A Phase 1/2 Study of Durvalumab and Monalizumab in Adult Subjects With Select Advanced Solid Tumors
Phase: PHASE1
Conditions: Advanced Solid Tumors
Sponsor: MedImmune LLC

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
1 of 206
Template 16.2
A Phase 1/2 Study of Durvalumab and Monalizumab in Adult 
Subjects with Select Advanced Solid Tumors
Sponsor Protocol Number: D419NC00001 
Application Number:
IND 127993 
EudraCT 2016-000662-38
Investigational Product:
Durvalumab and monalizumab (IPH2201)
Sponsor:
MedImmune, LLC, a wholly owned subsidiary of AstraZeneca 
PLC, 
 
Medical Monitor:
, Clinical Development, Early Oncology
Contract Research Organization: Covance
Protocol History, Date
Original Protocol, 09 December 2015
Amendment 1, 21 January 2016
Amendment 2, 10 January 2018
Amendment 3, 31 August 2018
Amendment 4, 22 February 2019
Amendment 5, 06 December 2019
Amendment 6, 31 May 2021
PPD
PPD
PPD
PPD

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
2 of 206
Template 16.2
PROTOCOL SYNOPSIS
TITLE
A Phase 1/2 Study of Durvalumab and Monalizumab in Adult Subjects with Select Advanced Solid Tumors
Rationale for Amendment 2: Due to the preliminary clinical activity signal observed with durvalumab in 
combination with monalizumab in the microsatellite-stable colorectal cancer (
CRC) cohort in Part 2 of the 
current study, Part 3 (Cohorts A 
) was added to the current study to evaluate further the combination of 
durvalumab and monalizumab with standard-of-care chemotherapeutic regimens with and without biologic 
agents (bevacizumab or cetuximab) in subjects with first-line (1L) or second-line (2L) 
CRC.
Rationale for Amendment 3: Due to the promising preliminary clinical activity signal observed with 
monalizumab in combination with cetuximab in subjects with recurrent or metastatic squamous cell carcinoma 
of the head and neck (NCT02643550; Cohen et al, 2018), Cohort C is being added to Part 3 (Cohorts C1A, C1B, 
C2A, and C2B) of the current study to understand better the exact mechanism of monalizumab in combination 
with cetuximab (ie, enhancement of antibody-dependent cellular cytotoxicity or adaptive immune response). 
This will be achieved by evaluating the combination of monalizumab with cetuximab in subjects with 
 
CRC that is 
 (Part 3, Cohort C2B) as well as 
 (Part 3, Cohort C1B). 
In addition, given the previously observed signal of durvalumab in combination with monalizumab in 
CRC from Part 2, the current study will also evaluate durvalumab in combination with monalizumab plus 
cetuximab in subjects with 
CRC that is 
 (Part 3, Cohort C2A) as well as
 
 (Part 3, Cohort C1A).
Rationale for Amendment 4: The primary reasons for the amendment were
 
to revise prior therapy inclusion 
criteria for subjects in Part 3 C Cohorts to match standard of care practice, and to update the process for 
identifying and reporting potential Hy’s Law and Hy’s Law cases.
A high-level overview of the study design, status update for each part of the study, total planned number of 
subjects, and currently enrolled number of subjects is presented below.
Rationale for Amendment 5: The primary reasons for Amendment 5 were to remove the toxicity modification 
guidelines to a separate standalone document according to updated Sponsor guideline, to align with other 
Sponsor guidelines, to allow re-treatment following relapse, and to add Schedules of Procedures for 
re-treatment.
Rationale for Amendment 6: The primary reasons for Amendment 6 were to: describe the continued treatment 
and monitoring of subjects still on study treatment at the time of the final data cut off, add study mitigation 
language to provide sites with measures that may be implemented if a participant is not able to visit a study site 
to ensure that the clinical trial can continue while minimizing risk to the participant, maintaining compliance 
with Good Clinical Practice, and minimizing risks to the study integrity;
 
 
 
Tumor Type
Treatment
Status Under 
Protocol 
Amendment 6
Total Planned 
Enrollment
Subjects 
Enrolled and 
Treated as of 24 
March 2020
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
3 of 206
Template 16.2
Tumor Type
Treatment
Status Under 
Protocol 
Amendment 6
Total Planned 
Enrollment
Subjects 
Enrolled and 
Treated as of 24 
March 2020
Part 3 (Dose Exploration in 
CRC)
1L 
CRC
Cohort A1: mFOLFOX6, 
bevacizumab, durvalumab 
1500 mg Q4W, and 
monalizumab 750 mg Q2W
Closed
18
18
Cohort A2: mFOLFOX6, 
cetuximab, durvalumab 
1500 mg Q4W, and 
monalizumab 750 mg Q2W
Closed
18
18
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
4 of 206
Template 16.2
Tumor Type
Treatment
Status Under 
Protocol 
Amendment 6
Total Planned 
Enrollment
Subjects 
Enrolled and 
Treated as of 24 
March 2020
1L = first-line;
 
mFOLFOX6 = a modified FOLFOX regimen of folinic acid/fluorouracil/oxaliplatin;
CRC =
 colorectal cancer; 
Q2W = every 2 weeks; 
Q4W = every 4 weeks;
.
 
HYPOTHESIS
Parts 1 and 2: The combination of durvalumab (MEDI4736; anti-programmed death ligand 1 [PD-L1] 
monoclonal antibody) and monalizumab (IPH2201; anti-NKG2a monoclonal antibody) administered to subjects 
with select advanced solid tumors will show acceptable safety and tolerability so as to permit further clinical 
testing in subsequent studies.
Part 3 (Cohorts A 
): The combination of durvalumab and monalizumab plus chemotherapy with or 
without a biologic agent (bevacizumab or cetuximab), as clinically indicated, administered to subjects with 
recurrent or metastatic 1L or 2L 
CRC will show acceptable safety and tolerability so as to permit further 
clinical testing in subsequent studies.
Part 3 (Cohorts C1A and C2A): The combination of durvalumab and monalizumab plus cetuximab 
administered to subjects with 
CRC that is 
 (C1A) or 
 
 (C2A) will show acceptable safety (C1A and C2A), tolerability (C1A and C2A), and antitumor 
activity (C1A only) so as to permit further clinical testing in subsequent studies.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
5 of 206
Template 16.2
Part 3 (Cohorts C1B and C2B): The combination of monalizumab plus cetuximab administered to subjects 
with 
CRC that is 
 (C1B) or 
 (C2B) will show 
acceptable safety (C1B and C2B), tolerability (C1B and C2B), and antitumor activity (C1B only) so as to permit 
further clinical testing in subsequent studies.
OBJECTIVES
Primaryobjective:
Part 1:
To assess safety and tolerability, describe the dose-limiting toxicities (DLTs), and determine the maximum
tolerated dose (MTD) or the highest protocol-defined dose level in the absence of establishing an MTD of
durvalumab in combination with monalizumab in subjects with advanced solid tumors.
Part 2:
To assess further the safety and tolerability of either the MTD or the highest protocol-defined dose level, in the 
absence of establishing an MTD, of durvalumab in combination with monalizumab in subjects with selected 
advanced solid tumors.
Part 3:
Cohorts A 
: To assess safety and tolerability of durvalumab in combination with monalizumab plus 
chemotherapy with or without a biologic agent (bevacizumab or cetuximab), as clinically indicated, in subjects 
with 1L or 2L 
CRC
Cohorts C1A and C2A: To assess safety (C1A and C2A) and tolerability (C1A and C2A) and evaluate the 
preliminary antitumor activity (C1A only) of durvalumab in combination with monalizumab plus cetuximab in 
subjects with 
CRC that is 
 (C1A) or 
 (C2A)
Cohorts C1B and C2B: To assess safety (C1B and C2B) and tolerability (C1B and C2B) and evaluate the 
preliminary antitumor activity (C1B only) of monalizumab in combination with cetuximab in subjects with 
 
CRC that is 
 (C1B) or 
 (C2B)
Secondaryobjectives:
1
To evaluate the preliminary antitumor activity of:

Durvalumab in combination with monalizumab in subjects with advanced solid tumors (Parts 1 and 
2)

Durvalumab in combination with monalizumab plus chemotherapy with or without a biologic agent 
(bevacizumab or cetuximab), as clinically indicated in subjects with 1L or 2L 
CRC (Part 3, 
Cohorts A 
)

Durvalumab in combination with monalizumab plus cetuximab in subjects with 
CRC that is 
 (Part 3, Cohort C2A)

Monalizumab in combination with cetuximab in subjects with 
CRC that is 
 
 (Part 3, Cohort C2B)
2
To further evaluate the antitumor activity of:

Durvalumab in combination with monalizumab plus cetuximab in subjects with 
CRC that is 
 (Part 3, Cohort C1A)

Monalizumab in combination with cetuximab in subjects with 
CRC that is 
 
(Part 3, Cohort C1B)
3
To describe the pharmacokinetics (PK) of: 

Durvalumab and monalizumab when administered in combination in subjects with advanced solid 
tumors (Parts 1 and 2)

Durvalumab and monalizumab when administered in combination with chemotherapy with or without 
a biologic agent (bevacizumab or cetuximab), as clinically indicated in subjects with 1L or 2L 
CRC (Part 3, Cohorts A 
)
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
6 of 206
Template 16.2

Durvalumab, monalizumab, and cetuximab when administered in combination in subjects with 
 
CRC that is 
 (Part 3, Cohort C1A)

Monalizumab and cetuximab when administered in combination in subjects with 
CRC that is 
 (Part 3, Cohort C1B)

Durvalumab and monalizumab when administered in combination with cetuximab in subjects with 
 
CRC that is 
 (Part 3, Cohort C2A)

Monalizumab when administered in combination with cetuximab in subjects with 
CRC that 
is 
 (Part 3, Cohort C2B)
4
To describe the immunogenicity of: 

Durvalumab and monalizumab when administered in combination in subjects with advanced solid 
tumors (Parts 1 and 2)

Durvalumab and monalizumab when administered in combination with chemotherapy with or without 
a biologic agent (bevacizumab or cetuximab), as clinically indicated in subjects with 1L or 2L 
CRC (Part 3, Cohorts A 
)

Durvalumab, monalizumab, and cetuximab when administered in combination in subjects with 
 
CRC that is 
 (Part 3, Cohort C1A)

Monalizumab and cetuximab when administered in combination in subjects with 
CRC that is 
 (Part 3, Cohort C1B)

Durvalumab and monalizumab when administered in combination with cetuximab in subjects with 
 
CRC that is 
 (Part 3, Cohort C2A)

Monalizumab when administered in combination with cetuximab in subjects with 
CRC that 
is 
 (Part 3, Cohort C2B)
5
To characterize the association between clinical outcomes and pre-treatment protein expression within the
tumor microenvironment when

Durvalumab is administered in combination with monalizumab in subjects with advanced solid 
tumors (Parts 1 and 2)

Durvalumab is administered in combination with monalizumab plus chemotherapy with or without a 
biologic agent (bevacizumab or cetuximab), as clinically indicated in subjects with 1L or 2L 
CRC (Part 3, Cohorts A 
)

Durvalumab is administered in combination with monalizumab plus cetuximab in subjects with 
 
CRC that is 
 or 
 (Part 3, Cohorts C1A and C2A, 
respectively)

Monalizumab is administered in combination with cetuximab in subjects with 
CRC that is 
 or 
 (Part 3, Cohorts C1B and C2B, respectively)
Exploratoryobjectives:
1
To evaluate additional candidate prognostic/predictive/pharmacodynamic biomarkers when 

Durvalumab is administered in combination with monalizumab in subjects with advanced solid 
tumors (Parts 1 and 2)

Durvalumab is administered in combination with monalizumab plus chemotherapy with or without a 
biologic agent (bevacizumab or cetuximab), as clinically indicated in subjects with 1L or 2L 
CRC (Part 3, Cohorts A 
)

Durvalumab is administered in combination with monalizumab plus cetuximab in subjects with 
 
CRC that is 
 or 
 (Part 3, Cohorts C1A and C2A, 
respectively)

Monalizumab is administered in combination with cetuximab in subjects with 
CRC that is 
 or 
 (Part 3, Cohorts C1B and C2B, respectively)
2

 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
7 of 206
Template 16.2

 
 

 

 
3
To evaluate the effect of the following treatment combinations on disease-related 
symptoms/functioning/health-related quality of life (HRQoL) and overall health status

Durvalumab in combination with monalizumab plus cetuximab in subjects with 
CRC that is 
 

Monalizumab in combination with cetuximab in subjects with 
CRC that is 
 
STUDY ENDPOINTS
Primaryendpoint:
The primary endpoint is safety as assessed by presence of adverse events (AEs), serious adverse events (SAEs),
DLTs, abnormal laboratory parameters, vital signs, and electrocardiogram (ECG) results. AEs will be graded
according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)
v4.03.
The primary endpoint for evaluating clinical activity in Part 3 (Cohorts C1A and C1B) is objective response 
(OR) by investigator assessment per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Secondaryendpoints:
4
The endpoints for assessment of antitumor activity include OR (primary endpoint for Cohorts C1A and 
C1B), disease control (DC), duration of response (DoR), and progression-free survival (PFS) by 
investigator assessment per RECIST v1.1. Overall survival (OS) will also be assessed.
5
The endpoints for assessment of PK include individual subject durvalumab, monalizumab, and cetuximab 
concentrations in serum at different time points after administration of these agents.
6
The endpoints for assessment of immunogenicity include the number and percentage of subjects who
develop detectable anti-drug antibodies (ADAs).
7
 
Exploratoryendpoints:
8
Additional candidate prognostic/predictive/pharmacodynamic biomarkers may include, but are not limited 
to: 
a.
Assessment of T- and natural killer (NK)-cell activation (eg, inducible costimulatory molecule 
expression) and proliferation (eg, Ki67 expression) measured by flow cytometry in blood, by 
immunohistochemistry (IHC) in tumors, and by mass spectrometry, DNA/RNA/miRNA (microRNA) 
assessments (RNAseq, exome sequence, single-cell RNA) in blood and tumors
b.
Assessment of the number and activity of CD8+ effector T cells and NK cells and expression of 
immunomodulatory proteins (eg, programmed death 1) within tumor biopsies using IHC
c.
 
d.
 
e.
 
i.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
8 of 206
Template 16.2
ii.
 
iii.
iv.
 
 
v.
vi.
 
vii.
viii.
9
 
10
Clinical outcome assessments include:
a.
Descriptive statistics for domain, subscale scores, and individual items at each time point and change 
from baseline as measured by the European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire (EORTC QLQ-C30)
b.
Time to deterioration and response status for domain, subscale scores, and individual items as 
measured by the EORTC QLQ-C30
c.
Descriptive statistics for subjects’ global impression of change of their overall health status at each 
time point as measured by the Patient Global Impression of Change
d.
Time to deterioration in Eastern Cooperative Oncology Group performance status ≥ 2
STUDY DESIGN
This is a Phase 1/2, multicenter, open-label, study of durvalumab and monalizumab to evaluate safety, 
tolerability, PK, immunogenicity, pharmacodynamics, and antitumor activity in adult subjects with advanced 
solid tumor malignancies at approximately 60 sites globally. The study consists of 3 parts: dose escalation 
(Part 1), dose expansion (Part 2), and dose exploration in 
CRC (Part 3). 
•
Part 1 will evaluate dose escalation of durvalumab in combination with monalizumab in subjects with 
select advanced solid tumor malignancies. 
•
Part 2 will evaluate further the identified dose of durvalumab in combination with monalizumab from Part 
1 in subjects with select advanced solid tumor malignancies. 
•
Part 3 (Cohorts A 
) will evaluate dose exploration of durvalumab in combination with 
monalizumab and chemotherapy, with or without a biologic agent (bevacizumab or cetuximab), as 
clinically indicated, in subjects with metastatic 1L or 2L 
CRC. 
•
Part 3 (Cohorts C1 and C2) will evaluate dose exploration of 1) durvalumab in combination with 
monalizumab plus cetuximab (Cohorts C1A and C2A) and 2) monalizumab in combination with 
cetuximab (Cohorts C1B and C2B) in subjects with 
CRC that is 
 or 
. 
Study treatment will be administered up to 3 years until unacceptable toxicity, documentation of confirmed 
progressive disease (PD), or documentation of subject withdrawal for another reason. Subjects who continue to 
receive clinical benefit after 3 years of treatment, will continue to receive the treatment on this study, via a 
rollover study requiring approval by the responsible Health Authority (HA) and ethics committee, or through 
another mechanism at the discretion of the sponsor. Tolerability data for all subjects will be evaluated regularly 
and subjects’ clinical response status classified according to RECIST v1.1. All subjects will be followed for 
survival until the end of study. The end of the study (“study completion”) is 5 years after the final subject is 
enrolled or the date the study is closed by the sponsor, whichever occurs first. 
Part 1: Dose Escalation
Subjects with advanced 
CRC, ovarian cancer, 
endometrial cancer, cervical cancer, 
castration-resistant prostate cancer, pancreatic adenocarcinoma and non-small cell lung cancer (NSCLC) will be 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
9 of 206
Template 16.2
enrolled in the dose-escalation part. Subjects in sequential cohorts will receive durvalumab (1500 mg every 4 
weeks [Q4W]) in combination with monalizumab at 
 planned dose levels (
 every 
2 weeks [Q2W]).
 
Escalation to the next dose level will be determined by using a modified toxicity probability interval (mTPI) 
algorithm, with a target DLT rate of ≥33% and an equivalence interval of 
. A minimum of 3 subjects 
will be enrolled to a dose level and the maximum number of subjects for each dose level will be capped at 12. A 
dose level will be considered unsafe if it has an estimated 95% or more probability of exceeding the target DLT 
rate of ≥33% with at least 3 subjects treated at that dose level. Up to 60 subjects could be enrolled in the dose-
escalation part to determine MTD. Given that the mTPI algorithm leads to a dose-escalation decision if there is 
no DLT in the first 3 subjects enrolled in a dose-level cohort, it is expected that the actual sample size observed 
will be fewer. Subjects will be dosed in a group size of 3. The first 3 subjects enrolled in the escalation part will 
be enrolled to dose-level Cohort 1. No escalation is allowed unless 3 or more evaluable subjects have been 
treated and evaluated through the DLT-evaluation period in a dose level. Intermediate dose levels may be 
explored based on emerging data at the discretion of the sponsor.
The MTD will be determined by isotonic regression analysis applied to DLT rates observed during the 
dose-escalation part.
In general, an AE will be considered a DLT if it is Grade 3 or higher, considered to be drug-related, and occurs 
within the DLT-evaluation period (defined as the time from start of the first dose of investigational product 
[durvalumab and monalizumab] until the planned administration of the second dose of durvalumab and the third 
dose of monalizumab; this corresponds to 28 days after the first dose of durvalumab and monalizumab or 14 
days after the second dose of monalizumab).
Administration of the first dose of investigational product will be staggered by a minimum of 24 hours between 
the first and second subjects in each dose-escalation cohort. Dose escalation will continue to the next higher 
dose level after all available safety data and any available PK data from subjects in that dose level and prior 
dose levels have been reviewed by a study-specific dose-escalation committee (DEC). The sponsor may halt 
dose escalation prior to determining the MTD based on emerging PK/pharmacodynamic, toxicity or response 
data. The dose-expansion part may be initiated once the MTD, or highest protocol-defined dose level in the 
absence of exceeding the MTD, is established in the dose-escalation part of the study.
Following completion of the Q2W dose escalation, an alternate treatment schedule(s) of durvalumab in 
combination with monalizumab (eg, monalizumab Q4W) may be explored based on PK, pharmacodynamic, 
safety, and response data. If this were to occur, the first group of 3 to 12 subjects will receive durvalumab in 
combination with monalizumab at the highest dose level that did not exceed the MTD using the durvalumab 
(Q4W) and monalizumab (Q2W) schedule. If the MTD is not exceeded at that dose level on a monalizumab 
Q4W schedule and provided this was not the highest protocol-defined dose, dose escalation may proceed with 
additional sequential cohorts of 3 to 12 subjects according to the aforementioned dose levels using the same 
mTPI algorithm.
Ongoing surveillance of pharmacodynamics, PK, clinical safety, and antitumor activity data will be performed 
throughout the dose-escalation part. Once the dose escalation has completed per the mTPI or the highest 
protocol-defined dose is evaluated, any dose level showing acceptable safety during dose escalation can be 
expanded to a total of up to 18 subjects with mandatory pre-treatment and on-treatment tumor biopsies. At the 
discretion of the sponsor, the expansion at a given dose level may be restricted to a specific tumor type(s) 
included in the dose-escalation part. These dose-escalation cohort expansions will provide additional PK, 
pharmacodynamic, and safety data to inform optimal dose-level selection for the dose-expansion part (Part 2) 
and subsequent clinical studies.
Part 2: Dose Expansion
The dose-expansion part will enroll 4 cohorts of approximately 40 subjects each with recurrent or metastatic 
CRC, ovarian cancer, endometrial cancer, or NSCLC. The dose level and schedule determined in the dose-
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
10 of 206
Template 16.2
escalation part will be used in the dose-expansion part, as agreed by the study-specific DEC. Additional dose 
levels not exceeding the MTD may be considered based on clinical and PK/pharmacodynamic data from the 
dose-escalation part.
Enrollment into dose-expansion cohorts may be discontinued at the discretion of the sponsor should emerging 
clinical or preclinical data suggest that continued treatment may not be beneficial to a given cohort. During dose 
expansion, subjects will be monitored for safety using the same DLT criteria employed during dose escalation.  
 
During the dose-expansion part, if a toxicity meeting criterion for discontinuation of treatment with the 
combination of durvalumab and monalizumab is observed in a subject in the NSCLC cohort, but the subject is 
receiving clinical benefit, the subject may be considered for monotherapy treatment with durvalumab. In this 
circumstance, the decision to treat NSCLC patients with monotherapy durvalumab will be based on factors such 
as known sensitivity/response of the tumor type to durvalumab and require agreement of the sponsor and 
treating investigator.
Enrollment may proceed up to approximately 40 subjects in the 
CRC, ovarian, and endometrial expansion 
cohorts 
. Enrollment may proceed up to approximately 40 
subjects in the NSCLC dose-expansion cohort 
.
Part 3: Dose Exploration in 
CRC
Subjects with advanced 
CRC will be enrolled in the dose-exploration part. 
Cohort A 
 Subjects:
Cohort A subjects (ie, Cohorts A1, A2, 
) must be systemic therapy-naïve in the recurrent/metastatic 
setting, and 
 must be naïve to irinotecan-containing treatment 
and must have progressed on an oxaliplatin-containing regimen in the first line of their treatment for 
recurrent/metastatic cancer. Based on the identified dose for durvalumab in combination with monalizumab 
from Part 1, subjects will receive durvalumab (1500 mg Q4W) in combination with monalizumab (750 mg 
Q2W) plus a standard chemotherapy regimen of a modified FOLFOX regimen comprised of folinic acid, 
fluorouracil, and oxaliplatin (mFOLFOX6 [Cohorts A1, A2, 
]) 
 in combination with bevacizumab (Cohorts A1 
) or cetuximab 
(Cohorts A2 
), 
. 
Initially, up to 6 subjects may be enrolled into each of the 4 chemotherapy cohorts with a biologic agent 
(Cohorts A1, A2, 
). Initiation of Cohorts 
 (chemotherapy cohorts without a biologic agent) 
will be staggered and dependent on emerging safety data from Cohorts A1 and A2, 
, 
respectively. Administration of the first dose of investigational products and chemotherapy will be staggered by
a minimum of 24 hours between the first and second subjects in all 6 cohorts and no more than 3 of the initial 
subjects in a given cohort will be dosed within 1 week. Subsequently, subjects may be enrolled continuously 
without pausing the enrollment for DEC review of aggregate safety data until a total of 6 subjects have been 
enrolled in a given cohort and observed thru the DLT observation period or > 2 subjects experience a DLT in a 
particular cohort prior to enrolling 6 subjects. Meetings of the study DEC will be held to review all available 
safety, PK, pharmacodynamic, immunogenicity, and clinical activity data to determine whether to continue 
enrollment at the current dose level, dose de-escalate, or stop further evaluation of the combination with 
chemotherapy, with or without a biologic agent, according to the mTPI algorithm. If the DEC decides to 
continue at the current dose level after the initial 6 subjects have been enrolled and evaluated for DLTs, 
enrollment may increase by up to an additional 12 subjects per chemotherapy cohort provided criteria for de-
escalation according to the mTPI algorithm are not met at any point based on ongoing assessment of safety. In 
addition, while enrollment is ongoing, the DEC will review aggregate safety data once a total of 12 or 18 
subjects in a given cohort have been enrolled and followed through the DLT-evaluation period.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
11 of 206
Template 16.2
Cohort C Subjects:
Cohort C subjects (ie, Cohorts C1 and C2) 
 
 
CRC that is 
 (Cohort C1) or 
 
(Cohort C2); prior standard chemotherapy must include i) fluoropyrimidines, irinotecan, and oxaliplatin; and ii) 
an anti-vascular endothelial growth factor (VEGF) monoclonal antibody (mAb; eg, bevacizumab); and iii) 
subjects in Cohort C2 must not have received prior anti-EGFR therapy (eg, cetuximab or panitumumab naïve). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For all cohorts in Part 3, safety will be monitored on an ongoing basis and aggregate safety data will be 
reviewed by the DEC at pre-specified intervals as described below. 
 
Dose modification of 
individual chemotherapy agents and/or the biologic agents for the management of toxicity in individual subjects 
will be allowed as per standard clinical practice 
 
.
TARGET SUBJECT POPULATION
In both the dose-escalation and dose-expansion parts of the study, male or female adult subjects ≥ 18 years of 
age, with select advanced solid tumors who are naïve to immunotherapy (subjects entering Part 1 [dose 
escalation] may have received prior immunotherapy) and subjects entering Parts 1 and 2 must have received and 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
12 of 206
Template 16.2
have progressed or are refractory to at least one line of standard systemic therapy in the recurrent/metastatic 
setting, appropriate for the specific tumor type, are eligible. 
Subjects with the following tumor types may be enrolled in each part of the study as specified below.
1
CRC
(a)
Part 1 and Part 2: Subjects who have received up to 3 lines of prior systemic therapy. 
(b)
Part 3 Cohort A (ie, Cohorts A1, A2 
): Subjects must be 1L chemotherapy-naïve in the 
recurrent/metastatic setting; subjects may have progressed ≥ 6 months after receiving an oxaliplatin 
chemotherapy regimen in the adjuvant setting. 
(i)
Subjects in Cohorts A1 
 can be enrolled regardless of 
 and 
location of colon primary tumor.
(ii)
Subjects in Cohort A2 are required to be
 and have a left-
sided colon primary tumor.
(c)
Part 3 
: Subjects must have received only 1 line of prior therapy 
containing oxaliplatin in the recurrent/metastatic setting and must be naïve to treatment containing an 
irinotecan combination. 
(i)
Subjects in 
 can be enrolled regardless of 
 and 
location of colon primary tumor.
(ii)
Subjects in 
 are required to be 
.
(d)
Part 3, Cohort C (ie, Cohorts C1A, C1B, C2A, and C2B): Subjects
 
prior standard 
chemotherapy must include i) fluoropyrimidines, irinotecan, and oxaliplatin; and ii) an anti-VEGF 
mAb (eg, bevacizumab); and iii) subjects in Cohorts C2A and C2B must not have received prior anti-
EGFR therapy (eg, cetuximab or panitumumab naïve).
(i)
Subjects in Cohort C1A and C1B are required to have documented 
.
(ii)
Subjects in Cohort C2A and C2B are required to be wild type for 
.
2
Ovarian cancer (Part 1 and Part 2): Subjects may have received up to 3 prior lines of systemic therapy 
(including standard and investigational therapies) in the recurrent/metastatic setting. All subjects must have 
previously received and progressed while on or within 6 months of completing a platinum-based regimen.
3
endometrial cancer (Part 1 and Part 2): Subjects who have received up to 2 lines of prior systemic 
therapy (including standard and investigational therapies) in the recurrent/metastatic setting and whose 
tumors must NOT have high-frequency microsatellite instability.
4
NSCLC (Part 1 and Part 2): Subjects must have histologically proven, stage IIIb or stage IV NSCLC or 
recurrent or PD following multi-modal therapy (radiation therapy, surgical resection or definitive 
chemoradiation) for locally advanced disease. Subjects with known sensitizing EGFR-mutation or 
anaplastic lymphoma kinase-rearrangement are excluded. All subjects’ tumors must be tested and shown to 
be wild type EGFR and anaplastic lymphoma kinase. Subjects must have received up to 2 lines of systemic 
therapy (including standard and investigational therapies) in the recurrent/metastatic setting.
5
Cervical cancer, castration-resistant prostate cancer, or pancreatic adenocarcinoma (Part 1 only) – Subjects 
may have received up to 2 prior lines of systemic therapy for recurrent/metastatic disease. Subjects with 
castration-resistant prostate cancer must have progressed following therapy with abiraterone or 
enzalutamide.
INVESTIGATIONAL PRODUCT, DOSAGE, AND MODE OF ADMINISTRATION
In the dose-escalation part of the study, sequential cohorts will receive durvalumab (1500 mg Q4W) in 
combination with monalizumab at 
 planned dose levels via IV infusion (
 Q2W). 
The combination of monalizumab 750 mg Q2W and durvalumab 1500 mg Q4W was deemed safe by the DEC; 
therefore, these doses and associated regimens will be employed in the dose expansion and exploration parts of 
the study.
Both durvalumab and monalizumab will be administered over approximately 60 minutes. On dosing days when 
both durvalumab and monalizumab are administered, durvalumab will be administered first with monalizumab 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
13 of 206
Template 16.2
starting 15 to 30 minutes after the completion of the durvalumab infusion. Ongoing monitoring of potential 
infusion reactions will be performed and pre-treatment of hypersensitivity and/or adjustment of infusion rate 
will be allowed as detailed in the protocol. 
In the dose-exploration part of the study, subjects will receive study treatment based on prior therapies received 
 (see Target Subject Population): 
•
In addition to durvalumab and monalizumab combination therapy, Cohort A subjects will also receive a 
regimen of 

mFOLFOX6 with bevacizumab (Cohort A1) or 

mFOLFOX6 with cetuximab (Cohort A2) or 

.
•
 
 


 

 
•
 
•
mFOLFOX6, 
, and the biologic agent (bevacizumab or cetuximab) will be administered according to 
standard-of-care prescribing information outlined in this protocol and summarized below: 
•
mFOLFOX6 (Cohorts A1, A2, 
): Oxaliplatin 85 mg/m2 IV infusion on Day 1 plus folinic acid 
400 mg/m2 IV infusion on Day 1 plus fluorouracil 400 mg/m2 IV bolus on Day 1, followed by 2400 mg/m2
administered by continuous IV infusion over 46 to 48 hours starting on Day 1; repeat Q2W.
•
•
Bevacizumab (Cohorts A1 
): 5 mg/kg IV infusion on Day 1 then Q2W.
•
Cetuximab (Cohorts A2 
): Loading dose of 400 mg/m2 IV infusion over 2 hours on Day 1, followed 
by maintenance dose of 250 mg/m2 IV infusion over 1 hour every week starting on Day 8. The cetuximab 
regimen may be changed to 500 mg/m2 IV infusion for approximately 2 hours Q2W after a subject has 
completed the 28-day DLT-evaluation period, at the investigator’s discretion and in accordance with 
institutional guidelines.
•
Cetuximab (Cohorts C1A, C1B, C2A, C2B): 500 mg/m2 IV infusion over 2 hours on Day 1 then 
500 mg/m2 IV infusion for approximately 2 hours Q2W starting on Day 15. 
STATISTICAL ANALYSIS PLAN
Sample Size
 
 
 Additional subjects 
may be required if additional cohorts or dosing schedules are explored.
Part 1: In the dose-escalation part, the number of subjects to be enrolled will depend upon the toxicities 
observed as the study progresses. Following an mTPI dose-escalation design for 5 dose levels, with a minimum 
of 3 subjects and a maximum of 12 subjects for each dose level, up to 60 evaluable subjects may be enrolled. An 
additional 6 subjects per dose level may be enrolled, up to a maximum of 18 subjects per dose level to provide 
additional PK, pharmacodynamic, and safety data.
Part 2: In the dose-expansion part, up to 160 subjects (40 subjects per tumor-type cohort) may be enrolled to 
obtain preliminary assessment of safety and antitumor activity in each tumor type. Enrollment may proceed up 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
14 of 206
Template 16.2
to approximately 40 subjects in the CRC, ovarian, and endometrial expansion cohorts 
 
. The observed 0/20 response gives an upper limit of a 1-sided 
% confidence 
interval (CI) of approximately %, which means that a response rate greater than % can be ruled out with 
% confidence and hence enrollment would be stopped for lack of desirable response rate.
Enrollment may proceed up to approximately 40 subjects in the NSCLC expansion cohort 
. Observing 1/20 response gives an upper limit of a 1-sided 
% CI of approximately 
%, which means that a response rate greater than 
% can be ruled out with 
% confidence and enrollment 
would be stopped for lack of desirable response rate.
Part 3 (Cohorts A 
): In Part 3 (dose exploration in 
CRC, Cohorts A1, A2, 
), the 
number of subjects to be enrolled will depend upon the toxicities observed as the study progresses. Based on an 
mTPI dose-escalation design for up to 2 dose levels, with a minimum of 3 subjects and a maximum of 
12 subjects for each dose level, up to 144 evaluable subjects (ie, 2 dose levels across 6 chemotherapy cohorts 
with or without a biologic agent) may be enrolled. An additional 6 subjects per dose level may be enrolled, up to 
a maximum of 18 subjects per dose level (ie, a total of 216 evaluable subjects in 2 dose levels across 
6 chemotherapy combination cohorts with or without a biologic agent) to provide additional PK, 
pharmacodynamic, and safety data.
Part 3 (Cohort C): In Part 3 (dose exploration in 
CRC, Cohorts C1 and C2), up to 100 subjects/cohort 
may be enrolled in Cohorts C1A and C1B. A total of 100 subjects would provide a width of < % between the 
observed objective response rate and its lower limit of the exact 
% CI. 
Up to 40 subjects/cohort may be enrolled in Cohorts C2A and C2B.
 
Statistical Analyses
Safety
The MTD will be determined by isotonic regression analysis (Ji et al, 2010) applied to DLT rates observed 
during the dose-escalation part. The MTD evaluation will be based on the DLT-evaluable Population, which 
includes all subjects enrolled in the dose-escalation part who receive investigational product per protocol and 
complete the safety follow-up through the DLT-evaluation period or who experience any DLT during the 
DLT- evaluation period.
Safety data, including AEs, SAEs, laboratory evaluations, vital signs, physical examinations, and ECG results 
will be summarized based on the As-treated Population. The As-treated Population includes all subjects who 
receive any investigational product. Summary statistics will be provided for AEs, SAEs, AE grade, severity, 
relationship to investigational products, clinical laboratory parameters, physical examinations, vital signs, and 
ECG. AEs will be graded according to the NCI CTCAE v4.03 and described by system organ class and 
preferred term using the Medical Dictionary for Regulatory Activities. Laboratory abnormalities with toxicity 
grades according to the NCI CTCAE v4.03 will be derived and summarized.
Antitumor activity
The analyses of antitumor activity will be based on the As-treated Population for the nonrandomized cohorts 
and on the Intent-to-treat (ITT) Population for the randomized cohorts. The ITT Population includes subjects 
who are randomized, and they will be analyzed according to the treatment group they were randomized to. The 
rates of OR and DC based on RECIST 1.1 will be summarized with 
% and 
% CIs based on the exact 
binomial distribution. Time-to-event endpoints (DoR, PFS, and OS) will be analyzed using the Kaplan-Meier 
method. Additional analyses of antitumor activity may be conducted in the Response-evaluable Population 
which includes subjects in the As-treated Population for the nonrandomized cohorts and in the ITT Population 
for the randomized cohorts, who have at least 1 post-baseline disease assessment, who died from any cause, or 
who discontinued due to clinical PD prior to any post-baseline tumor assessment.
Pharmacokinetics
Individual concentrations will be tabulated by dose cohort along with descriptive statistics. Individual cetuximab 
concentrations will also be summarized for Part 3, Cohort C1. Non-compartmental PK data analysis will be 
CCI
CCI
CC
CCI
CC
CCI
CCI
CCI
CCI
CC
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
15 of 206
Template 16.2
performed from each dose cohort with scheduled PK sample collection where data allow. Relevant descriptive 
statistics of non-compartmental PK parameters will be provided.
Anti-drug antibodies/immunogenicity
The immunogenic potential of durvalumab and monalizumab will be assessed by summarizing the number and 
percentage of subjects who develop detectable ADAs. The impact of ADAs on PK will be assessed if data 
allow. Samples will be collected for evaluating neutralizing capacity of ADAs in the future.
Pharmacodynamic biomarkers
Pharmacodynamic biomarkers will be analyzed descriptively. CD94/NKG2a receptor occupancy will be used to 
assess the pharmacodynamics of monalizumab.
Interim analysis 
For Part 3, Cohorts C1A, C1B, C2A, and C2B, an interim futility analysis will be performed after 20 subjects in 
each cohort are response-evaluable (including subjects who received the same dose during the DLT evaluation). 
Enrollment will stop 
. 
For Part 3, Cohorts C1A and C1B, a subsequent interim futility analysis will be performed after 40 subjects in 
each cohort are response-evaluable (including subjects who received the same dose during the DLT evaluation). 
Enrollment will stop 
. 
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
16 of 206
Template 16.2
TABLE OF CONTENTS
PROTOCOL SYNOPSIS...................................................................................................... 2
LIST OF ABBREVIATIONS ............................................................................................. 22
1
INTRODUCTION............................................................................................ 25
1.1
Disease Background ......................................................................................... 25
1.2
Monalizumab and Durvalumab Background ..................................................... 25
1.2.1
1.2.2
1.2.3
Durvalumab Background .................................................................................. 27
1.3
Summary of Nonclinical Experience................................................................. 27
1.3.1
Monalizumab Nonclinical Experience............................................................... 27
1.3.2
Durvalumab Nonclinical Experience................................................................. 27
1.4
Summary of Clinical Experience....................................................................... 27
1.4.1
Monalizumab Clinical Experience .................................................................... 27
1.4.1.1
Oncology Studies.............................................................................................. 28
1.4.2
Durvalumab Clinical Experience....................................................................... 30
1.4.3
Safety and Efficacy Results from the Current Ongoing Study ........................... 31
1.5
Rationale for Conducting the Study .................................................................. 35
1.5.1
Rationale for Evaluating Combinations of Durvalumab and Monalizumab with 
Chemotherapy and/or Biologic Agents.............................................................. 35
1.6
Benefit-Risk and Ethical Assessment................................................................ 38
1.6.1
Potential Benefits.............................................................................................. 38
1.6.2
Summary of Risks............................................................................................. 39
1.7
Research Hypotheses ........................................................................................ 40
1.7.1
Primary Hypothesis .......................................................................................... 40
1.7.2
Secondary Hypotheses...................................................................................... 40
2
OBJECTIVES AND ENDPOINTS................................................................... 41
2.1
Primary Objective and Associated Endpoints.................................................... 41
2.2
Secondary Objectives and Associated Endpoints............................................... 42
2.3
Exploratory Objectives and Associated Endpoints ............................................ 45
3
STUDY DESIGN ............................................................................................. 47
3.1
Description of the Study ................................................................................... 47
3.1.1
Overview…. ..................................................................................................... 47
3.1.2
Treatment Regimen........................................................................................... 52
3.1.2.1
Part 1: Dose Escalation ..................................................................................... 53
3.1.2.2
Part 2: Dose Expansion..................................................................................... 58
3.1.2.3
Part 3: Dose Exploration in
CRC ............................................................. 59
3.1.3
Management of Study Medication Related Toxicities ....................................... 64
3.1.3.1
Chemotherapy and Biologic Agent Dose Modification...................................... 64
3.2
Study Design and Dose Rationale ..................................................................... 66
3.2.1
Dose Rationale.................................................................................................. 66
3.2.1.1
Rationale for Monalizumab Dosing................................................................... 66
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
17 of 206
Template 16.2
3.2.1.2
Rationale for Durvalumab Dosing..................................................................... 67
3.2.1.3
Rationale for the Combination of Monalizumab and Durvalumab ..................... 68
3.2.1.4
Rationale for Cetuximab Dosing ....................................................................... 68
3.2.2
Rationale for Study Population ......................................................................... 68
3.2.3
Rationale for Dose-escalation Algorithm .......................................................... 70
3.2.4
Rationale for Endpoints .................................................................................... 70
3.3
Study Mitigation During Study Disruptions Due to Cases of Civil Crisis, 
Natural Disaster, or Public Health Crisis........................................................... 71
4
MATERIALS AND METHODS ...................................................................... 72
4.1
Subjects ............................................................................................................ 72
4.1.1
Number of Subjects .......................................................................................... 72
4.1.2
Inclusion Criteria .............................................................................................. 75
4.1.3
Exclusion Criteria ............................................................................................. 82
4.1.4
Subject Enrollment and Randomization ............................................................ 84
4.1.5
Withdrawal from the Study............................................................................... 85
4.1.5.1
Withdrawal from Treatment.............................................................................. 85
4.1.5.2
Withdrawal of Consent ..................................................................................... 85
4.1.6
Discontinuation of Investigational Product........................................................ 85
4.1.7
Treatment Beyond Progression ......................................................................... 86
4.1.8
Re-treatment Following Relapse ....................................................................... 86
4.1.9
Replacement of Subjects................................................................................... 87
4.1.10
Withdrawal of Informed Consent for Data and Biological Samples................... 87
4.2
Schedule of Study Procedures........................................................................... 88
4.2.1
Enrollment/Screening Period ............................................................................ 89
4.2.2
Treatment Period .............................................................................................. 90
4.2.3
Follow-up Period ............................................................................................ 111
4.3
Description of Study Procedures..................................................................... 115
4.3.1
Antitumor Activity.......................................................................................... 115
4.3.1.1
Tumor Evaluations.......................................................................................... 115
4.3.1.2
Evaluation of Response by Response Evaluation Criteria in Solid Tumors...... 116
4.3.1.3
4.3.2
Tissue Biopsies............................................................................................... 120
4.3.2.1
Fresh Tissue Biopsies ..................................................................................... 120
4.3.2.2
Archival Tumor Samples ................................................................................ 121
4.3.3
Patient Reported Outcomes (Part 3, Cohorts C1A and C1B only).................... 122
4.3.3.1
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire.................................................................................................. 124
4.3.3.2
Patient Global Impression of Change .............................................................. 125
4.3.4
Medical History, Physical Examination, Electrocardiogram, ECOG 
Performance Status, Weight, and Vital Signs .................................................. 125
4.3.4.1
Medical History and Physical Examination..................................................... 125
4.3.4.2
Electrocardiograms......................................................................................... 125
4.3.4.3
ECOG Performance Status.............................................................................. 126
4.3.4.4
Vital Signs...................................................................................................... 126
4.3.5
Clinical Laboratory Tests................................................................................ 126
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
18 of 206
Template 16.2
4.3.6
Pharmacokinetic Evaluation and Methods....................................................... 128
4.3.7
Immunogenicity Evaluation and Methods ....................................................... 128
4.3.8
4.3.9
Estimate of Volume of Blood to be Collected ................................................. 130
4.4
4.5
Investigational Products.................................................................................. 131
4.5.1
Identity of Investigational Product(s) .............................................................. 131
4.5.1.1
Investigational Product Inspection .................................................................. 132
4.5.1.2
Investigational Product Dose Preparation and Administration......................... 133
4.5.1.3
Treatment Administration............................................................................... 137
4.5.1.4
Monitoring of Dose Administration ................................................................ 137
4.5.1.5
Reporting Product Complaints ........................................................................ 138
4.5.2
Additional Study Medications......................................................................... 138
4.5.2.1
Standard-of-Care Chemotherapy/Biologic Agents........................................... 138
4.5.3
Labeling ......................................................................................................... 139
4.5.4
Storage ........................................................................................................... 139
4.5.5
Treatment Compliance.................................................................................... 139
4.5.6
Accountability ................................................................................................ 139
4.6
Treatment Assignment and Blinding ............................................................... 139
4.6.1
Methods for Assigning Treatment Groups....................................................... 139
4.6.2
Methods for Ensuring Blinding....................................................................... 140
4.7
Restrictions During the Study and Concomitant Treatment(s) ......................... 140
4.7.1
Permitted Concomitant Medications ............................................................... 140
4.7.2
Prohibited Concomitant Medications .............................................................. 141
4.8
Statistical Evaluation ...................................................................................... 141
4.8.1
General Considerations................................................................................... 141
4.8.2
Sample Size.................................................................................................... 142
4.8.2.1
Part 1 (Dose Escalation).................................................................................. 142
4.8.2.2
Part 2 (Dose Expansion) ................................................................................. 142
4.8.2.3
Part 3 (Dose Exploration in 
CRC).......................................................... 143
4.8.3
Efficacy .......................................................................................................... 144
4.8.3.1
Antitumor Activity.......................................................................................... 144
4.8.4
Safety ............................................................................................................. 145
4.8.4.1
Analysis of Adverse Events ............................................................................ 145
4.8.4.2
Analysis of Clinical Laboratory Parameters .................................................... 145
4.8.4.3
Analysis of Vital Signs ................................................................................... 146
4.8.4.4
Analysis of Electrocardiograms ...................................................................... 146
4.8.4.5
Analysis of ECOG Performance Status........................................................... 146
4.8.5
Analysis of Patient Reported Outcomes (Part 3, Cohort C1 only).................... 146
4.8.5.1
Analysis of the European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire.......................................................................... 146
4.8.5.2
Analysis of Patient Global Impression of Change............................................ 147
4.8.6
Analysis of Immunogenicity ........................................................................... 147
4.8.7
Analysis of Pharmacokinetics ......................................................................... 147
4.8.8
Analysis of Pharmacodynamic Biomarkers ..................................................... 148
4.8.9
Interim Analysis ............................................................................................. 148
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
19 of 206
Template 16.2
5
ASSESSMENT OF SAFETY ......................................................................... 148
5.1
Definition of Adverse Events.......................................................................... 148
5.2
Definition of Serious Adverse Events ............................................................. 149
5.3
Definition of Adverse Events of Special Interest............................................. 150
5.4
Recording of Adverse Events.......................................................................... 151
5.4.1
Time Period for Collection of Adverse Events ................................................ 152
5.4.2
Follow-up of Unresolved Adverse Events....................................................... 152
5.4.3
Deaths ............................................................................................................ 152
5.5
Reporting of Serious Adverse Events.............................................................. 152
5.6
Other Events Requiring Immediate Reporting................................................. 153
5.6.1
Overdose ........................................................................................................ 153
5.6.2
Potential Hy’s Law and Hy’s Law................................................................... 154
5.6.3
Pregnancy....................................................................................................... 154
5.6.3.1
Maternal Exposure.......................................................................................... 154
5.6.3.2
Paternal Exposure........................................................................................... 155
5.7
Safety Management During the Study............................................................. 155
6
STUDY AND DATA MANAGEMENT......................................................... 156
6.1
Training of Study Site Personnel..................................................................... 156
6.2
Monitoring of the Study.................................................................................. 156
6.2.1
Source Data .................................................................................................... 156
6.2.2
Study Agreements........................................................................................... 156
6.2.3
Archiving of Study Documents....................................................................... 157
6.3
Study Timetable and End of Study.................................................................. 157
6.4
Data Management........................................................................................... 158
6.5
Medical Monitor Coverage ............................................................................. 158
7
ETHICAL AND REGULATORY REQUIREMENTS.................................... 158
7.1
Subject Data Protection................................................................................... 158
7.2
Ethics and Regulatory Review ........................................................................ 159
7.3
Informed Consent ........................................................................................... 159
7.4
Changes to the Protocol and Informed Consent Form...................................... 160
7.5
Audits and Inspections.................................................................................... 160
8
REFERENCES............................................................................................... 161
9
CHANGES TO THE PROTOCOL ................................................................. 171
9.1
Protocol Amendment 6 ................................................................................... 171
9.2
Protocol Amendment 5 ................................................................................... 172
9.3
Protocol Amendment 4 ................................................................................... 175
9.4
Protocol Amendment 3 ................................................................................... 178
9.5
Protocol Amendment 2 ................................................................................... 187
9.6
Protocol Amendment 1 ................................................................................... 188
10
APPENDICES................................................................................................ 190

