.
CCI
CCI
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
185 of 187
Karrison TG. Versatile tests for comparing survival curves based on weighted log-rank 
statistics. Stata Journal. 2016;16(3):678-90.
Katou F, Ohtani H, Watanabe Y, Nakayama T, Yoshie O, Hashimoto K. Differing Phenotypes 
between Intraepithelial and Stromal Lymphocytes in Early-Stage Tongue Cancer. Cancer 
Research. 2007;67(23):11195.
Keytruda (pembrolizumab) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 
2021.
Kluetz PG, O'Connor DJ, Soltys K. Incorporating the patient experience into regulatory 
decision making in the USA, Europe, and Canada. Lancet Oncol. 2018;19(5):e267-e74.
Kol A, van Sccheltinga AT, Pool M, Gerdes C, de Vries E, de Jong S. ADCC Responses and 
blocking of EGFR-mediated Signaling and Cell Growth by Combining the Anti-EGFR 
Antibodies Imgatuzumab ad Cetuximab in NSCLC cells. Oncotarget. 2017;8(28):45432-46.
Lee N, Llano M, Carretero M, Ishitani A, Navarro F, Lopez-Botet M et al. HLA-E is a major 
ligand for the natural killer inhibitory receptor CD94/NKG2A. Proc Natl Acad Sci U S A. 
1998;95(9):5199-204.
Levy EM, Sycz G, Arriaga JM, Barrio MM, von Euw EM, Morales SB et al. Cetuximab-
mediated cellular cytotoxicity is inhibited by HLA-E membrane expression in colon cancer 
cells. Innate Immun. 2009;15(2):91-100.
Lin RS, Lin J, Roychoudhury S, Anderson KM, Hu T, Huang B et al. Alternative analysis 
methods for time to event endpoints under nonproportional hazards: a comparative analysis. 
Stat Biopharm Res. 2020;12(2):187-98.
Moy JD, Moskovitz JM, Ferris RL. Biological mechanisms of immune escape and 
implications for immunotherapy in head and neck squamous cell carcinoma. Eur J Cancer. 
2017;76152-66.
Nasman A, Andersson E, Nordfors C, Grun N, Johansson H, Munck-Wikland E et al. MHC 
class I expression in HPV positive and negative tonsillar squamous cell carcinoma in 
correlation to clinical outcome. Int J Cancer. 2013;132(1):72-81.
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
186 of 187
NCCN. Clinical practice guidelines in oncology: head and neck cancers. Version 3.2021 [cited 
Access Date]. Available from: https://www.nccn.org/guidelines/guidelines-
detail?category=1&id=1437.
Opdivo (nivolumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2021.
Rischin D, Harrington KJ, Greil R, Soulieres D, Tahara M, de Castro G et al. Protocol-
specified final analysis of the phase 3 KEYNOTE-048 trial of pembrolizumab (pembro) as 
first-line therapy for recurrent/metastatic head and neck squamous cell carcinoma (R/M 
HNSCC). Journal of Clinical Oncology. 2019;37(15_suppl):6000.
Silva TG, Crispim JC, Miranda FA, Hassumi MK, de Mello JM, Simoes RT et al. Expression 
of the nonclassical HLA-G and HLA-E molecules in laryngeal lesions as biomarkers of tumor 
invasiveness. Histol Histopathol. 2011;26(12):1487-97.
Taberna M, Mena M, Pavón MA, Alemany L, Gillison ML, Mesía R. Human papillomavirus-
related oropharyngeal cancer. Ann Oncol. 2017;28(10):2386-98.
Tinker AV, Hirte HW, Provencher DM, Butler MO, Ritter H, Tu D et al. Dose-ranging and 
cohort-expansion study of monalizumab (IPH2201) in advanced gynecologic malignancies:A 
trial of the Canadian Cancer Trials Group (CCTG):IND221. Clin Canc Res. 2019a;DOI: 
10.1158/078-0432.CCR-19-298.
Tinker AV, Hirte HW, Provencher DM, Butler MO, Ritter H, Tu D et al. Dose-ranging and 
cohort-expansion study of monalizumab(IPH2201) in advanced gynecologic malignancies:A 
trial of the Canadian Cancer Trials Group (CCTG):IND221. Clinical Cancer Research. 
2019b;clincanres.0298.2019.
van Montfoort N, Borst L, Korrer MJ, Sluijter M, Marijt KA, Santegoets SJ et al. NKG2A 
blockade potentiates CD8 T cell immunity induced by cancer vaccines. Cell. 
2018;175(7):1744-55.e15.
Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, Rolland F et al. Open-label, 
uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a 
single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head 
and neck who failed to respond to platinum-based therapy. J Clin Oncol. 2007;25(16):2171-7.
CCI
CCI

Clinical Study Protocol - 3.0
AstraZeneca
Monalizumab and cetuximab - D7310C00001
CONFIDENTIAL AND PROPRIETARY
187 of 187
Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-based dosing 
of monoclonal antibodies in adult clinical trials. J Clin Pharmacol. 2009;49(9):1012-24.

6,*1$785(3$*(
7KLVLVDUHSUHVHQWDWLRQRIDQHOHFWURQLFUHFRUGWKDWZDVVLJQHG
HOHFWURQLFDOO\DQGWKLVSDJHLVWKHPDQLIHVWDWLRQRIWKHHOHFWURQLFVLJQDWXUH
'RFXPHQW1DPHGFFVSDPHQGPHQW
'RFXPHQW7LWOH
'&&OLQLFDO6WXG\3URWRFRO$PHQGPHQW
'RFXPHQW,'
9HUVLRQ/DEHO
&855(17/$7(67$33529('
6HUYHU'DWH
GG000\\\\++PPµ87&¶=
6LJQHGE\
0HDQLQJRI6LJQDWXUH
-XO87&
&RQWHQW$SSURYDO
-XO87&
0DQDJHPHQW$SSURYDO
-XO87&
$XWKRU$SSURYDO
-XO87&
&RQWHQW$SSURYDO
PPD
CCI
CCI