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
20 of 206
Template 16.2
10.1
Signatures....................................................................................................... 190
10.2
Additional Safety Guidance ............................................................................ 193
10.3
National Institute of Allergy and Infectious Disease and Food and Allergy 
Anaphylaxis Network Guidance for Anaphylaxis Diagnosis ........................... 195
10.4
Actions Required in Cases of Increases in Liver Biochemistry and Evaluation 
of Hy’s law..................................................................................................... 196
10.4.1
Introduction .................................................................................................... 196
10.4.2
Definitions...................................................................................................... 196
10.4.2.1
Potential Hy’s Law ......................................................................................... 196
10.4.2.2
Hy’s Law........................................................................................................ 196
10.4.3
Identification of Potential Hy’s Law Cases ..................................................... 197
10.4.4
Follow-up ....................................................................................................... 197
10.4.4.1
Potential Hy’s Law Criteria Not Met............................................................... 197
10.4.4.2
Potential Hy’s Law Criteria Met ..................................................................... 197
10.4.5
Review and Assessment of Potential Hy’s Law Cases..................................... 198
10.4.6
Actions Required When Potential Hy’s Law Criteria Are Met Before and After 
Starting Study Treatment in Subjects .............................................................. 199
10.4.7
Actions Required for Repeat Episodes of Potential Hy’s Law ......................... 199
10.4.8
Laboratory Tests............................................................................................. 200
10.5
Patient Reported Outcomes............................................................................. 202
10.5.1
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire.................................................................................................. 202
10.5.2
Patient Global Impression of Change .............................................................. 204
10.6
Changes Related to Mitigation of Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis .............................................. 205
10.6.1
Reconsent/reassent of Study Subjects During Study Interruptions................... 205
10.6.2
Home or Remote Visit to Replace On-site Visit (where applicable) ................ 205
10.6.3
Telemedicine Visit to Replace On-site Visit (where applicable) ...................... 205
10.6.4
Data Capture During Telemedicine or Home/Remote Visits............................ 206
LIST OF IN-TEXT TABLES
Table 1
Primary Objectives and Associated Endpoints ......................................... 41
Table 2
Secondary Objectives and Associated Endpoints...................................... 42
Table 3
Exploratory Objectives and Associated Endpoints ................................... 45
Table 4
Durvalumab Treatment Modification and Toxicity Management 
Guidelines for Immune-related Adverse Events Level.............................. 55
Table 5
Study Overview and Status Update.......................................................... 73
Table 6
Highly Effective Methods of Contraception............................................. 81
Table 7
Schedule of Screening/Baseline Procedures............................................. 89
Table 8
Schedule of Treatment Period Study Procedures Weeks 1 to 26............... 92
Table 9
Schedule of Treatment Period Study Procedures Weeks 27 to End of 
Treatment ................................................................................................ 97

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
21 of 206
Template 16.2
Table 10
Table 11
Table 12
Schedule of Treatment Period Study Procedures for Re-treatment after 
Relapse – Re-treatment Weeks 1 to 26................................................... 105
Table 13
Schedule of Treatment Period Study Procedures for Re-treatment after 
Relapse – Re-treatment Weeks 27 to End of Treatment.......................... 108
Table 14
Schedule of Follow-up Procedures......................................................... 112
Table 15
Evaluation of Overall Response at a Single Time Point by RECIST V1.1118
Table 16
Table 17
Eastern Cooperative Oncology Group Performance Status..................... 126
Table 18
Identification of Investigational Products............................................... 131
Table 19
Estimated Objective Response Rate and
% Confidence Interval Out of 
20 and 40 Subjects, Respectively ........................................................... 143
Table 20
Observed Objective Response Rate with 
% Confidence Interval ........ 144
LIST OF IN-TEXT FIGURES
Figure 1
Study IPH2201-203: Percent Reduction of Target Lesion from Baseline.. 29
Figure 2
Figure 3
Study Flow Diagram................................................................................ 51
Figure 4
Study Part 3 (Dose Exploration) Flow Diagram for Cohorts A 
....... 62
Figure 5
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
22 of 206
Template 16.2
LIST OF ABBREVIATIONS
Abbreviation or 
Specialized Term
Definition
1L
first-line
2L
second-line
ADA
anti-drugantibody
ADCC
antibody-dependent cellular cytotoxicity
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartateaminotransferase
BP
blood pressure
CD
cluster of differentiation
CI
confidence interval
CNS
central nervous system
CR
complete response
CRC
colorectal cancer
CrCl
creatinine clearance
CSP
clinical study protocol
CSR
clinical study report
CT
computed tomography
CTL
cytotoxic T lymphocyte
CTLA
cytotoxic T lymphocyte antigen
DC
disease control
DCO
Data cut off
DCR
disease control rate
DEC
dose-escalation committee
DLT
dose-limitingtoxicity
DoR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EGFR
epidermal growth factor receptor
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire
Fc
fragment crystallizable
FOLFOX
a chemotherapy regimen comprised of folinic acid, fluorouracil, and oxaliplatin
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
23 of 206
Template 16.2
Abbreviation or 
Specialized Term
Definition
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HCP
Health Care Professional
HLA
human leukocyte antigen
HRQoL
health-related quality of life
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IFNγ
interferon-γ
Ig
Immunoglobulin
IHC
Immunohistochemistry
imAEs
immune-mediated adverse events
INR
international normalized ratio
irAE
immune-related adverse event
IRB
Institutional Review Board
IRR
infusion-relatedreaction
IV
Intravenous
IXRS
interactive voice/web response system
mAb
monoclonal antibody
mFOLFOX6
a modified FOLFOX regimen comprised of folinic acid, fluorouracil, and 
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
mTPI
modified toxicity probability interval
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NK
natural killer
NSCLC
non-small cell lung cancer
OR
objective response
ORR
objective response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PD
progressive disease
PD-1
programmed death 1
PD-L1
programmed death ligand 1
PFS
progression-free survival
PGIC
Patient Global Impression of Change
PK
pharmacokinetics
PR
partial response
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
24 of 206
Template 16.2
Abbreviation or 
Specialized Term
Definition
PRO
patient reported outcome
PT
preferred term
Q1W
every week
Q2W
every 2 weeks
Q4W
every 4 weeks
QoL
quality of life
QTcB
QT corrected using Bazett’s formula
QTcF
QT corrected using Fridericia’s formula
RA
rheumatoid arthritis
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SCCHN
squamous cell carcinoma of the head and neck
SD
stable disease
SID
subject identification
TBL
total bilirubin
TPV
third-party vendor
ULN
upper limit of normal
UPM
unit probability mass
USA
United States of America
VEGF
vascular endothelial growth factor
WFI
water for injection
w/v
weight per volume

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
25 of 206
Template 16.2
1
INTRODUCTION
1.1
Disease Background
Despite considerable advancements made during the last decade, patients with recurrent or 
metastatic solid tumors including non-small cell lung cancer (NSCLC), colorectal cancer 
(CRC), endometrial cancer, and ovarian cancer have poor outcomes with currently available 
therapies. For example, second-line (2L) and third-line (3L) therapies in metastatic CRC are 
typically irinotecan or epidermal growth factor receptor (EGFR)-targeting monoclonal 
antibody (mAb) based (Rougier et al, 1998; Van Cutsem et al, 2007). However, anticipated 
survival with multi-agent combination regimens remains less than 6 months (Peeters et al, 
2010). In addition, following initial treatment with systemic chemotherapy, median overall 
survival (OS) (Rougier et al, 1998) is 12.3 months for NSCLC (Sandler et al, 2006).
1.2
Monalizumab and Durvalumab Background
1.2.1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
26 of 206
Template 16.2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2.2
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
27 of 206
Template 16.2
 
 
1.2.3
Durvalumab Background
Durvalumab is a human IgG1 kappa mAb directed against human programmed cell death 
ligand 1 (PD-L1). Durvalumab is expressed in Chinese hamster ovary cells and has an overall 
molecular weight of approximately 149 kDa. Durvalumab selectively binds human PD-L1 
with high affinity and blocks its ability to bind to programmed death 1 (PD-1) and CD80. The 
fragment crystallizable (Fc) domain of durvalumab contains a triple mutation in the constant 
domain of the IgG1 heavy chain that reduces binding to the complement component C1q and 
the Fc gamma receptors responsible for mediating antibody-dependent cell-mediated 
cytotoxicity (Oganesyan et al, 2008).
1.3
Summary of Nonclinical Experience
1.3.1
Monalizumab Nonclinical Experience
For nonclinical information on monalizumab, refer to the current Investigator’s Brochure.
1.3.2
Durvalumab Nonclinical Experience
For nonclinical information on durvalumab, refer to the current Investigator’s Brochure.
1.4
Summary of Clinical Experience
Refer to the current Investigator’s Brochures for further details of the clinical experience 
obtained with monalizumab and durvalumab.
1.4.1
Monalizumab Clinical Experience
The safety and tolerability as well as single-dose and multiple-dose pharmacokinetic (PK) and 
pharmacodynamic properties of monalizumab were initially investigated in patients with 
active RA (NN8765-3658 trial [completed]). Monalizumab is now being developed for the 
treatment of various hematologic malignancies and solid tumors as monotherapy or in 
combination with other drugs. As of 23 April 2018, a total of 383 patients have been treated 
with monalizumab: 68 patients in the Phase 1 RA study and 315 patients in 
7 hematology/oncology studies.  
As of 23 April 2018, two studies are completed:

IPH2201-201 is a monotherapy, open-label, single-arm Phase 1b/2 study, assessing the 
pre-operative administration of monalizumab in patients with locally advanced resectable 
squamous cell carcinoma of the oral cavity.
 
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
28 of 206
Template 16.2

IND.221 is an investigator-sponsored study conducted by the Canadian Cancer Trials 
Group. It is a dose-ranging study of monalizumab in patients with gynecologic 
malignancies (ovarian, endometrial, and cervical cancer). This study is completed.
As of 23 April 2018, in addition to the current study (Section 1.4.3), the following 4 studies 
are ongoing:

IPH2201-202 is an open-label, Phase 1b/2a study of a combination of monalizumab and 
ibrutinib in patients with relapsed, refractory, or previously untreated chronic 
lymphocytic leukemia.

IPH2201-203 is a Phase 1b/2 study of a combination of monalizumab and cetuximab in 
subjects with HPV (+) and HPV (-) recurrent or metastatic SCCHN. 

PIRAT-IPC 2015-018 is an investigator-sponsored study conducted by the “Paoli 
Calmettes Institute” in France. This is an open-label, Phase 1, dose-ranging study of 
single-dose monalizumab administration in patients following HLA-matched allogeneic 
hematopoietic stem cell transplantation.

EORTC-1559-HNCG is an investigator-sponsored study conducted by EORTC. This is a 
pilot study of personalized biomarker-based treatment strategy or immunotherapy in 
patients with recurrent/metastatic SCCHN ("UPSTREAM").
1.4.1.1
Oncology Studies
As of 23 April 2018, in hematology/oncology trials, 315 patients have been treated with 
multiple intravenous (IV) doses of monalizumab at up to 10 mg/kg or 750 mg. Most of the 
reported adverse events (AEs) were of Grade 1 to 2. There was no obvious dose relationship 
for AEs. The most frequent (≥5%) AEs considered by the investigators as related to 
monalizumab in monotherapy were headache (23%), nausea (18%), fatigue (16%), vomiting 
(15%), anorexia (11%), diarrhea, abdominal pain, and sore throat (10% each), myalgia (8%), 
hot flashes, dry mouth, and other respiratory, thoracic and mediastinal disorders (7% each), 
blurred vision, dyspnea, and flu like symptoms (5% each). There were no deaths related to 
treatment. The safety data obtained did not change the overall safety or risk/benefit profile of 
monalizumab; the data supported continuation of the clinical development of monalizumab for 
the treatment of various malignancies as monotherapy and combination therapy 
(Monalizumab Investigator’s Brochure).
As of 23 April 2018, 57 subjects with SCCHN have been enrolled in IPH2201-203 and have 
received monalizumab every 2 weeks (Q2W) at doses of 0.4 to 10 mg/kg in combination with 
cetuximab every week (Q1W) according the approved labeling. A total of 57 subjects (100%) 
experienced at least one AE, and 42 subjects (74%) reported at least one AE considered as 
related to monalizumab or the combination with cetuximab. The most frequently reported 
treatment-related AEs were fatigue/asthenia (21%), rash and headache (11% each), nausea, 
hypomagnesemia, and hypophosphatemia (9% each), pyrexia and stomatitis (7% each), dry 
skin, pruritus, diarrhea, vomiting, decreased appetite, and weight decreased (5% each). 
Cetuximab-related toxicities (eg skin disorders) did not appear to be exacerbated by 

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
29 of 206
Template 16.2
monalizumab. Twenty-four subjects (42%) experienced at least one Grade 3 or Grade 4 AE, 
of which 7 subjects (12%) had at least one treatment-related event. The most frequent Grade 3 
to 4, treatment-related AE was hypophosphatemia, experienced by 3 subjects. Others were 
fatigue, stomatitis, colitis, interstitial lung disease, and lymphopenia (1 subject each). Three 
subjects discontinued treatment due to AEs, all of which were reported as serious (one subject 
experienced interstitial lung disease and colitis; these events occurred in the context of sepsis 
and were reported as related by the investigator but were considered as not related by the 
sponsor; one subject with cardiac history experienced dyspnea and atrial fibrillation; one 
subject experienced tracheostomy malfunction due to progressive disease [PD]). Three 
subjects (5%) experienced treatment-related serious adverse events (SAEs; one subject 
experienced interstitial lung disease and colitis which led to treatment discontinuation; one 
subject experienced hypophosphatemia; and one subject experienced dizziness). No IRRs or 
treatment-related deaths were reported. The overall safety profile of the combination was 
manageable and appeared similar to the single agent experience with either agent 
(Monalizumab Investigator’s Brochure). 
As of 09 March 2018, 26 subjects were evaluable for efficacy, which included 25 subjects 
with at least 1 post-baseline assessment and 1 subject who died due to PD at Week 8 without 
post-baseline assessment: 8 (31%) subjects had a best response of partial response (PR) and 
14 (54%) subjects had a best response of stable disease (SD; Figure 1). This response rate is 
higher than the historical data with single-agent cetuximab in this patient population 
(objective response rate [ORR] 13%). Refer to Cohen et al, 2018 for additional details.
Figure 1
Study IPH2201-203: Percent Reduction of Target Lesion from Baseline

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
30 of 206
Template 16.2
1.4.2
Durvalumab Clinical Experience
As of the data cut-off (DCO) date (12 July 2018), across the entire clinical development 
program, approximately 5127 patients have received durvalumab in AstraZeneca or 
MedImmune-sponsored interventional studies in multiple tumor types, stages of disease, and 
lines of therapy. Of these, 2229 patients received durvalumab monotherapy, 1573 patients 
received durvalumab in combination with tremelimumab, and 1325 patients received 
durvalumab in combination with an investigational and/or an approved product. An estimated 
8252 patients are currently enrolled in blinded studies. In addition, 1637 patients have 
participated in the durvalumab Early Access Program (Study D4194C00002 for patients with 
locally advanced, unresectable NSCLC whose disease has not progressed following platinum-
based chemoradiation therapy). The total post-marketing exposure to durvalumab to 12 July 
2018 was estimated to be approximately 1854 patient-years.
The safety profile of durvalumab as monotherapy and combined with other anticancer agents 
is consistent with the pharmacology of the target and other agents in the immune checkpoint 
inhibitor class. Most adverse drug reactions seen with the immune checkpoint inhibitor class 
of agents are thought to be due to the effects of inflammatory cells on specific tissues and 
could occur in any organ system. Adverse events of special interest (AESIs) and 
immune-mediated adverse events (imAEs)/immune-related adverse events (irAEs) observed 
with anti-PD-L1/PD-1 agents such as durvalumab and durvalumab in combination with 
tremelimumab include pneumonitis, hepatitis, diarrhea/colitis, intestinal perforation, 
endocrinopathies (hypothyroidism, hyperthyroidism, adrenal insufficiency, 
hypophysitis/hypopituitarism and type 1 diabetes mellitus), nephritis, rash/dermatitis, 
pancreatitis, myocarditis, myositis/polymyositis and rare/less frequent imAEs/irAEs including 
neuromuscular toxicities such as myasthenia gravis and Guillain-Barre syndrome. AESIs of 
IRRs are also included. AESIs, including imAEs/irAEs reported in AstraZeneca- or 
MedImmune-sponsored durvalumab studies are defined as AEs that include, but are not 
limited to, events with a potential inflammatory- or immune-mediated mechanism that may 
require more frequent monitoring and/or interventions such as corticosteroids, 
immunosuppressants, and/or endocrine therapy. A number of selected preferred terms (PTs) 
are used for each AESI category.  
In addition, in studies where the data are clean and validated, an adjudication process has been 
conducted to identify imAEs/irAEs. These are AESIs of special interest (excluding infusion 
related/hypersensitivity/anaphylactic reaction) consistent with an immune-mediated 
mechanism that required treatment with systemic corticosteroids, other immunosuppressants, 
or endocrine therapy and where there was no clear alternate etiology. Serologic, immunologic, 
and histologic (biopsy) data, as appropriate, were used to support the characterization of an 
imAE. These AESIs, including imAEs/irAEs, are manageable by available/established 
treatment guidelines as described in Section 3.1.3.  

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
31 of 206
Template 16.2
In the durvalumab clinical program, no tumor types appeared to be associated with unique 
AEs.
Refer to the current durvalumab Investigator’s Brochure for a complete summary of clinical 
information including safety, efficacy, and PK.
1.4.3
Safety and Efficacy Results from the Current Ongoing Study
Part 1 (Dose-escalation) and Part 2 (Dose-expansion)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
32 of 206
Template 16.2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
33 of 206
Template 16.2
Figure 2
 
Part 3 (Dose exploration in 
CRC)
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
34 of 206
Template 16.2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
35 of 206
Template 16.2
 
1.5
Rationale for Conducting the Study
Recent nonclinical and clinical research has demonstrated that the immune system is capable 
of targeting and eliminating cancers. Stimulating an antitumor immune response of the 
adaptive immune system by activating T cells through inhibition of cytotoxic T-lymphocyte 
antigen (CTLA)-4 has proven beneficial in patients with advanced metastatic melanoma (Hodi 
et al, 2010). Similarly, antibodies blocking the PD-1/PD-L1 pathway have demonstrated 
antitumor activity in multiple tumor types. For example, pembrolizumab and nivolumab have 
recently been approved for the treatment of melanoma and NSCLC (Dummer et al, 2015; 
Rizvi et al, 2015a; Weber et al, 2015). 
Despite the advances in targeting immune checkpoints such as PD-L1 to treat cancer, there 
remains an unmet need in many patients with solid tumors.
1.5.1
Rationale for Evaluating Combinations of Durvalumab and 
Monalizumab with Chemotherapy and/or Biologic Agents
Despite advances in chemotherapy regimens in combination with biologics in the treatment of 
CRC, a significant number of patients progress within 6 months after receiving either 
first or 2L chemotherapy. Furthermore, among patients who are beyond 2L treatment, even 
greater numbers progress within 6 months of their last treatment. Current investigations are 
now adding immunotherapeutics to chemotherapeutics, targeted therapies, and 
antiangiogenics to broaden antitumor responses. Immune checkpoint inhibitor therapy can 
provide durable responses, and using these agents in combination with standard-of-care 
chemotherapy and/or a biologic agent can theoretically extend this effect, potentially leading 
to benefit in patients who have a significant clinical unmet need.
Monotherapy with checkpoint inhibitors in subjects with 
CRC has resulted in limited or 
no antitumor activity. For example, an ORR of 0% was reported when pembrolizumab 
10 mg/kg Q2W was administered to subjects with microsatellite proficient CRC (Le et al, 
2015). On the other hand, studies of monotherapy with pembrolizumab 200 mg Q3W or 
10 mg/kg Q2W and nivolumab 3 mg/kg Q2W in subjects with microsatellite instability-high 
CRC or mismatch repair deficient CRC have reported an ORR of 36% for pembrolizumab 
(FDA, 2017a) and 28% for nivolumab (FDA, 2017b). 
Cytotoxic chemotherapy has been shown to modulate the immune response by several 
mechanisms, such as stimulating T-cell activation via increasing the expression of major 
histocompatibility complex-1 molecules (Liu et al, 2010), stimulating dendritic cell 
maturation (Liu et al, 2010), and inducing immunogenic cell death (a form of cell death that 
induces dendritic cells to stimulate tumor antigen presentation to T cells) (Kroemer et al, 
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
36 of 206
Template 16.2
2013), and reducing the immunosuppressive function of regulatory T cells (Zhang et al, 2008) 
and MDSCs (Kodumudi et al, 2010). Combining durvalumab, a PD-L1 antagonist, with 
cytotoxic agents may provide complementary benefit in mounting an effective antitumor 
immunity by promoting antigen presentation, increasing the production of protective T cells, 
and overcoming immunosuppression in the tumor bed (Mellman et al, 2011). A variety of 
approaches for combining PD-1 pathway blockers with other agents have been explored over 
the past few years in an effort to both improve the efficacy of therapy and/or position the 
treatment regimen for testing in treatment-naïve patients with a variety of cancers. Approaches 
have included combinations with other checkpoint inhibitors (eg, ipilimumab), 
immunostimulatory cytokines (eg, interferon-γ [IFNγ]), cytotoxic chemotherapy, anti-
angiogenic inhibitors, and small-molecule molecularly targeted therapies, many with 
promising results and an acceptable toxicity profile (Philips and Atkins, 2015). Data for 
durvalumab with or without tremelimumab plus standard platinum-based chemotherapy in 
advanced cancers are being generated from 2 ongoing Phase 1 studies; a MedImmune-
sponsored study (D4191SC0001, unpublished data on file) and a Phase 1b study conducted by 
the Canadian Cancer Trials Group (NCT02537418; Daaboul et al, 2017). The combinations 
tested were tolerable and manageable. 
The combination of immunotherapies and biologic agents may also be beneficial. In 
metastatic CRC, cetuximab is currently indicated for patients whose tumors do not have 
 
, as retrospective analysis shows that presence of these mutations correlates with 
lack of clinical benefit (Karapetis et al, 2008). While these data suggest that EGFR pathway 
inhibition is more important than ADCC in CRC, both mechanisms may contribute. 
Retrospective analysis of patients with wild type as well as KRAS mutant metastatic CRC, 
treated with cetuximab, shows a survival advantage for those with high-affinity Fc gamma 
receptor polymorphisms associated with improved antibody effector function (Liu et al, 2016). 
Monalizumab, via its effects on NK cells, could potentially enhance the ADCC activity of 
cetuximab (Ferris et al, 2018; Ochoa et al, 2017; Wang et al, 2015); in turn, cetuximab-
mediated tumor cell death could potentially lead to release of tumor antigens and enhance the 
antitumor immune response along with durvalumab and monalizumab (Ferris et al, 2018). 
Furthermore, there is evidence suggesting that an anti-angiogenesis agent such as 
bevacizumab could enhance the antitumor effects of checkpoint inhibitor therapy (Manegold 
et al, 2017; Wallin et al, 2016).
Checkpoint inhibitors in combination with chemotherapy have been tested in subjects with 
metastatic CRC. In an open-label Phase 1b study, subjects with refractory, metastatic CRC 
were treated with atezolizumab (an anti-PD-1 agent) 20 mg/kg Q3W in combination with 
bevacizumab 15 mg/kg Q3W (Arm A) and a group of oxaliplatin-naïve subjects with 
metastatic CRC received atezolizumab 14 mg/kg Q2W in combination with bevacizumab 
10 mg/kg Q2W and folinic acid, fluorouracil, and oxaliplatin (FOLFOX) at standard doses 
(Arm B). In Arm A (n=14), Grade 3 to 4 AEs regardless of attribution were 64%, including 
abdominal pain, hyperbilirubinemia and pneumonia (14% each). In Arm B (n=30), 73% of 
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
37 of 206
Template 16.2
subjects had Grade 3 to 4 AEs, including neutropenia (40%), diarrhea (13%), increased ALT 
(10%) and increased AST (10%). Grade ≥ 3 atezolizumab-related AEs were 7% in Arm A and 
20% in Arm B. For subjects with ≥ 1 tumor assessment, the unconfirmed ORR was 8% (1/13) 
in Arm A and 36% (9/25) in Arm B. The unconfirmed ORR was 44% (8/18) for Arm B first-
line (1L) subjects. Minimum follow-up was 1.9 months in Arm A and 2.2 months in Arm B. It 
was concluded that atezolizumab in combination with bevacizumab with or without FOLFOX 
was well tolerated with no unexpected toxicities. Clinical activity was observed with both 
treatment combinations (Bendell et al, 2015).
Another Phase 1b study evaluated nivolumab (3 mg/kg on days 1and 15 every 28-day cycle) 
in combination with capecitabine (1000 mg orally twice daily days 1 to 5 on, days 6 to 7 off, 
each 7-day period) and irinotecan (175 mg/m2 on day 1 every 14 days) in subjects with 
previously treated, metastatic CRC. Subjects were treated until disease progression or toxicity. 
All of the 9 subjects for whom data were available had treatment-related AEs (any grade). The 
most common (> 50% subjects) were fatigue (Grade 1), nausea (Grade 1), and diarrhea (Grade 
1). No IRRs were observed. There were no DLTs or study-related SAEs. Of 6 subjects 
evaluable for best overall response, 1 had a PR for 8 months, 1 had SD for 6 months, 1 had 
ongoing SD over 3 months, and 3 had disease progression. It was concluded that nivolumab in 
combination with capecitabine and irinotecan appeared to be safe in subjects with previously 
treated, metastatic CRC (Khemka et al, 2016). 
The mFOLFOX6 chemotherapy regimen in combination with pembrolizumab was evaluated 
in a Phase 2 study that enrolled subjects with untreated, unresectable CRC. During the safety 
run-in, 2 patients had Grade 3 febrile neutropenia and 1 had Grade 4 neutropenia. 
Consequently, the data safety monitoring committee recommended 20% dose reduction of the 
mFOLFOX6 regimen. Of the 27 evaluable subjects, 36.7% experienced Grade 3-4 toxicity 
during the median follow-up period of 24 weeks. Febrile neutropenia was not reported during 
the follow-up period and there was no Grade 5 toxicity observed. Reported responses were 1 
CR, 15 PRs, (ORR = 53%) and 14 SD. The authors concluded that combination therapy with 
mFOLFOX6 and pembrolizumab has acceptable toxicity in subjects with untreated, advanced 
CRC and clinical activity was demonstrated (Shahda et al, 2017). 
In summary, the preliminary efficacy, safety, and tolerability data generated to date for 
durvalumab alone and in combination with monalizumab, together with early positive signals 
observed with other PD-1/PD-L1 in combination with chemotherapy support the development 
of these combination therapies in the treatment of CRC. Based on the known lack of single-
agent activity of PD-1/PD-L1 antagonists in 
CRC and the initial promising antitumor 
activity seen with durvalumab in combination with the 750-mg dose of monalizumab 
administered Q2W
 
 
 and good tolerability, it was decided to evaluate 
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
38 of 206
Template 16.2
whether this preliminary antitumor activity of durvalumab in combination with monalizumab 
could be further improved with acceptable tolerability by adding a standard chemotherapy 
regimen of mFOLFOX6 
 with or without 
bevacizumab or cetuximab in subjects with 1L or 2L 
CRC, respectively. 
Based on promising antitumor activity and a favorable safety profile of monalizumab + 
cetuximab in subjects with recurrent or metastatic SCCHN (8 subjects with PR and 14 
subjects with SD out of 26 subjects [summarized in Section 1.4.1.1]) and the preliminary 
clinical activity of monalizumab + durvalumab in 
CRC (described above) observed in 
this ongoing study, the combination of monalizumab, durvalumab, and cetuximab and the 
combination of monalizumab and cetuximab will be evaluated in 
CRC in this study. 
Combining durvalumab and monalizumab with standard chemotherapy regimens and/or a 
biologic agent, as clinically indicated, for the treatment of 
 CRC appears to be promising 
based on the following rationale: 1) the potential to provide enhanced durability in efficacy as 
seen historically with biological agents in combination with chemotherapy in CRC and 
emerging data from the 
CRC cohort in the current study with durvalumab and 
monalizumab combination treatment; 2) the potential for enhanced clinical activity when 
combining checkpoint blockade with chemotherapy based on experience in the treatment of 
other solid tumors (eg, NSCLC and triple negative breast cancer); 3) and possible synergy of 
monalizumab with mAbs that elicit ADCC, such as cetuximab, including the potential to 
overcome resistance to such mAbs 
. 
Thus, the combination of a checkpoint inhibitor with a standard chemotherapy regimen and/or 
a biologic agent has the potential to improve treatment outcomes in settings where there is 
significant clinical unmet need.
1.6
Benefit-Risk and Ethical Assessment
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Council for Harmonisation 
(ICH)/Good Clinical Practice (GCP), and applicable regulatory requirements.
1.6.1
Potential Benefits
Emerging data with durvalumab in a monotherapy setting across a range of tumor types 
(Section 1.4.2), and in combination with tremelimumab in NSCLC, demonstrate encouraging 
clinical activity.
In the presence of monalizumab, CD94/NKG2a+ NK and T cells may kill target cells that also 
express ligands for activating receptors on the effector cell. Such activating ligands are 
generally not expressed on healthy cells and tissues but can be induced in transformed or 
infected cells or cells undergoing proliferative stress, such as in chronic inflammatory 
conditions. Hence, monalizumab does not induce the killing of healthy cells, but has been 
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
39 of 206
Template 16.2
shown to enhance killing of tumor cells and cells at sites of chronic inflammation. The 
antitumor activity of monalizumab has been demonstrated experimentally ex vivo, with 
malignant cell lines or fresh leukemic cells of patients, as well as in vivo in non-obese diabetic 
severe combined immunodeficiency mice infused with human NK cells and inoculated with 
patient leukemic cells (Ruggeri et al, 2016)
The combination of durvalumab and monalizumab has the opportunity to utilize both the 
innate and adaptive immune system to target tumor cells through potentially complementary 
mechanisms. Furthermore, using these agents in combination with standard-of-care 
chemotherapy and/or a biologic agent has the potential to enhance the antitumor effect. The 
encouraging preliminary safety and efficacy results from the current study are summarized in 
Section 1.4.3 and the rationale for evaluating a treatment regimen of durvalumab in 
combination with monalizumab plus a standard chemotherapy regimen and/or a biologic agent 
is presented in Section 1.5.1. The rationale for the study design and starting doses is described 
in Section 3.2. The results from this study will inform the design of future studies of the 
combination of durvalumab and monalizumab.
1.6.2
Summary of Risks
Immune-mediated reactions/immune-related adverse events (imAEs/irAEs), also considered 
to be AESIs, are important risks of immune checkpoint inhibitors, and are being closely 
monitored in clinical studies with durvalumab monotherapy and combination therapy. Risks 
with durvalumab include, but are not limited to, diarrhea/colitis, intestinal perforation, 
pneumonitis/interstitial lung disease, endocrinopathies (hypothyroidism, hyperthyroidism, 
type I diabetes mellitus, hypophysitis, and adrenal insufficiency), hepatitis/increases in 
transaminases, nephritis/increases in creatinine, pancreatitis/increases in amylase and lipase, 
rash/dermatitis, myocarditis, myositis/polymyositis, and other rare or less frequent 
inflammatory events including neurotoxicities, IRRs, hypersensitivity reactions, and 
infections/serious infections. See Section 5.3 for a summary of risks that are considered AESIs 
with durvalumab.
 
 
With regard to the potential risks of treatment with the durvalumab/monalizumab combination 
plus standard chemotherapy and/or a biologic agent, experience with the biologics cetuximab 
and bevacizumab combined with chemotherapy suggests the following as some of the 
theoretical risks: cytopenia, a need for transfusion support, an increased risk of infection, 
gastrointestinal AEs (ie, nausea, vomiting and diarrhea), stomatitis, mucositis, electrolyte 
imbalance, acute cholinergic syndrome, peripheral sensory neuropathy, cold-induced 
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
40 of 206
Template 16.2
paresthesias, renal dysfunction, skin disorders (ie, rash and palmar/plantar erythrodysesthesia), 
alopecia, hypertension, bleeding, thrombosis, infusion reactions, laryngopharyngeal 
dysesthesia, cardiotoxicity (eg, for coronary vasospasm) and liver and pulmonary toxicity (eg, 
for pneumonitis/interstitial lung disease).
These AESIs, including imAEs/irAEs, are manageable by available/established treatment 
guidelines as described in the toxicity management guidelines (see Section 3.1.3).
For information on all identified and potential risks with durvalumab and monalizumab, refer 
to the current Investigator’s Brochure for each respective agent.
1.7
Research Hypotheses
1.7.1
Primary Hypothesis
Parts 1 and 2: The combination of durvalumab (MEDI4736; anti-programmed death ligand 1 
[PD-L1] mAb) and monalizumab (anti-CD94/NKG2a mAb) administered to subjects with 
select advanced solid tumors will show acceptable safety and tolerability so as to permit 
further clinical testing in subsequent studies.
Part 3 (Cohorts A 
): The combination of durvalumab and monalizumab plus 
chemotherapy with or without a biologic agent (bevacizumab or cetuximab), as clinically 
indicated, administered to subjects with recurrent or metastatic 1L or 2L 
CRC will show 
acceptable safety and tolerability so as to permit further clinical testing in subsequent studies.
Part 3 (Cohorts C1A and C2A): The combination of durvalumab and monalizumab plus 
cetuximab administered to subjects with 
CRC that is 
 
 (C1A) or 
 (C2A) will show acceptable safety (C1A and C2A), 
tolerability (C1A and C2A), and antitumor activity (C1A only) so as to permit further clinical 
testing in subsequent studies.
Part 3 (Cohorts C1B and C2B): The combination of monalizumab plus cetuximab 
administered to subjects with 
CRC that is 
 (C1B) 
or 
 (C2B) will show acceptable safety (C1B and C2B), tolerability (C1B 
and C2B), and antitumor activity (C1B only) so as to permit further clinical testing in 
subsequent studies.
1.7.2
Secondary Hypotheses
The combination of durvalumab and monalizumab will demonstrate antitumor activity.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
41 of 206
Template 16.2
2
OBJECTIVES AND ENDPOINTS
2.1
Primary Objective and Associated Endpoints
Table 1
Primary Objectives and Associated Endpoints
Type
Objective
Endpoint
Safety
Part 1: To assess safety and tolerability, describe the 
DLTs, and determine the MTD or the highest protocol-
defined dose level in the absence of establishing an 
MTD of durvalumab in combination with 
monalizumab in subjects with advanced solid tumors
•
AEs
•
SAEs
•
DLTs
•
Abnormal laboratory 
parameters, vital signs, and 
ECG results
Part 2: To assess further the safety and tolerability of 
either the MTD or the highest protocol-defined dose 
level, in the absence of establishing an MTD, of 
durvalumab in combination with monalizumab in 
subjects with selected advanced solid tumors
Part 3 (Cohorts A 
): To assess safety and 
tolerability of durvalumab in combination with 
monalizumab plus chemotherapy with or without a 
biologic agent (bevacizumab or cetuximab), as 
clinically indicated, in subjects with 1L or 2L 
CRC
Part 3 (Cohorts C1A and C2A): To assess safety and 
tolerability of durvalumab in combination with 
monalizumab plus cetuximab in subjects with 
 
CRC that is 
 (C1A) or 
 
 (C2A)
Part 3 (Cohorts C1B and C2B): To assess safety and 
tolerability of monalizumab in combination with 
cetuximab in subjects with 
CRC that is 
 
 (C1B) or 
 (C2B)
Clinical 
activity
Part 3 (Cohort C1A): To evaluate the antitumor 
activity of durvalumab in combination with 
monalizumab plus cetuximab in subjects with 
 
CRC that is 
 
Part 3 (Cohort C1B): To evaluate the antitumor 
activity of monalizumab in combination with 
cetuximab in subjects with 
CRC that is 
 
OR by investigator assessment per 
RECIST v1.1
1L = first-line; 2L = second-line;
 AE = adverse event; DLT = dose-limiting toxicity; 
ECG = electrocardiogram; EGFR = epidermal growth factor receptor; mAb = monoclonal antibody; 
CRC =
 colorectal cancer; MTD = maximum tolerated dose; NCI CTCAE = National
Cancer Institute Common Terminology Criteria for Adverse Events; OR = objective response; 
RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; VEGF = vascular 
endothelial growth factor.
NOTE: Part 1 is dose escalation, Part 2 is dose expansion, and Part 3 is dose exploration in 
CRC. 
NOTE: Cohort A subjects must be systemic therapy-naïve in the recurrent/metastatic setting. 
 subjects 
must be naïve to irinotecan-containing treatment and must have progressed on an oxaliplatin-containing regimen 
in the first line of their treatment for recurrent/metastatic cancer. Cohort C subjects 
 
prior standard 
chemotherapy must include i) fluoropyrimidines, irinotecan, and oxaliplatin; and ii) an anti-VEGF mAb (eg, 
bevacizumab); and iii) subjects in Cohort C2 must not have received prior anti-EGFR therapy (eg, cetuximab or 
panitumumab naïve).
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
42 of 206
Template 16.2
AEs will be graded according to the NCI CTCAE v4.03.
See Figure 3 for a description of the cohorts.  
2.2
Secondary Objectives and Associated Endpoints
Table 2
Secondary Objectives and Associated Endpoints
Type
Objective
Endpoint
Clinical 
activity
Parts 1 and 2: To evaluate the preliminary antitumor 
activity of durvalumab in combination with 
monalizumab in subjects with advanced solid tumors
•
OR, DC, DoR, PFS by 
investigator assessment per 
RECIST v1.1
•
OS
Part 3 (Cohorts A 
): To evaluate the 
preliminary antitumor activity of durvalumab in 
combination with monalizumab plus chemotherapy 
with or without a biologic agent (bevacizumab or 
cetuximab), as clinically indicated, in subjects with 1L 
or 2L 
CRC 
Part 3 (Cohort C2A): To evaluate the antitumor 
activity of durvalumab in combination with 
monalizumab plus cetuximab in subjects with 
 
CRC that is 
Part 3 (Cohort C2B): To evaluate the antitumor 
activity of monalizumab in combination with 
cetuximab in subjects with 
CRC that is 
Part 3 (Cohort C1A): To further evaluate the 
antitumor activity of durvalumab in combination with 
monalizumab plus cetuximab in subjects with 
 
CRC that is 
Part 3 (Cohort C1B): To further evaluate the 
antitumor activity of monalizumab in combination 
with cetuximab in subjects with 
CRC that is 
•
DC, DoR, PFS by investigator 
assessment per RECIST v1.1
•
OS
PK
Parts 1 and 2: To describe the PK of durvalumab and 
monalizumab when administered in combination in 
subjects with advanced solid tumors
•
Individual subject 
durvalumab, monalizumab, 
and cetuximab 
concentrations in serum at 
different time points after 
administration of these 
agents will be summarized
Part 3 (Cohorts A 
): To describe the PK of 
durvalumab and monalizumab when administered in 
combination with chemotherapy with or without a 
biologic agent (bevacizumab or cetuximab), as 
clinically indicated, in subjects with 1L or 2L 
CRC
Part 3 (Cohorts C1A and C1B): To describe the PK 
of the following when administered in combination in 
subjects with 
CRC that is 
•
Durvalumab, monalizumab, and cetuximab 
(C1A)
•
Monalizumab and cetuximab (C1B)
Part 3 (Cohorts C2A and C2B): To describe the PK 
of the following when administered in combination 
with cetuximab in subjects with 
CRC that is 
•
Durvalumab and monalizumab (C2A)
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
43 of 206
Template 16.2
Table 2
Secondary Objectives and Associated Endpoints
Type
Objective
Endpoint
•
Monalizumab (C2B)
Immuno-
genicity
Parts 1 and 2: To describe the immunogenicity of 
durvalumab and monalizumab when administered in 
combination in subjects with advanced solid tumors
Part 3 (Cohorts A 
): To describe the 
immunogenicity of durvalumab and monalizumab 
when administered in combination with chemotherapy 
with or without a biologic agent (bevacizumab or 
cetuximab), as clinically indicated, in subjects with 1L 
or 2L 
CRC
Part 3 (Cohorts C1A and C1B): To describe the 
immunogenicity of the following when administered in 
combination in subjects with 
CRC that is 
•
Durvalumab, monalizumab, and cetuximab 
(C1A)
•
Monalizumab and cetuximab (C1B)
Part 3 (Cohorts C2A and C2B): To describe the 
immunogenicity of the following when administered in 
combination with cetuximab in subjects with 
 
CRC that is 
•
Durvalumab and monalizumab (C2A)
•
Monalizumab (C2B)
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
44 of 206
Template 16.2
1L = first-line; 2L = second-line;
DC = disease control; 
DoR = duration of response; EGFR = epidermal growth factor receptor;
mAb = monoclonal antibody;
CRC = 
colorectal cancer; OR = objective response; 
OS = overall survival; 
PFS = progression-free survival; 
PK = pharmacokinetic(s); RECIST = Response Evaluation Criteria in Solid Tumors; VEGF = vascular 
endothelial growth factor.
NOTE: Part 1 is dose escalation, Part 2 is dose expansion, and Part 3 is dose exploration.
NOTE: Cohort A subjects must be systemic therapy-naïve in the recurrent/metastatic setting. 
 subjects 
must be naïve to irinotecan-containing treatment and must have progressed on an oxaliplatin-containing regimen 
in the first line of their treatment for recurrent/metastatic cancer. Cohort C subjects 
 
prior standard 
chemotherapy must include i) fluoropyrimidines, irinotecan, and oxaliplatin; and ii) an anti-VEGF mAb (eg, 
bevacizumab); and iii) subjects in Cohort C2 must not have received prior anti-EGFR therapy (eg, cetuximab or 
panitumumab naïve).
See Figure 3 for a description of the cohorts.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
45 of 206
Template 16.2
2.3
Exploratory Objectives and Associated Endpoints
Table 3
Exploratory Objectives and Associated Endpoints
Type
Objective
Endpoint
Prognostic/ 
Predictive/ 
Pharmacodynamic
Parts 1 and 2: To evaluate 
additional candidate prognostic/ 
predictive/ pharmacodynamic 
biomarkers when durvalumab is 
administered in combination with
monalizumab in subjects with 
advanced solid tumors
•
Assessment of T- and NK-cell activation 
(eg, inducible costimulatory molecule 
expression) and proliferation (eg, Ki67 
expression) measured by flow cytometry in 
blood, by IHC in tumors and by mass 
spectrometry, DNA/ RNA/ miRNA 
assessments (RNAseq, exome sequence, 
scRNA) in blood and tumors
•
Assessment of the number and activity of 
CD8+ effector T and NK cells and 
expression of immunomodulatory proteins 
(eg, PD-1) within tumor biopsies using IHC
Part 3 (Cohorts A 
): To 
evaluate additional candidate 
prognostic/ predictive/ 
pharmacodynamic biomarkers 
when durvalumab is administered 
in combination with monalizumab 
plus chemotherapy with or without 
a biologic agent (bevacizumab or 
cetuximab), as clinically indicated, 
in subjects with 1L or 2L 
CRC
Part 3 (Cohorts C1A and C2A):
To evaluate additional candidate 
prognostic/ predictive/ 
pharmacodynamic biomarkers 
when durvalumab is administered 
in combination with monalizumab 
plus cetuximab in subjects with 
 
CRC that is 
 
(C1A) or 
 
(C2A)
Part 3 (Cohorts C1B and C2B): 
To evaluate additional candidate 
prognostic/ predictive/ 
pharmacodynamic biomarkers 
when monalizumab is administered 
in combination with cetuximab in 
subjects with 
CRC that is 
 (C1B) or 
 
 (C2B)
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
46 of 206
Template 16.2
Table 3
Exploratory Objectives and Associated Endpoints
Type
Objective
Endpoint
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
47 of 206
Template 16.2
Table 3
Exploratory Objectives and Associated Endpoints
Type
Objective
Endpoint
Clinical outcome 
assessments
To evaluate 
the effect of treatment with 
durvalumab in combination with 
monalizumab plus cetuximab on 
disease-related symptoms/ 
functioning/ HRQoL and overall 
health status in subjects with 
 
CRC that is 
To evaluate 
the effect of treatment with 
monalizumab in combination with 
cetuximab on disease-related 
symptoms/ functioning/ HRQoL 
and overall health status in subjects 
with 
CRC that is 
 
•
Descriptive statistics for domain, subscale 
scores, and individual items at each time 
point and change from baseline as 
measured by EORTC QLQ-C30
•
Time to deterioration and response status 
for each domain, subscale and individual 
items as measured by EORTC QLQ-C30
•
Descriptive statistics for subject’s global 
impression of change of their overall 
health status at each time point as 
measured by PGIC
•
Time to deterioration in ECOG 
performance status ≥2
1L = first-line; 2L = second-line; 
 CD = cluster of differentiation; CRC = colorectal cancer; 
 ECOG = Eastern Cooperative Oncology Group; 
EORTC QLQ-C30 = European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire; 
 
IHC = immunohistochemistry; 
mAb = monoclonal antibody; 
miRNA = microRNA;
 
 
NK = natural killer; 
PBMC = peripheral blood mononuclear cell; PD-1 = programmed 
death 1; PGIC = Patient Global Impression of Change; scRNA = single-cell RNA; VEGF = vascular endothelial 
growth factor.
NOTE: Part 1 is dose escalation, Part 2 is dose expansion, and Part 3 is dose exploration in 
CRC. 
NOTE: Cohort A subjects must be systemic therapy-naïve in the recurrent/metastatic setting. 
 subjects 
must be naïve to irinotecan-containing treatment and must have progressed on an oxaliplatin-containing regimen 
in the first line of their treatment for recurrent/metastatic cancer. Cohort C subjects 
 
prior standard 
chemotherapy must include i) fluoropyrimidines, irinotecan, and oxaliplatin; and ii) an anti-VEGF mAb (eg, 
bevacizumab); and iii) subjects in Cohort C2 must not have received prior anti-EGFR therapy (eg, cetuximab or 
panitumumab naïve).
See Figure 3 for a description of the cohorts.
3
STUDY DESIGN
3.1
Description of the Study
3.1.1
Overview….
This is a Phase 1/2, multicenter, open-label, study of durvalumab and monalizumab to 
evaluate the safety, tolerability, PK, immunogenicity, pharmacodynamics, and antitumor 
activity in adult subjects with advanced solid tumor malignancies at approximately 60 sites 
globally. The study consists of 3 parts: dose escalation (Part 1), dose expansion (Part 2), and 
dose exploration in 
CRC (Part 3). 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
48 of 206
Template 16.2

Part 1 will be dose escalation of durvalumab in combination with monalizumab in 
subjects with select advanced solid tumor malignancies. 

Part 2 will evaluate further the identified dose of durvalumab in combination with 
monalizumab from Part 1 in subjects with select advanced solid tumor malignancies. 

Part 3 (Cohorts A 
) will evaluate dose exploration of durvalumab in combination 
with monalizumab and chemotherapy with or without a biologic agent (bevacizumab or 
cetuximab), as clinically indicated, in subjects with metastatic 1L or 2L 
CRC. 

Part 3 (Cohorts C1 and C2) will evaluate dose exploration of 1) durvalumab in 
combination with monalizumab plus cetuximab (Cohorts C1A and C2A) and 2) 
monalizumab in combination with cetuximab (Cohorts C1B and C2B) in subjects with 
CRC that is 
 or 
. 
In Part 1 (dose escalation), subjects with recurrent or metastatic 
CRC, ovarian cancer, 
endometrial cancer, cervical cancer, castration-resistant prostate cancer, pancreatic 
adenocarcinoma, or NSCLC will be enrolled. In Part 2 (dose expansion), subjects with 
CRC, ovarian cancer, 
endometrial cancer, or NSCLC will be enrolled. In Part 3 
(dose exploration), subjects with 
CRC will be enrolled. See Figure 3 for a description of 
the cohorts.
Refer to Section 1.5.1 for a discussion of the rationale for adding a chemotherapy regimen 
with or without a biologic agent and Section 3.1.3.1 for information on chemotherapy dose 
modification.
Tolerability data for all subjects will be evaluated regularly and subjects’ clinical response 
status classified according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 
All subjects will be followed for survival until the end of study (Section 6.3). During the dose-
expansion phase, if a subject with NSCLC experiences a toxicity that meets the criteria for 
treatment discontinuation (Sections 4.1.6 and 4.1.7), but the subject is receiving clinical 
benefit, the subject may be considered for monotherapy treatment with durvalumab. In this 
circumstance, the decision to treat subjects with monotherapy durvalumab is based on its 
known efficacy in NSCLC patients and will require agreement between the sponsor and 
treating investigator. For a subject receiving durvalumab monotherapy, the same study 
assessments as for combination therapy should be followed (except for continued sampling for 
monalizumab PK and immunogenicity) (Table 9 and Table 14).
Part 1: Dose Escalation
In the dose-escalation part of the study, sequential cohorts will receive durvalumab in 
combination with monalizumab at 1 of the 4 planned dose levels described in Figure 3. The 
dose-escalation part will utilize a modified toxicity probability interval (mTPI) algorithm (Ji et 
al, 2010), which employs a simple beta-binomial Bayesian model. Decision rules are based on 
calculating the unit probability mass (UPM) of three intervals corresponding to underdosing, 
proper dosing, and overdosing in terms of toxicity. The three dosing intervals are associated 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
49 of 206
Template 16.2
with three different dose-escalation decisions. The underdosing interval corresponds to a dose 
escalation (E), overdosing corresponds to a dose de-escalation (D), and proper dosing 
corresponds to staying at the current dose (S). Given an interval and a probability distribution, 
the UPM of that interval is defined as the probability of the interval divided by the length of 
the interval. The mTPI design calculates the UPMs for the three dosing intervals, and the one 
with the largest UPM implies the corresponding dose-finding decision. The design for the 
dose-escalation part of the study uses a target DLT rate of ≥33% and an equivalence interval 
of 
 for dose-escalation/de-escalation decisions as well as MTD determination. A 
dose level will be considered unsafe, with no additional subjects enrolled at that dose level, if 
it has an estimated 95% or more probability of exceeding the target DLT rate of ≥ 33% (ie, P 
[DLT ≥ 33%|data] > 95%) with at least 3 subjects treated at that dose level.
A minimum of 3 subjects will be enrolled to a dose level cohort and evaluated for a 
dose-escalation/de-escalation decision (unless unacceptable toxicity is encountered prior to 
enrollment of 3 subjects), but the maximum number of subjects for each dose-level cohort will 
be capped at 12. Thus, based on 5 dose-level cohorts, a maximum of 60 subjects could be 
enrolled in the dose-escalation part. Given that mTPI leads to a dose-escalation decision if 
there is no DLT in the first 3 subjects enrolled in a dose-level cohort, it is expected that the 
actual sample size will be fewer.
Subjects will be dosed in a group size of three. The first 3 subjects enrolled in the escalation 
part will be enrolled to dose-level Cohort 1. No escalation is allowed unless 3 or more 
evaluable subjects have been treated and evaluated through the DLT-evaluation period in a 
dose level.
Ongoing surveillance of pharmacodynamics, PK, clinical safety, and antitumor activity data 
will be performed throughout the dose-escalation part. Once the dose escalation has completed 
per the mTPI or the highest protocol-defined dose is evaluated, any dose level showing 
acceptable safety during dose escalation can be expanded to a total of up to 18 subjects with 
mandatory pre-treatment and on-treatment tumor biopsies. At the discretion of the sponsor, 
the expansion at a given dose level may be restricted to a specific tumor type(s) included in 
the dose-escalation part. These dose-escalation cohort expansions will provide additional PK, 
pharmacodynamic, and safety data to inform optimal dose-level selection for the dose-
expansion part and subsequent clinical studies.
Part 2: Dose Expansion
The dose-expansion part will enroll 4 cohorts of approximately 40 subjects each with 
recurrent or metastatic 
CRC, ovarian cancer, 
endometrial cancer, or NSCLC. The 
dose level and schedule determined in the dose-escalation part will be used in the 
dose-expansion part, as agreed by the study-specific DEC. Additional dose levels not 
exceeding the MTD may be considered based on clinical and PK/pharmacodynamic data from 
the dose-escalation part.
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
50 of 206
Template 16.2
Part 3: Dose Exploration in 
CRC
Subjects with advanced 
CRC will be enrolled in the dose-exploration part. 
Cohorts A 
: Cohort A subjects (ie, Cohorts A1, A2, 
) must be systemic 
therapy-naïve in the recurrent/metastatic setting, and 
 
 must be naïve to irinotecan-containing treatment and must have progressed on an 
oxaliplatin-containing regimen in the first line of their treatment for recurrent/metastatic 
cancer. Based on the identified dose for durvalumab in combination with monalizumab from 
Part 1, subjects will receive durvalumab (1500 mg Q4W) in combination with monalizumab 
(750 mg Q2W) plus a standard chemotherapy regimen of mFOLFOX6 (Cohorts A1, A2, 
 
) 
 in combination with bevacizumab (Cohorts A1 
) or cetuximab (Cohorts A2 
) 
. 
Cohort C: Cohort C subjects (ie, Cohorts C1 and C2)
 
 
CRC that is 
 
 (Cohort C1) or 
 (Cohort C2); prior standard chemotherapy must 
include i) fluoropyrimidines, irinotecan, and oxaliplatin; and ii) an anti-vascular endothelial 
growth factor (VEGF) mAb (eg, bevacizumab); and iii) subjects in Cohort C2 must not have 
received prior anti-EGFR therapy (eg, cetuximab or panitumumab naïve). 
 
 
 
 
 
The study flow is presented in Figure 3.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
51 of 206
Template 16.2
Figure 3
Study Flow Diagram
Part 3: Dose exploration in 
CRC
Cohort and Chemotherapy or Biologic 
Regimen
Durvalumab Dose
Monalizumab Dose
Number of Subjectsd
A1: mFOLFOX6 + bevacizumab
1500 mg Q4W
750 mg Q2W
Up to 18
A2: mFOLFOX6 + cetuximab
1500 mg Q4W
750 mg Q2W
Up to 18
CRC = colorectal cancer;
EGFR = epidermal growth factor receptor; 
 
mAb = monoclonal antibody; mFOLFOX6 = folinic acid/fluorouracil/oxaliplatin;
 Q2W = every 2 weeks; Q4W = every 4 weeks; 
 
 VEGF = vascular endothelial growth factor.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
52 of 206
Template 16.2
The endpoints to be measured in this study are described in Section 2.
3.1.2
Treatment Regimen
Subjects will be treated in the dose-escalation (Part 1 [Section 3.1.2.1]), dose-expansion 
(Part 2 [Section 3.1.2.2]), or dose-exploration (Part 3 [Section 3.1.2.3]) part of the study 
(Section 3.1.1). 
Both durvalumab and monalizumab will be administered over approximately 60 minutes via 
IV infusion. On dosing days when both durvalumab and monalizumab are administered, 
durvalumab will be administered first with monalizumab starting 15 to 30 minutes after the 
completion of the durvalumab infusion.

In addition to the combination of durvalumab and monalizumab, subjects enrolled in Part 
3 Cohorts A 
 will also receive a standard Q2W regimen of folinic acid, fluorouracil, 
and oxaliplatin or irinotecan (mFOLFOX6 
 respectively) with or without 
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
53 of 206
Template 16.2
bevacizumab or cetuximab, as clinically indicated according to local prescribing 
guidelines (Section 3.1.2.3). 

 

 
Study treatment will be administered up to 3 years until unacceptable toxicity, documentation 
of confirmed PD, or documentation of subject withdrawal for another reason (Section 4.1.6). 
Study treatment may be continued beyond PD or following relapse if the subject meets the 
criteria described in Sections 4.1.7 and 4.1.8.
Subjects who continue to receive clinical benefit after 3 years of treatment will continue to 
receive the treatment on this study, via a rollover study requiring approval by the responsible 
Health Authority (HA) and ethics committee, or through another mechanism at the discretion 
of the sponsor. The sponsor reserves the right to terminate access to study treatment if any of 
the following occur:

The marketing application is rejected by the responsible HA.

The study is terminated due to safety concerns.

The subject can obtain medication from a government-sponsored or private health 
program.

Therapeutic alternatives become available in the local market.
3.1.2.1
Part 1: Dose Escalation
 
 
Dose escalation will continue to the next higher dose-level cohort after all available safety 
data and any available PK data from subjects in that dose level and prior dose levels have been 
reviewed by a study-specific DEC. The sponsor may halt dose escalation prior to determining 
the MTD based on emerging PK/pharmacodynamic, toxicity, or response data.
Intermediate dose levels of durvalumab in combination with monalizumab may also be 
evaluated based on available data.
 
 
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
54 of 206
Template 16.2
 
If the MTD is not exceeded at that dose level on a 
monalizumab Q4W schedule and provided this was not the highest protocol-defined dose, 
dose escalation may proceed with additional sequential cohorts of 3 to 12 subjects according 
to the mTPI algorithm.
Rules for Dose Escalation and Determination of MTD
1
The MTD will be determined based on assessment of DLT (see below in this section) 
according to the mTPI algorithm (Table 4) during the DLT-evaluation period. Subjects 
who do not meet criteria for DLT-evaluable Population will be replaced at the same dose 
level (Section 4.8.1). Subjects will be followed for safety throughout the study. If 
late-emerging AEs (occurring after the DLT-evaluation period) are observed, these events 
will be considered by the DEC during data reviews for dose-escalation decisions. All 
toxicities will be thoroughly reviewed with a study-specific DEC, prior to proceeding 
with a dose-escalation or dose de-escalation decision. The MTD will be determined by 
isotonic regression analysis (Ji et al, 2010) applied to the DLT rates observed during the 
dose-escalation part.
2
Administration of the first dose of investigational product will be staggered by a 
minimum of 24 hours between the first and second subjects in each dose-level cohort. 
Intra-subject dose escalation will not be allowed.
3
A minimum of 3 subjects will be enrolled in each dose-level cohort unless unacceptable 
toxicity is encountered prior to enrollment of the third subject which would require dose 
de-escalation per the mTPI design.
4
At the highest protocol-specified dose level, enrollment may be stopped if no DLTs are 
observed in the first 3 evaluable subjects.
5
Upon completion of the dose escalation per the mTPI design, additional subjects (up to a 
total of 18 per dose level) may be enrolled at any dose level considered safe as defined in 
the mTPI algorithm for further evaluation of safety, PK/pharmacodynamics, and 
response.
6
At the discretion of the sponsor, dose escalation may be stopped before an MTD is 
reached. In this case, an expanded cohort dose may be chosen based on an assessment of 
PK, pharmacodynamics, biomarker, safety, or response data.
A study-specific DEC (including at a minimum the sponsor medical monitor/clinical lead and 
all participating investigators who have enrolled subjects) will provide ongoing safety 
surveillance of the study, with regularly scheduled reviews of safety and other relevant data. 
The DEC may also meet to review data at other time points (eg, in response to AEs assessed 
as medically relevant by the medical monitor). The DEC will be responsible for 
dose-escalation or dose de-escalation decisions and making recommendations regarding 
further conduct of the study. All decisions by the DEC will be documented and shared with all 
participating sites in writing.
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
55 of 206
Template 16.2
Table 4
Durvalumab Treatment Modification and Toxicity Management 
Guidelines for Immune-related Adverse Events Level
Number of
Subjects
with
Toxicities
Number of Subjects Treated at Current Dose
1a
2a
3
4
5
6
7
8
9
10
11
12
0
E
E
E
E
E
E
E
E
E
E
E
E
1
D
S
S
S
S
E
E
E
E
E
E
E
2
DU
D
S
S
S
S
S
S
S
E
E
3
DU
DU
D
Db
S
S
S
S
S
Ec
4
DU
DU
DU
D
D
S
S
S
Dc
5
DU
DU
DU
DU
DU
D
S
Dc
6
DU
DU
DU
DU
DU
DU
D
7
DU
DU
DU
DU
DU
DU
8
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
10
DU
DU
DU
11
DU
DU
12
DU
D = de-escalate to the next lower dose level; DU = current dose is unacceptably toxic; E = escalate to the next 
higher dose level; S = stay at the current dose level.
Note: Target toxicity (%) ≥ 33% and equivalence interval =
Sample size cap for each dose level = 12
subjects.
a
The columns indicating the actions based on data from 1 or 2 subjects are included to reflect the
completeness of the modified toxicity probability interval (mTPI) design. However, in this study, a
minimum of 3 subjects will be enrolled at each dose level, unless unacceptable toxicity is seen.
b
The original mTPI algorithm was S for this case and is modified to D as the observed DLT rate is 50%.
c
The original mTPI algorithm was S for these cases and is modified to either E or D according to whether the
observed dose-limiting toxicity (DLT) rate is < or ≥the target toxicity of ≥ 33%, respectively.
Source: Modified from Ji et al, 2010.
Dose-limiting Toxicity
The period for DLT evaluation is defined as the time from start of the first dose of 
investigational product (durvalumab and monalizumab) until the planned administration of the 
second dose of durvalumab and the third dose of monalizumab and planned chemotherapy; 
this corresponds to 28 days after the first dose of durvalumab and monalizumab plus 
chemotherapy or 14 days after the second dose of monalizumab plus chemotherapy. Subjects 
who do not remain in the study or require dose modifications in the chemotherapy or the 
biologic component (Part 3, dose exploration) during the DLT-evaluation period, for reasons 
other than DLT, will be considered non-evaluable for DLT assessment and will be replaced 
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
56 of 206
Template 16.2
with another subject at the same dose level, but will still be considered when reviewing 
toxicity from this cohort.
Grading of DLTs will be according to the National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI CTCAE) v4.03. Toxicity that is clearly and directly related 
to the primary disease or to another etiology is excluded from this definition. A DLT will be 
defined during the dose-escalation part as any durvalumab- or monalizumab-related Grade 3 
or higher toxicity (with modifications or exceptions noted below) that occurs during the DLT-
evaluation period. All DLTs must be documented as AEs. The following will be considered 
DLTs:

Any Grade ≥ 3 noninfectious colitis irrespective of duration

Any Grade ≥ 3 noninfectious pneumonitis irrespective of duration

Liver transaminase elevation ≥ 5 × but ≤ 8 × upper limit of normal (ULN) that does not 
downgrade to Grade 2 within 7 days after onset with optimal medical management 
including systemic corticosteroids

Any Grade 4 imAE/irAE, excluding colitis or pneumonitis, that does not downgrade to 
Grade 2 within 7 days after the onset of the event despite optimal medical management 
including systemic corticosteroids or does not downgrade to ≤ Grade 1 within 14 days

Any Grade 3 or higher clinically significant (ie, requiring dose modification or dose delay 
of > 7 days to permit resolution) non-hematologic toxicity that occurs during the DLT-
evaluation period

Transaminase elevation > 8 × ULN or total bilirubin (TBL) > 5 × ULN will be considered 
a DLT regardless of duration or reversibility

Any increase in AST or ALT ≥ 3 × ULN and concurrent increase in TBL ≥ 2 × ULN, 
where no other reason can be found to explain the combination of increases, eg, elevated 
serum alkaline phosphatase (ALP) indicating cholestasis, viral hepatitis, another drug 
(Hy’s Law [HL] criteria) will be considered a DLT

Thrombocytopenia

Grade 3 or 4 thrombocytopenia, regardless of duration, associated with Grade 3 or 
higher hemorrhage

Grade 4 thrombocytopenia ≥ 7 days (Part 3 Cohorts A 
 subjects only)

Grade 4 thrombocytopenia regardless of duration (excluding Part 3 Cohorts A 
 
subjects)

Grade 3 thrombocytopenia that does not improve by at least 1 grade within 7 days 
(excluding Part 3 Cohorts A 
 subjects) 

Neutropenia and/or febrile neutropenia

Grade 4 febrile neutropenia of any duration

Grade 3 febrile neutropenia lasting ≥ 5 days while receiving maximal supportive care 
(Part 3 Cohorts A 
 subjects only)

Grade 3 febrile neutropenia regardless of duration or reversibility (excluding Part 3 
Cohorts A 
 subjects)
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
57 of 206
Template 16.2

Grade 4 neutropenia lasting > 7 days (Part 3 Cohorts A 
 subjects)

Grade 3 or 4 neutropenia that is not associated with fever or systemic infection or that 
does not improve by at least 1 grade within 7 days (excluding Part 3 Cohorts A 
 
subjects).

Anemia

Grade 4 anemia of any duration

Grade 3 anemia if associated with clinical sequelae or requires transfusion of > 2 
units of red blood cells
The definition of DLT for all subjects (except as noted below) excludes the following 
conditions:

Grade 3 fatigue for < 7 days

Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone replacement 
therapy with resolution of symptoms within 14 days of AE onset

Grade 3 inflammatory reaction attributed to a local antitumor response (eg, inflammatory 
reaction at sites of metastatic disease, lymph nodes, etc) that resolves to ≤ Grade 1 within 
30 days after onset

Concurrent vitiligo or alopecia of any AE grade

Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or 
symptoms and are reversed with appropriate maximal medical intervention within 7 days 
of onset

Grade 3 or 4 asymptomatic elevation in serum amylase or lipase that are not associated 
with either clinical signs or symptoms or radiographic features suggestive of pancreatitis

Grade 3 IRR (first occurrence and in the absence of steroid prophylaxis) that resolves 
within 6 hours of onset with appropriate clinical management

Grade 3 rigors or chills lasting < 6 hours that respond to optimum medical therapy

Grade 3 fever lasting ≤ 24 hours with or without medical therapy

Grade 3 or 4 lymphopenia (unless clinically significant)

Grade 3 diarrhea, nausea or vomiting in the absence of premedication that responds to 
therapy per institutional standards and improves by at least 1 grade within 3 days after 
onset.

Grade 4 diarrhea, nausea or vomiting will be a DLT regardless of duration or reversibility 

Grade 3 hypertension that can be controlled with medical therapy
Additional Information Regarding Dose-limiting Toxicity Criteria
 
 
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
58 of 206
Template 16.2
 
Abnormal Laboratory Results
In the absence of associated clinical signs or symptoms, isolated abnormal laboratory tests not 
specifically described above will not be considered as DLTs unless they are considered 
clinically significant (ie, requiring dose modification or dose delay of > 7 days to permit 
resolution of treatment-related toxicity).  
Adverse Events not Defined Above
imAEs/irAEs are defined as AEs of immune nature (ie, inflammatory) in the absence of a 
clear alternative etiology. While the rules for adjudicating DLTs in the context of dose 
escalation are specified above, an AE not listed above or occurring outside the DLT window 
may be defined as a DLT after a consultation with the sponsor and investigators, based on the 
emerging safety profile.
During dose expansion in all tumor groups and dose exploration in 
CRC, subjects will 
be monitored for safety according to the same criteria employed during dose escalation.
 
 
3.1.2.2
Part 2: Dose Expansion
The dose-expansion part of the study may be initiated at the sponsor’s discretion once the 
MTD, or highest protocol-defined dose level in the absence of exceeding the MTD, is 
established in the dose-escalation part of the study. In the dose-expansion part, subjects will 
receive durvalumab and monalizumab at the dose level and treatment schedule determined in 
the dose-escalation part. Additional dose levels not exceeding the MTD may be considered 
based on clinical and PK/pharmacodynamic data from the dose-escalation part.
Enrollment into dose-expansion cohorts may be discontinued at the discretion of the sponsor 
should emerging clinical or preclinical data suggest that continued treatment may not be 
beneficial to a given cohort. During dose expansion, subjects will be monitored for safety 
using the same DLT criteria employed during dose escalation. 
 
Enrollment may proceed up to approximately 40 subjects in the 
CRC, ovarian cancer, 
and endometrial expansion cohorts 
 
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
59 of 206
Template 16.2
. Enrollment may proceed up to approximately 40 subjects in the NSCLC 
expansion cohort 
.
3.1.2.3
Part 3: Dose Exploration in 
CRC
Subjects with advanced 
CRC will be enrolled in the dose-exploration part.
Cohorts A 
: Cohort A subjects (ie, Cohorts A1, A2, 
) must be systemic 
therapy-naïve in the recurrent/metastatic setting and 
 
 must be naïve to irinotecan-containing treatment and must have progressed on an 
oxaliplatin-containing regimen in the first line of their treatment for recurrent/metastatic 
cancer. Based on the identified dose for durvalumab in combination with monalizumab from 
Part 1, subjects will receive durvalumab (1500 mg Q4W) in combination with monalizumab 
(750 mg Q2W) plus a standard chemotherapy regimen of mFOLFOX6 (Cohorts A1, A2, 
 
) 
 in combination with bevacizumab (Cohorts A1 
) or cetuximab (Cohorts A2 
) 
 
. 
Cohort C: Cohort C subjects (ie, Cohorts C1 and C2) 
 
 
CRC that is 
 
 (Cohort C1) or 
 (Cohort C2); prior standard chemotherapy must 
include i) fluoropyrimidines, irinotecan, and oxaliplatin; and ii) an anti-VEGF mAb (eg, 
bevacizumab); and iii) subjects in Cohort C2 must not have received prior anti-EGFR therapy 
(eg, cetuximab or panitumumab naïve). 
 
 
 
 
 
The chemotherapy and biologic component (bevacizumab or cetuximab, when clinically 
indicated) should be prescribed according to local practice but the starting dose, sequence and 
days of administration for these standard-of-care regimens should not be modified unless there 
is toxicity, in order to maintain consistency across the subjects enrolled in the study. The
recommended regimens are as follows.
The mFOLFOX6 treatment (Cohorts A1, A2, 
) should contain:

Oxaliplatin 85 mg/m2 administered by IV infusion on Day 1

Folinic acid 400 mg/m2 administered by IV infusion on Day 1

Fluorouracil 400 mg/m2 administered by IV bolus on Day1 followed by 2400 mg/m2
administered by continuous IV infusion over 46 to 48 hours starting on Day 1.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
60 of 206
Template 16.2



The above chemotherapy regimens will be administered Q2W.
The biologic regimens are described below:

For Cohorts A1 
, bevacizumab (5 mg/kg IV infusion) will be administered on Day 
1, then Q2W according to institutional guidelines. 

For Cohorts A2 
, cetuximab loading dose (400 mg/m2 IV infusion over 2 hours) 
will be administered on Day 1, then maintenance dose (250 mg/m2 IV infusion over 
1 hour) Q1W will be administered starting on Day 8. The cetuximab regimen may be 
changed to 500 mg/m2 IV infusion for approximately 2 hours Q2W after a subject has 
completed the 28-day DLT-evaluation period, at the investigator’s discretion and in 
accordance with institutional guidelines (Benson et al, 2018; Pfeiffer et al, 2008; 
Tabernero et al, 2008).

For Cohorts C1A, C1B, C2A, and C2B, cetuximab (500 mg/m2 IV infusion over 2 hours) 
will be administered on Day 1 then 500 mg/m2 IV infusion for approximately 2 hours 
Q2W starting on Day 15 in accordance with institutional guidelines (Benson et al, 2018; 
Pfeiffer et al, 2008; Tabernero et al, 2008).
Treatment will be administered as described below for specific cohorts:

Part 3 Cohorts A 
: Durvalumab will be administered first with monalizumab starting 
15 to 30 minutes after the completion of the durvalumab infusion. Following an 
observation period of 15 to 30 minutes post end of monalizumab infusion, the infusion of 
the premedication and biologic component or chemotherapy can begin. 

Infusion of the biologic agent, when clinically indicated, should be prior to the 
chemotherapy according to standard practice. 

The pre-medications for chemotherapy should be administered within 1 hour prior to 
the start of chemotherapy. 

 
 
 
 

 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
61 of 206
Template 16.2
Safety will be monitored on an ongoing basis and aggregate safety data will be reviewed by 
the de-escalation committee at pre-specified intervals as described below.
 
 
 

 

 
 

Dose modification of individual chemotherapy agents and/or the biologic agents for the 
management of toxicity in individual subjects will be allowed as per standard clinical 
practice 
 
Cohort A 
 Subjects
Initially, up to 6 subjects may be enrolled into each of the 4 chemotherapy cohorts with a 
biologic agent (Cohorts A1, A2, 
). Initiation of Cohorts 
 (chemotherapy 
cohorts without a biological agent) will be staggered and dependent on emerging safety data 
from Cohorts A1 and A2, 
 respectively. Administration of the first 
dose of investigational products and chemotherapy will be staggered by a minimum of 
24 hours between the first and second subjects in all 6 cohorts and no more than 3 of the initial 
subjects in a given cohort will be dosed within 1 week. Subsequently, subjects may be 
enrolled continuously without pausing the enrollment for DEC review of aggregate safety data 
until a total of 6 subjects have been enrolled in a given cohort and observed through the DLT-
evaluation period or > 2 subjects experience a DLT in a particular cohort prior to enrolling 6 
subjects. Meetings of the study DEC will be held to review all available safety, PK, 
pharmacodynamic, immunogenicity, and clinical activity data to determine whether to 
continue enrollment at the current dose level, dose de-escalate, or stop further evaluation of 
the combination with chemotherapy with or without a biologic agent according to the mTPI 
algorithm. If the DEC decides to continue at the current dose level after the initial 6 subjects 
have been enrolled and evaluated for DLTs, enrollment may increase by up to an additional 12 
subjects per chemotherapy with or without a biologic agent cohort provided criteria for de-
escalation according to the mTPI algorithm are not met at any point based on ongoing 
assessment of safety. In addition, while enrollment is ongoing, the DEC will review aggregate 
safety data once a total of 12 or 18 subjects in a given cohort have been enrolled and followed 
through the DLT-evaluation period.
The design of study Part 3 is depicted in Figure 4 for Cohorts A 
.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
62 of 206
Template 16.2
Figure 4
Study Part 3 (Dose Exploration) Flow Diagram for Cohorts A 
Cohort C Subjects
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
63 of 206
Template 16.2
 
 
 
 
 
 
 
 
 
 
Figure 5
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
64 of 206
Template 16.2
3.1.3
Management of Study Medication Related Toxicities 
No dose reductions are permitted for durvalumab or monalizumab. However, doses may be 
held/omitted in the context of toxicity. Omitted doses will not be administered at a later date. 
Both hematologic and non-hematologic toxicities will be graded according to the NCI 
CTCAE v4.03. AEs for which a cause other than durvalumab or monalizumab can be clearly 
attributed will not require a dose delay.
Dosing will not be interrupted or discontinued for a laboratory toxicity that is deemed not to 
be clinically significant.
Treatment modifications and toxicity management guidelines for durvalumab and the toxicity 
management guidelines for monalizumab are provided within the Site Master File. For 
marketed study medications, please refer to the local product information for guidance on 
toxicity management. 
3.1.3.1
Chemotherapy and Biologic Agent Dose Modification
When a study treatment is partly or wholly delayed or withheld, the sites should follow their 
standard local prescribing practice and consider following the guidelines described below:

If chemotherapy and/or the biologic agent (bevacizumab or cetuximab) is withheld 
because of toxicity for more than 2 cycles (approximately 28 days), the chemotherapy 
and/or biologic component of study treatment is to be discontinued. However, if 
durvalumab and/or monalizumab are not implicated in the toxicity resulting in 
chemotherapy or biologic agent discontinuation, then durvalumab and/or monalizumab 
can be continued. NOTE: The approximate 28-day time period begins on the day that the 
next cycle of study treatment should have been administered but was withheld for 
toxicity.

If fluorouracil and folinic acid administration is delayed, irinotecan or oxaliplatin 
treatment is also to be delayed, although monalizumab and durvalumab administration 
can be continued without delay at the discretion of the investigator and sponsor.
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
65 of 206
Template 16.2

If fluorouracil and folinic acid treatment is to be discontinued, irinotecan, biologic agent, 
durvalumab and monalizumab can be administered but not oxaliplatin when using the 
mFOLFOX6 regimen. 

If irinotecan or oxaliplatin administration is to be delayed, fluorouracil and folinic acid 
treatment should also be delayed, although the biologic component, monalizumab and 
durvalumab administration can continue without delay.

If irinotecan or oxaliplatin administration is to be discontinued, fluorouracil, folinic acid, 
biologic agent, monalizumab, and durvalumab administration can continue.

If monalizumab and durvalumab are discontinued (ie, in the setting of a Grade 3-4 IRR or 
immune-mediated toxicity), treatment on study with
mFOLFOX6 along with 
the biologic agent can continue.

No folinic acid dose reductions are to be implemented; however, it should always be 
withheld when fluorouracil is to be held.

If a dose is reduced because of toxicity, it is not to be re-escalated to the starting level. 
However, subjects who require multiple-dose reductions during a cycle can, at the 
investigator’s discretion, begin the following cycle at 1 dose level higher than the final 
dose level during that cycle.
Chemotherapy dose modifications are presented in the table below. Dose modifications of 
each agent are to be made independently, based on the specific types of toxicity observed. If a 
dose reduction exceeding that represented by Dose Level -3 is required for any agent, that 
agent is to be discontinued.
Dose Level
Intravenous Agent
Initial Dose
-1
-2
-3
Irinotecan
180 mg/m2
150 mg/m2
120 mg/m2
100 mg/m2
Oxaliplatin
85 mg/m2
68 mg/m2
51 mg/m2
34 mg/m2
Fluorouracil bolus
400 mg/m2
200 mg/m2
0 mg/m2
0 mg/m2
Fluorouracil infusion
(over 46-48 hours)
2400 mg/m2
2000 mg/m2
1600 mg/m2
1200 mg/m2
Bevacizumab

There are no recommended dosage reductions. 

Temporary suspension is recommended for severe infusion reactions, at least 4 weeks 
prior to (and after) elective surgery, in moderate-to-severe proteinuria (ie, consider 
holding treatment when proteinuria ≥ 2 g/24 hours), or in patients with severe 
hypertension that is not controlled with medical management. 

Permanent discontinuation is recommended in patients who develop wound dehiscence 
and wound healing complications requiring intervention, necrotizing fasciitis, fistula 
(gastrointestinal and nongastrointestinal), gastrointestinal perforation, intra-abdominal 
abscess, hypertensive crisis, hypertensive encephalopathy, serious bleeding/hemorrhage, 
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
66 of 206
Template 16.2
severe arterial thromboembolic event, life-threatening (Grade 4) venous thromboembolic 
events (including pulmonary embolism), nephrotic syndrome, or PRES.
Cetuximab

Infusion reactions, Grade 1 or 2: Reduce the infusion rate by 50% and continue to use 
prophylactic antihistamines

Grade 3 or 4: Immediately and permanently discontinue

Pulmonary toxicity:

Acute onset or worsening pulmonary symptoms: Hold treatment

Interstitial lung disease: Permanently discontinue

Skin toxicity, mild to moderate: No dosage modification required

Acneiform rash, severe (Grade 3 or 4):

First occurrence: Delay cetuximab infusion 1 to 2 weeks
o
If improvement, continue at a dose of 250 mg/m2 if on Q1W regimen or 
500 mg/m2 if on Q2W regimen 
o
If no improvement, discontinue therapy

Second Occurrence: Delay cetuximab infusion 1 to 2 weeks
o
If improvement, continue at reduced dose of 200 mg/m2 if on Q1W regimen or 
400 mg/m2 if on Q2W regimen
o
If no improvement, discontinue therapy

Third occurrence: Delay cetuximab infusion 1 to 2 weeks
o
If improvement, continue at reduced dose of 150 mg/m2 if on Q1W regimen or 
300 mg/m2 if on Q2W regimen
o
If no improvement, discontinue therapy

Fourth occurrence: Discontinue therapy.
3.2
Study Design and Dose Rationale
3.2.1
Dose Rationale
3.2.1.1
Rationale for Monalizumab Dosing
As of 23 April 2018, 68 patients with RA have been exposed to IV or subcutaneous doses of 
monalizumab and 315 patients with cancer have been exposed to multiple IV doses of 
monalizumab. To date, the clinical data indicate no safety concerns for single or multiple 
doses of monalizumab up to 10 mg/kg IV and up to 4 mg/kg subcutaneously.
 
 
 
 
 
 
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
67 of 206
Template 16.2
 
 
 
 
 
 
3.2.1.2
Rationale for Durvalumab Dosing
The dose and schedule for durvalumab monotherapy were selected based on 2 sets of data: (1) 
the safety analysis of doses (0.1, 0.3, 1.0, 3.0, and 10 mg/kg Q2W) administered in Study CD-
ON-MEDI4736-1108 (a Phase 1/2 study to evaluate the safety, tolerability, and PK of IV 
durvalumab given as monotherapy in subjects with advanced solid tumors; and (2) PK profile 
simulations for durvalumab administered using 10 mg/kg Q2W and 20 mg/kg Q4W schedules.
After evaluation of the PK data from subjects enrolled in Study CD-ON-MEDI4736-1108, 
durvalumab exhibited nonlinear (dose-dependent) PK consistent with target-mediated drug 
disposition. Linear PK was observed at doses of 3 mg/kg and higher and is consistent with 
near complete target suppression, as reflected in target trough plasma concentrations of drug > 
100 μg/mL. This trough concentration is supported by soluble PD-L1 suppression data. 
Furthermore, the 10 mg/kg Q2W dose was not associated with any DLTs in the 
dose-escalation phase and was, therefore, selected for further evaluation in the dose-expansion 
phase of Study CD-ON-MEDI4736-1108.
A population PK model was developed using durvalumab monotherapy data from Phase 1 of 
Study CD-ON-MEDI4736-1108 (N = 292; doses = 0.1 to 10 mg/kg Q2W or 15 mg/kg every 3 
weeks; solid tumors) (Song et al, 2015). This population PK model adequately described 
monotherapy PK data and was utilized to predict expected PK exposures following 20 mg/kg 
Q4W dosing regimens (none of the monotherapy studies explored Q4W regimens). PK 
simulations indicate that a similar overall exposure as represented by area under the
concentration-time curves (4 weeks) is expected following both 10 mg/kg Q2W and 20 mg/kg 
Q4W regimens. However, median maximum observed concentration at steady state is 
expected to be higher with 20 mg/kg Q4W (approximately 1.5 fold) and median trough 
concentration at steady state is expected to be higher with 10 mg/kg Q2W (approximately 1.25 
fold).
Population PK analysis indicated only minor impact of body weight on PK of durvalumab 
(coefficient of ≤ 0.5). The impact of body weight-based (10 mg/kg Q2W) and fixed dosing 
(750 mg Q2W) of durvalumab was evaluated by comparing predicted steady state PK 
concentrations (5th, median and 95th percentiles) using the population PK model. A fixed 
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
68 of 206
Template 16.2
dose of 750 mg was selected to approximate 10 mg/kg (based on median body weight of 
~75 kg). A total of 1000 patients were simulated using body weight distribution of 40 to 
120 kg. Simulation results demonstrate that body weight-based and fixed dosing regimens 
yield similar median steady state PK concentrations with slightly less overall between-subject 
variability with fixed dosing regimen.
Similar findings have been reported by others (Ng et al, 2006; Wang et al, 2009; Zhang et al, 
2012; Narwal et al, 2013). Wang and colleagues investigated 12 mAbs and found that fixed 
and body size-based dosing perform similarly, with fixed dosing being better for 7 of 12 
antibodies (Wang et al, 2009). In addition, they investigated 18 therapeutic proteins and 
peptides and showed that fixed dosing performed better for 12 of 18 in terms of reducing the 
between-subject variability in PK/pharmacodynamics parameters (Zhang et al, 2012).
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar PK exposure and variability, a fixed 
dosing regimen is considered appropriate. Based on average body weight of 75 kg, a fixed 
dose of 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) is included in the current 
study. This dose is equivalent to 10 mg/kg Q2W, which has an acceptable safety profile 
(Section 1.4.2).
3.2.1.3
Rationale for the Combination of Monalizumab and Durvalumab
In the current ongoing study of monalizumab in combination with durvalumab in subjects 
with solid tumors (D419NC00001), dose escalation is complete. 
 
 
 The combination of monalizumab 750 mg Q2W and durvalumab 1500 mg Q4W was 
deemed safe by the DEC; therefore, these doses and associated regimens will be employed in 
the dose expansion and exploration parts of the study (Section 1.4.3).
3.2.1.4
Rationale for Cetuximab Dosing
The cetuximab regimen to be administered in Part 3 Cohorts A2 
 (400 mg/m2 initial 
dose followed by 250 mg/m2 Q1W starting on Day 8) is per the cetuximab label. The 
500 mg/m2 Q2W cetuximab regimen to be administered in combination with durvalumab and 
monalizumab in Part 3 Cohorts A2 
 (optional after the DLT-evaluation), C1A, and 
C2A, and in combination with monalizumab in Cohorts C1B and C2B is per institutional 
practice and NCCN guidelines (Benson et al, 2018; Pfeiffer et al, 2008; Tabernero et al, 
2008). The treatment regimen is detailed in Section 3.1.2.3.
3.2.2
Rationale for Study Population
The tumor types included in this study were selected based on unmet clinical need and 
underlying tumor biology. In both the dose-escalation (Part 1) and dose-expansion (Part 2) 
parts of the study, subjects with advanced solid tumors who have progressed or are refractory 
to at least 1 line of standard therapy will be enrolled. These populations are thought to 
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
69 of 206
Template 16.2
represent an unmet clinical need as currently available treatment options provide limited 
benefit.
All tumor types chosen for the dose-escalation and dose-expansion parts of the study have 
been shown to overexpress HLA-E, the ligand of CD94/NKG2a, and therefore may be 
appropriate for monalizumab treatment (Section 1.1). Emerging clinical data have 
demonstrated that PD-1/PD-L1 targeting agents may be clinically active among several tumor 
types (NSCLC, endometrial cancer, or high-grade serous epithelial ovarian cancer) selected 
for the expansion part (Le et al, 2015; Rizvi et al, 2015b; Disis et al, 2015). Initial clinical 
development of the combination of durvalumab and monalizumab will focus on these 4 
indications with unmet clinical need and biological rationale for targeting both the PD-L1 and 
CD94/NKG2a pathways. 
 
Specifically, in the NSCLC population, durvalumab has shown that clinical activity correlates 
with tumoral PD-L1 expression where ORR was higher in patients whose tumors are PD-L1-
positive as compared to those whose tumors are PD-L1-negative (Rizvi et al, 2015b). This 
study will evaluate the impact of PD-L1 expression on the clinical activity of the combination 
of durvalumab and monalizumab by enrolling both PD-L1-positive and PD-L1-negative 
NSCLC subjects.
Based on the known lack of single-agent activity of PD-1/PD-L1 antagonists in 
CRC 
and the initial promising antitumor activity seen with durvalumab in combination with the 
750-mg dose of monalizumab administered Q2W in subjects with 
CRC in the 
dose-escalation and dose-expansion parts of the study (see summary in Section 1.4.3) and 
good tolerability, it was decided to evaluate whether this preliminary antitumor activity of 
durvalumab in combination with monalizumab could be further improved with acceptable 
tolerability by adding a standard chemotherapy regimen of mFOLFOX6 
with or 
without bevacizumab or cetuximab in subjects with either 1L or 2L 
CRC, respectively. 
Acceptable tolerability profiles for PD-1/PD-L1 targeting drugs in combination with 
chemotherapeutic agents have been reported in other clinical studies of patients with 
metastatic CRC (Bendell et al, 2015; Shahda et al, 2017; Khemka et al, 2016).
Furthermore, based on promising antitumor activity and favorable safety profile of 
monalizumab + cetuximab in subject with recurrent or metastatic SCCHN (see summary in 
Section 1.4.1.1) and the preliminary clinical activity of monalizumab + durvalumab in 
CRC (described in Section 1.4.3) observed in this ongoing study, the combination of 
monalizumab, durvalumab, and cetuximab and the combination of monalizumab and 
cetuximab in 
CRC will be evaluated in Part 3 of this study. There is a strong 
rationale for combining cetuximab and monalizumab, alone and with durvalumab, in 
CRC, regardless of mutational status, as these agents target three distinct, interconnected 
aspects of the antitumor immune response: 1) Cetuximab promotes tumor cell killing, antigen 
release, and cytokine production via ADCC (a mechanism that is not dependent on 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
70 of 206
Template 16.2
); 2) monalizumab may enhance the activity of cetuximab by promoting NK 
activity; 3) addition of durvalumab may overcome suppression of the resulting adaptive 
immune response (Ferris et al, 2018).
For patients with refractory, metastatic CRC, there is a significant clinical unmet need for 
better treatment regimens than those currently available, as reported in Section 1.5.1.
3.2.3
Rationale for Dose-escalation Algorithm
The mTPI design used in the dose-escalation part is a model-based algorithm for 
dose-escalation/de-escalation decisions that incorporates data from all dose levels. The design 
maintains the practical considerations of the 3+3 design (minimal parametric assumptions 
regarding toxicity, and pre-determined dose-escalation/de-escalation rules with no in-trial 
modeling required), while improving reliability in determining the MTD according to a pre-
specified target toxicity. Simulation work has demonstrated improved operating 
characteristics with respect to both reliability and safety (Ji et al, 2010). Given that the 
dose-escalation design will provide evidence-based support for the dose-expansion cohorts, an 
approach that has higher likelihood of identifying the true MTD is favored, and minimizes the 
likelihood of having to change the dose based on emerging data during the dose-expansion 
part.
The mTPI algorithm used during the dose-escalation part (Part 1) will be used during the 
dose-exploration part (Part 3).
3.2.4
Rationale for Endpoints
The primary objectives of the study are to determine the safety, MTD or the highest 
protocol-defined dose in the absence of establishing an MTD. The occurrence of DLTs will be 
used to establish the MTD and thus the standard safety endpoints, such as AEs, SAEs, and 
deaths, will be included in the safety evaluation. As durvalumab in combination with 
monalizumab will be administered on a repeated dosing schedule, the development of 
anti-drug antibodies (ADAs) and its potential effect on the endpoints related to safety, PK, and 
clinical activity will also be assessed. Furthermore, the dose-exploration part of the study (Part 
3) will determine whether a standard chemotherapy regimen and/or a biologic agent can be 
added to the combination of durvalumab and monalizumab with acceptable safety and PK, 
and improved clinical activity.
The endpoints for assessment of antitumor activity are those routinely included in oncology 
studies and will include OR (primary endpoint for Part 3 Cohorts C1A and C1B), DC, 
duration of response (DoR), and progression-free survival (PFS), by investigator assessment 
per RECIST v1.1, as well as OS.
The PK of durvalumab is being examined to determine the effect of monalizumab on 
durvalumab PK parameters. Conversely, the PK of monalizumab is being examined to 
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
71 of 206
Template 16.2
determine the effect of durvalumab on monalizumab PK parameters. In Part 3, Cohorts C1A 
and C1B, the PK of cetuximab is being examined to determine the effect of durvalumab and 
monalizumab on cetuximab PK parameters.
 
 
 
 
 
 
 
 
Target engagement of monalizumab will be assessed through CD94/NKG2a receptor 
occupancy. These will allow the extent to which each drug interacts with their target at each 
dose to be assessed. T-cell and NK-cell proliferation and activation may also be assessed to 
determine the effects drug target engagement has on cell function. 
 
 
 Cetuximab is an EGFR inhibitor. The expression of EGFR will be evaluated in 
subjects treated with cetuximab to detect whether subjects with an increased pathway 
engagement will be more likely to respond to treatment. 
 
 
Changes in circulating 
protein levels of IFNγ and other proteins associated with immune cell activation may also be 
assessed as potential indicators of patient response.
3.3
Study 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 clinical study 
protocol (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 subjects 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 
subject’s ability to conduct or participate in the study. The investigator or designee should 
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
72 of 206
Template 16.2
contact the study sponsor representative 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 subjects, maintain 
compliance with Good Clinical Practice, 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/assent for the mitigation procedures (note, in the case of verbal 
consent/assent, the Informed Consent Form (ICF) should be signed at the subject’s next 
contact with the study site). 

Home or Remote visit: Performed by a site-qualified Health Care Professional (HCP) or 
HCP provided by a third-party vendor (TPV).

Telemedicine visit: Remote contact with the subjects using telecommunications 
technology, including phone calls, virtual or video visits, and mobile health devices.
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Section 10.6.
4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
 




CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
73 of 206
Template 16.2
Table 5
Study Overview and Status Update
Tumor 
Type
Treatment
Status Under 
Protocol 
Amendment 6
Total 
Planned 
Enrollment
Subjects 
Enrolled and 
Treated as of 24 
March 2020
Part 3 Dose Exploration in 
CRC
1L 
CRC
Cohort A1: mFOLFOX6, 
bevacizumab, durvalumab 1500 mg 
Q4W, and monalizumab 750 mg Q2W
Closed
18
18
Cohort A2: mFOLFOX6, cetuximab, 
durvalumab 1500 mg Q4W, and 
monalizumab 750 mg Q2W
Closed
18
18
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
74 of 206
Template 16.2
Table 5
Study Overview and Status Update
Tumor 
Type
Treatment
Status Under 
Protocol 
Amendment 6
Total 
Planned 
Enrollment
Subjects 
Enrolled and 
Treated as of 24 
March 2020
1L = first-line; 
 
 
 mFOLFOX6 = a modified FOLFOX regimen of folinic acid/fluorouracil/oxaliplatin; 
 
 
; 
CRC = 
 colorectal cancer; 
QW2 = every 2 
weeks; QW4 = every 4 weeks;
. 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
75 of 206
Template 16.2
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1
Written and signed informed consent and any locally required authorization (eg, Health 
Insurance Portability and Accountability Act in the United States of America [USA]) 
obtained from the subject/legal representative prior to performing any protocol-related 
procedures, including screening evaluations
2
Age ≥ 18 years at the time of study entry
3
In the dose-escalation part, subjects must have histologic documentation of advanced 
recurrent or metastatic 
CRC, NSCLC, 
endometrial cancer, high-grade serous 
epithelial ovarian cancer (including fallopian tubal carcinoma and peritoneal carcinoma), 
cervical cancer, castration-resistant prostate cancer, or pancreatic adenocarcinoma.
4
In the dose-expansion part, subjects must have histologic documentation of advanced 
recurrent or metastatic 
CRC, NSCLC, 
endometrial cancer, or high-grade 
serous epithelial ovarian cancer (including fallopian tubal carcinoma and peritoneal 
carcinoma).
5
Subjects entering Parts 1 and 2 (escalation and expansion) must have received and have 
progressed or are refractory to at least one line of standard systemic therapy in the 
recurrent/metastatic setting, appropriate for the specific tumor type. In addition, subjects 
must meet all of the tumor specific criteria below, with documented progression from 
previous therapy at study entry. Interval progression between two lines of therapy defines 
separate lines of therapy. Both standard and investigational treatments will count as lines 
of therapy when determining eligibility.
For all tumor types: No evidence of partial small bowel obstruction or small bowel 
obstruction within 4 weeks prior to the first scheduled dose of study treatment, and ability 
to maintain weight and hydration with oral intake only, without requirement for IV or 
supplemental enteral nutrition or hydration (ie, no G-tubes, J-tubes, total parenteral 
nutrition, or hydration requirements). Subjects with active/ongoing paracentesis are 
excluded.
(a) Ovarian:
(i)
Subjects may have received up to 3 prior lines of systemic therapy for 
recurrent/metastatic disease. All subjects must have previously received and 
progressed while on or within 6 months of completing a platinum-based 
regimen.
In dose expansion, approximately equal numbers of subjects will be enrolled 
from the following two groups: 1 to 2 versus 3 prior lines of treatment in the 
recurrent/metastatic setting
(b)
CRC:
(i)
All subjects need to have a documented mutation test during screening and 
confirmed tumor locations from disease assessment for enrollment
(ii) CRC cancers must NOT have a defective DNA mismatch repair (microsatellite 
instability) documented by testing. Testing may be done locally, and prior 
documentation of this testing is acceptable in lieu of running the test again. 
Defective DNA mismatch repair is defined by either:
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
76 of 206
Template 16.2

High-frequency microsatellite instability with changes detected in 2 or more 
panels of microsatellite markers (BAT-25, BAT-26, NR-21, NR-24, or 
MONO-27),
OR

Immunohistochemical analysis demonstrating absence of protein expression 
of any one or more of the following proteins: MLH1, MSH2, MSH6, or 
PMS2
(iii) Subjects entering Part 1 and Part 2 may have received up to 3 prior lines of 
systemic therapy for recurrent/metastatic disease

In Part 2 (dose expansion), approximately equal numbers of subjects will be 
enrolled from the following two groups: 1 to 2 versus 3 prior lines of 
treatment in the recurrent/metastatic setting
(iv) The following inclusion criteria apply to subjects entering Part 3 (by Cohort):
Prior therapy criteria

Part 3, Cohorts A1, A2, 
: subjects must be 1L chemotherapy-naïve in 
the recurrent/metastatic setting; subjects may have progressed ≥6 months 
after receiving an oxaliplatin chemotherapy regimen in the adjuvant setting. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 

Part 3, Cohorts C1A, C1B, C2A, C2B: subjects
 
 
Prior standard chemotherapy in the recurrent/metastatic setting must 
include ALL of the following agents:
-- Fluoropyrimidines, irinotecan and oxaliplatin
-- An anti-VEGF mAb (eg, bevacizumab)
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
77 of 206
Template 16.2
-- Subjects in Cohorts C2A and C2B must not have received prior
anti-EGFR therapy (eg, cetuximab or panitumumab naïve).
Subjects must have progressed based on imaging during or within 
3 months of the last administration of each standard chemotherapy.
Subjects who have withdrawn from standard treatment due to 
unacceptable toxicity warranting discontinuation of treatment and 
precluding retreatment with the same agent prior to progression of 
disease will also be eligible to enter the study.
Subjects who had received adjuvant chemotherapy and had recurrence 
during or within 6 months of completion of the adjuvant chemotherapy 
are allowed to count the adjuvant therapy as 1 regimen of 
chemotherapy.
Disease pathology criteria 

Part 3, Cohorts A1 
: subjects can be enrolled regardless of 
 and location of colon primary tumor.

Part 3, Cohort A2: subjects are required to be 
 
 and have a left-sided colon primary tumor. 
 

 

 
 

Part 3, Cohorts C1A and C1B: subjects are required to have documented 
.
 

Part 3, Cohorts C2A and C2B: subjects are required to be 
 
. 
 
 
Bevacizumab criteria

Part 3, Cohorts A1 
 where bevacizumab is the biologic component:
The subject has adequate coagulation function as defined by 
international normalized ratio (INR) < 1.5 × ULN and a partial 
thromboplastin time (or activated partial thromboplastin time) 
< 1.5 ULN if not receiving anticoagulation therapy. Subjects on 
full-dose anticoagulation must be on a stable dose (minimum duration 
14 days) of oral or parenteral (eg, low molecular weight heparin) 
anticoagulant therapy and if on oral anticoagulation with coumarin 
derivatives, must have an INR < 3 and have no clinically significant 
active bleeding (defined as Grade 2 or higher hemorrhage within 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
78 of 206
Template 16.2
14 days prior to first dose of study treatment) or pathological condition 
that carries a high risk of bleeding (eg, intact primary tumor with a 
history of clinically significant bleeding, or tumor involving major 
vessels or known esophageal varices).
NOTE: Subjects with a venous thrombosis are permitted to enroll,
including subjects on newer oral anticoagulants (eg, apixaban, 
rivaroxaban, dabigatran, etc), provided they are clinically stable, 
asymptomatic, and adequately treated with anticoagulation in the 
opinion of the investigator for at least 3 months prior to the first dose of 
study treatment.
The subject’s urinary protein is < 1+ on dipstick or routine urinalysis; if 
urine protein > 2+, a 24-hour urine must be collected and must 
demonstrate < 1000 mg of protein in 24 hours to allow participation in 
the study.
(c) NSCLC: Subjects must have histologically proven, stage IIIb or IV NSCLC or 
recurrent or PD following multi-modal therapy (radiation therapy, surgical resection 
or definitive chemo radiation) for locally advanced disease.
(i)
Subjects may have received up to 2 prior lines of systemic therapy for 
recurrent/metastatic disease. Prior therapies must have included a platinum-based 
regimen.
(ii) Maintenance therapy following platinum doublet-based chemotherapy will not 
be considered a separate line of therapy.
(iii) Prior platinum-containing adjuvant, neoadjuvant, or definitive chemoradiation 
therapy given for locally advanced disease is considered 1L therapy only if 
recurrent (local or metastatic) disease developed within 6 months of completing 
therapy. Subjects with recurrent disease > 6 months must also have progressed 
after a subsequent platinum-based chemotherapy regimen given to treat the 
recurrence.
(iv) PD-L1 status will be prospectively determined by IHC prior to enrollment in the 
dose-expansion part. A minimum of 10 of the initial 20 NSCLC subjects enrolled 
must have PD-L1+ tumors. Similarly, if enrollment in the NSCLC cohort 
continues up to approximately 40 subjects, a minimum of 20 subjects must have 
PD-L1+ tumors.
(v) Subjects with known sensitizing EGFR-mutation or anaplastic lymphoma 
kinase-rearrangement are excluded. All subjects’ tumors must be tested and 
shown to be wild type EGFR (by IHC or sequencing) and anaplastic lymphoma 
kinase (by IHC, fluorescence in-situ hybridization, or sequencing) in a Clinical 
Laboratory Improvement Amendments certified lab in the USA. Countries 
outside the USA must use one of the methods mentioned for EGFR-mutation and 
anaplastic lymphoma kinase-rearrangement testing that has regulatory approval 
in the country the subject is being enrolled.
(d)
endometrial cancer:
(i)
Subjects may have received up to 2 prior lines of systemic therapy for 
recurrent/metastatic disease.
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
79 of 206
Template 16.2
(ii)
 
 
 
 
 
(e) Cervical cancer, castration-resistant prostate cancer, or pancreatic adenocarcinoma 
(dose-escalation part only): Subjects may have received up to 2 prior lines of 
systemic therapy for recurrent/metastatic disease. Subjects with castration-resistant 
prostate cancer must have progressed following therapy with abiraterone or 
enzalutamide.
6
Tumor tissue requirements are as follows:
(a)
 
 
 
 
 
(b) The initial 20 subjects in each dose-expansion cohort must have at least one lesion 
amenable to biopsy and must provide a pre-treatment biopsy during the Screening 
Period, and, if clinically feasible, during Week 9. If a given dose-expansion cohort is 
expanded beyond the initial 20 subjects, additional subjects must consent to provide 
an archival tumor sample from a biopsy collected within 1 year prior to first dose of 
study drug or must provide a pre-treatment biopsy during the Screening Period. If 
clinically feasible, all dose-expansion subjects must provide a biopsy during Week 9.
(c) Subjects in Part 3 must consent to provide an archival tumor sample from a biopsy 
collected within 1 year prior to the first dose of study treatment or must provide a 
pre-treatment biopsy during the Screening Period.
(d) For subjects with CRC, the microsatellite stability testing pathology report will be 
available to the sponsor at screening.
7
Subjects must have at least one lesion that is measurable by RECIST v1.1 (Eisenhauer et 
al, 2009).
(a) A previously irradiated lesion can be considered a target lesion if the lesion is well 
defined, measurable per RECIST, and has clearly progressed during or after most 
recent therapy.
(b) Subjects undergoing fresh tumor biopsies must have additional non-target lesions that 
can be biopsied at acceptable risk as judged by the investigator or if no other lesion 
suitable for biopsy, then a RECIST target lesion used for biopsy must be ≥ 2 cm in 
longest diameter.
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
80 of 206
Template 16.2
8
Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1
9
As of Week 1 Day 1, subjects with central nervous system (CNS) metastases must have 
been treated and must be asymptomatic and meet the following:
(a) No concurrent treatment, inclusive of but not limited to surgery, radiation, and/or 
corticosteroids
(b) At least 28 days after CNS treatment, clinically stable with no symptoms of CNS 
metastasis or sequelae of radiation and at least 14 days since last dose of 
corticosteroids
NOTE: Subjects with clinical symptoms or cord compression or with leptomeningeal 
disease are excluded from the study
10 Adequate organ function as determined by:
(a) Hematological (criteria i – iii cannot be met with recent blood transfusions or require 
ongoing growth factor support within 2 weeks of starting study treatment):
(i)
Absolute neutrophil count ≥ 1.5 × 109/L (1,500/mm3)
(ii) Platelet count ≥ 100 × 109/L (100,000/mm3)
(iii) Hemoglobin ≥ 9.0 g/dL within first 2 weeks prior to first dose of study treatment
(b) Renal:
Calculated creatinine clearance* (CrCl) or 24 hour urine CrCl > 50 mL/min
*Cockcroft-Gault formula will be used to calculate CrCl
(c) Hepatic:
(i)
TBL ≤ 1.5 × ULN; for subjects with documented/suspected Gilbert's syndrome, 
bilirubin ≤ 3 × ULN
(ii) AST and ALT ≤ 2.5 × ULN (AST/ALT can be up to 5 × ULN in the presence of 
liver metastasis, but cannot be associated with elevated bilirubin)
(iii) Subjects with Gilbert’s syndrome are not permitted to enroll in Part 3, 
 
. Thus, subjects with a known history of or 
clinical evidence of Gilbert’s syndrome and those known to have the genotype 
UGT1A1*28/*28 are to be excluded from these cohorts.
11 Females of childbearing potential who are sexually active with a nonsterilized male 
partner must use at least one highly effective method of contraception from screening, 
and must agree to continue using such precautions for 6 months after the final dose of 
investigational product. It is strongly recommended for the male partner of a female 
subject to also use male condom plus spermicide throughout this period. Cessation of 
contraception after this point should be discussed with a responsible physician. Periodic 
abstinence, the rhythm method, and the withdrawal method are not acceptable methods of 
birth control.
(a) Females of childbearing potential are defined as those who are not surgically sterile 
(ie, surgical sterilization includes bilateral tubal ligation, bilateral oophorectomy, or 
hysterectomy) or postmenopausal (defined as 12 months with no menses without an 
alternative medical cause).
(b) A highly effective method of contraception is defined as one that results in a low 
failure rate (ie, less than 1% per year) when used consistently and correctly. The 
acceptable methods of contraception are described in Table 6.
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
81 of 206
Template 16.2
(c) Should a woman become pregnant or suspect she is pregnant while she or her partner 
is participating in this study, she must inform her treating physician immediately.
(d) Female subjects must refrain from egg cell donation and breastfeeding while on study 
and for 6 months after the final dose of investigational product.
12 Nonsterilized male subjects who are sexually active with a female partner of childbearing 
potential must use a male condom with spermicide from Day 1 through 6 months after 
receipt of the final dose of investigational product. It is strongly recommended for the 
female partner of a male subject to also us an effective method of contraception 
throughout this period (Table 6). In addition, male subjects must refrain from sperm 
donation while on treatment and for 6 months after the final dose of investigational
product.
Table 6
Highly Effective Methods of Contraception
Intrauterine Methods
Hormonal Methods
•
Copper T intrauterine device
•
Levonorgestrel-releasingintrauterine system) or
implant (eg, Mirena ®) a
•
Implants
•
Hormone injection
•
Intravaginal devices
•
Combined pill
•
Minipill
•
Patch
a
This is also considered a hormonal method.

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
82 of 206
Template 16.2
4.1.3
Exclusion Criteria
1
Prior treatment with immunotherapy agents, including, but not limited to: tumor necrosis 
factor receptor superfamily agonists or checkpoint inhibitors or NK-cell inhibitors 
including agents targeting KIR, PD-1, PD-L1, CTLA-4, OX40, CD27, CD137 (4-1BB), 
CD357 (GITR), and CD40. Prior treatment with antitumor vaccines may be permitted 
upon discussion with the medical monitor. NOTE: Subjects who have received prior anti-
PD-1, anti-PD-L1 or anti-CTLA-4 immunotherapy may be enrolled in Part 1 if they meet 
the following criteria:
(a) Must not have experienced a toxicity that led to permanent discontinuation of prior 
immunotherapy. 
(b) All AEs while receiving prior immunotherapy must have completely resolved or 
resolved to baseline prior to screening for this study.
(c) Must not have experienced a ≥ Grade 3 immune-related AE or an immune-related 
neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE: 
Subjects with endocrine AE of ≤ Grade 2 are permitted to enroll if they are stably 
maintained on appropriate replacement therapy and are asymptomatic.
(d) Must not have required the use of additional immunosuppression other than 
corticosteroids for the management of an AE, not have experienced recurrence of an 
AE if re-challenged, and not currently require maintenance doses of > 10 mg 
prednisone or equivalent per day.
2
Prior participation in clinical studies that include durvalumab alone or in combination, 
where the study has registrational intent and the analyses for the primary endpoint have 
not yet been completed
3
Known allergic reaction to any component of durvalumab, monalizumab, or any 
component of the chemotherapy regimens and biologics that will be administered in 
Part 3.
4
Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study or the follow-up period of an interventional study.
5
Receipt of any conventional or investigational anticancer therapy within 4 weeks prior to 
the first dose of study treatment.
6
Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer 
treatment. Concurrent use of hormones for non-cancer-related conditions (eg, insulin for 
diabetes and hormone replacement therapy) is acceptable. Local treatment (eg, by local 
surgery or radiotherapy) of isolated lesions for palliative intent is acceptable beyond the 
DLT-evaluation period with prior consultation and in agreement with the medical 
monitor.
7
Receipt of live attenuated vaccines within 30 days prior to the first dose of study 
treatment. Subjects, if enrolled, should not receive live or live attenuated vaccine during 
the study and 30 days after the last dose of investigational products.
8
Unresolved toxicities from prior anticancer therapy, defined as having not resolved to 
NCI CTCAE v4.03 Grade 0 or 1 with the exception of alopecia and laboratory values 
listed per the inclusion criteria. Subjects with irreversible toxicity that is not reasonably 
expected to be exacerbated by the study drug may be included (eg, hearing loss) after 
consultation with the medical monitor.

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
83 of 206
Template 16.2
9
Current or prior use of immunosuppressive medication within 14 days before the first 
dose. The following are exceptions to this criterion:
(a) Intranasal, inhaled, topical steroids or local steroid injections (eg, intra-articular 
injection), OR
(b) Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone 
or equivalent, OR
(c) Steroids as premedication for hypersensitivity reactions (eg, computed tomography 
[CT] scan premedication).
(d) Premedication with steroids for chemotherapy and biologic components in Part 3.
10 History of primary immunodeficiency or allogeneic transplantation.
11 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:
(a) Subjects with vitiligo or alopecia
(b) Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement 
(c) Any chronic skin condition that does not require systemic therapy
(d) Subjects without active disease in the last 5 years may be included but only after 
consultation with the study physician
(e) Subjects with celiac disease controlled by diet alone.
12 Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina 
pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, or psychiatric 
illness/social situations that would limit compliance with study requirement, substantially 
increase risk of incurring AEs from durvalumab and monalizumab, or compromise the 
ability of the subject to give written informed consent.
13 Major surgery (as defined by the investigator) within 28 days prior to first dose of study 
treatment or still recovering from prior surgery. Local surgery of isolated lesions for 
palliative intent is acceptable.
14 Positive test results for human immunodeficiency virus, acute hepatitis A, active hepatitis 
B, or C.
15 Females who are pregnant, lactating, or intend to become pregnant during their 
participation in this study.
16 Other invasive malignancy within 2 years except for noninvasive malignancies such as 
cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductal carcinoma 
in situ of the breast that has/have been surgically cured. Subjects with localized 
malignancy that was treated with curative intent (eg, localized breast cancer, prostate 
cancer) and who remain disease free and are considered of low likelihood for recurrence 
may be enrolled on a case-by-case basis with prior discussion and in agreement with the 
sponsor’s medical monitor.

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
84 of 206
Template 16.2
17 Any condition that, in the opinion of the investigator or sponsor, would interfere with 
evaluation of the investigational product or interpretation of subject safety or study 
results.
18 The following exclusion criteria apply to subjects enrolling in Part 3, Cohorts A1 
, 
in which bevacizumab will be the biologic component:
(a) Subjects with a history of uncontrolled hereditary or acquired bleeding or thrombotic 
disorders.
(b) The subject has undergone subcutaneous venous access device placement ≤ 7 days 
prior to the first dose of study treatment.
(c) The subject has had a serious nonhealing wound, ulcer, or bone fracture ≤ 28 days 
prior to first dose of study treatment.
(d) The subject has an elective or planned major surgery to be performed during the 
course of the study.
(e) The subject has experienced a Grade 3 or higher bleeding event ≤ 3 months prior to 
first dose of study treatment.
(f) The subject has either peptic ulcer disease associated with a bleeding event, or known 
active diverticulitis.
(g) The subject experienced any of the following during 1L therapy with a bevacizumab-
containing regimen: an arterial thrombotic/thromboembolic event, Grade 4 
hypertension, Grade 3 proteinuria, a Grade 3-4 bleeding event or bowel perforation.
19 Subjects enrolling in Part 3, 
, must not have experienced a toxicity that led to 
permanent discontinuation of prior therapy with cetuximab.
4.1.4
Subject Enrollment and Randomization
Study participation begins (ie, a subject is “enrolled”) once written informed consent is 
obtained. Once informed consent is obtained, a subject identification (SID) number will be 
assigned by a central system (eg, an interactive voice/web response system [IXRS]), and the 
screening evaluations may begin to assess study eligibility (inclusion/exclusion) criteria. The 
SID number will be used to identify the subject during the screening process and throughout 
study participation, if applicable. 
For the randomized Part 3 Cohorts C1 and C2, subjects who complete all screening 
procedures and meet the eligibility criteria will proceed to randomization. The site will access 
the IXRS system on or prior to the subject's Week 1 Day 1 visit and a unique randomization 
number will be provided. Treatment should start no more than 3 working days after being 
randomized. Subjects cannot be re-randomized.
A master log of all consented subjects will be maintained at the site and will document all 
screening failures (ie, subjects who are consented but do not meet study eligibility criteria 
and/or are not randomized), including the reason(s) for screening failure.
Subjects who fail to meet the inclusion/exclusion criteria (ie, screening failures) should not 
receive investigational product/or be randomized.
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
85 of 206
Template 16.2
4.1.5
Withdrawal from the Study
Subjects are at any time free to withdraw from the study (investigational product and 
assessments), without prejudice to further treatment (withdrawal of consent). Such subjects 
will always be asked about the reason(s) and the presence of any AEs. If possible, they will be 
seen and assessed by an investigator. AEs will be followed.
4.1.5.1
Withdrawal from Treatment
If a subject withdraws consent to further treatment, they will not receive any further 
investigational product(s), but may continue with further study observation. Subjects who 
decline to return to the site for evaluations will be offered follow-up by phone according to the 
schedule in Section 4.2.3 as an alternative. If a subject withdraws from further participation in 
the study, then no further study visits or data collection should take place.
4.1.5.2
Withdrawal of Consent
If a subject withdraws from further participation in the study, then no further study visits or 
data collection should take place.
4.1.6
Discontinuation of Investigational Product
An individual subject will not receive any further investigational product if any of the 
following occur in the subject in question:
1
Withdrawal of consent from the study
2
Withdrawal of consent from further treatment with investigational product
3
Lost to follow-up
4
An AE that, in the opinion of the investigator or the sponsor, contraindicates further 
dosing
5
Any AE that meets criteria for discontinuation from investigational product (refer to 
Section 3.1.3 for toxicity management guidelines) and refer to Section 3.1.3.1 for 
instructions on when to discontinue the biologic agents). (If a subject is receiving clinical 
benefit, monotherapy treatment with durvalumab can be considered for NSCLC subjects, 
see Section 4.1.7.)
6
Subject did not meet one or more inclusion criteria or was determined to have met one or 
more of the exclusion criteria for study participation at study entry and continuing 
treatment with investigational product might constitute a safety risk
7
Pregnancy or intent to become pregnant
8
Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal (eg, refusal to adhere to scheduled visits)
9
Initiation of alternative anticancer therapy including another investigational agent
10 Confirmation of PD or unconfirmed PD and the treatment criteria in the setting of PD are 
not met (ie, absence of clinical symptoms or signs indicating clinically significant PD; no 
decline in ECOG performance status indicating rapid decline; AND absence of rapid PD 
or threat to vital organs/critical anatomical sites requiring urgent alternative medical 
intervention)

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
86 of 206
Template 16.2
11 Investigator determination that the subject is no longer benefiting from the treatment 
regimen
Subjects who are permanently discontinued from receiving investigational product will be 
followed for safety per Section 5.4, including the collection of any protocol-specified blood
specimens, survival and subsequent anticancer treatment. If a subject withdraws consent, is 
lost to follow-up or is administered subsequent therapy, follow-up visits are no longer 
required. Subjects who decline to return to the site for evaluations and/or receive subsequent 
anticancer therapy, must be offered follow-up by phone per Table 14 as an alternative to 
obtain survival information as well as information on additional subsequent anticancer 
treatment.
4.1.7
Treatment Beyond Progression
For all subjects, if PD (based on RECIST v1.1) occurs, the subject may continue study 
treatment until one of the following criteria is met:
1
Confirmed PD: An initial assessment of PD by RECIST v1.1 will be confirmed by a 
repeat evaluation at the next tumor assessment time point, but no sooner than 4 weeks 
later. If any subsequent tumor assessment time point shows ≥ 20% increase in the overall 
tumor burden (the sum of diameters of target lesions and new lesions), when compared to 
the initial PD assessment (the sum of diameters of target lesions and new lesions), the 
subject would be deemed as having confirmed PD and must be discontinued.
2
Meets any of the other investigational product discontinuation criteria (Section 4.1.6)
3
Clinical symptoms or signs indicating clinically significant PD such as the benefit-risk 
ratio of continuing therapy is no longer justified.
4
Decline in ECOG performance status indicating rapid decline.
5
Rapid PD or threat to vital organs/critical anatomical sites (eg, spinal cord compression) 
requiring urgent alternative medical intervention, and/or continuation of study therapy 
would prevent institution of such intervention.
Subjects must provide separate consent to continue treatment when progression is first 
detected.
4.1.8
Re-treatment Following Relapse
A subject who has been treated for a minimum of 2 years and continues to experience CR, PR, 
or SD as demonstrated by radiographic measures may be considered for treatment 
discontinuation. Data from other immunotherapy studies suggest that subjects who initially 
derive clinical benefit from immunotherapy can derive benefit again once the subject has PD 
while off therapy (Wolchok et al, 2013; Hamid et al, 2013).  
Subjects who progress during the first 52 weeks after the last dose of study treatment will be 
eligible for re-treatment with the protocol-defined experimental medicines (same dose and 
schedule) as at the time of discontinuation, after consultation and in agreement with the 

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
87 of 206
Template 16.2
sponsor. The investigator may consider standard-of-care chemotherapy backbone with the 
experimental agent(s) as appropriate for the subject at time of re-treatment. The criteria listed 
below must not apply:
1
Meets any of the investigational product discontinuation criteria (see Section 4.1.6);
2
ECOG performance status > 2;
3
Rapid PD or threat to vital organs/critical anatomical sites (eg, spinal cord compression) 
requiring urgent alternative medical intervention.
4
Subject has had severe/refractory irAE or development of new autoimmune condition 
that, in the investigator’s opinion, poses undue risk to the subject. 
This option for re-treatment will be limited to one occasion and will apply only if the subject 
has not received any other anticancer treatment for their disease following study-treatment 
discontinuation. The study protocol must still be active, ie, the final database lock has not yet 
occurred. The subject will need to follow the schedule of study procedures as described in 
Section 4.2.2. Subjects must also be re-consented.
4.1.9
Replacement of Subjects
In the dose-escalation part, a minimum of 3 evaluable subjects is required unless unacceptable 
toxicity is seen in a dose-level cohort. For a dose-level cohort that has less than 3 evaluable 
subjects, subjects who do not meet the criteria for the DLT-evaluable Population (Section 
4.8.1) will be replaced. Subjects who fail DLT evaluation in the dose-exploration part, for 
reasons other than a DLT, will be replaced as necessary to obtain at least 6 evaluable subjects. 
Subjects enrolled in the dose-expansion part will not be replaced.
4.1.10
Withdrawal of Informed Consent for Data and Biological Samples
Biological Samples Obtained for the Main Study
Study data are protected by the use of an SID number, which is a number specific to the 
subject. The investigator is in control of the information that is needed to connect a study 
sample to a subject. A subject’s consent to the use of data does not have a specific expiration 
date, but the subject may withdraw consent at any time by notifying the investigator. If 
consent is withdrawn, any samples collected prior to that time may still be given to and used 
by the sponsor but no new data or samples will be collected unless specifically required to 
monitor safety of the subject.
Samples Obtained for Genetic Research or Future Research
Samples obtained for genetic research or future research will be labeled with a sample 
identification number linked to the SID number but will not be labeled with personal 
identifiers such as the subject’s name. If the subject withdraws consent for participating in the 
genetic research or future research, the sponsor will locate the subject’s sample and destroy it. 

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
88 of 206
Template 16.2
The coding of samples and results is to ensure that these research results are kept confidential 
by keeping the subject’s identity and these results separate.
This study involves the collection of biological samples, such as blood and samples of body 
tissue. These samples will be used to evaluate the presence of study drug, immune cells, 
proteins,
 
 in your tumor cells. This is different from genetic research 
looking at the DNA that is inherited from a patients’ parents, since it is a test evaluating how a 
patient’s cancer developed. Medimmune will be evaluating these changes to determine how 
the drugs are working and if there are situations in which the drugs work best. These 
biological samples will be used to conduct the main study and are not part of what is usually 
referred to as genetic research.  
If the subject consents to have his/her samples used for genetic research or future research, 
this additional research may not start immediately and may start at any time during the storage 
period. The subject’s sample(s), 
 will be stored by 
the sponsor with similar samples from other subjects at a secure central laboratory. The 
subject’s samples will not be kept for more than 25 years after the end of the study in which 
they were collected. If the subject chooses not to allow his/her study samples to be used for 
genetic research or future research, the samples will be destroyed by the sponsor once they are 
no longer required for the main study.
 
 
 
 
 
 
 
In this case only the remaining sample(s) will be destroyed
4.2
Schedule of Study Procedures
Whenever vital signs, 12-lead ECGs, and blood draws are scheduled for the same nominal 
time, the blood draws should occur last. The timing of the first 2 assessments should be such 
that it allows the blood draw (eg, PK blood sample) to occur at the proper nominal time. The 
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 
(EORTC QLQ-C30) and Patient Global Impression of Change (PGIC) questionnaire are being 
implemented in 
 
 these should be completed prior to any other study procedures that 
day; see Section 4.3.3 for instructions regarding these assessments.
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
89 of 206
Template 16.2
4.2.1
Enrollment/Screening Period
Table 7 shows all procedures to be conducted at screening/baseline. Screening procedures will 
be conducted within 28 days prior to the first dose of investigational product. The screening 
period may be extended an additional 7 days for subjects requiring prospective testing for 
tumoral PD-L1 expression.
Table 7
Schedule of Screening/Baseline Procedures
Study Period
Screening/Baseline
Procedure
Days -28 to -1
Written informed consent/ assignment of SID number
X
Verify eligibility criteria
X
Tumor and disease assessments
History of prior cancer treatment
X
Disease assessment by RECIST v1.1 (CT or MRI) a
X
Brain imaging a, b
X
Study procedures and examinations
Demographics (including age, sex, race, ethnicity)
X
Medical history (including smoking history) and prior imaging c
X
Physical examination (including height and weight)
X
ECOG performance status
X
12-lead ECG d
X
Vital signs (including temperature, BP, respiratory rate, pulse rate)
X
Assessment of AEs/SAEs
X
Concomitantmedications
X
Laboratory tests
Serum chemistry
X
Hematology
X
Coagulation parameters
X
Thyroid function
X
Urinalysis e
X
Serum pregnancy test
X
Hepatitis A, B and C; HIV-1
X
Other laboratory tests and assays
Archival tumor sample f
X
Fresh tumor biopsy f
X
Flowcytometry
X
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
90 of 206
Template 16.2
Table 7
Schedule of Screening/Baseline Procedures
Study Period
Screening/Baseline
Procedure
Days -28 to -1
Circulating soluble factors (serum)
X
Circulating soluble factors (plasma)
X
PBMC collection
X
Stool sample (Part 3, Cohorts C1A, C1B, C2A, and C2B only)
X g
AE = adverse event; BP = blood pressure; CT = computed tomography;
; 
DICOM = Digital Imaging and Communications in Medicine; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; HIV = human immunodeficiency virus;
; MRI = magnetic
resonance imaging;
PBMC = peripheral blood mononuclear cells;
RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; SID = subject
identification.
a
Previous scans for baseline disease and brain imaging that were performed within 6 weeks of dosing and 
meet the protocol requirements do not need to be repeated.
b
All subjects must receive a brain scan during the Screening Period.
c
If allowed by country: Prior imaging includes raw imaging data (eg, DICOM) of a previous disease 
assessment that has been performed between 4 weeks and 6 months prior to baseline scan obtained during 
screening.
d
At screening, a single ECG will be obtained.
e
If urine protein > 2+, a 24-hour urine must be collected and must demonstrate < 1000 mg of protein in 24 
hours to allow participation in the study.
f
For the initial subjects in each dose-escalation cohort, archival tumor from the subject should be collected. 
If not available, a fresh biopsy must be performed. Additional subjects enrolled in a dose-escalation cohort 
while the pharmacodynamics are further investigated, must have at least one lesion amenable to biopsy and 
must provide a pre-treatment biopsy during the screening period. Fresh biopsies are required for the initial 
20 subjects in each dose-expansion cohort. If enrollment in each dose-expansion cohort proceeds beyond 20 
subjects, archival tumor obtained within 1 year of enrollment or fresh biopsy obtained during screening is 
required. In Part 3, archival tumor sample obtained within 1 year of enrollment or fresh biopsy obtained 
during screening is required.
g
The stool sample can be collected anytime during screening, up to and including Day 1, provided it is 
collected prior to administration of the first dose of study drug(s).
4.2.2
Treatment Period
Procedures to be conducted during the treatment period presented in Table 8 for Weeks 1 to 
26 and in Table 9 for Weeks 27 to End of Treatment. At study visits when subjects do not 
receive investigational product, all of the pre-treatment assessments will be performed. The 
procedures presented in Table 8 for Weeks 1 to 26 and in Table 9 for Weeks 27 to End of 
Treatment should also be followed for NSCLC subjects receiving durvalumab monotherapy.
 
 
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
91 of 206
Template 16.2
For subjects undergoing re-treatment following relapse, procedures to be conducted are 
presented in Table 12 and Table 13.
Considerations when scheduling and conducting study visits:

The timing of ECGs and vital sign assessments should be such that it allows the blood 
draw (eg, PK blood sample) to occur at the exact nominal time.  The EORTC QLQ-C30 
and PGIC questionnaire, is being implemented in 
 
; these should be completed 
prior to any other study procedures that day; see Section 4.3.3 for instructions regarding 
these assessments.

All protocol required samples are collected predose unless otherwise indicated.

All dosing visits are to be scheduled based on the date of Week 1 Day 1 dosing. 

Future dosing visits are not to be recalibrated based on actual dosing dates unless 
approved by the sponsor.  

Subjects are to receive durvalumab and/or monalizumab (and if applicable chemotherapy 
and/or biologic) within a 5-day visit window (7-day visit window if the Q4W 
monalizumab schedule is investigated). The following guidelines should be followed as 
applicable:

If doses are not received within these visit windows, and the sponsor has not 
approved recalibration (see bullet above), the dose must be omitted and subjects 
should receive the next planned dose according to the schedule established at Week 1 
Day 1. 

In the event of scheduling shifts within the 5-day visit window, sequential doses of 
durvalumab and/or monalizumab (and if applicable bevacizumab and cetuximab 
[Q2W dosing schedules]) (eg, dose 1, dose 2) must not be administered less than 10 
days apart. 

In the event of scheduling shifts within the 5-day visit window, sequential doses of 
cetuximab (Q1W dosing schedule) (eg, dose 1, dose 2) must not be administered less 
than 6 days apart.

In the event of scheduling shifts within the 5-day visit window, sequential doses of 
chemotherapy (eg, dose 1, dose 2) must not be administered less than 14 days apart.

Disease assessment scans do not need to be performed on the same day as dosing and can 
be performed within a 7-day window of the dosing day.

If any subject experiences a toxicity related to investigational product, the management 
guidelines provided in Section 3.1.3 should be followed.
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
92 of 206
Template 16.2
Table 8
Schedule of Treatment Period Study Procedures Weeks 1 to 26
Study Period
Treatment Period: Weeks 1 to 26
Week/Day
W1 D1 W1 D2 W2 D1 W3 D1 W5 D1 W7 D1 W9 D1 W11 
D1
W13
D1
W15
D1
W17 D1
W19
D1
W21
D1
W23
D1
W25
D1
Procedure/Study Day
1
2
8
15
29
43
57
71
85
99
113
127
141
155
169
Enrollment
X
Tumor and disease assessments
Disease assessment by RECIST 
v1.1
 (CT or MRI and brain 
imaging [if metastasis found at 
baseline or symptomatic]) a
X
X
X
Fresh tumor biopsy b
X
(± 7D)
Study procedures and examinations
Physical examination
X c
X
X
X
X
X
X
X
ECOG performance status
X c
Xo
X
X
PGIC (Part 3, Cohorts C1A and C1B 
only)
X
X
X
X
X
X
Vital signs d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG 
e
X
X
X
X
Assessment of AEs/SAEs l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory tests
Serum chemistry l
X c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X c
X
X
X
X
X
X
X
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
93 of 206
Template 16.2
Table 8
Schedule of Treatment Period Study Procedures Weeks 1 to 26
Study Period
Treatment Period: Weeks 1 to 26
Week/Day
W1 D1 W1 D2 W2 D1 W3 D1 W5 D1 W7 D1 W9 D1 W11 
D1
W13
D1
W15
D1
W17 D1
W19
D1
W21
D1
W23
D1
W25
D1
Procedure/Study Day
1
2
8
15
29
43
57
71
85
99
113
127
141
155
169
Coagulation parameters
X c
X
X
X
X
X
X
X
Thyroid function tests
Xc
X
X
X
X
X
X
Urinalysis
X c
X
X
X
X
X
X
Urine or serum pregnancy test
X
X
X
X
X
X
X
Carcinoembryonic antigen for 
colorectal cancer and CA-125 for 
ovarian/endometrial cancer f
X
Xo
X
Pharmacokinetics
Durvalumab PK (not applicable for 
Part 3 Cohorts C1B and C2B)
X g
X
X
Xo
X g
X
Monalizumab PK
h
X g
X h
X h
X h
X h, o
X
g, h
X h
Cetuximab PK (Part 3, Cohorts C1A 
and C1B only)
Xg
X
X
Xo
X
g
X
Other laboratory tests and assays
CD94/NKG2a receptor occupancy
X
X
X
Durvalumab immunogenicity (not 
applicable for Part 3 Cohorts C1B and 
C2B)
X
X
X
X
Monalizumab immunogenicity
h
X
X
X 
h
X 
h
Cetuximab immunogenicity (Part 3, 
Cohorts C1A and C1B only)
X
X
Xo
X
Flow cytometry
X
X
X
X
X

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
94 of 206
Template 16.2
Table 8
Schedule of Treatment Period Study Procedures Weeks 1 to 26
Study Period
Treatment Period: Weeks 1 to 26
Week/Day
W1 D1 W1 D2 W2 D1 W3 D1 W5 D1 W7 D1 W9 D1 W11 
D1
W13
D1
W15
D1
W17 D1
W19
D1
W21
D1
W23
D1
W25
D1
Procedure/Study Day
1
2
8
15
29
43
57
71
85
99
113
127
141
155
169
Circulating soluble factors (serum)
X
X
Circulating soluble factors (plasma)
X
X
X
X
X
X
X
PBMC collection
X
X
X
X
X
X
Stool sample (Part 3, Cohorts C1A, 
C1B, C2A, and C2B only)
X p
Blood sample for future analysis m
X
Study treatment administration
Durvalumab administration (Q4W
dosing schedule; not applicable for 
Part 3 Cohorts C1B and C2B) 
i
X
X
X
X
X
X
X
Monalizumab administration (Q2W
dosing schedule) 
i
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemotherapy administration (Part 3 
Cohorts A1-
only; Q2W 
dosing schedule) j,k
X
X
X
X
X
X
X
X
X
X
X
X
X
Bevacizumab (Part 3, Cohorts A1 
 
 only; Q2W dosing schedule) k
X
X
X
X
X
X
X
X
X
X
X
X
X
Cetuximab (Part 3, Cohorts A2 
 
 only; Q1W dosing schedule) k,l, n
X
X
W3
W4
W5
W6
W7
W8
W9
W10
W11 W12 W13 W14 W15 W16
W17
W18
W19 W20 W21 W22 W23 W24 W25
W26
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
95 of 206
Template 16.2
Table 8
Schedule of Treatment Period Study Procedures Weeks 1 to 26
Study Period
Treatment Period: Weeks 1 to 26
Week/Day
W1 D1 W1 D2 W2 D1 W3 D1 W5 D1 W7 D1 W9 D1 W11 
D1
W13
D1
W15
D1
W17 D1
W19
D1
W21
D1
W23
D1
W25
D1
Procedure/Study Day
1
2
8
15
29
43
57
71
85
99
113
127
141
155
169
Cetuximab (Part 3, Cohorts C1A, 
C1B, C2A, and C2B only; Q2W 
dosing schedule) k, l, n
X
X
X
X
X
X
X
X
X
X
X
X
X
AE = adverse event; CT = computed tomography; 
; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology 
Group; EOI = end of infusion;
; MRI = magnetic resonance imaging; PBMC = peripheral blood mononuclear 
cells; PGIC = Patient Global Impression of Change; PK = pharmacokinetic; Q1W = every week; Q2W = every 2 weeks; Q4W = every 4 weeks; RECIST = 
Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; W = week. 
Note: On treatment days, evaluations and sample collections should be conducted prior to administration of durvalumab/monalizumab unless otherwise indicated. 
On nontreatment days, all of the pre-treatment assessments will be performed.
a
If post-baseline radiological imaging indicates progressive disease, a separate consent must be signed before the subject may continue treatment.
b
As clinically feasible, for subjects in dose escalation participating in pharmacodynamics expansion and for subjects in dose expansion who provided a fresh 
pre-treatment biopsy. As clinically feasible, subjects in Part 3 (dose exploration) who provided a fresh pre-treatment biopsy are encouraged to provide a 
biopsy at Week 9.
c
If tests are performed within 3 days prior to Week 1, Day 1, they do not need to be repeated. All safety laboratory results must be reviewed by the 
investigator or physician designee prior to administration of the scheduled dose of investigational product.
d
Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) will be measured on durvalumab and monalizumab treatment days according to the 
following schedule: within 30 minutes prior to the start of durvalumab and monalizumab infusion, approximately every 15 minutes during durvalumab and 
monalizumab infusion, at EOI of durvalumab and monalizumab, and at approximately 30 and 60 minutes post EOI of monalizumab. On Week1, Day 1, an 
additional 2-hour (± 15 minutes) post monalizumab EOI vital sign measurement will be required, while for Part 3 a 15- to 30-minute observation period 
would be sufficient prior to infusion of pre-medication for the biologic agent or chemotherapy but vital sign collection should continue approximately every 
30 minutes up to 2 hours after Monalizumab infusion. For subsequent doses, the additional 2-hour observation period will not be required unless clinically 
indicated (eg, subject experiences an infusion-related reaction).
e
On Week 1, Day 1, ECGs will be obtained in triplicate (all 3 within a 5-minute time period, at least 1 minute apart) within 30 minutes prior to start of 
durvalumab infusion, within 30 minutes post EOI of monalizumab, and between 2 and 6 hours post EOI of monalizumab. At all other time points, a single 
ECG will be obtained prior to investigational product(s) administration and as clinically indicated.
f
Sample to be taken prior to administration of investigational product.
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
96 of 206
Template 16.2
g
One predose sample will be collected prior to start of durvalumab infusion and an EOI (within 10 minutes) sample collected after the end of the durvalumab
infusion and after the end of the monalizumab infusion. For subjects in Cohort C1A, an EOI (within 10 minutes) sample will also be collected after the end 
of the cetuximab infusion. For subjects in Cohort C1B, one predose sample will be collected prior to start of monalizumab infusion and an EOI (within 10 
minutes) sample collected after the end of the monalizumab infusion and after the end of the cetuximab infusion. Post-dose PK samples are not applicable if 
the investigational product is not administered.
h
For subjects who continue in the study on durvalumab monotherapy (Section 3.1.1), a sample for monalizumab PK and immunogenicity should be taken 90
days (± 7 days) after the last dose of monalizumab. Further samples for monalizumab PK and immunogenicity are not required.
i
On study days when both durvalumab and monalizumab are administered, durvalumab will be administered first and the infusion duration will be 
approximately 60 minutes. The monalizumab infusion will start approximately 15 to 30 minutes post EOI of durvalumab and the infusion will be 
administered over approximately 60 minutes.
j
Infusion times for the biologic agent and chemotherapy should be according to the respective institutional guidelines. The biologic agent or chemotherapy 
regimen will be administered within 1 hour post end of the monalizumab infusion. The pre-medications for the biologic agent or chemotherapy can be 
administered after the 15- to 30-minute observation period post end of the monalizumab infusion.
k
During the days when the biologic agent and chemotherapy are administered, there should only be a 15- to 30-minute observation period post end of the 
monalizumab infusion, after which either pre-medication for the biologic agent or chemotherapy, or chemotherapy/biologic agent infusion can start.
l
The following should be assessed on the days of cetuximab administration: serum chemistry, all AEs, and concomitant medications.
m
Additional baseline blood samples will also be collected in a 10-mL red top tube in order to have serum samples collected at baseline for future analysis,
which includes, but is not limited to an autoimmune work-up (refer to the Laboratory Manual for the processing of this sample).
n
Cohorts A2 
: Cetuximab loading dose (400 mg/m2 IV infusion over approximately 2 hours) will be administered on Day 1, then maintenance dose 
(250 mg/m2 IV infusion over approximately 1 hour) Q1W will be administered starting on Day 8. The cetuximab regimen may be changed to 500 mg/m2 IV 
infusion for approximately 2 hours Q2W after a subject has completed the 28-day DLT-evaluation period, at the investigator’s discretion and in accordance 
with institutional guidelines.
Cohorts C1A, C1B, C2A, and C2B: Cetuximab (500 mg/m2 IV infusion over approximately 2 hours) will be administered on Day 1 then 500 mg/m2 IV 
infusion for approximately 2 hours Q2W starting on Day 15.
o
Assessment is optional if the subject is discontinuing treatment at the scheduled W9 D1 visit. 
p
Second stool sample can be collected ± 2 weeks from the W9 D1visit.
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
97 of 206
Template 16.2
Table 9
Schedule of Treatment Period Study Procedures Weeks 27 to End of Treatment
Study Period
Treatment Period: Weeks 27 to End of Treatment
Week/Day
W27 
D1
W29 
D1
W31 
D1
W33 
D1
W35 
D1
W37 
D1
W39 
D1
W41 
D1
W43 
D1
W45 
D1
W47 
D1
W49 
D1
W51 
D1
Cont.h
Procedure/Study Day
D183
D197
D201
D225
D239
D253
D267
D281
D295
D309
D323
D337
D351
Cont.
Tumor and disease assessments
Disease assessment by RECIST
v1.1
 (CT or MRI and
brain imaging [if metastasis found
at baseline or symptomatic]) a
X
X
X
W57 D1 (D393) 
then Q26W i
Study procedures and 
examinations
Physical examination
X
X
X
X
X
X
Q4W
ECOG performance status
X
X
X
W57 D1 (D393) 
then Q8W
PGIC (Part 3, Cohorts C1A and 
C1B only)
X
X
X
W57 D1 (D393) 
then Q8W
Vital signs b
X
X
X
X
X
X
X
X
X
X
X
X
X
Q2W
12-lead ECG
X
X
X
Assessment of AEs/SAEs f
X
X
X
X
X
X
X
X
X
X
X
X
X
Q2W
Concomitantmedications f
X
X
X
X
X
X
X
X
X
X
X
X
X
Q2W
Laboratory tests
Serum chemistry f 
X
X
X
X
X
X
X
X
X
X
X
X
X
Q4W
Hematology
X
X
X
X
X
X
Q4W
Coagulation parameters
X
X
X
X
X
X
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
98 of 206
Template 16.2
Table 9
Schedule of Treatment Period Study Procedures Weeks 27 to End of Treatment
Study Period
Treatment Period: Weeks 27 to End of Treatment
Week/Day
W27 
D1
W29 
D1
W31 
D1
W33 
D1
W35 
D1
W37 
D1
W39 
D1
W41 
D1
W43 
D1
W45 
D1
W47 
D1
W49 
D1
W51 
D1
Cont.h
Procedure/Study Day
D183
D197
D201
D225
D239
D253
D267
D281
D295
D309
D323
D337
D351
Cont.
Thyroid function tests
X
X
X
X
X
X
Q12W
Urinalysis
X
X
X
X
X
X
Q12W
Urine or serum pregnancy test
X
X
X
X
X
X
Q4W
Study treatment administration
Durvalumab administration (Q4W
dosing schedule; not applicable 
for Part 3 Cohorts C1B and 
C2B) c
X
X
X
X
X
X
Q4W
Monalizumab administration
(Q2W dosing schedule)c
X
X
X
X
X
X
X
X
X
X
X
X
X
Q2W
Chemotherapy administration 
(Part 3 Cohorts A1-
only; Q2W dosing schedule) d, e
X
X
X
X
X
X
X
X
X
X
X
X
X
Q2W
Bevacizumab (Part 3, Cohorts A1 
 only; Q2W dosing 
schedule) e
X
X
X
X
X
X
X
X
X
X
X
X
X
Q2W
Cetuximab (Part 3, Cohorts A2 
 only; Q1W dosing 
schedule) e, f, g
W27
W28
W29
W30
W31
W32
W33
W34
W35
W36
W37
W38
W39
W40
W41
W42
W43
W44
W45
W46
W47
W48
W49
W50
W51
W52
Q1W
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cetuximab (Part 3, Cohorts C1A, 
C1B, C2A, and C2B only; Q2W 
dosing schedule) e, f, g
X
X
X
X
X
X
X
X
X
X
X
X
X
Q2W
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
99 of 206
Template 16.2
AE = adverse event; CT = computed tomography; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion; 
EOT = end of treatment; 
 
; MRI = magnetic resonance imaging; PGIC = Patient Global Impression of Change; Q1W = every week; Q2W = 
every 2 weeks; Q4W = every 4 weeks; Q8W = every 8 weeks; Q12W = every 12 weeks; Q26W = every 26 weeks; RECIST = Response Evaluation Criteria in
Solid Tumors; SAE = serious adverse event; W = week.
Note: On treatment days, evaluations and sample collections should be conducted prior to administration of durvalumab unless otherwise indicated.
a
If a post-baseline radiological imaging indicates progressive disease, a separate consent must be signed before the subject may continue treatment.
b
Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) will be measured on durvalumab and monalizumab treatment days according to the
following schedule: within 30 minutes prior to the start of durvalumab and monalizumab administration, approximately every 15 minutes during durvalumab
and monalizumab administration, at the EOI of durvalumab and monalizumab, and at approximately 30 and 60 minutes post EOI of monalizumab.
c
On days when durvalumab and monalizumab are administered together, durvalumab will be administered first and the infusion duration will be approximately 
60 minutes. The monalizumab infusion will start approximately 15 to 30 minutes post EOI of durvalumab and the infusion will be administered over
approximately 60 minutes.
d
Infusion times for chemotherapy can be per the respective institutional guidelines. The chemotherapy regimen will be administered within 1 hour post end 
of the monalizumab infusion. The pre-medications for chemotherapy or biologic agent can begin after the 15- to 30-minute observation period post end of 
the monalizumab infusion.
e
During the days when the biologic agent and chemotherapy are administered, there should only be a 15- to 30-minute observation period post end of the 
monalizumab infusion, after which either pre-medication for the biologic agent or chemotherapy, or chemotherapy/biologic agent infusion can start.
f
The following should be assessed on the days of cetuximab administration: serum chemistry, all AEs, and concomitant medications.
g
Cohorts A2 
: Cetuximab loading dose (400 mg/m2 IV infusion over approximately 2 hours) will be administered on Day 1, then maintenance dose 
(250 mg/m2 IV infusion over approximately 1 hour) Q1W will be administered starting on Day 8. The cetuximab regimen may be changed to 500 mg/m2 IV 
infusion for approximately 2 hours Q2W after a subject has completed the 28-day DLT-evaluation period, at the investigator’s discretion and in accordance 
with institutional guidelines.
Cohorts C1A, C1B, C2A, and C2B: Cetuximab (500 mg/m2 IV infusion over approximately 2 hours) will be administered on Day 1 then 500 mg/m2 IV 
infusion for approximately 2 hours Q2W starting on Day 15.
h
Procedures can be performed as clinically indicated/more frequently if considered necessary by the investigator.
i
Imaging can be performed more frequently if required by Institutional Guidelines or if clinically indicated. 
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
100 of 206
Template 16.2
Table 10
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
101 of 206
Template 16.2
Table 10
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
102 of 206
Template 16.2
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
103 of 206
Template 16.2
Table 11
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
104 of 206
Template 16.2
Table 11
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
105 of 206
Template 16.2
Table 12
Schedule of Treatment Period Study Procedures for Re-treatment after Relapse – Re-treatment Weeks 1 
to 26
Study Period
Re-treatment Period: Re-treatment Weeks 1 to 26
Week/Day
Re-
baseline 
a
RW1
D1 
RW2
D1
RW3
D1
RW5
D1
RW7
D1
RW9
D1
RW11 
D1
RW13
D1
RW15
D1
RW17
D1
RW19
D1
RW21
D1
RW23
D1
RW25
D1
Written Informed Consent
X
Enrollment
X
Tumor and disease assessments
Disease assessment by RECIST 
v1.1
 (CT or MRI and brain 
imaging [if metastasis found at 
baseline or symptomatic]) b
X c
X
X
X
Study procedures and examinations
Physical examination
X
X c
X
X
X
X
X
X
ECOG performance status
X
X c
X 
X
X
Vital signs d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG 
e, 
X
X
X
k
X
k
X
k
Assessment of AEs/SAEs i
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications i
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory tests
Serum chemistry i, k
X
X c
X k
X k
X k
X k
X k
X k
X k
X k
X k
X k
X k
X k
X k
Hematology k
X
X c
X k
X k
X k
X k
X k
X k
X k
Coagulation parameters 
X
X c
X k
X k
X k
X k
X k
X k
X k
Thyroid function tests 
X
X c
X k
X k
X k
X k
X k
X k
Urinalysis 
X
X c
X k
X k
X k
X k
X k
X k
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
106 of 206
Template 16.2
Table 12
Schedule of Treatment Period Study Procedures for Re-treatment after Relapse – Re-treatment Weeks 1 
to 26
Study Period
Re-treatment Period: Re-treatment Weeks 1 to 26
Week/Day
Re-
baseline 
a
RW1
D1 
RW2
D1
RW3
D1
RW5
D1
RW7
D1
RW9
D1
RW11 
D1
RW13
D1
RW15
D1
RW17
D1
RW19
D1
RW21
D1
RW23
D1
RW25
D1
Urine or serum pregnancy test
X
X
X
X
X
X
X
X
Study treatment administration
Durvalumab administration (Q4W
dosing schedule; not applicable for 
Part 3 Cohorts C1B and C2B) 
f
X
X
X
X
X
X
X
Monalizumab administration (Q2W
dosing schedule) 
f
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemotherapy administration (Part 3 
Cohorts A1-
 only; 
Q2W dosing schedule) g,h
X
X
X
X
X
X
X
X
X
X
X
X
X
Bevacizumab (Part 3, Cohorts A1 
 only; Q2W dosing 
schedule) h
X
X
X
X
X
X
X
X
X
X
X
X
X
Cetuximab (Part 3, Cohorts A2 
 
only; Q1W dosing schedule) h,i, j
X
X
RW
3
RW
4
RW
5
RW
6
RW
7
RW
8
RW
9
RW
10
RW
11
RW
12
RW
13
RW
14
RW
15
RW
16
RW
17
RW
18
RW
19
RW
20
RW
21
RW
22
RW
23
RW
24
RW
25
RW
26
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cetuximab (Part 3, Cohorts C1A, 
C1B, C2A, and C2B only; Q2W 
dosing schedule) h, i, j
X
X
X
X
X
X
X
X
X
X
X
X
X
AE = adverse event; CT = computed tomography;; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion;
; MRI = magnetic resonance imaging; Q1W = every week; Q2W = every 2 weeks; Q4W = 
every 4 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; RW = re-treatment week; SAE = serious adverse event. 
Note: On treatment days, evaluations and sample collections should be conducted prior to administration of durvalumab/monalizumab unless otherwise indicated. 
On nontreatment days, all of the pre-treatment assessments will be performed.
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
107 of 206
Template 16.2
a
Re-baseline procedures to be conducted within 28 days of initiation of re-treatment 
b
If post-baseline radiological imaging indicates progressive disease, a separate consent must be signed before the subject may continue treatment.
c
If tests are performed within 3 days prior to re-treatment Week 1, Day 1, they do not need to be repeated. All safety laboratory results must be reviewed by 
the investigator or physician designee prior to administration of the scheduled dose of investigational product.
d
Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) will be measured on durvalumab and monalizumab treatment days according to the 
following schedule: within 30 minutes prior to the start of durvalumab and monalizumab infusion, approximately every 15 minutes during durvalumab and 
monalizumab infusion, at EOI of durvalumab and monalizumab, and at approximately 30 and 60 minutes post EOI of monalizumab. On Week1, Day 1, an 
additional 2-hour (± 15 minutes) post monalizumab EOI vital sign measurement will be required, while for Part 3 a 15- to 30-minute observation period 
would be sufficient prior to infusion of pre-medication for the biologic agent or chemotherapy but vital sign collection should continue approximately every 
30 minutes up to 2 hours after Monalizumab infusion. For subsequent doses, the additional 2-hour observation period will not be required unless clinically 
indicated (eg, subject experiences an infusion-related reaction).
e
On Week 1, Day 1, ECGs will be obtained in triplicate (all 3 within a 5-minute time period, at least 1 minute apart) within 30 minutes prior to start of 
durvalumab infusion, within 30 minutes post EOI of monalizumab, and between 2 and 6 hours post EOI of monalizumab. At all other time points, a single 
ECG will be obtained prior to investigational product(s) administration and as clinically indicated.
f
On study days when both durvalumab and monalizumab are administered, durvalumab will be administered first and the infusion duration will be 
approximately 60 minutes. The monalizumab infusion will start approximately 15 to 30 minutes post EOI of durvalumab and the infusion will be 
administered over approximately 60 minutes.
g
Infusion times for the biologic agent and chemotherapy should be according to the respective institutional guidelines. The biologic agent or chemotherapy 
regimen will be administered within 1 hour post end of the monalizumab infusion. The pre-medications for the biologic agent or chemotherapy can be 
administered after the 15- to 30-minute observation period post end of the monalizumab infusion.
h
During the days when the biologic agent and chemotherapy are administered, there should only be a 15- to 30-minute observation period post end of the 
monalizumab infusion, after which either pre-medication for the biologic agent or chemotherapy, or chemotherapy/biologic agent infusion can start.
i
The following should be assessed on the days of cetuximab administration: serum chemistry, all AEs, and concomitant medications.
j
Cohorts A2 
: Cetuximab loading dose (400 mg/m2 IV infusion over approximately 2 hours) will be administered on Day 1, then maintenance dose 
(250 mg/m2 IV infusion over approximately 1 hour) Q1W will be administered starting on Day 8. The cetuximab regimen may be changed to 500 mg/m2 IV 
infusion for approximately 2 hours Q2W after a subject has completed the 28-day DLT-evaluation period, at the investigator’s discretion and in accordance 
with institutional guidelines.
Cohorts C1A, C1B, C2A, and C2B: Cetuximab (500 mg/m2 IV infusion over approximately 2 hours) will be administered on Day 1 then 500 mg/m2 IV 
infusion for approximately 2 hours Q2W starting on Day 15.
k
Procedures can be performed as clinically indicated/less frequently if considered appropriate by the investigator or if not required by Institutional 
Guidelines with a minimum at the beginning of each cycle and at the end of treatment.
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
108 of 206
Template 16.2
Table 13
Schedule of Treatment Period Study Procedures for Re-treatment after Relapse – Re-treatment Weeks 27 to 
End of Treatment
Study Period
Treatment Period: Re-treatment Weeks 27 to End of Treatment
Week/Day
RW27 
D1
RW29 
D1
RW31 
D1
RW33 
D1
RW35 
D1
RW37 
D1
RW39 
D1
RW41 
D1
RW43 
D1
RW45 
D1
RW47 
D1
RW49 
D1
RW51 
D1
Cont.i
Tumor and disease assessments
Disease assessment by RECIST
v1.1
 (CT or MRI and
brain imaging [if metastasis found
at baseline or symptomatic]) a
X
X
X
RW57 D1 
(D393) then 
Q26W i
Study procedures and 
examinations
Physical examination
X
X
X
X
X
X
Q4W
ECOG performance status
X
X
X
RW57 D1 
(D393) then 
Q8W
Vital signs b
X
X
X
X
X
X
X
X
X
X
X
X
X
Q2W
12-lead ECG h
X
X
X
Assessment of AEs/SAEs f
X
X
X
X
X
X
X
X
X
X
X
X
X
Q2W
Concomitantmedications f
X
X
X
X
X
X
X
X
X
X
X
X
X
Q2W
Laboratory tests
Serum chemistry f, h
X
X
X
X
X
X
X
X
X
X
X
X
X
Q4W
Hematology h
X
X
X
X
X
X
Q4W
Coagulation parameters h
X
X
X
X
X
X
Thyroid function tests h
X
X
X
X
X
X
Q12W
Urinalysis h
X
X
X
X
X
X
Q12W
Urine or serum pregnancy test
X
X
X
X
X
X
Q4W
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
109 of 206
Template 16.2
Table 13
Schedule of Treatment Period Study Procedures for Re-treatment after Relapse – Re-treatment Weeks 27 to 
End of Treatment
Study Period
Treatment Period: Re-treatment Weeks 27 to End of Treatment
Week/Day
RW27 
D1
RW29 
D1
RW31 
D1
RW33 
D1
RW35 
D1
RW37 
D1
RW39 
D1
RW41 
D1
RW43 
D1
RW45 
D1
RW47 
D1
RW49 
D1
RW51 
D1
Cont.i
Study treatment administration
Durvalumab administration (Q4W
dosing schedule; not applicable for
Part 3 Cohorts C1B and C2B) c
X
X
X
X
X
X
Q4W
Monalizumab administration
(Q2W dosing schedule) c
X
X
X
X
X
X
X
X
X
X
X
X
X
Q2W
Chemotherapy administration 
(Part 3 Cohorts A1-
only; Q2W dosing schedule) d, e
X
X
X
X
X
X
X
X
X
X
X
X
X
Q2W
Bevacizumab (Part 3, Cohorts A1 
 only; Q2W dosing 
schedule) e
X
X
X
X
X
X
X
X
X
X
X
X
X
Q2W
Cetuximab (Part 3, Cohorts A2 
 only; Q1W dosing 
schedule) e, f, g
RW
27
RW
28
RW
29
RW
30
RW
31
RW
32
RW
33
RW
34
RW
35
RW
36
RW
37
RW
38
RW
39
RW
40
RW
41
RW
42
RW
43
RW
44
RW
45
RW
46
RW
47
RW
48
RW
49
RW
50
RW
51
RW
52
Q1W
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cetuximab (Part 3, Cohorts C1A, 
C1B, C2A, and C2B only; Q2W 
dosing schedule) e, f, g
X
X
X
X
X
X
X
X
X
X
X
X
X
Q2W
AE = adverse event; CT = computed tomography; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion; 
 MRI = magnetic resonance imaging; Q1W = every week; Q2W = every 2 weeks; Q4W = every
4 weeks; Q8W = every 8 weeks; Q12W = every 12 weeks; Q26W = every 26 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; RW = re-treatment 
week; SAE = serious adverse event.
Note: On treatment days, evaluations and sample collections should be conducted prior to administration of durvalumab unless otherwise indicated.
a
If a post-baseline radiological imaging indicates progressive disease, a separate consent must be signed before the subject may continue treatment.
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
110 of 206
Template 16.2
b
Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) will be measured on durvalumab and monalizumab treatment days according to the
following schedule: within 30 minutes prior to the start of durvalumab and monalizumab administration, approximately every 15 minutes during durvalumab
and monalizumab administration, at the EOI of durvalumab and monalizumab, and at approximately 30 and 60 minutes post EOI of monalizumab.
c
On days when durvalumab and monalizumab are administered together, durvalumab will be administered first and the infusion duration will be approximately 
60 minutes. The monalizumab infusion will start approximately 15 to 30 minutes post EOI of durvalumab and the infusion will be administered over
approximately 60 minutes.
d
Infusion times for chemotherapy can be per the respective institutional guidelines. The chemotherapy regimen will be administered within 1 hour post end 
of the monalizumab infusion. The pre-medications for chemotherapy or biologic agent can begin after the 15- to 30-minute observation period post end of 
the monalizumab infusion.
e
During the days when the biologic agent and chemotherapy are administered, there should only be a 15- to 30-minute observation period post end of the 
monalizumab infusion, after which either pre-medication for the biologic agent or chemotherapy, or chemotherapy/biologic agent infusion can start.
f
The following should be assessed on the days of cetuximab administration: serum chemistry, all AEs, and concomitant medications.
g
Cohorts A2 
: Cetuximab loading dose (400 mg/m2 IV infusion over approximately 2 hours) will be administered on Day 1, then maintenance dose 
(250 mg/m2 IV infusion over approximately 1 hour) Q1W will be administered starting on Day 8. The cetuximab regimen may be changed to 500 mg/m2 IV 
infusion for approximately 2 hours Q2W after a subject has completed the 28-day DLT-evaluation period, at the investigator’s discretion and in accordance 
with institutional guidelines.
Cohorts C1A, C1B, C2A, and C2B: Cetuximab (500 mg/m2 IV infusion over approximately 2 hours) will be administered on Day 1 then 500 mg/m2 IV 
infusion for approximately 2 hours Q2W starting on Day 15.
h
Procedures can be performed as clinically indicated/more frequently if considered necessary by the investigator.
i
Imaging can be performed more frequently if required by Institutional Guidelines or if clinically indicated. 
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
111 of 206
Template 16.2
4.2.3
Follow-up Period
Table 14 shows all procedures to be conducted during the end of treatment visit and follow-up 
period. Subjects will complete the end of treatment visit within 14 days of the last dose of 
investigational product (either last dose of durvalumab and monalizumab treatment, or last 
dose of durvalumab, if the subject receives durvalumab monotherapy).
 
 
All subjects are to 
complete the end of treatment visit, all follow-up visits, and be contacted for survival 
status/subsequent anticancer treatment in accordance with Table 14. If a subject discontinues 
from treatment and moves onto alternative anticancer treatment, the follow-up visits will no 
longer be required; however, survival follow-up assessments and collection of subsequent 
anticancer treatment information would be required as indicated in Table 14, unless the 
subject withdraws consent for further follow-up. Survival follow-up will continue until the 
End of Study as described in Section 6.3.
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
112 of 206
Template 16.2
Table 14
Schedule of Follow-up Procedures
Study Period
Follow-up Period
Procedure / Study Day or Month
End of
Treatment
(EOT)
Visit
Day 30 Post
Last Dose
± 3 Days
Day 90 Post
Last Dose
± 7 Days h
Q3M After Day 90
Post Last Dose up to
Month 12 Post Last
Dose ± 7 Days h
Q6M After
Month 12 Post
Last Dose
± 14 Days h
Disease assessments
Disease assessment by RECIST v1.1
(CT or MRI
and brain imaging [if metastasis found at baseline or
symptomatic])
a
X
X
X
X
Optional fresh tumor biopsy (when clinically feasible)
X
Subsequent anticancer therapy
b
X
X
X
X
Survival status
X
X
X
X
Study procedures and examinations
Physical examination
X
X
X
ECOG performance status
X
X
X
PGIC (Part 3, Cohorts C1A and C1B only)
X
c
X
X
d
X
d
Vital signs
X
X
X
12-lead ECG e
X
X
Assessment of AEs/SAEs
X
X
X
Concomitant medications
X
X
X
Laboratory tests
Serum chemistry
X
X
X
Hematology
X
X
X
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
113 of 206
Template 16.2
Table 14
Schedule of Follow-up Procedures
Study Period
Follow-up Period
Procedure / Study Day or Month
End of
Treatment
(EOT)
Visit
Day 30 Post
Last Dose
± 3 Days
Day 90 Post
Last Dose
± 7 Days h
Q3M After Day 90
Post Last Dose up to
Month 12 Post Last
Dose ± 7 Days h
Q6M After
Month 12 Post
Last Dose
± 14 Days h
Coagulation parameters
X
X
X
Thyroid function tests
X
X
X
Urinalysis
X
X
X
Urine pregnancy test
X
Pharmacokinetics
Durvalumab PK (not applicable for Part 3 Cohorts C1B and 
C2B)
X
Monalizumab PK
X f
Cetuximab PK (Part 3, Cohorts C1A and C1B only)
X
Other laboratory tests
CD94/NKG2a receptor occupancy
X
Durvalumabimmunogenicity (not applicable for Part 3 
Cohorts C1B and C2B)
X
Monalizumab immunogenicity
X f
Cetuximab immunogenicity (Part 3, Cohorts C1A and C1B 
only)
X
Flow cytometry
X g
Circulating soluble factors (plasma)
X g
X
PBMC collection
X g
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
114 of 206
Template 16.2
Table 14
Schedule of Follow-up Procedures
Study Period
Follow-up Period
Procedure / Study Day or Month
End of
Treatment
(EOT)
Visit
Day 30 Post
Last Dose
± 3 Days
Day 90 Post
Last Dose
± 7 Days h
Q3M After Day 90
Post Last Dose up to
Month 12 Post Last
Dose ± 7 Days h
Q6M After
Month 12 Post
Last Dose
± 14 Days h
AE = adverse event; CT = computed tomography;
; DCO = data cut off; ECG = electrocardiogram; ECOG = Eastern Cooperative
Oncology Group;
 EOT = End of Treatment;
; MRI = magnetic resonance imaging;
PBMC = peripheral blood mononuclear cells; PD = progressive disease;
PGIC = Patient Global Impression of Change; PK = pharmacokinetic; Q3M = every 3 months; Q6M = every 6 months; RECIST = Response Evaluation Criteria in
Solid Tumors; SAE = serious adverse event.
a
Disease assessments after the EOT Visit are not required for subjects discontinuing due to PD. The last dose disease assessment is not required if it has been 
< 28 days since the last disease assessment.
b
When a subject receives subsequent treatment for disease after study end, follow-up will be terminated, no further scans or assessment is required other than 
survival information and information about their subsequent anticancer therapy, if subject permits.
e
A single ECG will be obtained.
f
For subjects who continue in the study on durvalumab monotherapy (Section 3.1.1), a sample for monalizumab PK and immunogenicity should be taken 90 
days (± 7 days) after the last dose of monalizumab. Further samples for monalizumab PK are not required.
g
Assessments should be performed if EOT occurs at the scheduled Week 9 visit.
h
Follow-up assessments at Day 90, Q3M, and Q6M will only occur prior to DCO. After DCO, only follow-up of SAEs, overdoses, and pregnancies will 
continue until 90 days post last dose.
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
115 of 206
Template 16.2
4.3
Description of Study Procedures
4.3.1
Antitumor Activity
Tumor assessments will be based on RECIST v1.1 (Eisenhauer et al, 2009) and will be 
performed according to the schedule presented in Section 4.2. All subjects will be followed 
for survival according to the schedule in Table 14 through the end of the study.
Sites will be required to store electronic copies of all scans, and the sponsor will arrange for 
centralized storage of all imaging data. All imaging assessments, including unscheduled visit 
scans, will be collected on an ongoing basis and sent to the sponsor or designee for storage.
The centralized storage of imaging data would be for possible independent centralized third-
party blinded review of disease assessments. At the discretion of the sponsor, an independent 
central review of all scans used in the assessment of tumors by RECIST v1.1 
 
may be conducted. Guidelines for imaging collection and storage will be provided in a 
separate document. The management of subjects will be based solely upon the results of 
assessment conducted by the investigator based on RECIST v1.1 per protocol.
All tumor assessments should include the following evaluations: physical examination (with 
photograph and measurement of skin lesions as applicable), and cross-sectional imaging using 
CT or magnetic resonance imaging (MRI) scan.
Chest, abdomen, and pelvis CT/MRI scans are required at baseline for all subjects. Pelvic 
scans are not required post baseline for NSCLC tumor types if tumor lesions were not 
identified at baseline. For all other tumor types, pelvic scans are required at all post-baseline 
time points regardless of presence of tumor lesions at baseline.
All subjects must receive a brain CT/MRI scan during the Screening Period. Post-screening, if 
the subject has CNS metastases, a brain CT/MRI is required at each post-baseline assessment. 
If a subject becomes neurologically symptomatic during treatment outside of the setting where 
the subject has known CNS metastases, a brain CT/MRI is required.
The preferred method of systemic disease assessment is CT with contrast; if CT with contrast 
is contraindicated, CT without contrast is preferred over MRI. The preferred method for CNS 
imaging is MRI; if CT scan is performed, CT with contrast is required. The same method is 
preferred for all subsequent tumor assessments.
4.3.1.1
Tumor Evaluations
Physical examination
Lesions detected by physical examination will only be considered measurable if superficial, 
eg, skin nodules and palpable lymph nodes. Documentation by color photography, including 
ruler, is recommended for estimating the size of skin lesions.
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
116 of 206
Template 16.2
CT scan

CT scans should be performed with contiguous cuts in slice thickness of 5 mm or less. 
Spiral CT should be performed using a 5-mm contiguous reconstruction algorithm.

CT scans of hepatic tumors should be collected in the hepatic arterial, portal venous, and 
delayed phases.
MRI scans
MRI scans are acceptable for measurement of lesions provided that the same anatomical plane 
is used for serial assessments. If possible, the same imaging device should be used for serial 
evaluations. MRI scans of hepatic tumors should be performed in the precontrast, hepatic 
arterial, portal venous and delayed phases.
Measurability of Tumor Lesions
Tumor lesions will be categorized as follows:

Measurable Lesions - Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of:

10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the 
slice thickness and a minimum of 10 mm)

10 mm caliper measurement by clinical exam (when superficial)

Malignant lymph nodes are considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm)

Nonmeasurable Lesions - Nonmeasurable lesions are defined as all other lesions (or sites 
of disease), including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥ 10 to < 15 mm in short axis). Lesions considered truly nonmeasurable 
include the following: leptomeningeal disease, ascites, pleural/pericardial effusion, and 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.

Target Lesions - All lesions up to a maximum of 5 lesions total (and a maximum of 
2 lesions per organ) representative of all involved organs should be identified as target 
lesions. It may be the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.

Non-target Lesions - It is possible to record multiple non-target lesions involving the 
same organ as a single item on the electronic case report form (eCRF; eg, “multiple 
enlarged pelvic lymph nodes” or “multiple liver metastases”).
4.3.1.2
Evaluation of Response by Response Evaluation Criteria in Solid Tumors
Tumor response will be assessed by RECIST v1.1.

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
117 of 206
Template 16.2
Evaluation of Target Lesions

Complete Response - Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm (the sum may 
not be “0” if there are target nodes).

Partial Response - At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters.

Progressive Disease - At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: The appearance of one or more 
new lesions may be considered progression.)

Stable Disease - Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study.
Evaluation of Non-target Lesions

Complete Response - Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10 mm in short axis).

Non-complete Response/Non-PD - Persistence of one or more non- target lesion(s) and/or 
maintenance of tumor marker level above the normal limits.

Progressive Disease - Unequivocal progression of existing non-target lesions will be 
defined as the overall level of substantial worsening in non-target disease such that, even 
in presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. In the absence of measurable disease, 
change in nonmeasurable disease comparable in magnitude to the increase that would be 
required to declare PD for measurable disease. Examples include an increase in a pleural 
effusion from “trace” to “large,” an increase in lymphangitic disease from localized to 
widespread.
Appearance of New Lesions
The appearance of new lesions is considered PD according to RECIST v1.1. Considering the 
unique response kinetics that have been observed with immunotherapy, new lesions may not 
represent true disease progression. In the absence of rapid clinical deterioration, subjects may 
continue to receive study treatment until confirmed PD (Section 4.1.7).
Evaluation of Overall Response
Confirmation of CR, PR, as well as PD is required by a repeat, consecutive assessment no less 
than 4 weeks from the date of first documentation. If the next protocol-scheduled scan is due 
within 2 weeks after the confirmatory scan was obtained, the protocol-scheduled scan does not 
need to be done. Treatment of subjects may continue between the initial assessment of PD and 
confirmation of PD (which is not required by RECIST v1.1; see Section 4.1.7). These subjects 
may continue to receive durvalumab in combination with monalizumab beyond confirmed PD 

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
118 of 206
Template 16.2
in accordance with Section 4.1.7 and if investigators consider that subjects continue to receive 
benefit from treatment. In the absence of clinical deterioration, such modifications to the 
RECIST may discourage the early discontinuation of durvalumab in combination with 
monalizumab and provide a more complete evaluation of durvalumab in combination with 
monalizumab antitumor activity than would be seen with conventional response criteria.
Table 15 provides overall responses for all possible combinations of tumor responses in target 
and non-target lesions with or without the appearance of new lesions.
Table 15
Evaluation of Overall Response at a Single Time Point by RECIST V1.1
Target Lesions
Non-target Lesions
New Lesions
Overall Response
Complete response
Complete response
No
Complete response
No target lesion
a
Complete response
No
Complete response
Complete response
Not evaluable
b
No
Partial response
Complete response
Non-complete response/ non-
progressive disease
No
Partial response
Partial response
Non-progressive disease and not
evaluable
b
No
Partial response
Stable disease
Non-progressive disease and not
evaluable
b
No
Stable disease
Not all evaluated
Non-progressive disease
No
Not evaluable
No target lesion a
Not all evaluated
No
Not evaluable
No target lesion a
Non-complete response / non-
progressive disease
No
Non-complete response / 
non-progressive disease
Progressive disease
Any
Yes or No
Progressive disease
Any
Progressive disease
Yes or No
Progressive disease
Any
Any
Yes
Progressive disease
No target lesion a
Unequivocal progressive disease
Yes or No
Progressive disease
No target lesion a
Any
Yes
Progressive disease
RECIST = Response Evaluation Criteria in Solid Tumors.
a
Defined as no target lesions at baseline.
b
Not evaluable is defined as either when no or only a subset of lesion measurements are made at an 
assessment.
4.3.1.3
 
 
 
 
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
119 of 206
Template 16.2
 
Table 16
Table 16
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
120 of 206
Template 16.2
Table 16
4.3.2
Tissue Biopsies
4.3.2.1
Fresh Tissue Biopsies
 
 
Subjects enrolled in each dose-escalation cohort 
while the pharmacodynamics are further investigated, must have at least one lesion amenable 
to biopsy and must provide a pre-treatment biopsy during the Screening Period, and, if 
clinically feasible, during Week 9.
The initial 20 subjects in each dose-expansion cohort must have at least 1 lesion amenable to 
biopsy and must provide a pre-treatment biopsy. If a given dose-expansion cohort is expanded 
beyond the initial 20 subjects, additional subjects must consent to provide an archival tumor 
sample from a biopsy collected within 1 year prior to first dose of study drug or must provide 
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
121 of 206
Template 16.2
a pre-treatment biopsy during the Screening Period. If clinically feasible, all dose-expansion 
subjects must provide a biopsy during Week 9.
Subjects in each dose-exploration in 
CRC cohort must consent to provide an archival 
tumor sample from a biopsy collected within 1 year prior to the first dose of study treatment or 
must provide a pre-treatment biopsy during the Screening Period. If clinically feasible, all 
dose-exploration subjects who provided a fresh biopsy during screening are encouraged to 
provide an on-treatment biopsy during Week 9.
As noted, fresh tumor biopsies will be obtained on Week 9 Day 1 (± 7 days) if clinically 
feasible (ie, repeat biopsy does not pose unacceptable medical risk to a subject as determined 
by the investigator). Additional biopsies may also be performed if clinically indicated (eg, for 
mixed responses). For subjects requiring serial image-guided core needle tumor biopsy, those 
biopsies will be performed according to institutional practice.
For fresh tumor biopsies, the tumor lesion should not be used as a RECIST target lesion, 
unless there are no other tumors suitable for biopsy. If a RECIST target lesion is used for 
biopsy, the lesion must be ≥ 2 cm in longest diameter. If clinically practical, at each fresh 
tumor biopsy time point, subjects will undergo 4 core biopsies. The first and third core 
biopsies will be placed in formalin and processed for formalin-fixed, paraffin-embedded 
blocks, while the second and fourth core biopsies (if available) will be immediately frozen in 
liquid nitrogen or equivalent method and then stored at -80°C (-112°F). In exceptional cases, 
excisional or punch biopsies are permitted and may be substituted for the core biopsies if 
sufficiently large (4 mm or greater in diameter).
 
 Tumor samples 
from subjects with endometrial cancer may be tested for mismatch repair deficiency.
Tumor biopsies will be stored at MedImmune or an appropriate vendor selected by 
MedImmune. Core (tumor) biopsies may be used for correlative studies such as IHC, tumor 
mutation analysis,
 proteomic, and immunodiversity. Additional details for 
sample collection, processing, storage, and shipment will be provided in the Laboratory 
Manual.
4.3.2.2
Archival Tumor Samples
 
If a given dose-expansion cohort is expanded beyond the initial 20 subjects, additional 
subjects must consent to provide an archival tumor sample from a biopsy collected within 
1 year prior to first dose of study drug or must provide a pre-treatment biopsy during the 
Screening Period. Subjects in each dose-exploration in 
CRC cohort must consent to 
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
122 of 206
Template 16.2
provide an archival tumor sample from a biopsy collected within 1 year prior to the first dose 
of study treatment or must provide a pre-treatment biopsy during the Screening Period. 
Archival tumor samples must be formalin fixed and embedded in paraffin blocks for IHC
 
4.3.3
Patient Reported Outcomes 
A patient-reported outcome (PRO), a type of clinical outcome assessment, is an umbrella term 
referring to all outcomes and symptoms that are directly reported by the patient. PROs have 
become a significant endpoint when evaluating effectiveness of treatments in cancer clinical 
studies and regulatory decision making (Kluetz et al, 2018). In addition to assessing OS and 
other clinical endpoints in oncology clinical trials, it is important to assess the treatment 
impact on disease-related symptoms, functioning (eg, physical function), and other 
health-related quality of life (HRQoL) of the subject and thereby aid understanding of how 
clinical benefit relates to subject well-being and experience, and for making a comprehensive 
benefit-risk assessment. Moreover, PROs assist in the documentation of what specific 
symptoms and impacts are most important to subjects and how these relate to clinical 
outcomes.  
To evaluate the impact of study treatment on disease-related symptoms and 
functioning/HRQoL and overall health status, the following PROs will be administered in this 
study:

European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire (EORTC QLQ-C30) v3.0

Patient Global impression of Change (PGIC)
The EORTC QLQ-C30 was selected as the primary PRO for the study because it has good 
conceptual coverage of disease-related symptoms and impacts in the target patient population. 
Additionally, the EORTC QLQ-C30 is widely used in cancer clinical trials including CRC 
trials to characterize treatment effect from the patient perspective (Overman et al, 2017). 
Secondly, the PGIC is a single-item PRO questionnaire included to assess a subject’s 
perception of his or her overall change in health status since the start of study drug(s) 
administration.
Subjects will complete the PRO assessments by using an electronic PRO (ePRO) tablet device 
at the study site. Each site must allocate the responsibility for the administration of the ePRO 
tablet devices to a specific individual (eg, a research nurse or study coordinator), and, if 
possible, assign a back-up person to cover for that individual if he or she is absent. 
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
123 of 206
Template 16.2
The PRO questionnaires will:

be completed by the subjects to the best of their ability using an ePRO tablet device at the 
site.

take approximately 10 to 15 minutes for each subject to complete the questionnaires, 
hence the burden to the subject is low.

be administered according to the schedules in Section 4.2.
The following best practice guidelines should be followed when collecting PRO data using the 
ePRO tablet device:

The research nurse or appointed site staff must explain the value and relevance of 
participation to the subjects and inform them that these questions are being asked to find 
out from them directly how they feel. This can help motivate subjects to comply with data 
collection. The research nurse or appointed site staff should also stress that the 
information is confidential. Therefore, if the subject has any medical problems, he or she 
should discuss them with the doctor or research nurse separately from the ePRO 
assessment.

The research nurse or appointed site staff must train the subject on how to use the ePRO 
device using the materials and training provided by the ePRO vendor and provide 
guidance on whom to call if there are problems with the device.

PRO questionnaires must be completed in private and prior to any other study procedures 
(following informed consent) and before interaction with study staff, laboratory 
assessments (eg, blood draw), treatment administration, and before discussion of disease 
assessments and progress to avoid biasing the subject’s responses to the questions.

The EORTC QLQ-C30 should always be completed before the PGIC questionnaire.

The research nurse or appointed site staff must remind subjects that there are no right or 
wrong answers and must avoid introducing bias by not clarifying items.

The subject should not receive help from relatives, friends, or clinic staff to answer the 
PRO questionnaires.

Site staff must not read or complete the PRO questionnaires on behalf of the subject. If 
the subject is unable to read the questionnaire (eg, is blind or illiterate), that subject 
should be exempted from completing PRO questionnaires but may still participate in the 
study. It should be documented that the subject exempted in this regard.

The study nurse or appointed site staff must administer questionnaires available in the 
language that the subject speaks and understands. Questions should not be read in an 
available language and translated into another language for the subject.

The research nurse or appointed site staff must monitor compliance; minimizing missing 
data is a key aspect of study success. Compliance must be checked at each study visit.

If the subject cannot complete the questionnaire, the reason for this should be provided in 
the ePRO device.

It is vital that the ePRO reporting is initiated as specified in the study plan to capture the 
effect of study treatment.

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
124 of 206
Template 16.2
Data from the PRO assessments will not be made available to the treating physicians 
throughout the study. Patients should be informed of this and counseled through multiple
channels that they should contact their healthcare provider for any concerning symptoms they 
experience any time during their care.
4.3.3.1
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire
The EORTC QLQ-C30 is a self-administered PRO questionnaire and is to be completed by 
the subject without the assistance of the investigational site personnel. Questions are grouped 
into:

5 multi-item functional scales 

Physical (5 items)

Role (2 items)

Cognitive (2 items)

Emotional (4 items)

Social (2 items)

3 multi-item symptom scales

Fatigue (3 items)

Pain (2 items)

Nausea/vomiting (2 items)

Global measure of health status/quality of life (QoL) scale (2 items). 

5 single-item measures assessing additional symptoms commonly reported by cancer 
patients

Dyspnea

Loss of appetite

Insomnia

Constipation

Diarrhea

1 single-item measure concerning the perceived financial impact of the disease
All but 2 questions have 4-point scales: “Not at all,” “A little,” “Quite a bit,” and “Very 
much.” The 2 questions concerning global health status and QoL have 7-point scales with 
ratings ranging from “Very poor” to “Excellent.” For each of the 15 domains (9 multiple-item 
scales and 6 single-item scales), final scores are transformed such that they range from 0 to 
100, where higher scores indicate greater functioning, greater HRQoL, or greater level of 
symptoms (Aaronson et al, 1993). The EORTC QLQ-C30 questionnaire will be scored 

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
125 of 206
Template 16.2
according to the established scoring manual by the developer. Refer to Section 10.5.1 for a 
copy of the questionnaire.
4.3.3.2
Patient Global Impression of Change
The PGIC is a single-item PRO questionnaire included to assess how a subject perceives his 
or her overall change in health status since the start of study drug(s) administration. Subjects 
will select a single response from the following seven response options: Very Much 
Improved; Much Improved; Minimally Improved; No Change; Minimally Worse; Much 
Worse; and Very Much Worse. The PGIC is useful in characterizing the overall impact of the 
treatment. Refer to Section 10.5.2 for a copy of the questionnaire.
4.3.4
Medical History, Physical Examination, Electrocardiogram, ECOG 
Performance Status, Weight, and Vital Signs
4.3.4.1
Medical History and Physical Examination
Physical examinations will be performed according to institutional guidelines on study days 
noted in Section 4.2, and will include assessments of weight and height (Screening only).
Findings from medical history and physical examination shall be given a baseline grade. 
Increases in severity of pre-existing conditions during the study will be considered AEs, with 
resolution occurring when the grade returns to the prestudy grade or below.
4.3.4.2
Electrocardiograms
A single electrocardiogram (ECG) will be obtained during the Screening Period 
(Section 4.2.1). ECGs will be obtained during the treatment period according to the schedules 
in Section 4.2.2. On Day 1 of Week 1, ECGs will be obtained in triplicate (all 3 within a 
5-minute time period, at least 1 minute apart) as indicated in Table 8 and Table 10. At all 
other time points during the treatment period, a single ECG will be obtained prior to 
investigational product(s) administration and as clinically indicated (Section 4.2.2). During the 
follow-up period, a single ECG will be obtained according to the schedule in Section 4.2.3. 
In case of clinically significant ECG abnormalities, including an ECG that demonstrates a QT 
corrected using Fridericia’s formula (QTcF) value > 500 milliseconds, 2 additional 12-lead 
ECGs should be obtained over a brief period (eg, 30 minutes) to confirm prolongation by a 
medically-qualified person based on the average of manually over-read QTcF values from 3 
individual ECGs.
The same recorder will be used for each subject at each time point, if possible. Date and time 
settings should be checked at the start of each study day.
Skin preparation should be thorough and electrode positions should be according to standard 
12-lead ECG placement.

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
126 of 206
Template 16.2
The investigator may add extra 12-lead ECG safety assessments if there are any abnormal 
findings or if the investigator considers it is required for any other safety reason.
Paper tracings will be used for local management. In addition, digital copies of ECGs may be 
held by a central ECG provider and stored for potential independent analysis during or at the 
end of the study at the sponsor’s discretion. The independent review will not replace the local 
review by the investigator or other medically-qualified designee. Clinical interpretation and 
management of subjects for all ECGs will be done locally.
4.3.4.3
ECOG Performance Status
Performance status as determined by the ECOG scale (Oken et al, 1982; Table 17) will be 
recorded in the eCRF per the schedule in Section 4.2.
Table 17
Eastern Cooperative Oncology Group Performance Status
Grade
Performance Status Criteria
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light house work or office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more
than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
4.3.4.4
Vital Signs
Vital signs include temperature, blood pressure (BP), pulse rate, and respiratory rate will be 
measured on study days noted in Section 4.2.
4.3.5
Clinical Laboratory Tests
A Laboratory Manual will be provided to the sites that specifies the procedures for collection, 
processing, storage, and shipment of samples, as well as laboratory contact information, 
specific to this clinical research study. Urinalysis, chemistry and hematology samples will be 
analyzed at the local site laboratories. The carcinoembryonic antigen and CA-125 samples 
will be analyzed by a central laboratory. The tumor sample for subjects with endometrial 
cancer will be sent for microsatellite instability testing by a central laboratory.
Clinical laboratory safety tests including serum pregnancy tests will be performed in a 
licensed clinical laboratory. Urine pregnancy tests may be performed at the site using a 
licensed test (dipstick). Abnormal laboratory results should be repeated as soon as possible 
(preferably within 24 to 48 hours).

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
127 of 206
Template 16.2
The following clinical laboratory tests will be performed according to the schedules of 
procedures in Section 4.2.
Serum Chemistry
•
Calcium
•
Lipase
•
Chloride
•
Gamma-glutamyl transferase (GGT)
•
Magnesium
•
Lactate dehydrogenase (LDH)
•
Potassium
•
Uric acid
•
Sodium
•
Creatinine
•
Bicarbonate
•
Blood urea nitrogen (BUN)
•
Aspartate aminotransferase (AST)
•
Glucose
•
Alanine aminotransferase (ALT)
•
Albumin
•
Alkaline phosphatase (ALP)
•
Total protein
•
Total bilirubin
•
Triglycerides
•
Direct bilirubin
•
Cholesterol
•
Indirect bilirubin
•
Amylase
Notes for serum chemistries:
Tests for AST, ALT, ALP, direct bilirubin, indirect bilirubin, and total bilirubin must be conducted concurrently 
and assessed concurrently. Direct and indirect bilirubin are needed only if total bilirubin is not within normal 
range. If the clinical laboratory does not perform both direct bilirubin and indirect bilirubin, it is acceptable to 
assess one rather than both of these parameters. 
Urea is an acceptable alternative if BUN is not routinely tested.
Hematology
•
White blood cell count with differential
(neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils)
•
Platelet count
•
Hemoglobin
Coagulation
•
Prothrombin time
•
International normalized ratio (INR)
•
Activated partial thromboplastin time (APTT)
•
Fibrinogen
Urinalysis
•
Color
•
Glucose
•
Appearance
•
Ketones
•
Specific gravity
•
Blood
•
pH
•
Bilirubin
•
Protein

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
128 of 206
Template 16.2
Pregnancy Test (females of childbearing potential only)
•
Urine human chorionic gonadotropin (hCG)
•
Serum beta-hCG
Thyroid Function Tests 
•
Thyroid-stimulating hormone (TSH)
•
Free triiodothyronine (T3)
•
Free thyroxine (T4) 
Other Safety Tests
•
Hepatitis A antibody, hepatitis B surface antigen, hepatitis C antibody
•
Human immunodeficiency virus antibodies
•
Additional baseline blood samples will also be collected in a 10-mL red top tube in order to have serum 
samples collected at baseline for future analysis, which includes, but is not limited to an autoimmune work 
up (refer to the Laboratory Manual for the processing of this sample).
4.3.6
Pharmacokinetic Evaluation and Methods
Measurement of durvalumab, monalizumab, and cetuximab concentrations in serum will be 
performed using validated immunoassays.
Details for collection, aliquoting, storage, and shipment of serum samples for PK evaluations 
are presented in a separate Laboratory Manual.
Blood samples for measurement of durvalumab, monalizumab, and cetuximab concentrations 
in serum will be collected in samples taken according to the schedules of procedures presented 
in Section 4.2.
4.3.7
Immunogenicity Evaluation and Methods
Validated electrochemiluminescence assays using a Meso Scale Discovery platform will be 
used for the determination of ADA to durvalumab, monalizumab, and cetuximab in human 
serum.
Details for collection, aliquoting, storage, and shipment of serum samples for ADA 
evaluations are presented in a separate Laboratory Manual.
Blood samples for detection of durvalumab, monalizumab, and cetuximab ADA in serum will 
be collected in samples obtained according to the schedules of procedures presented in 
Section 4.2.
4.3.8
 
 
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
129 of 206
Template 16.2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
130 of 206
Template 16.2
 
 
4.3.9
Estimate of Volume of Blood to be Collected
A total of approximately 56 mL of blood will be collected during the initial screening 28-day 
period for all screening tests. No more than 77.5 mL of blood will be drawn for any one 
protocol visit during treatment. During the end of treatment/follow-up period, no more than 
approximately 44.5 mL of blood will be collected at any one follow-up visit. The total volume 
to be collected will depend on the length of a subject’s participation in the study.
4.4
 
 
 
1
 
2
3
 
4
5
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
131 of 206
Template 16.2
4.5
Investigational Products
4.5.1
Identity of Investigational Product(s)
MedImmune will provide the investigator(s) with investigational product (Table 18) using 
designated distribution centers. 
Table 18
Identification of Investigational Products
Investigational Product
Provider
Concentration and Formulation as Supplied
Durvalumab (MEDI4736)
MedImmune
Supplied as a vialed solution containing 500 mg 
(nominal) durvalumab per vial. The solution
contains 50 mg/mL durvalumab, 26 mM
histidine/histidine HCl, 275 mM trehalose
dihydrate, 0.02% (w/v) polysorbate 80, at pH 6.0 
and density of 1.054 g/mL. The label-claim volume 
is 10 mL.
Monalizumab (IPH2201)
MedImmune
Monalizumab (IPH2201)
MedImmune
Cetuximab (Part 3 Cohorts 
C1A and C1B only)
Merck Serono
Supplied as a vialed solution containing 500 mg 
(nominal) cetuximab per vial. The solution contains 
5 mg/mL cetuximab, sodium chloride, glycine, 
polysorbate 80, citric acid monohydrate, sodium 
hydroxide, and WFI. The label-claim volume is 
100 mL.
HCl = hydrochloride; WFI = water for injection; w/v = weight per volume.
 
 
Commercially available 0.9% (weight per volume [w/v]) saline or 5% (w/v) dextrose will be 
supplied by each site. 
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
132 of 206
Template 16.2
4.5.1.1
Investigational Product Inspection
Until Study-defined DCO: Investigational products will be supplied to the site in vials in 
coded kits. Each kit has a unique number that is printed on all labels within the kit (ie, the 
outer carton label and the label of each vial within the carton). Select the IXRS-assigned 
number of vials of investigational product required to prepare the subject’s dose. 
After Study-defined DCO: IXRS will no longer be utilized after the DCO. Sites will 
manually order investigational product from AstraZeneca.
Each vial selected for dose preparation should be inspected. If there are any defects noted with 
the investigational product(s), the investigator and site monitor should be notified 
immediately. Refer to the Product Complaint section (Section 4.5.1.5) for further instructions.
Durvalumab
Durvalumab will be supplied in 10-mL vials as a sterile, clear to opalescent, colorless to 
slightly yellow solution, free from visible particles, containing 500 mg (nominal) durvalumab 
per vial. 
 
 
 
 
 
 
 
 
 
Cetuximab
Cetuximab will be supplied in 100-mL vials as a solution containing 500 mg (nominal) 
cetuximab per vial.
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
133 of 206
Template 16.2
4.5.1.2
Investigational Product Dose Preparation and Administration
Durvalumab
The dose of durvalumab for administration must be prepared by the investigator’s or site’s 
designated investigational product manager using aseptic technique. 
Total time from needle puncture of a durvalumab vial to start of administration must not 
exceed:

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature
If the final product is stored at both refrigerated and ambient temperatures, the total time must 
not exceed 24 hours. 
A dose of 1500 mg (for subjects > 30 kg in weight) will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab concentration 
ranging from 1 to 15 mg/mL and delivered through an IV administration set with a 0.2- or 
0.22-μm filter. Add 30 mL (ie, 1500 mg) of durvalumab to the IV bag. The IV bag size should 
be selected such that the final concentration is within 1 to 15 mg/mL. Mix the bag by gently 
inverting to ensure homogeneity of the dose in the bag.
If the subject’s weight falls to ≤30 kg, weight-based dosing at 20 mg/kg will be administered 
using an IV bag size such that the final concentration is within 1 to 15 mg/mL. Fixed dosing 
of 1500 mg IV durvalumab Q4W may resume once the subject’s weight is > 30 kg.
Standard infusion time is 1 hour; however, if there are interruptions, the total allowed time 
must not exceed 8 hours at room temperature. 
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. Durvalumab does not contain preservatives, and any unused portion 
must be discarded. 
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
134 of 206
Template 16.2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
135 of 206
Template 16.2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cetuximab
The dose of cetuximab for administration must be prepared by the investigator’s or site’s 
designated investigational product manager using aseptic technique.
Cetuximab is being provided by MedImmune only for those subjects enrolled in Cohorts C1A 
and C1B, as it is being administered off-label at a dose of 500 mg/m2 in this study. Cetuximab 
will be sourced locally by study sites for all other cohorts where it is required. The cetuximab 
infusion, if applicable, will start 15 to 30 minutes after the end of the monalizumab infusion.
NOTE: The concentration of cetuximab provided for this study is 5 mg/mL, 100 mL 
(500 mg/vial).
The prepared dose of cetuximab will be administered through a 0.2 to 0.22-μm filter via an 
infusion pump or syringe pump. Since cetuximab is only compatible with sterile sodium 
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
136 of 206
Template 16.2
chloride (0.9%) solution for injection, it must not be mixed with other intravenously applied 
medicinal products. A separate infusion line must be used for the infusion, and the line must 
be flushed with sterile sodium chloride (0.9%) solution for injection at the end of infusion. 
Cetuximab 5 mg/mL is compatible with 

polyethylene, ethyl vinyl acetate or polyvinyl chloride bags

polyethylene, polyurethane, ethyl vinyl acetate, polyolefin thermoplastic, or polyvinyl 
chloride infusion sets

polypropylene syringes for syringe pump
Cetuximab 5 mg/mL is chemically and physically stable for up to 48 hours at 25°C, if the 
solution is prepared as described hereafter. However, since it does not contain any 
antimicrobial preservative or bacteriostatic agent, it is intended for immediate use. Care must 
be taken to ensure aseptic handling when preparing the infusion. Cetuximab 5 mg/mL must be 
prepared as follows:
For administration with infusion pump (diluted with sterile sodium chloride [0.9%] solution): 
Take an infusion bag of adequate size of sterile sodium chloride (0.9%) solution. Calculate the 
required volume of cetuximab. Remove an adequate volume of the sodium chloride solution 
from the infusion bag, using an appropriate sterile syringe with a suitable needle. Draw up the 
required volume of cetuximab from a vial. Transfer the cetuximab into the prepared infusion 
bag. Repeat this procedure until the calculated volume has been reached. Connect the infusion 
line and prime it with the diluted cetuximab before starting the infusion. Use a gravity drip or 
an infusion pump for administration. 
For administration with infusion pump (undiluted): 
Calculate the required volume of cetuximab. Take an appropriate sterile syringe (minimum 
50 mL) and attach a suitable needle. Draw up the required volume of cetuximab from a vial. 
Transfer the cetuximab into a sterile evacuated container or bag. Repeat this procedure until 
the calculated volume has been reached. Connect the infusion line and prime it with 
cetuximab before starting the infusion. 
For administration with a syringe pump: 
Calculate the required volume of cetuximab. Take an appropriate sterile syringe and attach a 
suitable needle. Draw up the required volume of cetuximab from a vial. Remove the needle 
and put the syringe into the syringe pump. Connect the infusion line to the syringe and start 
the infusion after priming the line with cetuximab or sterile sodium chloride (0.9%) solution. 
Repeat this procedure until the calculated volume has been infused. 

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
137 of 206
Template 16.2
All infusions of 500 mg/m2 cetuximab should be over approximately 2 hours. Alternatively, 
subsequent Q1W infusions of 250 mg/m2 cetuximab may be administered for approximately 1 
hour. An infusion rate of 10 mg/min must not be exceeded.
4.5.1.3
Treatment Administration
The first day of dosing is considered Day 1. Dose preparation and administration instructions 
are provided in Section 4.5.1.2. Durvalumab will be administered first. The monalizumab 
infusion will start 15 to 30 minutes after the end of the durvalumab infusion. Infusion of the 
pre-medication for cetuximab may begin following an observation of 15 to 30 minutes post 
end of monalizumab infusion and will be followed 30 minutes later by the cetuximab infusion, 
if applicable. A physician must be present at the site or immediately available to respond to 
emergencies during all administrations of investigational product. Fully functional 
resuscitation facilities should be available. Investigational product must not be administered 
via IV push or bolus but as an IV infusion. 
4.5.1.4
Monitoring of Dose Administration
Subjects will be monitored prior to, during, and after infusion of durvalumab and 
monalizumab. Monitoring of subjects receiving cetuximab infusion will be performed per 
label. Vital signs (temperature, BP, pulse rate, and respiratory rate) will be measured 
according to the schedule in Section 4.2.
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.
Primary prophylaxis against IRRs is not permitted during this study in order to avoid 
obscuring potential safety signals and enable a future assessment regarding whether 
premedication should be required for all subjects in future studies. Antihistamines or steroids 
can be administered per label prior to cetuximab infusion. However, at the discretion of the 
investigator, secondary prophylaxis (ie, prevention of IRR following initial episode) is 
appropriate and will be permitted with the following recommended regimen: acetaminophen 
(eg, 650 to 1000 mg) and diphenhydramine (eg, 12.5 to 25 mg) administered approximately 
30 minutes prior to the start of infusion of durvalumab and monalizumab. Consideration can 
be given to premedicating with nonsedating antihistamines (eg, cetirizine) at the discretion of 
the investigator. At the discretion of the investigator, administration of IV doses of meperidine 
(eg, 10 to 25 mg) and promethazine (eg, 12.5 to 25 mg) or their equivalents just prior to the 
start of infusion of durvalumab and monalizumab is permitted. Investigators may administer 
steroids at their discretion as clinically indicated and per their institution’s guidelines.

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
138 of 206
Template 16.2
Pre-treatment medications may need to be repeated during the course of the infusion; 
therefore, this should be taken into consideration when deciding on the dosage of the pre-
treatment medications.
In the event of a Grade ≤ 2 IRR, the infusion rate of durvalumab or monalizumab may be 
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 
50% of the initial rate until completion of the infusion. In subjects experiencing Grade ≤ 2 
IRR, subsequent infusions may be administered at 50% of the initial rate. If the IRR is Grade 
3 or higher in severity, treatment with durvalumab and monalizumab will be discontinued.
4.5.1.5
Reporting Product Complaints
Any defects with the investigational product must be reported immediately to the MedImmune 
Product Complaint Department by the site with further notification to the site monitor. All 
defects will be communicated to MedImmune and investigated further with the Product 
Complaint Department. During the investigation of the product complaint, all investigational 
product must be stored at labeled conditions unless otherwise instructed.
4.5.2
Additional Study Medications
4.5.2.1
Standard-of-Care Chemotherapy/Biologic Agents
Each standard-of-care agent (mFOLFOX6, 
, bevacizumab, and cetuximab [excluding 
Part 3 Cohorts C1A and C1B]) will be sourced as commercially available material/locally 
sourced, prescribed according to local regulations, and will be administered according to 
prescribing information or treatment guidance in general use by the investigating site. Please 
refer to Benson et al, 2018 and Van Cutsem et al, 2016 for treatment guidelines for the 
management of patients with metastatic CRC. Under certain circumstances when local 
sourcing is not feasible, a standard-of-care agent will be supplied centrally by AstraZeneca. 
This will be labeled with local language translated text in accordance with regulatory 
guidelines.
PPD
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
139 of 206
Template 16.2
4.5.3
Labeling
Labels for the investigational product will be prepared in accordance with Good
Manufacturing Practice (GMP) and local regulatory guidelines. The label will fulfill GMP 
Annex 13 requirements for labeling. Label text will be translated into local languages, as 
required.
4.5.4
Storage
Store durvalumab, monalizumab, and cetuximab at 2°C to 8°C (36°F to 46°F). Do not freeze. 
All investigational products should be kept in a secure and dry place. Investigational product 
must be kept in original packaging until use to prevent prolonged light exposure.
4.5.5
Treatment Compliance
Investigational product is administered by study site personnel, who will monitor compliance.
4.5.6
Accountability
The investigator’s or site’s designated investigational product manager is required to maintain 
accurate investigational product accountability records. Upon completion of the study, copies 
of investigational product accountability records will be returned to MedImmune. All unused 
investigational product will be returned to a MedImmune-authorized depot or disposed of 
upon authorization by MedImmune.
4.6
Treatment Assignment and Blinding
4.6.1
Methods for Assigning Treatment Groups
Part 1, Part 2, and Part 3 (Cohorts A1
)
Each subject who meets the eligibility criteria will be assigned open-label investigational 
product.
An IXRS will be used for assignment of unblinded investigational product.
The time between enrollment and the initiation of treatment should be as short as possible and 
no more than 1 business day. If there is a delay in the administration of investigational product 
such that it will not be administered within the specified timeframe, the study monitor must be 
notified immediately.
Part 3 (Cohorts C1A, C1B, C2A, and C2B)
An IXRS will be used for randomization to a treatment group and assignment of unblinded 
investigational product. A subject is considered randomized into the study when the 
investigator notifies the IXRS that the subject meets eligibility criteria and provides the 
location of the primary CRC tumor and baseline ALP level of the subject; the IXRS provides 
the assignment of unblinded investigational product to the subject.
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
140 of 206
Template 16.2
 
 
 
 
 
 
 
 
 
 
 
 
Randomizations of the C1 and C2 cohorts, respectively, will be stratified by the location of the 
primary tumor and baseline ALP levels. 

The location of the primary tumor is classified as left-sided, right-sided, or transverse. 

Baseline ALP level is classified as high (> 1.0 × ULN) or low (≤1.0 × ULN). Local 
laboratories can define their own ULN values as long as they do not deviate dramatically 
from 160 U/L, a typical benchmark ULN value for ALP.
4.6.2
Methods for Ensuring Blinding
This is an open-label study.
4.7
Restrictions During the Study and Concomitant Treatment(s)
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the clinical phase of the study (final study visit). Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the eCRF.
4.7.1
Permitted Concomitant Medications
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as “excluded” as 
listed in Section 4.7.2. Specifically, subjects should receive full supportive care during the 
study, including transfusions of blood and blood products, and treatment with antibiotics, 
growth factors, anti-emetics, anti-diarrheals, and analgesics, and other care as deemed 
appropriate, and in accordance with their institutional guidelines.
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
141 of 206
Template 16.2
4.7.2
Prohibited Concomitant Medications
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator.
The following medications are considered exclusionary during the study. The sponsor must be 
notified if a subject receives any of these during the study.
1
Any investigational anticancer therapy.
2
Any concurrent chemotherapy (other than per protocol chemotherapy), radiotherapy 
(except palliative radiotherapy after consultation with the medical monitor), 
immunotherapy, biologic or hormonal therapy for cancer treatment. Concurrent use of 
hormones for noncancer-related conditions (eg, insulin for diabetes and hormone 
replacement therapy) is acceptable.
3
Immunosuppressive medications including, but not limited to methotrexate, azathioprine, 
and tumor necrosis factor-α blockers are prohibited. The following are exceptions to this 
criterion:
(a) Use of immunosuppressive medications for the management of investigational 
product-related AEs.
(b) Systemic corticosteroids at physiologic doses not to exceed 10-12 mg/day of 
prednisone or its equivalent.
(c) Use of inhaled, topical, intranasal corticosteroids or local steroid injections (eg, intra-
articular injection).
(d) Temporary uses of corticosteroids for concurrent illnesses (eg, food allergies, CT 
scan contrast hypersensitivity, etc) or as premedication for subjects receiving 
chemotherapy are acceptable upon discussion with the medical monitor. NOTE:
Steroids should not be given concomitantly or used for premedication prior to the 
immune-oncologic infusions. 
4
Live attenuated vaccines during the study through 30 days after the last dose of 
investigational product.
5
Herbal and natural remedies should be avoided. Drugs with laxative properties for 
constipation should be used with caution through 90 days after the last day of study 
treatment.
4.8
Statistical Evaluation
4.8.1
General Considerations
Tabular summaries will be presented by treatment group. Categorical data will be summarized 
by the number and percentage of subjects in each category. Continuous variables will be 
summarized by descriptive statistics. Additional details of statistical analyses will be 
described in the statistical analysis plan.
The analysis populations are defined as following:

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
142 of 206
Template 16.2
Population
Description
Intent-to-treat (ITT) 
population
The ITT population includes subjects who are randomized. Subjects will be analyzed 
according to the treatment group they were randomized to. The ITT population is only 
applicable for the randomized cohorts.
As-treated 
population
The As-treated population includes subjects who receive any investigational products.
Subjects will be analyzed according to the treatment they actually received. The As-treated
Population will be used to evaluate baseline characteristics as well as all endpoints for the
safety and efficacy profiles.
Response-evaluable 
population
The Response-evaluable population includes subjects in the As-treated population for the 
nonrandomized cohorts and in the ITT Population for the randomized cohorts, who have at 
least 1 post-baseline disease assessment, who died from any cause, or who discontinued due 
to clinical progressive disease prior to any post-baseline tumor assessment.
DLT-Evaluable 
population
The DLT-Evaluable Population includes all subjects enrolled in the dose-escalation part who
receive at least 1 dose of investigational products and complete the safety follow-up through
the DLT-evaluation period or experience any DLT during the DLT-evaluation period.
4.8.2
Sample Size 
 
 
 Additional subjects may be 
required if additional cohorts or treatment schedules are explored.
4.8.2.1
Part 1 (Dose Escalation)
In Part 1 (dose escalation), the number of subjects to be enrolled will depend upon the 
toxicities observed as the study progresses. With a minimum of 3 subjects and a maximum of 
12 subjects enrolled for each dose level, up to 60 subjects may be enrolled following an mTPI 
design for 5 planned dose levels. An additional 6 subjects per dose level may be enrolled, up 
to a maximum of 18 subjects per dose level to provide additional PK, pharmacodynamic, and 
safety data. Additional subjects could be required if other dose levels or alternate treatment 
schedules are explored.
4.8.2.2
Part 2 (Dose Expansion)
In Part 2 (dose expansion), up to 160 subjects (approximately 40 subjects per tumor-type 
cohort) may be enrolled to obtain preliminary assessment of safety and antitumor activity in 
each tumor type. Enrollment may proceed up to approximately 40 subjects in the CRC, 
ovarian, and endometrial expansion cohorts 
. 
The observed 0/20 response gives an upper limit of a 1-sided 
% confidence interval (CI) of 
approximately %, which means that a response rate greater than % can be ruled out with 
% confidence and hence enrollment would be stopped for lack of desirable response rate. 
Enrollment may proceed up to approximately 40 subjects in the NSCLC expansion cohort  
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
143 of 206
Template 16.2
 Observing 1/20 response gives an upper limit 
of a 1-sided 
% CI of approximately 
%, which means that a response rate greater than 
% can be ruled out with 
% confidence and hence enrollment would be stopped for lack of 
desirable response rate.
 
 
 Table 19 provides the estimated ORR and its 
% CI based on the exact probability method for a range of possible responses out of 20 and 
40 subjects, respectively.
4.8.2.3
Part 3 (Dose Exploration in 
CRC)
In Part 3 (dose exploration, Cohorts A1, A2, 
), the number of subjects to 
be enrolled will depend upon the toxicities observed as the study progresses. Based on an 
mTPI dose-escalation design for 2 dose levels, with a minimum of 3 subjects and a maximum 
of 12 subjects for each dose level, up to 144 evaluable subjects (ie, 2 dose levels across 6 
chemotherapy combination cohorts with or without a biologic agent) may be enrolled. An 
additional 6 subjects per dose level may be enrolled, up to a maximum of 18 subjects per dose 
level (ie, a total of 216 evaluable subjects in 2 dose levels across 6 chemotherapy combination 
cohorts with or without a biologic agent) to provide additional PK, pharmacodynamic, and 
safety data. 
In Part 3 (dose exploration, Cohorts C1 and C2), up to 100 subjects/cohort may be enrolled in 
Cohorts C1A and C1B. A total of 100 subjects would provide a width of < % between the 
observed ORR and its lower limit of the exact 
% CI. Up to 40 subjects/cohort may be 
enrolled in Cohorts C2A and C2B.
 
Table 19 provides the estimated ORR and its 
% CI based on the exact probability method 
for a range of possible responses out of 20 and 40 subjects, respectively.
Table 19
Estimated Objective Response Rate and 
% Confidence Interval Out 
of 20 and 40 Subjects, Respectively
Sample Size
Number (%) of Responses
20
2 (10)
4 (20)
6 (30)
8 (40)
10 (50)
12 (60)
14 (70)
Lower limit of
% CI
%
%
%
%
%
%
%
Upper limit of
% CI
%
%
%
%
%
%
%
40
4 (10)
8 (20)
12 (30)
16 (40)
20 (50)
24 (60)
28 (70)
Lower limit of
% CI
%
%
%
%
%
%
%
Upper limit of
% CI
%
%
%
%
%
%
%
CI = confidence interval.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
144 of 206
Template 16.2
Table 20 provides the estimated ORR and the 
% CI based on the exact probability method 
for a range of possible responses out of 100 subjects. 
Table 20
Observed Objective Response Rate with 
% Confidence Interval
Cohort
Number of 
subjects
Number of 
Responses
ORR (%)
2-sided exact 
% CI (%)
C1 
100
10
10
100
11
11
100
15
15
100
17
17
100
23
23
100
25
25
CI = confidence interval; ORR = objective response rate.
For Cohort C1 
 
CRC, with a total of 100 subjects, there is a 
% chance of 
observing at least 
 responses (an ORR of 
% with the lower limit of the exact 
% CI 
excluding a historical response rate of 
%), if the true ORR is 
%. 
4.8.3
Efficacy
4.8.3.1
Antitumor Activity
The following endpoints will be analyzed. More details will be provided in the statistical 
analysis plan.

OR is defined as best overall response of confirmed CR or confirmed PR according to 
RECIST 1.1 guidelines. The best overall response is defined as the best response (in the 
order of CR, PR, SD, PD, and not evaluable) among all overall responses recorded from 
the start of treatment/or randomization until progression, or the last evaluable disease 
assessment in the absence of PD prior to the initiation of subsequent anticancer therapy or 
discontinuation from the study, whichever occurs first. The best overall response of CR or 
PR must be confirmed, which means a response of CR/PR is recorded at 1 visit and 
confirmed by repeat imaging not less than 28 days (4 weeks) after the visit when the 
response was first observed with no evidence of progression between the initial and 
CR/PR confirmation visit. The ORR will be estimated by the proportion of OR, and its 
% CI and 
% CI will be estimated using the exact binomial distribution.

DoR is defined as the duration from the first documentation of OR to the first documented 
disease progression or death due to any cause, whichever occurs first. For subjects who 
are alive and progression-free at the time of DCO for analysis, DoR will be censored at 
the last tumor assessment date. The DoR will only be evaluated for the subgroup of 
subjects with an OR using the Kaplan-Meier method.

DC is defined as CR, PR, or SD (subjects achieving SD will be included in the disease 
control rate (DCR) if they maintain SD for ≥ 8 weeks [± 7 days]) based on RECIST 1.1 
guidelines. The DCR will be estimated by the proportion of DC, and its 
% CI and 
% 
CI will be estimated using the exact binomial distribution.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
145 of 206
Template 16.2

PFS will be measured from the start of treatment/or randomization with investigational 
product until the first documentation of disease progression or death due to any cause, 
whichever occurs first. For subjects who are alive and progression-free at the time of 
DCO for analysis, PFS will be censored at the last tumor assessment date. The Kaplan-
Meier method (Kaplan and Meier, 1958) will be used to estimate the PFS curve and the 
PFS rate at time points of interest.

The OS will be determined as the time from the start of treatment/or randomization with 
investigational product until death due to any cause. For subjects who are alive at the time 
of DCO, OS will be censored on the last date when subjects are known to be alive. The 
Kaplan-Meier method will be used to estimate the OS curve and the OS rate at time 
points of interest.

Efficacy analyses will be based on the As-treated population according to RECIST v1.1 
per investigator assessment for the nonrandomized cohorts and on the ITT population 
according to RECIST v1.1 per investigator assessment for the randomized cohorts. 
Additional supportive analyses may be conducted in the ITT population according to 
RECIST v1.1 per Blinded Independent Central Review to inform internal program 
decisions and/or for potential interactions with regulatory agencies for future 
development.

Additional analyses of antitumor activity may be conducted in the Response-evaluable 
population.
4.8.4
Safety
The MTD will be determined by isotonic regression analysis (Ji et al, 2010) applied to the 
DLT rates observed during the dose-escalation part. MTD evaluation will be based on the 
DLT-evaluable population, which includes all subjects enrolled in the dose-escalation part 
who receive study treatment per protocol and complete the safety follow-up through the 
DLT-evaluation period or who experience any DLT during the DLT-evaluation period.
4.8.4.1
Analysis of Adverse Events
Summary statistics will be provided for AEs, SAEs, and AE grade, severity, and relationship 
to study drug, clinical laboratory parameters, physical examinations, vital signs, and ECG. 
AEs will be graded according to NCI CTCAE v4.03 and described by system organ class 
using the Medical Dictionary for Regulatory Activities PT. At each level of subject 
summarization, a subject will be counted once using the highest grade and level of causality if 
one or more occurrences of the same system organ class/PT is reported.
4.8.4.2
Analysis of Clinical Laboratory Parameters
Laboratory abnormalities with toxicity grades according to the NCI CTCAE v4.03 will be 
derived and summarized. Frequencies of maximum observed grade will be presented for each 
laboratory parameter as well as the rates of subjects with Grade 3-4 toxicities. A shift table, 
presenting the 2-way frequency tabulation for baseline and post-baseline grade at scheduled 

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
146 of 206
Template 16.2
time of evaluation as well as the worst post-baseline grade, will be provided for clinical 
laboratory tests.
4.8.4.3
Analysis of Vital Signs
Descriptive statistics will be provided for the vital signs measurements and changes from 
baseline by scheduled time of evaluation and by treatment arm including end of treatment visit 
as well as for the maximum and minimum post-baseline values.
4.8.4.4
Analysis of Electrocardiograms
ECG parameters (PR, QRS, QT, QTc corrected according to Bazett’s formula [QTcB], and 
QTcF) will be summarized using descriptive statistics for actual values and for changes from 
baseline by treatment arm by scheduled time of evaluation including end of treatment visit as 
well as for the maximum post-baseline values. The QTcF will be considered as the primary 
correction method to assess subject cardiac safety.
The notable ECG interval values in maximum absolute QTcF and QTcB intervals (new 
> 450 milliseconds, new > 480 milliseconds, new > 500 milliseconds) and the maximum 
absolute uncorrected QT intervals (new > 500 milliseconds) over all post-baseline evaluations, 
as well as in QTcF and QTcB maximum changes from baseline (> 30 and > 60 milliseconds) 
over all post-baseline evaluations will be summarized by treatment. “New” means the 
category of the QTc abnormality was not present at baseline and became present at least one 
post-baseline ECG assessment.
4.8.4.5
Analysis of ECOG Performance Status
Descriptive statistics will be provided for the ECOG performance status assessments and 
changes from baseline by scheduled time of evaluation and by treatment arm including end of 
treatment visit. 
4.8.5
Analysis of Patient Reported Outcomes (Part 3, Cohort C1 only)
4.8.5.1
Analysis of the European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire
The EORTC QLQ C-30 is described in Section 4.3.3.1 and a sample questionnaire is provided 
in Section 10.5.1. Domain, subscale, and individual item scores will be summarized 
descriptively at each time point. At each post-baseline assessment, the change in symptoms/ 
functioning/global health status score from baseline will be calculated for each domain, 
subscale, and item, and summarized using descriptive statistics. Additional exploratory 
analysis will be conducted to assess time to deterioration and response status for domains, 
subscales and individual items as measured by the EORTC QLQ-C30. Further details will be 
provided in the statistical analysis plan.
EORTC Scoring and Handling Missing Data: The EORTC QLQ-C30 consists of 
30 questions that can be combined to produce 5 functional scales (physical, role, cognitive, 

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
147 of 206
Template 16.2
emotional, and social), 3 symptom scales (fatigue, pain, and nausea/vomiting), and health 
status/QoL scale. The EORTC QLQ-C30 will be scored according to the EORTC QLQ-C30 
Scoring Manual by the developer (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.
Compliance rate summarizing PRO completion at each visit will be tabulated.
4.8.5.2
Analysis of Patient Global Impression of Change
The PGIC questionnaire is described in Section 4.3.3.2 and a sample questionnaire is provided 
in Section 10.5.2. Response on the PGIC will be summarized descriptively as number of 
subjects and corresponding percentages for each category in the questionnaire at each visit.
Compliance rate summarizing PRO completion at each visit will be tabulated.
4.8.6
Analysis of Immunogenicity
Only subjects who receive at least 1 dose of durvalumab and/or monalizumab, and provide at 
least 1 post-treatment sample, will be evaluated. The immunogenic potential of durvalumab 
and monalizumab will be assessed by summarizing the number and percentage of subjects 
who develop detectable ADAs. The immunogenic potential of cetuximab will also be assessed 
for Part 3, Cohorts C1A and C1B by summarizing the number and percentage of subjects who 
develop detectable ADAs. The impact of ADAs on PK will be assessed if data allow. Samples 
will be collected for evaluating neutralizing capacity of ADAs in the future.
4.8.7
Analysis of Pharmacokinetics
Only subjects who receive at least 1 dose of durvalumab and/or monalizumab, and provide at 
least 1 post-treatment sample, will be evaluated. Individual durvalumab and monalizumab 
concentrations will be tabulated by dose cohort along with descriptive statistics. Individual 
cetuximab concentrations will also be summarized for Part 3, Cohorts C1A and C1B.
Non-compartmental PK data analysis will be performed from each dose cohort with scheduled 
PK sample collection where data allow. Relevant descriptive statistics of non-compartmental 
PK parameters will be provided.

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
148 of 206
Template 16.2
4.8.8
Analysis of Pharmacodynamic Biomarkers
Analysis of pharmacodynamics biomarkers will be descriptive. 
 
 
 Changes in numbers and 
percentages of T cells and NK cells will be assessed in peripheral blood as well as the number 
and percentage of NK and T cells expressing activation and proliferation markers.
Summaries and analyses for exploratory pharmacodynamics/biomarkers may be reported 
outside the clinical study report (CSR) in a separate report.
4.8.9
Interim Analysis
For Part 3, Cohorts C1A, C1B, C2A, and C2B, an interim futility analysis will be performed 
after 20 subjects in each cohort are response-evaluable (including subjects who received the 
same dose during the DLT evaluation). Enrollment will stop 
 
. The observed 1/20 response gives an upper 
limit of a 1-sided 
% CI of approximately 
%, which means that a response rate greater 
than 
% can be ruled out with 
% confidence and hence enrollment would be stopped for 
lack of desirable response rate.
For Part 3, Cohorts C1A and C1B, a subsequent interim futility analysis will be performed 
after 40 subjects in each cohort are response-evaluable (including subjects who received the 
same dose during the DLT evaluation). Enrollment will stop 
 
. The observed 3/40 response gives an upper 
limit of a 1-sided 
% CI of approximately 
%, which means that a response rate greater 
than 
% can be ruled out with 
% confidence and hence enrollment would be stopped for 
lack of desirable response rate.
5
ASSESSMENT OF SAFETY
5.1
Definition of Adverse Events
The ICH Guideline for GCP E6(R1) defines an AE as: Any untoward medical occurrence in a 
patient or clinical investigation subject administered a pharmaceutical product and which does 
not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
An AE includes, but is not limited to any clinically significant worsening of a subject’s 
pre-existing condition. An abnormal laboratory finding (including ECG finding) that requires 
medical intervention by the investigator, or a finding judged by the investigator as medically 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
149 of 206
Template 16.2
significant should be reported as an AE. If clinical sequelae are associated with a laboratory 
abnormality, the diagnosis or medical condition should be reported (eg, renal failure, 
hematuria) not the laboratory abnormality (eg, elevated creatinine, urine red blood cell count 
increased). Abnormal laboratory values that are not, in the investigator's opinion, medically 
significant and do not require intervention should not be reported as AEs.
Adverse events may be treatment emergent (ie, occurring after initial receipt of investigational 
product) or non-treatment emergent. A non-treatment-emergent AE is any new sign or 
symptom, disease, or other untoward medical event that begins after written informed consent 
has been obtained but before the subject has received investigational product. 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition that did not 
worsen from baseline is not considered an AE (serious or nonserious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE.
Adverse Events Associated with Disease Progression
Disease progression can be considered as a worsening of a subject’s condition attributable to 
the disease for which the investigational product 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 a new metastasis or progression of existing metastasis related to the primary 
cancer under study should not be considered an AE. Events that are unequivocally due to 
disease progression should not be reported as an AE during the study. Death clearly resulting 
from disease progression should not be reported as an SAE (see reporting guidelines in 
Section 5.4.3).
New Cancers
The development of a new cancer should be regarded as an SAE. New cancers are those that 
are not the primary reason for the administration of the investigational product and have been 
identified after the subject’s inclusion in the study. New metastatic lesion(s) of the subject’s 
known cancer should not be reported as a new cancer
5.2
Definition of Serious Adverse Events
An SAE is any AE that:

Results in death

Is immediately life-threatening

Requires inpatient hospitalization or prolongation of existing hospitalization 

Results in persistent or significant disability/incapacity 

Is a congenital anomaly/birth defect in offspring of the subject

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
150 of 206
Template 16.2

Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above
Medical or scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in this situation. Examples of medically important events are intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions 
that do not result in hospitalizations; or development of drug dependency or drug abuse.
5.3
Definition of Adverse Events of Special Interest
An AESI is one of scientific and medical interest specific to understanding of the
investigational product and may require close monitoring and collecting additional 
information by the investigator to the sponsor. An AESI may be serious or nonserious. The 
rapid reporting of AESIs allows ongoing surveillance of these events in order to characterize 
and understand them in association with the use of this investigational product.
All AESIs should be recorded in the eCRF within 24 hours. In addition, AESIs that are also 
SAEs should be reported to MedImmune Patient Safety within 24 hours. Instructions to the 
site on how to record (in the eCRF) and report SAEs is provided in Section 5.4 and 
Section 5.5, respectively. The AESIs for this study are defined below.
AESIs for durvalumab include, but are not limited to, events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants and/or hormone replacement therapy. 
These AESIs are being closely monitored in clinical studies with durvalumab monotherapy 
and combination therapy. An imAE/irAE is defined as an AE that is associated with drug 
exposure and is consistent with an immune-mediated mechanism of action and where there is 
no clear alternate etiology. Serologic, immunologic, and histologic (biopsy) data, as 
appropriate, should be used to support an imAE/irAE diagnosis. Appropriate efforts should be 
made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the 
imAE/irAE.
If the investigator has any questions in regards to an AE being an imAE/irAE, the investigator 
should promptly contact the Study Physician.
AESIs observed with durvalumab include:

Diarrhea/colitis and intestinal perforation

Pneumonitis/interstitial lung disease

Hepatitis/transaminase increases

Endocrinopathies (ie, events of hypophysitis, hypopituitarism, adrenal insufficiency, 
hyper- and hypothyroidism, and type I diabetes mellitus)

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
151 of 206
Template 16.2

Rash/dermatitis

Nephritis/blood creatinine increases

Pancreatitis/serum lipase and amylase increases

Myocarditis

Myositis/polymyositis

Neuropathy/neuromuscular toxicity (eg, Guillain-Barre and myasthenia gravis)

Other inflammatory responses that are rare/less frequent with a potential immune-
mediated etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis and 
other events involving the eye, skin, hematological and rheumatological events.
In addition, IRRs 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 durvalumab Investigator’s Brochure. More specific guidelines for their 
evaluation and treatment are described in detail Section 3.1.3.
5.4
Recording of Adverse Events
Adverse events will be recorded on the eCRF using a recognized medical term or diagnosis 
that accurately reflects the event. Adverse events will be assessed by the investigator for 
severity, relationship to the investigational product, possible etiologies, and whether the event 
meets criteria of an SAE and therefore requires immediate notification to the sponsor 
(Section 5.5). Refer to Section 5.2 for the definition of SAEs and Section 10.2 for guidelines 
for assessment of severity and relationship. If an AE evolves into a condition that meets the 
regulatory definition of “serious,” it will be reported in the SAE Report Form.
Infusion of biological products is commonly associated with IRRs. Anaphylaxis and IRRs 
have some common manifestations and may be difficult to distinguish from each other. 
Infusion-related reactions are commonly observed during or shortly after the first time 
exposure to therapeutic mAbs delivered through IV infusion. These reactions are less common 
following subsequent exposures. Unlike IRRs, anaphylaxis is a rare event, usually occurring 
after subsequent exposure to an antigen, and it is most commonly accompanied by severe 
systemic skin and or mucosal reactions. The investigator is advised to carefully examine 
symptoms of adverse reactions observed during or shortly after exposure to durvalumab and 
monalizumab, and consider the above mentioned facts prior to making a final diagnosis. 
Reactions occurring at the time of or shortly after subsequent infusions of investigational 
product are to be judged by the investigator at his/her own discretion. For the investigator’s
convenience and in order to facilitate consistency in judgments, a copy of the National 
Institute of Allergy and Infectious Disease and Food and Allergy Anaphylaxis Network 
guidance for anaphylaxis diagnosis is provided in Section 10.3.

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
152 of 206
Template 16.2
5.4.1
Time Period for Collection of Adverse Events
AEs and SAEs will be collected from time of signature of informed consent, throughout the 
treatment period and including the follow-up period until 90 days after last treatment.
5.4.2
Follow-up of Unresolved Adverse Events
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the eCRF. 
MedImmune retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. Updates regarding SAEs that were 
ongoing at the time of the subject’s completion of study participation should be submitted to 
the study representative using a paper SAE follow-up form.
5.4.3
Deaths
All deaths that occur during the study, including the protocol-defined follow-up period must 
be reported as follows:

Death clearly the result of disease progression should be reported and documented in the 
eCRF but should not be reported as an SAE.

Where death is not due (or not clearly due) to disease progression, the AE causing the 
death must be reported as an SAE within 24 hours. The report should contain a comment 
regarding the co-involvement of disease progression, if appropriate, and should assign 
main and contributory causes of death.

Deaths with an unknown cause should always be reported as an SAE. A post-mortem 
(autopsy) 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 the appropriate sponsor 
representative(s) or designee within the usual timeframes. 
5.5
Reporting of Serious Adverse Events
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, IRBs/IECs, and investigators.
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary.

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
153 of 206
Template 16.2
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 Investigator’s Brochure and/or will notify the IRB/IEC, if appropriate 
according to local requirements.
SAEs have to be reported, whether or not considered casually related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF. 
If any SAE occurs during the course of the study, the investigator other site personnel will 
inform the appropriate sponsor representative(s) 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 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 will inform sponsor 
representatives of any follow-up information on a previously reported SAE within 1 calendar 
day; ie, immediately but no later than 24 hours of when he or she becomes aware of it.
Once the investigator or other site personnel indicate an AE is serious in the electronic data 
capture (EDC) system, an automated email alert is sent to inform the designated sponsor 
representative(s).
If the EDC system is not available, then the investigator or other study site personnel reports 
the SAE to the appropriate sponsor representative by telephone. The sponsor representative 
will advise the investigator/study site personnel how to proceed.
5.6
Other Events Requiring Immediate Reporting
5.6.1
Overdose
An overdose in this study is defined as a subject receiving a dose of investigational product 
that is greater than the dose that was intended to be given,

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 with a MedImmune investigational product occurs during the course of the 
study, then the investigator or other site personnel inform appropriate sponsor representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
154 of 206
Template 16.2
The designated sponsor representative works with the investigator to ensure that all relevant 
information is provided to the sponsor’s patient safety data entry site.
For overdoses associated with an SAE, the standard reporting timelines apply; see Section 5.5. 
5.6.2
Potential Hy’s Law and Hy’s Law
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN will need to be 
reported as SAEs. Refer to Section 10.4 for further instruction on cases of increases in liver 
biochemistry and evaluation of Hy’s Law.
5.6.3
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to the sponsor.
5.6.3.1
Maternal Exposure
Women of childbearing potential in this study who are sexually active with a nonsterilized 
male partner are required to use two forms of contraception as described in the inclusion 
criteria. Pregnancy should be avoided for at least 6 months after receiving investigational 
product or until the subject completes participation in the study, whichever is longer. If a 
subject becomes pregnant during the course of the study, investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be followed up for 2 weeks post-birth and 
documented even if the subject was discontinued from the study.
If a pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate sponsor representatives within 1 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 within 1 or 5 calendar days for SAEs (Section 5.5) and within 30 days 
for all other pregnancies.
The same timelines apply when outcome information is available.
The outcome of any conception occurring from the date of the first investigational product 
administration until 12 weeks after the last investigational product administration should be 

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
155 of 206
Template 16.2
followed up and documented. Information on the pregnancy of a subject’s partner must be 
obtained directly from the subject’s partner. Therefore, prior to obtaining information about 
the pregnancy, the investigator must obtain the consent of the subject’s partner.
5.6.3.2
Paternal Exposure
Nonsterilized male study subjects who are sexually active with a female partner of 
childbearing potential must use condoms and a spermicide from Day 1 through the end of the 
study follow-up period. 
Male subjects should refrain from fathering a child or donating sperm during the study and for 
12 weeks following the last dose. 
Pregnancy of the subject’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) should if possible be followed up for 2 weeks post-birth and 
documented. 
5.7
Safety Management During the Study
A study-specific DEC (including at a minimum the sponsor medical monitor/clinical lead, 
patient safety physician, and all participating investigators who have enrolled subjects) will 
provide ongoing safety surveillance of the study, with regularly scheduled reviews of safety 
and other relevant data. The DEC may also meet to review data at other time points (eg, in 
response to AEs assessed as medically relevant by the medical monitor). The DEC will be 
responsible for dose-escalation or dose de-escalation decisions and making recommendations 
regarding further conduct of the study. All decisions by the DEC will be documented and 
shared with all participating sites in writing.
A MedImmune safety review committee provides safety surveillance, guidance, and oversight 
for all clinical development studies in which MedImmune has sponsor accountabilities. 
Committee members include, but are not limited to, appropriate representatives from Patient 
Safety, Clinical Development, and Regulatory Affairs. The committee reviews 
protocol-specific safety data and assesses changes to the benefit/risk profile of the molecule 
during early phases of development. Based on review of safety data, the committee may 
suspend enrollment or subject dosing in clinical studies, request modification of study 
documents, or take other actions as deemed necessary.

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
156 of 206
Template 16.2
6
STUDY AND DATA MANAGEMENT
6.1
Training of Study Site Personnel
Before the first subject is entered into the study, a MedImmune representative will review and 
discuss the requirements of the CSP and related documents with the investigational staff and 
also train them in any study-specific procedures and system(s) utilized.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
6.2
Monitoring of the Study
During the study, a MedImmune representative will have regular contacts with the study site, 
including visits to:

Provide information and support to the investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
being performed

Perform source data verification (a comparison of the data in the eCRFs with the subject’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent of participating subjects. This will require 
direct access to all original records for each subject (eg, clinic charts)

Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject.
The MedImmune representative will be available between visits if the investigator(s) or other 
staff at the center needs information and advice about the study conduct.
6.2.1
Source Data
Refer to the Clinical Study Agreement for location of source data.
6.2.2
Study Agreements
The Principal Investigator at each center should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any 

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
157 of 206
Template 16.2
inconsistency between this CSP and the Clinical Study Agreement, the terms of CSP shall 
prevail with respect to the conduct of the study and the treatment of subjects and in all other 
respects, not relating to study conduct or treatment of subjects, the terms of the Clinical Study 
Agreement shall prevail.
Agreements between MedImmune and the Principal Investigator must be in place before any 
study-related procedures can take place, or subjects are enrolled.
6.2.3
Archiving of Study Documents
The investigator follows the principles outlined in the Clinical Study Agreement.
6.3
Study Timetable and End of Study
The study started in March 2016 and the last subject was enrolled in March 2020. The DCO in 
support of final database lock will occur approximately 19 months after the last subject 
recruited who was administered the first dose of investigational product.
Data analysis will be performed, and a CSR will be written based on this final database lock.
Any subjects still receiving investigational product at the time of this DCO will be able to 
continue to receive investigational product within the current study, as long as, in the 
investigator’s opinion, the subject is deriving clinical benefit and has not fulfilled any 
discontinuation criteria. This continued treatment period may be managed by the study team 
or the sponsor’s Post Analysis and Reporting Team [PART] program
During this continued treatment period:

Assessments will revert to the standard of care for each individual site. 

Data will not be entered into the clinical study database after the DCO date. 

Subjects will continue to be monitored for SAEs, overdoses, and pregnancies only, and 
these will be reported up to 90 days after the last dose of investigational product using 
paper-based SAE reporting. SAE data will be entered into the sponsor’s global safety 
database. 

The IXRS system will be closed at DCO, and sites will manually order investigational 
product. 

The investigational product accountability information must still be collected until all 
subjects have completed treatment, and investigational product dispensation and 
reconciliation will be handled by the study site at each subject’s visit. 

After the DCO for the CSR and database lock is completed, individual study sites will be 
closed once their final subject completes the 90-day follow-up visit. 

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
158 of 206
Template 16.2
6.4
Data Management 
Data management will be performed by MedImmune Data Management staff according to the 
Data Management Plan.
A Web Based Data Capture system will be used for data collection and query handling. The 
investigator will ensure that data are recorded on the eCRFs as specified in the study protocol 
and in accordance with the instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site.
6.5
Medical Monitor Coverage
Each subject will be provided with contact information for the principal investigator. In 
addition, each subject will receive a toll-free number intended to provide the subject’s 
physician access to a medical monitor 24 hours a day, 7 days a week in the event of an 
emergent situation where the subject’s health is deemed to be at risk. In this situation, when a 
subject presents to a medical facility where the treating physician or health care provider 
requires access to a physician who has knowledge of the investigational product and the CSP
and the principal investigator is not available, the treating physician or health care provider 
can contact a medical monitor through this system, which is managed by a TPV.
7
ETHICAL AND REGULATORY REQUIREMENTS
7.1
Subject Data Protection
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation. 
Data (clinical and biological samples) from this study may be used and may be combined with 
results from other studies for additional scientific-related research, based on agreement from 
the subject as defined in the ICF.
MedImmune will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, general physician or any other third party, unless 
required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the subject. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a subject. For example, in the case of a 
medical emergency, a MedImmune Medical Monitor or an investigator might know a 
subject’s identity and also have access to his or her genetic data. Also Regulatory authorities 

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
159 of 206
Template 16.2
may require access to the relevant files, though the subject’s medical information and the 
genetic files would remain physically separate.
7.2
Ethics and Regulatory Review
An IRB/IEC should approve the final study protocol, including the final version of the ICF
and any other written information and/or materials to be provided to the subjects. The 
investigator will ensure the distribution of these documents to the applicable IRB/IEC, and to 
the study site staff.
The opinion of the IRB/IEC should be given in writing. The investigator should submit the 
written approval to MedImmune before enrollment of any subject into the study. 
The IRB/IEC should approve all advertising used to recruit subjects for the study.
MedImmune should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the protocol should be re-approved by the IRB/IEC annually.
Before enrollment of any subject into the study, the final study protocol, including the final 
version of the ICF, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations.
MedImmune will handle the distribution of any of these documents to the national regulatory 
authorities.
MedImmune will provide Regulatory Authorities, IRB/IEC and Principal Investigators with 
safety updates/reports according to local requirements, including suspected unexpected serious
adverse reactions, where relevant.
Each Principal Investigator is responsible for providing the IRB/IEC with reports of any 
serious and unexpected adverse drug reactions from any other study conducted with the 
investigational product. MedImmune will provide this information to the Principal 
Investigator so that he/she can meet these reporting requirements.
7.3
Informed Consent
The Principal Investigator(s) at each center will:

Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study

Ensure each subject is notified that they are free to discontinue from the study at any time

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
160 of 206
Template 16.2

Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided

Ensure each subject provides signed and dated informed consent before conducting any 
procedure specifically for the study

Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study File

Ensure a copy of the signed ICF is given to the subject

Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the ICF that is approved by an IRB/IEC
7.4
Changes to the Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and MedImmune.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol.
The amendment is to be approved by the relevant IRB/IEC and if applicable, also the national 
regulatory authority approval, before implementation. Local requirements are to be followed 
for revised protocols.
MedImmune will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s). For distribution to IRB/IEC see Section 7.2.
If a protocol amendment requires a change to a site’s ICF, MedImmune and the site’s 
IRB/IEC are to approve the revised ICF before the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each IRB/IEC.
7.5
Audits and Inspections
Authorized representatives of MedImmune, a regulatory authority, or an IRB/IEC may 
perform audits or inspections at the center, including source data verification. The purpose of 
an audit or inspection is to systematically and independently examine all study-related 
activities and documents, to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, GCP, guidelines of the 
ICH, and any applicable regulatory requirements. The investigator will contact MedImmune 
immediately if contacted by a regulatory agency about an inspection at the site.

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
161 of 206
Template 16.2
8
REFERENCES
Aaronson et al, 1993
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.
 
 
Bendell et al, 2015
Bendell JC, Powderly JD, Hanyoung Lieu C, Eckhardt G, Hurwitz H, Hochster HS, et al. 
Safety and efficacy of MPDL3280A (anti-PDL1) in combination with bevacizumab (bev) 
and/or FOLFOX in patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol. 33, 
2015;(Suppl 3;Abstr 704).
Benson et al, 2018
Benson AB, Venook, AP, Al-Hawary MM, Cederquist L, Chen YJ, Ciombor KK, et al. Colon 
cancer, Version 2.2018, NCCN clinical practice guidelines in oncology. J Natl Compr Canc 
Netw. 2018;16:359-69.
 
 
 
 
 
Cohen et al, 2018
Cohen RB, 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. Poster AACR 2018 #CT158. 
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
162 of 206
Template 16.2
Available at https://www.innate-
pharma.com/sites/default/files/iph2201_mona_cetux_poster_clinic_bat_1.pdf.
Dummer et al, 2015
Dummer R, Goldinger SM, Paulitschke V, Levesque MP. Curing advanced melanoma by 
2025. Curr Opin Oncol. 2015;27(2):125-7.
Daaboul et al, 2017
Daaboul N, Gauthier I, Tu D, Brown-Walker P, Sun X, Hao D. Immune related adverse events 
(irAE) with platinum chemotherapy (CT) with durvalumab (D) ± tremelimumab (T): CCTG 
IND226. J Clin Oncol. 2017;35(Suppl):3058.
 
 
 
Disis et al, 2015
Disis ML, Patel MR, Pant S, Infante JR, Lockhart AC, Kelly K, et al. Avelumab 
(MSB0010718C), an anti-PD-L1 antibody, in patients with previously treated, recurrent or 
refractory ovarian cancer: a phase Ib, open-label expansion trial. J Clin Oncol. 
2015;33(Suppl;Abstr 5509).
 
 
Eisenhauer et al, 2009
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.
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
163 of 206
Template 16.2
Fayers et al, 2001
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of the 
EORTC Quality of Life Study Group. The EORTC QLQ-C30 Scoring Manual: 3rd Edition. 
European Organisation for Research and Treatment of Cancer, Brussels 2001.
FDA, 2017a
US Food and Drug Administration. FDA grants accelerated approval to pembrolizumab for 
first tissue/site agnostic indication. 2017. Available at: 
https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm560040.htm.
FDA, 2017b
US Food and Drug Administration. FDA grants nivolumab accelerated approval for MSI-H or 
dMMR colorectal cancer. 2017. Available at: 
https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm569366.htm.
Ferris et al, 2018
Ferris RL, Lenz HJ, Trotta AM, García-Foncillas J, Schulten J, Audhuy F, et al. Rationale for 
combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors: 
Harnessing innate and adaptive immunity through IgG1 isotype immune effector stimulation. 
Cancer Treat Rev. 2018;63:48-60.
 
 
 
 
Hamid et al, 2013
Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses 
with lambrolizumab (anti-PD-1) in melanoma. New Engl J Med. 2013:369(2):134-44. 
DOI:10.1056/NEJMoa1305133.
Hodi et al, 2010
Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved 
survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 
2010;363(8):711-23.
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
164 of 206
Template 16.2
 
 
Ji et al, 2010
Ji Y, Liu P, Li Y, Bekele BN. A modified toxicity probability interval method for dose-
finding trials. Clin Trials. 2010;7(6):653-63.
 
Kaplan and Meier, 1958
Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat 
Assoc. 1958;53:457-81.
Karapetis et al, 2008
Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC. Et al. K-ras 
mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 
2008;359(17):1757-65.
Khemka et al, 2016
Khemka V, Haire P, Waypa J, Weiss G. Phase Ib/II study of nivolumab plus CAPIRI: initial 
results of metastatic colon cancer and pancreatic adenocarcinoma patients. Ann Oncol. 
2016;27(Suppl 2):ii80-1.
Kluetz et al, 2018
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):e267-74.
Kodumudi et al, 2010
Kodumudi KN, Woan K, Gilvary DL, Sahakian E, Wei S, Djeu JY. A novel 
chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor 
cells in tumor bearers. Clin Cancer Res. 2010;16(18):4583-94.
Kroemer et al, 2013
Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu 
Rev Immunol. 2013;31:51-72
Le et al, 2015
Le DT, Uram JN, Bartlett BR, Kemberling H, Eyring AD, Skora AD, et al. PD-1 blockade in 
tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-20.
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
165 of 206
Template 16.2
Liu et al, 2010
Liu W, Fowler D, Smith P, Dalgleish A. Pre-treatment with chemotherapy can enhance the 
antigenicity and immunogenicity of tumours by promoting adaptive immune responses. Br J 
Cancer. 2010;102:115 23.
Liu et al, 2016
Liu G, Tu D, Lewis M, Cheng D, Sullivan LA, Chen Z, et al. Fc-γ Receptor Polymorphisms, 
Cetuximab Therapy, and Survival in the NCIC CTG CO.17 Trial of Colorectal Cancer. Clin 
Cancer Res. 2016;22(10):2435-44.
 
Manegold et al, 2017
Manegold C, Dingemans AC, Gray JE, Nakagawa K, Nicolson M, Peters S, et al. The 
Potential of Combined Immunotherapy and Antiangiogenesis for the Synergistic Treatment of 
Advanced NSCLC. J Thorac Oncol. 2017;12(2):194-207.
 
Mellman et al, 2011
Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 
2011;480:480-9.
Narwal et al, 2013
Narwal R, Roskos LK, Robbie GJ. (2013) Population pharmacokinetics of sifalimumab, an 
investigational anti-interferonalpha monoclonal antibody, in systemic lupus erythematosus. 
Clin Pharmacokinet. 52(11):1017-27.
Ng et al, 2006
Ng CM, Lum BL, Gimenez V, Kelsey S, Allison D. Rationale for fixed dosing of pertuzumab 
in cancer patients based on population pharmacokinetic analysis. Pharm Res. 
2006;23(6):1275-84.
Ochoa et al, 2017
Ochoa MC, Minute L, Rodrguez I, Garasa S, Perez-Ruiz E, Inogés S, et al. Antibody-
dependent cell cytotoxicity: immunotherapy strategies enhancing effector NK cells. Immunol 
Cell Biol 2017;95(4):347-55.
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
166 of 206
Template 16.2
Oken et al, 1982
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5(6):649-55.
Oganesyan et al, 2008
Oganesyan V, Gao C, Shirinian L, Wu H, Dall’Acqua WF. Structural characterization of a 
human Fc fragment engineered for lack of effector functions. Acta Crystallogr D Biol 
Crystallogr. 2008;64(6):700-4.
Overman et al, 2017
Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, et al. Nivolumab in 
patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high 
colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 
2017;18(9):1182-91.
 
 
Peeters et al, 2010
Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, et al. Randomized phase 
III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared 
with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. 
J Clin Oncol. 2010;28(31):4706-13.
 
Pfeiffer et al, 2008
Pfeiffer P, Nielsen D, Bjerregaard J, Qvortrup C, Yilmaz M, Jensen B. Biweekly cetuximab 
and irinotecan as third-line therapy in patients with advanced colorectal cancer after failure to 
irinotecan, oxaliplatin and 5-fluorouracil. Ann Oncol. 2008;19(6):1141-5.
Philips and Atkins, 2015
Philips GK, Atkins M. Therapeutic uses of anti-PD-1 and anti-PD-L1 antibodies. Int Immunol 
2015;27(1):39-46
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
167 of 206
Template 16.2
 
Rizvi et al, 2015a
Rizvi NA, Mazieres J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, et al. Activity and 
safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, 
refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. 
Lancet Oncol. 2015a;16(3):257-65.
Rizvi et al, 2015b
Rizvi NA, Brahmer JR, Ou SI, Segal NH, Khleif S, Hwu W, et al. Safety and clinical activity 
of MEDI4736, an anti-programmed cell death-ligand 1 (PD-L1) antibody, in patients with 
non-small cell lung cancer (NSCLC). J Clin Oncol. 2015b;33 (Suppl;Abstr 8032).
Rougier et al, 1998
Rougier P, Van Cutsem E, Bajetta E, Niederle N, Possinger K, Labianca R, et al. Randomised 
trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in 
patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1407-12. Erratum 
in: Lancet 1998;352(9140):1634.
 
 
Ruggeri et al, 2016
Ruggeri L, Urbani E, Andr P, Mancus A, Tosti A, Topini F, et al. Effects of anti-NKG2A 
antibody administration on leukemia and normal hematopoietic cells. Haematologica. 
2016;101:626-33.
Sandler et al, 2006
Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-
carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 
2006;355(24):2542-50. Erratum in: N Engl J Med 2007;356(3):318.
 
 
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
168 of 206
Template 16.2
Shahda et al, 2017
Shahda S, Noonan AM, Bekaii-Saab TS, O'Neil BH, Sehdev A, Labib Shaib W. A phase II 
study of pembrolizumab in combination with mFOLFOX6 for patients with advanced 
colorectal cancer. J Clin Oncol 2017;35(15-Suppl):3541.
 
 
 
Song et al, 2015
Song X, Pak M, Chavez C, Liang M, Lu H, Blake-Haskins AJ, et al. 203 Population 
pharmacokinetics of MEDI4736, a fully human antiprogrammed death ligand 1 (PD-L1) 
monoclonal antibody, in patients with advanced solid tumors. Eur J Cancer. 2015;51:S28.
Tabernero et al, 2008
Tabernero J, Pfeiffer P, Cervantes A. Administration of cetuximab every 2 weeks in the 
treatment of metastatic colorectal cancer: an effective, more convenient alternative to weekly 
administration?. Oncologist. 2008;13(2):113-9.
 
 
 
Van Cutsem et al, 2007
Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, et al. Open-label phase 
III trial of panitumumab plus best supportive care compared with best supportive care alone in 
patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 
2007;25(13):1658-64.
Van Cutsem et al, 2016
Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH Aderka D, et al. ESMO 
consensus guidelines for the management of patients with metastatic colorectal cancer. Ann 
Oncol. 2016;27(8):1386-422.
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
169 of 206
Template 16.2
 
 
Wallin et al, 2016
Wallin JJ, Bendell JC, Funke R, Sznol M, Korski K, Jones S, et al. Atezolizumab in 
combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal 
cell carcinoma. Nat Commun 2016Aug 30;7:1264. doi:10.1038/ncomms12624.
Wang et al, 2009
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.
Wang et al, 2015
Wang W, Erbe AK, Hank JA, Morris ZS, Sondel PM. NK cell-mediated antibody-dependent 
cellular cytotoxicity in cancer immunotherapy. Front Immunol 2015;6:368. 
Weber et al, 2015
Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. Nivolumab versus 
chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 
treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 
2015;16(4):375-84.
 
 
Wolchok et al, 2013
Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. 
Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-33.
 
Zhang et al, 2008
Zhang C, Wu S, Xue X, Li M, Qin X, Li W, et al. Anti-tumor immunotherapy by blockade of 
the PD-1/PD-L1 pathway with recombinant human PD-1-IgV. Cytotherapy 2008;10(7):711-9.
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
170 of 206
Template 16.2
Zhang et al, 2012
Zhang S, Shi R, Li C, Parivar K, Wang DD. Fixed dosing versus body size-based dosing of 
therapeutic peptides and proteins in adults. J Clin Pharmacol. 2012;52(1):18-28.

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
171 of 206
Template 16.2
9
CHANGES TO THE PROTOCOL
All changes described below have been incorporated into the current version of the protocol. 
9.1
Protocol Amendment 6
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 6. The primary reasons for Amendment 6 were to: describe the continued 
treatment and monitoring of subjects still on study treatment at the time of the final data cut 
off (DCO), add study mitigation language to provide sites with measures that may be 
implemented if a participant is not able to visit a study site to ensure that the clinical trial can 
continue while minimizing risk to the participant, maintaining compliance with Good Clinical 
Practice (GCP), and minimizing risks to the study integrity;
 
Major changes to the protocol are summarized below:
1
Section 3.1.3 (Management of Study Medication Related Toxicities): Section 3.1.3 was 
updated to remove the link to the TMG portal, which has been decommissioned. 
2
Section 3.3 (Study Mitigation During Study Disruptions Due to Cases of Civil Crisis, 
Natural Disaster, or Public Health Crisis); Section 10.6 (Changes Related to Mitigation of 
Study Disruptions Due to Cases of Civil Crisis, Natural Disaster, or Public Health Crisis):
The impact of COVID-19 has highlighted the risk to continuity of clinical trials during 
times of study disruption, whether by civil crisis, natural disaster, or public health crisis. 
These sections summarize and detail, respectively, the measures that may be implemented 
if a participant is not able to visit a study site to ensure that the clinical trial can continue 
while minimizing risk to the participant, maintaining compliance with GCP, and 
minimizing risks to study integrity. These changes will only be initiated at a time of study 
disruption.   
3
 
 
4
Section 6.3 (Study Timetable and End of Study): This section was updated to define study 
milestones and to confirm procedures for DCO, database lock, and clinical study report
production. This change was made to provide additional clarity.
Minor changes to the protocol are summarized below:
5
Updated change to front page to reflect change in personnel.
6
Updated Synopsis to align with changes in the body of the protocol.
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
172 of 206
Template 16.2
7
Section 2.2 (Table 2: Secondary Objectives and Associated Endpoints); Section 2.3 
(Table 3: Exploratory Objectives and Associated Endpoints): 
 
 
 
8
Section 4.1.1 (Number of Subjects): Table 5 was updated to include the most current 
enrollment numbers. 
9
Section 4.5.1 (Identity of Investigational Products): Table 18 was updated to provide 
additional clarity on the durvalumab and monalizumab investigational product provided 
in this study.
10 Section 4.5.1.1 (Investigational Product Inspection); Section 6.3 (Study Timetable and 
End of Study): These sections were updated to confirm that the use of interactive
voice/web response system (IXRS) will not continue after the time of DCO. Details of 
how to obtain supplies of investigational product once IXRS is decommissioned were 
added to Section 4.5.1.1. In addition, details on the presentation of monalizumab 
according to vial size were updated to provide additional clarity.
11 Section 4.5.1.2 (Dose Calculation) was removed as not required since fixed doses are 
used, and all relevant information is provided in the following section.  
12 Section 4.5.1.2, formerly Section 4.5.1.3 (Investigational Product Dose Preparation and 
Administration): This section was updated to provide separate instructions for the 
different vial sizes of monalizumab to provide additional clarity and to clarify storage 
conditions. 
13 Throughout, correction of grammatical and typographical errors. 
9.2
Protocol Amendment 5
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 5. The primary reasons for Amendment 5 were to remove the toxicity 
modification guidelines to a separate standalone document according to updated Sponsor 
guideline, to align with other Sponsor guidelines, to allow re-treatment following relapse, and 
to add Schedules of Procedures for re-treatment.
Major changes to the protocol are summarized below.
1
Section 1.4.2 (Durvalumab Clinical Experience); Section 1.4.3 (Safety and Efficacy 
Results from the Current Ongoing Study); Section 1.6.2 (Summary of Risks); Section 
4.1.6 (Discontinuation of Investigational Product); Section 4.2.2 (Treatment Period); 
Section 5.3 (Definition of Adverse Events of Special Interest): The location of 
information detailing management of study medication-related toxicities has been 
removed from these sections and reference made to Section 3.1.3 for details. 
2
Section 1.4.3 (Safety and Efficacy Results from the Current Ongoing Study); Section 
1.6.2 (Summary of Risks); Section 3.1.3 (Management of Study Medication Related 
Toxicities); Section 4.1.6 (Discontinuation of Investigational Product); Section 4.2.2 
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
173 of 206
Template 16.2
(Treatment Period): Information detailing management of study medication-related 
toxicities for monalizumab has been removed from these sections and reference made to 
Section 3.1.3 for details.
3
Section 1.6.2 (Summary of Risks): Information detailing risks for monalizumab has been 
updated to include the identified risk of infusion related reactions and a theoretical risk of 
immune-mediated events (including, but not limited to pancreatic, hepatic, renal, lung, 
skin, musculoskeletal, and endocrine disorders). Other potential risks for monalizumab 
are related to hypersensitivity, including anaphylaxis and serious allergic reactions, and 
immune complex disease.
4
Section 3.1.3 (Management of Study Medication Related Toxicities); Section 10.2 
(Management of Study Medication Related Toxicities): Section 10.2 was removed, and 
Section 3.1.3 was updated to confirm that study medication-related toxicities for 
durvalumab is to be maintained within the Site Master File. In addition, a version of the 
current Toxicity Management Guidelines is available through the following link: 
https://tmg.azirae.com. Details for management of study medication-related toxicities for 
monalizumab and marketed drugs were added to Section 3.1.3. 
5
Section 3.1.2 (Treatment Regimen); Section 4.1.8 (Treatment on Relapse); Section 4.2.2 
(Treatment Period): Subjects who progress during the first 52 weeks after the last dose of 
study treatment will be eligible for re-treatment with the protocol-defined experimental 
medicines (same dose and schedule) as at the time of discontinuation, after consultation 
and in agreement with the Sponsor. The Investigator may consider standard-of-care 
chemotherapy backbone with the experimental agent(s) as appropriate for the subject at 
time of re-treatment. The following criteria must not apply: Meets any of the 
investigational product discontinuation criteria; ECOG performance status > 2; Rapid PD 
or threat to vital organs/critical anatomical sites (eg, spinal cord compression) requiring 
urgent alternative medical intervention; Subject has had severe/refractory irAE or 
development of new autoimmune condition that, in the investigator’s opinion, poses 
undue risk to the subject. This option for re-treatment will be limited to one occasion and 
will apply only if the subject has not received any other anticancer treatment for their 
disease following study-treatment discontinuation. The study protocol must still be active, 
ie, the final database lock has not yet occurred. The subject will need to follow the 
schedule of study procedures as described in Section 4.2.2. Subjects must also be re-
consented. 
6
Section 3.1.2.3 (Part 3: Dose Exploration in 
CRC), Section 4.2.2 (Treatment Period; 
Table 8 Footnote n and Table 9 Footnote g), and Section 4.5.1.3 (Investigational Product 
Dose Preparation and Administration): The infusion time for all infusions of cetuximab at 
a dose of 500 mg/m2 was updated to approximately 2 hours in line with prescribing 
information. 
7
Section 4.1.2 (Inclusion Criteria; Table 6: Highly Effective Methods of Contraception): 
Intravaginal devices was added as an effective method of contraceptive and clarification 
of intrauterine devices was made in line with updated Sponsor guidance.
8
Section 4.2.2 (Treatment Period - Table 9 Schedule of Treatment Period Procedures 
Weeks 27 to End of Treatment): To reduce the burden on the study subjects, from week 
57 onwards, the number of assessments for disease assessment (from Q8W to Q26W), 
12-lead ECG (not required unless clinically indicated), serum chemistry (from Q2W to 
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
174 of 206
Template 16.2
Q4W), coagulation parameters (not required unless clinically indicated), and thyroid 
function tests (from Q4W to Q12W) have been reduced in number or ceased after 
consideration of data obtained to date. The statement that procedures can be performed as 
clinically indicated/more frequently if considered necessary by the Investigator or if 
required by Institutional Guidelines was added to allow for additional assessments if 
deemed necessary.
9
Section 4.8.1 (General Considerations): The definition of the ITT population was 
amended to include any subject who had been randomized, according to new Sponsor 
guidelines. 
10 Section 4.8.3.1 (Antitumor Activity): The time window for the scans for disease activity 
was amended from ± 3 days to ± 7 days in line with the time provided in Table 14 
(Schedule of Follow-up Assessments) and RECIST 1.1 guidelines. 
11 Section 5.1 (Definition of Adverse Events; Adverse Events Associated with Disease 
Progression): The clarification that events which are unequivocally due to disease 
progression should not be reported as AEs during the study was added to prevent 
overreporting of AEs.
12 Section 5.5 (Reporting of Serious Adverse Events): This section was updated to ensure 
that country-specific regulatory reporting requirements for SAEs are met, according to 
updated Sponsor guidelines. 
13 Section 5.6.3.1 (Maternal Exposure) and Section 5.6.3.2 (Paternal Exposure): The 
timeframe for follow up of the outcome of pregnancies of 2 weeks post-birth was added 
for clarification. 
Minor changes to the protocol are summarized below.
14 Updated synopsis to align with changes in the body of the protocol.
15 Throughout the document the abbreviation irAEs for immune-related adverse events has 
been expanded to include imAE (immune -modulated AEs) and both terms are presented 
together as imAEs/irAEs since these will be considered in the same way. 
16 Title Page; Section 10.1 (Signatures): The name of the Sponsor signatory and medical 
monitor was updated to reflect the change in personnel.
17 Section 1.4.1 (Monalizumab Clinical Experience): Data cut-off date was reiterated within 
the section for clarification.
18 Section 3.1.2.3 
; The subject 
description for Cohorts C1 and C2 was amended to include second-line subjects in line 
with the description provided below that patients had to have failed at least 1 but no more 
than 2 prior lines of therapy. This description was changed from a note to a footnote 
letter.
19 Section 3.1.2.3 (Part 3: Dose Exploration in 
CRC); Section 4.5.1.4 (Treatment 
Administration): Clarification was made that following an observation period of 15 to 30 
minutes post end of monalizumab infusion, the infusion of the premedication for 
cetuximab may begin and will be followed 30 minutes later by the cetuximab infusion.
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
175 of 206
Template 16.2
20 Section 3.1.3 (Management of Study Medication Related Toxicities): It was confirmed 
that the local product information should be used for guidance on toxicity management 
for marketed study medications. 
21 Section 4.3.5 (Clinical Laboratory Tests; Other Safety Tests): Hepatitis A antibody was 
added to list of tests as previously omitted in error. 
22 Section 4.5.1.1 (Investigational Product Inspection): The requirement for the durvalumab 
solution to be practically free from visible particles was removed for clarification.
23 Section 4.5.1.3 (Investigational Product Dose Preparation and Administration): The 
infusion time for cetuximab at a dose 250 mg/m2 was added as previously omitted in 
error, the requirement for the dose of durvalumab to be allowed to equilibrate at room 
temperature before use was removed as not required, the acceptability of polyethylene 
and polypropylene tubing for monalizumab infusion was removed as these tubes have not 
been assessed.
24 Section 4.5.4 (Storage): The term “secondary packaging” was replaced by the term 
“original packaging” as clarification of requirement.
9.3
Protocol Amendment 4
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 4. The primary reasons for the amendment were
 to 
revise prior therapy inclusion criteria for subjects in Part 3 C Cohorts to match 
standard-of-care practice, and to update the process for identifying and reporting potential 
Hy’s Law and Hy’s Law cases. Major changes to the protocol are summarized below.
1
Updated synopsis to align with changes in the body of the protocol.
2
Sections 1.4.1.1 (Rheumatoid Arthritis Study [NN8765-3658]) and 1.6.2 (Summary of 
Risks): Removed summary of RA study (Section 1.4.1.1 and second paragraph in Section 
1.6.2); this information is provided in the monalizumab Investigator’s Brochure.
3
Section 1.4.2 (Durvalumab Clinical Experience): Updated the clinical data as of the 
durvalumab Investigator’s Brochure version 13.0.
4
Section 1.4.3 (Safety and Efficacy Results from the Current Ongoing Study): Updated the 
clinical data as of the data cut-off date of 02 January 2019.
5
Section 1.6.2 (Summary of Risks): In the first paragraph, added text on the risks for 
durvalumab. Although already listed previously in Section 1.4.2 (Durvalumab Clinical 
Experience), the risks were also included in Section 1.6.2 for clarity.
6
Sections 2.1 (Primary Objectives and Associated Endpoints), 2.2 (Secondary Objectives 
and Associated Endpoints), 2.3 (Exploratory Objectives and Associated Endpoints), 3.1.1 
(Overview), and 3.1.2.3 (Part 3: Dose Exploration in 
CRC): Revised footnotes and 
text regarding prior therapy for Cohort C subjects to be consistent with the change in 
inclusion criterion 5b (iv) in Section 4.1.2 (Inclusion Criteria) described below.
7
Section 2.2 (Secondary Objectives and Associated Endpoints), 3.2.4 (Rationale for 
Endpoints), 4.3.8
, and 4.8.8 (Analysis of 
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
176 of 206
Template 16.2
Pharmacodynamic Biomarkers): In Table 2 (Secondary Objectives and Associated 
Endpoints), revised language for predictive endpoints to include EGFR and clarified that 
the endpoints include “but are not limited to 
 in 
pre-treatment tumor biopsies”. The corresponding objective for these endpoints was 
revised as “To characterize the association between clinical outcomes and pre-treatment 
protein expression within the tumor microenvironment”. As cetuximab is an EGFR 
inhibitor, EGFR expression will be evaluated in subjects treated with cetuximab to detect 
whether subjects with an increased pathway engagement will be more likely to respond to 
treatment. The rationale for this endpoint was added to Section 3.2.4, and text in Sections 
4.3.8 and 4.8.8 was revised to include EGFR.
8
Section 2.3 (Exploratory Objectives and Associated Endpoints): In Table 3 (Exploratory 
Objectives and Associated Endpoints) revised 
 
as described below:
9
Section 3.1.2.1 (Part 1: Dose Escalation): Under the subheading “Dose-limiting 
Toxicity”, DLT criteria for Grade 3 or 4 neutropenia were revised to “Grade 3 or 4 
neutropenia that is not associated with fever or systemic infection…” (bold indicates 
added text). Grade 3 or 4 neutropenia that is associated with fever or systemic infection is 
already covered by febrile neutropenia DLT criteria.
10
 
 
11 Section 4.1.1 (Number of Subjects): Updated Table 5 (Study Overview and Status 
Update) as of the data cut-off date of 02 January 2019.
12 Section 4.1.2 (Inclusion Criteria): Inclusion criterion 5b (iv) (Prior Therapy Criteria) for 
subjects in Part 3 Cohorts C1A, C1B, C2A, and C2B was revised to match 
standard-of-care practice to require that subjects
 must have contained fluoropyrimidines, 
irinotecan, oxaliplatin, and an anti-VEGF inhibitor (eg, bevacizumab) in the 
recurrent/metastatic setting. The change to allow at least 1 prior line of therapy was made 
so that subjects who have progressed after receiving FOLFOXIRI or equivalent 
fluoropyrimidine regimen, which contains oxaliplatin and irinotecan as first-line 
treatment, may qualify for enrollment in the study (previously, subjects were required to 
have received only 2 prior lines of treatment which must have contained 
fluoropyrimidines, irinotecan, and oxaliplatin). The requirement for prior treatment with 
bevacizumab was added to ensure subjects have received all standard-of- care agents 
prior to enrollment. Additionally the following criteria were added:
(a) Clarified that subjects must have progressed based on imaging during or within 
3 months of the last administration of each standard chemotherapy.
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
177 of 206
Template 16.2
(b) Added criterion to allow subjects who were intolerant to standard treatment to qualify 
for enrollment in the study.
(c) Clarified that subjects who had received adjuvant chemotherapy and had recurrence 
during or within 6 months of completion are allowed to count the adjuvant therapy as 
1 regimen.
13 Sections 4.2.1 (Enrollment/Screening Period) and 4.2.2 (Treatment Period): Moved stool 
sample assessment at Week 1, Day 1 in Table 8 (Schedule of Treatment Period Study 
Procedures Weeks 1 to 26) to Screening/baseline in Table 7 (Schedule of 
Screening/Baseline Procedures) and added footnote that the sample can be collected 
anytime during screening, up to and including Day 1, provided it is collected prior to 
administration of the first dose of study drug(s).
14 Section 4.2.2 (Treatment Period) and Table 9 (Schedule of Treatment Period Study 
Procedures Weeks 27 to End of Treatment): A statement regarding timing of disease 
assessment scans was added in Section 4.2.2 to clarify that scans can be performed within 
a 7-day window of the dosing day. In Table 9, the frequency for the assessments of ECG, 
coagulation parameters, and thyroid function tests after Week 51 (“Cont” column) was 
revised in Protocol Amendment 3. However, due to oversight, these changes were not 
listed in the Summary of Changes for Protocol Amendment 3 and are thus noted here:
(a) The frequency for ECG assessment was revised to “W57 D1 (D393) then Q12W” in 
Protocol Amendment 3 (Q8W in Protocol Amendment 2).
(b) The frequency for coagulation parameters was revised to “Q8W” in Protocol 
Amendment 3 (Q4W in Protocol Amendment 2).
(c) The frequency for urinalysis was revised to “Q12W” in Protocol Amendment 3 
(Q4W in Protocol Amendment 2).
15 Section 4.5.1 (Identity of Investigational Products) and Table 16 (Identification of 
Investigational Products), and Sections 4.5.1.1 (Investigational Product Inspection), 
4.5.1.2 (Dose Calculation), 
 
 
 
 
 
16 Section 4.5.1.3 (Investigational Product Dose Preparation and Administration): The 
following revisions were made:
(a) Removed requirement that IV administration filter be in-line for durvalumab, 
monalizumab, and cetuximab to allow flexibility for clinical sites.
(b) For durvalumab and monalizumab, added statement that for treatment arms that 
require administration of durvalumab and monalizumab on the same day, the total 
infusion time for both study drugs should not exceed 8 hours at room temperature 
(with a maximum of 4 hours for the durvalumab infusion). This statement was added 
to limit the combination infusion time since instructions for each drug permit up to 8 
hours per infusion.
17 Section 4.5.4 (Storage): Added storage information for cetuximab.
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
178 of 206
Template 16.2
18 Section 5.6.2 (Potential Hy’s Law and Hy’s Law): Revised section heading from “Hepatic 
Function Abnormality” to “Potential Hy’s Law and Hy’s Law” and added requirement to 
report these cases as SAEs to align with revised MedImmune requirements.
19 Section 7.1 (Ethical Conduct of the Study): Removed this section as this information is 
already stated in Section 1.6 (Benefit-Risk and Ethical Assessment). Subsequent sections 
were renumbered accordingly.
20 Section 7.1 (Subject Data Protection), previously number Section 7.2: Revised to align 
with preferred MedImmune standard language.
21 Section 10.1 (Signatures): Updated sponsor signature information.
22 Section 10.5 (Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law): Updated to align with revised MedImmune requirements.
9.4
Protocol Amendment 3
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 2. The primary reason for this Amendment was to update the clinical experience 
for monalizumab and to add treatment cohorts in Part 3 for subjects with 
CRC that is 
 or 
. Due to the preliminary clinical activity signal observed 
with durvalumab in combination with monalizumab in the 
CRC cohort in Part 2 of this 
study, Part 3 (Cohorts A 
) was added under Amendment 2 to evaluate further the 
combination of durvalumab and monalizumab with standard-of-care chemotherapeutic 
regimens with and without biologic agents (bevacizumab or cetuximab) in subjects with 1L or 
2L 
CRC. Due to the promising preliminary clinical activity signal observed with 
monalizumab in combination with cetuximab in subjects with recurrent or metastatic SCCHN 
(NCT02643550; Cohen et al, 2018), Cohort C is being added to Part 3 (Cohorts C1A, C1B, 
C2A, and C2B) of the current study under Amendment 3 to understand better the exact 
mechanism of monalizumab in combination with cetuximab (ie, enhancement of ADCC or 
adaptive immune response). This will be achieved by evaluating the combination of 
monalizumab with cetuximab in subjects with 
CRC that is 
 
(Part 3, Cohort C2B) as well as 
 (Part 3, Cohort C1B). In addition, given the 
previously observed signal of durvalumab in combination with monalizumab in 
CRC 
from Part 2, this study will also evaluate durvalumab in combination with monalizumab plus 
cetuximab in subjects with 
CRC that is 
 (Part 3, Cohort C2A) 
as well as 
 (Part 3, Cohort C1A. Major changes to the protocol are summarized 
below.
1
Title: The study title was revised to reflect that the study is Phase 1/2 (previously Phase 1) 
and IPH2201 was changed to monalizumab. This change is also reflected in the signature 
pages.
2
Synopsis: Updated to align with the body of the protocol.
3
Tables and figures were renumbered sequentially throughout the protocol 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
179 of 206
Template 16.2
4
Section 1.4.1 (Monalizumab Clinical Experience): Updated per most recent Monalizumab 
Investigator’s Brochure.
5
Section 1.4.1.2 (Oncology Studies) and Figure 1 (Study IPH2201-203: Percent Reduction 
of Target Lesion from Baseline): Added clinical efficacy for IPH2201-203 as of 
09 March 2018. Added Figure 1.
6
Section 1.4.3 (Safety and Efficacy Results from the Current Ongoing Study) and Figure 2 
 
 Updated clinical experience for the 
current study as of the data cut-off date of 23 April 2018 and per most recent 
Monalizumab Investigator’s Brochure. Updated title and data for Figure 2 (previously 
numbered Figure 1.4.3-1).
7
Section 1.5.1 (Rationale for Evaluating Combinations of Durvalumab and Monalizumab 
with Chemotherapy and/or Biologic Agents): Section renamed (previously “Rationale for 
evaluating durvalumab in combination with monalizumab and chemotherapy with or 
without a biologic agent”) and revised to include rationale for evaluating the combination 
of durvalumab and monalizumab plus cetuximab and the combination of monalizumab 
plus cetuximab in subjects with 
 or 
CRC.
8
Section 1.7.1 (Primary Hypothesis): Added primary hypothesis for Part 3, C Cohorts.
9
Section 2 (Objectives and Endpoints): Revised to present objectives and endpoints in 
tabular format. Added primary, secondary, and exploratory objectives and endpoints for 
Part 3, Cohorts C1 and C2. Specified primary and secondary endpoints for antitumor 
activity per RECIST v1.1 to be “by investigator assessment”. Revised exploratory 
endpoints as described below:
10 Sections 3.1.1 (Study Design - Overview), Figures 3 (Study Flow Diagram) and 5 (Study 
Part 3 [Dose Exploration] Flow Diagram for Cohorts C1 and C2), 
 
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
180 of 206
Template 16.2
 
 
 
 
 
Details for Cohorts C1 and C2 
were added to Figure 3 (previously numbered Figure 3.1.1-1). 
 
 The number of sites was revised to 60 (previously 30).
11 Sections 3.1.1 (Study Design - Overview), 3.1.2 (Treatment Regimen) and 3.2.5 (Post 
Study Access to Therapy): Moved text stating that subjects will receive treatment until 
unacceptable toxicity, documentation of PD, or subject withdrawal to Section 3.1.2 and 
specified maximum time of treatment in the study as 3 years. Moved text regarding post 
study access in Section 3.2.5 (section now deleted) to Section 3.1.2 and revised time 
period for treatment to 3 years (previously 2 years).
12 Section 3.1.2.1 (Part 1: Dose Escalation): The following revisions were made:

Under the subheading “Dose-limiting Toxicity”, revised bulleted list to specify 
Cohorts A 
 subjects where Part 3 is designated as these are applicable to 
subjects who are receiving chemotherapy. 

Revised first sentence of last paragraph to include dose exploration to “During dose 
expansion and dose exploration in 
CRC, subjects will be monitored for safety 
according to the same criteria employed during dose escalation” (bold indicates 
added text).
13 Section 3.1.2.3 (Part 3: Dose Exploration in 
CRC): For Cohorts A2 
 revised 
text to specify that the first infusion of cetuximab is over 2 hours and subsequent 
infusions of 250 mg/m2 are over 1 hour and that the cetuximab regimen may be changed 
to 500 mg/m2 IV infusion over 1 hour Q2W after a subject has completed the 28-day 
DLT-evaluation period, at the investigator’s discretion and in accordance with 
institutional guidelines.
14 Section 3.1.3.1 (Chemotherapy and Biologic Agent Dose Modification): Under 
cetuximab, the following revisions were made:

Revised criteria for infusion reactions to specify that infusion rate be reduced by 50% 
for Grade 1 or 2 infusion reactions and permanently discontinued for Grade 3 or 4 
infusion reactions to align with the label.

Revised dose modification for acneiform rash to include details for subjects who 
receive the cetuximab 500 mg/ m2 Q2W regimen. Specifically, 
o
Under first occurrence, revised first bullet to “If improvement, continue at a dose 
of 250 mg/m2 if on Q1W regimen or 500 mg/m2 if on Q2W regimen” (bold 
indicates added text).
o
Under second occurrence, revised first bullet to “If improvement, continue at 
reduced dose of 200 mg/m2 if on Q1W regimen or 400 mg/m2 if on Q2W 
regimen” (bold indicates added text).
o
Under third occurrence, revised first bullet to “If improvement, continue at 
reduced dose of 150 mg/m2 if on Q1W regimen or 300 mg/m2 if on Q2W 
regimen” (bold indicates added text).
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
181 of 206
Template 16.2
15 Section 3.2.1.3 (Rationale for the Combination of Monalizumab and Durvalumab) and 
3.2.1.4 (Rationale for Cetuximab Dosing): Added Section 3.2.1.3 with rationale for 
monalizumab/durvalumab combination dose used in dose expansion (Part 2) and dose 
exploration (Part 3). Added Section 3.2.1.4 with rationale for cetuximab regimen used in 
dose exploration (Part 3).
16 Section 3.2.2 (Rationale for Study Population): Added rationale for dose exploration of 
durvalumab and monalizumab plus cetuximab in subjects with 
CRC that is 
 
 or 
17 Section 3.2.4 (Rationale for Endpoints): Revised text in second paragraph to specify “by 
investigator assessment” for OR, DC, DoR, and PFS and to clarify OR as primary 
endpoint for Part 3, Cohort C1. Added statement that cetuximab PK is being examined for 
Part 3 (Cohorts C1A and C1B) in third paragraph.
18 Section 4.1.1 (Number of Subjects): 
 
 with addition of Table 5 (subsequent table 
numbers reordered).
19 Section 4.1.2 (Inclusion Criteria): The following revisions were made:
(a) Clarified that the first sentence of inclusion criterion 5, requiring at least one prior 
line of standard systemic therapy in the recurrent/metastatic setting, applies to 
subjects entering Parts 1 and 2.
(b) Moved criterion 5a (ii), which specified that subjects with ovarian cancer must not 
have evidence of partial small bowel obstruction or small bowel obstruction within 
4 weeks prior to the first scheduled dose of study treatment, to number 5 as this 
criterion is applicable for all tumor types (previously only specific for ovarian 
cancer).
(c) For inclusion criteria 5b (ii) and 5d (ii): Clarified that testing for microsatellite 
instability may be done locally and prior documentation of this testing is acceptable 
in lieu of running the test again.
(d) Under criterion 5b (iv), revised inclusion criteria for subjects in Part 3 A1 
 to 
specify INR < 3 for subjects on “oral anticoagulation with coumarin derivatives and 
must have and INR< 3 and have no significant active bleeding (defined as Grade 2
or higher hemorrhage within 14 days prior to first dose of study treatment”). 
Under “Note”, revised text to “Subjects with a venous thrombosis are permitted to 
enroll including subjects on newer oral anticoagulants (eg, apixaban, 
rivaroxaban, dabigatran, etc) provided they are clinically stable, asymptomatic, 
and adequately treated with anticoagulation in the opinion of the investigator for at 
least 3 months prior to the first dose of study treatment”, bold indicates added 
text. The change was made to distinguish parameters applicable for subjects on 
coumarin derivatives versus newer oral anticoagulants.
(e)
 
(f) Under criterion 5b (iv), added specific inclusion criteria for Cohorts C1 and C2.
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
182 of 206
Template 16.2
(g) For inclusion criterion 6b, revised time period for archival tumor sample to 1 year, 
previously 6 months.
(h) Added inclusion criterion 6c that subjects in dose-exploration cohorts (Part 3) must 
consent to provide an archival tumor sample from a biopsy collected within 1 year 
prior to the first dose of study drug or must provide a pre-treatment biopsy during the 
Screening Period.
(i)
Removed inclusion criterion 7c that specified results of imaging up to 6 months prior 
to screening are to be made available to the sponsor as this is not required for 
inclusion in the study.
20 Section 4.1.3 (Exclusion Criteria): The following revisions were made: 
(a) Removed the text “major surgery ≤ 28 days prior to first dose of study treatment” 
from exclusion criterion 18b, as this is already stated in exclusion criterion 13.
(b) Added exclusion criterion 19 that subjects enrolling in Part 3, 
 must not 
have experienced a toxicity that led to permanent discontinuation of prior therapy 
with cetuximab.
21 Section 4.1.4 (Subject Enrollment and Randomization): Added paragraph with details for 
subjects enrolled in the randomized portion of the study (Part 3 Cohorts C1 and C2) and 
revised section title to included randomization.
22 Section 4.2.1 (Enrollment/Screening Period): The following revisions were made to 
Table 7 (Schedule of Screening/Baseline Procedures [formerly Table 4.2.1-1]):
(a) For disease assessments, added footnote to allow subjects to use previous scans for 
baseline disease and brain imaging that were performed within 6 weeks of dosing and 
meet the protocol requirements.
(b) Included smoking history and added “and prior imaging” to the assessment for 
medical history, with a footnote that prior imaging includes raw imaging data (eg 
DICOM) of a previous disease assessment that has been performed between 4 weeks 
and 6 months prior to baseline scan obtained during screening if allowed by country, 
to collect data on tumor kinetics.
(c) Specified coagulation parameters as a separate row for clarification that prothrombin 
time, APTT, INR and fibrinogen are collected under coagulation panel. 
(d)
(e) Added assessment of serum for circulating soluble factors as both serum and plasma 
will be collected.
(f) In the footnote for archival tumor biopsy, revised the time period for archival tumor 
sample to 1 year, previously 6 months and added a statement that in Part 3, archival 
tumor sample from within 1 year of enrollment or fresh biopsy is required.
23 Section 4.2.2 (Treatment Period), Table 8 (Schedule of Treatment Study Procedures 
Weeks 1 to 26 [formerly Table 4.2.2-1]), Table 9 (Schedule of Treatment Study 
Procedures Weeks 27 to End of Treatment [formerly Table 4.2.2-2]), Table 10 (Schedule 
of Treatment Study Procedures Weeks 1 to 25 for Monalizumab Q4W [formerly 
Table 4.2.2-3]), and Table 11 (Schedule of Treatment Study Procedures Weeks 26 to End 
of Treatment for Monalizumab Q4W [formerly Table 4.2.2-4]): The following revisions 
were made:
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
183 of 206
Template 16.2
(a) Revisions were made in the text of Section 4.2.2 to clarify scheduling and conducting 
study visits. A statement was added that PRO questionnaires will be implemented for 
subjects in 
 with cross-reference to Section 4.3.3 for additional 
instructions.
(b) Table 8: The following revisions were made:
(i)
Added PRO assessments for Part 3, 
.
(ii) Added assessment for ECG at W17 D1 to correct omission.
(iii) Added assessment for hematology sample at Day 15.
(iv) Specified coagulation parameters as a separate row for clarification that 
prothrombin time, APTT, INR and fibrinogen are collected under coagulation 
panel. 
(v) For durvalumab PK and immunogenicity, specified that this is not applicable for 
Part 3 Cohorts C1B and C2B. Revised PK footnote to include details for 
cetuximab sample in these cohorts.
(vi) Added assessment for cetuximab PK and cetuximab immunogenicity in Part 3 
Cohorts C1A and C1B.
(vii)Removed assessment for soluble PD-L1 as this will not be measured.
(viii) Removed the W25 D1 assessment for flow cytometry.
(ix)
(x) Added assessment of serum for circulating soluble factors as both serum and 
plasma will be collected.
(xi) Added stool sample for Part 3 Cohorts C1A, C1B, C2A, and C2B only.
(xii)Added assessment of blood sample for future analysis at the Week 1 Day 1 visit 
with footnote that additional blood samples will also be collected at baseline for 
future analysis including but not limited to an autoimmune work-up.
(xiii) For durvalumab administration, specified that this is not applicable for Cohorts 
C1B and C2B.
(xiv) For chemotherapy administration, specified that this is applicable for Cohorts 
A1
.
(xv)Added footnote for the cetuximab Q1W regimen with dose and regimen for 
subjects in Cohorts A2 
 who can switch to Q2W after DLT-evaluation 
period per investigator’s discretion and in accordance with institutional 
guidelines.
(xvi) Added row for cetuximab administration (Q2W) for subjects in Cohorts C1A, 
C1B, C2A, and C2B with footnote to specify the details for the Q2W regimen 
and additional columns for dosing on W4 and W26.
(xvii) Revised footnote for tumor biopsy at Week 9 Day 1 to clarify that this is also 
for subjects in dose exploration who provided a fresh pre-treatment biopsy.
(xviii)
Revised footnote for infusion duration of monalizumab and durvalumab to 
be “approximately 60 minutes”, previously “60 minutes (± 5 minutes)”.
(xix) Added footnote for Week 9, Day 1 assessments of ECOG, CA for 
CRC/CA-125, durvalumab PK, monalizumab PK, cetuximab PK, and cetuximab 
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
184 of 206
Template 16.2
ADA that these assessments may be optionally collected if the subject is 
discontinuing treatment at the scheduled Week 9 Day 1 visit.
(c) Table 9: The following revisions were made:
(i)
Revised format of the table to specify specific visits from W27 D1 to EOT for 
clarity. The cetuximab dosing for Part 3, Cohorts A2 
 was removed for 
W26 as included in Table 8.
(ii) Added column for W1 for cetuximab Part 3, Cohorts A2 
, QW schedule.
(iii) Added PRO assessments for Part 3, Cohorts C1A and C1B.
(iv) Specified coagulation parameters as a separate row for clarification that 
prothrombin time, APTT, INR and fibrinogen are collected under coagulation 
panel. 
(v) For durvalumab administration, specified that this is not applicable for Cohorts 
C1B and C2B.
(vi) For chemotherapy administration, specified that this is applicable for Cohorts 
A1-
.
(vii)Revised cetuximab administration to be Q2W for subjects in Cohorts A2, 
 
C1A, C1B, C2A, and C2B with footnote with details for the Q1W and Q2W 
regimens and that subjects in Cohorts A2 
 on Q1W schedule can switch to 
Q2W after DLT-evaluation period per investigator’s discretion and in 
accordance with institutional guidelines.
(viii) Revised footnote for infusion duration of monalizumab and durvalumab to be 
“approximately 60 minutes”, previously “60 minutes (± 5 minutes)”.
(d) Table 10: The following revisions were made:
(i)
Added assessment for ECG at W17 D1 to correct omission.
(ii) Specified coagulation parameters as a separate row for clarification that 
prothrombin time, APTT, INR and fibrinogen are collected under coagulation 
panel.
(iii) Removed assessment for soluble PD-L1 as this will not be measured.
(iv) Removed the W25 D1 assessment for flow cytometry.
(v)
(vi) Added additional assessment for circulating soluble factors to specify both serum 
and plasma will be collected.
(vii)Added assessment of blood sample for future analysis at the Week 1 Day 1 visit 
with footnote that additional blood samples will also be collected at baseline for 
future analysis including but not limited to an autoimmune work-up.
(viii) Revised footnote for tumor biopsy at Week 9 Day 1 to clarify that this is also 
for subjects in dose exploration who provided a fresh pre-treatment biopsy.
(ix) Revised footnote for infusion duration of monalizumab and durvalumab to be 
“approximately 60 minutes”, previously “60 minutes (± 5 minutes)”.
(x) Added footnote for Week 9, Day 1 assessments of ECOG, durvalumab PK, 
monalizumab PK, and CD94/NKG2a receptor occupancy that these assessments 
CCI
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
185 of 206
Template 16.2
may be optionally collected if the subject is discontinuing treatment at the 
scheduled Week 9 Day 1 visit.
(e) Table 11: The following revisions were made:
(i)
Revised format of the table to specify specific visits from W29 D1 to EOT for 
clarity.
(ii) Specified coagulation parameters as a separate row for clarification that 
prothrombin time, APTT, INR and fibrinogen are collected under coagulation 
panel.
(iii) Revised footnote for infusion duration of monalizumab and durvalumab to be 
“approximately 60 minutes”, previously “60 minutes (± 5 minutes)”.
24 Section 4.2.3 (Follow-up Period) and Table 12 (Schedule of Follow-up Procedures 
formerly Table 4.2.3-1): The following revisions were made:
(a) Added PRO assessments for Part 3, Cohorts C1A and C1B. 
(b) Specified coagulation parameters as a separate row for clarification that prothrombin 
time, APTT, INR and fibrinogen are collected under coagulation panel.
(c) For durvalumab PK and immunogenicity, specified that this is not applicable for Part 
3 Cohorts C1B and C2B. 
(d) Added assessment for cetuximab PK and cetuximab immunogenicity in Part 3 
Cohorts C1A and C1B.
(e) Added assessments for plasma for flow cytometry, 
, circulating 
soluble factors (plasma), PBMC, and 
 with a 
footnote that the assessments should be performed if EOT occurs at the scheduled 
Week 9 visit.
25 Sections 4.3.2.1 (Fresh Tissue Biopsies) and 4.3.2.2 (Archival Tumor Samples): Added 
text that subjects in dose-exploration cohorts (Part 3) must consent to provide an archival 
tumor sample from a biopsy collected within 1 year prior to the first dose of study drug or 
must provide a pre-treatment biopsy during the Screening Period and if clinically feasible, 
dose-exploration subjects who provided a fresh biopsy during screening are encouraged to 
provide a biopsy during Week 9.
26 Section 4.3.3 (Patient Reported Outcomes [Part 3, Cohorts C1A and C1B Only]): Added 
new section with details of PRO assessments. Subsequent sections were renumbered 
accordingly.
27 Section 4.3.4.2 (Electrocardiograms [formerly Section 4.3.3.1]): First paragraph revised 
to align with Section 4.2. Added paragraph to specify that digital copies of ECGs can be 
held centrally and stored for potential independent analysis.
28 Section 4.3.5 (Clinical Laboratory Tests [formerly Section 4.3.4]): The following 
revisions were made:

Moved thyroid function test from “Serum Chemistry” to “Thyroid Function Tests” as 
it is not part of the serum chemistry panel. 

In the note under “Serum Chemistry”, added text to clarify that direct and indirect 
bilirubin are only needed if total bilirubin is not within normal range and that it is 
acceptable to assess one rather than both indirect and direct bilirubin. Added note to 
clarify that urea is an acceptable alternative if BUN is not routinely tested.
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
186 of 206
Template 16.2

Moved APTT and fibrinogen from “Hematology” to “Coagulation” for clarification.

Under “Other Safety Tests”, added bullet for additional baseline blood samples for 
future analysis including, but not limited to, an autoimmune work-up.
29 Section 4.3.8 
 
30 Section 4.3.9 (Estimate of Volume of Blood to be Collected [formerly Section 4.3.8]): 
Revised blood volume estimates for screening period to 56 mL (previously 44 mL), for 
treatment period to 77.5 mL (previously 64 mL), and for follow-up period to 44.5 mL 
(previously 36 mL) to be consistent with the changes to the study procedures.
31 Section 4.5 (Investigational Products): This section was reorganized for clarity and to 
include cetuximab as investigational product for Part 3 Cohorts C1A and C1B. The
following revisions were made:
(a) Section 4.5.1 (Identity of Investigation Products) and Table 16 (Identification of 
Investigational Products [formerly Table 4.5.1-1]): In Table 16, added cetuximab as 
investigational product for Part 3 Cohorts C1A and C1B. Deleted redundant text 
below the table.
(b) Section 4.5.1.1 (Investigational Product Inspection [formerly Section 4.5.1.3]): 
Added details for cetuximab.
(c) Section 4.5.1.2 (Dose Calculation): Added dose calculation for cetuximab.
(d) Section 4.5.1.3 (Investigational Product Dose Preparation and Administration 
[formerly Section 4.5.1.1]): The section was revised to include dose preparation and 
administration instructions. The dose preparation and administration instructions for 
durvalumab were updated. Reconstitution procedure for monalizumab was added. 
Details for cetuximab were added.
(e) Section 4.5.1.4 (Treatment Administration): Redundant text was deleted. Details for 
cetuximab were added.
(f) Section 4.5.1.5 (Monitoring of Dose Administration): A statement was added in the 
first paragraph that monitoring of the cetuximab infusion will be performed per the 
label. A statement was added in the third paragraph that antihistamines or steroids 
can be administered per label prior to cetuximab infusion. 
32 Section 4.6.1 (Methods for Assigning Treatment Groups): Added details for the 
randomization and stratification of subjects enrolled in Part 3 Cohorts C1 and C2.
33 Section 4.7.2 (Prohibited Concomitant Medication): Revised number 5 to clarify that all 
herbal and natural remedies should be avoided (previously, “herbal and natural remedies 
that may have immune-modulating effects should not be given concurrently unless agreed 
by the sponsor”).
34 Section 4.8.1 (General Considerations): Added definitions for ITT population and 
Response-evaluable population.
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
187 of 206
Template 16.2
35 Section 4.8.2 (Sample Size) and Table 19 (Observed Objective Response Rate with 
% 
Confidence Interval): 
 
 
Created numbered subheadings for Part 1 (Section 4.8.2.1), 
Part 2 (Section 4.8.2.2), and Part 3 (Section 4.8.2.3). Under Section 4.8.2.3 (Dose 
Exploration) added Table 19 for Cohort C1 and details for Part 3 C1 and C2 Cohorts.
36 Section 4.8.3.1 (Antitumor Efficacy): Added bullet that efficacy analyses are based on the 
As-treated population for the non-randomized cohorts and on the ITT for the randomized 
cohorts according to RECIST v1.1 by investigator assessment and that additional 
supportive analyses may be conducted in the ITT population according to RECIST v1.1 
per Blinded Independent Central Review to inform internal program decisions and/or for 
potential interactions with regulatory agencies for future development. 
37 Section 4.8.5 (Analysis of Patient Reported Outcomes [Part 3, Cohort C1 only]): Added 
new section with details for the analysis of PRO. Subsequent sections were renumbered 
accordingly.
38 Section 4.8.9 (Interim Analysis [formerly Section 4.8.8]): Added details for the interim 
analyses for Part 3, Cohorts C1 and C2.
39 Section 8: Revised references.
40 Section 10.6 (Appendix 7 [Patient Reported Outcomes]): Added new section with 
questionnaires for collection of PRO data.
9.5
Protocol Amendment 2
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 2. Major changes to the protocol are summarized below.
1
Synopsis: Updated to align with the body of the protocol.
2
Section 1.4 (Summary of Clinical Experience): Previous content replaced with summary 
clinical experience information from the current versions of the durvalumab and 
monalizumab Investigator’s Brochures and added a section on safety and efficacy data 
from the current study.
3
Section 1.5 (Rationale for Conducting the Study): Added a subsection providing the 
rationale for evaluating durvalumab in combination with monalizumab and chemotherapy 
plus bevacizumab or cetuximab.
4
Section 1.7.1 (Primary Hypothesis): Revised to include durvalumab in combination with 
monalizumab and chemotherapy plus bevacizumab or cetuximab administered to subjects 
with 
 colorectal cancer.
5
Section 2 (Objectives and Endpoints): Revised to include the use of chemotherapy plus 
bevacizumab or cetuximab with the durvalumab/monalizumab combination.
6
Section 3 (Study Design): Revised to include the addition of the dose-exploration part of 
the study (Part 3) in which subjects with advanced 
CRC will be treated with the 
combination of durvalumab and monalizumab and a chemotherapy regimen (mFOLFOX6 
 plus cetuximab or bevacizumab. As a consequence of the addition of Part 3 
CCI
CCI
CCI
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
188 of 206
Template 16.2
to the study and to assist in differentiating the 3 treatment parts, the dose escalation phase 
is now referred to as Part 1 and the dose-expansion phase is referred to as Part 2.
(a) Revised the bulleted list of DLTs and non-DLTs.
(b) Added Section 3.1.3.1 on chemotherapy and biologic agent dose modification. 
(c) Section 3.2.2: Added rationale for the new dose-exploration part of the study (Part 3).
7
Section 4.1.2 (Inclusion Criteria): added specific inclusion criteria that must be met by 
subjects enrolling in Part 3. 
8
Section 4.1.3 (Exclusion Criteria): Added to criterion 1: “Subjects who have received 
prior immunotherapy treatment may be enrolled in Part 1 (dose escalation) on a 
case-by-case basis with the agreement of the sponsor.” Added to criterion 3: “…or any 
component of the chemotherapy regimens that will be administered in Part 3.”
9
Section 4.1.9 (Consent for Data and Biological Samples): Added a study-specific 
explanation of how collected biological samples will be used to the subsection on Genetic 
Research.
10 Section 4.3.1.3 
 
11 Section 4.5 (Investigational Products): Revised instructions on preparation and 
administration of investigational products.
12 Section 4.8.2 (Sample Size): Updated to include a description of the sample size for the 
new dose-exploration part of the study (Part 3).
13 Section 5.3 (Definition of Adverse Events of Special Interest): Added rash and infusion-
related /hypersensitivity/anaphylactic reactions to the list of AESIs.
14 Section 8 (References): Added citation details for the following references, which have 
been used to support information added to Section 1.5.1: Bendell et al, 2015; Daaboul et 
al, 2017; FDA, 2017a; FDA, 2017b; Giantonio et al, 2007; Khemka et al, 2016; Kroemer 
et al, 2013; Liu et al, 2010; Mayer et al, 2015; Mellman et al, 2011; Muntasell et al, 2017; 
Pfirschke et al, 2016; Philips and Atkins, 2015; Postow et al, 2015; Ruggeri et al, 2016; 
 Shahda et al, 2017; Van Cutsem et al, 2012; Van Cutsem et al, 2016; 
Wallin et al, 2016; Wang et al, 2015; Zhang et al, 2012.
15 Section 10.2 Appendix 2 (Management of Study Medication Related Toxicities): 
Replaced with an updated version.
9.6
Protocol Amendment 1
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 1. Major changes to the protocol are summarized below.
1
Synopsis: Updated to align with the body of the protocol.
2
Section 3.1.1 (Overview of the Study): Added a statement, per the Agency’s request, to 
indicate that additional dose levels not exceeding the MTD may be considered based on 
clinical PK/pharmacodynamic data from the dose-escalation phase.
3
Section 3.1.2.2 (Dose-limiting Toxicity): Revised this section as follows per the Agency’s 
request:
CCI
CCI

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
189 of 206
Template 16.2
(a) Added text to the definition of DLT to indicate that Grade 3 or 4 laboratory 
abnormalities requiring hospitalization for the management of toxicities will be 
considered a DLT.
(b) Added text to the definition of DLT to indicate that any delay in monalizumab dosing 
due to a treatment-related AE will be considered a DLT.
(c) Removed the following statement: In the event of protocol permitted treatment delay 
of the second dose of monalizumab, the DLT period will be extended such that 
subjects are followed for 14 days after the second dose of monalizumab.
(d) Added the following exclusions to the DLT criteria:
(e) Grade 3 nausea/vomiting or Grade 4 vomiting in the absence of maximal medical 
therapy that resolves in 3 days
(f) Grade 3 hypertension that can be controlled with medical therapy
4
Section 3.1.2.3 (Dose Expansion): Added a statement, per the Agency’s request, to 
indicate that additional dose levels not exceeding the MTD may be considered based on 
clinical PK/pharmacodynamic data from the dose-escalation phase.
5
Section 4.1.2 (Inclusion Criteria): Revised this section as follows per the Agency’s 
request:
(a) Criterion 5a.i: Revised to require advanced ovarian cancer subjects to have 
previously received and progressed while on or within 6 months of completing a 
platinum-based regimen.
(b) Criterion 5e: Revised to require metastatic castration-resistant prostate cancer 
subjects to have progressed from either abiraterone or enzalutamide.
6
Section 10.2 (Appendix 2 - Management of Study Medication Related Toxicities): 
Revised this section, per the Agency’s request, to require permanent discontinuation of 
study drugs if the immune-mediated neurotoxicities are not resolved to ≤ Grade 1 within 
14 days.

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
190 of 206
Template 16.2
10
APPENDICES
10.1
Signatures

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
191 of 206
Template 16.2
Sponsor Signature(s)
A Phase 1/2 Study of Durvalumab and Monalizumab in Adult Subjects with Select Advanced 
Solid Tumors
I agree to the terms of this protocol.
Signature and date: 
, Clinical Development, Early Oncology
 
Office: 
Email: 
PPD
PPD
PPD
PPD
CCI
PPD

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
192 of 206
Template 16.2
Signature of Principal Investigator
A Phase 1/2 Study of Durvalumab and Monalizumab in Adult Subjects with Select Advanced 
Solid Tumors
I, the undersigned, have reviewed this protocol and all amendments, and I agree to conduct 
this protocol in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and are consistent with the International Conference on Harmonisation guidelines on 
Good Clinical Practice, any applicable laws and requirements, and any conditions required by 
a regulatory authority and/or Institutional Review Board/Independent Ethics Committee 
(IRB/IEC). 
I understand that the protocol may not be modified without written approval of the sponsor. 
All changes to the protocol must be submitted to the applicable regulatory authority and 
IRB/IEC, and must be approved by the IRB/IEC prior to implementation except when 
necessary to eliminate immediate hazards to the subjects or when the change(s), as deemed by 
the sponsor, involves only logistical or administrative changes. Documentation of IRB/IEC 
approval must be sent to the sponsor immediately upon receipt.
Signature and date: 
Name and title:  
Address including postal code: 
  
Telephone number: 
Site/Center Number (if available)
This document contains confidential information, which should not be copied, referred to, 
released, or published without written approval from MedImmune or AstraZeneca. 
Investigators are cautioned that the information in this protocol may be subject to change and 
revision.

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
193 of 206
Template 16.2
10.2
Additional Safety Guidance
Assessment of Severity
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. Severity will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) <<indicate version number as V4.03 
as provided in below. The determination of severity for all other events not listed in the 
CTCAE should be made by the investigator based upon medical judgment and the severity 
categories of Grade 1 to 5 as defined below.>>
Grade 1 (mild)
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not 
generally interfere with usual activities of daily living.
Grade 2 (moderate)
An event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual 
activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject.
Grade 3 (severe)
An event that requires intensive therapeutic intervention. The 
event interrupts usual activities of daily living, or significantly 
affects the clinical status of the subject.
Grade 4 (life threatening)
An event, and/or its immediate sequelae, that is associated with 
an imminent risk of death. 
Grade 5 (fatal)
Death (loss of life) as a result of an event.
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 5.2. A Grade 3 
AE need not necessarily be considered an SAE. For example, a Grade 3 headache that persists 
for several hours may not meet the regulatory definition of an SAE and would be considered a 
nonserious event, whereas a Grade 2 seizure resulting in a hospital admission would be 
considered an SAE.
Assessment of Relationship
Relationship to Investigational Product
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
investigational product.

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
194 of 206
Template 16.2
An event will be considered “not related” to use of the investigational product if any of the 
following tests are met:

An unreasonable temporal relationship between administration of the investigational 
product and the onset of the event (eg, the event occurred either before, or too long after, 
administration of the investigational product for it to be considered product-related)

A causal relationship between the investigational product and the event is biologically 
implausible (eg, death as a passenger in an automobile accident)

A clearly more likely alternative explanation for the event is present (eg, typical adverse 
reaction to a concomitant drug and/or typical disease-related event)
Individual AE/SAE reports will be considered “related” to use of the investigational product if 
the “not related” criteria are not met. 
“Related” implies that the event is considered to be “associated with the use of the drug” 
meaning that there is “a reasonable possibility” that the event may have been caused by the 
product under investigation (ie, there are facts, evidence, or arguments to suggest possible 
causation).
Relationship to Protocol Procedures
The investigator is also required to provide an assessment of relationship of SAEs to protocol 
procedures on the SAE Report Form. This includes nontreatment-emergent SAEs (ie, SAEs 
that occur prior to the administration of investigational product) as well as treatment-emergent 
SAEs. A protocol-related SAE may occur as a result of a procedure or intervention required 
during the study (eg, blood collection, washout of an existing medication). The following 
guidelines should be used by investigators to assess the relationship of SAEs to the protocol:
Protocol related:
The event occurred due to a procedure/intervention that was described 
in the protocol for which there is no alternative etiology present in the 
subject’s medical record.
Not protocol related: The event is related to an etiology other than the procedure/ 
intervention that was described in the protocol (the alternative etiology 
must be documented in the study subject’s medical record).

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
195 of 206
Template 16.2
10.3
National Institute of Allergy and Infectious Disease and Food and 
Allergy Anaphylaxis Network Guidance for Anaphylaxis 
Diagnosis
National Institute of Allergy and Infectious Disease and Food and Allergy Anaphylaxis 
Network define anaphylaxis as a serious allergic reaction that is rapid in onset and may cause 
death. They recognize 3 categories of anaphylaxis, with criteria designated to capture from 
80% of cases (category 1) to >95% of all cases of anaphylaxis (for all 3 categories). 
1
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING
(a) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow (PEF), hypoxemia)
(b) Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence)
2
Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours):
(a) Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula)
(b) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
(c) Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)
(d) Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3
Reduced BP after exposure to known allergen for that patient (minutes to several hours):
(a) Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP
(b) Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline
References
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report --
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117:391-7.

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
196 of 206
Template 16.2
10.4
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s law
10.4.1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report potential Hy’s Law cases and Hy’s Law cases. It is not intended to be a comprehensive 
guide to the management of elevated liver biochemistries. Specific guidance on managing 
liver abnormalities can be found in Section 1.1 of the protocol.
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a subject meets 
potential Hy’s Law criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of potential Hy’s Law and 
Hy’s Law events; this includes samples taken at scheduled study visits and other visits 
including all local laboratory evaluations even if collected outside of the study visits.
The investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible potential Hy’s Law events.
The investigator participates, together with MedImmune clinical project representatives, in 
review and assessment of cases meeting potential Hy’s Law criteria to agree whether Hy’s 
Law criteria are met. Hy’s Law criteria are met if there is no alternative explanation for the 
elevations in liver biochemistry other than Drug Induced Liver Injury (DILI) caused by the 
investigational product. 
The investigator is responsible for recording data pertaining to potential Hy’s Law/Hy’s Law 
cases and for reporting AEs and SAEs according to the outcome of the review and assessment 
in line with standard safety reporting processes.
10.4.2
Definitions
10.4.2.1
Potential Hy’s Law
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN at any point during the study 
following the start of investigational product irrespective of an increase in ALP.
10.4.2.2
Hy’s Law
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no other reason, other than 
the investigational product, can be found to explain the combination of increases; eg, elevated 
ALP indicating cholestasis, viral hepatitis, another drug.  

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
197 of 206
Template 16.2
For potential Hy’s Law and Hy’s Law the elevation in transaminases must precede or be 
coincident with (ie, on the same day) the elevation in TBL, but there is no specified timeframe 
within which the elevations in transaminases and TBL must occur.
10.4.3
Identification of Potential Hy’s Law Cases
In order to identify cases of potential Hy’s Law, it is important to perform a comprehensive 
review of laboratory data for any subject who meets any of the following identification criteria 
in isolation or in combination:

ALT ≥ 3 × ULN

AST ≥ 3 × ULN

TBL ≥ 2 × ULN
The investigator will, without delay, review each new laboratory report and if the 
identification criteria are met will:

Notify the sponsor study representative

Determine whether the subject meets potential Hy’s Law criteria (see Section 10.4.2) by 
reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory eCRF
10.4.4
Follow-up
10.4.4.1
Potential Hy’s Law Criteria Not Met
If the subject does not meet potential Hy’s Law criteria the investigator will:

Inform the study representative that the subject has not met potential Hy’s Law criteria.

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the study protocol.
10.4.4.2
Potential Hy’s Law Criteria Met
If the subject does meet potential Hy’s Law criteria the investigator will: 

Notify the sponsor study representative who will then inform the central study team. 

Within 1 day of potential Hy’s Law criteria being met, the investigator will report the 
case as an SAE of potential Hy’s Law; serious criteria ‘Important medical event’ and 
causality assessment ‘yes/related’ according to clinical study protocol process for SAE 
reporting.
The Medical Monitor contacts the investigator, to provide guidance, discuss and agree on an 
approach for the study subjects’ follow-up (including any further laboratory testing) and the 
continuous review of data. 

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
198 of 206
Template 16.2
Subsequent to this contact the investigator will:

Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated. 
Complete follow-up SAE Form as required. 

Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Medical Monitor. 

Complete the relevant eCRF Modules as information becomes available. 
10.4.5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where potential Hy’s Law 
criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the Medical 
Monitor will contact the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting potential Hy’s Law criteria other than DILI 
caused by the investigational product, to ensure timely analysis and reporting to health 
authorities per local requirements from the date potential Hy’s Law criteria were met. The 
Medical Monitor 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 an SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF

If the alternative explanation is an AE/SAE, update the previously submitted potential 
Hy’s Law 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 investigational product:

Send the updated SAE (report term ‘Hy’s Law’) according to sponsor’s standard 
processes. 

The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
199 of 206
Template 16.2

As there is no alternative explanation for the Hy’s Law 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 Hy’s Law, then it is assumed 
that there is no alternative explanation until such time as an informed decision can be made:

Provide any further update to the previously submitted SAE of ‘Potential Hy’s Law’ 
(report term now ‘Hy’s Law case’), ensuring causality assessment is related to the 
investigational product and seriousness criteria are medically important, according to the 
clinical study protocol 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 Hy’s Law criteria are still met. Update the previously submitted potential Hy’s 
Law SAE report following clinical study protocol process for SAE reporting, according to 
the outcome of the review, and amend the reported term if an alternative explanation for 
the liver biochemistry elevations is determined
10.4.6
Actions Required When Potential Hy’s Law Criteria Are Met Before 
and After Starting Study Treatment in Subjects
This section is applicable to subjects with liver metastases who meet potential Hy’s Law 
criteria on study treatment having previously met potential Hy’s Law criteria at a study visit 
prior to starting study treatment.
At the first on-study treatment occurrence of potential Hy’s Law criteria being met, the 
investigator will:

Determine if there has been a significant change in the subjects’ condition compared with 
the last visit where potential Hy’s Law criteria were met

If there is no significant change no action is required

If there is a significant change notify the study representative, who will inform the 
central study team, then follow the subsequent process described in Section 10.4.4.2
A ‘significant’ change in the subject’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 Medical Monitor if there is any uncertainty.
10.4.7
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a subject meets potential Hy’s Law criteria on study treatment 
and has already met potential Hy’s Law criteria at a previous on-study treatment visit.

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
200 of 206
Template 16.2
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
potential Hy’s Law 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 potential Hy’s Law 
criteria being met and answer the following question:

Was the alternative cause for the previous occurrence of potential Hy’s Law criteria being 
met found to be the disease under study (eg, chronic or progressing malignant disease, 
severe infection, or liver disease), or did the subject meet potential Hy’s Law criteria prior 
to starting study treatment and at their first on-study treatment visit as described in 
Section 10.4.6?
If No: Follow the process described in Section 10.4.4.2 for reporting potential Hy’s Law as an 
SAE. 
If Yes: Determine if there has been a significant change in the subject’s condition compared 
with when potential Hy’s Law 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 10.4.4.2 for 
reporting potential Hy’s Law as an SAE.
A ‘significant’ change in the subject’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 medical monitor if there is any uncertainty.
10.4.8
Laboratory Tests
To evaluate the underlying etiology of potential Hy’s Law cases, relevant laboratory tests will 
be performed as outlined in Section 4.3.5. Additional laboratory assessments may be 
performed as clinically indicated.
REFERENCES
Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Case 
definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther. 
2011;89(6):806-815.
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’:

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
201 of 206
Template 16.2
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
202 of 206
Template 16.2
10.5
Patient Reported Outcomes
10.5.1
European Organization for Research and Treatment of Cancer Quality 
of Life Questionnaire

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
203 of 206
Template 16.2

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
204 of 206
Template 16.2
10.5.2
Patient Global Impression of Change
PATIENT GLOBAL IMPRESSION OF CHANGE

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
205 of 206
Template 16.2
10.6
Changes Related to Mitigation of Study Disruptions Due to Cases 
of Civil Crisis, Natural Disaster, or Public Health Crisis
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 
subjects become infected with SARS-CoV-2 or similar pandemic infection) during which 
subjects 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 
notification from the Sponsor and instructions on how to perform these procedures will be 
provided at the time of implementation.
Please note that during civil crisis, natural disaster, or public health crisis, some study 
assessments and procedures may not be conducted due to international or local policies or 
guidelines, hospital or clinic restrictions, and other measures implemented to ensure the 
patient’s safety. If in doubt, please contact the AstraZeneca Study Physician.
10.6.1
Reconsent/reassent of Study Subjects During Study Interruptions
During study interruptions, it may not be possible for the subjects 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/reassent 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 10.6.2 to 10.6.4. Local and regional regulations and/or 
guidelines regarding reconsent of study subjects should be checked and followed. 
Reconsent/reassent may be verbal if allowed by local and regional guidelines (note, in the case 
of verbal reconsent/reassent, the Informed Consent Form should be signed at the subject’s 
next contact with the study site). Visiting the study sites for the sole purpose of obtaining 
reconsent/reassent should be avoided. 
10.6.2
Home or Remote Visit to Replace On-site Visit (where applicable)
A qualified Health Care Professional (HCP) from the study site or third-party vendor service 
will visit the subject’s home or other remote location as per local standard operating 
procedures, as applicable. Supplies will be provided for a safe and efficient visit. The qualified 
HCP will be expected to collect information per the clinical study protocol. 
10.6.3
Telemedicine Visit to Replace On-site Visit (where applicable)
In this appendix, the term ‘telemedicine visit’ refers to remote contact with the subject using 
telecommunications technology, including phone calls, virtual or video visits, and mobile 
health devices.

MedImmune
Protocol D419NC00001 Amendment 6
Durvalumab and monalizumab (IPH2201)
31May2021; Final
CONFIDENTIAL AND PROPRIETARY
206 of 206
Template 16.2
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 subjects will allow adverse events and concomitant medication to be reported and 
documented.  
10.6.4
Data Capture During Telemedicine or Home/Remote Visits
Data collected during telemedicine visits will be collected from the subject by a HCP.

SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d419nc00001-csp-amendment-6
Document Title:
D419NC00001 Clinical Study Protocol Amendment 6
Document ID:
Version Label:
3.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
01-Jun-2021 16:55 UTC
Author Approval
01-Jun-2021 18:06 UTC
Content Approval
01-Jun-2021 17:36 UTC
Content Approval
CCI
PPD
PPD
PPD
PPD